CA3166252A1 - Inhibitors of transglutaminases - Google Patents
Inhibitors of transglutaminasesInfo
- Publication number
- CA3166252A1 CA3166252A1 CA3166252A CA3166252A CA3166252A1 CA 3166252 A1 CA3166252 A1 CA 3166252A1 CA 3166252 A CA3166252 A CA 3166252A CA 3166252 A CA3166252 A CA 3166252A CA 3166252 A1 CA3166252 A1 CA 3166252A1
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- Prior art keywords
- oxo
- dihydropyridin
- oxoethyl
- carboxamido
- oxohexanediamide
- Prior art date
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
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Abstract
The invention relates to the compound of general formula (l) as novel inhibitors of transglutaminases, to methods for producing the inventive compounds, to pharmaceutical compositions containing said inventive compounds and to their use for the prophylaxis and treatment of diseases associated with transglutaminases, in particular transglutaminase 2.
Description
DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.
NOTE : Pour les tomes additionels, veuillez contacter le Bureau canadien des brevets JUMBO APPLICATIONS/PATENTS
THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE THAN ONE
VOLUME
NOTE: For additional volumes, please contact the Canadian Patent Office NOM DU FICHIER / FILE NAME:
NOTE POUR LE TOME / VOLUME NOTE:
I
Inhibitors of Transglutaminases Description The invention relates to novel inhibitors of transglutaminases, in particular transglutaminase 2, methods for their synthesis and to their use for the prophylaxis and treatment of diseases associated with transglutaminases, in particular transglutaminase
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.
NOTE : Pour les tomes additionels, veuillez contacter le Bureau canadien des brevets JUMBO APPLICATIONS/PATENTS
THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE THAN ONE
VOLUME
NOTE: For additional volumes, please contact the Canadian Patent Office NOM DU FICHIER / FILE NAME:
NOTE POUR LE TOME / VOLUME NOTE:
I
Inhibitors of Transglutaminases Description The invention relates to novel inhibitors of transglutaminases, in particular transglutaminase 2, methods for their synthesis and to their use for the prophylaxis and treatment of diseases associated with transglutaminases, in particular transglutaminase
2.
Background of the invention Transglutaminases are part of the class of transferases and according to EC
nomenclature they are correctly designated as "protein-glutamine: amine y-glutamyl transferases" (EC 2.3.2.13). They link the E-amino group of the amino acid lysine and the y-glutamyl group of the amino acid glutamine forming an isopeptide bond while ammonia is released. In the absence of suitable amines and/or under certain conditions, deamidation of the glutamine may occur resulting in the corresponding glutamic acid.
Additionally, transglutaminases play an important role in many therapeutic areas such as the cardiovascular diseases (thrombosis and atherosclerosis), autoimmune diseases (celiac disease, Duhring-Brocq-disease, gluten ataxia), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease), dermatological diseases (ichthyosis, psoriasis, acne) as well as in wound healing and inflammatory diseases (e.g. tissue fibrosis) (J.M. Wodzinska, Mini-Reviews in medical chemistry, 2005, 5, 279 - 292).
Celiac disease, a gluten intolerance, however, is one of the most important indications.
Celiac disease is characterized by a chronic inflammation of the mucosa of the small intestine. In susceptible patients, the intestinal epithelium is successively destroyed after ingestion of gluten-containing food resulting in reduced absorption of nutrients which again has massive impact on the patients affected and is for example associated with symptoms such as loss of weight, anemia, diarrhea, nausea, vomiting, loss of appetite and fatigue. Due to these findings, there is a large demand for the development of a medicament for the treatment of celiac disease as well as of other diseases associated with tissue transglutaminase (transglutaminase 2, TG2, tTG).
The tissue transglutaminase is a central element during pathogenesis. The endogenous enzyme catalyses the deamidation of gluten/gliadin in the small intestinal mucosa and thus triggers the inflammatory response. Therefore inhibitors of tissue transglutaminase are suitable to be used as active agents for medication.
Another very important group of indications for tissue transglutaminase inhibitors are fibrotic disorders. Fibrotic disorders are characterized by the accumulation of cross-2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 linked extracellular matrix proteins. Diabetic nephropathy, cystic fibrosis, idiopathic pulmonary fibrosis, kidney fibrosis as well as liver fibrosis belong to the most important fibrotic disorders to be addressed with the compounds disclosed.
US 9,434,763 B2 discloses pyridinone derivatives having a warhead comprising at least one acceptor-substituted double bond, such as a Michael System, as irreversible transglutaminase inhibitors. Alkylacetamido and arylacetamido pyridinones showed inhibitory activity regarding tissue transglutaminase TG2 in nanomolar range (IC50).
Tse et al. (J. Med. Chem. 2020, 63, 11585-11601) report on replacement of phenyl residues by non-classical bioisosteres, such as cubane and bicyclo[1.1.1]pentane (BCP), in anti-malarial triazolopyrazine compounds in order to alter compound solubility and metabolic stability. The authors further evaluated in vitro antiplasmodial activity of bioisosteric modified triazolopyrazines against the 3D7 strain of P.
falciparum.
Replacement of phenyl by bioisosteric saturated heterocyclic residues resulted in complete loss of activity. Adamantyl residues as well as other hydrocarbon-caged derivatives led to potency up to 2-9 times lower than the corresponding phenyl triazolopyrazine compounds. In contrast, higher potencies were achieved by replacing phenyl with closo-1,2- and 1,7-carborane isomers. The authors concluded that the effect of non classical bioiostere replacement on biological properties cannot be predicted accurately and that a considerable range of possible bioisosteres has to be tested first in order to identify a suitable replacement leading to the desired properties of a given molecule.
Subbaiah et al. (J. Med. Chem. 2021, 64, 19, 14046-14128) report on bioisosteres of the phenyl ring in lead optimization and drug design. It is noted that bioisosteric phenyl ring replacement with heterocyclic and carbocyclic moieties can lead to enhanced potency, solubility, and metabolic stability while reducing lipophilicity, plasma protein binding, phospholipidosis potential, and inhibition of cytochrome P450 enzymes and the hERG
channel. However, this effect depends strongly on the properties of the compound itself and the addressed target.
US 11,072,634 B2 discloses reversible transglutaminase inhibitors comprising an aldehyde, a ketone, an a-ketoaldehyde, an a-ketoketone, an a-ketoacid, an a-ketoester, an a-ketoamide or a halogenmethylketone as warhead. The inhibitors showed inhibitory activity regarding tissue transglutaminase TG2 in nanomolar and micromolar range (IC50).
The objective of the present invention is to provide novel, most probably reversible inhibitors of transglutaminases, in particular transglutaminase 2 and methods for the synthesis of said inhibitors as well as several uses of these inhibitors.
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30
Background of the invention Transglutaminases are part of the class of transferases and according to EC
nomenclature they are correctly designated as "protein-glutamine: amine y-glutamyl transferases" (EC 2.3.2.13). They link the E-amino group of the amino acid lysine and the y-glutamyl group of the amino acid glutamine forming an isopeptide bond while ammonia is released. In the absence of suitable amines and/or under certain conditions, deamidation of the glutamine may occur resulting in the corresponding glutamic acid.
Additionally, transglutaminases play an important role in many therapeutic areas such as the cardiovascular diseases (thrombosis and atherosclerosis), autoimmune diseases (celiac disease, Duhring-Brocq-disease, gluten ataxia), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease), dermatological diseases (ichthyosis, psoriasis, acne) as well as in wound healing and inflammatory diseases (e.g. tissue fibrosis) (J.M. Wodzinska, Mini-Reviews in medical chemistry, 2005, 5, 279 - 292).
Celiac disease, a gluten intolerance, however, is one of the most important indications.
Celiac disease is characterized by a chronic inflammation of the mucosa of the small intestine. In susceptible patients, the intestinal epithelium is successively destroyed after ingestion of gluten-containing food resulting in reduced absorption of nutrients which again has massive impact on the patients affected and is for example associated with symptoms such as loss of weight, anemia, diarrhea, nausea, vomiting, loss of appetite and fatigue. Due to these findings, there is a large demand for the development of a medicament for the treatment of celiac disease as well as of other diseases associated with tissue transglutaminase (transglutaminase 2, TG2, tTG).
The tissue transglutaminase is a central element during pathogenesis. The endogenous enzyme catalyses the deamidation of gluten/gliadin in the small intestinal mucosa and thus triggers the inflammatory response. Therefore inhibitors of tissue transglutaminase are suitable to be used as active agents for medication.
Another very important group of indications for tissue transglutaminase inhibitors are fibrotic disorders. Fibrotic disorders are characterized by the accumulation of cross-2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 linked extracellular matrix proteins. Diabetic nephropathy, cystic fibrosis, idiopathic pulmonary fibrosis, kidney fibrosis as well as liver fibrosis belong to the most important fibrotic disorders to be addressed with the compounds disclosed.
US 9,434,763 B2 discloses pyridinone derivatives having a warhead comprising at least one acceptor-substituted double bond, such as a Michael System, as irreversible transglutaminase inhibitors. Alkylacetamido and arylacetamido pyridinones showed inhibitory activity regarding tissue transglutaminase TG2 in nanomolar range (IC50).
Tse et al. (J. Med. Chem. 2020, 63, 11585-11601) report on replacement of phenyl residues by non-classical bioisosteres, such as cubane and bicyclo[1.1.1]pentane (BCP), in anti-malarial triazolopyrazine compounds in order to alter compound solubility and metabolic stability. The authors further evaluated in vitro antiplasmodial activity of bioisosteric modified triazolopyrazines against the 3D7 strain of P.
falciparum.
Replacement of phenyl by bioisosteric saturated heterocyclic residues resulted in complete loss of activity. Adamantyl residues as well as other hydrocarbon-caged derivatives led to potency up to 2-9 times lower than the corresponding phenyl triazolopyrazine compounds. In contrast, higher potencies were achieved by replacing phenyl with closo-1,2- and 1,7-carborane isomers. The authors concluded that the effect of non classical bioiostere replacement on biological properties cannot be predicted accurately and that a considerable range of possible bioisosteres has to be tested first in order to identify a suitable replacement leading to the desired properties of a given molecule.
Subbaiah et al. (J. Med. Chem. 2021, 64, 19, 14046-14128) report on bioisosteres of the phenyl ring in lead optimization and drug design. It is noted that bioisosteric phenyl ring replacement with heterocyclic and carbocyclic moieties can lead to enhanced potency, solubility, and metabolic stability while reducing lipophilicity, plasma protein binding, phospholipidosis potential, and inhibition of cytochrome P450 enzymes and the hERG
channel. However, this effect depends strongly on the properties of the compound itself and the addressed target.
US 11,072,634 B2 discloses reversible transglutaminase inhibitors comprising an aldehyde, a ketone, an a-ketoaldehyde, an a-ketoketone, an a-ketoacid, an a-ketoester, an a-ketoamide or a halogenmethylketone as warhead. The inhibitors showed inhibitory activity regarding tissue transglutaminase TG2 in nanomolar and micromolar range (IC50).
The objective of the present invention is to provide novel, most probably reversible inhibitors of transglutaminases, in particular transglutaminase 2 and methods for the synthesis of said inhibitors as well as several uses of these inhibitors.
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30
3 Said objective is solved by the technical teachings of the independent claims.
Further advantageous embodiments, aspects and details of the invention are evident from the dependent claims, the description and the examples.
Surprisingly, it has been found that reversible inhibitors having a chemical warhead as disclosed herein inhibit effectively transglutaminases including tissue transglutaminase called transglutaminase 2 or TG2. Herein these terms are used synonymous.
Preferably, such chemical warhead moiety is particularly selected from reversible warheads such as a-ketoamides. The compounds of the present invention act as selective inhibitors of transglutaminase 2.
In order to prove inventiveness of the compounds of the present application, reference compounds were synthesized and tested in comparison to the most similar compounds of the present application. A skilled person might notice compound A8 from our patent US 9,434,763 B2 which we introduce as Ref. 3 to highlight the inventive and preferred features of the claimed compounds. From US 9,434,763 B2, it is clear, that aromatic moieties (C-terminal) restrict the efficacy of those compounds (compare to Al, A8, A37, A44, A47). In sharp contrast, branched alkyl moieties are highly preferred as indicated by more potent compounds (A28, A29, A59, A61, A63, A67, A68, A79).
To illustrate the advantage of branched alkyl moieties over aromatic moieties, we refer to reference compounds Ref. 2 (ZED1227, US 9,434,763 B2) and Ref. 3 (A8, ZED1047).
Inhibition data were determined using the classical fluorescent transamidation assay (dansylcadaverine incorporation into methylated casein, DCC-assay) as described [Bach Id, C.; HiIs, M.; Gerlach, U.; Weber, J.; Pelzer, C.; Heil, A.;
Aeschlimann, D.;
Pasternack, R. Features of ZED1227: The First-In-Class Tissue Transglutaminase Inhibitor Undergoing Clinical Evaluation for the Treatment of Celiac Disease. Cells 2022, //, 1667. https://doi.org/10.3390/cells11101667]. Casein is one of the best known high molecular weight (24 kDa) protein substrates for transglutaminases.
Please note, the ICso value of Ref. 3 (A8) published in US 9,434,763 B2 cannot be compared to the present data, relying on a fluorogenic isopeptidase assay.
Measured in the DCC-assay, Ref. 2 (ICso = 53 nM) is 80-fold more potent compared to Ref. 3 (ICso = 4,268 nM).
Accordingly, a person skilled in the art of medicinal chemistry would choose branched alkyl moieties as lead structures, such excluding aromatic moieties, e.g. the phenyl group.
It is of common knowledge, that bridged cycloalkyl groups are non-classical bioisosters of the phenyl group. By replacement of the phenyl group in A8 by e.g. an adamantane 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30
Further advantageous embodiments, aspects and details of the invention are evident from the dependent claims, the description and the examples.
Surprisingly, it has been found that reversible inhibitors having a chemical warhead as disclosed herein inhibit effectively transglutaminases including tissue transglutaminase called transglutaminase 2 or TG2. Herein these terms are used synonymous.
Preferably, such chemical warhead moiety is particularly selected from reversible warheads such as a-ketoamides. The compounds of the present invention act as selective inhibitors of transglutaminase 2.
In order to prove inventiveness of the compounds of the present application, reference compounds were synthesized and tested in comparison to the most similar compounds of the present application. A skilled person might notice compound A8 from our patent US 9,434,763 B2 which we introduce as Ref. 3 to highlight the inventive and preferred features of the claimed compounds. From US 9,434,763 B2, it is clear, that aromatic moieties (C-terminal) restrict the efficacy of those compounds (compare to Al, A8, A37, A44, A47). In sharp contrast, branched alkyl moieties are highly preferred as indicated by more potent compounds (A28, A29, A59, A61, A63, A67, A68, A79).
To illustrate the advantage of branched alkyl moieties over aromatic moieties, we refer to reference compounds Ref. 2 (ZED1227, US 9,434,763 B2) and Ref. 3 (A8, ZED1047).
Inhibition data were determined using the classical fluorescent transamidation assay (dansylcadaverine incorporation into methylated casein, DCC-assay) as described [Bach Id, C.; HiIs, M.; Gerlach, U.; Weber, J.; Pelzer, C.; Heil, A.;
Aeschlimann, D.;
Pasternack, R. Features of ZED1227: The First-In-Class Tissue Transglutaminase Inhibitor Undergoing Clinical Evaluation for the Treatment of Celiac Disease. Cells 2022, //, 1667. https://doi.org/10.3390/cells11101667]. Casein is one of the best known high molecular weight (24 kDa) protein substrates for transglutaminases.
Please note, the ICso value of Ref. 3 (A8) published in US 9,434,763 B2 cannot be compared to the present data, relying on a fluorogenic isopeptidase assay.
Measured in the DCC-assay, Ref. 2 (ICso = 53 nM) is 80-fold more potent compared to Ref. 3 (ICso = 4,268 nM).
Accordingly, a person skilled in the art of medicinal chemistry would choose branched alkyl moieties as lead structures, such excluding aromatic moieties, e.g. the phenyl group.
It is of common knowledge, that bridged cycloalkyl groups are non-classical bioisosters of the phenyl group. By replacement of the phenyl group in A8 by e.g. an adamantane 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30
4 group, a skilled person would expect similar physico-chemical or biochemical properties excluding to invest efforts. Since aromatic moieties are clearly not preferred, bridged cycloalkyl groups would not be considered improving the compounds.
This is further supported by additional reference compounds. ZED3641 (Ref. 1, as disclosed in US 11,072,634 B2; reversible acting a-ketomethylamide analogue to Ref. 2, ZED1227) is about 15-fold more potent compared to Ref. 4 (compare table 1).
Ref. 4 is analogous to compound A8 disclosed in US 9,434,763 B2 with respect to the backbone proving again superiority of branched alkyl moieties compared to aromatic derivatives in combination with reversible acting warheads.
However, surprisingly, replacement of the preferred branched alkyl moieties by bridged cycloalkyl groups further significantly improve the potency of the compounds as shown in table 1. Therefore, we credit bridged cycloalkyl groups as disclosed with an outstanding inventive manner.
In summary, the inventive compounds rated "A" show efficacies of about 30-fold higher compared to Ref. 3 (A8, compare to table1).
Further, compounds with activities rated "B" or "C" are still preferred (lower ICso values) to Ref. 3 (A8). These compounds can also be considered inventive, since peripheric ligands affect physico-chemical or biochemical properties. Therefore, also less potent compounds might be of high value, depending on the application.
Thus, the present invention relates to compounds of the general formula (I):
H J (I) CN LR3 Ho wherein L represents ¨L1-L2¨;
L1 represents ¨CH2¨, ¨CH2CH2¨, ¨CH2CH2CH2¨, ¨CH2C0¨, or ¨CH2CH2C0¨;
L2 represents a bond, _NRN1_, _NRI41CH2¨, ¨NRI41CH2CH2¨, or ¨NRN1CH(CH3)¨, R1 represents , R2 represents 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30
This is further supported by additional reference compounds. ZED3641 (Ref. 1, as disclosed in US 11,072,634 B2; reversible acting a-ketomethylamide analogue to Ref. 2, ZED1227) is about 15-fold more potent compared to Ref. 4 (compare table 1).
Ref. 4 is analogous to compound A8 disclosed in US 9,434,763 B2 with respect to the backbone proving again superiority of branched alkyl moieties compared to aromatic derivatives in combination with reversible acting warheads.
However, surprisingly, replacement of the preferred branched alkyl moieties by bridged cycloalkyl groups further significantly improve the potency of the compounds as shown in table 1. Therefore, we credit bridged cycloalkyl groups as disclosed with an outstanding inventive manner.
In summary, the inventive compounds rated "A" show efficacies of about 30-fold higher compared to Ref. 3 (A8, compare to table1).
Further, compounds with activities rated "B" or "C" are still preferred (lower ICso values) to Ref. 3 (A8). These compounds can also be considered inventive, since peripheric ligands affect physico-chemical or biochemical properties. Therefore, also less potent compounds might be of high value, depending on the application.
Thus, the present invention relates to compounds of the general formula (I):
H J (I) CN LR3 Ho wherein L represents ¨L1-L2¨;
L1 represents ¨CH2¨, ¨CH2CH2¨, ¨CH2CH2CH2¨, ¨CH2C0¨, or ¨CH2CH2C0¨;
L2 represents a bond, _NRN1_, _NRI41CH2¨, ¨NRI41CH2CH2¨, or ¨NRN1CH(CH3)¨, R1 represents , R2 represents 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30
5 RN
- _. 0 Rs R11 _R8 -._ S Ra RzvS R8 ---\ / lr ,\ r Rlo R9 ; / R9 , R10 R9 ; R9 RN R9 ;
;
RN RN RN RN RN RN
RN
N, R11 N, _.. N, R11 N
_ - ii 0.8 i ___________ r --14N I iN
i er.
N N
Ro Rlo s, / R9 Rlo R9 Rlo , / , RN Rio Rio s ii 0 - 0 pp8 _____.(, .)7_ _ Rti_.(õ\,0,R8 --1 __--..
)-\.-\):IR8 R
N N ,\ __ N N N
Rio Rio , Rio R8 N '= , , ' , , RN RN
sR8 _..1SRa -,<N ,N
Rio R11 S R11 N, R
I ,N
) __ N N N N
N-r-CR8 Rio , Rio Rio , , , , , RN RN
,N, ,N, io RN
-__ , R12 R12 -------------------------------------------------------------------------- ) vl N N N , N, R N /') R13 ------------- R=-\ _________ i( ir Iii,N --\- N----u,,,,,_<,\,;j , , Rio ,,\¨N ; N-N ; N=N ; R14 N Rizt , , , N R12 , R12 1 q R.- r .- -\ i Rio_tsr>R13 N
\N \- R
R.4 C)---4 14 ;
N R14 N Ria N= R14 Rio , RN
Riz R12 Rii R12 S-----/Y,) 13 \% R12 i\I /') 13 ---\ TR ---TR
R104------r/ - \R14 R10_trnR13 C)---i13 R10 S-----\44 R10 , RN
, Rlo / N---/y,) '-/ 13 RN , R1."A R14 -------/".>7,, N
__ N----- \/\\I-R14 , , , R13 N,- Rii ,, RN RN
N,R9 Nli ----___Ri4 ..(cDp9 i" [ / ,I R10 N \J
Rio N s R1O - \ -7----R10 RN' Rlo N'S , , , ,S --R9 D.....:,9 ,S - - ),_ - N 1 1_1_ R o1R9 N\\ I N''' s: ----7-o)/¨R10 cr...,NR10 N R8 \s_...N N-_-_-N Rs 1 0 , a ,s - ,,,-- . N - - 0 S
R'-'-----\ il N6- R'a N ---- -7 Ru----N---N ; b-N , N-0 , o-N , N N
2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 a !`g Fri 6 X cD
, / ,' I I I I
I
,c) m , , , ' , c m i , a .,-0- z \-0 2Z
r)No) (,(j) ,r-z CZ-Az z/iz ----- /Cr)--Z---- (Z----o) H
/Z
rEP 2 \ / z--( Z zj z z /( 0 --------// \ ------;"---cn µ___-_ z i CD = M \ Zo / Z, \ /Z Z / \ Z cZ vC) Z N
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z cz----- e-----z --z \ //z \ / \z z-z z z-0 .. _________ .. ..
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..
I ,' , I I I I I
Cr)-Z
(z ________________________________________________________________ z \( z--(/
z z ,' 0 z I
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¨ _ --/ \
// \ Z/ Z/ \Z ¨/ \ / , , I ' 1 1 , 1 i i - ____________________________________ Z
0_ z --/ Z \
0 N 1 ,('-zi 1 Iz, z Z Z Zj Z z Z "cn i - C z----cn _ Z----Cn _ Z
-_ -_ --. ---;---õ,----N N N N
' , , -, '-IN 'r1;1 --Ir N, N NN, , -.fNI\I -, N N
1 f -N N , N I\I NN
N N
' -,,NN,N
N N
, , , , -,,NN -'NN -,,NN
1 N N N NN , , , NN N1,N N N
, . N. -, -,,N,N
N'N, 1\1 , , N, ''' 'NI -I
N9 N1\1 , N
, , 'r 1 NN , Ne , NN
, ''IrN
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N N , NN NN
, , NN NN-,N --N
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N,NN Th N,NN \1N , , , 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 H
NH
HN NH , , , , ., N NH , HN , NH, H, N=\ 0 N=N N=\ N-- - /(1\1 - -N
\ N
N/ \ " ,N
, , ' N¨ N¨ N¨ ¨N ¨N
- - \ - - \ - - \ /N - - -_ / N \ ,N
N N , , ________ , /¨N ¨N ¨N/¨\ /¨\
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- -________ - - / N \ /N N , ________________ ' , N N , , , i ¨ \
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N _________________________________________________________ N=\ N=\
- - -- /(N
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N N¨N , N // N
N=N N=N N=N N=N N=N
- ______________ - \ /N - - - - - - - - -, \ N /
N N
, , , N=\ N=\ N=\ N=\ N-- - /(1\1 - - -,\__. / N - - __ /N __ - - /N --\ /71 , \ \ N N \ ,N
N N , , N¨ N¨ N¨ N¨ N¨
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N¨ //, N¨N N N
, , , , ¨N N Ns ¨N ¨N
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N N N , , , , 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 /-N
--- /
\ N
N/ N //N
N-N N N __ , , , , _________ , -\/-\ -\ -\ -\
--- N -- --i --- --i / - ( /N ( /N ( \ SN N
N \ N1 \ , N N N
//
, ' - \
0 .
Ns /
Nss \ //N N N
// Ns N N-N
,-N , N-N , N N-// ,or wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 - R14, and R" and preferably with 1 to 3 of the substituents R13;
R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl, diem antyl, or hexamethylenetetraminyl and the afore-mentioned residues optionally contain one or more C=C double bond and/or are optionally substituted one or more of Ra, Rb, Rc, Rd, and Re;
Ra, Rb, Rc, Rd, and Re represents independently of each other -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C2H5, -CON H2 , -CONHCH3, -CON(CH3)2, -CONHC2H5, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H5, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2H5, -NHCOCH3, -NHCOC2H5, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C2H5, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3;
R4 represents -NR6R7;
R6 represents -CH2CH3, and R7 represents -H;
R9, R9, R19, R11, R12, R13, and R14 represent independently of each other -H, -F, -Cl, -Br, -1, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2F, -CH F2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2OH, -OCH3, -0C2H5, -0C3H7, -OCH(CH3)2, -0C(CH3)3, -0C4H9, 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 -OCHF2, -0CF3, -OCH2CF3, -0C2F5, -OCH2OCH3, -O-CyCIO-C3H5, -OCH2-cyclo-C3H5, -0-C2H4-cyclo-C3H5, -CHO, -COCH3, -COCF3, -00C21-15, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -COOK -COOCH3, -CO0C2H5, -CO0C3H7, -COOCH (CH3)2, -COOC(CH3)3, -00C-CH3, -00C-CF3, -00C-C2H5, -00C-C3H7, -00C-CH (CH3)2, -00C-C(CH3)3, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N (CH3)2, -N(C2H5)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5, -NHCOC3H7, -N HCOCH (CH3)2, -NHCOC(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CON HCH (CH3)2, -CON H-cyclo-C3H5, -CON
HC(CH3)3, -CON(CH3)2, -CON (C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -SO2NHCH(CH3)2, -SO2NH-cyclo-C3H5, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H5)2, -SO2N(C3H7)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C2H5, -NHSO2C3H7, -NHSO2CH
(CH3)2, -NHSO2C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -CECH, -CEC-CH3, -CH2-CECH, -Ph, -0-Ph, -0-CH2-Ph, N
r --Nn rTh N/N rN1 r rN
r N r N
/ _______________________________________ \ / __ \ / \
N\ /NH N\ Or N\ \
or R8 and R9 or R9 and R1 can form together one of the following five-membered or six-membered rings:
õo -- , N
-or ---%N
or R12 and R13 or R13 and R14 can form together one of the following five-membered or six-membered rings:
.0 ,0 ,0 ''N N
'0 H or I
R" represents -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH (CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 -cyclo-CsHo, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-05H9, -CH2F, -CH F2; -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3, -00C2H5, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -CO-cyclo-C3H5, -CO-cyclo-C4H7, -CO-cyclo-CsHo, -COOCH3, -CO0C2H5, -CO0C3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -S02CH3, -S02CF3, -S02C2H5, -S02C3H7, -S02CH(CH3)2, -S02-cyclo-C3H5, or -S02C(CH3)3;
rc -N1 represent -H, -CH3, or -CH2CH3;
or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomer, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
The inventors have found that the reversible inhibitors of formula (I) disclosed herein having a bridged bicyclic residue R3 exhibit increased potency over the compounds of the prior art. Particularly, it is demonstrated herein, that the inventive compounds have an improved inhibitory activity compared to the known compounds bearing aromatic moieties R3 instead of bridged bicyclic residues. In order to prove inventiveness of the compounds of the present application, known compounds from US 9,434,763 B2 and US 11,072,634 B2 (Reference 1 (E16 from US 11,072,634 B2), Reference 3 (A8 from US
9,434,763 B2), and Reference 4) were synthesized and tested as reference compounds in comparison to the most similar compounds of the present application. To this extent, inhibition data were determined using the classical fluorescent transamidation assay (dansylcadaverine incorporation into methylated casein, DCC-assay) as described in Buchold et al. [Buchold, C.; Nils, M.; Gerlach, U.; Weber, J.; Pelzer, C.;
Heil, A.;
Aeschlimann, D.; Pasternack, R. Features of ZED1227: The First-In-Class Tissue Transglutaminase Inhibitor Undergoing Clinical Evaluation for the Treatment of Celiac Disease. Cells 2022, 1/, 1667. https://doi.org/10.3390/cells11101667]. Casein is one of the best known high molecular weight (24 kDa) protein substrates for transglutaminases.
Inhibition data of the inventive compounds was compared with inhibition of compounds disclosed in US 9,434,763 B2, particularly, compound A8, which is denoted herein as Reference 3. It is noteworthy that the ICso values of compounds A8 published in US
9,434,763 B2 and E16 from US 11,072,634 B2 cannot be compared to the present data, relying on a fluorogenic isopeptidase assay.
Thus, the inventive compounds of formula (I) rated "A" showed efficacies of about 100-fold higher compared to Ref. 3 (A8). The same argumentation applies to Ref. 4.
Ref. 4 shows also that aromatic moiety of this reference comopund reduces the inhbibitory activity against TG2 strongly.
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Accordingly, a person skilled in the art would exclude aromatic moieties, e.g.
the phenyl group. It is of common knowledge, that bridged cycloalkyl groups are non-classical bioisosters of the phenyl group. By replacement of the phenyl group in A8 by e.g. an adamantane group, a skilled person would expect similar physico-chemical or biochemical properties excluding to invest efforts. Since aromatic moieties are clearly not preferred, bridged cycloalkyl groups would not be considered improving the compounds.
Surprisingly, the inventive compounds demonstrate that bridged cycloalkyl groups improve the potency of the compounds by orders of magnitude compared to the aromatic reference compounds. Therefore, we credit bridged cycloalkyl groups as disclosed with an outstanding inventive manner.
In another set of preferred compounds R2 represents RN
Rii 0 Ra -__ S R8 Rii \ S R8 --- -( Rio R9 ;
' R9 Rio R9 RN RN RN RN
Rii 0 __ wIi ON_R8 Rii N R8 Doi N, Rii N, __ N, ( lµi /1\1 i /N
/ ( --1K \I ir N
/ R9 R10 µ, , R9 Rio R9 R10 , , , , R10 R10 µi R10 Ril S _ R11 S R8 Rio ?!riR8 cl -N N¨ ) N __ N R8 , RN RN
RN RN
S 8 -, N ii ii ,N, ,N, _R RN
R N. < ,N wõ...),õ ,N N N N io N.
\¨N
Rio ' nio , __ N ' \Rio / N¨N
N=N
, , ' , = ' N r -------------------- -Ri3 Ri3 Ri3 Ri3 L.1 xj \-) \N \-) \-) , , ' Rii R14 ¨ \-J R14 Rio 0---"\-114 0- 21-113 R10 ; ; rk ; ;
RN
pp12 µ, RN
, Ri2 , R12 i\iy4' / 1\1---__/y Rio_tr/R13 ---TR13 N --- 1 \ RN
s-----1414 Rio R1,1 Rio R., , R13 ' 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 R12 Ri2 R11 s, ,,,------.õõ...---:-/,,,,, - 1 jL _ R13 ), Nv----R14 Rioill-- R., 1 A
S
R14 R14 Rio N __ N S
RN
RN RN
0=e ii R9 9 rN-/IR9 r Y1 y I_ . _ .R 9 R10 m R9 r_R
Rio R10 ,l' --/- R10 - \____/-----R10 L...,.,.,_....) ,--, rµNr"
N-----, , - /s1 -NI \ 1 N N p8 s)- S--7-1 - - Ni RsN ..
\N R8 \s-N \N----N Rs N-N b-N N---' , , - -O'N N N
_yN
- - -eNNH - - -eNNH N
- - A ¨_<N3 N _____ ( NN
- N N __ \( S S z c N
---eNN H - - -eNNH
IIN , NJN __ ( , ' _N _ N
- - -\ - -\13 N - - -eN0 N N __ \ ( IIN , NN3 0 7 , c N N
, , N
H S
-K7/ -II, - N N Ns H ' H
' S-_-N _ _7,__--/ ___N S __ _---:--- \N
\S-N - - -____ -- N
N S' N
, , ______n N 0 H
N __ / -----/ _ -__ri - -CT-) \ N -NI/ S'N'N N / N-0 , , , __________ 0 _ _ _e---- - /0---N, ....._N
\ -N - 7 N-N ) N 0 - \--N-1 - - -<71---O-N
H H , , , 0 -,.. N N
*4 , N
/ N
, N -, --' N
, / N
-- - N
-. , -, ,N
N 1\r N
2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 _ I -N
-I
NI,N / , N
, , -, N -, --'N 'N
N N
N
, -,,I\I N -,,NN
, - N
N N
N
N N N N
, N
I
N N- NN , , ,N N
II -, N N
1 f -1 i\il N
Nõ," N N
, -,,NN,N
N
, , , -,,NN -''NN -,,NN
N II
N,,, , 1 N f N--1\1 NN , N
, , -,,N, -,,rN -, N
N1,N , -, N. -, -,,N,N
NA
N , N N
, , N2 N A Nr N, N, , ir 1 NN , NN , NN
, '-'-IN
1 F\11 N,N
N-, N
N
2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 I I I
N N , 1\1N NN
--1\11 N.N
, N1\1-N
, , I I
N.NN N N.NN N , H
NH
HN NH
, , ., N NH , HN , NH H , , N=\ 9\ N=N N=\ N---- /(N
--N
)''---0 \ /N \ ,N
" , N¨ N¨ N¨ ¨N ¨N
/N -- \
--- / N ,N
N N _____________________________________ , / _________ N ' ¨N ¨N __\
/(N-- __________________________________________ / N \ //
________ N 1\1 N , ________________________________________ ' , _____ N , , , -- \ /\N
\ ¨\
--i /N
I\1 , --\ N --\ N
N -- .
N N
N N
, N=\ N=\
--- /(N 1 /N
\ / N\/ N / N N N
N N¨N N // N
, , , N=N N=N N=N N=N N=N
--- ____________________________________________ ---_/ --, \ ,N /
, _________ // , _____ N, N , , N=\ N=\ N=\ N=\ N--- /(N ---. /N --- /N ---\ /71, \ \ _______ N \ ,N
N N N , 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 N---- ______________________________ --- _____ \ _______ -- ---\ N
N N --- / N / N, /
N/ //
, N¨N N N __ ;
, , ¨N ¨N ¨N ' cNs ¨N
N N /KN
\ /71, \ _______ 1\1 , \ ,N
¨N ¨N /¨N ¨N ¨N
--- --i \ \
--- /
\ N N N N / N, /
N/ // N¨N N __ N ; , ____________________________________ , ¨\ ¨\
i¨\
,N N \ N
N , N=/ // N¨N N
, __\ 0 =
- -- -i /N
-- --N, \ N N N
// N, ,N N¨N ;
N , N¨N , N sINI/ , or ' wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 ¨ R14, and RN; and preferably with 1 to 3 of the substituents R11 ¨
R13; and the substituents R9 ¨R14, and RN have the meanings as defined informula (I); and more preferably R2 represents RN RN
0rR8 R11 0 R8 ____õ,s, _R8 R11 s R8 __ R8 Rii ,, R8 \ / (- \ , \ , \ , Ric) R9 R9 R10 R9 R9 Rio R9 ,' D9 r` , RN RN RN
Rii N,k. RN N, R11 0 __ R11 0 R8 -- -)" R8 I /(1 4 --121(\1 --\__, I(\ I ----- \ //
) _____________________________________________ N N N
Rio ss R9 Rio R9 Rio Rio , ' R10 Rio ,R10 Ril SN Rii S
O\ Rs -----SNR8 --CaR8 )\ /7-N 1 , //
N N N N
R8 N¨ µ R8 Rio Rio ' ' , , , , RN
___________ 'NI
N Rii N, ,N Rio ------ ,N 1\1\¨ri . N, N, D N
- ---'- N''`
/-) LI.,.,.õ,\,:j R13 ) ______________________ N
Rio N¨N ; N=N , D14 , " , R12 R12 R12 N R12 0---__//
R13 /`) R13 --------------------------- N/-) R13 R13 ---),IRA 13 \N \-) N R14 N R14 N R14 N R14 R10 R., , , 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 RN
R12 Ri2 RN
S---.../Y,) _ N-....//, 1 i D13 N,/Y,) --- ., R14 R14 N-----' ,A \jR
Rio Rio R., R14 \
_______________________ N71-.õ).___Riit N, R9 _ Rio ,NI ,R9 II 1 R13 9 f_ ' 4. 1 _____ S r-ii R
r /1 Rio R1._ R1._0 , , - R9 R9 p S
,I\I /¨R1 0--/-m, 1 __`-,N----- 1-µ N N
, ' Icl 0 s ---eNNH
\ \ \ __________________ N ( , S
, ---eNNH
-- A - - N -(3 N N \( , SNJ
S S y N
NH ---eNNH
IIN , NNN3 N __ ( -- A - N N
\(
- _. 0 Rs R11 _R8 -._ S Ra RzvS R8 ---\ / lr ,\ r Rlo R9 ; / R9 , R10 R9 ; R9 RN R9 ;
;
RN RN RN RN RN RN
RN
N, R11 N, _.. N, R11 N
_ - ii 0.8 i ___________ r --14N I iN
i er.
N N
Ro Rlo s, / R9 Rlo R9 Rlo , / , RN Rio Rio s ii 0 - 0 pp8 _____.(, .)7_ _ Rti_.(õ\,0,R8 --1 __--..
)-\.-\):IR8 R
N N ,\ __ N N N
Rio Rio , Rio R8 N '= , , ' , , RN RN
sR8 _..1SRa -,<N ,N
Rio R11 S R11 N, R
I ,N
) __ N N N N
N-r-CR8 Rio , Rio Rio , , , , , RN RN
,N, ,N, io RN
-__ , R12 R12 -------------------------------------------------------------------------- ) vl N N N , N, R N /') R13 ------------- R=-\ _________ i( ir Iii,N --\- N----u,,,,,_<,\,;j , , Rio ,,\¨N ; N-N ; N=N ; R14 N Rizt , , , N R12 , R12 1 q R.- r .- -\ i Rio_tsr>R13 N
\N \- R
R.4 C)---4 14 ;
N R14 N Ria N= R14 Rio , RN
Riz R12 Rii R12 S-----/Y,) 13 \% R12 i\I /') 13 ---\ TR ---TR
R104------r/ - \R14 R10_trnR13 C)---i13 R10 S-----\44 R10 , RN
, Rlo / N---/y,) '-/ 13 RN , R1."A R14 -------/".>7,, N
__ N----- \/\\I-R14 , , , R13 N,- Rii ,, RN RN
N,R9 Nli ----___Ri4 ..(cDp9 i" [ / ,I R10 N \J
Rio N s R1O - \ -7----R10 RN' Rlo N'S , , , ,S --R9 D.....:,9 ,S - - ),_ - N 1 1_1_ R o1R9 N\\ I N''' s: ----7-o)/¨R10 cr...,NR10 N R8 \s_...N N-_-_-N Rs 1 0 , a ,s - ,,,-- . N - - 0 S
R'-'-----\ il N6- R'a N ---- -7 Ru----N---N ; b-N , N-0 , o-N , N N
2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 a !`g Fri 6 X cD
, / ,' I I I I
I
,c) m , , , ' , c m i , a .,-0- z \-0 2Z
r)No) (,(j) ,r-z CZ-Az z/iz ----- /Cr)--Z---- (Z----o) H
/Z
rEP 2 \ / z--( Z zj z z /( 0 --------// \ ------;"---cn µ___-_ z i CD = M \ Zo / Z, \ /Z Z / \ Z cZ vC) Z N
\
CD 20 Z Z _ V 1/ _ CD
0- N, N) *
N) i N) ,r1 C) clo , , , , , I z _ \
z_.
z' -07 2Z N cn N c/37 ,(, - zi ¨ \ C z , , , /
¨ ¨
¨Kz \ /
z cz----- e-----z --z \ //z \ / \z z-z z z-0 .. _________ .. ..
.. .. ..
..
..
I ,' , I I I I I
Cr)-Z
(z ________________________________________________________________ z \( z--(/
z z ,' 0 z I
' / Z¨K Z
¨ _ --/ \
// \ Z/ Z/ \Z ¨/ \ / , , I ' 1 1 , 1 i i - ____________________________________ Z
0_ z --/ Z \
0 N 1 ,('-zi 1 Iz, z Z Z Zj Z z Z "cn i - C z----cn _ Z----Cn _ Z
-_ -_ --. ---;---õ,----N N N N
' , , -, '-IN 'r1;1 --Ir N, N NN, , -.fNI\I -, N N
1 f -N N , N I\I NN
N N
' -,,NN,N
N N
, , , , -,,NN -'NN -,,NN
1 N N N NN , , , NN N1,N N N
, . N. -, -,,N,N
N'N, 1\1 , , N, ''' 'NI -I
N9 N1\1 , N
, , 'r 1 NN , Ne , NN
, ''IrN
1 i\ii N
N N , NN NN
, , NN NN-,N --N
, NN, , I
N,NN Th N,NN \1N , , , 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 H
NH
HN NH , , , , ., N NH , HN , NH, H, N=\ 0 N=N N=\ N-- - /(1\1 - -N
\ N
N/ \ " ,N
, , ' N¨ N¨ N¨ ¨N ¨N
- - \ - - \ - - \ /N - - -_ / N \ ,N
N N , , ________ , /¨N ¨N ¨N/¨\ /¨\
( / N - - -\ sN
- -________ - - / N \ /N N , ________________ ' , N N , , , i ¨ \
N N
N _________________________________________________________ N=\ N=\
- - -- /(N
\ / N\/ N / N N N
N N¨N , N // N
N=N N=N N=N N=N N=N
- ______________ - \ /N - - - - - - - - -, \ N /
N N
, , , N=\ N=\ N=\ N=\ N-- - /(1\1 - - -,\__. / N - - __ /N __ - - /N --\ /71 , \ \ N N \ ,N
N N , , N¨ N¨ N¨ N¨ N¨
- 1 ) 1 1 N N N N\/ N /
N¨ //, N¨N N N
, , , , ¨N N Ns ¨N ¨N
, \/N , \ \ N \ ,N
N N N , , , , 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 /-N
--- /
\ N
N/ N //N
N-N N N __ , , , , _________ , -\/-\ -\ -\ -\
--- N -- --i --- --i / - ( /N ( /N ( \ SN N
N \ N1 \ , N N N
//
, ' - \
0 .
Ns /
Nss \ //N N N
// Ns N N-N
,-N , N-N , N N-// ,or wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 - R14, and R" and preferably with 1 to 3 of the substituents R13;
R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl, diem antyl, or hexamethylenetetraminyl and the afore-mentioned residues optionally contain one or more C=C double bond and/or are optionally substituted one or more of Ra, Rb, Rc, Rd, and Re;
Ra, Rb, Rc, Rd, and Re represents independently of each other -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C2H5, -CON H2 , -CONHCH3, -CON(CH3)2, -CONHC2H5, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H5, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2H5, -NHCOCH3, -NHCOC2H5, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C2H5, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3;
R4 represents -NR6R7;
R6 represents -CH2CH3, and R7 represents -H;
R9, R9, R19, R11, R12, R13, and R14 represent independently of each other -H, -F, -Cl, -Br, -1, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2F, -CH F2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2OH, -OCH3, -0C2H5, -0C3H7, -OCH(CH3)2, -0C(CH3)3, -0C4H9, 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 -OCHF2, -0CF3, -OCH2CF3, -0C2F5, -OCH2OCH3, -O-CyCIO-C3H5, -OCH2-cyclo-C3H5, -0-C2H4-cyclo-C3H5, -CHO, -COCH3, -COCF3, -00C21-15, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -COOK -COOCH3, -CO0C2H5, -CO0C3H7, -COOCH (CH3)2, -COOC(CH3)3, -00C-CH3, -00C-CF3, -00C-C2H5, -00C-C3H7, -00C-CH (CH3)2, -00C-C(CH3)3, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N (CH3)2, -N(C2H5)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5, -NHCOC3H7, -N HCOCH (CH3)2, -NHCOC(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CON HCH (CH3)2, -CON H-cyclo-C3H5, -CON
HC(CH3)3, -CON(CH3)2, -CON (C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -SO2NHCH(CH3)2, -SO2NH-cyclo-C3H5, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H5)2, -SO2N(C3H7)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C2H5, -NHSO2C3H7, -NHSO2CH
(CH3)2, -NHSO2C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -CECH, -CEC-CH3, -CH2-CECH, -Ph, -0-Ph, -0-CH2-Ph, N
r --Nn rTh N/N rN1 r rN
r N r N
/ _______________________________________ \ / __ \ / \
N\ /NH N\ Or N\ \
or R8 and R9 or R9 and R1 can form together one of the following five-membered or six-membered rings:
õo -- , N
-or ---%N
or R12 and R13 or R13 and R14 can form together one of the following five-membered or six-membered rings:
.0 ,0 ,0 ''N N
'0 H or I
R" represents -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH (CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 -cyclo-CsHo, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-05H9, -CH2F, -CH F2; -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3, -00C2H5, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -CO-cyclo-C3H5, -CO-cyclo-C4H7, -CO-cyclo-CsHo, -COOCH3, -CO0C2H5, -CO0C3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -S02CH3, -S02CF3, -S02C2H5, -S02C3H7, -S02CH(CH3)2, -S02-cyclo-C3H5, or -S02C(CH3)3;
rc -N1 represent -H, -CH3, or -CH2CH3;
or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomer, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
The inventors have found that the reversible inhibitors of formula (I) disclosed herein having a bridged bicyclic residue R3 exhibit increased potency over the compounds of the prior art. Particularly, it is demonstrated herein, that the inventive compounds have an improved inhibitory activity compared to the known compounds bearing aromatic moieties R3 instead of bridged bicyclic residues. In order to prove inventiveness of the compounds of the present application, known compounds from US 9,434,763 B2 and US 11,072,634 B2 (Reference 1 (E16 from US 11,072,634 B2), Reference 3 (A8 from US
9,434,763 B2), and Reference 4) were synthesized and tested as reference compounds in comparison to the most similar compounds of the present application. To this extent, inhibition data were determined using the classical fluorescent transamidation assay (dansylcadaverine incorporation into methylated casein, DCC-assay) as described in Buchold et al. [Buchold, C.; Nils, M.; Gerlach, U.; Weber, J.; Pelzer, C.;
Heil, A.;
Aeschlimann, D.; Pasternack, R. Features of ZED1227: The First-In-Class Tissue Transglutaminase Inhibitor Undergoing Clinical Evaluation for the Treatment of Celiac Disease. Cells 2022, 1/, 1667. https://doi.org/10.3390/cells11101667]. Casein is one of the best known high molecular weight (24 kDa) protein substrates for transglutaminases.
Inhibition data of the inventive compounds was compared with inhibition of compounds disclosed in US 9,434,763 B2, particularly, compound A8, which is denoted herein as Reference 3. It is noteworthy that the ICso values of compounds A8 published in US
9,434,763 B2 and E16 from US 11,072,634 B2 cannot be compared to the present data, relying on a fluorogenic isopeptidase assay.
Thus, the inventive compounds of formula (I) rated "A" showed efficacies of about 100-fold higher compared to Ref. 3 (A8). The same argumentation applies to Ref. 4.
Ref. 4 shows also that aromatic moiety of this reference comopund reduces the inhbibitory activity against TG2 strongly.
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Accordingly, a person skilled in the art would exclude aromatic moieties, e.g.
the phenyl group. It is of common knowledge, that bridged cycloalkyl groups are non-classical bioisosters of the phenyl group. By replacement of the phenyl group in A8 by e.g. an adamantane group, a skilled person would expect similar physico-chemical or biochemical properties excluding to invest efforts. Since aromatic moieties are clearly not preferred, bridged cycloalkyl groups would not be considered improving the compounds.
Surprisingly, the inventive compounds demonstrate that bridged cycloalkyl groups improve the potency of the compounds by orders of magnitude compared to the aromatic reference compounds. Therefore, we credit bridged cycloalkyl groups as disclosed with an outstanding inventive manner.
In another set of preferred compounds R2 represents RN
Rii 0 Ra -__ S R8 Rii \ S R8 --- -( Rio R9 ;
' R9 Rio R9 RN RN RN RN
Rii 0 __ wIi ON_R8 Rii N R8 Doi N, Rii N, __ N, ( lµi /1\1 i /N
/ ( --1K \I ir N
/ R9 R10 µ, , R9 Rio R9 R10 , , , , R10 R10 µi R10 Ril S _ R11 S R8 Rio ?!riR8 cl -N N¨ ) N __ N R8 , RN RN
RN RN
S 8 -, N ii ii ,N, ,N, _R RN
R N. < ,N wõ...),õ ,N N N N io N.
\¨N
Rio ' nio , __ N ' \Rio / N¨N
N=N
, , ' , = ' N r -------------------- -Ri3 Ri3 Ri3 Ri3 L.1 xj \-) \N \-) \-) , , ' Rii R14 ¨ \-J R14 Rio 0---"\-114 0- 21-113 R10 ; ; rk ; ;
RN
pp12 µ, RN
, Ri2 , R12 i\iy4' / 1\1---__/y Rio_tr/R13 ---TR13 N --- 1 \ RN
s-----1414 Rio R1,1 Rio R., , R13 ' 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 R12 Ri2 R11 s, ,,,------.õõ...---:-/,,,,, - 1 jL _ R13 ), Nv----R14 Rioill-- R., 1 A
S
R14 R14 Rio N __ N S
RN
RN RN
0=e ii R9 9 rN-/IR9 r Y1 y I_ . _ .R 9 R10 m R9 r_R
Rio R10 ,l' --/- R10 - \____/-----R10 L...,.,.,_....) ,--, rµNr"
N-----, , - /s1 -NI \ 1 N N p8 s)- S--7-1 - - Ni RsN ..
\N R8 \s-N \N----N Rs N-N b-N N---' , , - -O'N N N
_yN
- - -eNNH - - -eNNH N
- - A ¨_<N3 N _____ ( NN
- N N __ \( S S z c N
---eNN H - - -eNNH
IIN , NJN __ ( , ' _N _ N
- - -\ - -\13 N - - -eN0 N N __ \ ( IIN , NN3 0 7 , c N N
, , N
H S
-K7/ -II, - N N Ns H ' H
' S-_-N _ _7,__--/ ___N S __ _---:--- \N
\S-N - - -____ -- N
N S' N
, , ______n N 0 H
N __ / -----/ _ -__ri - -CT-) \ N -NI/ S'N'N N / N-0 , , , __________ 0 _ _ _e---- - /0---N, ....._N
\ -N - 7 N-N ) N 0 - \--N-1 - - -<71---O-N
H H , , , 0 -,.. N N
*4 , N
/ N
, N -, --' N
, / N
-- - N
-. , -, ,N
N 1\r N
2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 _ I -N
-I
NI,N / , N
, , -, N -, --'N 'N
N N
N
, -,,I\I N -,,NN
, - N
N N
N
N N N N
, N
I
N N- NN , , ,N N
II -, N N
1 f -1 i\il N
Nõ," N N
, -,,NN,N
N
, , , -,,NN -''NN -,,NN
N II
N,,, , 1 N f N--1\1 NN , N
, , -,,N, -,,rN -, N
N1,N , -, N. -, -,,N,N
NA
N , N N
, , N2 N A Nr N, N, , ir 1 NN , NN , NN
, '-'-IN
1 F\11 N,N
N-, N
N
2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 I I I
N N , 1\1N NN
--1\11 N.N
, N1\1-N
, , I I
N.NN N N.NN N , H
NH
HN NH
, , ., N NH , HN , NH H , , N=\ 9\ N=N N=\ N---- /(N
--N
)''---0 \ /N \ ,N
" , N¨ N¨ N¨ ¨N ¨N
/N -- \
--- / N ,N
N N _____________________________________ , / _________ N ' ¨N ¨N __\
/(N-- __________________________________________ / N \ //
________ N 1\1 N , ________________________________________ ' , _____ N , , , -- \ /\N
\ ¨\
--i /N
I\1 , --\ N --\ N
N -- .
N N
N N
, N=\ N=\
--- /(N 1 /N
\ / N\/ N / N N N
N N¨N N // N
, , , N=N N=N N=N N=N N=N
--- ____________________________________________ ---_/ --, \ ,N /
, _________ // , _____ N, N , , N=\ N=\ N=\ N=\ N--- /(N ---. /N --- /N ---\ /71, \ \ _______ N \ ,N
N N N , 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 N---- ______________________________ --- _____ \ _______ -- ---\ N
N N --- / N / N, /
N/ //
, N¨N N N __ ;
, , ¨N ¨N ¨N ' cNs ¨N
N N /KN
\ /71, \ _______ 1\1 , \ ,N
¨N ¨N /¨N ¨N ¨N
--- --i \ \
--- /
\ N N N N / N, /
N/ // N¨N N __ N ; , ____________________________________ , ¨\ ¨\
i¨\
,N N \ N
N , N=/ // N¨N N
, __\ 0 =
- -- -i /N
-- --N, \ N N N
// N, ,N N¨N ;
N , N¨N , N sINI/ , or ' wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 ¨ R14, and RN; and preferably with 1 to 3 of the substituents R11 ¨
R13; and the substituents R9 ¨R14, and RN have the meanings as defined informula (I); and more preferably R2 represents RN RN
0rR8 R11 0 R8 ____õ,s, _R8 R11 s R8 __ R8 Rii ,, R8 \ / (- \ , \ , \ , Ric) R9 R9 R10 R9 R9 Rio R9 ,' D9 r` , RN RN RN
Rii N,k. RN N, R11 0 __ R11 0 R8 -- -)" R8 I /(1 4 --121(\1 --\__, I(\ I ----- \ //
) _____________________________________________ N N N
Rio ss R9 Rio R9 Rio Rio , ' R10 Rio ,R10 Ril SN Rii S
O\ Rs -----SNR8 --CaR8 )\ /7-N 1 , //
N N N N
R8 N¨ µ R8 Rio Rio ' ' , , , , RN
___________ 'NI
N Rii N, ,N Rio ------ ,N 1\1\¨ri . N, N, D N
- ---'- N''`
/-) LI.,.,.õ,\,:j R13 ) ______________________ N
Rio N¨N ; N=N , D14 , " , R12 R12 R12 N R12 0---__//
R13 /`) R13 --------------------------- N/-) R13 R13 ---),IRA 13 \N \-) N R14 N R14 N R14 N R14 R10 R., , , 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 RN
R12 Ri2 RN
S---.../Y,) _ N-....//, 1 i D13 N,/Y,) --- ., R14 R14 N-----' ,A \jR
Rio Rio R., R14 \
_______________________ N71-.õ).___Riit N, R9 _ Rio ,NI ,R9 II 1 R13 9 f_ ' 4. 1 _____ S r-ii R
r /1 Rio R1._ R1._0 , , - R9 R9 p S
,I\I /¨R1 0--/-m, 1 __`-,N----- 1-µ N N
, ' Icl 0 s ---eNNH
\ \ \ __________________ N ( , S
, ---eNNH
-- A - - N -(3 N N \( , SNJ
S S y N
NH ---eNNH
IIN , NNN3 N __ ( -- A - N N
\(
6 y 11 Ni o N3 N , N , NN
, H N,--S N __ ___(//-1-N-N ___________________________________________ H H
S--...._-N ----r-N\ S ___(-1-'-\---N
---____ ---- N
N,...(/
, H
S-N-N/
0 ___,----µ 0,..--N / N
- Cf--r-N
H H , , , 0,N (----r-N\ 0 , i ..
N /
N, , 'N
, N
2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 - - - N
-, , -.N
N N N /
., -, -, I N'N N
-I
N,N / , N
, , -. N -, 'N 'N
N N
N
, ., -,,NN -,,N ,N
N N , I
N --.N % --- N N----õ,..-- ¨
, , , , --1rN 1(1\11 N , N NN , , -- -,,N N -, N N
f -N N,,, N NN , , -,,NN
- ---- -:-.,--- -:,1 Il I 1 N
N,,," N
N , -N
, , -,,NN,N
N N
, 1 II -,,NN
N,,, , NN -'''NN -,,NN
I
N II
N , - N
I 1 f NN , -,,N -,fN -, N
NN NN N,N
, , , N,N -. N,N
''I N'N
N, N I
N N-"N NN
' , , Ir 1 NN , NN
N N
2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 - --'1rN
N.N
I I
N N , 1\IN NN
I -'1 ' , --,r1 I -,,NN
N.NN N,NN
NN
H
NH
HN KNH , , ., N NH , HN H , NH , ' N=\ 0 N=N N=\ N---N
-- \ /
\ N
\ ' //N
, , ' N- N- N- -N -N
/N -- \
/ N
N _____________________ N , , / _________ N ' -N -N _ __ \
-- -- \ -1\-/(\N ----\
/N
1 N \ /71 N, N N
, , -- \
\ /N
--\
--i /N
N\\ , --*
N N
N _________________________________________________________ , N=\ N=\
-- --i /(N --- /N
\ / N / N / N N N
N
' N-N \IV \\ // N
, , ' , N=N N=N N=N N=N N=N
-- \ /N ---, -- -t _____ -- --, \ ,N
N N
, ' , 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 N=\ N=\ N=\ N=\ N--( \ //N, \ S \ ) N N /)', \ ,,N1 N
, N¨ NI/Z/ N //N
N¨N N \ __ , , 1 Z( N\\ N N N , - - ______________ -- i \ \
-- \\ // \
\ N NN \ / N / Ns /
N¨z/ N¨N N µ1\1 __ , ¨\ ---7\NI - - -- -, --i \
z(N z(N z(N
\ __________ NN, N N
N/ * __ //N N
\
, , , _ __________ \
- - Ns /
N s \ ,,N1 N N
// Ns N \N¨N ;
_____________ , N¨N , ' N sINIZ ,or wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 ¨ R14 and RN; and preferably with 1 to 3 of the substituents R11 ¨
R13; and the substituents R9 ¨R14 and RN have the meanings as defined herein.
Preferred; the unsubstituted bicyclic residues which can be substituted with 1 to 5 of the substituents R9 ¨ R14 and RN; have the following structure and the substituents R9 ¨ R14 and RN have the meanings as defined herein:
i\I R12 0 R12 S R12 - - ..eN - RN
Rio \ Rio \ Rio \ N __ ( Ria ' ' Ria , Ria , , , Riz , Rii Rii N Rii - - -NNI- RN - \
N N
N
S.NRii R13Y 7 R12 N
\( rC----Riz R13 R13-ez N
Riz , ; , R12, 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 -----eS ----N-RN ---N-RN
---eS
N __________________________________________ ( N , N/N---\
N Riz R130 0 R12 ' R13 R12 ; R13 ' , N R11 ____NN R11 R11 R134,y, ,c) 6 7 Riz N \( N _________________________________________________ \ N,13..._ N
R12 , N R13 Dp,13/N, ,L12 N Riz " N '`
' R12 ; R13 , 0 w2 S Riz R14 Ru R14 , 0 Riz N S
Rio R14 R10 , , ,r¨ \
-r-S/> _________________________________________ R 12 -_ / N-N \
iq R---¨N R NI-N1 -S
Rii R12 ; --S
R11 RN. R13 ; RN
, , S------N
_-N ,e R13 __ R N-... ---------1\1 12 ---$SX(N
S' ___--------:N
S-1\I ./( IN/( wi w2 ;
R13 ; Rii R12 R13 ;
, R11 12 N-0 \
-N R11 R12 ; 0 -R11 ; R11 -- &:1 R12 R-- --------- 13 1--Ne R13 --NO - 0-N />
N.0 ii RN1 R13 RN ; R13 ;
;
0,N R13 - __________ - N ____e R13 _"----T_____N 0 i , __ R12 -- -0 __ R12 RI 1 R12 ; " N 0-1\LN
R13 ; Rii ' , 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 -, N R13 . R12 I
, R12 R9 N N R13 Ri2 Rlo Rii R14 Rlo Rii R9 -, N
N IA
N
' , , R10 - N R13 -, N R12 -.
1 il R13 N R' Rlo N R12 N R11 , , , Ri2 NN
. -, -, Nr R9 III
N.N
R13 a N
R-R14 Rii Rlo Rii Rlo ' , , -, -, -, N N
, N R
N N R.-in RU Rii Rlo R11 , , , R11 Rlo R13 -, R9 ----, ---,-.-.--- -:-.---.---- -.,N
N-,N R9 R12 ---'" / 10 R.-R13 Rlo Rii R9 R14 , Rlo iv R13 R13 Rlo - NR12 - NR12 -,N R11 1 1 _...., 1 R9rN R9------,r---V---R11 R9--'-N---R12 , , , ''--1 N , R12 I I
R9-----Nr-M-AR12 R9-1\1-N I
R13 R13 ' , , N,R11 -'Nr1 N Ri2 ..
, --..- -,.., -,.., I I
N R._ 1 9 N R._ 1 9 NN
Rlo R13 Rlo R13 Rlo R13 , 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 R -,f NY NY R12 -,f NY NY R12 --.., --.., .=
I N N
N---,r-N--2----Rii Rlo Rlo R11 R10 , , , -,,N N N N R12 -----, N-----.----Ny- R12 -- ---, --,--.-.-----,-.----' I , II I -----õN:.---õ,ff-- N
N N
'rN R11 R1o7 NR11 R10 , R11 R10 , , - N N, - N N R12 - _ , N ,N , R12 N-----, --,---.-.--- --:----- ----, --,--- --,---9r-r1 N I ,,, - --- R12 R R9------r-e---- R11 , 1 -,f NY NY R13 -,,NN
R10iNI R12 N R12 1 ,
, H N,--S N __ ___(//-1-N-N ___________________________________________ H H
S--...._-N ----r-N\ S ___(-1-'-\---N
---____ ---- N
N,...(/
, H
S-N-N/
0 ___,----µ 0,..--N / N
- Cf--r-N
H H , , , 0,N (----r-N\ 0 , i ..
N /
N, , 'N
, N
2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 - - - N
-, , -.N
N N N /
., -, -, I N'N N
-I
N,N / , N
, , -. N -, 'N 'N
N N
N
, ., -,,NN -,,N ,N
N N , I
N --.N % --- N N----õ,..-- ¨
, , , , --1rN 1(1\11 N , N NN , , -- -,,N N -, N N
f -N N,,, N NN , , -,,NN
- ---- -:-.,--- -:,1 Il I 1 N
N,,," N
N , -N
, , -,,NN,N
N N
, 1 II -,,NN
N,,, , NN -'''NN -,,NN
I
N II
N , - N
I 1 f NN , -,,N -,fN -, N
NN NN N,N
, , , N,N -. N,N
''I N'N
N, N I
N N-"N NN
' , , Ir 1 NN , NN
N N
2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 - --'1rN
N.N
I I
N N , 1\IN NN
I -'1 ' , --,r1 I -,,NN
N.NN N,NN
NN
H
NH
HN KNH , , ., N NH , HN H , NH , ' N=\ 0 N=N N=\ N---N
-- \ /
\ N
\ ' //N
, , ' N- N- N- -N -N
/N -- \
/ N
N _____________________ N , , / _________ N ' -N -N _ __ \
-- -- \ -1\-/(\N ----\
/N
1 N \ /71 N, N N
, , -- \
\ /N
--\
--i /N
N\\ , --*
N N
N _________________________________________________________ , N=\ N=\
-- --i /(N --- /N
\ / N / N / N N N
N
' N-N \IV \\ // N
, , ' , N=N N=N N=N N=N N=N
-- \ /N ---, -- -t _____ -- --, \ ,N
N N
, ' , 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 N=\ N=\ N=\ N=\ N--( \ //N, \ S \ ) N N /)', \ ,,N1 N
, N¨ NI/Z/ N //N
N¨N N \ __ , , 1 Z( N\\ N N N , - - ______________ -- i \ \
-- \\ // \
\ N NN \ / N / Ns /
N¨z/ N¨N N µ1\1 __ , ¨\ ---7\NI - - -- -, --i \
z(N z(N z(N
\ __________ NN, N N
N/ * __ //N N
\
, , , _ __________ \
- - Ns /
N s \ ,,N1 N N
// Ns N \N¨N ;
_____________ , N¨N , ' N sINIZ ,or wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 ¨ R14 and RN; and preferably with 1 to 3 of the substituents R11 ¨
R13; and the substituents R9 ¨R14 and RN have the meanings as defined herein.
Preferred; the unsubstituted bicyclic residues which can be substituted with 1 to 5 of the substituents R9 ¨ R14 and RN; have the following structure and the substituents R9 ¨ R14 and RN have the meanings as defined herein:
i\I R12 0 R12 S R12 - - ..eN - RN
Rio \ Rio \ Rio \ N __ ( Ria ' ' Ria , Ria , , , Riz , Rii Rii N Rii - - -NNI- RN - \
N N
N
S.NRii R13Y 7 R12 N
\( rC----Riz R13 R13-ez N
Riz , ; , R12, 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 -----eS ----N-RN ---N-RN
---eS
N __________________________________________ ( N , N/N---\
N Riz R130 0 R12 ' R13 R12 ; R13 ' , N R11 ____NN R11 R11 R134,y, ,c) 6 7 Riz N \( N _________________________________________________ \ N,13..._ N
R12 , N R13 Dp,13/N, ,L12 N Riz " N '`
' R12 ; R13 , 0 w2 S Riz R14 Ru R14 , 0 Riz N S
Rio R14 R10 , , ,r¨ \
-r-S/> _________________________________________ R 12 -_ / N-N \
iq R---¨N R NI-N1 -S
Rii R12 ; --S
R11 RN. R13 ; RN
, , S------N
_-N ,e R13 __ R N-... ---------1\1 12 ---$SX(N
S' ___--------:N
S-1\I ./( IN/( wi w2 ;
R13 ; Rii R12 R13 ;
, R11 12 N-0 \
-N R11 R12 ; 0 -R11 ; R11 -- &:1 R12 R-- --------- 13 1--Ne R13 --NO - 0-N />
N.0 ii RN1 R13 RN ; R13 ;
;
0,N R13 - __________ - N ____e R13 _"----T_____N 0 i , __ R12 -- -0 __ R12 RI 1 R12 ; " N 0-1\LN
R13 ; Rii ' , 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 -, N R13 . R12 I
, R12 R9 N N R13 Ri2 Rlo Rii R14 Rlo Rii R9 -, N
N IA
N
' , , R10 - N R13 -, N R12 -.
1 il R13 N R' Rlo N R12 N R11 , , , Ri2 NN
. -, -, Nr R9 III
N.N
R13 a N
R-R14 Rii Rlo Rii Rlo ' , , -, -, -, N N
, N R
N N R.-in RU Rii Rlo R11 , , , R11 Rlo R13 -, R9 ----, ---,-.-.--- -:-.---.---- -.,N
N-,N R9 R12 ---'" / 10 R.-R13 Rlo Rii R9 R14 , Rlo iv R13 R13 Rlo - NR12 - NR12 -,N R11 1 1 _...., 1 R9rN R9------,r---V---R11 R9--'-N---R12 , , , ''--1 N , R12 I I
R9-----Nr-M-AR12 R9-1\1-N I
R13 R13 ' , , N,R11 -'Nr1 N Ri2 ..
, --..- -,.., -,.., I I
N R._ 1 9 N R._ 1 9 NN
Rlo R13 Rlo R13 Rlo R13 , 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 R -,f NY NY R12 -,f NY NY R12 --.., --.., .=
I N N
N---,r-N--2----Rii Rlo Rlo R11 R10 , , , -,,N N N N R12 -----, N-----.----Ny- R12 -- ---, --,--.-.-----,-.----' I , II I -----õN:.---õ,ff-- N
N N
'rN R11 R1o7 NR11 R10 , R11 R10 , , - N N, - N N R12 - _ , N ,N , R12 N-----, --,---.-.--- --:----- ----, --,--- --,---9r-r1 N I ,,, - --- R12 R R9------r-e---- R11 , 1 -,f NY NY R13 -,,NN
R10iNI R12 N R12 1 ,
7-õ-- N
Rii Rio Rii R9 y--.1 , , Rlo R11 , -,,N)Ni -, ,I\IN ,N )N
R9 -N R" Rlo R12 Rlo y......õ1õ--N y,.....õ1õ--y N R12 , , , - N,,, Ril N R11 -. N R12 ---- , I I f R97 r-rN N--N Rlo N ------. -------õ,,- N
N
Rio , Rio Rii -,NN ..,_ R12 -,,N R13 -_,-- õ,.. -,..õ. II II
R1Or NN, NrN R ------7"--ii NNR11 R , R10 R11 12 -, NN _ N
N-----. --------1,' R12 Ri2 N R1 Rii Ny<-.R9 rk , , , N. R10 ,,,,, NõR11 -. -, N -I I
N
R12 N: N
R9-NrN
, , , 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 R11 Nri\I R11 -, -,,N
_ I--,---'-c---, -=.---.-- I
NN I 12 N ----..T.7"-N%----R12 R9 R12 ; R9 N R11 `. , 'N '-'. N
I
,N 1 .
N-NR12 Ri2 N- R12---N----"-yN
R13 R13 R9 , , , I . I
NN N R'` NNR12 ..-_,.:L , W N
R9 R12, ; R9 , , N R12 R12 -' r-I - I
R13N NN-,N R-1\1-"N
R13 ; R9 , , R., p12 `.,N
¨ , ¨ . 'N
N,NrN I 1 N, N N R1¨, Rio N N R'`
' R14 ,, N R9 -, N_RN
RN¨N Rii R11 N¨RN Rio Rlo R13 1,, R13 R ¨ Ri.i . R12 R11 R9 Rio ; Rio R9 , __ R12 _ - R14 . R10 . R10 /N
N_( ---(:) N=N
9 =( N¨i -- \ /N--N R14 -- \ /R - - N
\ /N _ 1 / I 0µ
( R11 R14 \ N R11 Ri4 R11 "
R11 R13 \ //I
N _________ z( R12 R13 ; \
D12; R12 R12 R13 ; R12 R13 '' 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 \ ________ 1\/1R9r, N NR9 R9 R9 R9 N_ N¨ tR10 N_ N_ ¨N
/ R --___ ___________________ -- ________ z(R13 __ Dii R13 __ \ / Rii N/ R11 / R11 Rii \ N
R.,i, , , , Rlo R9 Rio Rlo R9 Rlo R9 ¨N
--( Dio __ R9 -___1\--/(N
--_ (R9 --$¨ ., -- \ /N
( Rii \ / ____________ Ri3 R11 __________ \ / R13 N / _____ R13 Rii R11 ifl R=-N N , \ /N
( 1, N
R12 R12 RU R12 IR¨ D., R12 ' , F` , , Rlo R9 Rlo R9 R11 R12 R11 R12 --( --( ---- R13 R13 -- /N --- /N
N N
z R11 \ / R13 N / __ R13 Rio \ /NI R9 \ N z( N NI N __ ( R9 Rlo ; ; , ;
N¨( N¨( -- R13 -) __ /N
( --- /N
R9 \ / Rlo Ns /2¨R1 N \ / Rlo N N N R11 N sN ____________ z( N¨N
' R9 R9 R12 R11 N
, , N=N N=N N=N N=N N=N
-- \ ;NI _____ /tRio it /(Rio _ x_ (Rio fR0 Rii R14 R13 \ /NI R13 \ / R11 R13 \ /
¨11 rc N / ___________________________________________________________ R11 10 ( ii N N
R12 R13 IR¨ R.. R12 R12 ; R13 R12 , , , , ___ Rlo Rlo Rlo Rlo N_( N_( N_( N¨( N¨T
-- /N -1 /N ) /N --- /N R10 ( R13 \ /N Ri \ S_Rii R13 \ / Rii N / ____ R11 o012 IA \ / N
NI
, ( ii N N
" ; ; ; ;
N_ N_ _ _ _$N¨/R9 R9 R1 o _ _ ii¨/ R1 _Rio ___$ _Rlo ¨
\ N N N R N / ____ R11 Ns / __ R11 N ______ z R
( z( 12 \ / ii N N
R12 R11 N¨N , R12 R12 , 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 ¨N
-- \ /1\1 .__ ( ¨N
-- \
\ /N ¨N
-- \ /N ¨N
R13 \i, /(Nii R13 \ NRii R13 \N / Ril N \ / __ R11 R. r,.. R12 Riz , rc , ' , , ¨N
__i Rlo ¨N
i¨N
--_$ _____________________________________ (R11 R10 R10 __ \ / R10 N
R12 \ N N Z R12 N N / __ R11 Ns / __ R11 N sN
; R12 R11 N¨N , Riz Riz R9 Rlo R9 R10 R9 R10 R9 R10 --( --( --( R9 R10 --( N --_ N --- z(N ¨( -- \ z( \ zZ( -- i /N
\ ,N R12 \ N
N N Riz \ _Rii __ Nµ\
S IA
R11 R11 R12 R11 ; R12 ; ; ' ;
¨( R11 R12 N / I R11 Rio \ N
N¨I4 R12 , Rio Rlo , , , Also preferred are the compounds of the general formual (I) R.1 H
(I) wherein L represents ¨L1¨L2¨;
LI represents ¨CH2C0¨;
L2 represents ¨NRI41¨; and R3 represents 1-adamantyl ; or L2 represents ¨NRN1CH2¨; and R3 represents 2-bicyclo[3.1.1]heptyl, and the afore-mentioned 1-adamantyl and 2-bicyclo[3.1.1]heptyl residues are optionally contain one or more C=C double bond and/or are optionally substituted one or more of Ra; Rb; Rc; Rd; and Re;
RI represents ''-N- R6 H
, 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 RN RN RN
Ril Il pli IV 8 - - N8 R2 represents 1 ----- '' ---R or ---"R
N ) N
R1 , __ N R10 -, ' , , R6 represents -C2H5;
Ra, Rb, Rc, Rd, and Re represents independently of each other -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C2H5, -CON H2, -CON HCH3, -CON(CH3)2, -CONN C2H5, -CH2CO2H , -CH2CO2CH3, -CH2CO2C2H5, -CH2CON H2, -CH2CON HCH3, -CH2CON (CH 3)2, -CH2CON HC2H5, -NHCOCH3, -NHCOC2H5, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C2H5, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3;
R6, R10, and R11 represent independently of each other -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH (CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2F, -CH F2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -OCH3, -0C2H5, -0C3H7, -OCH(CH3)2, -0C(CH3)3, -0C4H9, -OCHF2, -0CF3, -OCH2CF3, -0C2F5, -OCH2OCH3, -0-cyclo-C3H5, -OCH2-cyclo-C3H5, -0-C2H4-cyclo-C3H5, -CH 0, -COCH 3, -COCF3, -00C2H5, -00C3H7, -COCH (CH3)2, -00C(CH3)3, -COOH, -COOCH3, -CO0C2H5, -CO0C3H7, -COOCH(CH3)2, -COOC(CH3)3, -00C-CH3, -00C-CF3, -00C-C2H5, -00C-C3H7, -00C-CH (CH3)2, -00C-C(CH3)3, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -N HC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5, -NHCOC3H7, -NHCOCH(CH3)2, -NHCOC(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CON HCH (CH3)2, -CON H-cyclo-C3H5, -CON HC(CH3)3, -CON(CH3)2, -CON (C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -SO2NHCH(CH3)2, -SO2NH-cyclo-C3H5, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H5)2, -SO2N(C3H7)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C2H5, -NHSO2C3H7, -NHSO2CH (CH3)2, -NHSO2C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -CECH, -CEC-CH3, -CH2-CECH, -Ph, -0-Ph, -0-CH2-Ph, 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 / H
rN I
N H
N H
r rN
--NO N
--N/N
I H I
rN rN
/ _______________________________________ \ / \ / \
o o 0 N\ /NH _________________ N\ /N-;
or N\ 71 \;
RN represents -H, -CH3, -C2E-13, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H3, -cyclo-C4H7, -cyclo-C3I-19, -CH2-cyclo-C3H3, -CH2-cyclo-C4H7, -CH2-cyclo-C3H9, -CH2F, -CH F2; -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3, -00C21-13, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -CO-cyclo-C3H3, -CO-cyclo-C4H7, -CO-cyclo-C31-19, -COOCH3, -COOC2H3, -CO0C3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -S02CH3, -S02CF3, -S02C21-13, -S02C3H7, -S02CH(CH3)2, -S02-cyclo-C3H3, or -S02C(CH3)3;
RI" represent -H, -CH3, or -CH2CH3;
or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomer, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
In a preferred set of compounds RN RN RN
cr.- - 8 R2 represents Ri,) R8 or N
, , , and R8, R10, R11, and RN have the meanings as defined herein.
The residues bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl, diamantyl, and hexamethylenetetraminyl used herein, have the following parent structures respectively:
bicyclo[1.1.1]pentyl bicyclo[2.1.1]hexyl bicyclo[2.2.1]heptyl -2--L ...-- --bicyclo[3.1.1]heptyl bicyclo[2.2.2]octyl bicyclo[3.2.1]octyl 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 - -bicyclo[3.2.2]nonyl bicyclo[3.3.2]decyl bicyclo[3.3.3]undecyl 4-homoisotwistyl adamantyl diamantyl hexamethylenetetraminyl N,' N N
and the afore-mentioned residues optionally contain one or more C=C double bond and/or are substituted optionally one or more of Ra, Rb, Rc, Rd, and R.
Preferred are the compounds of the formula (la):
ON,R6 R2 N ,N L 'R-(1a), and L, R2, R3, R6 have the same meanings as defined in the formula (I) Preferably, the present invention relates to the comopund of the formula (I) (I) wherein L represents ¨L1¨L2¨ ;
L1 represents ¨CH2¨, ¨CH2CH2¨, ¨CH2CH2CH2¨, or ¨CH2C0¨, L2 represents ¨NR141¨, or ¨NRNICH2;;
and preferably L represents ¨CH2¨, ¨CH2CH2¨, ¨CH2CH2CH2¨, ¨CH2CONH¨, ¨CH2CONH¨CH2¨, ¨CH2CON(CH3)¨CH2¨, or ¨CH2CONH¨CH(CH3)¨, 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 o R1 represents -'')N-R6 H
, R2 represents RN RN RN
R11 1\1 i II
R11 N R8 --.R8 --( \_R8 0 ., N
N
,-, N9 /
" , " , RN RN RN RN RN
Rii \ s R8 _ _ __õ, iir R8 R1:__LNõr R8 R1=1, Rii ri, __ N, -\\
1 iN
K /N
( , R9 R10 R9 // 09 R10 sµ09 p .in .., 0.9 " 5 5 " 5 " N
1 .
CD -R11 0 R8 - _ ....,-ON _R8 Rtl),õSõ, _õS,õ _R8 -___,,N,N
., ? , -\
N¨ N , ' , __ N N N
R8 0, 1 0 R1 R1 0 R1 0 , , , RN RN RN
,N , R12 Ri 2 Rii ii 1 - ,1/4, N N N RN oi _N, ' goN pe13 /ri ic -------------------------------------------------------- . ., N / Rio NEN , D14 , " N
' , " , Ri2 , R13 ----------------------- R13 -- r ) R13 - - -\-ji RA 13 Rio_----er/R13 \N \-N Dia N= R14 N R14 Rio R.-, ()-11.4 "
RN
R' R12 Ri R12 S--_/y,) _ \ R12 N--__//
Rio4-----r/ ---TIRli Rio4-----r/ Ri3 ---$___ -0--13 Rio R14 S14 , Rlo , RN p12 R12 p12 N ,' - - -(\ 1 tR13 '-1 -R13 -----.,---`
II 1 N-%\-RN R1A .-, R14 R14 , , , , RN
R11 I, RN
\
. _____________________ ,A.Nr...õ14 , R9 0 R9 2/ N RioNI ---- __ R14 r_r R9 r /1 1 f) ___________ S _ _ 1_ R 0 N \J
R._ N
, 1\1-----S - "\___,----- Ri o ' N- ' ppl 0 ' ' , , , r<
ri R9 9 r Y, o) ,r\ R9 N\ II N
L-R'10 IN õ, _R10 \N-R8 \SI\I R8 ,S , ' R8 , N 1 S,-- N , N --.. ----(,:\
R''a s=- II N R8 z -- R8--N'N R8 N-N b-N N-C) , or 0-N -, , 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 R3 represents bicyclo[1.1.1]pentan-1-yl, bicyclo[2.1.1]hexan-1-yl, bicyclo[3.1.1]heptan-3-yl, bicyclo[2.2.1]heptan-2-yl, bicyclo[2.2.1]hept-5-en-2-yl, bicyclo[2.2.1]heptan-7-yl, bicyclo[2.2.1]heptan-2-yl, bicyclo[2.2.2]octan-2-yl, 1-adamantyl, 2-adamantyl , 4-homoisotwistyl, 1-diamantyl, or 4-diamantyl, and the afore-mentioned bicyclo[1.1.1]pentan-1-yl, bicyclo[2.1.1]hexan-1-yl, bicyclo[3.1.1]heptan-3-yl, bicyclo[2.2.1]heptan-2-yl, bicyclo[2.2.1]hept-5-en-2-yl, bicyclo[2.2.1]heptan-7-yl, bicyclo[2.2.1]heptan-2-yl, bicyclo[2.2.2]octan-2-yl, 1-adamantyl, 2-adamantyl , 4-homoisotwistyl, 1-diamantyl, or 4-diamantyl residues are optionally contain one or more C=C double bond and/or are optionally substituted one or more of Ra, Rb, Rc, Rd, and Re;
R6 represents ¨C2H5;
and R6, R6, R10, R11, R12, R13, R14, Ra; R13, Rc; Rd; Re ; RN and rt "N1 have the same meanings as defined in formula (I) or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomer, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
In some embodiments, the present invention relates to the comopund of the formula (I) H CN yL
H
(I) wherein L represents ¨I-1-1-2¨ ;
LI represents ¨CH2C0¨, L2 represents ¨NR141¨, and R3 represents 1-adamantyl; or I-2 represents ¨NR1ICH2¨, and R3 represents 2-bicyclo[3.1.1]heptyl, and the afore-mentioned 1-adamantyl and 2-bicyclo[3.1.1]heptyl residues are optionally contain one or more C=C double bond and/or are optionally substituted one or more of Ra, Rb, Rc, Rd, and Re;
,,,A ,R6 Ri represents N
H
, R2 represents 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 RN RN RN
R11 1\1 _ - R11 1\1 r R8 ---)--"IN---R8 ---s--0 Rs R11 0 Ra -_ S r, m8 1 ________________________________________________________________________ r r i __ , ___ ) ___________ N N
Rlo N Dio D10 R9 /' R9 R10 .-, rC9 lµ , " , RN RN RN RN RN
R11 s R8 __ N r-s8 R11 ii R8 R11 1\1, R11 rj, __ N, 1 ___________ r K i _____ ( ,, i ,N
( n , ,N
1, ( n . R9 R10 ___ R9 / n9 R10 sµ / , R._ nõo rµ rµ , rµ , Rio RN
o, ,,_ ,- Rii 0 R8 -___sõ-ON __R8 ),-.,._ N¨ 1 ----N \ ir N --) __ N S R8 N
N
R8 Dio Rio Rio RiO
, , ' , , , , RN RN RN
Rii ii ,1/4, - N N "N i N Ro - ,N, p¨
o R12 1 '' \\ /c \¨N ----\- N-------------------------------------------------------- u,,,,,,õ\,) N / o10 , N=1\1 , 0 '1,4 N
' , = , N R12 0 -/,) %% R12 ¨, TR13 ---------- I R- R = -12 ¨ ¨ -\- R1 o_(%.--..-- o 1,4r/ R13 \N \-) .-, '\-4 5 N Ri4 , N Ri4 , N Ri4 , Rlo RiA
N
S-R
pp12 R12 -/ 13 \ R12 i\i-/Y s 1 ' W 0 4.--------(> - - ,:j R
R 1 o _(---r> R13 0 ---\13 Rio Ria S14 , Rio Ria ,µ RN
13p. 12 R12 p12 R10 / i\I ----_/' ' - -- -(\ 1 tR13 13 ,,--------,õõ----"N`
N N--%\-'1A \7R
RN R., Ria Ria , RN
R11 1, RN
Niv_____ R14 --=' /1 ) --- N . R
R 1 _ r._" 9 rNiR9 __ i_ _Ro N \ j Rio N __ g 10_1 __ R14 v - S \___,------010 , K,) Ri\I `Rio ' , ' r Yi /1.r N\ X N
--/-_-, Rio - õ, _Rio , N
\
- ,." R8 \O
, R8 /S , ' , R8 N H
-- N - - N --N R,RS ,.. ---ii N6- Ro___i -------i R8--- 1 N'N R8 , N-N , b-N , N-1:3 , or 0--N -R6 represents ¨C2H5;
2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 and R8; R9; R113, R11, R12, R13, R14, Ra; Ri3; Rc; Rd; Re RN and RNi have the same meanings as defined in formula (I) or a diastereomer; an enantiomer; a mixture of diastereomers; a mixture of enantiomer; a racemate; a solvate; a hydrate; or a pharmaceutically acceptable salt thereof.
In some embodiments; the present invention relates to the comopund of the formula (I) (I) wherein L represents ¨L1¨L2¨;
LI represents ¨CH2C0¨;
L2 represents ¨NRI41¨; and R3 represents 1-adamantyl; or L2 represents ¨NRN1CH2¨; and R3 represents 2-bicyclo[3.1.1]heptyl, and the afore-mentioned 1-adamantyl and 2-bicyclo[3.1.1]heptyl residues are optionally contain one or more C=C double bond and/or are optionally substituted one or more of Ra; Rb; Rc; Rd; and Re;
RI represents R2 represents RN RN RN
) __ N
N
R10 R10 =
R6 represents ¨C2H5;
and R8; R113, R11, Ra; Ri3; Rc; Rd; Re RN and RN1 have the same meanings as defined in formula (I) or a diastereomer; an enantiomer; a mixture of diastereomers; a mixture of enantiomer; a racemate; a solvate; a hydrate; or a pharmaceutically acceptable salt thereof.
In some embodiments; the present invention relates to the compound of the formula (la):
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 '1\1-R6 H
0 _i,_, 0 H,)-L , L , R2i N 1 N R3 H
0 (1a), wherein L represents ¨L1¨L2¨;
L1 represents ¨CH2C0¨, L2 represents ¨NRI41¨, and R3 represents 1-adamantyl; or L2 represents ¨NRN1CH2¨, and R3 represents 2-bicyclo[3.1.1]heptyl, and the afore-mentioned 1-adamantyl and 2-bicyclo[3.1.1]heptyl residues are optionally contain one or more C=C double bond and/or are optionally substituted one or more of Ra, Rb, Rc, Rd, and Re;
R2 represents RN RN RN
N
Ri N
_N _Ra ___ N ,_,8 _ _ 0 R8 R1 _1 0 Ra -__ S ,-, m8 -\\ 'r ir 1 ______ r -\\ r r R10 N Rio Di R9 , R9 R10 ,-,9 I-C , RN RN RN RN RN
R11 S R8 N Rs R1N Rs Rii N, R11 II, -_ N, -14N I iN
/ K ¶
/ R9 R10 R9 / ,--,9 R10 `, / ,-,,-.-,n R10 ,--,9 N 1 o N 1 N
Rlo RN
S, Dp8 -_,..õ,,n.
x - R11 0 R8 J R =------ /7-----1 --- \ 8 ________________________________ N N N ) __ N N N
, RN RN RN
,N, R12 R12 Rii N,m N N ,N1 Rio N Nr--- ,N, DN 11 R=- 1 2 R =-1 ,r1 1/ - - y N----)'N ------------------- u,,,, \-) N
NEN , r-114 N
, , ' N
R12 R12 N R12 0---__//, %, R12 ------------ /') R13 N/-) Ri 3 R=-, r 1 ---,TR13 -\- 1, R10_tr>niR1 N R14 N R14 N et R10 R.-, 0"---R14 , RN
S ---__/ N----, R10 4--------r/ -\' R10_t---r> R13 ---,__---- M
(21-13 R10 R14 S"----414 , R10 R14 , 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 RN
R12 R1 / i\l-A -_, R12 R12 ---_-------7, -- 4 1 R13 - I R13 - L _I 1 N N'%\i4 ___\7 iA
, RN R14 R14 R-R
_____________ R11 N RN 2/ NIVR14 ii R9 r 9 r '/1 inX S R10-N1 ____ 14 riIIR
R=- N R RN,N\J1.<,..10 S
, , ri /R9 r / io m i --N'\ I N6-_Rf_Rio _. 1-------' N II - ,S,- - ,- a N, -- - ,-----N R'-'a ---\ 11 N li - R' ---- -/ -, or 0---N ;
R6 represents -C2H5;
Ra, Rb, Rc, Rd, and Re represents independently of each other -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C2H5, -CON H2 , -CONHCH3, -CON(CH3)2, -CONHC2F15, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H5, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2F15, -NHCOCH3, -NHCOC21-15, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C21-15, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3;
R6, R6, R10, R11, R12, R13, and R14 represent independently of each other -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2F, -CH F2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CH F2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2OH, -OCH3, -0C21-15, -0C3H7, -OCH(CH3)2, -0C(CH3)3, -0C4H9, -OCH F2, -0CF3, -OCH2CF3, -0C2 F5 , -OCH 20CH 3 , -0-CYCIO-C3H 5 , -OCH 2-CYCIO-C3 H5 , -0-C2H4-CYCIO-C3 H5 , -CHO, -COCH3, -COCF3, -00C21-15, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -COOK -COOCH3, -CO0C2H5, -CO0C3H7, -COOCH(CH3)2, -COOC(CH3)3, -00C-CH3, -00C-CF3, -00C-C2H5, -00C-C3H7, -00C-CH(CH3)2, -00C-C(CH3)3, -N H2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5, -NHCOC3H7, -NHCOCH(CH3)2, -NHCOC(CH3)3, -CON H2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONHCH(CH3)2, -CONH-cyclo-C3H5, 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 -CON HC(CH3)3, -CON(CH3)2, -CON (C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -SO2NH2, -SO2NHCH3, -SO2NHC21-15, -SO2NHC3H7, -SO2NHCH(CH3)2, -SO2NH-cyclo-C31-15, -SO2NHC(CH3)3, -S02N(CH3)2, -SO2N(C2H5)2, -SO2N(C3H7)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C21-15, -NHSO2C3H7, -N HSO2CH (CH3)2, -NHSO2C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -CECH, -CEC-CH3, -CH2-CECH, -Ph, -0-Ph, -0-CH2-Ph, N N N
,K - -Nn ---------------------- N/N
__J 0 r N r N
/ _______________________________________ \ / \ / \
N\ /NH N\ 71- ; or N\ /1\1 __ \;
RN represents -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH (CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-051-19, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-051-19, -CH2F, -CH F2; -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3, -00C21-15, -00C3H7, -COCH (CH3)2, -00C(CH3)3, -CO-cyclo-C3H5, -CO-cyclo-C4H7, -CO-cyclo-051-19, -COOCH3, -CO0C2H5, -CO0C3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -S02CH3, -S02CF3, -S02C21-15, -S02C3H7, -S02CH (CH3)2, -S02-cyclo-C3H5, or -S02C(CH3)3;
RNI represents -H, -CH3, or -C2F15;
or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomer, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
Preferably, the present invention relates to the compound of the formula (la):
0)-LN . R6 H
0 ( H 0 A N - L , H
0 (la);
wherein L represents -L1-L2- ;
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 L1 represents -CH2C0-, L2 represents -NRN1-, and R3 represents 1-adamantyl; or L2 represents -NRN1CH2-, and R3 represents 2-bicyclo[3.1.1]heptyl, and the afore-mentioned 1-adamantyl and 2-bicyclo[3.1.1]heptyl residues are optionally contain one or more C=C double bond and/or are optionally substituted one or more of Ra, Rb, Rc, Rd, and Re;
R2 represents RN RN RN
IV
R6 represents -C2H5;
Ra, Rb, Rc, Rd, and Re represents independently of each other -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C2H5, -CONH2, -CON HCH3, -CON(CH3)2, -CONN C2H5, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H5, -CH2CON H2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2F15, -NHCOCH3, -NHCOC21-15, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C21-15, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3;
R8, R10, and R11 represent independently of each other -H, -F, -Cl, -Br, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH (CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2F, -CH F2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CH F2, -CH2-CF3, -CH2-CH2CI -CH2-CH213r, -CH2-CH21, -OC H3, -0C2H5, -0C3H7, -OCH (CH3)2, -0C(CH3)3, -0C4H9, -OCH F2, -0CF3, -OCH2CF3, -0C2F5, -OCH20C H3, -0-CYCIO-C3H5, -OCH2-CYCIO-C3H5, -0-C2H4-CYCIO-C3H5, -CHO, -COCH3, -COCF3, -00C21-15, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -COOK -COOCH3, -CO0C2H5, -CO0C3H7, -COOCH(CH3)2, -COOC(CH3)3, -00C-CH3, -00C-CF3, -00C-C2H5, -00C-C3H7, -00C-CH (CH3)2, -00C-C(CH3)3, -N H2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N [CH (CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5, -NHCOC3H7, -NHCOCH(CH3)2, -NHCOC(CH3)3, -CONH2, -CONHCH3, -CON HC2H5, -CON HC3H7, -CONHCH (CH3)2, -CON H-cyclo-C3H5, -CON HC(CH3)3, -CON(CH3)2, -CON (C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2, 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 -CON[C(CH3)3]2, -SO2NH2, -SO2NHCH3, -SO2NHC21-13, -SO2NHC3H7, -SO2NHCH(CH3)2, -SO2NH-cyclo-C3H3, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H3)2, -SO2N(C3H7)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C21-13, -NHSO2C3H7, -N HSO2CH (CH3)2, -NHSO2C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -CECH, -CEC-CH3, -CH2-CECH, -Ph, -0-Ph, -0-CH2-Ph, r1\1 r1\1 rk1 - -NOrN
r N r N r N
/ _______________________________________ \ / __ \ / __ \
K(:) N\ /NH N\ or N\ \
R" represents -H, -CH3, -C2E-13, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH (CH3)2, -CH(CH3)-C2H3, -C(CH3)3, -cyclo-C3H3, -cyclo-C4H7, -cyclo-C31-19, -CH2-cyclo-C3H3, -CH2-cyclo-C4H7, -CH2-cyclo-C3H9, -CH2F, -CH F2; -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3, -00C21-13, -00C3H7, -COCH (CH3)2, -00C(CH3)3, -CO-cyclo-C3H3, -CO-cyclo-C4H7, -CO-cyclo-C31-19, -COOCH3, -COOC2H3, -CO0C3H7, -COOCH(CH3)2, -COOC(CH3)3, -000CH2Ph, -S02CH3, -S02CF3, -S02C21-13, -S02C3H7, -S02CH (CH3)2, -S02-cyclo-C3H3, or -S02C(CH3)3;
RI" represents -H, -CH3, or -C2F13;
or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomer, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
Preferalby, the compound of the invention has the formula (II):
ON
0 ( H 0 (II) I\O-L
N
0 Li wherein 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 L2 represents -NRI41-, and R3 represents 1-adamantyl; or L2 represents -NRNICH2-, and R3 represents 2-bicyclo[3.1.1]heptyl, and the afore-mentioned adamantyl and bicyclo[3.1.1]heptyl residues are optionally contain one or more C=C double bond and/or are optionally substituted one or more of Ra, Rb, Rc, Rd, and Re;
R2 represents RN RN RN
--- Ri __-R8 --IN-----R8 ) __ N Y __ N
, _____________________ N , , , Ra, Rb, Rc, Rd, and Re represents independently of each other -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C2H3, -CON H2, -CON HCH3, -CON(CH3)2, -CONN C2F13, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H3, -CH2CON H2, -CH2CONHCH3, .. -CH2CON(CH3)2, -CH2CONHC2H3, -NHCOCH3, -NHCOC21-13, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C21-13, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3;
R" represents -H, -CH3, -C2E-13, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH (CH3)2, -CH(CH3)-C2H3, -C(CH3)3, -cyclo-C3H3, -cyclo-C4H7, -cyclo-C3I-19, -CH2-cyclo-C3H3, -CH2-cyclo-C4H7, -CH2-cyclo-C3H9, -CH2F, -CHF2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3, -00C21-13, -00C3H7, -COCH (CH3)2, -00C(CH3)3, -CO-cyclo-C3H3, -CO-cyclo-C4H7, -CO-cyclo-C31-19, -COOCH3, -COOC2H3, -CO0C3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -S02CH3, -S02CF3, -S02C21-13, -S02C3H7, -S02CH(CH3)2, or -S02C(CH3)3;
RI" represent -H, -CH3, or -CH2CH3;
R8, R", and R" represent independently of each other -H, -F, -Cl, -Br, -I, -OH, -CN, -- -NO2, -CH3, -C2E-13, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH (CH3)-C2H3, -cyclo-C3H3, -CH2-cyclo-C3H3, -CH2F, -CHF2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CH F2, -CH2-CF3, -CH2-CH2CI , -CH2-CH2Br, -CH2-CH21, -OCH3, -0C2H5, -0C3H7, -OCH (CH3)2, -0C(CH3)3, -0C4H9, -OCH F2, -0CF3, -OCH2CF3, -0C2F5, 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 -OCH2OCH3, -0-cyclo-C3H3; -OCH2-cyclo-C3H3, -0-C2H4-cyclo-C3H3;
-CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -CECH; -CEC-CH3, -CH2-CECH, or -Ph;
or a diastereomer; an enantiomer; a mixture of diastereomers; a mixture of enantiomer; a racemate; a solvate; a hydrate; or a pharmaceutically acceptable salt thereof.
The term "1-adamantyl" and "2-bicyclo[3.1.1]heptyl" have the following structures respectively:
1-adamantyl Rd IR' Re 2-bicyclo[3.1.1]heptyl Rb Ra Ra Rb and Ra; Rb; Rc; Rd and Re have the same meanings as defined herein.
Preferred; 2-bicyclo[3.1.1]heptyl have the following structure:
Ra Rb ,or Rb and Ra and Rb; have the same meanings as defined herein.
More preferred; the compound has any one of the formulae (II-a) - (II-I), (11-b1)- (II-b2), and (III-a) - (III-I):
0 Rd Rc Re 0 (DN Rb Ra NrN1H N
Rb (II-a) (II-b) 0 1.4 0 0 0 a Ra Rb Rb R2 1-1jC
(II-bl) (II-b2) 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 0-1-,N.-----,..
N
H
HH 0 Rb R2 N Rc N N , L1 H
Ra Ra (II-c) (II-d) 0-L ..----õ, 0)- -----õ,, N N
H H N
Rb Ra Rb Ra 0 ( H 0 0 A H 0 Rc L Rc N L2 R2 A FIN %N )-LI N 0 Rd R2 N
0 0 Rd (II-e) (II-f) 0 0 Rd 0, A
-1\1 Rb Ra 0, JL
H Rc H Rc 0H 0 0 ( H 0 _ J1 NL2 H
(II-g) (II-h) ON 0,-,,)-1,N.----,õ
H Rb Ra H
N kli )-L
J1 NirL2 1\i _ J1 rL2 H Rd H
(II-i) (11-j) 0 0, A
N
' -1\1 rf_frj H H
0 JCH 0 0 JCL, 0 H
(II-k) (II-I) wherein L1, L2, R2, RN, Ra, Rb, Rc, Rd and Re have the same meanings as defined in the formula (I), preferred in the formula (la), more preferred in the formula (II).
2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 o Rd Rc Re o Rb Ra H H
0 ti 0 0 i_i 0 Ra Nr\lcriN)-L ,NH
1 N Tr N -y-LNcrN)-L NH
1 N-r Rb __N H 0 0 ____N H 0 0 'RN 'RN
(III-a) (III-b) oN 0 1 N
H I H
0 0 o 0 o id H
N H H
N,ryr N
R8 N Re 1 hl 1 -(XliC N
\ 0 0 0 I oa R. 0 R" t (11I-c) (11I-d) N
H (:))-LN
H
S Nj- N R8 H
N 1 N \ I H R8 N
Rio S R11 (11I-e) (III-f) ON N
H H
H H
,H
R8-? N
___ZAN R8-- __Ai_l N Rio N Rio 0 0 (11I-g) (11I-h) (21)-N11.-'1' 0 UN
'----1-11'=
H 0 ti 0 R13 0 1 hi NH
1 N N R13 s H
i i NljciNN-1N
Rl (iii-i) (nil) 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 o 0)-N
OA
H N' H
0 _rH 0 R13 0 N)-L NH H H
N r Rio Rio Ri2 R13 12 (III-k) (III-I) wherein LI, L2, R8, R10; R11, R12, R13, R11, RN, Ra; Rb; Rc; Rd and K i-ie have the same meanings as defined in the formula (I), preferred in the formula (la).
In a preferred embodmiment, the invention refers to the compound of the formulae (I), (la) and (II), wherein R3 represents , , ., d.--- , d-------K -----' , i ' ' ' ' , , , , ,,, ..
.--'s , , , , , i i , , , F
CI CF3 OH CO2Me i i , , F
F
. . ., . ' , F Br, , . . ., ., . .
.
CI OH
CO2H ;
CO2Me , CO2H
, , . 0 ., .
CON H2 ; C0NMe2 ; HN) CF3 , Br OH
' , ' _- ; ,- ; _-' ' , or Also preferred, R3 represents 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 F CI
. . . . .
F
CF3 jZOH ZCO2Me F 01 . . . . .
N
i i i . 1 ,or i = , ,, , , More preferred, R3 represents ' ., ,or .
In a preferred embodmiment, the invention refers to the compound of any one of the formulae (I), (la) and (II), (II-a) - (II-1), (II-b1)¨ (II-b2), wherein R2 represents RN RN
RN
R11 il ,,8 _ 0 D8 R 11 0 ,-,8 _ - R11 II R8 - - ,.---IIry - --s" r , .., rr, ___.,õ.s.r8 ¨, , , \ , \ , , , i __ N ) N N
R10 R10 010 R9 R9 R10 .-,9 " I-C , RN RN RN RN RN
R11 s R8 _____NrR8 R1,N,(Rõ R1:N:, Rii õ N, \ , -,\ , -\\ , , ,N __ i ,N
. , ,N
.õ ( , R9 Rio R9 . R9 R10 sµ , c9 D 1 .., r-,9 1 o N 1 " N 1 Rt....5 N
Rii 0, D8 - _ ,ON____ R8 - _ S .-,8 - _ _..,.., ,n , 0,- 1 r-- ii -\ ----- 1 IN
N
N N R10 __ N
R10 ________________________________________________________ N
Rio R8 ' 1 RN RN RN
N N ,N R10 N N, DN pp 1 3 R 1 3 N''' -------------------------------------------------------- ,, ., N / R10 , ' , ' N r` =N , o014 N R14 R12 R12 N R12 0 ---_// %
% R12 R13 N r R 1 3 - - - $__ , j R 1 3 R10_t----r> R13 N R14 N Ri4 N Ri4 Rio R.-, (:)----414 , , 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 RN
, N
R12 S ---./A 13 R12 -R1134/\1 - - R
R19-(/ 1 '1R13 -$%\
0----\2=-Ri3 R19 R14 S------Ri4 Rio , RN
RN RN . 0 R9 il Rl __ N S ' R19- R14 _ _r\_" RF9zio - -cr ''' Rio RN, N S
rµ , RN
0) I D
il R9 S - - -r -/i 9 , .
, N6-,''' --/_=-= R10 _R10 N,I
. - . N,..õ, -S: ---T - - ,----N R8-- N / ii R8-----N'-'-T--Fz u--- I/ -N'N , or O-N ;
wherein R8, R9, R10, R11, R12, R13, and R14, represent independently of each other -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2F, -CH F2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CH F2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2OH, -OCH3, -0C21-15, -0C3H7, -OCH(CH3)2, -0C(CH3)3, -0C4H9, -OCH F2, -0CF3, -OCH2CF3, -0C2F5, -OCH2OCH3, -0-CYCIO-C3H5, -OCH2-CYCIO-C3H5, -0-C2H4-CYCIO-C3H5, -CHO, -COCH3, -COCF3, -00C21-15, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -COOK -COOCH3, -CO0C2H5, -CO0C3H7, -COOCH(CH3)2, -COOC(CH3)3, -00C-CH3, -00C-CF3, -00C-C2H5, -00C-C3H7, -00C-CH(CH3)2, -00C-C(CH3)3, -N H2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5, -NHCOC3H7, -NHCOCH(CH3)2, -NHCOC(CH3)3, -CON H2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONHCH(CH3)2, -CONH-cyclo-C3H5, -CONHC(CH3)3, -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -SO2NHCH(CH3)2, -SO2NH-cyclo-C3H5, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H5)2, -SO2N(C3H7)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C2H5, -NHSO2C3H7, -NHSO2CH(CH3)2, 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 -NHSO2C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -CECH, -CEC-CH3, -CH2-CECH, -Ph, -0-Ph, -0-CH2-Ph, N
..K --No :1) -NrN1 __r rN N
_---1 r , NI
N N
r r r / __ \ / __ \ / __ \
N\ /NH N\ 71- , or N\
71 \;
Preferably, R8, R9, R", R11, R12, R13, and R14, represent independently of each other -H, -F, -Cl, -Br, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH (CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2F, -CH F2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CH F2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2OH, -OCH3, -0C2H5, -0C3H7, -OCH (CH3)2, -0C(CH3)3, -0C4H9, -OCH F2, -0CF3, -OCH2CF3, -0C2F5, - OCH20C H3, -0-CYCIO-C3H5, -OCH2-CYCIO-C3H5, -O-C2H4-CYCIO-C3H5, -CHO, -COCH3, -COCF3, -00C2H5, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -COOK -COOCH3, -CO0C2H5, -CO0C3H7, -COOCH(CH3)2, -COOC(CH3)3, -00C-CH3, -00C-CF3, -00C-C2H5, -00C-C3H7, -00C-CH (CH3)2, -00C-C(CH3)3, -N H2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N [CH (CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5, -NHCOC3H7, -NHCOCH(CH 3)2, -NHCOC(CH3)3, -CON H2, -CONHCH 3 , -CON HC2H5 , -CON HC3H7, -CONHCH (CH3)2, -CON H-cyclo-C3H5 , -CON HC(CH3)3, -CON(CH3)2, -CON (C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -Ph, -0-Ph, -0-CH2-Ph, or More preferably, R8, R9, R", R11, R12, R13, and R14, represent independently of each other -H, -F, -Cl, -Br, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C(CH3)3, -cyclo-C3H5, -CF3, -CH2OH, -OCH3, -0CF3, -CHO, -COCH3, -COOK -COOCH3, -NH2, -N(CH3)2, -CONH2, -SO2NH2, -Ph, or --R" represents -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH (CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-05H9, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-05H9, -CH2F, -CH F2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3, -00C21-15, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -CO-cyclo-C3H5, -CO-cyclo-C4H7, -CO-cyclo-051-19, -COOCH3, -CO0C2H5, -CO0C3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -S02CH3, -S02CF3, -S02C2H5, -S02C3H7, -S02CH(CH3)2, -S02-cyclo-C3H5, or -S02C(CH3)3;
Preferably, R" represents -H, -CH3, -C2H5, -CH(CH3)2, -cyclo-C3H5, -cyclo-C4H7, -cyclo-05H9, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-05H9, or -COCH3, more preferably, R" represents -H, -CH3, -C2H5, -CH(CH3)2, -cyclo-C4H7, -cyclo-05H9, or -COCH3.
In a preferred embodmiment, the invention refers to the compound of any one of the formulae (I), (la) and (II), (II-a) - (II-I), (II-b1)- (II-b2), R2 represents H I H
N I
N '9 9 H
N N N H
N H
N
N N
- - - -N ,N1 ,N1 ,N ,N ,N ,N
N N /
, , CI
I I I I
1 _ N , N___--- N H __-Br -----N--I\I - N 171 .---1\1 71 N N N N ) --N ; \--N ; , CI I I
- -HN 0 , - ---_ 7N --.. N , N , . -NC ---- N N N N
-/ i\I ____ iii\I
/
I ---N , __ H2N HN \ ,,=/
' ' , ' I I
I N, /õ_ , =
- _ N, N - 'N N N,N _ ,J\1 , - - 0_._-Br icl__--Cm N\-N -Y NH
1\1-"N N ; / ; / ; / ; N=N ;
, ---q-C1 --1S_z-Br ---q-S CI _ )SN Br' o - 1 \ f H2N/ \o-' , Br, Br ; Br ; CI ;
' --p-S Br Cli___S ci BrS Br 0 _\
N -- Me0-- - -)-----<\ - -Br , , S s 0__-Br --1S-CF3 '----3 N __ 1 N Br Br , , , S , - S , -S - ,S - N
- N, - NI
S - - NI, µIs-i H
- - -= II 1 µ II - Sµ 1 N
0 NN S-N _--N N----N
0 ;
, 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 s -- N's 0 H2N H
-- .----<\N--- ---- (-, -- (----HO , O-N , N-0 0-N HN--H -' NO2, , HN- Nr-o) N - - _.õ------, -._õ-----NO2 I I
-1-- ¨N-1\1,-- CO2Me -,CO2H .,, -, N,N '-. --.N N.---I N
I N I
, 0 , CI Br , I , 0 , , F , H
-- 0 ,- S S
N
/ / - \
0 , \
, , S , , , H
N
H
N H
F \
F
,-________________________________ -----,,__.\_,--$
N S N NL S N S H .. , HN
, , OH , , , 3%, ,...õ0 N - , , r , -I ---I
N-- or N N N N N , , , Also preferred, R2 represents H I H
N N N H
N H
N N
__ N
\ ---- N---N , ________________________________________ N N , ___ N , N N N
NN ,/ / , , , , / , CI
I I I I
H I )N N___¨ N__-Br --N , , Still more preferred, R2 represents 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 CI
11\1 Br )N I o ---q-CI
N / N / Br, Br , , S S
Br ClS
-- Br -- CI - S
r __-Br --p-S Br S Br CI ij-Br , CI , , Br , , ., NO2 0 p,- Sc --1S-CF3 --.,__..---,NO2 /----- j /----\ j \ #
N N , Br N CO2Me , N
-.0O2H 0 -- \ --' \ S
1 \
N -- \ -- , CI Br -- \
' , H
F H N
N H
S -- \ -- \
F ___(\N
\
, , F , N C, or .
In a preferred embodmiment, the invention refers to the compound of any one of the formulae (I), (la) and (II), (II-a) - (II-1), (II-b1) ¨ (II-b2), wherein L represents ¨CH2¨, ¨CH2CH2¨, ¨CH2CH2CH2¨, ¨CH2CONH¨, ¨CH2CONH¨CH2¨, ¨CH2CON(CH3)¨CH2¨, ¨CH2CONH¨CH(CH3)¨, Most preferred are the following compounds of formula (I):
Cpd Structure Name 1-1: 0 (S)-N1-ethyl-N6-(1-(2-(1-ON
adamantylamino)-2-oxoethyl)-2-oxo-1,2-H
0 1.4 0 dihydropyridin-3-y1)-5-(1-methy1-k imidazole-5-carboxamido)-2-NIN
. . a t.,,..,...) a oxohexanediamide \
1-2: 0 (S)-N1-ethy1-5-(1 H-imidazole-4-0N carboxamido)-N6-(1-(2-(1-H
0 0 adamantylamino)-2-oxoethyI)-2-oxo-1,2-N dihydropyridin-3-yI)-2-oxohexanediamide HNI1-1[1 1 N-rNH
---=---N 0 0 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 1-3: 0 (S)-N1-ethyl-N6-(1-(2-(1-ON adamantyl(methyl)amino)-2-oxoethyl)-2-H
O oxo-1,2-dihydropyridin-3-y1)-5-(1-methyl-1\iANN 1 H-imidazole-5-carboxamido)-2-NNI H
0 0 oxohexanediamide --NN
1-4: 0 (S)-N1-ethyl-N6-(1-(2-(3,5-ON
dimethyladamantane-1-amino)-2-H
O 0 oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)-NH 5-(1-methy1-1H-imidazole-5-NHNjc N I N( 0 ,!,.,,,,,) 0 carboxamido)-2-oxohexanediamide \
1-5: 0 (S)-N1-ethyl-N6-(1-(2-(3-O11L.N.-----õ, ethyladamantane-1-amino)-2-oxoethyl)-H
O 0 2-oxo-1,2-dihydropyridin-3-y1)-5-(1-N
N)..r NH methyl-I H-imidazole-5-carboxamido)-2-NHN
0 1,,õ...7,1 0 oxohexanediamide N
1-6: o (S)-N1-ethyl-N6-(1-(2-(3-oN cF3 trifluoromethyladamantane-1-amino)-2-H
O 0 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-H u N'N NH 5-(1-methy1-1H-imidazole-5-NN FIN (:c 8 carboxamido)-2-oxohexanediamide \
1-7: 0 (S)-N1-ethyl-N6-(1-(2-(3-ON N - OH
hydroxyadamantane-1-amino)-2-H
O 0 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-111 j- NH
1\l/N1 1 NM( 5-(1-methy1-1H-imidazole-5---N 0 0 carboxamido)-2-oxohexanediamide \
1-8: 0 (S)-N1-ethyl-N6-(1-(2-(3-F
O N fluoroadamantane-1-amino)-2-oxoethyly H
O 0 2-oxo-1,2-dihydropyridin-3-y1)-5-(1-'N NH methyl-I H-imidazole-5-carboxamido)-2-NHN N
_--N - 0 0 oxohexanediamide \
1-9: (S)-N1-ethyl-N6-(1-(2-(3-chloroadamantane-1-amino)-2-oxoethyly H
O 0 2-oxo-1,2-dihydropyridin-3-y1)-5-(1-H u N 'NNH methyl-I H-imidazole-5-carboxamido)-2-NHN r() 8 oxohexanediamide "N
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 1-10: (S)-N1-ethyl-N6-(1-(2-(3-N )--bromoadamantane-1-amino)-2-OL Br H
0 0 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-H I]
r\l/YN N 1 NThr NH 5-(1-methy1-1H-imidazole-5----N 0 0 carboxamido)-2-oxohexanediamide \
o I-11: (S)-N1-ethyl-N6-(1-(2-(3-methyl ON CO2Me H adamantane-3-carboxylate-1-amino)-2-oxoethyl)-2-oxo-1 ,2-di hydropyridin-3-y1)-1\1 ,NH
N -7.'=-=NI-1 1 N Tr 5-(1-methy1-1H-imidazole-5-carboxamido)-2-oxohexanediamide 1-12: 0 F F (S)-N1-ethyl-N6-(1-(2-(4,4-ON-----,, difluoroadamantane-1-amino)-2-H
0 0 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-H It N'NNH 5-(1-methy1-1H-imidazole-5-NN jc 0 8 carboxamido)-2-oxohexanediamide N
o 1-13: (S)-N1-(1-(2-(((1S,2R,5S)-6,6-0,,,,,,AN------õ, H dimethylbicyclo[3.1 .1]heptan-2-o o yl)methylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-2-(1-1\1_7--FIN µ1 H C) 0 methyl-I H-imidazole-5-carboxamido)-5-oxohexanediamide o 1-14: (S)-N1-(1-(2-(((1R,2R,5R)-6,6-OLN-----., H dimethylbicyclo[3.1 .1]heptan-2-o 0 H it H ei yl)methylamino)-2-oxoethy1)-2-oxo-1,2-NNN -NN'"
dihydropyridin-3-y1)-N6-ethyl-2-(1-\ methyl-I H-imidazole-5-carboxamido)-5-oxohexanediamide 1-15: 0 (S)-N1-ethyl-N6-(1-(2-(3-H ethyladamantane-1-amino)-2-oxoethyl)-o 0 2-oxo-1,2-dihydropyridin-3-y1)-5-(1-H it ,NH
H Ny ¨NN N methyl-I H-imidazole-4-carboxamido)-2-oxohexanediamide 1-16: 0 OJL
(S)-N1-ethyl-N6-(1-(2-(3----õ,, N--- H ethyladamantane-1-amino)-2-oxoethyl)-O H 0 2-oxo-1,2-dihydropyridin-3-y1)-5-(1-II
(N)N NH N'rN-r methyl-I H-imidazole-2-carboxamido)-2--H 0 0 oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 1-17: 0 (S)-2-(1,4-dimethy1-1H-imidazole-5-H carboxamido)-N6-ethyl-N1-(1-(2-(3-, õ r H
0 ethyladamantane-1-amino)-2-oxoethyl)-N
,Nj- -),(NH
N fl 1 N 2-oxo-1,2-dihydropyridin-3-y1)-5-" .. 0 ,1,,,._...;_j 0 "N oxohexanediamide o 1-18: o.õ)-N..---,,, (S)-N1-ethy1-5-(1-isobuty1-1H-imidazole-L.
H 4-carboxamido)-N6-(1-(2-(3-o 0 H i ethyladamantane-1-amino)-2-oxoethyl)-/---N:--N HNIN C)io NH
----\ \ 2-oxo-1,2-dihydropyridin-3-y1)-2-oxohexanediamide o 1-19: (S)-2-(1-cyclopenty1-1H-imidazole-4-o..--...õ
N
H carboxamido)-N6-ethyl-N1-(1-(2-(3-N N-{N1H ethyladamantane-1-amino)-2-oxoethyl)----N
H 0jJ6 2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide o 1-20: o-jt.N..---,,, (S)-2-(1-cyclobuty1-1H-imidazole-4-H carboxamido)-N6-ethyl-N1-(1-(2-(3-ethyladamantane-1-amino)-2-oxoethyl)-H 2-oxo-1,2-dihydropyridin-3-y1)-5-\_,--- 0 0 oxohexanediamide 1-21: 0 (S)-2-(1,4-dimethy1-1H-imidazole-5-H carboxamido)-N6-ethyl-N1-(1-(2-(3,5-0 H j dimethyladamantane-1-amino)-2-NH
N1)\FIN 0 N 0 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-\ 5-oxohexanediamide o 1-22: 0,)-1...N (S)-N1-ethyl-N6-(1-(2-(3,5--.õ,----.õ
H dimethyladamantane-1-amino)-2-o l oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-NH
¨NN Fi N 5-(1-methyl-1H-imidazole-4-H
carboxamido)-2-oxohexanediamide o 1-23: OAN (S)-N1-ethyl-N6-(1-(2-(3,5-H dimethyladamantane-1-amino)-2-o 0 N
/\ N(iF11)-N'-iNH oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-2-\_N H 0 0 carboxamido)-2-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 1-24: 0 (S)-2-(1,2-dimethy1-1H-imidazole-5-H carboxamido)-N6-ethyl-N1-(1-(2-(3,5-O H 0 dimethyladamantane-1-amino)-2-1\1)-NH oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide 1-25: 0 0,L.N (S)-N1-ethyl-N6-(1-(2-(3-H .----methyladamantane-1-amino)-2-O 0 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N[lji )-LI N rNH 5-(1-methy1-1H-imidazole-5----N \ 0 0 carboxamido)-2-oxohexanediamide 1-26: (S)-2-(2-chloro-1-methy1-1H-imidazole-5-{..N.---,, H carboxamido)-N6-ethyl-N1-(1-(2-(3,5-O 0 dimethyladamantane-1-amino)-2-N H
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-,--N \ 0 0 5-oxohexanediamide CI
1-27: 0 (S)-2-(1,2-dimethy1-1H-imidazole-5-H carboxamido)-N6-ethyl-N1-(1-(2-(3-O o methyladamantane-1-amino)-2-N FIN {NH
1\l/Ncr oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)--N \ H 0 8 5-oxohexanediamide 1-28: (S)-N1-ethyl-N6-(1-(2-(3,5,7-trimethy1-1-oN
H adamantylamino)-2-oxoethyl)-2-oxo-1,2-O H. o dihydropyridin-3-y1)-5-(1-methy1-1H-N NH
N
imidazole-5-carboxamido)-2-i--INN
0 .,,,,0 \ oxohexanediamide 1-29: o (S)-2-(2-chloro-1-methy1-1H-imidazole-5-0N----õ, H carboxamido)-N6-ethyl-N1-(1-(2-(3,5,7-O trimethy1-1-adamantylamino)-2-N Sil\ii--11 N c-INH
oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)--N \
5-oxohexanediamide CI
0..1.,N (S)-2-(benzofuran-2-carboxamido)-N6-,....õ1.----...õ,, H ethyl-N1-(1-(2-(2-adamantylamino)-2-1-30 o k o F oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-o NJcr 1\INNI
1 H 0 8 5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 o o..LN (S)-N1-ethyl-N6-(1-(2-(2-) H adamantylamino)-2-oxoethyl)-2-oxo-1,2-o o 1-31 H II H dihydropyridin-3-yI)-5-(3-0 NrN-.Kil.rN
1 H 0 0 methylbenzofuran-2-carboxamido)-2-oxohexanediamide o o)-N, (S)-2-(3-chlorobenzofuran-2-H carboxamido)-N6-ethyl-N1 -(1 -(2-(2-0 0 NJcr 0 adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-Nj-NrN
I H 1 I 0 0 dihydropyridin-3-yI)-5-oxohexanediamide CI
(S)-2-(4-bromobenzofuran-2-H carboxamido)-N6-ethyl-N1 -(1 -(2-(2-o 0 H ii H adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-NiJc 0 N'N.rN
I H dihydropyridin-3-yI)-5-oxohexanediamide Br 0 (S)-2-(benzo[b]thiophene-2-N`
H carboxamido)-N6-ethyl-N1 -(1 -(242-1-34 0 H ? H
S N. adamantylamino)-2-oxoethyl)-2-oxo-1,2-N N-INI
0 0 dihydropyridin-3-yI)-5-oxohexanediamide o 0 N (S)-N1-ethyl-5-(7-..---., H fluorobenzo[b]thiophene-2-o 1.4 0 H
1-35 NA carboxamido)-N6-(1 -(242----- N i IIIINI
S H 0 0 adamantylamino)-2-oxoethyl)-2-oxo-1,2-F dihydropyridin-3-y1)-2-oxohexanediamide ON (S)-2-(4,5-difluoro-1H-indole-2-H carboxamido)-N6-ethyl-N1 -(1 -(2-(2-o Nr E., 0 N N,A adamantylamino)-2-oxoethyl)-2-oxo-1,2-N-_r H N
I H I
0 0 dihydropyridin-3-yI)-5-oxohexanediamide F F
o-.N (S)-N1 -ethyl-N6-(1 -(242-. .JL ,---,,, H adamantylamino)-2-oxoethyl)-2-oxo-1,2-o iFi o N Nj-L dihydropyridin-3-y1)-5-(3-methy1-1 H.
N-rrµj I H U indole-2-carboxamido)-2-o o oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 o 0)N (S)-2-(1H-benzo[d]imidazole-2-H carboxamido)-N6-ethyl-N1-(1-(2-(2-FAo H
adamantylamino)-2-oxoethyl)-2-oxo-1,2-N 1 It o 'N
41 N H 0 _ (NN0 N dihydropyridin-3-yI)-5-oxohexanediamide o 011-.N (S)-2-(2,3-dihydro-1H-indene-2---",õ
H carboxamido)-N6-ethyl-N1-(1-(2-(2-1-39 o H 0 l'iN H adamantylamino)-2-oxoethyl)-2-oxo-N
_ Ji riµi H 1,2-dihydropyridin-3-yI)-5-oxohexanediamide o 0..,,,J-L.N (S)-N1-ethyl-N6-(1-(2-(2-.õ---,,, H adamantylamino)-2-oxoethyl)-2-oxo-o o 1-40 s_.A NH H
N 1,2-dihydropyridin-3-yI)-5-(4-methyl-F3c----- i Njcro 1 2-(trifluoromethyl)thiazole-5-N
carboxamido)-2-oxohexanediamide o o....}..N
(S)-2-(4-bromo-2-..----õ,õ
H (trifluoromethyl)thiazole-5-ki carboxamido)-N6-ethyl-N1-(1-(2-(2-1-41 F3c--e_ALIr 1 Nf N ' ' 0 0 adamantylamino)-2-oxoethyl)-2-oxo-Br 1,2-dihydropyridin-3-yI)-5-oxohexanediamide o N (S)-N1-ethyl-N6-(1-(2-(2-H adamantylamino)-2-oxoethyl)-2-oxo-1,2-o o 1-42 S_.)-L N IN1 I 1r\J I:1 dihydropyridin-3-y1)-5-(4-methyl-2-\ I H
N 0 0 phenylthiazole-5-carboxamido)-2-oxohexanediamide o 0.t.N.- (S)-2-(5-bromo-3-methylthiophene-2--..., H carboxamido)-N6-ethyl-N1-(1-(2-(2-o H
s o r[l adamantylamino)-2-oxoethyl)-2-oxo-1,2-\ i H 0 8 dihydropyridin-3-yI)-5-oxohexanediamide o (S)-2-(3,5-dibromothiophene-2-H carboxamido)-N6-ethyl-N1-(1-(2-(2-H N
Br 1-44 H adamantylamino)-2-oxoethyl)-2-oxo-Br N
\ I H 0 8 N 1,2-dihydropyridin-3-yI)-5-oxohexanediamide o oN (S)-2-(5-bromo-3-methylfuran-2-...---.......
H carboxamido)-N6-ethyl-N1-(1-(2-(2-H H
0 N Br1 HN N adamantylamino)-2-oxoethyl)-2-oxo-\ N
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 1,2-dihydropyridin-3-yI)-5-oxohexanediamide o o)N (S)-2-(2,5-dichlorothiophene-3-õ,,.. --,......
H carboxamido)-N6-ethyl-N1-(1-(2-(2-O r Fo 1-46 adamantylamino)-2-oxoethyl)-2-oxo-a /
s 0 1 hif 1 rnf 1,2-dihydropyridin-3-yI)-5-CI oxohexanediamide o 0 N (S)-2-(2,5-dibromothiophene-3----..õ
H carboxamido)-N6-ethyl-N1-(1-(2-(2-O r on 1-47 adamantylamino)-2-oxoethyl)-2-oxo-Thr rN, 0 1,2-dihydropyridin-3-yI)-5-s 0 Br oxohexanediamide o 0 ,N,- (S)-2-(2,5-dichlorothiazole-4--,..
H carboxamido)-N6-ethyl-N1-(1-(2-(2-1-48 N,, Nj-LNI -1 adamantylamino)-2-oxoethyl)-2-oxo-FI\1 CI----- I pi s o o 1,2-dihydropyridin-3-yI)-5-a oxohexanediamide o 0 .N (S)-2-(2,5-dimethylfuran-3-.--H carboxamido)-N6-ethyl-N1-(1-(2-(2-o o 1-49 adamantylamino)-2-oxoethyI)-2-oxo-/ 1 iljCr 1,2-dihydropyridin-3-yI)-5-o 0 0 oxohexanediamide o 0 .N (S)-2-(4-bromothiazole-2-.---,õ
H carboxamido)-N6-ethyl-N1-(1-(2-(2-1-50 0 SN f)l 0 H adamantylamino)-2-oxoethyI)-2-oxo-Nj-1 N-11\1 1,2-dihydropyridin-3-yI)-5-$ JN H 0 0 oxohexanediamide Br (S)-2-(4-bromothiophene-2-H carboxamido)-N6-ethyl-N1-(1-(2-(2-o ti o , s)tNJc(N H adamantylamino)-2-oxoethyl)-2-oxo-1 N-rNj 1,2-dihydropyridin-3-yI)-5-Br \ i H 0 0 oxohexanediamide 0-I-L.N (S)-2-(4-bromo-5-chlorothiophene-2-,,,...----,, H carboxamido)-N6-ethyl-N1-(1-(2-(2-1-52 F adamantylamino)-2-oxoethyl)-2-oxo-s N r\lANN-1 CI \ I H 0 8 1,2-dihydropyridin-3-yI)-5-Br oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 o oN (S)-2-(4,5-dibromothiophene-2----....õ
H carboxam ido)-N6-ethyl-N1 -(1-(2-(2-1-53 Nj -1 kli adamantylamino)-2-oxoethyl)-2-oxo-S
Br i N 1 N
\ i H 0 0 1,2-dihydropyridin-3-yI)-5-Br oxohexanediamide o 0y),N (S)-2-(4,5-dichlorothiophene-2-.--,õ
H carboxam ido)-N6-ethyl-N1 -(1-(2-(2-.(Fi 0 1-54 s i N Nj= kil adamantylamino)-2-oxoethyl)-2-oxo-ci , N-r \ i H 0 0 1,2-dihydropyridin-3-yI)-5-ci oxohexanediamide o ON.-------õ, (S)-2-((S)-1-acetylpyrrolidine-2-H carboxamido)-N6-ethyl-N1-(1-(2-(2-o , ,.., N_AN __.(fiy o H adamantylamino)-2-oxoethy1)-2-oxo-- NJ. N
N-r 1,2-dihydropyridin-3-yI)-5-oxohexanediamide o 0)-1,..N (S)-N1-ethyl-N6-(1 -(242-.----,,,..
H adamantylam ino)-2-oxoethyl)-2-oxo-1-56 o jcH 0 H 1,2-dihydropyridin-3-yI)-5-(1-methyl-Nj N
N/A1F1 1 N 1H-1 ,2,3-triazole-5-carboxam ido)-2-`1\\,1-N \ 0 0 oxohexanediamide o (S)-N1-ethyl-N6-(1 -(2-(2-------..õ
H adamantylam ino)-2-oxoethyl)-2-oxo-1-57 o o , H 1,2-dihydropyridin-3-yI)-2-oxo-5-(2H-HN 1 YiN
tetrazole-5-µN----,N o 0 carboxamido)hexanediamide o (S)-N1-ethyl-N6-(1 -(245-H hydroxyadamantane-2-am ino)-2-1-58 1\lj Nj ill oxoethyl)-2-oxo-1 ,2-dihyd ropyridin-3-1 N 1 N If H
0 0 yI)-2-oxo-5-(pyrazine-2-OH
carboxamido)hexanediamide o 0_,.-1-1..N (S)-N1-ethyl-N6-(1 -(245-...----.., H fluoroadamantane-2-am ino)-2-1-59 c ,jo. (rFi j H oxoethyl)-2-oxo-1,2-dihydropyridin-3-N 1 NI ThrN
= H y1)-2-oxo-54(S)-pyrrolidine-3-carboxamido)hexanediamide o (S)-N1-ethyl-N6-(1 -(245-H chloroadamantane-2-am ino)-2-1-60 H 0 (rH 0 Fd oxoethyI)-2-oxo-1,2-dihydropyridin-3-N Nj-Ni - N
= H
----..,....--- 0 0 CI
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 y1)-2-oxo-54(S)-piperidine-2-carboxamido)hexanediamide o (S)-N1-ethyl-N6-(1-(2-(5-0,-,,AN,---,, H bromoadamantane-2-amino)-2-0 r N 0 1-61 H oxoethy1)-2-oxo-1,2-dihydropyridin-3-HNNN , N-rN
H 0 0 Br y1)-2-oxo-5((R)-piperidine-3-carboxamido)hexanediamide o (S)-N1-ethyl-N6-(1-(2-(5-0,,,,:,A.N..^....õ
H methyladamantane-2-amino)-2-H oxoethy1)-2-oxo-1,2-dihydropyridin-3-N)AN N)-L
Ji NN
y1)-5-((R)-morpholine-3-H
carboxamido)-2-oxohexanediamide o o N (S)-N1-ethyl-N6-(1-(2-(2-H carbonitrileadamantane-2-amino)-2-x n H H CN oxoethyl)-2-oxo-1,2-dihydropyridin-3-i N
_ JNrN
H y1)-2-oxo-54(3S,4R)-quinuclidine-3-o o carboxamido)hexanediamide o 0AN (S)-methyl 3-(6-(ethylamino)-1-(1-(2----õ, H (methyl 2-aminoadamantane-2-1-64 o2N N jcrN,)HNNI-1 C 21VIe ,2-LJJ
0 0 LJi dihydropyridin-3-ylamino)-1,5,6-CO2Me trioxohexan-2-ylcarbamoy1)-5-nitrobenzoate o (S)-N1-(1-(2-(1-o H adamantylmethylamino)-2-oxoethyl)-1\110 N
H
1-65 o2N I N ii 2-oxo-1,2-dihydropyridin-3-y1)-N6-H
The 0 N 0 ethy1-2-(5-nitronicotinamido)-5-oxohexanediamide 0 5-((2S)-1-(1-(2-1-N
H adamantylmethylamino)-2-oxoethyl)-0 õ 0 H
1-66 1 Ho2cN Nj- ,N 2-oxo-1,2-dihydropyridin-3-ylamino)-H 1 N y The 6-(ethylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinic acid o o N (S)-N1-ethyl-N6-(1-(2-(2-H adamantyl(methyl)amino)-2-oxoethyl)-2-1-67 -r-----\- Nj_, oxo-1,2-dihydropyridin-3-y1)-5-(6-) ,N
hl N 1NTr methylimidazo[2,1-b]thiazole-5-carboxamido)-2-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 o (S)-N1-(1-(2-((1S,2R,4R)-,1 H bicyclo[2.2.1]heptan-2-ylamino)-2-H 0 oxoethyl)-2-oxo-1,2-dihydropyridin-3-0 N NNThrNH
1 H y1)-N6-ethy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 0 (S)-N1-ethy1-5-(3-methylbenzofuran-ON---....õ
2-ca-2-oxo-N6-(2-oxo-1-H
0 0 (2-oxo-24(1R,2S,4R)-1,7,7-0 N NN INH trimethylbicyclo[2.2.1]heptan-2-0 0 ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide o 0õ,.)L,N (S)-N1-(1-(2-((1R,2R,4S)-,.,-,õ.
H c H bicyclo[2.2.1Theptan-2-ylamino)-2-1-70 0 j 0 0 N oxoethyl)-2-oxo-1,2-dihydropyridin-3-N 1 Ni 0 0 y1)-N6-ethy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 0 (S)-N1-(1-(2-((1s,4R)-bicyclo[2.2.1]heptan-1-ylamino)-2-H
NNH y1)-N6-ethyl-2-(isonicotinamido)-5-N)LI N 0 Nt 0 H oxohexanediamide 0 (S)-N1-(1-(2-(bicyclo[2.2.1]heptan-7-0.N.---- õTr ylamino)-2-oxoethyl)-2-oxo-1,2-H
1-72 0 H 0 dihydropyridin-3-y1)-N6-ethyl-5-oxo-2-N N N
'A ,NH
1 I (pyridazine-4-NI.N H 0 0 carboxamido)hexanediamide (S)-N1-(1-(2-((1R,2R,4R)-N
H bicyclo[2.2.1]hept-5-en-2-ylamino)-2-1-73 0 iY jcH 0 oxoethyl)-2-oxo-1,2-dihydropyridin-3-NA ,NH iNi 1 N Ii y1)-N6-ethy1-5-oxo-2-(pyridazine-3-N-'1\1 carboxamido)hexanediamide o 0 N (2S)-N1-(1-(2-(bicyclo[2.2.2]octan-2-H ylamino)-2-oxoethyl)-2-oxo-1,2-1-74 0 JIIIIH ? H dihydropyridin-3-y1)-N6-ethy1-5-oxo-2-vy(N NI NQI
N (2H-1,2,3-triazole-4-i-k-N H 0 0 carboxamido)hexanediamide 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 o 0,.N (S)-N1-ethyl-5-(1-methyl-1 H-1,2,3-..-----õ, H triazole-4-carboxamido)-2-oxo-N6-(2-o jc H 0 H oxo-1-(2-oxo-2-((1 R,2R,4R)-1,7,7-/A N
_NJ ---- N Y-Ni trimethylbicyclo[2.2.1]heptan-2-sr\I--N H 0 0 ylamino)ethyl)-1 ,2-d ihydropyrid in-3-yl)hexanediamide o N (S)-N1-ethyl-5-(1-methyl-1 H-1 ,2,4-H triazole-3-carboxamido)-2-oxo-N6-(2-o o oxo-1- 2-oxo-2- 1R 2R 3R 5S -( (( õ , ) 1-76 1\1Y-NljcrEl I\1 ,ENI
1 N If ''. 2,6,6-trimethylbicyclo[3.1.1]heptan-3-N_N H 0 0 / ylamino)ethyl)-1 ,2-d ihydropyrid in-3-yl)hexanediam ide o 0N (S)-2-(benzofuran-3-carboxam ido)-.-----,,, H N6-ethyl-5-oxo-N1 -(2-oxo-1-(2-oxo-2-Nj-L L1 ((I S,2S,3S,5R)-2,6,6-1-77 1 N N n H 0 0 trimethylbicyclo[3.1.1]heptan-3-o s,-ylamino)ethyl)-1 ,2-d ihydropyrid in-3-yl)hexanediam ide o (S)-2-(benzo[b]thiophene-3-0,-,...A...N...---..õ
H carboxam ido)-N6-ethyl-N1 -(1-(2-(4-1-78 o jc H o F homoisotwistane-3-amino)-2-N N'AN-rN-1 1 H 0 0 oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-S
y1)-5-oxohexanediamide 0 (S)-N1-ethyl-N6-(1-(2-(diamantane-1-0-LN pg am ino)-2-oxoethyl)-2-oxo-1 ,2-H
0 di h dro rid in-3- 1 -5- 1-meth 1- H-1-79Y PY Y ) ( y 1 N 1\i /y N JC Filj-L NH pyrazole-4-carboxam ido)-2-/
11 r N - 0 0 oxohexanediamide /
o 0.N (S)-N1-ethyl-N6-(1-(2-(diamantane-4-.õ---,õ
H am ino)-2-oxoethyl)-2-oxo-1 ,2-H ? di hydropyrid in-3-y1)-5-(1-methy1-1 H-, L, H pyrazole-3-carboxam ido)-2-/ oxohexanediamide 0 0 (S)-N1-(1-(1-adamantylmethy1)-2-.-----..õ.õ
N oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-H
1-81 _ i:j: H 0 2- 1-meth 1-1H- razole-5-( Y PY
N N
carboxamido)-5-oxohexanediamide T -H
N---"\ 0 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 0 O N (S)-N1-(1((3-hydroxy-1-H
adamantyl)methyl)-2-oxo-1,2-0 0 di hydropyrid in-3-y1)-2-(4-cyclopropyl-H II
,S_1 ,NJCNN 1,2,3-th iadiazole-5-carboxam ido)-N6-H
N 0 ethyl-5-oxohexanediamide OH
0 (S)-N1-(1((3-bromo-1-H
N - adamantyl)methyl)-2-oxo-1,2-0 di hydropyrid in-3-y1)-N6-ethyl-5-oxo-1-83 - 1 JCI-d N (1 ,2,5-thiadiazole-3-N/ 1 r Y -N H
\S---N 0 carboxamido)hexanediamide Br 0 0 (S)-N1-(1-(2-adamantylmethyl)-2-N
oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-H
0 0 2-(4-(hydroxymethyl)-1 ,2,3-,, ,N thiadiazole-5-carboxam ido)-5-N 0 oxohexanediamide HO
OAN
(S)-2-(4-tert-butyl-1 H-pyrrole-3-H carboxam ido)-N1 -(1 -(241 -o N,cNH oll adamantylamino)ethyl)-2-oxo-1 ,2-N di hydropyrid in-3-y1)-N6-ethyl-5-HN H
0 oxohexanediamide o N (S)-2-(4-cyano-1-methyl-1 H-pyrrole-õ---.õ., H 2-carboxamido)-N1-(1-(1-0 hi o 1-86 adamantylam ino)propy1)-2-oxo-1 ,2-NC --- 1\lciNI N
\ N H 0 di hydropyrid in-3-y1)-N6-ethyl-5-\
oxohexanediamide (S)-N1-(1-(3-(2-adamantylamino)-3-0y1LN...--,_ H oxopropy1)-2-oxo-1 ,2-dihydropyridi n-1-87 0 rFi 0 0 3-y1)-N6-ethy1-2-(5-methoxyoxazole-Me0_7) -- H" 0 H
2-carboxamido)-5-oxohexanediamide o (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-oN------,õ
H ylamino)-2-oxoethyl)-2-oxo-1 ,2-H 0 di hydropyrid in-3-y1)-N6-ethyl-2-(3-o NJcrr\O-N(NFI
I H I 1 methylbenzofuran-2-carboxam ido)-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 o (S)-2-(2-acetyloxazole-4-0N-----õ,, H carboxamido)-N1-(1-(2-1-89 (bicyclo[1.1.1]pentan-1-ylamino)-2-L'\\ NDAN NN_rN,IH
oxoethyl)-2-oxo-1,2-dihydropyridin-3-o 0 o y1)-N6-ethy1-5-oxohexanediamide o 0 ,N (S)-N1-(1-(2-(bicyclo[2.1.1Thexan-1-..--., H ylamino)-2-oxoethyl)-2-oxo-1,2-1-90 0 ( Hr,__, 0 0_ J J H dihydropyridin-3-y1)-N6-ethyl-2-(2-C)I
isopropyloxdamideaizole-5-carboxamido)-5-N " 0 hexane oxo/ 0 (2S)-N1-(1-(2-(bicyclo[3.2.1]octan-8-0N----,, H ylamino)-2-oxoethyl)-2-oxo-1,2-1-91 \ ? o dihydropyridin-3-yI)-2-(3,5-j-10,1)1c i ji 1\1 H 1\1 dimethylisoxazole-4-carboxamido)-N 0 0 N6-ethyl-5-oxohexanediamide o 0N (S)-N1-ethyl-N6-(1-(2-(5-carboxy-2-.---,õ..., H aminoadamantane)-2-oxoethyl)-2-o o 1-92 H Li oxo-1,2-dihydropyridin-3-yI)-5-(4-r\r H 0 0 co2H methylpyrimidine-5-carboxamido)-2-oxohexanediamide 0 (5S)-N1-ethyl-N6-(1-(2-(4-N-----' H
0 H H 0 aminoadamantane-N,N-dimethy1-1-N NN-rN carboxamide)-2-oxoethyl)-2-oxo-1,2-N--...
dihydropyridin-3-yI)-2-oxo-5-(1,2,3,4-tetrahydronaphthalene-2-carboxamido)hexanediamide o 0,,A.N (S)-2-((S)-1,4-...--...õ
H diazabicyclo[2.2.2]octane-2-HcrFi 0 .._-- '..A INIA carboxamido)-N6-ethyl-N1-(1-(2-(2-H
0 0 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide o (S)-N1-ethy1-5-(1H-indole-3-0,N----..õ
H carboxamido)-N6-(1-(2-(2-1-95 o ciFi o 1- adamantylamino)-2-oxoethyl)-2-oxo-N ININThr1\11 I H 0 0 1,2-dihydropyridin-3-yI)-2-N
H oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 o (S)-N1-ethyl-N6-(1 -(242-0,=.,)--1-NN.---,,,, H adamantylamino)-2-oxoethyl)-2-oxo-F
o .rF., o 1-96 ------3)-L Nj-L N1 1,2-d ihydropyridin-3-yI)-5-(6-N's methylimidazo[2,1-b]thiazole-3-o 0 carboxamido)-2-oxohexanediamide o or\ ,o__ (S)-2-(benzo[d]thiazole-2-H carboxam ido)-N1 -(1 -(2-((1 S,2R,4R)-1-97 0 0 bicyclo[2.2.1]heptan-2-ylami no)-2-S ,i)-.N Nj-Nl_r NH
NI H i I oxoethyl)-2-oxo-1 ,2-dihyd ropyridin-3-y1)-N6-ethyl-5-oxohexanediamide o o N
(S)-N1-(1-(2-((1 S,2R,4R)-H bicyclo[2.2.1Theptan-2-ylami no)-2-o 0 '-'1"\-- oxoethyl)-2-oxo-1 ,2-dihyd ropyridin-3-NcrEN-111 NI ThrNH
y1)-N6-ethyl-2-(im idazo[2,1-E>5-:-N H o 0 b]thiazole-6-carboxamido)-5-s oxohexanediamide (S)-N1-(1-(2-((1 S,2R,4R)-0 N.--....õ ,0 H bicyclo[2.2.1]heptan-2-ylami no)-2-OHO , 0 oxoethyl)-2-oxo-1 2-dihyd ropyridin-3-1_99 F3c- --- . N N N-Thf - = ' - ' -r\J y1)-N6-ethy1-2-(4-hydroxy-6-(trifluoromethoxy)quinoline-3-carboxamido)-5-oxohexanediamide o 0 N-- (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1---õ, ,7L
H ylamino)-2-oxoethyl)-2-oxo-1 ,2-H 0 dihydropyridin-3-yI)-2-(cinnoline-3-Ncr\ij-.N(NI-1 I , H
0 0 carboxamido)-N6-ethyl-5-NN oxohexanediamide o O N (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-H ylamino)-2-oxoethyl)-2-oxo-1 ,2-o o 1-101 H II di hydropyrid in-3-y1)-N6-ethyl-2-(3-0 N.iN,NNH
i H 1 1 ethylbenzofu ran-2-carboxam ido)-5-oxohexanediamide o (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-0.N.."..õ
H ylamino)-2-oxoethyl)-2-oxo-1 ,2-1-102 di hydropyrid in-3-y1)-N6-ethy1-2-(1-N N Nj-r\JrNH
0 0 ethyl-1H-indole-2-carboxamido)-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 o (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-..,____)\
H ylam ino)-2-oxoethyl)-2-oxo-1,2-1-103 o ri_11 o di hydropyrid in-3-y1)-N6-ethy1-2-(2-N 1 N If methy1-1,8-naphthyridine-3-, H 0 I J 0 NN carboxamido)-5-oxohexanediamide o (S)-N1-(1-(2-(bicyclo[2.1.1Thexan-1-N
H ylam ino)-2-oxoethyl)-2-oxo-1,2-1-104 N,A NI di hydropyrid in-3-y1)-N6-ethy1-5-oxo-N N
H 0 8 19 (1,2,3,4-tetrahydroquinoline-6-N
H carboxamido)hexanediamide 0 N...--., (S)-N1-ethyl-N6-(1-(2-(2-carboxy-2-H
0 0 amino-5-0 u CO2H
(trifluoromethyl)adamantane)-2-H
1-105 HN CF3 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxo-5-(3-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)hexanediamide 0 N..---,,, (S)-N1-ethyl-N6-(1-(2-(5-H ethyladam antane-2-am ino)-2-1-106 oxoethyl)-2-oxo-1,2-dihyd ropyridin-3-N 0 u lor y1)-5-(1,6-naphthyridine-2-carboxamido)-2-oxohexanediamide o (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-oN
H ylam ino)-2-oxoethyl)-2-oxo-1,2-H di hydropyrid in-3-y1)-N6-ethy1-2-(2,6-1 Nj-naphthyridine-1 -carboxamido)-5-N H
oxohexanediamide 0 0)-1,,N (S)-2-(4-ami no-1,2 ,5-oxad iazole-3-..-----,.... .._.7L
H carboxam ido)-N1-(1-(2-1-108 H2N 0 0 (bicyclo[1.1.1]pentan-1-ylamino)-2-id L
N IYN HjC 11 NTh(NH oxoethyl)-2-oxo-1,2-dihydropyridin-3-6-N 0 0 y1)-N6-ethyl-5-oxohexanediamide o (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-oN
H
1-109 N ylam ino)-2-oxoethyl)-2-oxo-1,2-0 Jci-HC) di hydropyrid in-3-y1)-2-(6-N _ N ir NH
\ I H 0 0 (dimethylamino)benzofuran-2-N
/ carboxamido)-N6-ethy1-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 o (S)-2-(2-acetamidothiazole-5-0.N.---,õ ..4, H carboxam ido)-N1 -(1 -(2-1-110 o ) H o NH
(bicyclo[1.1.1]pentan-1-ylamino)-2-Nõ, oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-----\( N 0 0 0 y1)-N6-ethy1-5-oxohexanediamide o oN (S)-N4-(1 -(1 -(2-(bicyclo[1 .1.1]pentan-H 1-ylamino)-2-oxoethyl)-2-oxo-1,2-o o 1-111 0 ri NThr NH dihydropyridin-3-ylamino)-6-/ I iljCr I (ethylamino)-1,5,6-trioxohexan-2-y1)-1H-pyrrole-2,4-dicarboxamide (S)-N1-ethyl-N6-(1-(2-(1-acetylamino-H
0 0 4-am inoadam antane)-2-oxoethyl)-2-1-112 (:)N AN -rFNI 0 H2N oxo-1 ,2-d ihydropyrid in-3-yI)-2-oxo-5-N
H (5-sulfamoylfuran-3-carboxamido)hexanediamide O N--,,,, (S)-2-(benzofuran-5-carboxamido)-H N6-ethyl-N1 -(1-(2-(1 -acetylam ino-4-0 H Ij? H
1-113/ NN, am inoadamantane)-2-oxoethyl)-2-N N
H
N
H oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide (S)-2-(benzofuran-6-carboxamido)-H N6-ethyl-NI-(1-(2-(4-1-114 0 N NirN am inoadamantane-1-carboxamide)-\ H
0 <1 0 H NH2 2-oxoethyl)-2-oxo-1 ,2-d ihydropyridin-3-yI)-5-oxohexanediamide O N..----,, (S)-N1-ethyl-N6-(1-(2-(4-H
0 0 am inoadamantane-1-carboxamide)-H H t-i ____\7)-LN N,N_rN 2-oxoethyl)-2-oxo-1 ,2-d ihydropyridin-1-115 \I \N-0 " o 0 NH 3-y1)-5-(3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamido)-2-oxohexanediamide o (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-oN õ_...).
H ylam ino)-2-oxoethyl)-2-oxo-1 ,2-1-116 rFl 0 di hydropyrid in-3-y1)-N6-ethy1-2-(5-N NH
----Ni il _ 'I NThr methyl-1 ,2,4-oxadiazole-3-o-N o o carboxamido)-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 ID
13.)(N S (1-r(2d-in(13-3ic_yycol-oN[16.-1e.t1h]yple-5n_toaxn0-1-2-H _ - ylamino)-2-oxoethyl)-2-oxo-1,2-c 0 µ---)' d( i h) y- N 1 d r o- y InilAN lNH (1,2,3-thiadiazole-4-s I\ N' \F-N H 0 c) carboxamido)hexanediamide ID ID1 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-, H
N ylamino)-2-oxoethyl)-2-oxo-1,2-1-118 0 0 ---/L dihydropyridin-3-y1)-N6-ethy1-5-oxo-j-L N,sy -LriJci (1,2,4-thiadiazole-5-.--N 0 0 carboxamido)hexanediamide 0 0 N (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-H ____), ylamino)-2-oxoethyl)-2-oxo-1,2-ip 1.1 0 dihydropyridin-3-y1)-N6-ethy1-5-oxo-2-N
S Nj-L (NH (1,3,4-thiadiazole-2-N-N 0 0 carboxamido)hexanediamide o (S)-N1-ethy1-5-(4-formy1-1,2,3-0N.---,õ
H thiadiazole-5-carboxamido)-N6-(1-(2-, 0 H
1-120 NI,jcNriUN ii N (2-adamantylamino)-2-oxoethyl)-2-I
NJ H N H I 1 oxo-1,2-dihydropyridin-3-yI)-2-\ o o oxohexanediamide o 0 (S)-N1-ethyl-N6-(1-(2-(3,5-dimethyladamantane-1-amino)-2-H
1-121 0 jcH 0 oxoethyl)-2-oxo-1,2-dihydropyridin-3-AN N'ANNH yI)-5-(nicotinamido)-2-I H
0 0 oxohexanediamide N
Method for production of inventive compounds In some embodiments, the present invention relates to a method for the synthesis of a compound of formula (I), especially any compound of the formula (la):
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 0 N ,R6 H
N N R -L, 3 H
(la) As shown in Scheme 1, a method for producing the compound of the formula (la) comprising:
Step 1A: providing a compound 4a AcON,R6 H
PWNOH
H
0 4a;
Step 2A: performing coupling reaction of the compound 4a with a compound 5 H2N....... ....1_, , 1 N Rs' I
to obtain a compound 6a AcON-R6 H
PG3,Nk-11j- ,L ., 1 N 'R-H
6a;
Step 3A: deprotecting an amino protecting group PG3to obtain a compound 7a 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 AcON,R6 H
N R-7a;
Step 4A: performing coupling reaction of the compound 7a with a carboxylic acid (R2-CO2H 8) to obtain a compound 9a AcON,R6 H
---,.... ,...CH
H
9a;
Step 5A: performing oxidation reaction of the compound 9a to produce the compound of the formula (la) ON,R6 H
JCH
H
(la);
wherein L, R2, R3,and R6 have the same meanings as defined above in formula (la), and PG3 is an amino protecting group.
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Scheme 1 (b) coupling ¨ ¨ (c) deprotection PG1 & PG2 reaction 0 Ac0)-L N" R6 0 CEN¨R6 reprotection with PG3 OH _ + Ac0 )-N, R6 2a H 1) TFA H
PG1,N PG2 AcOH PG1.N_i PG2 2) PG320 PGNJcrOH
DCM
PG1 0 PG1 0 DMF, DIPEA H 0 4a 1 3a , Step 2A:
coupling reaction (HATU, DIPEA ) Ac0)-N - R6 Ac0 N - R6 H Step 3A H
0 H2N deprotection rE ,L. 2 PG3N N ,L.
1 N R- (TFA) 1 N R3 6a 7a Step 4A
R2¨CO2H 8 coupling reaction (HATU, DIPEA ) Y
AcO)-N,R6 0)-NR6.
H Step 5A H
2 0 0 oxidation 0 0 reaction R2 N N 'r Ni R3 H
0 1) K2CO3, Me0H H
2) Dess-Martin 9a periodinane la DMF
Optionally, Step 1A" is carried out before the step 1A:
(a) providing a protected aldehyde 1 1:::, H
l'Gl 0 I;
(b) performing a coupling reaction of the aldehyde 1 with an isocyanide (CN-R6) 2a to obtain an intermediate compound 3a 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 AcON'R6 H
-PG1 0 3a;
(c)deprotecting the protecting groups PG1 and PG2 of the compound 3a preferably under acidic condition and introducing an amino protecting group PG3 to obtain a compound 4a AcON-R6 H
PG3N Jc OH
-H 0 4a;
wherein R2, R6 have the same meanings as defined in formula (la), PG1 and PG3 are amino protecting groups, PG2 is a carboxyl protecting group.
Therefore, the following method for the production of compounds of the formula (la) is preferred:
Step 1A":
(a) providing a protected aldehyde 1 OH
PG1.NPG2 PG1 0 I;
(b) performing a coupling reaction of the aldehyde 1 with an isocyanide (CN-R6) 2a to obtain an intermediate compound 3a Ac0)-LN-R6 H
pG1N pG2 -PG1 0 3a;
(c) deprotecting the protecting groups PG1 and PG2 of the compound 3a preferably under acidic condition and introducing an amino protecting group PG3 to obtain a compound 4a 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Ac0)-LN-R6 H
PGNJCOH
H 0 4a;
Step 1A: providing a compound 4a Ac0)-LN-R6 H
PGNON
H 0 4a;
Step 2A: performing coupling reaction of the compound 4a with a compound 5 H2N )-L ,L, , N R3 to obtain a compound 6a Ac0)-LN-R6 H
, 0 , N R-6a;
Step 3A: deprotecting the amino protecting group PG3 to obtain a compound 7a Ac0)-LN-R6 H
H
H2NjcNN-1--R3 7a;
Step 4A: performing coupling reaction of the compound 7a with a carboxylic acid (R2-CO2H 8) to obtain a compound 9a Ac0)-N-R6 H
0 iCH 0 R2J-LN 1\1 ,L, 9a;
Step 5A: performing oxidation reaction of the compound 9a to produce the compound of the formula (la) 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 )-L
R2 N H 1 N L- 'R-(la);
wherein L, R2, R3,and R6 have the same meanings as defined above in the formula (la), and PG1 and PG3 are amino protecting groups, PG2 is a carboxyl protecting group.
In an alternative route first all protecting groups PG1 and PG2 are simultaneously removed and the protecting group PG3 is selectively introduced. Preferably, PG1 and PG3 are same.
The term "protecting groups" as used herein refers to commonly used protection groups in organic synthesis, preferably for amino and carboxyl groups.
PG1, PG3, and PG5 preferably are suitable protecting groups for amino groups. PG2 and PG4 preferably are suitable protecting groups for carboxyl groups. Preferably, PG1, PG3, and PG5 may be selected from the group consisting of or comprising: acetyl, benzoyl, benzyloxycarbonyl (Cbz), tert-butylcarbonyl, tert-butyloxycarbonyl (Boc), and fluorenylmethylenoxy group (Fmoc). PG2 and PG4 may be selected from the group consisting of or comprising:
methoxy, ethoxy, isobutoxy, tert-butoxy, benzyloxy; preferably, tert-butoxy group.
In Step 2A to promote the coupling reaction with amino group of intermediate compound, activating reagents are commonly used to activating carboxylic acid (õPeptide Coupling Reagents, More than a Letter Soup", Ayman El-Faham and Fernando Albericio, Chemical Reviews, 2011, ///(//), p.6557-6602). The activation may be introduced separate reaction or in situ reaction. Preferably, any of the following coupling reagent can be used to activate carobxylic acid group: BOP (Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate), PyBOP (Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafl uorophosphate), AOP
(7-(Azabenzotriazol-1-yl)oxy tris(dimethylamino)phosphonium hexafluorophosphate), PyAOP ((7-Azabenzotriazol-yloxy)tripyrrolidinophosphonium hexafluorophosphate), TBTU (2-(1H-Benzotriazole-1-y1)-1,1,3,3-tetramethylaminium tetrafluoroborate), EEDQ (N-Ethoxycarbony1-2-ethoxy-1,2-dihydroquinoline), Polyphosphoric Acid (PPA), DPPA (Diphenyl phosphoryl azide), HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), H BTU
(0-Benzotriazol-1-yl-N,N ,N',N'-tetramethyluronium hexafluorophosphate), HOBt (1-Hyd roxybenzotriazo le), HOAt (1-Hydroxy-7-azabenzotriazole), DCC (N,W-Dicyclohexylcarbodiimide), EDC (or EDAC or EDCI, 1-Ethyl-3-(3-dimethylaminopropyl)carbodiim ide), BOP-C1 (Bis(2-oxo-3-2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 oxazolidinyl)phosphinic chloride), TFFH
(Tetramethylfluoroformamidinium hexafluorophosphate), BroP (Bromo tris(dimethylamino) phosphonium hexafluorophosphate), PyBroP
(Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate) and CI P
(2-Chloro-1,3-dimethylimidazolidinium hexafluorophosphate), or further, similar acting reagents, providing an activated intermediate,or a mixture thereof.
Pharmaceutical Composition & Medical Use Therefore another aspect of the present invention relates to compounds according to the general formula (I) as medicine as well as their use in medicine. Especially preferred is the use as inhibitors of transglutaminases, in particular transglutaminsase 2 (TG2).
Thus the compounds of formula (I) described herein or according to the present invention may be administered themselves or in form of a pharmacologically acceptable salt.
The compounds of the present invention may form of a pharmacologically acceptable salt with organic or inorganic acids or bases. Examples of suitable acids for such acid addition salt formation are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, p-aminosalicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, sulfonic acid, phosphonic acid, perchloric acid, nitric acid, formic acid, propionic acid, gluconic acid, lactic acid, tartaric acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, methanesulfonic acid, ethanesulfonic acid, nitrous acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, p-toluenesulfonic acid, naphthylsulfonic acid, sulfanilic acid, camphorsulfonic acid, china acid, mandelic acid, o-methylmandelic acid, hydrogen-benzenesulfonic acid, picric acid, adipic acid, d-o-tolyltartaric acid, tartronic acid, (o, m, p)-toluic acid, naphthylamine sulfonic acid, trifluoroacetic acid, and other mineral or carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. Preferred is the mesylate salt, hydrochloride salt and the trifluoroacetate salt and especially preferred is the trifluoroacetate salt and the hydrochloride salt.
In the case the inventive compounds bear acidic groups, salts could also be formed with inorganic or organic bases. Examples for suitable inorganic or organic bases are, for example, NaOH, KOH, NH4OH, tetraalkylammonium hydroxide, lysine or arginine and the like. Salts may be prepared in a conventional manner using methods well known in the 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 art, for example by treatment of a solution of the compound of the general formula (I) with a solution of an acid, selected out of the group mentioned above.
Methods of Use In a further aspect of the present invention, the novel compounds according to the general formula (I) are used as pharmaceutically active agent, i.e. the compound of the formula (I) is used in medicine.
Furthermore, the present invention relates to a pharmaceutical composition comprising at least one compound according to the general formula (I), as an active ingredient or a pharmacologically acceptable salts thereof as an active ingredient, together with at least one pharmacologically acceptable carrier, excipient and/or diluent.
The compounds according to general formula (I) described herein are especially suitable for the treatment and prophylaxis of diseases associated with and/or caused by transglutaminase 2.
Celiac disease, a gluten intolerance is associated with tissue transglutaminase (TG 2).
Another very important group of indications for tissue transglutaminase inhibitors are fibrotic disorders. Fibrotic disorders are characterized by the accumulation of cross-linked extracellular matrix proteins. Diabetic nephropathy, cystic fibrosis, idiopathic pulmonary fibrosis, kidney fibrosis as well as liver fibrosis belong to the most important fibrotic disorders to be addressed with the compounds disclosed.
In the biological example B-1, it is proven that the inventive compounds as reversible inhibitors effectively inhibit the activity of TGs, especially TG2.
As used herein the term "inhibiting" or "inhibition" refers to the ability of a compound to downregulate, decrease, reduce, suppress, inactivate, or inhibit at least partially the activity of an enzyme, or the expression of an enzyme or protein.
Therefore, another aspect of the present invention is the use of the inventive compounds of the general formula (I), or the pharmaceutical composition thereof as described in the treatment or prophylaxis of autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, ocular diseases, and skin disorders.
Further aspects of the present invention relate to the use of the compounds of general formula (I) for the preparation of a pharmaceutical composition useful for prophylaxis 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 and/or treatment of autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, ocular diseases, and skin disorders.
In a further aspect of the present invention, a method for preventing and/or treating autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, ocular diseases, and skin disorders, which method comprises administering to a subject, in particular a human, a pharmaceutically effective amount of at least one compound of the general formula (I), to prevent and/or treat said autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, ocular diseases, and skin disorders.
Preferred, the autoimmune and inflammatory diseases comprises multiple sclerosis, celiac disease, Duhring-Brocq-disease (dermatitis herpetiformis), gluten ataxia, gluten neuropathy, diabetes, rheumatoid arthritis, Graves' disease, inflammatory bowel disease, systemic lupus erythematosus psoriasis, and gingivitis;
the vascular diseases comprise atherosclerosis, thrombosis, vascular stiffness;
the fibrotic diseases affecting the lung, the kidney, the liver, the skin or the gut like cystic fibrosis, kidney fibrosis and diabetic nephropathy, intestinal fibrosis, idiopathic lung fibrosis, liver fibrosis;
the liver diseases like alcoholic hepatitis, alcoholic steatohepatitis, nonalcoholic steatohepatitis, non-alcoholic fatty liver disease, liver cirrhosis, autoimmune hepatitis or liver inflammation;
the cholestatic liver diseases comprise primary biliary cholangitis and primary sclerosing cholangitis;
the cancer comprises glioblastoma, melanoma, pancreatic cancer, renal cell carcinoma, meningioma, and breast cancer, the neurodegenerative diseases comprise Parkinson's disease, Huntington's disease, or Alzheimer's disease, the ocular diseases comprise glaucoma, cataracts, macular degeneration, or uveitis;
the skin disorders comprise acne, psoriasis, scarring, and skin aging.
More preferred, the compound of the formula (I), or the pharmaceutical composition thereof is useful in the treatment or prophylaxis of celiac disease.
Furthermore, the compounds of the general formula (I), can be administered in form of their pharmaceutically active salts, optionally using essentially non-toxic pharmaceutically acceptable carriers, adjuvants or extenders. Medications are prepared in a known manner in a conventional solid or fluid carrier or in extenders and a conventional pharmaceutically acceptable adjuvant/expedient in a suitable dose. The preferred 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 preparations are provided in an administrable form suitable for oral application, such as pills, tablets, film tablets, coated tablets, capsules and powders.
Tablets, film tablets, coated tablets, gelatin capsules and opaque capsules are the preferred pharmaceutical formulations. Any pharmaceutical compositions contains at least one compound of the general formula (I), and/or pharmaceutically acceptable salts thereof in an amount of 5 mg to 500 mg, preferably 10 mg to 250 mg and most preferred in an amount of 10 to 100 mg per formulation.
Besides, the object of the present invention also includes pharmaceutical preparations for oral, parenteral, dermal, intradermal, intragastric, intracutaneous, intravascular, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal, percutaneous, rectal, subcutaneous, sublingual, topic, transdermal or inhalative application, containing, in addition to typical vehicles and extenders, a compound of the general formula (I), and/or a pharmaceutically acceptable salt thereof as active component.
The pharmaceutical compositions of the present invention contain one of the compounds of the formula (I) disclosed herein as active component, typically mixed with suitable carrier materials, selected with respect to the intended form of administration, i.e. tablets to be administered orally, capsules (filled either with a solid, a semi-solid or a liquid), powders, orally administrable gels, elixirs, dispersible granulates, syrups, suspensions and the like in accordance with conventional pharmaceutical practices. For example, the compound of the formula (I) can as active agent component be combined with any oral, non-toxic, pharmaceutically acceptable, inert carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms) and the like for the oral administration in form of tablets or capsules.
Moreover, suitable binders, lubricants, disintegrants and colorants can be added to the mixture if required. Powders and tablets can consist of said inert carriers to an extent from .. about 5% per weight to about 95% per weight of the inventive composition.
Suitable binders include starch, gelatin, natural sugars, sweeteners made of corn, natural and synthetic gums, such as acacia gum, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes. Possible lubricants for the use in said dosage forms include boric acid, sodium benzoate, sodium acetate, sodium chloride and the like.
Disintegrants include starch, methylcellulose, cyclodextrins, guar gum and the like. If required, sweeteners and flavor additives and preservatives can also be included. Some of the terms used above, namely disintegrants, extenders, lubricants, binders and the like are discussed in greater detail below.
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Additionally, the compositions of the present invention can be formulated in a form with sustained release to provide a controlled release rate of any one or more components or active components, in order to optimize the therapeutic effect, i.e. the inhibitory activity and the like. Suitable dosage forms for sustained release include layered tablets containing layers with varying degradation rates or controlled release polymeric matrices impregnated with the active components and in the form of a tablet or capsule containing such impregnated or encapsulated porous polymeric matrices.
Preparations in fluid form include solutions, suspensions and emulsions.
Exemplarily mentioned are water or water propylene glycol solutions for parenteral injections or the addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions.
Aerosol preparations suitable for inhalation may include solutions and solids in the form of powders which can be combined with a pharmaceutically acceptable carrier, such as a compressed inert gas, e.g. nitrogen.
For the preparation of suppositories a low melting wax, such as a mixture of fatty acid glycerides, e.g. cocoa butter, is melted firstly and the active component is homogenously dispersed therein by stirring or similar mixing operations. The melted homogenous mixture is then poured in fitting forms, cooled and thus hardened.
Further preparations in solid form which are to be converted into preparations in fluid form for either oral or parenteral administration shortly before use are included.
Such fluid forms include solutions, suspensions and emulsions.
Furthermore, the compounds of the present invention may be administered via transdermal application. The transdermal compositions can have the form of crèmes, lotions, aerosols and/or emulsions.
The term capsule refers to a special container or casing composed of methylcellulose, polyvinyl alcohols or denatured gelatins or starches, in which the active agents can be enclosed. Typically, hard shell capsules are prepared from mixtures of bones and porcine skin gelatins having comparatively high gel strength. The capsule itself can contain small amounts of colorants, opacifiers, softening agents and preservatives.
Tablet means a compressed or cast solid dosage form containing the active components with suitable extenders. The tablet can be produced by compressing mixtures or granulates obtained by wet granulation, dry granulation or compaction, which are known to the one skilled in the art.
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Oral gels refer to the active components dispersed or solubilized in a hydrophilic semi-solid matrix.
Powders for compositions refer to powder mixtures containing the active components and suitable extenders which can be suspended in water or juices.
Suitable extenders are substances which usually form the largest part of the composition or dosage form. Suitable extenders include sugars such as lactose, sucrose, mannitol and sorbitol; starches derived from wheat, corn, rice and potatoes; and celluloses such as microcrystalline cellulose. The amount of extenders in the composition can range from about 5 to about 95% per weight of the total composition, preferably form about 25 to about 75% per weight and further preferred from about 30 to about 60% per weight.
The term disintegrants refers to materials added to the composition in order to support disintegration and release of the medicinal substance. Suitable disintegrants include starches, modified starches which are soluble in cold water, such as sodium carboxymethyl starch; natural and synthetic gums such as locust bean gum, caraya, guar gum, tragacanth and agar; cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose, microcrystalline celluloses and crosslinked microcrystalline celluloses such as croscarmellose sodium; alginates such as alginic acid and sodium alginate; clays such as bentonites and foaming mixtures. The amount of disintegrants used in the composition can range from about 2 to 20% per weight of the composition and further preferred from about 5 to about 10% per weight.
Binders characterize substances binding or "gluing" powders to each other and they consequently serve as "glue" in the formulation. Binders add a cohesion starch which is already available in the extenders or the disintegrant. Suitable binders include sugar, such as sucrose; starches derived from wheat, corn, rice and potatoes; natural gums such as acacia gum, gelatin and tragacanth; derivatives of sea weed such as alginic acid, sodium alginate and ammonium calcium alginate, cellulose materials such as methyl cellulose and sodium carboxymethylcellulose and hydroxypropyl methylcellulose, polyvinylpyrrolidone and inorganic compounds, such as magnesium aluminum silicate.
The amount of binders in the composition can range from about 2 to about 20%
per weight of the total composition, preferably form about 3 to about 10% per weight and further preferred from about 3 to about 6% per weight.
The term lubricant refers to a substance added to the dosage form in order to allow for the tablet, granulate, etc. to be released from the casting mold or pressing mold, after compression, by reducing the friction. Suitable lubricants include metallic stearates such as magnesium stearate, calcium stearate or potassium stearate; stearic acid;
waxes with 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 high melting points and water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and D,L-leucine.
Due to the fact that lubricants have to be present on the surface of the granulates as well as between the granulates and parts of the tablet press they are typically added during the last step prior to compression. The amount of lubricants in the composition can range from about 0.2 to about 5% per weight of the total composition, preferably form about 0.5 to about 2% per weight and further preferred from about 0.3 to about 1.5 % per weight.
Lubricants are materials preventing caking and improving the flow characteristics of granulates so that the flow is smooth and uniform. Suitable lubricants include silicon dioxide and talc. The amount of lubricants in the composition can range from about 0.1 to about 5 % per weight of the total composition, preferably form about 0.5 to about 2 %
per weight.
Colorants are adjuvants coloring the composition or dosage form. Such adjuvants can include colorants having food quality which are adsorbed on a suitable adsorption means, such as clay or aluminum oxide. The amount of the colorant used can vary from about 0.1 to about 5% per weight of the composition and preferably from about 0.1 to about 1%
per weight.
As used herein, a "pharmaceutically effective amount" of a transglutaminase inhibitor is the amount or activity effective for achieving the desired physiological result, either in cells treated in vitro or in a patient treated in vivo. Specifically, a pharmaceutical effective amount is such an amount which is sufficient for inhibiting, for a certain period of time, one or more of the clinically defined pathological processes associated with transglutaminase 2. The effective amount can vary according to the specific compound of the formula (I) and additionally depends on a plurality of factors and conditions related to the subject to be treated and the severity of the disease. If, for example, an inhibitor is to be administered in vivo, factors such as age, weight and health of the patients as well as dose reaction curves and data regarding toxicity obtained from preclinical animal studies are amongst the data to be considered. If the inhibitor in form of the compound of the formula (I) described herein is to be brought in contact with the cells in vivo, a plurality of preclinical in vitro studies would be designed in order to determine parameters such as absorption, half-life, dose, toxicity, etc. Determining a pharmaceutically effective amount fora given pharmaceutically active ingredient is part of the ordinary skills of the one skilled in the art.
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Examples Following abbreviations used in the examples have the following meaning.
Boc (tert-butoxycarbonyl), Boc0Su (N-tert-butoxycarbonyloxy-succinimide) DCM
(dichloromethane), DMAP (4-(Dimethylamino)-pyridine), TEA (triethylamine), DMF
(dimethylformamide), DMP (Dess-Martin periodiane), DIPEA (N-Ethyldiisopropylamine), Glu (glutamic acid), EDC (1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide), TFA
(trifluoroacetic acid), THF (tetrahydrofuran), Et0Ac (ethyl acetate), HATU (1-[Bis(dimethylam ino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate), HOBt (hydroxybenzotriazole), MTBE (methyl tert-butyl ether), tBu (tert-butyl), Chemical Examples The following examples are intended to illustrate the invention with selected compounds without limiting the protecting scope of the present intellectual property right on these concrete examples. It is clear for a person skilled in the art that analogous compounds and compounds produced according to analogous synthetic ways fall under the protecting scope of the present intellectual property right.
Example I. Synthetic method 1 Scheme 1-1 OH chloroacetic acid 34 cl) 0 02NA, ___________ 02N ,OH
j\I NaP0 (a 0 1-adamantylamine EDC, DIPEA, DMF
10% Pd/C
j\I -01 Me0H JJ 0 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound ZED1657 2-(3-n itro-2-oxopy rid in-1(2H)-yl)acetic acid Chemical Formula: C7H6N205 Exact Mass: 198.03 Molecular Weight: 198.13 30.0 g (214 mmol) of 2-hydroxy-3-nitropyridine and 40.5 g (2 eq) of chloroacetic acid were suspended in 600 mL water. At 40 C, 245 g (3 eq) trisodium phosphate dodecahydrate were added, and the reaction was stirred at room temperature overnight. 250 mL
HCI
(32%) were added, and the suspension was stirred for another night at 4 C. The precipitate was filtered and dried.
Yield: 41.2 g, 97%; ESI-MS: 199.3 [M+H]
Preparation of compound ZED3912 NNH
N-(1-adamantyI)-2-(3-nitro-2-oxopyridin-1(2H)-yl)acetamide Chemical Formula: 017H21N304 Exact Mass: 331.15 Molecular Weight: 331.37 7.0 g (35.3 mmol) of ZED1657, 6.63 g (1 eq) of 1-adamantanamine hydrochloride and 4.77 g (1 eq) of HOBt were dissolved in 80 mL DMF and 7.38 mL (1.2 eq) DI PEA.
7.45 g (1.1 eq) of 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride were added and the reaction was stirred at room temperature overnight. The solvent was evaporated, and the residue was dissolved in 200 mL DCM. The solution was washed with each 100 mL
citric acid solution (10%), NaHCO3 solution (10%) and brine. The organic phase was dried over Na2SO4, filtered and the solvent was evaporated.
Yield: 10.3 g, 88%; ESI-MS: 332.4 [M+H]
Preparation of compound ZED3913 2-(3-amino-2-oxopyridin-1(2H)-y1)-N-(1-adamantyl)acetamide Chemical Formula: C17H23N302 Exact Mass: 301.18 Molecular Weight: 301.38 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 10.3 g (31.0 mmol) of ZED3912 were suspended in 200 mL Me0H before 1.0 g of palladium (10%) on activated carbon (unreduced) were added. The suspension was stirred overnight at room temperature under an atmosphere of hydrogen. The catalyst was filtered, and the solvent was evaporated.
Yield: 7.51 g, 78%
ESI-MS: 302.3 [M+H]+
Scheme. 1-2 C) OH 1. DMF, CH3I 0 H 1. Ethyl AcON
Cs2003 isocyanide 2. DMAP, ACN AcOH, DCM H
Boc20 2. TEA
Boo, ______________________ ).- Boo,N ________________________________ ,-Boc,N OH
N CO2tBu CO2tBu H H
3. DIBAL-H Boo 3. Boc20 Et20, -78 C DIPEA, DMF
ZED3913 ci 0 HATU, DMF
DIPEA
H2N,)-L ,NH
N if Ac(21)-N Ac0)-N
H H
? JCH 0 1) TEA, DCM 0 N _________________________________ NH ________ -4 I\1/ r_ii 1 N-r Boo,NJ(NFiNrNH
_--N 0 0 2) HATU, DIPEA, DMF H 0 0 N 1-methyl-1H-imidazole-I-1 b 5-carboxylic acid I-la 1 K2CO3, Me0H
HON
H H
0 0 Dess-Martin 0 0 )-L NH periodinane ____________________________________________ *- NYI\IjcNH1H N-r NH
NLY1,1 (10 N 1\1cc ____m H 0 0 -N DMF -N
1-1c 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 Preparation of compound ZED788 0 OMe BooN
. JC0tBu (S)-1-tert-butyl 5-methyl 2-(tert-butoxycarbonylamino)pentanedioate Chemical Formula: C15H27N06 Exact Mass: 317,18 Molecular Weight: 317,38 12.0 g of Boc-L-Glu-OtBu (39.6 mmol) and 7.09 g of cesium carbonate (21.8 mmol, 0.55 eq) were suspended in 100 ml of DMF and stirred for 1 h at room temperature.
2.47 ml iodomethane (39.6 mmol) we added, and the mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was dissolved in ethyl acetate and washed twice with each citric acid solution (10%), NaHCO3 solution (10%) and brine.
The organic phase was dried over Na2SO4, filtered and the solvent was evaporated. The raw product was used without further purification.
Yield: 13.4 g, >100%
ESI-MS: 318.3 [M+H]
Preparation of compound ZED720 0 OMe Boc,N OtBu Boo 0 (S)-1-tert-butyl 5-methyl 2-(bis(tert-butoxycarbonyl)amino)pentanedioate Chemical Formula: C20H35N08 Exact Mass: 417,24 Molecular Weight: 417,49 13.4 g of ZED788 (-39,6 mmol) and 986 mg of N,N-dimethy1-4-aminopyridine (DMAP) were dissolved in 30 ml of acetonitrile. 17.6 g of di-tert-butyl bicarbonate (77.1 mmol) in 100 ml of acetonitrile was added and the solution was stirred at room temperature overnight. The solvent was evaporated, and the residue was dissolved in ethyl acetate and washed twice with each citric acid solution (10%), NaHCO3 solution (10%) and brine.
The organic phase was dried over Na2SO4, filtered and the solvent was evaporated. The raw product was used without further purification.
Yield: 13.7 g, 83%
ESI-MS: 418.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound ZED721 O H
Boc ,N J(OtBu I3oc 0 (S)-tert-butyl 2-(bis(tert-butoxycarbonyhamino)-5-oxopentanoate Chemical Formula: C19H33N07 Exact Mass: 387,23 Molecular Weight: 387,47 13.7 g of ZED720 (32.8 mmol) were dissolved in 200 ml of dry diethyl ether and cooled to -78 C under argon atmosphere. 36.1 ml of diisobutylaluminum hydride (1M in hexane) were added dropwise and the solution was stirred for 30 min at -78 C before being quenched with potassium sodium tartrate (Rochelle salt) solution. The organic layer was separated, dried over Na2SO4, filtered, and concentrated to dryness. The raw product was used without further purification.
Yield: 13.3 g, >100%
ESI-MS: 388.3 [M+H]
Preparation of compound ZED3221 AcOjL N
Boc,NOH
(2S)-5-acetoxy-2-(tert-butoxycarbonylamino)-6-(ethylamino)-6-oxohexanoic acid Chemical Formula: C15H26N207 Exact Mass: 346.17 Molecular Weight: 346.38 7.0 g (18.1 mmol) of the aldehyde (S)-tert-butyl 2-(bis(tert-butoxycarbonyl)amino)-5-oxopentanoate (ZED721) were dissolved in 30 mL DCM. At 0 C 1.04 g (1.05 eq) ethyl isocyanide and 1.09 mL (1.05 eq) acetic acid were added, and the reaction was stirred at room temperature overnight. 35 mL TFA were added, and the reaction was stirred for another 3 h. The solvent was evaporated, and the residue was dissolved in 20 mL DMF.
6.29 mL (2 eq) DIPEA and 4.73 g (1.2 eq) di-tert-butyl dicarbonate in 5 mL DMF
were added and the reaction was stirred at room temperature overnight. The solvent was evaporated, and the residue was dissolved in DCM. After extraction with NaHCO3 solution (1.05 eq in water), 1.5 eq citric acid was added to the aqueous phase, followed by re-extraction with DCM. The organic phase was dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography.
Yield: 5.77 g, 92%
ESI-MS: 347.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound I-la Ac0j-L
Boc, A
NNH
0 Li (5S)-5-(tert-butoxycarbonylamino)-1-(ethylamino)-6-(1-(2-(1-adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-ylamino)-1 ,6-dioxohexan-2-y1 acetate Chemical Formula: C32F147N508 Exact Mass: 629.34 Molecular Weight: 629.74 5.77 g (16.7 mmol) of ZED3221, 6.33 g (1 eq) HATU and 5.02 g (1 eq) ZED3913 were dissolved in 100 mL DMF and 5.80 mL DIPEA (2 eq) and stirred at 45 C
overnight. The solvent was evaporated; the residue was dissolved in 50 mL Et0Ac and washed twice with each 35 mL citric acid solution (10%), NaHCO3 solution (10%) and brine.
The organic phase was dried over Na2SO4, filtered and the solvent was evaporated.
Yield: 7.41 g, 71%
ESI-MS: 630.5 [M+H]
Preparation of compound I-lb AcOAN
0 ( H 0 7.'''-zi)LNNJ-L NH
N
(5S)-1-(ethylamino)-6-(1-(2-(1-adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-d ihyd ropyrid in-3-ylamino)-5-(1 -methyl-1 H-imidazole-5-carboxamido)-1,6-dioxohexan-2-y1 acetate Chemical Formula: C32H43N707 Exact Mass: 637.32 Molecular Weight: 637.73 600 mg (0.95 mmol) of I-la were dissolved in 5 ml DCM/TFA (1:1) and stirred at room temperature for 1 h. The solvent was evaporated, and the residue was dissolved in 5 ml DMF. 120 mg (1 eq) 1-methyl-1H-imidazole-5-carboxylic acid, 362 mg (1 eq) HATU
and 332 pl (2 eq) DIPEA were added, and the reaction was stirred at room temperature overnight. The solvent was evaporated; the residue was dissolved in 25 mL
Et0Ac and washed with each 15 mL citric acid solution (10%), NaHCO3 solution (10%) and brine.
The organic phase was dried over Na2SO4, filtered and the solvent was evaporated.
Yield: 527 mg, 87%
ESI-MS: 638.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-1c 0 ti 0 (56)-N 1-ethyl-2-hydroxy-N6-(1 -(2-(1-adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyrid in-3-y1)-5-(1-methyl-1H-imidazole-5-carboxamido)hexanediamide Chemical Formula: C301-141N706 Exact Mass: 595.31 Molecular Weight: 595.69 527 mg (0.83 mmol) of 1-lb were dissolved in 7 ml Me0H. 171 mg (1.5 eq) potassium carbonate were added, and the reaction was stirred at room temperature for 1 h. The solution was diluted with DCM and washed with water. The organic phase was dried over Na2SO4, filtered and the solvent was evaporated.
Yield: 469 mg, 95%
ESI-MS: 596.5 [M+H]
Preparation of compound 1-1 iCH 0 N
N NH
(S)-N 1 -ethyl-N6-(1 -(2-(1-adamantylami no)-2-oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-y1)-5-(1-methyl-1H-imidazole-5-carboxamido)-2-oxohexanediamide Chemical Formula: C30F139N706 Exact Mass: 593.30 Molecular Weight: 593.67 469 mg (0.60 mmol) of I-1c were dissolved in 5 ml DMF. 534 mg (1.6 eq) Dess-Martin periodinane (DMP) were added and the reaction was stirred at room temperature over 2 h. The precipitate was filtered off and the filtrate was evaporated. The residue was purified by HPLC.
Yield: 362 mg, 77%
ESI-MS: 594.5 [M+H]
1H-NMR (DMSO-D6, 500 MHz, O [ppm]: 1.27 (t, 3H, ethyl-CH3), 1.74 (m, 6H, adamantyl-C4-H2), 1.97 // 2.15 (m // m, 1H // 1H, [3-CH2), 2.09 (m, 3H, adamantyl-C3-H), 2.17 (m, 6H, adamantyl-C2-H2), 3.23 (m, 2H, ethyl-CH2), 2.91 (t, 2H, y-CH2), 3.74 (s, 3H, imidazole-N-CH3), 4.54 (ddd, 1H, a-CH2), 4.61 (s, 2H, N-CH2), 6.26 (t, 1H, pyridinone-05-H), 7.31 (d, 1H, pyridinone-C6-H), 7.69 (s, 1H, imidazole-CH), 7.77 (s, 1H, imidazole-2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 CH), 8.04 (d, 1H, adamantyl-NH), 8.17 (d, 1H, pyridinone-C4-H), 8.44 (q, 1H, ethylamide-NH), 8.56 (d, 1H, a-NH), 9.16 (s, 1H, pyridinone-NH).
13C-NMR (DMSO-D6, 500 MHz, O [ppm]: 15.14 (ethyl-CH3), 24.54 (13-CH2), 29.19 (adamantyl-C3-H), 33.54 (imidazole-N-CH3), 33.71 (y-CH2), 34.41 (ethyl-CH2), 35.89 (adamantyl-C4-H2), 40.77 (adamantyl-C2-H2), 44.12 (adamantyl-C1), 51.74 (N-CH2), 52.42 (a-CH2), 104.66 (pyridinone-05-H), 122.39 (pyridinone-C4-H), 125.22 (im idazole-Cq), 127.92 (pyridinone-N-Cq), 132.85 (imidazole-CH), 133.27 (pyridinone-C6-H), 142.23 (imidazole-CH), 156.63 (pyridinone-C=0), 160.32 (imidazole-C=0), 161.10 (C=O-NH-CH2CH3), 165.75 (C=0-adamantylamide), 170.56 (C=O-NH-pyridinone), 198.43 (C=0-ethylam ide).
Preparation of compound 1-2 0 ti 0 HNYL IAN "
(S)-N1-ethy1-5-(1 H-imidazole-4-carboxamido)-N6-(1-(2-(1-adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-y1)-2-oxohexanediamide Chemical Formula: 029F137N706 Exact Mass: 579.28 Molecular Weight: 579.65 The synthesis of compound 1-2 was performed according to compound 1-1, using 1-Boc-imidazole-4-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid. The final product was obtained by deprotection (DCM/TFA) as described above and purified by HPLC.
Yield: 45 mg, 63% (last step) ESI-MS: 580.4 [M+H]
Preparation of compound 1-3 ? 0 N"-7N
(S)-N1 -ethyl-N6-(1 -(241 -adamantyl(methyl)amino)-2-oxoethyl)-2-oxo-1 ,2-di hydropyridin-3-yI)-5-(1 -methyl-1 H-imidazole-5-carboxamido)-2-oxohexanediamide Chemical Formula: C311-141N706 Exact Mass: 607.31 Molecular Weight: 607.70 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 The synthesis of compound 1-3 was performed according to compound 1-1, using N-methy1-1-adamantanamine instead of 1-adamantanamine in step 2 (according to ZED3912).
Yield: 26 mg, 52% (last step) ESI-MS: 608.5 [M+H]
Preparation of compound 1-4 0)-L
I\1YLN NH
N
(S)-N1-ethyl-N6-(1-(2-(3,5-dimethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-5-carboxamido)-2-oxohexanediamide Chemical Formula: C32H43N706 Exact Mass: 621.33 Molecular Weight: 621.73 To the a-hydroxyester precursor of compound 1-4 (382 mg, 0.61 mmol, prepared by using 3,5-dimethy1-1-adamantanamine in step 2 according to compound ZED3912) in 10 mL of acetonitrile, 1 mg of TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl, 1 mol%) were added.
88 mg of calcium hypochlorite (1 eq) were added at 0 C and the reaction mixture was stirred at 25 C for 2 h. The suspension was filtered, diluted with ethyl acetate and washed with NaHCO3 solution (10%) and brine. The organic phase was dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by HPLC.
Yield: 176 mg, 46%
ESI-MS: 622.5 [M+H]
Preparation of compound 1-5 0)LN
NYLNjcNA NH
(S)-N1-ethyl-N6-(1-(2-(3-ethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methyl-1H-imidazole-5-carboxamido)-2-oxohexanediamide Chemical Formula: C32H43N706 Exact Mass: 621.33 Molecular Weight: 621/3 To the a-hydroxyester precursor of compound 1-5 (162 mg, 0.26 mmol, prepared by using 3-ethyl-1-adamantanamine in step 2 according to compound ZED3912) in 5 ml DMSO, 145 mg of 2-iodoxybenzoic acid (IBX, 2 eq) were added and the reaction mixture was stirred at room temperature for 3 h. NaHCO3 solution (10%) was added and the 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 suspension was extracted with Et0Ac. The organic phase was dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by HPLC.
Yield: 59 mg, 37% (last step) ESI-MS: 622.5 [M+H]
Preparation of compound 1-6 oJL CF3 N NH
, N
N '/Y-LFINjor 0 (S)-N1-ethyl-N6-(1-(2-(3-trifluoromethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methyl-1H-imidazole-5-carboxamido)-2-oxohexanediamide Chemical Formula: C31F138F3N706 Exact Mass: 661.28 Molecular Weight: 661.67 The synthesis of compound 1-6 was performed according to compound 1-1, using 3-trifluoromethy1-1-adamantanamine instead of 1-adamantanamine in step 2 (according to ZED3912).
Yield: 36 mg, 51% (last step) ESI-MS: 662.4 [M+H]
Preparation of compound 1-7 OH
H j_LN
NH
N "-/YLN-rN
I
(S)-N1-ethyl-N6-(1-(2-(3-hydroxyadamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-5-carboxamido)-2-oxohexanediamide Chemical Formula: C30H39N707 Exact Mass: 609.29 Molecular Weight: 609.67 The synthesis of compound 1-7 was performed according to compound 1-1, using 3-hydroxy-1-adamantanamine instead of 1-adamantanamine in step 2 (according to ZED3912).
Yield: 21 mg, 45% (last step) ESI-MS: 610.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-8 HN N
NYLN(r H)-L N-r (S)-N1-ethyl-N6-(1-(2-(3-fluoroadamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-5-carboxamido)-2-oxonexanediamide Chemical Formula: C30H38FN706 Exact Mass: 611.29 Molecular Weight: 611.66 The synthesis of compound 1-8 was performed according to compound 1-1, using 3-fluoro-1-adamantanamine instead of 1-adamantanamine in step 2 (according to ZED3912).
Yield: 52 mg, 61% (last step) ESI-MS: 612.5 [M+H]
Preparation of compound 1-9 Cl N/y-LNicN)-L NH
N
(S)-N1-ethyl-N6-(1-(2-(3-chloroadamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methyl-1H-imidazole-5-carboxamido)-2-oxonexanediamide Chemical Formula: C301-138C1N706 Exact Mass: 627.26 Molecular Weight: 628.12 The synthesis of compound 1-9 was performed according to compound 1-1, using 3-chloro-1-adamantanamine instead of 1-adamantanamine in step 2 (according to ZED3912).
Yield: 49 mg, 68% (last step) ESI-MS: 628.3 / 630.3 [M+H]
Preparation of compound 1-10 Br NH
/Y-LN(1 N
(S)-N1-ethyl-N6-(1-(2-(3-bromoadamantane-l-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methyl-1H-imidazole-5-carboxamido)-2-oxohexanediamide Chemical Formula: C30H38BrN706 Exact Mass: 671.21 Molecular Weight: 672.57 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 The synthesis of compound 1-10 was performed according to compound 1-1, using bromo-1-adamantanamine instead of 1-adamantanamine in step 2 (according to ZED3912).
Yield: 59 mg, 71% (last step) ESI-MS: 672.3 / 674.3 [M+H]
Preparation of compound 1-11 CO2Me HN N
NYLNjc N-r (S)-N1-ethyl-N6-(1-(2-(3-methyl adamantane-3-carboxylate-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-5-carboxamido)-2-oxohexanediamide Chemical Formula: C32F141 N708 Exact Mass: 651.30 Molecular Weight: 651.71 The synthesis of compound 1-11 was performed according to compound 1-1, using methyl 3-aminoadamantane-1-carboxylate instead of 1-adamantanamine in step 2 (according to ZED3912).
Yield: 85 mg, 74% (last step) ESI-MS: 652.5 [M+H]
Preparation of compound 1-12 N -H
NAyLNjcrN)-L NH
N-r (S)-N1-ethyl-N6-(1-(2-(4,4-difluoroadamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-5-carboxamido)-2-oxohexanediamide Chemical Formula: C301-137F2N706 Exact Mass: 629.28 Molecular Weight: 629.65 The synthesis of compound 1-12 was performed according to compound 1-1, using 4,4-difluoro-1-adamantanamine instead of 1-adamantanamine in step 2 (according to ZED3912).
Yield: 23 mg, 47% (last step) ESI-MS: 630.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-13 O Li 0 NYL N
Nr (S)-N1-(1-(2-(((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-Amethylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C30H41N706 Exact Mass: 595.31 Molecular Weight: 595.69 The synthesis of compound 1-13 was performed according to compound 1-1, using (-)-cis-myrtanylamine instead of 1-adamantanamine in step 2 (according to ZED3912).
Yield: 74 mg, 68% (last step) ESI-MS: 596.5 [M+H]
Preparation of compound 1-14 OAN
O ti 0 NYLHN N Nr ¨ 0 0 (S)-N1-(1-(2-(((1R,2R,5R)-6,6-dimethylbicyclo[3.1.1]heptan-2-yhmethylamino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-y1)-N6-ethyl-2-(1-methyl-1 H-imidazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C301-141N706 Exact Mass: 595.31 Molecular Weight: 595.69 The synthesis of compound 1-14 was performed according to compound 1-1, using (-)-cis-(pinan-2-ylmethyl)amine instead of 1-adamantanamine in step 2 (according to ZED3912).
Yield: 52 mg, 63% (last step) ESI-MS: 596.5 [M+H]
Preparation of compound 1-15 O ti 0 j-L NH
¨1\l/AN(r N I
(S)-N1-ethyl-N6-(1-(2-(3-ethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-4-carboxamido)-2-oxohexanediamide Chemical Formula: C32H43N706 Exact Mass: 621.33 Molecular Weight: 621.73 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 The synthesis of compound 1-15 was performed according to compound 1-5, using methy1-1H-imidazole-4-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 26 mg, 67% (last step) ESI-MS: 622.5 [M+H]
Preparation of compound 1-16 0)-L N
N N NHN NH
\ H
\
(S)-N1-ethyl-N6-(1-(2-(3-ethyladamantane-l-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1 -methyl-1 H-imidazole-2-carboxamido)-2-oxohexanediamide Chemical Formula: C32F143N706 Exact Mass: 621.33 Molecular Weight: 621.73 The synthesis of compound 1-16 was performed according to compound 1-5, using methyl-1H-imidazole-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 46 mg, 71% (last step) ESI-MS: 622.5 [M+H]
.. Preparation of compound 1-17 0)-LN
N NH
N N
(S)-2-(1,4-dimethy1-1H-imidazole-5-carboxamido)-N6-ethyl-N1-(1-(2-(3-ethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C33F145N706 Exact Mass: 635.34 Molecular Weight: 635.75 The synthesis of compound 1-17 was performed according to compound 1-5, using 1,4-dimethy1-1H-imidazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b).
.. Yield: 69 mg, 75% (last step) ESI-MS: 636.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-18 H j_L
NNH
(S)-N1-ethy1-5-(1-isobuty1-1H-imidazole-4-carboxamido)-N6-(1-(2-(3-ethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxohexanediamide Chemical Formula: C35H49N706 Exact Mass: 663.37 Molecular Weight: 663.81 The synthesis of compound 1-18 was performed according to compound 1-5, using isobuty1-1H-imidazole-4-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 38 mg, 62% (last step) ESI-MS: 664.5 [M+H]
Preparation of compound 1-19 Nj-I NH
FiNjcor H NiTho (S)-2-(1-cyclopenty1-1H-imidazole-4-carboxamido)-N6-ethyl-N1-(1-(2-(3-ethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C36F149N706 Exact Mass: 675.37 Molecular Weight: 675.82 The synthesis of compound 1-19 was performed according to compound 1-5, using cyclopenty1-1H-im idazole-4-carboxylic acid instead of 1-methy1-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 24 mg, 57% (last step) ESI-MS: 676.5 [M+H]
Preparation of compound 1-20 Nj-L NH
N-r (S)-2-(1-cyclobuty1-1H-imidazole-4-carboxamido)-N6-ethyl-N1-(1-(2-(3-ethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C35H47N706 Exact Mass: 661.36 Molecular Weight: 661.79 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 The synthesis of compound 1-20 was performed according to compound 1-5, using cyclobuty1-1H-im idazole-4-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 32 mg, 66% (last step) ESI-MS: 662.5 [M+H]
Preparation of compound 1-21 0 ( H 0 NH
NNN, Chemical Formula: C33F145N706 Exact Mass: 635.34 Molecular Weight: 635.75 (S)-2-(1,4-dimethy1-1H-imidazole-5-carboxamido)-N6-ethyl-N1-(1-(2-(3,5-climethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide The synthesis of compound 1-21 was performed according to compound 1-4, using 1,4-dimethy1-1H-imidazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 25 mg, 56% (last step) ESI-MS: 636.5 [M+H]
Preparation of compound 1-22 JCH
N)-L NH
¨NYLN N
Chemical Formula: C32F143N706 Exact Mass: 621.33 Molecular Weight: 621.73 (S)-N1-ethyl-N6-(1-(2-(3,5-dimethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methyl-1H-imidazole-4-carboxamido)-2-oxohexanediamide The synthesis of compound 1-22 was performed according to compound 1-4, using methy1-1H-im idazole-4-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 45 mg, 77% (last step) ESI-MS: 622.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-23 N CNF1)- NH
Chemical Formula: C32F-143N706 Exact Mass: 621.33 Molecular Weight: 621.73 (S)-N1-ethyl-N6-(1-(2-(3,5-dimethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methyl-1 H-imidazole-2-carboxamido)-2-oxohexanediamide The synthesis of compound 1-23 was performed according to compound 1-4, using methy1-1H-im idazole-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic .. acid in step 6 (according to compound 1-1b).
Yield: 18 mg, 50% (last step) ESI-MS: 622.5 [M+H]
Preparation of compound 1-24 NA NH
1\1Th Chemical Formula: C33H4.5N706 Exact Mass: 635.34 Molecular Weight: 635/5 (S)-2-(1,2-dimethy1-1 H-imidazole-5-carboxamido)-N6-ethyl-N 1-(1-(2-(3,5-d imethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide The synthesis of compound 1-24 was performed according to compound 1-4, using 1,2-dimethy1-1H-imidazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 44 mg, 72% (last step) ESI-MS: 636.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-25 )LN
Nj-LN NH
N/YN
Chemical Formula: C311-141N706 Exact Mass: 607.31 Molecular Weight: 607.70 (S)-N1-ethyl-N6-(1-(2-(3-methyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-5-carboxamido)-2-oxohexanediamide The synthesis of compound 1-25 was performed according to compound 1-1 , using methy1-1-adamantanamine instead of 1-adamantanamine in step 2 (according to ZED3912). Yield: 37 mg, 59% (last step) ESI-MS: 608.5 [M+H]
Preparation of compound 1-26 0)-LN
N NH
N'r CI
Chemical Formula: C32H42C1N706 Exact Mass: 655.29 Molecular Weight: 656.17 (S)-2-(2-chloro-1-methy1-1H-imidazole-5-carboxamido)-N6-ethyl-N1-(1-(2-(3,5-dimethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide The synthesis of compound 1-26 was performed according to compound 1-4, using chloro-1-methyl-1H-imidazole-5-carboxylic acid instead of 1-methyl-1H-im idazole-5-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 57 mg, 71% (last step) ESI-MS: 656.5 / 658.5 [M+H]
Preparation of compound 1-27 Chemical Formula: C32F-143N706 Exact Mass: 621.33 Molecular Weight: 621.73 (S)-2-(1,2-dimethy1-1H-imidazole-5-carboxamido)-N6-ethyl-N1-(1-(2-(3-methyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 The synthesis of compound 1-27 was performed according to compound 1-25, using 1,2-dimethy1-1H-im idazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 29 mg, 52% (last step) ESI-MS: 622.5 [M+H]
Preparation of compound 1-28 Nj-L NH
'JCL NFI N
"
Chemical Formula: C33F-145N706 Exact Mass: 635.34 Molecular Weight: 635.75 (S)-N1-ethyl-N6-(1-(2-(3,5,7-trimethy1-1-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1 -methyl-1 H-imidazole-5-carboxamido)-2-oxohexanediamide The synthesis of compound 1-28 was performed according to compound 1-1, using 3,5,7-trimethy1-1-adamantanamineinstead of 1-adamantanamine in step 2 (according to ZED3912).
Yield: 48 mg, 63% (last step) ESI-MS: 636.5 [M+H]
Preparation of compound 1-29 NH
N-r CI
Chemical Formula: C33H44C1N706 Exact Mass: 669.30 Molecular Weight: 670.20 (S)-2-(2-ch loro-1 -methyl-1 H-imidazole-5-carboxamido)-N6-ethyl-N1 -(1 -(2-(3,5,7-trimethyl-1-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide The synthesis of compound 1-29 was performed according to compound 1-28, using chloro-1-methy1-1H-im idazole-5-carboxylic acid instead of 1-methyl-1H-im idazole-5-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 23 mg, 52% (last step) ESI-MS: 670.5 / 672.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-30 )LN
0 )-L
N-r I I
(S)-2-(benzofuran-2-carboxamido)-N6-ethyl-N1 -(1 -(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-idihydropyridin-3-yI)-5-oxohexanediamide Chemical Formula: C34H39N507 Exact Mass: 629.28 Molecular Weight: 629.70 The synthesis of compound 1-30 was performed according to compound 1-1, using adamantanamine instead of 1-adamantanamine in step 2 (according to ZED3912) and benzofuran-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b).
Yield: 73 mg, 68% (last step) ESI-MS: 630.4 [M+H]
Preparation of compound 1-31 o oLN
r-rC
(S)-N1-ethyl-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-clihydropyridin-3-y1)-5-(3-methylbenzofuran-2-carboxamido)-2-oxohexanediamide Chemical Formula: C35H41N507 Exact Mass: 643.30 Molecular Weight: 643.73 The synthesis of compound 1-31 was performed according to compound 1-30, using methylbenzo[b]furan-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 90 mg, 77% (last step) ESI-MS: 644.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-32 0 FNINFI).L
NN
I I
CI
(S)-2-(3-chlorobenzofuran-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C34.H38CIN507 Exact Mass: 663.25 Molecular Weight: 664.15 The synthesis of compound 1-32 was performed according to compound 1-30, using chlorobenzofuran-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 56 mg, 72% (last step) ESI-MS: 664.4 / 666.4 [M+H]
Preparation of compound 1-33 NN)-LNN
I H I
Br (S)-2-(4-bromobenzofuran-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C34H38BrN507 Exact Mass: 707.20 Molecular Weight: 708.60 The synthesis of compound 1-33 was performed according to compound 1-30, using bromo-1-benzofuran-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 64 mg, 69% (last step) ESI-MS: 708.3 / 710.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-34 0,-õ)-1,N------õ, H
S 1 NNI-1)-LI NNEI
i H 0 0 (S)-2-(benzo[b]thiophene-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C34.H39N506S
Exact Mass: 645.26 Molecular Weight: 645.77 The synthesis of compound 1-34 was performed according to compound 1-30, using benzo[b]thiophene-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 51 mg, 67% (last step) ESI-MS: 646.4 [M+H]
Preparation of compound 1-35 ON
H
N-11\iNMN
F
(S)-N1-ethyl-5-(7-fluorobenzo[b]thiophene-2-carboxamido)-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-clihydropyridin-3-y1)-2-oxohexanediamide Chemical Formula: C34H38FN506S
Exact Mass: 663.25 Molecular Weight: 663.76 The synthesis of compound 1-35 was performed according to compound 1-30, using fluorobenzo[b]thiophene-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 36 mg, 64% (last step) .. ESI-MS: 664.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-36 N N
F F
(S)-2-(4,5-difluoro-1H-indole-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C34F138F2N606 Exact Mass: 664.28 Molecular Weight: 664.70 The synthesis of compound 1-36 was performed according to compound 1-30, using 4,5-difluoro-1H-indole-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 48 mg, 67% (last step) ESI-MS: 665.4 [M+H]
Preparation of compound 1-37 0)L
N
0 (rH 0 N
(S)-N1-ethyl-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(3-methyl-1H-indole-2-carboxamido)-2-oxohexanediamide Chemical Formula: C35H42N606 Exact Mass: 642.32 Molecular Weight: 642.74 The synthesis of compound 1-37 was performed according to compound 1-30, using methyl-1H-indole-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 42 mg, 64% (last step) ESI-MS: 643.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-38 N
(S)-2-(1H-benzo[d]imidazole-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C33H35N706 Exact Mass: 629.30 Molecular Weight: 629.71 The synthesis of compound 1-38 was performed according to compound 1-30, using benzo[d]imidazole-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 26 mg, 55% (last step) ESI-MS: 630.5 [M+H]
Preparation of compound 1-39 N)^ N
(S)-2-(2,3-dihydro-1H-indene-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C35H43N506 Exact Mass: 629.32 Molecular Weight: 629.75 The synthesis of compound 1-39 was performed according to compound 1-30, using 2,3-dihydro-1H-indene-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 19 mg, 46% (last step) ESI-MS: 630.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-40 0)L
N -H
N
N
_ J1 r\irN
(S)-N1-ethyl-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-clihydropyridin-3-y1)-5-(4-methy1-2-(trifluoromethypthiazole-5-carboxamido)-2-oxohexanediamide Chemical Formula: C31F137F3N606S
Exact Mass: 678.24 Molecular Weight: 678.72 The synthesis of compound 1-40 was performed according to compound 1-30, using methy1-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 34 mg, 61% (last step) ESI-MS: 679.4 [M+H]
Preparation of compound 1-41 H
0 1.1 0 H
F3C.--K\ _IAN
H 0 :01 N
Br (S)-2-(4-bromo-2-(trifluoromethypthiazole-5-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C30H34BrF3N606S
Exact Mass: 742.14 Molecular Weight: 743.59 The synthesis of compound 1-41 was performed according to compound 1-30, using bromo-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 39 mg, 56% (last step) ESI-MS: 743.3 / 745.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-42 1\1¨
(S)-N1-ethyl-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(4-methy1-2-phenylthiazole-5-carboxamido)-2-oxohexanediamide Chemical Formula: C36H4.2N606S
Exact Mass: 686.29 Molecular Weight: 686.82 The synthesis of compound 1-42 was performed according to compound 1-30, using methy1-2-phenylthiazole-5-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 43 mg, 69% (last step) ESI-MS: 687.5 [M+H]
Preparation of compound 1-43 NN
Br \ H 0 I
(S)-2-(5-bromo-3-methylthiophene-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C31 H38BrN506S
Exact Mass: 687.17 Molecular Weight: 688.63 The synthesis of compound 1-43 was performed according to compound 1-30, using bromo-3-methylthiophene-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 55 mg, 67% (last step) ESI-MS: 688.3 /690.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-44 N
N
Br , N N
\I Ho I I
Br (S)-2-(3,5-dibromothiophene-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C30H35Br2N506S
Exact Mass: 751.07 Molecular Weight: 753.50 The synthesis of compound 1-44 was performed according to compound 1-30, using 3,5-dibromothiophene-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 43 mg, 60% (last step) ESI-MS: 752.2 / 754.2 / 756.2 [M+H]
Preparation of compound 1-45 0 Nj-L N
N
Br , N
\I Ho I
(S)-2-(5-bromo-3-methylfuran-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C31H38BrN507 Exact Mass: 671.20 Molecular Weight: 672.57 The synthesis of compound 1-45 was performed according to compound 1-30, using bromo-3-methylfuran-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 52 mg, 71% (last step) ESI-MS: 672.3 /674.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-46 0liN
H u CI , CI
(S)-2-(2,5-dichlorothiophene-3-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C30H35Cl2N506S
Exact Mass: 663.17 Molecular Weight: 664.60 The synthesis of compound 1-46 was performed according to compound 1-30, using 2,5-dichlorothiophene-3-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 85 mg, 72% (last step) ESI-MS: 664.3 / 666.3 [M+H]
Preparation of compound 1-47 N
0 jCH 0 N
Br Br (S)-2-(2,5-dibromothiophene-3-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C30H35Br2N506S
Exact Mass: 751.07 Molecular Weight: 753.50 The synthesis of compound 1-47 was performed according to compound 1-30, using 2,5-dibromothiophene-3-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 64 mg, 68% (last step) ESI-MS: 752.2 / 754.2 / 756.2 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-48 0)-L
N I NN
o o CI
(S)-2-(2,5-dichlorothiazole-4-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C29H34.Cl2N606S
Exact Mass: 664.16 Molecular Weight: 665.59 The synthesis of compound 1-48 was performed according to compound 1-30, using 2,5-dichlorothiazole-4-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 26 mg, 48% (last step) ESI-MS: 665.3 / 667.3 [M+H]
Preparation of compound 1-49 ON
0 ( H 0 NN
H
(S)-2-(2,5-dimethylfuran-3-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C32H41N507 Exact Mass: 607.30 Molecular Weight: 607.70 The synthesis of compound 1-49 was performed according to compound 1-30, using 2,5-dimethylfuran-3-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 53 mg, 74% (last step) ESI-MS: 608.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-50 N
H
SANJcr NH )-L N
Br (S)-2-(4-bromothiazole-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C29H35BrN606S
Exact Mass: 674.15 Molecular Weight: 675.59 The synthesis of compound 1-50 was performed according to compound 1-30, using bromothiazole-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 37 mg, 59% (last step) ESI-MS: 675.3 / 677.3 [M+H]
Preparation of compound 1-51 0)-LN
H
0 )C H 0 H
N N N
\ I H 0 1 1 Br (S)-2-(4-bromothiophene-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C30H36BrN506S
Exact Mass: 673.16 Molecular Weight: 674.61 The synthesis of compound 1-51 was performed according to compound 1-30, using bromothiophene-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 52 mg, 66% (last step) ESI-MS: 674.3 /676.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-52 0 r H 0 NN
CI\I Ho II
Br (S)-2-(4-bromo-5-chlorothiophene-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C30H35BrCIN506S
Exact Mass: 707.12 Molecular Weight: 709.05 The synthesis of compound 1-52 was performed according to compound 1-30, using bromo-5-chlorothiophene-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 48 mg, 65% (last step) ESI-MS: 708.2 / 710.2 [M+H]
Preparation of compound 1-53 Br\i Ho II
Br (S)-2-(4,5-dibromothiophene-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C30H356r2N506S
Exact Mass: 751.07 Molecular Weight: 753.50 The synthesis of compound 1-53 was performed according to compound 1-30, using 4,5-dibromothiophene-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 52 mg, 63% (last step) ESI-MS: 752.2 / 754.2 / 756.2 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-54 0, N
N
\ I Ho I I
CI
(S)-2-(4,5-dichlorothiophene-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C301-135Cl2N506S
Exact Mass: 663.17 Molecular Weight: 664.60 The synthesis of compound 1-54 was performed according to compound 1-30, using 4,5-dichlorothiophene-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 63 mg, 68% (last step) ESI-MS: 664.2 / 666.2 [M+H]
Preparation of compound 1-55 n 7NJ-L JGH 0 Nj-L
- N
cõ) H 0 _ r\irN
(S)-2-((S)-1-acetylpyrrolidine-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C32H4.4.N607 Exact Mass: 624.33 Molecular Weight: 624.73 The synthesis of compound 1-55 was performed according to compound 1-30, using (S)-1-acetylpyrrolidine-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 76 mg, 73% (last step) ESI-MS: 625.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-56 oLN
H
I N
N
(S)-N1-ethyl-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-1,2,3-triazole-5-carboxamido)-2-oxohexanediamide Chemical Formula: C29F138N806 Exact Mass: 594.29 Molecular Weight: 594.66 The synthesis of compound 1-56 was performed according to compound 1-30, using methyl-1H-1,2,3-triazole-5-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 50 mg, 61% (last step) ESI-MS: 595.5 [M+H]
Preparation of compound 1-57 N
HN H-(S)-N1-ethyl-N6-(1-(2-(2-adamantylamino)-2-oxoethy1)-2-oxo-1,2-clihydropyridin-3-y1)-2-oxo-5-(2H-tetrazole-5-carboxamido)hexanediamide Chemical Formula: C271-135N906 Exact Mass: 581.27 Molecular Weight: 581.62 The synthesis of compound 1-57 was performed according to compound 1-30, using tetrazole-5-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 32 mg, 48% (last step) ESI-MS: 582.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-58 ON
, N N
OH
(S)-N1-ethyl-N6-(1-(2-(5-hydroxyadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxo-5-(pyrazine-2-carboxamido)hexanediamide Chemical Formula: C30H37N707 Exact Mass: 607.28 Molecular Weight: 607.66 The synthesis of compound 1-58 was performed according to compound 1-1 , using hydroxy-2-adamantanamine instead of 1-adamantanamine in step 2 (according to ZED3912) and pyrazine-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 26 mg, 53% (last step) ESI-MS: 608.5 [M+H]
.. Preparation of compound 1-59 0llN
LNi(rH
N-rN
I I
HN¨ 0 0 (S)-N1-ethyl-N6-(1-(2-(5-fluoroadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxo-5-((S)-pyrrolidine-3-carboxamido)hexanediamide Chemical Formula: C30H41FN606 Exact Mass: 600.31 Molecular Weight: 600.68 The synthesis of compound 1-59 was performed according to compound 1-1 , using fluoro-2-adamantanamine instead of 1-adamantanamine in step 2 (according to ZED3912) and (S)-1-Boc-pyrrolidine-3-carboxylic acid instead of 1-methy1-1H-imidazole-.. 5-carboxylic acid in step 6 (according to compound I-1b). The final product was obtained by deprotection (DCM/TFA) as described above and purified by HPLC.
Yield: 35 mg, 83% (last step) ESI-MS: 601.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-60 o 0)-L
NA
- N
_ NThrN
= H
0 0 1ci (S)-N1-ethyl-N6-(1-(2-(5-chloroadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxo-5-((S)-piperidine-2-carboxamido)hexanediamide Chemical Formula: C31F143CIN606 Exact Mass: 630.29 Molecular Weight: 631.16 The synthesis of compound 1-60 was performed according to compound 1-1, using chloro-2-adamantanamine instead of 1-adamantanamine in step 2 (according to .. ZED3912) and (S)-1-Boc-piperidine-2-carboxylic acid instead of 1-methy1-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b). The final product was obtained by deprotection (DCM/TFA) as described above and purified by HPLC.
Yield: 37 mg, 78% (last step) ESI-MS: 631.4 / 633.4 [M+H]
Preparation of compound 1-61 NJC-iN)-L
, N
Br (S)-N1-ethyl-N6-(1-(2-(5-bromoadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxo-5-((R)-piperidine-3-carboxamido)hexanediamide Chemical Formula: C31H43BrN606 Exact Mass: 674.24 Molecular Weight: 675.61 The synthesis of compound 1-61 was performed according to compound 1-1, using bromo-2-adamantanamine instead of 1-adamantanamine in step 2 (according to ZED3912) and (R)-1-Boc-piperidine-3-carboxylic acid instead of 1-methy1-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b). The final product was obtained by deprotection (DCM/TFA) as described above and purified by HPLC.
Yield: 35 mg, 72% (last step) ESI-MS: 675.3 / 677.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-62 0 Nj-1 r\ir0N
(S)-N1-ethyl-N6-(1-(2-(5-methyladamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-((R)-morpholine-3-carboxamido)-2-oxohexanediamide Chemical Formula: C31H44N607 Exact Mass: 612.33 Molecular Weight: 612.72 The synthesis of compound 1-62 was performed according to compound 1-1 , using methy1-2-adamantanamine instead of 1-adamantanamine in step 2 (according to ZED3912) and (R)-4-Boc-morpholine-3-carboxylic acid instead of 1-methy1-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b). The final product was obtained by deprotection (DCM/TFA) as described above and purified by HPLC.
Yield: 31 mg, 80% (last step) ESI-MS: 613.5 [M+H]
Preparation of compound 1-63 0llN
N- H CN
(S)-N1-ethyl-N6-(1-(2-(2-carbonitrileadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxo-5-((3S,4R)-quinuclidine-3-carboxamido)hexanediamide Chemical Formula: C34H45N706 Exact Mass: 647.34 Molecular Weight: 647.76 The synthesis of compound 1-63 was performed according to compound 1-1 , using aminoadamantane-2-carbonitrile instead of 1-adamantanamine in step 2 (according to ZED3912) and quinuclidine-3-carboxylic acid instead of 1-methy1-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 24 mg, 56% (last step) ESI-MS: 648.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-64 H CO2Me Njc N
CO2Me (S)-methyl 3-(6-(ethylamino)-1-(1-(2-(methyl 2-aminoadamantane-2-carboxylate)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-1,5,6-trioxohexan-2-ylcarbamoy1)-5-nitrobenzoate Chemical Formula: C36H4.2N6012 Exact Mass: 750.29 Molecular Weight: 750.75 The synthesis of compound 1-64 was performed according to compound 1-1 , using methyl 2-aminoadamantane-2-carboxylate instead of 1-adamantanamine in step 2 (according to ZED3912) and mono-methyl 5-nitroisophthalate instead of 1-methyl-imidazole-5-carboxylic acid in step 6 (according to compound I-1b).
Yield: 46 mg, 71% (last step) ESI-MS: 751.5 [M+H]
Preparation of compound 1-65 ON
NrN
(S)-N1-(1-(2-(1-adamantylmethylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-2-(5-nitronicotinamido)-5-oxohexanediamide Chemical Formula: C32H39N708 Exact Mass: 649.29 Molecular Weight: 649.69 The synthesis of compound 1-65 was performed according to compound 1-1 , using adamantanemethylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 5-nitronicotinic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b).
Yield: 61 mg, 74% (last step) ESI-MS: 650.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-66 0, N
H
HO2CNJc N
J IN N
5-((2S)-1-(1-(2-1-adamantylmethylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(ethylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinic acid Chemical Formula: C34F142N608 Exact Mass: 662.31 Molecular Weight: 662.73 The synthesis of compound 1-66 was performed according to compound 1-1, using rimantadine instead of 1-adamantanamine in step 2 (according to ZED3912) and 3,5-pyridinedicarboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b).
Yield: 31 mg, 56% (last step) ESI-MS: 663.5 [M+H]
Preparation of compound 1-67 S, N
(S)-N1-ethyl-N6-(1-(2-(2-adamantyl(methyl)amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(6-methylimidazo[2,1-1D]thiazole-5-carboxamido)-2-oxohexanediamide Chemical Formula: C33H41N706S
Exact Mass: 663.28 Molecular Weight: 663.79 The synthesis of compound 1-67 was performed according to compound 1-1, using N-methyl-2-adamantanamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b).
Yield: 23 mg, 52% (last step) ESI-MS: 664.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-68 o hiN NH jC
(S)-N1-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-y1)-N6-ethy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C32H37N507 Exact Mass: 603.27 Molecular Weight: 603.67 The synthesis of compound 1-68 was performed according to compound 1-1, using ( )-endo-2-norbornylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 3-methylbenzo[b]furan-2-carboxylic acid instead of 1-methyl-1H-im idazole-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 106 mg, 78% (last step) ESI-MS: 604.4 [M+H]
Preparation of compound 1-69 N)-L N
o Nr N H
(S)-N1-ethy1-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide Chemical Formula: C35H43N507 Exact Mass: 645.32 Molecular Weight: 645.75 The synthesis of compound 1-69 was performed according to compound 1-1, using (R)-(+)-bornylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 3-methylbenzo[b]furan-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b).
Yield: 86 mg, 72% (last step) ESI-MS: 646.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-70 0 , Njc N
(S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C32H37N507 Exact Mass: 603.27 Molecular Weight: 603.67 The synthesis of compound 1-70 was performed according to compound 1-1, using exo-2-aminonorbornane instead of 1-adamantanamine in step 2 (according to ZED3912) and 3-methylbenzo[b]furan-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 94 mg, 79% (last step) ESI-MS: 604.4 [M+H]
Preparation of compound 1-71 NH
N
(S)-N1-(1-(2-((ls,4R)-bicyclo[2.2.1]heptan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-2-(isonicotinamido)-5-oxohexanediamide Chemical Formula: C28F-134N606 Exact Mass: 550.25 Molecular Weight: 550.61 The synthesis of compound 1-71 was performed according to compound 1-1, using bicyclo[2.2.1]heptan-1-ylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and isonicotinic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b).
Yield: 77 mg, 72% (last step) ESI-MS: 551.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-72 0 jcI N N NH
(S)-N1-(1-(2-(bicyclo[2.2.1]heptan-7-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-5-oxo-2-(pyridazine-4-carboxamido)hexanediamide Chemical Formula: C271-133N706 Exact Mass: 551.25 Molecular Weight: 551.59 The synthesis of compound 1-72 was performed according to compound 1-1, using bicyclo[2.2.1]heptan-7-ylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and pyridazine-4-carboxylic acid instead of 1-methy1-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 44 mg, 61% (last step) ESI-MS: 552.4 [M+H]
Preparation of compound 1-73 NN H
N NH
NjC1-1 .. N
(S)-N1-(1-(2-((1R,2R,4R)-bicyclo[2.2.1]hept-5-en-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-5-oxo-2-(pyridazine-3-carboxamido)hexanediamide Chemical Formula: C27F131 N706 Exact Mass: 549.23 Molecular Weight: 549.58 The synthesis of compound 1-73 was performed according to compound 1-1, using bicyclo[2.2.1]hept-5-en-2-amine instead of 1-adamantanamine in step 2 (according to ZED3912) and pyridazine-3-carboxylic acid instead of 1-methy1-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b).
Yield: 31 mg, 52% (last step) ESI-MS: 550.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-74 N
HµN-N 0 0 (2S)-N1-(1 -(2-(bicyclo[2.2.2]octan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-5-oxo-2-(2H-1,2,3-triazole-4-carboxamido)hexanediamide Chemical Formula: C26H341\1806 Exact Mass: 554.26 Molecular Weight: 554.60 The synthesis of compound 1-74 was performed according to compound 1-1, using bicyclo[2.2.2]oct-2-ylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 2H-1,2,3-triazole-4-carboxylic acid instead of 1-methy1-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 35 mg, 57% (last step) ESI-MS: 555.4 [M+H]
Preparation of compound 1-75 0 0 õ
,s ¨NYLNjEr H
N
(S)-N1-ethyl-5-(1-methyl-1 H-1 ,2,3-triazole-4-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1 R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yOhexanediamide Chemical Formula: C29H40N806 Exact Mass: 596.31 Molecular Weight: 596.68 The synthesis of compound 1-75 was performed according to compound 1-1, using (R)-(-)-isobornylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 1-methyl-1H-1,2,3-triazole-4-carboxylic acid instead of 1-methyl-1H-im idazole-carboxylic acid in step 6 (according to compound I-1b).
Yield: 44 mg, 68% (last step) ESI-MS: 597.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-76 0)-LN
YLN NH )'LN
(S)-N1-ethyl-5-(1-methyl-1H-1,2,4-triazole-3-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-24(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)ethyl)-1 ,2-dihydropyridin-3-yhhexanediamide Chemical Formula: C29H40N306 Exact Mass: 596.31 Molecular Weight: 596.68 The synthesis of compound 1-76 was performed according to compound 1-1, using (1R,2R,3R,5S)-(-)-isopinocampheylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 1-methyl-1H-1,2,4-triazole-3-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b).
Yield: 51 mg, 72% (last step) ESI-MS: 597.5 [M+H]
Preparation of compound 1-77 , N
r\ir N
H
(S)-2-(benzofuran-3-carboxamido)-N6-ethyl-5-oxo-N1-(2-oxo-1-(2-oxo-2-((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide Chemical Formula: C34H41N507 Exact Mass: 631.30 Molecular Weight: 631.72 The synthesis of compound 1-77 was performed according to compound 1-1, using (1S,2S,3S,5R)-(+)-isopinocampheylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and benzofuran-3-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b).
Yield: 66 mg, 75% (last step) ESI-MS: 632.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-78 N
, N N
I H I
(S)-2-(benzo[b]thiophene-3-carboxamido)-N6-ethyl-N1-(1-(2-(4-homoisotwistane-3-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C35H41 N506S
Exact Mass: 659.28 Molecular Weight: 659.79 The synthesis of compound 1-78 was performed according to compound 1-1 , using amino-4-homoisotwistane instead of 1-adamantanamine in step 2 (according to ZED3912) and benzo[b]thiophene-3-carboxylic acid instead of 1-methy1-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 42 mg, 59% (last step) ESI-MS: 660.4 [M+H]
Preparation of compound 1-79 N NH
"
(S)-N1-ethyl-N6-(1-(2-(diamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methyl-1H-pyrazole-4-carboxamido)-2-oxohexanediamide Chemical Formula: C34.H4.3N706 Exact Mass: 645.33 Molecular Weight: 645.75 The synthesis of compound 1-79 was performed according to compound 1-1 , using aminodiamantane instead of 1-adamantanamine in step 2 (according to ZED3912) and 1-methyl-1H-pyrazole-4-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b).
Yield: 28 mg, 53% (last step) ESI-MS: 646.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-80 0 )-L
N
H
e_LO f H Oil H
-rHN N /
(S)-N1-ethyl-N6-(1-(2-(diamantane-4-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methyl-1H-pyrazole-3-carboxamido)-2-oxohexanediamide Chemical Formula: C34F143N706 Exact Mass: 645.33 Molecular Weight: 645.75 The synthesis of compound 1-80 was performed according to compound 1-1 , using aminodiamantane instead of 1-adamantanamine in step 2 (according to ZED3912) and 1-methyl-1H-pyrazole-3-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 36 mg, 59% (last step) ESI-MS: 646.5 [M+H]
Scheme 1-3 New Building Block OH 1-(Bromomethyl)- 0 adamantane 02N ..õ,j\I --L, 02N j-, N
DMF, DIPEA
10% Pd/C
Me0H
H2Nj-L
j\I
1 Preparation of compound ZED4893 02N j-U\I
1-(1-adamantylmethyl)-3-nitropyridin-2(1H)-one Chemical Formula: C16H20N203 Exact Mass: 288.15 Molecular Weight: 288.34 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 500 mg (3.57 mmol) of 2-hydroxy-3-nitropyridine and 818 mg (1 eq) of 1-(bromomethyl)adamantane were dissolved in 10 mL DMF and 1.24 mL DIPEA (2 eq) and stirred at room temperature overnight. The solvent was evaporated; the residue was dissolved in 30 mL Et0Ac and washed twice with each 10 mL citric acid solution (10%), NaHCO3 solution (10%) and brine. The organic phase was dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by HPLC.
Yield: 484 mg, 47%
ESI-MS: 289.3 [M+H]
2 Preparation of compound ZED4894 H2Nj-N
3-amino-1-(1-adamantylmethyl)pyridin-2(1 H)-one Chemical Formula: C16H22N20 Exact Mass: 258.17 Molecular Weight: 258.36 484 mg (1.68 mmol) of ZED4893 were suspended in 30 mL Me0H before 50 mg of palladium (10%) on activated carbon (unreduced) were added. The suspension was stirred for 3 h at room temperature under an atmosphere of hydrogen. The catalyst was filtered, and the solvent was evaporated.
Yield: 339 mg, 78%
ESI-MS: 259.4 [M+H]
Preparation of compound 1-81 0 ( H 0 (, N
H
N-NN
(S)-N1-(1-(1-adamantylmethyl)-2-oxo-1 ,2-di hydropyridin-3-y1)-N6-ethyl-2-(1 -methyl-1 H-pyrazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C29H38N605 Exact Mass: 550.29 Molecular Weight: 550.65 The synthesis of compound 1-81 was performed according to compound 1-1, using ZED4894 instead of ZED3913 in step 5 (according to I-1a) and 1-methyl-1H-pyrazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b).
Yield: 43 mg, 65% (last step) ESI-MS: 551.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-82 ,SN
)-L
N
No IA
OH
(S)-N1-(14(3-hydroxy-1-adamantyl)methyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(4-cyclopropyl-1,2,3-thiadiazole-5-carboxamido)-N6-ethyl-5-oxohexanediamide Chemical Formula: C30H38N606S
Exact Mass: 610.26 Molecular Weight: 610.72 The synthesis of compound 1-82 was performed according to compound 1-81, using (bromomethyl)-1-adamantanol instead of 1-(bromomethyl)adamantane (according to ZED4893) and 4-cyclopropyl-[I,2,3]thiadiazole-5-carboxylic acid instead of 1-methyl-1H-pyrazole-5-carboxylic acid.
Yield: 26 mg, 46% (last step) ESI-MS: 611.4 [M+H]
Preparation of compound 1-83 N
H
N
N I Hr I ¨I
Br (S)-N1-(1-((3-bromo-1-adamantyl)methyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-5-oxo-2-(1,2,5-thiadiazole-3-carboxamido)hexanediamide Chemical Formula: C27H33BrN605S
Exact Mass: 632.14 Molecular Weight: 633.56 The synthesis of compound 1-83 was performed according to compound 1-81, using bromo-3-(bromomethyl)adamantane instead of 1-(bromomethyl)adamantane (according to ZED4893) and 1,2,5-thiadiazole-3-carboxylic acid instead of 1-methyl-1H-pyrazole-5-carboxylic acid.
Yield: 42 mg, 61% (last step) ESI-MS: 633.3 / 635.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-84 o N)-L
N
N, H
1\1 HO
(S)-N1-(1-(2-adamantylmethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-2-(4-(hydroxymethyl)-1,2,3-thiadiazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C28F-136N606S
Exact Mass: 584.24 Molecular Weight: 584.69 The synthesis of compound 1-84 was performed according to compound 1-81, using (bromomethyl)adamantane instead of 1-(bromomethyl)adamantane (according to ZED4893) and 4-((tetrahydro-2H-pyran-2-yloxy)methyl)-1,2,3-thiadiazole-5-carboxylic acid instead of 1-methyl-1H-pyrazole-5-carboxylic acid. The tetrahydropyranyl (Thp) protecting group was cleaved by TFA in the final step.
Yield: 15 mg, 68% (last step) ESI-MS: 585.4 [M+H]
Preparation of compound 1-85 0 ( H 0 N N
HN
(S)-2-(4-tert-buty1-1H-pyrrole-3-carboxamido)-N1-(1-(2-(1-adamantylamino)ethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-5-oxohexanediamide Chemical Formula: C34.H4.7N505 Exact Mass: 605.36 Molecular Weight: 605.77 The synthesis of compound 1-85 was performed according to compound 1-81, using 1-(2-bromoethyl)adamantane instead of 1-(bromomethyl)adamantane (according to ZED4893) and 5-tert-butyl-1H-pyrrole-3-carboxylic acid instead of 1-methyl-1H-pyrazole-5-carboxylic acid.
Yield: 32 mg, 58% (last step) ESI-MS: 606.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-86 N
NCNNjc NH
N \ 0 (S)-2-(4-cyano-1 -methyl-1 H-pyrrole-2-carboxamido)-N1-(1-(1-adamantylamino)propy1)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-5-oxohexanediamide Chemical Formula: 033H42N605 Exact Mass: 602.32 Molecular Weight: 602.72 The synthesis of compound 1-86 was performed according to compound 1-81, using 1-(3-bromopropyl)adamantane instead of 1-(bromomethyl)adamantane (according to ZED4893) and 4-cyano-1-methyl-1H-pyrrole-2-carboxylic acid instead of 1-methyl-pyrazole-5-carboxylic acid.
Yield: 28 mg, 51% (last step) ESI-MS: 603.5 [M+H]
Preparation of compound 1-87 0)-LN
0?LNJciNj-LN
(S)-N1-(1-(3-(2-adamantylamino)-3-oxopropy1)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-2-(5-methoxyoxazole-2-carboxamido)-5-oxohexanediamide Chemical Formula: C31H4oN608 Exact Mass: 624.29 Molecular Weight: 624.68 The synthesis of compound 1-87 was performed according to compound 1-1, using chloropropionic acid instead of chloroacetic acid (according to ZED1657) and 5-methoxyoxazole-2-carboxylic acid instead of 1-methyl-1H-pyrazole-5-carboxylic acid in step 6 (according to compound I-1b).
Yield: 39 mg, 64% (last step) ESI-MS: 625.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-88 N
(S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C30H33N507 Exact Mass: 575.24 Molecular Weight: 575.61 The synthesis of compound 1-88 was performed according to compound 1-1 , using bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 3-methylbenzo[b]furan-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b).
Yield: 107 mg, 81% (last step) ESI-MS: 576.4 [M+H]
Preparation of compound 1-89 0-(N
Nj-L NH
N
(S)-2-(2-acetyloxazole-4-carboxamido)-N1-(1-(2-(bicyclo[1A A ]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-5-oxohexanediamide Chemical Formula: C26H30N608 Exact Mass: 554.21 Molecular Weight: 554.55 The synthesis of compound 1-89 was performed according to compound 1-1 , using bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 2-acetyloxazole-4-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b).
Yield: 68 mg, 75% (last step) ESI-MS: 555.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-90 0)LN
U\IN
(S)-N1-(1-(2-(bicyclo[2.1A]hexan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-2-(2-isopropyloxazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C28H36N607 Exact Mass: 568.26 Molecular Weight: 568.62 The synthesis of compound 1-90 was performed according to compound 1-1, using bicyclo[2.1.1]hexan-1-amine instead of 1-adamantanamine in step 2 (according to ZED3912) and 2-isopropyloxazole-5-carboxylic acid instead of 1-methy1-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 46 mg, 60% (last step) ESI-MS: 569.4 [M+H]
Preparation of compound 1-91 0)-LN
NN
I I
\ 0 0 (2S)-N1-(1-(2-(bicyclo[3.2.1]octan-8-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(3,5-dimethylisoxazole-4-carboxamido)-N6-ethyl-5-oxohexanediamide Chemical Formula: C29H38N607 Exact Mass: 582.28 Molecular Weight: 582.65 The synthesis of compound 1-91 was performed according to compound 1-1, using bicyclo[3.2.1]octan-8-amine instead of 1-adamantanamine in step 2 (according to ZED3912) and 3,5-dimethylisoxazole-4-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b).
Yield: 32 mg, 54% (last step) ESI-MS: 583.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-92 0)-L N
NNCN N N
(S)-N1-ethyl-N6-(1-(2-(5-carboxy-2-aminoadamantane)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(4-methylpyrimidine-5-carboxamido)-2-oxohexanediamide Chemical Formula: C32H39N708 Exact Mass: 649.29 Molecular Weight: 649.69 The synthesis of compound 1-92 was performed according to compound 1-1 , using aminoadamantane-1-carboxylic acid instead of 1-adamantanamine in step 2 (according to ZED3912) and 4-methylpyrimidine-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b).
Yield: 35 mg, 46% (last step) ESI-MS: 650.5 [M+H]
Preparation of compound 1-93 N N N N
N
(5S)-N1-ethyl-N6-(1-(2-(4-aminoadamantane-N,N-dimethy1-1-carboxamide)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxo-5-(1,2,3,4-tetrahydronaphthalene-2-carboxamido)hexanediamide Chemical Formula: C37H45N507 Exact Mass: 67133 Molecular Weight: 671.78 The synthesis of compound 1-93 was performed according to compound 1-1 , using aminoadamantane-N,N-dimethy1-1-carboxamide instead of 1-adamantanamine in step (according to ZED3912) and 1,2,3,4-tetrahydronaphthalene-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b).
Yield: 31 mg, 55% (last step) ESI-MS: 672.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-94 oLN
N
N
(S)-2-((S)-1,4-diazabicyclo[2.2.2]octane-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C32F145N706 Exact Mass: 623.34 Molecular Weight: 623.74 The synthesis of compound 1-94 was performed according to compound 1-30, using 1,4-diazabicyclo[2.2.2]octane-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 39 mg, 58% (last step) ESI-MS: 624.5 [M+H]
Preparation of compound 1-95 N
N
(S)-N1-ethy1-5-(1H-indole-3-carboxamido)-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-clihydropyridin-3-y1)-2-oxohexanediamide Chemical Formula: C34H40N606 Exact Mass: 628.30 Molecular Weight: 628.72 The synthesis of compound 1-95 was performed according to compound 1-30, using indole-3-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 56 mg, 74% (last step) ESI-MS: 629.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-96 OAN
N Hjc (S)-N1-ethyl-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(6-methylimidazo[2,1-b]thiazole-3-carboxamido)-2-oxohexanediamide Chemical Formula: C32H39N706S
Exact Mass: 649.27 Molecular Weight: 649.76 The synthesis of compound 1-96 was performed according to compound 1-30, using methylimidazo[2,1-b][1,3]thiazole-3-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 33 mg, 56% (last step) ESI-MS: 650.5 [M+H]
Preparation of compound 1-97 o jcH 0 Nj-L NH
Ni (S)-2-(benzo[d]thiazole-2-carboxamido)-N1-(1-(2-(( IS,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-5-oxohexanediamide Chemical Formula: C30H34N606S
Exact Mass: 606.23 Molecular Weight: 606.69 The synthesis of compound 1-97 was performed according to compound 1-1, using ( )-endo-2-norbornylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 1,3-benzothiazole-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 45 mg, 73% (last step) ESI-MS: 607.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-98 NNjcN)-L NH
N
(S)-N1-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-2-(imidazo[2,1-b]thiazole-6-carboxamido)-5-oxohexanediamide Chemical Formula: C28H33N706S
Exact Mass: 595.22 Molecular Weight: 595.67 The synthesis of compound 1-98 was performed according to compound 1-1, using ( )-endo-2-norbornylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and imidazo[2,1-b][1,3]thiazole-6-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 26 mg, 50% (last step) ESI-MS: 596.4 [M+H]
Preparation of compound 1-99 ON
(õ0 N N)-L
NH
I H
(S)-N1-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-2-(4-hydroxy-6-(trifluoromethoxy)quinoline-3-carboxamido)-5-oxohexanediamide Chemical Formula: C33F135F3N608 Exact Mass: 700.25 Molecular Weight: 700.66 The synthesis of compound 1-99 was performed according to compound 1-1, using ( )-endo-2-norbornylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 4-hydroxy-6-(trifluoromethoxy)quinoline-3-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 15 mg, 42% (last step) ESI-MS: 701.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-100 o)LN
NH II
N NH
I ,N H- Y
(S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(cinnoline-3-carboxamido)-N6-ethyl-5-oxohexanediamide Chemical Formula: C29F131N706 Exact Mass: 573.23 Molecular Weight: 573.60 The synthesis of compound 1-100 was performed according to compound 1-1, using bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 3-cinnolinecarboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 37 mg, 65% (last step) ESI-MS: 574.4 [M+H]
Preparation of compound 1-101 N
(S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-2-(3-ethylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C31H35N507 Exact Mass: 589.25 Molecular Weight: 589.64 The synthesis of compound 1-101 was performed according to compound 1-1, using bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 3-ethylbenzofuran-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 55 mg, 73% (last step) ESI-MS: 590.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-102 N INHCr H NNH N
(S)-N1-(1-(2-(bicyclo[1.1.1]pentan-l-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-2-(1-ethyl-1H-indole-2-carboxamido)-5-oxohexanediamide Chemical Formula: C31H36N606 Exact Mass: 588.27 Molecular Weight: 588.65 The synthesis of compound 1-102 was performed according to compound 1-1, using bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 1-ethyl-1H-indole-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 43 mg, 68% (last step) ESI-MS: 589.4 [M+H]
Preparation of compound 1-103 N
NH
(S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-2-(2-methyl-1,8-naphthyridine-3-carboxamido)-5-oxohexanediamide Chemical Formula: C301-133N706 Exact Mass: 587.25 Molecular Weight: 587.63 The synthesis of compound 1-103 was performed according to compound 1-1, using bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 2-methyl-1,8-naphthyridine-3-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 40 mg, 64% (last step) ESI-MS: 588.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-104 )LN
U\IN
(S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-5-oxo-2-(1,2,3,4-tetrahydroquinoline-6-carboxamido)hexanediamide Chemical Formula: C31 H38 N1606 Exact Mass: 590.29 Molecular Weight: 590.67 The synthesis of compound 1-104 was performed according to compound 1-1, using bicyclo[2.1.1]hexan-1-amine instead of 1-adamantanamine in step 2 (according to ZED3912) and N-Boc-1,2,3,4-tetrahydroquinoline-6-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b). The final product was obtained by deprotection (DCM/TFA) as described above and purified by HPLC.
Yield: 27 mg, 73% (last step) ESI-MS: 591.4 [M+H]
Preparation of compound 1-105 ON N N
(S)-N1-ethyl-N6-(1-(2-(2-carboxy-2-amino-5-(trifluoromethyl)adamantane)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxo-5-(3-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)hexanediamide Chemical Formula: C37F141F3N609 Exact Mass: 770.29 Molecular Weight: 770.75 The synthesis of compound 1-105 was performed according to compound 1-1, using amino-5-(trifluoromethyl)adamantane-2-carboxylic acid instead of 1-adamantanamine in step 2 (according to ZED3912) and 3-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 19 mg, 44% (last step) ESI-MS: 771.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-106 otLN
N N
I I
(S)-N1-ethyl-N6-(1-(2-(5-ethyladamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1,6-naphthyridine-2-carboxamido)-2-oxohexanediamide Chemical Formula: C36F143N706 Exact Mass: 669.33 Molecular Weight: 669.77 The synthesis of compound 1-106 was performed according to compound 1-1, using ethyladamantane-2-amine instead of 1-adamantanamine in step 2 (according to ZED3912) and 1,6-naphthyridine-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 25 mg, 54% (last step) ESI-MS: 670.5 [M+H]
Preparation of compound 1-107 oN
N N
(S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-2-(2,6-naphthyridine-1-carboxamido)-5-oxohexanediamide Chemical Formula: C30H33N706 Exact Mass: 587.25 Molecular Weight: 587.63 The synthesis of compound 1-107 was performed according to compound 1-1, using bicyclo[2.1.1]hexan-1-amine instead of 1-adamantanamine in step 2 (according to ZED3912) and 2,6-naphthyridine-1-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 58 mg, 74% (last step) ESI-MS: 588.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-108 0-(N
H2N 0 0 -.4\
N I H
b-N 0 0 (S)-2-(4-amino-1,2,5-oxadiazole-3-carboxamido)-N1-(1-(2-(bicyclo[1A A ]pentan-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-5-oxohexanediamide Chemical Formula: C23H28N807 Exact Mass: 528.21 Molecular Weight: 528.52 The synthesis of compound 1-108 was performed according to compound 1-1, using bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 4-Boc-amino-1,2,5-oxadiazole-3-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b). The final product was obtained by deprotection (DCM/TFA) as described above and purified by HPLC.
Yield: 27 mg, 77% (last step) ESI-MS: 529.4 [M+H]
Preparation of compound 1-109 )-LN
Pi 0 0 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(6-(dimethylamino)benzofuran-2-carboxamido)-N6-ethyl-5-oxohexanediamide Chemical Formula: C3iH36N607 Exact Mass: 604.26 Molecular Weight: 604.65 The synthesis of compound 1-109 was performed according to compound 1-1, using bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 6-(dimethylamino)benzofuran-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 35 mg, 57% (last step) ESI-MS: 605.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-110 0)LN
0 jc H 0 e3A\IN JN NH
HN
(S)-2-(2-acetamidothiazole-5-carboxamido)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-5-oxohexanediamide Chemical Formula: C26H31 N1707S
Exact Mass: 585.20 Molecular Weight: 585.63 The synthesis of compound 1-110 was performed according to compound 1-1, using bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 2-acetylamino-5-thiazolecarboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 25 mg, 49% (last step) ESI-MS: 586.4 [M+H]
Preparation of compound 1-111 ON
H
0 Nj-L NH
jC
(S)-N4-(1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(ethylamino)-1,5,6-trioxohexan-2-y1)-1H-pyrrole-2,4-dicarboxamide Chemical Formula: C26H31N707 Exact Mass: 553.23 Molecular Weight: 553.57 The synthesis of compound 1-111 was performed according to compound 1-1, using bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 5-carbamoy1-1H-pyrrole-3-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 19 mg, 42% (last step) ESI-MS: 554.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-112 oLN
0,11 Nj-L
(S)-N1-ethyl-N6-(1-(2-(1-acetylamino-4-aminoadamantane)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxo-5-(5-sulfamoylfuran-3-carboxamido)hexanediamide Chemical Formula: C32H41 N7010S
Exact Mass: 715.26 Molecular Weight: 715.77 The synthesis of compound 1-112 was performed according to compound 1-1, using acetylamino-4-aminoadamantane instead of 1-adamantanamine in step 2 (according to ZED3912) and 5-sulfamoylfuran-3-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 24 mg, 53% (last step) ESI-MS: 716.4 [M+H]
Preparation of compound 1-113 Njc NH 0 (S)-2-(benzofuran-5-carboxamido)-N6-ethyl-N1-(1-(2-(1-acetylamino-4-aminoadamantane)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C36F142N608 Exact Mass: 686.31 Molecular Weight: 686.75 The synthesis of compound 1-113 was performed according to compound 1-1, using acetylamino-4-aminoadamantane instead of 1-adamantanamine in step 2 (according to ZED3912) and benzofuran-5-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 30 mg, 58% (last step) ESI-MS: 687.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-114 0 Njc NH )-LNN
(S)-2-(benzofuran-6-carboxamido)-N6-ethyl-N1-(1-(2-(4-aminoadamantane-1-carboxamide)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C35H4.0N608 Exact Mass: 672.29 Molecular Weight: 672.73 The synthesis of compound 1-114 was performed according to compound 1-1, using aminoadamantane-1-carboxamide instead of 1-adamantanamine in step 2 (according to ZED3912) and benzofuran-6-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 37 mg, 65% (last step) ESI-MS: 673.5 [M+H]
Preparation of compound 1-115 0)-(N
N
(S)-N1-ethyl-N6-(1-(2-(4-aminoadamantane-1-carboxamide)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(3-(1-methylcyclopropy1)-1,2,4-oxadiazole-5-carboxamido)-2-oxohexanediamide Chemical Formula: C33H4.2N808 Exact Mass: 678.31 Molecular Weight: 678.74 The synthesis of compound 1-115 was performed according to compound 1-1, using aminoadamantane-1-carboxamide instead of 1-adamantanamine in step 2 (according to ZED3912) and 3-(1-methylcyclopropyI)-1,2,4-oxadiazole-5-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 23 mg, 47% (last step) ESI-MS: 679.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-116 N
yLrilJc N NH
(S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-2-(5-methyl-1,2,4-oxadiazole-3-carboxamido)-5-oxohexanediamide Chemical Formula: C24H29N707 Exact Mass: 527.21 Molecular Weight: 527.53 The synthesis of compound 1-116 was performed according to compound 1-1, using bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 5-methyl-1,2,4-oxadiazole-3-carboxylic acid instead of benzofuran-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 36 mg, 62% (last step) ESI-MS: 528.4 [M+H]
Preparation of compound 1-117 /)?LN
N NH
(S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-5-oxo-2-(1,2,3-thiadiazole-4-carboxamido)hexanediamide Chemical Formula: C23H27N706S
Exact Mass: 529.17 Molecular Weight: 529.57 The synthesis of compound 1-117 was performed according to compound 1-1, using bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 1,2,3-thiadiazole-4-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 31 mg, 57% (last step) ESI-MS: 530.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-118 o S- N Jcri\lj- NH
ri y (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-5-oxo-2-(1,2,4-thiadiazole-5-carboxamido)hexanediamide Chemical Formula: 023H27N706S
Exact Mass: 529.17 Molecular Weight: 529.57 The synthesis of compound 1-118 was performed according to compound 1-1, using bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 1,2,4-thiadiazole-4-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 39 mg, 63% (last step) ESI-MS: 530.3 [M+H]
Preparation of compound 1-119 0)-LN
N.r NH N NH
(S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-5-oxo-2-(1,3,4-thiadiazole-2-carboxamido)hexanediamide Chemical Formula: C23H27N706S
Exact Mass: 529.17 Molecular Weight: 529.57 The synthesis of compound 1-119 was performed according to compound 1-1, using bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 1,3,4-thiadiazole-5-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 28 mg, 52% (last step) ESI-MS: 530.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-120 o m's Nc7 N
H I I
(S)-N1-ethy1-5-(4-formy1-1,2,3-thiadiazole-5-carboxamido)-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxohexanediamide Chemical Formula: C29H35N707S
Exact Mass: 625.23 Molecular Weight: 625/0 The synthesis of compound 1-120 was performed according to compound 1-30, using 4-(hydroxymethyl)-1,2,3-thiadiazole-5-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 17 mg, 41% (last step) ESI-MS: 626.4 [M+H]
Preparation of compound 1-121 0)-(N
NH
N(-1H N
(S)-N1-ethyl-N6-(1-(2-(3,5-dimethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(nicotinamido)-2-oxohexanediamide Chemical Formula: C31F138N606 Exact Mass: 590.29 Molecular Weight: 590.67 The synthesis of compound 1-120 was performed according to compound 1-1, using nicotinic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 56 mg, 60% (last step) ESI-MS: 591.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of reference compound Ref. 4 OA
N
N
)LN N
(S)-N1 -ethy1-5-(nicotinamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-(phenethylamino)ethyl)-1 ,2-dihydropyridin-3-yl)hexanediamide Chemical Formula: C29H32N606 Exact Mass: 560.24 Molecular Weight: 560.60 The synthesis of reference compound Ref. 4 was performed according to compound 1-1, using 2-phenylethylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and nicotinic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound l-lb).
Yield: 68 mg, 77% (last step) ESI-MS: 561.4 [M+H]
Biological Examples Example B-1. Inhibitory effect of the compounds according to the invention Transglutaminase assay For the determination of potency of inhibitors against tissue transglutaminase, the incorporation of dansylcadaverine into dimethylcasein (Zedira product T036, Lorand et a/., Anal Biochem, 1971, 44:221-31) was measured using recombinant human transglutaminase 2 (Zedira Product T022).
The tissue transglutaminase is diluted in buffer (50 mM Tris-HCI, 7.5 mM
CaCl2, 150 mM
NaCI, pH = 7.4). The final concentration of TG2 in the assay is 10 nM.
A 10 mM inhibitor stock solution is prepared in DMSO, and from this a serial 1:2-fold dilution series is prepared also in DMSO. Each of the initial dilutions is subsequently diluted 1:50-fold with buffer (50 mM Tris-HCI, 7.5 mM CaCl2, 150 mM NaCI, pH =
7.4) to yield the final working dilutions containing 2% (v/v) DMSO.
15 pl of inhibitor working dilution are added per well of a 96 well microtiter plate. As control, 15 pl of a 2% (v/v) DMSO solution prepared using the buffer mentioned above are added per well.
Immediately before starting the assay, 600 pl transglutaminase working solution are added to 11.4 ml assay buffer (50 mM Tris-HCI, 10 mM CaCl2, 10 mM glutathione, 2.5%
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 glycerol, 16.7 pM dansylcadaverine, 4 pM N,N-dimethylcasein, 200 mM NaCI, pH =
Rii Rio Rii R9 y--.1 , , Rlo R11 , -,,N)Ni -, ,I\IN ,N )N
R9 -N R" Rlo R12 Rlo y......õ1õ--N y,.....õ1õ--y N R12 , , , - N,,, Ril N R11 -. N R12 ---- , I I f R97 r-rN N--N Rlo N ------. -------õ,,- N
N
Rio , Rio Rii -,NN ..,_ R12 -,,N R13 -_,-- õ,.. -,..õ. II II
R1Or NN, NrN R ------7"--ii NNR11 R , R10 R11 12 -, NN _ N
N-----. --------1,' R12 Ri2 N R1 Rii Ny<-.R9 rk , , , N. R10 ,,,,, NõR11 -. -, N -I I
N
R12 N: N
R9-NrN
, , , 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 R11 Nri\I R11 -, -,,N
_ I--,---'-c---, -=.---.-- I
NN I 12 N ----..T.7"-N%----R12 R9 R12 ; R9 N R11 `. , 'N '-'. N
I
,N 1 .
N-NR12 Ri2 N- R12---N----"-yN
R13 R13 R9 , , , I . I
NN N R'` NNR12 ..-_,.:L , W N
R9 R12, ; R9 , , N R12 R12 -' r-I - I
R13N NN-,N R-1\1-"N
R13 ; R9 , , R., p12 `.,N
¨ , ¨ . 'N
N,NrN I 1 N, N N R1¨, Rio N N R'`
' R14 ,, N R9 -, N_RN
RN¨N Rii R11 N¨RN Rio Rlo R13 1,, R13 R ¨ Ri.i . R12 R11 R9 Rio ; Rio R9 , __ R12 _ - R14 . R10 . R10 /N
N_( ---(:) N=N
9 =( N¨i -- \ /N--N R14 -- \ /R - - N
\ /N _ 1 / I 0µ
( R11 R14 \ N R11 Ri4 R11 "
R11 R13 \ //I
N _________ z( R12 R13 ; \
D12; R12 R12 R13 ; R12 R13 '' 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 \ ________ 1\/1R9r, N NR9 R9 R9 R9 N_ N¨ tR10 N_ N_ ¨N
/ R --___ ___________________ -- ________ z(R13 __ Dii R13 __ \ / Rii N/ R11 / R11 Rii \ N
R.,i, , , , Rlo R9 Rio Rlo R9 Rlo R9 ¨N
--( Dio __ R9 -___1\--/(N
--_ (R9 --$¨ ., -- \ /N
( Rii \ / ____________ Ri3 R11 __________ \ / R13 N / _____ R13 Rii R11 ifl R=-N N , \ /N
( 1, N
R12 R12 RU R12 IR¨ D., R12 ' , F` , , Rlo R9 Rlo R9 R11 R12 R11 R12 --( --( ---- R13 R13 -- /N --- /N
N N
z R11 \ / R13 N / __ R13 Rio \ /NI R9 \ N z( N NI N __ ( R9 Rlo ; ; , ;
N¨( N¨( -- R13 -) __ /N
( --- /N
R9 \ / Rlo Ns /2¨R1 N \ / Rlo N N N R11 N sN ____________ z( N¨N
' R9 R9 R12 R11 N
, , N=N N=N N=N N=N N=N
-- \ ;NI _____ /tRio it /(Rio _ x_ (Rio fR0 Rii R14 R13 \ /NI R13 \ / R11 R13 \ /
¨11 rc N / ___________________________________________________________ R11 10 ( ii N N
R12 R13 IR¨ R.. R12 R12 ; R13 R12 , , , , ___ Rlo Rlo Rlo Rlo N_( N_( N_( N¨( N¨T
-- /N -1 /N ) /N --- /N R10 ( R13 \ /N Ri \ S_Rii R13 \ / Rii N / ____ R11 o012 IA \ / N
NI
, ( ii N N
" ; ; ; ;
N_ N_ _ _ _$N¨/R9 R9 R1 o _ _ ii¨/ R1 _Rio ___$ _Rlo ¨
\ N N N R N / ____ R11 Ns / __ R11 N ______ z R
( z( 12 \ / ii N N
R12 R11 N¨N , R12 R12 , 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 ¨N
-- \ /1\1 .__ ( ¨N
-- \
\ /N ¨N
-- \ /N ¨N
R13 \i, /(Nii R13 \ NRii R13 \N / Ril N \ / __ R11 R. r,.. R12 Riz , rc , ' , , ¨N
__i Rlo ¨N
i¨N
--_$ _____________________________________ (R11 R10 R10 __ \ / R10 N
R12 \ N N Z R12 N N / __ R11 Ns / __ R11 N sN
; R12 R11 N¨N , Riz Riz R9 Rlo R9 R10 R9 R10 R9 R10 --( --( --( R9 R10 --( N --_ N --- z(N ¨( -- \ z( \ zZ( -- i /N
\ ,N R12 \ N
N N Riz \ _Rii __ Nµ\
S IA
R11 R11 R12 R11 ; R12 ; ; ' ;
¨( R11 R12 N / I R11 Rio \ N
N¨I4 R12 , Rio Rlo , , , Also preferred are the compounds of the general formual (I) R.1 H
(I) wherein L represents ¨L1¨L2¨;
LI represents ¨CH2C0¨;
L2 represents ¨NRI41¨; and R3 represents 1-adamantyl ; or L2 represents ¨NRN1CH2¨; and R3 represents 2-bicyclo[3.1.1]heptyl, and the afore-mentioned 1-adamantyl and 2-bicyclo[3.1.1]heptyl residues are optionally contain one or more C=C double bond and/or are optionally substituted one or more of Ra; Rb; Rc; Rd; and Re;
RI represents ''-N- R6 H
, 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 RN RN RN
Ril Il pli IV 8 - - N8 R2 represents 1 ----- '' ---R or ---"R
N ) N
R1 , __ N R10 -, ' , , R6 represents -C2H5;
Ra, Rb, Rc, Rd, and Re represents independently of each other -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C2H5, -CON H2, -CON HCH3, -CON(CH3)2, -CONN C2H5, -CH2CO2H , -CH2CO2CH3, -CH2CO2C2H5, -CH2CON H2, -CH2CON HCH3, -CH2CON (CH 3)2, -CH2CON HC2H5, -NHCOCH3, -NHCOC2H5, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C2H5, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3;
R6, R10, and R11 represent independently of each other -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH (CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2F, -CH F2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -OCH3, -0C2H5, -0C3H7, -OCH(CH3)2, -0C(CH3)3, -0C4H9, -OCHF2, -0CF3, -OCH2CF3, -0C2F5, -OCH2OCH3, -0-cyclo-C3H5, -OCH2-cyclo-C3H5, -0-C2H4-cyclo-C3H5, -CH 0, -COCH 3, -COCF3, -00C2H5, -00C3H7, -COCH (CH3)2, -00C(CH3)3, -COOH, -COOCH3, -CO0C2H5, -CO0C3H7, -COOCH(CH3)2, -COOC(CH3)3, -00C-CH3, -00C-CF3, -00C-C2H5, -00C-C3H7, -00C-CH (CH3)2, -00C-C(CH3)3, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -N HC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5, -NHCOC3H7, -NHCOCH(CH3)2, -NHCOC(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CON HCH (CH3)2, -CON H-cyclo-C3H5, -CON HC(CH3)3, -CON(CH3)2, -CON (C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -SO2NHCH(CH3)2, -SO2NH-cyclo-C3H5, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H5)2, -SO2N(C3H7)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C2H5, -NHSO2C3H7, -NHSO2CH (CH3)2, -NHSO2C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -CECH, -CEC-CH3, -CH2-CECH, -Ph, -0-Ph, -0-CH2-Ph, 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 / H
rN I
N H
N H
r rN
--NO N
--N/N
I H I
rN rN
/ _______________________________________ \ / \ / \
o o 0 N\ /NH _________________ N\ /N-;
or N\ 71 \;
RN represents -H, -CH3, -C2E-13, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H3, -cyclo-C4H7, -cyclo-C3I-19, -CH2-cyclo-C3H3, -CH2-cyclo-C4H7, -CH2-cyclo-C3H9, -CH2F, -CH F2; -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3, -00C21-13, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -CO-cyclo-C3H3, -CO-cyclo-C4H7, -CO-cyclo-C31-19, -COOCH3, -COOC2H3, -CO0C3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -S02CH3, -S02CF3, -S02C21-13, -S02C3H7, -S02CH(CH3)2, -S02-cyclo-C3H3, or -S02C(CH3)3;
RI" represent -H, -CH3, or -CH2CH3;
or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomer, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
In a preferred set of compounds RN RN RN
cr.- - 8 R2 represents Ri,) R8 or N
, , , and R8, R10, R11, and RN have the meanings as defined herein.
The residues bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl, diamantyl, and hexamethylenetetraminyl used herein, have the following parent structures respectively:
bicyclo[1.1.1]pentyl bicyclo[2.1.1]hexyl bicyclo[2.2.1]heptyl -2--L ...-- --bicyclo[3.1.1]heptyl bicyclo[2.2.2]octyl bicyclo[3.2.1]octyl 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 - -bicyclo[3.2.2]nonyl bicyclo[3.3.2]decyl bicyclo[3.3.3]undecyl 4-homoisotwistyl adamantyl diamantyl hexamethylenetetraminyl N,' N N
and the afore-mentioned residues optionally contain one or more C=C double bond and/or are substituted optionally one or more of Ra, Rb, Rc, Rd, and R.
Preferred are the compounds of the formula (la):
ON,R6 R2 N ,N L 'R-(1a), and L, R2, R3, R6 have the same meanings as defined in the formula (I) Preferably, the present invention relates to the comopund of the formula (I) (I) wherein L represents ¨L1¨L2¨ ;
L1 represents ¨CH2¨, ¨CH2CH2¨, ¨CH2CH2CH2¨, or ¨CH2C0¨, L2 represents ¨NR141¨, or ¨NRNICH2;;
and preferably L represents ¨CH2¨, ¨CH2CH2¨, ¨CH2CH2CH2¨, ¨CH2CONH¨, ¨CH2CONH¨CH2¨, ¨CH2CON(CH3)¨CH2¨, or ¨CH2CONH¨CH(CH3)¨, 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 o R1 represents -'')N-R6 H
, R2 represents RN RN RN
R11 1\1 i II
R11 N R8 --.R8 --( \_R8 0 ., N
N
,-, N9 /
" , " , RN RN RN RN RN
Rii \ s R8 _ _ __õ, iir R8 R1:__LNõr R8 R1=1, Rii ri, __ N, -\\
1 iN
K /N
( , R9 R10 R9 // 09 R10 sµ09 p .in .., 0.9 " 5 5 " 5 " N
1 .
CD -R11 0 R8 - _ ....,-ON _R8 Rtl),õSõ, _õS,õ _R8 -___,,N,N
., ? , -\
N¨ N , ' , __ N N N
R8 0, 1 0 R1 R1 0 R1 0 , , , RN RN RN
,N , R12 Ri 2 Rii ii 1 - ,1/4, N N N RN oi _N, ' goN pe13 /ri ic -------------------------------------------------------- . ., N / Rio NEN , D14 , " N
' , " , Ri2 , R13 ----------------------- R13 -- r ) R13 - - -\-ji RA 13 Rio_----er/R13 \N \-N Dia N= R14 N R14 Rio R.-, ()-11.4 "
RN
R' R12 Ri R12 S--_/y,) _ \ R12 N--__//
Rio4-----r/ ---TIRli Rio4-----r/ Ri3 ---$___ -0--13 Rio R14 S14 , Rlo , RN p12 R12 p12 N ,' - - -(\ 1 tR13 '-1 -R13 -----.,---`
II 1 N-%\-RN R1A .-, R14 R14 , , , , RN
R11 I, RN
\
. _____________________ ,A.Nr...õ14 , R9 0 R9 2/ N RioNI ---- __ R14 r_r R9 r /1 1 f) ___________ S _ _ 1_ R 0 N \J
R._ N
, 1\1-----S - "\___,----- Ri o ' N- ' ppl 0 ' ' , , , r<
ri R9 9 r Y, o) ,r\ R9 N\ II N
L-R'10 IN õ, _R10 \N-R8 \SI\I R8 ,S , ' R8 , N 1 S,-- N , N --.. ----(,:\
R''a s=- II N R8 z -- R8--N'N R8 N-N b-N N-C) , or 0-N -, , 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 R3 represents bicyclo[1.1.1]pentan-1-yl, bicyclo[2.1.1]hexan-1-yl, bicyclo[3.1.1]heptan-3-yl, bicyclo[2.2.1]heptan-2-yl, bicyclo[2.2.1]hept-5-en-2-yl, bicyclo[2.2.1]heptan-7-yl, bicyclo[2.2.1]heptan-2-yl, bicyclo[2.2.2]octan-2-yl, 1-adamantyl, 2-adamantyl , 4-homoisotwistyl, 1-diamantyl, or 4-diamantyl, and the afore-mentioned bicyclo[1.1.1]pentan-1-yl, bicyclo[2.1.1]hexan-1-yl, bicyclo[3.1.1]heptan-3-yl, bicyclo[2.2.1]heptan-2-yl, bicyclo[2.2.1]hept-5-en-2-yl, bicyclo[2.2.1]heptan-7-yl, bicyclo[2.2.1]heptan-2-yl, bicyclo[2.2.2]octan-2-yl, 1-adamantyl, 2-adamantyl , 4-homoisotwistyl, 1-diamantyl, or 4-diamantyl residues are optionally contain one or more C=C double bond and/or are optionally substituted one or more of Ra, Rb, Rc, Rd, and Re;
R6 represents ¨C2H5;
and R6, R6, R10, R11, R12, R13, R14, Ra; R13, Rc; Rd; Re ; RN and rt "N1 have the same meanings as defined in formula (I) or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomer, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
In some embodiments, the present invention relates to the comopund of the formula (I) H CN yL
H
(I) wherein L represents ¨I-1-1-2¨ ;
LI represents ¨CH2C0¨, L2 represents ¨NR141¨, and R3 represents 1-adamantyl; or I-2 represents ¨NR1ICH2¨, and R3 represents 2-bicyclo[3.1.1]heptyl, and the afore-mentioned 1-adamantyl and 2-bicyclo[3.1.1]heptyl residues are optionally contain one or more C=C double bond and/or are optionally substituted one or more of Ra, Rb, Rc, Rd, and Re;
,,,A ,R6 Ri represents N
H
, R2 represents 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 RN RN RN
R11 1\1 _ - R11 1\1 r R8 ---)--"IN---R8 ---s--0 Rs R11 0 Ra -_ S r, m8 1 ________________________________________________________________________ r r i __ , ___ ) ___________ N N
Rlo N Dio D10 R9 /' R9 R10 .-, rC9 lµ , " , RN RN RN RN RN
R11 s R8 __ N r-s8 R11 ii R8 R11 1\1, R11 rj, __ N, 1 ___________ r K i _____ ( ,, i ,N
( n , ,N
1, ( n . R9 R10 ___ R9 / n9 R10 sµ / , R._ nõo rµ rµ , rµ , Rio RN
o, ,,_ ,- Rii 0 R8 -___sõ-ON __R8 ),-.,._ N¨ 1 ----N \ ir N --) __ N S R8 N
N
R8 Dio Rio Rio RiO
, , ' , , , , RN RN RN
Rii ii ,1/4, - N N "N i N Ro - ,N, p¨
o R12 1 '' \\ /c \¨N ----\- N-------------------------------------------------------- u,,,,,,õ\,) N / o10 , N=1\1 , 0 '1,4 N
' , = , N R12 0 -/,) %% R12 ¨, TR13 ---------- I R- R = -12 ¨ ¨ -\- R1 o_(%.--..-- o 1,4r/ R13 \N \-) .-, '\-4 5 N Ri4 , N Ri4 , N Ri4 , Rlo RiA
N
S-R
pp12 R12 -/ 13 \ R12 i\i-/Y s 1 ' W 0 4.--------(> - - ,:j R
R 1 o _(---r> R13 0 ---\13 Rio Ria S14 , Rio Ria ,µ RN
13p. 12 R12 p12 R10 / i\I ----_/' ' - -- -(\ 1 tR13 13 ,,--------,õõ----"N`
N N--%\-'1A \7R
RN R., Ria Ria , RN
R11 1, RN
Niv_____ R14 --=' /1 ) --- N . R
R 1 _ r._" 9 rNiR9 __ i_ _Ro N \ j Rio N __ g 10_1 __ R14 v - S \___,------010 , K,) Ri\I `Rio ' , ' r Yi /1.r N\ X N
--/-_-, Rio - õ, _Rio , N
\
- ,." R8 \O
, R8 /S , ' , R8 N H
-- N - - N --N R,RS ,.. ---ii N6- Ro___i -------i R8--- 1 N'N R8 , N-N , b-N , N-1:3 , or 0--N -R6 represents ¨C2H5;
2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 and R8; R9; R113, R11, R12, R13, R14, Ra; Ri3; Rc; Rd; Re RN and RNi have the same meanings as defined in formula (I) or a diastereomer; an enantiomer; a mixture of diastereomers; a mixture of enantiomer; a racemate; a solvate; a hydrate; or a pharmaceutically acceptable salt thereof.
In some embodiments; the present invention relates to the comopund of the formula (I) (I) wherein L represents ¨L1¨L2¨;
LI represents ¨CH2C0¨;
L2 represents ¨NRI41¨; and R3 represents 1-adamantyl; or L2 represents ¨NRN1CH2¨; and R3 represents 2-bicyclo[3.1.1]heptyl, and the afore-mentioned 1-adamantyl and 2-bicyclo[3.1.1]heptyl residues are optionally contain one or more C=C double bond and/or are optionally substituted one or more of Ra; Rb; Rc; Rd; and Re;
RI represents R2 represents RN RN RN
) __ N
N
R10 R10 =
R6 represents ¨C2H5;
and R8; R113, R11, Ra; Ri3; Rc; Rd; Re RN and RN1 have the same meanings as defined in formula (I) or a diastereomer; an enantiomer; a mixture of diastereomers; a mixture of enantiomer; a racemate; a solvate; a hydrate; or a pharmaceutically acceptable salt thereof.
In some embodiments; the present invention relates to the compound of the formula (la):
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 '1\1-R6 H
0 _i,_, 0 H,)-L , L , R2i N 1 N R3 H
0 (1a), wherein L represents ¨L1¨L2¨;
L1 represents ¨CH2C0¨, L2 represents ¨NRI41¨, and R3 represents 1-adamantyl; or L2 represents ¨NRN1CH2¨, and R3 represents 2-bicyclo[3.1.1]heptyl, and the afore-mentioned 1-adamantyl and 2-bicyclo[3.1.1]heptyl residues are optionally contain one or more C=C double bond and/or are optionally substituted one or more of Ra, Rb, Rc, Rd, and Re;
R2 represents RN RN RN
N
Ri N
_N _Ra ___ N ,_,8 _ _ 0 R8 R1 _1 0 Ra -__ S ,-, m8 -\\ 'r ir 1 ______ r -\\ r r R10 N Rio Di R9 , R9 R10 ,-,9 I-C , RN RN RN RN RN
R11 S R8 N Rs R1N Rs Rii N, R11 II, -_ N, -14N I iN
/ K ¶
/ R9 R10 R9 / ,--,9 R10 `, / ,-,,-.-,n R10 ,--,9 N 1 o N 1 N
Rlo RN
S, Dp8 -_,..õ,,n.
x - R11 0 R8 J R =------ /7-----1 --- \ 8 ________________________________ N N N ) __ N N N
, RN RN RN
,N, R12 R12 Rii N,m N N ,N1 Rio N Nr--- ,N, DN 11 R=- 1 2 R =-1 ,r1 1/ - - y N----)'N ------------------- u,,,, \-) N
NEN , r-114 N
, , ' N
R12 R12 N R12 0---__//, %, R12 ------------ /') R13 N/-) Ri 3 R=-, r 1 ---,TR13 -\- 1, R10_tr>niR1 N R14 N R14 N et R10 R.-, 0"---R14 , RN
S ---__/ N----, R10 4--------r/ -\' R10_t---r> R13 ---,__---- M
(21-13 R10 R14 S"----414 , R10 R14 , 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 RN
R12 R1 / i\l-A -_, R12 R12 ---_-------7, -- 4 1 R13 - I R13 - L _I 1 N N'%\i4 ___\7 iA
, RN R14 R14 R-R
_____________ R11 N RN 2/ NIVR14 ii R9 r 9 r '/1 inX S R10-N1 ____ 14 riIIR
R=- N R RN,N\J1.<,..10 S
, , ri /R9 r / io m i --N'\ I N6-_Rf_Rio _. 1-------' N II - ,S,- - ,- a N, -- - ,-----N R'-'a ---\ 11 N li - R' ---- -/ -, or 0---N ;
R6 represents -C2H5;
Ra, Rb, Rc, Rd, and Re represents independently of each other -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C2H5, -CON H2 , -CONHCH3, -CON(CH3)2, -CONHC2F15, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H5, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2F15, -NHCOCH3, -NHCOC21-15, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C21-15, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3;
R6, R6, R10, R11, R12, R13, and R14 represent independently of each other -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2F, -CH F2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CH F2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2OH, -OCH3, -0C21-15, -0C3H7, -OCH(CH3)2, -0C(CH3)3, -0C4H9, -OCH F2, -0CF3, -OCH2CF3, -0C2 F5 , -OCH 20CH 3 , -0-CYCIO-C3H 5 , -OCH 2-CYCIO-C3 H5 , -0-C2H4-CYCIO-C3 H5 , -CHO, -COCH3, -COCF3, -00C21-15, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -COOK -COOCH3, -CO0C2H5, -CO0C3H7, -COOCH(CH3)2, -COOC(CH3)3, -00C-CH3, -00C-CF3, -00C-C2H5, -00C-C3H7, -00C-CH(CH3)2, -00C-C(CH3)3, -N H2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5, -NHCOC3H7, -NHCOCH(CH3)2, -NHCOC(CH3)3, -CON H2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONHCH(CH3)2, -CONH-cyclo-C3H5, 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 -CON HC(CH3)3, -CON(CH3)2, -CON (C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -SO2NH2, -SO2NHCH3, -SO2NHC21-15, -SO2NHC3H7, -SO2NHCH(CH3)2, -SO2NH-cyclo-C31-15, -SO2NHC(CH3)3, -S02N(CH3)2, -SO2N(C2H5)2, -SO2N(C3H7)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C21-15, -NHSO2C3H7, -N HSO2CH (CH3)2, -NHSO2C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -CECH, -CEC-CH3, -CH2-CECH, -Ph, -0-Ph, -0-CH2-Ph, N N N
,K - -Nn ---------------------- N/N
__J 0 r N r N
/ _______________________________________ \ / \ / \
N\ /NH N\ 71- ; or N\ /1\1 __ \;
RN represents -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH (CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-051-19, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-051-19, -CH2F, -CH F2; -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3, -00C21-15, -00C3H7, -COCH (CH3)2, -00C(CH3)3, -CO-cyclo-C3H5, -CO-cyclo-C4H7, -CO-cyclo-051-19, -COOCH3, -CO0C2H5, -CO0C3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -S02CH3, -S02CF3, -S02C21-15, -S02C3H7, -S02CH (CH3)2, -S02-cyclo-C3H5, or -S02C(CH3)3;
RNI represents -H, -CH3, or -C2F15;
or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomer, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
Preferably, the present invention relates to the compound of the formula (la):
0)-LN . R6 H
0 ( H 0 A N - L , H
0 (la);
wherein L represents -L1-L2- ;
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 L1 represents -CH2C0-, L2 represents -NRN1-, and R3 represents 1-adamantyl; or L2 represents -NRN1CH2-, and R3 represents 2-bicyclo[3.1.1]heptyl, and the afore-mentioned 1-adamantyl and 2-bicyclo[3.1.1]heptyl residues are optionally contain one or more C=C double bond and/or are optionally substituted one or more of Ra, Rb, Rc, Rd, and Re;
R2 represents RN RN RN
IV
R6 represents -C2H5;
Ra, Rb, Rc, Rd, and Re represents independently of each other -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C2H5, -CONH2, -CON HCH3, -CON(CH3)2, -CONN C2H5, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H5, -CH2CON H2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2F15, -NHCOCH3, -NHCOC21-15, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C21-15, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3;
R8, R10, and R11 represent independently of each other -H, -F, -Cl, -Br, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH (CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2F, -CH F2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CH F2, -CH2-CF3, -CH2-CH2CI -CH2-CH213r, -CH2-CH21, -OC H3, -0C2H5, -0C3H7, -OCH (CH3)2, -0C(CH3)3, -0C4H9, -OCH F2, -0CF3, -OCH2CF3, -0C2F5, -OCH20C H3, -0-CYCIO-C3H5, -OCH2-CYCIO-C3H5, -0-C2H4-CYCIO-C3H5, -CHO, -COCH3, -COCF3, -00C21-15, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -COOK -COOCH3, -CO0C2H5, -CO0C3H7, -COOCH(CH3)2, -COOC(CH3)3, -00C-CH3, -00C-CF3, -00C-C2H5, -00C-C3H7, -00C-CH (CH3)2, -00C-C(CH3)3, -N H2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N [CH (CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5, -NHCOC3H7, -NHCOCH(CH3)2, -NHCOC(CH3)3, -CONH2, -CONHCH3, -CON HC2H5, -CON HC3H7, -CONHCH (CH3)2, -CON H-cyclo-C3H5, -CON HC(CH3)3, -CON(CH3)2, -CON (C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2, 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 -CON[C(CH3)3]2, -SO2NH2, -SO2NHCH3, -SO2NHC21-13, -SO2NHC3H7, -SO2NHCH(CH3)2, -SO2NH-cyclo-C3H3, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H3)2, -SO2N(C3H7)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C21-13, -NHSO2C3H7, -N HSO2CH (CH3)2, -NHSO2C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -CECH, -CEC-CH3, -CH2-CECH, -Ph, -0-Ph, -0-CH2-Ph, r1\1 r1\1 rk1 - -NOrN
r N r N r N
/ _______________________________________ \ / __ \ / __ \
K(:) N\ /NH N\ or N\ \
R" represents -H, -CH3, -C2E-13, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH (CH3)2, -CH(CH3)-C2H3, -C(CH3)3, -cyclo-C3H3, -cyclo-C4H7, -cyclo-C31-19, -CH2-cyclo-C3H3, -CH2-cyclo-C4H7, -CH2-cyclo-C3H9, -CH2F, -CH F2; -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3, -00C21-13, -00C3H7, -COCH (CH3)2, -00C(CH3)3, -CO-cyclo-C3H3, -CO-cyclo-C4H7, -CO-cyclo-C31-19, -COOCH3, -COOC2H3, -CO0C3H7, -COOCH(CH3)2, -COOC(CH3)3, -000CH2Ph, -S02CH3, -S02CF3, -S02C21-13, -S02C3H7, -S02CH (CH3)2, -S02-cyclo-C3H3, or -S02C(CH3)3;
RI" represents -H, -CH3, or -C2F13;
or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomer, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
Preferalby, the compound of the invention has the formula (II):
ON
0 ( H 0 (II) I\O-L
N
0 Li wherein 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 L2 represents -NRI41-, and R3 represents 1-adamantyl; or L2 represents -NRNICH2-, and R3 represents 2-bicyclo[3.1.1]heptyl, and the afore-mentioned adamantyl and bicyclo[3.1.1]heptyl residues are optionally contain one or more C=C double bond and/or are optionally substituted one or more of Ra, Rb, Rc, Rd, and Re;
R2 represents RN RN RN
--- Ri __-R8 --IN-----R8 ) __ N Y __ N
, _____________________ N , , , Ra, Rb, Rc, Rd, and Re represents independently of each other -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C2H3, -CON H2, -CON HCH3, -CON(CH3)2, -CONN C2F13, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H3, -CH2CON H2, -CH2CONHCH3, .. -CH2CON(CH3)2, -CH2CONHC2H3, -NHCOCH3, -NHCOC21-13, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C21-13, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3;
R" represents -H, -CH3, -C2E-13, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH (CH3)2, -CH(CH3)-C2H3, -C(CH3)3, -cyclo-C3H3, -cyclo-C4H7, -cyclo-C3I-19, -CH2-cyclo-C3H3, -CH2-cyclo-C4H7, -CH2-cyclo-C3H9, -CH2F, -CHF2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3, -00C21-13, -00C3H7, -COCH (CH3)2, -00C(CH3)3, -CO-cyclo-C3H3, -CO-cyclo-C4H7, -CO-cyclo-C31-19, -COOCH3, -COOC2H3, -CO0C3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -S02CH3, -S02CF3, -S02C21-13, -S02C3H7, -S02CH(CH3)2, or -S02C(CH3)3;
RI" represent -H, -CH3, or -CH2CH3;
R8, R", and R" represent independently of each other -H, -F, -Cl, -Br, -I, -OH, -CN, -- -NO2, -CH3, -C2E-13, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH (CH3)-C2H3, -cyclo-C3H3, -CH2-cyclo-C3H3, -CH2F, -CHF2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CH F2, -CH2-CF3, -CH2-CH2CI , -CH2-CH2Br, -CH2-CH21, -OCH3, -0C2H5, -0C3H7, -OCH (CH3)2, -0C(CH3)3, -0C4H9, -OCH F2, -0CF3, -OCH2CF3, -0C2F5, 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 -OCH2OCH3, -0-cyclo-C3H3; -OCH2-cyclo-C3H3, -0-C2H4-cyclo-C3H3;
-CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -CECH; -CEC-CH3, -CH2-CECH, or -Ph;
or a diastereomer; an enantiomer; a mixture of diastereomers; a mixture of enantiomer; a racemate; a solvate; a hydrate; or a pharmaceutically acceptable salt thereof.
The term "1-adamantyl" and "2-bicyclo[3.1.1]heptyl" have the following structures respectively:
1-adamantyl Rd IR' Re 2-bicyclo[3.1.1]heptyl Rb Ra Ra Rb and Ra; Rb; Rc; Rd and Re have the same meanings as defined herein.
Preferred; 2-bicyclo[3.1.1]heptyl have the following structure:
Ra Rb ,or Rb and Ra and Rb; have the same meanings as defined herein.
More preferred; the compound has any one of the formulae (II-a) - (II-I), (11-b1)- (II-b2), and (III-a) - (III-I):
0 Rd Rc Re 0 (DN Rb Ra NrN1H N
Rb (II-a) (II-b) 0 1.4 0 0 0 a Ra Rb Rb R2 1-1jC
(II-bl) (II-b2) 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 0-1-,N.-----,..
N
H
HH 0 Rb R2 N Rc N N , L1 H
Ra Ra (II-c) (II-d) 0-L ..----õ, 0)- -----õ,, N N
H H N
Rb Ra Rb Ra 0 ( H 0 0 A H 0 Rc L Rc N L2 R2 A FIN %N )-LI N 0 Rd R2 N
0 0 Rd (II-e) (II-f) 0 0 Rd 0, A
-1\1 Rb Ra 0, JL
H Rc H Rc 0H 0 0 ( H 0 _ J1 NL2 H
(II-g) (II-h) ON 0,-,,)-1,N.----,õ
H Rb Ra H
N kli )-L
J1 NirL2 1\i _ J1 rL2 H Rd H
(II-i) (11-j) 0 0, A
N
' -1\1 rf_frj H H
0 JCH 0 0 JCL, 0 H
(II-k) (II-I) wherein L1, L2, R2, RN, Ra, Rb, Rc, Rd and Re have the same meanings as defined in the formula (I), preferred in the formula (la), more preferred in the formula (II).
2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 o Rd Rc Re o Rb Ra H H
0 ti 0 0 i_i 0 Ra Nr\lcriN)-L ,NH
1 N Tr N -y-LNcrN)-L NH
1 N-r Rb __N H 0 0 ____N H 0 0 'RN 'RN
(III-a) (III-b) oN 0 1 N
H I H
0 0 o 0 o id H
N H H
N,ryr N
R8 N Re 1 hl 1 -(XliC N
\ 0 0 0 I oa R. 0 R" t (11I-c) (11I-d) N
H (:))-LN
H
S Nj- N R8 H
N 1 N \ I H R8 N
Rio S R11 (11I-e) (III-f) ON N
H H
H H
,H
R8-? N
___ZAN R8-- __Ai_l N Rio N Rio 0 0 (11I-g) (11I-h) (21)-N11.-'1' 0 UN
'----1-11'=
H 0 ti 0 R13 0 1 hi NH
1 N N R13 s H
i i NljciNN-1N
Rl (iii-i) (nil) 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 o 0)-N
OA
H N' H
0 _rH 0 R13 0 N)-L NH H H
N r Rio Rio Ri2 R13 12 (III-k) (III-I) wherein LI, L2, R8, R10; R11, R12, R13, R11, RN, Ra; Rb; Rc; Rd and K i-ie have the same meanings as defined in the formula (I), preferred in the formula (la).
In a preferred embodmiment, the invention refers to the compound of the formulae (I), (la) and (II), wherein R3 represents , , ., d.--- , d-------K -----' , i ' ' ' ' , , , , ,,, ..
.--'s , , , , , i i , , , F
CI CF3 OH CO2Me i i , , F
F
. . ., . ' , F Br, , . . ., ., . .
.
CI OH
CO2H ;
CO2Me , CO2H
, , . 0 ., .
CON H2 ; C0NMe2 ; HN) CF3 , Br OH
' , ' _- ; ,- ; _-' ' , or Also preferred, R3 represents 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 F CI
. . . . .
F
CF3 jZOH ZCO2Me F 01 . . . . .
N
i i i . 1 ,or i = , ,, , , More preferred, R3 represents ' ., ,or .
In a preferred embodmiment, the invention refers to the compound of any one of the formulae (I), (la) and (II), (II-a) - (II-1), (II-b1)¨ (II-b2), wherein R2 represents RN RN
RN
R11 il ,,8 _ 0 D8 R 11 0 ,-,8 _ - R11 II R8 - - ,.---IIry - --s" r , .., rr, ___.,õ.s.r8 ¨, , , \ , \ , , , i __ N ) N N
R10 R10 010 R9 R9 R10 .-,9 " I-C , RN RN RN RN RN
R11 s R8 _____NrR8 R1,N,(Rõ R1:N:, Rii õ N, \ , -,\ , -\\ , , ,N __ i ,N
. , ,N
.õ ( , R9 Rio R9 . R9 R10 sµ , c9 D 1 .., r-,9 1 o N 1 " N 1 Rt....5 N
Rii 0, D8 - _ ,ON____ R8 - _ S .-,8 - _ _..,.., ,n , 0,- 1 r-- ii -\ ----- 1 IN
N
N N R10 __ N
R10 ________________________________________________________ N
Rio R8 ' 1 RN RN RN
N N ,N R10 N N, DN pp 1 3 R 1 3 N''' -------------------------------------------------------- ,, ., N / R10 , ' , ' N r` =N , o014 N R14 R12 R12 N R12 0 ---_// %
% R12 R13 N r R 1 3 - - - $__ , j R 1 3 R10_t----r> R13 N R14 N Ri4 N Ri4 Rio R.-, (:)----414 , , 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 RN
, N
R12 S ---./A 13 R12 -R1134/\1 - - R
R19-(/ 1 '1R13 -$%\
0----\2=-Ri3 R19 R14 S------Ri4 Rio , RN
RN RN . 0 R9 il Rl __ N S ' R19- R14 _ _r\_" RF9zio - -cr ''' Rio RN, N S
rµ , RN
0) I D
il R9 S - - -r -/i 9 , .
, N6-,''' --/_=-= R10 _R10 N,I
. - . N,..õ, -S: ---T - - ,----N R8-- N / ii R8-----N'-'-T--Fz u--- I/ -N'N , or O-N ;
wherein R8, R9, R10, R11, R12, R13, and R14, represent independently of each other -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2F, -CH F2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CH F2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2OH, -OCH3, -0C21-15, -0C3H7, -OCH(CH3)2, -0C(CH3)3, -0C4H9, -OCH F2, -0CF3, -OCH2CF3, -0C2F5, -OCH2OCH3, -0-CYCIO-C3H5, -OCH2-CYCIO-C3H5, -0-C2H4-CYCIO-C3H5, -CHO, -COCH3, -COCF3, -00C21-15, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -COOK -COOCH3, -CO0C2H5, -CO0C3H7, -COOCH(CH3)2, -COOC(CH3)3, -00C-CH3, -00C-CF3, -00C-C2H5, -00C-C3H7, -00C-CH(CH3)2, -00C-C(CH3)3, -N H2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5, -NHCOC3H7, -NHCOCH(CH3)2, -NHCOC(CH3)3, -CON H2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONHCH(CH3)2, -CONH-cyclo-C3H5, -CONHC(CH3)3, -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -SO2NHCH(CH3)2, -SO2NH-cyclo-C3H5, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H5)2, -SO2N(C3H7)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C2H5, -NHSO2C3H7, -NHSO2CH(CH3)2, 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 -NHSO2C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -CECH, -CEC-CH3, -CH2-CECH, -Ph, -0-Ph, -0-CH2-Ph, N
..K --No :1) -NrN1 __r rN N
_---1 r , NI
N N
r r r / __ \ / __ \ / __ \
N\ /NH N\ 71- , or N\
71 \;
Preferably, R8, R9, R", R11, R12, R13, and R14, represent independently of each other -H, -F, -Cl, -Br, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH (CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2F, -CH F2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CH F2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2OH, -OCH3, -0C2H5, -0C3H7, -OCH (CH3)2, -0C(CH3)3, -0C4H9, -OCH F2, -0CF3, -OCH2CF3, -0C2F5, - OCH20C H3, -0-CYCIO-C3H5, -OCH2-CYCIO-C3H5, -O-C2H4-CYCIO-C3H5, -CHO, -COCH3, -COCF3, -00C2H5, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -COOK -COOCH3, -CO0C2H5, -CO0C3H7, -COOCH(CH3)2, -COOC(CH3)3, -00C-CH3, -00C-CF3, -00C-C2H5, -00C-C3H7, -00C-CH (CH3)2, -00C-C(CH3)3, -N H2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N [CH (CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5, -NHCOC3H7, -NHCOCH(CH 3)2, -NHCOC(CH3)3, -CON H2, -CONHCH 3 , -CON HC2H5 , -CON HC3H7, -CONHCH (CH3)2, -CON H-cyclo-C3H5 , -CON HC(CH3)3, -CON(CH3)2, -CON (C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -Ph, -0-Ph, -0-CH2-Ph, or More preferably, R8, R9, R", R11, R12, R13, and R14, represent independently of each other -H, -F, -Cl, -Br, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C(CH3)3, -cyclo-C3H5, -CF3, -CH2OH, -OCH3, -0CF3, -CHO, -COCH3, -COOK -COOCH3, -NH2, -N(CH3)2, -CONH2, -SO2NH2, -Ph, or --R" represents -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH (CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-05H9, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-05H9, -CH2F, -CH F2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3, -00C21-15, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -CO-cyclo-C3H5, -CO-cyclo-C4H7, -CO-cyclo-051-19, -COOCH3, -CO0C2H5, -CO0C3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -S02CH3, -S02CF3, -S02C2H5, -S02C3H7, -S02CH(CH3)2, -S02-cyclo-C3H5, or -S02C(CH3)3;
Preferably, R" represents -H, -CH3, -C2H5, -CH(CH3)2, -cyclo-C3H5, -cyclo-C4H7, -cyclo-05H9, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-05H9, or -COCH3, more preferably, R" represents -H, -CH3, -C2H5, -CH(CH3)2, -cyclo-C4H7, -cyclo-05H9, or -COCH3.
In a preferred embodmiment, the invention refers to the compound of any one of the formulae (I), (la) and (II), (II-a) - (II-I), (II-b1)- (II-b2), R2 represents H I H
N I
N '9 9 H
N N N H
N H
N
N N
- - - -N ,N1 ,N1 ,N ,N ,N ,N
N N /
, , CI
I I I I
1 _ N , N___--- N H __-Br -----N--I\I - N 171 .---1\1 71 N N N N ) --N ; \--N ; , CI I I
- -HN 0 , - ---_ 7N --.. N , N , . -NC ---- N N N N
-/ i\I ____ iii\I
/
I ---N , __ H2N HN \ ,,=/
' ' , ' I I
I N, /õ_ , =
- _ N, N - 'N N N,N _ ,J\1 , - - 0_._-Br icl__--Cm N\-N -Y NH
1\1-"N N ; / ; / ; / ; N=N ;
, ---q-C1 --1S_z-Br ---q-S CI _ )SN Br' o - 1 \ f H2N/ \o-' , Br, Br ; Br ; CI ;
' --p-S Br Cli___S ci BrS Br 0 _\
N -- Me0-- - -)-----<\ - -Br , , S s 0__-Br --1S-CF3 '----3 N __ 1 N Br Br , , , S , - S , -S - ,S - N
- N, - NI
S - - NI, µIs-i H
- - -= II 1 µ II - Sµ 1 N
0 NN S-N _--N N----N
0 ;
, 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 s -- N's 0 H2N H
-- .----<\N--- ---- (-, -- (----HO , O-N , N-0 0-N HN--H -' NO2, , HN- Nr-o) N - - _.õ------, -._õ-----NO2 I I
-1-- ¨N-1\1,-- CO2Me -,CO2H .,, -, N,N '-. --.N N.---I N
I N I
, 0 , CI Br , I , 0 , , F , H
-- 0 ,- S S
N
/ / - \
0 , \
, , S , , , H
N
H
N H
F \
F
,-________________________________ -----,,__.\_,--$
N S N NL S N S H .. , HN
, , OH , , , 3%, ,...õ0 N - , , r , -I ---I
N-- or N N N N N , , , Also preferred, R2 represents H I H
N N N H
N H
N N
__ N
\ ---- N---N , ________________________________________ N N , ___ N , N N N
NN ,/ / , , , , / , CI
I I I I
H I )N N___¨ N__-Br --N , , Still more preferred, R2 represents 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 CI
11\1 Br )N I o ---q-CI
N / N / Br, Br , , S S
Br ClS
-- Br -- CI - S
r __-Br --p-S Br S Br CI ij-Br , CI , , Br , , ., NO2 0 p,- Sc --1S-CF3 --.,__..---,NO2 /----- j /----\ j \ #
N N , Br N CO2Me , N
-.0O2H 0 -- \ --' \ S
1 \
N -- \ -- , CI Br -- \
' , H
F H N
N H
S -- \ -- \
F ___(\N
\
, , F , N C, or .
In a preferred embodmiment, the invention refers to the compound of any one of the formulae (I), (la) and (II), (II-a) - (II-1), (II-b1) ¨ (II-b2), wherein L represents ¨CH2¨, ¨CH2CH2¨, ¨CH2CH2CH2¨, ¨CH2CONH¨, ¨CH2CONH¨CH2¨, ¨CH2CON(CH3)¨CH2¨, ¨CH2CONH¨CH(CH3)¨, Most preferred are the following compounds of formula (I):
Cpd Structure Name 1-1: 0 (S)-N1-ethyl-N6-(1-(2-(1-ON
adamantylamino)-2-oxoethyl)-2-oxo-1,2-H
0 1.4 0 dihydropyridin-3-y1)-5-(1-methy1-k imidazole-5-carboxamido)-2-NIN
. . a t.,,..,...) a oxohexanediamide \
1-2: 0 (S)-N1-ethy1-5-(1 H-imidazole-4-0N carboxamido)-N6-(1-(2-(1-H
0 0 adamantylamino)-2-oxoethyI)-2-oxo-1,2-N dihydropyridin-3-yI)-2-oxohexanediamide HNI1-1[1 1 N-rNH
---=---N 0 0 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 1-3: 0 (S)-N1-ethyl-N6-(1-(2-(1-ON adamantyl(methyl)amino)-2-oxoethyl)-2-H
O oxo-1,2-dihydropyridin-3-y1)-5-(1-methyl-1\iANN 1 H-imidazole-5-carboxamido)-2-NNI H
0 0 oxohexanediamide --NN
1-4: 0 (S)-N1-ethyl-N6-(1-(2-(3,5-ON
dimethyladamantane-1-amino)-2-H
O 0 oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)-NH 5-(1-methy1-1H-imidazole-5-NHNjc N I N( 0 ,!,.,,,,,) 0 carboxamido)-2-oxohexanediamide \
1-5: 0 (S)-N1-ethyl-N6-(1-(2-(3-O11L.N.-----õ, ethyladamantane-1-amino)-2-oxoethyl)-H
O 0 2-oxo-1,2-dihydropyridin-3-y1)-5-(1-N
N)..r NH methyl-I H-imidazole-5-carboxamido)-2-NHN
0 1,,õ...7,1 0 oxohexanediamide N
1-6: o (S)-N1-ethyl-N6-(1-(2-(3-oN cF3 trifluoromethyladamantane-1-amino)-2-H
O 0 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-H u N'N NH 5-(1-methy1-1H-imidazole-5-NN FIN (:c 8 carboxamido)-2-oxohexanediamide \
1-7: 0 (S)-N1-ethyl-N6-(1-(2-(3-ON N - OH
hydroxyadamantane-1-amino)-2-H
O 0 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-111 j- NH
1\l/N1 1 NM( 5-(1-methy1-1H-imidazole-5---N 0 0 carboxamido)-2-oxohexanediamide \
1-8: 0 (S)-N1-ethyl-N6-(1-(2-(3-F
O N fluoroadamantane-1-amino)-2-oxoethyly H
O 0 2-oxo-1,2-dihydropyridin-3-y1)-5-(1-'N NH methyl-I H-imidazole-5-carboxamido)-2-NHN N
_--N - 0 0 oxohexanediamide \
1-9: (S)-N1-ethyl-N6-(1-(2-(3-chloroadamantane-1-amino)-2-oxoethyly H
O 0 2-oxo-1,2-dihydropyridin-3-y1)-5-(1-H u N 'NNH methyl-I H-imidazole-5-carboxamido)-2-NHN r() 8 oxohexanediamide "N
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 1-10: (S)-N1-ethyl-N6-(1-(2-(3-N )--bromoadamantane-1-amino)-2-OL Br H
0 0 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-H I]
r\l/YN N 1 NThr NH 5-(1-methy1-1H-imidazole-5----N 0 0 carboxamido)-2-oxohexanediamide \
o I-11: (S)-N1-ethyl-N6-(1-(2-(3-methyl ON CO2Me H adamantane-3-carboxylate-1-amino)-2-oxoethyl)-2-oxo-1 ,2-di hydropyridin-3-y1)-1\1 ,NH
N -7.'=-=NI-1 1 N Tr 5-(1-methy1-1H-imidazole-5-carboxamido)-2-oxohexanediamide 1-12: 0 F F (S)-N1-ethyl-N6-(1-(2-(4,4-ON-----,, difluoroadamantane-1-amino)-2-H
0 0 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-H It N'NNH 5-(1-methy1-1H-imidazole-5-NN jc 0 8 carboxamido)-2-oxohexanediamide N
o 1-13: (S)-N1-(1-(2-(((1S,2R,5S)-6,6-0,,,,,,AN------õ, H dimethylbicyclo[3.1 .1]heptan-2-o o yl)methylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-2-(1-1\1_7--FIN µ1 H C) 0 methyl-I H-imidazole-5-carboxamido)-5-oxohexanediamide o 1-14: (S)-N1-(1-(2-(((1R,2R,5R)-6,6-OLN-----., H dimethylbicyclo[3.1 .1]heptan-2-o 0 H it H ei yl)methylamino)-2-oxoethy1)-2-oxo-1,2-NNN -NN'"
dihydropyridin-3-y1)-N6-ethyl-2-(1-\ methyl-I H-imidazole-5-carboxamido)-5-oxohexanediamide 1-15: 0 (S)-N1-ethyl-N6-(1-(2-(3-H ethyladamantane-1-amino)-2-oxoethyl)-o 0 2-oxo-1,2-dihydropyridin-3-y1)-5-(1-H it ,NH
H Ny ¨NN N methyl-I H-imidazole-4-carboxamido)-2-oxohexanediamide 1-16: 0 OJL
(S)-N1-ethyl-N6-(1-(2-(3----õ,, N--- H ethyladamantane-1-amino)-2-oxoethyl)-O H 0 2-oxo-1,2-dihydropyridin-3-y1)-5-(1-II
(N)N NH N'rN-r methyl-I H-imidazole-2-carboxamido)-2--H 0 0 oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 1-17: 0 (S)-2-(1,4-dimethy1-1H-imidazole-5-H carboxamido)-N6-ethyl-N1-(1-(2-(3-, õ r H
0 ethyladamantane-1-amino)-2-oxoethyl)-N
,Nj- -),(NH
N fl 1 N 2-oxo-1,2-dihydropyridin-3-y1)-5-" .. 0 ,1,,,._...;_j 0 "N oxohexanediamide o 1-18: o.õ)-N..---,,, (S)-N1-ethy1-5-(1-isobuty1-1H-imidazole-L.
H 4-carboxamido)-N6-(1-(2-(3-o 0 H i ethyladamantane-1-amino)-2-oxoethyl)-/---N:--N HNIN C)io NH
----\ \ 2-oxo-1,2-dihydropyridin-3-y1)-2-oxohexanediamide o 1-19: (S)-2-(1-cyclopenty1-1H-imidazole-4-o..--...õ
N
H carboxamido)-N6-ethyl-N1-(1-(2-(3-N N-{N1H ethyladamantane-1-amino)-2-oxoethyl)----N
H 0jJ6 2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide o 1-20: o-jt.N..---,,, (S)-2-(1-cyclobuty1-1H-imidazole-4-H carboxamido)-N6-ethyl-N1-(1-(2-(3-ethyladamantane-1-amino)-2-oxoethyl)-H 2-oxo-1,2-dihydropyridin-3-y1)-5-\_,--- 0 0 oxohexanediamide 1-21: 0 (S)-2-(1,4-dimethy1-1H-imidazole-5-H carboxamido)-N6-ethyl-N1-(1-(2-(3,5-0 H j dimethyladamantane-1-amino)-2-NH
N1)\FIN 0 N 0 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-\ 5-oxohexanediamide o 1-22: 0,)-1...N (S)-N1-ethyl-N6-(1-(2-(3,5--.õ,----.õ
H dimethyladamantane-1-amino)-2-o l oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-NH
¨NN Fi N 5-(1-methyl-1H-imidazole-4-H
carboxamido)-2-oxohexanediamide o 1-23: OAN (S)-N1-ethyl-N6-(1-(2-(3,5-H dimethyladamantane-1-amino)-2-o 0 N
/\ N(iF11)-N'-iNH oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-2-\_N H 0 0 carboxamido)-2-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 1-24: 0 (S)-2-(1,2-dimethy1-1H-imidazole-5-H carboxamido)-N6-ethyl-N1-(1-(2-(3,5-O H 0 dimethyladamantane-1-amino)-2-1\1)-NH oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide 1-25: 0 0,L.N (S)-N1-ethyl-N6-(1-(2-(3-H .----methyladamantane-1-amino)-2-O 0 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N[lji )-LI N rNH 5-(1-methy1-1H-imidazole-5----N \ 0 0 carboxamido)-2-oxohexanediamide 1-26: (S)-2-(2-chloro-1-methy1-1H-imidazole-5-{..N.---,, H carboxamido)-N6-ethyl-N1-(1-(2-(3,5-O 0 dimethyladamantane-1-amino)-2-N H
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-,--N \ 0 0 5-oxohexanediamide CI
1-27: 0 (S)-2-(1,2-dimethy1-1H-imidazole-5-H carboxamido)-N6-ethyl-N1-(1-(2-(3-O o methyladamantane-1-amino)-2-N FIN {NH
1\l/Ncr oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)--N \ H 0 8 5-oxohexanediamide 1-28: (S)-N1-ethyl-N6-(1-(2-(3,5,7-trimethy1-1-oN
H adamantylamino)-2-oxoethyl)-2-oxo-1,2-O H. o dihydropyridin-3-y1)-5-(1-methy1-1H-N NH
N
imidazole-5-carboxamido)-2-i--INN
0 .,,,,0 \ oxohexanediamide 1-29: o (S)-2-(2-chloro-1-methy1-1H-imidazole-5-0N----õ, H carboxamido)-N6-ethyl-N1-(1-(2-(3,5,7-O trimethy1-1-adamantylamino)-2-N Sil\ii--11 N c-INH
oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)--N \
5-oxohexanediamide CI
0..1.,N (S)-2-(benzofuran-2-carboxamido)-N6-,....õ1.----...õ,, H ethyl-N1-(1-(2-(2-adamantylamino)-2-1-30 o k o F oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-o NJcr 1\INNI
1 H 0 8 5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 o o..LN (S)-N1-ethyl-N6-(1-(2-(2-) H adamantylamino)-2-oxoethyl)-2-oxo-1,2-o o 1-31 H II H dihydropyridin-3-yI)-5-(3-0 NrN-.Kil.rN
1 H 0 0 methylbenzofuran-2-carboxamido)-2-oxohexanediamide o o)-N, (S)-2-(3-chlorobenzofuran-2-H carboxamido)-N6-ethyl-N1 -(1 -(2-(2-0 0 NJcr 0 adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-Nj-NrN
I H 1 I 0 0 dihydropyridin-3-yI)-5-oxohexanediamide CI
(S)-2-(4-bromobenzofuran-2-H carboxamido)-N6-ethyl-N1 -(1 -(2-(2-o 0 H ii H adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-NiJc 0 N'N.rN
I H dihydropyridin-3-yI)-5-oxohexanediamide Br 0 (S)-2-(benzo[b]thiophene-2-N`
H carboxamido)-N6-ethyl-N1 -(1 -(242-1-34 0 H ? H
S N. adamantylamino)-2-oxoethyl)-2-oxo-1,2-N N-INI
0 0 dihydropyridin-3-yI)-5-oxohexanediamide o 0 N (S)-N1-ethyl-5-(7-..---., H fluorobenzo[b]thiophene-2-o 1.4 0 H
1-35 NA carboxamido)-N6-(1 -(242----- N i IIIINI
S H 0 0 adamantylamino)-2-oxoethyl)-2-oxo-1,2-F dihydropyridin-3-y1)-2-oxohexanediamide ON (S)-2-(4,5-difluoro-1H-indole-2-H carboxamido)-N6-ethyl-N1 -(1 -(2-(2-o Nr E., 0 N N,A adamantylamino)-2-oxoethyl)-2-oxo-1,2-N-_r H N
I H I
0 0 dihydropyridin-3-yI)-5-oxohexanediamide F F
o-.N (S)-N1 -ethyl-N6-(1 -(242-. .JL ,---,,, H adamantylamino)-2-oxoethyl)-2-oxo-1,2-o iFi o N Nj-L dihydropyridin-3-y1)-5-(3-methy1-1 H.
N-rrµj I H U indole-2-carboxamido)-2-o o oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 o 0)N (S)-2-(1H-benzo[d]imidazole-2-H carboxamido)-N6-ethyl-N1-(1-(2-(2-FAo H
adamantylamino)-2-oxoethyl)-2-oxo-1,2-N 1 It o 'N
41 N H 0 _ (NN0 N dihydropyridin-3-yI)-5-oxohexanediamide o 011-.N (S)-2-(2,3-dihydro-1H-indene-2---",õ
H carboxamido)-N6-ethyl-N1-(1-(2-(2-1-39 o H 0 l'iN H adamantylamino)-2-oxoethyl)-2-oxo-N
_ Ji riµi H 1,2-dihydropyridin-3-yI)-5-oxohexanediamide o 0..,,,J-L.N (S)-N1-ethyl-N6-(1-(2-(2-.õ---,,, H adamantylamino)-2-oxoethyl)-2-oxo-o o 1-40 s_.A NH H
N 1,2-dihydropyridin-3-yI)-5-(4-methyl-F3c----- i Njcro 1 2-(trifluoromethyl)thiazole-5-N
carboxamido)-2-oxohexanediamide o o....}..N
(S)-2-(4-bromo-2-..----õ,õ
H (trifluoromethyl)thiazole-5-ki carboxamido)-N6-ethyl-N1-(1-(2-(2-1-41 F3c--e_ALIr 1 Nf N ' ' 0 0 adamantylamino)-2-oxoethyl)-2-oxo-Br 1,2-dihydropyridin-3-yI)-5-oxohexanediamide o N (S)-N1-ethyl-N6-(1-(2-(2-H adamantylamino)-2-oxoethyl)-2-oxo-1,2-o o 1-42 S_.)-L N IN1 I 1r\J I:1 dihydropyridin-3-y1)-5-(4-methyl-2-\ I H
N 0 0 phenylthiazole-5-carboxamido)-2-oxohexanediamide o 0.t.N.- (S)-2-(5-bromo-3-methylthiophene-2--..., H carboxamido)-N6-ethyl-N1-(1-(2-(2-o H
s o r[l adamantylamino)-2-oxoethyl)-2-oxo-1,2-\ i H 0 8 dihydropyridin-3-yI)-5-oxohexanediamide o (S)-2-(3,5-dibromothiophene-2-H carboxamido)-N6-ethyl-N1-(1-(2-(2-H N
Br 1-44 H adamantylamino)-2-oxoethyl)-2-oxo-Br N
\ I H 0 8 N 1,2-dihydropyridin-3-yI)-5-oxohexanediamide o oN (S)-2-(5-bromo-3-methylfuran-2-...---.......
H carboxamido)-N6-ethyl-N1-(1-(2-(2-H H
0 N Br1 HN N adamantylamino)-2-oxoethyl)-2-oxo-\ N
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 1,2-dihydropyridin-3-yI)-5-oxohexanediamide o o)N (S)-2-(2,5-dichlorothiophene-3-õ,,.. --,......
H carboxamido)-N6-ethyl-N1-(1-(2-(2-O r Fo 1-46 adamantylamino)-2-oxoethyl)-2-oxo-a /
s 0 1 hif 1 rnf 1,2-dihydropyridin-3-yI)-5-CI oxohexanediamide o 0 N (S)-2-(2,5-dibromothiophene-3----..õ
H carboxamido)-N6-ethyl-N1-(1-(2-(2-O r on 1-47 adamantylamino)-2-oxoethyl)-2-oxo-Thr rN, 0 1,2-dihydropyridin-3-yI)-5-s 0 Br oxohexanediamide o 0 ,N,- (S)-2-(2,5-dichlorothiazole-4--,..
H carboxamido)-N6-ethyl-N1-(1-(2-(2-1-48 N,, Nj-LNI -1 adamantylamino)-2-oxoethyl)-2-oxo-FI\1 CI----- I pi s o o 1,2-dihydropyridin-3-yI)-5-a oxohexanediamide o 0 .N (S)-2-(2,5-dimethylfuran-3-.--H carboxamido)-N6-ethyl-N1-(1-(2-(2-o o 1-49 adamantylamino)-2-oxoethyI)-2-oxo-/ 1 iljCr 1,2-dihydropyridin-3-yI)-5-o 0 0 oxohexanediamide o 0 .N (S)-2-(4-bromothiazole-2-.---,õ
H carboxamido)-N6-ethyl-N1-(1-(2-(2-1-50 0 SN f)l 0 H adamantylamino)-2-oxoethyI)-2-oxo-Nj-1 N-11\1 1,2-dihydropyridin-3-yI)-5-$ JN H 0 0 oxohexanediamide Br (S)-2-(4-bromothiophene-2-H carboxamido)-N6-ethyl-N1-(1-(2-(2-o ti o , s)tNJc(N H adamantylamino)-2-oxoethyl)-2-oxo-1 N-rNj 1,2-dihydropyridin-3-yI)-5-Br \ i H 0 0 oxohexanediamide 0-I-L.N (S)-2-(4-bromo-5-chlorothiophene-2-,,,...----,, H carboxamido)-N6-ethyl-N1-(1-(2-(2-1-52 F adamantylamino)-2-oxoethyl)-2-oxo-s N r\lANN-1 CI \ I H 0 8 1,2-dihydropyridin-3-yI)-5-Br oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 o oN (S)-2-(4,5-dibromothiophene-2----....õ
H carboxam ido)-N6-ethyl-N1 -(1-(2-(2-1-53 Nj -1 kli adamantylamino)-2-oxoethyl)-2-oxo-S
Br i N 1 N
\ i H 0 0 1,2-dihydropyridin-3-yI)-5-Br oxohexanediamide o 0y),N (S)-2-(4,5-dichlorothiophene-2-.--,õ
H carboxam ido)-N6-ethyl-N1 -(1-(2-(2-.(Fi 0 1-54 s i N Nj= kil adamantylamino)-2-oxoethyl)-2-oxo-ci , N-r \ i H 0 0 1,2-dihydropyridin-3-yI)-5-ci oxohexanediamide o ON.-------õ, (S)-2-((S)-1-acetylpyrrolidine-2-H carboxamido)-N6-ethyl-N1-(1-(2-(2-o , ,.., N_AN __.(fiy o H adamantylamino)-2-oxoethy1)-2-oxo-- NJ. N
N-r 1,2-dihydropyridin-3-yI)-5-oxohexanediamide o 0)-1,..N (S)-N1-ethyl-N6-(1 -(242-.----,,,..
H adamantylam ino)-2-oxoethyl)-2-oxo-1-56 o jcH 0 H 1,2-dihydropyridin-3-yI)-5-(1-methyl-Nj N
N/A1F1 1 N 1H-1 ,2,3-triazole-5-carboxam ido)-2-`1\\,1-N \ 0 0 oxohexanediamide o (S)-N1-ethyl-N6-(1 -(2-(2-------..õ
H adamantylam ino)-2-oxoethyl)-2-oxo-1-57 o o , H 1,2-dihydropyridin-3-yI)-2-oxo-5-(2H-HN 1 YiN
tetrazole-5-µN----,N o 0 carboxamido)hexanediamide o (S)-N1-ethyl-N6-(1 -(245-H hydroxyadamantane-2-am ino)-2-1-58 1\lj Nj ill oxoethyl)-2-oxo-1 ,2-dihyd ropyridin-3-1 N 1 N If H
0 0 yI)-2-oxo-5-(pyrazine-2-OH
carboxamido)hexanediamide o 0_,.-1-1..N (S)-N1-ethyl-N6-(1 -(245-...----.., H fluoroadamantane-2-am ino)-2-1-59 c ,jo. (rFi j H oxoethyl)-2-oxo-1,2-dihydropyridin-3-N 1 NI ThrN
= H y1)-2-oxo-54(S)-pyrrolidine-3-carboxamido)hexanediamide o (S)-N1-ethyl-N6-(1 -(245-H chloroadamantane-2-am ino)-2-1-60 H 0 (rH 0 Fd oxoethyI)-2-oxo-1,2-dihydropyridin-3-N Nj-Ni - N
= H
----..,....--- 0 0 CI
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 y1)-2-oxo-54(S)-piperidine-2-carboxamido)hexanediamide o (S)-N1-ethyl-N6-(1-(2-(5-0,-,,AN,---,, H bromoadamantane-2-amino)-2-0 r N 0 1-61 H oxoethy1)-2-oxo-1,2-dihydropyridin-3-HNNN , N-rN
H 0 0 Br y1)-2-oxo-5((R)-piperidine-3-carboxamido)hexanediamide o (S)-N1-ethyl-N6-(1-(2-(5-0,,,,:,A.N..^....õ
H methyladamantane-2-amino)-2-H oxoethy1)-2-oxo-1,2-dihydropyridin-3-N)AN N)-L
Ji NN
y1)-5-((R)-morpholine-3-H
carboxamido)-2-oxohexanediamide o o N (S)-N1-ethyl-N6-(1-(2-(2-H carbonitrileadamantane-2-amino)-2-x n H H CN oxoethyl)-2-oxo-1,2-dihydropyridin-3-i N
_ JNrN
H y1)-2-oxo-54(3S,4R)-quinuclidine-3-o o carboxamido)hexanediamide o 0AN (S)-methyl 3-(6-(ethylamino)-1-(1-(2----õ, H (methyl 2-aminoadamantane-2-1-64 o2N N jcrN,)HNNI-1 C 21VIe ,2-LJJ
0 0 LJi dihydropyridin-3-ylamino)-1,5,6-CO2Me trioxohexan-2-ylcarbamoy1)-5-nitrobenzoate o (S)-N1-(1-(2-(1-o H adamantylmethylamino)-2-oxoethyl)-1\110 N
H
1-65 o2N I N ii 2-oxo-1,2-dihydropyridin-3-y1)-N6-H
The 0 N 0 ethy1-2-(5-nitronicotinamido)-5-oxohexanediamide 0 5-((2S)-1-(1-(2-1-N
H adamantylmethylamino)-2-oxoethyl)-0 õ 0 H
1-66 1 Ho2cN Nj- ,N 2-oxo-1,2-dihydropyridin-3-ylamino)-H 1 N y The 6-(ethylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinic acid o o N (S)-N1-ethyl-N6-(1-(2-(2-H adamantyl(methyl)amino)-2-oxoethyl)-2-1-67 -r-----\- Nj_, oxo-1,2-dihydropyridin-3-y1)-5-(6-) ,N
hl N 1NTr methylimidazo[2,1-b]thiazole-5-carboxamido)-2-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 o (S)-N1-(1-(2-((1S,2R,4R)-,1 H bicyclo[2.2.1]heptan-2-ylamino)-2-H 0 oxoethyl)-2-oxo-1,2-dihydropyridin-3-0 N NNThrNH
1 H y1)-N6-ethy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 0 (S)-N1-ethy1-5-(3-methylbenzofuran-ON---....õ
2-ca-2-oxo-N6-(2-oxo-1-H
0 0 (2-oxo-24(1R,2S,4R)-1,7,7-0 N NN INH trimethylbicyclo[2.2.1]heptan-2-0 0 ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide o 0õ,.)L,N (S)-N1-(1-(2-((1R,2R,4S)-,.,-,õ.
H c H bicyclo[2.2.1Theptan-2-ylamino)-2-1-70 0 j 0 0 N oxoethyl)-2-oxo-1,2-dihydropyridin-3-N 1 Ni 0 0 y1)-N6-ethy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 0 (S)-N1-(1-(2-((1s,4R)-bicyclo[2.2.1]heptan-1-ylamino)-2-H
NNH y1)-N6-ethyl-2-(isonicotinamido)-5-N)LI N 0 Nt 0 H oxohexanediamide 0 (S)-N1-(1-(2-(bicyclo[2.2.1]heptan-7-0.N.---- õTr ylamino)-2-oxoethyl)-2-oxo-1,2-H
1-72 0 H 0 dihydropyridin-3-y1)-N6-ethyl-5-oxo-2-N N N
'A ,NH
1 I (pyridazine-4-NI.N H 0 0 carboxamido)hexanediamide (S)-N1-(1-(2-((1R,2R,4R)-N
H bicyclo[2.2.1]hept-5-en-2-ylamino)-2-1-73 0 iY jcH 0 oxoethyl)-2-oxo-1,2-dihydropyridin-3-NA ,NH iNi 1 N Ii y1)-N6-ethy1-5-oxo-2-(pyridazine-3-N-'1\1 carboxamido)hexanediamide o 0 N (2S)-N1-(1-(2-(bicyclo[2.2.2]octan-2-H ylamino)-2-oxoethyl)-2-oxo-1,2-1-74 0 JIIIIH ? H dihydropyridin-3-y1)-N6-ethy1-5-oxo-2-vy(N NI NQI
N (2H-1,2,3-triazole-4-i-k-N H 0 0 carboxamido)hexanediamide 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 o 0,.N (S)-N1-ethyl-5-(1-methyl-1 H-1,2,3-..-----õ, H triazole-4-carboxamido)-2-oxo-N6-(2-o jc H 0 H oxo-1-(2-oxo-2-((1 R,2R,4R)-1,7,7-/A N
_NJ ---- N Y-Ni trimethylbicyclo[2.2.1]heptan-2-sr\I--N H 0 0 ylamino)ethyl)-1 ,2-d ihydropyrid in-3-yl)hexanediamide o N (S)-N1-ethyl-5-(1-methyl-1 H-1 ,2,4-H triazole-3-carboxamido)-2-oxo-N6-(2-o o oxo-1- 2-oxo-2- 1R 2R 3R 5S -( (( õ , ) 1-76 1\1Y-NljcrEl I\1 ,ENI
1 N If ''. 2,6,6-trimethylbicyclo[3.1.1]heptan-3-N_N H 0 0 / ylamino)ethyl)-1 ,2-d ihydropyrid in-3-yl)hexanediam ide o 0N (S)-2-(benzofuran-3-carboxam ido)-.-----,,, H N6-ethyl-5-oxo-N1 -(2-oxo-1-(2-oxo-2-Nj-L L1 ((I S,2S,3S,5R)-2,6,6-1-77 1 N N n H 0 0 trimethylbicyclo[3.1.1]heptan-3-o s,-ylamino)ethyl)-1 ,2-d ihydropyrid in-3-yl)hexanediam ide o (S)-2-(benzo[b]thiophene-3-0,-,...A...N...---..õ
H carboxam ido)-N6-ethyl-N1 -(1-(2-(4-1-78 o jc H o F homoisotwistane-3-amino)-2-N N'AN-rN-1 1 H 0 0 oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-S
y1)-5-oxohexanediamide 0 (S)-N1-ethyl-N6-(1-(2-(diamantane-1-0-LN pg am ino)-2-oxoethyl)-2-oxo-1 ,2-H
0 di h dro rid in-3- 1 -5- 1-meth 1- H-1-79Y PY Y ) ( y 1 N 1\i /y N JC Filj-L NH pyrazole-4-carboxam ido)-2-/
11 r N - 0 0 oxohexanediamide /
o 0.N (S)-N1-ethyl-N6-(1-(2-(diamantane-4-.õ---,õ
H am ino)-2-oxoethyl)-2-oxo-1 ,2-H ? di hydropyrid in-3-y1)-5-(1-methy1-1 H-, L, H pyrazole-3-carboxam ido)-2-/ oxohexanediamide 0 0 (S)-N1-(1-(1-adamantylmethy1)-2-.-----..õ.õ
N oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-H
1-81 _ i:j: H 0 2- 1-meth 1-1H- razole-5-( Y PY
N N
carboxamido)-5-oxohexanediamide T -H
N---"\ 0 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 0 O N (S)-N1-(1((3-hydroxy-1-H
adamantyl)methyl)-2-oxo-1,2-0 0 di hydropyrid in-3-y1)-2-(4-cyclopropyl-H II
,S_1 ,NJCNN 1,2,3-th iadiazole-5-carboxam ido)-N6-H
N 0 ethyl-5-oxohexanediamide OH
0 (S)-N1-(1((3-bromo-1-H
N - adamantyl)methyl)-2-oxo-1,2-0 di hydropyrid in-3-y1)-N6-ethyl-5-oxo-1-83 - 1 JCI-d N (1 ,2,5-thiadiazole-3-N/ 1 r Y -N H
\S---N 0 carboxamido)hexanediamide Br 0 0 (S)-N1-(1-(2-adamantylmethyl)-2-N
oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-H
0 0 2-(4-(hydroxymethyl)-1 ,2,3-,, ,N thiadiazole-5-carboxam ido)-5-N 0 oxohexanediamide HO
OAN
(S)-2-(4-tert-butyl-1 H-pyrrole-3-H carboxam ido)-N1 -(1 -(241 -o N,cNH oll adamantylamino)ethyl)-2-oxo-1 ,2-N di hydropyrid in-3-y1)-N6-ethyl-5-HN H
0 oxohexanediamide o N (S)-2-(4-cyano-1-methyl-1 H-pyrrole-õ---.õ., H 2-carboxamido)-N1-(1-(1-0 hi o 1-86 adamantylam ino)propy1)-2-oxo-1 ,2-NC --- 1\lciNI N
\ N H 0 di hydropyrid in-3-y1)-N6-ethyl-5-\
oxohexanediamide (S)-N1-(1-(3-(2-adamantylamino)-3-0y1LN...--,_ H oxopropy1)-2-oxo-1 ,2-dihydropyridi n-1-87 0 rFi 0 0 3-y1)-N6-ethy1-2-(5-methoxyoxazole-Me0_7) -- H" 0 H
2-carboxamido)-5-oxohexanediamide o (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-oN------,õ
H ylamino)-2-oxoethyl)-2-oxo-1 ,2-H 0 di hydropyrid in-3-y1)-N6-ethyl-2-(3-o NJcrr\O-N(NFI
I H I 1 methylbenzofuran-2-carboxam ido)-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 o (S)-2-(2-acetyloxazole-4-0N-----õ,, H carboxamido)-N1-(1-(2-1-89 (bicyclo[1.1.1]pentan-1-ylamino)-2-L'\\ NDAN NN_rN,IH
oxoethyl)-2-oxo-1,2-dihydropyridin-3-o 0 o y1)-N6-ethy1-5-oxohexanediamide o 0 ,N (S)-N1-(1-(2-(bicyclo[2.1.1Thexan-1-..--., H ylamino)-2-oxoethyl)-2-oxo-1,2-1-90 0 ( Hr,__, 0 0_ J J H dihydropyridin-3-y1)-N6-ethyl-2-(2-C)I
isopropyloxdamideaizole-5-carboxamido)-5-N " 0 hexane oxo/ 0 (2S)-N1-(1-(2-(bicyclo[3.2.1]octan-8-0N----,, H ylamino)-2-oxoethyl)-2-oxo-1,2-1-91 \ ? o dihydropyridin-3-yI)-2-(3,5-j-10,1)1c i ji 1\1 H 1\1 dimethylisoxazole-4-carboxamido)-N 0 0 N6-ethyl-5-oxohexanediamide o 0N (S)-N1-ethyl-N6-(1-(2-(5-carboxy-2-.---,õ..., H aminoadamantane)-2-oxoethyl)-2-o o 1-92 H Li oxo-1,2-dihydropyridin-3-yI)-5-(4-r\r H 0 0 co2H methylpyrimidine-5-carboxamido)-2-oxohexanediamide 0 (5S)-N1-ethyl-N6-(1-(2-(4-N-----' H
0 H H 0 aminoadamantane-N,N-dimethy1-1-N NN-rN carboxamide)-2-oxoethyl)-2-oxo-1,2-N--...
dihydropyridin-3-yI)-2-oxo-5-(1,2,3,4-tetrahydronaphthalene-2-carboxamido)hexanediamide o 0,,A.N (S)-2-((S)-1,4-...--...õ
H diazabicyclo[2.2.2]octane-2-HcrFi 0 .._-- '..A INIA carboxamido)-N6-ethyl-N1-(1-(2-(2-H
0 0 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide o (S)-N1-ethy1-5-(1H-indole-3-0,N----..õ
H carboxamido)-N6-(1-(2-(2-1-95 o ciFi o 1- adamantylamino)-2-oxoethyl)-2-oxo-N ININThr1\11 I H 0 0 1,2-dihydropyridin-3-yI)-2-N
H oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 o (S)-N1-ethyl-N6-(1 -(242-0,=.,)--1-NN.---,,,, H adamantylamino)-2-oxoethyl)-2-oxo-F
o .rF., o 1-96 ------3)-L Nj-L N1 1,2-d ihydropyridin-3-yI)-5-(6-N's methylimidazo[2,1-b]thiazole-3-o 0 carboxamido)-2-oxohexanediamide o or\ ,o__ (S)-2-(benzo[d]thiazole-2-H carboxam ido)-N1 -(1 -(2-((1 S,2R,4R)-1-97 0 0 bicyclo[2.2.1]heptan-2-ylami no)-2-S ,i)-.N Nj-Nl_r NH
NI H i I oxoethyl)-2-oxo-1 ,2-dihyd ropyridin-3-y1)-N6-ethyl-5-oxohexanediamide o o N
(S)-N1-(1-(2-((1 S,2R,4R)-H bicyclo[2.2.1Theptan-2-ylami no)-2-o 0 '-'1"\-- oxoethyl)-2-oxo-1 ,2-dihyd ropyridin-3-NcrEN-111 NI ThrNH
y1)-N6-ethyl-2-(im idazo[2,1-E>5-:-N H o 0 b]thiazole-6-carboxamido)-5-s oxohexanediamide (S)-N1-(1-(2-((1 S,2R,4R)-0 N.--....õ ,0 H bicyclo[2.2.1]heptan-2-ylami no)-2-OHO , 0 oxoethyl)-2-oxo-1 2-dihyd ropyridin-3-1_99 F3c- --- . N N N-Thf - = ' - ' -r\J y1)-N6-ethy1-2-(4-hydroxy-6-(trifluoromethoxy)quinoline-3-carboxamido)-5-oxohexanediamide o 0 N-- (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1---õ, ,7L
H ylamino)-2-oxoethyl)-2-oxo-1 ,2-H 0 dihydropyridin-3-yI)-2-(cinnoline-3-Ncr\ij-.N(NI-1 I , H
0 0 carboxamido)-N6-ethyl-5-NN oxohexanediamide o O N (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-H ylamino)-2-oxoethyl)-2-oxo-1 ,2-o o 1-101 H II di hydropyrid in-3-y1)-N6-ethyl-2-(3-0 N.iN,NNH
i H 1 1 ethylbenzofu ran-2-carboxam ido)-5-oxohexanediamide o (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-0.N.."..õ
H ylamino)-2-oxoethyl)-2-oxo-1 ,2-1-102 di hydropyrid in-3-y1)-N6-ethy1-2-(1-N N Nj-r\JrNH
0 0 ethyl-1H-indole-2-carboxamido)-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 o (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-..,____)\
H ylam ino)-2-oxoethyl)-2-oxo-1,2-1-103 o ri_11 o di hydropyrid in-3-y1)-N6-ethy1-2-(2-N 1 N If methy1-1,8-naphthyridine-3-, H 0 I J 0 NN carboxamido)-5-oxohexanediamide o (S)-N1-(1-(2-(bicyclo[2.1.1Thexan-1-N
H ylam ino)-2-oxoethyl)-2-oxo-1,2-1-104 N,A NI di hydropyrid in-3-y1)-N6-ethy1-5-oxo-N N
H 0 8 19 (1,2,3,4-tetrahydroquinoline-6-N
H carboxamido)hexanediamide 0 N...--., (S)-N1-ethyl-N6-(1-(2-(2-carboxy-2-H
0 0 amino-5-0 u CO2H
(trifluoromethyl)adamantane)-2-H
1-105 HN CF3 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxo-5-(3-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)hexanediamide 0 N..---,,, (S)-N1-ethyl-N6-(1-(2-(5-H ethyladam antane-2-am ino)-2-1-106 oxoethyl)-2-oxo-1,2-dihyd ropyridin-3-N 0 u lor y1)-5-(1,6-naphthyridine-2-carboxamido)-2-oxohexanediamide o (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-oN
H ylam ino)-2-oxoethyl)-2-oxo-1,2-H di hydropyrid in-3-y1)-N6-ethy1-2-(2,6-1 Nj-naphthyridine-1 -carboxamido)-5-N H
oxohexanediamide 0 0)-1,,N (S)-2-(4-ami no-1,2 ,5-oxad iazole-3-..-----,.... .._.7L
H carboxam ido)-N1-(1-(2-1-108 H2N 0 0 (bicyclo[1.1.1]pentan-1-ylamino)-2-id L
N IYN HjC 11 NTh(NH oxoethyl)-2-oxo-1,2-dihydropyridin-3-6-N 0 0 y1)-N6-ethyl-5-oxohexanediamide o (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-oN
H
1-109 N ylam ino)-2-oxoethyl)-2-oxo-1,2-0 Jci-HC) di hydropyrid in-3-y1)-2-(6-N _ N ir NH
\ I H 0 0 (dimethylamino)benzofuran-2-N
/ carboxamido)-N6-ethy1-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 o (S)-2-(2-acetamidothiazole-5-0.N.---,õ ..4, H carboxam ido)-N1 -(1 -(2-1-110 o ) H o NH
(bicyclo[1.1.1]pentan-1-ylamino)-2-Nõ, oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-----\( N 0 0 0 y1)-N6-ethy1-5-oxohexanediamide o oN (S)-N4-(1 -(1 -(2-(bicyclo[1 .1.1]pentan-H 1-ylamino)-2-oxoethyl)-2-oxo-1,2-o o 1-111 0 ri NThr NH dihydropyridin-3-ylamino)-6-/ I iljCr I (ethylamino)-1,5,6-trioxohexan-2-y1)-1H-pyrrole-2,4-dicarboxamide (S)-N1-ethyl-N6-(1-(2-(1-acetylamino-H
0 0 4-am inoadam antane)-2-oxoethyl)-2-1-112 (:)N AN -rFNI 0 H2N oxo-1 ,2-d ihydropyrid in-3-yI)-2-oxo-5-N
H (5-sulfamoylfuran-3-carboxamido)hexanediamide O N--,,,, (S)-2-(benzofuran-5-carboxamido)-H N6-ethyl-N1 -(1-(2-(1 -acetylam ino-4-0 H Ij? H
1-113/ NN, am inoadamantane)-2-oxoethyl)-2-N N
H
N
H oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide (S)-2-(benzofuran-6-carboxamido)-H N6-ethyl-NI-(1-(2-(4-1-114 0 N NirN am inoadamantane-1-carboxamide)-\ H
0 <1 0 H NH2 2-oxoethyl)-2-oxo-1 ,2-d ihydropyridin-3-yI)-5-oxohexanediamide O N..----,, (S)-N1-ethyl-N6-(1-(2-(4-H
0 0 am inoadamantane-1-carboxamide)-H H t-i ____\7)-LN N,N_rN 2-oxoethyl)-2-oxo-1 ,2-d ihydropyridin-1-115 \I \N-0 " o 0 NH 3-y1)-5-(3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamido)-2-oxohexanediamide o (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-oN õ_...).
H ylam ino)-2-oxoethyl)-2-oxo-1 ,2-1-116 rFl 0 di hydropyrid in-3-y1)-N6-ethy1-2-(5-N NH
----Ni il _ 'I NThr methyl-1 ,2,4-oxadiazole-3-o-N o o carboxamido)-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 ID
13.)(N S (1-r(2d-in(13-3ic_yycol-oN[16.-1e.t1h]yple-5n_toaxn0-1-2-H _ - ylamino)-2-oxoethyl)-2-oxo-1,2-c 0 µ---)' d( i h) y- N 1 d r o- y InilAN lNH (1,2,3-thiadiazole-4-s I\ N' \F-N H 0 c) carboxamido)hexanediamide ID ID1 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-, H
N ylamino)-2-oxoethyl)-2-oxo-1,2-1-118 0 0 ---/L dihydropyridin-3-y1)-N6-ethy1-5-oxo-j-L N,sy -LriJci (1,2,4-thiadiazole-5-.--N 0 0 carboxamido)hexanediamide 0 0 N (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-H ____), ylamino)-2-oxoethyl)-2-oxo-1,2-ip 1.1 0 dihydropyridin-3-y1)-N6-ethy1-5-oxo-2-N
S Nj-L (NH (1,3,4-thiadiazole-2-N-N 0 0 carboxamido)hexanediamide o (S)-N1-ethy1-5-(4-formy1-1,2,3-0N.---,õ
H thiadiazole-5-carboxamido)-N6-(1-(2-, 0 H
1-120 NI,jcNriUN ii N (2-adamantylamino)-2-oxoethyl)-2-I
NJ H N H I 1 oxo-1,2-dihydropyridin-3-yI)-2-\ o o oxohexanediamide o 0 (S)-N1-ethyl-N6-(1-(2-(3,5-dimethyladamantane-1-amino)-2-H
1-121 0 jcH 0 oxoethyl)-2-oxo-1,2-dihydropyridin-3-AN N'ANNH yI)-5-(nicotinamido)-2-I H
0 0 oxohexanediamide N
Method for production of inventive compounds In some embodiments, the present invention relates to a method for the synthesis of a compound of formula (I), especially any compound of the formula (la):
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 0 N ,R6 H
N N R -L, 3 H
(la) As shown in Scheme 1, a method for producing the compound of the formula (la) comprising:
Step 1A: providing a compound 4a AcON,R6 H
PWNOH
H
0 4a;
Step 2A: performing coupling reaction of the compound 4a with a compound 5 H2N....... ....1_, , 1 N Rs' I
to obtain a compound 6a AcON-R6 H
PG3,Nk-11j- ,L ., 1 N 'R-H
6a;
Step 3A: deprotecting an amino protecting group PG3to obtain a compound 7a 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 AcON,R6 H
N R-7a;
Step 4A: performing coupling reaction of the compound 7a with a carboxylic acid (R2-CO2H 8) to obtain a compound 9a AcON,R6 H
---,.... ,...CH
H
9a;
Step 5A: performing oxidation reaction of the compound 9a to produce the compound of the formula (la) ON,R6 H
JCH
H
(la);
wherein L, R2, R3,and R6 have the same meanings as defined above in formula (la), and PG3 is an amino protecting group.
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Scheme 1 (b) coupling ¨ ¨ (c) deprotection PG1 & PG2 reaction 0 Ac0)-L N" R6 0 CEN¨R6 reprotection with PG3 OH _ + Ac0 )-N, R6 2a H 1) TFA H
PG1,N PG2 AcOH PG1.N_i PG2 2) PG320 PGNJcrOH
DCM
PG1 0 PG1 0 DMF, DIPEA H 0 4a 1 3a , Step 2A:
coupling reaction (HATU, DIPEA ) Ac0)-N - R6 Ac0 N - R6 H Step 3A H
0 H2N deprotection rE ,L. 2 PG3N N ,L.
1 N R- (TFA) 1 N R3 6a 7a Step 4A
R2¨CO2H 8 coupling reaction (HATU, DIPEA ) Y
AcO)-N,R6 0)-NR6.
H Step 5A H
2 0 0 oxidation 0 0 reaction R2 N N 'r Ni R3 H
0 1) K2CO3, Me0H H
2) Dess-Martin 9a periodinane la DMF
Optionally, Step 1A" is carried out before the step 1A:
(a) providing a protected aldehyde 1 1:::, H
l'Gl 0 I;
(b) performing a coupling reaction of the aldehyde 1 with an isocyanide (CN-R6) 2a to obtain an intermediate compound 3a 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 AcON'R6 H
-PG1 0 3a;
(c)deprotecting the protecting groups PG1 and PG2 of the compound 3a preferably under acidic condition and introducing an amino protecting group PG3 to obtain a compound 4a AcON-R6 H
PG3N Jc OH
-H 0 4a;
wherein R2, R6 have the same meanings as defined in formula (la), PG1 and PG3 are amino protecting groups, PG2 is a carboxyl protecting group.
Therefore, the following method for the production of compounds of the formula (la) is preferred:
Step 1A":
(a) providing a protected aldehyde 1 OH
PG1.NPG2 PG1 0 I;
(b) performing a coupling reaction of the aldehyde 1 with an isocyanide (CN-R6) 2a to obtain an intermediate compound 3a Ac0)-LN-R6 H
pG1N pG2 -PG1 0 3a;
(c) deprotecting the protecting groups PG1 and PG2 of the compound 3a preferably under acidic condition and introducing an amino protecting group PG3 to obtain a compound 4a 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Ac0)-LN-R6 H
PGNJCOH
H 0 4a;
Step 1A: providing a compound 4a Ac0)-LN-R6 H
PGNON
H 0 4a;
Step 2A: performing coupling reaction of the compound 4a with a compound 5 H2N )-L ,L, , N R3 to obtain a compound 6a Ac0)-LN-R6 H
, 0 , N R-6a;
Step 3A: deprotecting the amino protecting group PG3 to obtain a compound 7a Ac0)-LN-R6 H
H
H2NjcNN-1--R3 7a;
Step 4A: performing coupling reaction of the compound 7a with a carboxylic acid (R2-CO2H 8) to obtain a compound 9a Ac0)-N-R6 H
0 iCH 0 R2J-LN 1\1 ,L, 9a;
Step 5A: performing oxidation reaction of the compound 9a to produce the compound of the formula (la) 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 )-L
R2 N H 1 N L- 'R-(la);
wherein L, R2, R3,and R6 have the same meanings as defined above in the formula (la), and PG1 and PG3 are amino protecting groups, PG2 is a carboxyl protecting group.
In an alternative route first all protecting groups PG1 and PG2 are simultaneously removed and the protecting group PG3 is selectively introduced. Preferably, PG1 and PG3 are same.
The term "protecting groups" as used herein refers to commonly used protection groups in organic synthesis, preferably for amino and carboxyl groups.
PG1, PG3, and PG5 preferably are suitable protecting groups for amino groups. PG2 and PG4 preferably are suitable protecting groups for carboxyl groups. Preferably, PG1, PG3, and PG5 may be selected from the group consisting of or comprising: acetyl, benzoyl, benzyloxycarbonyl (Cbz), tert-butylcarbonyl, tert-butyloxycarbonyl (Boc), and fluorenylmethylenoxy group (Fmoc). PG2 and PG4 may be selected from the group consisting of or comprising:
methoxy, ethoxy, isobutoxy, tert-butoxy, benzyloxy; preferably, tert-butoxy group.
In Step 2A to promote the coupling reaction with amino group of intermediate compound, activating reagents are commonly used to activating carboxylic acid (õPeptide Coupling Reagents, More than a Letter Soup", Ayman El-Faham and Fernando Albericio, Chemical Reviews, 2011, ///(//), p.6557-6602). The activation may be introduced separate reaction or in situ reaction. Preferably, any of the following coupling reagent can be used to activate carobxylic acid group: BOP (Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate), PyBOP (Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafl uorophosphate), AOP
(7-(Azabenzotriazol-1-yl)oxy tris(dimethylamino)phosphonium hexafluorophosphate), PyAOP ((7-Azabenzotriazol-yloxy)tripyrrolidinophosphonium hexafluorophosphate), TBTU (2-(1H-Benzotriazole-1-y1)-1,1,3,3-tetramethylaminium tetrafluoroborate), EEDQ (N-Ethoxycarbony1-2-ethoxy-1,2-dihydroquinoline), Polyphosphoric Acid (PPA), DPPA (Diphenyl phosphoryl azide), HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), H BTU
(0-Benzotriazol-1-yl-N,N ,N',N'-tetramethyluronium hexafluorophosphate), HOBt (1-Hyd roxybenzotriazo le), HOAt (1-Hydroxy-7-azabenzotriazole), DCC (N,W-Dicyclohexylcarbodiimide), EDC (or EDAC or EDCI, 1-Ethyl-3-(3-dimethylaminopropyl)carbodiim ide), BOP-C1 (Bis(2-oxo-3-2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 oxazolidinyl)phosphinic chloride), TFFH
(Tetramethylfluoroformamidinium hexafluorophosphate), BroP (Bromo tris(dimethylamino) phosphonium hexafluorophosphate), PyBroP
(Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate) and CI P
(2-Chloro-1,3-dimethylimidazolidinium hexafluorophosphate), or further, similar acting reagents, providing an activated intermediate,or a mixture thereof.
Pharmaceutical Composition & Medical Use Therefore another aspect of the present invention relates to compounds according to the general formula (I) as medicine as well as their use in medicine. Especially preferred is the use as inhibitors of transglutaminases, in particular transglutaminsase 2 (TG2).
Thus the compounds of formula (I) described herein or according to the present invention may be administered themselves or in form of a pharmacologically acceptable salt.
The compounds of the present invention may form of a pharmacologically acceptable salt with organic or inorganic acids or bases. Examples of suitable acids for such acid addition salt formation are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, p-aminosalicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, sulfonic acid, phosphonic acid, perchloric acid, nitric acid, formic acid, propionic acid, gluconic acid, lactic acid, tartaric acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, methanesulfonic acid, ethanesulfonic acid, nitrous acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, p-toluenesulfonic acid, naphthylsulfonic acid, sulfanilic acid, camphorsulfonic acid, china acid, mandelic acid, o-methylmandelic acid, hydrogen-benzenesulfonic acid, picric acid, adipic acid, d-o-tolyltartaric acid, tartronic acid, (o, m, p)-toluic acid, naphthylamine sulfonic acid, trifluoroacetic acid, and other mineral or carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. Preferred is the mesylate salt, hydrochloride salt and the trifluoroacetate salt and especially preferred is the trifluoroacetate salt and the hydrochloride salt.
In the case the inventive compounds bear acidic groups, salts could also be formed with inorganic or organic bases. Examples for suitable inorganic or organic bases are, for example, NaOH, KOH, NH4OH, tetraalkylammonium hydroxide, lysine or arginine and the like. Salts may be prepared in a conventional manner using methods well known in the 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 art, for example by treatment of a solution of the compound of the general formula (I) with a solution of an acid, selected out of the group mentioned above.
Methods of Use In a further aspect of the present invention, the novel compounds according to the general formula (I) are used as pharmaceutically active agent, i.e. the compound of the formula (I) is used in medicine.
Furthermore, the present invention relates to a pharmaceutical composition comprising at least one compound according to the general formula (I), as an active ingredient or a pharmacologically acceptable salts thereof as an active ingredient, together with at least one pharmacologically acceptable carrier, excipient and/or diluent.
The compounds according to general formula (I) described herein are especially suitable for the treatment and prophylaxis of diseases associated with and/or caused by transglutaminase 2.
Celiac disease, a gluten intolerance is associated with tissue transglutaminase (TG 2).
Another very important group of indications for tissue transglutaminase inhibitors are fibrotic disorders. Fibrotic disorders are characterized by the accumulation of cross-linked extracellular matrix proteins. Diabetic nephropathy, cystic fibrosis, idiopathic pulmonary fibrosis, kidney fibrosis as well as liver fibrosis belong to the most important fibrotic disorders to be addressed with the compounds disclosed.
In the biological example B-1, it is proven that the inventive compounds as reversible inhibitors effectively inhibit the activity of TGs, especially TG2.
As used herein the term "inhibiting" or "inhibition" refers to the ability of a compound to downregulate, decrease, reduce, suppress, inactivate, or inhibit at least partially the activity of an enzyme, or the expression of an enzyme or protein.
Therefore, another aspect of the present invention is the use of the inventive compounds of the general formula (I), or the pharmaceutical composition thereof as described in the treatment or prophylaxis of autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, ocular diseases, and skin disorders.
Further aspects of the present invention relate to the use of the compounds of general formula (I) for the preparation of a pharmaceutical composition useful for prophylaxis 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 and/or treatment of autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, ocular diseases, and skin disorders.
In a further aspect of the present invention, a method for preventing and/or treating autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, ocular diseases, and skin disorders, which method comprises administering to a subject, in particular a human, a pharmaceutically effective amount of at least one compound of the general formula (I), to prevent and/or treat said autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, ocular diseases, and skin disorders.
Preferred, the autoimmune and inflammatory diseases comprises multiple sclerosis, celiac disease, Duhring-Brocq-disease (dermatitis herpetiformis), gluten ataxia, gluten neuropathy, diabetes, rheumatoid arthritis, Graves' disease, inflammatory bowel disease, systemic lupus erythematosus psoriasis, and gingivitis;
the vascular diseases comprise atherosclerosis, thrombosis, vascular stiffness;
the fibrotic diseases affecting the lung, the kidney, the liver, the skin or the gut like cystic fibrosis, kidney fibrosis and diabetic nephropathy, intestinal fibrosis, idiopathic lung fibrosis, liver fibrosis;
the liver diseases like alcoholic hepatitis, alcoholic steatohepatitis, nonalcoholic steatohepatitis, non-alcoholic fatty liver disease, liver cirrhosis, autoimmune hepatitis or liver inflammation;
the cholestatic liver diseases comprise primary biliary cholangitis and primary sclerosing cholangitis;
the cancer comprises glioblastoma, melanoma, pancreatic cancer, renal cell carcinoma, meningioma, and breast cancer, the neurodegenerative diseases comprise Parkinson's disease, Huntington's disease, or Alzheimer's disease, the ocular diseases comprise glaucoma, cataracts, macular degeneration, or uveitis;
the skin disorders comprise acne, psoriasis, scarring, and skin aging.
More preferred, the compound of the formula (I), or the pharmaceutical composition thereof is useful in the treatment or prophylaxis of celiac disease.
Furthermore, the compounds of the general formula (I), can be administered in form of their pharmaceutically active salts, optionally using essentially non-toxic pharmaceutically acceptable carriers, adjuvants or extenders. Medications are prepared in a known manner in a conventional solid or fluid carrier or in extenders and a conventional pharmaceutically acceptable adjuvant/expedient in a suitable dose. The preferred 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 preparations are provided in an administrable form suitable for oral application, such as pills, tablets, film tablets, coated tablets, capsules and powders.
Tablets, film tablets, coated tablets, gelatin capsules and opaque capsules are the preferred pharmaceutical formulations. Any pharmaceutical compositions contains at least one compound of the general formula (I), and/or pharmaceutically acceptable salts thereof in an amount of 5 mg to 500 mg, preferably 10 mg to 250 mg and most preferred in an amount of 10 to 100 mg per formulation.
Besides, the object of the present invention also includes pharmaceutical preparations for oral, parenteral, dermal, intradermal, intragastric, intracutaneous, intravascular, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal, percutaneous, rectal, subcutaneous, sublingual, topic, transdermal or inhalative application, containing, in addition to typical vehicles and extenders, a compound of the general formula (I), and/or a pharmaceutically acceptable salt thereof as active component.
The pharmaceutical compositions of the present invention contain one of the compounds of the formula (I) disclosed herein as active component, typically mixed with suitable carrier materials, selected with respect to the intended form of administration, i.e. tablets to be administered orally, capsules (filled either with a solid, a semi-solid or a liquid), powders, orally administrable gels, elixirs, dispersible granulates, syrups, suspensions and the like in accordance with conventional pharmaceutical practices. For example, the compound of the formula (I) can as active agent component be combined with any oral, non-toxic, pharmaceutically acceptable, inert carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms) and the like for the oral administration in form of tablets or capsules.
Moreover, suitable binders, lubricants, disintegrants and colorants can be added to the mixture if required. Powders and tablets can consist of said inert carriers to an extent from .. about 5% per weight to about 95% per weight of the inventive composition.
Suitable binders include starch, gelatin, natural sugars, sweeteners made of corn, natural and synthetic gums, such as acacia gum, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes. Possible lubricants for the use in said dosage forms include boric acid, sodium benzoate, sodium acetate, sodium chloride and the like.
Disintegrants include starch, methylcellulose, cyclodextrins, guar gum and the like. If required, sweeteners and flavor additives and preservatives can also be included. Some of the terms used above, namely disintegrants, extenders, lubricants, binders and the like are discussed in greater detail below.
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Additionally, the compositions of the present invention can be formulated in a form with sustained release to provide a controlled release rate of any one or more components or active components, in order to optimize the therapeutic effect, i.e. the inhibitory activity and the like. Suitable dosage forms for sustained release include layered tablets containing layers with varying degradation rates or controlled release polymeric matrices impregnated with the active components and in the form of a tablet or capsule containing such impregnated or encapsulated porous polymeric matrices.
Preparations in fluid form include solutions, suspensions and emulsions.
Exemplarily mentioned are water or water propylene glycol solutions for parenteral injections or the addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions.
Aerosol preparations suitable for inhalation may include solutions and solids in the form of powders which can be combined with a pharmaceutically acceptable carrier, such as a compressed inert gas, e.g. nitrogen.
For the preparation of suppositories a low melting wax, such as a mixture of fatty acid glycerides, e.g. cocoa butter, is melted firstly and the active component is homogenously dispersed therein by stirring or similar mixing operations. The melted homogenous mixture is then poured in fitting forms, cooled and thus hardened.
Further preparations in solid form which are to be converted into preparations in fluid form for either oral or parenteral administration shortly before use are included.
Such fluid forms include solutions, suspensions and emulsions.
Furthermore, the compounds of the present invention may be administered via transdermal application. The transdermal compositions can have the form of crèmes, lotions, aerosols and/or emulsions.
The term capsule refers to a special container or casing composed of methylcellulose, polyvinyl alcohols or denatured gelatins or starches, in which the active agents can be enclosed. Typically, hard shell capsules are prepared from mixtures of bones and porcine skin gelatins having comparatively high gel strength. The capsule itself can contain small amounts of colorants, opacifiers, softening agents and preservatives.
Tablet means a compressed or cast solid dosage form containing the active components with suitable extenders. The tablet can be produced by compressing mixtures or granulates obtained by wet granulation, dry granulation or compaction, which are known to the one skilled in the art.
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Oral gels refer to the active components dispersed or solubilized in a hydrophilic semi-solid matrix.
Powders for compositions refer to powder mixtures containing the active components and suitable extenders which can be suspended in water or juices.
Suitable extenders are substances which usually form the largest part of the composition or dosage form. Suitable extenders include sugars such as lactose, sucrose, mannitol and sorbitol; starches derived from wheat, corn, rice and potatoes; and celluloses such as microcrystalline cellulose. The amount of extenders in the composition can range from about 5 to about 95% per weight of the total composition, preferably form about 25 to about 75% per weight and further preferred from about 30 to about 60% per weight.
The term disintegrants refers to materials added to the composition in order to support disintegration and release of the medicinal substance. Suitable disintegrants include starches, modified starches which are soluble in cold water, such as sodium carboxymethyl starch; natural and synthetic gums such as locust bean gum, caraya, guar gum, tragacanth and agar; cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose, microcrystalline celluloses and crosslinked microcrystalline celluloses such as croscarmellose sodium; alginates such as alginic acid and sodium alginate; clays such as bentonites and foaming mixtures. The amount of disintegrants used in the composition can range from about 2 to 20% per weight of the composition and further preferred from about 5 to about 10% per weight.
Binders characterize substances binding or "gluing" powders to each other and they consequently serve as "glue" in the formulation. Binders add a cohesion starch which is already available in the extenders or the disintegrant. Suitable binders include sugar, such as sucrose; starches derived from wheat, corn, rice and potatoes; natural gums such as acacia gum, gelatin and tragacanth; derivatives of sea weed such as alginic acid, sodium alginate and ammonium calcium alginate, cellulose materials such as methyl cellulose and sodium carboxymethylcellulose and hydroxypropyl methylcellulose, polyvinylpyrrolidone and inorganic compounds, such as magnesium aluminum silicate.
The amount of binders in the composition can range from about 2 to about 20%
per weight of the total composition, preferably form about 3 to about 10% per weight and further preferred from about 3 to about 6% per weight.
The term lubricant refers to a substance added to the dosage form in order to allow for the tablet, granulate, etc. to be released from the casting mold or pressing mold, after compression, by reducing the friction. Suitable lubricants include metallic stearates such as magnesium stearate, calcium stearate or potassium stearate; stearic acid;
waxes with 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 high melting points and water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and D,L-leucine.
Due to the fact that lubricants have to be present on the surface of the granulates as well as between the granulates and parts of the tablet press they are typically added during the last step prior to compression. The amount of lubricants in the composition can range from about 0.2 to about 5% per weight of the total composition, preferably form about 0.5 to about 2% per weight and further preferred from about 0.3 to about 1.5 % per weight.
Lubricants are materials preventing caking and improving the flow characteristics of granulates so that the flow is smooth and uniform. Suitable lubricants include silicon dioxide and talc. The amount of lubricants in the composition can range from about 0.1 to about 5 % per weight of the total composition, preferably form about 0.5 to about 2 %
per weight.
Colorants are adjuvants coloring the composition or dosage form. Such adjuvants can include colorants having food quality which are adsorbed on a suitable adsorption means, such as clay or aluminum oxide. The amount of the colorant used can vary from about 0.1 to about 5% per weight of the composition and preferably from about 0.1 to about 1%
per weight.
As used herein, a "pharmaceutically effective amount" of a transglutaminase inhibitor is the amount or activity effective for achieving the desired physiological result, either in cells treated in vitro or in a patient treated in vivo. Specifically, a pharmaceutical effective amount is such an amount which is sufficient for inhibiting, for a certain period of time, one or more of the clinically defined pathological processes associated with transglutaminase 2. The effective amount can vary according to the specific compound of the formula (I) and additionally depends on a plurality of factors and conditions related to the subject to be treated and the severity of the disease. If, for example, an inhibitor is to be administered in vivo, factors such as age, weight and health of the patients as well as dose reaction curves and data regarding toxicity obtained from preclinical animal studies are amongst the data to be considered. If the inhibitor in form of the compound of the formula (I) described herein is to be brought in contact with the cells in vivo, a plurality of preclinical in vitro studies would be designed in order to determine parameters such as absorption, half-life, dose, toxicity, etc. Determining a pharmaceutically effective amount fora given pharmaceutically active ingredient is part of the ordinary skills of the one skilled in the art.
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Examples Following abbreviations used in the examples have the following meaning.
Boc (tert-butoxycarbonyl), Boc0Su (N-tert-butoxycarbonyloxy-succinimide) DCM
(dichloromethane), DMAP (4-(Dimethylamino)-pyridine), TEA (triethylamine), DMF
(dimethylformamide), DMP (Dess-Martin periodiane), DIPEA (N-Ethyldiisopropylamine), Glu (glutamic acid), EDC (1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide), TFA
(trifluoroacetic acid), THF (tetrahydrofuran), Et0Ac (ethyl acetate), HATU (1-[Bis(dimethylam ino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate), HOBt (hydroxybenzotriazole), MTBE (methyl tert-butyl ether), tBu (tert-butyl), Chemical Examples The following examples are intended to illustrate the invention with selected compounds without limiting the protecting scope of the present intellectual property right on these concrete examples. It is clear for a person skilled in the art that analogous compounds and compounds produced according to analogous synthetic ways fall under the protecting scope of the present intellectual property right.
Example I. Synthetic method 1 Scheme 1-1 OH chloroacetic acid 34 cl) 0 02NA, ___________ 02N ,OH
j\I NaP0 (a 0 1-adamantylamine EDC, DIPEA, DMF
10% Pd/C
j\I -01 Me0H JJ 0 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound ZED1657 2-(3-n itro-2-oxopy rid in-1(2H)-yl)acetic acid Chemical Formula: C7H6N205 Exact Mass: 198.03 Molecular Weight: 198.13 30.0 g (214 mmol) of 2-hydroxy-3-nitropyridine and 40.5 g (2 eq) of chloroacetic acid were suspended in 600 mL water. At 40 C, 245 g (3 eq) trisodium phosphate dodecahydrate were added, and the reaction was stirred at room temperature overnight. 250 mL
HCI
(32%) were added, and the suspension was stirred for another night at 4 C. The precipitate was filtered and dried.
Yield: 41.2 g, 97%; ESI-MS: 199.3 [M+H]
Preparation of compound ZED3912 NNH
N-(1-adamantyI)-2-(3-nitro-2-oxopyridin-1(2H)-yl)acetamide Chemical Formula: 017H21N304 Exact Mass: 331.15 Molecular Weight: 331.37 7.0 g (35.3 mmol) of ZED1657, 6.63 g (1 eq) of 1-adamantanamine hydrochloride and 4.77 g (1 eq) of HOBt were dissolved in 80 mL DMF and 7.38 mL (1.2 eq) DI PEA.
7.45 g (1.1 eq) of 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride were added and the reaction was stirred at room temperature overnight. The solvent was evaporated, and the residue was dissolved in 200 mL DCM. The solution was washed with each 100 mL
citric acid solution (10%), NaHCO3 solution (10%) and brine. The organic phase was dried over Na2SO4, filtered and the solvent was evaporated.
Yield: 10.3 g, 88%; ESI-MS: 332.4 [M+H]
Preparation of compound ZED3913 2-(3-amino-2-oxopyridin-1(2H)-y1)-N-(1-adamantyl)acetamide Chemical Formula: C17H23N302 Exact Mass: 301.18 Molecular Weight: 301.38 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 10.3 g (31.0 mmol) of ZED3912 were suspended in 200 mL Me0H before 1.0 g of palladium (10%) on activated carbon (unreduced) were added. The suspension was stirred overnight at room temperature under an atmosphere of hydrogen. The catalyst was filtered, and the solvent was evaporated.
Yield: 7.51 g, 78%
ESI-MS: 302.3 [M+H]+
Scheme. 1-2 C) OH 1. DMF, CH3I 0 H 1. Ethyl AcON
Cs2003 isocyanide 2. DMAP, ACN AcOH, DCM H
Boc20 2. TEA
Boo, ______________________ ).- Boo,N ________________________________ ,-Boc,N OH
N CO2tBu CO2tBu H H
3. DIBAL-H Boo 3. Boc20 Et20, -78 C DIPEA, DMF
ZED3913 ci 0 HATU, DMF
DIPEA
H2N,)-L ,NH
N if Ac(21)-N Ac0)-N
H H
? JCH 0 1) TEA, DCM 0 N _________________________________ NH ________ -4 I\1/ r_ii 1 N-r Boo,NJ(NFiNrNH
_--N 0 0 2) HATU, DIPEA, DMF H 0 0 N 1-methyl-1H-imidazole-I-1 b 5-carboxylic acid I-la 1 K2CO3, Me0H
HON
H H
0 0 Dess-Martin 0 0 )-L NH periodinane ____________________________________________ *- NYI\IjcNH1H N-r NH
NLY1,1 (10 N 1\1cc ____m H 0 0 -N DMF -N
1-1c 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 Preparation of compound ZED788 0 OMe BooN
. JC0tBu (S)-1-tert-butyl 5-methyl 2-(tert-butoxycarbonylamino)pentanedioate Chemical Formula: C15H27N06 Exact Mass: 317,18 Molecular Weight: 317,38 12.0 g of Boc-L-Glu-OtBu (39.6 mmol) and 7.09 g of cesium carbonate (21.8 mmol, 0.55 eq) were suspended in 100 ml of DMF and stirred for 1 h at room temperature.
2.47 ml iodomethane (39.6 mmol) we added, and the mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was dissolved in ethyl acetate and washed twice with each citric acid solution (10%), NaHCO3 solution (10%) and brine.
The organic phase was dried over Na2SO4, filtered and the solvent was evaporated. The raw product was used without further purification.
Yield: 13.4 g, >100%
ESI-MS: 318.3 [M+H]
Preparation of compound ZED720 0 OMe Boc,N OtBu Boo 0 (S)-1-tert-butyl 5-methyl 2-(bis(tert-butoxycarbonyl)amino)pentanedioate Chemical Formula: C20H35N08 Exact Mass: 417,24 Molecular Weight: 417,49 13.4 g of ZED788 (-39,6 mmol) and 986 mg of N,N-dimethy1-4-aminopyridine (DMAP) were dissolved in 30 ml of acetonitrile. 17.6 g of di-tert-butyl bicarbonate (77.1 mmol) in 100 ml of acetonitrile was added and the solution was stirred at room temperature overnight. The solvent was evaporated, and the residue was dissolved in ethyl acetate and washed twice with each citric acid solution (10%), NaHCO3 solution (10%) and brine.
The organic phase was dried over Na2SO4, filtered and the solvent was evaporated. The raw product was used without further purification.
Yield: 13.7 g, 83%
ESI-MS: 418.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound ZED721 O H
Boc ,N J(OtBu I3oc 0 (S)-tert-butyl 2-(bis(tert-butoxycarbonyhamino)-5-oxopentanoate Chemical Formula: C19H33N07 Exact Mass: 387,23 Molecular Weight: 387,47 13.7 g of ZED720 (32.8 mmol) were dissolved in 200 ml of dry diethyl ether and cooled to -78 C under argon atmosphere. 36.1 ml of diisobutylaluminum hydride (1M in hexane) were added dropwise and the solution was stirred for 30 min at -78 C before being quenched with potassium sodium tartrate (Rochelle salt) solution. The organic layer was separated, dried over Na2SO4, filtered, and concentrated to dryness. The raw product was used without further purification.
Yield: 13.3 g, >100%
ESI-MS: 388.3 [M+H]
Preparation of compound ZED3221 AcOjL N
Boc,NOH
(2S)-5-acetoxy-2-(tert-butoxycarbonylamino)-6-(ethylamino)-6-oxohexanoic acid Chemical Formula: C15H26N207 Exact Mass: 346.17 Molecular Weight: 346.38 7.0 g (18.1 mmol) of the aldehyde (S)-tert-butyl 2-(bis(tert-butoxycarbonyl)amino)-5-oxopentanoate (ZED721) were dissolved in 30 mL DCM. At 0 C 1.04 g (1.05 eq) ethyl isocyanide and 1.09 mL (1.05 eq) acetic acid were added, and the reaction was stirred at room temperature overnight. 35 mL TFA were added, and the reaction was stirred for another 3 h. The solvent was evaporated, and the residue was dissolved in 20 mL DMF.
6.29 mL (2 eq) DIPEA and 4.73 g (1.2 eq) di-tert-butyl dicarbonate in 5 mL DMF
were added and the reaction was stirred at room temperature overnight. The solvent was evaporated, and the residue was dissolved in DCM. After extraction with NaHCO3 solution (1.05 eq in water), 1.5 eq citric acid was added to the aqueous phase, followed by re-extraction with DCM. The organic phase was dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography.
Yield: 5.77 g, 92%
ESI-MS: 347.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound I-la Ac0j-L
Boc, A
NNH
0 Li (5S)-5-(tert-butoxycarbonylamino)-1-(ethylamino)-6-(1-(2-(1-adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-ylamino)-1 ,6-dioxohexan-2-y1 acetate Chemical Formula: C32F147N508 Exact Mass: 629.34 Molecular Weight: 629.74 5.77 g (16.7 mmol) of ZED3221, 6.33 g (1 eq) HATU and 5.02 g (1 eq) ZED3913 were dissolved in 100 mL DMF and 5.80 mL DIPEA (2 eq) and stirred at 45 C
overnight. The solvent was evaporated; the residue was dissolved in 50 mL Et0Ac and washed twice with each 35 mL citric acid solution (10%), NaHCO3 solution (10%) and brine.
The organic phase was dried over Na2SO4, filtered and the solvent was evaporated.
Yield: 7.41 g, 71%
ESI-MS: 630.5 [M+H]
Preparation of compound I-lb AcOAN
0 ( H 0 7.'''-zi)LNNJ-L NH
N
(5S)-1-(ethylamino)-6-(1-(2-(1-adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-d ihyd ropyrid in-3-ylamino)-5-(1 -methyl-1 H-imidazole-5-carboxamido)-1,6-dioxohexan-2-y1 acetate Chemical Formula: C32H43N707 Exact Mass: 637.32 Molecular Weight: 637.73 600 mg (0.95 mmol) of I-la were dissolved in 5 ml DCM/TFA (1:1) and stirred at room temperature for 1 h. The solvent was evaporated, and the residue was dissolved in 5 ml DMF. 120 mg (1 eq) 1-methyl-1H-imidazole-5-carboxylic acid, 362 mg (1 eq) HATU
and 332 pl (2 eq) DIPEA were added, and the reaction was stirred at room temperature overnight. The solvent was evaporated; the residue was dissolved in 25 mL
Et0Ac and washed with each 15 mL citric acid solution (10%), NaHCO3 solution (10%) and brine.
The organic phase was dried over Na2SO4, filtered and the solvent was evaporated.
Yield: 527 mg, 87%
ESI-MS: 638.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-1c 0 ti 0 (56)-N 1-ethyl-2-hydroxy-N6-(1 -(2-(1-adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyrid in-3-y1)-5-(1-methyl-1H-imidazole-5-carboxamido)hexanediamide Chemical Formula: C301-141N706 Exact Mass: 595.31 Molecular Weight: 595.69 527 mg (0.83 mmol) of 1-lb were dissolved in 7 ml Me0H. 171 mg (1.5 eq) potassium carbonate were added, and the reaction was stirred at room temperature for 1 h. The solution was diluted with DCM and washed with water. The organic phase was dried over Na2SO4, filtered and the solvent was evaporated.
Yield: 469 mg, 95%
ESI-MS: 596.5 [M+H]
Preparation of compound 1-1 iCH 0 N
N NH
(S)-N 1 -ethyl-N6-(1 -(2-(1-adamantylami no)-2-oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-y1)-5-(1-methyl-1H-imidazole-5-carboxamido)-2-oxohexanediamide Chemical Formula: C30F139N706 Exact Mass: 593.30 Molecular Weight: 593.67 469 mg (0.60 mmol) of I-1c were dissolved in 5 ml DMF. 534 mg (1.6 eq) Dess-Martin periodinane (DMP) were added and the reaction was stirred at room temperature over 2 h. The precipitate was filtered off and the filtrate was evaporated. The residue was purified by HPLC.
Yield: 362 mg, 77%
ESI-MS: 594.5 [M+H]
1H-NMR (DMSO-D6, 500 MHz, O [ppm]: 1.27 (t, 3H, ethyl-CH3), 1.74 (m, 6H, adamantyl-C4-H2), 1.97 // 2.15 (m // m, 1H // 1H, [3-CH2), 2.09 (m, 3H, adamantyl-C3-H), 2.17 (m, 6H, adamantyl-C2-H2), 3.23 (m, 2H, ethyl-CH2), 2.91 (t, 2H, y-CH2), 3.74 (s, 3H, imidazole-N-CH3), 4.54 (ddd, 1H, a-CH2), 4.61 (s, 2H, N-CH2), 6.26 (t, 1H, pyridinone-05-H), 7.31 (d, 1H, pyridinone-C6-H), 7.69 (s, 1H, imidazole-CH), 7.77 (s, 1H, imidazole-2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 CH), 8.04 (d, 1H, adamantyl-NH), 8.17 (d, 1H, pyridinone-C4-H), 8.44 (q, 1H, ethylamide-NH), 8.56 (d, 1H, a-NH), 9.16 (s, 1H, pyridinone-NH).
13C-NMR (DMSO-D6, 500 MHz, O [ppm]: 15.14 (ethyl-CH3), 24.54 (13-CH2), 29.19 (adamantyl-C3-H), 33.54 (imidazole-N-CH3), 33.71 (y-CH2), 34.41 (ethyl-CH2), 35.89 (adamantyl-C4-H2), 40.77 (adamantyl-C2-H2), 44.12 (adamantyl-C1), 51.74 (N-CH2), 52.42 (a-CH2), 104.66 (pyridinone-05-H), 122.39 (pyridinone-C4-H), 125.22 (im idazole-Cq), 127.92 (pyridinone-N-Cq), 132.85 (imidazole-CH), 133.27 (pyridinone-C6-H), 142.23 (imidazole-CH), 156.63 (pyridinone-C=0), 160.32 (imidazole-C=0), 161.10 (C=O-NH-CH2CH3), 165.75 (C=0-adamantylamide), 170.56 (C=O-NH-pyridinone), 198.43 (C=0-ethylam ide).
Preparation of compound 1-2 0 ti 0 HNYL IAN "
(S)-N1-ethy1-5-(1 H-imidazole-4-carboxamido)-N6-(1-(2-(1-adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-y1)-2-oxohexanediamide Chemical Formula: 029F137N706 Exact Mass: 579.28 Molecular Weight: 579.65 The synthesis of compound 1-2 was performed according to compound 1-1, using 1-Boc-imidazole-4-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid. The final product was obtained by deprotection (DCM/TFA) as described above and purified by HPLC.
Yield: 45 mg, 63% (last step) ESI-MS: 580.4 [M+H]
Preparation of compound 1-3 ? 0 N"-7N
(S)-N1 -ethyl-N6-(1 -(241 -adamantyl(methyl)amino)-2-oxoethyl)-2-oxo-1 ,2-di hydropyridin-3-yI)-5-(1 -methyl-1 H-imidazole-5-carboxamido)-2-oxohexanediamide Chemical Formula: C311-141N706 Exact Mass: 607.31 Molecular Weight: 607.70 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 The synthesis of compound 1-3 was performed according to compound 1-1, using N-methy1-1-adamantanamine instead of 1-adamantanamine in step 2 (according to ZED3912).
Yield: 26 mg, 52% (last step) ESI-MS: 608.5 [M+H]
Preparation of compound 1-4 0)-L
I\1YLN NH
N
(S)-N1-ethyl-N6-(1-(2-(3,5-dimethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-5-carboxamido)-2-oxohexanediamide Chemical Formula: C32H43N706 Exact Mass: 621.33 Molecular Weight: 621.73 To the a-hydroxyester precursor of compound 1-4 (382 mg, 0.61 mmol, prepared by using 3,5-dimethy1-1-adamantanamine in step 2 according to compound ZED3912) in 10 mL of acetonitrile, 1 mg of TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl, 1 mol%) were added.
88 mg of calcium hypochlorite (1 eq) were added at 0 C and the reaction mixture was stirred at 25 C for 2 h. The suspension was filtered, diluted with ethyl acetate and washed with NaHCO3 solution (10%) and brine. The organic phase was dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by HPLC.
Yield: 176 mg, 46%
ESI-MS: 622.5 [M+H]
Preparation of compound 1-5 0)LN
NYLNjcNA NH
(S)-N1-ethyl-N6-(1-(2-(3-ethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methyl-1H-imidazole-5-carboxamido)-2-oxohexanediamide Chemical Formula: C32H43N706 Exact Mass: 621.33 Molecular Weight: 621/3 To the a-hydroxyester precursor of compound 1-5 (162 mg, 0.26 mmol, prepared by using 3-ethyl-1-adamantanamine in step 2 according to compound ZED3912) in 5 ml DMSO, 145 mg of 2-iodoxybenzoic acid (IBX, 2 eq) were added and the reaction mixture was stirred at room temperature for 3 h. NaHCO3 solution (10%) was added and the 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 suspension was extracted with Et0Ac. The organic phase was dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by HPLC.
Yield: 59 mg, 37% (last step) ESI-MS: 622.5 [M+H]
Preparation of compound 1-6 oJL CF3 N NH
, N
N '/Y-LFINjor 0 (S)-N1-ethyl-N6-(1-(2-(3-trifluoromethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methyl-1H-imidazole-5-carboxamido)-2-oxohexanediamide Chemical Formula: C31F138F3N706 Exact Mass: 661.28 Molecular Weight: 661.67 The synthesis of compound 1-6 was performed according to compound 1-1, using 3-trifluoromethy1-1-adamantanamine instead of 1-adamantanamine in step 2 (according to ZED3912).
Yield: 36 mg, 51% (last step) ESI-MS: 662.4 [M+H]
Preparation of compound 1-7 OH
H j_LN
NH
N "-/YLN-rN
I
(S)-N1-ethyl-N6-(1-(2-(3-hydroxyadamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-5-carboxamido)-2-oxohexanediamide Chemical Formula: C30H39N707 Exact Mass: 609.29 Molecular Weight: 609.67 The synthesis of compound 1-7 was performed according to compound 1-1, using 3-hydroxy-1-adamantanamine instead of 1-adamantanamine in step 2 (according to ZED3912).
Yield: 21 mg, 45% (last step) ESI-MS: 610.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-8 HN N
NYLN(r H)-L N-r (S)-N1-ethyl-N6-(1-(2-(3-fluoroadamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-5-carboxamido)-2-oxonexanediamide Chemical Formula: C30H38FN706 Exact Mass: 611.29 Molecular Weight: 611.66 The synthesis of compound 1-8 was performed according to compound 1-1, using 3-fluoro-1-adamantanamine instead of 1-adamantanamine in step 2 (according to ZED3912).
Yield: 52 mg, 61% (last step) ESI-MS: 612.5 [M+H]
Preparation of compound 1-9 Cl N/y-LNicN)-L NH
N
(S)-N1-ethyl-N6-(1-(2-(3-chloroadamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methyl-1H-imidazole-5-carboxamido)-2-oxonexanediamide Chemical Formula: C301-138C1N706 Exact Mass: 627.26 Molecular Weight: 628.12 The synthesis of compound 1-9 was performed according to compound 1-1, using 3-chloro-1-adamantanamine instead of 1-adamantanamine in step 2 (according to ZED3912).
Yield: 49 mg, 68% (last step) ESI-MS: 628.3 / 630.3 [M+H]
Preparation of compound 1-10 Br NH
/Y-LN(1 N
(S)-N1-ethyl-N6-(1-(2-(3-bromoadamantane-l-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methyl-1H-imidazole-5-carboxamido)-2-oxohexanediamide Chemical Formula: C30H38BrN706 Exact Mass: 671.21 Molecular Weight: 672.57 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 The synthesis of compound 1-10 was performed according to compound 1-1, using bromo-1-adamantanamine instead of 1-adamantanamine in step 2 (according to ZED3912).
Yield: 59 mg, 71% (last step) ESI-MS: 672.3 / 674.3 [M+H]
Preparation of compound 1-11 CO2Me HN N
NYLNjc N-r (S)-N1-ethyl-N6-(1-(2-(3-methyl adamantane-3-carboxylate-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-5-carboxamido)-2-oxohexanediamide Chemical Formula: C32F141 N708 Exact Mass: 651.30 Molecular Weight: 651.71 The synthesis of compound 1-11 was performed according to compound 1-1, using methyl 3-aminoadamantane-1-carboxylate instead of 1-adamantanamine in step 2 (according to ZED3912).
Yield: 85 mg, 74% (last step) ESI-MS: 652.5 [M+H]
Preparation of compound 1-12 N -H
NAyLNjcrN)-L NH
N-r (S)-N1-ethyl-N6-(1-(2-(4,4-difluoroadamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-5-carboxamido)-2-oxohexanediamide Chemical Formula: C301-137F2N706 Exact Mass: 629.28 Molecular Weight: 629.65 The synthesis of compound 1-12 was performed according to compound 1-1, using 4,4-difluoro-1-adamantanamine instead of 1-adamantanamine in step 2 (according to ZED3912).
Yield: 23 mg, 47% (last step) ESI-MS: 630.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-13 O Li 0 NYL N
Nr (S)-N1-(1-(2-(((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-Amethylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C30H41N706 Exact Mass: 595.31 Molecular Weight: 595.69 The synthesis of compound 1-13 was performed according to compound 1-1, using (-)-cis-myrtanylamine instead of 1-adamantanamine in step 2 (according to ZED3912).
Yield: 74 mg, 68% (last step) ESI-MS: 596.5 [M+H]
Preparation of compound 1-14 OAN
O ti 0 NYLHN N Nr ¨ 0 0 (S)-N1-(1-(2-(((1R,2R,5R)-6,6-dimethylbicyclo[3.1.1]heptan-2-yhmethylamino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-y1)-N6-ethyl-2-(1-methyl-1 H-imidazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C301-141N706 Exact Mass: 595.31 Molecular Weight: 595.69 The synthesis of compound 1-14 was performed according to compound 1-1, using (-)-cis-(pinan-2-ylmethyl)amine instead of 1-adamantanamine in step 2 (according to ZED3912).
Yield: 52 mg, 63% (last step) ESI-MS: 596.5 [M+H]
Preparation of compound 1-15 O ti 0 j-L NH
¨1\l/AN(r N I
(S)-N1-ethyl-N6-(1-(2-(3-ethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-4-carboxamido)-2-oxohexanediamide Chemical Formula: C32H43N706 Exact Mass: 621.33 Molecular Weight: 621.73 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 The synthesis of compound 1-15 was performed according to compound 1-5, using methy1-1H-imidazole-4-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 26 mg, 67% (last step) ESI-MS: 622.5 [M+H]
Preparation of compound 1-16 0)-L N
N N NHN NH
\ H
\
(S)-N1-ethyl-N6-(1-(2-(3-ethyladamantane-l-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1 -methyl-1 H-imidazole-2-carboxamido)-2-oxohexanediamide Chemical Formula: C32F143N706 Exact Mass: 621.33 Molecular Weight: 621.73 The synthesis of compound 1-16 was performed according to compound 1-5, using methyl-1H-imidazole-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 46 mg, 71% (last step) ESI-MS: 622.5 [M+H]
.. Preparation of compound 1-17 0)-LN
N NH
N N
(S)-2-(1,4-dimethy1-1H-imidazole-5-carboxamido)-N6-ethyl-N1-(1-(2-(3-ethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C33F145N706 Exact Mass: 635.34 Molecular Weight: 635.75 The synthesis of compound 1-17 was performed according to compound 1-5, using 1,4-dimethy1-1H-imidazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b).
.. Yield: 69 mg, 75% (last step) ESI-MS: 636.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-18 H j_L
NNH
(S)-N1-ethy1-5-(1-isobuty1-1H-imidazole-4-carboxamido)-N6-(1-(2-(3-ethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxohexanediamide Chemical Formula: C35H49N706 Exact Mass: 663.37 Molecular Weight: 663.81 The synthesis of compound 1-18 was performed according to compound 1-5, using isobuty1-1H-imidazole-4-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 38 mg, 62% (last step) ESI-MS: 664.5 [M+H]
Preparation of compound 1-19 Nj-I NH
FiNjcor H NiTho (S)-2-(1-cyclopenty1-1H-imidazole-4-carboxamido)-N6-ethyl-N1-(1-(2-(3-ethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C36F149N706 Exact Mass: 675.37 Molecular Weight: 675.82 The synthesis of compound 1-19 was performed according to compound 1-5, using cyclopenty1-1H-im idazole-4-carboxylic acid instead of 1-methy1-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 24 mg, 57% (last step) ESI-MS: 676.5 [M+H]
Preparation of compound 1-20 Nj-L NH
N-r (S)-2-(1-cyclobuty1-1H-imidazole-4-carboxamido)-N6-ethyl-N1-(1-(2-(3-ethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C35H47N706 Exact Mass: 661.36 Molecular Weight: 661.79 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 The synthesis of compound 1-20 was performed according to compound 1-5, using cyclobuty1-1H-im idazole-4-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 32 mg, 66% (last step) ESI-MS: 662.5 [M+H]
Preparation of compound 1-21 0 ( H 0 NH
NNN, Chemical Formula: C33F145N706 Exact Mass: 635.34 Molecular Weight: 635.75 (S)-2-(1,4-dimethy1-1H-imidazole-5-carboxamido)-N6-ethyl-N1-(1-(2-(3,5-climethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide The synthesis of compound 1-21 was performed according to compound 1-4, using 1,4-dimethy1-1H-imidazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 25 mg, 56% (last step) ESI-MS: 636.5 [M+H]
Preparation of compound 1-22 JCH
N)-L NH
¨NYLN N
Chemical Formula: C32F143N706 Exact Mass: 621.33 Molecular Weight: 621.73 (S)-N1-ethyl-N6-(1-(2-(3,5-dimethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methyl-1H-imidazole-4-carboxamido)-2-oxohexanediamide The synthesis of compound 1-22 was performed according to compound 1-4, using methy1-1H-im idazole-4-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 45 mg, 77% (last step) ESI-MS: 622.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-23 N CNF1)- NH
Chemical Formula: C32F-143N706 Exact Mass: 621.33 Molecular Weight: 621.73 (S)-N1-ethyl-N6-(1-(2-(3,5-dimethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methyl-1 H-imidazole-2-carboxamido)-2-oxohexanediamide The synthesis of compound 1-23 was performed according to compound 1-4, using methy1-1H-im idazole-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic .. acid in step 6 (according to compound 1-1b).
Yield: 18 mg, 50% (last step) ESI-MS: 622.5 [M+H]
Preparation of compound 1-24 NA NH
1\1Th Chemical Formula: C33H4.5N706 Exact Mass: 635.34 Molecular Weight: 635/5 (S)-2-(1,2-dimethy1-1 H-imidazole-5-carboxamido)-N6-ethyl-N 1-(1-(2-(3,5-d imethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide The synthesis of compound 1-24 was performed according to compound 1-4, using 1,2-dimethy1-1H-imidazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 44 mg, 72% (last step) ESI-MS: 636.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-25 )LN
Nj-LN NH
N/YN
Chemical Formula: C311-141N706 Exact Mass: 607.31 Molecular Weight: 607.70 (S)-N1-ethyl-N6-(1-(2-(3-methyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-5-carboxamido)-2-oxohexanediamide The synthesis of compound 1-25 was performed according to compound 1-1 , using methy1-1-adamantanamine instead of 1-adamantanamine in step 2 (according to ZED3912). Yield: 37 mg, 59% (last step) ESI-MS: 608.5 [M+H]
Preparation of compound 1-26 0)-LN
N NH
N'r CI
Chemical Formula: C32H42C1N706 Exact Mass: 655.29 Molecular Weight: 656.17 (S)-2-(2-chloro-1-methy1-1H-imidazole-5-carboxamido)-N6-ethyl-N1-(1-(2-(3,5-dimethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide The synthesis of compound 1-26 was performed according to compound 1-4, using chloro-1-methyl-1H-imidazole-5-carboxylic acid instead of 1-methyl-1H-im idazole-5-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 57 mg, 71% (last step) ESI-MS: 656.5 / 658.5 [M+H]
Preparation of compound 1-27 Chemical Formula: C32F-143N706 Exact Mass: 621.33 Molecular Weight: 621.73 (S)-2-(1,2-dimethy1-1H-imidazole-5-carboxamido)-N6-ethyl-N1-(1-(2-(3-methyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 The synthesis of compound 1-27 was performed according to compound 1-25, using 1,2-dimethy1-1H-im idazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 29 mg, 52% (last step) ESI-MS: 622.5 [M+H]
Preparation of compound 1-28 Nj-L NH
'JCL NFI N
"
Chemical Formula: C33F-145N706 Exact Mass: 635.34 Molecular Weight: 635.75 (S)-N1-ethyl-N6-(1-(2-(3,5,7-trimethy1-1-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1 -methyl-1 H-imidazole-5-carboxamido)-2-oxohexanediamide The synthesis of compound 1-28 was performed according to compound 1-1, using 3,5,7-trimethy1-1-adamantanamineinstead of 1-adamantanamine in step 2 (according to ZED3912).
Yield: 48 mg, 63% (last step) ESI-MS: 636.5 [M+H]
Preparation of compound 1-29 NH
N-r CI
Chemical Formula: C33H44C1N706 Exact Mass: 669.30 Molecular Weight: 670.20 (S)-2-(2-ch loro-1 -methyl-1 H-imidazole-5-carboxamido)-N6-ethyl-N1 -(1 -(2-(3,5,7-trimethyl-1-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide The synthesis of compound 1-29 was performed according to compound 1-28, using chloro-1-methy1-1H-im idazole-5-carboxylic acid instead of 1-methyl-1H-im idazole-5-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 23 mg, 52% (last step) ESI-MS: 670.5 / 672.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-30 )LN
0 )-L
N-r I I
(S)-2-(benzofuran-2-carboxamido)-N6-ethyl-N1 -(1 -(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-idihydropyridin-3-yI)-5-oxohexanediamide Chemical Formula: C34H39N507 Exact Mass: 629.28 Molecular Weight: 629.70 The synthesis of compound 1-30 was performed according to compound 1-1, using adamantanamine instead of 1-adamantanamine in step 2 (according to ZED3912) and benzofuran-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b).
Yield: 73 mg, 68% (last step) ESI-MS: 630.4 [M+H]
Preparation of compound 1-31 o oLN
r-rC
(S)-N1-ethyl-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-clihydropyridin-3-y1)-5-(3-methylbenzofuran-2-carboxamido)-2-oxohexanediamide Chemical Formula: C35H41N507 Exact Mass: 643.30 Molecular Weight: 643.73 The synthesis of compound 1-31 was performed according to compound 1-30, using methylbenzo[b]furan-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 90 mg, 77% (last step) ESI-MS: 644.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-32 0 FNINFI).L
NN
I I
CI
(S)-2-(3-chlorobenzofuran-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C34.H38CIN507 Exact Mass: 663.25 Molecular Weight: 664.15 The synthesis of compound 1-32 was performed according to compound 1-30, using chlorobenzofuran-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 56 mg, 72% (last step) ESI-MS: 664.4 / 666.4 [M+H]
Preparation of compound 1-33 NN)-LNN
I H I
Br (S)-2-(4-bromobenzofuran-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C34H38BrN507 Exact Mass: 707.20 Molecular Weight: 708.60 The synthesis of compound 1-33 was performed according to compound 1-30, using bromo-1-benzofuran-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 64 mg, 69% (last step) ESI-MS: 708.3 / 710.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-34 0,-õ)-1,N------õ, H
S 1 NNI-1)-LI NNEI
i H 0 0 (S)-2-(benzo[b]thiophene-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C34.H39N506S
Exact Mass: 645.26 Molecular Weight: 645.77 The synthesis of compound 1-34 was performed according to compound 1-30, using benzo[b]thiophene-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 51 mg, 67% (last step) ESI-MS: 646.4 [M+H]
Preparation of compound 1-35 ON
H
N-11\iNMN
F
(S)-N1-ethyl-5-(7-fluorobenzo[b]thiophene-2-carboxamido)-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-clihydropyridin-3-y1)-2-oxohexanediamide Chemical Formula: C34H38FN506S
Exact Mass: 663.25 Molecular Weight: 663.76 The synthesis of compound 1-35 was performed according to compound 1-30, using fluorobenzo[b]thiophene-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 36 mg, 64% (last step) .. ESI-MS: 664.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-36 N N
F F
(S)-2-(4,5-difluoro-1H-indole-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C34F138F2N606 Exact Mass: 664.28 Molecular Weight: 664.70 The synthesis of compound 1-36 was performed according to compound 1-30, using 4,5-difluoro-1H-indole-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 48 mg, 67% (last step) ESI-MS: 665.4 [M+H]
Preparation of compound 1-37 0)L
N
0 (rH 0 N
(S)-N1-ethyl-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(3-methyl-1H-indole-2-carboxamido)-2-oxohexanediamide Chemical Formula: C35H42N606 Exact Mass: 642.32 Molecular Weight: 642.74 The synthesis of compound 1-37 was performed according to compound 1-30, using methyl-1H-indole-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 42 mg, 64% (last step) ESI-MS: 643.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-38 N
(S)-2-(1H-benzo[d]imidazole-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C33H35N706 Exact Mass: 629.30 Molecular Weight: 629.71 The synthesis of compound 1-38 was performed according to compound 1-30, using benzo[d]imidazole-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 26 mg, 55% (last step) ESI-MS: 630.5 [M+H]
Preparation of compound 1-39 N)^ N
(S)-2-(2,3-dihydro-1H-indene-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C35H43N506 Exact Mass: 629.32 Molecular Weight: 629.75 The synthesis of compound 1-39 was performed according to compound 1-30, using 2,3-dihydro-1H-indene-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 19 mg, 46% (last step) ESI-MS: 630.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-40 0)L
N -H
N
N
_ J1 r\irN
(S)-N1-ethyl-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-clihydropyridin-3-y1)-5-(4-methy1-2-(trifluoromethypthiazole-5-carboxamido)-2-oxohexanediamide Chemical Formula: C31F137F3N606S
Exact Mass: 678.24 Molecular Weight: 678.72 The synthesis of compound 1-40 was performed according to compound 1-30, using methy1-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 34 mg, 61% (last step) ESI-MS: 679.4 [M+H]
Preparation of compound 1-41 H
0 1.1 0 H
F3C.--K\ _IAN
H 0 :01 N
Br (S)-2-(4-bromo-2-(trifluoromethypthiazole-5-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C30H34BrF3N606S
Exact Mass: 742.14 Molecular Weight: 743.59 The synthesis of compound 1-41 was performed according to compound 1-30, using bromo-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 39 mg, 56% (last step) ESI-MS: 743.3 / 745.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-42 1\1¨
(S)-N1-ethyl-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(4-methy1-2-phenylthiazole-5-carboxamido)-2-oxohexanediamide Chemical Formula: C36H4.2N606S
Exact Mass: 686.29 Molecular Weight: 686.82 The synthesis of compound 1-42 was performed according to compound 1-30, using methy1-2-phenylthiazole-5-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 43 mg, 69% (last step) ESI-MS: 687.5 [M+H]
Preparation of compound 1-43 NN
Br \ H 0 I
(S)-2-(5-bromo-3-methylthiophene-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C31 H38BrN506S
Exact Mass: 687.17 Molecular Weight: 688.63 The synthesis of compound 1-43 was performed according to compound 1-30, using bromo-3-methylthiophene-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 55 mg, 67% (last step) ESI-MS: 688.3 /690.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-44 N
N
Br , N N
\I Ho I I
Br (S)-2-(3,5-dibromothiophene-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C30H35Br2N506S
Exact Mass: 751.07 Molecular Weight: 753.50 The synthesis of compound 1-44 was performed according to compound 1-30, using 3,5-dibromothiophene-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 43 mg, 60% (last step) ESI-MS: 752.2 / 754.2 / 756.2 [M+H]
Preparation of compound 1-45 0 Nj-L N
N
Br , N
\I Ho I
(S)-2-(5-bromo-3-methylfuran-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C31H38BrN507 Exact Mass: 671.20 Molecular Weight: 672.57 The synthesis of compound 1-45 was performed according to compound 1-30, using bromo-3-methylfuran-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 52 mg, 71% (last step) ESI-MS: 672.3 /674.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-46 0liN
H u CI , CI
(S)-2-(2,5-dichlorothiophene-3-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C30H35Cl2N506S
Exact Mass: 663.17 Molecular Weight: 664.60 The synthesis of compound 1-46 was performed according to compound 1-30, using 2,5-dichlorothiophene-3-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 85 mg, 72% (last step) ESI-MS: 664.3 / 666.3 [M+H]
Preparation of compound 1-47 N
0 jCH 0 N
Br Br (S)-2-(2,5-dibromothiophene-3-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C30H35Br2N506S
Exact Mass: 751.07 Molecular Weight: 753.50 The synthesis of compound 1-47 was performed according to compound 1-30, using 2,5-dibromothiophene-3-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 64 mg, 68% (last step) ESI-MS: 752.2 / 754.2 / 756.2 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-48 0)-L
N I NN
o o CI
(S)-2-(2,5-dichlorothiazole-4-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C29H34.Cl2N606S
Exact Mass: 664.16 Molecular Weight: 665.59 The synthesis of compound 1-48 was performed according to compound 1-30, using 2,5-dichlorothiazole-4-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 26 mg, 48% (last step) ESI-MS: 665.3 / 667.3 [M+H]
Preparation of compound 1-49 ON
0 ( H 0 NN
H
(S)-2-(2,5-dimethylfuran-3-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C32H41N507 Exact Mass: 607.30 Molecular Weight: 607.70 The synthesis of compound 1-49 was performed according to compound 1-30, using 2,5-dimethylfuran-3-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 53 mg, 74% (last step) ESI-MS: 608.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-50 N
H
SANJcr NH )-L N
Br (S)-2-(4-bromothiazole-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C29H35BrN606S
Exact Mass: 674.15 Molecular Weight: 675.59 The synthesis of compound 1-50 was performed according to compound 1-30, using bromothiazole-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 37 mg, 59% (last step) ESI-MS: 675.3 / 677.3 [M+H]
Preparation of compound 1-51 0)-LN
H
0 )C H 0 H
N N N
\ I H 0 1 1 Br (S)-2-(4-bromothiophene-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C30H36BrN506S
Exact Mass: 673.16 Molecular Weight: 674.61 The synthesis of compound 1-51 was performed according to compound 1-30, using bromothiophene-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 52 mg, 66% (last step) ESI-MS: 674.3 /676.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-52 0 r H 0 NN
CI\I Ho II
Br (S)-2-(4-bromo-5-chlorothiophene-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C30H35BrCIN506S
Exact Mass: 707.12 Molecular Weight: 709.05 The synthesis of compound 1-52 was performed according to compound 1-30, using bromo-5-chlorothiophene-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 48 mg, 65% (last step) ESI-MS: 708.2 / 710.2 [M+H]
Preparation of compound 1-53 Br\i Ho II
Br (S)-2-(4,5-dibromothiophene-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C30H356r2N506S
Exact Mass: 751.07 Molecular Weight: 753.50 The synthesis of compound 1-53 was performed according to compound 1-30, using 4,5-dibromothiophene-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 52 mg, 63% (last step) ESI-MS: 752.2 / 754.2 / 756.2 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-54 0, N
N
\ I Ho I I
CI
(S)-2-(4,5-dichlorothiophene-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C301-135Cl2N506S
Exact Mass: 663.17 Molecular Weight: 664.60 The synthesis of compound 1-54 was performed according to compound 1-30, using 4,5-dichlorothiophene-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 63 mg, 68% (last step) ESI-MS: 664.2 / 666.2 [M+H]
Preparation of compound 1-55 n 7NJ-L JGH 0 Nj-L
- N
cõ) H 0 _ r\irN
(S)-2-((S)-1-acetylpyrrolidine-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C32H4.4.N607 Exact Mass: 624.33 Molecular Weight: 624.73 The synthesis of compound 1-55 was performed according to compound 1-30, using (S)-1-acetylpyrrolidine-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 76 mg, 73% (last step) ESI-MS: 625.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-56 oLN
H
I N
N
(S)-N1-ethyl-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-1,2,3-triazole-5-carboxamido)-2-oxohexanediamide Chemical Formula: C29F138N806 Exact Mass: 594.29 Molecular Weight: 594.66 The synthesis of compound 1-56 was performed according to compound 1-30, using methyl-1H-1,2,3-triazole-5-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 50 mg, 61% (last step) ESI-MS: 595.5 [M+H]
Preparation of compound 1-57 N
HN H-(S)-N1-ethyl-N6-(1-(2-(2-adamantylamino)-2-oxoethy1)-2-oxo-1,2-clihydropyridin-3-y1)-2-oxo-5-(2H-tetrazole-5-carboxamido)hexanediamide Chemical Formula: C271-135N906 Exact Mass: 581.27 Molecular Weight: 581.62 The synthesis of compound 1-57 was performed according to compound 1-30, using tetrazole-5-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 32 mg, 48% (last step) ESI-MS: 582.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-58 ON
, N N
OH
(S)-N1-ethyl-N6-(1-(2-(5-hydroxyadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxo-5-(pyrazine-2-carboxamido)hexanediamide Chemical Formula: C30H37N707 Exact Mass: 607.28 Molecular Weight: 607.66 The synthesis of compound 1-58 was performed according to compound 1-1 , using hydroxy-2-adamantanamine instead of 1-adamantanamine in step 2 (according to ZED3912) and pyrazine-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 26 mg, 53% (last step) ESI-MS: 608.5 [M+H]
.. Preparation of compound 1-59 0llN
LNi(rH
N-rN
I I
HN¨ 0 0 (S)-N1-ethyl-N6-(1-(2-(5-fluoroadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxo-5-((S)-pyrrolidine-3-carboxamido)hexanediamide Chemical Formula: C30H41FN606 Exact Mass: 600.31 Molecular Weight: 600.68 The synthesis of compound 1-59 was performed according to compound 1-1 , using fluoro-2-adamantanamine instead of 1-adamantanamine in step 2 (according to ZED3912) and (S)-1-Boc-pyrrolidine-3-carboxylic acid instead of 1-methy1-1H-imidazole-.. 5-carboxylic acid in step 6 (according to compound I-1b). The final product was obtained by deprotection (DCM/TFA) as described above and purified by HPLC.
Yield: 35 mg, 83% (last step) ESI-MS: 601.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-60 o 0)-L
NA
- N
_ NThrN
= H
0 0 1ci (S)-N1-ethyl-N6-(1-(2-(5-chloroadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxo-5-((S)-piperidine-2-carboxamido)hexanediamide Chemical Formula: C31F143CIN606 Exact Mass: 630.29 Molecular Weight: 631.16 The synthesis of compound 1-60 was performed according to compound 1-1, using chloro-2-adamantanamine instead of 1-adamantanamine in step 2 (according to .. ZED3912) and (S)-1-Boc-piperidine-2-carboxylic acid instead of 1-methy1-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b). The final product was obtained by deprotection (DCM/TFA) as described above and purified by HPLC.
Yield: 37 mg, 78% (last step) ESI-MS: 631.4 / 633.4 [M+H]
Preparation of compound 1-61 NJC-iN)-L
, N
Br (S)-N1-ethyl-N6-(1-(2-(5-bromoadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxo-5-((R)-piperidine-3-carboxamido)hexanediamide Chemical Formula: C31H43BrN606 Exact Mass: 674.24 Molecular Weight: 675.61 The synthesis of compound 1-61 was performed according to compound 1-1, using bromo-2-adamantanamine instead of 1-adamantanamine in step 2 (according to ZED3912) and (R)-1-Boc-piperidine-3-carboxylic acid instead of 1-methy1-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b). The final product was obtained by deprotection (DCM/TFA) as described above and purified by HPLC.
Yield: 35 mg, 72% (last step) ESI-MS: 675.3 / 677.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-62 0 Nj-1 r\ir0N
(S)-N1-ethyl-N6-(1-(2-(5-methyladamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-((R)-morpholine-3-carboxamido)-2-oxohexanediamide Chemical Formula: C31H44N607 Exact Mass: 612.33 Molecular Weight: 612.72 The synthesis of compound 1-62 was performed according to compound 1-1 , using methy1-2-adamantanamine instead of 1-adamantanamine in step 2 (according to ZED3912) and (R)-4-Boc-morpholine-3-carboxylic acid instead of 1-methy1-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b). The final product was obtained by deprotection (DCM/TFA) as described above and purified by HPLC.
Yield: 31 mg, 80% (last step) ESI-MS: 613.5 [M+H]
Preparation of compound 1-63 0llN
N- H CN
(S)-N1-ethyl-N6-(1-(2-(2-carbonitrileadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxo-5-((3S,4R)-quinuclidine-3-carboxamido)hexanediamide Chemical Formula: C34H45N706 Exact Mass: 647.34 Molecular Weight: 647.76 The synthesis of compound 1-63 was performed according to compound 1-1 , using aminoadamantane-2-carbonitrile instead of 1-adamantanamine in step 2 (according to ZED3912) and quinuclidine-3-carboxylic acid instead of 1-methy1-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 24 mg, 56% (last step) ESI-MS: 648.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-64 H CO2Me Njc N
CO2Me (S)-methyl 3-(6-(ethylamino)-1-(1-(2-(methyl 2-aminoadamantane-2-carboxylate)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-1,5,6-trioxohexan-2-ylcarbamoy1)-5-nitrobenzoate Chemical Formula: C36H4.2N6012 Exact Mass: 750.29 Molecular Weight: 750.75 The synthesis of compound 1-64 was performed according to compound 1-1 , using methyl 2-aminoadamantane-2-carboxylate instead of 1-adamantanamine in step 2 (according to ZED3912) and mono-methyl 5-nitroisophthalate instead of 1-methyl-imidazole-5-carboxylic acid in step 6 (according to compound I-1b).
Yield: 46 mg, 71% (last step) ESI-MS: 751.5 [M+H]
Preparation of compound 1-65 ON
NrN
(S)-N1-(1-(2-(1-adamantylmethylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-2-(5-nitronicotinamido)-5-oxohexanediamide Chemical Formula: C32H39N708 Exact Mass: 649.29 Molecular Weight: 649.69 The synthesis of compound 1-65 was performed according to compound 1-1 , using adamantanemethylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 5-nitronicotinic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b).
Yield: 61 mg, 74% (last step) ESI-MS: 650.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-66 0, N
H
HO2CNJc N
J IN N
5-((2S)-1-(1-(2-1-adamantylmethylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(ethylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinic acid Chemical Formula: C34F142N608 Exact Mass: 662.31 Molecular Weight: 662.73 The synthesis of compound 1-66 was performed according to compound 1-1, using rimantadine instead of 1-adamantanamine in step 2 (according to ZED3912) and 3,5-pyridinedicarboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b).
Yield: 31 mg, 56% (last step) ESI-MS: 663.5 [M+H]
Preparation of compound 1-67 S, N
(S)-N1-ethyl-N6-(1-(2-(2-adamantyl(methyl)amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(6-methylimidazo[2,1-1D]thiazole-5-carboxamido)-2-oxohexanediamide Chemical Formula: C33H41N706S
Exact Mass: 663.28 Molecular Weight: 663.79 The synthesis of compound 1-67 was performed according to compound 1-1, using N-methyl-2-adamantanamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b).
Yield: 23 mg, 52% (last step) ESI-MS: 664.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-68 o hiN NH jC
(S)-N1-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-y1)-N6-ethy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C32H37N507 Exact Mass: 603.27 Molecular Weight: 603.67 The synthesis of compound 1-68 was performed according to compound 1-1, using ( )-endo-2-norbornylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 3-methylbenzo[b]furan-2-carboxylic acid instead of 1-methyl-1H-im idazole-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 106 mg, 78% (last step) ESI-MS: 604.4 [M+H]
Preparation of compound 1-69 N)-L N
o Nr N H
(S)-N1-ethy1-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide Chemical Formula: C35H43N507 Exact Mass: 645.32 Molecular Weight: 645.75 The synthesis of compound 1-69 was performed according to compound 1-1, using (R)-(+)-bornylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 3-methylbenzo[b]furan-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b).
Yield: 86 mg, 72% (last step) ESI-MS: 646.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-70 0 , Njc N
(S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C32H37N507 Exact Mass: 603.27 Molecular Weight: 603.67 The synthesis of compound 1-70 was performed according to compound 1-1, using exo-2-aminonorbornane instead of 1-adamantanamine in step 2 (according to ZED3912) and 3-methylbenzo[b]furan-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 94 mg, 79% (last step) ESI-MS: 604.4 [M+H]
Preparation of compound 1-71 NH
N
(S)-N1-(1-(2-((ls,4R)-bicyclo[2.2.1]heptan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-2-(isonicotinamido)-5-oxohexanediamide Chemical Formula: C28F-134N606 Exact Mass: 550.25 Molecular Weight: 550.61 The synthesis of compound 1-71 was performed according to compound 1-1, using bicyclo[2.2.1]heptan-1-ylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and isonicotinic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b).
Yield: 77 mg, 72% (last step) ESI-MS: 551.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-72 0 jcI N N NH
(S)-N1-(1-(2-(bicyclo[2.2.1]heptan-7-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-5-oxo-2-(pyridazine-4-carboxamido)hexanediamide Chemical Formula: C271-133N706 Exact Mass: 551.25 Molecular Weight: 551.59 The synthesis of compound 1-72 was performed according to compound 1-1, using bicyclo[2.2.1]heptan-7-ylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and pyridazine-4-carboxylic acid instead of 1-methy1-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 44 mg, 61% (last step) ESI-MS: 552.4 [M+H]
Preparation of compound 1-73 NN H
N NH
NjC1-1 .. N
(S)-N1-(1-(2-((1R,2R,4R)-bicyclo[2.2.1]hept-5-en-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-5-oxo-2-(pyridazine-3-carboxamido)hexanediamide Chemical Formula: C27F131 N706 Exact Mass: 549.23 Molecular Weight: 549.58 The synthesis of compound 1-73 was performed according to compound 1-1, using bicyclo[2.2.1]hept-5-en-2-amine instead of 1-adamantanamine in step 2 (according to ZED3912) and pyridazine-3-carboxylic acid instead of 1-methy1-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b).
Yield: 31 mg, 52% (last step) ESI-MS: 550.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-74 N
HµN-N 0 0 (2S)-N1-(1 -(2-(bicyclo[2.2.2]octan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-5-oxo-2-(2H-1,2,3-triazole-4-carboxamido)hexanediamide Chemical Formula: C26H341\1806 Exact Mass: 554.26 Molecular Weight: 554.60 The synthesis of compound 1-74 was performed according to compound 1-1, using bicyclo[2.2.2]oct-2-ylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 2H-1,2,3-triazole-4-carboxylic acid instead of 1-methy1-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 35 mg, 57% (last step) ESI-MS: 555.4 [M+H]
Preparation of compound 1-75 0 0 õ
,s ¨NYLNjEr H
N
(S)-N1-ethyl-5-(1-methyl-1 H-1 ,2,3-triazole-4-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1 R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yOhexanediamide Chemical Formula: C29H40N806 Exact Mass: 596.31 Molecular Weight: 596.68 The synthesis of compound 1-75 was performed according to compound 1-1, using (R)-(-)-isobornylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 1-methyl-1H-1,2,3-triazole-4-carboxylic acid instead of 1-methyl-1H-im idazole-carboxylic acid in step 6 (according to compound I-1b).
Yield: 44 mg, 68% (last step) ESI-MS: 597.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-76 0)-LN
YLN NH )'LN
(S)-N1-ethyl-5-(1-methyl-1H-1,2,4-triazole-3-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-24(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)ethyl)-1 ,2-dihydropyridin-3-yhhexanediamide Chemical Formula: C29H40N306 Exact Mass: 596.31 Molecular Weight: 596.68 The synthesis of compound 1-76 was performed according to compound 1-1, using (1R,2R,3R,5S)-(-)-isopinocampheylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 1-methyl-1H-1,2,4-triazole-3-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b).
Yield: 51 mg, 72% (last step) ESI-MS: 597.5 [M+H]
Preparation of compound 1-77 , N
r\ir N
H
(S)-2-(benzofuran-3-carboxamido)-N6-ethyl-5-oxo-N1-(2-oxo-1-(2-oxo-2-((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide Chemical Formula: C34H41N507 Exact Mass: 631.30 Molecular Weight: 631.72 The synthesis of compound 1-77 was performed according to compound 1-1, using (1S,2S,3S,5R)-(+)-isopinocampheylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and benzofuran-3-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b).
Yield: 66 mg, 75% (last step) ESI-MS: 632.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-78 N
, N N
I H I
(S)-2-(benzo[b]thiophene-3-carboxamido)-N6-ethyl-N1-(1-(2-(4-homoisotwistane-3-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C35H41 N506S
Exact Mass: 659.28 Molecular Weight: 659.79 The synthesis of compound 1-78 was performed according to compound 1-1 , using amino-4-homoisotwistane instead of 1-adamantanamine in step 2 (according to ZED3912) and benzo[b]thiophene-3-carboxylic acid instead of 1-methy1-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 42 mg, 59% (last step) ESI-MS: 660.4 [M+H]
Preparation of compound 1-79 N NH
"
(S)-N1-ethyl-N6-(1-(2-(diamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methyl-1H-pyrazole-4-carboxamido)-2-oxohexanediamide Chemical Formula: C34.H4.3N706 Exact Mass: 645.33 Molecular Weight: 645.75 The synthesis of compound 1-79 was performed according to compound 1-1 , using aminodiamantane instead of 1-adamantanamine in step 2 (according to ZED3912) and 1-methyl-1H-pyrazole-4-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b).
Yield: 28 mg, 53% (last step) ESI-MS: 646.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-80 0 )-L
N
H
e_LO f H Oil H
-rHN N /
(S)-N1-ethyl-N6-(1-(2-(diamantane-4-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methyl-1H-pyrazole-3-carboxamido)-2-oxohexanediamide Chemical Formula: C34F143N706 Exact Mass: 645.33 Molecular Weight: 645.75 The synthesis of compound 1-80 was performed according to compound 1-1 , using aminodiamantane instead of 1-adamantanamine in step 2 (according to ZED3912) and 1-methyl-1H-pyrazole-3-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 36 mg, 59% (last step) ESI-MS: 646.5 [M+H]
Scheme 1-3 New Building Block OH 1-(Bromomethyl)- 0 adamantane 02N ..õ,j\I --L, 02N j-, N
DMF, DIPEA
10% Pd/C
Me0H
H2Nj-L
j\I
1 Preparation of compound ZED4893 02N j-U\I
1-(1-adamantylmethyl)-3-nitropyridin-2(1H)-one Chemical Formula: C16H20N203 Exact Mass: 288.15 Molecular Weight: 288.34 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 500 mg (3.57 mmol) of 2-hydroxy-3-nitropyridine and 818 mg (1 eq) of 1-(bromomethyl)adamantane were dissolved in 10 mL DMF and 1.24 mL DIPEA (2 eq) and stirred at room temperature overnight. The solvent was evaporated; the residue was dissolved in 30 mL Et0Ac and washed twice with each 10 mL citric acid solution (10%), NaHCO3 solution (10%) and brine. The organic phase was dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by HPLC.
Yield: 484 mg, 47%
ESI-MS: 289.3 [M+H]
2 Preparation of compound ZED4894 H2Nj-N
3-amino-1-(1-adamantylmethyl)pyridin-2(1 H)-one Chemical Formula: C16H22N20 Exact Mass: 258.17 Molecular Weight: 258.36 484 mg (1.68 mmol) of ZED4893 were suspended in 30 mL Me0H before 50 mg of palladium (10%) on activated carbon (unreduced) were added. The suspension was stirred for 3 h at room temperature under an atmosphere of hydrogen. The catalyst was filtered, and the solvent was evaporated.
Yield: 339 mg, 78%
ESI-MS: 259.4 [M+H]
Preparation of compound 1-81 0 ( H 0 (, N
H
N-NN
(S)-N1-(1-(1-adamantylmethyl)-2-oxo-1 ,2-di hydropyridin-3-y1)-N6-ethyl-2-(1 -methyl-1 H-pyrazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C29H38N605 Exact Mass: 550.29 Molecular Weight: 550.65 The synthesis of compound 1-81 was performed according to compound 1-1, using ZED4894 instead of ZED3913 in step 5 (according to I-1a) and 1-methyl-1H-pyrazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b).
Yield: 43 mg, 65% (last step) ESI-MS: 551.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-82 ,SN
)-L
N
No IA
OH
(S)-N1-(14(3-hydroxy-1-adamantyl)methyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(4-cyclopropyl-1,2,3-thiadiazole-5-carboxamido)-N6-ethyl-5-oxohexanediamide Chemical Formula: C30H38N606S
Exact Mass: 610.26 Molecular Weight: 610.72 The synthesis of compound 1-82 was performed according to compound 1-81, using (bromomethyl)-1-adamantanol instead of 1-(bromomethyl)adamantane (according to ZED4893) and 4-cyclopropyl-[I,2,3]thiadiazole-5-carboxylic acid instead of 1-methyl-1H-pyrazole-5-carboxylic acid.
Yield: 26 mg, 46% (last step) ESI-MS: 611.4 [M+H]
Preparation of compound 1-83 N
H
N
N I Hr I ¨I
Br (S)-N1-(1-((3-bromo-1-adamantyl)methyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-5-oxo-2-(1,2,5-thiadiazole-3-carboxamido)hexanediamide Chemical Formula: C27H33BrN605S
Exact Mass: 632.14 Molecular Weight: 633.56 The synthesis of compound 1-83 was performed according to compound 1-81, using bromo-3-(bromomethyl)adamantane instead of 1-(bromomethyl)adamantane (according to ZED4893) and 1,2,5-thiadiazole-3-carboxylic acid instead of 1-methyl-1H-pyrazole-5-carboxylic acid.
Yield: 42 mg, 61% (last step) ESI-MS: 633.3 / 635.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-84 o N)-L
N
N, H
1\1 HO
(S)-N1-(1-(2-adamantylmethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-2-(4-(hydroxymethyl)-1,2,3-thiadiazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C28F-136N606S
Exact Mass: 584.24 Molecular Weight: 584.69 The synthesis of compound 1-84 was performed according to compound 1-81, using (bromomethyl)adamantane instead of 1-(bromomethyl)adamantane (according to ZED4893) and 4-((tetrahydro-2H-pyran-2-yloxy)methyl)-1,2,3-thiadiazole-5-carboxylic acid instead of 1-methyl-1H-pyrazole-5-carboxylic acid. The tetrahydropyranyl (Thp) protecting group was cleaved by TFA in the final step.
Yield: 15 mg, 68% (last step) ESI-MS: 585.4 [M+H]
Preparation of compound 1-85 0 ( H 0 N N
HN
(S)-2-(4-tert-buty1-1H-pyrrole-3-carboxamido)-N1-(1-(2-(1-adamantylamino)ethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-5-oxohexanediamide Chemical Formula: C34.H4.7N505 Exact Mass: 605.36 Molecular Weight: 605.77 The synthesis of compound 1-85 was performed according to compound 1-81, using 1-(2-bromoethyl)adamantane instead of 1-(bromomethyl)adamantane (according to ZED4893) and 5-tert-butyl-1H-pyrrole-3-carboxylic acid instead of 1-methyl-1H-pyrazole-5-carboxylic acid.
Yield: 32 mg, 58% (last step) ESI-MS: 606.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-86 N
NCNNjc NH
N \ 0 (S)-2-(4-cyano-1 -methyl-1 H-pyrrole-2-carboxamido)-N1-(1-(1-adamantylamino)propy1)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-5-oxohexanediamide Chemical Formula: 033H42N605 Exact Mass: 602.32 Molecular Weight: 602.72 The synthesis of compound 1-86 was performed according to compound 1-81, using 1-(3-bromopropyl)adamantane instead of 1-(bromomethyl)adamantane (according to ZED4893) and 4-cyano-1-methyl-1H-pyrrole-2-carboxylic acid instead of 1-methyl-pyrazole-5-carboxylic acid.
Yield: 28 mg, 51% (last step) ESI-MS: 603.5 [M+H]
Preparation of compound 1-87 0)-LN
0?LNJciNj-LN
(S)-N1-(1-(3-(2-adamantylamino)-3-oxopropy1)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-2-(5-methoxyoxazole-2-carboxamido)-5-oxohexanediamide Chemical Formula: C31H4oN608 Exact Mass: 624.29 Molecular Weight: 624.68 The synthesis of compound 1-87 was performed according to compound 1-1, using chloropropionic acid instead of chloroacetic acid (according to ZED1657) and 5-methoxyoxazole-2-carboxylic acid instead of 1-methyl-1H-pyrazole-5-carboxylic acid in step 6 (according to compound I-1b).
Yield: 39 mg, 64% (last step) ESI-MS: 625.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-88 N
(S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C30H33N507 Exact Mass: 575.24 Molecular Weight: 575.61 The synthesis of compound 1-88 was performed according to compound 1-1 , using bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 3-methylbenzo[b]furan-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b).
Yield: 107 mg, 81% (last step) ESI-MS: 576.4 [M+H]
Preparation of compound 1-89 0-(N
Nj-L NH
N
(S)-2-(2-acetyloxazole-4-carboxamido)-N1-(1-(2-(bicyclo[1A A ]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-5-oxohexanediamide Chemical Formula: C26H30N608 Exact Mass: 554.21 Molecular Weight: 554.55 The synthesis of compound 1-89 was performed according to compound 1-1 , using bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 2-acetyloxazole-4-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b).
Yield: 68 mg, 75% (last step) ESI-MS: 555.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-90 0)LN
U\IN
(S)-N1-(1-(2-(bicyclo[2.1A]hexan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-2-(2-isopropyloxazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C28H36N607 Exact Mass: 568.26 Molecular Weight: 568.62 The synthesis of compound 1-90 was performed according to compound 1-1, using bicyclo[2.1.1]hexan-1-amine instead of 1-adamantanamine in step 2 (according to ZED3912) and 2-isopropyloxazole-5-carboxylic acid instead of 1-methy1-1H-imidazole-5-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 46 mg, 60% (last step) ESI-MS: 569.4 [M+H]
Preparation of compound 1-91 0)-LN
NN
I I
\ 0 0 (2S)-N1-(1-(2-(bicyclo[3.2.1]octan-8-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(3,5-dimethylisoxazole-4-carboxamido)-N6-ethyl-5-oxohexanediamide Chemical Formula: C29H38N607 Exact Mass: 582.28 Molecular Weight: 582.65 The synthesis of compound 1-91 was performed according to compound 1-1, using bicyclo[3.2.1]octan-8-amine instead of 1-adamantanamine in step 2 (according to ZED3912) and 3,5-dimethylisoxazole-4-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b).
Yield: 32 mg, 54% (last step) ESI-MS: 583.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-92 0)-L N
NNCN N N
(S)-N1-ethyl-N6-(1-(2-(5-carboxy-2-aminoadamantane)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(4-methylpyrimidine-5-carboxamido)-2-oxohexanediamide Chemical Formula: C32H39N708 Exact Mass: 649.29 Molecular Weight: 649.69 The synthesis of compound 1-92 was performed according to compound 1-1 , using aminoadamantane-1-carboxylic acid instead of 1-adamantanamine in step 2 (according to ZED3912) and 4-methylpyrimidine-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b).
Yield: 35 mg, 46% (last step) ESI-MS: 650.5 [M+H]
Preparation of compound 1-93 N N N N
N
(5S)-N1-ethyl-N6-(1-(2-(4-aminoadamantane-N,N-dimethy1-1-carboxamide)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxo-5-(1,2,3,4-tetrahydronaphthalene-2-carboxamido)hexanediamide Chemical Formula: C37H45N507 Exact Mass: 67133 Molecular Weight: 671.78 The synthesis of compound 1-93 was performed according to compound 1-1 , using aminoadamantane-N,N-dimethy1-1-carboxamide instead of 1-adamantanamine in step (according to ZED3912) and 1,2,3,4-tetrahydronaphthalene-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b).
Yield: 31 mg, 55% (last step) ESI-MS: 672.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-94 oLN
N
N
(S)-2-((S)-1,4-diazabicyclo[2.2.2]octane-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C32F145N706 Exact Mass: 623.34 Molecular Weight: 623.74 The synthesis of compound 1-94 was performed according to compound 1-30, using 1,4-diazabicyclo[2.2.2]octane-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 39 mg, 58% (last step) ESI-MS: 624.5 [M+H]
Preparation of compound 1-95 N
N
(S)-N1-ethy1-5-(1H-indole-3-carboxamido)-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-clihydropyridin-3-y1)-2-oxohexanediamide Chemical Formula: C34H40N606 Exact Mass: 628.30 Molecular Weight: 628.72 The synthesis of compound 1-95 was performed according to compound 1-30, using indole-3-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 56 mg, 74% (last step) ESI-MS: 629.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-96 OAN
N Hjc (S)-N1-ethyl-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(6-methylimidazo[2,1-b]thiazole-3-carboxamido)-2-oxohexanediamide Chemical Formula: C32H39N706S
Exact Mass: 649.27 Molecular Weight: 649.76 The synthesis of compound 1-96 was performed according to compound 1-30, using methylimidazo[2,1-b][1,3]thiazole-3-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 33 mg, 56% (last step) ESI-MS: 650.5 [M+H]
Preparation of compound 1-97 o jcH 0 Nj-L NH
Ni (S)-2-(benzo[d]thiazole-2-carboxamido)-N1-(1-(2-(( IS,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-5-oxohexanediamide Chemical Formula: C30H34N606S
Exact Mass: 606.23 Molecular Weight: 606.69 The synthesis of compound 1-97 was performed according to compound 1-1, using ( )-endo-2-norbornylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 1,3-benzothiazole-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 45 mg, 73% (last step) ESI-MS: 607.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-98 NNjcN)-L NH
N
(S)-N1-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-2-(imidazo[2,1-b]thiazole-6-carboxamido)-5-oxohexanediamide Chemical Formula: C28H33N706S
Exact Mass: 595.22 Molecular Weight: 595.67 The synthesis of compound 1-98 was performed according to compound 1-1, using ( )-endo-2-norbornylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and imidazo[2,1-b][1,3]thiazole-6-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 26 mg, 50% (last step) ESI-MS: 596.4 [M+H]
Preparation of compound 1-99 ON
(õ0 N N)-L
NH
I H
(S)-N1-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-2-(4-hydroxy-6-(trifluoromethoxy)quinoline-3-carboxamido)-5-oxohexanediamide Chemical Formula: C33F135F3N608 Exact Mass: 700.25 Molecular Weight: 700.66 The synthesis of compound 1-99 was performed according to compound 1-1, using ( )-endo-2-norbornylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 4-hydroxy-6-(trifluoromethoxy)quinoline-3-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 15 mg, 42% (last step) ESI-MS: 701.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-100 o)LN
NH II
N NH
I ,N H- Y
(S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(cinnoline-3-carboxamido)-N6-ethyl-5-oxohexanediamide Chemical Formula: C29F131N706 Exact Mass: 573.23 Molecular Weight: 573.60 The synthesis of compound 1-100 was performed according to compound 1-1, using bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 3-cinnolinecarboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 37 mg, 65% (last step) ESI-MS: 574.4 [M+H]
Preparation of compound 1-101 N
(S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-2-(3-ethylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C31H35N507 Exact Mass: 589.25 Molecular Weight: 589.64 The synthesis of compound 1-101 was performed according to compound 1-1, using bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 3-ethylbenzofuran-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 55 mg, 73% (last step) ESI-MS: 590.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-102 N INHCr H NNH N
(S)-N1-(1-(2-(bicyclo[1.1.1]pentan-l-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-2-(1-ethyl-1H-indole-2-carboxamido)-5-oxohexanediamide Chemical Formula: C31H36N606 Exact Mass: 588.27 Molecular Weight: 588.65 The synthesis of compound 1-102 was performed according to compound 1-1, using bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 1-ethyl-1H-indole-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 43 mg, 68% (last step) ESI-MS: 589.4 [M+H]
Preparation of compound 1-103 N
NH
(S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-2-(2-methyl-1,8-naphthyridine-3-carboxamido)-5-oxohexanediamide Chemical Formula: C301-133N706 Exact Mass: 587.25 Molecular Weight: 587.63 The synthesis of compound 1-103 was performed according to compound 1-1, using bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 2-methyl-1,8-naphthyridine-3-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 40 mg, 64% (last step) ESI-MS: 588.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-104 )LN
U\IN
(S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-5-oxo-2-(1,2,3,4-tetrahydroquinoline-6-carboxamido)hexanediamide Chemical Formula: C31 H38 N1606 Exact Mass: 590.29 Molecular Weight: 590.67 The synthesis of compound 1-104 was performed according to compound 1-1, using bicyclo[2.1.1]hexan-1-amine instead of 1-adamantanamine in step 2 (according to ZED3912) and N-Boc-1,2,3,4-tetrahydroquinoline-6-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b). The final product was obtained by deprotection (DCM/TFA) as described above and purified by HPLC.
Yield: 27 mg, 73% (last step) ESI-MS: 591.4 [M+H]
Preparation of compound 1-105 ON N N
(S)-N1-ethyl-N6-(1-(2-(2-carboxy-2-amino-5-(trifluoromethyl)adamantane)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxo-5-(3-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)hexanediamide Chemical Formula: C37F141F3N609 Exact Mass: 770.29 Molecular Weight: 770.75 The synthesis of compound 1-105 was performed according to compound 1-1, using amino-5-(trifluoromethyl)adamantane-2-carboxylic acid instead of 1-adamantanamine in step 2 (according to ZED3912) and 3-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 19 mg, 44% (last step) ESI-MS: 771.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-106 otLN
N N
I I
(S)-N1-ethyl-N6-(1-(2-(5-ethyladamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1,6-naphthyridine-2-carboxamido)-2-oxohexanediamide Chemical Formula: C36F143N706 Exact Mass: 669.33 Molecular Weight: 669.77 The synthesis of compound 1-106 was performed according to compound 1-1, using ethyladamantane-2-amine instead of 1-adamantanamine in step 2 (according to ZED3912) and 1,6-naphthyridine-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 25 mg, 54% (last step) ESI-MS: 670.5 [M+H]
Preparation of compound 1-107 oN
N N
(S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-2-(2,6-naphthyridine-1-carboxamido)-5-oxohexanediamide Chemical Formula: C30H33N706 Exact Mass: 587.25 Molecular Weight: 587.63 The synthesis of compound 1-107 was performed according to compound 1-1, using bicyclo[2.1.1]hexan-1-amine instead of 1-adamantanamine in step 2 (according to ZED3912) and 2,6-naphthyridine-1-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 58 mg, 74% (last step) ESI-MS: 588.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-108 0-(N
H2N 0 0 -.4\
N I H
b-N 0 0 (S)-2-(4-amino-1,2,5-oxadiazole-3-carboxamido)-N1-(1-(2-(bicyclo[1A A ]pentan-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-5-oxohexanediamide Chemical Formula: C23H28N807 Exact Mass: 528.21 Molecular Weight: 528.52 The synthesis of compound 1-108 was performed according to compound 1-1, using bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 4-Boc-amino-1,2,5-oxadiazole-3-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b). The final product was obtained by deprotection (DCM/TFA) as described above and purified by HPLC.
Yield: 27 mg, 77% (last step) ESI-MS: 529.4 [M+H]
Preparation of compound 1-109 )-LN
Pi 0 0 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(6-(dimethylamino)benzofuran-2-carboxamido)-N6-ethyl-5-oxohexanediamide Chemical Formula: C3iH36N607 Exact Mass: 604.26 Molecular Weight: 604.65 The synthesis of compound 1-109 was performed according to compound 1-1, using bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 6-(dimethylamino)benzofuran-2-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 35 mg, 57% (last step) ESI-MS: 605.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-110 0)LN
0 jc H 0 e3A\IN JN NH
HN
(S)-2-(2-acetamidothiazole-5-carboxamido)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-5-oxohexanediamide Chemical Formula: C26H31 N1707S
Exact Mass: 585.20 Molecular Weight: 585.63 The synthesis of compound 1-110 was performed according to compound 1-1, using bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 2-acetylamino-5-thiazolecarboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 25 mg, 49% (last step) ESI-MS: 586.4 [M+H]
Preparation of compound 1-111 ON
H
0 Nj-L NH
jC
(S)-N4-(1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(ethylamino)-1,5,6-trioxohexan-2-y1)-1H-pyrrole-2,4-dicarboxamide Chemical Formula: C26H31N707 Exact Mass: 553.23 Molecular Weight: 553.57 The synthesis of compound 1-111 was performed according to compound 1-1, using bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 5-carbamoy1-1H-pyrrole-3-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 19 mg, 42% (last step) ESI-MS: 554.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-112 oLN
0,11 Nj-L
(S)-N1-ethyl-N6-(1-(2-(1-acetylamino-4-aminoadamantane)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxo-5-(5-sulfamoylfuran-3-carboxamido)hexanediamide Chemical Formula: C32H41 N7010S
Exact Mass: 715.26 Molecular Weight: 715.77 The synthesis of compound 1-112 was performed according to compound 1-1, using acetylamino-4-aminoadamantane instead of 1-adamantanamine in step 2 (according to ZED3912) and 5-sulfamoylfuran-3-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 24 mg, 53% (last step) ESI-MS: 716.4 [M+H]
Preparation of compound 1-113 Njc NH 0 (S)-2-(benzofuran-5-carboxamido)-N6-ethyl-N1-(1-(2-(1-acetylamino-4-aminoadamantane)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C36F142N608 Exact Mass: 686.31 Molecular Weight: 686.75 The synthesis of compound 1-113 was performed according to compound 1-1, using acetylamino-4-aminoadamantane instead of 1-adamantanamine in step 2 (according to ZED3912) and benzofuran-5-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 30 mg, 58% (last step) ESI-MS: 687.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-114 0 Njc NH )-LNN
(S)-2-(benzofuran-6-carboxamido)-N6-ethyl-N1-(1-(2-(4-aminoadamantane-1-carboxamide)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C35H4.0N608 Exact Mass: 672.29 Molecular Weight: 672.73 The synthesis of compound 1-114 was performed according to compound 1-1, using aminoadamantane-1-carboxamide instead of 1-adamantanamine in step 2 (according to ZED3912) and benzofuran-6-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 37 mg, 65% (last step) ESI-MS: 673.5 [M+H]
Preparation of compound 1-115 0)-(N
N
(S)-N1-ethyl-N6-(1-(2-(4-aminoadamantane-1-carboxamide)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(3-(1-methylcyclopropy1)-1,2,4-oxadiazole-5-carboxamido)-2-oxohexanediamide Chemical Formula: C33H4.2N808 Exact Mass: 678.31 Molecular Weight: 678.74 The synthesis of compound 1-115 was performed according to compound 1-1, using aminoadamantane-1-carboxamide instead of 1-adamantanamine in step 2 (according to ZED3912) and 3-(1-methylcyclopropyI)-1,2,4-oxadiazole-5-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 23 mg, 47% (last step) ESI-MS: 679.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-116 N
yLrilJc N NH
(S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-2-(5-methyl-1,2,4-oxadiazole-3-carboxamido)-5-oxohexanediamide Chemical Formula: C24H29N707 Exact Mass: 527.21 Molecular Weight: 527.53 The synthesis of compound 1-116 was performed according to compound 1-1, using bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 5-methyl-1,2,4-oxadiazole-3-carboxylic acid instead of benzofuran-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 36 mg, 62% (last step) ESI-MS: 528.4 [M+H]
Preparation of compound 1-117 /)?LN
N NH
(S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-5-oxo-2-(1,2,3-thiadiazole-4-carboxamido)hexanediamide Chemical Formula: C23H27N706S
Exact Mass: 529.17 Molecular Weight: 529.57 The synthesis of compound 1-117 was performed according to compound 1-1, using bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 1,2,3-thiadiazole-4-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 31 mg, 57% (last step) ESI-MS: 530.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-118 o S- N Jcri\lj- NH
ri y (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-5-oxo-2-(1,2,4-thiadiazole-5-carboxamido)hexanediamide Chemical Formula: 023H27N706S
Exact Mass: 529.17 Molecular Weight: 529.57 The synthesis of compound 1-118 was performed according to compound 1-1, using bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 1,2,4-thiadiazole-4-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 39 mg, 63% (last step) ESI-MS: 530.3 [M+H]
Preparation of compound 1-119 0)-LN
N.r NH N NH
(S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-5-oxo-2-(1,3,4-thiadiazole-2-carboxamido)hexanediamide Chemical Formula: C23H27N706S
Exact Mass: 529.17 Molecular Weight: 529.57 The synthesis of compound 1-119 was performed according to compound 1-1, using bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and 1,3,4-thiadiazole-5-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 28 mg, 52% (last step) ESI-MS: 530.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of compound 1-120 o m's Nc7 N
H I I
(S)-N1-ethy1-5-(4-formy1-1,2,3-thiadiazole-5-carboxamido)-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxohexanediamide Chemical Formula: C29H35N707S
Exact Mass: 625.23 Molecular Weight: 625/0 The synthesis of compound 1-120 was performed according to compound 1-30, using 4-(hydroxymethyl)-1,2,3-thiadiazole-5-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound 1-1b).
Yield: 17 mg, 41% (last step) ESI-MS: 626.4 [M+H]
Preparation of compound 1-121 0)-(N
NH
N(-1H N
(S)-N1-ethyl-N6-(1-(2-(3,5-dimethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(nicotinamido)-2-oxohexanediamide Chemical Formula: C31F138N606 Exact Mass: 590.29 Molecular Weight: 590.67 The synthesis of compound 1-120 was performed according to compound 1-1, using nicotinic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).
Yield: 56 mg, 60% (last step) ESI-MS: 591.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Preparation of reference compound Ref. 4 OA
N
N
)LN N
(S)-N1 -ethy1-5-(nicotinamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-(phenethylamino)ethyl)-1 ,2-dihydropyridin-3-yl)hexanediamide Chemical Formula: C29H32N606 Exact Mass: 560.24 Molecular Weight: 560.60 The synthesis of reference compound Ref. 4 was performed according to compound 1-1, using 2-phenylethylamine instead of 1-adamantanamine in step 2 (according to ZED3912) and nicotinic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound l-lb).
Yield: 68 mg, 77% (last step) ESI-MS: 561.4 [M+H]
Biological Examples Example B-1. Inhibitory effect of the compounds according to the invention Transglutaminase assay For the determination of potency of inhibitors against tissue transglutaminase, the incorporation of dansylcadaverine into dimethylcasein (Zedira product T036, Lorand et a/., Anal Biochem, 1971, 44:221-31) was measured using recombinant human transglutaminase 2 (Zedira Product T022).
The tissue transglutaminase is diluted in buffer (50 mM Tris-HCI, 7.5 mM
CaCl2, 150 mM
NaCI, pH = 7.4). The final concentration of TG2 in the assay is 10 nM.
A 10 mM inhibitor stock solution is prepared in DMSO, and from this a serial 1:2-fold dilution series is prepared also in DMSO. Each of the initial dilutions is subsequently diluted 1:50-fold with buffer (50 mM Tris-HCI, 7.5 mM CaCl2, 150 mM NaCI, pH =
7.4) to yield the final working dilutions containing 2% (v/v) DMSO.
15 pl of inhibitor working dilution are added per well of a 96 well microtiter plate. As control, 15 pl of a 2% (v/v) DMSO solution prepared using the buffer mentioned above are added per well.
Immediately before starting the assay, 600 pl transglutaminase working solution are added to 11.4 ml assay buffer (50 mM Tris-HCI, 10 mM CaCl2, 10 mM glutathione, 2.5%
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 glycerol, 16.7 pM dansylcadaverine, 4 pM N,N-dimethylcasein, 200 mM NaCI, pH =
8.0).
285 pl of this reaction mix are added per well containing the inhibitor.
Increase in fluorescence is measured using Aex = 330 nm and Aem = 500 nm at 37 C for 30 min. A slope of the increase in fluorescence between 20 and 30 min is calculated for determination of the ICso value (inhibitor concentration at which 50% of the initial activity is blocked).
Analysis of enzymatic activity is performed by calculation of the slope of an increase in fluorescence intensity. ICso values are calculated by plotting the enzymatic activity (as percentage from control containing 2% DMSO instead of inhibitor) against the inhibitor concentration. ICso is defined as the inhibitor concentration blocking 50% of initial enzyme activity.
The inhibitory activity of the inventive compounds in regard to tissue transglutaminase (TG2) is shown in the following table 1 using ICso-values.
Table 1. efficacy of reversible TG2 inhibitors A: ICso < 150 nM, B: 150 nM ICso <600 nM, C: 600 nM ICso < 3,500 nM, D: 3,500 nM ICso < 10,000 nM
ICso I C50 Compound Compound TG2 [nM] TG2 [nM]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 Ref. 1 C 1-121 A
Ref. 2 A
Ref. 3 D Ref. 4 D
Ref. 1 (ZED3641) Ref. 2 (ZED1227) 00Me o)-LN
H
H H
1\1 N .----,,,,,N.õ..---,,_,--NN -c NH')N-M-IN'----'"-----/YNcN
.--N 0 0 N \
Ref. 3 (A8, ZED1047) Ref. 4 o,o o 0)*.N.-----,...., H
0 u 0 0 0 H H
Nljc-rINI
II NN
0 1\ljcrNH') _ JI NN
I H I ,, H
l\r Example B-2. logD values of the inventive compounds 10 In order to classify the inventive compounds according to their lipophilicity, LogD values (distribution coefficient) were determined by means of the well-established shake flask method, measuring the partition of a compound between an octanol and phosphate-buffered saline (PBS, pH 7.4) by HPLC.
Compounds with a moderate lipophilicity (LogD values from 0 to 3) are usually 15 advantaged for oral absorption, being in balance between solubility and permeability.
However, sophisticated formulation of a compound might improve oral bioavailability for highly lipophilic compounds.
Table 2. logD values of reversible TG2 inhibitors 20 A: logD < 1, B: 1 logD < 3, C: 3 logD < 5 Compound logD Compound logD
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 1_55 B 1-115 A
Ref. 1 A 1-121 A
Ref. 2 B
Ref. 3 B Ref. 4 A
Example B-3. Caco-2 permeability assay of the inventive compounds Permeability coefficients (Papp values) were obtained from Caco-2 barrier studies predicting oral/intestinal bioavailability of the tested compounds. The assays were performed by using CacoReadyTM ready-to-use kits from ReadyCell according to the manufacturers protocol.
It is considered that compounds bearing Papp values above 1x10-6 cm/s are classified as permeable whereas compounds bearing Papp values below 1x10-6 cm/s are classified as not permeable.
Table 3. Caco2 permeability assay of reversible TG2 inhibitors A: Papp < 1x10-6 cm/s, B: Papp 1x10-6 cm/s Papp < 10x10-6 cm/s 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Papp [CM/S] Papp [CM/S]
Compound Compound x10-6 x10-6 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 Ref. 1 A 1-121 A
Ref. 2 A
Ref. 3 A Ref. 4 A
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 1541. A compound of the general formula (I):
0 (0 H (I) 7,.N yL R3 wherein L represents ¨1_1-L2¨;
LI represents ¨CH2¨, ¨CH2CH2¨, ¨CH2CH2CH2¨, ¨CH2C0¨, or ¨CH2CH2C0¨;
L2 represents a bond, ¨NRI41¨, ¨NRN1CH2¨, ¨NRN1CH2CH2¨, or ¨NRNICH(CH3)¨;
R1 represents 0 =
' R2 represents RN
- _ 0 Rs Rii 0 Ra - _ S Rs R11 S Rs --Rlo R9 ;
' R9 Rlo R9 ;
' R9 Rlo R9 ;
, , RN RN RN RN RN
RN
R11 N R8 R11 N, Rii N, R11 N _ _ --14N 1 iN
.,), K n ----R1,...1 11R8 ) _________________________________________________________ N
N
/ R9 Rlo µ, / Ro R.- IR Rlo , / , RN Rlo Rlo R1-1.(:)_...- Ril 0R8 --_0 R8 os)--..-- R8 13) Y __________ N ) __ N N Y __ N
; R10 ; , ; R8 ' N -\ , RN RN
\
os?..R10 R1, 5._._ RiR8 -- S R8 .---11N Rt,l,c11-N
N.--1\ R8 N
N \ n';
, N
R1)8 N R10 N , ; ;
' RN RN
,N, ,Nx_Rlo RN R12 R12 - - ---N'N'IRN
i( / Rlo ,, \-1\1 LI xj \-) ; N¨N ; N=N ; ------- R14 N R14 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 R13 N R13 R13 ---,,\TR
\N \-) Ria RioR13 N Ria N=Ria N Ria Rio (:)----\44 , RN
R11 , N---/y R12 S---/y,) , R12 - --TR13 ---, R10_<)---r/ -\ R1013 7R13 0"---13 R10 R14 S"---14 R10 R14 %
% RN
Rlo / N---/y,) '-1 /') 13 -- 4 1 71 R13 II 1 +R13 N N----' c7R
RN , R14 , R14 R._A
R11 ,, RN RN
. R9 . __________ Niv...._R14 (1 N, R9 0,1 Rio_---N1 14 \1R9 r Rio N __ S , R NS - \____,------R10 RN Rio , , R...ki 9 R9 ,S -- ),,,,__ --_ _Rio 4/, in N \ X N./ II --o) ". --/--, io ¨R N----R'" \N R8 \s_N N-_-_N
-' , ,S -- Fi8 N ' 0 ,S.õ,,,-- / ,- 0 N,, - 0 .---N Ru----\ il N6- Ru---- -I - R8---NI-- ---R8 N-N b-N WO
, , S
---N, N _yN
N __________ ( Nj N( i - N N N __ \( S S z S S z N
, ----eNS ---eNS ----eNH ---eNNH
IIN, ITij N __ ( 0 01\ij ..N _ N
-- \ --( ----eN0 ----eN0 ---eN0 N N __ \( Z
o N3 , N
, , , H
N,_-S
--N- /N S
H, S---___-N ____N
__C:1; --1/ S--_- ___C-r\----/___N--(/N
S-NN
, , , , H
N,.-0 N
--A-NI
S-N
-1\1/
--"1-.), 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 0--__-N _NI
-N
H H
p-...__N
/
, i ..
N
/ N , , _ N -- --'N
, N
-- -, N -N
N
, ., I -I
, ' -, N -, --'N 'N
N 1\11 N
, _ -_,1\1 I\1 -_,I\IN
- N
N N le 1 , ., N
NN I
1\1 1\1 N
-, -, 1rN 'rNii '-'r N, N NN, , '-- -, N N -, N. N
N,s, NN NN, -,fl\IN
--%
N
Nk," NN N
, -_,NN,N
--..._õ----__ Th\l N, , , -,,, ---!NN I\I N -,1\IN
1 1\1 I II
I 1 , f N N--N --, ------õ,--,N NN, , , 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 -,,N
Nle , Nie , N.N
, I\IN -,,N,N
'N
IV , N, , N. -, I\1 -,,I\I
'Nil N,2 N N N--N
, , , N N , 1\1-N1-, NN
, -' '-lr"N
N,N
N-, N I
1\1-N N , N N N
I I I
NN
, NN--N NN-,N
-,,N,N
I I
N. NN N N
el\I
, H
NH
HN NH , , ., N NH , HN , NH H , , N=\ 0 N=N N=\ N---N
\ N
N- N- N- -N -N
--- ;IV - ---- / N \ JV
N' N
-- __ N \
\ //IV
N, /
___________________________________ , _______ ' N ______________________ , --\ /,\N
-\
I\1 , --\ N --\ N -- N =
N
N IV N/ //
, 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 N=\ N=\
--- /(1\1 \ / N\/ N / N
N
N N¨N 'IV N //N
N=N N=N N=N N=N N=N
' N --, \ /N / N
, ________ , __________________________________ , N=\ N=\ N=\ N=\ N---( \ /71; \ S \ N
/ N N N , \
N/ N //N
N¨N N N/
, ---\ N , \ /71; \ S N N , ____ ¨\ ,N N N
, ¨N ¨N _¨N
-- --i ) \ ) \
/
N / N¨N N N
, ______________________________________________ , ¨\ ___\
-- N ---\ N \ S N S
N ; N¨//
N¨N N
* *
Ns /
Ns \ /IV N N
" N, /N N¨N -N N¨N ; N si\l/ , or ______________________ , , wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 ¨ R14 and R" ; and preferably with 1 to 3 of the substituents R11 ¨
R13;
R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl;
diamantyl;
or hexamethylenetetraminyl and the afore-mentioned residues optionally contain one or more C=C double bond(s) and/or are optionally substituted by one or more of Ra; Rb; Rc; Rd; and Re;
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Ra, Rb, Rc, Rd, and Re represent independently of each other -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C2H5, -CONH2, -CON HCH3, -CON(CH3)2, -CON HC2F15, -CH2CO2H, -CH2CO2CH3, -CH2CO2C21-15, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2F15, -NHCOCH3, -NHCOC21-15, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C21-15, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3;
R4 represents -N R6R7;
R6 represents -CH2CH3; and R7 represents -H;
R6, R6, R10, R11, R12, R13, and R14 represent independently of each other -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH (CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2F, -CH F2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2OH, -OCH3, -0C2H5, -0C3H7, -OCH(CH3)2, -0C(CH3)3, -0C4H9, -OCH F2, -0CF3, -OCH 2C F3 , -0C2F5, -OCH2OCH3, -0-cyclo-C3H5, -OCH2-cyclo-C3H5, -0-C2H4-cyclo-C3H5, -CHO, -COCH3, -COCF3, -00C2H5, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -COOH, -COOCH3, -CO0C2H5, -CO0C3H7, -COOCH(CH3)2, -COOC(CH3)3, -00C-CH3, -00C-CF3, -00C-C2H5, -00C-C3H7, -00C-CH (CH3)2, -00C-C(CH3)3, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -N HC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5, -NHCOC3H7, -NHCOCH(CH3)2, -NHCOC(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CON HCH (CH3)2, -CON H-cyclo-C3H5, -CON HC(CH3)3, -CON(CH3)2, -CON (C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -SO2NHCH(CH3)2, -SO2NH-cyclo-C3H5, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H5)2, -SO2N(C3H7)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C2H5, -NHSO2C3H7, -NHSO2CH (CH3)2, -NHSO2C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -CECH, -CEC-CH3, -CH2-CECH, -Ph, -0-Ph, -0-CH2-Ph, 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 I\1 H
I\1 H
N
--N
, , , , 1\1 1\1 r N r r / __ \ / __ \ / __ \ __ -N\ /NH, --N\ N-/ , or - -N N
\ ________________________________________________________________ / \ =
, , or R8 and R9 or R9 and R1 can form together one of the following five-membered or six-membered rings:
ci _-1-d --- -- --- --I\1 ---N --- -----) -- -- 1 --_1 '-./ ''0 --,% --.% '-, '-.N 'le, __1\1 õ-N - ,N
-I
-'1\1 'N or ---1\1-or R12 and R13 or R13 and R14 can form together one of the following five-membered or six-membered rings:
,o ,ici ,,ici ,-C) ,-0__-_.0 -0 --0 ,,.--..., , --./ '--O ''I:Y H or I - , Ri4 represents -H, -CH3, -C2F13, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H3, -C(CH3)3, -cyclo-C3H3, -cyclo-C4H7, -cyclo-C31-19, -CH2-cyclo-C3H3, -CH2-cyclo-C4H7, -CH2-cyclo-C3H9, -CH2F, -CHF2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CH F2; -CF12-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3, -00C21-13, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -CO-cyclo-C3H3, -CO-cyclo-C4H7, -CO-cyclo-C31-19, -COOCH 3;
-COOC2H3, -CO0C3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -S02CH3, -S02CF3, -S02C21-13, -S02C3H7, -S02CH(CH3)2, -S02-cyclo-C3H3, or -S02C(CH3)3;
RNi represents -H, -CH3, or -CH2CH3;
or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomer, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
2. The compound according to Claim 1, wherein 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 R2 represents RN
- 0 Ra R11 0 Ra _ _ S ,-, - 8 Rt1 S
Ro - - 11 R8 r -\\ r ( R1 R9 ; ' R9 R10 .-,9 ; ' R9 R10 ; K
RN RN RN RN
R11 N R8 R11 N, R11 ri, _ _ ,N,N R11 ON
_ _ R11 0 pp 8 N
/ ____________________________________ l( Y /K ir 1 -----N N
R9 R10 s, / R9 R10 R9 R10 /
- _2:)____ R8 ,_ R10 Ril SN Rii S R8 . -0? 10) R8 C/./ ir 1 N \ N
¨7 R N
Rlo N R8 N
N \ R- Rio , , RN RN RN
RN
S Ra - - N -õ, õ
Rii ri N
, ,N, _Rlo -\___ 1 N
N I ir N ________ N N ,N, N, '"
DN
--- N
R1 , R10, , , ,/ , N-N ; N=N ;
I R13 (R13 N/ R13 r Ri3 \N
-----Ria N-Ria N R14 N-Ria N Ria , RN
i\i ---- R12 0___-y 13 s 13 i\i -,) 3 I
-\- -- 'p -R14 R14 R14 iA
Rlo Rlo R1 o R -, RN
RN
sµ
N)---- R14 ii R9 r >1 iX ____________________________________________________ _ )...i _ R1.4 \-i)R14 ' .o. -n N S cõ, ' , , , ri R9 r\
\____ i___ 9 R9 _ ir_ -/* R 1 0 --/ __ , Ri n N \ 1\
\ I l/
IT
<:., m _ -\S-N
R8 ,S, - - R8 S)- - - N II
__-N R' . S - ---- il N./ Rµ-' IT - . N, - ---- -I N
\N=N R8 , N-N ; b-N
, N-0 - - - -N N
, , Icl 0 s ---eNNH
\ \ \ N __ ( , i S
, , ; , , , 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 N _ N
---eNNH ---( --(N ---eNS
N N __ \( SNjz S , N
---eNNH ---eNNH
IIN , i\il\IJ N __ ( 0 ONjz -- A -N N N __ \( , NiNj o ciN, N
H s N--...._-S
Nr-1, -- --- N -) --.1------) N N-N-S
, S----N
-k-N, ------S-N ---c_rN
N
S-N-N/ ----N, --C----) , N-0 -----N-N No ------N, H H , , -C-----Q
-, I\1 ., N /
N, , -, N -, ' N
-- - N
-. , -N
I II
N 1\r N /
-, N, I 'N
-I
N.N / , N
, ' -, N -. --'N 'N
N N
N
, -,,I\I I\1 -,,I\IN
-,N I
N
- N
I N I
IN 1\1-N
2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 _ I
- - - -- - z Z /z¨Z /z¨Z 7/ // Z Z Z \ / Z - Z /¨Z
Z¨ - Z Z¨
) Z\ , Z\ , Z\ Z ) Z' ZZ ) Z
) Z-Z K Z
/ ) Z)/ Z2/ Z)/ \ Z2/ \ ZZ ZZ \ Z \ Z 0 /
/ / 2/ µ Z Z
¨Z Z ¨/ ¨ ¨ Z , ¨/ , ¨/ , ¨Z ¨/ ¨Z ¨Z
¨/
--Z - - z ______________________ - z - - z __ - z -2 z \ z' 'z z/z 'z z"¨ z\ z' \ 0 'z z' ¨'z z"¨ \ z z/z 'z T
z" z¨z / z / _______ z ) /\ zz z)z __ z)z \ z)z __ \ z/z z/z z4 ¨z z ¨/ ¨ z ¨/ ¨/ z c z z __ z , _/ , _/
/
_ I
z e5 cõ
i 51
285 pl of this reaction mix are added per well containing the inhibitor.
Increase in fluorescence is measured using Aex = 330 nm and Aem = 500 nm at 37 C for 30 min. A slope of the increase in fluorescence between 20 and 30 min is calculated for determination of the ICso value (inhibitor concentration at which 50% of the initial activity is blocked).
Analysis of enzymatic activity is performed by calculation of the slope of an increase in fluorescence intensity. ICso values are calculated by plotting the enzymatic activity (as percentage from control containing 2% DMSO instead of inhibitor) against the inhibitor concentration. ICso is defined as the inhibitor concentration blocking 50% of initial enzyme activity.
The inhibitory activity of the inventive compounds in regard to tissue transglutaminase (TG2) is shown in the following table 1 using ICso-values.
Table 1. efficacy of reversible TG2 inhibitors A: ICso < 150 nM, B: 150 nM ICso <600 nM, C: 600 nM ICso < 3,500 nM, D: 3,500 nM ICso < 10,000 nM
ICso I C50 Compound Compound TG2 [nM] TG2 [nM]
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 Ref. 1 C 1-121 A
Ref. 2 A
Ref. 3 D Ref. 4 D
Ref. 1 (ZED3641) Ref. 2 (ZED1227) 00Me o)-LN
H
H H
1\1 N .----,,,,,N.õ..---,,_,--NN -c NH')N-M-IN'----'"-----/YNcN
.--N 0 0 N \
Ref. 3 (A8, ZED1047) Ref. 4 o,o o 0)*.N.-----,...., H
0 u 0 0 0 H H
Nljc-rINI
II NN
0 1\ljcrNH') _ JI NN
I H I ,, H
l\r Example B-2. logD values of the inventive compounds 10 In order to classify the inventive compounds according to their lipophilicity, LogD values (distribution coefficient) were determined by means of the well-established shake flask method, measuring the partition of a compound between an octanol and phosphate-buffered saline (PBS, pH 7.4) by HPLC.
Compounds with a moderate lipophilicity (LogD values from 0 to 3) are usually 15 advantaged for oral absorption, being in balance between solubility and permeability.
However, sophisticated formulation of a compound might improve oral bioavailability for highly lipophilic compounds.
Table 2. logD values of reversible TG2 inhibitors 20 A: logD < 1, B: 1 logD < 3, C: 3 logD < 5 Compound logD Compound logD
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 1_55 B 1-115 A
Ref. 1 A 1-121 A
Ref. 2 B
Ref. 3 B Ref. 4 A
Example B-3. Caco-2 permeability assay of the inventive compounds Permeability coefficients (Papp values) were obtained from Caco-2 barrier studies predicting oral/intestinal bioavailability of the tested compounds. The assays were performed by using CacoReadyTM ready-to-use kits from ReadyCell according to the manufacturers protocol.
It is considered that compounds bearing Papp values above 1x10-6 cm/s are classified as permeable whereas compounds bearing Papp values below 1x10-6 cm/s are classified as not permeable.
Table 3. Caco2 permeability assay of reversible TG2 inhibitors A: Papp < 1x10-6 cm/s, B: Papp 1x10-6 cm/s Papp < 10x10-6 cm/s 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Papp [CM/S] Papp [CM/S]
Compound Compound x10-6 x10-6 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 Ref. 1 A 1-121 A
Ref. 2 A
Ref. 3 A Ref. 4 A
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 1541. A compound of the general formula (I):
0 (0 H (I) 7,.N yL R3 wherein L represents ¨1_1-L2¨;
LI represents ¨CH2¨, ¨CH2CH2¨, ¨CH2CH2CH2¨, ¨CH2C0¨, or ¨CH2CH2C0¨;
L2 represents a bond, ¨NRI41¨, ¨NRN1CH2¨, ¨NRN1CH2CH2¨, or ¨NRNICH(CH3)¨;
R1 represents 0 =
' R2 represents RN
- _ 0 Rs Rii 0 Ra - _ S Rs R11 S Rs --Rlo R9 ;
' R9 Rlo R9 ;
' R9 Rlo R9 ;
, , RN RN RN RN RN
RN
R11 N R8 R11 N, Rii N, R11 N _ _ --14N 1 iN
.,), K n ----R1,...1 11R8 ) _________________________________________________________ N
N
/ R9 Rlo µ, / Ro R.- IR Rlo , / , RN Rlo Rlo R1-1.(:)_...- Ril 0R8 --_0 R8 os)--..-- R8 13) Y __________ N ) __ N N Y __ N
; R10 ; , ; R8 ' N -\ , RN RN
\
os?..R10 R1, 5._._ RiR8 -- S R8 .---11N Rt,l,c11-N
N.--1\ R8 N
N \ n';
, N
R1)8 N R10 N , ; ;
' RN RN
,N, ,Nx_Rlo RN R12 R12 - - ---N'N'IRN
i( / Rlo ,, \-1\1 LI xj \-) ; N¨N ; N=N ; ------- R14 N R14 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 R13 N R13 R13 ---,,\TR
\N \-) Ria RioR13 N Ria N=Ria N Ria Rio (:)----\44 , RN
R11 , N---/y R12 S---/y,) , R12 - --TR13 ---, R10_<)---r/ -\ R1013 7R13 0"---13 R10 R14 S"---14 R10 R14 %
% RN
Rlo / N---/y,) '-1 /') 13 -- 4 1 71 R13 II 1 +R13 N N----' c7R
RN , R14 , R14 R._A
R11 ,, RN RN
. R9 . __________ Niv...._R14 (1 N, R9 0,1 Rio_---N1 14 \1R9 r Rio N __ S , R NS - \____,------R10 RN Rio , , R...ki 9 R9 ,S -- ),,,,__ --_ _Rio 4/, in N \ X N./ II --o) ". --/--, io ¨R N----R'" \N R8 \s_N N-_-_N
-' , ,S -- Fi8 N ' 0 ,S.õ,,,-- / ,- 0 N,, - 0 .---N Ru----\ il N6- Ru---- -I - R8---NI-- ---R8 N-N b-N WO
, , S
---N, N _yN
N __________ ( Nj N( i - N N N __ \( S S z S S z N
, ----eNS ---eNS ----eNH ---eNNH
IIN, ITij N __ ( 0 01\ij ..N _ N
-- \ --( ----eN0 ----eN0 ---eN0 N N __ \( Z
o N3 , N
, , , H
N,_-S
--N- /N S
H, S---___-N ____N
__C:1; --1/ S--_- ___C-r\----/___N--(/N
S-NN
, , , , H
N,.-0 N
--A-NI
S-N
-1\1/
--"1-.), 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 0--__-N _NI
-N
H H
p-...__N
/
, i ..
N
/ N , , _ N -- --'N
, N
-- -, N -N
N
, ., I -I
, ' -, N -, --'N 'N
N 1\11 N
, _ -_,1\1 I\1 -_,I\IN
- N
N N le 1 , ., N
NN I
1\1 1\1 N
-, -, 1rN 'rNii '-'r N, N NN, , '-- -, N N -, N. N
N,s, NN NN, -,fl\IN
--%
N
Nk," NN N
, -_,NN,N
--..._õ----__ Th\l N, , , -,,, ---!NN I\I N -,1\IN
1 1\1 I II
I 1 , f N N--N --, ------õ,--,N NN, , , 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 -,,N
Nle , Nie , N.N
, I\IN -,,N,N
'N
IV , N, , N. -, I\1 -,,I\I
'Nil N,2 N N N--N
, , , N N , 1\1-N1-, NN
, -' '-lr"N
N,N
N-, N I
1\1-N N , N N N
I I I
NN
, NN--N NN-,N
-,,N,N
I I
N. NN N N
el\I
, H
NH
HN NH , , ., N NH , HN , NH H , , N=\ 0 N=N N=\ N---N
\ N
N- N- N- -N -N
--- ;IV - ---- / N \ JV
N' N
-- __ N \
\ //IV
N, /
___________________________________ , _______ ' N ______________________ , --\ /,\N
-\
I\1 , --\ N --\ N -- N =
N
N IV N/ //
, 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 N=\ N=\
--- /(1\1 \ / N\/ N / N
N
N N¨N 'IV N //N
N=N N=N N=N N=N N=N
' N --, \ /N / N
, ________ , __________________________________ , N=\ N=\ N=\ N=\ N---( \ /71; \ S \ N
/ N N N , \
N/ N //N
N¨N N N/
, ---\ N , \ /71; \ S N N , ____ ¨\ ,N N N
, ¨N ¨N _¨N
-- --i ) \ ) \
/
N / N¨N N N
, ______________________________________________ , ¨\ ___\
-- N ---\ N \ S N S
N ; N¨//
N¨N N
* *
Ns /
Ns \ /IV N N
" N, /N N¨N -N N¨N ; N si\l/ , or ______________________ , , wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 ¨ R14 and R" ; and preferably with 1 to 3 of the substituents R11 ¨
R13;
R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl;
diamantyl;
or hexamethylenetetraminyl and the afore-mentioned residues optionally contain one or more C=C double bond(s) and/or are optionally substituted by one or more of Ra; Rb; Rc; Rd; and Re;
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Ra, Rb, Rc, Rd, and Re represent independently of each other -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C2H5, -CONH2, -CON HCH3, -CON(CH3)2, -CON HC2F15, -CH2CO2H, -CH2CO2CH3, -CH2CO2C21-15, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2F15, -NHCOCH3, -NHCOC21-15, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C21-15, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3;
R4 represents -N R6R7;
R6 represents -CH2CH3; and R7 represents -H;
R6, R6, R10, R11, R12, R13, and R14 represent independently of each other -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH (CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2F, -CH F2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2OH, -OCH3, -0C2H5, -0C3H7, -OCH(CH3)2, -0C(CH3)3, -0C4H9, -OCH F2, -0CF3, -OCH 2C F3 , -0C2F5, -OCH2OCH3, -0-cyclo-C3H5, -OCH2-cyclo-C3H5, -0-C2H4-cyclo-C3H5, -CHO, -COCH3, -COCF3, -00C2H5, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -COOH, -COOCH3, -CO0C2H5, -CO0C3H7, -COOCH(CH3)2, -COOC(CH3)3, -00C-CH3, -00C-CF3, -00C-C2H5, -00C-C3H7, -00C-CH (CH3)2, -00C-C(CH3)3, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -N HC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5, -NHCOC3H7, -NHCOCH(CH3)2, -NHCOC(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CON HCH (CH3)2, -CON H-cyclo-C3H5, -CON HC(CH3)3, -CON(CH3)2, -CON (C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -SO2NHCH(CH3)2, -SO2NH-cyclo-C3H5, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H5)2, -SO2N(C3H7)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C2H5, -NHSO2C3H7, -NHSO2CH (CH3)2, -NHSO2C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -CECH, -CEC-CH3, -CH2-CECH, -Ph, -0-Ph, -0-CH2-Ph, 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 I\1 H
I\1 H
N
--N
, , , , 1\1 1\1 r N r r / __ \ / __ \ / __ \ __ -N\ /NH, --N\ N-/ , or - -N N
\ ________________________________________________________________ / \ =
, , or R8 and R9 or R9 and R1 can form together one of the following five-membered or six-membered rings:
ci _-1-d --- -- --- --I\1 ---N --- -----) -- -- 1 --_1 '-./ ''0 --,% --.% '-, '-.N 'le, __1\1 õ-N - ,N
-I
-'1\1 'N or ---1\1-or R12 and R13 or R13 and R14 can form together one of the following five-membered or six-membered rings:
,o ,ici ,,ici ,-C) ,-0__-_.0 -0 --0 ,,.--..., , --./ '--O ''I:Y H or I - , Ri4 represents -H, -CH3, -C2F13, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H3, -C(CH3)3, -cyclo-C3H3, -cyclo-C4H7, -cyclo-C31-19, -CH2-cyclo-C3H3, -CH2-cyclo-C4H7, -CH2-cyclo-C3H9, -CH2F, -CHF2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CH F2; -CF12-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3, -00C21-13, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -CO-cyclo-C3H3, -CO-cyclo-C4H7, -CO-cyclo-C31-19, -COOCH 3;
-COOC2H3, -CO0C3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -S02CH3, -S02CF3, -S02C21-13, -S02C3H7, -S02CH(CH3)2, -S02-cyclo-C3H3, or -S02C(CH3)3;
RNi represents -H, -CH3, or -CH2CH3;
or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomer, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
2. The compound according to Claim 1, wherein 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 R2 represents RN
- 0 Ra R11 0 Ra _ _ S ,-, - 8 Rt1 S
Ro - - 11 R8 r -\\ r ( R1 R9 ; ' R9 R10 .-,9 ; ' R9 R10 ; K
RN RN RN RN
R11 N R8 R11 N, R11 ri, _ _ ,N,N R11 ON
_ _ R11 0 pp 8 N
/ ____________________________________ l( Y /K ir 1 -----N N
R9 R10 s, / R9 R10 R9 R10 /
- _2:)____ R8 ,_ R10 Ril SN Rii S R8 . -0? 10) R8 C/./ ir 1 N \ N
¨7 R N
Rlo N R8 N
N \ R- Rio , , RN RN RN
RN
S Ra - - N -õ, õ
Rii ri N
, ,N, _Rlo -\___ 1 N
N I ir N ________ N N ,N, N, '"
DN
--- N
R1 , R10, , , ,/ , N-N ; N=N ;
I R13 (R13 N/ R13 r Ri3 \N
-----Ria N-Ria N R14 N-Ria N Ria , RN
i\i ---- R12 0___-y 13 s 13 i\i -,) 3 I
-\- -- 'p -R14 R14 R14 iA
Rlo Rlo R1 o R -, RN
RN
sµ
N)---- R14 ii R9 r >1 iX ____________________________________________________ _ )...i _ R1.4 \-i)R14 ' .o. -n N S cõ, ' , , , ri R9 r\
\____ i___ 9 R9 _ ir_ -/* R 1 0 --/ __ , Ri n N \ 1\
\ I l/
IT
<:., m _ -\S-N
R8 ,S, - - R8 S)- - - N II
__-N R' . S - ---- il N./ Rµ-' IT - . N, - ---- -I N
\N=N R8 , N-N ; b-N
, N-0 - - - -N N
, , Icl 0 s ---eNNH
\ \ \ N __ ( , i S
, , ; , , , 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 N _ N
---eNNH ---( --(N ---eNS
N N __ \( SNjz S , N
---eNNH ---eNNH
IIN , i\il\IJ N __ ( 0 ONjz -- A -N N N __ \( , NiNj o ciN, N
H s N--...._-S
Nr-1, -- --- N -) --.1------) N N-N-S
, S----N
-k-N, ------S-N ---c_rN
N
S-N-N/ ----N, --C----) , N-0 -----N-N No ------N, H H , , -C-----Q
-, I\1 ., N /
N, , -, N -, ' N
-- - N
-. , -N
I II
N 1\r N /
-, N, I 'N
-I
N.N / , N
, ' -, N -. --'N 'N
N N
N
, -,,I\I I\1 -,,I\IN
-,N I
N
- N
I N I
IN 1\1-N
2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 _ I
- - - -- - z Z /z¨Z /z¨Z 7/ // Z Z Z \ / Z - Z /¨Z
Z¨ - Z Z¨
) Z\ , Z\ , Z\ Z ) Z' ZZ ) Z
) Z-Z K Z
/ ) Z)/ Z2/ Z)/ \ Z2/ \ ZZ ZZ \ Z \ Z 0 /
/ / 2/ µ Z Z
¨Z Z ¨/ ¨ ¨ Z , ¨/ , ¨/ , ¨Z ¨/ ¨Z ¨Z
¨/
--Z - - z ______________________ - z - - z __ - z -2 z \ z' 'z z/z 'z z"¨ z\ z' \ 0 'z z' ¨'z z"¨ \ z z/z 'z T
z" z¨z / z / _______ z ) /\ zz z)z __ z)z \ z)z __ \ z/z z/z z4 ¨z z ¨/ ¨ z ¨/ ¨/ z c z z __ z , _/ , _/
/
_ I
z e5 cõ
i 51
9 - .
N
i c ?
z7/ / __ ; Z ¨z \ z7/ __ V , ¨z r% ,- z\- /_ rz\ , z\ , __ z\ . ._ 0 / z)/ z)/ __ \ z)/ µz z)/ z)/ z)/ µz 0 ((z ¨/ ¨ ¨ ¨/ , ¨z , ¨z , ¨z , ¨z - :wc' ' ca!
z Qo / I 1 Lucn (9, , , ct a q a, , ,r a ' r v ., HN , NH H , ;
N=\ 0 N=N N=\ N--¨ ¨N
¨ ¨ \ / -- \ /N ¨ ¨ ¨_ \ N
N/ \ ' ,,N
, N¨ N¨ N¨ ¨N ¨N
¨ ¨
¨ -- / N
N N
, ¨ ¨ _______________________ -- \ ¨ --\ /(N
¨ / N \ /IV \ /
N N , ________________________ ' , ______ N , ¨ ¨ \ /\N
¨
\
1\1 ¨\
, \ N \ N
//
N/
N N
N N
, , N=\ N=\
¨ ¨ ¨, /(N
N s / N
N¨N
N N N //N
N
N=N N=N N=N N=N N=N
¨ ¨ \ -- ______________ -- ¨.__ -- ¨, \ ,N
N N
, ______ // , , , , N=\ N=\ N=\ N=\ N-- ¨ /N ¨ ¨ ¨_ /N ) /N --- 51 __ --( \/N , \ N, \ N \ ,N
/ N N , N¨ N¨ N¨ N¨ N-- ¨ __________ ¨ ¨ \ i 1 N
\ N -- / N / N / / N N //' N¨N, N, N __ , , ¨N ¨N ¨N ¨N ¨N
, /N ¨ ¨ /N N
\/N , \ \ N \ ,N
N N N , , , , ¨N ¨N _¨N ¨N ¨N
¨ ¨ __________ ¨ ¨i \ \
--N N /
\ N , N / N /
N/ //
N¨N N N
, ' , , 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 ¨\
---, N -- N --i /N
\ N \ S N S
N , N¨// //N N¨N N
, , -- . -- =
--i /N --N, \ ,N N N
N N N¨N ;
N _____________ , N¨N , N sis\l¨//
, , wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 ¨ R14 and RN; and preferably with 1 to 3 of the substituents R11 ¨
R13;
and the substituents R9 ¨ R14 and RN have the meanings as defined in claim 1.
3. The compound according to Claim 1, wherein RN RN RN
R11 il -R11 N R8 ---Ii\_¨R8 R2 represents 1 ---N
N
RN
- _ 0 R8 R11 0 R8 - __ S R8 R11 S R8 11 R10 R9 ;
/ R9 R10 R9 ;
/ R9 R10 R9 ;
, , R11 N R8 R11 N, R11 N, N , ---cji - - --L i\i - - R11 0 R8 , , R9 R10 ,R9 Rlo R9 N¨ 8 N
1 1 1 1 N , 1 RN RN RN
¨8 R11 S _._ S
N ) __ N N - 11 N I ,N, --, ____.R8 -_. -NI R11.õcN,N
)--- \ .' , N N N
, ______________________________________________________________________ i( Rio Rio Rio Rio , , R
, , , , , io , , RN
N iz ,N Rlo /-R13 1 /-) R13 N/
"Nr---, ¨
)¨N LI _ \ -)R13 -- \N
, , N=N , ------R14 N R14 N R14 N
, N R12 0---/y,) , % R12 _() R13 ---, TR"
-\' 1 A
Q14 Rio_tr>R13 õ, Rlo N R14 Rlo R.-, R14 (:)---13 ;
, RN , R12 R12 %
%
s-r/, -- p 13 % R12 1\11 /') p13 R10 /
Rio_Ri3 - - ¨
R14 R14 fl Rio S------4 14 R10 , , , RN
' 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 N \ s= v_____ R14 \R13 - -c\7R N) ----"- n 7 __ S
R1.A , R14 R14 Ri., N
, R11 i, RN RN RN
0,11:e ril /IR9 _ _R10 R1ONII ----- R14 (N
rNR9 R9 R1 N \J o) N-:"----S - "\___,------- Ri 0 ,N' R10 , , , rµ
\)LRm 9 R9 ,S - - - -- -1_--, R10 ,IL R1 N\ Z
N I
, - µ.1`i \N R8 \S-N
N 1 )' . S, - - . Nõ,---,-7- - - ,-- N6- "
R8 NO , \O-N , N-0 or O-N
, , , and R8, R9, R10, R11, R12, R13, KI-114, and R" have the meanings as defined in claim 1.
4. The compound according to Claim 1, wherein 0 (,..N..õ0 H (I) Ho wherein L represents ¨L1¨L2¨;
L1 represents ¨CH2C0¨, L2 represents ¨NRNI¨, and R3 represents 1-adamantyl; or L2 represents ¨NRNICH2¨, and R3 represents 2-bicyclo[3.1.1]heptyl, and the afore-mentioned 1-adamantyl and 2-bicyclo[3.1.1]heptyl residues optionally contain one or more C=C double bond(s) and/or are optionally substituted by one or more of Ra, Rb, Rc, Rd, and Re;
R1 represents =
, H
RN RN RN
ii _ _ _ N
R2 represents 1 ----- ¨R8 , N N N
, , , 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 RN
-__ 0 Ra R11 rRa R8 S Ra 0 R1 \ / 1 __Isr -\\ r ( Rlo R9 ;
' R9 R10 R9 ;
' R9 R10 -' ; ;
R,,, 11 ON _R8 RN RN RN RN Rio R11 N R8 R11 N, R11 N \ N, 1 ___________ ( ----¶ I N
/ /K ---LIK\I
\ / C)\) I ir-, Ro R10 s, , R9 Rlo R9 N¨K ._...8 ___ N
;
, RN RN RN
8 R11 S S li 8 -_ ' -- __-R ----- - - --___ 'N R1:1 ,I1,N
,, N N
)--N ) __ N Y __ N N )\ N i( Rlo ' Rio ' Rio , Rio , , ,/
R10, RN
, RN
R12 R12 R12 Riz ,N wo /-1 --------------------- N/
N ---N, Dp N
N''` ¨R13 -- R13 ------------------\¨N Q A \N R13 , , N=N , ------- D14 I\1 R14 N
Ri4 N R14 , '` , R12 _F;v11 , N Ri2 0---/Y,) 13 %
RioRi3 wo N Ri4 R10 0---\44 0----\43 RN , R12 Riz , , S--_./y _ , R12 i\l----r/ R13 R10R13 wo /
- -$___---) -ffl Rio R14 N s-----414 ; Rio R14 , RN
, , R12 R12 p12 -1 _________________ N
i\i---/A
--- 1 \,tR13 ` s= V.___ 14 N R
N----.%\- c__\R13 R14 R14 R.-A
w_n N
, R11 ,, RN RN RN
---.. ,--1 rN /IR9 R10-11--- ________ R14 r_.IIR9 rN!rZ9 __ R10 N \J _ _Rio N S - "\____/------ Ri 0 ; rµ mr\l' R10 o) 1_79 N \ X N
I ..
N- --/, _R10 õ,R10 N
\
.' ,.1`1 R8 \S-N
R8 S-,-- R8 ). -NT N
----<\
S: 7-- , N R8 ---e- - - N R.-- 8 -Nr-N , R8 N-N , 0-N , N- , or , R6 represents ¨C2H5;
and R6, R6, R113, R11, R12, R13, R14, Ra; R13, Rc; Rd; Re ; RN and rt"Isll have the same meanings as defined in claim 1 or a diastereomer, an enantiomer, a mixture of 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 diastereomers, a mixture of enantiomer, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
5. The compound according to Claim 1 0r4 represented by formula (II):
oN
H
o N H 0 (II) H
wherein L2 represents -NIRN1-, and R3 represents 1-adamantyl; or L2 represents -NR111CH2-, and R3 represents 2-bicyclo[3.1.1]heptyl, and the afore-mentioned 1-adamantyl and 2-bicyclo[3.1.1]heptyl residues optionally contain one or more C=C double bond(s) and/or are optionally substituted by one or more of Ra, Rb, Rc, Rd, and Re;
RN RN RN
Rli"Ncr- Rii 11R8 -- il R8 .
R2 represents or N
N
R1 , / R10 , Ra, Rb, Rc, Rd, and Re represent independently of each other -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -0O2H, -CO2CH3, -0O2C2H5, -CONH2, -CON HCH3, -CON(CH3)2, -CONN C2F15, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H5, -CH2CON H2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC21-15, -NHCOCH3, -NHCOC21-15, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C21-15, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3;
RN represents -H, -CH3, -C2F-15, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-051-19, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-051-19, -CH2F, -CHF2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3, -00C21-15, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -CO-cyclo-C3H5, -CO-cyclo-C4H7, -CO-cyclo-051-19, -COOCH3, 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 -COOC2H3, -CO0C3H7, -COOCH (CH3)2, -COOC(CH3)3, -COOCH2Ph, -S02CH3, -S02CF3, -S02C2H3, -S02C3H7, -S02CH(CH3)2, or -S02C(CH3)3;
RI" represents -H, -CH3, or -CH2CH3;
R8, R", and R" represent independently of each other -H, -F, -Cl, -Br, -1, -OH, -CN, -NO2, -CH3, -C2F13, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH (CH3)2, -CH(CH3)-C2H3, -cyclo-C3H3, -CH2-cyclo-C3H3, -CH2F, -CHF2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -OCH3, -0C21-13, -0C3H7, -OCH(CH3)2, -0C(CH3)3, -0C4H9, -OCHF2, -0CF3, -OCH2CF3, -0C2F5, -OCH2OCH3, -0-cyclo-C3H3, -OCH2-cyclo-C3H3, -0-C2H4-cyclo-C3H3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -CECH, -CEC-CH3, -CH2-CECH, or -Ph, or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomer, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
6. The compound according to any one of claims 1õ wherein the compound has any one of the formula (II-a) - (II-1), (II-b1)- (II-b2), and (III-a) - (I11-1):
0 Rd Rc Re 0 0)LN Rb Ra 0 H (rH
N NH
Ra R2 N 1\ N R2 N N
Rb 0 0 HjC
(II-a) (II-b) ON N
NH Ra 2)-rµi NH N H
R2 N Rb R -Rb (II-b1) (II-b2) Ra 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 0 (II-d) N
H
0 H 0 Rb A N
H
Ra (II-C) (31AN 0 N
H H Rb Ra Rb Ra 1 N Rc A N L2 H H 0 0 Rd 0 0 Rd (II-e) (II-f) 0 0 Rd Rb Ra 0)-LN,---.õ
H RC H Rc 0 H 0 0 ( H 0 H
(II-g) (II-h) OA ()N
N
H Rb Ra H
0H 0 Rc 0 A JCH 0 ----k N L2 A N ..-----,.. L2 H
R2 N 0 0 Rd 1 N R2 N 1 N
(Iki) (11-j) (31)-H H
R2A N 1 N N -------õ,..- L2 H
H
(II-k) (II-I) 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 o Rd Rc Re 0 OAN Rb Ra 0N
H H
0 H 0 0 0 Ra N N cFNIA NH
N r\i 1 N Rb 0 0 _____N H 0 ,i,,.,,,J, .. 0 'RN 'RN
(III-a) (III-b) H H
N H 0, H
N H
R8 \ 1 rii Re-eil'14 0 b ,p; N A
Rio i- R11 C) (11I-d) 0 )-L 0 '-- N-...'' H 0-LN------õ,, H
N
R8 \ 1 ril 1 N R8 NI If 0 0 o o R10 s R11 (11I-e) (III-f) 0)-N 0N
H H
0 0 0 (,H 0 H H
S Elm N N N õ,___J-1-...
,----..,,õ N
R8-- _e[ijc N 0 R -- _e H
_ il "
'19 (11I-g) (11I-h) H ON
R13 0 N ...õ.õ,-11-.. N H
..----..,..õ-N H
i 1 R13 S
N
I H
0 0 1 INACI _ il '''fN
(Ill-i) (III-D
2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 0)-L o N
0.A
H N
H
0 jcH 0 N N )-LNH
N
I H
Rio Rio Riz R13 12 (11I-k) (111-I) wherein L1; L2, R2; R8, R10; R11, R12, R13, R14, RN, Ra; Rb; Rc; Rd and K i-ie have the same meanings as defined in claim 1.
7. The compound according to any one of the claims 1 ¨ 5, wherein R3 represents ----- ----.--/j[-, , , .d1--______________________________ , , _.
-- , ,s , , , , , fiZF Zci jZCF3 jZOH jZCO2Me F
F
., ., ., ., Br ; CI OH
., CO2Me ', ', ', 0 '=
CO2H CONH2 ; CONMe2;
H
Br OH
CO2H , ' CF3 -- , -- , -" , , , or -8. The compound according to any one of the claims 1, - 7, wherein R2 represents 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 N
H I H
N I
N '9 4 N N H
N H H
N
N
t ---N --,N ,N ,N ,N ,N
N ,N ,N
N , , I I I
I I I
N,õ-Br _________ .--, _____ p N Y N ) N N
N N , , / , CI CI
I
--)N N, vt 0 , 'N NN HN - ----NINN ----N NN N
- NC--0. _i \\
I N
H2N HN \ , I H I I
N, I N N, ,N
/\1 C-_-----_ -...,1\1,N Ni, ;I\I (\ ,N r\cLii , NN N \\ ii , 2 __ / , ! N
N=I\1 S
---q,-Br -- , s CI --__--Br 0-- -= \ / \ / \ / \ //
H2N 0 Br, Br , Br , CI , ' , Br N_S Br 0 \ __ --, yS Br CI SCI
IV Me0 Br S rsc S
Br - - - -)O¨Br --)S__--CF3 N
, ,S -- S --H , N' N
Ni\iFi , 5N S.,,,-/--ll Nr/ IT 1\1/ - s .. N
--____Il \ N 0 N-N S-N _--N 0 , , ,S --H
1\lis\v. )--,-/ -- ci\___<\N,T,- ' (111:_ N I (--- --HO 0-N N-0 0-N HN-2- \/
, , , H -N -----", ',NO2 HN
.--- 1\1)-- N_ I I
"O N- - ¨N,-- CO2Me -_,CO2H , -N,N ---/ ---N N'.--- 0 I
I N I N I
-IV
,-, -- \
NI
, , 0 0 , , /
0 _ -- \ / -- _ \ \
Br , I , 0 , , 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 F
\
0 , S
\
-<\
N¨L-S H HN
OH
-N
N N NN or 9. The compound according to claim 1 selected from the group consisting of:
Compound Name 1-1: (S)-N1-ethyl-N6-(1-(2-(1-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-im idazole-5-carboxamido)-2-oxohexanediamide, 1-2: (S)-N1-ethy1-5-(1H-im idazole-4-carboxam ido)-N6-(1-(2-(1-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxohexanediamide, 1-3: (S)-N1-ethyl-N6-(1-(2-(1-adamantyl(methyl)amino)-2-oxoethyl)-2-oxo-1,2-dihyd ropyridin-3-y1)-5-(1-methy1-1H-im idazole-5-carboxam ido)-2-oxohexanediam ide, 1-4: (S)-N1-ethyl-N6-(1-(2-(3,5-dimethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-5-carboxamido)-2-oxohexanediamide, 1-5: (S)-N1-ethyl-N6-(1-(2-(3-ethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-im idazole-5-carboxam ido)-2-oxohexanediam ide, 1-6: (S)-N1-ethyl-N6-(1-(2-(3-trifluoromethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-5-carboxamido)-2-oxohexanediamide, 1-7: (S)-N1-ethyl-N6-(1-(2-(3-hydroxyadamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-5-carboxamido)-2-oxohexanediamide, 1-8: (S)-N1-ethyl-N6-(1-(2-(3-fluoroadamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-im idazole-5-carboxam ido)-2-oxohexanediam ide, 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 1-9: (S)-N1-ethyl-N6-(1-(2-(3-chloroadamantane-1-amino)-2-oxoethyl)-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-5-carboxamido)-2-oxohexanediamide, 1-10: (S)-N1-ethyl-N6-(1-(2-(3-bromoadamantane-1-amino)-2-oxoethyl)-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-5-carboxamido)-2-oxohexanediamide, 1-11: (S)-N1-ethyl-N6-(1-(2-(3-methyl adamantane-3-ca rboxylate-1-am ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-5-carboxam ido)-2-oxohexanediam ide, 1-12: (S)-N1-ethyl-N6-(1-(2-(4,4-difluoroadamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-5-carboxamido)-2-oxohexanediamide, 1-13: (S)-N1-(1-(2-(((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide, 1-14: (S)-N1-(1-(2-(((1R,2R,5R)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide, 1-15: (S)-N1-ethyl-N6-(1-(2-(3-ethyladamantane-1-amino)-2-oxoethyl)-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-4-carboxamido)-2-oxohexanediamide, 1-16: (S)-N1-ethyl-N6-(1-(2-(3-ethyladamantane-1-amino)-2-oxoethyl)-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-2-carboxamido)-2-oxohexanediamide, 1-17: (S)-2-(1,4-dimethy1-1H-imidazole-5-carboxamido)-N6-ethyl-N1-(1-(2-(3-ethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, 1-18: (S)-N1-ethy1-5-(1-isobuty1-1H-imidazole-4-carboxamido)-N6-(1-(2-(3-ethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxohexanediamide, 1-19: (S)-2-(1-cyclopenty1-1H-imidazole-4-carboxamido)-N6-ethyl-N1-(1-(2-(3-ethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, 1-20: (S)-2-(1-cyclobuty1-1H-imidazole-4-carboxamido)-N6-ethyl-N1-(1-(2-(3-ethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, 1-21: (S)-2-(1,4-d imethy1-1H-im idazole-5-carboxamido)-N6-ethyl-N1-(1-(2-(3,5-d imethyladam antane-1-am i no)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 1-22: (S)-N1-ethyl-N6-(1-(2-(3,5-dimethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-4-carboxamido)-2-oxohexanediamide, 1-23: (S)-N1-ethyl-N6-(1-(2-(3,5-dimethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-2-carboxamido)-2-oxohexanediamide, 1-24: (S)-2-(1,2-d imethy1-1H-im idazole-5-carboxamido)-N6-ethyl-N1-(1-(2-(3,5-d imethyladam antane-1-am i no)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, 1-25: (S)-N1-ethyl-N6-(1-(2-(3-methyladamantane-1-amino)-2-oxoethyl)-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-5-carboxamido)-2-oxohexanediamide, 1-26: (S)-2-(2-chloro-1-methy1-1H-imidazole-5-carboxamido)-N6-ethyl-(1-(2-(3,5-dimethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, 1-27: (S)-2-(1,2-dimethy1-1H-imidazole-5-carboxamido)-N6-ethyl-N1-(1-(2-(3-methyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, 1-28: (S)-N1-ethyl-N6-(1-(2-(3,5,7-trimethy1-1-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methyl-1H-imidazole-5-carboxamido)-2-oxohexanediamide, 1-29: (S)-2-(2-chloro-1-methy1-1H-imidazole-5-carboxamido)-N6-ethyl-(1-(2-(3,5,7-trimethy1-1-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(benzofuran-2-carboxam ido)-N6-ethyl-N1-(1-(2-(2-1-30 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-N1-ethyl-N6-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-1-31 dihydropyridin-3-y1)-5-(3-methylbenzofuran-2-carboxamido)-2-oxohexanediamide, (S)-2-(3-chlorobenzofuran-2-carboxam ido)-N6-ethyl-N1-(1-(2-(2-1-32 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(4-bromobenzofuran-2-carboxam ido)-N6-ethyl-N1-(1-(2-(2-1-33 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(benzo[b]thiophene-2-carboxam ido)-N6-ethyl-N1-(1-(2-(2-1-34 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 (S)-N1-ethy1-5-(7-fluorobenzo[b]thiophene-2-carboxamido)-N6-(1-(2-1-35 (2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-oxohexanediamide, (S)-2-(4,5-difluoro-1H-indole-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-1-36 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-N1-ethyl-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-1-37 dihydropyridin-3-y1)-5-(3-methy1-1H-indole-2-carboxamido)-2-oxohexanediamide, (S)-2-(1H-benzo[d]imidazole-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-1-38 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(2,3-dihydro-1H-indene-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-1-39 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-N1-ethyl-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-1-40 dihydropyridin-3-y1)-5-(4-methy1-2-(trifluoromethyl)thiazole-5-carboxamido)-2-oxohexanediamide, (S)-2-(4-bromo-2-(trifluoromethyl)thiazole-5-carboxamido)-N6-ethyl-1-41 N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-N1-ethyl-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-1-42 dihydropyridin-3-y1)-5-(4-methy1-2-phenylthiazole-5-carboxamido)-2-oxohexanediamide, (S)-2-(5-bromo-3-methylthiophene-2-carboxamido)-N6-ethyl-N1-(1-1-43 (2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(3,5-dibromothiophene-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-1-44 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(5-bromo-3-methylfuran-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-1-45 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(2,5-dichlorothiophene-3-carboxamido)-N6-ethyl-N1-(1-(2-(2-1-46 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(2,5-dibromothiophene-3-carboxamido)-N6-ethyl-N1-(1-(2-(2-1-47 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 (S)-2-(2, 5-dich lorothiazole-4-carboxam ido)-N6-ethyl-N 1-(1-(2-(2-1-48 adamantylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(2, 5-dimethylfuran-3-carboxam ido)-N6-ethyl-N 1-(1-(2-(2-1-49 adamantylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(4-bromothiazole-2-carboxam ido)-N6-ethyl-N 1-(1-(2-(2-1-50 adamantylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(4-bromothiophene-2-carboxam ido)-N6-ethyl-N1-(1-(2-(2-1-51 adamantylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(4-bromo-5-chlorothiophene-2-carboxam ido)-N6-ethyl-N 1-(1-1-52 (2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(4,5-dibromothiophene-2-carboxam ido)-N6-ethyl-N 1-(1-(2-(2-1-53 adamantylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(4,5-dichlorothiophene-2-carboxam ido)-N6-ethyl-N 1-(1-(2-(2-1-54 adamantylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-((S)-1-acetylpyrrolidine-2-carboxam ido)-N6-ethyl-N 1-(1-(2-(2-1-55 adamantylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-N1-ethyl-N6-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-1-56 dihydropyridin-3-y1)-5-(1-methy1-1H-1,2,3-triazole-5-carboxam ido)-2-oxohexanediamide, (S)-N1-ethyl-N6-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-1-57 di hyd ropyridin-3-y1)-2-oxo-5-(2 H-tetrazole-5-carboxam ido)hexanediamide, (S)-N1-ethyl-N6-(1-(2-(5-hydroxyadamantane-2-am ino)-2-oxoethyl)-1-58 2-oxo-1,2-dihydropyridin-3-y1)-2-oxo-5-(pyrazine-2-carboxam ido)hexanediamide, (S)-N1-ethyl-N6-(1-(2-(5-fluoroadamantane-2-am ino)-2-oxoethyl)-2-1-59 oxo-1,2-dihydropyridin-3-y1)-2-oxo-5-((S)-pyrrolidine-3-carboxam ido)hexanediamide, (S)-N1-ethyl-N6-(1-(2-(5-chloroadamantane-2-am ino)-2-oxoethyl)-2-1-60 oxo-1,2-dihydropyridin-3-y1)-2-oxo-5-((S)-piperidine-2-carboxam ido)hexanediamide, 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 (S)-N1-ethyl-N6-(1-(2-(5-bromoadamantane-2-amino)-2-oxoethyl)-2-1-61 oxo-1,2-dihydropyridin-3-y1)-2-oxo-5-((R)-piperidine-3-carboxamido)hexanediamide, (S)-N1-ethyl-N6-(1-(2-(5-methyladamantane-2-amino)-2-oxoethyl)-2-1-62 oxo-1,2-dihydropyridin-3-y1)-5-((R)-morpholine-3-carboxamido)-oxohexanediamide, (S)-N1-ethyl-N6-(1-(2-(2-carbonitrileadamantane-2-amino)-2-1-63 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxo-54(3S,4R)-quinuclidine-3-carboxamido)hexanediamide, (S)-methyl 3-(6-(ethylamino)-1-(1-(2-(methyl 2-aminoadamantane-2-1-64 carboxylate)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-1,5,6-trioxohexan-2-ylcarbamoy1)-5-nitrobenzoate, (S)-N1-(1-(2-(1-adamantylmethylamino)-2-oxoethyl)-2-oxo-1,2-1-65 dihydropyridin-3-y1)-N6-ethy1-2-(5-nitronicotinamido)-5-oxohexanediamide, 54(2S)-1-(1-(2-1-adamantylmethylamino)-2-oxoethyl)-2-oxo-1,2-1-66 dihydropyridin-3-ylamino)-6-(ethylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinic acid, (S)-N1-ethyl-N6-(1-(2-(2-adamantyl(methyl)amino)-2-oxoethyl)-2-1-67 oxo-1,2-dihydropyridin-3-y1)-5-(6-methylimidazo[2,1-b]thiazole-carboxamido)-2-oxohexanediamide, (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-1-68 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide, (S)-N1-ethy1-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-1-69 oxo-1-(2-oxo-2-((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide, (S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-1-70 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide, (S)-N1-(1-(2-((1s,4R)-bicyclo[2.2.1]heptan-1-ylamino)-2-oxoethyl)-2-1-71 oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-2-(isonicotinamido)-5-oxohexanediamide, (S)-N1-(1-(2-(bicyclo[2.2.1]heptan-7-ylamino)-2-oxoethyl)-2-oxo-1,2-1-72 dihydropyridin-3-y1)-N6-ethy1-5-oxo-2-(pyridazine-4-carboxamido)hexanediamide, (S)-N1-(1-(2-((1R,2R,4R)-bicyclo[2.2.1]hept-5-en-2-ylamino)-2-1-73 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-5-oxo-2-(pyridazine-3-carboxamido)hexanediamide, 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 (2S)-N1-(1-(2-(bicyclo[2.2.2]octan-2-ylam ino)-2-oxoethyl)-2-oxo-1,2-1-74 dihydropyridin-3-y1)-N6-ethy1-5-oxo-2-(2H-1,2,3-triazole-4-carboxamido)hexanediamide, (S)-N1-ethy1-5-(1-methyl-1H-1,2,3-triazole-4-carboxam ido)-2-oxo-1 75 N6-(2-oxo-1-(2-oxo-2-((1R,2R,4R)-1,7 ,7--trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-y1)hexanediamide, (S)-N1-ethy1-5-(1-methyl-1H-1,2,4-triazole-3-carboxam ido)-2-oxo-1 76 N6-(2-oxo-1-(2-oxo-2-((1R,2R,3R,5S)-2,6,6--trimethylbicyclo[3.1.1]heptan-3-ylamino)ethyl)-1,2-dihydropyridin-3-y1)hexanediamide, (S)-2-(benzofuran-3-carboxam ido)-N6-ethy1-5-oxo-N1-(2-oxo-1-(2-1-77 oxo-2-((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)ethyl)-1,2-dihydropyridin-3-y1)hexanediamide, (S)-2-(benzo[b]thiophene-3-carboxam ido)-N6-ethyl-N 1-(1-(2-(4-1-78 homoisotwistane-3-am ino)-2-oxoethyl)-2-oxo-1,2-d ihydropyrid in-3-y1)-5-oxohexanediam ide, (S)-N1-ethyl-N6-(1-(2-(diamantane-1-am ino)-2-oxoethyl)-2-oxo-1,2-1-79 dihydropyridin-3-y1)-5-(1-methy1-1H-pyrazole-4-carboxamido)-2-oxohexanediamide, (S)-N1-ethyl-N6-(1-(2-(diamantane-4-am ino)-2-oxoethyl)-2-oxo-1,2-1-80 dihydropyridin-3-y1)-5-(1-methy1-1H-pyrazole-3-carboxamido)-2-oxohexanediamide, 1 81 (S)-N1-(1-(1-adamantylmethyl)-2-oxo-1,2-d ihydropyrid in-3-y1)--ethyl-2-(1-methy1-1H-pyrazole-5-carboxamido)-5-oxohexanediamide, (S)-N1-(14(3-hydroxy-1-adamantyl)methyl)-2-oxo-1 ,2-1-82 dihydropyridin-3-y1)-2-(4-cyclopropy1-1,2,3-thiadiazole-5-carboxam ido)-N6-ethyl-5-oxohexanediam ide, (S)-N1 -(14(3-bromo-1 -adamantyl)methyl)-2-oxo-1 ,2-d ihydropyrid in-1-83 3-y1)-N6-ethy1-5-oxo-2-(1,2,5-thiadiazole-3-carboxamido)hexanediamide, (S)-N1-(1-(2-adamantylmethyl)-2-oxo-1,2-d ihydropyrid in-3-y1)-N6-1-84 ethy1-2-(4-(hydroxymethyl)-1,2,3-thiadiazole-5-carboxamido)-5-oxohexanediamide, (S)-2-(4-tert-butyl-1H-pyrrole-3-carboxam ido)-N1-(1-(2-(1-1-85 adamantylamino)ethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-oxohexanediamide, 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 (S)-2-(4-cyano-1-methy1-1H-pyrrole-2-carboxam ido)-N1-(1-(1-1-86 adamantylamino)propy1)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-oxohexanediamide, (S)-N1-(1-(3-(2-adamantylam ino)-3-oxopropy1)-2-oxo-1,2-1-87 dihydropyridin-3-y1)-N6-ethy1-2-(5-methoxyoxazole-2-carboxamido)-5-oxohexanediamide, (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-1-88 dihydropyridin-3-y1)-N6-ethy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide, (S)-2-(2-acetyloxazole-4-carboxam ido)-N1-(1-(2-1-89 (bicyclo[1.1.11pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-5-oxohexanediamide, (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-1-90 dihydropyridin-3-y1)-N6-ethy1-2-(2-isopropyloxazole-5-carboxamido)-5-oxohexanediamide, (2S)-N1-(1-(2-(bicyclo[3.2.1]octan-8-ylam ino)-2-oxoethyl)-2-oxo-1,2-1-91 dihydropyridin-3-y1)-2-(3,5-dimethylisoxazole-4-carboxamido)-ethy1-5-oxohexanediamide, (S)-N1-ethyl-N6-(1-(2-(5-carboxy-2-am inoadamantane)-2-oxoethyl)-1-92 2-oxo-1,2-dihydropyridin-3-y1)-5-(4-methylpyrimidine-5-carboxamido)-2-oxohexanediamide, (5S)-N1-ethyl-N6-(1-(2-(4-aminoadamantane-N,N-dimethy1-1-1-93 carboxamide)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxo-(1,2,3,4-tetrahydronaphthalene-2-carboxamido)hexanediamide, (S)-2-((S)-1,4-diazabicyclo[2.2.2]octane-2-carboxam ido)-N6-ethyl-1-94 N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-N1-ethy1-5-(1H-indole-3-carboxam ido)-N6-(1-(2-(2-1-95 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxohexanediamide, (S)-N1-ethyl-N6-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-1-96 dihydropyridin-3-y1)-5-(6-methylimidazo[2,1-b]thiazole-3-carboxamido)-2-oxohexanediamide, (S)-2-(benzo[d]thiazole-2-carboxam ido)-N1-(1-(2-((1S,2R,4R)-1-97 bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-5-oxohexanediamide, (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylam ino)-2-1-98 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-2-(imidazo[2,1-b]thiazole-6-carboxamido)-5-oxohexanediamide, 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylam ino)-2-1-99 oxoethyl)-2-oxo-1,2-di hydro pyridi n-3-y1)-N6-ethy1-2-(4-hydroxy-6-(trifluoromethoxy)quinoli ne-3-carboxam ido)-5-oxohexanediam ide, (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-1-100 dihydropyridin-3-y1)-2-(cinnoline-3-carboxamido)-N6-ethy1-5-oxohexanediamide, (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-1-101 dihydropyridin-3-y1)-N6-ethy1-2-(3-ethylbenzofuran-2-carboxamido)-5-oxohexanediamide, (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-1-102 dihydropyridin-3-y1)-N6-ethy1-2-(1-ethy1-1H-indole-2-carboxamido)-5-oxohexanediamide, (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-1-103 dihydropyridin-3-y1)-N6-ethy1-2-(2-methy1-1,8-naphthyridine-3-carboxamido)-5-oxohexanediamide, (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-1-104 dihydropyridin-3-y1)-N6-ethy1-5-oxo-2-(1,2,3,4-tetrahydroquinoline-6-carboxamido)hexanediamide, (S)-N1-ethyl-N6-(1-(2-(2-carboxy-2-am ino-5-1105 (trifluoromethyl)adamantane)-2-oxoethyl)-2-oxo-1,2-d ihydropyrid in--3-y1)-2-oxo-5-(3-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)hexanediamide, (S)-N1-ethyl-N6-(1-(2-(5-ethyladamantane-2-am ino)-2-oxoethyl)-2-1-106 oxo-1,2-dihydropyridin-3-y1)-5-(1,6-naphthyridine-2-carboxamido)-2-oxohexanediamide, (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-1-107 dihydropyridin-3-y1)-N6-ethy1-2-(2,6-naphthyridine-1-carboxamido)-5-oxohexanediamide, (S)-2-(4-am ino-1,2, 5-oxadiazole-3-carboxamido)-N 1-(1-(2-1-108 (bicyclo[1.1.11pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-5-oxohexanediamide, (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-1-109 dihyd ropyridin-3-y1)-2-(6-(d imethylami no)benzofu ran-2-carboxam ido)-N6-ethyl-5-oxohexanediam ide, (S)-2-(2-acetam idoth iazole-5-carboxam ido)-N 1-(1-(2-1-110 (bicyclo[1.1.11pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-5-oxohexanediamide, 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 (S)-N4-(1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1-111 1,2-dihydropyridin-3-ylamino)-6-(ethylamino)-1,5,6-trioxohexan-2-yI)-1H-pyrrole-2,4-dicarboxamide, (S)-N1-ethyl-N6-(1-(2-(1-acetylamino-4-aminoadamantane)-2-1-112 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxo-5-(5-sulfamoylfuran-3-carboxamido)hexanediamide, (S)-2-(benzofuran-5-carboxamido)-N6-ethyl-N1-(1-(2-(1-1-113 acetylamino-4-aminoadamantane)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(benzofuran-6-carboxamido)-N6-ethyl-N1-(1-(2-(4-1-114 aminoadamantane-1-carboxamide)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-N1-ethyl-N6-(1-(2-(4-aminoadamantane-1-carboxamide)-2-1-115 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(3-(1-methylcyclopropy1)-1,2,4-oxadiazole-5-carboxamido)-2-oxohexanediamide, (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-1-116 dihydropyridin-3-y1)-N6-ethy1-2-(5-methy1-1,2,4-oxadiazole-3-carboxamido)-5-oxohexanediamide, (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-1-117 dihydropyridin-3-y1)-N6-ethy1-5-oxo-2-(1,2,3-thiadiazole-carboxamido)hexanediamide, (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-1-118 dihydropyridin-3-y1)-N6-ethy1-5-oxo-2-(1,2,4-thiadiazole-carboxamido)hexanediamide, (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-1-119 dihydropyridin-3-y1)-N6-ethy1-5-oxo-2-(1,3,4-thiadiazole-carboxamido)hexanediamide, (S)-N1-ethy1-5-(4-formy1-1,2,3-thiadiazole-5-carboxamido)-N6-(1-(2-1-120 (2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxohexanediamide, (S)-N1-ethyl-N6-(1-(2-(3,5-dimethyladamantane-1-amino)-2-1-121 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(nicotinamido)-oxohexanediamide or a pharmaceutically acceptable salt thereof.
N
i c ?
z7/ / __ ; Z ¨z \ z7/ __ V , ¨z r% ,- z\- /_ rz\ , z\ , __ z\ . ._ 0 / z)/ z)/ __ \ z)/ µz z)/ z)/ z)/ µz 0 ((z ¨/ ¨ ¨ ¨/ , ¨z , ¨z , ¨z , ¨z - :wc' ' ca!
z Qo / I 1 Lucn (9, , , ct a q a, , ,r a ' r v ., HN , NH H , ;
N=\ 0 N=N N=\ N--¨ ¨N
¨ ¨ \ / -- \ /N ¨ ¨ ¨_ \ N
N/ \ ' ,,N
, N¨ N¨ N¨ ¨N ¨N
¨ ¨
¨ -- / N
N N
, ¨ ¨ _______________________ -- \ ¨ --\ /(N
¨ / N \ /IV \ /
N N , ________________________ ' , ______ N , ¨ ¨ \ /\N
¨
\
1\1 ¨\
, \ N \ N
//
N/
N N
N N
, , N=\ N=\
¨ ¨ ¨, /(N
N s / N
N¨N
N N N //N
N
N=N N=N N=N N=N N=N
¨ ¨ \ -- ______________ -- ¨.__ -- ¨, \ ,N
N N
, ______ // , , , , N=\ N=\ N=\ N=\ N-- ¨ /N ¨ ¨ ¨_ /N ) /N --- 51 __ --( \/N , \ N, \ N \ ,N
/ N N , N¨ N¨ N¨ N¨ N-- ¨ __________ ¨ ¨ \ i 1 N
\ N -- / N / N / / N N //' N¨N, N, N __ , , ¨N ¨N ¨N ¨N ¨N
, /N ¨ ¨ /N N
\/N , \ \ N \ ,N
N N N , , , , ¨N ¨N _¨N ¨N ¨N
¨ ¨ __________ ¨ ¨i \ \
--N N /
\ N , N / N /
N/ //
N¨N N N
, ' , , 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 ¨\
---, N -- N --i /N
\ N \ S N S
N , N¨// //N N¨N N
, , -- . -- =
--i /N --N, \ ,N N N
N N N¨N ;
N _____________ , N¨N , N sis\l¨//
, , wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 ¨ R14 and RN; and preferably with 1 to 3 of the substituents R11 ¨
R13;
and the substituents R9 ¨ R14 and RN have the meanings as defined in claim 1.
3. The compound according to Claim 1, wherein RN RN RN
R11 il -R11 N R8 ---Ii\_¨R8 R2 represents 1 ---N
N
RN
- _ 0 R8 R11 0 R8 - __ S R8 R11 S R8 11 R10 R9 ;
/ R9 R10 R9 ;
/ R9 R10 R9 ;
, , R11 N R8 R11 N, R11 N, N , ---cji - - --L i\i - - R11 0 R8 , , R9 R10 ,R9 Rlo R9 N¨ 8 N
1 1 1 1 N , 1 RN RN RN
¨8 R11 S _._ S
N ) __ N N - 11 N I ,N, --, ____.R8 -_. -NI R11.õcN,N
)--- \ .' , N N N
, ______________________________________________________________________ i( Rio Rio Rio Rio , , R
, , , , , io , , RN
N iz ,N Rlo /-R13 1 /-) R13 N/
"Nr---, ¨
)¨N LI _ \ -)R13 -- \N
, , N=N , ------R14 N R14 N R14 N
, N R12 0---/y,) , % R12 _() R13 ---, TR"
-\' 1 A
Q14 Rio_tr>R13 õ, Rlo N R14 Rlo R.-, R14 (:)---13 ;
, RN , R12 R12 %
%
s-r/, -- p 13 % R12 1\11 /') p13 R10 /
Rio_Ri3 - - ¨
R14 R14 fl Rio S------4 14 R10 , , , RN
' 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 N \ s= v_____ R14 \R13 - -c\7R N) ----"- n 7 __ S
R1.A , R14 R14 Ri., N
, R11 i, RN RN RN
0,11:e ril /IR9 _ _R10 R1ONII ----- R14 (N
rNR9 R9 R1 N \J o) N-:"----S - "\___,------- Ri 0 ,N' R10 , , , rµ
\)LRm 9 R9 ,S - - - -- -1_--, R10 ,IL R1 N\ Z
N I
, - µ.1`i \N R8 \S-N
N 1 )' . S, - - . Nõ,---,-7- - - ,-- N6- "
R8 NO , \O-N , N-0 or O-N
, , , and R8, R9, R10, R11, R12, R13, KI-114, and R" have the meanings as defined in claim 1.
4. The compound according to Claim 1, wherein 0 (,..N..õ0 H (I) Ho wherein L represents ¨L1¨L2¨;
L1 represents ¨CH2C0¨, L2 represents ¨NRNI¨, and R3 represents 1-adamantyl; or L2 represents ¨NRNICH2¨, and R3 represents 2-bicyclo[3.1.1]heptyl, and the afore-mentioned 1-adamantyl and 2-bicyclo[3.1.1]heptyl residues optionally contain one or more C=C double bond(s) and/or are optionally substituted by one or more of Ra, Rb, Rc, Rd, and Re;
R1 represents =
, H
RN RN RN
ii _ _ _ N
R2 represents 1 ----- ¨R8 , N N N
, , , 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 RN
-__ 0 Ra R11 rRa R8 S Ra 0 R1 \ / 1 __Isr -\\ r ( Rlo R9 ;
' R9 R10 R9 ;
' R9 R10 -' ; ;
R,,, 11 ON _R8 RN RN RN RN Rio R11 N R8 R11 N, R11 N \ N, 1 ___________ ( ----¶ I N
/ /K ---LIK\I
\ / C)\) I ir-, Ro R10 s, , R9 Rlo R9 N¨K ._...8 ___ N
;
, RN RN RN
8 R11 S S li 8 -_ ' -- __-R ----- - - --___ 'N R1:1 ,I1,N
,, N N
)--N ) __ N Y __ N N )\ N i( Rlo ' Rio ' Rio , Rio , , ,/
R10, RN
, RN
R12 R12 R12 Riz ,N wo /-1 --------------------- N/
N ---N, Dp N
N''` ¨R13 -- R13 ------------------\¨N Q A \N R13 , , N=N , ------- D14 I\1 R14 N
Ri4 N R14 , '` , R12 _F;v11 , N Ri2 0---/Y,) 13 %
RioRi3 wo N Ri4 R10 0---\44 0----\43 RN , R12 Riz , , S--_./y _ , R12 i\l----r/ R13 R10R13 wo /
- -$___---) -ffl Rio R14 N s-----414 ; Rio R14 , RN
, , R12 R12 p12 -1 _________________ N
i\i---/A
--- 1 \,tR13 ` s= V.___ 14 N R
N----.%\- c__\R13 R14 R14 R.-A
w_n N
, R11 ,, RN RN RN
---.. ,--1 rN /IR9 R10-11--- ________ R14 r_.IIR9 rN!rZ9 __ R10 N \J _ _Rio N S - "\____/------ Ri 0 ; rµ mr\l' R10 o) 1_79 N \ X N
I ..
N- --/, _R10 õ,R10 N
\
.' ,.1`1 R8 \S-N
R8 S-,-- R8 ). -NT N
----<\
S: 7-- , N R8 ---e- - - N R.-- 8 -Nr-N , R8 N-N , 0-N , N- , or , R6 represents ¨C2H5;
and R6, R6, R113, R11, R12, R13, R14, Ra; R13, Rc; Rd; Re ; RN and rt"Isll have the same meanings as defined in claim 1 or a diastereomer, an enantiomer, a mixture of 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 diastereomers, a mixture of enantiomer, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
5. The compound according to Claim 1 0r4 represented by formula (II):
oN
H
o N H 0 (II) H
wherein L2 represents -NIRN1-, and R3 represents 1-adamantyl; or L2 represents -NR111CH2-, and R3 represents 2-bicyclo[3.1.1]heptyl, and the afore-mentioned 1-adamantyl and 2-bicyclo[3.1.1]heptyl residues optionally contain one or more C=C double bond(s) and/or are optionally substituted by one or more of Ra, Rb, Rc, Rd, and Re;
RN RN RN
Rli"Ncr- Rii 11R8 -- il R8 .
R2 represents or N
N
R1 , / R10 , Ra, Rb, Rc, Rd, and Re represent independently of each other -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -0O2H, -CO2CH3, -0O2C2H5, -CONH2, -CON HCH3, -CON(CH3)2, -CONN C2F15, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H5, -CH2CON H2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC21-15, -NHCOCH3, -NHCOC21-15, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C21-15, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3;
RN represents -H, -CH3, -C2F-15, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-051-19, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-051-19, -CH2F, -CHF2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3, -00C21-15, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -CO-cyclo-C3H5, -CO-cyclo-C4H7, -CO-cyclo-051-19, -COOCH3, 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 -COOC2H3, -CO0C3H7, -COOCH (CH3)2, -COOC(CH3)3, -COOCH2Ph, -S02CH3, -S02CF3, -S02C2H3, -S02C3H7, -S02CH(CH3)2, or -S02C(CH3)3;
RI" represents -H, -CH3, or -CH2CH3;
R8, R", and R" represent independently of each other -H, -F, -Cl, -Br, -1, -OH, -CN, -NO2, -CH3, -C2F13, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH (CH3)2, -CH(CH3)-C2H3, -cyclo-C3H3, -CH2-cyclo-C3H3, -CH2F, -CHF2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -OCH3, -0C21-13, -0C3H7, -OCH(CH3)2, -0C(CH3)3, -0C4H9, -OCHF2, -0CF3, -OCH2CF3, -0C2F5, -OCH2OCH3, -0-cyclo-C3H3, -OCH2-cyclo-C3H3, -0-C2H4-cyclo-C3H3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -CECH, -CEC-CH3, -CH2-CECH, or -Ph, or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomer, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
6. The compound according to any one of claims 1õ wherein the compound has any one of the formula (II-a) - (II-1), (II-b1)- (II-b2), and (III-a) - (I11-1):
0 Rd Rc Re 0 0)LN Rb Ra 0 H (rH
N NH
Ra R2 N 1\ N R2 N N
Rb 0 0 HjC
(II-a) (II-b) ON N
NH Ra 2)-rµi NH N H
R2 N Rb R -Rb (II-b1) (II-b2) Ra 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 0 (II-d) N
H
0 H 0 Rb A N
H
Ra (II-C) (31AN 0 N
H H Rb Ra Rb Ra 1 N Rc A N L2 H H 0 0 Rd 0 0 Rd (II-e) (II-f) 0 0 Rd Rb Ra 0)-LN,---.õ
H RC H Rc 0 H 0 0 ( H 0 H
(II-g) (II-h) OA ()N
N
H Rb Ra H
0H 0 Rc 0 A JCH 0 ----k N L2 A N ..-----,.. L2 H
R2 N 0 0 Rd 1 N R2 N 1 N
(Iki) (11-j) (31)-H H
R2A N 1 N N -------õ,..- L2 H
H
(II-k) (II-I) 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 o Rd Rc Re 0 OAN Rb Ra 0N
H H
0 H 0 0 0 Ra N N cFNIA NH
N r\i 1 N Rb 0 0 _____N H 0 ,i,,.,,,J, .. 0 'RN 'RN
(III-a) (III-b) H H
N H 0, H
N H
R8 \ 1 rii Re-eil'14 0 b ,p; N A
Rio i- R11 C) (11I-d) 0 )-L 0 '-- N-...'' H 0-LN------õ,, H
N
R8 \ 1 ril 1 N R8 NI If 0 0 o o R10 s R11 (11I-e) (III-f) 0)-N 0N
H H
0 0 0 (,H 0 H H
S Elm N N N õ,___J-1-...
,----..,,õ N
R8-- _e[ijc N 0 R -- _e H
_ il "
'19 (11I-g) (11I-h) H ON
R13 0 N ...õ.õ,-11-.. N H
..----..,..õ-N H
i 1 R13 S
N
I H
0 0 1 INACI _ il '''fN
(Ill-i) (III-D
2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 0)-L o N
0.A
H N
H
0 jcH 0 N N )-LNH
N
I H
Rio Rio Riz R13 12 (11I-k) (111-I) wherein L1; L2, R2; R8, R10; R11, R12, R13, R14, RN, Ra; Rb; Rc; Rd and K i-ie have the same meanings as defined in claim 1.
7. The compound according to any one of the claims 1 ¨ 5, wherein R3 represents ----- ----.--/j[-, , , .d1--______________________________ , , _.
-- , ,s , , , , , fiZF Zci jZCF3 jZOH jZCO2Me F
F
., ., ., ., Br ; CI OH
., CO2Me ', ', ', 0 '=
CO2H CONH2 ; CONMe2;
H
Br OH
CO2H , ' CF3 -- , -- , -" , , , or -8. The compound according to any one of the claims 1, - 7, wherein R2 represents 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 N
H I H
N I
N '9 4 N N H
N H H
N
N
t ---N --,N ,N ,N ,N ,N
N ,N ,N
N , , I I I
I I I
N,õ-Br _________ .--, _____ p N Y N ) N N
N N , , / , CI CI
I
--)N N, vt 0 , 'N NN HN - ----NINN ----N NN N
- NC--0. _i \\
I N
H2N HN \ , I H I I
N, I N N, ,N
/\1 C-_-----_ -...,1\1,N Ni, ;I\I (\ ,N r\cLii , NN N \\ ii , 2 __ / , ! N
N=I\1 S
---q,-Br -- , s CI --__--Br 0-- -= \ / \ / \ / \ //
H2N 0 Br, Br , Br , CI , ' , Br N_S Br 0 \ __ --, yS Br CI SCI
IV Me0 Br S rsc S
Br - - - -)O¨Br --)S__--CF3 N
, ,S -- S --H , N' N
Ni\iFi , 5N S.,,,-/--ll Nr/ IT 1\1/ - s .. N
--____Il \ N 0 N-N S-N _--N 0 , , ,S --H
1\lis\v. )--,-/ -- ci\___<\N,T,- ' (111:_ N I (--- --HO 0-N N-0 0-N HN-2- \/
, , , H -N -----", ',NO2 HN
.--- 1\1)-- N_ I I
"O N- - ¨N,-- CO2Me -_,CO2H , -N,N ---/ ---N N'.--- 0 I
I N I N I
-IV
,-, -- \
NI
, , 0 0 , , /
0 _ -- \ / -- _ \ \
Br , I , 0 , , 2489-CIPO-DESCRIPTION-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 F
\
0 , S
\
-<\
N¨L-S H HN
OH
-N
N N NN or 9. The compound according to claim 1 selected from the group consisting of:
Compound Name 1-1: (S)-N1-ethyl-N6-(1-(2-(1-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-im idazole-5-carboxamido)-2-oxohexanediamide, 1-2: (S)-N1-ethy1-5-(1H-im idazole-4-carboxam ido)-N6-(1-(2-(1-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxohexanediamide, 1-3: (S)-N1-ethyl-N6-(1-(2-(1-adamantyl(methyl)amino)-2-oxoethyl)-2-oxo-1,2-dihyd ropyridin-3-y1)-5-(1-methy1-1H-im idazole-5-carboxam ido)-2-oxohexanediam ide, 1-4: (S)-N1-ethyl-N6-(1-(2-(3,5-dimethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-5-carboxamido)-2-oxohexanediamide, 1-5: (S)-N1-ethyl-N6-(1-(2-(3-ethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-im idazole-5-carboxam ido)-2-oxohexanediam ide, 1-6: (S)-N1-ethyl-N6-(1-(2-(3-trifluoromethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-5-carboxamido)-2-oxohexanediamide, 1-7: (S)-N1-ethyl-N6-(1-(2-(3-hydroxyadamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-5-carboxamido)-2-oxohexanediamide, 1-8: (S)-N1-ethyl-N6-(1-(2-(3-fluoroadamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-im idazole-5-carboxam ido)-2-oxohexanediam ide, 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 1-9: (S)-N1-ethyl-N6-(1-(2-(3-chloroadamantane-1-amino)-2-oxoethyl)-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-5-carboxamido)-2-oxohexanediamide, 1-10: (S)-N1-ethyl-N6-(1-(2-(3-bromoadamantane-1-amino)-2-oxoethyl)-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-5-carboxamido)-2-oxohexanediamide, 1-11: (S)-N1-ethyl-N6-(1-(2-(3-methyl adamantane-3-ca rboxylate-1-am ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-5-carboxam ido)-2-oxohexanediam ide, 1-12: (S)-N1-ethyl-N6-(1-(2-(4,4-difluoroadamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-5-carboxamido)-2-oxohexanediamide, 1-13: (S)-N1-(1-(2-(((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide, 1-14: (S)-N1-(1-(2-(((1R,2R,5R)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide, 1-15: (S)-N1-ethyl-N6-(1-(2-(3-ethyladamantane-1-amino)-2-oxoethyl)-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-4-carboxamido)-2-oxohexanediamide, 1-16: (S)-N1-ethyl-N6-(1-(2-(3-ethyladamantane-1-amino)-2-oxoethyl)-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-2-carboxamido)-2-oxohexanediamide, 1-17: (S)-2-(1,4-dimethy1-1H-imidazole-5-carboxamido)-N6-ethyl-N1-(1-(2-(3-ethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, 1-18: (S)-N1-ethy1-5-(1-isobuty1-1H-imidazole-4-carboxamido)-N6-(1-(2-(3-ethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxohexanediamide, 1-19: (S)-2-(1-cyclopenty1-1H-imidazole-4-carboxamido)-N6-ethyl-N1-(1-(2-(3-ethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, 1-20: (S)-2-(1-cyclobuty1-1H-imidazole-4-carboxamido)-N6-ethyl-N1-(1-(2-(3-ethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, 1-21: (S)-2-(1,4-d imethy1-1H-im idazole-5-carboxamido)-N6-ethyl-N1-(1-(2-(3,5-d imethyladam antane-1-am i no)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 1-22: (S)-N1-ethyl-N6-(1-(2-(3,5-dimethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-4-carboxamido)-2-oxohexanediamide, 1-23: (S)-N1-ethyl-N6-(1-(2-(3,5-dimethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-2-carboxamido)-2-oxohexanediamide, 1-24: (S)-2-(1,2-d imethy1-1H-im idazole-5-carboxamido)-N6-ethyl-N1-(1-(2-(3,5-d imethyladam antane-1-am i no)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, 1-25: (S)-N1-ethyl-N6-(1-(2-(3-methyladamantane-1-amino)-2-oxoethyl)-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-5-carboxamido)-2-oxohexanediamide, 1-26: (S)-2-(2-chloro-1-methy1-1H-imidazole-5-carboxamido)-N6-ethyl-(1-(2-(3,5-dimethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, 1-27: (S)-2-(1,2-dimethy1-1H-imidazole-5-carboxamido)-N6-ethyl-N1-(1-(2-(3-methyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, 1-28: (S)-N1-ethyl-N6-(1-(2-(3,5,7-trimethy1-1-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methyl-1H-imidazole-5-carboxamido)-2-oxohexanediamide, 1-29: (S)-2-(2-chloro-1-methy1-1H-imidazole-5-carboxamido)-N6-ethyl-(1-(2-(3,5,7-trimethy1-1-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(benzofuran-2-carboxam ido)-N6-ethyl-N1-(1-(2-(2-1-30 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-N1-ethyl-N6-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-1-31 dihydropyridin-3-y1)-5-(3-methylbenzofuran-2-carboxamido)-2-oxohexanediamide, (S)-2-(3-chlorobenzofuran-2-carboxam ido)-N6-ethyl-N1-(1-(2-(2-1-32 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(4-bromobenzofuran-2-carboxam ido)-N6-ethyl-N1-(1-(2-(2-1-33 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(benzo[b]thiophene-2-carboxam ido)-N6-ethyl-N1-(1-(2-(2-1-34 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 (S)-N1-ethy1-5-(7-fluorobenzo[b]thiophene-2-carboxamido)-N6-(1-(2-1-35 (2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-oxohexanediamide, (S)-2-(4,5-difluoro-1H-indole-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-1-36 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-N1-ethyl-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-1-37 dihydropyridin-3-y1)-5-(3-methy1-1H-indole-2-carboxamido)-2-oxohexanediamide, (S)-2-(1H-benzo[d]imidazole-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-1-38 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(2,3-dihydro-1H-indene-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-1-39 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-N1-ethyl-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-1-40 dihydropyridin-3-y1)-5-(4-methy1-2-(trifluoromethyl)thiazole-5-carboxamido)-2-oxohexanediamide, (S)-2-(4-bromo-2-(trifluoromethyl)thiazole-5-carboxamido)-N6-ethyl-1-41 N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-N1-ethyl-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-1-42 dihydropyridin-3-y1)-5-(4-methy1-2-phenylthiazole-5-carboxamido)-2-oxohexanediamide, (S)-2-(5-bromo-3-methylthiophene-2-carboxamido)-N6-ethyl-N1-(1-1-43 (2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(3,5-dibromothiophene-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-1-44 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(5-bromo-3-methylfuran-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-1-45 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(2,5-dichlorothiophene-3-carboxamido)-N6-ethyl-N1-(1-(2-(2-1-46 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(2,5-dibromothiophene-3-carboxamido)-N6-ethyl-N1-(1-(2-(2-1-47 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 (S)-2-(2, 5-dich lorothiazole-4-carboxam ido)-N6-ethyl-N 1-(1-(2-(2-1-48 adamantylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(2, 5-dimethylfuran-3-carboxam ido)-N6-ethyl-N 1-(1-(2-(2-1-49 adamantylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(4-bromothiazole-2-carboxam ido)-N6-ethyl-N 1-(1-(2-(2-1-50 adamantylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(4-bromothiophene-2-carboxam ido)-N6-ethyl-N1-(1-(2-(2-1-51 adamantylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(4-bromo-5-chlorothiophene-2-carboxam ido)-N6-ethyl-N 1-(1-1-52 (2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(4,5-dibromothiophene-2-carboxam ido)-N6-ethyl-N 1-(1-(2-(2-1-53 adamantylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(4,5-dichlorothiophene-2-carboxam ido)-N6-ethyl-N 1-(1-(2-(2-1-54 adamantylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-((S)-1-acetylpyrrolidine-2-carboxam ido)-N6-ethyl-N 1-(1-(2-(2-1-55 adamantylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-N1-ethyl-N6-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-1-56 dihydropyridin-3-y1)-5-(1-methy1-1H-1,2,3-triazole-5-carboxam ido)-2-oxohexanediamide, (S)-N1-ethyl-N6-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-1-57 di hyd ropyridin-3-y1)-2-oxo-5-(2 H-tetrazole-5-carboxam ido)hexanediamide, (S)-N1-ethyl-N6-(1-(2-(5-hydroxyadamantane-2-am ino)-2-oxoethyl)-1-58 2-oxo-1,2-dihydropyridin-3-y1)-2-oxo-5-(pyrazine-2-carboxam ido)hexanediamide, (S)-N1-ethyl-N6-(1-(2-(5-fluoroadamantane-2-am ino)-2-oxoethyl)-2-1-59 oxo-1,2-dihydropyridin-3-y1)-2-oxo-5-((S)-pyrrolidine-3-carboxam ido)hexanediamide, (S)-N1-ethyl-N6-(1-(2-(5-chloroadamantane-2-am ino)-2-oxoethyl)-2-1-60 oxo-1,2-dihydropyridin-3-y1)-2-oxo-5-((S)-piperidine-2-carboxam ido)hexanediamide, 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 (S)-N1-ethyl-N6-(1-(2-(5-bromoadamantane-2-amino)-2-oxoethyl)-2-1-61 oxo-1,2-dihydropyridin-3-y1)-2-oxo-5-((R)-piperidine-3-carboxamido)hexanediamide, (S)-N1-ethyl-N6-(1-(2-(5-methyladamantane-2-amino)-2-oxoethyl)-2-1-62 oxo-1,2-dihydropyridin-3-y1)-5-((R)-morpholine-3-carboxamido)-oxohexanediamide, (S)-N1-ethyl-N6-(1-(2-(2-carbonitrileadamantane-2-amino)-2-1-63 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxo-54(3S,4R)-quinuclidine-3-carboxamido)hexanediamide, (S)-methyl 3-(6-(ethylamino)-1-(1-(2-(methyl 2-aminoadamantane-2-1-64 carboxylate)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-1,5,6-trioxohexan-2-ylcarbamoy1)-5-nitrobenzoate, (S)-N1-(1-(2-(1-adamantylmethylamino)-2-oxoethyl)-2-oxo-1,2-1-65 dihydropyridin-3-y1)-N6-ethy1-2-(5-nitronicotinamido)-5-oxohexanediamide, 54(2S)-1-(1-(2-1-adamantylmethylamino)-2-oxoethyl)-2-oxo-1,2-1-66 dihydropyridin-3-ylamino)-6-(ethylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinic acid, (S)-N1-ethyl-N6-(1-(2-(2-adamantyl(methyl)amino)-2-oxoethyl)-2-1-67 oxo-1,2-dihydropyridin-3-y1)-5-(6-methylimidazo[2,1-b]thiazole-carboxamido)-2-oxohexanediamide, (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-1-68 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide, (S)-N1-ethy1-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-1-69 oxo-1-(2-oxo-2-((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide, (S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-1-70 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide, (S)-N1-(1-(2-((1s,4R)-bicyclo[2.2.1]heptan-1-ylamino)-2-oxoethyl)-2-1-71 oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-2-(isonicotinamido)-5-oxohexanediamide, (S)-N1-(1-(2-(bicyclo[2.2.1]heptan-7-ylamino)-2-oxoethyl)-2-oxo-1,2-1-72 dihydropyridin-3-y1)-N6-ethy1-5-oxo-2-(pyridazine-4-carboxamido)hexanediamide, (S)-N1-(1-(2-((1R,2R,4R)-bicyclo[2.2.1]hept-5-en-2-ylamino)-2-1-73 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-5-oxo-2-(pyridazine-3-carboxamido)hexanediamide, 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 (2S)-N1-(1-(2-(bicyclo[2.2.2]octan-2-ylam ino)-2-oxoethyl)-2-oxo-1,2-1-74 dihydropyridin-3-y1)-N6-ethy1-5-oxo-2-(2H-1,2,3-triazole-4-carboxamido)hexanediamide, (S)-N1-ethy1-5-(1-methyl-1H-1,2,3-triazole-4-carboxam ido)-2-oxo-1 75 N6-(2-oxo-1-(2-oxo-2-((1R,2R,4R)-1,7 ,7--trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-y1)hexanediamide, (S)-N1-ethy1-5-(1-methyl-1H-1,2,4-triazole-3-carboxam ido)-2-oxo-1 76 N6-(2-oxo-1-(2-oxo-2-((1R,2R,3R,5S)-2,6,6--trimethylbicyclo[3.1.1]heptan-3-ylamino)ethyl)-1,2-dihydropyridin-3-y1)hexanediamide, (S)-2-(benzofuran-3-carboxam ido)-N6-ethy1-5-oxo-N1-(2-oxo-1-(2-1-77 oxo-2-((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)ethyl)-1,2-dihydropyridin-3-y1)hexanediamide, (S)-2-(benzo[b]thiophene-3-carboxam ido)-N6-ethyl-N 1-(1-(2-(4-1-78 homoisotwistane-3-am ino)-2-oxoethyl)-2-oxo-1,2-d ihydropyrid in-3-y1)-5-oxohexanediam ide, (S)-N1-ethyl-N6-(1-(2-(diamantane-1-am ino)-2-oxoethyl)-2-oxo-1,2-1-79 dihydropyridin-3-y1)-5-(1-methy1-1H-pyrazole-4-carboxamido)-2-oxohexanediamide, (S)-N1-ethyl-N6-(1-(2-(diamantane-4-am ino)-2-oxoethyl)-2-oxo-1,2-1-80 dihydropyridin-3-y1)-5-(1-methy1-1H-pyrazole-3-carboxamido)-2-oxohexanediamide, 1 81 (S)-N1-(1-(1-adamantylmethyl)-2-oxo-1,2-d ihydropyrid in-3-y1)--ethyl-2-(1-methy1-1H-pyrazole-5-carboxamido)-5-oxohexanediamide, (S)-N1-(14(3-hydroxy-1-adamantyl)methyl)-2-oxo-1 ,2-1-82 dihydropyridin-3-y1)-2-(4-cyclopropy1-1,2,3-thiadiazole-5-carboxam ido)-N6-ethyl-5-oxohexanediam ide, (S)-N1 -(14(3-bromo-1 -adamantyl)methyl)-2-oxo-1 ,2-d ihydropyrid in-1-83 3-y1)-N6-ethy1-5-oxo-2-(1,2,5-thiadiazole-3-carboxamido)hexanediamide, (S)-N1-(1-(2-adamantylmethyl)-2-oxo-1,2-d ihydropyrid in-3-y1)-N6-1-84 ethy1-2-(4-(hydroxymethyl)-1,2,3-thiadiazole-5-carboxamido)-5-oxohexanediamide, (S)-2-(4-tert-butyl-1H-pyrrole-3-carboxam ido)-N1-(1-(2-(1-1-85 adamantylamino)ethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-oxohexanediamide, 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 (S)-2-(4-cyano-1-methy1-1H-pyrrole-2-carboxam ido)-N1-(1-(1-1-86 adamantylamino)propy1)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-oxohexanediamide, (S)-N1-(1-(3-(2-adamantylam ino)-3-oxopropy1)-2-oxo-1,2-1-87 dihydropyridin-3-y1)-N6-ethy1-2-(5-methoxyoxazole-2-carboxamido)-5-oxohexanediamide, (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-1-88 dihydropyridin-3-y1)-N6-ethy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide, (S)-2-(2-acetyloxazole-4-carboxam ido)-N1-(1-(2-1-89 (bicyclo[1.1.11pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-5-oxohexanediamide, (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-1-90 dihydropyridin-3-y1)-N6-ethy1-2-(2-isopropyloxazole-5-carboxamido)-5-oxohexanediamide, (2S)-N1-(1-(2-(bicyclo[3.2.1]octan-8-ylam ino)-2-oxoethyl)-2-oxo-1,2-1-91 dihydropyridin-3-y1)-2-(3,5-dimethylisoxazole-4-carboxamido)-ethy1-5-oxohexanediamide, (S)-N1-ethyl-N6-(1-(2-(5-carboxy-2-am inoadamantane)-2-oxoethyl)-1-92 2-oxo-1,2-dihydropyridin-3-y1)-5-(4-methylpyrimidine-5-carboxamido)-2-oxohexanediamide, (5S)-N1-ethyl-N6-(1-(2-(4-aminoadamantane-N,N-dimethy1-1-1-93 carboxamide)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxo-(1,2,3,4-tetrahydronaphthalene-2-carboxamido)hexanediamide, (S)-2-((S)-1,4-diazabicyclo[2.2.2]octane-2-carboxam ido)-N6-ethyl-1-94 N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-N1-ethy1-5-(1H-indole-3-carboxam ido)-N6-(1-(2-(2-1-95 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxohexanediamide, (S)-N1-ethyl-N6-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-1-96 dihydropyridin-3-y1)-5-(6-methylimidazo[2,1-b]thiazole-3-carboxamido)-2-oxohexanediamide, (S)-2-(benzo[d]thiazole-2-carboxam ido)-N1-(1-(2-((1S,2R,4R)-1-97 bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-5-oxohexanediamide, (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylam ino)-2-1-98 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-2-(imidazo[2,1-b]thiazole-6-carboxamido)-5-oxohexanediamide, 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylam ino)-2-1-99 oxoethyl)-2-oxo-1,2-di hydro pyridi n-3-y1)-N6-ethy1-2-(4-hydroxy-6-(trifluoromethoxy)quinoli ne-3-carboxam ido)-5-oxohexanediam ide, (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-1-100 dihydropyridin-3-y1)-2-(cinnoline-3-carboxamido)-N6-ethy1-5-oxohexanediamide, (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-1-101 dihydropyridin-3-y1)-N6-ethy1-2-(3-ethylbenzofuran-2-carboxamido)-5-oxohexanediamide, (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-1-102 dihydropyridin-3-y1)-N6-ethy1-2-(1-ethy1-1H-indole-2-carboxamido)-5-oxohexanediamide, (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-1-103 dihydropyridin-3-y1)-N6-ethy1-2-(2-methy1-1,8-naphthyridine-3-carboxamido)-5-oxohexanediamide, (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-1-104 dihydropyridin-3-y1)-N6-ethy1-5-oxo-2-(1,2,3,4-tetrahydroquinoline-6-carboxamido)hexanediamide, (S)-N1-ethyl-N6-(1-(2-(2-carboxy-2-am ino-5-1105 (trifluoromethyl)adamantane)-2-oxoethyl)-2-oxo-1,2-d ihydropyrid in--3-y1)-2-oxo-5-(3-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)hexanediamide, (S)-N1-ethyl-N6-(1-(2-(5-ethyladamantane-2-am ino)-2-oxoethyl)-2-1-106 oxo-1,2-dihydropyridin-3-y1)-5-(1,6-naphthyridine-2-carboxamido)-2-oxohexanediamide, (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-1-107 dihydropyridin-3-y1)-N6-ethy1-2-(2,6-naphthyridine-1-carboxamido)-5-oxohexanediamide, (S)-2-(4-am ino-1,2, 5-oxadiazole-3-carboxamido)-N 1-(1-(2-1-108 (bicyclo[1.1.11pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-5-oxohexanediamide, (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-1-109 dihyd ropyridin-3-y1)-2-(6-(d imethylami no)benzofu ran-2-carboxam ido)-N6-ethyl-5-oxohexanediam ide, (S)-2-(2-acetam idoth iazole-5-carboxam ido)-N 1-(1-(2-1-110 (bicyclo[1.1.11pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-5-oxohexanediamide, 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 (S)-N4-(1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1-111 1,2-dihydropyridin-3-ylamino)-6-(ethylamino)-1,5,6-trioxohexan-2-yI)-1H-pyrrole-2,4-dicarboxamide, (S)-N1-ethyl-N6-(1-(2-(1-acetylamino-4-aminoadamantane)-2-1-112 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxo-5-(5-sulfamoylfuran-3-carboxamido)hexanediamide, (S)-2-(benzofuran-5-carboxamido)-N6-ethyl-N1-(1-(2-(1-1-113 acetylamino-4-aminoadamantane)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(benzofuran-6-carboxamido)-N6-ethyl-N1-(1-(2-(4-1-114 aminoadamantane-1-carboxamide)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-N1-ethyl-N6-(1-(2-(4-aminoadamantane-1-carboxamide)-2-1-115 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(3-(1-methylcyclopropy1)-1,2,4-oxadiazole-5-carboxamido)-2-oxohexanediamide, (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-1-116 dihydropyridin-3-y1)-N6-ethy1-2-(5-methy1-1,2,4-oxadiazole-3-carboxamido)-5-oxohexanediamide, (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-1-117 dihydropyridin-3-y1)-N6-ethy1-5-oxo-2-(1,2,3-thiadiazole-carboxamido)hexanediamide, (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-1-118 dihydropyridin-3-y1)-N6-ethy1-5-oxo-2-(1,2,4-thiadiazole-carboxamido)hexanediamide, (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-1-119 dihydropyridin-3-y1)-N6-ethy1-5-oxo-2-(1,3,4-thiadiazole-carboxamido)hexanediamide, (S)-N1-ethy1-5-(4-formy1-1,2,3-thiadiazole-5-carboxamido)-N6-(1-(2-1-120 (2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxohexanediamide, (S)-N1-ethyl-N6-(1-(2-(3,5-dimethyladamantane-1-amino)-2-1-121 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(nicotinamido)-oxohexanediamide or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising a compound of any one of the claims 1 ¨ 9 as an active ingredient, together with at least one pharmaceutically acceptable carrier, excipient and/or diluent.
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30
11. Compound according to any one of the claims 1 ¨ 9 for use in medicine.
12. Compound according to any one of the claims 1 ¨ 9 or the pharmaceutical composition according to claim 8 for use in the treatment or prophylaxis of autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, ocular diseases, and skin disorders.
13. Compound for use, or the pharmaceutical composition for use according to claim 12, wherein the autoimmune and inflammatory diseases comprises multiple sclerosis, celiac disease, Duhring-Brocq-disease (dermatitis herpetiformis), gluten ataxia, gluten neuropathy, diabetes, rheumatoid arthritis, Graves' disease, inflammatory bowel disease, systemic lupus erythematosus psoriasis, and gingivitis;
the vascular diseases comprise atherosclerosis, thrombosis, vascular stiffness;
the fibrotic diseases affecting the lung, the kidney, the liver, the skin or the gut like cystic fibrosis, kidney fibrosis and diabetic nephropathy, intestinal fibrosis, idiopathic lung fibrosis, liver fibrosis;
the liver diseases like alcoholic hepatitis, alcoholic steatohepatitis, nonalcoholic steatohepatitis, non-alcoholic fatty liver disease, liver cirrhosis, autoimmune hepatitis or liver inflammation;
the cholestatic liver diseases comprise primary biliary cholangitis and primary sclerosing cholangitis;
the cancer comprises glioblastoma, melanoma, pancreatic cancer, renal cell carcinoma, meningioma, and breast cancer, the neurodegenerative diseases comprise Parkinson's disease, Huntington's disease, or Alzheimer's disease;
the ocular diseases comprise glaucoma, cataracts, macular degeneration, or uveitis;
and the skin disorders comprise acne, psoriasis, scarring, and skin aging.
the vascular diseases comprise atherosclerosis, thrombosis, vascular stiffness;
the fibrotic diseases affecting the lung, the kidney, the liver, the skin or the gut like cystic fibrosis, kidney fibrosis and diabetic nephropathy, intestinal fibrosis, idiopathic lung fibrosis, liver fibrosis;
the liver diseases like alcoholic hepatitis, alcoholic steatohepatitis, nonalcoholic steatohepatitis, non-alcoholic fatty liver disease, liver cirrhosis, autoimmune hepatitis or liver inflammation;
the cholestatic liver diseases comprise primary biliary cholangitis and primary sclerosing cholangitis;
the cancer comprises glioblastoma, melanoma, pancreatic cancer, renal cell carcinoma, meningioma, and breast cancer, the neurodegenerative diseases comprise Parkinson's disease, Huntington's disease, or Alzheimer's disease;
the ocular diseases comprise glaucoma, cataracts, macular degeneration, or uveitis;
and the skin disorders comprise acne, psoriasis, scarring, and skin aging.
14. Compound for use, or the pharmaceutical composition for use according to any one of the claims 12 and 13 in the treatment or prophylaxis of celiac disease.
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30
15. A method for producing the compound of formula (la) according to claim 1 comprising:
Step 1A: providing a compound 4a AcON-R6 H
PGNJ((OH
H 0 4a;
Step 2A: performing coupling reaction of the compound 4a with a compound 5 H2N)-L _I__ , N R3 to obtain a compound 6a Ac0-LN-R6 H
, N R-6a;
Step 3A: deprotecting an amino protecting group PG3to obtain a compound 7a Ac0)-LN-R6 H
H
H2Nj(iNN-1¨R3 7a;
Step 4A: performing coupling reaction of the compound 7a with a carboxylic acid (R2-CO2H 8) to obtain a compound 9a AcO)-N-R6 H
0 iCH 0 R2N J-L 1\1 N ,L
, 'R3 9a;
Step 5A: performing oxidation reaction of the compound 9a to produce the 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 compound of the formula (la) ON.R6 H
A N)-L ,L, , R2 N , N R-(1a), wherein L, R2, R3, and R6 have the same meanings as defined in claim 1, and PG3 is an amino protecting group.
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Inhibitors of Transglutaminases Description The invention relates to novel inhibitors of transglutaminases, in particular transglutaminase 2, methods for their synthesis and to their use for the prophylaxis and treatment of diseases associated with transglutaminases, in particular transglutaminase 2.
Background of the invention Transglutaminases are part of the class of transferases and according to EC
nomenclature they are correctly designated as "protein-glutamine: amine y-glutamyl transferases" (EC 2.3.2.13). They link the E-amino group of the amino acid lysine and the y-glutamyl group of the amino acid glutamine forming an isopeptide bond while ammonia is released. In the absence of suitable amines and/or under certain conditions, deamidation of the glutamine may occur resulting in the corresponding glutamic acid.
Additionally, transglutaminases play an important role in many therapeutic areas such as the cardiovascular diseases (thrombosis and atherosclerosis), autoimmune diseases (celiac disease, Duhring-Brocq-disease, gluten ataxia), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease), dermatological diseases (ichthyosis, psoriasis, acne) as well as in wound healing and inflammatory diseases (e.g. tissue fibrosis) (J.M. Wodzinska, Mini-Reviews in medical chemistry, 2005, 5, 279 - 292).
Celiac disease, a gluten intolerance, however, is one of the most important indications.
Celiac disease is characterized by a chronic inflammation of the mucosa of the small intestine. In susceptible patients, the intestinal epithelium is successively destroyed after ingestion of gluten-containing food resulting in reduced absorption of nutrients which again has massive impact on the patients affected and is for example associated with symptoms such as loss of weight, anemia, diarrhea, nausea, vomiting, loss of appetite and fatigue. Due to these findings, there is a large demand for the development of a medicament for the treatment of celiac disease as well as of other diseases associated with tissue transglutaminase (transglutaminase 2, TG2, tTG).
The tissue transglutaminase is a central element during pathogenesis. The endogenous enzyme catalyses the deamidation of gluten/gliadin in the small intestinal mucosa and thus triggers the inflammatory response. Therefore inhibitors of tissue transglutaminase are suitable to be used as active agents for medication.
Another very important group of indications for tissue transglutaminase inhibitors are fibrotic disorders. Fibrotic disorders are characterized by the accumulation of cross-2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 linked extracellular matrix proteins. Diabetic nephropathy, cystic fibrosis, idiopathic pulmonary fibrosis, kidney fibrosis as well as liver fibrosis belong to the most important fibrotic disorders to be addressed with the compounds disclosed.
.. US 9,434,763 B2 discloses pyridinone derivatives having a warhead comprising at least one acceptor-substituted double bond, such as a Michael System, as irreversible transglutaminase inhibitors. Alkylacetamido and arylacetamido pyridinones showed inhibitory activity regarding tissue transglutaminase TG2 in nanomolar range (IC50).
Tse et al. (J. Med. Chem. 2020, 63, 11585-11601) report on replacement of phenyl residues by non-classical bioisosteres, such as cubane and bicyclo[1.1.1]pentane (BCP), in anti-malarial triazolopyrazine compounds in order to alter compound solubility and metabolic stability. The authors further evaluated in vitro antiplasmodial activity of bioisosteric modified triazolopyrazines against the 3D7 strain of P.
falciparum.
Replacement of phenyl by bioisosteric saturated heterocyclic residues resulted in complete loss of activity. Adamantyl residues as well as other hydrocarbon-caged derivatives led to potency up to 2-9 times lower than the corresponding phenyl triazolopyrazine compounds. In contrast, higher potencies were achieved by replacing phenyl with closo-1,2- and 1,7-carborane isomers. The authors concluded that the effect __ of non classical bioiostere replacement on biological properties cannot be predicted accurately and that a considerable range of possible bioisosteres has to be tested first in order to identify a suitable replacement leading to the desired properties of a given molecule.
Subbaiah et al. (J. Med. Chem. 2021, 64, 19, 14046-14128) report on bioisosteres of the phenyl ring in lead optimization and drug design. It is noted that bioisosteric phenyl ring replacement with heterocyclic and carbocyclic moieties can lead to enhanced potency, solubility, and metabolic stability while reducing lipophilicity, plasma protein binding, phospholipidosis potential, and inhibition of cytochrome P450 enzymes and the hERG
channel. However, this effect depends strongly on the properties of the compound itself and the addressed target.
US 11,072,634 B2 discloses reversible transglutaminase inhibitors comprising an aldehyde, a ketone, an a-ketoaldehyde, an a-ketoketone, an a-ketoacid, an a-ketoester, an a-ketoamide or a halogenmethylketone as warhead. The inhibitors showed inhibitory activity regarding tissue transglutaminase TG2 in nanomolar and micromolar range (IC50).
The objective of the present invention is to provide novel, most probably reversible inhibitors of transglutaminases, in particular transglutaminase 2 and methods for the synthesis of said inhibitors as well as several uses of these inhibitors.
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 Said objective is solved by the technical teachings of the independent claims.
Further advantageous embodiments, aspects and details of the invention are evident from the dependent claims, the description and the examples.
Surprisingly, it has been found that reversible inhibitors having a chemical warhead as disclosed herein inhibit effectively transglutaminases including tissue transglutaminase called transglutaminase 2 or TG2. Herein these terms are used synonymous.
Preferably, such chemical warhead moiety is particularly selected from reversible warheads such as a-ketoamides. The compounds of the present invention act as selective inhibitors of transglutaminase 2.
In order to prove inventiveness of the compounds of the present application, reference compounds were synthesized and tested in comparison to the most similar compounds of the present application. A skilled person might notice compound A8 from our patent US 9,434,763 B2 which we introduce as Ref. 3 to highlight the inventive and preferred features of the claimed compounds. From US 9,434,763 B2, it is clear, that aromatic moieties (C-terminal) restrict the efficacy of those compounds (compare to Al, A8, A37, A44, A47). In sharp contrast, branched alkyl moieties are highly preferred as indicated by more potent compounds (A28, A29, A59, A61, A63, A67, A68, A79).
To illustrate the advantage of branched alkyl moieties over aromatic moieties, we refer to reference compounds Ref. 2 (ZED1227, US 9,434,763 B2) and Ref. 3 (A8, ZED1047).
Inhibition data were determined using the classical fluorescent transamidation assay (dansylcadaverine incorporation into methylated casein, DCC-assay) as described [Bach Id, C.; HiIs, M.; Gerlach, U.; Weber, J.; Pelzer, C.; Heil, A.;
Aeschlimann, D.;
Pasternack, R. Features of ZED1227: The First-In-Class Tissue Transglutaminase Inhibitor Undergoing Clinical Evaluation for the Treatment of Celiac Disease. Cells 2022, //, 1667. https://doi.org/10.3390/cells11101667]. Casein is one of the best known high molecular weight (24 kDa) protein substrates for transglutaminases.
Please note, the ICso value of Ref. 3 (A8) published in US 9,434,763 B2 cannot be compared to the present data, relying on a fluorogenic isopeptidase assay.
Measured in the DCC-assay, Ref. 2 (ICso = 53 nM) is 80-fold more potent compared to Ref. 3 (ICso = 4,268 nM).
Accordingly, a person skilled in the art of medicinal chemistry would choose branched alkyl moieties as lead structures, such excluding aromatic moieties, e.g. the phenyl group.
It is of common knowledge, that bridged cycloalkyl groups are non-classical bioisosters of the phenyl group. By replacement of the phenyl group in A8 by e.g. an adamantane 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 group, a skilled person would expect similar physico-chemical or biochemical properties excluding to invest efforts. Since aromatic moieties are clearly not preferred, bridged cycloalkyl groups would not be considered improving the compounds.
This is further supported by additional reference compounds. ZED3641 (Ref. 1, as disclosed in US 11,072,634 B2; reversible acting a-ketomethylamide analogue to Ref. 2, ZED1227) is about 10-fold more potent compared to Ref. 6 (compare table 1).
Ref. 6 is analogous to compound A8 disclosed in US 9,434,763 B2 with respect to the backbone proving again superiority of branched alkyl moieties compared to aromatic derivatives in combination with reversible acting warheads.
However, surprisingly, replacement of the preferred branched alkyl moieties by bridged cycloalkyl groups further significantly improve the potency of the compounds as shown in table 1. Therefore, we credit bridged cycloalkyl groups as disclosed with an outstanding inventive manner.
In summary, the inventive compounds rated "A" show efficacies of about 100-fold higher compared to Ref. 3 (A8, compare to table1).
Further, compounds with activities rated "B" or "C" are still preferred (lower ICso values) to Ref. 3 (A8). These compounds can also be considered inventive, since peripheric ligands affect physico-chemical or biochemical properties. Therefore, also less potent compounds might be of high value, depending on the application.
Thus, the present invention relates to compounds of the general formula (I):
H J (I) CN L R3 Ho wherein L represents ¨L1¨ or _L1-L2¨; preferably ¨1_1-L2¨;;
L1 represents ¨CH2¨, ¨CH2CH2¨, ¨CH2CH2CH2¨, ¨CH2C0¨, or ¨CH2CH2C0¨;
L2 represents a bond, ¨NRN1¨, ¨NRN1CH2¨, ¨NRN1CH2CH2¨, or ¨NRN1CH(C1-13)¨, R1 represents , R2 represents 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 RN RN
___ 0 R8 R1.0 R8 _ _ S .-,8 R1S R8 - _ li Ra R1'11 Ra Irm , __________________________________________ r , __ ( Rlo R9 , R9 R10 R9 , R9 Rlo R9 , I-C,_,9 , RN RN RN RN RN
RN N, R N \ __ N, R11 il RN
_ _ 4 4 K il K---- R8 -----\_4N
R, 1 IN R8 N
N
N
Rlo s, , R9 R10 R9 Rlo , Rio ' , Rio , , R1 , Rtl,c(0õ, __ Rzc,0õ,_ R8 - - 15 r ¨ R8 0 ---- ' - _8 _A,..R1C) R1:J.,6_ _ _ \ /7--- o y N N N 1\A
R10 , ' R10 N - R8 ? N.¨ \ R8 n10 N
/
, I-µ , RN RN RN
Rii s R8 -_).,,SN Ra --,._1\i, RNN N, , ,N Rlo Ri o,N, N _RN
, ______ N N
, , , K
- _NI, DN ---------- /') ppl3 /`) R13 ------- iq R.- N/ 1, R.- 1,1 R .-- '' N''` ft j .- \) \N
, N=14 , ---- 1-µo14 , N R14 , 1\1-R14 , N Ria ' N Ria , RN
R12 R12 Riz RN
0----//, S-----, N-----' R2 ---U tR13 ii--.//µ .../-----.....
Rlo R14 R10 R14 Rlo ,--, - / R14 N-----\--N1A ,\-) , , RN
p RN
`s 14 Ni yR9 ,õ------..,---`
H 12 I 1 R13 n 71\1)7¨NsR
(ri R9 r N 1R9 \-' n14 , I-C n1,, N , IA - \___,--------mio, R10 , , R8 R8, 0Rlo ,S,, (--_ , , ' R9 ,S N I/
_R10 ,-- " _Rio N--/ N _., N \ 1 --N I S)'-- ---N
\
,-s( IN R8' \S-N N'N R8 , , õ,--,-- 0 R8----S il NhT IR----- Ru---- il ---N-N b-N , N- , 0-N N , , H
\ \ \ --N , , , , , , ' , _ ¨ -eNNH -- _ -(N _<N -- NH --eNS
N N __ \( S S z S S 7 N
----eNS ----eNS ---eNNH ---eNNH
N N __ ( Ni Nj , Nj , 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 /
-N ----(N3 N( 11 0 Nj \N , N , , 0 z N
, , H S
- --N& - ----N----$ -\ --1, N-H N -N
'S
---S H , S --____--N _ y/Th_-N S ___C-1-N
----:-\------N-,.. \S-I -- N -,õ(/N S-1\1-//
, N-,õ_-0 H
N
-- ------N---N&o NJ'N-0 H H
/
, -, I\1 ., N
N
-, N ., ., ' N
, N , , ., -.,1\1 -, ,N
N Th\r N /
. . N,N
I -I
NN , N
, -. N -.
' N 'N
N N
N
, ., -, ,1\1 I\1 - N, N
N
N
1\1 NN N le , N , N N N , , N -, N N , f -N , NN N N , N NNI IVN
"
2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 -õNN,N
-,! N N
I
1\1- N , , , -,,I\IN -,,I\IN -,,NN
1 1 f N--N NN N N , -,,1\1 -, N -, ,I\I
1\i-Ni-, NN N1,N
, , 1\1-N leN N"
' N -,,1\1 -,,1\1 N N
'N
N,N
N:N I
I I
NN, NN NN
, , 1 -r N,N NN-.N NN:1\1 ' , , - - , -1r N '-,-I --'1 'N
I
N,NN N,NN
1\IN
' H -, NH
HN KNH , , N NH, HN , NH, H' N=\ CR\ N=N N=\ N---N
\ N
N/ \ //N
__________________________________________________________ // , 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 N¨ N¨ N¨ ¨N ¨N
/N
¨ _______________________ ¨ ¨ N
N' N", /¨N ¨N ¨N ¨ \
¨ ¨ ¨ ¨\ // ¨ ¨ \
N / N
( /71 , -- \ /N
I\
N N , ____________________ ¨-N\ , , , I\1 , ¨ ¨
\ '/N ¨ ¨
\ N ¨ =
N N
N N N¨// // , , N=\ N=\
¨ ¨ /(1\1 ¨ ¨ ¨. /N
\ / N\/ N / N N N S
N N¨N sIV // N
N=N N=N N=N N=N N=N
\ /jv N /
N, N /
, , N=\ N=\ N=\ N=\ N-- ¨ /(N ¨ ¨ /N ¨ ¨ /N ¨ ¨ 5 N1 ¨ ¨ __ \//N , \ S \ _______ 1\1 / , N
N N
, , , N¨ N¨ N¨ N¨ N-- ¨ ________ ¨ ¨ _________ \ ¨ ¨ _____ ¨ ¨ __ \ N N N ¨ ¨ / N / N /
N¨// // N¨N N sIV __ , ' , , , ¨N ¨N ¨Ns ¨N ¨N
, ¨ ¨ --, /s(N ¨ ¨ ;IV ¨ ¨ /N ¨ ¨ i / N ¨ ¨
\//N , \ S \ _______ 1\1 , N
N N N
, , , ¨N ¨N /¨N ¨N ¨N
¨ ¨ /
\ N N
N N
// N¨N \\_N
, _______ ' , ' N ___ , ¨ \
/ ¨ ¨ N ¨7 / /
N ¨ ¨ i N ¨ ¨ / N -- i /N
( ( ( N N N \ S N S
N N // , N¨N N
__________ , , ¨ ¨ = ¨ ¨ * ¨ ¨
Ns, \ ,N N /N N N N /
N , / ss or 1V , N¨N N ¨N ;
, N , 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 - R14 and R" ; and preferably with 1 to 3 of the substituents R11 - R13;
R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl, diamantyl, hexamethylenetetraminyl and the afore-mentioned residues optionally contain one or more C=C double bond(s) and/or are optionally substituted by one or more of Ra, Rb, Rc, Rd, and Re;
Ra, Rb, Rc, Rd, and Re represents independently of each other -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C21-13, -CON H2, -CONHCH3, -CON(CH3)2, -CONHC2H3, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H3, -CH2CON H2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2H3, -NHCOCH3, -NHCOC21-13, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C21-13, -NHSO2CHF2, -NHSO2CF3, -NHSO2CH2CF3;
R4 represents -NR6R7;
R6 and R7 represent independently of each other -H, -CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3, -cyclo-C3H3, -cyclo-C4H7, -cyclo-C31-19, -cyclo-C6H11, -CH2-cyclo-C3H3, -CH2-cyclo-C4H7, -CH2-cyclo-C31-19, -CH2-cyclo-C6H11, -Ph, -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2, or -NR6R7 is -N(C2F13)2, - -N - -N - -NO
or N/ \
\ ___________________________________________________________________ / =
R6, R9, R10, R11, R12, R13, and R14 represent independently of each other -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2F13, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H3, -C(CH3)3, -cyclo-C3H3, -CH2-cyclo-C3H3, -CH2OH, -CH2F, -CHF2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CH F2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -OCH3, -0C21-13, -0C3H7, -OCH(CH3)2, -0C(CH3)3, -0C4H9, -OCHF2, -0CF3, -OCH2CF3, -0C2F3, -OCH2OCH3, -0-cyclo-C3H3, -OCH2-cyclo-C3H3, -0-C2H4-cyclo-C3H3, -CHO, -COC H3, -COCF3, -00C2H5, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -COOK -COOCH3, -COOC2H3, -CO0C3H7, 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 -COOCH (CH3)2, -COOC(CH3)3, -00C-CH3, -00C-CF3, -00C-C2H5, -00C-C3H7, -00C-CH(CH3)2, -00C-C(CH3)3, -N H2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5, -NHCOC3H7, -NHCOCH(CH3)2, -NHCOC(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONHCH(CH3)2, -CON H-cyclo-C3H5, -CONHC(CH3)3, -CON(CH3)2, -CON (C2H5)2, -CON (C3H7)2, -CON [CH(CH3)2]2, -CON[C(CH3)3]2, -SO2N H2; -SO2N H CH3; -SO2NH C2H5, -SO2NHC3H7, -SO2NHCH (CH3)2, -SO2NH-cyclo-C3H5, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H5)2, -SO2N(C3H7)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C2H5, -NHSO2C3H7, -NHSO2CH (CH3)2, -NHSO2C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -CECH, -CEC-CH3, -CH2-CECH, -Ph, -0-Ph, -0-CH2-Ph, = ----------------------------- -NO _1\1/N
1\1 1\1 r r r r 1\1 r r r --N NH --N N- --N N
KO- , or \ ____ ;
or R8 and R9 or R9 and R19 can form together one of the following five-membered or six-membered rings:
I
'N , or -'--1\1;
or R12 and R13 or R13 and R14 can form together one of the following five-membered or six-membered rings:
.0 o-0 .0 - -0 - -0 H or I
R" represents -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-05H9, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-05H9, -CH2F, -CHF2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CH F2; -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3, -00C2H5, -00C3H7, -COCH (CH3)2, -00C(CH3)3, -CO-cyclo-C3H5, 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 ¨CO¨cyclo-C4H7, ¨CO¨cyclo-CsHo, ¨COOCI-13, ¨CO0C2H5, ¨CO0C31-17, ¨COOCH(CH3)2, ¨COOC(C1-13)3, ¨COOCH2Ph, ¨SO2CH3, ¨SO2CF3, ¨S02C2H5, ¨S02C31-17, ¨S02CH(CH3)2, ¨S02¨cyclo¨C31-15, or ¨S02C(CH3)3;
RI" represent ¨H, ¨CF13, or ¨CH2CH3;
or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomers, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
The inventors have found that the reversible inhibitors of formula (1) disclosed herein having a bridged bicyclic residue R3 exhibit increased potency over the compounds of the prior art. Particularly, it is demonstrated herein, that the inventive compounds have an improved inhibitory activity compared to the known compounds bearing aromatic moieties R3 instead of bridged bicyclic residues.
In order to prove inventiveness of the compounds of the present application, known compounds from US 9,434,763 B2 and US 11,072,634 B2 (Reference 1 (E16 from US 11,072,634 B2), Reference 3 (A8 from US
9,434,763 B2), and Reference 6) were synthesized and tested as reference compounds in comparison to the most similar compounds of the present application. To this extent, inhibition data were determined using the classical fluorescent transamidation assay (dansylcadaverine incorporation into methylated casein, DCC-assay) as described in Buchold et al. [Buchold, C.; Nils, M.; Gerlach, U.; Weber, J.; Pelzer, C.;
Heil, A.;
Aeschlimann, D.; Pastemack, R. Features of ZED1227:
The First-In-Class Tissue Transglutaminase Inhibitor Undergoing Clinical Evaluation for the Treatment of Celiac Disease.
Cells 2022, 1/, 1667.
https://doi.org/10.3390/cells11101667]. Casein is one of the best known high molecular weight (24 kDa) protein substrates for transglutaminases. Inhibition data of the inventive compounds was compared with inhibition of compounds disclosed in US 9,434,763 B2, particularly, compound A8, which is denoted herein as Reference 3. It is noteworthy that the ICso values of compounds A8 published in US 9,434,763 B2 and E16 from US 11,072,634 B2 cannot be compared to the present data, relying on a fluorogenic isopeptidase assay.
Thus, the inventive compounds of formula (I) rated "A" showed efficacies of about 100-fold higher compared to Ref. 3 (A8). The same argumentation applies to Ref. 6 which is except of the phenylethyl group identical to compound 11-111. Ref. 6 is more than 25-times less potent in comparison to compound 11-111 as evident from Table 1.
This finding was particularly surprising as a skilled person would not have expected an improved inhibitory activity of the inventive compounds bearing a bridged bicyclic residue over the compounds of the prior art bearing aromatic residues since it is common knowledge that bridged bicyclic groups or bridged cycloalkyl groups are non-classical 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 bioisosters of the phenyl group, such that a skilled person would only expect to obtain a compound having similar physico-chemical and biological properties, including inhibitory activity, when replacing a phenyl group with a bridged bicyclic group. As aromatic moieties showed lower potency, bridged cycloalkyl groups would not be considered improving the physico-chemical and biological properties of the compounds.
The residues bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl, diamantyl, and hexamethylenetetraminyl used herein, have the following parent structures respectively:
bicyclo[1.1.1]pentyl bicyclo[2.1.1]hexyl bicyclo[2.2.1]heptyl -- -bicyclo[3.1.1]heptyl bicyclo[2.2.2]octyl bicyclo[3.2.1]octyl - -- -bicyclo[3.2.2]nonyl bicyclo[3.3.2]decyl bicyclo[3.3.3]undecyl 4-homoisotwistyl adamantyl diamantyl hexamethylenetetraminyl N ¨N
and the afore-mentioned residues optionally contain one or more C=C double bond(s) such as bicyclo[2.2.1]hept-5-enyl (s. 11-97) and/or are optionally substituted by one or more .. of Ra; Rb; ¨c, rc Rd, and R.
The unsubstituted bicyclic residues which can be substituted with 1 to 5 of the substituents R9 ¨ R14 and RN ; have the following structure and the substituents R9 ¨
and RN have the meanings as defined herein:
Ri Ri o Ri 0 \ N __ ( Ria ' Ria 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 _ -( _rN Rii ___ N R11 Z N-R - \N __ Z--- N -----NS
N R13.7S R12 N __ \( S-----Rii -R12 ; ; R12, ;
N N
----eS - - -eN-R -- --NN-R
----NS
N _________ \ R13 N R._ 12 N, N Ri2 RR1300 v z Ri2 ; R13 R12 ; R13 ; ;
R11 ___ _NI, R11 R11 -(N __ r N ---e0 Ri3-4kr,õo 6 7 R12 N __ \( N ______________________________________________ \
NNN \ Ri2 N Ri2 , ' R12 ; ' R13 ;
N
; ;
R4,.,. R10 R14 R10 RI , A
, R.12 RN\ R13 R11 R.1 N,S
-$ N N "---1.-S -,e R13 __ , , _<õ,-,--L-___Ri2 _ _ N,e __ R12 R13 R11 R12 ; N" NI-1'1-s Rii R12 R11 RN R13 ; RN
, , Rii S N
)11,e R13 -- -'/Ni , N
S-1\le S-1\1/ Rii R12 INI---</ I-C NI.) ' R13 ; R.. .-,IG R13 ;
;
RN\ R13 ,..--$ N -N,e R13 --__ / -- _________________________________________________________ N R11 R ; " 0 S-N-N
R11 , R11 , ;
ON
_ _(-----rO
-$
R12 __ R13 / \ --_N ,e R13 _ _<,------r-N
, __ R12 N-1\ie N-N-0 R11 R12 RN R13 ; RN ' ; R13 ; 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 ,N
- --$¨N ,e R13 _ _ _-----i___-__-N R 0 p12 ¨ /
0-"N
Rii R12 1--IN ¨ 0-1\1-N/ R13 ' R13 , R11 Rtet R10 R11 R9 R14 -, N R13 -, R12 -, R13 ----- N
-, IA N R9 R13 o10 N
--- --- N
Rio R10 , , , Fµ
os10 N R13 R12 -. - -, , N
R13 N R"n Rlo N R12 R11 ' NN
-. R' -, -_ N-R9 I
N,N ---- N
R12 .
' , , N N
N
N Rin '' N R10 R11 R11 IA n10 , R11 , , -, R9 --- ---N-,N R9 R12 I
----- .--' io R13 R10 R11 R9 R¨
R14 , R10 R11 I 1 ..õ._ I
R9-N Ro --y-----N!"---Rii Ro-----N--- R12 , , , ., N -,.., -,.., , I I
R9-----NR12 R9-1\1-N I
R13 R13 ' 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 TIL -, N R11 ,, ', -,..õ. -,..õ, NrAl N I Ri2 .9._ Rlo R13 Rlo R13 Rlo R13 , R2 -.Nr NY NY R12 -,f NY NY R12 .µ
1 N r-rN
N NRii N NRii Rlo Rlo R11 Rlo , , ' -------, NY Ny R12 -- -2, N---,-.-.-2N---,-.-.-2 R12 N I
II I ,¨õN-------.õ1.7.--N
N !Rii Rlo , Rlo , , - N NN R12 N N R12, -- - -,--- N--=:,.----Ny-R1 ,,, ---y--...T-- -,.- N .
-, R9 R9----y--- N-2.-- R11 , 1 'N
R10iNI R12 R12 Rii Rio Rii R9 1 --,.,r---, , R10 R11 , -,,NN N --, 1 'N -,,N
1 ' N
õ,...-- ....,-...I.õ,. R" ,,,, Rlo R¨ ..----. 2.---,y---1-,. 1, Rlo R ..----. 2.----y2..-1-,. 1, N N ¨
Rlo Rii Rii ' , , - N R11 -,,N R12 - N R11 --. --,.
II
N:N I 10 N N N
2,--------- N
R
Rio , Rio Rii -. NR12 -,NN R13 - N Ri2 , .....,. 11 1 NN, N N Rii RlorNNRii R12 , R10 R11 , , NN
N I
----. 2-----y--I-2 ,. R9 R12 Ri2 N Rm Ri 1 N
Rii Rlo Rii Rlo , , , 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 R12 Rm Rlo ., N. N R10 N R11 ' -, ------L-, -----:,..---I I
N
R9 N-,N
R9-NrN
' , ;
-. I\I Ru NR11 R11 -, , -.,N
I I
NN 1 N ---õri"---N%---R9 R12 ' R9 R10 R11 Rm R11 R10 -, NrNI R11 -.
N----,,--k-....,,--j-=-:
,N
N-N\IR12 Ri2 N- R12---N--------y-%N
R13 R13 R9 , , , Rm Ru Rm Ru Nr-rN
IR
, N N R
_----N-=R12 -1--'`
R9 R12, ; R9 , Rlo R11 R10 R11 -, Nr"1 -' R10 R11 N
- - R12 .
- --õ,,. --õ,,.
R13-NN NN-,N-"N
Rm ; R9 , , p12 ., --õ, --õ, ¨ p12 -.,N
- 1 1\1 N.INI-IN I I
N.
N N R1-,/ Rio N N R'`
Rm , I
R12 __ R14 R1 ., N NR
R9 .
.
R4IL,, R4I 4 I R12 R11 R9 R10 ; R10 R9 ;
R9 R11 R11 R9 N R9 Rm N. m R-RN R10 R10 'RN
, ;
2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 R9 o R9 R9 N¨( --10 N=N
N=( --) /(1\1 --N R14 -- \ / R9 _11=_Rio Rii Ri4 R11 \ N R11 R14 R11 N
N /( Rii R13 R12 R13 ; \ __ //
õ, \ õ., 012 R12 R12 R13 1R, R ¨
, ;
" ;
N N¨ N¨ N¨ _______________ ¨N
/ R1 1 _ _ \ / R10 _ _ _. / R10 _ _ __ / R10 - \
R13 \ / __ R1 R13 __ \ / Rh1 N \ / Rh1 _________ N\\ / Rh1 R11 \ /N
N N 2 ( R12 R12 R13 R12 R13 R12 R õ, ¨
R.,õ, , , , , --( --( /
--.__ ¨R9 ___ R10 _ - i R9 - - \
/ N - - \ N
Rii \ / _________ Ri3 R11 ______________ \ z R13 N / R13 R11 \
/(N R11 \ _R13 R12 R12 R11 R12 R12õ¨ D 1õ., .., R12 ; ; " ; ;
¨ ( ¨ ( - - ----_ / N --i /N
Rii \ / R13 N\ / _____ R13 R10 R13 R13 \ N R9 \ N N N
N ) N N( /( ; ; ; ;
N¨( N¨( R13 - - R13 -- -- / N --- .. /N
-- - -( N / R19 N \ / R19 N N __ N -S R11 \ /
N N /( Ro Rio N
N¨N
' R9 R9 R12 .-, I-C11 R12 ; , , ;
N=N N=N
___\ tRi 0 ___t / R10 N=N N=N N=N
-- \ ;NI ___ \_ /Rio Rio R11 11 R14 R13 n 1 \ //IN
1, \ 1 R13 \ / R11 __ R13 \ / R11 N /
Rii N N
R12 R13 ; IR¨ R.1 R12 ; R12 ; Ri3 R12 ; ;
_ :¨
N¨( N¨( N¨( N¨( N -- \ /N ) /N
\
\
// \ _Rii R13 \ / Rii -- --,-Rii R \ ,N
õ, /( , N N N
Ric ID 11 R12 R12 R13 R12 R11 'N
2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 N¨ N¨
_ _ _ . c ¨ z R9 R10 :9 R10 ,/, _R10 _ __. _R10 ¨
\ z Rio \ N N N N / ____ R11 N, / __ R11 N _______ /( /( R12 \ / R11 N N
R11 R12 R11 N¨N , R12 R12 , , , ¨N
-- \ /N
( ¨N
-- \ /N _iR
/
_N
--__.$1:(µN ¨N
--i ;1\1 ¨N
__ \ io \ Nz/
R13 _________ , /(N R13 \ 1\/1 R11 R13 \N z R11 1\1 / R11 R12 N
R,¨ 0,..ii . R12 R12 , R13 R12 R11 Fµ , , , , --1\1/ R10 --R9\--Nz ¨N ¨N
¨N Rio two tRio Rio --_ _________________________________ R124 4 /( R12 R11 N N N
N N / __ R11 N, / __ Rii \ /
N N
, R12 R11 N¨N , Riz R12 R12 ¨( R9 R10 \ /1\1 --_ N --i /(1\1 --( -- ( \ /( --_$ /N --,N R12 D
\ , _ \ N N N R12 11 \ R11 N \ -S IA
N N __ /( /( N¨N N
R11 R11 R12 0411 , R12 Fµ , , ¨( R11 R12 R11 R12 --i /N
N, / __________ R11 Rio \ N N N N N
N, / R10 N 14 sN __ /( N¨N,/ , R10 , R10 , or N¨N
R =
, One embodiment is directed to compounds of the general formula (I):
(NH yl-R3 (I) H
wherein L represents ¨L1¨ or ¨L1-L2¨; preferably ¨L1-L2¨;
L1 represents ¨CH2¨, ¨CH2CH2¨, ¨CH2CH2CH2¨, ¨CH2C0¨, or ¨CH2CH2C0¨;
R1 represents -'--H-R4 , 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 R2 represents RN RN
__ ,0 R8 Rii 0 R8 _____S ,R8 R11 s,R8 ___...,,,,,R8 R1,, ,,,R8 Ri0 R9 / R9 R10 R9 / R9 R10 R9 . N,-,9 , R11 11µ R11 II, R11 0 --1 /1\1 1 /N ---- Ri---1 C:1__- R8 - - -(:)---- R8 0?--Z
, K a, ) N N __ Y N N¨
cl\) Rio ____ ss / R. Rio Rio R8 N¨ ' , , , , RN RN RN
,, Rio Ri_i S, _ Rii S D8 -__S___R8 - -_N-I\I Rii N, ,N, _Rio ----",N N ir N¨
RIR - Rlo , Rlo Rio , ' , Rio_...N,N_RN
_ N. _ N, DN --- R13 R13 R1-3 ------------------------------------------------------------------------- ) -N''` LI xj = - N-N , N=N , -"---- R14 , N R14 , N
Ria , RN
R12 N R12 0-/,) 13 S----/Y,) 13 N----__A
I '1 D13 N/-) Ri3 -\-) -\-) \- \- R.,1, R1, ., N Ria N Ria R10 R10 R10 R14 , , RN
s)/ N___Rizt N R9 N-----\
¨R13 R14 L j 7R13 - iA x) ---& ____________________________________________________ S ( .2....i _ ni. - R14 \-R14 0 '._in N
----\ -7---- Ri 0 , , , , , m ,N, R9 ril /1R9 m 9 R9 ,s,,-r /1 _ R10 ¨R R10 \
"- ---/--= 10 "--/--= N \ N
N -\ I
R8 S'N
' , R8 ,S,-' R8 . N II - N6-S - .- . N -- . N,-- 0 - ---N R8--- 1 Ru--- Ru----- -S)-\N-=-"N R8 N-N b-N N-0 , H
\
, , N
, , , , , , N
NH NH - N
---eN ---eN - ---eNS
--_,N3 N N __ \( ---eNNH ---eNNH
N
, NNJ\ N __ ( 0 Nj 0 z , 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 /
-N ----(N3 N( 11 0 Nj \N , N , , 0 z N
, , H S
- --N& - ----N----$ -\ --1, N-H N -N
'S
-S H , S --___-- N _ y/Th_-N S ___C-1---N
----:-\------N-,.. \S-I -- N -,õ(/N S-1\1-//
, N-,õ_-0 H
N
-- ------N---N&o NJ'N-0 H H
0---r-N N
/
, -, I\1 ., N
N
-, N ., ., ' N
, N , , ., -.,1\1 -, ,N
N Th\r N /
. . N,N
I -I
NN , N
, -. N -.
' N 'N
N N
N
, ., -, ,1\1 I\1 - N, N
N
N
1\1 NN N le , N , N N N , , N -, N N , f -N , NN N N , N N le leN
"
2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 -õNN,N
-,! N N
I
1\1- N , , , -,,I\IN -,,I\IN -,,NN
1 1 f N--N NN N N , -,,1\1 -, N -, ,I\I
1\i-Ni-, NN N1,N
, , 1\1-N leN N"
' N -,,1\1 -,,1\1 N N
'N
N,N
N:N I
I I
NN, NN NN
, , 1 -r N,N NN-.N NN:1\1 ' , , - - , -1r N '-,-I --'1 'N
I
N,NN N,NN
1\IN
' H -, NH
HN KNH , , N NH, HN , NH, H' N=\ CR\ N=N N=\ N---N
\ N
N/ \ //N
__________________________________________________________ // , 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 N¨ N¨ N¨ ¨N ¨N
/N
¨ _______________________ ¨ ¨ N
N' N", /¨N ¨N ¨N ¨ \
¨ ¨ ¨ ¨\ // ¨ ¨ \
N / N
( /71 , -- \ /N
I\
N N , ____________________ ¨-N\ , , , I\1 , ¨ ¨
\ '/N ¨ ¨
\ N ¨ =
N N
N N N¨// // , , N=\ N=\
¨ ¨ /(1\1 ¨ ¨ ¨. /N
\ / N\/ N / N N N S
N N¨N sIV // N
N=N N=N N=N N=N N=N
\ /jv N /
N, N /
, , N=\ N=\ N=\ N=\ N-- ¨ /(N ¨ ¨ /N ¨ ¨ /N ¨ ¨ 5 N1 ¨ ¨ __ \//N , \ S \ _______ 1\1 / , N
N N
, , , N¨ N¨ N¨ N¨ N-- ¨ ________ ¨ ¨ _________ \ ¨ ¨ _____ ¨ ¨ __ \ N N N ¨ ¨ / N / N /
N¨// // N¨N N sIV __ , ' , , , ¨N ¨N ¨Ns ¨N ¨N
, ¨ ¨ --, /s(N ¨ ¨ ;IV ¨ ¨ /N ¨ ¨ i / N ¨ ¨
\//N , \ S \ _______ 1\1 , N
N N N
, , , ¨N ¨N /¨N ¨N ¨N
¨ ¨ /
\ N N
N N
// N¨N \\_N
, _______ ' , ' N ___ , ¨ \
/ ¨ ¨ N ¨7 / /
N ¨ ¨ i N ¨ ¨ / N -- i /N
( ( ( N N N \ S N S
N N // , N¨N N
__________ , , ¨ ¨ = ¨ ¨ * ¨ ¨
Ns, \ ,N N /N N N N /
N , / ss or 1V , N¨N N ¨N ;
, N , 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9- R14 and R" ; and preferably with 1 to 3 of the substituents R11- R13;
wherein i) L2 represents a bond, -NRN1CH2-, -NRN1CH2CH2-, or -NRN1CH(CH3)-; and R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, 1-bicyclo[3.1.1]heptyl, 3-bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, diamantyl, hexamethylenetetraminyl and the afore-mentioned residues optionally contain one or more C=C double bond(s) and/or are optionally substituted by one or more of Ra, Rb, Rc, Rd, and Re; or ii) L2 represents a bond, -NRI41-, -NRN1CH2CH2-, or -NRN1CH(CH3)-; and R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, 2-adamantyl, diamantyl, hexamethylenetetraminyl and the afore-mentioned residues optionally contain one or more C=C double bond(s) and/or are optionally substituted by one or more of Ra, Rb, Rc, Rd, and Re;
Ra, Rb, Rc, Rd, and Re represents independently of each other -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C21-15, -CON H2, -CONHCH3, -CON(CH3)2, -CONHC2H5, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H5, -CH2CON H2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2H5, -NHCOCH3, -NHCOC21-15, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C21-15, -NHSO2CHF2, -NHSO2CF3, -NHSO2CH2CF3;
R4 represents -NR6R7;
R6 and R7 represent independently of each other -H, -CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-051-19, -cyclo-C6H11, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-051-19, -CH2-cyclo-C6H11, -Ph, -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2, or -NR6R7 is -N(C2F15)2, - -N -10 - -NO or N/ \\ /
=
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 R8, R9, R10, R11, R12, R13, and R14 represent independently of each other -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2F15, -C3H7, -CH (CH3)2, -C4H9, -CH2-CH (CH3)2, -CH (CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2OH, -CH2F, -CHF2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CH F2; -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -OCH3, -0C21-15, -0C3H7, -OCH (CH 3)2, -0C(CH3)3, -0C4H9, -OCHF2, -0CF3, -OCH2CF3, -0C2F5, -OCH2OCH3, -0-cyclo-C3H5, -OCH2-cyclo-C3H5, -0-C2H4-cyclo-C3H5, -CHO, -COC H3; -COCF3, -00C2H5, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -COOK -COOCH3, -CO0C2H5, -CO0C3H7, -COOCH (CH 3)2, -COOC(CH3)3, -00C-CH3, -00C-CF3, -00C-C2H5, -00C-C3H7, -00C-CH(CH3)2, -00C-C(CH3)3, -N H2, -NHCH3, -NHC2F15, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2F15)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC21-15, -NHCOC3H7, -NHCOCH(CH3)2, -NHCOC(CH3)3, -CONH2, -CONHCH3, -CONHC2F15, -CONHC3H7, -CONHCH(CH3)2, -CONH-cyclo-C3F15, -CONHC(CH3)3, -CON(CH 3)2, -CON (C2F15)2, -CON (C3H7)2, -CON [CH(CH3)2]2, -CON[C(CH3)3]2, -SO2N H2; -SO2N H CH3; -SO2NH C2H5, -SO2NHC3H7, -SO2NHCH (CH3)2, -SO2NH-cyclo-C31-15, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H5)2, -SO2N(C3H7)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C21-15, -NHSO2C3H7, -NHSO2CH (CH3)2, -NHSO2C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -CECH, -CEC-CH3, -CH2-CECH, -Ph, -0-Ph, -0-CH2-Ph, = ----------------------- -NO
r rN r r N\ /NH N\ N\
or or R8 and R9 or R9 and R1 can form together one of the following five-membered or six-membered rings:
õ-0 ,-N
- -'I\1 or '-%1\I
' or R12 and R13 or R13 and R14 can form together one of the following five-membered or six-membered rings:
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 ,0 ,O\
_ --O --O -N
H or I
R" represents -H, -CH3, -C2F13, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H3, -C(CH3)3, -cyclo-C3H3, -cyclo-C4H7, -cyclo-C31-19, -CH2-cyclo-C3H3, -CH2-cyclo-C4H7, -CH2-cyclo-C31-19, -CH2F, -CHF2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CH F2; -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3, -00C21-13, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -CO-cyclo-C3H3, -CO-cyclo-C4H7, -CO-cyclo-C31-19, -COOCH3, -COOC2H3, -CO0C3H7, -COOCH (CH3)2, -COOC(CH3)3, -COOCH2Ph, -S02CH3, -S02CF3, -S02C21-13, -S02C3H7, -S02CH(CH3)2, -S02-cyclo-C3H3, or -S02C(CH3)3;
RNi represent -H, -CH3, or -CH2CH3;
or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomers, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
In one embodiment the herein disclosed inventive compounds, the moiety -L-R3 is not or In one embodiment of the herein disclosed inventive compounds, L represents -1_1-L2-;
L1 represents -CH2-, or -CH2C0-; and L2 represents a bond, -NH-, -NHCH2-, -NHCH2CH2-, or -NHCH(CH3)-.
In one embodiment of the herein disclosed inventive compounds, L represents -CH2-, -CH2CO-NH-, -CH2CO-NH-CH2-, or -CH2CO-NH-CH(CH3)-.
In preferred embodiments of the inventive compound of formula (I), R2 represents 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 0C-90-ZZOZ peAieoef alea/an5a aleCI
xoop-vzomeovvod-a3z-Noadiens3a-odo-satz r ' N
rp 0, ,N
N N ) __ N N
HNN-__ HN-__ , Ny s, , , s, )\ NI N N N ) __ N
r 1-11\1-_,..
N -- N --, , , , , ' N , , \ \ \
H
, , , 4 /2- gei =L -9'el --NQ N-N 81 N---:-N\ N-S\ 0 N ---\ -' :V---N
-Q-9e1 N --i , , -L,- t S -1/-,e N \ \
- ---( -' ..., Ii N
- ' S 6'u , 0:1 -' S' oH 0:1 , H o [H ---C-\ õ N 0 OiT .:1 I----N ,.., r 0,7/ ) 0, ,, -)--H,,,-) 6 IN s __ /
' _______________________________________________________________ NH NH NH
, C[H
171.H 171.H VI.H OM
1-\
E N
[H¨ 1 C[el, 1 _ _ H Z
/----- cM,,, 1 >-z[U z0:1 Z[H
N [ - - -NH
v[eir___0_1 KH 0[H .fr[:I.N t[H .N t[H .N
N\ ---------------------------------------------------------------------/:/"--S /-----0 zM N zM zM
zM z[el N M , , Kel 17 N,N N-N ,' ,i_ni Ni' NI_ ,_,,N-\
---------------------- N- 'N --- 'N --zM Z[H NH NU-N'Ny oM 00:I N'N
NH
' ' , ' 9H
/ /
OM ' ____ N-(-()M N50M N __ (/ N ( NIIN\ _--( el-- --N z;_____N N
o k,__?
sH
0:1 N.N -_ 0:1 s-- 9 S [[el - - s õ?:1 NH
NH OM
, , , , , sH o[H ' 0[H 6H 0H 6H\ / µs OM
N N N __ (/
N ____________________________________ ( 0 9ei-- _ 771 "µ, u - - 0 [[el N 'N -- N N
'N [___M N [0=1 oH
NH NH NH
, , , , 6H / 6H 0H 6H = 6H OM 6H / 6H OM
) / \
2e1)N [[H 9e1 N ' --S [[H 9H 5 - - 8H)0 H 9H 0 - -NH NH
Z I=Z
/
-N - - --(N3 N( 11 Nj \N , Ni , , 0 0 z N
, , H S
- --N& - ----N----$ -\ --1, 1\r"
H N -N
'S
-S H , S --____--N _ y/Th_-N S __ _C-1----N
----:-\--- ---N,..._ \S-I - - N -...(/N S-1\1-//
, N-,..._-0 H
N
- - ------N1-"N&o NI'N-0 H H
0---r-N N
/
, -, I\1 ., i -N
/ N
-, N ., ., 'N
, ., -.,1\1 - , ,N
N Th\r N /
. . N,N
I -I
NN
, -. N -. -, 'N 'N
N N
N
, ., -,,1\1 I\1 - N, N
N
N '---, 1\1 NN Nle , N , N N N , , N -, N N , f -NNi , NN N N , N NNI leN
"
2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 -õNN,N
-,! N N
I
1\1- N , , , -,,I\IN -,,I\IN -,,NN
1 1 f N--N NN N N , -,,1\1 -, N -, ,I\I
1\i-Ni-, NN N1,N
, , 1\1-N leN N"
' N -,,1\1 -,,1\1 N N
'N
N,N
N:N I
I I
NN, NN NN
, , 1 -r N,N NN-.N NN:1\1 ' , , - - , -1r N '-,-I --'1 'N
I
N,NN N,NN
1\IN
' H -, NH
HN KNH , , N NH, HN , NH, H' N=\ CR\ N=N N=\ N---N
\ N
N/ \ //N
__________________________________________________________ // , 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 N¨ N¨ N¨ ¨N ¨N
/N
¨ _______________________ ¨ ¨ N
N' N", /¨N ¨N ¨N ¨ \
¨ ¨ ¨ ¨\ // ¨ ¨ \
N / N
( /71 , -- \ /N
I\
N N , ____________________ ¨-N\ , , , I\1 , ¨ ¨
\ '/N ¨ ¨
\ N ¨ =
N N
N N N¨// // , , N=\ N=\
¨ ¨ /(1\1 ¨ ¨ ¨. /N
\ / N\/ N / N N N S
N N¨N sIV // N
N=N N=N N=N N=N N=N
\ /jv N /
N, N /
, , N=\ N=\ N=\ N=\ N-- ¨ /(N ¨ ¨ /N ¨ ¨ /N ¨ ¨ 5 N1 ¨ ¨ __ \//N , \ S \ _______ 1\1 / , N
N N
, , , N¨ N¨ N¨ N¨ N-- ¨ ________ ¨ ¨ _________ \ ¨ ¨ _____ ¨ ¨ __ \ N N N ¨ ¨ / N / N /
N¨// // N¨N N sIV __ , ' , , , ¨N ¨N ¨Ns ¨N ¨N
, ¨ ¨ --, /s(N ¨ ¨ ;IV ¨ ¨ /N ¨ ¨ i / N ¨ ¨
\//N , \ S \ _______ 1\1 , N
N N N
, , , ¨N ¨N /¨N ¨N ¨N
¨ ¨ /
\ N N
N N
// N¨N \\_N
, _______ ' , ' N ___ , ¨ \
/ ¨ ¨ N ¨7 / /
N ¨ ¨ i N ¨ ¨ / N -- i /N
( ( ( N N N \ S N S
N N // , N¨N N
__________ , , ¨ ¨ = ¨ ¨ * ¨ ¨
Ns, \ ,N N /N N N N /
N , / ss or 1V , N¨N N ¨N ;
, N , 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 ¨ R14 and R" ; and preferably with 1 to 3 of the substituents R11 ¨ R13 and the substituents R9 ¨ R14 and RN3 have the meanings as defined herein.
In even more preferred embodiments, R2 represents:
RN RN
__ 0 R8 R11 0 R8 ___ S R8 R1SN _R8 __, N
1 , __ (-- \ , \ , . .
Rlo _____ R9 , R9 R10 R9 , R9 R10 R9 / R9 , RN RN RN RN RN
Ri 1 ri, RN __ N,N R11 ii _ R
_ RN
N R8 - - il I /i\i ---tii(\i 1 /
( 1 N N
-\\ _____________________________________________________ I--R10 ss , R9 R1- R9 R10 R10 ; ' R10 , , ;
R10 , , R1_R10 R11 SN _ 0,/,/._ R0õ. _R8 --<0R8 0 ----... --R8 ,c,µ ir-\ /7--- o?' N N )\ N N-2-r-R8 Rlo , Ri 0 __ N R8 N¨ R = lo N
, , ' RN
RN R
. N RN
R1- S R8 - - _S R8 - - _\I , N RiNN , N,I\rL _Rio RioN_RN
, \ i N N N N N
Rlo Rlo , N-N
, , , , /') ) 13 ------------------------------------- 3 --- N/ 11 r 3 - ,N, DoN ------------ pp13 - -c N-F\
U,,,,.,,,;::\,, J . s \_) R - \IIR1 \_) R.- R1 , N=N , mr-,14 N Rizt N R1,4 N Ria N Ria , , R-' R12 R12 Riz RN
s---/Y j\i-/
, R12 i\L..._õ, 12 R R-----%\- x) Rlo 14 Rlo 14 ol, ¨ Rlo 14 N
R1."A
, ' RN
s \ ,õ---------../,',` 014 , N, R9 r /I
-1 j R13 il Nv--F\ 9 r /1 -- Rio R1 S r_.IIR
_Rlo ) \i-R14 .--,._ _________ N - \ ----7--- Rio R4' , N,S 1 -- ' 1-( R9 ,S -- , ,--- . , _R , u N\\ 1 N
N I - - ---N
,-s(N R8 \S-N s\N'N R8 -' ' , N,- - N --R---õ \ n N- R---- I R8--- 1 N-N b-N N-0 0-N
' , ' H
\ \ \ N __ \( , N
, , 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 S N,--S
-¨N
ONj N , , , I I I
N
N
., ., -_,1\1 N
I
N,N I N N , H - -NH ., N NH , , H
' ' N_ or N, wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 - R14 and RN ; and preferably with 1 to 3 of the substituents R11 - R13 and the substituents R9 - R14 and RN have the meanings as defined herein.
Thus, the present invention relates to compounds of the general formula (I):
H (I) N ,LR3 Ho wherein L represents -L1- or -L1-L2-; preferably -L1-L2-;
L1 represents -CH2-, or -CH2C0-;
L2 represents a bond, -NH-, -NHCH2-, -NHCH2CH2-, or -NHCH(CH3)-, R1 represents -'--H-R4 ' R2 represents RN RN
_ 0 R rx 8 mil o -<8 ______srR8 Rsr,õ __ R8 Rii\i, R8 r I r /
R10 R9 / R9 R10 1,9 / R9 R10 1-,9 ' R9 RN RN RN RN
Rii , 1\1 R -R111 N R8 - -),,,IIN Rs Rtt\sõON __ Rii ON _R8 / \ /7---1 __________________________________________________________________ r N N N , N N
R10 ss Rto R10 R10 /
' 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 Ri (1 ni 0 R8 R8 \ R8 , R10 RS. _ _ RSN _ R8 - - IS R8 - - _._-- 0, --),----,-- 02 Cl ZT \ ir Y ______ N N \ N p= t N N N
Ri 0 RN RN
RN Ri2 Ri Rii lj N 1\1=--Rio Rio(rN , N _ RN
õ ,N, /') pp 13 --------------------------------------------------- /') LI \_) R13 ,) ________ N N-N ------ R14 N R
i 4 ;
N R12 0 ---__/y S---../y N /-) Ri 3 -\ -$____, 1 A
R 1-r R14 RN
Ri2 RN
N--__//,) Ri2 - - -R 13 _ _ 4i \ I ----r/õ Ri3 ' - < - - - - - - --/') 13 R10 ; ni. -R14 N ----%\IA 1 A ; R
\/\\-; R14 R14 ' ' RN RN
N R9 ri , R9 0) _ N II
R8 R.a i u n \ N \ I R8 N-. s( :
N
, S --N,., R8---- 1 N II R8----- --/ R''p, N-N , b---N , N-C) , O'N N , Or N
, R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, 10 bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl, diamantyl, hexamethylenetetraminyl and the afore-mentioned residues optionally contain one or more C=C double bond(s) and/or are optionally substituted by one or more of Ra, Rb, Rc, Rd, and Re;
Ra, Rb, Rc, Rd, and Re represents independently of each other -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C21-15, -CON H2, -CONHCH3, -CON(CH3)2, -CONHC2H5, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H5, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2F15, -NHCOCH3, -NHCOC21-15, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C21-15, -NHSO2CHF2, -NHSO2CF3, -NHSO2CH2CF3;
R4 represents -NR6R7;
R6 and R7 represent independently of each other -H, -CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)2, 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 -CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-05H9, -cyclo-C6H11, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-05H9, -CH2-cyclo-C6H1 1, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2, or -NR8R7 is -N(C2F15)2, --I\1 --I0 --NO
or N/ \
\ __ / =
R8, R9, R10, R11, R12, R13, and R14 represent independently of each other -H, -F, -CI, -Br, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH (CH3)2, -C4H9, -CH2-CH (CH3)2, -CH
(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2OH, -CH2F, -CHF2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CH F2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -OCH3, -0C2H5, -0C3H7, -OCH (CH3)2, -0C(CH3)3, -0C4H9, -OCHF2, -0CF3, -OCH2CF3, -0C2F5, -OCH2OCH3, -0-cyclo-C3H5, -OCH2-cyclo-C3H5, -0-C2H4-cyclo-C3H5, -CHO, -COC H3, -COCF3, -00C2H5, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -COOK -COOCH3, -CO0C2H5, -CO0C3H7, -COOCH (CH3)2, -COOC(CH3)3, -00C-CH3, -00C-CF3, -00C-C2H5, -00C-C3H7, -00C-CH(CH3)2, -00C-C(CH3)3, -N H2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5, -NHCOC3H7, -NHCOCH(CH3)2, -NHCOC(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONHCH(CH3)2, -CON H-cyclo-C3H5, -CONHC(CH3)3, -CON(CH3)2, -CON (C2H5)2, -CON (C3H7)2, -CON [CH(CH3)2]2, -CON[C(CH3)3]2, -SO2N H2, -SO2N H CH3; -SO2NH C2H5, -SO2NHC3H7, -SO2NHCH (CH3)2, -SO2NH-cyclo-C3H5, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H5)2, -SO2N(C3H7)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C2H5, -NHSO2C3H7, -NHSO2CH (CH3)2, -NHSO2C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -CECH, -CEC-CH3, -CH2-CECH, -Ph, -0-Ph, -0-CH2-Ph, H I H H
=--. -NO ------------- t-N/
Li N____ r , , I H I
N N N
r r r / __ \ / __ \ / __ \
0 (:) (:) --N \ / / NH --N\ /N- --N\ /N \ .
, or \
or R8 and R9 or R9 and R1 can form together one of the following five-membered or six-membered rings:
2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 H _,ID ,N
_ - ) --- --- - ---N - -- -1 -- -1 '-,/ ''0 '-,% '-.% '- --,N
---N ,N
or ----%N . , or R12 and R13 or R13 and R14 can form together one of the following five-membered or six-membered rings:
,0 ,o ,,0 ,-C) ,-() --- _.13 - ) - -0 --0 , C) 0 '-,/ '', -' H or I -R" represents -H, -CH3, -C2F13, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H3, -C(CH3)3, -cyclo-C3H3, -cyclo-C4H7, -cyclo-C31-19, -CH2-cyclo-C3H3, -CH2-cyclo-C4H7, -CH2-cyclo-C31-19, -CH2F, -CHF2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CH F2; -CF12-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3, -00C21-13, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -CO-cyclo-C3H3, -CO-cyclo-C4H7, -CO-cyclo-C31-19, -COOCH3, -COOC2H3, -CO0C3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -S02CH3, -S02CF3, -S02C21-13, -S02C3H7, -S02CH(CH3)2, -S02-cyclo-C3H3, or -S02C(CH3)3;
or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomers, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
Preferred are the compounds of the formula (lb):
0,,, ii A N , L , H
0 (Ib);
and L, R2, R3, R6, R7 have the same meanings as defined in the formula (I) Preferred are the compounds of the formula (lb):
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 ON,R6 H L
R2AN ')-NIõR3 H
(lb) wherein L represents ¨L1¨ or ¨L1-L2¨; preferably ¨L1-L2¨;;
L1 represents ¨CH2¨, ¨CH2CH2¨, ¨CH2CH2CH2¨, ¨CH2C0¨, or ¨CH2CH2C0¨;
L2 represents a bond, ¨NRI41¨, ¨NRN1CH2¨, ¨NRN1CH2CH2¨, or ¨NRN1CH(CH3)¨;
R2 represents RN RN
0 R8 R11 0 R8 -__ S Rs R11 S Rs -_ N Rs R11N Rs Rlo R9 / R9 Rlo R9 / R9 Rio R9 , mg R , RN RN RN wo R11 rj, R11 rj, /NI
r.,,i), ( n R1:JON __ RON _R8 - - __õ-ON____.R8 \ ir , __ N \
N N¨
Ri 0 `s / R9 i-K - R. R10 , , , , , ' )1 ,, 1 R8 2xRio Rzc.,\õ_ RSRs ---1SR8 --<1\1:N Rttc., N ,N
N N )\ N
, __ N
N¨ ', R8 Rio , /' N Rio , Rio , , , Rio.,..N ,N_RN N .,,Nr, _Rio \¨N
N - N, ,-,N R13 NI'm -- LI, \') = N-N , N IA=N , ------ n, 14 N et , , ---/Y,) 13 R13 r -\' \N
N Rizt N Rizt N Rizt Rio R14 Rio R14 , RN
N---__A RN
Ny, ---TR13 9 __ - - -(\ 1 tR13 \7R
R14 r_.IR
N
Rio - \ -7---Rio R.,iA
N R14, , , , _r_ /R910' r\zi:
N
Ri - H
7R13 , NI.-S
S
.A Ri_- n _______________________ N _ R
c-N----) , , RN
H
ii R9 N , , , , D____R:k, R9 r -/i i n _ R10 \ / /TiiiiIJi el---/_-= R1 :, k , _R . u 0) , II , 0 , S , ' , ,µ.11 , 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 N_ '===õ,, ,S -' -_,N, \N
I - N\ \ I
R8 R8 ' R8 S
) N6-- -- ---N R8---- ii NhT- Ru---- -1 \S-N N R8 or , R`-'a -- ii 0-N ;
R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl, diamantyl, hexamethylenetetraminyl, and the afore-mentioned residues optionally contain one or more C=C double bond(s) and/or are optionally substituted with one or more of Ra, Rb, Rc, Rd, and Re;
Ra, Rb, Rc, Rd, and Re represents independently of each other -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C2H3, -CON H2, -CONHCH3, -CON(CH3)2, -CONHC2F13, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H3, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CON HC2F13, -NHCOCH3, -NH COC21-13, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C21-13, -NHSO2CHF2, -NHSO2CF3, -NHSO2CH2CF3;
R4 represents -NR6R7;
R6 and R7 represent independently of each other -H, -CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3, -cyclo-C3H3, -cyclo-C4H7, -cyclo-C31-19, -cyclo-C6H11, -CH2-cyclo-C3H3, -CH2-cyclo-C4H7, -CH2-cyclo-C31-19, -CH2-cyclo-C6H11, -Ph, -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2, or -NR6R7 is -N(C2F13)2, - -N N/-- --NO or __ N/ \\
/ =
RN represents -H, -CH3, -C2E-13, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H3, -C(CH3)3, -cyclo-C3H3, -cyclo-C4H7, 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 -cyclo-05H9, -CH2-cyclo-C3H5, -CH2F, -CH F2; -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3, -00C21-15, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -COOCH3, -CO0C2H5, -CO0C3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -S02CH3, -S02CF3, -S02C21-15, -S02C3H7, -S02CH(CH3)2, or -S02C(CH3)3;
RNi represent -H, -CH3, or -CH2CH3;
and R8- R14 have the meanings as defined above for formula (I);
or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomers, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
Preferably, R2 represents RN RN
__ _ 0 8 R11 0 R8 - _ R8 R1,srR8 ___,,c,,, R8 R1,_,,,,,,,,, R
Rlo _____ R9 / R9 Rlo R9 , R9 Rlo R9 /
,,,,,9 '`
, RN RN RN Rio Rii N, R11 N, -_)(11.N R1:1),,,O.N __ Ro, _R8 - _ )õ-O.N___ Rs I /1\1 1 N
/ l( /K \ ir N \ Ir-N \ // 0, N N- NR:
Rlo ss / Ro R10 Ro Rio , Rlo N.
Rii RN ;
, , , Rio ', R8 ______ R10 Rti,Sr _ R1_1SR8 - -IS \r-R8 - - 1 : --_c m (:)?zy N N N N \ ..
N
R8 , Rio , / Rio Rio /, N
RN ;
, N N Rio Rio N_RN
" ,N, DN R - R=-----V LI -- _\õ.) \-) , N-N ; N=N ; -------R14 N
, R12 R12 N R12 0---./Y,) s N'/,) r ---__)R13 ---$____) R13 R13 R13 Ri3 - \ 44 \ N \' \' , N Ri4 ; N Ri4 , Rlo RI4 , Rlo R14 , RN
Dp. 12 RN
i\l-/y4' R12 R12 p12 N---__/Y, -- -\TR13 \,tR13 ''l /') 13 ,õ------`
R14 N----%\ 1 A __\7 R
Rio R., Rizt Rizt , 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 ss R
RN
17\)1R9R9 R N o 0) Di 0 N\\ S\)- N R8 ¨R N R8 \s-N R8 ' Nhi R8I 8 b¨N N¨C) , or O¨N
Preferably, -NR6R7 of the formula (lb) represents -NH2, -NHCH3, -N(CH3)2, -NHCH(CH3)2, -NHCH2CH2CH3, -NH-CH2CH=CH2, -NHCH2CH2CH2CH3, -NHCH2CH(CH3)2, -NHC(CH3)3, -NHCH2CH2CH2CH2CH3, -NH-cyclo-C3F15, -NH-cyclo-C4H7, -NH-cyclo-051-19, -NH-cyclo-C6Hii, -NHCH2-cyclo-C3F15, -NHCH2-cyclo-C4H7, -NHCH2-cyclo-051-19, -NHCH2-cyclo-C6H11, -NHCH2-Ph, -NHCH2OCH3, -NHCH2OCH2CH3, -NHCH2CH2OCH3, -NHCH2CH2NHCH3, -NHCH2CH2N(CH3)2, - ¨N ¨10 --NO
--N
or In some embodiments, the present invention relates to the compound of the formula (I), IRI
JC
R2 N N R3 (I) wherein L represents -L1- or -L1-L2-; preferably -L1-L2-;;
L1 represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2C0-, or -CH2CH2C0-;
L2 represents a bond, -NRNI-, -NRNICH2-, -NRN1CH2CH2-, or -NRN1CH(CH3)-;
R1 represents ''N-R6 R2 represents 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 RN RN
0 Rs R10 Ra -_ S Rs R1: .!õsR8 ___,,R8 i__rR8 \ , r 1 __ r ,\ , ,\ , ,\ , R10 R9 / __ , R10 R9 , R9 R10 R9 R1, /
,Ii N , RN RN RN Rlo R11 ii, Rii N N;, N __ , Ril 0 R( ii 0 R 8 - - 0 R8 R10 sµ R K = - Rn R10 I\1 R
, ---\_4 I /N
/ ( ---, ----/ I
1---- \)-------R8 / :, P.
, / , , , RN
ii \
R8 /_______. R10 Rtl.õ.(\õSNit _ _ R1_SR8 - -1S)r-R8 - R8 , Rio R10 R10 __ N
N N N -' /
RN RN RN
N. RN R12 -- õK.- N Rij1i ,N,\1 _ R1o.N,N_RN .. N,N, _Rio _ ,N, ,N, DN
R -\ " .1 N N =r\i \ r )=N --\\ ,N ---- N''`
------------------------------------------------------------------------LI,.,.,.,,,:\,,,j Rio , , N-N N=N
, R12 R12 R12 0 , r N 1 ,1211 N/-) R13 R1 -3 R1'-', R- -\-iA
\-) , N Ria , N Ria , N Ria , N Ria ' R10 R."
, RN
R12 p12 RN
S--/y,) 13 i\i--/' s RN N2 RN
S
) - - R - - - ¨R13 r_.R ¨4 1 R13 N
R14 R14 _ N'%\-iA
R10 R10 \____ -R10 ni..-, , , , I-µ , H
R13 N .
L j ¨A - ii __ N77----R14 NSõ-S
- c S
R14 R14 Do._ in N -N--.,_?
Fµ
RN RN H ,, ,N, R9 r 1 i m 9 r /1 _ Rio \ / / ' N- --/--\
¨R 1 o _ 1::1) , , -, 0 s , , , i i õ.
_Rto N
,;(IN N N N N) , , R8 R8 ,S - - R8 =, N,S NI' II
\\ I
ff St\ 7 N ,--N R . S,------ il N-.-NN N Ra \s-N NN Ra N-N b-N
, , R8 N,--IR'--- -/ R8--- 1 N-0 or 0-N -R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl, diamantyl, hexamethylenetetraminyl, and the afore-mentioned residues optionally contain one or more C=C double bond(s) and/or are substituted with one or more of Ra, Rb, Rc, Rd, and Re;
R6 represents -H, -CH3, -CH2CH=CH2, -cyclo-C3H5, -CH2CH2CH2CH2CH3;
and R8 - R14, Ra; Rt.; Rc; Rd; Re; RN; and rc -N1 have the meanings and preferred meanings as defined herein.
Also preferred are compounds of the general formula (I), J
(I) CINI 71- R3 Ho wherein L represents -L1- or L1 represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2C0-, -CH2CH2C0-;
L2 is a bond, -NR'-, -NRN1CH2-, -NRN1CH2CH2-, or -NRN1CH(CH3)-;
R1 represents , R2 represents RN RN
____,I;IrR8 Rii Ri______i 0 R8 ____.s R8 w______.1 s R8 -\ r r ,\ r ,\ __ r )\ , \ , Ri0 R9 / __ R9 Ri0 R9 / R9 Ri0 R9 / R9 ;
RN RN RN
R11 1;1, R11 1;1, __ 11, Rii 0 __ Ri:).,0R8 -__(:)___Rs N
Rio `, ; R9 Rio R9 Rio , , rµ
mio , , R N
RN
Rti)rs, __ RS, _R8 S, Rs --).-N-N Ri_i N, \ rk __ 1 ,N li - - -1\IRN
N N N IN N
Rio , rµ mio Rlo , N¨N N=N
, , R12 R12 R12 Ri2 Ri2 N ,. , --:-.7 pp 13 r N4) R¨ 13 \') , R14 N R14 N R14 N R14 , N R14 , , 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 RN
N - - - / .,.__ Rl W
-R13 - - -S_____\T R13 - - iis__j\T R13 N
0 41 ,õ R14 Wu N-----\%\
µµ), ________________________ N-- R14 N R9 ri R9 iR13 S r_IiR9 _r_ % R10 _Tr- '/R10 R14i- W N - \-->R1 _ - m R10 or -- " , , R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl, diamantyl, hexamethylenetetraminyl, and the afore-mentioned residues optionally contain one or more C=C double bond and/or are substituted one or more of Ra, Rb, Rc, Rd, and Re;
Ra, Rb, Rc, Rd, and Re represents independently of each other -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C2H5, -CONH2, -CONHCH3, -CON(CH3)2, -CONHC2H5, -CH2CO2H, -CH2CO2CH3, 15 -CH2CO2C2H5, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2H5, -NHCOCH3, -NHCOC2H5, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C2H5, -NHSO2CHF2, -NHSO2CF3, -NHSO2CH2CF3;
R4 represents -NR6R7;
R6 and R7 represent independently of each other -H, -CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-05H9, -cyclo-C6H11, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-05H9, -CH2-cyclo-C6H11, -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2, or -NR6R7 represents or --N \ / =
R" represents -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 -cyclo-05H9, -CH2-cyclo-C3H5, -CH2F, -CHF2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3, -00C21-15, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -COOCH3, -CO0C2H5, -CO0C3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -S02CH3, -S02CF3, -S02C21-15, -S02C3H7, -S02CH(CH3)2, or -S02C(CH3)3;
RNi represent -H, -CH3, or -CH2CH3;
or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomers, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
Also preferred are compounds of the formula (I) or (lb), wherein L1 represents -CH2-, or -CH2C0-;
L2 represents a bond, -NR'-, -NRN1CH2-, or -NRN1CH(CH3)-;
R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 4-homoisotwistyl, adamantyl, or diamantyl, and the afore-mentioned residues optionally contain one or more C=C double bond(s) and/or are substituted by one or more of Ra, Rb, Rc, Rd; and Re; and Ra, Rb, Rc, Rd; Re and RI" have the same meanings as defined herein.
Preferably, R2 of the formula (I) or (lb) represents Rio R9 R11 0 RR R8 -__ S R8 R11 R8 R8 S
R8 , , N
,-,9 ' R9 N- .= , RN RN RN
nn Rio Rii SN Ril Sõ8 -- SR8 -- ri ___ Rc NN
0, /7--- --i /7---- -,r,,, , N
R8 Rio , Rio Rio Rio RN
Ri2 Ri2 Ri2 ,N R Rio_(rN,N _ RN
N io ---\-N
=r\j N, p N 1R 3 R13 -R=-, N=N R14 N R14 N
' R'"
Ri2 Ri2 Ri2 RN
0--/y,) S --/y,) iN --/y,., R12 ---,\ TI R13 , i \ 1 - - - - - - ---' '/----i - , . - - - = - - - "
'----/, -\R14 - - -\ 1 \ _T R13 R13 R 1-r R14 N-----\--1A
Rio Rio Rio ni.."
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 N v ri /R9 \ __Ri 4 N R9 rN r' r 1 1 1 n S (- )..õ. _ 9 _ _ _ _R10 - 1 - TR 0 /
D.- /
N - -\____/"--1---Ri 0 , , " , , R8 R8 ,S -. R8 ,\ S - ' N II ,,,-! N i N/ - - S)- - - -.--N
a, R',S ----- il NhT
N R8 \s-N \Ns-- N R8 N - N b-N
, , n N, - ' n N, R ---- -] R --- 1/
N-0 or , and R8¨ R14 and RN have the meanings as defined in formula (I) or (lb).
Preferred are compounds having any one of the formulae (IV-a) ¨ (IV-o) and (V-a) ¨ (V-d):
A ,R6 0)-LN , R6 NH
H
0 H 0 Rb 0 c 0 RC
A N L Ra R2. NH NH N
1 .L2 Rb 1-. `= ' I-U
H
Ra (IV-a) (IV-b) o 0 oANR6 0 N-R6 "
H H Rb Ra 0H 0 0 NN 1_ H 0 A ,,..,..-1-1.., 2 CNN L2 Rc a H
0 0 Rd IR' Rb (IV-d) (IV-c) a OAN , R6 ON, R Rb R
H Rb Ra H RC
o( 0 0 Rc 0 H 0 N N ,L2 , il NL2 H Rd H
(IV-e) (IV-f) 0 Rd 0 -H Rc H Rb Ra A H II
H
0 0 Rd (IV-g) (IV-h) 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 0 . 6 N R oA6 Ra NR -H
Rb A
H
0 JCH 0 IR' 0 0 I N L Rd H H
(IV-i ) (IV+
OA N , R6 i. .: OA N .R6 [7:p H H
R2 A N 1 N R2)- N crN
_ J1 NL
H
(IV-k) (IV-I) o o Q_ANFIR6 cl__H HR6 --- N
(IV-m) (IV-n) 0 .R6 N
H
0 ,C 0 0 H 0 R2,/NH NH 1 , 2 N/\1- 0 N 1 2 O
Rio (IV-o) (V-a) 0 o o R6 o )-L R6 N - N -H H
S N .-R8 hi N 1 2 ..-----,,,_,... -,R3 R- 8 S N N N L2 H
\ I 1 -- I 1 Ri 0 R10 (V-C) (V-b) 0 N .R6 H
Rii 0 N ki L2,, R3 R12 /7 \ \ I hi 1 I
(/ \ R10 o 0 (V-d) 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 and R2, R3, R6, R8; Rs; R10, R11, R12, R13, Ra; R13, Rc; Rd L and - . 2 have the same meanings as defined herein, preferably as defined in formula (I) or (lb).
Also preferred are the compounds of any of the formula (IVa-1), 0)-R6 H
H Rb N
, JI N N
H
0 0 Ra (IVa-1) wherein R6 represents ¨H, ¨CF13, ¨CH(CH3)2, ¨CH2CH2C1-13, ¨CH2CH=CH2, ¨CH2CH2CH2CH3, ¨CH2CH(CH3)2, ¨C(CH3)3, ¨CH2CH2CH2CH2CH3, ¨cyclo-C3H5, ¨cyclo-05H8, ¨cyclo-C8H11 or ¨CH2¨cyclo-C3H5.
and R2, Ra, and Rb have the same meanings as defined above.
Preferably, in the compounds of formula (I) or (lb), Ra and Rb represent independently of each other ¨H, ¨F, ¨Cl, ¨Br, ¨OH, ¨CN, ¨CF13, ¨C2H5, or ¨0O2Me.
Preferably, in any of the formula (I), (lb), (IV-a) ¨ (IV-o), or (IVa-1):
R2 represents o r0 Br , -- Br 0 Br 0 \ /
s Br , S _ _ S
- S CI \\/ p , -B-rY-1-Br \ /
S Br Br Br Br, , -ySz-Br -- - S CI -- r- S B y S
Br CI Br , Br , CI Me() Br , , .--\ I
S _ \ /
-CI CI B
CI r-õD____S
\ / Br HN
0 S, \ .-- Nõ-Me0 ---)\1--- H N3 0 N-NBr, N-N
, , \
\s Br s C I ------s Br ------s_.-- CI BrS
Br CI-----cS-C1 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 0C-90-ZZOZ peAieoef alea/an5a aleCI
xoop-vzonnottod-a3z-Noadiens3a-odo-68tz pue N-0 JO ' N-C) k ----LN
-- N --' , NZH
, El-----N\\N \\ N I \\ N _õ- 1 \=\ N 1 \ \N 1 \ N " - S/
N-N NN.
N-S N N \NN
õ0 ----s'1\1 õ- S JUN I
-- S .--- / N 1 1 , - -----N 'W , :
N H 0 [
WN
__, \ _,, / ,-' 1 N 1 ---=
co , HO s\>- , , ---, , N N J
--- N
- - J
\
H N
N H
H
'c'- , , , \ , _le s --\ -- \ __ __ \ __ , /
N N S S S
, , , 0 0 ' ' J9 10 \ __ N------9 /9---r-N ,--7N---- ...--\-------"A
\
0 \
,¨NH J9 , --N
NH - , N
- N H -- -NN) / __, N
H
' N
N ' .,1\1 N
-N '-- '-- -N '-- - elf\lz00-- Hz00-- zON --, 91/\1z00 1 HN --__ iii¨\\ iii¨\\ N ____ N Ii Ni' N ,N N ,N N-N N, NN
zON ., 1 I N N 1 , N-N , ' -----(5--NN \--N\
NH N \ // N N N
\-----IN-- -- 10-5¨<-- -_ -S ---I, N N N N N N
Lld'-s-- elAlOs- - cdo _ _OS 9 J -- c --s-s 5 ZCZ
R6 represents ¨H, ¨CH3, ¨CH(CH3)2, ¨CH2CH2CH3, ¨CH2CH=CH2, ¨CH2CH2CH2CH3, ¨CH2CH(CH3)2, ¨C(CH3)3, ¨CH2CH2CH2CH2CH3, ¨cyclo-C3H3, ¨cyclo-C31-19, ¨cyclo-C6H11 or ¨CH2¨cyclo-C3H3.
Due to the specially selected substituents R2 on the N-terminal side and substituents R3 on the C-terminal side and of the inventive compound according to the invention the steric dimension can be adjusted very precisely, so that a binding pocket of a desired target molecule may be addressed with highly matching measurements.
Preferred, are the compound of any of the formulae (I), (lb), (IV-a) ¨ (IV-o), and (V-a) ¨ (V-d), wherein R3 represents , , , , , .,, , ' , , , , ., .
' F Br ; CI OH
CO2H CONH2 CONMe2 Nj H, CO2Me ,, CO2H Br OH
CF3, F
F
F jZci ZcF3 ZOH jZco2Me i , , , , or .
Surprisingly, it was found that the inventive compounds bound to the transglutaminase 2 reversibly and inhibit the transglutaminase effectively. The electrophilic warheads in combination with the preferred embodiment specifically react with highly nucleophilic 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 thiols in the active site of the transglutaminase 2. Accordingly, it was found that potential unspecific reactions with off-targets are reduced.
In one embodiment, the present invention refers to the compound selected from the group consisting of:
11-2: oANI (S)-2-(benzofuran-2-carboxamido)-N1 -(1 -(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-H 1 ,2-dihydropyridin-3-y1)-N6-methy1-5-N
I H I oxohexanediamide o o 11-3: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-o 0 H N6-methy1-2-(3-methylbenzofuran-2-I H carboxamido)-5-oxohexanediamide o o 11-4: (S)-2-(3-ch lorobenzofuran-2-0 1\1 carboxamido)-N1 -(1 -(2-(2-H
0 N N adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-I H
0 0 dihydropyridin-3-y1)-N6-methy1-5-cI
oxohexanediamide 11-5: (S)-2-(4-bromobenzofuran-2-0)-LNJ
carboxamido)-N1 -(1 -(2-(2-H adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-o I H 0 0 dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Br 11-6: ON (S)-2-(4-bromobenzofuran-2-carboxamido)-N1 -(1 -(2-(2-H adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-S N
I 0 0 dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-7: OLN (S)-2-(benzo[b]thiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-HH 2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-s I H 0 0 5-oxohexanediamide Br 11-8: 0)-L (S)-2-(5-bromobenzo[b]thiophene-2-NJ
carboxamido)-N1 -(1 -(2-(2-oH 0 N adamantylamino)-2-oxoethyl)-2-oxo-1 HN ThiNj 0 0 dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 o 11-9: (S)-2-(1H-indole-2-carboxamido)-N1-(1-(2-o,A --N
H (2-adamantylamino)-2-oxoethyl)-2-oxo-FN1 i o UN Ed 1,2-dihydropyridin-3-y1)-N6-methy1-5-, NThr H
0 0 oxohexanediamide o 11-10: ON (S)-2-(4,5-difluoro-1H-indole-2-H carboxamido)-N1-(1-(2-(2-H adamantylamino)-2-oxoethyl)-2-oxo-1,2-H N r\jAN-IN
I H 0 0 dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide F F
11-1 1: 0)-1\1 (S)-N1-(1-(2-(2-adamantylamino)-2-H oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-o H 0 H H N6-methy1-2-(3-methy1-1H-indole-2-N N,A
N NN carboxamido)-5-oxohexanediamide 11-12:
o,)-LN (S)-2-(1H-benzo[d]imidazole-2-H carboxamido)-N1-(1-(2-(2-0 N rEi 0 I, " NThr IR1 adamantylamino)-2-oxoethyl)-2-oxo-1,2-iii,j H 0 0 dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide o 11-13: (S)-2-(2,3-dihydro-1H-indene-2-o N
H carboxamido)-N1-(1-(2-(2-O 0 adamantylamino)-2-oxoethy1)-2-oxo-1,2-N N
H , Ji dihydropyridin-3-y1)-N6-methy1-5-o o oxohexanediamide o 11-14: OAN (S)--(2-bromo-4-methylthiazole-5-H carboxamido)-N1-(1-(2-(2-o H o s -FNI1 adamantylamino)-2-oxoethyl)-2-oxo-1,2-N
Br--- k)-L'Fir i NI
0 0 dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide o 11-15: (S)-N1-(1-(2-(2-adamantylamino)-2-0)-LN
H oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-o H 0 _N' N6-methyl-2-(4-methyl-2-F3c___ekHN_A 1 N ff E
N 0 0 (trifluoromethyl)thiazole-5-carboxamido)-5-oxohexanediamide o 11-16: 0)-N (S)-2-(4-bromo-2-(trifluoromethyl)thiazole-H 5-carboxamido)-N1-(1-(2-(2-o F
F3c-- H o S_Aõ, NJLI\jr NI adamantylamino)-2-oxoethyl)-2-oxo-1,2-- 1 [sil N 0 0 dihydropyridin-3-y1)-N6-methy1-5-Br oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 o 11-17: OAN (S)-2-(2,4-dichlorothiazole-5-H carboxamido)-N1 -(1 -(2-(2-o , o j-L adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-ci----N s __I\Icki H 0 0 dihydropyridin-3-y1)-N6-methyl-5-CI
oxohexanediamide o 11-18: 0 (S)-N1-(1-(2-(2-adamantylamino)-2-r\J
H oxoethyl)-2-oxo-1 ,2-d i hydropyrid in-3-y1)-2-0 o s-L N r11J-Nil (2-methoxy-4-methylthiazole-5-Me0--- 1 H
N 0 0 carboxamido)-N6-methyl-5-oxohexanediamide o 11-19: (S)-N1-(1-(2-(2-adamantylamino)-2-H oxoethyl)-2-oxo-1 ,2-d i hydropyrid in-3-y1)-= \s 1 N N,CN N,Q1, N6-methy1-2-(4-methy1-2-phenylthiazole-5-N carboxamido)-5-oxohexanediamide o 11-20:
oN (S)-2-(2,4-dimethylthiazole-5-H carboxamido)-N1 -(1 -(2-(2-o o s__A fl- H adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-----N1 il 1 NifN
dihydropyridin-3-y1)-N6-methy1-5-0 o oxohexanediamide o 11-21: o N (S)-2-(5-bromo-3-methylthiophene-2-)-L
H carboxamido)-N1 -(1 -(2-(2-Br1 o H ? H adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-S N N
\ 1 N N
dihydropyridin-3-y1)-N6-methyl-5-H o o oxohexanediamide o 11-22: 0)-N (S)-2-(3,5-dibromothiophene-2-H carboxamido)-N1 -(1 -(2-(2-Br o H N H adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-s Br N N N
Tr \ I H 0 0 dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide o 11-23: oN (S)-2-(5-bromothiophene-2-carboxamido)-H N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-o s o ci.1 H
Nj-LNN 2-oxo-1 ,2-d i hydropyrid in-3-y1)-N6-methyl-5-oxohexanediamide o 11-24: oN (S)-2-(5-chlorothiophene-2-carboxamido)-H N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-CI\ ( o H H 2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-s Nj -HN 1 Nr -iNj 5-oxohexanediamide o o 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 o 11-25: oN (S)-2-(5-bromo-3-methylfuran-2-H carboxamido)-N1 -(1 -(2-(2-Br o o 0 ( )-L
El H
NNN adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-, \ I HN 0 8 dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide o 11-26: oN (S)-2-(5-chlorofuran-2-carboxamido)-H (1-(2-(2-adamantylamino)-2-oxoethyl)-2-H oxo-1 ,2-dihydropyridin-3-y1)-N6-methy1-5-N , N
CI \I H I I N oxohexanediamide o o o 11-27: Ol-L.N (S)-2-(5-chlorothiophene-3-carboxamido)-y.-H N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-CI
o 0 H H 2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-N )-LNThiN
I 5-oxohexanediamide s 0 11-28: oAN (S)-2-(2,5-dichlorothiophene-3-H carboxamido)-N1 -(1 -(2-(2-o 0 H
N2- N adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-a /1 N 1 N'Ir s 0 0 dihydropyridin-3-y1)-N6-methy1-5-ci oxohexanediamide o 11-29: o)LN (S)-2-(2,5-dibromothiophene-3-H carboxamido)-N1 -(1 -(2-(2-o (H 0 N)-L kil Br / 1 N'i 1 N,'.r adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-S 0 0 dihydropyridin-3-y1)-N6-methyl-5-Br oxohexanediamide o 11-30: oN (S)-2-(5-bromothiophene-3-carboxamido)-H N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-o o H 2-oxo-1 ,2-d i hydropyrid in-3-y1)-N6-methyl-Br / 1 hic i NI -rNi 5-oxohexanediamide s 0 11-31: o)N (S)-2-(2-chloro-5-methylthiazole-4-,t. ..---H carboxamido)-N1 -(1 -(2-(2-o 0 H)L
I\11 adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-CI N
i N, 0 0 dihydropyridin-3-y1)-N6-methyl-5-s oxohexanediamide o 11-32: 0)-I\J (S)-2-(2,5-dichlorothiazole-4-L
H carboxamido)-N1 -(1 -(2-(2-o 0 H H adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-ci---1 0 N 1 NI N dihydropyridin-3-y1)-N6-methyl-5-s 0 CI oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 o 11-33: 0N (S)-2-(2,5-dibromothiazole-4-H carboxamido)-N1 -(1 -(2-(2-Br o H o adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-0 i j-LN
, i EN11 dihydropyridin-3-y1)-N6-methyl-5-/s - 0 Br oxohexanediamide o 11-34: oN (S)-2-(2-bromo-5-methylthiazole-4-H carboxamido)-N1 -(1 -(2-(2-Br-- 0 rFi 0 adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-N__)-LN NThili H
S 0 0 dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide o 11-35: O N (S)-2-(2-bromothiazole-4-carboxamido)-H N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-o H o H 2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-o Br----(NjAHN fiNI
/ 5-oxohexanediamide s - - il N N
11-36: ON (S)-2-(2-chlorothiazole-4-carboxamido)-H N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-o 0 H)L 2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-a-----N N 1 NI LI 5-oxohexanediamide s 0 11-37: N (S)-2-(2,5-dimethylfuran-3-carboxamido)-H N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-o ti 0 H 2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-/ N-11\1-ANN 5-oxohexanediamide 11-38: o N (S)-2-(4,5-dimethylthiazole-2-H carboxamido)-N1 -(1 -(2-(2-o H 0 H adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-s,IAN N,AN N
H 0 0 dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-39: 0 O N (S)-2-(4-bromothiazole-2-carboxamido)-H N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-o N S H 0 H 2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-N N 5-oxohexanediamide 5AH 0 ,-,0,,N
Br 11-40: O N (S)-2-(4-bromothiophene-2-carboxamido)-H N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-H 2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-s 0 Nr NH
5-oxohexanediamide \ 1 H 0 Br 0 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-41:
0-N (S)-2-(4-bromo-3-methylthiophene-2-H carboxamido)-N1-(1-(2-(2-s H adamantylamino)-2-oxoethyl)-2-oxo-1,2-NN.rN
\I N H I 1 dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide Br 11-42: 0 (S)-2-(3-bromothiophene-2-carboxamido)-ON
H N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-s N H 2-oxo-1,2-dihydropyridin-3-yI)-N6-methyl-H 0 .iNNfN
5-oxohexanediamide \I 1 1 Br 11-43: (S)-2-(3-chloro-4-methylthiophene-2-ON
H carboxamido)-N1-(1-(2-(2-H adamantylamino)-2-oxoethyl)-2-oxo-1,2-s NNN),iN
\ I H i I dihydropyridin-3-y1)-N6-methyl-5-a 0 oxohexanediamide o 11-44: o,,,)-I (S)-2-(4-bromo-5-chlorothiophene-2-.,-.. --HN carboxamido)-N1-(1-(2-(2-CI
o s o --.IRI adamantylamino)-2-oxoethyl)-2-oxo-1,2-N II
\ I N H 0 0 dihydropyridin-3-y1)-N6-methyl-5-Br oxohexanediamide o 11-45: o)LN (S)-2-(4,5-dibromothiophene-2-H carboxamido)-N1-(1-(2-(2-Br -_7('N
o .. jo s 1 -y --k1 adamantylamino)-2-oxoethyl)-2-oxo-1,2-\ i H 0 0 dihydropyridin-3-y1)-N6-methyl-5-Br oxohexanediamide o 11-46: oN (S)-2-(4,5-dibromo-3-methoxythiophene-H carboxamido)-N1-(1-(2-(2-Br o s o -ciRilj-L NI adamantylamino)-2-oxoethyl)-2-oxo-1,2-OMe NThr 0 H N 0 0 dihydropyridin-3-y1)-N6-methyl-5-Br oxohexanediamide o 11-47: 0 (S)-2-(4-bromofuran-2-carboxamido)-N1-N
H (1-(2-(2-adamantylamino)-2-oxoethyl)-2-o o H oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-0 r\jciNNrN
oxohexanediamide \ I H 0 Br 0 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 o 11-48: ON (S)-2-(4,5-dibromofuran-2-carboxamido)-H N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-o o o NciRlij-L _NI 2-oxo-1,2-d i hydropyrid in-3-y1)-N6-methyl-Br N if \I H 0 0 5-oxohexanediamide Br 11-49: o..,JL.N...-(S)-2-(4,5-dichlorothiophene-2-H carboxamido)-N1-(1-(2-(2-o s o ci., adamantylamino)-2-oxoethy1)-2-oxo-1,2-ci 1 N 1 N Thr Ed \ , H 0 0 dihydropyridin-3-y1)-N6-methy1-5-CI oxohexanediamide o 11-50: 0)-N (S)-2-((S)-1-acetylpyrrolidine-2-H carboxamido)-N1-(1-(2-(2-N¨) N cFNI)"N ld adamantylamino)-2-oxoethy1)-2-oxo-1,2-, \ _ j H , JIi 0 0 dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide 11-51: o OAN
(S)-N1-(1-(2-(2-adamantylamino)-2-H oxoethyl)-2-oxo-1,2-d i hydropyrid in-3-y1)-H
0 0 N6-methyl-2-(1-methy1-1H-1,2,3-triazole-5-NilJ FRI 1 NrN
carboxamido)-5-oxohexanediamide 11-52: 0)-I\J (S)-N1-(1-(2-(2-adamantylamino)-2-L
H oxoethyl)-2-oxo-1,2-d i hydropyrid in-3-y1)-0 o N6-methyl-5-oxo-2-(2H-tetrazole-5-N
HNs'NN:IAN FIN H jiN'io FN1 carboxamido)hexanediamide 11-53: 0)-LI\J (S)-N1-(1-(2-(2-adamantylamino)-2-H
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-0 N6-methyl-5-oxo-2-(pyrazine-2-N)-LI\J
0 rEl H
N
carboxamido)hexanediamide I H _ JI NTh(N
11-54: 0 (S)-N1-(1-(2-(2-adamantylamino)-2-H ---N oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-\ 0 iF1 0 H N6-methyl-24(S)-1-methylpyrrol id ine-2-N )-LNf N carboxamido)-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 O r\I (S)-N1-(1-(2-(2-adamantylamino)-2-H oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-0 0 H N6-methyl-5-oxo-2((S)-pyrrolidine-3-H
_-AN-IN'Al N-rN carboxamido)hexanediamide HN¨ H 0 0 11-56: o O N (S)-24(2S,4S)-4-bromopyrrolidine-2-H carboxamido)-N1-(1-(2-(2-E
H
0 adamantylamino)-2-oxoethyl)-2-oxo-1,2-d J EN_I
dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide 11-58: 0 0It. (S)-N1-(1-(2-(2-adamantylamino)-2-,....,-H--N oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-H N6-methyl-5-oxo-2-((S)-piperidine-2-NA N)-L carboxamido)hexanediamide Nnf ---õ,--- 0 0 11-59: Or\j (S)-N1-(1-(2-(2-adamantylamino)-2-H oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-0 0 H N6-methyl-5-oxo-2-((R)-piperidine-3-HNNFdj-L
N
carboxamido)hexanediamide H 0 INo 11-60: o OAN (S)-N1-(1-(2-(2-adamantylamino)-2-H
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-I- N6-methyl-24(R)-((R)-3-N))-NciNNIVI carboxamido)-5-oxohexanediamide H
11-61: oAN (S)-N1-(1-(2-(2-adamantylamino)-2-H oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N
N- 0 r H ? H N6-methy1-5-oxo-2-(quinuclidine-3-NnN
Ii NN carboxamido)hexanediamide H
11-62: okN (S)-methyl 3-(1-(1-(2-(2-adamantylamino)-y.-H 2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(methylamino)-1,5,6-N-1 N 'AI N Fd H
0 0 trioxohexan-2-ylcarbamoy1)-5-nitrobenzoate CO2Me 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 o 11-63: 0AN (S)-N1-(1-(2-(2-adamantylamino)-2-H oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-o 0 H H
02N N. i-ir1µ12-N.rN N6-methy1-2-(5-nitronicotinamido)-5-0 0 oxohexanediamide N
11-64: o-LI\j (S)-5-(1-(1-(2-(2-adamantylamino)-2-) H oxoethyl)-2-oxo-1,2-dihydropyridin-3-rEl 0 ylamino)-6-(methylamino)-1,5,6-i N, rNI H
0 0 trioxohexan-2-ylcarbamoyl)nicotinic acid N
11-65: (S)-methyl 5-(1-(1-(2-(2-adamantylamino)-0.N..-H 2-oxoethyl)-2-oxo-1,2-dihydropyridin-0(rFi 0 ylamino)-6-(methylamino)-1,5,6-Me02CN N AN
i H 0 8 a trioxohexan-2-ylcarbamoyl)nicotinate N
11-66: oN (S)-N1-(1-(2-(2-adamantylamino)-2-H oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-S 0 o f-'-'N N'II H it H N6-methyl-2-(6-methylimidazo[2,1 -N
__A
\\ I H b]thiazole-5-carboxamido)-5-oxohexanediamide o 11-67: o -N (S)-N1-(1-(2-(2-adamantyl(methyl)amino)-...)L. --H 2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-o 0 I N6-methyl-2-(3-methylbenzofuran-2-0 N .iN12-N N
I H I 1 carboxamido)-5-oxohexanediamide 0 o o 11-68: (S)-N1-(1-(2-(5-hydroxyadamantane-2-H amino)-2-oxoethyl)-2-oxo-1,2-o o O N id NI
N Thr dihydropyridin-3-y1)-N6-methyl-2-(3-1 H 0 0 methylbenzofuran-2-carboxamido)-5-OH
oxohexanediamide o 11-69: 0 N (S)-N1-(1-(2-(5-fluoroadamantane-2-H amino)-2-oxoethyl)-2-oxo-1,2-o o O N IR11)L H dihydropyridin-3-y1)-N6-methy1-2-(3-N N
methylbenzofuran-2-carboxamido)-5-o 0 F oxohexanediamide o 11-70: o,AN (S)-N1-(1-(2-(5-chloroadamantane-2-H amino)-2-oxoethyl)-2-oxo-1,2-o o -,N1 dihydropyridin-3-y1)-N6-methy1-2-(3-N ri I H 0 0 methylbenzofuran-2-carboxamido)-5-ci oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 o 11-71: OAN (S)-N1-(1-(2-(5-bromoadamantane-2-H amino)-2-oxoethyl)-2-oxo-1,2-0 H 0 dihydropyridin-3-y1)-N6-methyl-2-(3-o N.r1\1AN,r1 I H 0 8 methylbenzofuran-2-carboxamido)-5-Br oxohexanediamide o 11-72: 0)NI (S)-N1-(1-(2-(5-methyladamantane-2-L
H amino)-2-oxoethyl)-2-oxo-1,2-o 0 H II H dihydropyridin-3-y1)-N6-methy1-2-(3-ol N.iNNrN
methylbenzofuran-2-carboxamido)-5-oxohexanediamide o 11-73: (S)-N1-(1-(2-(2-carbonitrileadamantane-2-OANI
H amino)-2-oxoethyl)-2-oxo-1,2-o , 0 H CN dihydropyridin-3-y1)-N6-methyl-2-(3-0 f N N
methylbenzofuran-2-carboxamido)-5-oxohexanediamide o 11-74: o-LN (S)-N1-(1-(2-(2-methyl adamantane-H carboxylate-2-amino)-2-oxoethyl)-2-oxo-o 0 H II H CO2Me 1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-O I
0 NNN.irµi methylbenzofuran-2-carboxamido)-5-oxohexanediamide o 11-87: 0 (S)-N1-(1-(2-(1-adamantylmethylamino)-N
H oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-H ii h N N6-methyl-2-(3-methylbenzofuran-2-0 N ,NrN
i H
0 0 carboxamido)-5-oxohexanediamide o 11-88: 0N (S)-N1-(1-(2-(1-(1-H adamantyl)ethanamino)-2-oxoethyl)-2-oxo-O H ?
O N, rl 1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-, N 1 NThr i H
0 0 methylbenzofuran-2-carboxamido)-5-oxohexanediamide o 11-90: O N (S)-N1-(1-(2-((1R,2S,4S)-H bicyclo[2.2.1]heptan-2-ylamino)-2-o 0 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-o NiNNThiNFI
I H I 1 N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-92: o (S)-N1-methy1-5-(3-methylbenzofuran-2-oN carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-H
0 0 ((1S,2S,4R)-1,7,7-0 N NNNH 1 H trimethylbicyclo[2.2.1Theptan-2-0 0 ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 o 11-94: oN (S)-N1-(1-(2-((1R,2R,4S)-H bicyclo[2.2.1]heptan-2-ylamino)-2-F
O rFi 0 oxoethyl)-2-oxo-1,2-d i hydropyrid in-3-y1)-O N NO-LN,N11=/_L
N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-95: (S)-N1-(1-(2-(bicyclo[2.2.1]heptan-1-0 N ylamino)-2-oxoethyl)-2-oxo-1,2-H
0 H 0 d\_..
di hydropyridi n-3-y1)-N6-methy1-2-(3-ii 0 N N 2-NH methylbenzofuran-2-carboxamido)-5-0 0 oxohexanediamide 11-96: 0 (S)-N1-(1-(2-(bicyclo[2.2.1]heptan-7--....)-.. .-- T
ylami no)-2-oxoethyl)-2-oxo-1,2-0 0 di hydropyridi n-3-y1)-N6-methy1-2-(3-0 NNNThrNH methylbenzofuran-2-carboxamido)-5-0 0 oxohexanediamide o 11-97: (S)-N1-(1-(2-(bicyclo[2.2.1]hept-5-en-2-oN
H ylamino)-2-oxoethyl)-2-oxo-1,2-o 0 di hydropyridi n-3-y1)-N6-methy1-2-(3-O NJciN 2-Nr NH
I H I 1 methylbenzofuran-2-carboxamido)-5-o o oxohexanediamide o 11-98: 0N (2S)-N1-(1-(2-(bicyclo[2.2.2]octan-2-H ylami no)-2-oxoethyl)-2-oxo-1,2-N o H di hydropyridi n-3-y1)-N6-methy1-2-(3-O iN N II N
H o methylbenzofuran-2-carboxamido)-5-1 1TIII o oxohexanediamide o 11-99: 0)N (S)-N1-methy1-5-(3-methylbenzofuran-2-H carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-O o ((1R,2R,4R)-1,7,7-H ii H
O N NN_,1\1 ssµ
tri methyl bicyclo[2.2.1]heptan-2-0 0 ylamino)ethyl)-1,2-dihydropyridi n-3-yl)hexanediamide o 11-100: oN (S)-N1-methy1-5-(3-methylbenzofuran-2-H carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-O o O INic illNMIft, 1 ((1R,2R,3R,5S)-2,6,6-tri methyl bicyclo[3.1.1]heptan-3-H
ylamino)ethyl)-1,2-dihydropyridi n-3-yl)hexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 o 11-101:
oN (S)-N1-methy1-5-(3-methylbenzofuran-2-H carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-o o ((1S,2S,3S,5R)-2,6,6-o NINII
I H 0 0 trimethylbicyclo[3.1.1]heptan-3-ylamino)ethyl)-1,2-dihydropyridin-3-yhhexanediamide o 11-103: (S)-N1-(1-(2-(4-homoisotwistane-3-o, )-L
N
H amino)-2-oxoethyl)-2-oxo-1,2-o 0 H dihydropyridin-3-y1)-N6-methyl-2-(3-O NiNNThiN
I H I 1 methylbenzofuran-2-carboxamido)-5-0 0 oxohexanediamide o 11-104: (S)-N1-(1-(2-(diamantane-1-amino)-2-Or\i pj H oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-o 0 N6-methy1-2-(3-methylbenzofuran-2-o Nini 2-N( NH
I H I 1 carboxamido)-5-oxohexanediamide o 11-105: (S)-N1-(1-(2-(diamantane-4-amino)-2-H oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-NN HN6-methy1-2-(3-methylbenzofuran-2-I H
0 0 carboxamido)-5-oxohexanediamide 11-107: 0 0 (S)-N1-(1-(1-adamantylmethyl)-2-oxo-1,2--,....)-L.
H .--N dihydropyridin-3-y1)-N6-methyl-2-(3-O 0 methylbenzofuran-2-carboxamido)-H II
O NJcr N 2-cN oxohexanediamide 11-108: 0 (2S)-N1-(1-((3-hydroxy-1-0 .--N adamantypmethyl)-2-oxo-1,2-H
O 0 dihydropyridin-3-y1)-N6-methy1-2-(3-H II
O N N N methylbenzofuran-2-carboxamido)-0 oxohexanediamide OH
11-109: 0 (2S)-N1-(1-((3-bromo-1-0 .--N adamantypmethyl)-2-oxo-1,2-H
O 0 dihydropyridin-3-y1)-N6-methy1-2-(3-H II
O 1\iciN2-N methylbenzofuran-2-carboxamido)-5-0 oxohexanediamide Br 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-110: (S)-N1-(1-(2-adamantylmethyl)-2-oxo-1,2-0...,)-1-.. ---N dihydropyridin-3-y1)-N6-methy1-2-(3-H
0 H 0 methylbenzofuran-2-carboxamido)-5-0 NNN oxohexanediamide 11-111: 0 0)-L (S)-N1-(1-(2-(2-adamantylamino)-2-H N oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N H 011 H N6-methyl-2-(nicotinamido)-5-I N INThiN
H
0 0 oxohexanediamide N
11-112: 0)N (S)-2-(isonicotinamido)-N1-(1-(2-(2--H adamantylamino)-2-oxoethyl)-2-oxo-1,2-O rH 011 H dihydropyridin-3-y1)-N6-methyl-5-H
rAN N 'N N oxohexanediamide I -11-113: OAr\j (S)-N1-(1-(2-(2-adamantylamino)-2-H oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-O r1-1 OH N6-methyl-5-oxo-2-(pyridazine-4-N
H
r)-LNI
H- yN N N
carboxamido)hexanediamide I
.N 0 0 11-114: 0)-L (S)-N1-(1-(2-(2-adamantylamino)-2-H
N oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-O jcH 011 * H N6-methyl-5-oxo-2-(pyridazine-3-NN carboxamido)hexanediamide -11-115: 0)-LN (S)-N1-cyclopropyl-N6-(1-(2-(2-H adamantylamino)-2-oxoethyl)-2-oxo-1,2-o 0 H i i H dihydropyridin-3-y1)-5-(3-O N.iNINfl,rN
I 1-1 0 I I methylbenzofuran-2-carboxamido)-2-o oxohexanediamide o 11-116: (S)-N1-(1-(2-(2-adamantylamino)-2-H oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-o H 0u H (3-methylbenzofuran-2-carboxamido)-5-o N N N
N oxo-N6-pentylhexanediamide 11-117: (S)-N1-allyl-N6-(1-(2-(2-adamantylamino)-0)-LN
H 2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-o o N
HA H 5-(3-methylbenzofuran-2-carboxamido)-o N N -1N
oxohexanediamide I H U
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 o 11-118: (S)-N1-(1-(2-(2-adamantylamino)-2-0-LNH2 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-o H 0 H (3-methylbenzofuran-2-carboxamido)-5-0 N 1\1)-LNN
I H I 1 0 oxohexanediamide 11-119: 0)-1\1 (S)-N1-ally1-5-(benzofuran-2-L
H carboxamido)-N6-(1-(2-(2-O H ? H adamantylamino)-2-oxoethy1)-2-oxo-1,2-N
dihydropyridin-3-y1)-2-oxohexanediamide 11-120: OAN (S)-2-(benzofuran-2-carboxamido)-N6-H isopropyl-N1-(1-(2-(2-adamantylamino)-2-O H ? H oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)-5-o 0 N, 1 NN
oxohexanediamide 11-121: o)N L (S)-2-(benzofuran-2-carboxamido)-N6-H cyclopropyl-N1-(1-(2-(2-adamantylamino)-NH
H 2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-O 0 )L(:) 0 1 NN
5-oxohexanediamide 11-122: 9 140 o (S)-2-(benzofuran-2-carboxamido)-N1-(1-H
N (2-(2-adamantylamino)-2-oxoethyl)-2-oxo-H
O 0 1,2-dihydropyridin-3-y1)-5-oxo-0 NiJciNNrN phenylhexanediamide 11-123: 0 (S)-2-(benzofuran-2-carboxamido)-N6-'Ail 10 benzyl-N1-(1-(2-(2-adamantylamino)-2-o 0 H oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)-5-o o NL 0 1 H NN
oxohexanediamide o 11-124: (S)-2-(benzofuran-2-carboxamido)-N1-(1-)-LN H2 (2-(2-adamantylamino)-2-oxoethyl)-2-oxo-H 1,2-dihydropyridin-3-y1)-5-NH )L(:) oxohexanediamide o o o 11-125: (S)-2-(2,5-dichlorothiophene-3-0)-LN H2 carboxamido)-N1-(1-(2-(2-o 0 H H adamantylamino)-2-oxoethy1)-2-oxo-1,2-NNN
dihydropyridin-3-y1)-5-oxohexanediamide CI
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 o 11-126: (S)-N1-(1-(2-(2-adamantylamino)-2-o)-NH2 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-o , o s -õ, N,)- (4-methyl-2-(trifluoromethyl)thiazole-5-F3c--- k) pi j)' carboxamido)-5-oxohexanediamide 11-127: o (S)-N1-(1-(2-(2-adamantylamino)-2-NH2 oxoethyl)-2-oxo-1,2-d i hydropyrid in-3-y1)-2-O 0 (1 -methyl-1 H-1 ,2,3-triazole-5-H H
N, l\iN _ Ji NMI N carboxamido)-5-oxohexanediamide 11-128: (2S)-N1-(1-(2-((1R,2R,4S)-0)-LN
H bicyclo[2.2.1]heptan-2-ylamino)-2-o 0 H H oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-NN
CI / 1 hi N )- 1 1 1 "IL (2,5-dichlorothiophene-3-carboxamido)-s 0 o CI N6-methyl-5-oxohexanediamide o 11-129: oN (2S)-N1-(1-(2-((1R,2R,4S)-H bicyclo[2.2.1]heptan-2-ylamino)-2-o Ei 0 H,,d oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-k, N)-LNrN
F3C¨<77 r Ari 1 N6-methyl-2-(4-methyl-2-(trifluoromethyl)thiazole-5-carboxamido)-5-oxohexanediamide 11-130: (2S)-N1-(1-(2-((1 R,2R,4S)-0 )-L
H
N bicyclo[2.2.1]heptan-2-ylamino)-2-O 11 0 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-j N H
N-rN-3_ N6-methyl-2-(1 -methyl-1 H-1 ,2,3-triazole-5-N
c, 0 FiNci carboxamido)-5-oxohexanediamide 11-131: 0 (S)-N1-(1-(2-(2-adamantylamino)-2-0)-Lr\i H oxoethyl)-2-oxo-1,2-d i hydropyrid in-3-y1)-O id H 0 N6-methyl-5-oxo-2-(2H-1,2,3-tri azole-4-N
'-lAN
N I H I NI carboxamido)hexanediamide \N-N 0 0 H
11-132: 0 (S)-N1-(1-(2-(2-adamantylamino)-2-N
H oxoethyl)-2-oxo-1,2-d i hydropyrid in-3-y1)-0 0 J H N6-methyl-5-oxo-2-(1H-1,2,3-triazole-HNEll 1 NTh(N carboxamido)hexanediamide fel 0 0 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-133: Or\j (S)-N1-(1-(2-(2-adamantylamino)-2-H oxoethyl)-2-oxo-1,2-d i hydropyrid in-3-y1)-H N6-methyl-2-(1 -methyl-1 H-1 ,2,3-triazole-4-¨No HN IrICI-O(cIN carboxamido)-5-oxohexanediamide \W-N '-----11-134: 0 0 1\1 (S)-N1-(1-(2-(2-adamantylamino)-2-H oxoethyl)-2-oxo-1,2-d i hydropyrid in-3-y1)-N?L H H N6-methy1-5-oxo-2-(1H-1,2,4-triazole-I INI ii N(N
carboxamido)hexanediamide H
11-135: O N (S)-N1-(1-(2-(2-adamantylamino)-2-H oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-o 0 id 11 N6-methyl-2-(1 -methyl-1 H-1 ,2,4-triazole-3-NAINI 1 N( carboxamido)-5-oxohexanediamide /
11-136: O (S)-2-(benzofuran-3-carboxamido)-N1-(1-N
H (2-(2-adamantylamino)-2-oxoethyl)-2-oxo-IcLA 11 1,2-dihydropyridin-3-y1)-N6-methy1-5-o1 INICI 1 Yi oxohexanediamide o 11-137: ON (S)-2-(benzo[b]thiophene-3-carboxamido)-H N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-o o H 2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-s1 NC I NniN
0 0 5-oxohexanediamide o 11-138 0 -.N (S)-N1-(1-(2-(2-adamantylamino)-2-) H oxoethyl)-2-oxo-1,2-d i hydropyrid in-3-y1)-W
N6-methyl-2-(1 -methyl-1 H-pyrazole-3-NjrH A N
carboxamido)-5-oxohexanediamide /
11-139 o)-. (S)-N1-(1-(2-(2-adamantylamino)-2-N
H oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-H N6-methyl-2-(1 -methyl-1 H-pyrazole-4-NV NicH-A N.,,N
,NYH 0 8 carboxamido)-5-oxohexanediamide /
o 11-140 0)N (S)-N1-(1-(2-(2-adamantylamino)-2-H oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-H N6-methyl-2-(1 -methyl-1 H-pyrazole-5-<.- (j) NicH Ac)NN carboxamido)-5-oxohexanediamide NIII:H1 0 8 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-141 ON (S)-N1-(1-(2-(2-adamantylamino)-2-H oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-H ii H N6-methyl-2-(4-methyl-1,2,3-thiadiazole-5-,sNJc N,N..rN
N, I H carboxamido)-5-oxohexanediamide \N 0 0 11-142 OAN (S)-N1-(1-(2-(2-adamantylamino)-2-H oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)-/ 0 N_r FNI 0 H N6-methyl-5-oxo-2-(1,2,5-thiadiazole-3-NN
NfIrF1 carboxamido)hexanediamide 11-143 O N (S)-2-(4-iodo-1 -methyl-1 H-pyrazole-H carboxamido)-N1 -(1 -(242-I 0 jcH 0 H adamantylamino)-2-oxoethy1)-2-oxo-1,2-N N)' il Nrr\j dihydropyridin-3-y1)-N6-methy1-5-\ oxohexanediamide 11-144 (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-d i hydropyrid in-3-y1)-2-0 ,CLN f FNI II
H (1 -methyl-1 H-pyrazole-5-carboxamido)-5-NN oxohexanediamide 11-145 (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-d i hydropyrid in-3-y1)-2-H 9 H (4-methyl-1,2,3-thiadiazole-5-ci i) I(carboxamido)-5-oxohexanediamide iv 0 0 o 11-146 (S)-2-(benzofuran-2-carboxamido)-N1-(1-o (2-((1 R,2R,4S)-bicyclo[2.2.1]heptan-2-NH9NThry. ylamino)-2-oxoethyl)-2-oxo-1 ,2-I I-I 0 0 dihydropyridin-3-y1)-5-oxohexanediamide o 11-147 (S)-N1-(1-(2-((1R,2R,4S)-o bicyclo[2.2.1]heptan-2-ylamino)-2-H 9 oxoethyl)-2-oxo-1,2-d i hydropyrid in-3-y1)-2-0 N NNThr I H 0 0 ----1-.- (3-methyl benzofuran-2-carboxa mido)-5-oxohexanediamide o 11-148 (S)-2-(benzofuran-2-carboxamido)-N1-(1 -NH2 -i (2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-o kilj NH ylamino)-2-oxoethyl)-2-oxo-1 ,2-I FNI 1 Nr 0 0 dihydropyridin-3-y1)-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-149 N H2 (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-0 o o ri_i Nj-LN NH oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-N
I H 0 0 (3-methyl benzofuran-2-carboxa mido)-5-oxohexanediamide o 11-150 NH2 (S)-2-(benzofuran-2-carboxamido)-5-oxo-o 0 o Ni -(2-oxo-1 -(2-oxo-2-((1 R,2S,4R)-1 ,7, 7-tri methyl bicyclo[2.2.1]heptan-2-0 N NNThrN1H
I H 0 0 ylamino)ethyl)-1 ,2-dihydropyridi n-3-yl)hexanediamide 11-151 (S)-2-(3-methylbenzofuran-2-NH2 carboxamido)-5-oxo-N1-(2-oxo-1 -(2-oxo-2-((1R,2S,4R)-1 ,7,7-0 N.r1\12-.N_r NH
I H I I tri methyl bicyclo[2.2.1Theptan-2-ylamino)ethyl)-1 ,2-dihydropyridi n-3-yl)hexanediamide 11-152 0N (S)-N1-(1-(2-((1 R,2R,4S)-H bicyclo[2.2.1]heptan-2-ylamino)-2-0 jc H 0 H A oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-,s, N i p 1 ", ri 'c..___1.. N6-methyl-2-(4-methyl-1 ,2,3-th lad iazole-5-'N 0 0 carboxamido)-5-oxohexanediamide 11-153 ON (S)-N1-(1-(2-((1 R,2R,4S)-H bicyclo[2.2.1]heptan-2-ylamino)-2-0 (it N jcErci H H _.. oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)-NN N6-methyl-2-(1 -methyl-1 H-pyrazole-5-N--- \ carboxamido)-5-oxohexanediamide 11-154 0 (S)-N1-(1-(2-((1S,2R,4R)-A N
H bicyclo[2.2.1]heptan-2-ylamino)-2-0 j(i N El ,NH 0 oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)-jci F3C¨S_KIII 1 y h N6-methyl-2-(4-methyl-2-(trifluoromethyl)thiazole-5-carboxamido)-5-oxohexanediamide 11-155 (S)-N1-(1-(24(1S,2R,4R)-ON
H bicyclo[2.2.1]heptan-2-ylamino)-2-0( 0 NH oxoethyl)-2-oxo-1,2-d i hydropyrid in-3-y1)-2-(2,5-dichlorothiophene-3-carboxamido)-s 0 0 CI N6-methyl-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-156 0A (S)-N1-(1-(2-((1S,2R,4R)-N
H obxiColOy20.-22.:10xhoe_it,a2n:d2ih-yldarmopinyorid-2in--3_yo-Y [ i P Y ) O 0 '--1 N, 1 1 NI NH
ciRliJ-N6-methy1-2-(4-methy1-1,2,3-th lad iazole-5-carboxamido)-5-oxohexanediamide 11-157 (S)-N1-(1-(2-((1S,2R,4R)-H bicyclo[2.2.1]heptan-2-ylamino)-2-0 0 oxoethyl)-2-oxo-1,2-d i hydropyrid in-3-y1)-id jN NH
Nr'-'-'--7)-Njcr N6-methyl-2-(1-methy1-1H-1,2,3-triazole-5-carboxamido)-5-oxohexanediamide 11-158 (S)-N1-(1-(24(1S,2R,4R)-0)-LN
H bicyclo[2.2.1]heptan-2-ylamino)-2-O 0 T1 H oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-<
H
N ,NH
N if -----)ANcr 1 N6-methyl-2-(1-methy1-1H-pyrazole-5-\ carboxamido)-5-oxohexanediamide 11-159 (S)-Ni-methyl-5-(4-methyl-2-H (trifluoromethypth iazole-5-carboxamido)-2-0 0 oxo-N6-(2-oxo-1-(2-oxo-2-((1R,2S,4R)-S idN if ,NH
F3C--- F\ici 1,7,7-trimethylbicyclo[2.2.1Theptan-2-N i0 0 ylamino)ethyl)-1,2-dihydropyridi n-3-yl)hexanediamide 11-160 OA N (S)-2-(2,5-dichlorothiophene-3-H carboxamido)-N6-methy1-5-oxo-N1-(2-oxo-Lf(0 0 1-(2-oxo-24(1R,2S,4R)-1,7,7-N 1 N'-r NH trimethylbicyclo[2.2.1Th Cl eptan-2-S 0 0 ylamino)ethyl)-1,2-dihydropyridi n-3-yl)hexanediamide 11-161 (S)-N1-methy1-5-(4-methy1-1,2,3-H th lad iazole-5-carboxamido)-2-oxo-N6-(2-0 0 oxo-1-(2-oxo-2-((1R,2S,4R)-1,7,7-H II
N
N/S_kANjcr 1 yThr NH tri methyl bicyclo[2.2.1Theptan-2-N 0 0 ylamino)ethyl)-1,2-dihydropyridi n-3-yhhexanediamide 11-162 (S)-N1-methy1-5-(1-methy1-1H-1,2,3-Oli N
H triazole-5-carboxamido)-2-oxo-N6-(2-oxo-I? H 0 1-(2-oxo-2-((1R,2S,4R)-1,7,7-N NH tri methyl bicyclo[2.2.1]heptan-2-NN
i\i-N \ ylamino)ethyl)-1,2-dihydropyridi n-3-yl)hexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-163 (S)-N1-methy1-5-(1-methy1-1H-pyrazole-5-H carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-,it N 0 ((1R,2S,4R)-1,7,7-ill )-LNr NH trimethylbicyclo[2.2.1]heptan-2-'El 0 0 N-N \ ylamino)ethyl)-1,2-dihydropyridi n-3-yl)hexanediamide o 11-164 N (2S)-2-(4-tert-butyl-1H-pyrrole-3-o H carboxamido)-N6-methyl-N1-(1-(2-(1-o o adamantylamino)ethyl)-2-oxo-1,2-N
HN --- FiNjcorill N dihydropyridin-3-yI)-5-oxohexanediamide ¨
o 11-165 0)-.LNI (2S)-2-(4-cyano-1-methy1-1H-pyrrole-2-H carboxamido)-N6-methyl-N1-(1-(3-(1-H o adamantylamino)propyI)-2-oxo-1,2-o NN
\ N H 0 dihydropyridin-3-yI)-5-oxohexanediamide \
o 11-166 (S)-N1-(1-(3-(2-adamantylamino)-3-H oxopropy1)-2-oxo-1,2-dihydropyridin-3-y1)-0?LN N,)-NN 2-(5-methoxyoxazole-2-carboxamido)-N6-MeON H 0 H
methyl-5-oxohexanediamide o 11-167 0 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-1\1 H ylamino)-2-oxoethyl)-2-oxo-1,2-O H o dihydropyridin-3-y1)-N6-methy1-2-(3-0 N_iNNNH
I H 0 8 methylbenzofuran-2-carboxamido)-5-oxohexanediamide o 11-168 0 ,1 (S)-2-(2-acetyloxazole-4-carboxamido)-H N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-o o j( FdN.rN,IH 2-oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)-J h' N6-methy1-5-oxohexanediamide o 0 o o 11-169 0)-.N (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-H ylamino)-2-oxoethyl)-2-oxo-1,2-o o H II H dihydropyridin-3-y1)-N6-methy1-2-(3-o NrN,IN,N) I H 0 8 methylbenzofuran-2-carboxamido)-5-oxohexanediamide o 11-170 0 (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-1\1 H ylamino)-2-oxoethyl)-2-oxo-1,2-o 0 H li H dihydropyridin-3-y1)-2-(2-isopropyloxazole-oiNNN
5-carboxamido)-N6-methy1-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 o 11-171 ON (2S)-2-(benzofuran-2-carboxamido)-N1-(1-H 0 (2-(bicyclo[3.2.1]octan-8-ylamino)-2-o H
-2N(INI oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-I H 0 0 N6-methyl-5-oxohexanediamide 11-172 (2S)-N1-(1-(2-(bicyclo[3.2.1]octan-8-H ylamino)-2-oxoethyl)-2-oxo-1,2-H dihydropyridin-3-y1)-2-(3,5---- N NH
N N dimethylisoxazole-4-carboxamido)-N6-L, H
'NJ- 0 0 methyl-5-oxohexanediamide o 11-173 O (S)-N1-(1-(2-(5-carboxy-2-NI
H aminoadamantane)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(4-LI H n 0 CO2H methylpyrimidine-5-carboxamido)-5-1 '' oxohexanediamide o 11-174 0 N (2S)-N1-(1-(2-(4-aminoadamantane-N,N-o H dimethy1-1-carboxamide)-2-oxoethyl)-2-o N 1 N Tr I oxo-1,2-dihydropyridin-3-y1)-N6-methy1-H
0 0 N-..._ oxo-2-(1,2,3,4-tetrahydronaphthalene-2-o carboxamido)hexanediamide o 11-175 (S)-24(S)-1,4-diazabicyclo[2.2.2]octane-2-0N--v H ? carboxamido)-N6-tert-butyl-N1-(1-(2-(2-H I H
_1._'_\_j r\j---ANJc,NNThrN adamantylamino)-2-oxoethyl)-2-oxo-1,2-H
0 0 dihydropyridin-3-y1)-5-oxohexanediamide o 11-176 (S)-N1-tert-buty1-5-(1H-indole-3-H carboxamido)-N6-(1-(2-(2-H
N kil adamantylamino)-2-oxoethyl)-2-oxo-1,2-H
i N 0 0 U dihydropyridin-3-y1)-2-oxohexanediamide H
11-177 (S)-N1-tert-butyl-N6-(1-(2-(2-H adamantylamino)-2-oxoethyl)-2-oxo-1,2-A) jc( Fii 9 dihydropyridin-3-y1)-5-(6-N 0 rjmor methylimidazo[2,1-b]thiazole-3-s carboxamido)-2-oxohexanediamide 11-178 0 ji) (S)-2-(benzo[d]thiazole-2-carboxamido)-ON
H N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-S):)1111j- 0 N_r NH 2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-cyclopenty1-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-179 ojNiL) (S)-N1-(1-(24(16,2R,4R)-H bicyclo[2.2.1]heptan-2-ylamino)-2-0 EIJ o oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)-N NNH
NAYFINjc N6-cyclopenty1-2-(imidazo[2,1-b]thiazole-6-carboxamido)-5-oxohexanediamide s 11-180 o 0 n (S)-N1-(1-(24(16,2R,4R)-N
H OH 0 bicyclo[2.2.1Theptan-2-ylamino)-2-, 0 N NNThrNH oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N N6-cyclopenty1-2-(4-hydroxy-6-(trifluoromethoxy)quinoline-3-carboxamido)-5-oxohexanediamide 11-181 o AJO (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-oN
H ylamino)-2-oxoethyl)-2-oxo-1,2-o dihydropyridin-3-y1)-2-(cinnoline-3-o JEI
N,A NH
N 1 N n carboxamido)-N6-cyclohexy1-5-N oxohexanediamide 11-182 o n (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-0A1\1 H ylamino)-2-oxoethyl)-2-oxo-1,2-o di hydropyridin-3-y1)-N6-cyclohexy1-2-(3-o NiCri 1\1Hj-N,r1 NH
I H 0 0 ethylbenzofuran-2-carboxamido)-5-oxohexanediamide ojN,0 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-H ylamino)-2-oxoethyl)-2-oxo-1,2-Th o o di hydropyridin-3-y1)-N6-cyclohexy1-2-(1-N
N 1 ri_rH NThrNH
j-ethy1-1H-indole-2-carboxamido)-5-o o o( sx )o_ hNeix_ aon-e(2d _i a( bmi ci dy e 11-184 c 1 0 o n [1.1.1]pentan-1-N
H ylamino)-2-oxoethyl)-2-oxo-1,2-o di hydropyridin-3-y1)-N6-cyclohexy1-2-(2-Nj. ,NH
methyl-1,8-naphthyridine-3-carboxamido)-NN 5-oxohexanediamide 11-185 O (S)-N1-(1-(2-(bicyclo[2.1.1Thexan-1-N
H ylamino)-2-oxoethyl)-2-oxo-1,2-H di hydropyridin-3-y1)-N6-methy1-5-oxo-N 'iNj1 N, N (1,2,3,4-tetrahydroquinoline-6-N carboxamido)hexanediamide H
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 o 11-186 0 N_, (S)-N1-(1-(2-(2-carboxy-2-amino-5-H (trifluoromethypadamantane)-2-oxoethyly o o o NNANJ(N c02H
2-oxo-1,2-dihydropyridin-3-yI)-N6-methyl-HN 0 0 CF3 5-oxo-2-(3-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)hexanediamide o 11-187 0 N (S)-N1-(1-(2-(5-ethyladamantane-2-o H amino)-2-oxoethyl)-2-oxo-1,2-o H
1\1N kll,ANN dihydropyridin-3-y1)-N6-methy1-2-(1,6-r\il H 0 0 naphthyridine-2-carboxamido)-5-oxohexanediamide 11-188 (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-H ylamino)-2-oxoethyl)-2-oxo-1,2-H dihydropyridin-3-y1)-N6-methy1-2-(2,6-Njt., 1 rirN naphthyridine-1-carboxamido)-5-oxohexanediamide 11-189 (S)-2-(4-amino-1,2,5-oxadiazole-3-ajt.
'------ N
H carboxamido)-N1-(1-(2-H2N 0 0 (bicyclo[1.1.1]pentan-1-ylamino)-2-INI
Y(N Nr.----,irNH
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N I H
b-N 0 0 N6-methyl-5-oxohexanediamide o 11-190 0}1..N (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-,,,....--H ylamino)-2-oxoethyl)-2-oxo-1,2-o o 0 N NH dihydropyridin-3-yI)-2-(6-\
N 1 H 0 8 (dimethylamino)benzofuran-2-/ carboxamido)-N6-methy1-5-oxohexanediamide o 11-191 ojN--(S)-2-(2-acetamidothiazole-5-., H carboxamido)-N1-(1-(2-NH
(bicyclo[1.1.1]pentan-1-ylamino)-2-s ,,,Jcki FINI--- DA" N if oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-o N6-methyl-5-oxohexanediamide o 11-192 0IL.N (S)-N4-(1-(1-(2-(bicyclo[1.1.1]pentan-.,-H j ylamino)-2-.oxoethyl)-2-oxo-1,2-o o N
0 HN , dihydropyndm-3-ylamino)-6-/ NrF-IN if I H 0 0 (methylamino)-1,5,6-trioxohexan-2-yI)-pyrrole-2,4-dicarboxamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 0 ________________________________________________________________________ 11-193 0 N (S)-N1-(1-(2-(1-acetylamino-4-H
aminoadamantane)-2-oxoethyl)-2-oxo-1,2-0,t(JAN N,ANThrN
0 dihydropyridin-3-y1)-N6-methyl-5-oxo-2-(5-NJ
H sulfamoylfuran-3-carboxamido)hexanediamide o 11-194 0 N (S)-2-(benzofuran-5-carboxamido)-N1-(1-H
(2-(1-acetylamino-4-aminoadamantane)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-H
0 Nj H N6-methyl-5-oxohexanediamide o 11-195 0 N,-- (S)-2-(benzofuran-6-carboxamido)-N1-(1-H
H (2-(4-aminoadamantane-1-carboxamide)-NJ,) ENI
0 N 1 N-r 2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-\ H
0 0 NH2 N6-methyl-5-oxohexanediamide o 11-196 o- o (S)-N1-(1-(2-(4-aminoadamantane-1-H carboxamide)-2-oxoethyl)-2-oxo-1,2-r[i H
A e N r,j,---,õ,,,N dihydropyridin-3-y1)-N6-methy1-2-(3-(1-NH2 methylcyclopropyI)-1,2,4-oxadiazole-5-o carboxamido)-5-oxohexanediamide 11-197 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-OAN
H ylamino)-2-oxoethyl)-2-oxo-1,2-0 (.rr\I i 0 H j,. dihydropyridin-3-y1)-N6-methy1-2-(5-NINI N,r NH
methyl-1,2,4-oxadiazole-3-carboxamido)-5-oxohexanediamide 11-198 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-0)-LN
H ylamino)-2-oxoethyl)-2-oxo-1,2-0 0 dihydropyridin-3-y1)-N6-methyl-5-oxo-S/
NNH ANcrEA (1,2,3-thiadiazole-4-carboxamido)hexanediamide 11-199 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-N
H ylamino)-2-oxoethyl)-2-oxo-1,2-0 H 0 ----)' dihydropyridin-3-y1)-N6-methyl-5-oxo-N,3,7AN N NH
..----N/ _r H I I (1,2,4-thiadiazole-5-carboxamido)hexanediamide 11-200 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-OAN
H ylamino)-2-oxoethyl)-2-oxo-1,2-0 ( id 0 dihydropyridin-3-y1)-N6-methyl-5-oxo-e-,AN-NThrNH
(1,3,4-thiadiazole-2-carboxamido)hexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-201 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-N
H ylamino)-2-oxoethyl)-2-oxo-1,2-H ii? dihydropyridin-3-y1)-2-(4-cyclopropy1-1,2,3-N, I h' 1 N, MCNH
thiadiazole-5-carboxamido)-N6-methy1-5-oxohexanediamide o 11-202 0).N (S)-2-(4-cyclopropy1-1,2,3-thiadiazole-5-H carboxamido)-N1-(1-(2-(2-H adamantylamino)-2-oxoethyl)-2-oxo-1,2-N
N',SHI\jjCi N NI dihydropyridin-3-y1)-N6-methy1-5-N 0 o oxohexanediamide o 11-203 0).N (S)-2-(4-isopropyl-1,2,3-thiadiazole-H carboxamido)-N1-(1-(2-(2-o 0 r H
H adamantylamino)-2-oxoethyl)-2-oxo-1,2-r,,,s NfN')N-rN
N I H dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide o 11-204 0)N (S)-2-(4-ethy1-1,2,3-thiadiazole-5--.
H carboxamido)-N1-(1-(2-(2-o 0 H
N'S N( H
N)- ,N adamantylamino)-2-oxoethyl)-2-oxo-1,2-N IT
dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide o 11-205 0 (S)-2-(4-formy1-1,2,3-thiadiazole-5-N
H carboxamido)-N1-(1-(2-(2-H
FN11 adamantylamino)-2-oxoethyl)-2-oxo-1,2-,S
dihydropyridin-3-y1)-N6-methy1-5-\N H 0 oxohexanediamide o o 11-206 (S)-2-(4-(hydroxymethyl)-1,2,3-thiadiazole-N
H 5-carboxamido)-N1-(1-(2-(2-H il N H adamantylamino)-2-oxoethyl)-2-oxo-1,2-NJrN
kr,\ I 1 H 0 c N2-.0 dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide HO
11-207 OJt (S)-N1-(1-(2-(1-adamantylamino)-2-N
H oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-0 H 0 N6-methyl-2-(1-methyl-1H-imidazole-5-ii 1\l/YN N'l N'r NH
carboxamido)-5-oxohexanediamide \\ Ki ¨ 0 ...,..,0 '-------IIN
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-208 0 (S)-N1-(1-(2-(((1 S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-21,1AN k-11 yl)methylamino)-2-oxoethyl)-2-oxo-1,2-N
H 0 0 dihydropyridin-3-y1)-N6-methy1-2-(1-methyl-1 H-imidazole-2-carboxamido)-5-oxohexanediamide 11-209 0 (S)-N1-(1-(2-(((1 R,2R,5R)-6,6-dimethylbicyclo[3.1.1]heptan-2-o o HeN FIN NOThr yl)methylamino)-2-oxoethyl)-2-oxo-1,2-0 o dihydropyridin-3-y1)-2-(1H-imidazole-4-carboxamido)-N6-methyl-5-oxohexanediamide (S)-N1-(1-(2-(3,5-dimethyladamantane-1-N
amino)-2-oxoethyl)-2-oxo-1 ,2-11-210 o jcr H 0 dihydropyridin-3-y1)-N6-methyl-2-(1-NH
Thr methyl-1 H-imidazole-5-carboxamido)-5--N
oxohexanediamide (S)-N1-(1-(2-(3,5,7-trimethy1-1-adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-y1)-N6-methy1-2-(1-N N NH f'''=----/A-r NThr methyl-1 H-imidazole-5-carboxamido)-5-oxohexanediamide or a pharmaceutically acceptable salt thereof.
Especially preferred are the following compounds:
11-2: (S)-2-(benzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-3: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-4: (S)-2-(3-chlorobenzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-5: (S)-2-(4-bromobenzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-6: (S)-2-(4-bromobenzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-7: (S)-2-(benzo[b]thiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-8: (S)-2-(5-bromobenzo[b]thiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-9: (S)-2-(1 H-indole-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-10: (S)-2-(4,5-difluoro-1 H-indole-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-11 : (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methy1-1H-indole-2-carboxamido)-5-oxohexanediamide 11-12: (S)-2-(1 H-benzo[d]imidazole-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-13: (S)-2-(2,3-dihydro-1 H-indene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-14: (S)--(2-bromo-4-methylthiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-15: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(4-methy1-2-(trifluoromethypthiazole-5-carboxamido)-5-oxohexanediamide 11-16: (S)-2-(4-bromo-2-(trifluoromethyl)thiazole-5-carboxamido)-N1-(1 -(242-adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-17: (S)-2-(2,4-dichlorothiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-18: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(2-methoxy-4-methylthiazole-5-carboxamido)-N6-methy1-5-oxohexanediamide 11-19: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(4-methy1-2-phenylthiazole-5-carboxamido)-5-oxohexanediamide 11-21: (S)-2-(5-bromo-3-methylthiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-22: (S)-2-(3,5-dibromothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-23: (S)-2-(5-bromothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-24: (S)-2-(5-chlorothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-25: (S)-2-(5-bromo-3-methylfuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-26: (S)-2-(5-chlorofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-27: (S)-2-(5-chlorothiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-28: (S)-2-(2,5-dichlorothiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-29: (S)-2-(2,5-dibromothiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-30: (S)-2-(5-bromothiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-31: (S)-2-(2-chloro-5-methylthiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-32: (S)-2-(2,5-dichlorothiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-33: (S)-2-(2,5-dibromothiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-34: (S)-2-(2-bromo-5-methylthiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-35: (S)-2-(2-bromothiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-36: (S)-2-(2-chlorothiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-37: (S)-2-(2,5-dimethylfuran-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-39: (S)-2-(4-bromothiazole-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-40: (S)-2-(4-bromothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-41: (S)-2-(4-bromo-3-methylthiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-42: (S)-2-(3-bromothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-44: (S)-2-(4-bromo-5-chlorothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-45: (S)-2-(4,5-dibromothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-46: (S)-2-(4,5-dibromo-3-methoxythiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-47: (S)-2-(4-bromofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-48: (S)-2-(4,5-dibromofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-49: (S)-2-(4,5-dichlorothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-50: (S)-24(S)-1-acetylpyrrolidine-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide 11-51: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-1,2,3-triazole-5-carboxamido)-5-oxohexanediamide 11-51 (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(pyrazine-2-carboxamido)hexanediamide 11-54: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-24(S)-1-methylpyrrolidine-2-carboxamido)-5-oxohexanediamide 11-55: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-24(S)-pyrrolidine-3-carboxamido)hexanediamide 11-56: (S)-24(2S,4S)-4-bromopyrrolidine-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-58: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-24(S)-piperidine-2-carboxamido)hexanediamide 11-59: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-24(R)-piperidine-3-carboxamido)hexanediamide 11-60: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-24(R)-morpholine-3-carboxamido)-5-oxohexanediamide 11-61: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(quinuclidine-3-carboxamido)hexanediamide 11-62: (S)-methyl 3-(1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-ylcarbamoy1)-5-nitrobenzoate 11-61 (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(5-nitronicotinamido)-5-oxohexanediamide 11-64: (S)-5-(1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinic acid 11-65: (S)-methyl 5-(1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinate 11-68: (S)-N1-(1-(2-(5-hydroxyadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-69: (S)-N1-(1-(2-(5-fluoroadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-70: (S)-N1-(1-(2-(5-chloroadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-71: (S)-N1-(1-(2-(5-bromoadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-72: (S)-N1-(1-(2-(5-methyladamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-71 (S)-N1-(1-(2-(2-carbonitrileadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-di hydropyrid in-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-87: (S)-N1-(1-(2-(1-adamantylmethylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-88: (S)-N1-(1-(2-(1-(1-adamantypethanamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-90: (S)-N1-(1-(24(1R,2S,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-92: (S)-N1-methy1-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1S,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide 11-94: (S)-N1-(1-(24(1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-95: (S)-N1-(1-(2-(bicyclo[2.2.1]heptan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-96: (S)-N1-(1-(2-(bicyclo[2.2.1]heptan-7-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-97: (S)-N1-(1-(2-(bicyclo[2.2.1]hept-5-en-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-98: (2S)-N1-(1-(2-(bicyclo[2.2.2]octan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-99: (S)-N1-methy1-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide 11-100: (S)-N1-methy1-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide 11-101: (S)-N1-methy1-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide 11-103: (S)-N1-(1-(2-(4-homoisotwistane-3-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-104: (S)-N1-(1-(2-(diamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-105: (S)-N1-(1-(2-(diamantane-4-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-107: (S)-N1-(1-(1-adamantylmethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-108: (2S)-N1-(14(3-hydroxy-1-adamantypmethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-109: (2S)-N1-(14(3-bromo-1-adamantypmethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-110: (S)-N1-(1-(2-adamantylmethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-111: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(nicotinamido)-5-oxohexanediamide 11-112: (S)-2-(isonicotinamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-113: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(pyridazine-4-carboxamido)hexanediamide 11-114: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(pyridazine-3-carboxamido)hexanediamide 11-116: (S)-N1-cyclopropyl-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-0-5-(3-methylbenzofuran-2-carboxamido)-2-oxohexanediamide 11-116: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(3-methylbenzofuran-2-carboxamido)-5-oxo-N6-pentylhexanediamide 11-117: (S)-N1-allyl-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(3-methylbenzofuran-2-carboxamido)-2-oxohexanediamide 11-119: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-119: (S)-N1-ally1-5-(benzofuran-2-carboxamido)-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxohexanediamide 11-120: (S)-2-(benzofuran-2-carboxamido)-N6-isopropyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide 11-121: (S)-2-(benzofuran-2-carboxamido)-N6-cyclopropyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide 11-124: (S)-2-(benzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-0-5-oxohexanediamide 11-126: (S)-2-(2,5-dichlorothiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide 11-126: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(4-methy1-2-(trifluoromethypthiazole-5-carboxamido)-5-oxohexanediamide 11-127: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(1-methy1-1H-1,2,3-triazole-5-carboxamido)-5-oxohexanediamide 11-129: (2S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(2,5-dichlorothiophene-3-carboxamido)-N6-methyl-5-oxohexanediamide 11-129: (2S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(4-methyl-2-(trifluoromethypthiazole-5-carboxamido)-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-130: (2S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-di hydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-1,2,3-triazole-5-carboxamido)-5-oxohexanediamide 11-131: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(2H-1,2,3-triazole-4-carboxamido)hexanediamide 11-135: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-1,2,4-triazole-3-carboxamido)-5-oxohexanediamide 11-136: (S)-2-(benzofuran-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-137: (S)-2-(benzo[b]thiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-138 (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-pyrazole-3-carboxamido)-5-oxohexanediamide 11-139 (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-pyrazole-4-carboxamido)-5-oxohexanediamide 11-140 (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-pyrazole-5-carboxamido)-5-oxohexanediamide 11-141 (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(4-methy1-1,2,3-thiadiazole-5-carboxamido)-5-oxohexanediamide 11-142 (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1,2,5-thiadiazole-3-carboxamido)hexanediamide 11-145 (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(4-methy1-1,2,3-thiadiazole-5-carboxamido)-5-oxohexanediamide 11-146 (S)-2-(benzofuran-2-carboxamido)-N1-(1-(24(1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide 11-147 (S)-N1-(1-(24(1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-di hydropyridin-3-y1)-2-(3-methylbenzofuran-2-carboxamido)-5-oxo hexanediamide 11-148 (S)-2-(benzofuran-2-carboxamido)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide 11-149 (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-di hydropyridin-3-y1)-2-(3-methylbenzofuran-2-carboxamido)-5-oxo hexanediamide 11-150 (S)-2-(benzofuran-2-carboxamido)-5-oxo-N1-(2-oxo-1-(2-oxo-24(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yhhexanediamide 11-151 (S)-2-(3-methylbenzofuran-2-carboxamido)-5-oxo-N1-(2-oxo-1-(2-oxo-2-((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide 11-152 (S)-N1-(1-(24(1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-di hydropyridin-3-y1)-N6-methy1-2-(4-methy1-1,2,3-th iadiazole-5-carboxamido)-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-154 (S)-N1-(1-(2-((1 S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1 ,2-di hydropyrid in-3-y1)-N6-methy1-2-(4-methy1-2-(trifluoromethyl)th iazole-5-carboxamido)-5-oxohexanediamide 11-155 (S)-N1-(1-(2-((1 S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-y1)-2-(2,5-dichlorothiophene-3-carboxamido)-N6-methy1-5-oxohexanediamide 11-156 (S)-N1-(1-(2-((1 S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1 ,2-di hydropyrid in-3-y1)-N6-methy1-2-(4-methy1-1,2, 3-th iadiazole-5-carboxamido)-5-oxohexanediamide 11-157 (S)-N1-(1-(2-((1 S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1 ,2-di hydropyrid in-3-y1)-N6-methy1-2-(1 -methyl-1 H-1 ,2,3-triazole-5-carboxamido)-5-oxohexanediamide 11-158 (S)-N1-(1-(2-((1 S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1 ,2-di hydropyrid in-3-y1)-N6-methy1-2-(1 -methyl-1 H-pyrazole-5-carboxamido)-5-oxohexanediamide 11-159 (S)-N1-methy1-5-(4-methy1-2-(trifluoromethypthiazole-5-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yphexanediamide 11-160 (S)-2-(2,5-dichlorothiophene-3-carboxamido)-N6-methy1-5-oxo-N1-(2-oxo-1-(2-oxo-2-((1 R,2S,4R)-1 ,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide 11-161 (S)-N1-methy1-5-(4-methy1-1 ,2,3-thiad iazole-5-carboxamido)-2-oxo-N6-(2-oxo-1 -(2-oxo-24(1 R,2S,4R)-1 ,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1 ,2-dihydropyridin-3-yl)hexanediamide 11-162 (S)-N1-methy1-5-(1-methy1-1 H-1 ,2,3-triazole-5-carboxamido)-2-oxo-N6-(2-oxo-1 -(2-oxo-24(1 R,2S,4R)-1 ,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1 ,2-dihydropyridin-3-yl)hexanediamide 11-163 (S)-N1-methy1-5-(1-methy1-1 H-pyrazole-5-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1 R,2S,4R)-1 ,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide 11-167 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-168 (S)-2-(2-acetyloxazole-4-carboxamido)-N1-(1-(2-(bicyclo[1 .1 .1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-di hydropyrid in-3-y1)-N6-methy1-5-oxohexaned iamide 11-169 (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-170 (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(2-isopropyloxazole-5-carboxamido)-N6-methyl-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-171 (2S)-2-(benzofuran-2-carboxamido)-N1-(1-(2-(bicyclo[3.2.1]octan-8-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-172 (2S)-N1-(1-(2-(bicyclo[3.2.1]octan-8-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(3,5-dimethylisoxazole-4-carboxamido)-N6-methy1-5-oxohexanediamide 11-173 (S)-N1-(1-(2-(5-carboxy-2-aminoadamantane)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(4-methylpyrimidine-5-carboxamido)-5-oxohexanediamide 11-174 (2S)-N1 -(1-(2-(4-aminoadamantane-N,N-d imethyl-1 -carboxamide)-2-oxoethyl)-2-oxo-1,2-d ihydropyrid in-3-y1)-N6-methyl-5-oxo-2-(1 ,2,3,4-tetrahydronaphthalene-2-carboxamido)hexanediamide 11-178 (S)-2-(benzo[d]thiazole-2-carboxamido)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-cyclopentyl-5-oxohexanediamide 11-182 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-cyclohexy1-2-(3-ethylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-183 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-cyclohexy1-2-(1-ethy1-1H-indole-2-carboxamido)-5-oxohexanediamide 11-194 (S)-2-(benzofuran-5-carboxamido)-N1-(1-(2-(1-acetylamino-4-aminoadamantane)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-195 (S)-2-(benzofuran-6-carboxamido)-N1-(1-(2-(4-aminoadamantane-1-carboxamide)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-198 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1,2,3-thiadiazole-4-carboxamido)hexanediamide 11-199 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1,2,4-thiadiazole-5-carboxamido)hexanediamide 11-200 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1,3,4-thiadiazole-2-carboxamido)hexanediamide 11-201 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(4-cyclopropy1-1,2,3-thiadiazole-5-carboxamido)-N6-methyl-5-oxohexanediamide 11-202 (S)-2-(4-cyclopropy1-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide 11-203 (S)-2-(4-isopropy1-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide 11-204 (S)-2-(4-ethy1-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide 11-205 (S)-2-(4-formy1-1 ,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-206 (S)-244-(hydroxymethyl)-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide 11-207 (S)-N1-(1-(2-(1-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(3,5-dimethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-11-210 dihydropyridin-3-y1)-N6-methy1-241-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (S)-N1 -(1-(2-(3,5,7-trimethyl-1 -adamantylam ino)-2-oxoethyl)-2-oxo-1 ,2-11-211 dihydropyridin-3-y1)-N6-methy1-241-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide or a pharmaceutically acceptable salt thereof.
Method for production of inventive compounds In some embodiments, the present invention relates to a method for the synthesis of a compound of formula (I), especially any compound of the formula (lb):
OA N .R6 ---.
Ao N H o )-L ,, , H
0 (lb) The compound of the formula (lb) can be produced and thus, the present invention relates to a method for producing the compound of formula (lb) comprising the following steps in the following order:
Step 1B: providing a compound 4b Ac0)-L
PGNKOH
H 0 4b;
Step 2B: performing coupling reaction of the compound 4b with a compound 5 H2N N)-L , L , IR' , to obtain a compound 6b 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 Ac0 N , R6 i_i R70 PG3Ni\O- ,L.
6b;
Step 3B: deprotecting an amino protecting group PG3to obtain a compound 7b Ac0)-N , R6 HN rl N , L
1 'R3 0 7b;
Step 4B: performing coupling reaction of the compound 7b with a carboxylic acid (R2-CO2H 8) to obtain a compound 9b Ac0)-N L , R6 1 N" 'R3 9b;
Step 5B: performing oxidation reaction of the compound 9b to produce the compound of the formula (lb) OA .R6 --.. N
R2AN N , N L .
(1b);
wherein L, R2, R3, R6 and R7 have the same meanings as defined above in the formula (lb), and PG3 is an amino protecting group.
AcO N
-L , R6 In the step 5B the chemical warhead precursor i H
i may be firstly converted to HO , R6 N HO N
, R6 ' H ; H
i under a basic condition such as treating with K2CO3, and then 0)-L N .R6 is converted to the corresponding chemical warhead H
by an oxidation 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 method, preferably by using Dess-Martin periodinane (DMP), iodoxybenzoic acid (IBX), or hypochlorite/TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) in a polar solvent, as described in the chemical examples.
In an alternative route first all protecting groups PG1 and PG2 are simultaneously removed and the protecting group PG3 is selectively introduced. Preferably, PG1 and PG3 are same.
The term "protecting groups" as used herein refers to commonly used protection groups in organic synthesis, preferably for amino and carboxyl groups. PG1, PG3, and PG5 preferably are suitable protecting groups for amino groups. PG2 and PG4 preferably are suitable protecting groups for carboxyl groups. Preferably, PG1, PG3, and PG5 may be selected from the group consisting of or comprising: acetyl, benzoyl, benzyloxycarbonyl (Cbz), tert-butylcarbonyl, tert-butyloxycarbonyl (Boc), and fluorenylmethylenoxy group (Fmoc). PG2 and PG4 may be selected from the group consisting of or comprising:
methoxy, ethoxy, isobutoxy, tert-butoxy, benzyloxy; preferably, tert-butoxy group.
In Step 2B, to promote the coupling reaction with amino group of intermediate compound, activating reagents are commonly used to activating carboxylic acid (õPeptide Coupling Reagents, More than a Letter Soup", Ayman El-Faham and Fernando Albericio, Chemical Reviews, 2011, 111(11), p.6557-6602). The activation may be introduced separate reaction or in situ reaction. Preferably, any of the following coupling reagent can be used to activate carobxylic acid group: BOP (Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate), PyBOP (Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate), AOP (7-(Azabenzotriazol-1-yl)oxy tris(dimethylamino)phosphonium hexafluorophosphate), PyAOP ((7-Azabenzotriazol-yloxy)tripyrrolidinophosphonium hexafluorophosphate), TBTU (2-(1H-Benzotriazole-1-y1)-1,1,3,3-tetramethylaminium tetrafluoroborate), EEDQ (N-Ethoxycarbony1-2-ethoxy-1,2-dihydroquinoline), Polyphosphoric Acid (PPA), DPPA (Diphenyl phosphoryl azide), HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), H BTU
(0-Benzotriazol-1-yl-N,N ,N',N'-tetramethyluronium hexafluorophosphate), HOBt (1-Hyd roxybenzotriazo le), HOAt (1-Hydroxy-7-azabenzotriazole), DCC (N,W-Dicyclohexylcarbodiimide), EDC (or EDAC or EDCI, 1-Ethy1-3-(3-dimethylam inopropyl)carbodi im ide), BOP-C1 (Bis(2-oxo-3-oxazolidinyl)phosphinic chloride), TFFH
(Tetram ethylfl uo roformam id i n i um hexafluorophosphate), BroP (Bromo tris(d imethylam ino) phosphonium hexafluorophosphate), PyBroP
(Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate) and CI P
(2-Chloro-1,3-dimethylimidazolidinium 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 hexafluorophosphate), or further, similar acting reagents, providing an activated intermediate,or a mixture thereof.
Pharmaceutical Composition & Medical Use Therefore another aspect of the present invention relates to compounds according to the general formula (I) as medicine as well as their use in medicine. Especially preferred is the use as inhibitors of transglutaminases, in particular transglutaminase 2 (TG2).
Thus the compounds of formula (I) described herein or according to the present invention may be administered themselves or in form of a pharmacologically acceptable salt.
The compounds of the present invention may form of a pharmacologically acceptable salt with organic or inorganic acids or bases. Examples of suitable acids for such acid addition salt formation are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, p-aminosalicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, sulfonic acid, phosphonic acid, perchloric acid, nitric acid, formic acid, propionic acid, gluconic acid, lactic acid, tartaric acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, methanesulfonic acid, ethanesulfonic acid, nitrous acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, p-toluenesulfonic acid, naphthylsulfonic acid, sulfanilic acid, camphorsulfonic acid, china acid, mandelic acid, o-methylmandelic acid, hydrogen-benzenesulfonic acid, picric acid, adipic acid, d-o-tolyltartaric acid, tartronic acid, (o, m, p)-toluic acid, naphthylamine sulfonic acid, trifluoroacetic acid, and other mineral or carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. Preferred is the mesylate salt, hydrochloride salt and the trifluoroacetate salt and especially preferred is the trifluoroacetate salt and the hydrochloride salt.
In the case the inventive compounds bear acidic groups, salts could also be formed with inorganic or organic bases. Examples for suitable inorganic or organic bases are, for example, NaOH, KOH, NH4OH, tetraalkylammonium hydroxide, lysine or arginine and the like. Salts may be prepared in a conventional manner using methods well known in the art, for example by treatment of a solution of the compound of the general formula (I) with a solution of an acid, selected out of the group mentioned above.
Methods of Use 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 In a further aspect of the present invention, the novel compounds according to the general formula (I) are used as pharmaceutically active agent, i.e. the compound of the formula (I) is used in medicine.
Furthermore, the present invention relates to a pharmaceutical composition comprising at least one compound according to the general formula (I), as an active ingredient or a pharmacologically acceptable salts thereof as an active ingredient, together with at least one pharmacologically acceptable carrier, excipient and/or diluent.
The compounds according to general formula (I) described herein are especially suitable for the treatment and prophylaxis of diseases associated with and/or caused by transglutaminase 2.
Celiac disease, a gluten intolerance is associated with tissue transglutaminase (TG 2).
Another very important group of indications for tissue transglutaminase inhibitors are fibrotic disorders. Fibrotic disorders are characterized by the accumulation of cross-linked extracellular matrix proteins. Diabetic nephropathy, cystic fibrosis, idiopathic pulmonary fibrosis, kidney fibrosis as well as liver fibrosis belong to the most important fibrotic disorders to be addressed with the compounds disclosed.
In the biological example B-I, it is proven that the inventive compounds as reversible and irreversible TG inhibitors effectively inhibit the activity of TGs, especially TG2.
As used herein the term "inhibiting" or "inhibition" refers to the ability of a compound to downregulate, decrease, reduce, suppress, inactivate, or inhibit at least partially the activity of an enzyme, or the expression of an enzyme or protein.
Therefore, another aspect of the present invention is the use of the inventive compounds of the general formula (I), or the pharmaceutical composition thereof as described in the treatment or prophylaxis of autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, ocular diseases, and skin disorders.
Further aspects of the present invention relate to the use of the compounds of general formula (I) for the preparation of a pharmaceutical composition useful for prophylaxis and/or treatment of autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, ocular diseases, and skin disorders.
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 In a further aspect of the present invention, a method for preventing and/or treating autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, ocular diseases, and skin disorders, which method comprises administering to a subject, in particular a human, a pharmaceutically effective amount of at least one compound of the general formula (I), to prevent and/or treat said autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, ocular diseases, and skin disorders.
Preferred, the autoimmune and inflammatory diseases comprises multiple sclerosis, celiac disease, Duhring-Brocq-disease (dermatitis herpetiformis), gluten ataxia, gluten neuropathy, diabetes, rheumatoid arthritis, Graves' disease, inflammatory bowel disease, systemic lupus erythematosus psoriasis, and gingivitis;
the vascular diseases comprise atherosclerosis, thrombosis, vascular stiffness;
the fibrotic diseases affecting the lung, the kidney, the liver, the skin or the gut like cystic fibrosis, kidney fibrosis and diabetic nephropathy, intestinal fibrosis, idiopathic lung fibrosis, liver fibrosis;
the liver diseases like alcoholic hepatitis, alcoholic steatohepatitis, nonalcoholic steatohepatitis, non-alcoholic fatty liver disease, liver cirrhosis, autoimmune hepatitis or liver inflammation;
.. the cholestatic liver diseases comprise primary biliary cholangitis and primary sclerosing cholangitis;
the cancer comprises glioblastoma, melanoma, pancreatic cancer, renal cell carcinoma, meningioma, and breast cancer, the neurodegenerative diseases comprise Parkinson's disease, Huntington's disease, or Alzheimer's disease, the ocular diseases comprise glaucoma, cataracts, macular degeneration, or uveitis;
the skin disorders comprise acne, psoriasis, scarring, and skin aging.
More preferred, the compound of the formula (I), or the pharmaceutical composition thereof is useful in the treatment or prophylaxis of celiac disease.
Furthermore, the compounds of the general formula (I), can be administered in form of their pharmaceutically active salts, optionally using essentially non-toxic pharmaceutically acceptable carriers, adjuvants or extenders. Medications are prepared in a known manner in a conventional solid or fluid carrier or in extenders and a conventional pharmaceutically acceptable adjuvant/expedient in a suitable dose. The preferred preparations are provided in an administrable form suitable for oral application, such as pills, tablets, film tablets, coated tablets, capsules and powders.
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 Tablets, film tablets, coated tablets, gelatine capsules and opaque capsules are the preferred pharmaceutical formulations. Any pharmaceutical compositions contains at least one compound of the general formula (I), and/or pharmaceutically acceptable salts thereof in an amount of 5 mg to 500 mg, preferably 10 mg to 250 mg and most preferred in an amount of 10 to 100 mg per formulation.
Besides, the object of the present invention also includes pharmaceutical preparations for oral, parenteral, dermal, intradermal, intragastric, intracutaneous, intravascular, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal, percutaneous, rectal, subcutaneous, sublingual, topic, transdermal or inhalative application, containing, in addition to typical vehicles and extenders, a compound of the general formula (I), and/or a pharmaceutically acceptable salt thereof as active component.
The pharmaceutical compositions of the present invention contain one of the compounds of the formula (I) disclosed herein as active component, typically mixed with suitable carrier materials, selected with respect to the intended form of administration, i.e. tablets to be administered orally, capsules (filled either with a solid, a semi-solid or a liquid), powders, orally administrable gels, elixirs, dispersible granulates, syrups, suspensions .. and the like in accordance with conventional pharmaceutical practices. For example, the compound of the formula (I) can as active agent component be combined with any oral, non-toxic, pharmaceutically acceptable, inert carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms) and the like for the oral administration in form of tablets or capsules.
.. Moreover, suitable binders, lubricants, disintegrants and colorants can be added to the mixture if required. Powders and tablets can consist of said inert carriers to an extent from about 5% per weight to about 95% per weight of the inventive composition.
Suitable binders include starch, gelatine, natural sugars, sweeteners made of corn, natural and synthetic gums, such as acacia gum, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes. Possible lubricants for the use in said dosage forms include boric acid, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrants include starch, methylcellulose, cyclodextrins, guar gum and the like. If required, sweeteners and flavor additives and preservatives can also be .. included. Some of the terms used above, namely disintegrants, extenders, lubricants, binders and the like are discussed in greater detail below.
Additionally, the compositions of the present invention can be formulated in a form with sustained release to provide a controlled release rate of any one or more components or active components, in order to optimize the therapeutic effect, i.e. the inhibitory activity 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 and the like. Suitable dosage forms for sustained release include layered tablets containing layers with varying degradation rates or controlled release polymeric matrices impregnated with the active components and in the form of a tablet or capsule containing such impregnated or encapsulated porous polymeric matrices.
Preparations in fluid form include solutions, suspensions and emulsions.
Exemplarily mentioned are water or water propylene glycol solutions for parenteral injections or the addition of sweeteners and opacifiers for oral solutions, suspensions, and emulsions.
Aerosol preparations suitable for inhalation may include solutions and solids in the form of powders which can be combined with a pharmaceutically acceptable carrier, such as a compressed inert gas, e.g. nitrogen.
For the preparation of suppositories a low melting wax, such as a mixture of fatty acid glycerides, e.g. cocoa butter, is melted firstly and the active component is homogenously dispersed therein by stirring or similar mixing operations. The melted homogenous mixture is then poured in fitting forms, cooled and thus hardened.
Further preparations in solid form which are to be converted into preparations in fluid form for either oral or parenteral administration shortly before use are included.
Such fluid forms include solutions, suspensions and emulsions.
Furthermore, the compounds of the present invention may be administered via transdermal application. The transdermal compositions can have the form of crèmes, lotions, aerosols and/or emulsions.
The term capsule refers to a special container or casing composed of methylcellulose, polyvinyl alcohols or denatured gelatins or starches, in which the active agents can be enclosed. Typically, hard shell capsules are prepared from mixtures of bones and porcine skin gelatins having comparatively high gel strength. The capsule itself can contain small amounts of colorants, opacifiers, softening agents and preservatives.
Tablet means a compressed or cast solid dosage form containing the active components with suitable extenders. The tablet can be produced by compressing mixtures or granulates obtained by wet granulation, dry granulation or compaction, which are known to the one skilled in the art.
Oral gels refer to the active components dispersed or solubilized in a hydrophilic semi-solid matrix.
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 Powders for compositions refer to powder mixtures containing the active components and suitable extenders which can be suspended in water or juices.
Suitable extenders are substances which usually form the largest part of the composition or dosage form. Suitable extenders include sugars such as lactose, sucrose, mannitol and sorbitol; starches derived from wheat, corn, rice and potatoes; and celluloses such as microcrystalline cellulose. The amount of extenders in the composition can range from about 5 to about 95% per weight of the total composition, preferably form about 25 to about 75% per weight and further preferred from about 30 to about 60% per weight.
The term disintegrants refers to materials added to the composition in order to support disintegration and release of the medicinal substance. Suitable disintegrants include starches, modified starches which are soluble in cold water, such as sodium carboxymethyl starch; natural and synthetic gums such as locust bean gum, caraya, guar gum, tragacanth and agar; cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose, microcrystalline celluloses and crosslinked microcrystalline celluloses such as croscarmellose sodium; alginates such as alginic acid and sodium alginate; clays such as bentonites and foaming mixtures. The amount of disintegrants used in the composition can range from about 2 to 20% per weight of the composition and further preferred from about 5 to about 10% per weight.
Binders characterize substances binding or "gluing" powders to each other and they consequently serve as "glue" in the formulation. Binders add a cohesion starch which is already available in the extenders or the disintegrant. Suitable binders include sugar, such as sucrose; starches derived from wheat, corn, rice and potatoes; natural gums such as acacia gum, gelatine and tragacanth; derivatives of sea weed such as alginic acid, sodium alginate and ammonium calcium alginate, cellulose materials such as methyl cellulose and sodium carboxymethylcellulose and hydroxypropyl methylcellulose, polyvinylpyrrolidone and inorganic compounds, such as magnesium aluminium silicate.
The amount of binders in the composition can range from about 2 to about 20%
per weight of the total composition, preferably form about 3 to about 10% per weight and further preferred from about 3 to about 6% per weight.
The term lubricant refers to a substance added to the dosage form in order to allow for the tablet, granulate, etc. to be released from the casting mold or pressing mold, after compression, by reducing the friction. Suitable lubricants include metallic stearates such as magnesium stearate, calcium stearate or potassium stearate; stearic acid;
waxes with high melting points and water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and D,L-leucine.
Due to the fact that lubricants have to be present on the surface of the granulates as well as 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 between the granulates and parts of the tablet press they are typically added during the last step prior to compression. The amount of lubricants in the composition can range from about 0.2 to about 5% per weight of the total composition, preferably form about 0.5 to about 2% per weight and further preferred from about 0.3 to about 1.5 % per weight.
Lubricants are materials preventing caking and improving the flow characteristics of granulates so that the flow is smooth and uniform. Suitable lubricants include silicon dioxide and talc. The amount of lubricants in the composition can range from about 0.1 to about 5 % per weight of the total composition, preferably form about 0.5 to about 2 %
per weight.
Colorants are adjuvants coloring the composition or dosage form. Such adjuvants can include colorants having food quality which are adsorbed on a suitable adsorption means, such as clay or aluminium oxide. The amount of the colorant used can vary from about 0.1 to about 5% per weight of the composition and preferably from about 0.1 to about 1%
per weight.
As used herein, a "pharmaceutically effective amount" of a transglutaminase inhibitor is the amount or activity effective for achieving the desired physiological result, either in cells treated in vitro or in a patient treated in vivo. Specifically, a pharmaceutical effective amount is such an amount which is sufficient for inhibiting, for a certain period of time, one or more of the clinically defined pathological processes associated with transglutaminase 2. The effective amount can vary according to the specific compound of the formula (I) and additionally depends on a plurality of factors and conditions related to the subject to be treated and the severity of the disease. If, for example, an inhibitor is to be administered in vivo, factors such as age, weight and health of the patients as well as dose reaction curves and data regarding toxicity obtained from preclinical animal studies are amongst the data to be considered. If the inhibitor in form of the compound of the formula (I) described herein is to be brought in contact with the cells in vivo, a plurality of preclinical in vitro studies would be designed in order to determine parameters such as absorption, half-life, dose, toxicity, etc. Determining a pharmaceutically effective amount fora given pharmaceutically active ingredient is part of the ordinary skills of the one skilled in the art.
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 Examples Following abbreviations used in the examples have the following meaning.
Boc (tert-butoxycarbonyl), Boc0Su (N-tert-butoxycarbonyloxy-succinim ide) DCM (dichloromethane), DMAP (4-(Dimethylamino)-pyridine), TEA (triethylamine), DMF (dimethylformamide), DMP (Dess-Martin periodiane), DIPEA
(N-Ethyldiisopropylamine), Glu (glutamic acid), EDC
(1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide), TFA (trifluoroacetic acid), THF
(tetrahydrofuran), Et0Ac (ethyl acetate), HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate), HOBt (hydroxybenzotriazole), MTBE
(methyl tert-butyl ether), tBu (tert-butyl), Chemical Examples The following examples are intended to illustrate the invention with selected compounds without limiting the protecting scope of the present intellectual property right on these concrete examples. It is clear for a person skilled in the art that analogous compounds and compounds produced according to analogous synthetic ways fall under the protecting scope of the present intellectual property right.
Example II. Synthetic method 11 Scheme 11-1 OH Chloroacetic acid 0 02N Na3PO4 (acl) ...õ..AN 02N N OH
I2-Adamantylamine EDC, DIPEA, DMF
10% Pd/C
H Me0H 0 H
H2NAN N -. ________ 02N ).L N
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 1 Preparation of compound ZED1657 02N)-L NThrOH
2-(3-nitro-2-oxopyridin-1(2H)-yl)acetic acid Chemical Formula: C7H6N205 Exact Mass: 198.03 Molecular Weight: 198.13 30.0 g (214 mmol) of 2-hydroxy-3-nitropyridine and 40.5 g (2 eq) of chloroacetic acid were suspended in 600 mL water. At 40 C, 245 g (3 eq) trisodium phosphate dodecahydrate were added, and the reaction was stirred at room temperature overnight. 250 mL
HCI
(32%) were added, and the suspension was stirred for another night at 4 C. The precipitate was filtered and dried. Yield: 41.2 g, 97% ESI-MS: 199.3 [M+H]
2 Preparation of compound ZED3905 Tof N-(2-adamantyI)-2-(3-nitro-2-oxopyridin-1(2H)-yl)acetamide Chemical Formula: 017H21N304 Exact Mass: 331.15 Molecular Weight: 331.37 17.0 g (85.8 mmol) of ZED1657, 16.1 g (1 eq) of 2-adamantanamine hydrochloride and 11.6 g (1 eq) of HOBt were dissolved in 200 mL DMF and 17.9 mL (1.2 eq) DIPEA.
18.1 g (1.1 eq) of 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride were added and the reaction was stirred at room temperature overnight. The solvent was evaporated, and the residue was dissolved in 500 mL DCM. The solution was washed with each mL citric acid solution (10%), NaHCO3 solution (10%) and brine. The organic phase was dried over Na2SO4, filtered and the solvent was evaporated.
Yield: 24.1 g, 85% ESI-MS: 332.4 [M+H]
3 Preparation of compound ZED3906 H2Nj-( N-IN
2-(3-amino-2-oxopyridin-1(2H)-y1)-N-(2-adamantyl)acetamide Chemical Formula: C17H23N302 Exact Mass: 301.18 Molecular Weight: 301.38 24.2 g (73.0 mmol) of ZED3905 were suspended in 600 mL Me0H before 2.42 g of palladium (10%) on activated carbon (unreduced) were added. The suspension was stirred overnight at room temperature under an atmosphere of hydrogen. The catalyst was filtered, and the solvent was evaporated. Yield: 15.7 g, 71% ESI-MS: 302.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 Scheme 11-2 OH 1. DMF, CH3I OH 1. Methyl AcOAN
Cs2003 isocyanide 2. DMAP, ACN AcOH, DCM
Boc20 2. TFA
Boc, Boc, Boc,N OH
N CO2tBu N CO2tBu 3. DIBAL-H Boc 3. Boc.20 0 Et20, -78 C DIPEA, DMF
N HATU, DMF
o DIPEA
Ac0j-N Ac0j-LN
H
1) TFA, DCM
__________________________________________________________ Boc,NcrN
1NrCr 0 0 2) 3-Methylbenzo[b]- 0 0 furan-2-carboxylic acid HATU, DIPEA, DMF
K2CO3, Me0H
OAN
0 0 Dess-Martin 0 0 0 IRLA periodinane H
N
1-1Cr U\Irr\I oI DMF 1NrCr U\IThrN
Preparation of compound ZED788 0 OMe Boc,NOtBu (S)-1-tert-butyl 5-methyl 2-(tert-butoxycarbonylamino)pentanedioate Chemical Formula: C15H27N06 Exact Mass: 317,18 Molecular Weight: 317,38 12.0 g of Boc-L-Glu-OtBu (39.6 mmol) and 7.09 g of cesium carbonate (21.8 mmol, 0.55 eq) were suspended in 100 ml of DMF and stirred for 1 h at room temperature.
2.47 ml iodomethane (39.6 mmol) we added, and the mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was dissolved in ethyl acetate and washed twice with each citric acid solution (10%), NaHCO3 solution (10%) and brine.
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 The organic phase was dried over Na2SO4, filtered and the solvent was evaporated. The raw product was used without further purification.
Yield: 13.4 g, >100%
ESI-MS: 318.3 [M+H]
Preparation of compound ZED720 00Me Boo, OtBu 60c 0 (S)-1-tert-butyl 5-methyl 2-(bis(tert-butoxycarbonyl)amino)pentanedioate Chemical Formula: C201-135N08 Exact Mass: 417,24 Molecular Weight: 417,49 13.4 g of ZED788 (-39,6 mmol) and 986 mg of N,N-dimethy1-4-aminopyridine (DMAP) were dissolved in 30 ml of acetonitrile. 17.6 g of di-tert-butyl bicarbonate (77.1 mmol) in 100 ml of acetonitrile was added and the solution was stirred at room temperature overnight. The solvent was evaporated, and the residue was dissolved in ethyl acetate and washed twice with each citric acid solution (10%), NaHCO3 solution (10%) and brine.
The organic phase was dried over Na2SO4, filtered and the solvent was evaporated. The raw product was used without further purification.
Yield: 13.7 g, 83%
ESI-MS: 418.3 [M+H]
Preparation of compound ZED721 Boc,NJC0tBu Boo 0 (S)-tert-butyl 2-(bis(tert-butoxycarbonyl)amino)-5-oxopentanoate Chemical Formula: C19H33N07 Exact Mass: 387,23 Molecular Weight: 387,47 13.7 g of ZED720 (32.8 mmol) were dissolved in 200 ml of dry diethyl ether and cooled to -78 C under argon atmosphere. 36.1 ml of diisobutylaluminum hydride (1M in hexane) were added dropwise and the solution was stirred for 30 min at -78 C before being quenched with potassium sodium tartrate (Rochelle salt) solution. The organic layer was separated, dried over Na2SO4, filtered, and concentrated to dryness. The raw product was used without further purification.
Yield: 13.3 g, >100%
ESI-MS: 388.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 4 Preparation of compound ZED3632 AcON
Boc ,N (rOH
(2S)-5-acetoxy-2-(tert-butoxycarbonylamino)-6-(methylamino)-6-oxohexanoic acid Chemical Formula: C14H24N207 Exact Mass: 332,16 Molecular Weight: 332,35 .. 15.0 g (38.7 mmol) of the aldehyde (S)-tert-butyl 2-(bis(tert-butoxycarbonyl)amino)-5-oxopentanoate (ZED721) were dissolved in 60 mL DCM. At 0 C 2.42 mL (1.05 eq) methyl isocyanide and 2.33 mL (1.05 eq) acetic acid were added, and the reaction was stirred at room temperature overnight. 75 mL TFA were added, and the reaction was stirred for another 3 h. The solvent was evaporated, and the residue was dissolved in 40 mL DMF.
13.2 mL (2 eq) DIPEA and 10.4 g (46.6 mmol) di-tert-butyl dicarbonate in 10 mL
DMF
were added and the reaction was stirred at room temperature overnight. The solvent was evaporated, and the residue was dissolved in DCM. After extraction with NaHCO3 solution (1.05 eq in water), 1.5 eq citric acid was added to the aqueous phase, followed by re-extraction with DCM. The organic phase was dried over Na2SO4, filtered and the solvent .. was evaporated. The residue was purified by flash chromatography.
Yield: 12.5 g, 95%
ESI-MS: 333.5 [M+H]
5 Preparation of compound ZED3907 Ac0j-BocNLN
_ JI N
(5S)-5-(tert-butoxycarbonylamino)-6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-1-(methylamino)-1,6-dioxohexan-2-ylacetate Chemical Formula: C31H45N508 Exact Mass: 615.33 Molecular Weight: 615.72 19.8 g (59.5 mmol) of ZED3632, 22.6 g (1 eq) HATU and 17.9 g (1 eq) ZED3906 were dissolved in 400 mL DMF and 20.8 mL DIPEA (2 eq) and stirred at 45 C
overnight. The solvent was evaporated; the residue was dissolved in 200 mL Et0Ac and washed twice with each 150 mL citric acid solution (10%), NaHCO3 solution (10%) and brine.
The organic phase was dried over Na2SO4, filtered and the solvent was evaporated.
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 Yield: 27.4 g, 75%
ESI-MS: 616.4 [M+H]
6 Preparation of compound ZED3264 Ac0j-N
I NThr NH
I H
(5S)-6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-1-(methylamino)-5-(3-methylbenzofuran-2-carboxamido)-1,6-dioxohexan-2-ylacetate Chemical Formula: C36F-143N508 Exact Mass: 673.31 Molecular Weight: 673.76 480 mg (0.78 mmol) of ZED3907 were dissolved in 4 ml DCM/TFA (1:1) and stirred at room temperature for 1 h. The solvent was evaporated, and the residue was dissolved in 4 ml DMF. 137 mg (1 eq) 3-methylbenzo[b]furan-2-carboxylic acid, 296 mg (1 eq) HATU
and 272 pl (2 eq) DIPEA were added, and the reaction was stirred at room temperature overnight. The solvent was evaporated; the residue was dissolved in 20 mL
Et0Ac and washed with each 10 mL citric acid solution (10%), NaHCO3 solution (10%) and brine.
The organic phase was dried over Na2SO4, filtered and the solvent was evaporated.
Yield: 409 mg, 78%
ESI-MS: 674.4 [M+H]
7 Preparation of compound ZED3266 H0)-LN
0 Njcr NH N
(2S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-hydroxy-A6-methyl-2-(3-methylbenzofuran-2-carboxamido)hexanediamide Chemical Formula: C34H41N507 Exact Mass: 631.30 Molecular Weight: 631.72 409 mg (0.61 mmol) of ZED3264 were dissolved in 5 ml Me0H. 126 mg (1.5 eq) potassium carbonate were added, and the reaction was stirred at room temperature for 1 h. The solution was diluted with DCM and washed with water. The organic phase was dried over Na2SO4, filtered and the solvent was evaporated.
Yield: 377 mg, 98%
ESI-MS: 632.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 8 Preparation of compound 11-3 0)-N
H
H II H
0 NJCNNThr N
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C34H39N507 Exact Mass: 629.28 Molecular Weight: 629.70 377 mg (0.60 mmol) of ZED3266 were dissolved in 2 ml DMF. 405 mg (1.6 eq) Dess-Martin periodinane (DMP) were added and the reaction was stirred at room temperature over 2 h. The precipitate was filtered off and the filtrate was evaporated.
The residue was purified by HPLC.
Yield: 314 mg, 67%
ESI-MS: 630.4 [M+H]
1H-NMR (DMSO-D6, 500 MHz, 8 [ppm]: 1.46 // 1.98 (d lid, 2H //2H, adamantyl-C4-H2), 1.68 // 1.78 (m, 4H, adamantyl-C4-H2), 1.71 (m, 2H, adamantyl-C1-H), 1.75 (m, 2H, adamantyl-C6-H2), 1.78 (m, 2H, adamantyl-05-H), 2.05 II 2.16 (m //m, 1H // 1H, 13-CH2), 2.53 (s, 3H, benzofuran-CH3), 2.64 (d, 3H, amide-N-CH3), 2.96 (t, 2H, y-CH2), 3.82 (m, 1H, adamantyl-C2-H), 4.64 (s, 2H, N-CH2), 4.70 (ddd, 1H, a-CH2), 6.25 (t, 1H, pyridinone-C5-H), 7.33 (d, 1H, pyridinone-C6-H), 7.36 (t, 1H, benzofuran-CH), 7.51 (t, 1H, benzofuran-CH), 7.63 (d, 1H, benzofuran-CH), 7.76 (d, 1H, benzofuran-CH), 8.06 (d, 1H, adamantyl-NH), 8.21 (d, 1H, pyridinone-C4-H), 8.54 (q, 1H, methylamide-NH), 8.87 (d, 1H, a-NH), 9.36 (s, 1H, pyridinone-NH).
13C-NMR (DMSO-D6, 500 MHz, 8 [ppm]: 8.62 (benzofuran-CH3), 24.50 (13-CH2), 25.37 (amide-N-CH3), 26.57 // 26.62 (adamantyl-05-H), 30.83 (adamantyl-C4-H2), 31.35 (adamantyl-C1-H), 33.61 (y-CH2), 36.66 (adamantyl-C4'-H2), 37.01 (adamantyl-C6-H2), 51.64 (N-CH2), 52.80 (a-CH2), 53.24 (adamantyl-C2-H), 104.51 (pyridinone-05-H), 111.55 (benzofuran-CH), 121.09 (benzofuran-CH), 121.72 (benzofuran-Cq), 122.53 (pyridinone-C4-H), 123.19 (benzofuran-CH), 127.28 (pyridinone-N-Cq), 127.89 (benzofuran-CH), 129.02 (benzofuran-Cq), 133.27 (pyridinone-C6-H), 142.31 (benzofuran-Cq), 152.68 (benzofuran-Cq), 156.55 (pyridinone-C=0), 159.59 (benzofuran-C=0), 161.32 (C=O-NH-CH3), 165.65 (C=0-adamantylamide), 170.42 (C=O-NH-pyridinone), 198.06 (C=0-methylamide).
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 9 Preparation of compound 11-2 N
H
0 1 õ,J(rNFIL
1 N-rN
il 0 0 (S)-2-( benzofu ran-2-carboxamido)-N 1-(1-(2-(2-adamantylamin o)-2-oxoethyl)-2-oxo-1,2-d i hyd ropyrid in-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: 033H37N507 Exact Mass: 615.27 Molecular Weight: 615.68 To the a-hydroxyester precursor of compound 11-2 (242 mg, 0.39 mmol, prepared by using benzofuran-2-carboxylic acid in step 6 according to compound ZED3264) in 8 mL
of .. acetonitrile, 1 mg of TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl, 1 mol%) were added.
56 mg of calcium hypochlorite (1 eq) were added at 0 C and the reaction mixture was stirred at 25 C for 2 h. The suspension was filtered, diluted with ethyl acetate and washed with NaHCO3 solution (10%) and brine. The organic phase was dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by HPLC.
Yield: 102 mg, 42%
ESI-MS: 616.3 [M+H]
10 Preparation of compound 11-4 0 N....,),. ..,--H
H
0 1 rrc NH )-L
1 N -rN
C
(S)-2-(3-chlorobenzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C33H36CIN507 Exact Mass: 649.23 Molecular Weight: 650.12 To the a-hydroxyester precursor of compound 11-4 (124 mg, 0.19 mmol, prepared by using 3-chlorobenzofuran-2-carboxylic acid in step 6 according to compound ZED3264) in 4 ml DMSO, 106 mg of 2-iodoxybenzoic acid (IBX, 2 eq) were added and the reaction mixture was stirred at room temperature for 3 h. NaHCO3 solution (10%) was added and the suspension was extracted with Et0Ac. The organic phase was dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by HPLC.
Yield: 37 mg, 30% (last step) ESI-MS: 650.3 / 652.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11 Preparation of compound 11-5 0)-LN
N
o hijCr Br (S)-2-(4-bromobenzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C33H36BrN507 Exact Mass: 693.18 Molecular Weight: 694.57 The synthesis of compound 11-5 was performed according to compound 11-3, using bromo-1-benzofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 69 mg, 72% (last step) ESI-MS: 694.3 / 696.3 [M+H]
12 Preparation of compound 11-6 N
N
I i'dr (S)-2-(benzo[b]thiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: 033H37N506S
Exact Mass: 631.25 Molecular Weight: 631.74 The synthesis of compound 11-6 was performed according to compound 11-3, using benzo[b]thiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 287 mg, 76% (last step) ESI-MS: 632.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 13 Preparation of compound 11-7 N
/SN
N
N
I H
Br (S)-2-(5-bromobenzo[b]thiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide Chemical Formula: C33H36BrN506S
Exact Mass: 709.16 Molecular Weight: 710.64 The synthesis of compound 11-7 was performed according to compound 11-3, using bromobenzo[b]thiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 145 mg, 59% (last step) ESI-MS: 710.2 / 712.2 [M+H]
14 Preparation of compound 11-8 OAN
N NH N N
(S)-2-(7-fluorobenzo[b]thiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide Chemical Formula: C33H36FN506S
Exact Mass: 649.24 Molecular Weight: 649.73 The synthesis of compound 11-8 was performed according to compound 11-3, using fluorobenzo[b]thiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 78 mg, 71% (last step) ESI-MS: 650.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 15 Preparation of compound 11-9 o o ).N
H
0 õ 0 H H
N kl1)-L
I H I I
(S)-2-(1H-indole-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C33H38N606 Exact Mass: 614.29 Molecular Weight: 614.69 The synthesis of compound 11-9 was performed according to compound 11-3, using indole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 57 mg, 69% (last step) ESI-MS: 615.4 [M+H]
Step 1A: providing a compound 4a AcON-R6 H
PGNJ((OH
H 0 4a;
Step 2A: performing coupling reaction of the compound 4a with a compound 5 H2N)-L _I__ , N R3 to obtain a compound 6a Ac0-LN-R6 H
, N R-6a;
Step 3A: deprotecting an amino protecting group PG3to obtain a compound 7a Ac0)-LN-R6 H
H
H2Nj(iNN-1¨R3 7a;
Step 4A: performing coupling reaction of the compound 7a with a carboxylic acid (R2-CO2H 8) to obtain a compound 9a AcO)-N-R6 H
0 iCH 0 R2N J-L 1\1 N ,L
, 'R3 9a;
Step 5A: performing oxidation reaction of the compound 9a to produce the 2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 compound of the formula (la) ON.R6 H
A N)-L ,L, , R2 N , N R-(1a), wherein L, R2, R3, and R6 have the same meanings as defined in claim 1, and PG3 is an amino protecting group.
2489-CIPO-DESCRIPTION-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Inhibitors of Transglutaminases Description The invention relates to novel inhibitors of transglutaminases, in particular transglutaminase 2, methods for their synthesis and to their use for the prophylaxis and treatment of diseases associated with transglutaminases, in particular transglutaminase 2.
Background of the invention Transglutaminases are part of the class of transferases and according to EC
nomenclature they are correctly designated as "protein-glutamine: amine y-glutamyl transferases" (EC 2.3.2.13). They link the E-amino group of the amino acid lysine and the y-glutamyl group of the amino acid glutamine forming an isopeptide bond while ammonia is released. In the absence of suitable amines and/or under certain conditions, deamidation of the glutamine may occur resulting in the corresponding glutamic acid.
Additionally, transglutaminases play an important role in many therapeutic areas such as the cardiovascular diseases (thrombosis and atherosclerosis), autoimmune diseases (celiac disease, Duhring-Brocq-disease, gluten ataxia), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease), dermatological diseases (ichthyosis, psoriasis, acne) as well as in wound healing and inflammatory diseases (e.g. tissue fibrosis) (J.M. Wodzinska, Mini-Reviews in medical chemistry, 2005, 5, 279 - 292).
Celiac disease, a gluten intolerance, however, is one of the most important indications.
Celiac disease is characterized by a chronic inflammation of the mucosa of the small intestine. In susceptible patients, the intestinal epithelium is successively destroyed after ingestion of gluten-containing food resulting in reduced absorption of nutrients which again has massive impact on the patients affected and is for example associated with symptoms such as loss of weight, anemia, diarrhea, nausea, vomiting, loss of appetite and fatigue. Due to these findings, there is a large demand for the development of a medicament for the treatment of celiac disease as well as of other diseases associated with tissue transglutaminase (transglutaminase 2, TG2, tTG).
The tissue transglutaminase is a central element during pathogenesis. The endogenous enzyme catalyses the deamidation of gluten/gliadin in the small intestinal mucosa and thus triggers the inflammatory response. Therefore inhibitors of tissue transglutaminase are suitable to be used as active agents for medication.
Another very important group of indications for tissue transglutaminase inhibitors are fibrotic disorders. Fibrotic disorders are characterized by the accumulation of cross-2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 linked extracellular matrix proteins. Diabetic nephropathy, cystic fibrosis, idiopathic pulmonary fibrosis, kidney fibrosis as well as liver fibrosis belong to the most important fibrotic disorders to be addressed with the compounds disclosed.
.. US 9,434,763 B2 discloses pyridinone derivatives having a warhead comprising at least one acceptor-substituted double bond, such as a Michael System, as irreversible transglutaminase inhibitors. Alkylacetamido and arylacetamido pyridinones showed inhibitory activity regarding tissue transglutaminase TG2 in nanomolar range (IC50).
Tse et al. (J. Med. Chem. 2020, 63, 11585-11601) report on replacement of phenyl residues by non-classical bioisosteres, such as cubane and bicyclo[1.1.1]pentane (BCP), in anti-malarial triazolopyrazine compounds in order to alter compound solubility and metabolic stability. The authors further evaluated in vitro antiplasmodial activity of bioisosteric modified triazolopyrazines against the 3D7 strain of P.
falciparum.
Replacement of phenyl by bioisosteric saturated heterocyclic residues resulted in complete loss of activity. Adamantyl residues as well as other hydrocarbon-caged derivatives led to potency up to 2-9 times lower than the corresponding phenyl triazolopyrazine compounds. In contrast, higher potencies were achieved by replacing phenyl with closo-1,2- and 1,7-carborane isomers. The authors concluded that the effect __ of non classical bioiostere replacement on biological properties cannot be predicted accurately and that a considerable range of possible bioisosteres has to be tested first in order to identify a suitable replacement leading to the desired properties of a given molecule.
Subbaiah et al. (J. Med. Chem. 2021, 64, 19, 14046-14128) report on bioisosteres of the phenyl ring in lead optimization and drug design. It is noted that bioisosteric phenyl ring replacement with heterocyclic and carbocyclic moieties can lead to enhanced potency, solubility, and metabolic stability while reducing lipophilicity, plasma protein binding, phospholipidosis potential, and inhibition of cytochrome P450 enzymes and the hERG
channel. However, this effect depends strongly on the properties of the compound itself and the addressed target.
US 11,072,634 B2 discloses reversible transglutaminase inhibitors comprising an aldehyde, a ketone, an a-ketoaldehyde, an a-ketoketone, an a-ketoacid, an a-ketoester, an a-ketoamide or a halogenmethylketone as warhead. The inhibitors showed inhibitory activity regarding tissue transglutaminase TG2 in nanomolar and micromolar range (IC50).
The objective of the present invention is to provide novel, most probably reversible inhibitors of transglutaminases, in particular transglutaminase 2 and methods for the synthesis of said inhibitors as well as several uses of these inhibitors.
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 Said objective is solved by the technical teachings of the independent claims.
Further advantageous embodiments, aspects and details of the invention are evident from the dependent claims, the description and the examples.
Surprisingly, it has been found that reversible inhibitors having a chemical warhead as disclosed herein inhibit effectively transglutaminases including tissue transglutaminase called transglutaminase 2 or TG2. Herein these terms are used synonymous.
Preferably, such chemical warhead moiety is particularly selected from reversible warheads such as a-ketoamides. The compounds of the present invention act as selective inhibitors of transglutaminase 2.
In order to prove inventiveness of the compounds of the present application, reference compounds were synthesized and tested in comparison to the most similar compounds of the present application. A skilled person might notice compound A8 from our patent US 9,434,763 B2 which we introduce as Ref. 3 to highlight the inventive and preferred features of the claimed compounds. From US 9,434,763 B2, it is clear, that aromatic moieties (C-terminal) restrict the efficacy of those compounds (compare to Al, A8, A37, A44, A47). In sharp contrast, branched alkyl moieties are highly preferred as indicated by more potent compounds (A28, A29, A59, A61, A63, A67, A68, A79).
To illustrate the advantage of branched alkyl moieties over aromatic moieties, we refer to reference compounds Ref. 2 (ZED1227, US 9,434,763 B2) and Ref. 3 (A8, ZED1047).
Inhibition data were determined using the classical fluorescent transamidation assay (dansylcadaverine incorporation into methylated casein, DCC-assay) as described [Bach Id, C.; HiIs, M.; Gerlach, U.; Weber, J.; Pelzer, C.; Heil, A.;
Aeschlimann, D.;
Pasternack, R. Features of ZED1227: The First-In-Class Tissue Transglutaminase Inhibitor Undergoing Clinical Evaluation for the Treatment of Celiac Disease. Cells 2022, //, 1667. https://doi.org/10.3390/cells11101667]. Casein is one of the best known high molecular weight (24 kDa) protein substrates for transglutaminases.
Please note, the ICso value of Ref. 3 (A8) published in US 9,434,763 B2 cannot be compared to the present data, relying on a fluorogenic isopeptidase assay.
Measured in the DCC-assay, Ref. 2 (ICso = 53 nM) is 80-fold more potent compared to Ref. 3 (ICso = 4,268 nM).
Accordingly, a person skilled in the art of medicinal chemistry would choose branched alkyl moieties as lead structures, such excluding aromatic moieties, e.g. the phenyl group.
It is of common knowledge, that bridged cycloalkyl groups are non-classical bioisosters of the phenyl group. By replacement of the phenyl group in A8 by e.g. an adamantane 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 group, a skilled person would expect similar physico-chemical or biochemical properties excluding to invest efforts. Since aromatic moieties are clearly not preferred, bridged cycloalkyl groups would not be considered improving the compounds.
This is further supported by additional reference compounds. ZED3641 (Ref. 1, as disclosed in US 11,072,634 B2; reversible acting a-ketomethylamide analogue to Ref. 2, ZED1227) is about 10-fold more potent compared to Ref. 6 (compare table 1).
Ref. 6 is analogous to compound A8 disclosed in US 9,434,763 B2 with respect to the backbone proving again superiority of branched alkyl moieties compared to aromatic derivatives in combination with reversible acting warheads.
However, surprisingly, replacement of the preferred branched alkyl moieties by bridged cycloalkyl groups further significantly improve the potency of the compounds as shown in table 1. Therefore, we credit bridged cycloalkyl groups as disclosed with an outstanding inventive manner.
In summary, the inventive compounds rated "A" show efficacies of about 100-fold higher compared to Ref. 3 (A8, compare to table1).
Further, compounds with activities rated "B" or "C" are still preferred (lower ICso values) to Ref. 3 (A8). These compounds can also be considered inventive, since peripheric ligands affect physico-chemical or biochemical properties. Therefore, also less potent compounds might be of high value, depending on the application.
Thus, the present invention relates to compounds of the general formula (I):
H J (I) CN L R3 Ho wherein L represents ¨L1¨ or _L1-L2¨; preferably ¨1_1-L2¨;;
L1 represents ¨CH2¨, ¨CH2CH2¨, ¨CH2CH2CH2¨, ¨CH2C0¨, or ¨CH2CH2C0¨;
L2 represents a bond, ¨NRN1¨, ¨NRN1CH2¨, ¨NRN1CH2CH2¨, or ¨NRN1CH(C1-13)¨, R1 represents , R2 represents 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 RN RN
___ 0 R8 R1.0 R8 _ _ S .-,8 R1S R8 - _ li Ra R1'11 Ra Irm , __________________________________________ r , __ ( Rlo R9 , R9 R10 R9 , R9 Rlo R9 , I-C,_,9 , RN RN RN RN RN
RN N, R N \ __ N, R11 il RN
_ _ 4 4 K il K---- R8 -----\_4N
R, 1 IN R8 N
N
N
Rlo s, , R9 R10 R9 Rlo , Rio ' , Rio , , R1 , Rtl,c(0õ, __ Rzc,0õ,_ R8 - - 15 r ¨ R8 0 ---- ' - _8 _A,..R1C) R1:J.,6_ _ _ \ /7--- o y N N N 1\A
R10 , ' R10 N - R8 ? N.¨ \ R8 n10 N
/
, I-µ , RN RN RN
Rii s R8 -_).,,SN Ra --,._1\i, RNN N, , ,N Rlo Ri o,N, N _RN
, ______ N N
, , , K
- _NI, DN ---------- /') ppl3 /`) R13 ------- iq R.- N/ 1, R.- 1,1 R .-- '' N''` ft j .- \) \N
, N=14 , ---- 1-µo14 , N R14 , 1\1-R14 , N Ria ' N Ria , RN
R12 R12 Riz RN
0----//, S-----, N-----' R2 ---U tR13 ii--.//µ .../-----.....
Rlo R14 R10 R14 Rlo ,--, - / R14 N-----\--N1A ,\-) , , RN
p RN
`s 14 Ni yR9 ,õ------..,---`
H 12 I 1 R13 n 71\1)7¨NsR
(ri R9 r N 1R9 \-' n14 , I-C n1,, N , IA - \___,--------mio, R10 , , R8 R8, 0Rlo ,S,, (--_ , , ' R9 ,S N I/
_R10 ,-- " _Rio N--/ N _., N \ 1 --N I S)'-- ---N
\
,-s( IN R8' \S-N N'N R8 , , õ,--,-- 0 R8----S il NhT IR----- Ru---- il ---N-N b-N , N- , 0-N N , , H
\ \ \ --N , , , , , , ' , _ ¨ -eNNH -- _ -(N _<N -- NH --eNS
N N __ \( S S z S S 7 N
----eNS ----eNS ---eNNH ---eNNH
N N __ ( Ni Nj , Nj , 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 /
-N ----(N3 N( 11 0 Nj \N , N , , 0 z N
, , H S
- --N& - ----N----$ -\ --1, N-H N -N
'S
---S H , S --____--N _ y/Th_-N S ___C-1-N
----:-\------N-,.. \S-I -- N -,õ(/N S-1\1-//
, N-,õ_-0 H
N
-- ------N---N&o NJ'N-0 H H
/
, -, I\1 ., N
N
-, N ., ., ' N
, N , , ., -.,1\1 -, ,N
N Th\r N /
. . N,N
I -I
NN , N
, -. N -.
' N 'N
N N
N
, ., -, ,1\1 I\1 - N, N
N
N
1\1 NN N le , N , N N N , , N -, N N , f -N , NN N N , N NNI IVN
"
2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 -õNN,N
-,! N N
I
1\1- N , , , -,,I\IN -,,I\IN -,,NN
1 1 f N--N NN N N , -,,1\1 -, N -, ,I\I
1\i-Ni-, NN N1,N
, , 1\1-N leN N"
' N -,,1\1 -,,1\1 N N
'N
N,N
N:N I
I I
NN, NN NN
, , 1 -r N,N NN-.N NN:1\1 ' , , - - , -1r N '-,-I --'1 'N
I
N,NN N,NN
1\IN
' H -, NH
HN KNH , , N NH, HN , NH, H' N=\ CR\ N=N N=\ N---N
\ N
N/ \ //N
__________________________________________________________ // , 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 N¨ N¨ N¨ ¨N ¨N
/N
¨ _______________________ ¨ ¨ N
N' N", /¨N ¨N ¨N ¨ \
¨ ¨ ¨ ¨\ // ¨ ¨ \
N / N
( /71 , -- \ /N
I\
N N , ____________________ ¨-N\ , , , I\1 , ¨ ¨
\ '/N ¨ ¨
\ N ¨ =
N N
N N N¨// // , , N=\ N=\
¨ ¨ /(1\1 ¨ ¨ ¨. /N
\ / N\/ N / N N N S
N N¨N sIV // N
N=N N=N N=N N=N N=N
\ /jv N /
N, N /
, , N=\ N=\ N=\ N=\ N-- ¨ /(N ¨ ¨ /N ¨ ¨ /N ¨ ¨ 5 N1 ¨ ¨ __ \//N , \ S \ _______ 1\1 / , N
N N
, , , N¨ N¨ N¨ N¨ N-- ¨ ________ ¨ ¨ _________ \ ¨ ¨ _____ ¨ ¨ __ \ N N N ¨ ¨ / N / N /
N¨// // N¨N N sIV __ , ' , , , ¨N ¨N ¨Ns ¨N ¨N
, ¨ ¨ --, /s(N ¨ ¨ ;IV ¨ ¨ /N ¨ ¨ i / N ¨ ¨
\//N , \ S \ _______ 1\1 , N
N N N
, , , ¨N ¨N /¨N ¨N ¨N
¨ ¨ /
\ N N
N N
// N¨N \\_N
, _______ ' , ' N ___ , ¨ \
/ ¨ ¨ N ¨7 / /
N ¨ ¨ i N ¨ ¨ / N -- i /N
( ( ( N N N \ S N S
N N // , N¨N N
__________ , , ¨ ¨ = ¨ ¨ * ¨ ¨
Ns, \ ,N N /N N N N /
N , / ss or 1V , N¨N N ¨N ;
, N , 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 - R14 and R" ; and preferably with 1 to 3 of the substituents R11 - R13;
R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl, diamantyl, hexamethylenetetraminyl and the afore-mentioned residues optionally contain one or more C=C double bond(s) and/or are optionally substituted by one or more of Ra, Rb, Rc, Rd, and Re;
Ra, Rb, Rc, Rd, and Re represents independently of each other -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C21-13, -CON H2, -CONHCH3, -CON(CH3)2, -CONHC2H3, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H3, -CH2CON H2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2H3, -NHCOCH3, -NHCOC21-13, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C21-13, -NHSO2CHF2, -NHSO2CF3, -NHSO2CH2CF3;
R4 represents -NR6R7;
R6 and R7 represent independently of each other -H, -CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3, -cyclo-C3H3, -cyclo-C4H7, -cyclo-C31-19, -cyclo-C6H11, -CH2-cyclo-C3H3, -CH2-cyclo-C4H7, -CH2-cyclo-C31-19, -CH2-cyclo-C6H11, -Ph, -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2, or -NR6R7 is -N(C2F13)2, - -N - -N - -NO
or N/ \
\ ___________________________________________________________________ / =
R6, R9, R10, R11, R12, R13, and R14 represent independently of each other -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2F13, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H3, -C(CH3)3, -cyclo-C3H3, -CH2-cyclo-C3H3, -CH2OH, -CH2F, -CHF2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CH F2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -OCH3, -0C21-13, -0C3H7, -OCH(CH3)2, -0C(CH3)3, -0C4H9, -OCHF2, -0CF3, -OCH2CF3, -0C2F3, -OCH2OCH3, -0-cyclo-C3H3, -OCH2-cyclo-C3H3, -0-C2H4-cyclo-C3H3, -CHO, -COC H3, -COCF3, -00C2H5, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -COOK -COOCH3, -COOC2H3, -CO0C3H7, 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 -COOCH (CH3)2, -COOC(CH3)3, -00C-CH3, -00C-CF3, -00C-C2H5, -00C-C3H7, -00C-CH(CH3)2, -00C-C(CH3)3, -N H2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5, -NHCOC3H7, -NHCOCH(CH3)2, -NHCOC(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONHCH(CH3)2, -CON H-cyclo-C3H5, -CONHC(CH3)3, -CON(CH3)2, -CON (C2H5)2, -CON (C3H7)2, -CON [CH(CH3)2]2, -CON[C(CH3)3]2, -SO2N H2; -SO2N H CH3; -SO2NH C2H5, -SO2NHC3H7, -SO2NHCH (CH3)2, -SO2NH-cyclo-C3H5, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H5)2, -SO2N(C3H7)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C2H5, -NHSO2C3H7, -NHSO2CH (CH3)2, -NHSO2C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -CECH, -CEC-CH3, -CH2-CECH, -Ph, -0-Ph, -0-CH2-Ph, = ----------------------------- -NO _1\1/N
1\1 1\1 r r r r 1\1 r r r --N NH --N N- --N N
KO- , or \ ____ ;
or R8 and R9 or R9 and R19 can form together one of the following five-membered or six-membered rings:
I
'N , or -'--1\1;
or R12 and R13 or R13 and R14 can form together one of the following five-membered or six-membered rings:
.0 o-0 .0 - -0 - -0 H or I
R" represents -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-05H9, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-05H9, -CH2F, -CHF2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CH F2; -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3, -00C2H5, -00C3H7, -COCH (CH3)2, -00C(CH3)3, -CO-cyclo-C3H5, 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 ¨CO¨cyclo-C4H7, ¨CO¨cyclo-CsHo, ¨COOCI-13, ¨CO0C2H5, ¨CO0C31-17, ¨COOCH(CH3)2, ¨COOC(C1-13)3, ¨COOCH2Ph, ¨SO2CH3, ¨SO2CF3, ¨S02C2H5, ¨S02C31-17, ¨S02CH(CH3)2, ¨S02¨cyclo¨C31-15, or ¨S02C(CH3)3;
RI" represent ¨H, ¨CF13, or ¨CH2CH3;
or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomers, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
The inventors have found that the reversible inhibitors of formula (1) disclosed herein having a bridged bicyclic residue R3 exhibit increased potency over the compounds of the prior art. Particularly, it is demonstrated herein, that the inventive compounds have an improved inhibitory activity compared to the known compounds bearing aromatic moieties R3 instead of bridged bicyclic residues.
In order to prove inventiveness of the compounds of the present application, known compounds from US 9,434,763 B2 and US 11,072,634 B2 (Reference 1 (E16 from US 11,072,634 B2), Reference 3 (A8 from US
9,434,763 B2), and Reference 6) were synthesized and tested as reference compounds in comparison to the most similar compounds of the present application. To this extent, inhibition data were determined using the classical fluorescent transamidation assay (dansylcadaverine incorporation into methylated casein, DCC-assay) as described in Buchold et al. [Buchold, C.; Nils, M.; Gerlach, U.; Weber, J.; Pelzer, C.;
Heil, A.;
Aeschlimann, D.; Pastemack, R. Features of ZED1227:
The First-In-Class Tissue Transglutaminase Inhibitor Undergoing Clinical Evaluation for the Treatment of Celiac Disease.
Cells 2022, 1/, 1667.
https://doi.org/10.3390/cells11101667]. Casein is one of the best known high molecular weight (24 kDa) protein substrates for transglutaminases. Inhibition data of the inventive compounds was compared with inhibition of compounds disclosed in US 9,434,763 B2, particularly, compound A8, which is denoted herein as Reference 3. It is noteworthy that the ICso values of compounds A8 published in US 9,434,763 B2 and E16 from US 11,072,634 B2 cannot be compared to the present data, relying on a fluorogenic isopeptidase assay.
Thus, the inventive compounds of formula (I) rated "A" showed efficacies of about 100-fold higher compared to Ref. 3 (A8). The same argumentation applies to Ref. 6 which is except of the phenylethyl group identical to compound 11-111. Ref. 6 is more than 25-times less potent in comparison to compound 11-111 as evident from Table 1.
This finding was particularly surprising as a skilled person would not have expected an improved inhibitory activity of the inventive compounds bearing a bridged bicyclic residue over the compounds of the prior art bearing aromatic residues since it is common knowledge that bridged bicyclic groups or bridged cycloalkyl groups are non-classical 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 bioisosters of the phenyl group, such that a skilled person would only expect to obtain a compound having similar physico-chemical and biological properties, including inhibitory activity, when replacing a phenyl group with a bridged bicyclic group. As aromatic moieties showed lower potency, bridged cycloalkyl groups would not be considered improving the physico-chemical and biological properties of the compounds.
The residues bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl, diamantyl, and hexamethylenetetraminyl used herein, have the following parent structures respectively:
bicyclo[1.1.1]pentyl bicyclo[2.1.1]hexyl bicyclo[2.2.1]heptyl -- -bicyclo[3.1.1]heptyl bicyclo[2.2.2]octyl bicyclo[3.2.1]octyl - -- -bicyclo[3.2.2]nonyl bicyclo[3.3.2]decyl bicyclo[3.3.3]undecyl 4-homoisotwistyl adamantyl diamantyl hexamethylenetetraminyl N ¨N
and the afore-mentioned residues optionally contain one or more C=C double bond(s) such as bicyclo[2.2.1]hept-5-enyl (s. 11-97) and/or are optionally substituted by one or more .. of Ra; Rb; ¨c, rc Rd, and R.
The unsubstituted bicyclic residues which can be substituted with 1 to 5 of the substituents R9 ¨ R14 and RN ; have the following structure and the substituents R9 ¨
and RN have the meanings as defined herein:
Ri Ri o Ri 0 \ N __ ( Ria ' Ria 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 _ -( _rN Rii ___ N R11 Z N-R - \N __ Z--- N -----NS
N R13.7S R12 N __ \( S-----Rii -R12 ; ; R12, ;
N N
----eS - - -eN-R -- --NN-R
----NS
N _________ \ R13 N R._ 12 N, N Ri2 RR1300 v z Ri2 ; R13 R12 ; R13 ; ;
R11 ___ _NI, R11 R11 -(N __ r N ---e0 Ri3-4kr,õo 6 7 R12 N __ \( N ______________________________________________ \
NNN \ Ri2 N Ri2 , ' R12 ; ' R13 ;
N
; ;
R4,.,. R10 R14 R10 RI , A
, R.12 RN\ R13 R11 R.1 N,S
-$ N N "---1.-S -,e R13 __ , , _<õ,-,--L-___Ri2 _ _ N,e __ R12 R13 R11 R12 ; N" NI-1'1-s Rii R12 R11 RN R13 ; RN
, , Rii S N
)11,e R13 -- -'/Ni , N
S-1\le S-1\1/ Rii R12 INI---</ I-C NI.) ' R13 ; R.. .-,IG R13 ;
;
RN\ R13 ,..--$ N -N,e R13 --__ / -- _________________________________________________________ N R11 R ; " 0 S-N-N
R11 , R11 , ;
ON
_ _(-----rO
-$
R12 __ R13 / \ --_N ,e R13 _ _<,------r-N
, __ R12 N-1\ie N-N-0 R11 R12 RN R13 ; RN ' ; R13 ; 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 ,N
- --$¨N ,e R13 _ _ _-----i___-__-N R 0 p12 ¨ /
0-"N
Rii R12 1--IN ¨ 0-1\1-N/ R13 ' R13 , R11 Rtet R10 R11 R9 R14 -, N R13 -, R12 -, R13 ----- N
-, IA N R9 R13 o10 N
--- --- N
Rio R10 , , , Fµ
os10 N R13 R12 -. - -, , N
R13 N R"n Rlo N R12 R11 ' NN
-. R' -, -_ N-R9 I
N,N ---- N
R12 .
' , , N N
N
N Rin '' N R10 R11 R11 IA n10 , R11 , , -, R9 --- ---N-,N R9 R12 I
----- .--' io R13 R10 R11 R9 R¨
R14 , R10 R11 I 1 ..õ._ I
R9-N Ro --y-----N!"---Rii Ro-----N--- R12 , , , ., N -,.., -,.., , I I
R9-----NR12 R9-1\1-N I
R13 R13 ' 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 TIL -, N R11 ,, ', -,..õ. -,..õ, NrAl N I Ri2 .9._ Rlo R13 Rlo R13 Rlo R13 , R2 -.Nr NY NY R12 -,f NY NY R12 .µ
1 N r-rN
N NRii N NRii Rlo Rlo R11 Rlo , , ' -------, NY Ny R12 -- -2, N---,-.-.-2N---,-.-.-2 R12 N I
II I ,¨õN-------.õ1.7.--N
N !Rii Rlo , Rlo , , - N NN R12 N N R12, -- - -,--- N--=:,.----Ny-R1 ,,, ---y--...T-- -,.- N .
-, R9 R9----y--- N-2.-- R11 , 1 'N
R10iNI R12 R12 Rii Rio Rii R9 1 --,.,r---, , R10 R11 , -,,NN N --, 1 'N -,,N
1 ' N
õ,...-- ....,-...I.õ,. R" ,,,, Rlo R¨ ..----. 2.---,y---1-,. 1, Rlo R ..----. 2.----y2..-1-,. 1, N N ¨
Rlo Rii Rii ' , , - N R11 -,,N R12 - N R11 --. --,.
II
N:N I 10 N N N
2,--------- N
R
Rio , Rio Rii -. NR12 -,NN R13 - N Ri2 , .....,. 11 1 NN, N N Rii RlorNNRii R12 , R10 R11 , , NN
N I
----. 2-----y--I-2 ,. R9 R12 Ri2 N Rm Ri 1 N
Rii Rlo Rii Rlo , , , 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 R12 Rm Rlo ., N. N R10 N R11 ' -, ------L-, -----:,..---I I
N
R9 N-,N
R9-NrN
' , ;
-. I\I Ru NR11 R11 -, , -.,N
I I
NN 1 N ---õri"---N%---R9 R12 ' R9 R10 R11 Rm R11 R10 -, NrNI R11 -.
N----,,--k-....,,--j-=-:
,N
N-N\IR12 Ri2 N- R12---N--------y-%N
R13 R13 R9 , , , Rm Ru Rm Ru Nr-rN
IR
, N N R
_----N-=R12 -1--'`
R9 R12, ; R9 , Rlo R11 R10 R11 -, Nr"1 -' R10 R11 N
- - R12 .
- --õ,,. --õ,,.
R13-NN NN-,N-"N
Rm ; R9 , , p12 ., --õ, --õ, ¨ p12 -.,N
- 1 1\1 N.INI-IN I I
N.
N N R1-,/ Rio N N R'`
Rm , I
R12 __ R14 R1 ., N NR
R9 .
.
R4IL,, R4I 4 I R12 R11 R9 R10 ; R10 R9 ;
R9 R11 R11 R9 N R9 Rm N. m R-RN R10 R10 'RN
, ;
2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 R9 o R9 R9 N¨( --10 N=N
N=( --) /(1\1 --N R14 -- \ / R9 _11=_Rio Rii Ri4 R11 \ N R11 R14 R11 N
N /( Rii R13 R12 R13 ; \ __ //
õ, \ õ., 012 R12 R12 R13 1R, R ¨
, ;
" ;
N N¨ N¨ N¨ _______________ ¨N
/ R1 1 _ _ \ / R10 _ _ _. / R10 _ _ __ / R10 - \
R13 \ / __ R1 R13 __ \ / Rh1 N \ / Rh1 _________ N\\ / Rh1 R11 \ /N
N N 2 ( R12 R12 R13 R12 R13 R12 R õ, ¨
R.,õ, , , , , --( --( /
--.__ ¨R9 ___ R10 _ - i R9 - - \
/ N - - \ N
Rii \ / _________ Ri3 R11 ______________ \ z R13 N / R13 R11 \
/(N R11 \ _R13 R12 R12 R11 R12 R12õ¨ D 1õ., .., R12 ; ; " ; ;
¨ ( ¨ ( - - ----_ / N --i /N
Rii \ / R13 N\ / _____ R13 R10 R13 R13 \ N R9 \ N N N
N ) N N( /( ; ; ; ;
N¨( N¨( R13 - - R13 -- -- / N --- .. /N
-- - -( N / R19 N \ / R19 N N __ N -S R11 \ /
N N /( Ro Rio N
N¨N
' R9 R9 R12 .-, I-C11 R12 ; , , ;
N=N N=N
___\ tRi 0 ___t / R10 N=N N=N N=N
-- \ ;NI ___ \_ /Rio Rio R11 11 R14 R13 n 1 \ //IN
1, \ 1 R13 \ / R11 __ R13 \ / R11 N /
Rii N N
R12 R13 ; IR¨ R.1 R12 ; R12 ; Ri3 R12 ; ;
_ :¨
N¨( N¨( N¨( N¨( N -- \ /N ) /N
\
\
// \ _Rii R13 \ / Rii -- --,-Rii R \ ,N
õ, /( , N N N
Ric ID 11 R12 R12 R13 R12 R11 'N
2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 N¨ N¨
_ _ _ . c ¨ z R9 R10 :9 R10 ,/, _R10 _ __. _R10 ¨
\ z Rio \ N N N N / ____ R11 N, / __ R11 N _______ /( /( R12 \ / R11 N N
R11 R12 R11 N¨N , R12 R12 , , , ¨N
-- \ /N
( ¨N
-- \ /N _iR
/
_N
--__.$1:(µN ¨N
--i ;1\1 ¨N
__ \ io \ Nz/
R13 _________ , /(N R13 \ 1\/1 R11 R13 \N z R11 1\1 / R11 R12 N
R,¨ 0,..ii . R12 R12 , R13 R12 R11 Fµ , , , , --1\1/ R10 --R9\--Nz ¨N ¨N
¨N Rio two tRio Rio --_ _________________________________ R124 4 /( R12 R11 N N N
N N / __ R11 N, / __ Rii \ /
N N
, R12 R11 N¨N , Riz R12 R12 ¨( R9 R10 \ /1\1 --_ N --i /(1\1 --( -- ( \ /( --_$ /N --,N R12 D
\ , _ \ N N N R12 11 \ R11 N \ -S IA
N N __ /( /( N¨N N
R11 R11 R12 0411 , R12 Fµ , , ¨( R11 R12 R11 R12 --i /N
N, / __________ R11 Rio \ N N N N N
N, / R10 N 14 sN __ /( N¨N,/ , R10 , R10 , or N¨N
R =
, One embodiment is directed to compounds of the general formula (I):
(NH yl-R3 (I) H
wherein L represents ¨L1¨ or ¨L1-L2¨; preferably ¨L1-L2¨;
L1 represents ¨CH2¨, ¨CH2CH2¨, ¨CH2CH2CH2¨, ¨CH2C0¨, or ¨CH2CH2C0¨;
R1 represents -'--H-R4 , 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 R2 represents RN RN
__ ,0 R8 Rii 0 R8 _____S ,R8 R11 s,R8 ___...,,,,,R8 R1,, ,,,R8 Ri0 R9 / R9 R10 R9 / R9 R10 R9 . N,-,9 , R11 11µ R11 II, R11 0 --1 /1\1 1 /N ---- Ri---1 C:1__- R8 - - -(:)---- R8 0?--Z
, K a, ) N N __ Y N N¨
cl\) Rio ____ ss / R. Rio Rio R8 N¨ ' , , , , RN RN RN
,, Rio Ri_i S, _ Rii S D8 -__S___R8 - -_N-I\I Rii N, ,N, _Rio ----",N N ir N¨
RIR - Rlo , Rlo Rio , ' , Rio_...N,N_RN
_ N. _ N, DN --- R13 R13 R1-3 ------------------------------------------------------------------------- ) -N''` LI xj = - N-N , N=N , -"---- R14 , N R14 , N
Ria , RN
R12 N R12 0-/,) 13 S----/Y,) 13 N----__A
I '1 D13 N/-) Ri3 -\-) -\-) \- \- R.,1, R1, ., N Ria N Ria R10 R10 R10 R14 , , RN
s)/ N___Rizt N R9 N-----\
¨R13 R14 L j 7R13 - iA x) ---& ____________________________________________________ S ( .2....i _ ni. - R14 \-R14 0 '._in N
----\ -7---- Ri 0 , , , , , m ,N, R9 ril /1R9 m 9 R9 ,s,,-r /1 _ R10 ¨R R10 \
"- ---/--= 10 "--/--= N \ N
N -\ I
R8 S'N
' , R8 ,S,-' R8 . N II - N6-S - .- . N -- . N,-- 0 - ---N R8--- 1 Ru--- Ru----- -S)-\N-=-"N R8 N-N b-N N-0 , H
\
, , N
, , , , , , N
NH NH - N
---eN ---eN - ---eNS
--_,N3 N N __ \( ---eNNH ---eNNH
N
, NNJ\ N __ ( 0 Nj 0 z , 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 /
-N ----(N3 N( 11 0 Nj \N , N , , 0 z N
, , H S
- --N& - ----N----$ -\ --1, N-H N -N
'S
-S H , S --___-- N _ y/Th_-N S ___C-1---N
----:-\------N-,.. \S-I -- N -,õ(/N S-1\1-//
, N-,õ_-0 H
N
-- ------N---N&o NJ'N-0 H H
0---r-N N
/
, -, I\1 ., N
N
-, N ., ., ' N
, N , , ., -.,1\1 -, ,N
N Th\r N /
. . N,N
I -I
NN , N
, -. N -.
' N 'N
N N
N
, ., -, ,1\1 I\1 - N, N
N
N
1\1 NN N le , N , N N N , , N -, N N , f -N , NN N N , N N le leN
"
2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 -õNN,N
-,! N N
I
1\1- N , , , -,,I\IN -,,I\IN -,,NN
1 1 f N--N NN N N , -,,1\1 -, N -, ,I\I
1\i-Ni-, NN N1,N
, , 1\1-N leN N"
' N -,,1\1 -,,1\1 N N
'N
N,N
N:N I
I I
NN, NN NN
, , 1 -r N,N NN-.N NN:1\1 ' , , - - , -1r N '-,-I --'1 'N
I
N,NN N,NN
1\IN
' H -, NH
HN KNH , , N NH, HN , NH, H' N=\ CR\ N=N N=\ N---N
\ N
N/ \ //N
__________________________________________________________ // , 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 N¨ N¨ N¨ ¨N ¨N
/N
¨ _______________________ ¨ ¨ N
N' N", /¨N ¨N ¨N ¨ \
¨ ¨ ¨ ¨\ // ¨ ¨ \
N / N
( /71 , -- \ /N
I\
N N , ____________________ ¨-N\ , , , I\1 , ¨ ¨
\ '/N ¨ ¨
\ N ¨ =
N N
N N N¨// // , , N=\ N=\
¨ ¨ /(1\1 ¨ ¨ ¨. /N
\ / N\/ N / N N N S
N N¨N sIV // N
N=N N=N N=N N=N N=N
\ /jv N /
N, N /
, , N=\ N=\ N=\ N=\ N-- ¨ /(N ¨ ¨ /N ¨ ¨ /N ¨ ¨ 5 N1 ¨ ¨ __ \//N , \ S \ _______ 1\1 / , N
N N
, , , N¨ N¨ N¨ N¨ N-- ¨ ________ ¨ ¨ _________ \ ¨ ¨ _____ ¨ ¨ __ \ N N N ¨ ¨ / N / N /
N¨// // N¨N N sIV __ , ' , , , ¨N ¨N ¨Ns ¨N ¨N
, ¨ ¨ --, /s(N ¨ ¨ ;IV ¨ ¨ /N ¨ ¨ i / N ¨ ¨
\//N , \ S \ _______ 1\1 , N
N N N
, , , ¨N ¨N /¨N ¨N ¨N
¨ ¨ /
\ N N
N N
// N¨N \\_N
, _______ ' , ' N ___ , ¨ \
/ ¨ ¨ N ¨7 / /
N ¨ ¨ i N ¨ ¨ / N -- i /N
( ( ( N N N \ S N S
N N // , N¨N N
__________ , , ¨ ¨ = ¨ ¨ * ¨ ¨
Ns, \ ,N N /N N N N /
N , / ss or 1V , N¨N N ¨N ;
, N , 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9- R14 and R" ; and preferably with 1 to 3 of the substituents R11- R13;
wherein i) L2 represents a bond, -NRN1CH2-, -NRN1CH2CH2-, or -NRN1CH(CH3)-; and R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, 1-bicyclo[3.1.1]heptyl, 3-bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, diamantyl, hexamethylenetetraminyl and the afore-mentioned residues optionally contain one or more C=C double bond(s) and/or are optionally substituted by one or more of Ra, Rb, Rc, Rd, and Re; or ii) L2 represents a bond, -NRI41-, -NRN1CH2CH2-, or -NRN1CH(CH3)-; and R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, 2-adamantyl, diamantyl, hexamethylenetetraminyl and the afore-mentioned residues optionally contain one or more C=C double bond(s) and/or are optionally substituted by one or more of Ra, Rb, Rc, Rd, and Re;
Ra, Rb, Rc, Rd, and Re represents independently of each other -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C21-15, -CON H2, -CONHCH3, -CON(CH3)2, -CONHC2H5, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H5, -CH2CON H2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2H5, -NHCOCH3, -NHCOC21-15, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C21-15, -NHSO2CHF2, -NHSO2CF3, -NHSO2CH2CF3;
R4 represents -NR6R7;
R6 and R7 represent independently of each other -H, -CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-051-19, -cyclo-C6H11, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-051-19, -CH2-cyclo-C6H11, -Ph, -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2, or -NR6R7 is -N(C2F15)2, - -N -10 - -NO or N/ \\ /
=
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 R8, R9, R10, R11, R12, R13, and R14 represent independently of each other -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2F15, -C3H7, -CH (CH3)2, -C4H9, -CH2-CH (CH3)2, -CH (CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2OH, -CH2F, -CHF2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CH F2; -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -OCH3, -0C21-15, -0C3H7, -OCH (CH 3)2, -0C(CH3)3, -0C4H9, -OCHF2, -0CF3, -OCH2CF3, -0C2F5, -OCH2OCH3, -0-cyclo-C3H5, -OCH2-cyclo-C3H5, -0-C2H4-cyclo-C3H5, -CHO, -COC H3; -COCF3, -00C2H5, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -COOK -COOCH3, -CO0C2H5, -CO0C3H7, -COOCH (CH 3)2, -COOC(CH3)3, -00C-CH3, -00C-CF3, -00C-C2H5, -00C-C3H7, -00C-CH(CH3)2, -00C-C(CH3)3, -N H2, -NHCH3, -NHC2F15, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2F15)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC21-15, -NHCOC3H7, -NHCOCH(CH3)2, -NHCOC(CH3)3, -CONH2, -CONHCH3, -CONHC2F15, -CONHC3H7, -CONHCH(CH3)2, -CONH-cyclo-C3F15, -CONHC(CH3)3, -CON(CH 3)2, -CON (C2F15)2, -CON (C3H7)2, -CON [CH(CH3)2]2, -CON[C(CH3)3]2, -SO2N H2; -SO2N H CH3; -SO2NH C2H5, -SO2NHC3H7, -SO2NHCH (CH3)2, -SO2NH-cyclo-C31-15, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H5)2, -SO2N(C3H7)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C21-15, -NHSO2C3H7, -NHSO2CH (CH3)2, -NHSO2C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -CECH, -CEC-CH3, -CH2-CECH, -Ph, -0-Ph, -0-CH2-Ph, = ----------------------- -NO
r rN r r N\ /NH N\ N\
or or R8 and R9 or R9 and R1 can form together one of the following five-membered or six-membered rings:
õ-0 ,-N
- -'I\1 or '-%1\I
' or R12 and R13 or R13 and R14 can form together one of the following five-membered or six-membered rings:
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 ,0 ,O\
_ --O --O -N
H or I
R" represents -H, -CH3, -C2F13, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H3, -C(CH3)3, -cyclo-C3H3, -cyclo-C4H7, -cyclo-C31-19, -CH2-cyclo-C3H3, -CH2-cyclo-C4H7, -CH2-cyclo-C31-19, -CH2F, -CHF2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CH F2; -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3, -00C21-13, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -CO-cyclo-C3H3, -CO-cyclo-C4H7, -CO-cyclo-C31-19, -COOCH3, -COOC2H3, -CO0C3H7, -COOCH (CH3)2, -COOC(CH3)3, -COOCH2Ph, -S02CH3, -S02CF3, -S02C21-13, -S02C3H7, -S02CH(CH3)2, -S02-cyclo-C3H3, or -S02C(CH3)3;
RNi represent -H, -CH3, or -CH2CH3;
or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomers, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
In one embodiment the herein disclosed inventive compounds, the moiety -L-R3 is not or In one embodiment of the herein disclosed inventive compounds, L represents -1_1-L2-;
L1 represents -CH2-, or -CH2C0-; and L2 represents a bond, -NH-, -NHCH2-, -NHCH2CH2-, or -NHCH(CH3)-.
In one embodiment of the herein disclosed inventive compounds, L represents -CH2-, -CH2CO-NH-, -CH2CO-NH-CH2-, or -CH2CO-NH-CH(CH3)-.
In preferred embodiments of the inventive compound of formula (I), R2 represents 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 0C-90-ZZOZ peAieoef alea/an5a aleCI
xoop-vzomeovvod-a3z-Noadiens3a-odo-satz r ' N
rp 0, ,N
N N ) __ N N
HNN-__ HN-__ , Ny s, , , s, )\ NI N N N ) __ N
r 1-11\1-_,..
N -- N --, , , , , ' N , , \ \ \
H
, , , 4 /2- gei =L -9'el --NQ N-N 81 N---:-N\ N-S\ 0 N ---\ -' :V---N
-Q-9e1 N --i , , -L,- t S -1/-,e N \ \
- ---( -' ..., Ii N
- ' S 6'u , 0:1 -' S' oH 0:1 , H o [H ---C-\ õ N 0 OiT .:1 I----N ,.., r 0,7/ ) 0, ,, -)--H,,,-) 6 IN s __ /
' _______________________________________________________________ NH NH NH
, C[H
171.H 171.H VI.H OM
1-\
E N
[H¨ 1 C[el, 1 _ _ H Z
/----- cM,,, 1 >-z[U z0:1 Z[H
N [ - - -NH
v[eir___0_1 KH 0[H .fr[:I.N t[H .N t[H .N
N\ ---------------------------------------------------------------------/:/"--S /-----0 zM N zM zM
zM z[el N M , , Kel 17 N,N N-N ,' ,i_ni Ni' NI_ ,_,,N-\
---------------------- N- 'N --- 'N --zM Z[H NH NU-N'Ny oM 00:I N'N
NH
' ' , ' 9H
/ /
OM ' ____ N-(-()M N50M N __ (/ N ( NIIN\ _--( el-- --N z;_____N N
o k,__?
sH
0:1 N.N -_ 0:1 s-- 9 S [[el - - s õ?:1 NH
NH OM
, , , , , sH o[H ' 0[H 6H 0H 6H\ / µs OM
N N N __ (/
N ____________________________________ ( 0 9ei-- _ 771 "µ, u - - 0 [[el N 'N -- N N
'N [___M N [0=1 oH
NH NH NH
, , , , 6H / 6H 0H 6H = 6H OM 6H / 6H OM
) / \
2e1)N [[H 9e1 N ' --S [[H 9H 5 - - 8H)0 H 9H 0 - -NH NH
Z I=Z
/
-N - - --(N3 N( 11 Nj \N , Ni , , 0 0 z N
, , H S
- --N& - ----N----$ -\ --1, 1\r"
H N -N
'S
-S H , S --____--N _ y/Th_-N S __ _C-1----N
----:-\--- ---N,..._ \S-I - - N -...(/N S-1\1-//
, N-,..._-0 H
N
- - ------N1-"N&o NI'N-0 H H
0---r-N N
/
, -, I\1 ., i -N
/ N
-, N ., ., 'N
, ., -.,1\1 - , ,N
N Th\r N /
. . N,N
I -I
NN
, -. N -. -, 'N 'N
N N
N
, ., -,,1\1 I\1 - N, N
N
N '---, 1\1 NN Nle , N , N N N , , N -, N N , f -NNi , NN N N , N NNI leN
"
2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 -õNN,N
-,! N N
I
1\1- N , , , -,,I\IN -,,I\IN -,,NN
1 1 f N--N NN N N , -,,1\1 -, N -, ,I\I
1\i-Ni-, NN N1,N
, , 1\1-N leN N"
' N -,,1\1 -,,1\1 N N
'N
N,N
N:N I
I I
NN, NN NN
, , 1 -r N,N NN-.N NN:1\1 ' , , - - , -1r N '-,-I --'1 'N
I
N,NN N,NN
1\IN
' H -, NH
HN KNH , , N NH, HN , NH, H' N=\ CR\ N=N N=\ N---N
\ N
N/ \ //N
__________________________________________________________ // , 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 N¨ N¨ N¨ ¨N ¨N
/N
¨ _______________________ ¨ ¨ N
N' N", /¨N ¨N ¨N ¨ \
¨ ¨ ¨ ¨\ // ¨ ¨ \
N / N
( /71 , -- \ /N
I\
N N , ____________________ ¨-N\ , , , I\1 , ¨ ¨
\ '/N ¨ ¨
\ N ¨ =
N N
N N N¨// // , , N=\ N=\
¨ ¨ /(1\1 ¨ ¨ ¨. /N
\ / N\/ N / N N N S
N N¨N sIV // N
N=N N=N N=N N=N N=N
\ /jv N /
N, N /
, , N=\ N=\ N=\ N=\ N-- ¨ /(N ¨ ¨ /N ¨ ¨ /N ¨ ¨ 5 N1 ¨ ¨ __ \//N , \ S \ _______ 1\1 / , N
N N
, , , N¨ N¨ N¨ N¨ N-- ¨ ________ ¨ ¨ _________ \ ¨ ¨ _____ ¨ ¨ __ \ N N N ¨ ¨ / N / N /
N¨// // N¨N N sIV __ , ' , , , ¨N ¨N ¨Ns ¨N ¨N
, ¨ ¨ --, /s(N ¨ ¨ ;IV ¨ ¨ /N ¨ ¨ i / N ¨ ¨
\//N , \ S \ _______ 1\1 , N
N N N
, , , ¨N ¨N /¨N ¨N ¨N
¨ ¨ /
\ N N
N N
// N¨N \\_N
, _______ ' , ' N ___ , ¨ \
/ ¨ ¨ N ¨7 / /
N ¨ ¨ i N ¨ ¨ / N -- i /N
( ( ( N N N \ S N S
N N // , N¨N N
__________ , , ¨ ¨ = ¨ ¨ * ¨ ¨
Ns, \ ,N N /N N N N /
N , / ss or 1V , N¨N N ¨N ;
, N , 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 ¨ R14 and R" ; and preferably with 1 to 3 of the substituents R11 ¨ R13 and the substituents R9 ¨ R14 and RN3 have the meanings as defined herein.
In even more preferred embodiments, R2 represents:
RN RN
__ 0 R8 R11 0 R8 ___ S R8 R1SN _R8 __, N
1 , __ (-- \ , \ , . .
Rlo _____ R9 , R9 R10 R9 , R9 R10 R9 / R9 , RN RN RN RN RN
Ri 1 ri, RN __ N,N R11 ii _ R
_ RN
N R8 - - il I /i\i ---tii(\i 1 /
( 1 N N
-\\ _____________________________________________________ I--R10 ss , R9 R1- R9 R10 R10 ; ' R10 , , ;
R10 , , R1_R10 R11 SN _ 0,/,/._ R0õ. _R8 --<0R8 0 ----... --R8 ,c,µ ir-\ /7--- o?' N N )\ N N-2-r-R8 Rlo , Ri 0 __ N R8 N¨ R = lo N
, , ' RN
RN R
. N RN
R1- S R8 - - _S R8 - - _\I , N RiNN , N,I\rL _Rio RioN_RN
, \ i N N N N N
Rlo Rlo , N-N
, , , , /') ) 13 ------------------------------------- 3 --- N/ 11 r 3 - ,N, DoN ------------ pp13 - -c N-F\
U,,,,.,,,;::\,, J . s \_) R - \IIR1 \_) R.- R1 , N=N , mr-,14 N Rizt N R1,4 N Ria N Ria , , R-' R12 R12 Riz RN
s---/Y j\i-/
, R12 i\L..._õ, 12 R R-----%\- x) Rlo 14 Rlo 14 ol, ¨ Rlo 14 N
R1."A
, ' RN
s \ ,õ---------../,',` 014 , N, R9 r /I
-1 j R13 il Nv--F\ 9 r /1 -- Rio R1 S r_.IIR
_Rlo ) \i-R14 .--,._ _________ N - \ ----7--- Rio R4' , N,S 1 -- ' 1-( R9 ,S -- , ,--- . , _R , u N\\ 1 N
N I - - ---N
,-s(N R8 \S-N s\N'N R8 -' ' , N,- - N --R---õ \ n N- R---- I R8--- 1 N-N b-N N-0 0-N
' , ' H
\ \ \ N __ \( , N
, , 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 S N,--S
-¨N
ONj N , , , I I I
N
N
., ., -_,1\1 N
I
N,N I N N , H - -NH ., N NH , , H
' ' N_ or N, wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 - R14 and RN ; and preferably with 1 to 3 of the substituents R11 - R13 and the substituents R9 - R14 and RN have the meanings as defined herein.
Thus, the present invention relates to compounds of the general formula (I):
H (I) N ,LR3 Ho wherein L represents -L1- or -L1-L2-; preferably -L1-L2-;
L1 represents -CH2-, or -CH2C0-;
L2 represents a bond, -NH-, -NHCH2-, -NHCH2CH2-, or -NHCH(CH3)-, R1 represents -'--H-R4 ' R2 represents RN RN
_ 0 R rx 8 mil o -<8 ______srR8 Rsr,õ __ R8 Rii\i, R8 r I r /
R10 R9 / R9 R10 1,9 / R9 R10 1-,9 ' R9 RN RN RN RN
Rii , 1\1 R -R111 N R8 - -),,,IIN Rs Rtt\sõON __ Rii ON _R8 / \ /7---1 __________________________________________________________________ r N N N , N N
R10 ss Rto R10 R10 /
' 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 Ri (1 ni 0 R8 R8 \ R8 , R10 RS. _ _ RSN _ R8 - - IS R8 - - _._-- 0, --),----,-- 02 Cl ZT \ ir Y ______ N N \ N p= t N N N
Ri 0 RN RN
RN Ri2 Ri Rii lj N 1\1=--Rio Rio(rN , N _ RN
õ ,N, /') pp 13 --------------------------------------------------- /') LI \_) R13 ,) ________ N N-N ------ R14 N R
i 4 ;
N R12 0 ---__/y S---../y N /-) Ri 3 -\ -$____, 1 A
R 1-r R14 RN
Ri2 RN
N--__//,) Ri2 - - -R 13 _ _ 4i \ I ----r/õ Ri3 ' - < - - - - - - --/') 13 R10 ; ni. -R14 N ----%\IA 1 A ; R
\/\\-; R14 R14 ' ' RN RN
N R9 ri , R9 0) _ N II
R8 R.a i u n \ N \ I R8 N-. s( :
N
, S --N,., R8---- 1 N II R8----- --/ R''p, N-N , b---N , N-C) , O'N N , Or N
, R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, 10 bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl, diamantyl, hexamethylenetetraminyl and the afore-mentioned residues optionally contain one or more C=C double bond(s) and/or are optionally substituted by one or more of Ra, Rb, Rc, Rd, and Re;
Ra, Rb, Rc, Rd, and Re represents independently of each other -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C21-15, -CON H2, -CONHCH3, -CON(CH3)2, -CONHC2H5, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H5, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2F15, -NHCOCH3, -NHCOC21-15, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C21-15, -NHSO2CHF2, -NHSO2CF3, -NHSO2CH2CF3;
R4 represents -NR6R7;
R6 and R7 represent independently of each other -H, -CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)2, 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 -CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-05H9, -cyclo-C6H11, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-05H9, -CH2-cyclo-C6H1 1, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2, or -NR8R7 is -N(C2F15)2, --I\1 --I0 --NO
or N/ \
\ __ / =
R8, R9, R10, R11, R12, R13, and R14 represent independently of each other -H, -F, -CI, -Br, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH (CH3)2, -C4H9, -CH2-CH (CH3)2, -CH
(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2OH, -CH2F, -CHF2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CH F2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -OCH3, -0C2H5, -0C3H7, -OCH (CH3)2, -0C(CH3)3, -0C4H9, -OCHF2, -0CF3, -OCH2CF3, -0C2F5, -OCH2OCH3, -0-cyclo-C3H5, -OCH2-cyclo-C3H5, -0-C2H4-cyclo-C3H5, -CHO, -COC H3, -COCF3, -00C2H5, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -COOK -COOCH3, -CO0C2H5, -CO0C3H7, -COOCH (CH3)2, -COOC(CH3)3, -00C-CH3, -00C-CF3, -00C-C2H5, -00C-C3H7, -00C-CH(CH3)2, -00C-C(CH3)3, -N H2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5, -NHCOC3H7, -NHCOCH(CH3)2, -NHCOC(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONHCH(CH3)2, -CON H-cyclo-C3H5, -CONHC(CH3)3, -CON(CH3)2, -CON (C2H5)2, -CON (C3H7)2, -CON [CH(CH3)2]2, -CON[C(CH3)3]2, -SO2N H2, -SO2N H CH3; -SO2NH C2H5, -SO2NHC3H7, -SO2NHCH (CH3)2, -SO2NH-cyclo-C3H5, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H5)2, -SO2N(C3H7)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C2H5, -NHSO2C3H7, -NHSO2CH (CH3)2, -NHSO2C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -CECH, -CEC-CH3, -CH2-CECH, -Ph, -0-Ph, -0-CH2-Ph, H I H H
=--. -NO ------------- t-N/
Li N____ r , , I H I
N N N
r r r / __ \ / __ \ / __ \
0 (:) (:) --N \ / / NH --N\ /N- --N\ /N \ .
, or \
or R8 and R9 or R9 and R1 can form together one of the following five-membered or six-membered rings:
2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 H _,ID ,N
_ - ) --- --- - ---N - -- -1 -- -1 '-,/ ''0 '-,% '-.% '- --,N
---N ,N
or ----%N . , or R12 and R13 or R13 and R14 can form together one of the following five-membered or six-membered rings:
,0 ,o ,,0 ,-C) ,-() --- _.13 - ) - -0 --0 , C) 0 '-,/ '', -' H or I -R" represents -H, -CH3, -C2F13, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H3, -C(CH3)3, -cyclo-C3H3, -cyclo-C4H7, -cyclo-C31-19, -CH2-cyclo-C3H3, -CH2-cyclo-C4H7, -CH2-cyclo-C31-19, -CH2F, -CHF2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CH F2; -CF12-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3, -00C21-13, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -CO-cyclo-C3H3, -CO-cyclo-C4H7, -CO-cyclo-C31-19, -COOCH3, -COOC2H3, -CO0C3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -S02CH3, -S02CF3, -S02C21-13, -S02C3H7, -S02CH(CH3)2, -S02-cyclo-C3H3, or -S02C(CH3)3;
or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomers, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
Preferred are the compounds of the formula (lb):
0,,, ii A N , L , H
0 (Ib);
and L, R2, R3, R6, R7 have the same meanings as defined in the formula (I) Preferred are the compounds of the formula (lb):
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 ON,R6 H L
R2AN ')-NIõR3 H
(lb) wherein L represents ¨L1¨ or ¨L1-L2¨; preferably ¨L1-L2¨;;
L1 represents ¨CH2¨, ¨CH2CH2¨, ¨CH2CH2CH2¨, ¨CH2C0¨, or ¨CH2CH2C0¨;
L2 represents a bond, ¨NRI41¨, ¨NRN1CH2¨, ¨NRN1CH2CH2¨, or ¨NRN1CH(CH3)¨;
R2 represents RN RN
0 R8 R11 0 R8 -__ S Rs R11 S Rs -_ N Rs R11N Rs Rlo R9 / R9 Rlo R9 / R9 Rio R9 , mg R , RN RN RN wo R11 rj, R11 rj, /NI
r.,,i), ( n R1:JON __ RON _R8 - - __õ-ON____.R8 \ ir , __ N \
N N¨
Ri 0 `s / R9 i-K - R. R10 , , , , , ' )1 ,, 1 R8 2xRio Rzc.,\õ_ RSRs ---1SR8 --<1\1:N Rttc., N ,N
N N )\ N
, __ N
N¨ ', R8 Rio , /' N Rio , Rio , , , Rio.,..N ,N_RN N .,,Nr, _Rio \¨N
N - N, ,-,N R13 NI'm -- LI, \') = N-N , N IA=N , ------ n, 14 N et , , ---/Y,) 13 R13 r -\' \N
N Rizt N Rizt N Rizt Rio R14 Rio R14 , RN
N---__A RN
Ny, ---TR13 9 __ - - -(\ 1 tR13 \7R
R14 r_.IR
N
Rio - \ -7---Rio R.,iA
N R14, , , , _r_ /R910' r\zi:
N
Ri - H
7R13 , NI.-S
S
.A Ri_- n _______________________ N _ R
c-N----) , , RN
H
ii R9 N , , , , D____R:k, R9 r -/i i n _ R10 \ / /TiiiiIJi el---/_-= R1 :, k , _R . u 0) , II , 0 , S , ' , ,µ.11 , 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 N_ '===õ,, ,S -' -_,N, \N
I - N\ \ I
R8 R8 ' R8 S
) N6-- -- ---N R8---- ii NhT- Ru---- -1 \S-N N R8 or , R`-'a -- ii 0-N ;
R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl, diamantyl, hexamethylenetetraminyl, and the afore-mentioned residues optionally contain one or more C=C double bond(s) and/or are optionally substituted with one or more of Ra, Rb, Rc, Rd, and Re;
Ra, Rb, Rc, Rd, and Re represents independently of each other -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C2H3, -CON H2, -CONHCH3, -CON(CH3)2, -CONHC2F13, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H3, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CON HC2F13, -NHCOCH3, -NH COC21-13, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C21-13, -NHSO2CHF2, -NHSO2CF3, -NHSO2CH2CF3;
R4 represents -NR6R7;
R6 and R7 represent independently of each other -H, -CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3, -cyclo-C3H3, -cyclo-C4H7, -cyclo-C31-19, -cyclo-C6H11, -CH2-cyclo-C3H3, -CH2-cyclo-C4H7, -CH2-cyclo-C31-19, -CH2-cyclo-C6H11, -Ph, -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2, or -NR6R7 is -N(C2F13)2, - -N N/-- --NO or __ N/ \\
/ =
RN represents -H, -CH3, -C2E-13, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H3, -C(CH3)3, -cyclo-C3H3, -cyclo-C4H7, 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 -cyclo-05H9, -CH2-cyclo-C3H5, -CH2F, -CH F2; -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3, -00C21-15, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -COOCH3, -CO0C2H5, -CO0C3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -S02CH3, -S02CF3, -S02C21-15, -S02C3H7, -S02CH(CH3)2, or -S02C(CH3)3;
RNi represent -H, -CH3, or -CH2CH3;
and R8- R14 have the meanings as defined above for formula (I);
or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomers, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
Preferably, R2 represents RN RN
__ _ 0 8 R11 0 R8 - _ R8 R1,srR8 ___,,c,,, R8 R1,_,,,,,,,,, R
Rlo _____ R9 / R9 Rlo R9 , R9 Rlo R9 /
,,,,,9 '`
, RN RN RN Rio Rii N, R11 N, -_)(11.N R1:1),,,O.N __ Ro, _R8 - _ )õ-O.N___ Rs I /1\1 1 N
/ l( /K \ ir N \ Ir-N \ // 0, N N- NR:
Rlo ss / Ro R10 Ro Rio , Rlo N.
Rii RN ;
, , , Rio ', R8 ______ R10 Rti,Sr _ R1_1SR8 - -IS \r-R8 - - 1 : --_c m (:)?zy N N N N \ ..
N
R8 , Rio , / Rio Rio /, N
RN ;
, N N Rio Rio N_RN
" ,N, DN R - R=-----V LI -- _\õ.) \-) , N-N ; N=N ; -------R14 N
, R12 R12 N R12 0---./Y,) s N'/,) r ---__)R13 ---$____) R13 R13 R13 Ri3 - \ 44 \ N \' \' , N Ri4 ; N Ri4 , Rlo RI4 , Rlo R14 , RN
Dp. 12 RN
i\l-/y4' R12 R12 p12 N---__/Y, -- -\TR13 \,tR13 ''l /') 13 ,õ------`
R14 N----%\ 1 A __\7 R
Rio R., Rizt Rizt , 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 ss R
RN
17\)1R9R9 R N o 0) Di 0 N\\ S\)- N R8 ¨R N R8 \s-N R8 ' Nhi R8I 8 b¨N N¨C) , or O¨N
Preferably, -NR6R7 of the formula (lb) represents -NH2, -NHCH3, -N(CH3)2, -NHCH(CH3)2, -NHCH2CH2CH3, -NH-CH2CH=CH2, -NHCH2CH2CH2CH3, -NHCH2CH(CH3)2, -NHC(CH3)3, -NHCH2CH2CH2CH2CH3, -NH-cyclo-C3F15, -NH-cyclo-C4H7, -NH-cyclo-051-19, -NH-cyclo-C6Hii, -NHCH2-cyclo-C3F15, -NHCH2-cyclo-C4H7, -NHCH2-cyclo-051-19, -NHCH2-cyclo-C6H11, -NHCH2-Ph, -NHCH2OCH3, -NHCH2OCH2CH3, -NHCH2CH2OCH3, -NHCH2CH2NHCH3, -NHCH2CH2N(CH3)2, - ¨N ¨10 --NO
--N
or In some embodiments, the present invention relates to the compound of the formula (I), IRI
JC
R2 N N R3 (I) wherein L represents -L1- or -L1-L2-; preferably -L1-L2-;;
L1 represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2C0-, or -CH2CH2C0-;
L2 represents a bond, -NRNI-, -NRNICH2-, -NRN1CH2CH2-, or -NRN1CH(CH3)-;
R1 represents ''N-R6 R2 represents 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 RN RN
0 Rs R10 Ra -_ S Rs R1: .!õsR8 ___,,R8 i__rR8 \ , r 1 __ r ,\ , ,\ , ,\ , R10 R9 / __ , R10 R9 , R9 R10 R9 R1, /
,Ii N , RN RN RN Rlo R11 ii, Rii N N;, N __ , Ril 0 R( ii 0 R 8 - - 0 R8 R10 sµ R K = - Rn R10 I\1 R
, ---\_4 I /N
/ ( ---, ----/ I
1---- \)-------R8 / :, P.
, / , , , RN
ii \
R8 /_______. R10 Rtl.õ.(\õSNit _ _ R1_SR8 - -1S)r-R8 - R8 , Rio R10 R10 __ N
N N N -' /
RN RN RN
N. RN R12 -- õK.- N Rij1i ,N,\1 _ R1o.N,N_RN .. N,N, _Rio _ ,N, ,N, DN
R -\ " .1 N N =r\i \ r )=N --\\ ,N ---- N''`
------------------------------------------------------------------------LI,.,.,.,,,:\,,,j Rio , , N-N N=N
, R12 R12 R12 0 , r N 1 ,1211 N/-) R13 R1 -3 R1'-', R- -\-iA
\-) , N Ria , N Ria , N Ria , N Ria ' R10 R."
, RN
R12 p12 RN
S--/y,) 13 i\i--/' s RN N2 RN
S
) - - R - - - ¨R13 r_.R ¨4 1 R13 N
R14 R14 _ N'%\-iA
R10 R10 \____ -R10 ni..-, , , , I-µ , H
R13 N .
L j ¨A - ii __ N77----R14 NSõ-S
- c S
R14 R14 Do._ in N -N--.,_?
Fµ
RN RN H ,, ,N, R9 r 1 i m 9 r /1 _ Rio \ / / ' N- --/--\
¨R 1 o _ 1::1) , , -, 0 s , , , i i õ.
_Rto N
,;(IN N N N N) , , R8 R8 ,S - - R8 =, N,S NI' II
\\ I
ff St\ 7 N ,--N R . S,------ il N-.-NN N Ra \s-N NN Ra N-N b-N
, , R8 N,--IR'--- -/ R8--- 1 N-0 or 0-N -R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl, diamantyl, hexamethylenetetraminyl, and the afore-mentioned residues optionally contain one or more C=C double bond(s) and/or are substituted with one or more of Ra, Rb, Rc, Rd, and Re;
R6 represents -H, -CH3, -CH2CH=CH2, -cyclo-C3H5, -CH2CH2CH2CH2CH3;
and R8 - R14, Ra; Rt.; Rc; Rd; Re; RN; and rc -N1 have the meanings and preferred meanings as defined herein.
Also preferred are compounds of the general formula (I), J
(I) CINI 71- R3 Ho wherein L represents -L1- or L1 represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2C0-, -CH2CH2C0-;
L2 is a bond, -NR'-, -NRN1CH2-, -NRN1CH2CH2-, or -NRN1CH(CH3)-;
R1 represents , R2 represents RN RN
____,I;IrR8 Rii Ri______i 0 R8 ____.s R8 w______.1 s R8 -\ r r ,\ r ,\ __ r )\ , \ , Ri0 R9 / __ R9 Ri0 R9 / R9 Ri0 R9 / R9 ;
RN RN RN
R11 1;1, R11 1;1, __ 11, Rii 0 __ Ri:).,0R8 -__(:)___Rs N
Rio `, ; R9 Rio R9 Rio , , rµ
mio , , R N
RN
Rti)rs, __ RS, _R8 S, Rs --).-N-N Ri_i N, \ rk __ 1 ,N li - - -1\IRN
N N N IN N
Rio , rµ mio Rlo , N¨N N=N
, , R12 R12 R12 Ri2 Ri2 N ,. , --:-.7 pp 13 r N4) R¨ 13 \') , R14 N R14 N R14 N R14 , N R14 , , 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 RN
N - - - / .,.__ Rl W
-R13 - - -S_____\T R13 - - iis__j\T R13 N
0 41 ,õ R14 Wu N-----\%\
µµ), ________________________ N-- R14 N R9 ri R9 iR13 S r_IiR9 _r_ % R10 _Tr- '/R10 R14i- W N - \-->R1 _ - m R10 or -- " , , R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl, diamantyl, hexamethylenetetraminyl, and the afore-mentioned residues optionally contain one or more C=C double bond and/or are substituted one or more of Ra, Rb, Rc, Rd, and Re;
Ra, Rb, Rc, Rd, and Re represents independently of each other -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C2H5, -CONH2, -CONHCH3, -CON(CH3)2, -CONHC2H5, -CH2CO2H, -CH2CO2CH3, 15 -CH2CO2C2H5, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2H5, -NHCOCH3, -NHCOC2H5, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C2H5, -NHSO2CHF2, -NHSO2CF3, -NHSO2CH2CF3;
R4 represents -NR6R7;
R6 and R7 represent independently of each other -H, -CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-05H9, -cyclo-C6H11, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-05H9, -CH2-cyclo-C6H11, -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2, or -NR6R7 represents or --N \ / =
R" represents -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 -cyclo-05H9, -CH2-cyclo-C3H5, -CH2F, -CHF2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3, -00C21-15, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -COOCH3, -CO0C2H5, -CO0C3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -S02CH3, -S02CF3, -S02C21-15, -S02C3H7, -S02CH(CH3)2, or -S02C(CH3)3;
RNi represent -H, -CH3, or -CH2CH3;
or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomers, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
Also preferred are compounds of the formula (I) or (lb), wherein L1 represents -CH2-, or -CH2C0-;
L2 represents a bond, -NR'-, -NRN1CH2-, or -NRN1CH(CH3)-;
R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 4-homoisotwistyl, adamantyl, or diamantyl, and the afore-mentioned residues optionally contain one or more C=C double bond(s) and/or are substituted by one or more of Ra, Rb, Rc, Rd; and Re; and Ra, Rb, Rc, Rd; Re and RI" have the same meanings as defined herein.
Preferably, R2 of the formula (I) or (lb) represents Rio R9 R11 0 RR R8 -__ S R8 R11 R8 R8 S
R8 , , N
,-,9 ' R9 N- .= , RN RN RN
nn Rio Rii SN Ril Sõ8 -- SR8 -- ri ___ Rc NN
0, /7--- --i /7---- -,r,,, , N
R8 Rio , Rio Rio Rio RN
Ri2 Ri2 Ri2 ,N R Rio_(rN,N _ RN
N io ---\-N
=r\j N, p N 1R 3 R13 -R=-, N=N R14 N R14 N
' R'"
Ri2 Ri2 Ri2 RN
0--/y,) S --/y,) iN --/y,., R12 ---,\ TI R13 , i \ 1 - - - - - - ---' '/----i - , . - - - = - - - "
'----/, -\R14 - - -\ 1 \ _T R13 R13 R 1-r R14 N-----\--1A
Rio Rio Rio ni.."
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 N v ri /R9 \ __Ri 4 N R9 rN r' r 1 1 1 n S (- )..õ. _ 9 _ _ _ _R10 - 1 - TR 0 /
D.- /
N - -\____/"--1---Ri 0 , , " , , R8 R8 ,S -. R8 ,\ S - ' N II ,,,-! N i N/ - - S)- - - -.--N
a, R',S ----- il NhT
N R8 \s-N \Ns-- N R8 N - N b-N
, , n N, - ' n N, R ---- -] R --- 1/
N-0 or , and R8¨ R14 and RN have the meanings as defined in formula (I) or (lb).
Preferred are compounds having any one of the formulae (IV-a) ¨ (IV-o) and (V-a) ¨ (V-d):
A ,R6 0)-LN , R6 NH
H
0 H 0 Rb 0 c 0 RC
A N L Ra R2. NH NH N
1 .L2 Rb 1-. `= ' I-U
H
Ra (IV-a) (IV-b) o 0 oANR6 0 N-R6 "
H H Rb Ra 0H 0 0 NN 1_ H 0 A ,,..,..-1-1.., 2 CNN L2 Rc a H
0 0 Rd IR' Rb (IV-d) (IV-c) a OAN , R6 ON, R Rb R
H Rb Ra H RC
o( 0 0 Rc 0 H 0 N N ,L2 , il NL2 H Rd H
(IV-e) (IV-f) 0 Rd 0 -H Rc H Rb Ra A H II
H
0 0 Rd (IV-g) (IV-h) 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 0 . 6 N R oA6 Ra NR -H
Rb A
H
0 JCH 0 IR' 0 0 I N L Rd H H
(IV-i ) (IV+
OA N , R6 i. .: OA N .R6 [7:p H H
R2 A N 1 N R2)- N crN
_ J1 NL
H
(IV-k) (IV-I) o o Q_ANFIR6 cl__H HR6 --- N
(IV-m) (IV-n) 0 .R6 N
H
0 ,C 0 0 H 0 R2,/NH NH 1 , 2 N/\1- 0 N 1 2 O
Rio (IV-o) (V-a) 0 o o R6 o )-L R6 N - N -H H
S N .-R8 hi N 1 2 ..-----,,,_,... -,R3 R- 8 S N N N L2 H
\ I 1 -- I 1 Ri 0 R10 (V-C) (V-b) 0 N .R6 H
Rii 0 N ki L2,, R3 R12 /7 \ \ I hi 1 I
(/ \ R10 o 0 (V-d) 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 and R2, R3, R6, R8; Rs; R10, R11, R12, R13, Ra; R13, Rc; Rd L and - . 2 have the same meanings as defined herein, preferably as defined in formula (I) or (lb).
Also preferred are the compounds of any of the formula (IVa-1), 0)-R6 H
H Rb N
, JI N N
H
0 0 Ra (IVa-1) wherein R6 represents ¨H, ¨CF13, ¨CH(CH3)2, ¨CH2CH2C1-13, ¨CH2CH=CH2, ¨CH2CH2CH2CH3, ¨CH2CH(CH3)2, ¨C(CH3)3, ¨CH2CH2CH2CH2CH3, ¨cyclo-C3H5, ¨cyclo-05H8, ¨cyclo-C8H11 or ¨CH2¨cyclo-C3H5.
and R2, Ra, and Rb have the same meanings as defined above.
Preferably, in the compounds of formula (I) or (lb), Ra and Rb represent independently of each other ¨H, ¨F, ¨Cl, ¨Br, ¨OH, ¨CN, ¨CF13, ¨C2H5, or ¨0O2Me.
Preferably, in any of the formula (I), (lb), (IV-a) ¨ (IV-o), or (IVa-1):
R2 represents o r0 Br , -- Br 0 Br 0 \ /
s Br , S _ _ S
- S CI \\/ p , -B-rY-1-Br \ /
S Br Br Br Br, , -ySz-Br -- - S CI -- r- S B y S
Br CI Br , Br , CI Me() Br , , .--\ I
S _ \ /
-CI CI B
CI r-õD____S
\ / Br HN
0 S, \ .-- Nõ-Me0 ---)\1--- H N3 0 N-NBr, N-N
, , \
\s Br s C I ------s Br ------s_.-- CI BrS
Br CI-----cS-C1 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 0C-90-ZZOZ peAieoef alea/an5a aleCI
xoop-vzonnottod-a3z-Noadiens3a-odo-68tz pue N-0 JO ' N-C) k ----LN
-- N --' , NZH
, El-----N\\N \\ N I \\ N _õ- 1 \=\ N 1 \ \N 1 \ N " - S/
N-N NN.
N-S N N \NN
õ0 ----s'1\1 õ- S JUN I
-- S .--- / N 1 1 , - -----N 'W , :
N H 0 [
WN
__, \ _,, / ,-' 1 N 1 ---=
co , HO s\>- , , ---, , N N J
--- N
- - J
\
H N
N H
H
'c'- , , , \ , _le s --\ -- \ __ __ \ __ , /
N N S S S
, , , 0 0 ' ' J9 10 \ __ N------9 /9---r-N ,--7N---- ...--\-------"A
\
0 \
,¨NH J9 , --N
NH - , N
- N H -- -NN) / __, N
H
' N
N ' .,1\1 N
-N '-- '-- -N '-- - elf\lz00-- Hz00-- zON --, 91/\1z00 1 HN --__ iii¨\\ iii¨\\ N ____ N Ii Ni' N ,N N ,N N-N N, NN
zON ., 1 I N N 1 , N-N , ' -----(5--NN \--N\
NH N \ // N N N
\-----IN-- -- 10-5¨<-- -_ -S ---I, N N N N N N
Lld'-s-- elAlOs- - cdo _ _OS 9 J -- c --s-s 5 ZCZ
R6 represents ¨H, ¨CH3, ¨CH(CH3)2, ¨CH2CH2CH3, ¨CH2CH=CH2, ¨CH2CH2CH2CH3, ¨CH2CH(CH3)2, ¨C(CH3)3, ¨CH2CH2CH2CH2CH3, ¨cyclo-C3H3, ¨cyclo-C31-19, ¨cyclo-C6H11 or ¨CH2¨cyclo-C3H3.
Due to the specially selected substituents R2 on the N-terminal side and substituents R3 on the C-terminal side and of the inventive compound according to the invention the steric dimension can be adjusted very precisely, so that a binding pocket of a desired target molecule may be addressed with highly matching measurements.
Preferred, are the compound of any of the formulae (I), (lb), (IV-a) ¨ (IV-o), and (V-a) ¨ (V-d), wherein R3 represents , , , , , .,, , ' , , , , ., .
' F Br ; CI OH
CO2H CONH2 CONMe2 Nj H, CO2Me ,, CO2H Br OH
CF3, F
F
F jZci ZcF3 ZOH jZco2Me i , , , , or .
Surprisingly, it was found that the inventive compounds bound to the transglutaminase 2 reversibly and inhibit the transglutaminase effectively. The electrophilic warheads in combination with the preferred embodiment specifically react with highly nucleophilic 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 thiols in the active site of the transglutaminase 2. Accordingly, it was found that potential unspecific reactions with off-targets are reduced.
In one embodiment, the present invention refers to the compound selected from the group consisting of:
11-2: oANI (S)-2-(benzofuran-2-carboxamido)-N1 -(1 -(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-H 1 ,2-dihydropyridin-3-y1)-N6-methy1-5-N
I H I oxohexanediamide o o 11-3: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-o 0 H N6-methy1-2-(3-methylbenzofuran-2-I H carboxamido)-5-oxohexanediamide o o 11-4: (S)-2-(3-ch lorobenzofuran-2-0 1\1 carboxamido)-N1 -(1 -(2-(2-H
0 N N adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-I H
0 0 dihydropyridin-3-y1)-N6-methy1-5-cI
oxohexanediamide 11-5: (S)-2-(4-bromobenzofuran-2-0)-LNJ
carboxamido)-N1 -(1 -(2-(2-H adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-o I H 0 0 dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Br 11-6: ON (S)-2-(4-bromobenzofuran-2-carboxamido)-N1 -(1 -(2-(2-H adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-S N
I 0 0 dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-7: OLN (S)-2-(benzo[b]thiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-HH 2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-s I H 0 0 5-oxohexanediamide Br 11-8: 0)-L (S)-2-(5-bromobenzo[b]thiophene-2-NJ
carboxamido)-N1 -(1 -(2-(2-oH 0 N adamantylamino)-2-oxoethyl)-2-oxo-1 HN ThiNj 0 0 dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 o 11-9: (S)-2-(1H-indole-2-carboxamido)-N1-(1-(2-o,A --N
H (2-adamantylamino)-2-oxoethyl)-2-oxo-FN1 i o UN Ed 1,2-dihydropyridin-3-y1)-N6-methy1-5-, NThr H
0 0 oxohexanediamide o 11-10: ON (S)-2-(4,5-difluoro-1H-indole-2-H carboxamido)-N1-(1-(2-(2-H adamantylamino)-2-oxoethyl)-2-oxo-1,2-H N r\jAN-IN
I H 0 0 dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide F F
11-1 1: 0)-1\1 (S)-N1-(1-(2-(2-adamantylamino)-2-H oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-o H 0 H H N6-methy1-2-(3-methy1-1H-indole-2-N N,A
N NN carboxamido)-5-oxohexanediamide 11-12:
o,)-LN (S)-2-(1H-benzo[d]imidazole-2-H carboxamido)-N1-(1-(2-(2-0 N rEi 0 I, " NThr IR1 adamantylamino)-2-oxoethyl)-2-oxo-1,2-iii,j H 0 0 dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide o 11-13: (S)-2-(2,3-dihydro-1H-indene-2-o N
H carboxamido)-N1-(1-(2-(2-O 0 adamantylamino)-2-oxoethy1)-2-oxo-1,2-N N
H , Ji dihydropyridin-3-y1)-N6-methy1-5-o o oxohexanediamide o 11-14: OAN (S)--(2-bromo-4-methylthiazole-5-H carboxamido)-N1-(1-(2-(2-o H o s -FNI1 adamantylamino)-2-oxoethyl)-2-oxo-1,2-N
Br--- k)-L'Fir i NI
0 0 dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide o 11-15: (S)-N1-(1-(2-(2-adamantylamino)-2-0)-LN
H oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-o H 0 _N' N6-methyl-2-(4-methyl-2-F3c___ekHN_A 1 N ff E
N 0 0 (trifluoromethyl)thiazole-5-carboxamido)-5-oxohexanediamide o 11-16: 0)-N (S)-2-(4-bromo-2-(trifluoromethyl)thiazole-H 5-carboxamido)-N1-(1-(2-(2-o F
F3c-- H o S_Aõ, NJLI\jr NI adamantylamino)-2-oxoethyl)-2-oxo-1,2-- 1 [sil N 0 0 dihydropyridin-3-y1)-N6-methy1-5-Br oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 o 11-17: OAN (S)-2-(2,4-dichlorothiazole-5-H carboxamido)-N1 -(1 -(2-(2-o , o j-L adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-ci----N s __I\Icki H 0 0 dihydropyridin-3-y1)-N6-methyl-5-CI
oxohexanediamide o 11-18: 0 (S)-N1-(1-(2-(2-adamantylamino)-2-r\J
H oxoethyl)-2-oxo-1 ,2-d i hydropyrid in-3-y1)-2-0 o s-L N r11J-Nil (2-methoxy-4-methylthiazole-5-Me0--- 1 H
N 0 0 carboxamido)-N6-methyl-5-oxohexanediamide o 11-19: (S)-N1-(1-(2-(2-adamantylamino)-2-H oxoethyl)-2-oxo-1 ,2-d i hydropyrid in-3-y1)-= \s 1 N N,CN N,Q1, N6-methy1-2-(4-methy1-2-phenylthiazole-5-N carboxamido)-5-oxohexanediamide o 11-20:
oN (S)-2-(2,4-dimethylthiazole-5-H carboxamido)-N1 -(1 -(2-(2-o o s__A fl- H adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-----N1 il 1 NifN
dihydropyridin-3-y1)-N6-methy1-5-0 o oxohexanediamide o 11-21: o N (S)-2-(5-bromo-3-methylthiophene-2-)-L
H carboxamido)-N1 -(1 -(2-(2-Br1 o H ? H adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-S N N
\ 1 N N
dihydropyridin-3-y1)-N6-methyl-5-H o o oxohexanediamide o 11-22: 0)-N (S)-2-(3,5-dibromothiophene-2-H carboxamido)-N1 -(1 -(2-(2-Br o H N H adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-s Br N N N
Tr \ I H 0 0 dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide o 11-23: oN (S)-2-(5-bromothiophene-2-carboxamido)-H N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-o s o ci.1 H
Nj-LNN 2-oxo-1 ,2-d i hydropyrid in-3-y1)-N6-methyl-5-oxohexanediamide o 11-24: oN (S)-2-(5-chlorothiophene-2-carboxamido)-H N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-CI\ ( o H H 2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-s Nj -HN 1 Nr -iNj 5-oxohexanediamide o o 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 o 11-25: oN (S)-2-(5-bromo-3-methylfuran-2-H carboxamido)-N1 -(1 -(2-(2-Br o o 0 ( )-L
El H
NNN adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-, \ I HN 0 8 dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide o 11-26: oN (S)-2-(5-chlorofuran-2-carboxamido)-H (1-(2-(2-adamantylamino)-2-oxoethyl)-2-H oxo-1 ,2-dihydropyridin-3-y1)-N6-methy1-5-N , N
CI \I H I I N oxohexanediamide o o o 11-27: Ol-L.N (S)-2-(5-chlorothiophene-3-carboxamido)-y.-H N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-CI
o 0 H H 2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-N )-LNThiN
I 5-oxohexanediamide s 0 11-28: oAN (S)-2-(2,5-dichlorothiophene-3-H carboxamido)-N1 -(1 -(2-(2-o 0 H
N2- N adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-a /1 N 1 N'Ir s 0 0 dihydropyridin-3-y1)-N6-methy1-5-ci oxohexanediamide o 11-29: o)LN (S)-2-(2,5-dibromothiophene-3-H carboxamido)-N1 -(1 -(2-(2-o (H 0 N)-L kil Br / 1 N'i 1 N,'.r adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-S 0 0 dihydropyridin-3-y1)-N6-methyl-5-Br oxohexanediamide o 11-30: oN (S)-2-(5-bromothiophene-3-carboxamido)-H N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-o o H 2-oxo-1 ,2-d i hydropyrid in-3-y1)-N6-methyl-Br / 1 hic i NI -rNi 5-oxohexanediamide s 0 11-31: o)N (S)-2-(2-chloro-5-methylthiazole-4-,t. ..---H carboxamido)-N1 -(1 -(2-(2-o 0 H)L
I\11 adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-CI N
i N, 0 0 dihydropyridin-3-y1)-N6-methyl-5-s oxohexanediamide o 11-32: 0)-I\J (S)-2-(2,5-dichlorothiazole-4-L
H carboxamido)-N1 -(1 -(2-(2-o 0 H H adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-ci---1 0 N 1 NI N dihydropyridin-3-y1)-N6-methyl-5-s 0 CI oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 o 11-33: 0N (S)-2-(2,5-dibromothiazole-4-H carboxamido)-N1 -(1 -(2-(2-Br o H o adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-0 i j-LN
, i EN11 dihydropyridin-3-y1)-N6-methyl-5-/s - 0 Br oxohexanediamide o 11-34: oN (S)-2-(2-bromo-5-methylthiazole-4-H carboxamido)-N1 -(1 -(2-(2-Br-- 0 rFi 0 adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-N__)-LN NThili H
S 0 0 dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide o 11-35: O N (S)-2-(2-bromothiazole-4-carboxamido)-H N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-o H o H 2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-o Br----(NjAHN fiNI
/ 5-oxohexanediamide s - - il N N
11-36: ON (S)-2-(2-chlorothiazole-4-carboxamido)-H N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-o 0 H)L 2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-a-----N N 1 NI LI 5-oxohexanediamide s 0 11-37: N (S)-2-(2,5-dimethylfuran-3-carboxamido)-H N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-o ti 0 H 2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-/ N-11\1-ANN 5-oxohexanediamide 11-38: o N (S)-2-(4,5-dimethylthiazole-2-H carboxamido)-N1 -(1 -(2-(2-o H 0 H adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-s,IAN N,AN N
H 0 0 dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-39: 0 O N (S)-2-(4-bromothiazole-2-carboxamido)-H N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-o N S H 0 H 2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-N N 5-oxohexanediamide 5AH 0 ,-,0,,N
Br 11-40: O N (S)-2-(4-bromothiophene-2-carboxamido)-H N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-H 2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-s 0 Nr NH
5-oxohexanediamide \ 1 H 0 Br 0 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-41:
0-N (S)-2-(4-bromo-3-methylthiophene-2-H carboxamido)-N1-(1-(2-(2-s H adamantylamino)-2-oxoethyl)-2-oxo-1,2-NN.rN
\I N H I 1 dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide Br 11-42: 0 (S)-2-(3-bromothiophene-2-carboxamido)-ON
H N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-s N H 2-oxo-1,2-dihydropyridin-3-yI)-N6-methyl-H 0 .iNNfN
5-oxohexanediamide \I 1 1 Br 11-43: (S)-2-(3-chloro-4-methylthiophene-2-ON
H carboxamido)-N1-(1-(2-(2-H adamantylamino)-2-oxoethyl)-2-oxo-1,2-s NNN),iN
\ I H i I dihydropyridin-3-y1)-N6-methyl-5-a 0 oxohexanediamide o 11-44: o,,,)-I (S)-2-(4-bromo-5-chlorothiophene-2-.,-.. --HN carboxamido)-N1-(1-(2-(2-CI
o s o --.IRI adamantylamino)-2-oxoethyl)-2-oxo-1,2-N II
\ I N H 0 0 dihydropyridin-3-y1)-N6-methyl-5-Br oxohexanediamide o 11-45: o)LN (S)-2-(4,5-dibromothiophene-2-H carboxamido)-N1-(1-(2-(2-Br -_7('N
o .. jo s 1 -y --k1 adamantylamino)-2-oxoethyl)-2-oxo-1,2-\ i H 0 0 dihydropyridin-3-y1)-N6-methyl-5-Br oxohexanediamide o 11-46: oN (S)-2-(4,5-dibromo-3-methoxythiophene-H carboxamido)-N1-(1-(2-(2-Br o s o -ciRilj-L NI adamantylamino)-2-oxoethyl)-2-oxo-1,2-OMe NThr 0 H N 0 0 dihydropyridin-3-y1)-N6-methyl-5-Br oxohexanediamide o 11-47: 0 (S)-2-(4-bromofuran-2-carboxamido)-N1-N
H (1-(2-(2-adamantylamino)-2-oxoethyl)-2-o o H oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-0 r\jciNNrN
oxohexanediamide \ I H 0 Br 0 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 o 11-48: ON (S)-2-(4,5-dibromofuran-2-carboxamido)-H N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-o o o NciRlij-L _NI 2-oxo-1,2-d i hydropyrid in-3-y1)-N6-methyl-Br N if \I H 0 0 5-oxohexanediamide Br 11-49: o..,JL.N...-(S)-2-(4,5-dichlorothiophene-2-H carboxamido)-N1-(1-(2-(2-o s o ci., adamantylamino)-2-oxoethy1)-2-oxo-1,2-ci 1 N 1 N Thr Ed \ , H 0 0 dihydropyridin-3-y1)-N6-methy1-5-CI oxohexanediamide o 11-50: 0)-N (S)-2-((S)-1-acetylpyrrolidine-2-H carboxamido)-N1-(1-(2-(2-N¨) N cFNI)"N ld adamantylamino)-2-oxoethy1)-2-oxo-1,2-, \ _ j H , JIi 0 0 dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide 11-51: o OAN
(S)-N1-(1-(2-(2-adamantylamino)-2-H oxoethyl)-2-oxo-1,2-d i hydropyrid in-3-y1)-H
0 0 N6-methyl-2-(1-methy1-1H-1,2,3-triazole-5-NilJ FRI 1 NrN
carboxamido)-5-oxohexanediamide 11-52: 0)-I\J (S)-N1-(1-(2-(2-adamantylamino)-2-L
H oxoethyl)-2-oxo-1,2-d i hydropyrid in-3-y1)-0 o N6-methyl-5-oxo-2-(2H-tetrazole-5-N
HNs'NN:IAN FIN H jiN'io FN1 carboxamido)hexanediamide 11-53: 0)-LI\J (S)-N1-(1-(2-(2-adamantylamino)-2-H
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-0 N6-methyl-5-oxo-2-(pyrazine-2-N)-LI\J
0 rEl H
N
carboxamido)hexanediamide I H _ JI NTh(N
11-54: 0 (S)-N1-(1-(2-(2-adamantylamino)-2-H ---N oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-\ 0 iF1 0 H N6-methyl-24(S)-1-methylpyrrol id ine-2-N )-LNf N carboxamido)-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 O r\I (S)-N1-(1-(2-(2-adamantylamino)-2-H oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-0 0 H N6-methyl-5-oxo-2((S)-pyrrolidine-3-H
_-AN-IN'Al N-rN carboxamido)hexanediamide HN¨ H 0 0 11-56: o O N (S)-24(2S,4S)-4-bromopyrrolidine-2-H carboxamido)-N1-(1-(2-(2-E
H
0 adamantylamino)-2-oxoethyl)-2-oxo-1,2-d J EN_I
dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide 11-58: 0 0It. (S)-N1-(1-(2-(2-adamantylamino)-2-,....,-H--N oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-H N6-methyl-5-oxo-2-((S)-piperidine-2-NA N)-L carboxamido)hexanediamide Nnf ---õ,--- 0 0 11-59: Or\j (S)-N1-(1-(2-(2-adamantylamino)-2-H oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-0 0 H N6-methyl-5-oxo-2-((R)-piperidine-3-HNNFdj-L
N
carboxamido)hexanediamide H 0 INo 11-60: o OAN (S)-N1-(1-(2-(2-adamantylamino)-2-H
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-I- N6-methyl-24(R)-((R)-3-N))-NciNNIVI carboxamido)-5-oxohexanediamide H
11-61: oAN (S)-N1-(1-(2-(2-adamantylamino)-2-H oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N
N- 0 r H ? H N6-methy1-5-oxo-2-(quinuclidine-3-NnN
Ii NN carboxamido)hexanediamide H
11-62: okN (S)-methyl 3-(1-(1-(2-(2-adamantylamino)-y.-H 2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(methylamino)-1,5,6-N-1 N 'AI N Fd H
0 0 trioxohexan-2-ylcarbamoy1)-5-nitrobenzoate CO2Me 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 o 11-63: 0AN (S)-N1-(1-(2-(2-adamantylamino)-2-H oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-o 0 H H
02N N. i-ir1µ12-N.rN N6-methy1-2-(5-nitronicotinamido)-5-0 0 oxohexanediamide N
11-64: o-LI\j (S)-5-(1-(1-(2-(2-adamantylamino)-2-) H oxoethyl)-2-oxo-1,2-dihydropyridin-3-rEl 0 ylamino)-6-(methylamino)-1,5,6-i N, rNI H
0 0 trioxohexan-2-ylcarbamoyl)nicotinic acid N
11-65: (S)-methyl 5-(1-(1-(2-(2-adamantylamino)-0.N..-H 2-oxoethyl)-2-oxo-1,2-dihydropyridin-0(rFi 0 ylamino)-6-(methylamino)-1,5,6-Me02CN N AN
i H 0 8 a trioxohexan-2-ylcarbamoyl)nicotinate N
11-66: oN (S)-N1-(1-(2-(2-adamantylamino)-2-H oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-S 0 o f-'-'N N'II H it H N6-methyl-2-(6-methylimidazo[2,1 -N
__A
\\ I H b]thiazole-5-carboxamido)-5-oxohexanediamide o 11-67: o -N (S)-N1-(1-(2-(2-adamantyl(methyl)amino)-...)L. --H 2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-o 0 I N6-methyl-2-(3-methylbenzofuran-2-0 N .iN12-N N
I H I 1 carboxamido)-5-oxohexanediamide 0 o o 11-68: (S)-N1-(1-(2-(5-hydroxyadamantane-2-H amino)-2-oxoethyl)-2-oxo-1,2-o o O N id NI
N Thr dihydropyridin-3-y1)-N6-methyl-2-(3-1 H 0 0 methylbenzofuran-2-carboxamido)-5-OH
oxohexanediamide o 11-69: 0 N (S)-N1-(1-(2-(5-fluoroadamantane-2-H amino)-2-oxoethyl)-2-oxo-1,2-o o O N IR11)L H dihydropyridin-3-y1)-N6-methy1-2-(3-N N
methylbenzofuran-2-carboxamido)-5-o 0 F oxohexanediamide o 11-70: o,AN (S)-N1-(1-(2-(5-chloroadamantane-2-H amino)-2-oxoethyl)-2-oxo-1,2-o o -,N1 dihydropyridin-3-y1)-N6-methy1-2-(3-N ri I H 0 0 methylbenzofuran-2-carboxamido)-5-ci oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 o 11-71: OAN (S)-N1-(1-(2-(5-bromoadamantane-2-H amino)-2-oxoethyl)-2-oxo-1,2-0 H 0 dihydropyridin-3-y1)-N6-methyl-2-(3-o N.r1\1AN,r1 I H 0 8 methylbenzofuran-2-carboxamido)-5-Br oxohexanediamide o 11-72: 0)NI (S)-N1-(1-(2-(5-methyladamantane-2-L
H amino)-2-oxoethyl)-2-oxo-1,2-o 0 H II H dihydropyridin-3-y1)-N6-methy1-2-(3-ol N.iNNrN
methylbenzofuran-2-carboxamido)-5-oxohexanediamide o 11-73: (S)-N1-(1-(2-(2-carbonitrileadamantane-2-OANI
H amino)-2-oxoethyl)-2-oxo-1,2-o , 0 H CN dihydropyridin-3-y1)-N6-methyl-2-(3-0 f N N
methylbenzofuran-2-carboxamido)-5-oxohexanediamide o 11-74: o-LN (S)-N1-(1-(2-(2-methyl adamantane-H carboxylate-2-amino)-2-oxoethyl)-2-oxo-o 0 H II H CO2Me 1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-O I
0 NNN.irµi methylbenzofuran-2-carboxamido)-5-oxohexanediamide o 11-87: 0 (S)-N1-(1-(2-(1-adamantylmethylamino)-N
H oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-H ii h N N6-methyl-2-(3-methylbenzofuran-2-0 N ,NrN
i H
0 0 carboxamido)-5-oxohexanediamide o 11-88: 0N (S)-N1-(1-(2-(1-(1-H adamantyl)ethanamino)-2-oxoethyl)-2-oxo-O H ?
O N, rl 1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-, N 1 NThr i H
0 0 methylbenzofuran-2-carboxamido)-5-oxohexanediamide o 11-90: O N (S)-N1-(1-(2-((1R,2S,4S)-H bicyclo[2.2.1]heptan-2-ylamino)-2-o 0 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-o NiNNThiNFI
I H I 1 N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-92: o (S)-N1-methy1-5-(3-methylbenzofuran-2-oN carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-H
0 0 ((1S,2S,4R)-1,7,7-0 N NNNH 1 H trimethylbicyclo[2.2.1Theptan-2-0 0 ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 o 11-94: oN (S)-N1-(1-(2-((1R,2R,4S)-H bicyclo[2.2.1]heptan-2-ylamino)-2-F
O rFi 0 oxoethyl)-2-oxo-1,2-d i hydropyrid in-3-y1)-O N NO-LN,N11=/_L
N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-95: (S)-N1-(1-(2-(bicyclo[2.2.1]heptan-1-0 N ylamino)-2-oxoethyl)-2-oxo-1,2-H
0 H 0 d\_..
di hydropyridi n-3-y1)-N6-methy1-2-(3-ii 0 N N 2-NH methylbenzofuran-2-carboxamido)-5-0 0 oxohexanediamide 11-96: 0 (S)-N1-(1-(2-(bicyclo[2.2.1]heptan-7--....)-.. .-- T
ylami no)-2-oxoethyl)-2-oxo-1,2-0 0 di hydropyridi n-3-y1)-N6-methy1-2-(3-0 NNNThrNH methylbenzofuran-2-carboxamido)-5-0 0 oxohexanediamide o 11-97: (S)-N1-(1-(2-(bicyclo[2.2.1]hept-5-en-2-oN
H ylamino)-2-oxoethyl)-2-oxo-1,2-o 0 di hydropyridi n-3-y1)-N6-methy1-2-(3-O NJciN 2-Nr NH
I H I 1 methylbenzofuran-2-carboxamido)-5-o o oxohexanediamide o 11-98: 0N (2S)-N1-(1-(2-(bicyclo[2.2.2]octan-2-H ylami no)-2-oxoethyl)-2-oxo-1,2-N o H di hydropyridi n-3-y1)-N6-methy1-2-(3-O iN N II N
H o methylbenzofuran-2-carboxamido)-5-1 1TIII o oxohexanediamide o 11-99: 0)N (S)-N1-methy1-5-(3-methylbenzofuran-2-H carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-O o ((1R,2R,4R)-1,7,7-H ii H
O N NN_,1\1 ssµ
tri methyl bicyclo[2.2.1]heptan-2-0 0 ylamino)ethyl)-1,2-dihydropyridi n-3-yl)hexanediamide o 11-100: oN (S)-N1-methy1-5-(3-methylbenzofuran-2-H carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-O o O INic illNMIft, 1 ((1R,2R,3R,5S)-2,6,6-tri methyl bicyclo[3.1.1]heptan-3-H
ylamino)ethyl)-1,2-dihydropyridi n-3-yl)hexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 o 11-101:
oN (S)-N1-methy1-5-(3-methylbenzofuran-2-H carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-o o ((1S,2S,3S,5R)-2,6,6-o NINII
I H 0 0 trimethylbicyclo[3.1.1]heptan-3-ylamino)ethyl)-1,2-dihydropyridin-3-yhhexanediamide o 11-103: (S)-N1-(1-(2-(4-homoisotwistane-3-o, )-L
N
H amino)-2-oxoethyl)-2-oxo-1,2-o 0 H dihydropyridin-3-y1)-N6-methyl-2-(3-O NiNNThiN
I H I 1 methylbenzofuran-2-carboxamido)-5-0 0 oxohexanediamide o 11-104: (S)-N1-(1-(2-(diamantane-1-amino)-2-Or\i pj H oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-o 0 N6-methy1-2-(3-methylbenzofuran-2-o Nini 2-N( NH
I H I 1 carboxamido)-5-oxohexanediamide o 11-105: (S)-N1-(1-(2-(diamantane-4-amino)-2-H oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-NN HN6-methy1-2-(3-methylbenzofuran-2-I H
0 0 carboxamido)-5-oxohexanediamide 11-107: 0 0 (S)-N1-(1-(1-adamantylmethyl)-2-oxo-1,2--,....)-L.
H .--N dihydropyridin-3-y1)-N6-methyl-2-(3-O 0 methylbenzofuran-2-carboxamido)-H II
O NJcr N 2-cN oxohexanediamide 11-108: 0 (2S)-N1-(1-((3-hydroxy-1-0 .--N adamantypmethyl)-2-oxo-1,2-H
O 0 dihydropyridin-3-y1)-N6-methy1-2-(3-H II
O N N N methylbenzofuran-2-carboxamido)-0 oxohexanediamide OH
11-109: 0 (2S)-N1-(1-((3-bromo-1-0 .--N adamantypmethyl)-2-oxo-1,2-H
O 0 dihydropyridin-3-y1)-N6-methy1-2-(3-H II
O 1\iciN2-N methylbenzofuran-2-carboxamido)-5-0 oxohexanediamide Br 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-110: (S)-N1-(1-(2-adamantylmethyl)-2-oxo-1,2-0...,)-1-.. ---N dihydropyridin-3-y1)-N6-methy1-2-(3-H
0 H 0 methylbenzofuran-2-carboxamido)-5-0 NNN oxohexanediamide 11-111: 0 0)-L (S)-N1-(1-(2-(2-adamantylamino)-2-H N oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N H 011 H N6-methyl-2-(nicotinamido)-5-I N INThiN
H
0 0 oxohexanediamide N
11-112: 0)N (S)-2-(isonicotinamido)-N1-(1-(2-(2--H adamantylamino)-2-oxoethyl)-2-oxo-1,2-O rH 011 H dihydropyridin-3-y1)-N6-methyl-5-H
rAN N 'N N oxohexanediamide I -11-113: OAr\j (S)-N1-(1-(2-(2-adamantylamino)-2-H oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-O r1-1 OH N6-methyl-5-oxo-2-(pyridazine-4-N
H
r)-LNI
H- yN N N
carboxamido)hexanediamide I
.N 0 0 11-114: 0)-L (S)-N1-(1-(2-(2-adamantylamino)-2-H
N oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-O jcH 011 * H N6-methyl-5-oxo-2-(pyridazine-3-NN carboxamido)hexanediamide -11-115: 0)-LN (S)-N1-cyclopropyl-N6-(1-(2-(2-H adamantylamino)-2-oxoethyl)-2-oxo-1,2-o 0 H i i H dihydropyridin-3-y1)-5-(3-O N.iNINfl,rN
I 1-1 0 I I methylbenzofuran-2-carboxamido)-2-o oxohexanediamide o 11-116: (S)-N1-(1-(2-(2-adamantylamino)-2-H oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-o H 0u H (3-methylbenzofuran-2-carboxamido)-5-o N N N
N oxo-N6-pentylhexanediamide 11-117: (S)-N1-allyl-N6-(1-(2-(2-adamantylamino)-0)-LN
H 2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-o o N
HA H 5-(3-methylbenzofuran-2-carboxamido)-o N N -1N
oxohexanediamide I H U
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 o 11-118: (S)-N1-(1-(2-(2-adamantylamino)-2-0-LNH2 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-o H 0 H (3-methylbenzofuran-2-carboxamido)-5-0 N 1\1)-LNN
I H I 1 0 oxohexanediamide 11-119: 0)-1\1 (S)-N1-ally1-5-(benzofuran-2-L
H carboxamido)-N6-(1-(2-(2-O H ? H adamantylamino)-2-oxoethy1)-2-oxo-1,2-N
dihydropyridin-3-y1)-2-oxohexanediamide 11-120: OAN (S)-2-(benzofuran-2-carboxamido)-N6-H isopropyl-N1-(1-(2-(2-adamantylamino)-2-O H ? H oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)-5-o 0 N, 1 NN
oxohexanediamide 11-121: o)N L (S)-2-(benzofuran-2-carboxamido)-N6-H cyclopropyl-N1-(1-(2-(2-adamantylamino)-NH
H 2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-O 0 )L(:) 0 1 NN
5-oxohexanediamide 11-122: 9 140 o (S)-2-(benzofuran-2-carboxamido)-N1-(1-H
N (2-(2-adamantylamino)-2-oxoethyl)-2-oxo-H
O 0 1,2-dihydropyridin-3-y1)-5-oxo-0 NiJciNNrN phenylhexanediamide 11-123: 0 (S)-2-(benzofuran-2-carboxamido)-N6-'Ail 10 benzyl-N1-(1-(2-(2-adamantylamino)-2-o 0 H oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)-5-o o NL 0 1 H NN
oxohexanediamide o 11-124: (S)-2-(benzofuran-2-carboxamido)-N1-(1-)-LN H2 (2-(2-adamantylamino)-2-oxoethyl)-2-oxo-H 1,2-dihydropyridin-3-y1)-5-NH )L(:) oxohexanediamide o o o 11-125: (S)-2-(2,5-dichlorothiophene-3-0)-LN H2 carboxamido)-N1-(1-(2-(2-o 0 H H adamantylamino)-2-oxoethy1)-2-oxo-1,2-NNN
dihydropyridin-3-y1)-5-oxohexanediamide CI
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 o 11-126: (S)-N1-(1-(2-(2-adamantylamino)-2-o)-NH2 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-o , o s -õ, N,)- (4-methyl-2-(trifluoromethyl)thiazole-5-F3c--- k) pi j)' carboxamido)-5-oxohexanediamide 11-127: o (S)-N1-(1-(2-(2-adamantylamino)-2-NH2 oxoethyl)-2-oxo-1,2-d i hydropyrid in-3-y1)-2-O 0 (1 -methyl-1 H-1 ,2,3-triazole-5-H H
N, l\iN _ Ji NMI N carboxamido)-5-oxohexanediamide 11-128: (2S)-N1-(1-(2-((1R,2R,4S)-0)-LN
H bicyclo[2.2.1]heptan-2-ylamino)-2-o 0 H H oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-NN
CI / 1 hi N )- 1 1 1 "IL (2,5-dichlorothiophene-3-carboxamido)-s 0 o CI N6-methyl-5-oxohexanediamide o 11-129: oN (2S)-N1-(1-(2-((1R,2R,4S)-H bicyclo[2.2.1]heptan-2-ylamino)-2-o Ei 0 H,,d oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-k, N)-LNrN
F3C¨<77 r Ari 1 N6-methyl-2-(4-methyl-2-(trifluoromethyl)thiazole-5-carboxamido)-5-oxohexanediamide 11-130: (2S)-N1-(1-(2-((1 R,2R,4S)-0 )-L
H
N bicyclo[2.2.1]heptan-2-ylamino)-2-O 11 0 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-j N H
N-rN-3_ N6-methyl-2-(1 -methyl-1 H-1 ,2,3-triazole-5-N
c, 0 FiNci carboxamido)-5-oxohexanediamide 11-131: 0 (S)-N1-(1-(2-(2-adamantylamino)-2-0)-Lr\i H oxoethyl)-2-oxo-1,2-d i hydropyrid in-3-y1)-O id H 0 N6-methyl-5-oxo-2-(2H-1,2,3-tri azole-4-N
'-lAN
N I H I NI carboxamido)hexanediamide \N-N 0 0 H
11-132: 0 (S)-N1-(1-(2-(2-adamantylamino)-2-N
H oxoethyl)-2-oxo-1,2-d i hydropyrid in-3-y1)-0 0 J H N6-methyl-5-oxo-2-(1H-1,2,3-triazole-HNEll 1 NTh(N carboxamido)hexanediamide fel 0 0 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-133: Or\j (S)-N1-(1-(2-(2-adamantylamino)-2-H oxoethyl)-2-oxo-1,2-d i hydropyrid in-3-y1)-H N6-methyl-2-(1 -methyl-1 H-1 ,2,3-triazole-4-¨No HN IrICI-O(cIN carboxamido)-5-oxohexanediamide \W-N '-----11-134: 0 0 1\1 (S)-N1-(1-(2-(2-adamantylamino)-2-H oxoethyl)-2-oxo-1,2-d i hydropyrid in-3-y1)-N?L H H N6-methy1-5-oxo-2-(1H-1,2,4-triazole-I INI ii N(N
carboxamido)hexanediamide H
11-135: O N (S)-N1-(1-(2-(2-adamantylamino)-2-H oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-o 0 id 11 N6-methyl-2-(1 -methyl-1 H-1 ,2,4-triazole-3-NAINI 1 N( carboxamido)-5-oxohexanediamide /
11-136: O (S)-2-(benzofuran-3-carboxamido)-N1-(1-N
H (2-(2-adamantylamino)-2-oxoethyl)-2-oxo-IcLA 11 1,2-dihydropyridin-3-y1)-N6-methy1-5-o1 INICI 1 Yi oxohexanediamide o 11-137: ON (S)-2-(benzo[b]thiophene-3-carboxamido)-H N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-o o H 2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-s1 NC I NniN
0 0 5-oxohexanediamide o 11-138 0 -.N (S)-N1-(1-(2-(2-adamantylamino)-2-) H oxoethyl)-2-oxo-1,2-d i hydropyrid in-3-y1)-W
N6-methyl-2-(1 -methyl-1 H-pyrazole-3-NjrH A N
carboxamido)-5-oxohexanediamide /
11-139 o)-. (S)-N1-(1-(2-(2-adamantylamino)-2-N
H oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-H N6-methyl-2-(1 -methyl-1 H-pyrazole-4-NV NicH-A N.,,N
,NYH 0 8 carboxamido)-5-oxohexanediamide /
o 11-140 0)N (S)-N1-(1-(2-(2-adamantylamino)-2-H oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-H N6-methyl-2-(1 -methyl-1 H-pyrazole-5-<.- (j) NicH Ac)NN carboxamido)-5-oxohexanediamide NIII:H1 0 8 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-141 ON (S)-N1-(1-(2-(2-adamantylamino)-2-H oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-H ii H N6-methyl-2-(4-methyl-1,2,3-thiadiazole-5-,sNJc N,N..rN
N, I H carboxamido)-5-oxohexanediamide \N 0 0 11-142 OAN (S)-N1-(1-(2-(2-adamantylamino)-2-H oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)-/ 0 N_r FNI 0 H N6-methyl-5-oxo-2-(1,2,5-thiadiazole-3-NN
NfIrF1 carboxamido)hexanediamide 11-143 O N (S)-2-(4-iodo-1 -methyl-1 H-pyrazole-H carboxamido)-N1 -(1 -(242-I 0 jcH 0 H adamantylamino)-2-oxoethy1)-2-oxo-1,2-N N)' il Nrr\j dihydropyridin-3-y1)-N6-methy1-5-\ oxohexanediamide 11-144 (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-d i hydropyrid in-3-y1)-2-0 ,CLN f FNI II
H (1 -methyl-1 H-pyrazole-5-carboxamido)-5-NN oxohexanediamide 11-145 (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-d i hydropyrid in-3-y1)-2-H 9 H (4-methyl-1,2,3-thiadiazole-5-ci i) I(carboxamido)-5-oxohexanediamide iv 0 0 o 11-146 (S)-2-(benzofuran-2-carboxamido)-N1-(1-o (2-((1 R,2R,4S)-bicyclo[2.2.1]heptan-2-NH9NThry. ylamino)-2-oxoethyl)-2-oxo-1 ,2-I I-I 0 0 dihydropyridin-3-y1)-5-oxohexanediamide o 11-147 (S)-N1-(1-(2-((1R,2R,4S)-o bicyclo[2.2.1]heptan-2-ylamino)-2-H 9 oxoethyl)-2-oxo-1,2-d i hydropyrid in-3-y1)-2-0 N NNThr I H 0 0 ----1-.- (3-methyl benzofuran-2-carboxa mido)-5-oxohexanediamide o 11-148 (S)-2-(benzofuran-2-carboxamido)-N1-(1 -NH2 -i (2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-o kilj NH ylamino)-2-oxoethyl)-2-oxo-1 ,2-I FNI 1 Nr 0 0 dihydropyridin-3-y1)-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-149 N H2 (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-0 o o ri_i Nj-LN NH oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-N
I H 0 0 (3-methyl benzofuran-2-carboxa mido)-5-oxohexanediamide o 11-150 NH2 (S)-2-(benzofuran-2-carboxamido)-5-oxo-o 0 o Ni -(2-oxo-1 -(2-oxo-2-((1 R,2S,4R)-1 ,7, 7-tri methyl bicyclo[2.2.1]heptan-2-0 N NNThrN1H
I H 0 0 ylamino)ethyl)-1 ,2-dihydropyridi n-3-yl)hexanediamide 11-151 (S)-2-(3-methylbenzofuran-2-NH2 carboxamido)-5-oxo-N1-(2-oxo-1 -(2-oxo-2-((1R,2S,4R)-1 ,7,7-0 N.r1\12-.N_r NH
I H I I tri methyl bicyclo[2.2.1Theptan-2-ylamino)ethyl)-1 ,2-dihydropyridi n-3-yl)hexanediamide 11-152 0N (S)-N1-(1-(2-((1 R,2R,4S)-H bicyclo[2.2.1]heptan-2-ylamino)-2-0 jc H 0 H A oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-,s, N i p 1 ", ri 'c..___1.. N6-methyl-2-(4-methyl-1 ,2,3-th lad iazole-5-'N 0 0 carboxamido)-5-oxohexanediamide 11-153 ON (S)-N1-(1-(2-((1 R,2R,4S)-H bicyclo[2.2.1]heptan-2-ylamino)-2-0 (it N jcErci H H _.. oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)-NN N6-methyl-2-(1 -methyl-1 H-pyrazole-5-N--- \ carboxamido)-5-oxohexanediamide 11-154 0 (S)-N1-(1-(2-((1S,2R,4R)-A N
H bicyclo[2.2.1]heptan-2-ylamino)-2-0 j(i N El ,NH 0 oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)-jci F3C¨S_KIII 1 y h N6-methyl-2-(4-methyl-2-(trifluoromethyl)thiazole-5-carboxamido)-5-oxohexanediamide 11-155 (S)-N1-(1-(24(1S,2R,4R)-ON
H bicyclo[2.2.1]heptan-2-ylamino)-2-0( 0 NH oxoethyl)-2-oxo-1,2-d i hydropyrid in-3-y1)-2-(2,5-dichlorothiophene-3-carboxamido)-s 0 0 CI N6-methyl-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-156 0A (S)-N1-(1-(2-((1S,2R,4R)-N
H obxiColOy20.-22.:10xhoe_it,a2n:d2ih-yldarmopinyorid-2in--3_yo-Y [ i P Y ) O 0 '--1 N, 1 1 NI NH
ciRliJ-N6-methy1-2-(4-methy1-1,2,3-th lad iazole-5-carboxamido)-5-oxohexanediamide 11-157 (S)-N1-(1-(2-((1S,2R,4R)-H bicyclo[2.2.1]heptan-2-ylamino)-2-0 0 oxoethyl)-2-oxo-1,2-d i hydropyrid in-3-y1)-id jN NH
Nr'-'-'--7)-Njcr N6-methyl-2-(1-methy1-1H-1,2,3-triazole-5-carboxamido)-5-oxohexanediamide 11-158 (S)-N1-(1-(24(1S,2R,4R)-0)-LN
H bicyclo[2.2.1]heptan-2-ylamino)-2-O 0 T1 H oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-<
H
N ,NH
N if -----)ANcr 1 N6-methyl-2-(1-methy1-1H-pyrazole-5-\ carboxamido)-5-oxohexanediamide 11-159 (S)-Ni-methyl-5-(4-methyl-2-H (trifluoromethypth iazole-5-carboxamido)-2-0 0 oxo-N6-(2-oxo-1-(2-oxo-2-((1R,2S,4R)-S idN if ,NH
F3C--- F\ici 1,7,7-trimethylbicyclo[2.2.1Theptan-2-N i0 0 ylamino)ethyl)-1,2-dihydropyridi n-3-yl)hexanediamide 11-160 OA N (S)-2-(2,5-dichlorothiophene-3-H carboxamido)-N6-methy1-5-oxo-N1-(2-oxo-Lf(0 0 1-(2-oxo-24(1R,2S,4R)-1,7,7-N 1 N'-r NH trimethylbicyclo[2.2.1Th Cl eptan-2-S 0 0 ylamino)ethyl)-1,2-dihydropyridi n-3-yl)hexanediamide 11-161 (S)-N1-methy1-5-(4-methy1-1,2,3-H th lad iazole-5-carboxamido)-2-oxo-N6-(2-0 0 oxo-1-(2-oxo-2-((1R,2S,4R)-1,7,7-H II
N
N/S_kANjcr 1 yThr NH tri methyl bicyclo[2.2.1Theptan-2-N 0 0 ylamino)ethyl)-1,2-dihydropyridi n-3-yhhexanediamide 11-162 (S)-N1-methy1-5-(1-methy1-1H-1,2,3-Oli N
H triazole-5-carboxamido)-2-oxo-N6-(2-oxo-I? H 0 1-(2-oxo-2-((1R,2S,4R)-1,7,7-N NH tri methyl bicyclo[2.2.1]heptan-2-NN
i\i-N \ ylamino)ethyl)-1,2-dihydropyridi n-3-yl)hexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-163 (S)-N1-methy1-5-(1-methy1-1H-pyrazole-5-H carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-,it N 0 ((1R,2S,4R)-1,7,7-ill )-LNr NH trimethylbicyclo[2.2.1]heptan-2-'El 0 0 N-N \ ylamino)ethyl)-1,2-dihydropyridi n-3-yl)hexanediamide o 11-164 N (2S)-2-(4-tert-butyl-1H-pyrrole-3-o H carboxamido)-N6-methyl-N1-(1-(2-(1-o o adamantylamino)ethyl)-2-oxo-1,2-N
HN --- FiNjcorill N dihydropyridin-3-yI)-5-oxohexanediamide ¨
o 11-165 0)-.LNI (2S)-2-(4-cyano-1-methy1-1H-pyrrole-2-H carboxamido)-N6-methyl-N1-(1-(3-(1-H o adamantylamino)propyI)-2-oxo-1,2-o NN
\ N H 0 dihydropyridin-3-yI)-5-oxohexanediamide \
o 11-166 (S)-N1-(1-(3-(2-adamantylamino)-3-H oxopropy1)-2-oxo-1,2-dihydropyridin-3-y1)-0?LN N,)-NN 2-(5-methoxyoxazole-2-carboxamido)-N6-MeON H 0 H
methyl-5-oxohexanediamide o 11-167 0 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-1\1 H ylamino)-2-oxoethyl)-2-oxo-1,2-O H o dihydropyridin-3-y1)-N6-methy1-2-(3-0 N_iNNNH
I H 0 8 methylbenzofuran-2-carboxamido)-5-oxohexanediamide o 11-168 0 ,1 (S)-2-(2-acetyloxazole-4-carboxamido)-H N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-o o j( FdN.rN,IH 2-oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)-J h' N6-methy1-5-oxohexanediamide o 0 o o 11-169 0)-.N (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-H ylamino)-2-oxoethyl)-2-oxo-1,2-o o H II H dihydropyridin-3-y1)-N6-methy1-2-(3-o NrN,IN,N) I H 0 8 methylbenzofuran-2-carboxamido)-5-oxohexanediamide o 11-170 0 (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-1\1 H ylamino)-2-oxoethyl)-2-oxo-1,2-o 0 H li H dihydropyridin-3-y1)-2-(2-isopropyloxazole-oiNNN
5-carboxamido)-N6-methy1-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 o 11-171 ON (2S)-2-(benzofuran-2-carboxamido)-N1-(1-H 0 (2-(bicyclo[3.2.1]octan-8-ylamino)-2-o H
-2N(INI oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-I H 0 0 N6-methyl-5-oxohexanediamide 11-172 (2S)-N1-(1-(2-(bicyclo[3.2.1]octan-8-H ylamino)-2-oxoethyl)-2-oxo-1,2-H dihydropyridin-3-y1)-2-(3,5---- N NH
N N dimethylisoxazole-4-carboxamido)-N6-L, H
'NJ- 0 0 methyl-5-oxohexanediamide o 11-173 O (S)-N1-(1-(2-(5-carboxy-2-NI
H aminoadamantane)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(4-LI H n 0 CO2H methylpyrimidine-5-carboxamido)-5-1 '' oxohexanediamide o 11-174 0 N (2S)-N1-(1-(2-(4-aminoadamantane-N,N-o H dimethy1-1-carboxamide)-2-oxoethyl)-2-o N 1 N Tr I oxo-1,2-dihydropyridin-3-y1)-N6-methy1-H
0 0 N-..._ oxo-2-(1,2,3,4-tetrahydronaphthalene-2-o carboxamido)hexanediamide o 11-175 (S)-24(S)-1,4-diazabicyclo[2.2.2]octane-2-0N--v H ? carboxamido)-N6-tert-butyl-N1-(1-(2-(2-H I H
_1._'_\_j r\j---ANJc,NNThrN adamantylamino)-2-oxoethyl)-2-oxo-1,2-H
0 0 dihydropyridin-3-y1)-5-oxohexanediamide o 11-176 (S)-N1-tert-buty1-5-(1H-indole-3-H carboxamido)-N6-(1-(2-(2-H
N kil adamantylamino)-2-oxoethyl)-2-oxo-1,2-H
i N 0 0 U dihydropyridin-3-y1)-2-oxohexanediamide H
11-177 (S)-N1-tert-butyl-N6-(1-(2-(2-H adamantylamino)-2-oxoethyl)-2-oxo-1,2-A) jc( Fii 9 dihydropyridin-3-y1)-5-(6-N 0 rjmor methylimidazo[2,1-b]thiazole-3-s carboxamido)-2-oxohexanediamide 11-178 0 ji) (S)-2-(benzo[d]thiazole-2-carboxamido)-ON
H N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-S):)1111j- 0 N_r NH 2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-cyclopenty1-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-179 ojNiL) (S)-N1-(1-(24(16,2R,4R)-H bicyclo[2.2.1]heptan-2-ylamino)-2-0 EIJ o oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)-N NNH
NAYFINjc N6-cyclopenty1-2-(imidazo[2,1-b]thiazole-6-carboxamido)-5-oxohexanediamide s 11-180 o 0 n (S)-N1-(1-(24(16,2R,4R)-N
H OH 0 bicyclo[2.2.1Theptan-2-ylamino)-2-, 0 N NNThrNH oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N N6-cyclopenty1-2-(4-hydroxy-6-(trifluoromethoxy)quinoline-3-carboxamido)-5-oxohexanediamide 11-181 o AJO (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-oN
H ylamino)-2-oxoethyl)-2-oxo-1,2-o dihydropyridin-3-y1)-2-(cinnoline-3-o JEI
N,A NH
N 1 N n carboxamido)-N6-cyclohexy1-5-N oxohexanediamide 11-182 o n (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-0A1\1 H ylamino)-2-oxoethyl)-2-oxo-1,2-o di hydropyridin-3-y1)-N6-cyclohexy1-2-(3-o NiCri 1\1Hj-N,r1 NH
I H 0 0 ethylbenzofuran-2-carboxamido)-5-oxohexanediamide ojN,0 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-H ylamino)-2-oxoethyl)-2-oxo-1,2-Th o o di hydropyridin-3-y1)-N6-cyclohexy1-2-(1-N
N 1 ri_rH NThrNH
j-ethy1-1H-indole-2-carboxamido)-5-o o o( sx )o_ hNeix_ aon-e(2d _i a( bmi ci dy e 11-184 c 1 0 o n [1.1.1]pentan-1-N
H ylamino)-2-oxoethyl)-2-oxo-1,2-o di hydropyridin-3-y1)-N6-cyclohexy1-2-(2-Nj. ,NH
methyl-1,8-naphthyridine-3-carboxamido)-NN 5-oxohexanediamide 11-185 O (S)-N1-(1-(2-(bicyclo[2.1.1Thexan-1-N
H ylamino)-2-oxoethyl)-2-oxo-1,2-H di hydropyridin-3-y1)-N6-methy1-5-oxo-N 'iNj1 N, N (1,2,3,4-tetrahydroquinoline-6-N carboxamido)hexanediamide H
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 o 11-186 0 N_, (S)-N1-(1-(2-(2-carboxy-2-amino-5-H (trifluoromethypadamantane)-2-oxoethyly o o o NNANJ(N c02H
2-oxo-1,2-dihydropyridin-3-yI)-N6-methyl-HN 0 0 CF3 5-oxo-2-(3-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)hexanediamide o 11-187 0 N (S)-N1-(1-(2-(5-ethyladamantane-2-o H amino)-2-oxoethyl)-2-oxo-1,2-o H
1\1N kll,ANN dihydropyridin-3-y1)-N6-methy1-2-(1,6-r\il H 0 0 naphthyridine-2-carboxamido)-5-oxohexanediamide 11-188 (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-H ylamino)-2-oxoethyl)-2-oxo-1,2-H dihydropyridin-3-y1)-N6-methy1-2-(2,6-Njt., 1 rirN naphthyridine-1-carboxamido)-5-oxohexanediamide 11-189 (S)-2-(4-amino-1,2,5-oxadiazole-3-ajt.
'------ N
H carboxamido)-N1-(1-(2-H2N 0 0 (bicyclo[1.1.1]pentan-1-ylamino)-2-INI
Y(N Nr.----,irNH
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N I H
b-N 0 0 N6-methyl-5-oxohexanediamide o 11-190 0}1..N (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-,,,....--H ylamino)-2-oxoethyl)-2-oxo-1,2-o o 0 N NH dihydropyridin-3-yI)-2-(6-\
N 1 H 0 8 (dimethylamino)benzofuran-2-/ carboxamido)-N6-methy1-5-oxohexanediamide o 11-191 ojN--(S)-2-(2-acetamidothiazole-5-., H carboxamido)-N1-(1-(2-NH
(bicyclo[1.1.1]pentan-1-ylamino)-2-s ,,,Jcki FINI--- DA" N if oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-o N6-methyl-5-oxohexanediamide o 11-192 0IL.N (S)-N4-(1-(1-(2-(bicyclo[1.1.1]pentan-.,-H j ylamino)-2-.oxoethyl)-2-oxo-1,2-o o N
0 HN , dihydropyndm-3-ylamino)-6-/ NrF-IN if I H 0 0 (methylamino)-1,5,6-trioxohexan-2-yI)-pyrrole-2,4-dicarboxamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 0 ________________________________________________________________________ 11-193 0 N (S)-N1-(1-(2-(1-acetylamino-4-H
aminoadamantane)-2-oxoethyl)-2-oxo-1,2-0,t(JAN N,ANThrN
0 dihydropyridin-3-y1)-N6-methyl-5-oxo-2-(5-NJ
H sulfamoylfuran-3-carboxamido)hexanediamide o 11-194 0 N (S)-2-(benzofuran-5-carboxamido)-N1-(1-H
(2-(1-acetylamino-4-aminoadamantane)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-H
0 Nj H N6-methyl-5-oxohexanediamide o 11-195 0 N,-- (S)-2-(benzofuran-6-carboxamido)-N1-(1-H
H (2-(4-aminoadamantane-1-carboxamide)-NJ,) ENI
0 N 1 N-r 2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-\ H
0 0 NH2 N6-methyl-5-oxohexanediamide o 11-196 o- o (S)-N1-(1-(2-(4-aminoadamantane-1-H carboxamide)-2-oxoethyl)-2-oxo-1,2-r[i H
A e N r,j,---,õ,,,N dihydropyridin-3-y1)-N6-methy1-2-(3-(1-NH2 methylcyclopropyI)-1,2,4-oxadiazole-5-o carboxamido)-5-oxohexanediamide 11-197 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-OAN
H ylamino)-2-oxoethyl)-2-oxo-1,2-0 (.rr\I i 0 H j,. dihydropyridin-3-y1)-N6-methy1-2-(5-NINI N,r NH
methyl-1,2,4-oxadiazole-3-carboxamido)-5-oxohexanediamide 11-198 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-0)-LN
H ylamino)-2-oxoethyl)-2-oxo-1,2-0 0 dihydropyridin-3-y1)-N6-methyl-5-oxo-S/
NNH ANcrEA (1,2,3-thiadiazole-4-carboxamido)hexanediamide 11-199 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-N
H ylamino)-2-oxoethyl)-2-oxo-1,2-0 H 0 ----)' dihydropyridin-3-y1)-N6-methyl-5-oxo-N,3,7AN N NH
..----N/ _r H I I (1,2,4-thiadiazole-5-carboxamido)hexanediamide 11-200 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-OAN
H ylamino)-2-oxoethyl)-2-oxo-1,2-0 ( id 0 dihydropyridin-3-y1)-N6-methyl-5-oxo-e-,AN-NThrNH
(1,3,4-thiadiazole-2-carboxamido)hexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-201 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-N
H ylamino)-2-oxoethyl)-2-oxo-1,2-H ii? dihydropyridin-3-y1)-2-(4-cyclopropy1-1,2,3-N, I h' 1 N, MCNH
thiadiazole-5-carboxamido)-N6-methy1-5-oxohexanediamide o 11-202 0).N (S)-2-(4-cyclopropy1-1,2,3-thiadiazole-5-H carboxamido)-N1-(1-(2-(2-H adamantylamino)-2-oxoethyl)-2-oxo-1,2-N
N',SHI\jjCi N NI dihydropyridin-3-y1)-N6-methy1-5-N 0 o oxohexanediamide o 11-203 0).N (S)-2-(4-isopropyl-1,2,3-thiadiazole-H carboxamido)-N1-(1-(2-(2-o 0 r H
H adamantylamino)-2-oxoethyl)-2-oxo-1,2-r,,,s NfN')N-rN
N I H dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide o 11-204 0)N (S)-2-(4-ethy1-1,2,3-thiadiazole-5--.
H carboxamido)-N1-(1-(2-(2-o 0 H
N'S N( H
N)- ,N adamantylamino)-2-oxoethyl)-2-oxo-1,2-N IT
dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide o 11-205 0 (S)-2-(4-formy1-1,2,3-thiadiazole-5-N
H carboxamido)-N1-(1-(2-(2-H
FN11 adamantylamino)-2-oxoethyl)-2-oxo-1,2-,S
dihydropyridin-3-y1)-N6-methy1-5-\N H 0 oxohexanediamide o o 11-206 (S)-2-(4-(hydroxymethyl)-1,2,3-thiadiazole-N
H 5-carboxamido)-N1-(1-(2-(2-H il N H adamantylamino)-2-oxoethyl)-2-oxo-1,2-NJrN
kr,\ I 1 H 0 c N2-.0 dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide HO
11-207 OJt (S)-N1-(1-(2-(1-adamantylamino)-2-N
H oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-0 H 0 N6-methyl-2-(1-methyl-1H-imidazole-5-ii 1\l/YN N'l N'r NH
carboxamido)-5-oxohexanediamide \\ Ki ¨ 0 ...,..,0 '-------IIN
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-208 0 (S)-N1-(1-(2-(((1 S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-21,1AN k-11 yl)methylamino)-2-oxoethyl)-2-oxo-1,2-N
H 0 0 dihydropyridin-3-y1)-N6-methy1-2-(1-methyl-1 H-imidazole-2-carboxamido)-5-oxohexanediamide 11-209 0 (S)-N1-(1-(2-(((1 R,2R,5R)-6,6-dimethylbicyclo[3.1.1]heptan-2-o o HeN FIN NOThr yl)methylamino)-2-oxoethyl)-2-oxo-1,2-0 o dihydropyridin-3-y1)-2-(1H-imidazole-4-carboxamido)-N6-methyl-5-oxohexanediamide (S)-N1-(1-(2-(3,5-dimethyladamantane-1-N
amino)-2-oxoethyl)-2-oxo-1 ,2-11-210 o jcr H 0 dihydropyridin-3-y1)-N6-methyl-2-(1-NH
Thr methyl-1 H-imidazole-5-carboxamido)-5--N
oxohexanediamide (S)-N1-(1-(2-(3,5,7-trimethy1-1-adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-y1)-N6-methy1-2-(1-N N NH f'''=----/A-r NThr methyl-1 H-imidazole-5-carboxamido)-5-oxohexanediamide or a pharmaceutically acceptable salt thereof.
Especially preferred are the following compounds:
11-2: (S)-2-(benzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-3: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-4: (S)-2-(3-chlorobenzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-5: (S)-2-(4-bromobenzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-6: (S)-2-(4-bromobenzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-7: (S)-2-(benzo[b]thiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-8: (S)-2-(5-bromobenzo[b]thiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-9: (S)-2-(1 H-indole-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-10: (S)-2-(4,5-difluoro-1 H-indole-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-11 : (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methy1-1H-indole-2-carboxamido)-5-oxohexanediamide 11-12: (S)-2-(1 H-benzo[d]imidazole-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-13: (S)-2-(2,3-dihydro-1 H-indene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-14: (S)--(2-bromo-4-methylthiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-15: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(4-methy1-2-(trifluoromethypthiazole-5-carboxamido)-5-oxohexanediamide 11-16: (S)-2-(4-bromo-2-(trifluoromethyl)thiazole-5-carboxamido)-N1-(1 -(242-adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-17: (S)-2-(2,4-dichlorothiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-18: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(2-methoxy-4-methylthiazole-5-carboxamido)-N6-methy1-5-oxohexanediamide 11-19: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(4-methy1-2-phenylthiazole-5-carboxamido)-5-oxohexanediamide 11-21: (S)-2-(5-bromo-3-methylthiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-22: (S)-2-(3,5-dibromothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-23: (S)-2-(5-bromothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-24: (S)-2-(5-chlorothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-25: (S)-2-(5-bromo-3-methylfuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-26: (S)-2-(5-chlorofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-27: (S)-2-(5-chlorothiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-28: (S)-2-(2,5-dichlorothiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-29: (S)-2-(2,5-dibromothiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-30: (S)-2-(5-bromothiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-31: (S)-2-(2-chloro-5-methylthiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-32: (S)-2-(2,5-dichlorothiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-33: (S)-2-(2,5-dibromothiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-34: (S)-2-(2-bromo-5-methylthiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-35: (S)-2-(2-bromothiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-36: (S)-2-(2-chlorothiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-37: (S)-2-(2,5-dimethylfuran-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-39: (S)-2-(4-bromothiazole-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-40: (S)-2-(4-bromothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-41: (S)-2-(4-bromo-3-methylthiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-42: (S)-2-(3-bromothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-44: (S)-2-(4-bromo-5-chlorothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-45: (S)-2-(4,5-dibromothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-46: (S)-2-(4,5-dibromo-3-methoxythiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-47: (S)-2-(4-bromofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-48: (S)-2-(4,5-dibromofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-49: (S)-2-(4,5-dichlorothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-50: (S)-24(S)-1-acetylpyrrolidine-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide 11-51: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-1,2,3-triazole-5-carboxamido)-5-oxohexanediamide 11-51 (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(pyrazine-2-carboxamido)hexanediamide 11-54: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-24(S)-1-methylpyrrolidine-2-carboxamido)-5-oxohexanediamide 11-55: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-24(S)-pyrrolidine-3-carboxamido)hexanediamide 11-56: (S)-24(2S,4S)-4-bromopyrrolidine-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-58: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-24(S)-piperidine-2-carboxamido)hexanediamide 11-59: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-24(R)-piperidine-3-carboxamido)hexanediamide 11-60: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-24(R)-morpholine-3-carboxamido)-5-oxohexanediamide 11-61: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(quinuclidine-3-carboxamido)hexanediamide 11-62: (S)-methyl 3-(1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-ylcarbamoy1)-5-nitrobenzoate 11-61 (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(5-nitronicotinamido)-5-oxohexanediamide 11-64: (S)-5-(1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinic acid 11-65: (S)-methyl 5-(1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinate 11-68: (S)-N1-(1-(2-(5-hydroxyadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-69: (S)-N1-(1-(2-(5-fluoroadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-70: (S)-N1-(1-(2-(5-chloroadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-71: (S)-N1-(1-(2-(5-bromoadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-72: (S)-N1-(1-(2-(5-methyladamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-71 (S)-N1-(1-(2-(2-carbonitrileadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-di hydropyrid in-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-87: (S)-N1-(1-(2-(1-adamantylmethylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-88: (S)-N1-(1-(2-(1-(1-adamantypethanamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-90: (S)-N1-(1-(24(1R,2S,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-92: (S)-N1-methy1-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1S,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide 11-94: (S)-N1-(1-(24(1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-95: (S)-N1-(1-(2-(bicyclo[2.2.1]heptan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-96: (S)-N1-(1-(2-(bicyclo[2.2.1]heptan-7-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-97: (S)-N1-(1-(2-(bicyclo[2.2.1]hept-5-en-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-98: (2S)-N1-(1-(2-(bicyclo[2.2.2]octan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-99: (S)-N1-methy1-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide 11-100: (S)-N1-methy1-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide 11-101: (S)-N1-methy1-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide 11-103: (S)-N1-(1-(2-(4-homoisotwistane-3-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-104: (S)-N1-(1-(2-(diamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-105: (S)-N1-(1-(2-(diamantane-4-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-107: (S)-N1-(1-(1-adamantylmethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-108: (2S)-N1-(14(3-hydroxy-1-adamantypmethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-109: (2S)-N1-(14(3-bromo-1-adamantypmethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-110: (S)-N1-(1-(2-adamantylmethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-111: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(nicotinamido)-5-oxohexanediamide 11-112: (S)-2-(isonicotinamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-113: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(pyridazine-4-carboxamido)hexanediamide 11-114: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(pyridazine-3-carboxamido)hexanediamide 11-116: (S)-N1-cyclopropyl-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-0-5-(3-methylbenzofuran-2-carboxamido)-2-oxohexanediamide 11-116: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(3-methylbenzofuran-2-carboxamido)-5-oxo-N6-pentylhexanediamide 11-117: (S)-N1-allyl-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(3-methylbenzofuran-2-carboxamido)-2-oxohexanediamide 11-119: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-119: (S)-N1-ally1-5-(benzofuran-2-carboxamido)-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxohexanediamide 11-120: (S)-2-(benzofuran-2-carboxamido)-N6-isopropyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide 11-121: (S)-2-(benzofuran-2-carboxamido)-N6-cyclopropyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide 11-124: (S)-2-(benzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-0-5-oxohexanediamide 11-126: (S)-2-(2,5-dichlorothiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide 11-126: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(4-methy1-2-(trifluoromethypthiazole-5-carboxamido)-5-oxohexanediamide 11-127: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(1-methy1-1H-1,2,3-triazole-5-carboxamido)-5-oxohexanediamide 11-129: (2S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(2,5-dichlorothiophene-3-carboxamido)-N6-methyl-5-oxohexanediamide 11-129: (2S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(4-methyl-2-(trifluoromethypthiazole-5-carboxamido)-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-130: (2S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-di hydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-1,2,3-triazole-5-carboxamido)-5-oxohexanediamide 11-131: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(2H-1,2,3-triazole-4-carboxamido)hexanediamide 11-135: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-1,2,4-triazole-3-carboxamido)-5-oxohexanediamide 11-136: (S)-2-(benzofuran-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-137: (S)-2-(benzo[b]thiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-138 (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-pyrazole-3-carboxamido)-5-oxohexanediamide 11-139 (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-pyrazole-4-carboxamido)-5-oxohexanediamide 11-140 (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-pyrazole-5-carboxamido)-5-oxohexanediamide 11-141 (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(4-methy1-1,2,3-thiadiazole-5-carboxamido)-5-oxohexanediamide 11-142 (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1,2,5-thiadiazole-3-carboxamido)hexanediamide 11-145 (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(4-methy1-1,2,3-thiadiazole-5-carboxamido)-5-oxohexanediamide 11-146 (S)-2-(benzofuran-2-carboxamido)-N1-(1-(24(1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide 11-147 (S)-N1-(1-(24(1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-di hydropyridin-3-y1)-2-(3-methylbenzofuran-2-carboxamido)-5-oxo hexanediamide 11-148 (S)-2-(benzofuran-2-carboxamido)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide 11-149 (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-di hydropyridin-3-y1)-2-(3-methylbenzofuran-2-carboxamido)-5-oxo hexanediamide 11-150 (S)-2-(benzofuran-2-carboxamido)-5-oxo-N1-(2-oxo-1-(2-oxo-24(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yhhexanediamide 11-151 (S)-2-(3-methylbenzofuran-2-carboxamido)-5-oxo-N1-(2-oxo-1-(2-oxo-2-((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide 11-152 (S)-N1-(1-(24(1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-di hydropyridin-3-y1)-N6-methy1-2-(4-methy1-1,2,3-th iadiazole-5-carboxamido)-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-154 (S)-N1-(1-(2-((1 S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1 ,2-di hydropyrid in-3-y1)-N6-methy1-2-(4-methy1-2-(trifluoromethyl)th iazole-5-carboxamido)-5-oxohexanediamide 11-155 (S)-N1-(1-(2-((1 S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-y1)-2-(2,5-dichlorothiophene-3-carboxamido)-N6-methy1-5-oxohexanediamide 11-156 (S)-N1-(1-(2-((1 S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1 ,2-di hydropyrid in-3-y1)-N6-methy1-2-(4-methy1-1,2, 3-th iadiazole-5-carboxamido)-5-oxohexanediamide 11-157 (S)-N1-(1-(2-((1 S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1 ,2-di hydropyrid in-3-y1)-N6-methy1-2-(1 -methyl-1 H-1 ,2,3-triazole-5-carboxamido)-5-oxohexanediamide 11-158 (S)-N1-(1-(2-((1 S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1 ,2-di hydropyrid in-3-y1)-N6-methy1-2-(1 -methyl-1 H-pyrazole-5-carboxamido)-5-oxohexanediamide 11-159 (S)-N1-methy1-5-(4-methy1-2-(trifluoromethypthiazole-5-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yphexanediamide 11-160 (S)-2-(2,5-dichlorothiophene-3-carboxamido)-N6-methy1-5-oxo-N1-(2-oxo-1-(2-oxo-2-((1 R,2S,4R)-1 ,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide 11-161 (S)-N1-methy1-5-(4-methy1-1 ,2,3-thiad iazole-5-carboxamido)-2-oxo-N6-(2-oxo-1 -(2-oxo-24(1 R,2S,4R)-1 ,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1 ,2-dihydropyridin-3-yl)hexanediamide 11-162 (S)-N1-methy1-5-(1-methy1-1 H-1 ,2,3-triazole-5-carboxamido)-2-oxo-N6-(2-oxo-1 -(2-oxo-24(1 R,2S,4R)-1 ,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1 ,2-dihydropyridin-3-yl)hexanediamide 11-163 (S)-N1-methy1-5-(1-methy1-1 H-pyrazole-5-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1 R,2S,4R)-1 ,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide 11-167 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-168 (S)-2-(2-acetyloxazole-4-carboxamido)-N1-(1-(2-(bicyclo[1 .1 .1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-di hydropyrid in-3-y1)-N6-methy1-5-oxohexaned iamide 11-169 (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-170 (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(2-isopropyloxazole-5-carboxamido)-N6-methyl-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-171 (2S)-2-(benzofuran-2-carboxamido)-N1-(1-(2-(bicyclo[3.2.1]octan-8-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-172 (2S)-N1-(1-(2-(bicyclo[3.2.1]octan-8-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(3,5-dimethylisoxazole-4-carboxamido)-N6-methy1-5-oxohexanediamide 11-173 (S)-N1-(1-(2-(5-carboxy-2-aminoadamantane)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(4-methylpyrimidine-5-carboxamido)-5-oxohexanediamide 11-174 (2S)-N1 -(1-(2-(4-aminoadamantane-N,N-d imethyl-1 -carboxamide)-2-oxoethyl)-2-oxo-1,2-d ihydropyrid in-3-y1)-N6-methyl-5-oxo-2-(1 ,2,3,4-tetrahydronaphthalene-2-carboxamido)hexanediamide 11-178 (S)-2-(benzo[d]thiazole-2-carboxamido)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-cyclopentyl-5-oxohexanediamide 11-182 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-cyclohexy1-2-(3-ethylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-183 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-cyclohexy1-2-(1-ethy1-1H-indole-2-carboxamido)-5-oxohexanediamide 11-194 (S)-2-(benzofuran-5-carboxamido)-N1-(1-(2-(1-acetylamino-4-aminoadamantane)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-195 (S)-2-(benzofuran-6-carboxamido)-N1-(1-(2-(4-aminoadamantane-1-carboxamide)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-198 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1,2,3-thiadiazole-4-carboxamido)hexanediamide 11-199 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1,2,4-thiadiazole-5-carboxamido)hexanediamide 11-200 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1,3,4-thiadiazole-2-carboxamido)hexanediamide 11-201 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(4-cyclopropy1-1,2,3-thiadiazole-5-carboxamido)-N6-methyl-5-oxohexanediamide 11-202 (S)-2-(4-cyclopropy1-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide 11-203 (S)-2-(4-isopropy1-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide 11-204 (S)-2-(4-ethy1-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide 11-205 (S)-2-(4-formy1-1 ,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-206 (S)-244-(hydroxymethyl)-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide 11-207 (S)-N1-(1-(2-(1-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(3,5-dimethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-11-210 dihydropyridin-3-y1)-N6-methy1-241-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (S)-N1 -(1-(2-(3,5,7-trimethyl-1 -adamantylam ino)-2-oxoethyl)-2-oxo-1 ,2-11-211 dihydropyridin-3-y1)-N6-methy1-241-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide or a pharmaceutically acceptable salt thereof.
Method for production of inventive compounds In some embodiments, the present invention relates to a method for the synthesis of a compound of formula (I), especially any compound of the formula (lb):
OA N .R6 ---.
Ao N H o )-L ,, , H
0 (lb) The compound of the formula (lb) can be produced and thus, the present invention relates to a method for producing the compound of formula (lb) comprising the following steps in the following order:
Step 1B: providing a compound 4b Ac0)-L
PGNKOH
H 0 4b;
Step 2B: performing coupling reaction of the compound 4b with a compound 5 H2N N)-L , L , IR' , to obtain a compound 6b 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 Ac0 N , R6 i_i R70 PG3Ni\O- ,L.
6b;
Step 3B: deprotecting an amino protecting group PG3to obtain a compound 7b Ac0)-N , R6 HN rl N , L
1 'R3 0 7b;
Step 4B: performing coupling reaction of the compound 7b with a carboxylic acid (R2-CO2H 8) to obtain a compound 9b Ac0)-N L , R6 1 N" 'R3 9b;
Step 5B: performing oxidation reaction of the compound 9b to produce the compound of the formula (lb) OA .R6 --.. N
R2AN N , N L .
(1b);
wherein L, R2, R3, R6 and R7 have the same meanings as defined above in the formula (lb), and PG3 is an amino protecting group.
AcO N
-L , R6 In the step 5B the chemical warhead precursor i H
i may be firstly converted to HO , R6 N HO N
, R6 ' H ; H
i under a basic condition such as treating with K2CO3, and then 0)-L N .R6 is converted to the corresponding chemical warhead H
by an oxidation 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 method, preferably by using Dess-Martin periodinane (DMP), iodoxybenzoic acid (IBX), or hypochlorite/TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) in a polar solvent, as described in the chemical examples.
In an alternative route first all protecting groups PG1 and PG2 are simultaneously removed and the protecting group PG3 is selectively introduced. Preferably, PG1 and PG3 are same.
The term "protecting groups" as used herein refers to commonly used protection groups in organic synthesis, preferably for amino and carboxyl groups. PG1, PG3, and PG5 preferably are suitable protecting groups for amino groups. PG2 and PG4 preferably are suitable protecting groups for carboxyl groups. Preferably, PG1, PG3, and PG5 may be selected from the group consisting of or comprising: acetyl, benzoyl, benzyloxycarbonyl (Cbz), tert-butylcarbonyl, tert-butyloxycarbonyl (Boc), and fluorenylmethylenoxy group (Fmoc). PG2 and PG4 may be selected from the group consisting of or comprising:
methoxy, ethoxy, isobutoxy, tert-butoxy, benzyloxy; preferably, tert-butoxy group.
In Step 2B, to promote the coupling reaction with amino group of intermediate compound, activating reagents are commonly used to activating carboxylic acid (õPeptide Coupling Reagents, More than a Letter Soup", Ayman El-Faham and Fernando Albericio, Chemical Reviews, 2011, 111(11), p.6557-6602). The activation may be introduced separate reaction or in situ reaction. Preferably, any of the following coupling reagent can be used to activate carobxylic acid group: BOP (Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate), PyBOP (Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate), AOP (7-(Azabenzotriazol-1-yl)oxy tris(dimethylamino)phosphonium hexafluorophosphate), PyAOP ((7-Azabenzotriazol-yloxy)tripyrrolidinophosphonium hexafluorophosphate), TBTU (2-(1H-Benzotriazole-1-y1)-1,1,3,3-tetramethylaminium tetrafluoroborate), EEDQ (N-Ethoxycarbony1-2-ethoxy-1,2-dihydroquinoline), Polyphosphoric Acid (PPA), DPPA (Diphenyl phosphoryl azide), HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), H BTU
(0-Benzotriazol-1-yl-N,N ,N',N'-tetramethyluronium hexafluorophosphate), HOBt (1-Hyd roxybenzotriazo le), HOAt (1-Hydroxy-7-azabenzotriazole), DCC (N,W-Dicyclohexylcarbodiimide), EDC (or EDAC or EDCI, 1-Ethy1-3-(3-dimethylam inopropyl)carbodi im ide), BOP-C1 (Bis(2-oxo-3-oxazolidinyl)phosphinic chloride), TFFH
(Tetram ethylfl uo roformam id i n i um hexafluorophosphate), BroP (Bromo tris(d imethylam ino) phosphonium hexafluorophosphate), PyBroP
(Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate) and CI P
(2-Chloro-1,3-dimethylimidazolidinium 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 hexafluorophosphate), or further, similar acting reagents, providing an activated intermediate,or a mixture thereof.
Pharmaceutical Composition & Medical Use Therefore another aspect of the present invention relates to compounds according to the general formula (I) as medicine as well as their use in medicine. Especially preferred is the use as inhibitors of transglutaminases, in particular transglutaminase 2 (TG2).
Thus the compounds of formula (I) described herein or according to the present invention may be administered themselves or in form of a pharmacologically acceptable salt.
The compounds of the present invention may form of a pharmacologically acceptable salt with organic or inorganic acids or bases. Examples of suitable acids for such acid addition salt formation are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, p-aminosalicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, sulfonic acid, phosphonic acid, perchloric acid, nitric acid, formic acid, propionic acid, gluconic acid, lactic acid, tartaric acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, methanesulfonic acid, ethanesulfonic acid, nitrous acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, p-toluenesulfonic acid, naphthylsulfonic acid, sulfanilic acid, camphorsulfonic acid, china acid, mandelic acid, o-methylmandelic acid, hydrogen-benzenesulfonic acid, picric acid, adipic acid, d-o-tolyltartaric acid, tartronic acid, (o, m, p)-toluic acid, naphthylamine sulfonic acid, trifluoroacetic acid, and other mineral or carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. Preferred is the mesylate salt, hydrochloride salt and the trifluoroacetate salt and especially preferred is the trifluoroacetate salt and the hydrochloride salt.
In the case the inventive compounds bear acidic groups, salts could also be formed with inorganic or organic bases. Examples for suitable inorganic or organic bases are, for example, NaOH, KOH, NH4OH, tetraalkylammonium hydroxide, lysine or arginine and the like. Salts may be prepared in a conventional manner using methods well known in the art, for example by treatment of a solution of the compound of the general formula (I) with a solution of an acid, selected out of the group mentioned above.
Methods of Use 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 In a further aspect of the present invention, the novel compounds according to the general formula (I) are used as pharmaceutically active agent, i.e. the compound of the formula (I) is used in medicine.
Furthermore, the present invention relates to a pharmaceutical composition comprising at least one compound according to the general formula (I), as an active ingredient or a pharmacologically acceptable salts thereof as an active ingredient, together with at least one pharmacologically acceptable carrier, excipient and/or diluent.
The compounds according to general formula (I) described herein are especially suitable for the treatment and prophylaxis of diseases associated with and/or caused by transglutaminase 2.
Celiac disease, a gluten intolerance is associated with tissue transglutaminase (TG 2).
Another very important group of indications for tissue transglutaminase inhibitors are fibrotic disorders. Fibrotic disorders are characterized by the accumulation of cross-linked extracellular matrix proteins. Diabetic nephropathy, cystic fibrosis, idiopathic pulmonary fibrosis, kidney fibrosis as well as liver fibrosis belong to the most important fibrotic disorders to be addressed with the compounds disclosed.
In the biological example B-I, it is proven that the inventive compounds as reversible and irreversible TG inhibitors effectively inhibit the activity of TGs, especially TG2.
As used herein the term "inhibiting" or "inhibition" refers to the ability of a compound to downregulate, decrease, reduce, suppress, inactivate, or inhibit at least partially the activity of an enzyme, or the expression of an enzyme or protein.
Therefore, another aspect of the present invention is the use of the inventive compounds of the general formula (I), or the pharmaceutical composition thereof as described in the treatment or prophylaxis of autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, ocular diseases, and skin disorders.
Further aspects of the present invention relate to the use of the compounds of general formula (I) for the preparation of a pharmaceutical composition useful for prophylaxis and/or treatment of autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, ocular diseases, and skin disorders.
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 In a further aspect of the present invention, a method for preventing and/or treating autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, ocular diseases, and skin disorders, which method comprises administering to a subject, in particular a human, a pharmaceutically effective amount of at least one compound of the general formula (I), to prevent and/or treat said autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, ocular diseases, and skin disorders.
Preferred, the autoimmune and inflammatory diseases comprises multiple sclerosis, celiac disease, Duhring-Brocq-disease (dermatitis herpetiformis), gluten ataxia, gluten neuropathy, diabetes, rheumatoid arthritis, Graves' disease, inflammatory bowel disease, systemic lupus erythematosus psoriasis, and gingivitis;
the vascular diseases comprise atherosclerosis, thrombosis, vascular stiffness;
the fibrotic diseases affecting the lung, the kidney, the liver, the skin or the gut like cystic fibrosis, kidney fibrosis and diabetic nephropathy, intestinal fibrosis, idiopathic lung fibrosis, liver fibrosis;
the liver diseases like alcoholic hepatitis, alcoholic steatohepatitis, nonalcoholic steatohepatitis, non-alcoholic fatty liver disease, liver cirrhosis, autoimmune hepatitis or liver inflammation;
.. the cholestatic liver diseases comprise primary biliary cholangitis and primary sclerosing cholangitis;
the cancer comprises glioblastoma, melanoma, pancreatic cancer, renal cell carcinoma, meningioma, and breast cancer, the neurodegenerative diseases comprise Parkinson's disease, Huntington's disease, or Alzheimer's disease, the ocular diseases comprise glaucoma, cataracts, macular degeneration, or uveitis;
the skin disorders comprise acne, psoriasis, scarring, and skin aging.
More preferred, the compound of the formula (I), or the pharmaceutical composition thereof is useful in the treatment or prophylaxis of celiac disease.
Furthermore, the compounds of the general formula (I), can be administered in form of their pharmaceutically active salts, optionally using essentially non-toxic pharmaceutically acceptable carriers, adjuvants or extenders. Medications are prepared in a known manner in a conventional solid or fluid carrier or in extenders and a conventional pharmaceutically acceptable adjuvant/expedient in a suitable dose. The preferred preparations are provided in an administrable form suitable for oral application, such as pills, tablets, film tablets, coated tablets, capsules and powders.
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 Tablets, film tablets, coated tablets, gelatine capsules and opaque capsules are the preferred pharmaceutical formulations. Any pharmaceutical compositions contains at least one compound of the general formula (I), and/or pharmaceutically acceptable salts thereof in an amount of 5 mg to 500 mg, preferably 10 mg to 250 mg and most preferred in an amount of 10 to 100 mg per formulation.
Besides, the object of the present invention also includes pharmaceutical preparations for oral, parenteral, dermal, intradermal, intragastric, intracutaneous, intravascular, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal, percutaneous, rectal, subcutaneous, sublingual, topic, transdermal or inhalative application, containing, in addition to typical vehicles and extenders, a compound of the general formula (I), and/or a pharmaceutically acceptable salt thereof as active component.
The pharmaceutical compositions of the present invention contain one of the compounds of the formula (I) disclosed herein as active component, typically mixed with suitable carrier materials, selected with respect to the intended form of administration, i.e. tablets to be administered orally, capsules (filled either with a solid, a semi-solid or a liquid), powders, orally administrable gels, elixirs, dispersible granulates, syrups, suspensions .. and the like in accordance with conventional pharmaceutical practices. For example, the compound of the formula (I) can as active agent component be combined with any oral, non-toxic, pharmaceutically acceptable, inert carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms) and the like for the oral administration in form of tablets or capsules.
.. Moreover, suitable binders, lubricants, disintegrants and colorants can be added to the mixture if required. Powders and tablets can consist of said inert carriers to an extent from about 5% per weight to about 95% per weight of the inventive composition.
Suitable binders include starch, gelatine, natural sugars, sweeteners made of corn, natural and synthetic gums, such as acacia gum, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes. Possible lubricants for the use in said dosage forms include boric acid, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrants include starch, methylcellulose, cyclodextrins, guar gum and the like. If required, sweeteners and flavor additives and preservatives can also be .. included. Some of the terms used above, namely disintegrants, extenders, lubricants, binders and the like are discussed in greater detail below.
Additionally, the compositions of the present invention can be formulated in a form with sustained release to provide a controlled release rate of any one or more components or active components, in order to optimize the therapeutic effect, i.e. the inhibitory activity 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 and the like. Suitable dosage forms for sustained release include layered tablets containing layers with varying degradation rates or controlled release polymeric matrices impregnated with the active components and in the form of a tablet or capsule containing such impregnated or encapsulated porous polymeric matrices.
Preparations in fluid form include solutions, suspensions and emulsions.
Exemplarily mentioned are water or water propylene glycol solutions for parenteral injections or the addition of sweeteners and opacifiers for oral solutions, suspensions, and emulsions.
Aerosol preparations suitable for inhalation may include solutions and solids in the form of powders which can be combined with a pharmaceutically acceptable carrier, such as a compressed inert gas, e.g. nitrogen.
For the preparation of suppositories a low melting wax, such as a mixture of fatty acid glycerides, e.g. cocoa butter, is melted firstly and the active component is homogenously dispersed therein by stirring or similar mixing operations. The melted homogenous mixture is then poured in fitting forms, cooled and thus hardened.
Further preparations in solid form which are to be converted into preparations in fluid form for either oral or parenteral administration shortly before use are included.
Such fluid forms include solutions, suspensions and emulsions.
Furthermore, the compounds of the present invention may be administered via transdermal application. The transdermal compositions can have the form of crèmes, lotions, aerosols and/or emulsions.
The term capsule refers to a special container or casing composed of methylcellulose, polyvinyl alcohols or denatured gelatins or starches, in which the active agents can be enclosed. Typically, hard shell capsules are prepared from mixtures of bones and porcine skin gelatins having comparatively high gel strength. The capsule itself can contain small amounts of colorants, opacifiers, softening agents and preservatives.
Tablet means a compressed or cast solid dosage form containing the active components with suitable extenders. The tablet can be produced by compressing mixtures or granulates obtained by wet granulation, dry granulation or compaction, which are known to the one skilled in the art.
Oral gels refer to the active components dispersed or solubilized in a hydrophilic semi-solid matrix.
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 Powders for compositions refer to powder mixtures containing the active components and suitable extenders which can be suspended in water or juices.
Suitable extenders are substances which usually form the largest part of the composition or dosage form. Suitable extenders include sugars such as lactose, sucrose, mannitol and sorbitol; starches derived from wheat, corn, rice and potatoes; and celluloses such as microcrystalline cellulose. The amount of extenders in the composition can range from about 5 to about 95% per weight of the total composition, preferably form about 25 to about 75% per weight and further preferred from about 30 to about 60% per weight.
The term disintegrants refers to materials added to the composition in order to support disintegration and release of the medicinal substance. Suitable disintegrants include starches, modified starches which are soluble in cold water, such as sodium carboxymethyl starch; natural and synthetic gums such as locust bean gum, caraya, guar gum, tragacanth and agar; cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose, microcrystalline celluloses and crosslinked microcrystalline celluloses such as croscarmellose sodium; alginates such as alginic acid and sodium alginate; clays such as bentonites and foaming mixtures. The amount of disintegrants used in the composition can range from about 2 to 20% per weight of the composition and further preferred from about 5 to about 10% per weight.
Binders characterize substances binding or "gluing" powders to each other and they consequently serve as "glue" in the formulation. Binders add a cohesion starch which is already available in the extenders or the disintegrant. Suitable binders include sugar, such as sucrose; starches derived from wheat, corn, rice and potatoes; natural gums such as acacia gum, gelatine and tragacanth; derivatives of sea weed such as alginic acid, sodium alginate and ammonium calcium alginate, cellulose materials such as methyl cellulose and sodium carboxymethylcellulose and hydroxypropyl methylcellulose, polyvinylpyrrolidone and inorganic compounds, such as magnesium aluminium silicate.
The amount of binders in the composition can range from about 2 to about 20%
per weight of the total composition, preferably form about 3 to about 10% per weight and further preferred from about 3 to about 6% per weight.
The term lubricant refers to a substance added to the dosage form in order to allow for the tablet, granulate, etc. to be released from the casting mold or pressing mold, after compression, by reducing the friction. Suitable lubricants include metallic stearates such as magnesium stearate, calcium stearate or potassium stearate; stearic acid;
waxes with high melting points and water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and D,L-leucine.
Due to the fact that lubricants have to be present on the surface of the granulates as well as 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 between the granulates and parts of the tablet press they are typically added during the last step prior to compression. The amount of lubricants in the composition can range from about 0.2 to about 5% per weight of the total composition, preferably form about 0.5 to about 2% per weight and further preferred from about 0.3 to about 1.5 % per weight.
Lubricants are materials preventing caking and improving the flow characteristics of granulates so that the flow is smooth and uniform. Suitable lubricants include silicon dioxide and talc. The amount of lubricants in the composition can range from about 0.1 to about 5 % per weight of the total composition, preferably form about 0.5 to about 2 %
per weight.
Colorants are adjuvants coloring the composition or dosage form. Such adjuvants can include colorants having food quality which are adsorbed on a suitable adsorption means, such as clay or aluminium oxide. The amount of the colorant used can vary from about 0.1 to about 5% per weight of the composition and preferably from about 0.1 to about 1%
per weight.
As used herein, a "pharmaceutically effective amount" of a transglutaminase inhibitor is the amount or activity effective for achieving the desired physiological result, either in cells treated in vitro or in a patient treated in vivo. Specifically, a pharmaceutical effective amount is such an amount which is sufficient for inhibiting, for a certain period of time, one or more of the clinically defined pathological processes associated with transglutaminase 2. The effective amount can vary according to the specific compound of the formula (I) and additionally depends on a plurality of factors and conditions related to the subject to be treated and the severity of the disease. If, for example, an inhibitor is to be administered in vivo, factors such as age, weight and health of the patients as well as dose reaction curves and data regarding toxicity obtained from preclinical animal studies are amongst the data to be considered. If the inhibitor in form of the compound of the formula (I) described herein is to be brought in contact with the cells in vivo, a plurality of preclinical in vitro studies would be designed in order to determine parameters such as absorption, half-life, dose, toxicity, etc. Determining a pharmaceutically effective amount fora given pharmaceutically active ingredient is part of the ordinary skills of the one skilled in the art.
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 Examples Following abbreviations used in the examples have the following meaning.
Boc (tert-butoxycarbonyl), Boc0Su (N-tert-butoxycarbonyloxy-succinim ide) DCM (dichloromethane), DMAP (4-(Dimethylamino)-pyridine), TEA (triethylamine), DMF (dimethylformamide), DMP (Dess-Martin periodiane), DIPEA
(N-Ethyldiisopropylamine), Glu (glutamic acid), EDC
(1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide), TFA (trifluoroacetic acid), THF
(tetrahydrofuran), Et0Ac (ethyl acetate), HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate), HOBt (hydroxybenzotriazole), MTBE
(methyl tert-butyl ether), tBu (tert-butyl), Chemical Examples The following examples are intended to illustrate the invention with selected compounds without limiting the protecting scope of the present intellectual property right on these concrete examples. It is clear for a person skilled in the art that analogous compounds and compounds produced according to analogous synthetic ways fall under the protecting scope of the present intellectual property right.
Example II. Synthetic method 11 Scheme 11-1 OH Chloroacetic acid 0 02N Na3PO4 (acl) ...õ..AN 02N N OH
I2-Adamantylamine EDC, DIPEA, DMF
10% Pd/C
H Me0H 0 H
H2NAN N -. ________ 02N ).L N
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 1 Preparation of compound ZED1657 02N)-L NThrOH
2-(3-nitro-2-oxopyridin-1(2H)-yl)acetic acid Chemical Formula: C7H6N205 Exact Mass: 198.03 Molecular Weight: 198.13 30.0 g (214 mmol) of 2-hydroxy-3-nitropyridine and 40.5 g (2 eq) of chloroacetic acid were suspended in 600 mL water. At 40 C, 245 g (3 eq) trisodium phosphate dodecahydrate were added, and the reaction was stirred at room temperature overnight. 250 mL
HCI
(32%) were added, and the suspension was stirred for another night at 4 C. The precipitate was filtered and dried. Yield: 41.2 g, 97% ESI-MS: 199.3 [M+H]
2 Preparation of compound ZED3905 Tof N-(2-adamantyI)-2-(3-nitro-2-oxopyridin-1(2H)-yl)acetamide Chemical Formula: 017H21N304 Exact Mass: 331.15 Molecular Weight: 331.37 17.0 g (85.8 mmol) of ZED1657, 16.1 g (1 eq) of 2-adamantanamine hydrochloride and 11.6 g (1 eq) of HOBt were dissolved in 200 mL DMF and 17.9 mL (1.2 eq) DIPEA.
18.1 g (1.1 eq) of 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride were added and the reaction was stirred at room temperature overnight. The solvent was evaporated, and the residue was dissolved in 500 mL DCM. The solution was washed with each mL citric acid solution (10%), NaHCO3 solution (10%) and brine. The organic phase was dried over Na2SO4, filtered and the solvent was evaporated.
Yield: 24.1 g, 85% ESI-MS: 332.4 [M+H]
3 Preparation of compound ZED3906 H2Nj-( N-IN
2-(3-amino-2-oxopyridin-1(2H)-y1)-N-(2-adamantyl)acetamide Chemical Formula: C17H23N302 Exact Mass: 301.18 Molecular Weight: 301.38 24.2 g (73.0 mmol) of ZED3905 were suspended in 600 mL Me0H before 2.42 g of palladium (10%) on activated carbon (unreduced) were added. The suspension was stirred overnight at room temperature under an atmosphere of hydrogen. The catalyst was filtered, and the solvent was evaporated. Yield: 15.7 g, 71% ESI-MS: 302.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 Scheme 11-2 OH 1. DMF, CH3I OH 1. Methyl AcOAN
Cs2003 isocyanide 2. DMAP, ACN AcOH, DCM
Boc20 2. TFA
Boc, Boc, Boc,N OH
N CO2tBu N CO2tBu 3. DIBAL-H Boc 3. Boc.20 0 Et20, -78 C DIPEA, DMF
N HATU, DMF
o DIPEA
Ac0j-N Ac0j-LN
H
1) TFA, DCM
__________________________________________________________ Boc,NcrN
1NrCr 0 0 2) 3-Methylbenzo[b]- 0 0 furan-2-carboxylic acid HATU, DIPEA, DMF
K2CO3, Me0H
OAN
0 0 Dess-Martin 0 0 0 IRLA periodinane H
N
1-1Cr U\Irr\I oI DMF 1NrCr U\IThrN
Preparation of compound ZED788 0 OMe Boc,NOtBu (S)-1-tert-butyl 5-methyl 2-(tert-butoxycarbonylamino)pentanedioate Chemical Formula: C15H27N06 Exact Mass: 317,18 Molecular Weight: 317,38 12.0 g of Boc-L-Glu-OtBu (39.6 mmol) and 7.09 g of cesium carbonate (21.8 mmol, 0.55 eq) were suspended in 100 ml of DMF and stirred for 1 h at room temperature.
2.47 ml iodomethane (39.6 mmol) we added, and the mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was dissolved in ethyl acetate and washed twice with each citric acid solution (10%), NaHCO3 solution (10%) and brine.
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 The organic phase was dried over Na2SO4, filtered and the solvent was evaporated. The raw product was used without further purification.
Yield: 13.4 g, >100%
ESI-MS: 318.3 [M+H]
Preparation of compound ZED720 00Me Boo, OtBu 60c 0 (S)-1-tert-butyl 5-methyl 2-(bis(tert-butoxycarbonyl)amino)pentanedioate Chemical Formula: C201-135N08 Exact Mass: 417,24 Molecular Weight: 417,49 13.4 g of ZED788 (-39,6 mmol) and 986 mg of N,N-dimethy1-4-aminopyridine (DMAP) were dissolved in 30 ml of acetonitrile. 17.6 g of di-tert-butyl bicarbonate (77.1 mmol) in 100 ml of acetonitrile was added and the solution was stirred at room temperature overnight. The solvent was evaporated, and the residue was dissolved in ethyl acetate and washed twice with each citric acid solution (10%), NaHCO3 solution (10%) and brine.
The organic phase was dried over Na2SO4, filtered and the solvent was evaporated. The raw product was used without further purification.
Yield: 13.7 g, 83%
ESI-MS: 418.3 [M+H]
Preparation of compound ZED721 Boc,NJC0tBu Boo 0 (S)-tert-butyl 2-(bis(tert-butoxycarbonyl)amino)-5-oxopentanoate Chemical Formula: C19H33N07 Exact Mass: 387,23 Molecular Weight: 387,47 13.7 g of ZED720 (32.8 mmol) were dissolved in 200 ml of dry diethyl ether and cooled to -78 C under argon atmosphere. 36.1 ml of diisobutylaluminum hydride (1M in hexane) were added dropwise and the solution was stirred for 30 min at -78 C before being quenched with potassium sodium tartrate (Rochelle salt) solution. The organic layer was separated, dried over Na2SO4, filtered, and concentrated to dryness. The raw product was used without further purification.
Yield: 13.3 g, >100%
ESI-MS: 388.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 4 Preparation of compound ZED3632 AcON
Boc ,N (rOH
(2S)-5-acetoxy-2-(tert-butoxycarbonylamino)-6-(methylamino)-6-oxohexanoic acid Chemical Formula: C14H24N207 Exact Mass: 332,16 Molecular Weight: 332,35 .. 15.0 g (38.7 mmol) of the aldehyde (S)-tert-butyl 2-(bis(tert-butoxycarbonyl)amino)-5-oxopentanoate (ZED721) were dissolved in 60 mL DCM. At 0 C 2.42 mL (1.05 eq) methyl isocyanide and 2.33 mL (1.05 eq) acetic acid were added, and the reaction was stirred at room temperature overnight. 75 mL TFA were added, and the reaction was stirred for another 3 h. The solvent was evaporated, and the residue was dissolved in 40 mL DMF.
13.2 mL (2 eq) DIPEA and 10.4 g (46.6 mmol) di-tert-butyl dicarbonate in 10 mL
DMF
were added and the reaction was stirred at room temperature overnight. The solvent was evaporated, and the residue was dissolved in DCM. After extraction with NaHCO3 solution (1.05 eq in water), 1.5 eq citric acid was added to the aqueous phase, followed by re-extraction with DCM. The organic phase was dried over Na2SO4, filtered and the solvent .. was evaporated. The residue was purified by flash chromatography.
Yield: 12.5 g, 95%
ESI-MS: 333.5 [M+H]
5 Preparation of compound ZED3907 Ac0j-BocNLN
_ JI N
(5S)-5-(tert-butoxycarbonylamino)-6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-1-(methylamino)-1,6-dioxohexan-2-ylacetate Chemical Formula: C31H45N508 Exact Mass: 615.33 Molecular Weight: 615.72 19.8 g (59.5 mmol) of ZED3632, 22.6 g (1 eq) HATU and 17.9 g (1 eq) ZED3906 were dissolved in 400 mL DMF and 20.8 mL DIPEA (2 eq) and stirred at 45 C
overnight. The solvent was evaporated; the residue was dissolved in 200 mL Et0Ac and washed twice with each 150 mL citric acid solution (10%), NaHCO3 solution (10%) and brine.
The organic phase was dried over Na2SO4, filtered and the solvent was evaporated.
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 Yield: 27.4 g, 75%
ESI-MS: 616.4 [M+H]
6 Preparation of compound ZED3264 Ac0j-N
I NThr NH
I H
(5S)-6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-1-(methylamino)-5-(3-methylbenzofuran-2-carboxamido)-1,6-dioxohexan-2-ylacetate Chemical Formula: C36F-143N508 Exact Mass: 673.31 Molecular Weight: 673.76 480 mg (0.78 mmol) of ZED3907 were dissolved in 4 ml DCM/TFA (1:1) and stirred at room temperature for 1 h. The solvent was evaporated, and the residue was dissolved in 4 ml DMF. 137 mg (1 eq) 3-methylbenzo[b]furan-2-carboxylic acid, 296 mg (1 eq) HATU
and 272 pl (2 eq) DIPEA were added, and the reaction was stirred at room temperature overnight. The solvent was evaporated; the residue was dissolved in 20 mL
Et0Ac and washed with each 10 mL citric acid solution (10%), NaHCO3 solution (10%) and brine.
The organic phase was dried over Na2SO4, filtered and the solvent was evaporated.
Yield: 409 mg, 78%
ESI-MS: 674.4 [M+H]
7 Preparation of compound ZED3266 H0)-LN
0 Njcr NH N
(2S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-hydroxy-A6-methyl-2-(3-methylbenzofuran-2-carboxamido)hexanediamide Chemical Formula: C34H41N507 Exact Mass: 631.30 Molecular Weight: 631.72 409 mg (0.61 mmol) of ZED3264 were dissolved in 5 ml Me0H. 126 mg (1.5 eq) potassium carbonate were added, and the reaction was stirred at room temperature for 1 h. The solution was diluted with DCM and washed with water. The organic phase was dried over Na2SO4, filtered and the solvent was evaporated.
Yield: 377 mg, 98%
ESI-MS: 632.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 8 Preparation of compound 11-3 0)-N
H
H II H
0 NJCNNThr N
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C34H39N507 Exact Mass: 629.28 Molecular Weight: 629.70 377 mg (0.60 mmol) of ZED3266 were dissolved in 2 ml DMF. 405 mg (1.6 eq) Dess-Martin periodinane (DMP) were added and the reaction was stirred at room temperature over 2 h. The precipitate was filtered off and the filtrate was evaporated.
The residue was purified by HPLC.
Yield: 314 mg, 67%
ESI-MS: 630.4 [M+H]
1H-NMR (DMSO-D6, 500 MHz, 8 [ppm]: 1.46 // 1.98 (d lid, 2H //2H, adamantyl-C4-H2), 1.68 // 1.78 (m, 4H, adamantyl-C4-H2), 1.71 (m, 2H, adamantyl-C1-H), 1.75 (m, 2H, adamantyl-C6-H2), 1.78 (m, 2H, adamantyl-05-H), 2.05 II 2.16 (m //m, 1H // 1H, 13-CH2), 2.53 (s, 3H, benzofuran-CH3), 2.64 (d, 3H, amide-N-CH3), 2.96 (t, 2H, y-CH2), 3.82 (m, 1H, adamantyl-C2-H), 4.64 (s, 2H, N-CH2), 4.70 (ddd, 1H, a-CH2), 6.25 (t, 1H, pyridinone-C5-H), 7.33 (d, 1H, pyridinone-C6-H), 7.36 (t, 1H, benzofuran-CH), 7.51 (t, 1H, benzofuran-CH), 7.63 (d, 1H, benzofuran-CH), 7.76 (d, 1H, benzofuran-CH), 8.06 (d, 1H, adamantyl-NH), 8.21 (d, 1H, pyridinone-C4-H), 8.54 (q, 1H, methylamide-NH), 8.87 (d, 1H, a-NH), 9.36 (s, 1H, pyridinone-NH).
13C-NMR (DMSO-D6, 500 MHz, 8 [ppm]: 8.62 (benzofuran-CH3), 24.50 (13-CH2), 25.37 (amide-N-CH3), 26.57 // 26.62 (adamantyl-05-H), 30.83 (adamantyl-C4-H2), 31.35 (adamantyl-C1-H), 33.61 (y-CH2), 36.66 (adamantyl-C4'-H2), 37.01 (adamantyl-C6-H2), 51.64 (N-CH2), 52.80 (a-CH2), 53.24 (adamantyl-C2-H), 104.51 (pyridinone-05-H), 111.55 (benzofuran-CH), 121.09 (benzofuran-CH), 121.72 (benzofuran-Cq), 122.53 (pyridinone-C4-H), 123.19 (benzofuran-CH), 127.28 (pyridinone-N-Cq), 127.89 (benzofuran-CH), 129.02 (benzofuran-Cq), 133.27 (pyridinone-C6-H), 142.31 (benzofuran-Cq), 152.68 (benzofuran-Cq), 156.55 (pyridinone-C=0), 159.59 (benzofuran-C=0), 161.32 (C=O-NH-CH3), 165.65 (C=0-adamantylamide), 170.42 (C=O-NH-pyridinone), 198.06 (C=0-methylamide).
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 9 Preparation of compound 11-2 N
H
0 1 õ,J(rNFIL
1 N-rN
il 0 0 (S)-2-( benzofu ran-2-carboxamido)-N 1-(1-(2-(2-adamantylamin o)-2-oxoethyl)-2-oxo-1,2-d i hyd ropyrid in-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: 033H37N507 Exact Mass: 615.27 Molecular Weight: 615.68 To the a-hydroxyester precursor of compound 11-2 (242 mg, 0.39 mmol, prepared by using benzofuran-2-carboxylic acid in step 6 according to compound ZED3264) in 8 mL
of .. acetonitrile, 1 mg of TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl, 1 mol%) were added.
56 mg of calcium hypochlorite (1 eq) were added at 0 C and the reaction mixture was stirred at 25 C for 2 h. The suspension was filtered, diluted with ethyl acetate and washed with NaHCO3 solution (10%) and brine. The organic phase was dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by HPLC.
Yield: 102 mg, 42%
ESI-MS: 616.3 [M+H]
10 Preparation of compound 11-4 0 N....,),. ..,--H
H
0 1 rrc NH )-L
1 N -rN
C
(S)-2-(3-chlorobenzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C33H36CIN507 Exact Mass: 649.23 Molecular Weight: 650.12 To the a-hydroxyester precursor of compound 11-4 (124 mg, 0.19 mmol, prepared by using 3-chlorobenzofuran-2-carboxylic acid in step 6 according to compound ZED3264) in 4 ml DMSO, 106 mg of 2-iodoxybenzoic acid (IBX, 2 eq) were added and the reaction mixture was stirred at room temperature for 3 h. NaHCO3 solution (10%) was added and the suspension was extracted with Et0Ac. The organic phase was dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by HPLC.
Yield: 37 mg, 30% (last step) ESI-MS: 650.3 / 652.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11 Preparation of compound 11-5 0)-LN
N
o hijCr Br (S)-2-(4-bromobenzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C33H36BrN507 Exact Mass: 693.18 Molecular Weight: 694.57 The synthesis of compound 11-5 was performed according to compound 11-3, using bromo-1-benzofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 69 mg, 72% (last step) ESI-MS: 694.3 / 696.3 [M+H]
12 Preparation of compound 11-6 N
N
I i'dr (S)-2-(benzo[b]thiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: 033H37N506S
Exact Mass: 631.25 Molecular Weight: 631.74 The synthesis of compound 11-6 was performed according to compound 11-3, using benzo[b]thiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 287 mg, 76% (last step) ESI-MS: 632.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 13 Preparation of compound 11-7 N
/SN
N
N
I H
Br (S)-2-(5-bromobenzo[b]thiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide Chemical Formula: C33H36BrN506S
Exact Mass: 709.16 Molecular Weight: 710.64 The synthesis of compound 11-7 was performed according to compound 11-3, using bromobenzo[b]thiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 145 mg, 59% (last step) ESI-MS: 710.2 / 712.2 [M+H]
14 Preparation of compound 11-8 OAN
N NH N N
(S)-2-(7-fluorobenzo[b]thiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide Chemical Formula: C33H36FN506S
Exact Mass: 649.24 Molecular Weight: 649.73 The synthesis of compound 11-8 was performed according to compound 11-3, using fluorobenzo[b]thiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 78 mg, 71% (last step) ESI-MS: 650.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 15 Preparation of compound 11-9 o o ).N
H
0 õ 0 H H
N kl1)-L
I H I I
(S)-2-(1H-indole-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C33H38N606 Exact Mass: 614.29 Molecular Weight: 614.69 The synthesis of compound 11-9 was performed according to compound 11-3, using indole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 57 mg, 69% (last step) ESI-MS: 615.4 [M+H]
16 Preparation of compound 11-10 0......õ..k. ---N
H
0 (rH 0 H H
N N Nj-LNN
, F F
(S)-2-(4,5-difluoro-1H-indole-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C33F136F2N606 Exact Mass: 650.27 Molecular Weight: 650.67 The synthesis of compound 11-10 was performed according to compound 11-3, using 4,5-difluoro-1H-indole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 47 mg, 65% (last step) ESI-MS: 651.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
H
0 (rH 0 H H
N N Nj-LNN
, F F
(S)-2-(4,5-difluoro-1H-indole-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C33F136F2N606 Exact Mass: 650.27 Molecular Weight: 650.67 The synthesis of compound 11-10 was performed according to compound 11-3, using 4,5-difluoro-1H-indole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 47 mg, 65% (last step) ESI-MS: 651.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
17 Preparation of compound 11-11 I H I I
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methyl-1H-indole-2-carboxamido)-5-oxohexanediamide Chemical Formula: C34H40N606 Exact Mass: 628.30 Molecular Weight: 628.72 The synthesis of compound 11-11 was performed according to compound 11-3, using 3-methyl-1H-indole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 58 mg, 72% (last step) ESI-MS: 629.4 [M+H]
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methyl-1H-indole-2-carboxamido)-5-oxohexanediamide Chemical Formula: C34H40N606 Exact Mass: 628.30 Molecular Weight: 628.72 The synthesis of compound 11-11 was performed according to compound 11-3, using 3-methyl-1H-indole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 58 mg, 72% (last step) ESI-MS: 629.4 [M+H]
18 Preparation of compound 11-12 =)LN
NTh'N
(S)-2-(1H-benzo[d]imidazole-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide Chemical Formula: C32F-137N706 Exact Mass: 615.28 Molecular Weight: 615.68 The synthesis of compound 11-12 was performed according to compound 11-3, using 1H-benzo[d]imidazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 27 mg, 48% (last step) ESI-MS: 616.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
NTh'N
(S)-2-(1H-benzo[d]imidazole-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide Chemical Formula: C32F-137N706 Exact Mass: 615.28 Molecular Weight: 615.68 The synthesis of compound 11-12 was performed according to compound 11-3, using 1H-benzo[d]imidazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 27 mg, 48% (last step) ESI-MS: 616.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
19 Preparation of compound 11-13 N
N N
r\iN
(S)-2-(2,3-dihydro-1H-indene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C34F141N506 Exact Mass: 615.31 Molecular Weight: 615.72 The synthesis of compound 11-13 was performed according to compound 11-3, using 2,3-dihydro-1H-indene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 38 mg, 61% (last step) ESI-MS: 616.4 [M+H]
N N
r\iN
(S)-2-(2,3-dihydro-1H-indene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C34F141N506 Exact Mass: 615.31 Molecular Weight: 615.72 The synthesis of compound 11-13 was performed according to compound 11-3, using 2,3-dihydro-1H-indene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 38 mg, 61% (last step) ESI-MS: 616.4 [M+H]
20 Preparation of compound 11-14 [\11N N
N
Br (S)-2-(2-bromo-4-methylthiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C29H35BrN606S
Exact Mass: 674.15 Molecular Weight: 675.59 The synthesis of compound 11-14 was performed according to compound 11-3, using 2-bromo-4-methylthiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 98 mg, 70% (last step) ESI-MS: 675.2 /677.2 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
N
Br (S)-2-(2-bromo-4-methylthiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C29H35BrN606S
Exact Mass: 674.15 Molecular Weight: 675.59 The synthesis of compound 11-14 was performed according to compound 11-3, using 2-bromo-4-methylthiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 98 mg, 70% (last step) ESI-MS: 675.2 /677.2 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
21 Preparation of compound 11-15 ON
N
S Nr N
.1-(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(4-methyl-2-(trifluoromethyl)thiazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C30H36F3N606S
Exact Mass: 664.23 Molecular Weight: 664.70 The synthesis of compound 11-15 was performed according to compound 11-3, using 4-methyl-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 67 mg, 51% (last step) ESI-MS: 665.4 [M+H]
N
S Nr N
.1-(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(4-methyl-2-(trifluoromethyl)thiazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C30H36F3N606S
Exact Mass: 664.23 Molecular Weight: 664.70 The synthesis of compound 11-15 was performed according to compound 11-3, using 4-methyl-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 67 mg, 51% (last step) ESI-MS: 665.4 [M+H]
22 Preparation of compound 11-16 N
F3C---e_fL N NTh o o Br (S)-2-(4-bromo-2-(trifluoromethyl)thiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide Chemical Formula: C29H32BrF3N606S
Exact Mass: 728.12 Molecular Weight: 729.57 The synthesis of compound 11-16 was performed according to compound 11-3, using 4-bromo-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 136 mg, 63% (last step) ESI-MS: 729.3 / 731.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
F3C---e_fL N NTh o o Br (S)-2-(4-bromo-2-(trifluoromethyl)thiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide Chemical Formula: C29H32BrF3N606S
Exact Mass: 728.12 Molecular Weight: 729.57 The synthesis of compound 11-16 was performed according to compound 11-3, using 4-bromo-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 136 mg, 63% (last step) ESI-MS: 729.3 / 731.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
23 Preparation of compound 11-17 OAN
0 r H 0 N
CI
(S)-2-(2,4-dichlorothiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C28F132C12N606S
Exact Mass: 650.15 Molecular Weight: 651.56 The synthesis of compound 11-17 was performed according to compound 11-3, using 2,4-dichlorothiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid .. in step 6 (according to ZED3264).
Yield: 102 mg, 71% (last step) ESI-MS: 651.2 / 653.2 [M+H]
0 r H 0 N
CI
(S)-2-(2,4-dichlorothiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C28F132C12N606S
Exact Mass: 650.15 Molecular Weight: 651.56 The synthesis of compound 11-17 was performed according to compound 11-3, using 2,4-dichlorothiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid .. in step 6 (according to ZED3264).
Yield: 102 mg, 71% (last step) ESI-MS: 651.2 / 653.2 [M+H]
24 Preparation of compound 11-18 ,S NN N
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(2-methoxy-4-methylthiazole-5-carboxamido)-N6-methy1-5-oxohexanediamide Chemical Formula: C30H38N607S
Exact Mass: 626.25 Molecular Weight: 626.72 The synthesis of compound 11-18 was performed according to compound 11-3, using 2-methoxy-4-methylthiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-carboxylic acid in step 6 (according to ZED3264).
Yield: 56 mg, 63% (last step) .. ESI-MS: 627.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(2-methoxy-4-methylthiazole-5-carboxamido)-N6-methy1-5-oxohexanediamide Chemical Formula: C30H38N607S
Exact Mass: 626.25 Molecular Weight: 626.72 The synthesis of compound 11-18 was performed according to compound 11-3, using 2-methoxy-4-methylthiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-carboxylic acid in step 6 (according to ZED3264).
Yield: 56 mg, 63% (last step) .. ESI-MS: 627.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
25 Preparation of compound 11-19 OA N
0 õ 0 S N m H ¨I
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(4-methy1-2-phenylthiazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C35H4.0N606S
Exact Mass: 672.27 Molecular Weight: 672.79 The synthesis of compound 11-19 was performed according to compound 11-3, using 4-methyl-2-phenylthiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 46 mg, 67% (last step) ESI-MS: 673.4 [M+H]
0 õ 0 S N m H ¨I
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(4-methy1-2-phenylthiazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C35H4.0N606S
Exact Mass: 672.27 Molecular Weight: 672.79 The synthesis of compound 11-19 was performed according to compound 11-3, using 4-methyl-2-phenylthiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 46 mg, 67% (last step) ESI-MS: 673.4 [M+H]
26 Preparation of compound 11-20 oR
/S H
N N N
N
(S)-2-(2,4-dimethylthiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-clihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: 030H38N606S
Exact Mass: 610.26 Molecular Weight: 610.72 The synthesis of compound 11-20 was performed according to compound 11-3, using 2,4-dimethylthiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 216 mg, 77% (last step) ESI-MS: 611.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
/S H
N N N
N
(S)-2-(2,4-dimethylthiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-clihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: 030H38N606S
Exact Mass: 610.26 Molecular Weight: 610.72 The synthesis of compound 11-20 was performed according to compound 11-3, using 2,4-dimethylthiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 216 mg, 77% (last step) ESI-MS: 611.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
27 Preparation of compound 11-21 0 jc 0 Br \I H 0 0 (S)-2-(5-bromo-3-methylthiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C301-1366rN506S
Exact Mass: 673.16 Molecular Weight: 674.61 The synthesis of compound 11-21 was performed according to compound 11-3, using 5-bromo-3-methylthiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-.. carboxylic acid in step 6 (according to ZED3264).
Yield: 178 mg, 79% (last step) ESI-MS: 674.2 / 676.2.4 [M+H]
Exact Mass: 673.16 Molecular Weight: 674.61 The synthesis of compound 11-21 was performed according to compound 11-3, using 5-bromo-3-methylthiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-.. carboxylic acid in step 6 (according to ZED3264).
Yield: 178 mg, 79% (last step) ESI-MS: 674.2 / 676.2.4 [M+H]
28 Preparation of compound 11-22 0)-L
N
Br N(rN')-LNN
\ I H 0 Br (S)-2-(3,5-dibromothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-clihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C29H33Br2N506S
Exact Mass: 737.05 Molecular Weight: 739.48 The synthesis of compound 11-22 was performed according to compound 11-3, using 3,5-dibromothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 89 mg, 67% (last step) ESI-MS: 738.2 / 740.2 / 742.2 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
N
Br N(rN')-LNN
\ I H 0 Br (S)-2-(3,5-dibromothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-clihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C29H33Br2N506S
Exact Mass: 737.05 Molecular Weight: 739.48 The synthesis of compound 11-22 was performed according to compound 11-3, using 3,5-dibromothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 89 mg, 67% (last step) ESI-MS: 738.2 / 740.2 / 742.2 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
29 Preparation of compound 11-23 N
Nj-LNN
Br \I H 0 0 (S)-2-(5-bromothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C29H34BrN506S
Exact Mass: 659.14 Molecular Weight: 660.58 The synthesis of compound 11-23 was performed according to compound 11-3, using 5-bromothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 141 mg, 72% (last step) ESI-MS: 660.2 / 662.2 [M+H]
Nj-LNN
Br \I H 0 0 (S)-2-(5-bromothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C29H34BrN506S
Exact Mass: 659.14 Molecular Weight: 660.58 The synthesis of compound 11-23 was performed according to compound 11-3, using 5-bromothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 141 mg, 72% (last step) ESI-MS: 660.2 / 662.2 [M+H]
30 Preparation of compound 11-24 0 0 r H
(S)-2-(5-chlorothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C29H34CIN506S
Exact Mass: 615.19 Molecular Weight: 616.13 The synthesis of compound 11-24 was performed according to compound 11-3, using 5-chlorothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 117 mg, 78% (last step) .. ESI-MS: 616.3 /618.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
(S)-2-(5-chlorothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C29H34CIN506S
Exact Mass: 615.19 Molecular Weight: 616.13 The synthesis of compound 11-24 was performed according to compound 11-3, using 5-chlorothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 117 mg, 78% (last step) .. ESI-MS: 616.3 /618.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
31 Preparation of compound 11-25 N
Nj-LN
Br \I Ho I I
(S)-2-(5-bromo-3-methylfuran-2-carboxamido)-N1 -(1 -(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-311)-N6-methy1-5-oxohexanediamide Chemical Formula: C30H36BrN507 Exact Mass: 657.18 Molecular Weight: 658.54 The synthesis of compound 11-25 was performed according to compound 11-3, using 5-bromo-3-methylfuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 173 mg, 72% (last step) ESI-MS: 658.2 / 660.2 [M+H]
Nj-LN
Br \I Ho I I
(S)-2-(5-bromo-3-methylfuran-2-carboxamido)-N1 -(1 -(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-311)-N6-methy1-5-oxohexanediamide Chemical Formula: C30H36BrN507 Exact Mass: 657.18 Molecular Weight: 658.54 The synthesis of compound 11-25 was performed according to compound 11-3, using 5-bromo-3-methylfuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 173 mg, 72% (last step) ESI-MS: 658.2 / 660.2 [M+H]
32 Preparation of compound 11-26 CI \I H 0 I I
(S)-2-(5-chlorofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C29H34.CIN507 Exact Mass: 599.21 Molecular Weight: 600.06 The synthesis of compound 11-26 was performed according to compound 11-3, using 5-chlorofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 127 mg, 56% (last step) ESI-MS: 600.3 /602.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
(S)-2-(5-chlorofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C29H34.CIN507 Exact Mass: 599.21 Molecular Weight: 600.06 The synthesis of compound 11-26 was performed according to compound 11-3, using 5-chlorofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 127 mg, 56% (last step) ESI-MS: 600.3 /602.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
33 Preparation of compound 11-27 N
N N
CI / ric (S)-2-(5-chlorothiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C29H34.CIN506S
Exact Mass: 615.19 Molecular Weight: 616.13 The synthesis of compound 11-27 was performed according to compound 11-3, using 5-chlorothiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 112 mg, 65% (last step) ESI-MS: 616.3 /618.3 [M+H]
N N
CI / ric (S)-2-(5-chlorothiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C29H34.CIN506S
Exact Mass: 615.19 Molecular Weight: 616.13 The synthesis of compound 11-27 was performed according to compound 11-3, using 5-chlorothiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 112 mg, 65% (last step) ESI-MS: 616.3 /618.3 [M+H]
34 Preparation of compound 11-28 OAN
H u CI / FNicNNI
CI
(S)-2-(2,5-dichlorothiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C29H33Cl2N506S
Exact Mass: 649.15 Molecular Weight: 650.57 The synthesis of compound 11-28 was performed according to compound 11-3, using 2,5-dichlorothiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 319 mg, 77% (last step) ESI-MS: 650.3 /652.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
H u CI / FNicNNI
CI
(S)-2-(2,5-dichlorothiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C29H33Cl2N506S
Exact Mass: 649.15 Molecular Weight: 650.57 The synthesis of compound 11-28 was performed according to compound 11-3, using 2,5-dichlorothiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 319 mg, 77% (last step) ESI-MS: 650.3 /652.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
35 Preparation of compound 11-29 o ON
N
Br /
Br (S)-2-(2,5-dibromothiophene-3-carboxamido)-N141-(242-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide Chemical Formula: C29H33Br2N506S
Exact Mass: 737.05 Molecular Weight: 739.48 The synthesis of compound 11-29 was performed according to compound 11-3, using 2,5-dibromothiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 98 mg, 52% (last step) ESI-MS: 738.2 / 740.2 / 742.2 [M+H]
N
Br /
Br (S)-2-(2,5-dibromothiophene-3-carboxamido)-N141-(242-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide Chemical Formula: C29H33Br2N506S
Exact Mass: 737.05 Molecular Weight: 739.48 The synthesis of compound 11-29 was performed according to compound 11-3, using 2,5-dibromothiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 98 mg, 52% (last step) ESI-MS: 738.2 / 740.2 / 742.2 [M+H]
36 Preparation of compound 11-30 ll 0 jCH 0 Br (S)-2-(5-bromothiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C29H34BrN506S
Exact Mass: 659.14 Molecular Weight: 660.58 The synthesis of compound 11-30 was performed according to compound 11-3, using 5-bromothiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 171 mg, 73% (last step) ESI-MS: 660.2 /662.2 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
Exact Mass: 659.14 Molecular Weight: 660.58 The synthesis of compound 11-30 was performed according to compound 11-3, using 5-bromothiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 171 mg, 73% (last step) ESI-MS: 660.2 /662.2 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
37 Preparation of compound 11-31 (S)-2-(2-chloro-5-methylthiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C29H38C1N606S
Exact Mass: 630.20 Molecular Weight: 631.14 The synthesis of compound 11-31 was performed according to compound 11-3, using 2-chloro-5-methylthiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 32 mg, 41% (last step) ESI-MS: 631.3 / 633.3 [M+H]
Exact Mass: 630.20 Molecular Weight: 631.14 The synthesis of compound 11-31 was performed according to compound 11-3, using 2-chloro-5-methylthiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 32 mg, 41% (last step) ESI-MS: 631.3 / 633.3 [M+H]
38 Preparation of compound 11-32 ou H NH
CI
(S)-2-(2,5-dichlorothiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C28H32Cl2N606S
Exact Mass: 650.15 Molecular Weight: 651.56 The synthesis of compound 11-32 was performed according to compound 11-3, using 2,5-dichlorothiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 41 mg, 35% (last step) ESI-MS: 651.2 /653.2 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
CI
(S)-2-(2,5-dichlorothiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C28H32Cl2N606S
Exact Mass: 650.15 Molecular Weight: 651.56 The synthesis of compound 11-32 was performed according to compound 11-3, using 2,5-dichlorothiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 41 mg, 35% (last step) ESI-MS: 651.2 /653.2 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
39 Preparation of compound 11-33 N
N
Br (S)-2-(2,5-dibromothiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide Chemical Formula: C28H32Br2N606S
Exact Mass: 738.05 Molecular Weight: 740.46 The synthesis of compound 11-33 was performed according to compound 11-3, using 2,5-dibromothiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 21 mg, 32% (last step) ESI-MS: 739.2 / 741.2 / 743.2 [M+H]
N
Br (S)-2-(2,5-dibromothiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide Chemical Formula: C28H32Br2N606S
Exact Mass: 738.05 Molecular Weight: 740.46 The synthesis of compound 11-33 was performed according to compound 11-3, using 2,5-dibromothiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 21 mg, 32% (last step) ESI-MS: 739.2 / 741.2 / 743.2 [M+H]
40 Preparation of compound 11-34 ll N
N
(S)-2-(2-bromo-5-methylthiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide Chemical Formula: C29H35BrN606S
Exact Mass: 674.15 Molecular Weight: 675.59 The synthesis of compound 11-34 was performed according to compound 11-3, using 2-bromo-5-methylthiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 42 mg, 57% (last step) ESI-MS: 675.2 /677.2 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
N
(S)-2-(2-bromo-5-methylthiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide Chemical Formula: C29H35BrN606S
Exact Mass: 674.15 Molecular Weight: 675.59 The synthesis of compound 11-34 was performed according to compound 11-3, using 2-bromo-5-methylthiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 42 mg, 57% (last step) ESI-MS: 675.2 /677.2 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
41 Preparation of compound 11-35 N
N
(S)-2-(2-bromothiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C28H33BrN606S
Exact Mass: 660.14 Molecular Weight: 661.57 The synthesis of compound 11-35 was performed according to compound 11-3, using 2-bromothiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 66 mg, 46% (last step) ESI-MS: 661.2 / 663.2 [M+H]
N
(S)-2-(2-bromothiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C28H33BrN606S
Exact Mass: 660.14 Molecular Weight: 661.57 The synthesis of compound 11-35 was performed according to compound 11-3, using 2-bromothiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 66 mg, 46% (last step) ESI-MS: 661.2 / 663.2 [M+H]
42 Preparation of compound 11-36 C1--</N3A N N
(S)-2-(2-chlorothiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C28H33CIN606S
Exact Mass: 616.19 Molecular Weight: 617.12 The synthesis of compound 11-36 was performed according to compound 11-3, using 2-chlorothiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 74 mg, 58% (last step) ESI-MS: 617.3 /619.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
(S)-2-(2-chlorothiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C28H33CIN606S
Exact Mass: 616.19 Molecular Weight: 617.12 The synthesis of compound 11-36 was performed according to compound 11-3, using 2-chlorothiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 74 mg, 58% (last step) ESI-MS: 617.3 /619.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
43 Preparation of compound 11-37 N
0 ( H 0 (S)-2-(2,5-dimethylfuran-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C31H39N507 Exact Mass: 593.28 Molecular Weight: 593.67 The synthesis of compound 11-37 was performed according to compound 11-3, using 2,5-dimethylfuran-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 152 mg, 73% (last step) ESI-MS: 594.4 [M+H]
0 ( H 0 (S)-2-(2,5-dimethylfuran-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C31H39N507 Exact Mass: 593.28 Molecular Weight: 593.67 The synthesis of compound 11-37 was performed according to compound 11-3, using 2,5-dimethylfuran-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 152 mg, 73% (last step) ESI-MS: 594.4 [M+H]
44 Preparation of compound 11-38 N
N
1_SeNJ(or u\IN
(S)-2-(4,5-dimethylthiazole-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide Chemical Formula: C30H38N606S
Exact Mass: 610.26 Molecular Weight: 610.72 The synthesis of compound 11-38 was performed according to compound 11-3, using 4,5-dimethylthiazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 46 mg, 38% (last step) ESI-MS: 611.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
N
1_SeNJ(or u\IN
(S)-2-(4,5-dimethylthiazole-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide Chemical Formula: C30H38N606S
Exact Mass: 610.26 Molecular Weight: 610.72 The synthesis of compound 11-38 was performed according to compound 11-3, using 4,5-dimethylthiazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 46 mg, 38% (last step) ESI-MS: 611.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
45 Preparation of compound 11-39 0)-LN
SAN
5_1N H o 0 Br (S)-2-(4,5-dimethylthiazole-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-clihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C28H33-RrN606S
Exact Mass: 660.14 Molecular Weight: 661.57 The synthesis of compound 11-39 was performed according to compound 11-3, using 4-bromothiazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 84 mg, 68% (last step) ESI-MS: 661.2 / 663.2 [M+H]
SAN
5_1N H o 0 Br (S)-2-(4,5-dimethylthiazole-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-clihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C28H33-RrN606S
Exact Mass: 660.14 Molecular Weight: 661.57 The synthesis of compound 11-39 was performed according to compound 11-3, using 4-bromothiazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 84 mg, 68% (last step) ESI-MS: 661.2 / 663.2 [M+H]
46 Preparation of compound 11-40 0)-LN
Nci\iINN
\ H 0 Br (S)-2-(4-bromothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C29H34BrN506S
Exact Mass: 659.14 Molecular Weight: 660.58 The synthesis of compound 11-40 was performed according to compound 11-3, using 4-bromothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 163 mg, 73% (last step) ESI-MS: 660.2 /662.2 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
Nci\iINN
\ H 0 Br (S)-2-(4-bromothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C29H34BrN506S
Exact Mass: 659.14 Molecular Weight: 660.58 The synthesis of compound 11-40 was performed according to compound 11-3, using 4-bromothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 163 mg, 73% (last step) ESI-MS: 660.2 /662.2 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
47 Preparation of compound 11-41 0)L
N
H
0 ti 0 H
S
, NjcNNN
\I H 0 0 Br (S)-2-(4-bromo-3-methylthiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C301-136BrN506S
Exact Mass: 673.16 Molecular Weight: 674.61 The synthesis of compound 11-41 was performed according to compound 11-3, using 4-bromo-3-methylthiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 114 mg, 68% (last step) ESI-MS: 674.2 / 676.2 [M+H]
N
H
0 ti 0 H
S
, NjcNNN
\I H 0 0 Br (S)-2-(4-bromo-3-methylthiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C301-136BrN506S
Exact Mass: 673.16 Molecular Weight: 674.61 The synthesis of compound 11-41 was performed according to compound 11-3, using 4-bromo-3-methylthiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 114 mg, 68% (last step) ESI-MS: 674.2 / 676.2 [M+H]
48 Preparation of compound 11-42 .A
H
H
N jcr N ).L N
\I H 0 0 Br (S)-2-(3-bromothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C29H34.BrN506S
Exact Mass: 659.14 Molecular Weight: 660.58 The synthesis of compound 11-42 was performed according to compound 11-3, using 3-bromothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 149 mg, 76% (last step) ESI-MS: 660.2 /662.2 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
H
H
N jcr N ).L N
\I H 0 0 Br (S)-2-(3-bromothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C29H34.BrN506S
Exact Mass: 659.14 Molecular Weight: 660.58 The synthesis of compound 11-42 was performed according to compound 11-3, using 3-bromothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 149 mg, 76% (last step) ESI-MS: 660.2 /662.2 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
49 Preparation of compound 11-43 ON
N
\ hIjorH
CI
(S)-2-(3-chloro-4-methylthiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C301-136CIN506S
Exact Mass: 629.21 Molecular Weight: 630.15 The synthesis of compound 11-43 was performed according to compound 11-3, using 3-chloro-4-methylthiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-carboxylic acid in step 6 (according to ZED3264).
Yield: 110 mg, 64% (last step) ESI-MS: 630.3 / 632.3 [M+H]
N
\ hIjorH
CI
(S)-2-(3-chloro-4-methylthiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C301-136CIN506S
Exact Mass: 629.21 Molecular Weight: 630.15 The synthesis of compound 11-43 was performed according to compound 11-3, using 3-chloro-4-methylthiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-carboxylic acid in step 6 (according to ZED3264).
Yield: 110 mg, 64% (last step) ESI-MS: 630.3 / 632.3 [M+H]
50 Preparation of compound 11-44 N
0 jcH
N
N
\ I H 0 0 Br (S)-2-(4-bromo-5-chlorothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C29H33BrCIN506S
Exact Mass: 693.10 Molecular Weight: 695.02 The synthesis of compound 11-44 was performed according to compound 11-3, using 4-bromo-5-chlorothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 126 mg, 59% (last step) ESI-MS: 694.2 / 696.2 / 698.2 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
0 jcH
N
N
\ I H 0 0 Br (S)-2-(4-bromo-5-chlorothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C29H33BrCIN506S
Exact Mass: 693.10 Molecular Weight: 695.02 The synthesis of compound 11-44 was performed according to compound 11-3, using 4-bromo-5-chlorothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 126 mg, 59% (last step) ESI-MS: 694.2 / 696.2 / 698.2 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
51 Preparation of compound 11-45 o Br \I H 0 0 Br (S)-2-(4,5-dibromothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide Chemical Formula: C29H33Br2N506S
Exact Mass: 737.05 Molecular Weight: 739.48 The synthesis of compound 11-45 was performed according to compound 11-3, using 4,5-dibromothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 89 mg, 51% (last step) ESI-MS: 738.2 / 740.2 / 742.2 [M+H]
Exact Mass: 737.05 Molecular Weight: 739.48 The synthesis of compound 11-45 was performed according to compound 11-3, using 4,5-dibromothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 89 mg, 51% (last step) ESI-MS: 738.2 / 740.2 / 742.2 [M+H]
52 Preparation of compound 11-46 o N
NjcH 0 l\i)LI N
Br \I H 0 0 OMe Br (S)-2-(4,5-dibromo-3-methoxythiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide Chemical Formula: C301-135Br2N507S
Exact Mass: 767.06 Molecular Weight: 769.50 The synthesis of compound 11-46 was performed according to compound 11-3, using 4,5-dibromo-3-methoxythiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 59 mg, 40% (last step) ESI-MS: 768.2 / 770.2 / 772.2 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
NjcH 0 l\i)LI N
Br \I H 0 0 OMe Br (S)-2-(4,5-dibromo-3-methoxythiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide Chemical Formula: C301-135Br2N507S
Exact Mass: 767.06 Molecular Weight: 769.50 The synthesis of compound 11-46 was performed according to compound 11-3, using 4,5-dibromo-3-methoxythiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 59 mg, 40% (last step) ESI-MS: 768.2 / 770.2 / 772.2 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
53 Preparation of compound 11-47 0 Li 0 \ I H 0 0 Br (S)-2-(4-bromofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C29H34BrN507 Exact Mass: 643.16 Molecular Weight: 644.51 The synthesis of compound 11-47 was performed according to compound 11-3, using 4-bromofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in .. step 6 (according to ZED3264).
Yield: 90 mg, 69% (last step) ESI-MS: 644.3 / 646.3 [M+H]
Yield: 90 mg, 69% (last step) ESI-MS: 644.3 / 646.3 [M+H]
54 Preparation of compound 11-48 0 hi 0 N(-r Br N
\ H 0 Br (S)-2-(4,5-dibromofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C29H33Br2N507 Exact Mass: 721.07 Molecular Weight: 723.41 The synthesis of compound 11-48 was performed according to compound 11-3, using 4,5-dibromofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 72 mg, 56% (last step) ESI-MS: 722.2 / 724.2 / 726.2 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
\ H 0 Br (S)-2-(4,5-dibromofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C29H33Br2N507 Exact Mass: 721.07 Molecular Weight: 723.41 The synthesis of compound 11-48 was performed according to compound 11-3, using 4,5-dibromofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 72 mg, 56% (last step) ESI-MS: 722.2 / 724.2 / 726.2 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
55 Preparation of compound 11-49 N
N )LNN
CI
\I H I
CI
(S)-2-(4,5-dichlorothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethy1)-2-oxo-1,2-clihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide Chemical Formula: C29H33Cl2N506S
Exact Mass: 649.15 Molecular Weight: 650.57 The synthesis of compound 11-49 was performed according to compound 11-3, using 4,5-dichlorothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic __ acid in step 6 (according to ZED3264).
Yield: 55 mg, 48% (last step) ESI-MS: 650.3 / 652.3 [M+H]
N )LNN
CI
\I H I
CI
(S)-2-(4,5-dichlorothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethy1)-2-oxo-1,2-clihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide Chemical Formula: C29H33Cl2N506S
Exact Mass: 649.15 Molecular Weight: 650.57 The synthesis of compound 11-49 was performed according to compound 11-3, using 4,5-dichlorothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic __ acid in step 6 (according to ZED3264).
Yield: 55 mg, 48% (last step) ESI-MS: 650.3 / 652.3 [M+H]
56 Preparation of compound 11-50 )'(N
Nj_ N NH J-(i NN
(S)-2-((S)-1-acetylpyrrolidine-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide Chemical Formula: C31H42N607 Exact Mass: 610.31 Molecular Weight: 610/0 The synthesis of compound 11-50 was performed according to compound 11-3, using (S)-1-acetylpyrrolidine-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 190 mg, 78% (last step) ESI-MS: 611.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
Nj_ N NH J-(i NN
(S)-2-((S)-1-acetylpyrrolidine-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide Chemical Formula: C31H42N607 Exact Mass: 610.31 Molecular Weight: 610/0 The synthesis of compound 11-50 was performed according to compound 11-3, using (S)-1-acetylpyrrolidine-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 190 mg, 78% (last step) ESI-MS: 611.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
57 Preparation of compound 11-51 C)AN
NH
NThr N
N".
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(1-methyl-1 H-1,2,3-triazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C281--136N806 Exact Mass: 580.28 Molecular Weight: 580.64 The synthesis of compound 11-51 was performed according to compound 11-3, using 1-methyl-1H-1,2,3-triazole-5-carboxylic acid instead of 3-methylbenzo[b]fu ran-carboxylic acid in step 6 (according to ZED3264).
Yield: 28 mg, 35% (last step) ESI-MS: 581.4 [M+H]
NH
NThr N
N".
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(1-methyl-1 H-1,2,3-triazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C281--136N806 Exact Mass: 580.28 Molecular Weight: 580.64 The synthesis of compound 11-51 was performed according to compound 11-3, using 1-methyl-1H-1,2,3-triazole-5-carboxylic acid instead of 3-methylbenzo[b]fu ran-carboxylic acid in step 6 (according to ZED3264).
Yield: 28 mg, 35% (last step) ESI-MS: 581.4 [M+H]
58 Preparation of compound 11-52 0)-LN
N
HN I
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxo-2-(2H-tetrazole-5-carboxamido)hexanediamide Chemical Formula: C26H33N906 Exact Mass: 567.26 Molecular Weight: 567.60 The synthesis of compound 11-52 was performed according to compound 11-3, using 2H-tetrazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 23 mg, 31% (last step) ESI-MS: 568.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
N
HN I
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxo-2-(2H-tetrazole-5-carboxamido)hexanediamide Chemical Formula: C26H33N906 Exact Mass: 567.26 Molecular Weight: 567.60 The synthesis of compound 11-52 was performed according to compound 11-3, using 2H-tetrazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 23 mg, 31% (last step) ESI-MS: 568.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
59 Preparation of compound 11-53 OAN
_ (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxo-2-(pyrazine-2-carboxamido)hexanediamide Chemical Formula: C29F135N706 Exact Mass: 577.26 Molecular Weight: 577.63 The synthesis of compound 11-53 was performed according to compound 11-3, using pyrazine-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 79 mg, 74% (last step) ESI-MS: 578.3 [M+H]
_ (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxo-2-(pyrazine-2-carboxamido)hexanediamide Chemical Formula: C29F135N706 Exact Mass: 577.26 Molecular Weight: 577.63 The synthesis of compound 11-53 was performed according to compound 11-3, using pyrazine-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 79 mg, 74% (last step) ESI-MS: 578.3 [M+H]
60 Preparation of compound 11-54 o N
H
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-((S)-1-methylpyrrolidine-2-carboxamido)-5-oxohexanediamide Chemical Formula: C30F142N606 Exact Mass: 582.32 Molecular Weight: 582.69 The synthesis of compound 11-54 was performed according to compound 11-3, using (S)-1-methylpyrrolidine-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 68 mg, 82% (last step) ESI-MS: 583.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
H
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-((S)-1-methylpyrrolidine-2-carboxamido)-5-oxohexanediamide Chemical Formula: C30F142N606 Exact Mass: 582.32 Molecular Weight: 582.69 The synthesis of compound 11-54 was performed according to compound 11-3, using (S)-1-methylpyrrolidine-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 68 mg, 82% (last step) ESI-MS: 583.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
61 Preparation of compound 11-55 N
H
NN
I I
HN¨ 0 0 (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxo-24(S)-pyrrolidine-3-carboxamido)hexanediamide Chemical Formula: C29F140N606 Exact Mass: 568.30 Molecular Weight: 568.66 The synthesis of compound 11-55 was performed according to compound 11-3, using (S)-1-Boc-pyrrolidine-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). The final product was obtained by deprotection (DCM/TFA) as described above and purified by HPLC.
Yield: 43 mg, 79% (last step) ESI-MS: 569.4 [M+H]
H
NN
I I
HN¨ 0 0 (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxo-24(S)-pyrrolidine-3-carboxamido)hexanediamide Chemical Formula: C29F140N606 Exact Mass: 568.30 Molecular Weight: 568.66 The synthesis of compound 11-55 was performed according to compound 11-3, using (S)-1-Boc-pyrrolidine-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). The final product was obtained by deprotection (DCM/TFA) as described above and purified by HPLC.
Yield: 43 mg, 79% (last step) ESI-MS: 569.4 [M+H]
62 Preparation of compound 11-56 oN
JC
I I
(S)-2-((2S,4S)-4-bromopyrrolidine-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C291-139BrN606 Exact Mass: 646.21 Molecular Weight: 647.56 The synthesis of compound 11-56 was performed according to compound 11-3, using (2S,4S)-1-Boc-4-bromopyrrolidine-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). The final product was obtained by deprotection (DCM/TFA) as described above and purified by HPLC.
Yield: 45 mg, 73% (last step) ESI-MS: 647.3 / 649.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
JC
I I
(S)-2-((2S,4S)-4-bromopyrrolidine-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C291-139BrN606 Exact Mass: 646.21 Molecular Weight: 647.56 The synthesis of compound 11-56 was performed according to compound 11-3, using (2S,4S)-1-Boc-4-bromopyrrolidine-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). The final product was obtained by deprotection (DCM/TFA) as described above and purified by HPLC.
Yield: 45 mg, 73% (last step) ESI-MS: 647.3 / 649.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
63 Preparation of compound 11-58 o*
N
- N N
= H
(S)-N1-(1-(242-adamantylamino)-2-oxoethyl)-2-oxo-1,2-clihydropyridin-3-y1)-N6-methyl-5-oxo-2-((S)-piperidine-2-carboxamido)hexanediamide Chemical Formula: C30F142N606 Exact Mass: 582.32 Molecular Weight: 582.69 The synthesis of compound 11-58 was performed according to compound 11-3, using (S)-1-Boc-piperidine-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). The final product was obtained by deprotection (DCM/TFA) as described above and purified by HPLC.
Yield: 53 mg, 86% (last step) ESI-MS: 583.4 [M+H]
N
- N N
= H
(S)-N1-(1-(242-adamantylamino)-2-oxoethyl)-2-oxo-1,2-clihydropyridin-3-y1)-N6-methyl-5-oxo-2-((S)-piperidine-2-carboxamido)hexanediamide Chemical Formula: C30F142N606 Exact Mass: 582.32 Molecular Weight: 582.69 The synthesis of compound 11-58 was performed according to compound 11-3, using (S)-1-Boc-piperidine-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). The final product was obtained by deprotection (DCM/TFA) as described above and purified by HPLC.
Yield: 53 mg, 86% (last step) ESI-MS: 583.4 [M+H]
64 Preparation of compound 11-59 o õA.
N
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-((R)-piperidine-3-carboxamido)hexanediamide Chemical Formula: C30F142N606 Exact Mass: 582.32 Molecular Weight: 582.69 The synthesis of compound 11-59 was performed according to compound 11-3, using (R)-1-Boc-piperidine-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). The final product was obtained by deprotection (DCM/TFA) as described above and purified by HPLC.
Yield: 43 mg, 77% (last step) ESI-MS: 583.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
N
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-((R)-piperidine-3-carboxamido)hexanediamide Chemical Formula: C30F142N606 Exact Mass: 582.32 Molecular Weight: 582.69 The synthesis of compound 11-59 was performed according to compound 11-3, using (R)-1-Boc-piperidine-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). The final product was obtained by deprotection (DCM/TFA) as described above and purified by HPLC.
Yield: 43 mg, 77% (last step) ESI-MS: 583.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
65 Preparation of compound 11-60 N
N
N
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-((R)-morpholine-3-carboxamido)-5-oxohexanediamide Chemical Formula: C29H4.0N607 Exact Mass: 584.30 Molecular Weight: 584.66 The synthesis of compound 11-60 was performed according to compound 11-3, using (R)-4-Boc-morpholine-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). The final product was obtained by deprotection (DCM/TFA) as described above and purified by HPLC.
Yield: 67 mg, 85% (last step) ESI-MS: 585.4 [M+H]
N
N
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-((R)-morpholine-3-carboxamido)-5-oxohexanediamide Chemical Formula: C29H4.0N607 Exact Mass: 584.30 Molecular Weight: 584.66 The synthesis of compound 11-60 was performed according to compound 11-3, using (R)-4-Boc-morpholine-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). The final product was obtained by deprotection (DCM/TFA) as described above and purified by HPLC.
Yield: 67 mg, 85% (last step) ESI-MS: 585.4 [M+H]
66 Preparation of compound 11-61 N
N- H
N
JI N
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxo-2-(quinuclidine-3-carboxamido)hexanediamide Chemical Formula: C321-144N606 Exact Mass: 608.33 Molecular Weight: 608.73 The synthesis of compound 11-61 was performed according to compound 11-3, using quinuclidine-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 24 mg, 54% (last step) ESI-MS: 609.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
N- H
N
JI N
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxo-2-(quinuclidine-3-carboxamido)hexanediamide Chemical Formula: C321-144N606 Exact Mass: 608.33 Molecular Weight: 608.73 The synthesis of compound 11-61 was performed according to compound 11-3, using quinuclidine-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 24 mg, 54% (last step) ESI-MS: 609.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
67 Preparation of compound 11-62 NN
I I
CO2Me (S)-methyl 3-(1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-ylcarbamoy1)-5-nitrobenzoate Chemical Formula: C331-138N6010 Exact Mass: 678.26 Molecular Weight: 678.69 The synthesis of compound 11-62 was performed according to compound 11-3, using mono-methyl 5-nitroisophthalate instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 57 mg, 66% (last step) ESI-MS: 679.3 [M+H]
I I
CO2Me (S)-methyl 3-(1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-ylcarbamoy1)-5-nitrobenzoate Chemical Formula: C331-138N6010 Exact Mass: 678.26 Molecular Weight: 678.69 The synthesis of compound 11-62 was performed according to compound 11-3, using mono-methyl 5-nitroisophthalate instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 57 mg, 66% (last step) ESI-MS: 679.3 [M+H]
68 Preparation of compound 11-63 N
H
N)-L
N
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(5-nitronicotinamido)-5-oxohexanediamide Chemical Formula: 030F-135N708 Exact Mass: 621.25 Molecular Weight: 621.64 The synthesis of compound 11-63 was performed according to compound 11-3, using 5-nitronicotinic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 76 mg, 65% (last step) ESI-MS: 622.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
H
N)-L
N
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(5-nitronicotinamido)-5-oxohexanediamide Chemical Formula: 030F-135N708 Exact Mass: 621.25 Molecular Weight: 621.64 The synthesis of compound 11-63 was performed according to compound 11-3, using 5-nitronicotinic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 76 mg, 65% (last step) ESI-MS: 622.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
69 Preparation of compound 11-64 N
H
HO2CLNJ(rN
N
(S)-5-(1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinic acid Chemical Formula: C31F136N608 Exact Mass: 620.26 Molecular Weight: 620.65 The synthesis of compound 11-64 was performed according to compound 11-3, using 3,5-pyridinedicarboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 16 mg, 52% (last step) ESI-MS: 621.3 [M+H]
H
HO2CLNJ(rN
N
(S)-5-(1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinic acid Chemical Formula: C31F136N608 Exact Mass: 620.26 Molecular Weight: 620.65 The synthesis of compound 11-64 was performed according to compound 11-3, using 3,5-pyridinedicarboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 16 mg, 52% (last step) ESI-MS: 621.3 [M+H]
70 Preparation of compound 11-65 H JL
Me02CNJc N
(S)-methyl 5-(1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinate Chemical Formula: C32F138N608 Exact Mass: 634.28 Molecular Weight: 634.68 The synthesis of compound 11-65 was performed according to compound 11-3, using 5-(methoxycarbonyl)nicotinic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 34 mg, 62% (last step) .. ESI-MS: 635.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
Me02CNJc N
(S)-methyl 5-(1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinate Chemical Formula: C32F138N608 Exact Mass: 634.28 Molecular Weight: 634.68 The synthesis of compound 11-65 was performed according to compound 11-3, using 5-(methoxycarbonyl)nicotinic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 34 mg, 62% (last step) .. ESI-MS: 635.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
71 Preparation of compound 11-66 0 =)0 I N Nj-L
N
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(6-methylimidazo[2,1-1D]thiazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C31 H37N706S
Exact Mass: 635.25 Molecular Weight: 635.73 The synthesis of compound 11-66 was performed according to compound 11-3, using 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 45 mg, 37% (last step) ESI-MS: 636.4 [M+H]
N
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(6-methylimidazo[2,1-1D]thiazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C31 H37N706S
Exact Mass: 635.25 Molecular Weight: 635.73 The synthesis of compound 11-66 was performed according to compound 11-3, using 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 45 mg, 37% (last step) ESI-MS: 636.4 [M+H]
72 Preparation of compound 11-67 OA
N
OHO I
I H
(S)-N1-(1-(2-(2-adamantyl(methyl)amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yI)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C35 H41 N507 Exact Mass: 643.30 Molecular Weight: 643.73 The synthesis of compound 11-67 was performed according to compound 11-3, using N-methyl-2-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 66 mg, 45% (last step) ESI-MS: 644.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
N
OHO I
I H
(S)-N1-(1-(2-(2-adamantyl(methyl)amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yI)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C35 H41 N507 Exact Mass: 643.30 Molecular Weight: 643.73 The synthesis of compound 11-67 was performed according to compound 11-3, using N-methyl-2-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 66 mg, 45% (last step) ESI-MS: 644.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
73 Preparation of compound 11-68 0,)1, N
0 N Nj-L
N , I H
(S)-N1-(1-(2-(5-hydroxyadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C341-130\1508 Exact Mass: 645.28 Molecular Weight: 645.70 The synthesis of compound 11-68 was performed according to compound 11-3, using 5-hydroxy-2-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 21 mg, 34% (last step) ESI-MS: 646.4 [M+H]
0 N Nj-L
N , I H
(S)-N1-(1-(2-(5-hydroxyadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C341-130\1508 Exact Mass: 645.28 Molecular Weight: 645.70 The synthesis of compound 11-68 was performed according to compound 11-3, using 5-hydroxy-2-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 21 mg, 34% (last step) ESI-MS: 646.4 [M+H]
74 Preparation of compound 11-69 N
N N I H
(S)-N1-(1-(2-(5-fluoroadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C34H38FN507 Exact Mass: 647.28 Molecular Weight: 647.69 The synthesis of compound 11-69 was performed according to compound 11-3, using 5-fluoro-2-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 48 mg, 57% (last step) ESI-MS: 648.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
N N I H
(S)-N1-(1-(2-(5-fluoroadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C34H38FN507 Exact Mass: 647.28 Molecular Weight: 647.69 The synthesis of compound 11-69 was performed according to compound 11-3, using 5-fluoro-2-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 48 mg, 57% (last step) ESI-MS: 648.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
75 Preparation of compound 11-70 OAN
o il(r (S)-N1-(1-(2-(5-chloroadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: 034.H380IN507 Exact Mass: 663.25 Molecular Weight: 664.15 The synthesis of compound 11-70 was performed according to compound 11-3, using 5-chloro-2-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 45 mg, 35% (last step) ESI-MS: 664.3 / 666.3 [M+H]
o il(r (S)-N1-(1-(2-(5-chloroadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: 034.H380IN507 Exact Mass: 663.25 Molecular Weight: 664.15 The synthesis of compound 11-70 was performed according to compound 11-3, using 5-chloro-2-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 45 mg, 35% (last step) ESI-MS: 664.3 / 666.3 [M+H]
76 Preparation of compound 11-71 )-L
0 Nj-L
I H
0 0 Br (S)-N1-(1-(2-(5-bromoadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C34.H38BrN507 Exact Mass: 707.20 Molecular Weight: 708.60 The synthesis of compound 11-71 was performed according to compound 11-3, using 5-bromo-2-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 31 mg, 34% (last step) ESI-MS: 708.3 / 710.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
0 Nj-L
I H
0 0 Br (S)-N1-(1-(2-(5-bromoadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C34.H38BrN507 Exact Mass: 707.20 Molecular Weight: 708.60 The synthesis of compound 11-71 was performed according to compound 11-3, using 5-bromo-2-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 31 mg, 34% (last step) ESI-MS: 708.3 / 710.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
77 Preparation of compound 11-72 oU
N NN
(S)-N1-(1-(2-(5-methyladamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C35H41N507 Exact Mass: 643.30 Molecular Weight: 643.73 The synthesis of compound 11-72 was performed according to compound 11-3, using 5-methyl-2-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 68 mg, 54% (last step) ESI-MS: 644.4 [M+H]
N NN
(S)-N1-(1-(2-(5-methyladamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C35H41N507 Exact Mass: 643.30 Molecular Weight: 643.73 The synthesis of compound 11-72 was performed according to compound 11-3, using 5-methyl-2-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 68 mg, 54% (last step) ESI-MS: 644.4 [M+H]
78 Preparation of compound 11-73 o-JN
, N NrN
I H I
(S)-N1-(1-(2-(2-carbonitrileadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C35H38N607 Exact Mass: 654.28 Molecular Weight: 654.71 The synthesis of compound 11-73 was performed according to compound 11-3, using 2-aminoadamantane-2-carbonitrile instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 26 mg, 46% (last step) ESI-MS: 655.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
, N NrN
I H I
(S)-N1-(1-(2-(2-carbonitrileadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C35H38N607 Exact Mass: 654.28 Molecular Weight: 654.71 The synthesis of compound 11-73 was performed according to compound 11-3, using 2-aminoadamantane-2-carbonitrile instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 26 mg, 46% (last step) ESI-MS: 655.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
79 Preparation of compound 11-74 H CO2Me N , (S)-N1-(1-(2-(2-methyl adamantane-2-carboxylate-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C36H41N509 Exact Mass: 687.29 Molecular Weight: 687.74 The synthesis of compound 11-74 was performed according to compound 11-3, using 2-methyl 2-aminoadamantane-2-carboxylate instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 38 mg, 61% (last step) ESI-MS: 688.4 [M+H]
Yield: 38 mg, 61% (last step) ESI-MS: 688.4 [M+H]
80 Preparation of compound 11-87 N
N
NrN
(S)-N1-(1-(2-(1-adamantylmethylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C35H41N507 Exact Mass: 643.30 Molecular Weight: 643.73 The synthesis of compound 11-87 was performed according to compound 11-3, using 1-adamantanemethylamine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 43 mg, 53% (last step) ESI-MS: 644.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
N
NrN
(S)-N1-(1-(2-(1-adamantylmethylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C35H41N507 Exact Mass: 643.30 Molecular Weight: 643.73 The synthesis of compound 11-87 was performed according to compound 11-3, using 1-adamantanemethylamine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 43 mg, 53% (last step) ESI-MS: 644.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
81 Preparation of compound 11-88 N
N
o i'dC
(S)-N1-(1-(2-(1-(1-adamantyl)ethanamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C35 H41 N507 Exact Mass: 643.30 Molecular Weight: 643.73 The synthesis of compound 11-88 was performed according to compound 11-2, using 1-rimantadine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 31 mg, 41% (last step) ESI-MS: 644.4 [M+H]
N
o i'dC
(S)-N1-(1-(2-(1-(1-adamantyl)ethanamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C35 H41 N507 Exact Mass: 643.30 Molecular Weight: 643.73 The synthesis of compound 11-88 was performed according to compound 11-2, using 1-rimantadine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 31 mg, 41% (last step) ESI-MS: 644.4 [M+H]
82 Preparation of compound 11-90 0)-L N
N NH
oI i'dr (S)-N1-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C31 H35N 507 Exact Mass: 589.25 Molecular Weight: 589.64 The synthesis of compound 11-90 was performed according to compound 11-3, using ( )-endo-2-norbornylamine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 67 mg, 65% (last step) ESI-MS: 590.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
N NH
oI i'dr (S)-N1-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C31 H35N 507 Exact Mass: 589.25 Molecular Weight: 589.64 The synthesis of compound 11-90 was performed according to compound 11-3, using ( )-endo-2-norbornylamine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 67 mg, 65% (last step) ESI-MS: 590.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
83 Preparation of compound 11-92 0)LN
o N iljCr NnrN
(S)-N1-methyl-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yOhexanediamide Chemical Formula: 034 H41 N507 Exact Mass: 631.30 Molecular Weight: 631.72 The synthesis of compound 11-92 was performed according to compound 11-3, using (R)-(+)-bornylamine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 52 mg, 66% (last step) ESI-MS: 632.5 [M+H]
o N iljCr NnrN
(S)-N1-methyl-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yOhexanediamide Chemical Formula: 034 H41 N507 Exact Mass: 631.30 Molecular Weight: 631.72 The synthesis of compound 11-92 was performed according to compound 11-3, using (R)-(+)-bornylamine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 52 mg, 66% (last step) ESI-MS: 632.5 [M+H]
84 Preparation of compound 11-94 oUN
0 iCH 0 N
(S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: 031 H35N507 Exact Mass: 589.25 Molecular Weight: 589.64 The synthesis of compound 11-94 was performed according to compound 11-3, using exo-2-aminonorbornane instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 62 mg, 68% (last step) ESI-MS: 590.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
0 iCH 0 N
(S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: 031 H35N507 Exact Mass: 589.25 Molecular Weight: 589.64 The synthesis of compound 11-94 was performed according to compound 11-3, using exo-2-aminonorbornane instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 62 mg, 68% (last step) ESI-MS: 590.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
85 Preparation of compound 11-95 0)LN
0 rHH0 , (S)-N1-(1-(2-(bicyclo[2.2.Theptan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C31H35N507 Exact Mass: 589.25 Molecular Weight: 589.64 The synthesis of compound 11-95 was performed according to compound 11-3, using bicyclo[2.2.1]heptan-1-ylamine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 14 mg, 32% (last step) ESI-MS: 590.4 [M+H]
0 rHH0 , (S)-N1-(1-(2-(bicyclo[2.2.Theptan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C31H35N507 Exact Mass: 589.25 Molecular Weight: 589.64 The synthesis of compound 11-95 was performed according to compound 11-3, using bicyclo[2.2.1]heptan-1-ylamine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 14 mg, 32% (last step) ESI-MS: 590.4 [M+H]
86 Preparation of compound 11-96 CDN
0 NANr NH
, N
(S)-N1-(1-(2-(bicyclo[2.2.1]heptan-7-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C31H35N507 Exact Mass: 589.25 Molecular Weight: 589.64 The synthesis of compound 11-96 was performed according to compound 11-3, using bicyclo[2.2.1]heptan-7-ylamine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 36 mg, 53% (last step) ESI-MS: 590.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
0 NANr NH
, N
(S)-N1-(1-(2-(bicyclo[2.2.1]heptan-7-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C31H35N507 Exact Mass: 589.25 Molecular Weight: 589.64 The synthesis of compound 11-96 was performed according to compound 11-3, using bicyclo[2.2.1]heptan-7-ylamine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 36 mg, 53% (last step) ESI-MS: 590.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
87 Preparation of compound 11-97 N
r\ir I H
(S)-N1-(1-(2-(bicyclo[2.2.1]hept-5-en-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C31H33N507 Exact Mass: 587.24 Molecular Weight: 587.62 The synthesis of compound 11-97 was performed according to compound 11-3, using bicyclo[2.2.1]hept-5-en-2-amine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 21 mg, 44% (last step) ESI-MS: 588.4 [M+H]
r\ir I H
(S)-N1-(1-(2-(bicyclo[2.2.1]hept-5-en-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C31H33N507 Exact Mass: 587.24 Molecular Weight: 587.62 The synthesis of compound 11-97 was performed according to compound 11-3, using bicyclo[2.2.1]hept-5-en-2-amine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 21 mg, 44% (last step) ESI-MS: 588.4 [M+H]
88 Preparation of compound 11-98 N
N MN
(2S)-N1-(1-(2-(bicyclo[2.2.2]octan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C32H37N507 Exact Mass: 603.27 Molecular Weight: 603.67 The synthesis of compound 11-98 was performed according to compound 11-3, using bicyclo[2.2.2]oct-2-ylamine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 25 mg, 41% (last step) ESI-MS: 604.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
N MN
(2S)-N1-(1-(2-(bicyclo[2.2.2]octan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C32H37N507 Exact Mass: 603.27 Molecular Weight: 603.67 The synthesis of compound 11-98 was performed according to compound 11-3, using bicyclo[2.2.2]oct-2-ylamine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 25 mg, 41% (last step) ESI-MS: 604.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
89 Preparation of compound 11-99 N
N
I H
(S)-N1-methyl-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-y1)hexanediamide Chemical Formula: C34H41N507 Exact Mass: 631.30 Molecular Weight: 631.72 The synthesis of compound 11-99 was performed according to compound 11-3, using (R)-(-)-isobornylamine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 27 mg, 48% (last step) ESI-MS: 632.5 [M+H]
N
I H
(S)-N1-methyl-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-y1)hexanediamide Chemical Formula: C34H41N507 Exact Mass: 631.30 Molecular Weight: 631.72 The synthesis of compound 11-99 was performed according to compound 11-3, using (R)-(-)-isobornylamine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 27 mg, 48% (last step) ESI-MS: 632.5 [M+H]
90 Preparation of compound 11-100 ou N
(S)-N1-methyl-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)ethyl)-1,2-dihydropyridin-3-y1)hexanediamide Chemical Formula: C34H41N507 Exact Mass: 631.30 Molecular Weight: 631.72 The synthesis of compound 11-100 was performed according to compound 11-3, using (1R,2R,3R,5S)-(-)-isopinocampheylamine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 17 mg, 39% (last step) ESI-MS: 632.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
(S)-N1-methyl-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)ethyl)-1,2-dihydropyridin-3-y1)hexanediamide Chemical Formula: C34H41N507 Exact Mass: 631.30 Molecular Weight: 631.72 The synthesis of compound 11-100 was performed according to compound 11-3, using (1R,2R,3R,5S)-(-)-isopinocampheylamine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 17 mg, 39% (last step) ESI-MS: 632.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
91 Preparation of compound 11-101 0 Njc NHJN NH
(S)-N1-methyl-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide Chemical Formula: C34H41N507 Exact Mass: 631.30 Molecular Weight: 631.72 The synthesis of compound 11-101 was performed according to compound 11-3, using (1S,2S,3S,5R)-(+)-isopinocampheylamine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 25 mg, 41% (last step) ESI-MS: 632.5 [M+H]
(S)-N1-methyl-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide Chemical Formula: C34H41N507 Exact Mass: 631.30 Molecular Weight: 631.72 The synthesis of compound 11-101 was performed according to compound 11-3, using (1S,2S,3S,5R)-(+)-isopinocampheylamine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 25 mg, 41% (last step) ESI-MS: 632.5 [M+H]
92 Preparation of compound 11-103 N
H
N
oI hijC
(S)-N1-(1-(2-(4-homoisotwistane-3-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: 035H41N507 Exact Mass: 643.30 Molecular Weight: 643.73 The synthesis of compound 11-103 was performed according to compound 11-3, using 3-amino-4-homoisotwistane instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 12 mg, 28% (last step) ESI-MS: 644.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
H
N
oI hijC
(S)-N1-(1-(2-(4-homoisotwistane-3-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: 035H41N507 Exact Mass: 643.30 Molecular Weight: 643.73 The synthesis of compound 11-103 was performed according to compound 11-3, using 3-amino-4-homoisotwistane instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 12 mg, 28% (last step) ESI-MS: 644.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
93 Preparation of compound 11-104 0)-L
N
o (S)-N1-(1-(2-(diamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C38H4.3N507 Exact Mass: 681.32 Molecular Weight: 681.78 The synthesis of compound 11-104 was performed according to compound 11-3, using 1-aminodiamantane instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 17 mg, 35% (last step) ESI-MS: 682.5 [M+H]
N
o (S)-N1-(1-(2-(diamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C38H4.3N507 Exact Mass: 681.32 Molecular Weight: 681.78 The synthesis of compound 11-104 was performed according to compound 11-3, using 1-aminodiamantane instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 17 mg, 35% (last step) ESI-MS: 682.5 [M+H]
94 Preparation of compound 11-105 N
0 H LC) (S)-N1-(1-(2-(diamantane-4-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C38H4.3N507 Exact Mass: 681.32 Molecular Weight: 681.78 The synthesis of compound 11-105 was performed according to compound 11-3, using 4-aminodiamantane instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 8 mg, 26% (last step) ESI-MS: 682.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 Scheme 11-3 New Building Block OH 1-(Bromomethyl)- 0 adamantane 02Nj\I --1*-. 02N j-______________________________________ . , N
DMF, DIPEA
I10% Pd/C
Me0H
H2Nj-LN
0 H LC) (S)-N1-(1-(2-(diamantane-4-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C38H4.3N507 Exact Mass: 681.32 Molecular Weight: 681.78 The synthesis of compound 11-105 was performed according to compound 11-3, using 4-aminodiamantane instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 8 mg, 26% (last step) ESI-MS: 682.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 Scheme 11-3 New Building Block OH 1-(Bromomethyl)- 0 adamantane 02Nj\I --1*-. 02N j-______________________________________ . , N
DMF, DIPEA
I10% Pd/C
Me0H
H2Nj-LN
95 Preparation of compound ZED4893 02N j-Ul 1-(1-adamantylmethyl)-3-nitropyridin-2(1H)-one Chemical Formula: C16H20N203 Exact Mass: 288.15 Molecular Weight: 288.34 500 mg (3.57 mmol) of 2-hydroxy-3-nitropyridine and 818 mg (1 eq) of 1-(bromomethyl)adamantane were dissolved in 10 mL DMF and 1.24 mL DIPEA (2 eq) and stirred at room temperature overnight. The solvent was evaporated; the residue was dissolved in 30 mL Et0Ac and washed twice with each 10 mL citric acid solution (10%), NaHCO3 solution (10%) and brine. The organic phase was dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by HPLC.
Yield: 484 mg, 47% ESI-MS: 289.3 [M+H]
Yield: 484 mg, 47% ESI-MS: 289.3 [M+H]
96 Preparation of compound ZED4894 H2Nj-j\I
3-amino-1-(1-adamantylmethyl)pyridin-2(1H)-one Chemical Formula: C16H22N20 Exact Mass: 258.17 Molecular Weight: 258.36 484 mg (1.68 mmol) of ZED4893 were suspended in 30 mL Me0H before 50 mg of palladium (10%) on activated carbon (unreduced) were added. The suspension was 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 stirred for 3 h at room temperature under an atmosphere of hydrogen. The catalyst was filtered, and the solvent was evaporated.
Yield: 339 mg, 78%
ESI-MS: 259.4 [M+H]
3-amino-1-(1-adamantylmethyl)pyridin-2(1H)-one Chemical Formula: C16H22N20 Exact Mass: 258.17 Molecular Weight: 258.36 484 mg (1.68 mmol) of ZED4893 were suspended in 30 mL Me0H before 50 mg of palladium (10%) on activated carbon (unreduced) were added. The suspension was 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 stirred for 3 h at room temperature under an atmosphere of hydrogen. The catalyst was filtered, and the solvent was evaporated.
Yield: 339 mg, 78%
ESI-MS: 259.4 [M+H]
97 Preparation of compound 11-107 0)-LN
0 )C,, H
, N N
I H
(S)-N1-(1-(1-adamantylmethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: 033F138N406 Exact Mass: 586.28 Molecular Weight: 586.68 The synthesis of compound 11-107 was performed according to compound 11-3, using ZED4894 instead of ZED3906 in step 5 (according to ZED3907).
Yield: 41 mg, 49% (last step) ESI-MS: 587.4 [M+H]
0 )C,, H
, N N
I H
(S)-N1-(1-(1-adamantylmethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: 033F138N406 Exact Mass: 586.28 Molecular Weight: 586.68 The synthesis of compound 11-107 was performed according to compound 11-3, using ZED4894 instead of ZED3906 in step 5 (according to ZED3907).
Yield: 41 mg, 49% (last step) ESI-MS: 587.4 [M+H]
98 Preparation of compound 11-108 0)L
N
N
I H
OH
(2S)-N1-(1-((3-hydroxy-1-adamantypmethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: 033H38N407 Exact Mass: 602.27 Molecular Weight: 602.68 The synthesis of compound 11-108 was performed according to compound 11-107, using 3-(bromomethyl)-1-adamantanol instead of 1-(bromomethyl)adamantane (according to ZED4893).
Yield: 16 mg, 36% (last step) ESI-MS: 603.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
N
N
I H
OH
(2S)-N1-(1-((3-hydroxy-1-adamantypmethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: 033H38N407 Exact Mass: 602.27 Molecular Weight: 602.68 The synthesis of compound 11-108 was performed according to compound 11-107, using 3-(bromomethyl)-1-adamantanol instead of 1-(bromomethyl)adamantane (according to ZED4893).
Yield: 16 mg, 36% (last step) ESI-MS: 603.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
99 Preparation of compound 11-109 N
, N N
I H
Br (2S)-N1-(1-((3-bromo-1-adamantyl)methyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C33H3713rN4.06 Exact Mass: 664.19 Molecular Weight: 665.57 The synthesis of compound 11-109 was performed according to compound 11-107, using 1-bromo-3-(bromomethyl)adamantane instead of 1-(bromomethyl)adamantane (according to ZED4893).
Yield: 24 mg, 41% (last step) ESI-MS: 665.3 / 667.3 [M+H]
, N N
I H
Br (2S)-N1-(1-((3-bromo-1-adamantyl)methyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C33H3713rN4.06 Exact Mass: 664.19 Molecular Weight: 665.57 The synthesis of compound 11-109 was performed according to compound 11-107, using 1-bromo-3-(bromomethyl)adamantane instead of 1-(bromomethyl)adamantane (according to ZED4893).
Yield: 24 mg, 41% (last step) ESI-MS: 665.3 / 667.3 [M+H]
100 Preparation of compound 11-110 N
I H
(S)-N1-(1-(2-adamantylmethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C33F1381\1406 Exact Mass: 586.28 Molecular Weight: 586.68 The synthesis of compound 11-110 was performed according to compound 11-107, using 2-(bromomethyl)adamantane instead of 1-(bromomethyl)adamantane (according to ZED4893).
Yield: 46 mg, 62% (last step) ESI-MS: 587.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
I H
(S)-N1-(1-(2-adamantylmethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C33F1381\1406 Exact Mass: 586.28 Molecular Weight: 586.68 The synthesis of compound 11-110 was performed according to compound 11-107, using 2-(bromomethyl)adamantane instead of 1-(bromomethyl)adamantane (according to ZED4893).
Yield: 46 mg, 62% (last step) ESI-MS: 587.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
101 Preparation of compound 11-111 OAN
Njci NH
N
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(nicotinamido)-5-oxohexanediamide Chemical Formula: C301-136N606 Exact Mass: 576.27 Molecular Weight: 576.64 The synthesis of compound 11-111 was performed according to compound 11-3, using nicotinic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 65 mg, 46% (last step) ESI-MS: 577.4 [M+H]
Njci NH
N
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(nicotinamido)-5-oxohexanediamide Chemical Formula: C301-136N606 Exact Mass: 576.27 Molecular Weight: 576.64 The synthesis of compound 11-111 was performed according to compound 11-3, using nicotinic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 65 mg, 46% (last step) ESI-MS: 577.4 [M+H]
102 Preparation of compound 11-112 N
J.LN J3,1L
1 1\11N1 (S)-2-(isonicotinamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C30F136N606 Exact Mass: 576.27 Molecular Weight: 576.64 The synthesis of compound 11-112 was performed according to compound 11-3, using isonicotinic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 47 mg, 52% (last step) ESI-MS: 577.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
J.LN J3,1L
1 1\11N1 (S)-2-(isonicotinamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C30F136N606 Exact Mass: 576.27 Molecular Weight: 576.64 The synthesis of compound 11-112 was performed according to compound 11-3, using isonicotinic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 47 mg, 52% (last step) ESI-MS: 577.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
103 Preparation of compound 11-113 N
N
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxo-2-(pyridazine-4-carboxamido)hexanediamide Chemical Formula: C29F135N706 Exact Mass: 577.26 Molecular Weight: 577.63 The synthesis of compound 11-113 was performed according to compound 11-3, using pyridazine-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 34 mg, 46% (last step) ESI-MS: 578.4 [M+H]
N
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxo-2-(pyridazine-4-carboxamido)hexanediamide Chemical Formula: C29F135N706 Exact Mass: 577.26 Molecular Weight: 577.63 The synthesis of compound 11-113 was performed according to compound 11-3, using pyridazine-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 34 mg, 46% (last step) ESI-MS: 578.4 [M+H]
104 Preparation of compound 11-114 NN
N N
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxo-2-(pyridazine-3-carboxamido)hexanediamide Chemical Formula: C29F135N706 Exact Mass: 577.26 Molecular Weight: 577.63 The synthesis of compound 11-114 was performed according to compound 11-3, using pyridazine-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 43 mg, 56% (last step) ESI-MS: 578.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
N N
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxo-2-(pyridazine-3-carboxamido)hexanediamide Chemical Formula: C29F135N706 Exact Mass: 577.26 Molecular Weight: 577.63 The synthesis of compound 11-114 was performed according to compound 11-3, using pyridazine-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 43 mg, 56% (last step) ESI-MS: 578.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
105 Preparation of compound 11-115 N
o (S)-N1-cyclopropyl-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(3-methylbenzofuran-2-carboxamido)-2-oxohexanediamide Chemical Formula: C36H41N507 Exact Mass: 655.30 Molecular Weight: 655.74 The synthesis of compound 11-115 was performed according to compound 11-3, using cyclopropyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632).
Yield: 47 mg, 64% (last step) ESI-MS: 656.5 [M+H]
o (S)-N1-cyclopropyl-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(3-methylbenzofuran-2-carboxamido)-2-oxohexanediamide Chemical Formula: C36H41N507 Exact Mass: 655.30 Molecular Weight: 655.74 The synthesis of compound 11-115 was performed according to compound 11-3, using cyclopropyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632).
Yield: 47 mg, 64% (last step) ESI-MS: 656.5 [M+H]
106 Preparation of compound 11-116 H 1:1:j o hijC
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(3-methylbenzofuran-2-carboxamido)-5-oxo-N6-pentylhexanediamide Chemical Formula: C38H47N507 Exact Mass: 685.35 Molecular Weight: 685.81 The synthesis of compound 11-116 was performed according to compound 11-3, using pentyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632).
Yield: 87 mg, 71% (last step) ESI-MS: 686.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(3-methylbenzofuran-2-carboxamido)-5-oxo-N6-pentylhexanediamide Chemical Formula: C38H47N507 Exact Mass: 685.35 Molecular Weight: 685.81 The synthesis of compound 11-116 was performed according to compound 11-3, using pentyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632).
Yield: 87 mg, 71% (last step) ESI-MS: 686.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
107 Preparation of compound 11-117 0 N)-L
N
QJNH
(S)-N1-allyl-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(3-methylbenzofuran-2-carboxamido)-2-oxohexanediamide Chemical Formula: C36H41N507 Exact Mass: 655.30 Molecular Weight: 655.74 The synthesis of compound 11-117 was performed according to compound 11-3, using allyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632).
Yield: 42 mg, 63% (last step) ESI-MS: 656.5 [M+H]
Scheme 11-4 OH HO CN HO CN HO-NH
H202, LiOH
Boc.N(OtBu Et3N, CH2C'12 Boc.N OtBu Me0H Boc.N OtBu lioc 0 Lc 0 Lc 0 11 1) Ac20, NEt3 2) TFA/DCM
DMAP, DCM 3) Boc20 DIPEA, DMF
(t) H 0 AcOANH2 H2N
I :1'1N a AcONH2 k 0 HATU, DMF BocN OtBu r\iN
1) TFA/DCM 16 2) 3-Methylbenzo[b]-furan-2-carboxylic acid y HATU, DIPEA, DMF
AcOAN H2NH2 1) K2CO3, Me0H
H
Nj-N-rNj 2) Dess-Martin Iljcr I H I
0 0 periodinane 0 0 DMF
Preparation of compound 10 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 HO CN
Boc ,N ,,OtBu I3oc 0 (2 S)-ter t-butyl 2-(bis(tert-butoxycarbonyl)amino)-5-cyano-5-hydroxypentanoate Chemical Formula: C20H34N207 Exact Mass: 414,24 Molecular Weight: 414,49 15.0 g (38.7 mmol) of the aldehyde (S)-tert-butyl 2-(bis(tert-butoxycarbonyl)amino)-5-oxopentanoate (ZED721) were dissolved in 150 ml DCM. 6.42 ml (46.3 mmol) trimethylamine and 7.37 ml (79.9 mmol) acetone cyanohydrin were added, and the reaction was stirred at room temperature overnight. The solution was washed twice with each citric acid solution (10%) and brine. The organic phase was dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography.
Yield: 16.2 g, >100%
ESI-MS: 437.6 [M+Na]
Preparation of compound 11 H0)-L NH2 Boc,N OtBu Boo 0 (2S)-tert-butyl 6-amino-2-(bis(tert-butoxycarbonyhamino)-5-hydroxy-6-oxohexanoate Chemical Formula: 020H36N208 Exact Mass: 432,25 Molecular Weight: 432,51 16.2 g (-38.6 mmol) of cyanohydrin 10 were dissolved in 95 ml Me0H at 4 C and 1.91 g (45.5 mmol) lithium hydroxide monohydrate were added. 18.6 ml hydrogen peroxide (35%) were added dropwise, and the reaction was stirred at room temperature for 1.5 h before quenching with sodium thiosulfate solution (5%). The aqueous phase was extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography.
Yield: 8.61 g, 52%
ESI-MS: 455.2 [M+Na]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 Preparation of compound 15 Ac0)-LNH2 Boc,NJc OtBu Boo 0 (2S)-tert-butyl 5-acetoxy-6-amino-2-(bis(tert-butoxycarbonyl)amino)-6-oxohexanoate Chemical Formula: C22H38N209 Exact Mass: 474,26 Molecular Weight: 474,55 8.61 g (19.9 mmol) of hydroxyamide 10 were dissolved in 55 ml DCM. 3.45 ml (24.9 mmol) 1.91 g (45.5 mmol) trimethylamine, 2.12 ml acetic anhydride and 62 mg (0.50 mmol) DMAP were added, and the reaction was stirred at room temperature for 3 h. After washing with water and brine, the organic phase was dried over Na2SO4, filtered and the solvent was evaporated. The product precipitates from MTBE solution by addition of hexane.
Yield: 8.08 g, 86%
ESI-MS: 475.5 [M+H]
Preparation of compound 16 AcONH2 Boc,NJCOH
(2S)-5-acetoxy-6-amino-2-(tert-butoxycarbonylamino)-6-oxohexanoic acid Chemical Formula: C13H22N207 Exact Mass: 318,14 Molecular Weight: 318,32 8.08 g (17.0 mmol) of 15 were dissolved in 140 ml DCM/TFA (1:1) and stirred at room temperature for 3 h. The solvent was evaporated, and the residue was dissolved in 40 ml DMF. 5.80 ml (2 eq) DIPEA and 4.55 g (20.4 mmol)di-tert-butyl dicarbonate in 20 ml DMF
were added and the reaction was stirred at room temperature overnight. The solvent was evaporated, and the residue was dissolved in 80 ml Et0Ac. After extraction with NaHCO3 .. solution (1.05 eq in water), the product precipitates from the aqueous phase by addition of 1.5 eq citric acid.
Yield: 1.64 g,30%
ESI-MS: 319.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
N
QJNH
(S)-N1-allyl-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(3-methylbenzofuran-2-carboxamido)-2-oxohexanediamide Chemical Formula: C36H41N507 Exact Mass: 655.30 Molecular Weight: 655.74 The synthesis of compound 11-117 was performed according to compound 11-3, using allyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632).
Yield: 42 mg, 63% (last step) ESI-MS: 656.5 [M+H]
Scheme 11-4 OH HO CN HO CN HO-NH
H202, LiOH
Boc.N(OtBu Et3N, CH2C'12 Boc.N OtBu Me0H Boc.N OtBu lioc 0 Lc 0 Lc 0 11 1) Ac20, NEt3 2) TFA/DCM
DMAP, DCM 3) Boc20 DIPEA, DMF
(t) H 0 AcOANH2 H2N
I :1'1N a AcONH2 k 0 HATU, DMF BocN OtBu r\iN
1) TFA/DCM 16 2) 3-Methylbenzo[b]-furan-2-carboxylic acid y HATU, DIPEA, DMF
AcOAN H2NH2 1) K2CO3, Me0H
H
Nj-N-rNj 2) Dess-Martin Iljcr I H I
0 0 periodinane 0 0 DMF
Preparation of compound 10 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 HO CN
Boc ,N ,,OtBu I3oc 0 (2 S)-ter t-butyl 2-(bis(tert-butoxycarbonyl)amino)-5-cyano-5-hydroxypentanoate Chemical Formula: C20H34N207 Exact Mass: 414,24 Molecular Weight: 414,49 15.0 g (38.7 mmol) of the aldehyde (S)-tert-butyl 2-(bis(tert-butoxycarbonyl)amino)-5-oxopentanoate (ZED721) were dissolved in 150 ml DCM. 6.42 ml (46.3 mmol) trimethylamine and 7.37 ml (79.9 mmol) acetone cyanohydrin were added, and the reaction was stirred at room temperature overnight. The solution was washed twice with each citric acid solution (10%) and brine. The organic phase was dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography.
Yield: 16.2 g, >100%
ESI-MS: 437.6 [M+Na]
Preparation of compound 11 H0)-L NH2 Boc,N OtBu Boo 0 (2S)-tert-butyl 6-amino-2-(bis(tert-butoxycarbonyhamino)-5-hydroxy-6-oxohexanoate Chemical Formula: 020H36N208 Exact Mass: 432,25 Molecular Weight: 432,51 16.2 g (-38.6 mmol) of cyanohydrin 10 were dissolved in 95 ml Me0H at 4 C and 1.91 g (45.5 mmol) lithium hydroxide monohydrate were added. 18.6 ml hydrogen peroxide (35%) were added dropwise, and the reaction was stirred at room temperature for 1.5 h before quenching with sodium thiosulfate solution (5%). The aqueous phase was extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography.
Yield: 8.61 g, 52%
ESI-MS: 455.2 [M+Na]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 Preparation of compound 15 Ac0)-LNH2 Boc,NJc OtBu Boo 0 (2S)-tert-butyl 5-acetoxy-6-amino-2-(bis(tert-butoxycarbonyl)amino)-6-oxohexanoate Chemical Formula: C22H38N209 Exact Mass: 474,26 Molecular Weight: 474,55 8.61 g (19.9 mmol) of hydroxyamide 10 were dissolved in 55 ml DCM. 3.45 ml (24.9 mmol) 1.91 g (45.5 mmol) trimethylamine, 2.12 ml acetic anhydride and 62 mg (0.50 mmol) DMAP were added, and the reaction was stirred at room temperature for 3 h. After washing with water and brine, the organic phase was dried over Na2SO4, filtered and the solvent was evaporated. The product precipitates from MTBE solution by addition of hexane.
Yield: 8.08 g, 86%
ESI-MS: 475.5 [M+H]
Preparation of compound 16 AcONH2 Boc,NJCOH
(2S)-5-acetoxy-6-amino-2-(tert-butoxycarbonylamino)-6-oxohexanoic acid Chemical Formula: C13H22N207 Exact Mass: 318,14 Molecular Weight: 318,32 8.08 g (17.0 mmol) of 15 were dissolved in 140 ml DCM/TFA (1:1) and stirred at room temperature for 3 h. The solvent was evaporated, and the residue was dissolved in 40 ml DMF. 5.80 ml (2 eq) DIPEA and 4.55 g (20.4 mmol)di-tert-butyl dicarbonate in 20 ml DMF
were added and the reaction was stirred at room temperature overnight. The solvent was evaporated, and the residue was dissolved in 80 ml Et0Ac. After extraction with NaHCO3 .. solution (1.05 eq in water), the product precipitates from the aqueous phase by addition of 1.5 eq citric acid.
Yield: 1.64 g,30%
ESI-MS: 319.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
108 Preparation of compound 11-118 0 j 0 NNHiNNH
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C33H37N507 Exact Mass: 615.27 Molecular Weight: 615.68 The synthesis of compound 11-118 was performed according to compound 11-3, using compound 16 instead of ZED3632 in step 5 (according to ZED3907).
Yield: 158 mg, 56% (last step) ESI-MS: 616.4 [M+H]
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C33H37N507 Exact Mass: 615.27 Molecular Weight: 615.68 The synthesis of compound 11-118 was performed according to compound 11-3, using compound 16 instead of ZED3632 in step 5 (according to ZED3907).
Yield: 158 mg, 56% (last step) ESI-MS: 616.4 [M+H]
109 Preparation of compound 11-119 0 jN
0 NcNNN
Chemical Formula: 035H39N507 Exact Mass: 641.28 Molecular Weight: 641.71 (S)-N1-ally1-5-(benzofuran-2-carboxamido)-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxohexanediamide The synthesis of compound 11-119 was performed according to compound 11-2, using allyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632).
Yield: 56 mg, 71% (last step) ESI-MS: 642.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
0 NcNNN
Chemical Formula: 035H39N507 Exact Mass: 641.28 Molecular Weight: 641.71 (S)-N1-ally1-5-(benzofuran-2-carboxamido)-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxohexanediamide The synthesis of compound 11-119 was performed according to compound 11-2, using allyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632).
Yield: 56 mg, 71% (last step) ESI-MS: 642.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
110 Preparation of compound 11-120 oJ
N
o 11jCr Chemical Formula: C35H41N507 Exact Mass: 643.30 Molecular Weight: 643.73 (S)-2-(benzofuran-2-carboxamido)-N6-isopropyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide The synthesis of compound 11-120 was performed according to compound 11-2, using isopropyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632).
Yield: 62 mg, 65% (last step) ESI-MS: 644.5 [M+H]
N
o 11jCr Chemical Formula: C35H41N507 Exact Mass: 643.30 Molecular Weight: 643.73 (S)-2-(benzofuran-2-carboxamido)-N6-isopropyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide The synthesis of compound 11-120 was performed according to compound 11-2, using isopropyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632).
Yield: 62 mg, 65% (last step) ESI-MS: 644.5 [M+H]
111 Preparation of compound 11-121 0 NjcNjN
Chemical Formula: C35H39N507 Exact Mass: 641.28 Molecular Weight: 641.71 (S)-2-(benzofuran-2-carboxamido)-N6-cyclopropyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide The synthesis of compound 11-121 was performed according to compound 11-2, using cyclopropyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632).
Yield: 44 mg, 51% (last step) ESI-MS: 642.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
Chemical Formula: C35H39N507 Exact Mass: 641.28 Molecular Weight: 641.71 (S)-2-(benzofuran-2-carboxamido)-N6-cyclopropyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide The synthesis of compound 11-121 was performed according to compound 11-2, using cyclopropyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632).
Yield: 44 mg, 51% (last step) ESI-MS: 642.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
112 Preparation of compound 11-122 0)-L
N
Chemical Formula: C35H39N507 Exact Mass: 677.28 Molecular Weight: 677.75 (S)-2-(benzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxo-N6-phenylhexanediamide The synthesis of compound 11-122 was performed according to compound 11-2, using phenyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632).
Yield: 37 mg, 56% (last step) ESI-MS: 678.4 [M+H]
N
Chemical Formula: C35H39N507 Exact Mass: 677.28 Molecular Weight: 677.75 (S)-2-(benzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxo-N6-phenylhexanediamide The synthesis of compound 11-122 was performed according to compound 11-2, using phenyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632).
Yield: 37 mg, 56% (last step) ESI-MS: 678.4 [M+H]
113 Preparation of compound 11-123 (21A
N
LNCNNN
Chemical Formula: C39H41 N507 Exact Mass: 691,30 Molecular Weight: 691,77 (S)-2-(benzofuran-2-carboxamido)-N6-benzyl-N1-(1-(242-adamantylaminoy 2-oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-y1)-5-oxohexanediamide The synthesis of compound 11-123 was performed according to compound 11-2, using benzyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632).
Yield: 46 mg, 52% (last step) ESI-MS: 692.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
N
LNCNNN
Chemical Formula: C39H41 N507 Exact Mass: 691,30 Molecular Weight: 691,77 (S)-2-(benzofuran-2-carboxamido)-N6-benzyl-N1-(1-(242-adamantylaminoy 2-oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-y1)-5-oxohexanediamide The synthesis of compound 11-123 was performed according to compound 11-2, using benzyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632).
Yield: 46 mg, 52% (last step) ESI-MS: 692.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
114 Preparation of compound 11-124 0)-L
0 Nj-L
N'IN
Chemical Formula: 032H35N507 Exact Mass: 601.25 Molecular Weight: 601.65 (S)-2-(benzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide The synthesis of compound 11-124 was performed according to compound 11-118, using benzofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 96 mg, 81% (last step) ESI-MS: 602.4 [M+H]
0 Nj-L
N'IN
Chemical Formula: 032H35N507 Exact Mass: 601.25 Molecular Weight: 601.65 (S)-2-(benzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide The synthesis of compound 11-124 was performed according to compound 11-118, using benzofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 96 mg, 81% (last step) ESI-MS: 602.4 [M+H]
115 Preparation of compound 11-125 OliNH2 0 ( H 0 CI /
CI
Chemical Formula: C25F131C12N506S
Exact Mass: 635.14 Molecular Weight: 636.55 (S)-2-(2,5-dichlorothiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide The synthesis of compound 11-125 was performed according to compound 11-124, using 2,5-dichlorothiophene-3-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 78 mg, 71% (last step) ESI-MS: 636.3 /638.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
CI
Chemical Formula: C25F131C12N506S
Exact Mass: 635.14 Molecular Weight: 636.55 (S)-2-(2,5-dichlorothiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide The synthesis of compound 11-125 was performed according to compound 11-124, using 2,5-dichlorothiophene-3-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 78 mg, 71% (last step) ESI-MS: 636.3 /638.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
116 Preparation of compound 11-126 0)-L
S JCH
N
NN
Chemical Formula: C29H33F3N606S
Exact Mass: 650.21 Molecular Weight: 650.67 (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(4-methyl-2-(trifluoromethyl)thiazole-5-carboxamido)-5-oxohexanediamide The synthesis of compound 11-126 was performed according to compound 11-124, using 4-methyl-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 53 mg, 67% (last step) ESI-MS: 651.3 [M+H]
S JCH
N
NN
Chemical Formula: C29H33F3N606S
Exact Mass: 650.21 Molecular Weight: 650.67 (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(4-methyl-2-(trifluoromethyl)thiazole-5-carboxamido)-5-oxohexanediamide The synthesis of compound 11-126 was performed according to compound 11-124, using 4-methyl-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 53 mg, 67% (last step) ESI-MS: 651.3 [M+H]
117 Preparation of compound 11-127 OA
H
NN
Chemical Formula: C27H34N806 Exact Mass: 566.26 Molecular Weight: 566.61 (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(1 -methyl-1 H-1 ,2,3-triazole-5-carboxamido)-5-oxohexanediamide The synthesis of compound 11-127 was performed according to compound 11-124, using 1-methyl-1H-1,2,3-triazole-5-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 26 mg, 49% (last step) ESI-MS: 567.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
H
NN
Chemical Formula: C27H34N806 Exact Mass: 566.26 Molecular Weight: 566.61 (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(1 -methyl-1 H-1 ,2,3-triazole-5-carboxamido)-5-oxohexanediamide The synthesis of compound 11-127 was performed according to compound 11-124, using 1-methyl-1H-1,2,3-triazole-5-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 26 mg, 49% (last step) ESI-MS: 567.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
118 Preparation of compound 11-128 o o )^LN
H
H H
Nj-L Nõ,,c3i.
CI
'''r s 0 0 CI
(2S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(2,5-dichlorothiophene-3-carboxamido)-N6-methyl-5-oxohexanediamide Chemical Formula: C26H29Cl2N506S
Exact Mass: 609.12 Molecular Weight: 610.51 The synthesis of compound 11-128 was performed according to compound 11-97, using 2,5-dichlorothiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 53 mg, 73% (last step) ESI-MS: 610.3 /612.3 [M+H]
H
H H
Nj-L Nõ,,c3i.
CI
'''r s 0 0 CI
(2S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(2,5-dichlorothiophene-3-carboxamido)-N6-methyl-5-oxohexanediamide Chemical Formula: C26H29Cl2N506S
Exact Mass: 609.12 Molecular Weight: 610.51 The synthesis of compound 11-128 was performed according to compound 11-97, using 2,5-dichlorothiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 53 mg, 73% (last step) ESI-MS: 610.3 /612.3 [M+H]
119 Preparation of compound 11-129 o ON
H
0 jc H 0 H
S Nj-N N...õ.cL
F3C N-----/ i i I-1 1 I
(2S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(4-methyl-2-(trifluoromethyl)thiazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: 027H31F3N606S
Exact Mass: 624.20 Molecular Weight: 624.63 The synthesis of compound 11-129 was performed according to compound 11-97, using 4-methyl-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 42 mg, 60% (last step) ESI-MS: 625.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
H
0 jc H 0 H
S Nj-N N...õ.cL
F3C N-----/ i i I-1 1 I
(2S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(4-methyl-2-(trifluoromethyl)thiazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: 027H31F3N606S
Exact Mass: 624.20 Molecular Weight: 624.63 The synthesis of compound 11-129 was performed according to compound 11-97, using 4-methyl-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 42 mg, 60% (last step) ESI-MS: 625.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
120 Preparation of compound 11-130 NN
0)-L
N
H H
1\1--NN 0 0 (2S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(1-methyl-1H-1,2,3-triazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C25H32N806 Exact Mass: 540.24 Molecular Weight: 540.57 The synthesis of compound 11-130 was performed according to compound 11-97, using 1-methyl-1H-1,2,3-triazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 15 mg, 39% (last step) ESI-MS: 541.3 [M+H]
0)-L
N
H H
1\1--NN 0 0 (2S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(1-methyl-1H-1,2,3-triazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C25H32N806 Exact Mass: 540.24 Molecular Weight: 540.57 The synthesis of compound 11-130 was performed according to compound 11-97, using 1-methyl-1H-1,2,3-triazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 15 mg, 39% (last step) ESI-MS: 541.3 [M+H]
121 Preparation of compound 11-131 0)-L
H
N
Y-LN
\N-N 0 0 Chemical Formula: C27H341\1806 Exact Mass: 566.26 Molecular Weight: 566.61 (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yI)-N6-methyl-5-oxo-2-(2H-1,2,3-triazole-4-carboxamido)hexanediamide The synthesis of compound 11-131 was performed according to compound 11-3, using 2H-1,2,3-triazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 28 mg, 56% (last step) ESI-MS: 567.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
H
N
Y-LN
\N-N 0 0 Chemical Formula: C27H341\1806 Exact Mass: 566.26 Molecular Weight: 566.61 (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yI)-N6-methyl-5-oxo-2-(2H-1,2,3-triazole-4-carboxamido)hexanediamide The synthesis of compound 11-131 was performed according to compound 11-3, using 2H-1,2,3-triazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 28 mg, 56% (last step) ESI-MS: 567.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
122 Preparation of compound 11-132 0)-L
N
0 ( H0 HN Ay-LN N
Chemical Formula: C271-134N806 Exact Mass: 566.26 Molecular Weight: 566.61 (S)-N1-(1 -(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1 H-1 ,2,3-triazole-4-carboxamido)hexanediamide The synthesis of compound 11-132 was performed according to compound 11-3, using 1H-1,2,3-triazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 14 mg, 45% (last step) ESI-MS: 567.4 [M+H]
N
0 ( H0 HN Ay-LN N
Chemical Formula: C271-134N806 Exact Mass: 566.26 Molecular Weight: 566.61 (S)-N1-(1 -(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1 H-1 ,2,3-triazole-4-carboxamido)hexanediamide The synthesis of compound 11-132 was performed according to compound 11-3, using 1H-1,2,3-triazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 14 mg, 45% (last step) ESI-MS: 567.4 [M+H]
123 Preparation of compound 11-133 N
N-r-N 0 0 Chemical Formula: C28H36N806 Exact Mass: 580.28 Molecular Weight: 580.64 (S)-N1 -(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(1 -methyl-1 H-1,2,3-triazole-4-carboxamido)-5-oxohexanediamide The synthesis of compound 11-133 was performed according to compound 11-3, using 1-methyl-1H-1,2,3-triazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 36 mg, 61% (last step) ESI-MS: 581.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
N-r-N 0 0 Chemical Formula: C28H36N806 Exact Mass: 580.28 Molecular Weight: 580.64 (S)-N1 -(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(1 -methyl-1 H-1,2,3-triazole-4-carboxamido)-5-oxohexanediamide The synthesis of compound 11-133 was performed according to compound 11-3, using 1-methyl-1H-1,2,3-triazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 36 mg, 61% (last step) ESI-MS: 581.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
124 Preparation of compound 11-134 NN
Chemical Formula: C27H34N806 Exact Mass: 566.26 Molecular Weight: 566.61 (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1H-1,2,4-triazole-3-carboxamido)hexanediamide The synthesis of compound 11-134 was performed according to compound 11-3, using 1H-1,2,4-triazole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 21 mg, 43% (last step) ESI-MS: 567.4 [M+H]
Chemical Formula: C27H34N806 Exact Mass: 566.26 Molecular Weight: 566.61 (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1H-1,2,4-triazole-3-carboxamido)hexanediamide The synthesis of compound 11-134 was performed according to compound 11-3, using 1H-1,2,4-triazole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 21 mg, 43% (last step) ESI-MS: 567.4 [M+H]
125 Preparation of compound 11-135 0)-( N
N
JI NN
Chemical Formula: C28H36N806 Exact Mass: 580.28 Molecular Weight: 580.64 (S)-N1 -(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1 H-1 ,2,4-triazole-3-carboxamido)-5-oxohexanediamide The synthesis of compound 11-135 was performed according to compound 11-3, using 1-methyl-1H-1,2,4-triazole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 39 mg, 67% (last step) ESI-MS: 581.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
N
JI NN
Chemical Formula: C28H36N806 Exact Mass: 580.28 Molecular Weight: 580.64 (S)-N1 -(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1 H-1 ,2,4-triazole-3-carboxamido)-5-oxohexanediamide The synthesis of compound 11-135 was performed according to compound 11-3, using 1-methyl-1H-1,2,4-triazole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 39 mg, 67% (last step) ESI-MS: 581.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
126 Preparation of compound 11-136 N
N
o I HjjCr II NrN
Chemical Formula: C33H37N507 Exact Mass: 615.27 Molecular Weight: 615.68 (S)-2-(benzofuran-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide The synthesis of compound 11-136 was performed according to compound 11-3, using benzofuran-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 56 mg, 71% (last step) ESI-MS: 616.4 [M+H]
N
o I HjjCr II NrN
Chemical Formula: C33H37N507 Exact Mass: 615.27 Molecular Weight: 615.68 (S)-2-(benzofuran-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide The synthesis of compound 11-136 was performed according to compound 11-3, using benzofuran-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 56 mg, 71% (last step) ESI-MS: 616.4 [M+H]
127 Preparation of compound 11-137 N)-L
H NrNEI
Chemical Formula: C33H37N506S
Exact Mass: 631.25 Molecular Weight: 631.74 (S)-2-(benzo[b]thiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide The synthesis of compound 11-137 was performed according to compound 11-3, using benzo[b]thiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 49 mg, 64% (last step) ESI-MS: 632.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
H NrNEI
Chemical Formula: C33H37N506S
Exact Mass: 631.25 Molecular Weight: 631.74 (S)-2-(benzo[b]thiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide The synthesis of compound 11-137 was performed according to compound 11-3, using benzo[b]thiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 49 mg, 64% (last step) ESI-MS: 632.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
128 Preparation of compound 11-138 N
NEIHNThrN
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(1-methyl-1H-pyrazole-3-carboxamido)-5-oxohexanediamide Chemical Formula: C29F-137N706 Exact Mass: 579.28 Molecular Weight: 579.65 The synthesis of compound 11-138 was performed according to compound 11-3, using 1-methyl-1H-pyrazole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 43 mg, 59% (last step) ESI-MS: 580.4 [M+H]
NEIHNThrN
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(1-methyl-1H-pyrazole-3-carboxamido)-5-oxohexanediamide Chemical Formula: C29F-137N706 Exact Mass: 579.28 Molecular Weight: 579.65 The synthesis of compound 11-138 was performed according to compound 11-3, using 1-methyl-1H-pyrazole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 43 mg, 59% (last step) ESI-MS: 580.4 [M+H]
129 Preparation of compound 11-139 N
H
N m N, I H 1 41 I
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-pyrazole-4-carboxamido)-5-oxohexanediamide Chemical Formula: C29F-137N706 Exact Mass: 579.28 Molecular Weight: 579.65 The synthesis of compound 11-139 was performed according to compound 11-3, using 1-methyl-1H-pyrazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 53 mg, 62% (last step) ESI-MS: 580.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
H
N m N, I H 1 41 I
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-pyrazole-4-carboxamido)-5-oxohexanediamide Chemical Formula: C29F-137N706 Exact Mass: 579.28 Molecular Weight: 579.65 The synthesis of compound 11-139 was performed according to compound 11-3, using 1-methyl-1H-pyrazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 53 mg, 62% (last step) ESI-MS: 580.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
130 Preparation of compound 11-140 N
OHO H
*LN N N
, H
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(1-methyl-1H-pyrazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C29F-137N706 Exact Mass: 579.28 Molecular Weight: 579.65 The synthesis of compound 11-140 was performed according to compound 11-3, using 1-methyl-1H-pyrazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 39 mg, 48% (last step) ESI-MS: 580.4 [M+H]
OHO H
*LN N N
, H
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(1-methyl-1H-pyrazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C29F-137N706 Exact Mass: 579.28 Molecular Weight: 579.65 The synthesis of compound 11-140 was performed according to compound 11-3, using 1-methyl-1H-pyrazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 39 mg, 48% (last step) ESI-MS: 580.4 [M+H]
131 Preparation of compound 11-141 N
N
No I H
, yThvN
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(4-methy1-1,2,3-thiadiazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C28H35N706S
Exact Mass: 597.24 Molecular Weight: 597.69 The synthesis of compound 11-141 was performed according to compound 11-3, using 4-methyl-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 54 mg, 58% (last step) ESI-MS: 598.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
N
No I H
, yThvN
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(4-methy1-1,2,3-thiadiazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C28H35N706S
Exact Mass: 597.24 Molecular Weight: 597.69 The synthesis of compound 11-141 was performed according to compound 11-3, using 4-methyl-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 54 mg, 58% (last step) ESI-MS: 598.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
132 Preparation of compound 11-142 0 ( H0 N NThv N
H
\S-N
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxo-2-(1,2,5-thiadiazole-3-carboxamido)hexanediamide Chemical Formula: C27H33N706S
Exact Mass: 583.22 Molecular Weight: 583.66 The synthesis of compound 11-142 was performed according to compound 11-3, using 1,2,5-thiadiazole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 36 mg, 43% (last step) ESI-MS: 584.4 [M+H]
H
\S-N
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxo-2-(1,2,5-thiadiazole-3-carboxamido)hexanediamide Chemical Formula: C27H33N706S
Exact Mass: 583.22 Molecular Weight: 583.66 The synthesis of compound 11-142 was performed according to compound 11-3, using 1,2,5-thiadiazole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 36 mg, 43% (last step) ESI-MS: 584.4 [M+H]
133 Preparation of compound 11-143 ON
N N
N-NN
(S)-2-(4-iodo-1-methyl-1H-pyrazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide Chemical Formula: C29H36IN706 Exact Mass: 705.18 Molecular Weight: 705.54 The synthesis of compound 11-143 was performed according to compound 11-3, using 4-iodo-1-methyl-1H-pyrazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 24 mg, 49% (last step) ESI-MS: 706.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
N N
N-NN
(S)-2-(4-iodo-1-methyl-1H-pyrazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide Chemical Formula: C29H36IN706 Exact Mass: 705.18 Molecular Weight: 705.54 The synthesis of compound 11-143 was performed according to compound 11-3, using 4-iodo-1-methyl-1H-pyrazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 24 mg, 49% (last step) ESI-MS: 706.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
134 Preparation of compound 11-144 0)L
jOt NH 0 N
N
Hs, I I
(S)-N1 -(1 -(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-y1)-2-(1-methy1-1 H-pyrazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C28H35N706 Exact Mass: 565.26 Molecular Weight: 565.62 The synthesis of compound 11-144 was performed according to compound 11-118, using 1-methyl-1H-pyrazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 26 mg, 68% (last step) ESI-MS: 566.4 [M+H]
jOt NH 0 N
N
Hs, I I
(S)-N1 -(1 -(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-y1)-2-(1-methy1-1 H-pyrazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C28H35N706 Exact Mass: 565.26 Molecular Weight: 565.62 The synthesis of compound 11-144 was performed according to compound 11-118, using 1-methyl-1H-pyrazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 26 mg, 68% (last step) ESI-MS: 566.4 [M+H]
135 Preparation of compound 11-145 OA
N
µ1\1 0 0 (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-y1)-244-methyl-I ,2,3-thiadiazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: 027H33N706S
Exact Mass: 583.22 Molecular Weight: 583.66 The synthesis of compound 11-145 was performed according to compound 11-118, using 4-methyl-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-carboxylic acid in step 6 (according to ZED3264).
Yield: 35 mg, 62% (last step) ESI-MS: 584.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
N
µ1\1 0 0 (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-y1)-244-methyl-I ,2,3-thiadiazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: 027H33N706S
Exact Mass: 583.22 Molecular Weight: 583.66 The synthesis of compound 11-145 was performed according to compound 11-118, using 4-methyl-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-carboxylic acid in step 6 (according to ZED3264).
Yield: 35 mg, 62% (last step) ESI-MS: 584.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
136 Preparation of compound 11-146 N
o IF\11 N
(S)-2-(benzofuran-2-carboxamido)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C29F131N507 Exact Mass: 561.22 Molecular Weight: 561.59 The synthesis of compound 11-146 was performed according to compound 11-118, using benzofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264) and using exo-2-aminonorbornane instead of 2-adamantan-amine in step 2 (according to ZED3905).
Yield: 43 mg, 60% (last step) ESI-MS: 562.4 [M+H]
o IF\11 N
(S)-2-(benzofuran-2-carboxamido)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C29F131N507 Exact Mass: 561.22 Molecular Weight: 561.59 The synthesis of compound 11-146 was performed according to compound 11-118, using benzofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264) and using exo-2-aminonorbornane instead of 2-adamantan-amine in step 2 (according to ZED3905).
Yield: 43 mg, 60% (last step) ESI-MS: 562.4 [M+H]
137 Preparation of compound 11-147 0)L
N
(S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C30H33N507 Exact Mass: 575.24 Molecular Weight: 575.61 The synthesis of compound 11-147 was performed according to compound 11-118, using using exo-2-aminonorbornane instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 56 mg, 67% (last step) ESI-MS: 576.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
N
(S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C30H33N507 Exact Mass: 575.24 Molecular Weight: 575.61 The synthesis of compound 11-147 was performed according to compound 11-118, using using exo-2-aminonorbornane instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 56 mg, 67% (last step) ESI-MS: 576.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
138 Preparation of compound 11-148 oI 'NI
(S)-2-(benzofuran-2-carboxamido)-N1-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C29H31N507 Exact Mass: 561.22 Molecular Weight: 561.59 The synthesis of compound 11-148 was performed according to compound 11-118, using benzofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264) and using ( )-endo-2-aminonorbornane instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 49 mg, 66% (last step) ESI-MS: 562.4 [M+H]
(S)-2-(benzofuran-2-carboxamido)-N1-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C29H31N507 Exact Mass: 561.22 Molecular Weight: 561.59 The synthesis of compound 11-148 was performed according to compound 11-118, using benzofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264) and using ( )-endo-2-aminonorbornane instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 49 mg, 66% (last step) ESI-MS: 562.4 [M+H]
139 Preparation of compound 11-149 OI'0 N.r NiNH
(S)-N1-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C30H33N507 Exact Mass: 575.24 Molecular Weight: 575.61 The synthesis of compound 11-149 was performed according to compound 11-118, using using ( )-endo-2-aminonorbornane instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 64 mg, 75% (last step) ESI-MS: 576.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
(S)-N1-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C30H33N507 Exact Mass: 575.24 Molecular Weight: 575.61 The synthesis of compound 11-149 was performed according to compound 11-118, using using ( )-endo-2-aminonorbornane instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 64 mg, 75% (last step) ESI-MS: 576.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
140 Preparation of compound 11-150 NHfNN2 NjLr NH
o (S)-2-(benzofuran-2-carboxamido)-5-oxo-N1-(2-oxo-1-(2-oxo-2-((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide Chemical Formula: C32H37N507 Exact Mass: 603.27 Molecular Weight: 603.67 The synthesis of compound 11-150 was performed according to compound 11-118, using benzofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264) and using (R)-(+)-bornylamine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 38 mg, 53% (last step) ESI-MS: 604.4 [M+H]
o (S)-2-(benzofuran-2-carboxamido)-5-oxo-N1-(2-oxo-1-(2-oxo-2-((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide Chemical Formula: C32H37N507 Exact Mass: 603.27 Molecular Weight: 603.67 The synthesis of compound 11-150 was performed according to compound 11-118, using benzofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264) and using (R)-(+)-bornylamine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 38 mg, 53% (last step) ESI-MS: 604.4 [M+H]
141 Preparation of compound 11-151 0)-L
0 Nr N2-KN.r NH
(S)-2-(3-methylbenzofuran-2-carboxamido)-5-oxo-N1-(2-oxo-1-(2-oxo-2-((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide Chemical Formula: C33H39N507 Exact Mass: 617.28 Molecular Weight: 617.69 The synthesis of compound 11-151 was performed according to compound 11-118, using using (R)-(+)-bornylamine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 31 mg, 59% (last step) ESI-MS: 618.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
0 Nr N2-KN.r NH
(S)-2-(3-methylbenzofuran-2-carboxamido)-5-oxo-N1-(2-oxo-1-(2-oxo-2-((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide Chemical Formula: C33H39N507 Exact Mass: 617.28 Molecular Weight: 617.69 The synthesis of compound 11-151 was performed according to compound 11-118, using using (R)-(+)-bornylamine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 31 mg, 59% (last step) ESI-MS: 618.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
142 Preparation of compound 11-152 COL' N
N, H jJ
1\1 0 0 (S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(4-methy1-1,2,3-thiadiazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C25H31 N706S
Exact Mass: 557.21 Molecular Weight: 557.62 The synthesis of compound 11-152 was performed according to compound 11-94, using 4-methyl-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 53 mg, 68% (last step) ESI-MS: 558.4 [M+H]
N, H jJ
1\1 0 0 (S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(4-methy1-1,2,3-thiadiazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C25H31 N706S
Exact Mass: 557.21 Molecular Weight: 557.62 The synthesis of compound 11-152 was performed according to compound 11-94, using 4-methyl-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 53 mg, 68% (last step) ESI-MS: 558.4 [M+H]
143 Preparation of compound 11-153 N
0 ( H 0 Y-LNNJ-L
N N
\ H
(S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-pyrazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C26H33N706 Exact Mass: 539.25 Molecular Weight: 539.58 The synthesis of compound 11-153 was performed according to compound 11-94, using 1-methyl-1H-pyrazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 60 mg, 67% (last step) ESI-MS: 540.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
0 ( H 0 Y-LNNJ-L
N N
\ H
(S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-pyrazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C26H33N706 Exact Mass: 539.25 Molecular Weight: 539.58 The synthesis of compound 11-153 was performed according to compound 11-94, using 1-methyl-1H-pyrazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 60 mg, 67% (last step) ESI-MS: 540.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
144 Preparation of compound 11-154 (DAN
0 jcr H 0 )-LTh F3C ________________________ SNNN(NH
N ,,r (S)-N1-(1-(2-((16,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(4-methyl-2-(trifluoromethypthiazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C27H31F3N606S
Exact Mass: 624.20 Molecular Weight: 624.63 The synthesis of compound 11-154 was performed according to compound 11-90, using 4-methyl-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 68 mg, 74% (last step) ESI-MS: 625.3 [M+H]
0 jcr H 0 )-LTh F3C ________________________ SNNN(NH
N ,,r (S)-N1-(1-(2-((16,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(4-methyl-2-(trifluoromethypthiazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C27H31F3N606S
Exact Mass: 624.20 Molecular Weight: 624.63 The synthesis of compound 11-154 was performed according to compound 11-90, using 4-methyl-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 68 mg, 74% (last step) ESI-MS: 625.3 [M+H]
145 Preparation of compound 11-155 N
H ?
NH
CI
(S)-N1-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(2,5-dichlorothiophene-3-carboxamido)-N6-methyl-5-oxohexanediamide Chemical Formula: C26H29Cl2N506S
Exact Mass: 609.12 Molecular Weight: 610.51 The synthesis of compound 11-155 was performed according to compound 11-90, using 2,5-dichlorothiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 74 mg, 68% (last step) ESI-MS: 610.3 /612.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
H ?
NH
CI
(S)-N1-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(2,5-dichlorothiophene-3-carboxamido)-N6-methyl-5-oxohexanediamide Chemical Formula: C26H29Cl2N506S
Exact Mass: 609.12 Molecular Weight: 610.51 The synthesis of compound 11-155 was performed according to compound 11-90, using 2,5-dichlorothiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 74 mg, 68% (last step) ESI-MS: 610.3 /612.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
146 Preparation of compound 11-156 0 jc H 0 :S N NH
(S)-N1-(1-(2-((16,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(4-methyl-1,2,3-thiadiazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C25H31N706S
Exact Mass: 557.21 Molecular Weight: 557.62 The synthesis of compound 11-156 was performed according to compound 11-90, using 4-methyl-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 56 mg, 61% (last step) ESI-MS: 558.4 [M+H]
(S)-N1-(1-(2-((16,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(4-methyl-1,2,3-thiadiazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C25H31N706S
Exact Mass: 557.21 Molecular Weight: 557.62 The synthesis of compound 11-156 was performed according to compound 11-90, using 4-methyl-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 56 mg, 61% (last step) ESI-MS: 558.4 [M+H]
147 Preparation of compound 11-157 0)-(N
(I? NH NH
(S)-N1-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(1-methyl-1H-1,2,3-triazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C25F132N806 Exact Mass: 540.24 Molecular Weight: 540.57 The synthesis of compound 11-157 was performed according to compound 11-90, using 1-methyl-1H-1,2,3-triazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 34 mg, 52% (last step) ESI-MS: 541.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
(I? NH NH
(S)-N1-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(1-methyl-1H-1,2,3-triazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C25F132N806 Exact Mass: 540.24 Molecular Weight: 540.57 The synthesis of compound 11-157 was performed according to compound 11-90, using 1-methyl-1H-1,2,3-triazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 34 mg, 52% (last step) ESI-MS: 541.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
148 Preparation of compound 11-158 jOt N 0 N
N-NN
(S)-N1-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(1-methyl-1H-pyrazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C26H33N706 Exact Mass: 539.25 Molecular Weight: 539.58 The synthesis of compound 11-158 was performed according to compound 11-90, using 1-methyl-1H-pyrazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 55 mg, 64% (last step) ESI-MS: 540.4 [M+H]
N-NN
(S)-N1-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(1-methyl-1H-pyrazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C26H33N706 Exact Mass: 539.25 Molecular Weight: 539.58 The synthesis of compound 11-158 was performed according to compound 11-90, using 1-methyl-1H-pyrazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 55 mg, 64% (last step) ESI-MS: 540.4 [M+H]
149 Preparation of compound 11-159 NH
(S)-N1-methyl-5-(4-methyl-2-(trifluoromethyl)thiazole-5-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide Chemical Formula: C30H37F3N606S
Exact Mass: 666.24 Molecular Weight: 666.71 The synthesis of compound 11-159 was performed according to compound 11-92, using 4-methyl-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 52 mg, 57% (last step) ESI-MS: 667.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
(S)-N1-methyl-5-(4-methyl-2-(trifluoromethyl)thiazole-5-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide Chemical Formula: C30H37F3N606S
Exact Mass: 666.24 Molecular Weight: 666.71 The synthesis of compound 11-159 was performed according to compound 11-92, using 4-methyl-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 52 mg, 57% (last step) ESI-MS: 667.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
150 Preparation of compound 11-160 N
H
_NH
CI / r CI
(S)-2-(2,5-dichlorothiophene-3-carboxamido)-N6-methyl-5-oxo-N1-(2-oxo-1-(2-oxo-2-((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide Chemical Formula: C29H35Cl2N506S
Exact Mass: 651.17 Molecular Weight: 652.59 The synthesis of compound 11-160 was performed according to compound 11-92, using 2,5-dichlorothiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 66 mg, 61% (last step) ESI-MS: 652.3 / 654.3 [M+H]
H
_NH
CI / r CI
(S)-2-(2,5-dichlorothiophene-3-carboxamido)-N6-methyl-5-oxo-N1-(2-oxo-1-(2-oxo-2-((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide Chemical Formula: C29H35Cl2N506S
Exact Mass: 651.17 Molecular Weight: 652.59 The synthesis of compound 11-160 was performed according to compound 11-92, using 2,5-dichlorothiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 66 mg, 61% (last step) ESI-MS: 652.3 / 654.3 [M+H]
151 Preparation of compound 11-161 N
N NH
I
µ1\1 0 0 (S)-N1-methyl-5-(4-methyl-1,2,3-thiadiazole-5-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yOhexanediamide Chemical Formula: C28H37N706S
Exact Mass: 599.25 Molecular Weight: 599.70 The synthesis of compound 11-161 was performed according to compound 11-92, using 4-methyl-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 41 mg, 51% (last step) ESI-MS: 600.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
N NH
I
µ1\1 0 0 (S)-N1-methyl-5-(4-methyl-1,2,3-thiadiazole-5-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yOhexanediamide Chemical Formula: C28H37N706S
Exact Mass: 599.25 Molecular Weight: 599.70 The synthesis of compound 11-161 was performed according to compound 11-92, using 4-methyl-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 41 mg, 51% (last step) ESI-MS: 600.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
152 Preparation of compound 11-162 N
J(0 rN NH
N
0 0 \1-1\1 (S)-N1 -methyl-5-(1 -methyl-1 H-1,2,3-triazole-5-carboxamido)-2-oxo-N6-(2-oxo-1 -(2-oxo-2-((1 R,2S,4R)-1 ,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yOhexanediamide Chemical Formula: C28H38N806 Exact Mass: 582.29 Molecular Weight: 582.65 The synthesis of compound 11-162 was performed according to compound 11-92, using 1-methyl-1H-1,2,3-triazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 28 mg, 46% (last step) ESI-MS: 583.5 [M+H]
J(0 rN NH
N
0 0 \1-1\1 (S)-N1 -methyl-5-(1 -methyl-1 H-1,2,3-triazole-5-carboxamido)-2-oxo-N6-(2-oxo-1 -(2-oxo-2-((1 R,2S,4R)-1 ,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yOhexanediamide Chemical Formula: C28H38N806 Exact Mass: 582.29 Molecular Weight: 582.65 The synthesis of compound 11-162 was performed according to compound 11-92, using 1-methyl-1H-1,2,3-triazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 28 mg, 46% (last step) ESI-MS: 583.5 [M+H]
153 Preparation of compound 11-163 N
a)L
N
N N NH
N--"\ 0 0 (S)-N1-methy1-5-(1 -methyl-1 H-pyrazole-5-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yOhexanediamide Chemical Formula: C29H39N706 Exact Mass: 581.30 Molecular Weight: 581.66 The synthesis of compound 11-163 was performed according to compound 11-92, using 1-methyl-1H-pyrazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 44 mg, 58% (last step) ESI-MS: 582.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
a)L
N
N N NH
N--"\ 0 0 (S)-N1-methy1-5-(1 -methyl-1 H-pyrazole-5-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yOhexanediamide Chemical Formula: C29H39N706 Exact Mass: 581.30 Molecular Weight: 581.66 The synthesis of compound 11-163 was performed according to compound 11-92, using 1-methyl-1H-pyrazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 44 mg, 58% (last step) ESI-MS: 582.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
154 Preparation of compound 11-164 0)-LN
N N
(2S)-2-(4-tert-buty1-1H-pyrrole-3-carboxamido)-N6-methyl-N1-(1-(2-(2-adamantylamino)ethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C33H45N505 Exact Mass: 591.34 Molecular Weight: 591.74 The synthesis of compound 11-164 was performed according to compound 11-107, using 1-(2-bromoethyl)adamantane instead of 1-(bromomethyl)adamantane (according to ZED4893) and 5-tert-butyl-1H-pyrrole-3-carboxylic acid instead of 3-methyl-benzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 32 mg, 56% (last step) ESI-MS: 592.5 [M+H]
N N
(2S)-2-(4-tert-buty1-1H-pyrrole-3-carboxamido)-N6-methyl-N1-(1-(2-(2-adamantylamino)ethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C33H45N505 Exact Mass: 591.34 Molecular Weight: 591.74 The synthesis of compound 11-164 was performed according to compound 11-107, using 1-(2-bromoethyl)adamantane instead of 1-(bromomethyl)adamantane (according to ZED4893) and 5-tert-butyl-1H-pyrrole-3-carboxylic acid instead of 3-methyl-benzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 32 mg, 56% (last step) ESI-MS: 592.5 [M+H]
155 Preparation of compound 11-165 N
NC N c NH N
(2S)-2-(4-cyano-1-methy1-1H-pyrrole-2-carboxamido)-N6-methyl-N 1-(1-(3-(1-adamantylami no)propy1)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexaned iamide Chemical Formula: 032H40N605 Exact Mass: 588.31 Molecular Weight: 588.70 The synthesis of compound 11-165 was performed according to compound 11-107, using 1-(3-bromopropyl)adamantane instead of 1-(bromomethyl)adamantane (according to ZED4893) and 4-cyano-1-methyl-1H-pyrrole-2-carboxylic acid instead of 3-methyl-benzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 27 mg, 48% (last step) ESI-MS: 589.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
NC N c NH N
(2S)-2-(4-cyano-1-methy1-1H-pyrrole-2-carboxamido)-N6-methyl-N 1-(1-(3-(1-adamantylami no)propy1)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexaned iamide Chemical Formula: 032H40N605 Exact Mass: 588.31 Molecular Weight: 588.70 The synthesis of compound 11-165 was performed according to compound 11-107, using 1-(3-bromopropyl)adamantane instead of 1-(bromomethyl)adamantane (according to ZED4893) and 4-cyano-1-methyl-1H-pyrrole-2-carboxylic acid instead of 3-methyl-benzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 27 mg, 48% (last step) ESI-MS: 589.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
156 Preparation of compound 11-166 0)-L
N
0?LNjcFr1J-LN
Me (S)-N1-(1-(3-(2-adamantylamino)-3-oxopropy1)-2-oxo-1,2-dihydropyridin-3-y1)-2-(5-methoxyoxazole-2-carboxamido)-N6-methy1-5-oxohexanediamide Chemical Formula: C301-138N608 Exact Mass: 610.28 Molecular Weight: 610.66 The synthesis of compound 11-166 was performed according to compound 11-3, using 3-chloropropionic acid instead of chloroacetic acid (according to ZED1657) and 5-methoxyoxazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 31 mg, 59% (last step) ESI-MS: 611.4 [M+H]
N
0?LNjcFr1J-LN
Me (S)-N1-(1-(3-(2-adamantylamino)-3-oxopropy1)-2-oxo-1,2-dihydropyridin-3-y1)-2-(5-methoxyoxazole-2-carboxamido)-N6-methy1-5-oxohexanediamide Chemical Formula: C301-138N608 Exact Mass: 610.28 Molecular Weight: 610.66 The synthesis of compound 11-166 was performed according to compound 11-3, using 3-chloropropionic acid instead of chloroacetic acid (according to ZED1657) and 5-methoxyoxazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 31 mg, 59% (last step) ESI-MS: 611.4 [M+H]
157 Preparation of compound 11-167 N
Nr (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C29F131N507 Exact Mass: 561.22 Molecular Weight: 561.59 The synthesis of compound 11-167 was performed according to compound 11-3, using 1-bicyclo[1.1.1]pentylamine instead of 2-adamantanamine in step 2 (according to ZED3905).
.. Yield: 45 mg, 67% (last step) ESI-MS: 562.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
Nr (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C29F131N507 Exact Mass: 561.22 Molecular Weight: 561.59 The synthesis of compound 11-167 was performed according to compound 11-3, using 1-bicyclo[1.1.1]pentylamine instead of 2-adamantanamine in step 2 (according to ZED3905).
.. Yield: 45 mg, 67% (last step) ESI-MS: 562.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
158 Preparation of compound 11-168 o N
0 Na,õ11,,N N NH
H I H N-r (S)-2-(2-acetyloxazole-4-carboxamido)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-311)-N6-methyl-5-oxohexanediamide Chemical Formula: C25F128N608 Exact Mass: 540.20 Molecular Weight: 540.53 The synthesis of compound 11-168 was performed according to compound 11-167, using 2-acetyloxazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 26 mg, 48% (last step) ESI-MS: 541.4 [M+H]
0 Na,õ11,,N N NH
H I H N-r (S)-2-(2-acetyloxazole-4-carboxamido)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-311)-N6-methyl-5-oxohexanediamide Chemical Formula: C25F128N608 Exact Mass: 540.20 Molecular Weight: 540.53 The synthesis of compound 11-168 was performed according to compound 11-167, using 2-acetyloxazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 26 mg, 48% (last step) ESI-MS: 541.4 [M+H]
159 Preparation of compound 11-169 ON
N
(S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-311)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C30H33N507 Exact Mass: 575.24 Molecular Weight: 575.61 The synthesis of compound 11-169 was performed according to compound 11-3, using bicyclo[2.1.1]hexan-1-amine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 33 mg, 61% (last step) ESI-MS: 576.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
N
(S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-311)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C30H33N507 Exact Mass: 575.24 Molecular Weight: 575.61 The synthesis of compound 11-169 was performed according to compound 11-3, using bicyclo[2.1.1]hexan-1-amine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 33 mg, 61% (last step) ESI-MS: 576.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
160 Preparation of compound 11-170 OA
N
o o (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(2-isopropyloxazole-5-carboxamido)-N6-methyl-5-oxohexanediamide Chemical Formula: C27H34.N607 Exact Mass: 554.25 Molecular Weight: 554.59 The synthesis of compound 11-170 was performed according to compound 11-169, using 2-isopropyloxazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 32 mg, 54% (last step) ESI-MS: 555.4 [M+H]
N
o o (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(2-isopropyloxazole-5-carboxamido)-N6-methyl-5-oxohexanediamide Chemical Formula: C27H34.N607 Exact Mass: 554.25 Molecular Weight: 554.59 The synthesis of compound 11-170 was performed according to compound 11-169, using 2-isopropyloxazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 32 mg, 54% (last step) ESI-MS: 555.4 [M+H]
161 Preparation of compound 11-171 N
0 H ?
N
o jC 1' (2S)-2-(benzofuran-2-carboxamido)-N1-(1-(2-(bicyclo[3.2.1]octan-8-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yh-N6-methyl-5-oxohexanediamide Chemical Formula: C31H35N507 Exact Mass: 589.25 Molecular Weight: 589.64 The synthesis of compound 11-171 was performed according to compound 11-2, using bicyclo[3.2.1]octan-8-amine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 42 mg, 60% (last step) ESI-MS: 590.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
0 H ?
N
o jC 1' (2S)-2-(benzofuran-2-carboxamido)-N1-(1-(2-(bicyclo[3.2.1]octan-8-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yh-N6-methyl-5-oxohexanediamide Chemical Formula: C31H35N507 Exact Mass: 589.25 Molecular Weight: 589.64 The synthesis of compound 11-171 was performed according to compound 11-2, using bicyclo[3.2.1]octan-8-amine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 42 mg, 60% (last step) ESI-MS: 590.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
162 Preparation of compound 11-172 ON
NjcH N
H
(2S)-N1-(1-(2-(bicyclo[3.2.1]octan-8-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(3,5-dimethylisoxazole-4-carboxamido)-N6-methyl-5-oxohexanediamide Chemical Formula: C28H36N607 Exact Mass: 568.26 Molecular Weight: 568.62 The synthesis of compound 11-172 was performed according to compound 11-171, using 3,5-dimethylisoxazole-4-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 35 mg, 58% (last step) ESI-MS: 569.4 [M+H]
NjcH N
H
(2S)-N1-(1-(2-(bicyclo[3.2.1]octan-8-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(3,5-dimethylisoxazole-4-carboxamido)-N6-methyl-5-oxohexanediamide Chemical Formula: C28H36N607 Exact Mass: 568.26 Molecular Weight: 568.62 The synthesis of compound 11-172 was performed according to compound 11-171, using 3,5-dimethylisoxazole-4-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 35 mg, 58% (last step) ESI-MS: 569.4 [M+H]
163 Preparation of compound 11-173 0)-L
N
0 ti 0 N-LNjC-r N
H 0 NTh0r (S)-N1-(1-(2-(5-carboxy-2-aminoadamantane)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(4-methylpyrimidine-5-carboxamido)-5-oxohexanediamide Chemical Formula: C31F-137N708 Exact Mass: 635.27 Molecular Weight: 635.67 The synthesis of compound 11-173 was performed according to compound 11-3, using 4-aminoadamantane-1-carboxylic acid instead of 2-adamantanamine in step 2 (according to ZED3905) and 4-methylpyrimidine-5-carboxylic acid instead of 3-methyl-benzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 25 mg, 49% (last step) ESI-MS: 636.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
N
0 ti 0 N-LNjC-r N
H 0 NTh0r (S)-N1-(1-(2-(5-carboxy-2-aminoadamantane)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(4-methylpyrimidine-5-carboxamido)-5-oxohexanediamide Chemical Formula: C31F-137N708 Exact Mass: 635.27 Molecular Weight: 635.67 The synthesis of compound 11-173 was performed according to compound 11-3, using 4-aminoadamantane-1-carboxylic acid instead of 2-adamantanamine in step 2 (according to ZED3905) and 4-methylpyrimidine-5-carboxylic acid instead of 3-methyl-benzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 25 mg, 49% (last step) ESI-MS: 636.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
164 Preparation of compound 11-174 N
NN
N, (2S)-N1-(1-(2-(4-aminoadamantane-N,N-dimethy1-1-carboxamide)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxo-241,2,3,4-tetrahydronaphthalene-2-carboxamido)hexanediamide Chemical Formula: C38H48N607 Exact Mass: 700.36 Molecular Weight: 700.82 The synthesis of compound 11-174 was performed according to compound 11-3, using 4-aminoadamantane-N,N-dimethy1-1-carboxamide instead of 2-adamantanamine in step (according to ZED3905) and 1,2,3,4-tetrahydronaphthalene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 33 mg, 56% (last step) ESI-MS: 701.5 [M+H]
NN
N, (2S)-N1-(1-(2-(4-aminoadamantane-N,N-dimethy1-1-carboxamide)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxo-241,2,3,4-tetrahydronaphthalene-2-carboxamido)hexanediamide Chemical Formula: C38H48N607 Exact Mass: 700.36 Molecular Weight: 700.82 The synthesis of compound 11-174 was performed according to compound 11-3, using 4-aminoadamantane-N,N-dimethy1-1-carboxamide instead of 2-adamantanamine in step (according to ZED3905) and 1,2,3,4-tetrahydronaphthalene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 33 mg, 56% (last step) ESI-MS: 701.5 [M+H]
165 Preparation of compound 11-175 N
1\jr N
(S)-24(S)-1,4-diazabicyclo[2.2.2]octane-2-carboxamido)-N6-tert-butyl-N141-(242-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C34H49N706 Exact Mass: 651.37 Molecular Weight: 651.80 The synthesis of compound 11-175 was performed according to compound 11-3, using tert-butyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632) and 1,4-diazabicyclo[2.2.2]octane-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-.. carboxylic acid in step 6 (according to ZED3264).
Yield: 39 mg, 53% (last step) ESI-MS: 652.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
1\jr N
(S)-24(S)-1,4-diazabicyclo[2.2.2]octane-2-carboxamido)-N6-tert-butyl-N141-(242-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Chemical Formula: C34H49N706 Exact Mass: 651.37 Molecular Weight: 651.80 The synthesis of compound 11-175 was performed according to compound 11-3, using tert-butyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632) and 1,4-diazabicyclo[2.2.2]octane-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-.. carboxylic acid in step 6 (according to ZED3264).
Yield: 39 mg, 53% (last step) ESI-MS: 652.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
166 Preparation of compound 11-176 (S)-N1-tert-buty1-5-(1H-indole-3-carboxamido)-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxohexanediamide Chemical Formula: C36F144N606 Exact Mass: 656.33 Molecular Weight: 656.77 The synthesis of compound 11-176 was performed according to compound 11-3, using tert-butyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632) and 1H-indole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 52 mg, 62% (last step) ESI-MS: 657.5 [M+H]
Yield: 52 mg, 62% (last step) ESI-MS: 657.5 [M+H]
167 Preparation of compound 11-177 0)-( N -H
N,--/N3AN
N )=-L
N
-Ns I H 0 0 (S)-N1-tert-butyl-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(6-methylimidazo[2,1-b]thiazole-3-carboxamido)-2-oxohexanediamide Chemical Formula: C34H43N706S
Exact Mass: 677.30 Molecular Weight: 677.81 The synthesis of compound 11-177 was performed according to compound 11-3, using tert-butyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632) and 6-methylimidazo[2,1-b][1,3]thiazole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 42 mg, 53% (last step) ESI-MS: 678.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
N,--/N3AN
N )=-L
N
-Ns I H 0 0 (S)-N1-tert-butyl-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(6-methylimidazo[2,1-b]thiazole-3-carboxamido)-2-oxohexanediamide Chemical Formula: C34H43N706S
Exact Mass: 677.30 Molecular Weight: 677.81 The synthesis of compound 11-177 was performed according to compound 11-3, using tert-butyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632) and 6-methylimidazo[2,1-b][1,3]thiazole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 42 mg, 53% (last step) ESI-MS: 678.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
168 Preparation of compound 11-178 JN
1? t\li 9 s (S)-2-(benzo[d]thiazole-2-carboxamido)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-cyclopenty1-5-oxohexanediamide Chemical Formula: 033H38N606S
Exact Mass: 646.26 Molecular Weight: 646.76 The synthesis of compound 11-178 was performed according to compound 11-90, using cyclopentyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632) and 1,3-benzothiazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 54 mg, 61% (last step) ESI-MS: 647.4 [M+H]
1? t\li 9 s (S)-2-(benzo[d]thiazole-2-carboxamido)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-cyclopenty1-5-oxohexanediamide Chemical Formula: 033H38N606S
Exact Mass: 646.26 Molecular Weight: 646.76 The synthesis of compound 11-178 was performed according to compound 11-90, using cyclopentyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632) and 1,3-benzothiazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 54 mg, 61% (last step) ESI-MS: 647.4 [M+H]
169 Preparation of compound 11-179 NH
N
N7-2)LFI
S/
(S)-N1-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-cyclopenty1-2-(imidazo[2,1-b]thiazole-6-carboxamido)-5-oxohexanediamide Chemical Formula: C31H37N706S
Exact Mass: 635.25 Molecular Weight: 635.73 The synthesis of compound 11-179 was performed according to compound 11-90, using cyclopentyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632) and imidazo[2,1-b][1,3]thiazole-6-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 36 mg, 51% (last step) ESI-MS: 636.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
N
N7-2)LFI
S/
(S)-N1-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-cyclopenty1-2-(imidazo[2,1-b]thiazole-6-carboxamido)-5-oxohexanediamide Chemical Formula: C31H37N706S
Exact Mass: 635.25 Molecular Weight: 635.73 The synthesis of compound 11-179 was performed according to compound 11-90, using cyclopentyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632) and imidazo[2,1-b][1,3]thiazole-6-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 36 mg, 51% (last step) ESI-MS: 636.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
170 Preparation of compound 11-180 0 9 L) OH
IN HC N NH
(S)-N1 -(1 -(2-((1 S,2R,4R)-bicyclo[2.2.1 ]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-y1)-N6-cyclopenty1-2-(4-hydroxy-6-(trifluoromethoxy)quinoline-3-carboxamido)-5-oxohexanediamide Chemical Formula: 036H39F3N608 Exact Mass: 740.28 Molecular Weight: 740.73 The synthesis of compound 11-180 was performed according to compound 11-90, using cyclopentyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632) __ and 4-hydroxy-6-(trifluoromethoxy)quinoline-3-carboxylic acid instead of 3-methyl-benzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 19 mg, 41% (last step) ESI-MS: 741.5 [M+H]
IN HC N NH
(S)-N1 -(1 -(2-((1 S,2R,4R)-bicyclo[2.2.1 ]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-y1)-N6-cyclopenty1-2-(4-hydroxy-6-(trifluoromethoxy)quinoline-3-carboxamido)-5-oxohexanediamide Chemical Formula: 036H39F3N608 Exact Mass: 740.28 Molecular Weight: 740.73 The synthesis of compound 11-180 was performed according to compound 11-90, using cyclopentyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632) __ and 4-hydroxy-6-(trifluoromethoxy)quinoline-3-carboxylic acid instead of 3-methyl-benzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 19 mg, 41% (last step) ESI-MS: 741.5 [M+H]
171 Preparation of compound 11-181 NN N
)- NH
-r (S)-N1-(1-(2-(bicyclo[1.1.1]9entan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(cinnoline-3-carboxamido)-N6-cyclohexyl-5-oxohexanediamide Chemical Formula: C33F-137N706 Exact Mass: 627.28 Molecular Weight: 627.69 The synthesis of compound 11-181 was performed according to compound 11-167, using cyclohexyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632) and 3-cinnolinecarboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 37 mg, 56% (last step) ESI-MS: 628.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
)- NH
-r (S)-N1-(1-(2-(bicyclo[1.1.1]9entan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(cinnoline-3-carboxamido)-N6-cyclohexyl-5-oxohexanediamide Chemical Formula: C33F-137N706 Exact Mass: 627.28 Molecular Weight: 627.69 The synthesis of compound 11-181 was performed according to compound 11-167, using cyclohexyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632) and 3-cinnolinecarboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 37 mg, 56% (last step) ESI-MS: 628.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
172 Preparation of compound 11-182 j-L NH
I H
(S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-cyclohexy1-2-(3-ethylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C35H41N507 Exact Mass: 643.30 Molecular Weight: 643.73 The synthesis of compound 11-182 was performed according to compound 11-167, using cyclohexyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632) and 3-ethylbenzofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 53 mg, 68% (last step) ESI-MS: 644.5 [M+H]
I H
(S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-cyclohexy1-2-(3-ethylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C35H41N507 Exact Mass: 643.30 Molecular Weight: 643.73 The synthesis of compound 11-182 was performed according to compound 11-167, using cyclohexyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632) and 3-ethylbenzofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 53 mg, 68% (last step) ESI-MS: 644.5 [M+H]
173 Preparation of compound 11-183 /NN
Nj-LNNH
I H
(S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethy1)-2-oxo-1,2-clihydropyridin-3-y1)-N6-cyclohexy1-2-(1 H-indole-2-carboxamido)-5-oxohexanediamide Chemical Formula: C35F142N606 Exact Mass: 642.32 Molecular Weight: 642.74 The synthesis of compound 11-183 was performed according to compound 11-167, using cyclohexyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632) and 1-ethyl-1H-indole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 41 mg, 57% (last step) ESI-MS: 643.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
Nj-LNNH
I H
(S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethy1)-2-oxo-1,2-clihydropyridin-3-y1)-N6-cyclohexy1-2-(1 H-indole-2-carboxamido)-5-oxohexanediamide Chemical Formula: C35F142N606 Exact Mass: 642.32 Molecular Weight: 642.74 The synthesis of compound 11-183 was performed according to compound 11-167, using cyclohexyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632) and 1-ethyl-1H-indole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 41 mg, 57% (last step) ESI-MS: 643.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
174 Preparation of compound 11-184 ou NC) NN)L NH
N
H
(S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-cyclohexyl-2-(2-methyl-1,8-naphthyridine-3-carboxamido)-5-oxohexanediamide Chemical Formula: C34H39N706 Exact Mass: 641.30 Molecular Weight: 641.72 The synthesis of compound 11-184 was performed according to compound 11-167, using cyclohexyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632) and 2-methyl-1,8-naphthyridine-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 26 mg, 54% (last step) ESI-MS: 642.5 [M+H]
N
H
(S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-cyclohexyl-2-(2-methyl-1,8-naphthyridine-3-carboxamido)-5-oxohexanediamide Chemical Formula: C34H39N706 Exact Mass: 641.30 Molecular Weight: 641.72 The synthesis of compound 11-184 was performed according to compound 11-167, using cyclohexyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632) and 2-methyl-1,8-naphthyridine-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 26 mg, 54% (last step) ESI-MS: 642.5 [M+H]
175 Preparation of compound 11-185 ).LN
NTh'N
(S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxo-2-(1,2,3,4-tetrahydroquinoline-6-carboxamido)hexanediamide Chemical Formula: C301-136N606 Exact Mass: 576.27 Molecular Weight: 576.64 The synthesis of compound 11-185 was performed according to compound 11-169, using N-Boc-1,2,3,4-tetrahydroquinoline-6-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). The final product was obtained by deprotection (DCM/TFA) as described above and purified by HPLC.
Yield: 39 mg, 61% (last step) ESI-MS: 577.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
NTh'N
(S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxo-2-(1,2,3,4-tetrahydroquinoline-6-carboxamido)hexanediamide Chemical Formula: C301-136N606 Exact Mass: 576.27 Molecular Weight: 576.64 The synthesis of compound 11-185 was performed according to compound 11-169, using N-Boc-1,2,3,4-tetrahydroquinoline-6-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). The final product was obtained by deprotection (DCM/TFA) as described above and purified by HPLC.
Yield: 39 mg, 61% (last step) ESI-MS: 577.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
176 Preparation of compound 11-186 )LN
0 ( H 0 NN
N-vN
HJ!JN 0 0 CF3 (S)-N1-(1-(2-(2-carboxy-2-amino-5-(trifluoromethyl)adamantane)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(3-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)hexanediamide Chemical Formula: C36H39F3N609 Exact Mass: 756.27 Molecular Weight: 756.72 The synthesis of compound 11-186 was performed according to compound 11-3, using 2-amino-5-(trifluoromethyl)adamantane-2-carboxylic acid instead of 2-adamantanamine in step 2 (according to ZED3905) and 3-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 12 mg, 36% (last step) ESI-MS: 757.4 [M+H]
0 ( H 0 NN
N-vN
HJ!JN 0 0 CF3 (S)-N1-(1-(2-(2-carboxy-2-amino-5-(trifluoromethyl)adamantane)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(3-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)hexanediamide Chemical Formula: C36H39F3N609 Exact Mass: 756.27 Molecular Weight: 756.72 The synthesis of compound 11-186 was performed according to compound 11-3, using 2-amino-5-(trifluoromethyl)adamantane-2-carboxylic acid instead of 2-adamantanamine in step 2 (according to ZED3905) and 3-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 12 mg, 36% (last step) ESI-MS: 757.4 [M+H]
177 Preparation of compound 11-187 0)-L
N
N HJ-L
N 1\jrN
(S)-N1-(1-(2-(5-ethyladamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1,6-naphthyridine-2-carboxamido)-5-oxohexanediamide Chemical Formula: C35H41N706 Exact Mass: 655.31 Molecular Weight: 655.74 The synthesis of compound 11-187 was performed according to compound 11-3, using 5-ethyladamantane-2-amine instead of 2-adamantanamine in step 2 (according to ZED3905) and 1,6-naphthyridine-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 26 mg, 51% (last step) ESI-MS: 656.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
N
N HJ-L
N 1\jrN
(S)-N1-(1-(2-(5-ethyladamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1,6-naphthyridine-2-carboxamido)-5-oxohexanediamide Chemical Formula: C35H41N706 Exact Mass: 655.31 Molecular Weight: 655.74 The synthesis of compound 11-187 was performed according to compound 11-3, using 5-ethyladamantane-2-amine instead of 2-adamantanamine in step 2 (according to ZED3905) and 1,6-naphthyridine-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 26 mg, 51% (last step) ESI-MS: 656.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
178 Preparation of compound 11-188 0)-L
N
*LN
NN
H 0 'le, (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(2,6-naphthyridine-1-carboxamido)-5-oxohexanediamide Chemical Formula: C29F131N706 Exact Mass: 573.23 Molecular Weight: 573.60 The synthesis of compound 11-188 was performed according to compound 11-169, using 2,6-naphthyridine-1-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 33 mg, 56% (last step) ESI-MS: 574.4 [M+H]
N
*LN
NN
H 0 'le, (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(2,6-naphthyridine-1-carboxamido)-5-oxohexanediamide Chemical Formula: C29F131N706 Exact Mass: 573.23 Molecular Weight: 573.60 The synthesis of compound 11-188 was performed according to compound 11-169, using 2,6-naphthyridine-1-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 33 mg, 56% (last step) ESI-MS: 574.4 [M+H]
179 Preparation of compound 11-189 0)-L N
N)-L rNH
YLN
N HjC N
(S)-2-(4-amino-1,2,5-oxadiazole-3-carboxamido)-N1-(1-(2-(bicyclo[1.1.1]pentan-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide Chemical Formula: C22H26N807 Exact Mass: 514.19 Molecular Weight: 514.49 The synthesis of compound 11-189 was performed according to compound 11-167, using 4-Boc-amino-1,2,5-oxadiazole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). The amine was deprotected by TFA in the final step.
Yield: 16 mg, 69% (last step) ESI-MS: 515.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
N)-L rNH
YLN
N HjC N
(S)-2-(4-amino-1,2,5-oxadiazole-3-carboxamido)-N1-(1-(2-(bicyclo[1.1.1]pentan-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide Chemical Formula: C22H26N807 Exact Mass: 514.19 Molecular Weight: 514.49 The synthesis of compound 11-189 was performed according to compound 11-167, using 4-Boc-amino-1,2,5-oxadiazole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). The amine was deprotected by TFA in the final step.
Yield: 16 mg, 69% (last step) ESI-MS: 515.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
180 Preparation of compound 11-190 0)-LN
0 iCH 0 0 N Nj-Nr NH
, \N I H 0 0 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(6-(dimethylamino)benzofuran-2-carboxamido)-N6-methyl-5-oxohexanediamide Chemical Formula: C30H34N607 Exact Mass: 590.25 Molecular Weight: 590.63 The synthesis of compound 11-190 was performed according to compound 11-167, using 6-(dimethylamino)benzofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-carboxylic acid in step 6 (according to ZED3264).
Yield: 38 mg, 55% (last step) ESI-MS: 591.4 [M+H]
0 iCH 0 0 N Nj-Nr NH
, \N I H 0 0 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(6-(dimethylamino)benzofuran-2-carboxamido)-N6-methyl-5-oxohexanediamide Chemical Formula: C30H34N607 Exact Mass: 590.25 Molecular Weight: 590.63 The synthesis of compound 11-190 was performed according to compound 11-167, using 6-(dimethylamino)benzofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-carboxylic acid in step 6 (according to ZED3264).
Yield: 38 mg, 55% (last step) ESI-MS: 591.4 [M+H]
181 Preparation of compound 11-191 N
0 )(vH 0 N)-LNNH
(S)-2-(2-acetamidothiazole-5-carboxamido)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide Chemical Formula: C25H29N707S
Exact Mass: 571.18 Molecular Weight: 571.61 The synthesis of compound 11-191 was performed according to compound 11-167, using 2-acetylamino-5-thiazolecarboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 21 mg, 46% (last step) ESI-MS: 572.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
0 )(vH 0 N)-LNNH
(S)-2-(2-acetamidothiazole-5-carboxamido)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide Chemical Formula: C25H29N707S
Exact Mass: 571.18 Molecular Weight: 571.61 The synthesis of compound 11-191 was performed according to compound 11-167, using 2-acetylamino-5-thiazolecarboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 21 mg, 46% (last step) ESI-MS: 572.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
182 Preparation of compound 11-192 N
(S)-N4-(1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-y1)-1H-pyrrole-2,4-dicarboxamide Chemical Formula: C25H29N707 Exact Mass: 539.21 Molecular Weight: 539.54 The synthesis of compound 11-192 was performed according to compound 11-167, using 5-carbamoy1-1H-pyrrole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 13 mg, 38% (last step) ESI-MS: 540.4 [M+H]
(S)-N4-(1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-y1)-1H-pyrrole-2,4-dicarboxamide Chemical Formula: C25H29N707 Exact Mass: 539.21 Molecular Weight: 539.54 The synthesis of compound 11-192 was performed according to compound 11-167, using 5-carbamoy1-1H-pyrrole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 13 mg, 38% (last step) ESI-MS: 540.4 [M+H]
183 Preparation of compound 11-193 o N
011 Nj-L
FN11 I NI rNEI 0 (S)-N1-(1-(2-(1-acetylamino-4-aminoadamantane)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(5-sulfamoylfuran-3-carboxamido)hexanediamide Chemical Formula: C31H39N7010S
Exact Mass: 701.25 Molecular Weight: 701.75 The synthesis of compound 11-193 was performed according to compound 11-3, using 1-acetylamino-4-aminoadamantane instead of 2-adamantanamine in step 2 (according to ZED3905) and 5-sulfamoylfuran-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 10 mg, 27% (last step) ESI-MS: 702.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
011 Nj-L
FN11 I NI rNEI 0 (S)-N1-(1-(2-(1-acetylamino-4-aminoadamantane)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(5-sulfamoylfuran-3-carboxamido)hexanediamide Chemical Formula: C31H39N7010S
Exact Mass: 701.25 Molecular Weight: 701.75 The synthesis of compound 11-193 was performed according to compound 11-3, using 1-acetylamino-4-aminoadamantane instead of 2-adamantanamine in step 2 (according to ZED3905) and 5-sulfamoylfuran-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 10 mg, 27% (last step) ESI-MS: 702.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
184 Preparation of compound 11-194 0)-L
N
Njc H')-L
N NTh'N
NJL
(S)-2-(benzofuran-5-carboxamido)-N1-(1-(2-(1-acetylamino-4-aminoadamantane)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C35H4.0N608 Exact Mass: 672.29 Molecular Weight: 672.73 The synthesis of compound 11-194 was performed according to compound 11-3, using 1-acetylamino-4-aminoadamantane instead of 2-adamantanamine in step 2 (according to ZED3905) and benzofuran-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 23 mg, 52% (last step) ESI-MS: 673.5 [M+H]
N
Njc H')-L
N NTh'N
NJL
(S)-2-(benzofuran-5-carboxamido)-N1-(1-(2-(1-acetylamino-4-aminoadamantane)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C35H4.0N608 Exact Mass: 672.29 Molecular Weight: 672.73 The synthesis of compound 11-194 was performed according to compound 11-3, using 1-acetylamino-4-aminoadamantane instead of 2-adamantanamine in step 2 (according to ZED3905) and benzofuran-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 23 mg, 52% (last step) ESI-MS: 673.5 [M+H]
185 Preparation of compound 11-195 0)-L
N
(S)-2-(benzofuran-6-carboxamido)-N1-(1-(2-(4-aminoadamantane-1-carboxamide)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C34.H38N608 Exact Mass: 658.28 Molecular Weight: 658.70 The synthesis of compound 11-195 was performed according to compound 11-3, using 4-aminoadamantane-1-carboxamide instead of 2-adamantanamine in step 2 (according to ZED3905) and benzofuran-6-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 26 mg, 57% (last step) ESI-MS: 659.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
N
(S)-2-(benzofuran-6-carboxamido)-N1-(1-(2-(4-aminoadamantane-1-carboxamide)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide Chemical Formula: C34.H38N608 Exact Mass: 658.28 Molecular Weight: 658.70 The synthesis of compound 11-195 was performed according to compound 11-3, using 4-aminoadamantane-1-carboxamide instead of 2-adamantanamine in step 2 (according to ZED3905) and benzofuran-6-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 26 mg, 57% (last step) ESI-MS: 659.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
186 Preparation of compound 11-196 N
IR11)-LNN
(S)-N1-(1-(2-(4-aminoadamantane-1-carboxamide)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-(1-methylcyclopropy1)-1,2,4-oxadiazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C32H40N308 Exact Mass: 664.30 Molecular Weight: 664.71 The synthesis of compound 11-196 was performed according to compound 11-3, using 4-aminoadamantane-1-carboxamide instead of 2-adamantanamine in step 2 (according to ZED3905) and 3-(1-methylcyclopropyI)-1,2,4-oxadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 15 mg, 38% (last step) ESI-MS: 665.5 [M+H]
IR11)-LNN
(S)-N1-(1-(2-(4-aminoadamantane-1-carboxamide)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-(1-methylcyclopropy1)-1,2,4-oxadiazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C32H40N308 Exact Mass: 664.30 Molecular Weight: 664.71 The synthesis of compound 11-196 was performed according to compound 11-3, using 4-aminoadamantane-1-carboxamide instead of 2-adamantanamine in step 2 (according to ZED3905) and 3-(1-methylcyclopropyI)-1,2,4-oxadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 15 mg, 38% (last step) ESI-MS: 665.5 [M+H]
187 Preparation of compound 11-197 N)-L
0-NH o0 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(5-methyl-1,2,4-oxadiazole-3-carboxamido)-5-oxohexanediamide Chemical Formula: C23H27N707 Exact Mass: 513.20 Molecular Weight: 513.50 The synthesis of compound 11-197 was performed according to compound 11-167, using 5-methyl-1,2,4-oxadiazole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 36 mg, 58% (last step) ESI-MS: 514.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
0-NH o0 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(5-methyl-1,2,4-oxadiazole-3-carboxamido)-5-oxohexanediamide Chemical Formula: C23H27N707 Exact Mass: 513.20 Molecular Weight: 513.50 The synthesis of compound 11-197 was performed according to compound 11-167, using 5-methyl-1,2,4-oxadiazole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 36 mg, 58% (last step) ESI-MS: 514.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
188 Preparation of compound 11-198 oliN
N NH
N
S
(S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxo-2-(1,2,3-thiadiazole-4-carboxamido)hexanediamide Chemical Formula: C22H25N706S
Exact Mass: 515.16 Molecular Weight: 515.54 The synthesis of compound 11-198 was performed according to compound 11-167, using 1,2,3-thiadiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 29 mg, 48% (last step) ESI-MS: 516.3 [M+H]
N NH
N
S
(S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxo-2-(1,2,3-thiadiazole-4-carboxamido)hexanediamide Chemical Formula: C22H25N706S
Exact Mass: 515.16 Molecular Weight: 515.54 The synthesis of compound 11-198 was performed according to compound 11-167, using 1,2,3-thiadiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 29 mg, 48% (last step) ESI-MS: 516.3 [M+H]
189 Preparation of compound 11-199 N
)0L H 0 N NH
/ 'Y
(S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxo-2-(1,2,4-thiadiazole-5-carboxamido)hexanediamide Chemical Formula: C22H25N706S
Exact Mass: 515.16 Molecular Weight: 515.54 The synthesis of compound 11-199 was performed according to compound 11-167, using 1,2,4-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 35 mg, 56% (last step) ESI-MS: 516.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
)0L H 0 N NH
/ 'Y
(S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxo-2-(1,2,4-thiadiazole-5-carboxamido)hexanediamide Chemical Formula: C22H25N706S
Exact Mass: 515.16 Molecular Weight: 515.54 The synthesis of compound 11-199 was performed according to compound 11-167, using 1,2,4-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 35 mg, 56% (last step) ESI-MS: 516.3 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
190 Preparation of compound 11-200 o N
S ( H
Nj-L NH
N-r (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxo-2-(1,3,4-thiadiazole-2-carboxamido)hexanediamide Chemical Formula: C22H25N706S
Exact Mass: 515.16 Molecular Weight: 515.54 The synthesis of compound 11-200 was performed according to compound 11-167, using 1,3,4-thiadiazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 24 mg, 41% (last step) ESI-MS: 516.3 [M+H]
S ( H
Nj-L NH
N-r (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxo-2-(1,3,4-thiadiazole-2-carboxamido)hexanediamide Chemical Formula: C22H25N706S
Exact Mass: 515.16 Molecular Weight: 515.54 The synthesis of compound 11-200 was performed according to compound 11-167, using 1,3,4-thiadiazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 24 mg, 41% (last step) ESI-MS: 516.3 [M+H]
191 Preparation of compound 11-201 N NH
N I 1_1 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(4-cyclopropy1-1,2,3-thiadiazole-5-carboxamido)-N6-methyl-5-oxohexanediamide Chemical Formula: C25H29N706S
Exact Mass: 555.19 Molecular Weight: 555.61 The synthesis of compound 11-201 was performed according to compound 11-167, using 4-cyclopropyl-[1,2,3]thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 43 mg, 67% (last step) ESI-MS: 556.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
N I 1_1 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(4-cyclopropy1-1,2,3-thiadiazole-5-carboxamido)-N6-methyl-5-oxohexanediamide Chemical Formula: C25H29N706S
Exact Mass: 555.19 Molecular Weight: 555.61 The synthesis of compound 11-201 was performed according to compound 11-167, using 4-cyclopropyl-[1,2,3]thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 43 mg, 67% (last step) ESI-MS: 556.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
192 Preparation of compound 11-202 ON
0 ( H 0 _ JI NrN
N I H
\ 0 0 (S)-2-(4-cyclopropy1-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide Chemical Formula: 0301-137N706S
Exact Mass: 623.25 Molecular Weight: 623.72 The synthesis of compound 11-202 was performed according to compound 11-3, using 4-cyclopropyl-[1,2,3]thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 42 mg, 56% (last step) ESI-MS: 624.4 [M+H]
0 ( H 0 _ JI NrN
N I H
\ 0 0 (S)-2-(4-cyclopropy1-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide Chemical Formula: 0301-137N706S
Exact Mass: 623.25 Molecular Weight: 623.72 The synthesis of compound 11-202 was performed according to compound 11-3, using 4-cyclopropyl-[1,2,3]thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 42 mg, 56% (last step) ESI-MS: 624.4 [M+H]
193 Preparation of compound 11-203 ,S Nr N
N H NrN
\N 0 0 (S)-2-(4-isopropy1-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide Chemical Formula: C30H39N706S
Exact Mass: 625.27 Molecular Weight: 625.74 The synthesis of compound 11-203 was performed according to compound 11-3, using 4-(propan-2-yI)-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 36 mg, 52% (last step) ESI-MS: 626.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
N H NrN
\N 0 0 (S)-2-(4-isopropy1-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide Chemical Formula: C30H39N706S
Exact Mass: 625.27 Molecular Weight: 625.74 The synthesis of compound 11-203 was performed according to compound 11-3, using 4-(propan-2-yI)-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 36 mg, 52% (last step) ESI-MS: 626.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
194 Preparation of compound 11-204 li N
NN
N I H
(S)-2-(4-ethy1-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide Chemical Formula: C29H37N706S
Exact Mass: 611.25 Molecular Weight: 611.71 The synthesis of compound 11-204 was performed according to compound 11-3, using 4-ethyl-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 33 mg, 47% (last step) ESI-MS: 612.4 [M+H]
NN
N I H
(S)-2-(4-ethy1-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide Chemical Formula: C29H37N706S
Exact Mass: 611.25 Molecular Weight: 611.71 The synthesis of compound 11-204 was performed according to compound 11-3, using 4-ethyl-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 33 mg, 47% (last step) ESI-MS: 612.4 [M+H]
195 Preparation of compound 11-205 N
SNCNNN
N
(S)-2-(4-formy1-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxonexanediamide Chemical Formula: C28H33N707S
Exact Mass: 611.22 Molecular Weight: 611.67 The synthesis of compound 11-205 was performed according to compound 11-3, using 4-(hydroxymethyl)-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 13 mg, 32% (last step) ESI-MS: 612.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
SNCNNN
N
(S)-2-(4-formy1-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxonexanediamide Chemical Formula: C28H33N707S
Exact Mass: 611.22 Molecular Weight: 611.67 The synthesis of compound 11-205 was performed according to compound 11-3, using 4-(hydroxymethyl)-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 13 mg, 32% (last step) ESI-MS: 612.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
196 Preparation of compound 11-206 OA
o N
,S NNYLNN
No I H
HO
(S)-2-(4-(hydroxymethyl)-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide Chemical Formula: C28H35N707S
Exact Mass: 613.23 Molecular Weight: 613.69 The synthesis of compound 11-206 was performed according to compound 11-3, using 4-((tetrahydro-2H-pyran-2-yloxy)methyl)-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). The tetrahydropyranyl (Thp) protecting group was cleaved by TFA in the final step.
Yield: 9 mg, 46% (last step) ESI-MS: 614.4 [M+H]
o N
,S NNYLNN
No I H
HO
(S)-2-(4-(hydroxymethyl)-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide Chemical Formula: C28H35N707S
Exact Mass: 613.23 Molecular Weight: 613.69 The synthesis of compound 11-206 was performed according to compound 11-3, using 4-((tetrahydro-2H-pyran-2-yloxy)methyl)-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). The tetrahydropyranyl (Thp) protecting group was cleaved by TFA in the final step.
Yield: 9 mg, 46% (last step) ESI-MS: 614.4 [M+H]
197 Preparation of compound 11-207 0 ( H 011 N ,/y-LNNNNH
(S)-N1-(1-(2-(1-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-imidazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C29F-137N706 Exact Mass: 579.28 Molecular Weight: 579.65 The synthesis of compound 11-207 was performed according to compound 11-3, using 1-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905) and 1-methyl-1H-imidazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic .. acid in step 6 (according to ZED3264).
Yield: 64 mg, 71% (last step) ESI-MS: 580.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
(S)-N1-(1-(2-(1-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-imidazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C29F-137N706 Exact Mass: 579.28 Molecular Weight: 579.65 The synthesis of compound 11-207 was performed according to compound 11-3, using 1-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905) and 1-methyl-1H-imidazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic .. acid in step 6 (according to ZED3264).
Yield: 64 mg, 71% (last step) ESI-MS: 580.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
198 Preparation of compound 11-208 0)-LN
1j11 NH N
(S)-N1-(1-(2-(((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(1-methyl-1H-imidazole-2-carboxamido)-5-oxohexanediamide Chemical Formula: C29H39N706 Exact Mass: 581.30 Molecular Weight: 581.66 The synthesis of compound 11-208 was performed according to compound 11-3, using (-)-cis-myrtanylamine instead of 2-adamantanamine in step 2 (according to ZED3905) and 1-methyl-1H-imidazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 43 mg, 59% (last step) ESI-MS: 582.5 [M+H]
1j11 NH N
(S)-N1-(1-(2-(((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(1-methyl-1H-imidazole-2-carboxamido)-5-oxohexanediamide Chemical Formula: C29H39N706 Exact Mass: 581.30 Molecular Weight: 581.66 The synthesis of compound 11-208 was performed according to compound 11-3, using (-)-cis-myrtanylamine instead of 2-adamantanamine in step 2 (according to ZED3905) and 1-methyl-1H-imidazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 43 mg, 59% (last step) ESI-MS: 582.5 [M+H]
199 Preparation of compound 11-209 0)-L
N
HNYNN"..
(S)-N1-(1-(2-(((1R,2R,5R)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(1H-imidazole-4-carboxamido)-N6-methyl-5-oxohexanediamide Chemical Formula: 028F137N706 Exact Mass: 567.28 Molecular Weight: 567.64 The synthesis of compound 11-209 was performed according to compound 11-3, using (-)-cis-myrtanylamine instead of 2-adamantanamine in step 2 (according to ZED3905) and 1-methyl-1H-imidazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 31 mg, 55% (last step) ESI-MS: 568.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
N
HNYNN"..
(S)-N1-(1-(2-(((1R,2R,5R)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(1H-imidazole-4-carboxamido)-N6-methyl-5-oxohexanediamide Chemical Formula: 028F137N706 Exact Mass: 567.28 Molecular Weight: 567.64 The synthesis of compound 11-209 was performed according to compound 11-3, using (-)-cis-myrtanylamine instead of 2-adamantanamine in step 2 (according to ZED3905) and 1-methyl-1H-imidazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 31 mg, 55% (last step) ESI-MS: 568.4 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
200 Preparation of compound 11-210 ON
N/ANf;J-LNThNH
(S)-N1-(1-(2-(3,5-dimethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-imidazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C311-141N706 Exact Mass: 607.31 Molecular Weight: 607.70 The synthesis of compound 11-210 was performed according to compound 11-3, using 3,5-dimethy1-1-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905) and 1-methyl-1H-imidazole-5-carboxylic acid instead of 3-methyl-benzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 46 mg, 66% (last step) ESI-MS: 608.5 [M+H]
N/ANf;J-LNThNH
(S)-N1-(1-(2-(3,5-dimethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-imidazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C311-141N706 Exact Mass: 607.31 Molecular Weight: 607.70 The synthesis of compound 11-210 was performed according to compound 11-3, using 3,5-dimethy1-1-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905) and 1-methyl-1H-imidazole-5-carboxylic acid instead of 3-methyl-benzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 46 mg, 66% (last step) ESI-MS: 608.5 [M+H]
201 Preparation of compound 11-211 )*LN
'IN
(S)-N1-(1-(2-(3,5,7-trimethy1-1-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C32F-143N706 Exact Mass: 621.33 Molecular Weight: 621.73 The synthesis of compound 11-211 was performed according to compound 11-3, using 3,5,7-trimethy1-1-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905) and 1-methyl-1H-imidazole-5-carboxylic acid instead of 3-methyl-benzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 53 mg, 70% (last step) ESI-MS: 622.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
'IN
(S)-N1-(1-(2-(3,5,7-trimethy1-1-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide Chemical Formula: C32F-143N706 Exact Mass: 621.33 Molecular Weight: 621.73 The synthesis of compound 11-211 was performed according to compound 11-3, using 3,5,7-trimethy1-1-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905) and 1-methyl-1H-imidazole-5-carboxylic acid instead of 3-methyl-benzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 53 mg, 70% (last step) ESI-MS: 622.5 [M+H]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
202 Preparation of Reference Compound 6 OA
NjEr N)'L N-r I I
(S)-N 1 -methy1-5-(nicotinamido)-2-oxo-N6-(2-oxo-1 -(2-oxo-2-(phenethylamino)ethyl)-1 ,2-dihydropyridin-3-yl)hexanediamide Chemical Formula: C28H30N606 Exact Mass: 546.22 Molecular Weight: 546.57 The synthesis of reference compound 6 was performed according to compound 11-3, using 2-phenylethylamine instead of 2-adamantanamine in step 2 (according to ZED3905) and nicotinic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 89 mg, 79% (last step) ESI-MS: 547.4 [M+H]
Biological Examples Example B-1. Inhibitory effect of the compounds according to the invention Transglutaminase assay For the determination of potency of inhibitors against tissue transglutaminase, the incorporation of dansylcadaverine into dimethylcasein (Zedira product T036, Lorand et a/., Anal Biochem, 1971, 44:221-31) was measured using recombinant human transglutaminase 2 (Zedira Product T022).
The tissue transglutaminase is diluted in buffer (50 mM Tris-HCI, 7.5 mM
CaCl2, 150 mM
NaCI, pH = 7.4). The final concentration of TG2 in the assay is 10 nM.
A 10 mM inhibitor stock solution is prepared in DMSO, and from this a serial 1:2-fold dilution series is prepared also in DMSO. Each of the initial dilutions is subsequently diluted 1:50-fold with buffer (50 mM Tris-HCI, 7.5 mM CaCl2, 150 mM NaCI, pH =
7.4) to yield the final working dilutions containing 2% (v/v) DMSO.
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 15 pl of inhibitor working dilution are added per well of a 96 well microtiter plate. As control, 15 pl of a 2% (v/v) DMSO solution prepared using the buffer mentioned above are added per well.
Immediately before starting the assay, 600 pl transglutaminase working solution are added to 11.4 ml assay buffer (50 mM Tris-HCI, 10 mM CaCl2, 10 mM glutathione, 2.5%
glycerol, 16.7 pM dansylcadaverine, 4 pM N,N-dimethylcasein, 200 mM NaCI, pH =
8.0).
285 pl of this reaction mix are added per well containing the inhibitor.
Increase in fluorescence is measured using Aex = 330 nm and Aem = 500 nm at 37 C for 30 min. A slope of the increase in fluorescence between 20 and 30 min is calculated for determination of the ICso value (inhibitor concentration at which 50% of the initial activity is blocked).
Analysis of enzymatic activity is performed by calculation of the slope of an increase in fluorescence intensity. ICso values are calculated by plotting the enzymatic activity (as percentage from control containing 2% DMSO instead of inhibitor) against the inhibitor concentration. ICso is defined as the inhibitor concentration blocking 50% of initial enzyme activity.
The inhibitory activity of the inventive compounds in regard to tissue transglutaminase (TG2) is shown in the following table 1 using ICso-values.
Table 1. efficacy of reversible TG2 inhibitors A: ICso <40 nM, B: 40 nM ICso < 400 nM, C: 400 nM ICso < 2,500 nM, D: 2,500 nM ICso < 10,000 nM
ICso IC50 Compound Compound TG2 [nM] TG2 [nM]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 2489-ClPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 2489-ClPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 11-115 B Ref. 1 C
11-116 B Ref. 2 B
Ref. 6 D Ref. 3 D
Ref. 1 (ZED3641) Ref. 2 (ZED1227) 00Me ON %
H
N H H
NNN N
ThiN
/Y1\1 NN..-----yNõ,,,_õ.---õ, /Y c H
Ref. 3 (A8, ZED1047) Ref. 6 o,,o o o).N
H
OHOH
ll 0 fH Oil H
1 HN NN-rN
0 0HN- yNN-rN
I
1\1 1\1 Example B-2. logD values of the inventive compounds In order to classify the inventive compounds according to their lipophilicity, LogD values (distribution coefficient) were determined by means of the well-established shake flask method, measuring the partition of a compound between an octanol and phosphate-buffered saline (PBS, pH 7.4) by HPLC.
The LogD is pH dependent and is a "predictor" for in-vivo properties. LogD
combines lipophilicity (intrinsic structural property of the molecule, logP) and ionizability (pKa).
Compounds with a moderate lipophilicity (LogD values from 0 to 3) are usually advantaged for oral absorption, being in balance between solubility and permeability.
However, sophisticated formulation of a compound might improve oral bioavailability for highly lipophilic compounds.
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 Table 2. logD values of reversible TG2 inhibitors A: logD <1, B: 1 logD <3, C: 3 logD <5 Compound logD Compound logD
2489-ClPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 2489-ClPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 11-115 C Ref. 1 A
11-116 C Ref. 2 B
Ref. 6 A Ref. 3 B
Example B-3. Caco-2 permeability assay of the inventive compounds Permeability coefficients (Papp values) were obtained from Caco-2 barrier studies predicting oral/intestinal bioavailability of the tested compounds. The assays were performed by using CacoReadyTM ready-to-use kits from ReadyCell according to the manufacturers protocol.
It is considered that compounds bearing Papp values above 1x10-6 cm/s are classified as permeable whereas compounds bearing Papp values below 1x10-6 cm/s are classified as not permeable.
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 Table 3. Caco2 permeability assay of reversible TG2 inhibitors A: Papp < 1X10-6 CM/S, B: Papp 1X10-6 CM/S Papp < 10X10-6 CM/S
C: Papp 10X10-6 CM/S
Papp [CM/S] Papp [CM/S]
Compound Compound x10-6 x10-6 2489-ClPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 2489-ClPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 11-115 B Ref. 1 A
11-116 B Ref. 2 A
Ref. 6 A Ref. 3 A
Bioavailability studies Presumed from promising Papp values (permeability coefficients, see below), the inventors had proven the oral bioavailability of the inhibitors of the present application by the representative compounds 11-3, 11-15, and 11-28. For this selected set of representative compounds, pharmacokinetic profiles were determined in male C57BL/6 mice (N=3, each). Briefly, the compounds were administered as single-dose soluble, oral formulation [20 mg/ml in PBS / (2-HydroxypropyI)-R-cyclodextrin formulation] at 200 mg/kg.
Plasma samples were taken at (0, 0.25, 0.5, 1, 2, 4, and 6 hours) and analyzed by LC-MS to determine the concentration of the representative compounds.
The calculated pharmacokinetic parameters are summarized in the table.
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 Cmax Cmax AUCt Kei MRT t112 CL/F Vd/F
[ng/m L] [nM] [ng/m L*h] [l/h] [h] [h] [L/h/kg]
[L/h/kg]
11-3 13,594 21,588 12,023 1.0 1.0 0.7 16.6 16.3 0.87 11-28 15,143 23,277 14,468 0.6 1.6 1.1 14.8 23.8 0.98 11-15 32,322 48,626 36,878 0.9 1.1 0.9 6.1 7.5 0.93 Cmax: maximum plasma concentration.
AUCt: area under the plasma concentration time curve from administration to last observed concentration at time t measured by trapezoidal rules.
Kel: is estimated by the linear regression of the logarithm of the terminal concentration as a function of time. Point used to calculate the Kel are selected the 'Best Fit' option of Winnonlin.
MRT: mean residence time.
t112: is calculated by application of the equation In2 /
CL/F: apparent plasma clearance calculated as follow: Dose/AUCinf.
Vd/F (L/kg): apparent volume of distribution following administration. The parameter are calculated as Vd/F = (CL/F) / Kei R2: correlation coefficient.
Papp [CM/Si IC50 [nM] ICoo [nM]
*10-6 11-3 23 180 8.4 11-28 24 240 7.4 11-15 35 375 5.9 The corresponding PK profiles reveal that the plasma levels for all representative compounds exceed the ICoo for 3.5 hours and the ICso during the whole study (6 hours).
In summary, the high cmax values observed in the PK-studies exceed the ICoo levels >100-times. We therefore expect to occupy all active TG2 accessible.
Additionally, in a multiple-dosing PK study, 11-3 was orally administered to 3 mice with 200 mg/kg doses (dose volume 10 mL/kg) twice daily (12 h intervals). After the animals were sacrificed, the liver and lung were removed. The homogenates of the respective tissues were analyzed by LC-MS to determine the concentration of the compound. The tissue concentration in lung and liver after the eighth dose (four days) was 6,800 and 10,400 ng/g, respectively, showing that the compound reaches the tissue at pharmacological active concentration.
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 3961. A compound of the general formula (I):
H (I) R2 N 1 Ny R3 wherein L represents ¨L1¨ or _L1-L2¨; preferably ¨L1-L2¨;
L1 represents ¨CH2¨, ¨CH2CH2¨, ¨CH2CH2CH2¨, ¨CH2C0¨, or ¨CH2CH2C0¨;
L2 represents a bond, ¨NRNI¨, ¨NRNICH2¨, ¨NRNICH2CH2¨, or ¨NRNICH(CH3)¨;
R1 represents R2 represents RN
-, 0 r-t8 1 __________ rm R11 1 0 R8 r __ s R8 Rii , s ,R8 __ \,,,/ R8 / R9 R10 R9 ; R9 Rlo R9 ;
' , , RN RN RN RN RN RN
R11 N R8 R11 N, Rii \I N, 011 1\1 __ \ / --I4N -1_1K 1 /NI
i)n ( '------ R1.1 11 R8 ) ________________________________________________________ N
/ R9 R10 `s / R9 R.- R9 Rlo N
, ' , ri 8 Doll 0 _ R1_1 0R 8 -.._ 0 .-,i-c8 - _-- ?'''- -0 Os) Y ____________ N ) __ N N )\ __ N N-; R10 ; ; R10 ; R8 N------' RN
RN
R10 R11 S __ 11 -_ SN_R8 -_ 1\1, N 11 IJ, 0µ ---22-Z 1 RS R8 ii-- __ --.-Qi----- 1 ____ ri ii RI
4\1 N R8 Ri0 R10 R10 , , , , ' RN RN ,,,,,, R12 ,N R10 Rio_."1,N_RN
N
//
=Nj II, N, N rl '/'''l D13 ''''''' NN LI ".\,,,j .µ
' N¨N ; N=N ; -."------- R14 N. R14 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 R12 R12 N R12 0 - = - ./ y, S - = = _ / y, ------------------- R13 N2 R13 ri, , ___L IR13 ___<\)\____L IR13 ----------------------------------------- ¨R13 -\
\ii \- R14 Ria N R14 N-R14 NyR14 Rlo Rio , RN
NI - = - ./ y, R12 p12 - - -TR13l 13 õ..----"`
R14 N-----%\-1A c____\7R
14.
Rlo R." R14 R._ , RN RN RN
9 ,ii, R9 rri /IR9 N- -/,R9 S rR
R10 Rio 0) _ R10 N _______ - Rio _ \ -7----Dio -R8 R8 ,S-, " , -R9 ,S -- ., N II
1\--7_, N , 1 NV T- -- ,---N
N
N _R10 I s)'''''T
\
. R8 \S-N \NI:=N , , . S, - - 1\1,-- . N..õõ--R ---- 1/ d--- R8--- -1 Ru---- 0 ji -N-N b-N , NI -- -- 0-N N
H
\ \ \ ---, N
, , , , , N ---eNNH ---eNNH ---( --( N
- N N __ \( S S z S S z N
---eNNH ---eNNH
11 NINN3 N __ ( 0 ()NJ
N, _rN N ----eN0 ---eN0 ,3 NI
- N ___eN0 N
, \( N
N Nj , \
0 0 7 N , H S
NI_ s N
___ , --1"D5 H H , S _NI N
s _---------\N
S-1\i/2 , NO H
N
, , 0 0 ___"'-µ 0,N _NI
-----N--N \NI-N-07 H , H
, 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 _ \ F
z N O _ _ z - z -__ - z-z- z - z z z -i / \ 7, / r z r z7, z c i z / \ z/ \
z' \ / `z / C / z)/ z)/
`z z)/ z' \ z' \ z' z' `z , ¨z , z ¨ ¨/ ¨/ ¨z z --/ ¨ ¨
z z v=i , , , ' ' ) ____ z (y, , , _ _ co z z z_z , z z , / \ \ / \ Z/ / \ / 3Z//- Z Z/ / Z Z/ Z ' 1 , C r 9 - / \ Z / \
Z Z Z) / \ Z/ I \ Z I \ Z) /- Z) /
µZ Z) / \ Z)/ \ Z? / \ Z Z/ Z Z/
Zy ¨ ¨ __ / ¨ ¨ ¨/ ¨Z -=Z --/ ¨
¨/ ¨/ -=Z
tT7Z i j j j N O
, e?
, cc :s< 9 "0 N
.4 N
0,1 0 0 , ,r - _________________________________ \\ - Z Z Z
0r a) ZVk' Z/ \ / \ Z Z/ \\Z / µµZ c /
Z/ / Z---Z / \ Z/ r Z c µµZ
w a.) r`i Ce z i---\\ Z 0 a) / \
iz" ca Cy Z / \ Z Z/ \ / \Z ( \ / Z2/
Z)/ \ Z)/ \ Z Zi/ Z/ Z/ (Z 1- a ce --, ¨Z , ¨ ¨/ ¨Z ¨Z Z ¨
¨/ ¨ ¨
(,) =
1 , , , Lu 0, 1 ' 9 a) o ct ,r a õ
I\IN -.N,N
N
N , 1 1\r' N-,N TheN
' , N - , ,1\1 ''IrN
NN
, ---''rN
N.N
N-,N I
, NN 1\INI NN
, , '--ry N.N NN--N , , --N.
NN N.NN 1 1\IN
H -, HN NH , , , , ., N NH , HN , NH, H' N=\ 0 N=N N=\ N---N
\ N
, N- N- N- -N -N
--- \ --/N __ ------N N/
, N ' -N -N -\ -\
1 (N
- /
N
\ //1\1 , \ /
N, N , N , , \ \ 1 -- \ iN --- zN
1\1 --\ /1\1 , 2 -- 1 N N
, N , ______________________________ N N \\ , , 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 N=\ N=\
/N
\ / N\/ N / N¨N N //N
N S
N \IV
N
N=N N=N N=N N=N N=N
\ N ,,N, N / N /
, _______ z/ , N=\ N=\ N=\ N=\ N---\
\ //N, \ S \ _______ I\1 / , N
N N N
, \ --N /
/ // N¨N \\_N N
, , , , ' , \ /71, \ S \ _______ I\1 , N
N N N
' ¨N ¨N --? /¨N
-- ________________ --i --i --i /
N¨ N //N
V/ N¨N N __ I
, , , ¨\ ___\
N ; N¨ // N¨N N
--Ns, \ /1\1 N N N N N /
_______________ , N¨N N N ; /
sis¨/ N / or ¨N - \l wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 ¨ R14 and R" ; and preferably with 1 to 3 of the substituents R11 ¨
R13;
R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl;
diamantyl;
hexamethylenetetraminyl and the afore-mentioned residues optionally contain one or more C=C double bond(s) and/or are optionally substituted by one or more of Ra; Ri3; Rc; Rd; and Re;
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 Ra, Rb, Rc, Rd, and Re represent independently of each other -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C2H5, -CONH2, -CONHCH3, -CON(CH3)2, -CONHC2F15, -CH2CO2H, -CH2CO2CH3, -CH2CO2C21-15, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2F15, -NHCOCH3, -NHCOC21-15, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C21-15, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3;
R4 represents -NR6R7;
R6 and R7 represent independently of each other -H, -CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-05H9, -cyclo-C6H11, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-05H9, -CH2-cyclo-C6H11, -Ph, -CH2-Ph , -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2NHCH3, or -CH2CH2N(CH3)2, or -NR6R7 is -N(C2H5)2, - -N - -N - -NO
or N/ \
\ ___________________________________________________________________________ / =
, R8, R9, R10, R11, R12, R13, and R14 represent independently of each other -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH (CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2OH, -CH2F, -CH F2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -OCH3, -0C2H5, -0C3H7, -OCH(CH3)2, -0C(CH3)3, -0C4H9, -OCH F2, -0CF3, -OCH2CF3, -0C2F5, -OCH2OCH3, -0-CYCIO-C3H5, -OCH2-CYCIO-C3H5, -0-C2H4-CYCIO-C3H5, -CH 0, -COCH3, -COCF3, -00C2H5, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -COOH, -COOCH3, -CO0C2H5, -CO0C3H7, -COOCH (CH3)2, -COOC(CH3)3, -00C-CH3, -00C-CF3, -00C-C2H5, -00C-C3H7, -00C-CH(CH3)2, -00C-C(CH3)3, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -N HC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5, -NHCOC3H7, -NHCOCH (CH3)2, -NHCOC(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CON HCH (CH3)2, -CON H-cyclo-C3H5, -CON HC(CH3)3, -CON(CH3)2, -CON (C2H5)2, -CON(C3H7)2, -CON [CH(CH3)2]2, -CON [C(CH3)3]2, -SO2N H2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -SO2NHCH(CH3)2, -SO2NH-cyclo-C3H5, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H5)2, 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 -SO2N(C3H7)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C2H5, -NHSO2C3H7, -NHSO2CH (CH3)2, -NHSO2C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -CECH, -CEC-CH3, -CH2-CECH, -Ph, -0-Ph, -0-CH2-Ph, r1\1 * -NO IL:12)1 -Nr-N -- r r1\1 r1\1 r / __ \ / __ \ / __ \
N\ /NH N\ or N\ /N
or R8 and R9 or R9 and R19 can form together one of the following five-membered or six-membered rings:
__o _1\1 - I
or ---%N
or R12 and R13 or R13 and R14 can form together one of the following five-membered or six-membered rings:
.0 .0 .-H or I =
RN represents -H, -CH3, -C2F15, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH (CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-051-19, -CH2-cyclo-C3F15, -CH2-cyclo-C4H7, -CH2-cyclo-051-19, -CH2F, -CHF2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CH F2; -CF12-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3, -00C21-15, -00C3H7, -COCH (CH3)2, -00C(CH3)3, -CO-cyclo-C3H5, -CO-cyclo-C4H7, -CO-cyclo-051-19, -COOCH 3;
-COOC2H5, -COOC3H7 -COOCH (C H3)2, -COOC(CH3)3, -000CH2Ph, -S02CH3, -S02CF3, -S02C21-15, -S02C3H7, -S02CH (CH3)2, -S02-cyclo-C3H5, or -S02C(CH3)3;
RN1 represents -H, -CH3, or -CH2CH3;
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomers, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, wherein R2 represents R1:LS R8 RN
-... 0 r,8 1 _______________ rm R11 0 R8 \ , __ S Rs 1 __ r , ___ r __ ,, \ , R8 R10 R9 / R9 R10 D9 ' R9 Rio R9 ;
' , rµ , , RN RN RN RN
Rii N Rs Rii N, RN N, __ N, 1(\1 1 iN RI-1.0x __ Rii 0 ii -1 ---, i) __ ( N N
, Ro Rio ss , R9 R.,,r, 09 R10 /
; F\ ;
R10 nµ
pp10 R11 5 ' --0,---R8 i_s)--,'' R8 A- _,- ...... --1 N
R1S,,s _R8 0s) Os ir \ ir-)--N `-', _ N
N N¨ N
Rio R8 N¨ - R8 Rio ' ,,, ' , , R" RN RN RN
\ 1 -._ S R8 -__1,,,, Rii N, ,N Itt Rio ----- ,N
Rio ,N,N_RN
N
) __________________________________ N
Rio Rio N-N
, , , ,N, pp L1,,.,. -)R1=3 13 R=- r =rl ¨R=-----V N--"
..õ.j = - \
R - -------------------------------------------------------------------N=N , Dia N Ria N Ria N Ria "
RN
Riz Riz Riz RN
0----/Y,) S-----_,) i\i----/Y ,) i\i----/Y,) ---R13 -- ---, ¨R13 --- 1 \TR13 Ria Ria Ria N----%\- iA
Rio Rio Rio R.-, Riz ,µ
R r_ N, R9 Riz _I _] ii 7--- 9 r R13 N ."R /1 _ --. __ S
Ria R..14 R._in N --\___,-------Rio , , , , S..õ1,--_ R10 pi0 N/r---"` DA 10 N, µ _,K N I
s -- )---¨IA \ N R8 \ `
, S NO 'N , S,-- R8 1\1/, II S,,,,' 1\1,-- . N
R8---- ,-- 0 )\--N -ii N./ IT R8---- -/ Ru-----R8 , N-N b-N WC' , 0-N N
, , , H
\ \ \ ---, N
, ' , , , 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 ---eNNH ---eNNH
(i \ IN
N ______ ( 1,\ij N N __ \( S S 7 S S y , N
---eNNH ---eNNH
ITIN3 N __ ( , -- A - - N N --(N3 N( Z
-_,7,0 i ________________________________ \N , N
NJ
, , , H S
----7Nr-S H N1 .-- -- -e------N&\ -N
'S
' -- H
' , , S------N __N S ___ /(--'-\--- N
---:-\-- N
-k-N,õ// \S-I N,// S'INI
, , H
N 0,_-N
-------N-No N-N-0 -----N, ------0-N&\
H H
j0---r-N -w 0 /
-"Q
-, I\1 ., i --I I I
N /
/ N
-, N -- -, ' N
, .. 1\1 -.,N
I II
N Th\r N /
-, NõN
I -I
NN
, -. N -. -, 'N 'N
N N
N
.. 1\1 I\1 -.,z1\1N
N 1\rz '--1 N
1\1 Nle , , , 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 '-'N '---N
I
N , N NN, , N N
I II -.fNI\I
Nõ, " NN NN, , , ---- -:-,-,--- :-..1 N
NK," N N
, -..,...,.----.._ " , N N , N, , - N, 'N -,,1\1N -,,N ,N
1\1 N , 1 N f -1\1-"Ni NN NN N.N
N'N' , , N,N -.N,N
N, 1\1 N
N -,,1\1 -, 1\1 ' NN, NN N N
-, --IN 'N
NN NN I
N
, NN N NN
, , ' ., N.N NN-,N :N
, NN , , I
N.
NN N,NN NN
' _, Icl NH
HN NH , , 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 HN H , NH , ' N=\ 0 N=N N=\ N---- \ /NI --\ N
N/ \ /IV
___________________________________________________________ ' , ' N¨ N¨ N¨ ¨N ¨N
¨ ¨ _____________ \ ¨ ¨ \ ¨ ¨ \ ;IV ¨ ¨
¨ ¨ ¨¨ ________________ / N\
N' , N, _¨N ¨N ¨N \ /¨\
N
-- ¨\ /N z( ¨ ¨ ¨ ¨ / N ¨-\1\1 , N
N, N
______________________ , , , \ ¨ \
N , \ / N/ __ \ N 1\1 N ¨ ¨ =
N N
N \\ // , , N=\ N=\
¨ ¨ ¨ ¨
¨ ¨ /(1\1 \ / N / Ns / N
N¨N S
N
N sN N //N
, , , N=N N=N N=N N=N N=N
¨ ¨ \ ;NI ¨ ¨ ¨ ¨ ¨ ¨ ___ 1 N
\ ,,N N /
N _________________________________________________________ N=\ N=\ N=\ N,\ N-- ¨ z(N ¨ ¨ ¨\ z N ¨ ¨ /N ¨ ¨ ____ /N¨ ¨
\//N , \ S \ N\/ N
N, N / N
, ______________________ , , N¨ N¨ N¨ N¨ N-- ¨ __________ ¨ ¨ _________ \
N N
\ ¨ ¨ __ \ N ¨ ¨ / N\ ¨N, V / N /
N/ //, N¨N, \ I __ , , ¨N ¨N Ns ¨N ¨N
-- zs(N ¨ ¨ \ /N¨ ¨ i ¨ ¨N , i / N ___ ¨ ¨
N
\//N , \ S I\1 , N N N
, , , ¨N ¨N /¨N _ _ _¨N ¨N
¨ ¨ __________ ¨ ¨ i ¨ ¨ /
\ N N\/ N /
N //N
N¨N _N 'IV
' , , , , 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 __\ __\
- - m --- m --i N --- /N -- --i /N
\ '\ /( \ ,N ( N N N \ S N S
N ; N¨// // N-N N
, , ¨\
Nss ___________ \ ,N N N
/ N N N, /
N N-N ; N Ni or \N-N ;
, , , wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 ¨ R14 and RN; and preferably with 1 to 3 of the substituents R11 ¨
R13 and the substituents R9 ¨ R14 and RN have the meanings as defined in claim 1.
3. The compound according to claim 1, wherein R2 represents RN
0 m - ,O r,8 1 __ r R11 0 R8 \ , __ 1 S Rs r Rii S R8 \ / -_ ii \ / R8 R10 R9 ; / R9 R10 R9 ; / R9 R10 R9 ;
;
;
RN RN RN RN RN RN
R11 N R8 R11 N, R11 N, _ _ N, N I
R=___(-r__R 8 K _ -\
N \ i N
/ R9 Rlo ss / R.n R10 R.,,,, Rlo RN Rio N 8 Ril 0 R
_ 11 0 IR 8 - - 0 R8 - - 1---R - , ?-0 - 0? R8 Y __ N ) N ________ N Y N R1 R Rio Rio R8 N¨ ' , RN RN
, , R10 RZyS, _ Rii s ,rµ8 -_,SR8 --õ,1`1,N Rii N, C)\2 ir" 'N
R
N R8 __ N N N N io Rio Rio , ,N Nir--R10 R10.,,N ,N e. RN
\
, N , õN, oN ------------ r1 -R = -N-F\
\
, N-N ; N=N ; I-C.--,14 N
;
N R12 0---__/' s I , p13 S/,) 13 R13 N/ Ri3 r \
,,, 1 A
N R14 N R14 N R14 R10 R." R10 R., , RN
D. 12 RN
N' ,712 N--/y,' s R12 ,õ------.../,:',2 p12 - - -\TR13 - - 1 \ R." TR13 ''/ 13 -ji 1 R14 N--%\- 1 A R14 R
\/\\--Rio Ri 4 , , , , 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 RN \ R:
v____ R14 N R9 rii-/,R9 2, ___________ N rNiR9in Ri0 inX S ri ¨ __ _IR ,., R._ N - \___,------- N .-,1 o 0 , , , ,S, - -R9 ,S - - R8 R8 - S NI , I
N\ N6- \ I . )---)\--N
õ, R10 , \" N R8 \S-N i\l'N , R8 Rd N, R ---- 1/ N' - R8--- -I R'a ----- 1/
N-N \O-N N-C) , H
\ \ \ N __ \( , , , N
, , , - -- -eN NH ¨ --eN0 - - S
N TI
N
- -c _________________________________________________________ \ N
IJ
' I
I I
N
, - N N '' ---NN I N N
, NH ., . ., ., . NH
N NH , , H
N¨\
- - -_ or N, wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 ¨ R14 and RN; and preferably with 1 to 3 of the substituents R11 ¨
R13 and the substituents R9 ¨ R14 and RN have the meanings as defined in claim I.
4. The compound according to claim 1, wherein the compound has the formula (lb) 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 --- -N
i H
N ,L, 3 H
(lb) wherein L represents ¨L1¨ or _L1-L2¨; preferably ¨1_1-L2¨;
L1 represents ¨CH2¨, ¨CH2CH2¨, ¨CH2CH2CH2¨, ¨CH2C0¨, or ¨CH2CH2C0¨;
L2 represents a bond, ¨NRNI¨, ¨NRNICH2¨, ¨NRNICH2CH2¨, or ¨NRNICH(CH3)¨;
R2 represents RN
R11 0 Rs - _ S R8 R11 S R8 -- 8 \-11( R
R10 R9 ;
' R9 R10 R9 ;
' R9 R10 , ; "
, RN RN RN RN
R8 R11 , Rii N , R11 0 N _ _ Rii 0 R 8 / ( n --1(\1 ---\ -----__--) ________________________________________________________ N N
R9 R10 `, / Ro R10 R9 R10 , = , ; Rlo N Os N¨ 0? R10 Rii S
R8 0?,----x ------- - - R1-_.1 S R8 ) N
R19 R8 N¨ ' R8 Rio __ N N /
, , RN
RN RN RN
-_ S Rs - _ ,s,N,,s, N Rii N, rill 1 __ /N RioN,N....RN Nio N ¨1\¨N ,N
R10 Rio , ' N¨N
, ; ' , ' , , R13 , D N
--------------------------- ¨ R R ----------------------------- N/
- N' \ NR13 N=N R14 N R14 N R14 N
, RN
R12 R12 Riz R12 0---__ _ S----_.// _ N--__// RN
N
r --R,, ---R ' - - R13 R14 R14 R14 _ (NR
N R14 Rlo Rlo R10 ;
N---__/y, - S H
--- 1 \R13 N .%\
-7 \ 7R ----" i A
R
r-,.., , , R14 R14 , 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 RN H
, ri R9 N , , NR14 Nk.õ..-S rN,R910 _r /I
R1 ON) ___________ S -R -, ; 0 , õ
D___I_Im 9 R9 /
R10 ,1\1\1-1./=-= R10 N NN
; S ,µ.
, ' , , N N , ,Sx - N , I Nks_NI
N N NN/ \N R8 , ,S - IR
- ;t3 N7T ,S,-- ,- n N,-' n N-------N IR`-'n ---\ II NT R --- -! R ----- 1/
R8 N-N \O-N IN- Or , , , R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl, diamantyl, hexamethylenetetraminyl, and the afore-mentioned residues optionally contain one or more C=C double bond(s) and/or are substituted by one or more of Ra, Rb, Rc, Rd, and Re;
Ra, Rb, Rc, Rd, and Re represent independently of each other -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C2H5, -CONH2, -CONHCH3, -CON(CH3)2, -CONHC2F15, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H5, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2F15, -NHCOCH3, -NHCOC21-15, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C21-15, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3;
R4 represents -NR6R7;
R6 and R7 represent independently of each other -H, -CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-05H9, -cyclo-C6H11, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-05H9, -CH2-cyclo-C6H11, -Ph, -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2, or -NR6R7 is -N(C2H5)2, - -1\I -10 - NO
or N/\ ).
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 RI4 represents -H, -CH3, -C2E-13, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H3, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-051-19, -CH2-cyclo-C3F15, -CH2F, -CH F2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3, -00C21-15, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -COOCH3, -CO0C2H5, -CO0C3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -S02CH3, -S02CF3, -S02C21-15, -S02C3H7, -S02CH(CH3)2, or -S02C(CH3)3;
RNi represent -H, -CH3, or -CH2CH3;
and R8 - R14 have the meanings as defined in formula (I);
or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomers, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
5. The compound according to any one of claims 1 - 4, wherein L1 represents -CH2-, or -CH2C0-;
L2 represents a bond, -NR'-, -NR1ICH2-, or -NRNICH(CH3)-;
R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 4-homoisotwistyl, adamantyl, or diamantyl, and the afore-mentioned residues optionally contain one or more C=C double bond(s) and/or are substituted by one or more of Ra, Rb, Rc, Rd, and Re;
and Ra, Rb, Rc, Rd, Re and RI" have the same meanings as defined in claim I.
6. The compound according to any one of the claims 1 - 5, wherein R2 represents Rio 0 R8 _ S R8 RSrR8 C)\ C)\) R
Rii3 R9 R9 Rio R9 R8 N-N
RN RN
µ` R10 R11 S R11 S 8 S R8 - R8 C)\
) __________________________________ N
R- Rio Rio Rio RN RN
Riz Riz Rii N\ Rio N. RN pe, 13 N N--- -- u .=
N=N N
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 RN
R12 R12 Ri 2 R12 0 S /Y,) N
----------- /') R13 - - j-R13 - - T R13 \ ---_ ¨R13 -\R14 i, N R14 R10 R ., R10 R10 R14 , , , , _r /TR%) 111=Z:
N ----/Y,) . . . . / - - - - - - -----/, µs I
N\ -%-R14 A-) 1 (1 _________________________________________ S r_. R9 R14 p . _ N
, ' ' , ' ' , , ri R9 , N
D._.1, 9 (D) i 4. --/R1 0 N6' -\N
, 0 , S R8 \S-N
, , , N 1 , S,-- , N, - - N
R - - - -,---N , S)- N6- R'a --i -1 R`-'Q ---R8 N-N \O-N N "C) Or , , , and R8 - R14 and RN have the meanings as defined in claim 1 or 2.
7. The compound according to any one of the claims 1 -6, wherein the compound has any one of the formulae (IV-a) - (IV-o) and (V-a) - (V-d):
0 )16 )-L NH
NR
"6 H 0 c 0 RC
N
0 ( H 0 Rb R2j NH 1 NI-1 1- ,1 N-1¨L2 A )-L Rb HO 0 Ra Ra (IV-a) (IV-b) o o o .
NR6 o)L N. R6 H H Rb Ra 0 A 0 0 ( H 0 H
Rc H 0 0 RRb Ra H
0 0 Rd b (IV-d) (IV-c) o o o AN, R6 0 )-L N- R6 Rb Ra H Rb Ra H Rc 0 H 0 Rc 0 0 A j(H
H
0 0 Rd H
(IV-a) (IV-f) 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 O Rd 0 (DA R6 0 R6 N - N -H Rc H Rb Ra 0 0 0 0 Rc A H II
1111N ...-----õ,õ. L2 H
AN
0Ji 0 Rd (IV-g) (IV-h) 0)- R6 N - Ra oN - R6 H
Rb j H
0 H 0 Rc 0 H 0 H
0 0 Rd H
(IV-i ) (IV-j) 0AN R6 if :!:.;:C c:1)- N , R6 7p -H H
0 iCH 0 0 0 ..----õ,_õ L2 A N
J
(IV-k) (IV-I) o o o NI- .R6 N
0 0 0 ,d 0 (IV-m) (IV-n) 0, NH . R6 0 N R6 - -H
0 I\1)-L 12 ...--,...õ_õ. -__ R2 NH ).Ntr " - N L2 1 R8 \ I hi 1 N ._ R3 Ri 0 (IV-o) (V-a) 0 o o)-N ,R6 (DN - R6 H H
,----,_.___R3 SN /CH
N
R8 \ 1 N N 1 N R8 1 N L2-- R3 R10 Rio (V-c) (V-b) 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 0 )-L N , R6 H
0 iFi 0 R1i 0 N L2 N
R12 d I
\ 0 0 Rio R13 ¨
(V-d) and R2; R3, R6, R8, R9, R1 0 ; R1 1 ; R1 2 ; R1 3 ; Ra ; RI3 ; Rc ; Rd L
and - . 2 have the same meanings as defined in claim 1.
8. The compound according to any one of the claims 1 ¨ 7, wherein R2 represents o 0 -- -(:)¨ Br -._ q ____O______ 0- " 0 -S -*
(:)-Br Br, ; Br ;
s B r \_-S --- Br - -\ // \ / y __ , _.-- -----u-C1 S S
Br Br, ; Br) ; Br , S ---1Sr ci __-CSBr -----Sz-C1 --- S Br 'Br, CI , Br ; Br ; CI ; Me Br ;
--"' I CI
S S S Br __- Br ci C --1 S Br HN
NC ___ 0---, \
, , S
N ,--H2N N meo - - - <72 1N1 - - - ,)-----(/ ) 0 I
H ; 0 0--J N - N-NBr , , S,/ sr 5 __-C1 -------s__-Br -------s_-C1 Br----s Br - - I N N ) __ N N N
N --N , , CI __---C1 -jS--CF3 -- --)S __ Br - - -S__-C1 - -N N N ) __ N ) N
CI ; Br -js,_-0Me -js-Ph :-.-)s-- ISN-CI ' C_ //\---NH
N N N N N // <=
N-N
I ftIcl NI, ,H 1 ,N
,N,,..,.--- 1 -,,N,N NN ',N ,N
N\ N\
1 HN/"'----1 \\ , __ > / >\ __ N )\ N N N
N
N N , 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 N,,CO2H -,._õ..--.--.., ,CO2Me N=N , CO2Me 1\1" N , The , The H
N
N ,N'-,1\1 N C)r--- / c I ---I 1\1 N
0-- \ __________ -::
-- Br''' -, H H
1\1- \ \
1\1õ.
r,_ HN"-HN---r: \/ 0 ._-------1N- -- ___ ___-N
N S ;
-N---- --------------- 0 -- \ -- \ -- \
--S-- __________ N \
; CI Br , IJO1, I , S
-- \
, o ; o----- s , , , , F H
S H \ N
S N N
-- \
Br H
N
H S
F ___ ----<\ --F N N
OH ;
.- -------------------------------- u ,, \ --H - ---N N-'N NN
:
, I\L -S -- ,S --fel"! ----N N) \s-i\I s-1--- N's-'-' <\ 11--N \ jrN
'N,--N *- N N---,,1,1 \N
;
S ;
õ--,S - ,S -- H2N
\\ \\ I
N N \ N N I N
.\\ _..
\N \N N N H N
ci\?,),-- N ---0 ; HO, N-0 O'N , or , N --O-N and R6 represents -H, -CH3, -CH(CH3)2, -CH2CH2CH3, -CH2CH=CH2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CH2CH2CH2CH3, -cyclo-C3H3, -cyclo-C3119, -cyclo-C6H11 or -CH2-cyclo-C3H3.
2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 9. The compound according to claim 1 selected from the group consisting of:
Compound Name 11-2: (S)-2-(benzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-3: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-4: (S)-2-(3-chlorobenzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-5: (S)-2-(4-bromobenzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-6: (S)-2-(4-bromobenzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-7: (S)-2-(benzo[b]thiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-8: (S)-2-(5-bromobenzo[b]thiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-9: (S)-2-(1H-indole-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-10: (S)-2-(4,5-difluoro-1H-indole-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-11: (S)-N1-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methy1-1H-indole-2-carboxamido)-5-oxohexanediamide 11-12: (S)-2-(1H-benzo[d]imidazole-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-13: (S)-2-(2,3-dihydro-1H-indene-2-carboxam ido)-N 1414242-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediam ide 11-14: (S)--(2-bromo-4-methylthiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 methyl-5-oxohexanediamide 11-15: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(4-methy1-2-(trifluoromethyl)thiazole-5-carboxamido)-5-oxohexanediamide 11-16: (S)-2-(4-bromo-2-(trifluoromethyl)thiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-17: (S)-2-(2,4-dichlorothiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-18: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(2-methoxy-4-methylthiazole-5-carboxamido)-N6-methy1-5-oxohexanediamide 11-19: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(4-methy1-2-phenylthiazole-5-carboxamido)-5-oxohexanediamide 11-20: (S)-2-(2,4-dimethylthiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-21: (S)-2-(5-bromo-3-methylthiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-22: (S)-2-(3,5-dibromothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-23: (S)-2-(5-bromothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-24: (S)-2-(5-chlorothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-25: (S)-2-(5-bromo-3-methylfuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-26: (S)-2-(5-chlorofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-27: (S)-2-(5-chlorothiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 methyl-5-oxohexanediamide 11-28: (S)-2-(2,5-dichlorothiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-29: (S)-2-(2,5-dibromothiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-30: (S)-2-(5-bromothiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-31: (S)-2-(2-chloro-5-methylthiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-32: (S)-2-(2,5-dichlorothiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-33: (S)-2-(2,5-dibromothiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-34: (S)-2-(2-bromo-5-methylthiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-35: (S)-2-(2-bromothiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-36: (S)-2-(2-chlorothiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-37: (S)-2-(2,5-dimethylfuran-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-38: (S)-2-(4,5-dimethylthiazole-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-39: (S)-2-(4-bromothiazole-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-40: (S)-2-(4-bromothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 methyl-5-oxohexanediamide 11-41: (S)-2-(4-bromo-3-methylthiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-42: (S)-2-(3-bromothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-43: (S)-2-(3-chloro-4-methylthiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-44: (S)-2-(4-bromo-5-chlorothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-45: (S)-2-(4,5-dibromothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-46: (S)-2-(4,5-dibromo-3-methoxythiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-47: (S)-2-(4-bromofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-48: (S)-2-(4,5-dibromofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-49: (S)-2-(4,5-dichlorothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-50: (S)-2-((S)-1-acetylpyrrolidine-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-51: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-1,2,3-triazole-5-carboxamido)-5-oxohexanediamide 11-52: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(2H-tetrazole-5-carboxamido)hexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-53: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(pyrazine-2-carboxamido)hexanediamide 11-54: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-24(S)-1-methylpyrrolidine-2-carboxamido)-5-oxohexanediamide 11-55: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-24(S)-pyrrolidine-3-carboxamido)hexanediamide 11-56: (S)-2-((2S,4S)-4-bromopyrrolidine-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-58: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-24(S)-piperidine-2-carboxamido)hexanediamide 11-59: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-24(R)-piperidine-3-carboxamido)hexanediamide 11-60: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-24(R)-morpholine-3-carboxamido)-5-oxohexanediamide 11-61: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(quinuclidine-3-carboxamido)hexanediamide 11-62: (S)-methyl 3-(1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-ylcarbamoy1)-5-nitrobenzoate 11-63: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(5-nitronicotinamido)-5-oxohexanediamide 11-64: (S)-5-(1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinic acid 11-65: (S)-methyl 5-(1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinate 11-66: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(6-methylimidazo[2,1-b]thiazole-5-carboxamido)-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-67: (S)-N1-(1-(2-(2-adamantyl(methyl)am ino)-2-oxoethyl)-2-oxo-1,2-dihyd ropyridin-3-y1)-N6-methyl-2-(3-methylbenzofu ran-2-carboxam ido)-5-oxohexanediam ide 11-68: (S)-N1-(1-(2-(5-hyd roxyadam antane-2-am i no)-2-oxoethyl)-2-oxo-1,2-di hyd ropyrid in-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxam ido)-5-oxohexanediam ide 11-69: (S)-N1-(1-(2-(5-fluoroadamantane-2-am ino)-2-oxoethyl)-2-oxo-1,2-dihyd ropyridin-3-y1)-N6-methy1-2-(3-methylbenzofu ran-2-carboxam ido)-5-oxohexanediam ide 11-70: (S)-N1-(1-(2-(5-chloroadamantane-2-am ino)-2-oxoethyl)-2-oxo-1,2-dihyd ropyridin-3-y1)-N6-methy1-2-(3-methylbenzofu ran-2-carboxam ido)-5-oxohexanediam ide 11-71: (S)-N1-(1-(2-(5-bromoadamantane-2-am ino)-2-oxoethyl)-2-oxo-1,2-dihyd ropyridin-3-y1)-N6-methy1-2-(3-methylbenzofu ran-2-carboxam ido)-5-oxohexanediam ide 11-72: (S)-N1-(1-(2-(5-methyladamantane-2-am ino)-2-oxoethyl)-2-oxo-1,2-dihyd ropyridin-3-y1)-N6-methy1-2-(3-methylbenzofu ran-2-carboxam ido)-5-oxohexanediam ide 11-73: (S)-N1-(1-(2-(2-carbonitrileadamantane-2-am ino)-2-oxoethyl)-2-oxo-1,2-di hyd ropyrid in-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxam ido)-5-oxohexanediam ide 11-74: (S)-N1-(1-(2-(2-methyl ad am antane-2-carboxylate-2-am ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediam ide 11-87: (S)-N1-(1-(2-(1-adamantylmethylam ino)-2-oxoethyl)-2-oxo-1,2-dihyd ropyridin-3-y1)-N6-methy1-2-(3-methylbenzofu ran-2-carboxam ido)-5-oxohexanediam ide 11-88: (S)-N1-(1-(2-(1-(1-adamantyl)ethanamino)-2-oxoethyl )-2-oxo-1,2-dihyd ropyridin-3-y1)-N6-methy1-2-(3-methylbenzofu ran-2-carboxam ido)-5-oxohexanediam ide 11-90: (S)-N1-(1-(2-((1R,2S,4S)-bicyclo[2.2.1]heptan-2-ylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediam ide 11-92: (S)-N1-methy1-5-(3-methylbenzofuran-2-carboxam ido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1S ,2S,4R)-1,7,7-trimethyl bicyclo[2 .2.11 heptan-2-ylam ino)ethyl)-1,2-di hydropyrid in-3-yl)hexanediam ide 11-94: (S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediam ide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-95: (S)-N1-(1-(2-(bicyclo[2.2.1]heptan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-dihyd ropyridin-3-y1)-N6-methyl-2-(3-methylbenzofu ran-2-carboxam ido)-5-oxohexanediam ide 11-96: (S)-N1-(1-(2-(bicyclo[2.2.1]heptan-7-ylam ino)-2-oxoethyl)-2-oxo-1,2-dihyd ropyridin-3-y1)-N6-methy1-2-(3-methylbenzofu ran-2-carboxam ido)-5-oxohexanediam ide 11-97: (S)-N1-(1-(2-(bicyclo[2.2.1]hept-5-en-2-ylam ino)-2-oxoethyl)-2-oxo-1,2-di hyd ropyrid in-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxam ido)-5-oxohexanediam ide 11-98: (2S)-N1-(1-(2-(bicyclo[2.2.2]octan-2-ylam ino)-2-oxoethyl)-2-oxo-1,2-dihyd ropyrid in-3-y1)-N6-methyl-2-(3-methylbenzofu ran-2-carboxam ido)-5-oxohexanediam ide 11-99: (S)-N1-methy1-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-y1)hexanediamide 11-100: (S)-N1-methy1-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide 11-101: (S)-N1-methy1-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide 11-103: (S)-N1-(1-(2-(4-homoisotwistane-3-am ino)-2-oxoethyl )-2-oxo-1,2-dihyd ropyrid in-3-y1)-N6-methyl-2-(3-methylbenzofu ran-2-carboxam ido)-5-oxohexanediamide 11-104: (S)-N1-(1-(2-(d iamantane-1-am i no)-2-oxoethyl)-2-oxo-1,2-dihyd ropyrid in-3-y1)-N6-methyl-2-(3-methylbenzofu ran-2-carboxam ido)-5-oxohexanediam ide 11-105: (S)-N1-(1-(2-(d iamantane-4-am i no)-2-oxoethyl)-2-oxo-1,2-dihyd ropyrid in-3-y1)-N6-methyl-2-(3-methylbenzofu ran-2-carboxam ido)-5-oxohexanediam ide 11-107: (S)-N1-(1-(1-adamantylmethyl)-2-oxo-1,2-d ihydropyrid in-3-y1)-methyl-2-(3-methyl benzofu ran-2-carboxam ido)-5-oxohexaned jam ide 11-108: (2S)-N1-(14(3-hydroxy-1-adamantyl)methyl)-2-oxo-1 ,2-dihyd ropyrid in-3-y1)-N6-methyl-2-(3-methylbenzofu ran-2-carboxam ido)-5-oxohexanediam ide 11-109: (2S)-N1-(14(3-bromo-1-adamantyl)methyl)-2-oxo-1 ,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-110: (S)-N1-(1-(2-adamantylmethyl)-2-oxo-1,2-d ihydropyrid in-3-y1)-methyl-2-(3-methyl benzofu ran-2-carboxam ido)-5-oxohexaned jam ide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-111: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(nicotinamido)-5-oxohexanediamide 11-112: (S)-2-(isonicotinamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 0-113: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(pyridazine-4-carboxamido)hexanediamide 11-114: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(pyridazine-3-carboxamido)hexanediamide 11-115: (S)-N1-cyclopropyl-N6-(1-(2-(2-adamantylamino)-2-oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)-5-(3-methylbenzofuran-2-carboxamido)-2-oxohexanediamide 11-116: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)-2-(3-methylbenzofuran-2-carboxamido)-5-oxo-N6-pentylhexanediamide 11-117: (S)-N1-allyl-N6-(1-(2-(2-adamantylamino)-2-oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)-5-(3-methylbenzofuran-2-carboxamido)-2-oxohexanediamide 11-115: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-119: (S)-N1-ally1-5-(benzofuran-2-carboxamido)-N6-(1-(2-(2-adamantylamino)-2-oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxohexanediamide 11-120: (S)-2-(benzofuran-2-carboxamido)-N6-isopropyl-N1-(1-(2-(2-adamantylamino)-2-oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide 11-121: (S)-2-(benzofuran-2-carboxamido)-N6-cyclopropyl-N1-(1-(2-(2-adamantylamino)-2-oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide 11-122: (S)-2-(benzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxo-N6-phenylhexanediamide 11-123: (S)-2-(benzofuran-2-carboxamido)-N6-benzyl-N1-(1-(2-(2-adamantylamino)-2-oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide 11-124: (S)-2-(benzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 8-125: (S)-2-(2,5-dichlorothiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide 11-126: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(4-methy1-2-(trifluoromethyl)thiazole-5-carboxamido)-5-oxohexanediamide 8-127: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(1-methy1-1H-1,2,3-triazole-5-carboxamido)-5-oxohexanediamide 8-128: (2S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridi n-3-y1 )-2-(2,5-d ich broth iophene-3-carboxam ido)-N6-methyl-5-oxohexanediamide 11-129: (2S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(4-methyl-2-(trifluoromethyl)thiazole-5-carboxamido)-5-oxohexanediamide 8-130: (2S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridi n-3-y1)-N6-methy1-2-(1-methy1-1H-1,2 ,3-triazole-5-carboxam ido)-5-oxohexanediam ide 8-131: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(2H-1,2,3-triazole-4-carboxamido)hexanediamide 11-132: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1H-1,2,3-triazole-4-carboxamido)hexanediamide 8-133: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-1,2,3-triazole-4-carboxamido)-5-oxohexanediamide 8-134: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1H-1,2,4-triazole-3-carboxamido)hexanediamide 8-135: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-1,2,4-triazole-3-carboxamido)-5-oxohexanediamide 8-136: (S)-2-(benzofuran-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 8-137: (S)-2-(benzo[b]thiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 (S)-N1-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-11-138 dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-pyrazole-3-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-11-139 dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-pyrazole-4-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-11-140 dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-pyrazole-5-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-11-141 dihydropyridin-3-y1)-N6-methy1-2-(4-methy1-1,2,3-thiadiazole-5-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-11-142 dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1,2,5-thiadiazole-3-carboxamido)hexanediamide (S)-2-(4-iodo-1-methy1-1H-pyrazole-5-carboxam ido)-N1-(1-(2-(2-11-143 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide (S)-N1-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-11-144 dihydropyridin-3-y1)-2-(1-methy1-1H-pyrazole-5-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-II-145 dihyd ropyridin-3-y1)-2-(4-methy1-1,2,3-thi ad iazole-5-carboxam ido)-5-oxohexanediam ide (S)-2-(benzofuran-2-carboxam ido)-N1-(1-(2-((1R,2R,4S)-11-146 bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide (S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylam ino)-2-11-147 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(3-methylbenzofuran-carboxamido)-5-oxohexanediamide (S)-2-(benzofuran-2-carboxam ido)-N1-(1-(2-((1S ,2R,4R)-11-148 bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide (S)-N1-(1-(2-((1S,2R,4R)-b icyclo[2.2.1]heptan-2-ylam ino)-2-II-149 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(3-methylbenzofuran-carboxamido)-5-oxohexanediamide (S)-2-(benzofuran-2-carboxam ido)-5-oxo-N1-(2-oxo-1-(2-oxo-2-11-150 ((1R,25,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 (S)-2-(3-methylbenzofuran-2-carboxam ido)-5-oxo-N1-(2-oxo-1-(2-11-151 oxo-2-((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-y1)hexanediamide (S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylam ino)-2-11-152 oxoethyl)-2-oxo-1,2-dihydropyridi n-3-y1)-N6-methyl-2-(4-methyl-1,2 ,3-thiadiazole-5-carboxam ido)-5-oxohexaned iam ide (S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylam ino)-2-11-153 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-pyrazole-5-carboxamido)-5-oxohexanediamide (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylam ino)-2-11-154 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(4-methy1-(trifluoromethyl)thiazole-5-carboxamido)-5-oxohexanediamide (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylam ino)-2-11-155 oxoethyl)-2-oxo-1,2-dihydropyridi n-3-y1 )-2-(2,5-d ich broth iophene-3-carboxam ido)-N6-methyl-5-oxohexanediam ide (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylam ino)-2-11-156 oxoethyl)-2-oxo-1,2-dihydropyridi n-3-y1)-N6-methyl-2-(4-methyl-1,2 ,3-thiadiazole-5-carboxam ido)-5-oxohexaned iam ide (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylam ino)-2-11-157 oxoethyl)-2-oxo-1,2-dihydropyridi n-3-y1)-N6-methy1-2-(1-methy1-1H-1,2 ,3-triazole-5-carboxam ido)-5-oxohexaned iam ide (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylam ino)-2-11-158 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-pyrazole-5-carboxamido)-5-oxohexanediamide (S)-N1-methy1-5-(4-methy1-2-(trifl uoromethyl)thiazole-5-11159 carboxam ido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1R,2S,4R)-1,7,7--trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide (S)-2-(2,5-dich lorothiophene-3-carboxam ido)-N6-methy1-5-oxo-N1-11-160 (2-oxo-1-(2-oxo-2-((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide (S)-N1-methy1-5-(4-methy1-1,2 ,3-th iadiazole-5-carboxam ido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1R,2S,4R)-1,7,7-11-161 trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide (S)-N1-methy1-5-(1-methy1-1H-1,2,3-triazole-5-carboxam ido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1R,2S,4R)-1,7,7-11-162 trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide (S)-N1-methy1-5-(1-methy1-1H-pyrazole-5-carboxam ido)-2-oxo-N6-11-163 (2-oxo-1-(2-oxo-2-((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 (2S)-2-(4-tert-butyl-1H-pyrrole-3-carboxam ido)-N6-methyl-N1-(1-(2-11-164 (1-adamantylamino)ethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide (2S)-2-(4-cyano-1-methyl-1H-pyrrole-2-carboxam ido)-N6-methyl-N1-11-165 (1-(3-(1-adamantylamino)propy1)-2-oxo-1,2-dihydropyridin-3-y1)-oxohexanediamide (S)-N1-(1-(3-(2-adamantylam ino)-3-oxopropy1)-2-oxo-1,2-11-166 dihydropyridin-3-y1)-2-(5-methoxyoxazole-2-carboxamido)-N6-methy1-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-167 dihyd ropyridin-3-y1)-N6-methyl-2-(3-methylbenzofu ran-2-carboxam ido)-5-oxohexanediam ide (S)-2-(2-acetyloxazole-4-carboxam ido)-N1-(1-(2-11-168 (bicyclo[1.1.11pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-169 dihyd ropyridin-3-y1)-N6-methyl-2-(3-methylbenzofu ran-2-carboxam ido)-5-oxohexanediam ide (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-170 dihydropyridin-3-y1)-2-(2-isopropyloxazole-5-carboxamido)-N6-methy1-5-oxohexanediamide (2S)-2-(benzofuran-2-carboxam ido)-N1-(1-(2-(bicyclo[3.2.1]octan-8-11-171 ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-oxohexanediamide (2S)-N1-(1-(2-(bicyclo[3.2.1]octan-8-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-172 dihydropyridin-3-y1)-2-(3,5-dimethylisoxazole-4-carboxamido)-methy1-5-oxohexanediamide (S)-N1-(1-(2-(5-carboxy-2-am inoadam anta ne)-2-oxoethyl)-2-oxo-11-173 1,2-di hyd ropyrid in-3-y1)-N6-methyl-2-(4-methylpyrim idi ne-carboxam ido)-5-oxohexanediam ide (2S)-N1-(1-(2-(4-am i noadamantane-N ,N-dimethy1-1-carboxam ide)-2-11-174 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1,2,3,4-tetrahydronaphthalene-2-carboxamido)hexanediamide (S)-2-((S)-1,4-diazabicyclo[2.2.2]octane-2-carboxam ido)-N6-tert-11-175 butyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide (S)-N1-tert-buty1-5-(1H-indole-3-carboxam ido)-N6-(1-(2-(2-11-176 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 (S)-N1-tert-butyl-N6-(1-(2-(2-adam antylam i no)-2-oxoethyl)-2-oxo-11-177 1,2-di hyd ropyrid in-3-y1)-5-(6-methylim idazo[2,1-b]th iazole-3-carboxam ido)-2-oxohexanediam ide (S)-2-(benzo[d]thiazole-2-carboxam ido)-N1-(1-(2-((1S,2R,4R)-11-178 bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-cyclopenty1-5-oxohexanediamide (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylam ino)-2-11-179 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-cyclopenty1-2-(imidazo[2,1-13]thiazole-6-carboxamido)-5-oxohexanediamide (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylam ino)-2-11180 oxoethyl)-2-oxo-1,2-di hydro pyridi n-3-y1)-N6-cyclo penty1-2-(4--hydroxy-6-(trifluoromethoxy)quinoline-3-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-181 dihydropyridin-3-y1)-2-(cinnoline-3-carboxamido)-N6-cyclohexy1-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-182 dihydropyridin-3-y1)-N6-cyclohexy1-2-(3-ethylbenzofuran-2-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-183 dihydropyridin-3-y1)-N6-cyclohexy1-2-(1-ethy1-1H-indole-2-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-194 dihydropyridin-3-y1)-N6-cyclohexy1-2-(2-methy1-1,8-naphthyridine-3-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-185 dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1,2,3,4-tetrahydroquinoline-6-carboxamido)hexanediamide (S)-N1-(1-(2-(2-carboxy-2-am ino-5-(trifluoromethyl)adamantane)-2-11-186 oxoethyl)-2-oxo-1,2-dihydropyridi n-3-y1)-N6-methy1-5-oxo-2-(3-oxo-1,2 ,3,4-tetrahyd roisoqui noline-6-carboxam ido)hexanediamide (S)-N1-(1-(2-(5-ethyladamantane-2-am ino)-2-oxoethyl)-2-oxo-1,2-11-187 dihydropyridin-3-y1)-N6-methy1-2-(1,6-naphthyridine-2-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-188 dihydropyridin-3-y1)-N6-methy1-2-(2,6-naphthyridine-1-carboxamido)-5-oxohexanediamide (S)-2-(4-am ino-1,2,5-oxadiazole-3-carboxamido)-N1-(1-(2-11-189 (bicyclo[1.1.11pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-11-190 dihydropyridin-3-y1)-2-(6-(dimethylamino)benzofuran-2-carboxamido)-N6-methy1-5-oxohexanediamide (S)-2-(2-acetamidothiazole-5-carboxamido)-N1-(1-(2-11-191 (bicyclo[1.1.11pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide (S)-N4-(1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-11-192 1,2-dihydropyridin-3-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-y1)-1H-pyrrole-2,4-dicarboxamide (S)-N1-(1-(2-(1-acetylamino-4-aminoadamantane)-2-oxoethyl)-2-11-193 oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(5-sulfamoylfuran-3-carboxamido)hexanediamide (S)-2-(benzofuran-5-carboxamido)-N1-(1-(2-(1-acetylamino-4-11-194 aminoadamantane)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide (S)-2-(benzofuran-6-carboxamido)-N1-(1-(2-(4-aminoadamantane-1-11-195 carboxamide)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide (S)-N1-(1-(2-(4-aminoadamantane-1-carboxamide)-2-oxoethyl)-2-11-196 oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-(1-methylcyclopropy1)-1,2,4-oxadiazole-5-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-11-197 dihydropyridin-3-y1)-N6-methy1-2-(5-methy1-1,2,4-oxadiazole-3-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-11-198 dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1,2,3-thiadiazole-4-carboxamido)hexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-11-199 dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1,2,4-thiadiazole-5-carboxamido)hexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-11-200 dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1,3,4-thiadiazole-2-carboxamido)hexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-11-201 dihydropyridin-3-y1)-2-(4-cyclopropy1-1,2,3-thiadiazole-5-carboxamido)-N6-methy1-5-oxohexanediamide (S)-2-(4-cyclopropy1-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-11-202 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 (S)-2-(4-isopropyl-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-11-203 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide (S)-2-(4-ethyl-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-11-204 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide (S)-2-(4-formy1-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-11-205 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide (S)-2-(4-(hydroxymethyl)-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-11-206 (2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide (S)-N1-(1-(2-(1-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-11-207 y1)-N6-methy1-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(((1 6,2R,56)-6,6-dimethylbicyclo[3.1.1]heptan-2-11-208 yl)methylamino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methyl-1 H-imidazole-2-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(((1 R,2R,5R)-6,6-dimethylbicyclo[3.1.1]heptan-2-11-209 yl)methylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(1H-imidazole-4-carboxamido)-N6-methyl-5-oxohexanediamide (S)-N1-(1-(2-(3,5-dimethyladamantane-l-amino)-2-oxoethyl)-2-oxo-1,2-11-210 dihydropyridin-3-y1)-N6-methy1-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(3,5,7-trimethy1-1-adamantylamino)-2-oxoethyl)-2-oxo-1,2-11-211 dihydropyridin-3-y1)-N6-methy1-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising a compound of any one of the claims 1 ¨ 9 as an active ingredient, together with at least one pharmaceutically acceptable carrier, excipient and/or diluent.
11. Compound according to any one of the claims 1 ¨ 9 for use in medicine.
12. Compound according to any one of the claims 1 ¨ 9 or the pharmaceutical composition according to claim 9 for use in the treatment or prophylaxis of autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, ocular diseases, and skin disorders.
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 13. Compound for use, or the pharmaceutical composition for use according to claim 12, wherein the autoimmune and inflammatory diseases comprise multiple sclerosis, celiac disease, Duhring-Brocq-disease (dermatitis herpetiformis), gluten ataxia, gluten neuropathy, diabetes, rheumatoid arthritis, Graves' disease, inflammatory bowel disease, systemic lupus erythematosus psoriasis, and gingivitis; wherein the vascular diseases comprise atherosclerosis, thrombosis, vascular stiffness;
wherein the fibrotic diseases affect the lung, the kidney, the liver, the skin or the gut like cystic fibrosis, kidney fibrosis and diabetic nephropathy, intestinal fibrosis, idiopathic lung fibrosis, liver fibrosis; wherein the liver diseases comprise alcoholic hepatitis, alcoholic steatohepatitis, nonalcoholic steatohepatitis, non-alcoholic fatty liver disease, liver cirrhosis, autoimmune hepatitis or liver inflammation; wherein the cholestatic liver diseases comprise primary biliary cholangitis and primary sclerosing cholangitis; wherein the cancer comprises glioblastoma, melanoma, pancreatic cancer, renal cell carcinoma, meningioma, and breast cancer, wherein the neurodegenerative diseases comprise Parkinson's disease, Huntington's disease, or Alzheimer's disease, wherein the ocular diseases comprise glaucoma, cataracts, macular degeneration, or uveitis; and wherein the skin disorders comprise acne, psoriasis, scarring, and skin aging.
14. Compound for use, or the pharmaceutical composition for use according to any one of the claims 12 and 13 in the treatment or prophylaxis of celiac disease.
15. A method for producing the compound of formula (lb) according to claim 1 or 3 comprising:
Step 1B: providing a compound 4b Ac0)-LN -R6 ' H 0 4b;
Step 2B: performing coupling reaction of the compound 4b with a compound 5 H2N)-L L
, N- 'R3 to obtain a compound 6b 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 Ac0 , R6 PG3Ni\O- _L.
N R-6b;
Step 3B: deprotecting an amino protecting group PG3to obtain a compound 7b Ac0)-L , R6 N 'R-7b;
Step 4B: performing coupling reaction of the compound 7b with a carboxylic acid (R2-CO2H 8) to obtain a compound 9b Ac0 , R6 R2A N ,L.
N R-9b;
Step 5B: performing oxidation reaction of the compound 9b to produce the compound of the formula (lb) N
(1b);
wherein L, R2, R3, R6 and R7 have the same meanings as defined in claim 1, and PG3 is an amino protecting group.
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 Inhibitors of Transglutaminases Description The invention relates to novel inhibitors of transglutaminases, in particular transglutaminase 2, methods for their synthesis and to their use for the prophylaxis and treatment of diseases associated with transglutaminases, in particular transglutaminase 2.
Background of the invention Transglutaminases are part of the class of transferases and according to EC
nomenclature they are correctly designated as "protein-glutamine: amine y-glutamyl transferases" (EC 2.3.2.13). They link the E-amino group of the amino acid lysine and the y-glutamyl group of the amino acid glutamine forming an isopeptide bond while ammonia is released. In the absence of suitable amines and/or under certain conditions, deamidation of the glutamine may occur resulting in the corresponding glutamic acid.
Additionally, transglutaminases play an important role in many therapeutic areas such as the cardiovascular diseases (thrombosis and atherosclerosis), autoimmune diseases (celiac disease, Duhring-Brocq-disease, gluten ataxia), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease), dermatological diseases (ichthyosis, psoriasis, acne) as well as in wound healing and inflammatory diseases (e.g. tissue fibrosis) (J.M. Wodzinska, Mini-Reviews in medical chemistry, 2005, 5, 279 - 292).
Celiac disease, a gluten intolerance, however, is one of the most important indications.
Celiac disease is characterized by a chronic inflammation of the mucosa of the small intestine. In susceptible patients, the intestinal epithelium is successively destroyed after ingestion of gluten-containing food resulting in reduced absorption of nutrients which again has massive impact on the patients affected and is for example associated with symptoms such as loss of weight, anemia, diarrhea, nausea, vomiting, loss of appetite and fatigue. Due to these findings, there is a large demand for the development of a medicament for the treatment of celiac disease as well as of other diseases associated with tissue transglutaminase (transglutaminase 2, TG2, tTG).
The tissue transglutaminase is a central element during pathogenesis. The endogenous enzyme catalyses the deamidation of gluten/gliadin in the small intestinal mucosa and thus triggers the inflammatory response. Therefore inhibitors of tissue transglutaminase are suitable to be used as active agents for medication.
Another very important group of indications for tissue transglutaminase inhibitors are fibrotic disorders. Fibrotic disorders are characterized by the accumulation of cross-2489-CIPO-DESCRIPTION-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 linked extracellular matrix proteins. Diabetic nephropathy, cystic fibrosis, idiopathic pulmonary fibrosis, kidney fibrosis as well as liver fibrosis belong to the most important fibrotic disorders to be addressed with the compounds disclosed.
US 9,434,763 B2 discloses pyridinone derivatives having a warhead comprising at least one acceptor-substituted double bond, such as a Michael System, as irreversible transglutaminase inhibitors. Alkylacetamido and arylacetamido pyridinones showed inhibitory activity regarding tissue transglutaminase TG2 in nanomolar range (IC50).
Tse et al. (J. Med. Chem. 2020, 63, 11585-11601) report on replacement of phenyl residues by non-classical bioisosteres, such as cubane and bicyclo[1.1.1]pentane (BCP), in anti-malarial triazolopyrazine compounds in order to alter compound solubility and metabolic stability. The authors further evaluated in vitro antiplasmodial activity of bioisosteric modified triazolopyrazines against the 3D7 strain of P.
falciparum.
Replacement of phenyl by bioisosteric saturated heterocyclic residues resulted in complete loss of activity. Adamantyl residues as well as other hydrocarbon-caged derivatives led to potency up to 2-9 times lower than the corresponding phenyl triazolopyrazine compounds. In contrast, higher potencies were achieved by replacing phenyl with closo-1,2- and 1,7-carborane isomers. The authors concluded that the effect of non classical bioiostere replacement on biological properties cannot be predicted accurately and that a considerable range of possible bioisosteres has to be tested first in order to identify a suitable replacement leading to the desired properties of a given molecule.
Subbaiah et al. (J. Med. Chem. 2021, 64, 19, 14046-14128) report on bioisosteres of the phenyl ring in lead optimization and drug design. It is noted that bioisosteric phenyl ring replacement with heterocyclic and carbocyclic moieties can lead to enhanced potency, solubility, and metabolic stability while reducing lipophilicity, plasma protein binding, phospholipidosis potential, and inhibition of cytochrome P450 enzymes and the hERG
channel. However, this effect depends strongly on the properties of the compound itself and the addressed target.
US 11,072,634 B2 discloses reversible transglutaminase inhibitors comprising an aldehyde, a ketone, an a-ketoaldehyde, an a-ketoketone, an a-ketoacid, an a-ketoester, an a-ketoamide or a halogenmethylketone as warhead. The inhibitors showed inhibitory activity regarding tissue transglutaminase TG2 in nanomolar and micromolar range (IC50).
The objective of the present invention is to provide novel, most probably irreversible inhibitors of transglutaminases, in particular transglutaminase 2 and methods for the synthesis of said inhibitors as well as several uses of these inhibitors.
2489-CIPO-DESCRIPTION-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 Said objective is solved by the technical teachings of the independent claims.
Further advantageous embodiments, aspects and details of the invention are evident from the dependent claims, the description, and the examples.
Surprisingly, it has been found that irreversible inhibitors having a chemical warhead as disclosed herein inhibit effectively transglutaminases including tissue transglutaminase called transglutaminase 2 or TG2. Herein these terms are used synonymous.
Preferably, such chemical warhead moiety is particularly selected from irreversible warheads such as a,R-unsaturated-ketoester, a,R-unsaturated ketoamide and a,R-unsaturated-sulfone. The compounds of the present invention act as selective inhibitors of transglutaminase 2.
Thus, the present invention relates to compounds of the general formula (I):
C
(I) NH 7I-R3 Ho wherein L represents ¨L1¨ or ¨L1-L2¨; preferably ¨L1-L2¨;
L1 represents ¨CH2¨, ¨CH2CH2¨, ¨CH2CH2CH2¨, ¨CH2C0¨, or ¨CH2CH2C0¨;
L2 represents a bond, ¨NRI41¨, ¨NRN1CH2¨, ¨NRN1CH2CH2¨, or ¨NRN1CH(CH3)¨, 0 0õ0 R1 represents or ,,-)Sl,R4 .
R2 represents RN RN
_O R8 Ril 0 R8 _ _ _S R8 __ IR11 S R8 - _ _.$-Ii.,(R8 Rii \i, r , r ,\ r r , ,R8 , RN RN RN RN RN
R11 N , R1i 1 \ N -, N, RN RN
Rii lj R8 I R
/ l( - I --- - -¨
N
N
Rio µ, ; ' R9 Rio R9 ; Rio R10 ;
w0 R1,1 S
R , i 0, iv 0 R8 -___,,ON R8 _--\ ir --1--- \ ir ? 9 R8 1' 13 Rio N N N N 'N Rio R8 N¨ ' R8 Rio 2489-CIPO-DESCRIPTION-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 RN RN RN
N
R11,S, _R8 --1S\¨R8 ----- ', N N N R11 __ N D10 R10 N_RN
--\\ /7--- ____ , N ,N NQ--1` TC=N
,) ' RiO , , R10 , , ' , , N r", 0,, (11R9 LI
----------------------------------------------------------------- ¨R=-N-N NN - \____,-----Rio ------ R14 N R14 N R14 , RN
R12 N R12 0- 13 S/ 13 i\i I , N/-) Ri3 r Ri 3 - TR - - -R - - Dp13 -., N R14 N R14 Rlo R14 R14 Rio Rlo R14 , ' pp12 pp12 RN
R13 I 7rN_ ), N N R14 , R9 ¨ I 1 R13 r /1 N---\-R14R14 R14 00._ in Fµ N __ S __ _R10 RN R8 R8 ,S,--R9 ,S,-' II
NI S)--- r\i"---N
r /I
R1 0 &/--, R1 0 No j( N Ro \s--N \N-_---N Ro . N , - . N, - 0 R8--\- <SM-Ii -- N-. Ru-- '/ . R ---- il - - --N-N , b-N , N-0 , 0-N N
' , , H
N 0 S s , N , , , , , , , , _N _, ---eNNH ---eNNH N
---\ -13 ---eNS
N( NN - N N __ \( S S z S S y N
---eNNH
N( N, NNJ\ N __ ( N _ N ----eN0 ---eN0 ----(1\1 --(,N3 ----eN0 N __ \( II
6 y N , Ni vlo , N NN
, , , H
N,S N
, , S,--N
s N
H
2489-CIPO-DESCRIPTION-ZED-P04404W026.docx Date Recue/Date Received 2022-06-30 O W
Fri 6 X o o , , ,, , , , , 1 o , ' , 1 , , , ' c c, Z_ CD 2 /_ ___________________________ Z= Z_ Z) /_ n) H
/z \ /z z z(\ z $ /z $ / \ / Z/z rp' 2 \ __ /K \ /( CD m Z Z S Z \ , Z Z S Z Z
Z / Z Z Z
_ Z / Z \ // \ i Z / \ ___________ // \ Z Z /
__ µZµ / _ // -C) . .'10 , --CD
o_ R
N) c) N) p , N) ..
a) i 1 07C 2z3 , , , / , Z z ' ' z/ z z/ Z Z=Z ¨Z z/¨Z z=z Z_ z/
/¨
, ________________ 0 \ ____ /( \ /( /K \ _____ /( \ / / \
\ z z z /K \ / \
.4,.
Z Z Z Z Z
// Z-Z
_ -e0 e(:) 6 z( N Z
, , , , , ' ' , ,' -Z=z Z=z _ ________________________________________ /_ Z= Z /
_____________________ /_ Z= Z_ Z \ / \ / \ /
\ .Z Z. .Z \ .Z \ / Z\ / Z\
\
\_ \ S \ S Z Z \ Z \ Z \ / Z / \ Z \ S Z / \ Z
\ /
Z / // Z¨// Z¨// Z ' ' \ __ // Z
Z Z¨// Z 1 1 _ ________________________________________________________ Z Z
\ cZN
--,,N
Nle , Nie , N.N
, I\IN -,,N,N
'N
IV , N, , N. -, I\1 -,,I\I
'Nil N,2 N N N--N
, , , N N , 1\1-N1-, NN
, -' '-lr"N
N,N
N-, N I
1\1-N N , N N N
I I I
NN
, NN--N NN-,N
-,,N,N
I I
N. NN N N
el\I
, H
NH
HN NH , , ., N NH , HN , NH H , , N=\ 0 N=N N=\ N---N
\ N
N- N- N- -N -N
--- ;IV - ---- / N \ JV
N' N
-- __ N \
\ //IV
N, /
___________________________________ , _______ ' N ______________________ , --\ /,\N
-\
I\1 , --\ N --\ N -- N =
N
N IV N/ //
, 2489-CIPO-DESCRIPTION-ZED-P04404W026.docx Date Recue/Date Received 2022-06-30 N=\ N=\
--- /(1\1 \ / N\/ N / N
N
N N¨N 'IV N //N
N=N N=N N=N N=N N=N
' N --, \ ,,N, _________________________________________________________ / N
, , N=\ N=\ N=\ N=\ N---( \ /71; \ S \ N
/ N N N , ' \ _______________________________________________________________ N IV// N //N
N¨N N \
, ---\ N , \ /71; \ S N N , ____ ¨\ ,N N N
' ¨N ¨N _¨N
-- --i ) \ ) \
/
N / N¨N N __ \IV
, _________________________________________________ , ¨\ ___\
-- N ---\ /IV \ N \ S N S
N ; N¨//
N¨N N
* *
N N
Ns\
N / s \ /IV N N
" N \ N N-N
or ; ¨N ; N N¨//
, , , wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 -R14; and RN; and preferably with 1 to 3 of the substituents R11 - R13;
R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl;
diamantyl; or hexamethylenetetraminyl and the afore-mentioned residues optionally contain one or more C=C double bond(s) and/or are optionally substituted by one or more of Ra; Ri3; Rc;
Rd; and Re;
2489-CIPO-DESCRIPTION-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 Ra, Rb, Rc, Rd, and Re represent independently of each other -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C2H5, -CON H2, -CONN CH3, -CON(CH3)2, -CONHC2F15, -CH2CO2H, -CH2CO2CH3, 5 -CH2CO2C2H5, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2F15, -NHCOCH3, -NH COC21-15, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C21-15, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3;
R4 represents -R5, -0R5 or -NR6R7;
R5 represents -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH (CH3)2, -C(CH3)3, -CH2CH2CH2CH2CH3, -CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-051-19, -cyclo-C6H11, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-051-19, -CH2-cyclo-C6H11, -Ph, -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, or -CH2CH2OCH2CH3;
R6 and R7 represent independently of each other -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, 20 -CH2CH(CH3)2, -C(CH3)3, -CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-051-19, -cyclo-C6H11, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-051-19, -CH2-cyclo-C6H11, -Ph, -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2, or -NR6R7 represents - -N - -N - NO
or i\i/ \
\ ______________________________________________________________________ / -, R6, R5, R10, R11, R12, R13, and R14 represent independently of each other -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2F15, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH (CH3)2, -CH (CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2OH, -CH2F, -CHF2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CH F2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -OCH3, -0C21-15, -0C3H7, -OCH (CH3)2, -0C(CH3)3, -0C4H9, -OCHF2, -0CF3, -OCH2CF3, -0C2F5, -OCH2OCH3, -0-cyclo-C3H5, -OCH2-cyclo-C3H5, -0-C2H4-cyclo-C3H5, -CHO, -COC H3, -COC F3, -00C2H5, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -COOK -COOCH3, -CO0C2H5, -CO0C3H7, -COOCH (CH3)2, -COOC(CH3)3, -00C-CH3, -00C-CF3, -00C-C2H5, -00C-C3H7, -00C-CH(CH3)2, -00C-C(CH3)3, -N H2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, 2489-CIPO-DESCRIPTION-ZED-P04404W026.docx Date Recue/Date Received 2022-06-30 DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.
NOTE : Pour les tomes additionels, veuillez contacter le Bureau canadien des brevets JUMBO APPLICATIONS/PATENTS
THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE THAN ONE
VOLUME
NOTE: For additional volumes, please contact the Canadian Patent Office NOM DU FICHIER / FILE NAME:
NOTE POUR LE TOME / VOLUME NOTE:
NjEr N)'L N-r I I
(S)-N 1 -methy1-5-(nicotinamido)-2-oxo-N6-(2-oxo-1 -(2-oxo-2-(phenethylamino)ethyl)-1 ,2-dihydropyridin-3-yl)hexanediamide Chemical Formula: C28H30N606 Exact Mass: 546.22 Molecular Weight: 546.57 The synthesis of reference compound 6 was performed according to compound 11-3, using 2-phenylethylamine instead of 2-adamantanamine in step 2 (according to ZED3905) and nicotinic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 89 mg, 79% (last step) ESI-MS: 547.4 [M+H]
Biological Examples Example B-1. Inhibitory effect of the compounds according to the invention Transglutaminase assay For the determination of potency of inhibitors against tissue transglutaminase, the incorporation of dansylcadaverine into dimethylcasein (Zedira product T036, Lorand et a/., Anal Biochem, 1971, 44:221-31) was measured using recombinant human transglutaminase 2 (Zedira Product T022).
The tissue transglutaminase is diluted in buffer (50 mM Tris-HCI, 7.5 mM
CaCl2, 150 mM
NaCI, pH = 7.4). The final concentration of TG2 in the assay is 10 nM.
A 10 mM inhibitor stock solution is prepared in DMSO, and from this a serial 1:2-fold dilution series is prepared also in DMSO. Each of the initial dilutions is subsequently diluted 1:50-fold with buffer (50 mM Tris-HCI, 7.5 mM CaCl2, 150 mM NaCI, pH =
7.4) to yield the final working dilutions containing 2% (v/v) DMSO.
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 15 pl of inhibitor working dilution are added per well of a 96 well microtiter plate. As control, 15 pl of a 2% (v/v) DMSO solution prepared using the buffer mentioned above are added per well.
Immediately before starting the assay, 600 pl transglutaminase working solution are added to 11.4 ml assay buffer (50 mM Tris-HCI, 10 mM CaCl2, 10 mM glutathione, 2.5%
glycerol, 16.7 pM dansylcadaverine, 4 pM N,N-dimethylcasein, 200 mM NaCI, pH =
8.0).
285 pl of this reaction mix are added per well containing the inhibitor.
Increase in fluorescence is measured using Aex = 330 nm and Aem = 500 nm at 37 C for 30 min. A slope of the increase in fluorescence between 20 and 30 min is calculated for determination of the ICso value (inhibitor concentration at which 50% of the initial activity is blocked).
Analysis of enzymatic activity is performed by calculation of the slope of an increase in fluorescence intensity. ICso values are calculated by plotting the enzymatic activity (as percentage from control containing 2% DMSO instead of inhibitor) against the inhibitor concentration. ICso is defined as the inhibitor concentration blocking 50% of initial enzyme activity.
The inhibitory activity of the inventive compounds in regard to tissue transglutaminase (TG2) is shown in the following table 1 using ICso-values.
Table 1. efficacy of reversible TG2 inhibitors A: ICso <40 nM, B: 40 nM ICso < 400 nM, C: 400 nM ICso < 2,500 nM, D: 2,500 nM ICso < 10,000 nM
ICso IC50 Compound Compound TG2 [nM] TG2 [nM]
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 2489-ClPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 2489-ClPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 11-115 B Ref. 1 C
11-116 B Ref. 2 B
Ref. 6 D Ref. 3 D
Ref. 1 (ZED3641) Ref. 2 (ZED1227) 00Me ON %
H
N H H
NNN N
ThiN
/Y1\1 NN..-----yNõ,,,_õ.---õ, /Y c H
Ref. 3 (A8, ZED1047) Ref. 6 o,,o o o).N
H
OHOH
ll 0 fH Oil H
1 HN NN-rN
0 0HN- yNN-rN
I
1\1 1\1 Example B-2. logD values of the inventive compounds In order to classify the inventive compounds according to their lipophilicity, LogD values (distribution coefficient) were determined by means of the well-established shake flask method, measuring the partition of a compound between an octanol and phosphate-buffered saline (PBS, pH 7.4) by HPLC.
The LogD is pH dependent and is a "predictor" for in-vivo properties. LogD
combines lipophilicity (intrinsic structural property of the molecule, logP) and ionizability (pKa).
Compounds with a moderate lipophilicity (LogD values from 0 to 3) are usually advantaged for oral absorption, being in balance between solubility and permeability.
However, sophisticated formulation of a compound might improve oral bioavailability for highly lipophilic compounds.
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 Table 2. logD values of reversible TG2 inhibitors A: logD <1, B: 1 logD <3, C: 3 logD <5 Compound logD Compound logD
2489-ClPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 2489-ClPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 11-115 C Ref. 1 A
11-116 C Ref. 2 B
Ref. 6 A Ref. 3 B
Example B-3. Caco-2 permeability assay of the inventive compounds Permeability coefficients (Papp values) were obtained from Caco-2 barrier studies predicting oral/intestinal bioavailability of the tested compounds. The assays were performed by using CacoReadyTM ready-to-use kits from ReadyCell according to the manufacturers protocol.
It is considered that compounds bearing Papp values above 1x10-6 cm/s are classified as permeable whereas compounds bearing Papp values below 1x10-6 cm/s are classified as not permeable.
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 Table 3. Caco2 permeability assay of reversible TG2 inhibitors A: Papp < 1X10-6 CM/S, B: Papp 1X10-6 CM/S Papp < 10X10-6 CM/S
C: Papp 10X10-6 CM/S
Papp [CM/S] Papp [CM/S]
Compound Compound x10-6 x10-6 2489-ClPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 2489-ClPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 11-115 B Ref. 1 A
11-116 B Ref. 2 A
Ref. 6 A Ref. 3 A
Bioavailability studies Presumed from promising Papp values (permeability coefficients, see below), the inventors had proven the oral bioavailability of the inhibitors of the present application by the representative compounds 11-3, 11-15, and 11-28. For this selected set of representative compounds, pharmacokinetic profiles were determined in male C57BL/6 mice (N=3, each). Briefly, the compounds were administered as single-dose soluble, oral formulation [20 mg/ml in PBS / (2-HydroxypropyI)-R-cyclodextrin formulation] at 200 mg/kg.
Plasma samples were taken at (0, 0.25, 0.5, 1, 2, 4, and 6 hours) and analyzed by LC-MS to determine the concentration of the representative compounds.
The calculated pharmacokinetic parameters are summarized in the table.
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 Cmax Cmax AUCt Kei MRT t112 CL/F Vd/F
[ng/m L] [nM] [ng/m L*h] [l/h] [h] [h] [L/h/kg]
[L/h/kg]
11-3 13,594 21,588 12,023 1.0 1.0 0.7 16.6 16.3 0.87 11-28 15,143 23,277 14,468 0.6 1.6 1.1 14.8 23.8 0.98 11-15 32,322 48,626 36,878 0.9 1.1 0.9 6.1 7.5 0.93 Cmax: maximum plasma concentration.
AUCt: area under the plasma concentration time curve from administration to last observed concentration at time t measured by trapezoidal rules.
Kel: is estimated by the linear regression of the logarithm of the terminal concentration as a function of time. Point used to calculate the Kel are selected the 'Best Fit' option of Winnonlin.
MRT: mean residence time.
t112: is calculated by application of the equation In2 /
CL/F: apparent plasma clearance calculated as follow: Dose/AUCinf.
Vd/F (L/kg): apparent volume of distribution following administration. The parameter are calculated as Vd/F = (CL/F) / Kei R2: correlation coefficient.
Papp [CM/Si IC50 [nM] ICoo [nM]
*10-6 11-3 23 180 8.4 11-28 24 240 7.4 11-15 35 375 5.9 The corresponding PK profiles reveal that the plasma levels for all representative compounds exceed the ICoo for 3.5 hours and the ICso during the whole study (6 hours).
In summary, the high cmax values observed in the PK-studies exceed the ICoo levels >100-times. We therefore expect to occupy all active TG2 accessible.
Additionally, in a multiple-dosing PK study, 11-3 was orally administered to 3 mice with 200 mg/kg doses (dose volume 10 mL/kg) twice daily (12 h intervals). After the animals were sacrificed, the liver and lung were removed. The homogenates of the respective tissues were analyzed by LC-MS to determine the concentration of the compound. The tissue concentration in lung and liver after the eighth dose (four days) was 6,800 and 10,400 ng/g, respectively, showing that the compound reaches the tissue at pharmacological active concentration.
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 3961. A compound of the general formula (I):
H (I) R2 N 1 Ny R3 wherein L represents ¨L1¨ or _L1-L2¨; preferably ¨L1-L2¨;
L1 represents ¨CH2¨, ¨CH2CH2¨, ¨CH2CH2CH2¨, ¨CH2C0¨, or ¨CH2CH2C0¨;
L2 represents a bond, ¨NRNI¨, ¨NRNICH2¨, ¨NRNICH2CH2¨, or ¨NRNICH(CH3)¨;
R1 represents R2 represents RN
-, 0 r-t8 1 __________ rm R11 1 0 R8 r __ s R8 Rii , s ,R8 __ \,,,/ R8 / R9 R10 R9 ; R9 Rlo R9 ;
' , , RN RN RN RN RN RN
R11 N R8 R11 N, Rii \I N, 011 1\1 __ \ / --I4N -1_1K 1 /NI
i)n ( '------ R1.1 11 R8 ) ________________________________________________________ N
/ R9 R10 `s / R9 R.- R9 Rlo N
, ' , ri 8 Doll 0 _ R1_1 0R 8 -.._ 0 .-,i-c8 - _-- ?'''- -0 Os) Y ____________ N ) __ N N )\ __ N N-; R10 ; ; R10 ; R8 N------' RN
RN
R10 R11 S __ 11 -_ SN_R8 -_ 1\1, N 11 IJ, 0µ ---22-Z 1 RS R8 ii-- __ --.-Qi----- 1 ____ ri ii RI
4\1 N R8 Ri0 R10 R10 , , , , ' RN RN ,,,,,, R12 ,N R10 Rio_."1,N_RN
N
//
=Nj II, N, N rl '/'''l D13 ''''''' NN LI ".\,,,j .µ
' N¨N ; N=N ; -."------- R14 N. R14 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 R12 R12 N R12 0 - = - ./ y, S - = = _ / y, ------------------- R13 N2 R13 ri, , ___L IR13 ___<\)\____L IR13 ----------------------------------------- ¨R13 -\
\ii \- R14 Ria N R14 N-R14 NyR14 Rlo Rio , RN
NI - = - ./ y, R12 p12 - - -TR13l 13 õ..----"`
R14 N-----%\-1A c____\7R
14.
Rlo R." R14 R._ , RN RN RN
9 ,ii, R9 rri /IR9 N- -/,R9 S rR
R10 Rio 0) _ R10 N _______ - Rio _ \ -7----Dio -R8 R8 ,S-, " , -R9 ,S -- ., N II
1\--7_, N , 1 NV T- -- ,---N
N
N _R10 I s)'''''T
\
. R8 \S-N \NI:=N , , . S, - - 1\1,-- . N..õõ--R ---- 1/ d--- R8--- -1 Ru---- 0 ji -N-N b-N , NI -- -- 0-N N
H
\ \ \ ---, N
, , , , , N ---eNNH ---eNNH ---( --( N
- N N __ \( S S z S S z N
---eNNH ---eNNH
11 NINN3 N __ ( 0 ()NJ
N, _rN N ----eN0 ---eN0 ,3 NI
- N ___eN0 N
, \( N
N Nj , \
0 0 7 N , H S
NI_ s N
___ , --1"D5 H H , S _NI N
s _---------\N
S-1\i/2 , NO H
N
, , 0 0 ___"'-µ 0,N _NI
-----N--N \NI-N-07 H , H
, 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 _ \ F
z N O _ _ z - z -__ - z-z- z - z z z -i / \ 7, / r z r z7, z c i z / \ z/ \
z' \ / `z / C / z)/ z)/
`z z)/ z' \ z' \ z' z' `z , ¨z , z ¨ ¨/ ¨/ ¨z z --/ ¨ ¨
z z v=i , , , ' ' ) ____ z (y, , , _ _ co z z z_z , z z , / \ \ / \ Z/ / \ / 3Z//- Z Z/ / Z Z/ Z ' 1 , C r 9 - / \ Z / \
Z Z Z) / \ Z/ I \ Z I \ Z) /- Z) /
µZ Z) / \ Z)/ \ Z? / \ Z Z/ Z Z/
Zy ¨ ¨ __ / ¨ ¨ ¨/ ¨Z -=Z --/ ¨
¨/ ¨/ -=Z
tT7Z i j j j N O
, e?
, cc :s< 9 "0 N
.4 N
0,1 0 0 , ,r - _________________________________ \\ - Z Z Z
0r a) ZVk' Z/ \ / \ Z Z/ \\Z / µµZ c /
Z/ / Z---Z / \ Z/ r Z c µµZ
w a.) r`i Ce z i---\\ Z 0 a) / \
iz" ca Cy Z / \ Z Z/ \ / \Z ( \ / Z2/
Z)/ \ Z)/ \ Z Zi/ Z/ Z/ (Z 1- a ce --, ¨Z , ¨ ¨/ ¨Z ¨Z Z ¨
¨/ ¨ ¨
(,) =
1 , , , Lu 0, 1 ' 9 a) o ct ,r a õ
I\IN -.N,N
N
N , 1 1\r' N-,N TheN
' , N - , ,1\1 ''IrN
NN
, ---''rN
N.N
N-,N I
, NN 1\INI NN
, , '--ry N.N NN--N , , --N.
NN N.NN 1 1\IN
H -, HN NH , , , , ., N NH , HN , NH, H' N=\ 0 N=N N=\ N---N
\ N
, N- N- N- -N -N
--- \ --/N __ ------N N/
, N ' -N -N -\ -\
1 (N
- /
N
\ //1\1 , \ /
N, N , N , , \ \ 1 -- \ iN --- zN
1\1 --\ /1\1 , 2 -- 1 N N
, N , ______________________________ N N \\ , , 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 N=\ N=\
/N
\ / N\/ N / N¨N N //N
N S
N \IV
N
N=N N=N N=N N=N N=N
\ N ,,N, N / N /
, _______ z/ , N=\ N=\ N=\ N=\ N---\
\ //N, \ S \ _______ I\1 / , N
N N N
, \ --N /
/ // N¨N \\_N N
, , , , ' , \ /71, \ S \ _______ I\1 , N
N N N
' ¨N ¨N --? /¨N
-- ________________ --i --i --i /
N¨ N //N
V/ N¨N N __ I
, , , ¨\ ___\
N ; N¨ // N¨N N
--Ns, \ /1\1 N N N N N /
_______________ , N¨N N N ; /
sis¨/ N / or ¨N - \l wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 ¨ R14 and R" ; and preferably with 1 to 3 of the substituents R11 ¨
R13;
R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl;
diamantyl;
hexamethylenetetraminyl and the afore-mentioned residues optionally contain one or more C=C double bond(s) and/or are optionally substituted by one or more of Ra; Ri3; Rc; Rd; and Re;
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 Ra, Rb, Rc, Rd, and Re represent independently of each other -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C2H5, -CONH2, -CONHCH3, -CON(CH3)2, -CONHC2F15, -CH2CO2H, -CH2CO2CH3, -CH2CO2C21-15, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2F15, -NHCOCH3, -NHCOC21-15, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C21-15, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3;
R4 represents -NR6R7;
R6 and R7 represent independently of each other -H, -CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-05H9, -cyclo-C6H11, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-05H9, -CH2-cyclo-C6H11, -Ph, -CH2-Ph , -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2NHCH3, or -CH2CH2N(CH3)2, or -NR6R7 is -N(C2H5)2, - -N - -N - -NO
or N/ \
\ ___________________________________________________________________________ / =
, R8, R9, R10, R11, R12, R13, and R14 represent independently of each other -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH (CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2OH, -CH2F, -CH F2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -OCH3, -0C2H5, -0C3H7, -OCH(CH3)2, -0C(CH3)3, -0C4H9, -OCH F2, -0CF3, -OCH2CF3, -0C2F5, -OCH2OCH3, -0-CYCIO-C3H5, -OCH2-CYCIO-C3H5, -0-C2H4-CYCIO-C3H5, -CH 0, -COCH3, -COCF3, -00C2H5, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -COOH, -COOCH3, -CO0C2H5, -CO0C3H7, -COOCH (CH3)2, -COOC(CH3)3, -00C-CH3, -00C-CF3, -00C-C2H5, -00C-C3H7, -00C-CH(CH3)2, -00C-C(CH3)3, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -N HC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5, -NHCOC3H7, -NHCOCH (CH3)2, -NHCOC(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CON HCH (CH3)2, -CON H-cyclo-C3H5, -CON HC(CH3)3, -CON(CH3)2, -CON (C2H5)2, -CON(C3H7)2, -CON [CH(CH3)2]2, -CON [C(CH3)3]2, -SO2N H2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -SO2NHCH(CH3)2, -SO2NH-cyclo-C3H5, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H5)2, 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 -SO2N(C3H7)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C2H5, -NHSO2C3H7, -NHSO2CH (CH3)2, -NHSO2C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -CECH, -CEC-CH3, -CH2-CECH, -Ph, -0-Ph, -0-CH2-Ph, r1\1 * -NO IL:12)1 -Nr-N -- r r1\1 r1\1 r / __ \ / __ \ / __ \
N\ /NH N\ or N\ /N
or R8 and R9 or R9 and R19 can form together one of the following five-membered or six-membered rings:
__o _1\1 - I
or ---%N
or R12 and R13 or R13 and R14 can form together one of the following five-membered or six-membered rings:
.0 .0 .-H or I =
RN represents -H, -CH3, -C2F15, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH (CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-051-19, -CH2-cyclo-C3F15, -CH2-cyclo-C4H7, -CH2-cyclo-051-19, -CH2F, -CHF2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CH F2; -CF12-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3, -00C21-15, -00C3H7, -COCH (CH3)2, -00C(CH3)3, -CO-cyclo-C3H5, -CO-cyclo-C4H7, -CO-cyclo-051-19, -COOCH 3;
-COOC2H5, -COOC3H7 -COOCH (C H3)2, -COOC(CH3)3, -000CH2Ph, -S02CH3, -S02CF3, -S02C21-15, -S02C3H7, -S02CH (CH3)2, -S02-cyclo-C3H5, or -S02C(CH3)3;
RN1 represents -H, -CH3, or -CH2CH3;
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomers, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, wherein R2 represents R1:LS R8 RN
-... 0 r,8 1 _______________ rm R11 0 R8 \ , __ S Rs 1 __ r , ___ r __ ,, \ , R8 R10 R9 / R9 R10 D9 ' R9 Rio R9 ;
' , rµ , , RN RN RN RN
Rii N Rs Rii N, RN N, __ N, 1(\1 1 iN RI-1.0x __ Rii 0 ii -1 ---, i) __ ( N N
, Ro Rio ss , R9 R.,,r, 09 R10 /
; F\ ;
R10 nµ
pp10 R11 5 ' --0,---R8 i_s)--,'' R8 A- _,- ...... --1 N
R1S,,s _R8 0s) Os ir \ ir-)--N `-', _ N
N N¨ N
Rio R8 N¨ - R8 Rio ' ,,, ' , , R" RN RN RN
\ 1 -._ S R8 -__1,,,, Rii N, ,N Itt Rio ----- ,N
Rio ,N,N_RN
N
) __________________________________ N
Rio Rio N-N
, , , ,N, pp L1,,.,. -)R1=3 13 R=- r =rl ¨R=-----V N--"
..õ.j = - \
R - -------------------------------------------------------------------N=N , Dia N Ria N Ria N Ria "
RN
Riz Riz Riz RN
0----/Y,) S-----_,) i\i----/Y ,) i\i----/Y,) ---R13 -- ---, ¨R13 --- 1 \TR13 Ria Ria Ria N----%\- iA
Rio Rio Rio R.-, Riz ,µ
R r_ N, R9 Riz _I _] ii 7--- 9 r R13 N ."R /1 _ --. __ S
Ria R..14 R._in N --\___,-------Rio , , , , S..õ1,--_ R10 pi0 N/r---"` DA 10 N, µ _,K N I
s -- )---¨IA \ N R8 \ `
, S NO 'N , S,-- R8 1\1/, II S,,,,' 1\1,-- . N
R8---- ,-- 0 )\--N -ii N./ IT R8---- -/ Ru-----R8 , N-N b-N WC' , 0-N N
, , , H
\ \ \ ---, N
, ' , , , 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 ---eNNH ---eNNH
(i \ IN
N ______ ( 1,\ij N N __ \( S S 7 S S y , N
---eNNH ---eNNH
ITIN3 N __ ( , -- A - - N N --(N3 N( Z
-_,7,0 i ________________________________ \N , N
NJ
, , , H S
----7Nr-S H N1 .-- -- -e------N&\ -N
'S
' -- H
' , , S------N __N S ___ /(--'-\--- N
---:-\-- N
-k-N,õ// \S-I N,// S'INI
, , H
N 0,_-N
-------N-No N-N-0 -----N, ------0-N&\
H H
j0---r-N -w 0 /
-"Q
-, I\1 ., i --I I I
N /
/ N
-, N -- -, ' N
, .. 1\1 -.,N
I II
N Th\r N /
-, NõN
I -I
NN
, -. N -. -, 'N 'N
N N
N
.. 1\1 I\1 -.,z1\1N
N 1\rz '--1 N
1\1 Nle , , , 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 '-'N '---N
I
N , N NN, , N N
I II -.fNI\I
Nõ, " NN NN, , , ---- -:-,-,--- :-..1 N
NK," N N
, -..,...,.----.._ " , N N , N, , - N, 'N -,,1\1N -,,N ,N
1\1 N , 1 N f -1\1-"Ni NN NN N.N
N'N' , , N,N -.N,N
N, 1\1 N
N -,,1\1 -, 1\1 ' NN, NN N N
-, --IN 'N
NN NN I
N
, NN N NN
, , ' ., N.N NN-,N :N
, NN , , I
N.
NN N,NN NN
' _, Icl NH
HN NH , , 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 HN H , NH , ' N=\ 0 N=N N=\ N---- \ /NI --\ N
N/ \ /IV
___________________________________________________________ ' , ' N¨ N¨ N¨ ¨N ¨N
¨ ¨ _____________ \ ¨ ¨ \ ¨ ¨ \ ;IV ¨ ¨
¨ ¨ ¨¨ ________________ / N\
N' , N, _¨N ¨N ¨N \ /¨\
N
-- ¨\ /N z( ¨ ¨ ¨ ¨ / N ¨-\1\1 , N
N, N
______________________ , , , \ ¨ \
N , \ / N/ __ \ N 1\1 N ¨ ¨ =
N N
N \\ // , , N=\ N=\
¨ ¨ ¨ ¨
¨ ¨ /(1\1 \ / N / Ns / N
N¨N S
N
N sN N //N
, , , N=N N=N N=N N=N N=N
¨ ¨ \ ;NI ¨ ¨ ¨ ¨ ¨ ¨ ___ 1 N
\ ,,N N /
N _________________________________________________________ N=\ N=\ N=\ N,\ N-- ¨ z(N ¨ ¨ ¨\ z N ¨ ¨ /N ¨ ¨ ____ /N¨ ¨
\//N , \ S \ N\/ N
N, N / N
, ______________________ , , N¨ N¨ N¨ N¨ N-- ¨ __________ ¨ ¨ _________ \
N N
\ ¨ ¨ __ \ N ¨ ¨ / N\ ¨N, V / N /
N/ //, N¨N, \ I __ , , ¨N ¨N Ns ¨N ¨N
-- zs(N ¨ ¨ \ /N¨ ¨ i ¨ ¨N , i / N ___ ¨ ¨
N
\//N , \ S I\1 , N N N
, , , ¨N ¨N /¨N _ _ _¨N ¨N
¨ ¨ __________ ¨ ¨ i ¨ ¨ /
\ N N\/ N /
N //N
N¨N _N 'IV
' , , , , 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 __\ __\
- - m --- m --i N --- /N -- --i /N
\ '\ /( \ ,N ( N N N \ S N S
N ; N¨// // N-N N
, , ¨\
Nss ___________ \ ,N N N
/ N N N, /
N N-N ; N Ni or \N-N ;
, , , wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 ¨ R14 and RN; and preferably with 1 to 3 of the substituents R11 ¨
R13 and the substituents R9 ¨ R14 and RN have the meanings as defined in claim 1.
3. The compound according to claim 1, wherein R2 represents RN
0 m - ,O r,8 1 __ r R11 0 R8 \ , __ 1 S Rs r Rii S R8 \ / -_ ii \ / R8 R10 R9 ; / R9 R10 R9 ; / R9 R10 R9 ;
;
;
RN RN RN RN RN RN
R11 N R8 R11 N, R11 N, _ _ N, N I
R=___(-r__R 8 K _ -\
N \ i N
/ R9 Rlo ss / R.n R10 R.,,,, Rlo RN Rio N 8 Ril 0 R
_ 11 0 IR 8 - - 0 R8 - - 1---R - , ?-0 - 0? R8 Y __ N ) N ________ N Y N R1 R Rio Rio R8 N¨ ' , RN RN
, , R10 RZyS, _ Rii s ,rµ8 -_,SR8 --õ,1`1,N Rii N, C)\2 ir" 'N
R
N R8 __ N N N N io Rio Rio , ,N Nir--R10 R10.,,N ,N e. RN
\
, N , õN, oN ------------ r1 -R = -N-F\
\
, N-N ; N=N ; I-C.--,14 N
;
N R12 0---__/' s I , p13 S/,) 13 R13 N/ Ri3 r \
,,, 1 A
N R14 N R14 N R14 R10 R." R10 R., , RN
D. 12 RN
N' ,712 N--/y,' s R12 ,õ------.../,:',2 p12 - - -\TR13 - - 1 \ R." TR13 ''/ 13 -ji 1 R14 N--%\- 1 A R14 R
\/\\--Rio Ri 4 , , , , 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 RN \ R:
v____ R14 N R9 rii-/,R9 2, ___________ N rNiR9in Ri0 inX S ri ¨ __ _IR ,., R._ N - \___,------- N .-,1 o 0 , , , ,S, - -R9 ,S - - R8 R8 - S NI , I
N\ N6- \ I . )---)\--N
õ, R10 , \" N R8 \S-N i\l'N , R8 Rd N, R ---- 1/ N' - R8--- -I R'a ----- 1/
N-N \O-N N-C) , H
\ \ \ N __ \( , , , N
, , , - -- -eN NH ¨ --eN0 - - S
N TI
N
- -c _________________________________________________________ \ N
IJ
' I
I I
N
, - N N '' ---NN I N N
, NH ., . ., ., . NH
N NH , , H
N¨\
- - -_ or N, wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 ¨ R14 and RN; and preferably with 1 to 3 of the substituents R11 ¨
R13 and the substituents R9 ¨ R14 and RN have the meanings as defined in claim I.
4. The compound according to claim 1, wherein the compound has the formula (lb) 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 --- -N
i H
N ,L, 3 H
(lb) wherein L represents ¨L1¨ or _L1-L2¨; preferably ¨1_1-L2¨;
L1 represents ¨CH2¨, ¨CH2CH2¨, ¨CH2CH2CH2¨, ¨CH2C0¨, or ¨CH2CH2C0¨;
L2 represents a bond, ¨NRNI¨, ¨NRNICH2¨, ¨NRNICH2CH2¨, or ¨NRNICH(CH3)¨;
R2 represents RN
R11 0 Rs - _ S R8 R11 S R8 -- 8 \-11( R
R10 R9 ;
' R9 R10 R9 ;
' R9 R10 , ; "
, RN RN RN RN
R8 R11 , Rii N , R11 0 N _ _ Rii 0 R 8 / ( n --1(\1 ---\ -----__--) ________________________________________________________ N N
R9 R10 `, / Ro R10 R9 R10 , = , ; Rlo N Os N¨ 0? R10 Rii S
R8 0?,----x ------- - - R1-_.1 S R8 ) N
R19 R8 N¨ ' R8 Rio __ N N /
, , RN
RN RN RN
-_ S Rs - _ ,s,N,,s, N Rii N, rill 1 __ /N RioN,N....RN Nio N ¨1\¨N ,N
R10 Rio , ' N¨N
, ; ' , ' , , R13 , D N
--------------------------- ¨ R R ----------------------------- N/
- N' \ NR13 N=N R14 N R14 N R14 N
, RN
R12 R12 Riz R12 0---__ _ S----_.// _ N--__// RN
N
r --R,, ---R ' - - R13 R14 R14 R14 _ (NR
N R14 Rlo Rlo R10 ;
N---__/y, - S H
--- 1 \R13 N .%\
-7 \ 7R ----" i A
R
r-,.., , , R14 R14 , 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 RN H
, ri R9 N , , NR14 Nk.õ..-S rN,R910 _r /I
R1 ON) ___________ S -R -, ; 0 , õ
D___I_Im 9 R9 /
R10 ,1\1\1-1./=-= R10 N NN
; S ,µ.
, ' , , N N , ,Sx - N , I Nks_NI
N N NN/ \N R8 , ,S - IR
- ;t3 N7T ,S,-- ,- n N,-' n N-------N IR`-'n ---\ II NT R --- -! R ----- 1/
R8 N-N \O-N IN- Or , , , R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl, diamantyl, hexamethylenetetraminyl, and the afore-mentioned residues optionally contain one or more C=C double bond(s) and/or are substituted by one or more of Ra, Rb, Rc, Rd, and Re;
Ra, Rb, Rc, Rd, and Re represent independently of each other -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C2H5, -CONH2, -CONHCH3, -CON(CH3)2, -CONHC2F15, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H5, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2F15, -NHCOCH3, -NHCOC21-15, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C21-15, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3;
R4 represents -NR6R7;
R6 and R7 represent independently of each other -H, -CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-05H9, -cyclo-C6H11, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-05H9, -CH2-cyclo-C6H11, -Ph, -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2, or -NR6R7 is -N(C2H5)2, - -1\I -10 - NO
or N/\ ).
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 RI4 represents -H, -CH3, -C2E-13, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H3, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-051-19, -CH2-cyclo-C3F15, -CH2F, -CH F2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3, -00C21-15, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -COOCH3, -CO0C2H5, -CO0C3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -S02CH3, -S02CF3, -S02C21-15, -S02C3H7, -S02CH(CH3)2, or -S02C(CH3)3;
RNi represent -H, -CH3, or -CH2CH3;
and R8 - R14 have the meanings as defined in formula (I);
or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomers, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
5. The compound according to any one of claims 1 - 4, wherein L1 represents -CH2-, or -CH2C0-;
L2 represents a bond, -NR'-, -NR1ICH2-, or -NRNICH(CH3)-;
R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 4-homoisotwistyl, adamantyl, or diamantyl, and the afore-mentioned residues optionally contain one or more C=C double bond(s) and/or are substituted by one or more of Ra, Rb, Rc, Rd, and Re;
and Ra, Rb, Rc, Rd, Re and RI" have the same meanings as defined in claim I.
6. The compound according to any one of the claims 1 - 5, wherein R2 represents Rio 0 R8 _ S R8 RSrR8 C)\ C)\) R
Rii3 R9 R9 Rio R9 R8 N-N
RN RN
µ` R10 R11 S R11 S 8 S R8 - R8 C)\
) __________________________________ N
R- Rio Rio Rio RN RN
Riz Riz Rii N\ Rio N. RN pe, 13 N N--- -- u .=
N=N N
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 RN
R12 R12 Ri 2 R12 0 S /Y,) N
----------- /') R13 - - j-R13 - - T R13 \ ---_ ¨R13 -\R14 i, N R14 R10 R ., R10 R10 R14 , , , , _r /TR%) 111=Z:
N ----/Y,) . . . . / - - - - - - -----/, µs I
N\ -%-R14 A-) 1 (1 _________________________________________ S r_. R9 R14 p . _ N
, ' ' , ' ' , , ri R9 , N
D._.1, 9 (D) i 4. --/R1 0 N6' -\N
, 0 , S R8 \S-N
, , , N 1 , S,-- , N, - - N
R - - - -,---N , S)- N6- R'a --i -1 R`-'Q ---R8 N-N \O-N N "C) Or , , , and R8 - R14 and RN have the meanings as defined in claim 1 or 2.
7. The compound according to any one of the claims 1 -6, wherein the compound has any one of the formulae (IV-a) - (IV-o) and (V-a) - (V-d):
0 )16 )-L NH
NR
"6 H 0 c 0 RC
N
0 ( H 0 Rb R2j NH 1 NI-1 1- ,1 N-1¨L2 A )-L Rb HO 0 Ra Ra (IV-a) (IV-b) o o o .
NR6 o)L N. R6 H H Rb Ra 0 A 0 0 ( H 0 H
Rc H 0 0 RRb Ra H
0 0 Rd b (IV-d) (IV-c) o o o AN, R6 0 )-L N- R6 Rb Ra H Rb Ra H Rc 0 H 0 Rc 0 0 A j(H
H
0 0 Rd H
(IV-a) (IV-f) 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 O Rd 0 (DA R6 0 R6 N - N -H Rc H Rb Ra 0 0 0 0 Rc A H II
1111N ...-----õ,õ. L2 H
AN
0Ji 0 Rd (IV-g) (IV-h) 0)- R6 N - Ra oN - R6 H
Rb j H
0 H 0 Rc 0 H 0 H
0 0 Rd H
(IV-i ) (IV-j) 0AN R6 if :!:.;:C c:1)- N , R6 7p -H H
0 iCH 0 0 0 ..----õ,_õ L2 A N
J
(IV-k) (IV-I) o o o NI- .R6 N
0 0 0 ,d 0 (IV-m) (IV-n) 0, NH . R6 0 N R6 - -H
0 I\1)-L 12 ...--,...õ_õ. -__ R2 NH ).Ntr " - N L2 1 R8 \ I hi 1 N ._ R3 Ri 0 (IV-o) (V-a) 0 o o)-N ,R6 (DN - R6 H H
,----,_.___R3 SN /CH
N
R8 \ 1 N N 1 N R8 1 N L2-- R3 R10 Rio (V-c) (V-b) 2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 0 )-L N , R6 H
0 iFi 0 R1i 0 N L2 N
R12 d I
\ 0 0 Rio R13 ¨
(V-d) and R2; R3, R6, R8, R9, R1 0 ; R1 1 ; R1 2 ; R1 3 ; Ra ; RI3 ; Rc ; Rd L
and - . 2 have the same meanings as defined in claim 1.
8. The compound according to any one of the claims 1 ¨ 7, wherein R2 represents o 0 -- -(:)¨ Br -._ q ____O______ 0- " 0 -S -*
(:)-Br Br, ; Br ;
s B r \_-S --- Br - -\ // \ / y __ , _.-- -----u-C1 S S
Br Br, ; Br) ; Br , S ---1Sr ci __-CSBr -----Sz-C1 --- S Br 'Br, CI , Br ; Br ; CI ; Me Br ;
--"' I CI
S S S Br __- Br ci C --1 S Br HN
NC ___ 0---, \
, , S
N ,--H2N N meo - - - <72 1N1 - - - ,)-----(/ ) 0 I
H ; 0 0--J N - N-NBr , , S,/ sr 5 __-C1 -------s__-Br -------s_-C1 Br----s Br - - I N N ) __ N N N
N --N , , CI __---C1 -jS--CF3 -- --)S __ Br - - -S__-C1 - -N N N ) __ N ) N
CI ; Br -js,_-0Me -js-Ph :-.-)s-- ISN-CI ' C_ //\---NH
N N N N N // <=
N-N
I ftIcl NI, ,H 1 ,N
,N,,..,.--- 1 -,,N,N NN ',N ,N
N\ N\
1 HN/"'----1 \\ , __ > / >\ __ N )\ N N N
N
N N , 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 N,,CO2H -,._õ..--.--.., ,CO2Me N=N , CO2Me 1\1" N , The , The H
N
N ,N'-,1\1 N C)r--- / c I ---I 1\1 N
0-- \ __________ -::
-- Br''' -, H H
1\1- \ \
1\1õ.
r,_ HN"-HN---r: \/ 0 ._-------1N- -- ___ ___-N
N S ;
-N---- --------------- 0 -- \ -- \ -- \
--S-- __________ N \
; CI Br , IJO1, I , S
-- \
, o ; o----- s , , , , F H
S H \ N
S N N
-- \
Br H
N
H S
F ___ ----<\ --F N N
OH ;
.- -------------------------------- u ,, \ --H - ---N N-'N NN
:
, I\L -S -- ,S --fel"! ----N N) \s-i\I s-1--- N's-'-' <\ 11--N \ jrN
'N,--N *- N N---,,1,1 \N
;
S ;
õ--,S - ,S -- H2N
\\ \\ I
N N \ N N I N
.\\ _..
\N \N N N H N
ci\?,),-- N ---0 ; HO, N-0 O'N , or , N --O-N and R6 represents -H, -CH3, -CH(CH3)2, -CH2CH2CH3, -CH2CH=CH2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CH2CH2CH2CH3, -cyclo-C3H3, -cyclo-C3119, -cyclo-C6H11 or -CH2-cyclo-C3H3.
2489-CIPO-DESCRIPTION-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 9. The compound according to claim 1 selected from the group consisting of:
Compound Name 11-2: (S)-2-(benzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-3: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-4: (S)-2-(3-chlorobenzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-5: (S)-2-(4-bromobenzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-6: (S)-2-(4-bromobenzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-7: (S)-2-(benzo[b]thiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-8: (S)-2-(5-bromobenzo[b]thiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-9: (S)-2-(1H-indole-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-10: (S)-2-(4,5-difluoro-1H-indole-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-11: (S)-N1-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methy1-1H-indole-2-carboxamido)-5-oxohexanediamide 11-12: (S)-2-(1H-benzo[d]imidazole-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-13: (S)-2-(2,3-dihydro-1H-indene-2-carboxam ido)-N 1414242-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediam ide 11-14: (S)--(2-bromo-4-methylthiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 methyl-5-oxohexanediamide 11-15: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(4-methy1-2-(trifluoromethyl)thiazole-5-carboxamido)-5-oxohexanediamide 11-16: (S)-2-(4-bromo-2-(trifluoromethyl)thiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-17: (S)-2-(2,4-dichlorothiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-18: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(2-methoxy-4-methylthiazole-5-carboxamido)-N6-methy1-5-oxohexanediamide 11-19: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(4-methy1-2-phenylthiazole-5-carboxamido)-5-oxohexanediamide 11-20: (S)-2-(2,4-dimethylthiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-21: (S)-2-(5-bromo-3-methylthiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-22: (S)-2-(3,5-dibromothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-23: (S)-2-(5-bromothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-24: (S)-2-(5-chlorothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-25: (S)-2-(5-bromo-3-methylfuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-26: (S)-2-(5-chlorofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-27: (S)-2-(5-chlorothiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 methyl-5-oxohexanediamide 11-28: (S)-2-(2,5-dichlorothiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-29: (S)-2-(2,5-dibromothiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-30: (S)-2-(5-bromothiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-31: (S)-2-(2-chloro-5-methylthiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-32: (S)-2-(2,5-dichlorothiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-33: (S)-2-(2,5-dibromothiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-34: (S)-2-(2-bromo-5-methylthiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-35: (S)-2-(2-bromothiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-36: (S)-2-(2-chlorothiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-37: (S)-2-(2,5-dimethylfuran-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-38: (S)-2-(4,5-dimethylthiazole-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-39: (S)-2-(4-bromothiazole-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-40: (S)-2-(4-bromothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 methyl-5-oxohexanediamide 11-41: (S)-2-(4-bromo-3-methylthiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-42: (S)-2-(3-bromothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-43: (S)-2-(3-chloro-4-methylthiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-44: (S)-2-(4-bromo-5-chlorothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-45: (S)-2-(4,5-dibromothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-46: (S)-2-(4,5-dibromo-3-methoxythiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-47: (S)-2-(4-bromofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-48: (S)-2-(4,5-dibromofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-49: (S)-2-(4,5-dichlorothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-50: (S)-2-((S)-1-acetylpyrrolidine-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-51: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-1,2,3-triazole-5-carboxamido)-5-oxohexanediamide 11-52: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(2H-tetrazole-5-carboxamido)hexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-53: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(pyrazine-2-carboxamido)hexanediamide 11-54: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-24(S)-1-methylpyrrolidine-2-carboxamido)-5-oxohexanediamide 11-55: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-24(S)-pyrrolidine-3-carboxamido)hexanediamide 11-56: (S)-2-((2S,4S)-4-bromopyrrolidine-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-58: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-24(S)-piperidine-2-carboxamido)hexanediamide 11-59: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-24(R)-piperidine-3-carboxamido)hexanediamide 11-60: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-24(R)-morpholine-3-carboxamido)-5-oxohexanediamide 11-61: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(quinuclidine-3-carboxamido)hexanediamide 11-62: (S)-methyl 3-(1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-ylcarbamoy1)-5-nitrobenzoate 11-63: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(5-nitronicotinamido)-5-oxohexanediamide 11-64: (S)-5-(1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinic acid 11-65: (S)-methyl 5-(1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinate 11-66: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(6-methylimidazo[2,1-b]thiazole-5-carboxamido)-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-67: (S)-N1-(1-(2-(2-adamantyl(methyl)am ino)-2-oxoethyl)-2-oxo-1,2-dihyd ropyridin-3-y1)-N6-methyl-2-(3-methylbenzofu ran-2-carboxam ido)-5-oxohexanediam ide 11-68: (S)-N1-(1-(2-(5-hyd roxyadam antane-2-am i no)-2-oxoethyl)-2-oxo-1,2-di hyd ropyrid in-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxam ido)-5-oxohexanediam ide 11-69: (S)-N1-(1-(2-(5-fluoroadamantane-2-am ino)-2-oxoethyl)-2-oxo-1,2-dihyd ropyridin-3-y1)-N6-methy1-2-(3-methylbenzofu ran-2-carboxam ido)-5-oxohexanediam ide 11-70: (S)-N1-(1-(2-(5-chloroadamantane-2-am ino)-2-oxoethyl)-2-oxo-1,2-dihyd ropyridin-3-y1)-N6-methy1-2-(3-methylbenzofu ran-2-carboxam ido)-5-oxohexanediam ide 11-71: (S)-N1-(1-(2-(5-bromoadamantane-2-am ino)-2-oxoethyl)-2-oxo-1,2-dihyd ropyridin-3-y1)-N6-methy1-2-(3-methylbenzofu ran-2-carboxam ido)-5-oxohexanediam ide 11-72: (S)-N1-(1-(2-(5-methyladamantane-2-am ino)-2-oxoethyl)-2-oxo-1,2-dihyd ropyridin-3-y1)-N6-methy1-2-(3-methylbenzofu ran-2-carboxam ido)-5-oxohexanediam ide 11-73: (S)-N1-(1-(2-(2-carbonitrileadamantane-2-am ino)-2-oxoethyl)-2-oxo-1,2-di hyd ropyrid in-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxam ido)-5-oxohexanediam ide 11-74: (S)-N1-(1-(2-(2-methyl ad am antane-2-carboxylate-2-am ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediam ide 11-87: (S)-N1-(1-(2-(1-adamantylmethylam ino)-2-oxoethyl)-2-oxo-1,2-dihyd ropyridin-3-y1)-N6-methy1-2-(3-methylbenzofu ran-2-carboxam ido)-5-oxohexanediam ide 11-88: (S)-N1-(1-(2-(1-(1-adamantyl)ethanamino)-2-oxoethyl )-2-oxo-1,2-dihyd ropyridin-3-y1)-N6-methy1-2-(3-methylbenzofu ran-2-carboxam ido)-5-oxohexanediam ide 11-90: (S)-N1-(1-(2-((1R,2S,4S)-bicyclo[2.2.1]heptan-2-ylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediam ide 11-92: (S)-N1-methy1-5-(3-methylbenzofuran-2-carboxam ido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1S ,2S,4R)-1,7,7-trimethyl bicyclo[2 .2.11 heptan-2-ylam ino)ethyl)-1,2-di hydropyrid in-3-yl)hexanediam ide 11-94: (S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediam ide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-95: (S)-N1-(1-(2-(bicyclo[2.2.1]heptan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-dihyd ropyridin-3-y1)-N6-methyl-2-(3-methylbenzofu ran-2-carboxam ido)-5-oxohexanediam ide 11-96: (S)-N1-(1-(2-(bicyclo[2.2.1]heptan-7-ylam ino)-2-oxoethyl)-2-oxo-1,2-dihyd ropyridin-3-y1)-N6-methy1-2-(3-methylbenzofu ran-2-carboxam ido)-5-oxohexanediam ide 11-97: (S)-N1-(1-(2-(bicyclo[2.2.1]hept-5-en-2-ylam ino)-2-oxoethyl)-2-oxo-1,2-di hyd ropyrid in-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxam ido)-5-oxohexanediam ide 11-98: (2S)-N1-(1-(2-(bicyclo[2.2.2]octan-2-ylam ino)-2-oxoethyl)-2-oxo-1,2-dihyd ropyrid in-3-y1)-N6-methyl-2-(3-methylbenzofu ran-2-carboxam ido)-5-oxohexanediam ide 11-99: (S)-N1-methy1-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-y1)hexanediamide 11-100: (S)-N1-methy1-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide 11-101: (S)-N1-methy1-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide 11-103: (S)-N1-(1-(2-(4-homoisotwistane-3-am ino)-2-oxoethyl )-2-oxo-1,2-dihyd ropyrid in-3-y1)-N6-methyl-2-(3-methylbenzofu ran-2-carboxam ido)-5-oxohexanediamide 11-104: (S)-N1-(1-(2-(d iamantane-1-am i no)-2-oxoethyl)-2-oxo-1,2-dihyd ropyrid in-3-y1)-N6-methyl-2-(3-methylbenzofu ran-2-carboxam ido)-5-oxohexanediam ide 11-105: (S)-N1-(1-(2-(d iamantane-4-am i no)-2-oxoethyl)-2-oxo-1,2-dihyd ropyrid in-3-y1)-N6-methyl-2-(3-methylbenzofu ran-2-carboxam ido)-5-oxohexanediam ide 11-107: (S)-N1-(1-(1-adamantylmethyl)-2-oxo-1,2-d ihydropyrid in-3-y1)-methyl-2-(3-methyl benzofu ran-2-carboxam ido)-5-oxohexaned jam ide 11-108: (2S)-N1-(14(3-hydroxy-1-adamantyl)methyl)-2-oxo-1 ,2-dihyd ropyrid in-3-y1)-N6-methyl-2-(3-methylbenzofu ran-2-carboxam ido)-5-oxohexanediam ide 11-109: (2S)-N1-(14(3-bromo-1-adamantyl)methyl)-2-oxo-1 ,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-110: (S)-N1-(1-(2-adamantylmethyl)-2-oxo-1,2-d ihydropyrid in-3-y1)-methyl-2-(3-methyl benzofu ran-2-carboxam ido)-5-oxohexaned jam ide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-111: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(nicotinamido)-5-oxohexanediamide 11-112: (S)-2-(isonicotinamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 0-113: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(pyridazine-4-carboxamido)hexanediamide 11-114: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(pyridazine-3-carboxamido)hexanediamide 11-115: (S)-N1-cyclopropyl-N6-(1-(2-(2-adamantylamino)-2-oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)-5-(3-methylbenzofuran-2-carboxamido)-2-oxohexanediamide 11-116: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)-2-(3-methylbenzofuran-2-carboxamido)-5-oxo-N6-pentylhexanediamide 11-117: (S)-N1-allyl-N6-(1-(2-(2-adamantylamino)-2-oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)-5-(3-methylbenzofuran-2-carboxamido)-2-oxohexanediamide 11-115: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-119: (S)-N1-ally1-5-(benzofuran-2-carboxamido)-N6-(1-(2-(2-adamantylamino)-2-oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxohexanediamide 11-120: (S)-2-(benzofuran-2-carboxamido)-N6-isopropyl-N1-(1-(2-(2-adamantylamino)-2-oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide 11-121: (S)-2-(benzofuran-2-carboxamido)-N6-cyclopropyl-N1-(1-(2-(2-adamantylamino)-2-oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide 11-122: (S)-2-(benzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxo-N6-phenylhexanediamide 11-123: (S)-2-(benzofuran-2-carboxamido)-N6-benzyl-N1-(1-(2-(2-adamantylamino)-2-oxoethy1)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide 11-124: (S)-2-(benzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 8-125: (S)-2-(2,5-dichlorothiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide 11-126: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(4-methy1-2-(trifluoromethyl)thiazole-5-carboxamido)-5-oxohexanediamide 8-127: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(1-methy1-1H-1,2,3-triazole-5-carboxamido)-5-oxohexanediamide 8-128: (2S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridi n-3-y1 )-2-(2,5-d ich broth iophene-3-carboxam ido)-N6-methyl-5-oxohexanediamide 11-129: (2S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(4-methyl-2-(trifluoromethyl)thiazole-5-carboxamido)-5-oxohexanediamide 8-130: (2S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridi n-3-y1)-N6-methy1-2-(1-methy1-1H-1,2 ,3-triazole-5-carboxam ido)-5-oxohexanediam ide 8-131: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(2H-1,2,3-triazole-4-carboxamido)hexanediamide 11-132: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1H-1,2,3-triazole-4-carboxamido)hexanediamide 8-133: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-1,2,3-triazole-4-carboxamido)-5-oxohexanediamide 8-134: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1H-1,2,4-triazole-3-carboxamido)hexanediamide 8-135: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-1,2,4-triazole-3-carboxamido)-5-oxohexanediamide 8-136: (S)-2-(benzofuran-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 8-137: (S)-2-(benzo[b]thiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 (S)-N1-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-11-138 dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-pyrazole-3-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-11-139 dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-pyrazole-4-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-11-140 dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-pyrazole-5-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-11-141 dihydropyridin-3-y1)-N6-methy1-2-(4-methy1-1,2,3-thiadiazole-5-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-11-142 dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1,2,5-thiadiazole-3-carboxamido)hexanediamide (S)-2-(4-iodo-1-methy1-1H-pyrazole-5-carboxam ido)-N1-(1-(2-(2-11-143 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide (S)-N1-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-11-144 dihydropyridin-3-y1)-2-(1-methy1-1H-pyrazole-5-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-II-145 dihyd ropyridin-3-y1)-2-(4-methy1-1,2,3-thi ad iazole-5-carboxam ido)-5-oxohexanediam ide (S)-2-(benzofuran-2-carboxam ido)-N1-(1-(2-((1R,2R,4S)-11-146 bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide (S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylam ino)-2-11-147 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(3-methylbenzofuran-carboxamido)-5-oxohexanediamide (S)-2-(benzofuran-2-carboxam ido)-N1-(1-(2-((1S ,2R,4R)-11-148 bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide (S)-N1-(1-(2-((1S,2R,4R)-b icyclo[2.2.1]heptan-2-ylam ino)-2-II-149 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(3-methylbenzofuran-carboxamido)-5-oxohexanediamide (S)-2-(benzofuran-2-carboxam ido)-5-oxo-N1-(2-oxo-1-(2-oxo-2-11-150 ((1R,25,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 (S)-2-(3-methylbenzofuran-2-carboxam ido)-5-oxo-N1-(2-oxo-1-(2-11-151 oxo-2-((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-y1)hexanediamide (S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylam ino)-2-11-152 oxoethyl)-2-oxo-1,2-dihydropyridi n-3-y1)-N6-methyl-2-(4-methyl-1,2 ,3-thiadiazole-5-carboxam ido)-5-oxohexaned iam ide (S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylam ino)-2-11-153 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-pyrazole-5-carboxamido)-5-oxohexanediamide (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylam ino)-2-11-154 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(4-methy1-(trifluoromethyl)thiazole-5-carboxamido)-5-oxohexanediamide (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylam ino)-2-11-155 oxoethyl)-2-oxo-1,2-dihydropyridi n-3-y1 )-2-(2,5-d ich broth iophene-3-carboxam ido)-N6-methyl-5-oxohexanediam ide (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylam ino)-2-11-156 oxoethyl)-2-oxo-1,2-dihydropyridi n-3-y1)-N6-methyl-2-(4-methyl-1,2 ,3-thiadiazole-5-carboxam ido)-5-oxohexaned iam ide (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylam ino)-2-11-157 oxoethyl)-2-oxo-1,2-dihydropyridi n-3-y1)-N6-methy1-2-(1-methy1-1H-1,2 ,3-triazole-5-carboxam ido)-5-oxohexaned iam ide (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylam ino)-2-11-158 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-pyrazole-5-carboxamido)-5-oxohexanediamide (S)-N1-methy1-5-(4-methy1-2-(trifl uoromethyl)thiazole-5-11159 carboxam ido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1R,2S,4R)-1,7,7--trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide (S)-2-(2,5-dich lorothiophene-3-carboxam ido)-N6-methy1-5-oxo-N1-11-160 (2-oxo-1-(2-oxo-2-((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide (S)-N1-methy1-5-(4-methy1-1,2 ,3-th iadiazole-5-carboxam ido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1R,2S,4R)-1,7,7-11-161 trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide (S)-N1-methy1-5-(1-methy1-1H-1,2,3-triazole-5-carboxam ido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1R,2S,4R)-1,7,7-11-162 trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide (S)-N1-methy1-5-(1-methy1-1H-pyrazole-5-carboxam ido)-2-oxo-N6-11-163 (2-oxo-1-(2-oxo-2-((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 (2S)-2-(4-tert-butyl-1H-pyrrole-3-carboxam ido)-N6-methyl-N1-(1-(2-11-164 (1-adamantylamino)ethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide (2S)-2-(4-cyano-1-methyl-1H-pyrrole-2-carboxam ido)-N6-methyl-N1-11-165 (1-(3-(1-adamantylamino)propy1)-2-oxo-1,2-dihydropyridin-3-y1)-oxohexanediamide (S)-N1-(1-(3-(2-adamantylam ino)-3-oxopropy1)-2-oxo-1,2-11-166 dihydropyridin-3-y1)-2-(5-methoxyoxazole-2-carboxamido)-N6-methy1-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-167 dihyd ropyridin-3-y1)-N6-methyl-2-(3-methylbenzofu ran-2-carboxam ido)-5-oxohexanediam ide (S)-2-(2-acetyloxazole-4-carboxam ido)-N1-(1-(2-11-168 (bicyclo[1.1.11pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-169 dihyd ropyridin-3-y1)-N6-methyl-2-(3-methylbenzofu ran-2-carboxam ido)-5-oxohexanediam ide (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-170 dihydropyridin-3-y1)-2-(2-isopropyloxazole-5-carboxamido)-N6-methy1-5-oxohexanediamide (2S)-2-(benzofuran-2-carboxam ido)-N1-(1-(2-(bicyclo[3.2.1]octan-8-11-171 ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-oxohexanediamide (2S)-N1-(1-(2-(bicyclo[3.2.1]octan-8-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-172 dihydropyridin-3-y1)-2-(3,5-dimethylisoxazole-4-carboxamido)-methy1-5-oxohexanediamide (S)-N1-(1-(2-(5-carboxy-2-am inoadam anta ne)-2-oxoethyl)-2-oxo-11-173 1,2-di hyd ropyrid in-3-y1)-N6-methyl-2-(4-methylpyrim idi ne-carboxam ido)-5-oxohexanediam ide (2S)-N1-(1-(2-(4-am i noadamantane-N ,N-dimethy1-1-carboxam ide)-2-11-174 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1,2,3,4-tetrahydronaphthalene-2-carboxamido)hexanediamide (S)-2-((S)-1,4-diazabicyclo[2.2.2]octane-2-carboxam ido)-N6-tert-11-175 butyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide (S)-N1-tert-buty1-5-(1H-indole-3-carboxam ido)-N6-(1-(2-(2-11-176 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 (S)-N1-tert-butyl-N6-(1-(2-(2-adam antylam i no)-2-oxoethyl)-2-oxo-11-177 1,2-di hyd ropyrid in-3-y1)-5-(6-methylim idazo[2,1-b]th iazole-3-carboxam ido)-2-oxohexanediam ide (S)-2-(benzo[d]thiazole-2-carboxam ido)-N1-(1-(2-((1S,2R,4R)-11-178 bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-cyclopenty1-5-oxohexanediamide (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylam ino)-2-11-179 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-cyclopenty1-2-(imidazo[2,1-13]thiazole-6-carboxamido)-5-oxohexanediamide (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylam ino)-2-11180 oxoethyl)-2-oxo-1,2-di hydro pyridi n-3-y1)-N6-cyclo penty1-2-(4--hydroxy-6-(trifluoromethoxy)quinoline-3-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-181 dihydropyridin-3-y1)-2-(cinnoline-3-carboxamido)-N6-cyclohexy1-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-182 dihydropyridin-3-y1)-N6-cyclohexy1-2-(3-ethylbenzofuran-2-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-183 dihydropyridin-3-y1)-N6-cyclohexy1-2-(1-ethy1-1H-indole-2-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-194 dihydropyridin-3-y1)-N6-cyclohexy1-2-(2-methy1-1,8-naphthyridine-3-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-185 dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1,2,3,4-tetrahydroquinoline-6-carboxamido)hexanediamide (S)-N1-(1-(2-(2-carboxy-2-am ino-5-(trifluoromethyl)adamantane)-2-11-186 oxoethyl)-2-oxo-1,2-dihydropyridi n-3-y1)-N6-methy1-5-oxo-2-(3-oxo-1,2 ,3,4-tetrahyd roisoqui noline-6-carboxam ido)hexanediamide (S)-N1-(1-(2-(5-ethyladamantane-2-am ino)-2-oxoethyl)-2-oxo-1,2-11-187 dihydropyridin-3-y1)-N6-methy1-2-(1,6-naphthyridine-2-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-188 dihydropyridin-3-y1)-N6-methy1-2-(2,6-naphthyridine-1-carboxamido)-5-oxohexanediamide (S)-2-(4-am ino-1,2,5-oxadiazole-3-carboxamido)-N1-(1-(2-11-189 (bicyclo[1.1.11pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-11-190 dihydropyridin-3-y1)-2-(6-(dimethylamino)benzofuran-2-carboxamido)-N6-methy1-5-oxohexanediamide (S)-2-(2-acetamidothiazole-5-carboxamido)-N1-(1-(2-11-191 (bicyclo[1.1.11pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide (S)-N4-(1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-11-192 1,2-dihydropyridin-3-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-y1)-1H-pyrrole-2,4-dicarboxamide (S)-N1-(1-(2-(1-acetylamino-4-aminoadamantane)-2-oxoethyl)-2-11-193 oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(5-sulfamoylfuran-3-carboxamido)hexanediamide (S)-2-(benzofuran-5-carboxamido)-N1-(1-(2-(1-acetylamino-4-11-194 aminoadamantane)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide (S)-2-(benzofuran-6-carboxamido)-N1-(1-(2-(4-aminoadamantane-1-11-195 carboxamide)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide (S)-N1-(1-(2-(4-aminoadamantane-1-carboxamide)-2-oxoethyl)-2-11-196 oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-(1-methylcyclopropy1)-1,2,4-oxadiazole-5-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-11-197 dihydropyridin-3-y1)-N6-methy1-2-(5-methy1-1,2,4-oxadiazole-3-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-11-198 dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1,2,3-thiadiazole-4-carboxamido)hexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-11-199 dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1,2,4-thiadiazole-5-carboxamido)hexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-11-200 dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1,3,4-thiadiazole-2-carboxamido)hexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-11-201 dihydropyridin-3-y1)-2-(4-cyclopropy1-1,2,3-thiadiazole-5-carboxamido)-N6-methy1-5-oxohexanediamide (S)-2-(4-cyclopropy1-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-11-202 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 (S)-2-(4-isopropyl-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-11-203 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide (S)-2-(4-ethyl-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-11-204 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide (S)-2-(4-formy1-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-11-205 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide (S)-2-(4-(hydroxymethyl)-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-11-206 (2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide (S)-N1-(1-(2-(1-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-11-207 y1)-N6-methy1-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(((1 6,2R,56)-6,6-dimethylbicyclo[3.1.1]heptan-2-11-208 yl)methylamino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methyl-1 H-imidazole-2-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(((1 R,2R,5R)-6,6-dimethylbicyclo[3.1.1]heptan-2-11-209 yl)methylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(1H-imidazole-4-carboxamido)-N6-methyl-5-oxohexanediamide (S)-N1-(1-(2-(3,5-dimethyladamantane-l-amino)-2-oxoethyl)-2-oxo-1,2-11-210 dihydropyridin-3-y1)-N6-methy1-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(3,5,7-trimethy1-1-adamantylamino)-2-oxoethyl)-2-oxo-1,2-11-211 dihydropyridin-3-y1)-N6-methy1-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising a compound of any one of the claims 1 ¨ 9 as an active ingredient, together with at least one pharmaceutically acceptable carrier, excipient and/or diluent.
11. Compound according to any one of the claims 1 ¨ 9 for use in medicine.
12. Compound according to any one of the claims 1 ¨ 9 or the pharmaceutical composition according to claim 9 for use in the treatment or prophylaxis of autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, ocular diseases, and skin disorders.
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 13. Compound for use, or the pharmaceutical composition for use according to claim 12, wherein the autoimmune and inflammatory diseases comprise multiple sclerosis, celiac disease, Duhring-Brocq-disease (dermatitis herpetiformis), gluten ataxia, gluten neuropathy, diabetes, rheumatoid arthritis, Graves' disease, inflammatory bowel disease, systemic lupus erythematosus psoriasis, and gingivitis; wherein the vascular diseases comprise atherosclerosis, thrombosis, vascular stiffness;
wherein the fibrotic diseases affect the lung, the kidney, the liver, the skin or the gut like cystic fibrosis, kidney fibrosis and diabetic nephropathy, intestinal fibrosis, idiopathic lung fibrosis, liver fibrosis; wherein the liver diseases comprise alcoholic hepatitis, alcoholic steatohepatitis, nonalcoholic steatohepatitis, non-alcoholic fatty liver disease, liver cirrhosis, autoimmune hepatitis or liver inflammation; wherein the cholestatic liver diseases comprise primary biliary cholangitis and primary sclerosing cholangitis; wherein the cancer comprises glioblastoma, melanoma, pancreatic cancer, renal cell carcinoma, meningioma, and breast cancer, wherein the neurodegenerative diseases comprise Parkinson's disease, Huntington's disease, or Alzheimer's disease, wherein the ocular diseases comprise glaucoma, cataracts, macular degeneration, or uveitis; and wherein the skin disorders comprise acne, psoriasis, scarring, and skin aging.
14. Compound for use, or the pharmaceutical composition for use according to any one of the claims 12 and 13 in the treatment or prophylaxis of celiac disease.
15. A method for producing the compound of formula (lb) according to claim 1 or 3 comprising:
Step 1B: providing a compound 4b Ac0)-LN -R6 ' H 0 4b;
Step 2B: performing coupling reaction of the compound 4b with a compound 5 H2N)-L L
, N- 'R3 to obtain a compound 6b 2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 Ac0 , R6 PG3Ni\O- _L.
N R-6b;
Step 3B: deprotecting an amino protecting group PG3to obtain a compound 7b Ac0)-L , R6 N 'R-7b;
Step 4B: performing coupling reaction of the compound 7b with a carboxylic acid (R2-CO2H 8) to obtain a compound 9b Ac0 , R6 R2A N ,L.
N R-9b;
Step 5B: performing oxidation reaction of the compound 9b to produce the compound of the formula (lb) N
(1b);
wherein L, R2, R3, R6 and R7 have the same meanings as defined in claim 1, and PG3 is an amino protecting group.
2489-CIPO-DESCRIPTION-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 Inhibitors of Transglutaminases Description The invention relates to novel inhibitors of transglutaminases, in particular transglutaminase 2, methods for their synthesis and to their use for the prophylaxis and treatment of diseases associated with transglutaminases, in particular transglutaminase 2.
Background of the invention Transglutaminases are part of the class of transferases and according to EC
nomenclature they are correctly designated as "protein-glutamine: amine y-glutamyl transferases" (EC 2.3.2.13). They link the E-amino group of the amino acid lysine and the y-glutamyl group of the amino acid glutamine forming an isopeptide bond while ammonia is released. In the absence of suitable amines and/or under certain conditions, deamidation of the glutamine may occur resulting in the corresponding glutamic acid.
Additionally, transglutaminases play an important role in many therapeutic areas such as the cardiovascular diseases (thrombosis and atherosclerosis), autoimmune diseases (celiac disease, Duhring-Brocq-disease, gluten ataxia), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease), dermatological diseases (ichthyosis, psoriasis, acne) as well as in wound healing and inflammatory diseases (e.g. tissue fibrosis) (J.M. Wodzinska, Mini-Reviews in medical chemistry, 2005, 5, 279 - 292).
Celiac disease, a gluten intolerance, however, is one of the most important indications.
Celiac disease is characterized by a chronic inflammation of the mucosa of the small intestine. In susceptible patients, the intestinal epithelium is successively destroyed after ingestion of gluten-containing food resulting in reduced absorption of nutrients which again has massive impact on the patients affected and is for example associated with symptoms such as loss of weight, anemia, diarrhea, nausea, vomiting, loss of appetite and fatigue. Due to these findings, there is a large demand for the development of a medicament for the treatment of celiac disease as well as of other diseases associated with tissue transglutaminase (transglutaminase 2, TG2, tTG).
The tissue transglutaminase is a central element during pathogenesis. The endogenous enzyme catalyses the deamidation of gluten/gliadin in the small intestinal mucosa and thus triggers the inflammatory response. Therefore inhibitors of tissue transglutaminase are suitable to be used as active agents for medication.
Another very important group of indications for tissue transglutaminase inhibitors are fibrotic disorders. Fibrotic disorders are characterized by the accumulation of cross-2489-CIPO-DESCRIPTION-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 linked extracellular matrix proteins. Diabetic nephropathy, cystic fibrosis, idiopathic pulmonary fibrosis, kidney fibrosis as well as liver fibrosis belong to the most important fibrotic disorders to be addressed with the compounds disclosed.
US 9,434,763 B2 discloses pyridinone derivatives having a warhead comprising at least one acceptor-substituted double bond, such as a Michael System, as irreversible transglutaminase inhibitors. Alkylacetamido and arylacetamido pyridinones showed inhibitory activity regarding tissue transglutaminase TG2 in nanomolar range (IC50).
Tse et al. (J. Med. Chem. 2020, 63, 11585-11601) report on replacement of phenyl residues by non-classical bioisosteres, such as cubane and bicyclo[1.1.1]pentane (BCP), in anti-malarial triazolopyrazine compounds in order to alter compound solubility and metabolic stability. The authors further evaluated in vitro antiplasmodial activity of bioisosteric modified triazolopyrazines against the 3D7 strain of P.
falciparum.
Replacement of phenyl by bioisosteric saturated heterocyclic residues resulted in complete loss of activity. Adamantyl residues as well as other hydrocarbon-caged derivatives led to potency up to 2-9 times lower than the corresponding phenyl triazolopyrazine compounds. In contrast, higher potencies were achieved by replacing phenyl with closo-1,2- and 1,7-carborane isomers. The authors concluded that the effect of non classical bioiostere replacement on biological properties cannot be predicted accurately and that a considerable range of possible bioisosteres has to be tested first in order to identify a suitable replacement leading to the desired properties of a given molecule.
Subbaiah et al. (J. Med. Chem. 2021, 64, 19, 14046-14128) report on bioisosteres of the phenyl ring in lead optimization and drug design. It is noted that bioisosteric phenyl ring replacement with heterocyclic and carbocyclic moieties can lead to enhanced potency, solubility, and metabolic stability while reducing lipophilicity, plasma protein binding, phospholipidosis potential, and inhibition of cytochrome P450 enzymes and the hERG
channel. However, this effect depends strongly on the properties of the compound itself and the addressed target.
US 11,072,634 B2 discloses reversible transglutaminase inhibitors comprising an aldehyde, a ketone, an a-ketoaldehyde, an a-ketoketone, an a-ketoacid, an a-ketoester, an a-ketoamide or a halogenmethylketone as warhead. The inhibitors showed inhibitory activity regarding tissue transglutaminase TG2 in nanomolar and micromolar range (IC50).
The objective of the present invention is to provide novel, most probably irreversible inhibitors of transglutaminases, in particular transglutaminase 2 and methods for the synthesis of said inhibitors as well as several uses of these inhibitors.
2489-CIPO-DESCRIPTION-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 Said objective is solved by the technical teachings of the independent claims.
Further advantageous embodiments, aspects and details of the invention are evident from the dependent claims, the description, and the examples.
Surprisingly, it has been found that irreversible inhibitors having a chemical warhead as disclosed herein inhibit effectively transglutaminases including tissue transglutaminase called transglutaminase 2 or TG2. Herein these terms are used synonymous.
Preferably, such chemical warhead moiety is particularly selected from irreversible warheads such as a,R-unsaturated-ketoester, a,R-unsaturated ketoamide and a,R-unsaturated-sulfone. The compounds of the present invention act as selective inhibitors of transglutaminase 2.
Thus, the present invention relates to compounds of the general formula (I):
C
(I) NH 7I-R3 Ho wherein L represents ¨L1¨ or ¨L1-L2¨; preferably ¨L1-L2¨;
L1 represents ¨CH2¨, ¨CH2CH2¨, ¨CH2CH2CH2¨, ¨CH2C0¨, or ¨CH2CH2C0¨;
L2 represents a bond, ¨NRI41¨, ¨NRN1CH2¨, ¨NRN1CH2CH2¨, or ¨NRN1CH(CH3)¨, 0 0õ0 R1 represents or ,,-)Sl,R4 .
R2 represents RN RN
_O R8 Ril 0 R8 _ _ _S R8 __ IR11 S R8 - _ _.$-Ii.,(R8 Rii \i, r , r ,\ r r , ,R8 , RN RN RN RN RN
R11 N , R1i 1 \ N -, N, RN RN
Rii lj R8 I R
/ l( - I --- - -¨
N
N
Rio µ, ; ' R9 Rio R9 ; Rio R10 ;
w0 R1,1 S
R , i 0, iv 0 R8 -___,,ON R8 _--\ ir --1--- \ ir ? 9 R8 1' 13 Rio N N N N 'N Rio R8 N¨ ' R8 Rio 2489-CIPO-DESCRIPTION-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 RN RN RN
N
R11,S, _R8 --1S\¨R8 ----- ', N N N R11 __ N D10 R10 N_RN
--\\ /7--- ____ , N ,N NQ--1` TC=N
,) ' RiO , , R10 , , ' , , N r", 0,, (11R9 LI
----------------------------------------------------------------- ¨R=-N-N NN - \____,-----Rio ------ R14 N R14 N R14 , RN
R12 N R12 0- 13 S/ 13 i\i I , N/-) Ri3 r Ri 3 - TR - - -R - - Dp13 -., N R14 N R14 Rlo R14 R14 Rio Rlo R14 , ' pp12 pp12 RN
R13 I 7rN_ ), N N R14 , R9 ¨ I 1 R13 r /1 N---\-R14R14 R14 00._ in Fµ N __ S __ _R10 RN R8 R8 ,S,--R9 ,S,-' II
NI S)--- r\i"---N
r /I
R1 0 &/--, R1 0 No j( N Ro \s--N \N-_---N Ro . N , - . N, - 0 R8--\- <SM-Ii -- N-. Ru-- '/ . R ---- il - - --N-N , b-N , N-0 , 0-N N
' , , H
N 0 S s , N , , , , , , , , _N _, ---eNNH ---eNNH N
---\ -13 ---eNS
N( NN - N N __ \( S S z S S y N
---eNNH
N( N, NNJ\ N __ ( N _ N ----eN0 ---eN0 ----(1\1 --(,N3 ----eN0 N __ \( II
6 y N , Ni vlo , N NN
, , , H
N,S N
, , S,--N
s N
H
2489-CIPO-DESCRIPTION-ZED-P04404W026.docx Date Recue/Date Received 2022-06-30 O W
Fri 6 X o o , , ,, , , , , 1 o , ' , 1 , , , ' c c, Z_ CD 2 /_ ___________________________ Z= Z_ Z) /_ n) H
/z \ /z z z(\ z $ /z $ / \ / Z/z rp' 2 \ __ /K \ /( CD m Z Z S Z \ , Z Z S Z Z
Z / Z Z Z
_ Z / Z \ // \ i Z / \ ___________ // \ Z Z /
__ µZµ / _ // -C) . .'10 , --CD
o_ R
N) c) N) p , N) ..
a) i 1 07C 2z3 , , , / , Z z ' ' z/ z z/ Z Z=Z ¨Z z/¨Z z=z Z_ z/
/¨
, ________________ 0 \ ____ /( \ /( /K \ _____ /( \ / / \
\ z z z /K \ / \
.4,.
Z Z Z Z Z
// Z-Z
_ -e0 e(:) 6 z( N Z
, , , , , ' ' , ,' -Z=z Z=z _ ________________________________________ /_ Z= Z /
_____________________ /_ Z= Z_ Z \ / \ / \ /
\ .Z Z. .Z \ .Z \ / Z\ / Z\
\
\_ \ S \ S Z Z \ Z \ Z \ / Z / \ Z \ S Z / \ Z
\ /
Z / // Z¨// Z¨// Z ' ' \ __ // Z
Z Z¨// Z 1 1 _ ________________________________________________________ Z Z
\ cZN
--,,N
Nle , Nie , N.N
, I\IN -,,N,N
'N
IV , N, , N. -, I\1 -,,I\I
'Nil N,2 N N N--N
, , , N N , 1\1-N1-, NN
, -' '-lr"N
N,N
N-, N I
1\1-N N , N N N
I I I
NN
, NN--N NN-,N
-,,N,N
I I
N. NN N N
el\I
, H
NH
HN NH , , ., N NH , HN , NH H , , N=\ 0 N=N N=\ N---N
\ N
N- N- N- -N -N
--- ;IV - ---- / N \ JV
N' N
-- __ N \
\ //IV
N, /
___________________________________ , _______ ' N ______________________ , --\ /,\N
-\
I\1 , --\ N --\ N -- N =
N
N IV N/ //
, 2489-CIPO-DESCRIPTION-ZED-P04404W026.docx Date Recue/Date Received 2022-06-30 N=\ N=\
--- /(1\1 \ / N\/ N / N
N
N N¨N 'IV N //N
N=N N=N N=N N=N N=N
' N --, \ ,,N, _________________________________________________________ / N
, , N=\ N=\ N=\ N=\ N---( \ /71; \ S \ N
/ N N N , ' \ _______________________________________________________________ N IV// N //N
N¨N N \
, ---\ N , \ /71; \ S N N , ____ ¨\ ,N N N
' ¨N ¨N _¨N
-- --i ) \ ) \
/
N / N¨N N __ \IV
, _________________________________________________ , ¨\ ___\
-- N ---\ /IV \ N \ S N S
N ; N¨//
N¨N N
* *
N N
Ns\
N / s \ /IV N N
" N \ N N-N
or ; ¨N ; N N¨//
, , , wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 -R14; and RN; and preferably with 1 to 3 of the substituents R11 - R13;
R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl;
diamantyl; or hexamethylenetetraminyl and the afore-mentioned residues optionally contain one or more C=C double bond(s) and/or are optionally substituted by one or more of Ra; Ri3; Rc;
Rd; and Re;
2489-CIPO-DESCRIPTION-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 Ra, Rb, Rc, Rd, and Re represent independently of each other -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C2H5, -CON H2, -CONN CH3, -CON(CH3)2, -CONHC2F15, -CH2CO2H, -CH2CO2CH3, 5 -CH2CO2C2H5, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2F15, -NHCOCH3, -NH COC21-15, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C21-15, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3;
R4 represents -R5, -0R5 or -NR6R7;
R5 represents -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH (CH3)2, -C(CH3)3, -CH2CH2CH2CH2CH3, -CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-051-19, -cyclo-C6H11, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-051-19, -CH2-cyclo-C6H11, -Ph, -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, or -CH2CH2OCH2CH3;
R6 and R7 represent independently of each other -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, 20 -CH2CH(CH3)2, -C(CH3)3, -CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-051-19, -cyclo-C6H11, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-051-19, -CH2-cyclo-C6H11, -Ph, -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2, or -NR6R7 represents - -N - -N - NO
or i\i/ \
\ ______________________________________________________________________ / -, R6, R5, R10, R11, R12, R13, and R14 represent independently of each other -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2F15, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH (CH3)2, -CH (CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2OH, -CH2F, -CHF2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CH F2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -OCH3, -0C21-15, -0C3H7, -OCH (CH3)2, -0C(CH3)3, -0C4H9, -OCHF2, -0CF3, -OCH2CF3, -0C2F5, -OCH2OCH3, -0-cyclo-C3H5, -OCH2-cyclo-C3H5, -0-C2H4-cyclo-C3H5, -CHO, -COC H3, -COC F3, -00C2H5, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -COOK -COOCH3, -CO0C2H5, -CO0C3H7, -COOCH (CH3)2, -COOC(CH3)3, -00C-CH3, -00C-CF3, -00C-C2H5, -00C-C3H7, -00C-CH(CH3)2, -00C-C(CH3)3, -N H2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, 2489-CIPO-DESCRIPTION-ZED-P04404W026.docx Date Recue/Date Received 2022-06-30 DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.
NOTE : Pour les tomes additionels, veuillez contacter le Bureau canadien des brevets JUMBO APPLICATIONS/PATENTS
THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE THAN ONE
VOLUME
NOTE: For additional volumes, please contact the Canadian Patent Office NOM DU FICHIER / FILE NAME:
NOTE POUR LE TOME / VOLUME NOTE:
Claims (15)
H (1) õ...-----.. ,..--(,...N........ L
wherein L represents ¨L1-L2¨;
Ll represents ¨CH2¨, ¨CH2CH2¨, ¨CH2CH2CH2¨, ¨CH2C0¨, or ¨CH2CH2C0¨;
L2 represents a bond, ¨NR141¨, ¨NRN1CH2¨, ¨NRN1CH2CH2¨, or ¨NRN1CH(CH3)¨;
RI represents 0 =
, R2 represents RN
-... 0 i-,8 1 __________ rm D 1 0 8 . ,Il r R -- S R8 1 __________________________________________ r Rti --S R8 -\\ r ,,, __ \ , R8 R10 R9 / __ R9 R1 0 R9 ;
' RN RN RN RN RN
RN
R11 1\1 R8 R11 1\1N , R11 1I\I \1, R11 11 _ _ R -1\1R 8 \ / --14 ---ti 1 / N -----K n ) __ N N
' , R9 R19 ss / R9 R.-4 IR R1c, , RN Rlo Rlo N s Rii c 0 0 pp8 -( õ/?__ Ril,cc0,,,ir R8 - - --Cii.--- . , :
\)(R8 R10 , R10 , , " D10 R8 N¨ , ' , , RN
RN
,µ
pm Dil S _ -11 S Rs -- S R8 - - 11' 11 ri , ,- )7_ rc _ õ,..õ.(c < < ,N R__ ,,N
) ______________________ N )\ __ N )\ __ N
) ________________________________________________________________________ N
N
N R8 Rlo Rlo Rlo , RN RN
,N, RN R12 R12 N,N _R10 i( / R19 ,, \\ ir )N --1 ,N ---ei'N-RN LL, \-) ; N-N ; N=N ; ------ D.14 N R14 "
2489-CIPO-CLAIMS-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 R12 R12 N R12 0---__ 13 'µ R12 R13 N R13 R13 - - -\TR
\- R14 R10_e--- (:)r/R13 R14 N=R14 N=R14 Rio ---\44 N\N , RN
, N---/y,) R1 S---/y,) , R12 ,7R13 R10_<)---r/ -\ R1013 %
% RN
N
Rlo / N--/y,) '-1 /') 13 II 1 +R13 N----- c7R
i RN , Rizi R14 R._A
, R11 ,, RN RN
. R9 (1R9 N, R9 R 0,1 R10_--- N1 14 \1 r /1 Rlo N \J
R10 N _________ S
NS - \____,-----R10 RN Rio , R....9 R9 -_ _Rio in N\
o) 'N. --/--, lo ¨R N----R'" \N R8 \s-N N-_-_N
' , ,S -- F8 N ''' . ,S ,,,-- ,,-,,, -.---N Ru----\ il N6-/ .. R8-----N -/ - R8---e1I-- -- 0 -R8 N-N b-N N-0 0-N N
, , , S
---N, N .__, ---eNNH ---eNNH N
--- - \ j ---eNS
N __________ ( Nj N __ \ - N __ N N __ \( S S z S S y N
----eNS ---eNS ----eNH ---eNNH
IIN, ITij N __ ( 0 01\ij , ..N N _ -- \ -_<N3 ___eN0 ___eNo N N __ \( Z, NJ
o 6 7 , N
N N
, , , H
N----S
\N-1\1- i , , S N ----- ____N
_/ S-____,-\_ ___e----r---\----___N--(/N
S-NN
, , , , H
--A-NI
SN
--"1-.), 2489-CIPO-CLAIMS-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 0-__N _NI
-N
H H
p-...,__N
/
, i ..
N
/ N , , , N -- --'N
-- -, N -N
N /
, ., I -I
, ' -, N -, --'N 'N
N 1\11 N
, , -,,I\I I\1 -,,I\IN
- N
N lie 1 N
, , , ., N
NN I
1\1 1\1 N
, -, -, 1rN 'rNii '-'r N, N NN, , ' N N - N. N
I f , f ' Nn " , NN NN, -,f1\1N
--!
N
Nn," NN N
, -,,NN,N
n, " , Th\l N, 1 , , -,,, ---!NN I\I N -.1\1N
1 1\1 I II
Th\l N , I 1 , f N--N --.. --õ----õ,--,N
N NN, 2489-CIPO-CLAIMS-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 -,,N -,,rN -, N
Nle , Nie , N.N
, I\IN -,,N,N
'N
IV , N
N. -, I\1 -,,I\I
'Nil N,2 N N
N--N
, , , N N , 1\1-N1-, NN
, -' '-lr"N
N,N
1\1-N -,,N '-'-'N
N N , N NN
I I I
N.N
, NN--N NN-,N
-,,N,N
I I
N.NN N N
el\I
, H
NH
HN NH , , ., N NH , H
HN
N=\ 0 N=N N=\ N---N
\ N
N/
, , --- / N \ JV
N _____________________________________________________________ N
/N 1 sN
--- ___________________________________ \
/ N \ //IV
N ______________________________________________ N , ' -- \ )V
\ _/ /N
-\
--i I\1 \ N , ---- =
N IV _______ N/ __ N N
, , 2489-CIPO-CLAIMS-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 N=\ N=\
--- /(1\1 \ / N¨N N / N / N //N
N
N 'IV
N
N=N N=N N=N N=N N=N
' ¨.__ --\ ,,N N /
N
, , ________ , ________________________________ , N=\ N=\ N=\ N=\ N---( \ /71; \ S \ N ¨\ ,N
/ N N N , \
N/ //N N¨N N __ \IV /
, -- \ /1\1 -- /I , --i /N -- \
N
\ /71; \ S ; N ___ , ,N N N
, -- --i ) \ ) \
/
N/ //, N¨N N __ \IV /
______________________________________________ , ¨\ ___\
\ S N S
N ; N¨ N //N
N¨N N
_ ___________ \
* *
Ns /
Ns \ /IV N N
" N, /N ¨N -1\1 N¨N ; N si\l/ , or ______________________ , , wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 ¨ R14 and R" ; and preferably with 1 to 3 of the substituents R11 ¨
R13;
R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl;
diamantyl;
or hexamethylenetetraminyl and the afore-mentioned residues optionally contain one or more C=C double bond(s) and/or are optionally substituted by one or more of Ra; Rb; Rc; Rd; and Re;
2489-CIPO-CLAIMS-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 Ra, Rb, Rc, Rd, and Re represent independently of each other -H, -F, -CI, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C21-15, -CONH2, -CON HCH3, -CON(CH3)2, -CON HC2F1s, -CH2CO2H, -CH2CO2CH3, -CH2CO2C21-15, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2Hs, -NHCOCH3, -NHCOC21-15, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C21-15, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3;
R4 represents -N R6R7;
R6 represents -CH2CH3; and R7 represents -H;
R6, R6, R10, R11, R12, R13, and R14 represent independently of each other -H, -F, -CI, -Br, -1, -OH, -CN, -NO2, -CH3, -C2HS, -C3H7, -CH (CH3)2, -C4H9, -CH2-CH (CH3)2, -CH (CH3)-C2H5, -C(C H3)3, -CyCIO-C3H5, -CH2-CyCIO-C3H5, -CH2F, -CH F2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2OH, -OCH3, -0C21-15, -0C3H7, -OCH(CH3)2, -0C(CH3)3, -0C4H9, -OCH F2, -0CF3, -OC H 2C F3 , -0C2F5, -OCH2OCH3, -0-cyclo-C31-15, -OCH2-cyclo-C3Hs, -0-C2H4-cyclo-C3Hs, -CHO, -COCH3, -COCF3, -00C21-15, -00C3H7, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2Hs, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -00C-CH3, -00C-CF3, -00C-C2Hs, -00C-C3H7, -00C-CH (CH3)2, -00C-C (C H3)3, -NH2, -NHCH3, -NHC21-15, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C21-15)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC21-15, -NHCOC3H7, -NHCOCH(CH3)2, -NHCOC(CH3)3, -CONH2, -CONHCH3, -CONHC21-15, -CONHC3H7, -CON HCH (CH3)2, -CON H-cyclo-C31-15, -CON HC(CH3)3, -CON(CH3)2, -CON (C2E-15)2, -CON (C3H7)2, -CON [CH (CH3)2]2, -CON[C(CH3)3]2, -502N H2 , -SO2NHCH3, -SO2NHC2HS, -SO2NHC3H7, -SO2NHCH(CH3)2, -SO2NH-cyclo-C3Hs, -SO2NHC(CH3)3, -502N(CH3)2, -502N(C2H5)2, -502N(C3H7)2, -502N[CH(CH3)2]2, -502N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C21-15, -NHSO2C3H7, -NHSO2CH (CH3)2, -NHSO2C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -CECH, -CEC-CH3, -CH2-CECH, -Ph, -0-Ph, -0-CH2-Ph, 2489-CIPO-CLAIMS-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 I\1 H
I\1 H
N
- N/N
,K --No ,- , , , , , 1\1 1\1 r N r r / __ \ / __ \ / __ \ __ -N\ / NH --N\ N-or - -N N
\ ________________________________________________________________ / \ =
, , or R8 and R9 or R9 and R1 can form together one of the following five-membered or six-membered rings:
ci --) _-1-d --- -- --- --I\1 ---N -------- '-./ 0 --,% --.% '-, '-.N 'le, __1\1 - --I
'1\1 '1\I or -- -%1\I -or R12 and R13 or R13 and R14 can form together one of the following five-membered or six-membered rings:
,o ,ici 0 - -0 -0 -,ici ,-C) ,__-- _I II - - ,,.--..., _.0,1, -N '-1\1 --./ ---O '-0 H or I - , , RN represents -H, -CH3, -C2F13, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H3, -C(CH3)3, -cyclo-C3H3, -cyclo-C4H7, -cyclo-C31-19, -CH2-cyclo-C3H3, -CH2-cyclo-C4H7, -CH2-cyclo-C3H9, -CH2F, -CHF2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CH F2; -CF12-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3, -00C21-13, -00C3H7, -COCH(CH3)2, -COC(CH3)3, -CO-cyclo-C3H3, -CO-cyclo-C4H7, -CO-cyclo-C31-19, -COOCH 3;
-COOC2H3, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -SO2CH3, -SO2CF3, -SO2C21-13, -502C3H7, -SO2CH(CH3)2, -502-cyclo-C3H3, or -502C(CH3)3;
RN1 represents -H, -CH3, or -CH2CH3;
or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomer, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
2. The compound according to Claim 1, wherein 2489-CIPO-CLAIMS-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 R2 represents RN
- 0 R8 R11 0 Ra _ _ ,_,õ,srR8 Rõs R8 __ ,, R8 , , , , -,, r ( R18 R9 ; / R9 R10 I-C .-,9 ; ' R9 ; ; " ;
RN RN RN RN
R11 N R8 Rli N, R11 N, __<N,N
R11 0, __ Rii 0, p8 / \ _____ /
in K o /7- 1 r--N N
Ro wo s, / R9 R.., iR, Rlo , R10 Rlo , \__ 0, __R8 cl? _ õ R8 )_ _' Rlo R11._<SN___.
RS, _Rs Ir )r 0: 7 __________________ N N N N¨ N
wo R8 N = R-A Rlo , , , RN RN RN
RN
õ1 S w Ra --õ1-m i i N:N
N N
Ni N,Nr_wo \ ,N, N, DN
- - -c\ ,N ---N'"
; R10 ; , ' ,/¨N ; N¨N ; N=N
;
LI N' r , \-) \ N=
-) -'"--- R14 N-R14 N R14 N\R14 N=R14 , RN
i\i ----/A R12 I , pp13 i\i -\- - - - ¨
wo R14 wo R14 Rlo R.-, R14 N' iA
, RN RN
, \ ii R9 ii R9 r >1 S cõ: )...i _ R14 R14 D .... N --\ "7----wo , ' , " in , Rlo ri R9 - ' _ir_-/fRlo r\--/-_, in N,\ I-N -IN
i ,r\i- -/_-- Rlo <:-., 11/41 _R ¨
N \
R8 ,s, - - R8 S)--- N II
R' ,, ,S,------\ il , N./ R
IT- . N,------ -/ --\N=N R8 , N-N , b-N
, N-0 , 0-N , --- ---N N
Icl 0 s ----eNNH
\ \ \ N __ ( , i S
2489-CIPO-CLAIMS-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 N _ N
---eNNH ---( --(N ---eNS
N N __ \( SNjz S , N
---eNNH ---eNNH
IIN , Nil\1J N __ ( 0 ONjz N N N __ \( , NiNJ
o ciN, N
' H S
N--...._-S
, S ---_- N
-k-N, ------S-N ---c_rN
N-...__-0 H
N
S-N-N/ ----N, --C----) , N-0 -----N-N N-N-0 ------N, H H , , -C-----Q
-, I\1 ., N /
N, , 'N
-- - N
-, , -N
I II
N 1\r N /
-, N, I 'N
-I
N,N / , 1\1 -, N -, --'N 'N
N N
N
, -,,I\I I\1 -,,I\IN
-,N I
N
- N
I N I
IN 1\1-N
2489-CIPO-CLAIMS-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 _ I
- - - - - -- - _ z -Z //¨Z //¨Z // Z Z Z \ , Z _ Z /¨Z // Z-Z Z¨ , - Z¨
-) Z\ , Z\ , Z\ /Z , c , Z' Z/ ) Z ) Z Z
Z
/ ) Z)/ Z Z2/ Z)/ Z)/ \ Z/ Z/ \ Z
\ Z 0 / / / Z2/ c ¨Z Z ¨/ ¨ ¨ , ¨/ , ¨/ , ¨Z
¨/ ¨Z ¨Z ¨/
-IZ
-'; \ Z// // Z ; Z//¨
) Z\ z// Z\ , __ c Z Z Z Z Z Z - __ ¨, //
- Z Z Z¨\ Z \
/ \ Z / Z)/ Z)/ \ Z)/ \ \ Z Z / Z//
Z ¨/ ¨/
/ µµZ
/ \Z
c ¨/
µ Z Z Z
/ µ / µ
, ¨/ , ¨/ , ¨
I
Z
cc'?) cs) N
i P, RN
r.
CV
a ) ^ ^ ^ " ^
" 0 >
z // / z Z \ z/
: sz ¨z r,z ,z- zz, z\ zz,_ z,z\ z, zz\ /z\
__________ 0 ______________________________________ (( z / \ / ______ µ z / _______ \ z 0 / ; ;z1 Z)/ \ Z)/ µ Z Z)/ Z)/ µZ
¨Z Z ¨ ¨/ ¨ ¨ ¨/ , ¨Z , ¨Z , ¨Z
, ¨Z - : .018 ,P
a) ,r a Ct r (1) = 'i-Da ' 1 I 3 (9, , / , i (1) a) O ct a q a) ' ,r a r v ., H
' N=\ 0 N=N N=\ N-- ¨ ¨, /(1\1 ¨ ¨N
¨ ¨ \ / -- \ /N ¨ ¨ ¨_ \ N
N/ \ ' ,,N
, N¨ N¨ N¨ ¨N ¨N
¨ ¨
¨ -- / N //1\1 NN ' , , ______ , ¨ ( ¨ -- / N \ /IV \ /
N N , ________________________ ' , ______ N , ¨ ¨ \ /\
\ ¨\ *
--i /N
, \ '/N \ N
N
N N N //N
N=\ N=\
¨ ¨ ¨, /(N
\ / N / N s / N
N¨N
N N N //N
N
, N=N N=N N=N N=N N=N
N¨.__ -- ¨, \ ,, NN , ______ ' , , , , N=\ N=\ N=\ N=\ N-- ¨ /N ¨ ¨ ¨_ /N ¨ ¨ /N --- 51 -- \
( \ /71 , \ \ N
/ N N N , , N¨ N¨ N¨ N¨ N¨
\
\ N N N -- / N / N /
N/ //
, N¨N N N
, ¨N ¨N ¨N ¨N ¨N
, ¨
/N ¨ ¨ \ /N ¨ ¨ ;IV N
N
\ /71 , \ \ N
N, N ________________ , , , ¨N ¨N _¨N _N _N
¨ ¨ __________ ¨ ¨i \ \
--\ N N N / N / N /
N/ //
N¨N N N
, , , , , 2489-CIPO-CLAIMS-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 /N
) /N --i \ N \ S N S
N , N¨// N //N
N¨N N
, , -- . -- =
--i /N --Nµ, \ 1\1 N N
N N N¨N ;
N _____________ , N¨N , N sis\l¨//
, , wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 ¨ R14 and RN; and preferably with 1 to 3 of the substituents R11 ¨
R13;
and the substituents R9 ¨ R14 and RN have the meanings as defined in claim 1.
3. The compound according to Claim 1, wherein RN RN RN
R11 N R8 ---Ii\__¨R8 R2 represents )\__ 8 N
N
, RN
-__ 0 R8 R11 0 Ra -__ S Ra Rli S Ra ---Rlo R9 ;
' R9 Rlo R9 ;
' R9 Rlo R9 ;
, , RN RN RN RN Rlo R11 N R8 Rli N, Rii N, N, --1_111 ------LII ,- Rii 0 R8 \ / 0?--- I -----, , R9 R10 `, R9 Rlo R9 N¨ 8 ____________ N
1 1 1 1 N , 1 RN RN RN
¨8 R11 S _._ N ) __ N S N - 11 . ,N, --, ____.R8 -_. -NI Rti.õcN,N
)--N \ .' , N N N
, __ i( , , ; ; ; ; ; ; ;
RN
N --,N Rlo R N/
N, Dp N -- ¨R13 ---- R13 -------------------\\ ,, - - -= N'"
)¨N LL, , ; N=N , ------R14 N R14 N R14 N
, N R12 0----/y,) , % R13 R12 _() R13 ---,T
iA
u R1o_t---r>R13 õ, Rlo N R14 Rlo R.-, R14. 0-----k3 ;
, RN , R12 R12 , , s-r/, pe 13 % R12 1\1 /
- 1_____\T
R10 _.------r>R13 - - R10 -,..______1,.,.,,g . .
Rlo R14 S----- 14 R10 -4 RN
' 2489-CIPO-CLAIMS-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 N----"\ s= V_____R14 __\R13 \7 i - n z __ S
R1.A , R14 R14 R1., N
, RN RN RN
0,11:e 9 ril _ _R10 R1ONII ----- _____ R14 r_IR __r_ Rlo rµ NT9R10 N \J o) N-:>---S --\___,-------R10 ,/,1 , L7Z9 R9 ,S -- ---"- -1-R10 ,ILR1 0 N \ Z
N I
,-.1`i IV R8 \S-N
R8 i:8 N 1 N R . N R8----- R8---S,-- , Nõ-- N --)'--,-7--- ,---6--S ---- i/ --I 1 'N'N , R8 NO , sO-N , N-0 or 0-N
, ; ;
and R8, R0, R10, R11, R12, R13, K1-114, and R" have the meanings as defined in claim 1.
4. The compound according to Claim 1; wherein 0 (,..N..õ0 H (1) H
wherein L represents ¨L1¨L2¨;
Ll represents ¨CH2C0¨;
L2 represents ¨NR141¨; and R3 represents 1-adamantyl; or L2 represents ¨NRN1CH2¨; and R3 represents 2-bicyclo[3.1.1]heptyl, and the afore-mentioned 1-adamantyl and 2-bicyclo[3.1.1]heptyl residues optionally contain one or more C=C double bond(s) and/or are optionally substituted by one or more of Ra, Rb, Rc, Rd, and Re;
R1 represents =
, H
RN RN RN
R11 1\1 -__ ii R2 represents -- - - Riiii R8 1 ----- ¨R8 ;
N N N
, , , 2489-CIPO-CLAIMS-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 RN
-\
-_ 1 R11 0r R8 Ra R1 --\ / ---1sr\ S r Rs ( R10 R9 ;
/ R9 R10 R9 ; I-C
/ R9 R10 ,-,9 ;
R11 ON _R8 R11 II R8 R11 N, R11 N \ N, 1 ___________ ( --14N I N
/ /K --"LIK\1 \ / 0\) I ir-, __ N
R9 R10 s, , R9 R10 R9 N¨ ,__,8 , 1 1 1 1 K , 1 RN RN RN
0 8 R11 S S 8 -_ ' __-R ----- ._-- --- ,--R -___ li'N R1-il ,I1,N /
,N, N N
)--N ) __ N Y __ N N )\ N ( Rlo ' R10 ' Rlo ' Rlo , , ,/
, , RN
,N Rlo R N
N ------------------------------------------- ¨R13 -- R13 ---- 13 \¨N Q A,:ej \N
N=N , ------- o14 IV =Rl4 N
F\
R12 _R11 , N R12 0---__ 13 % R12 ) R
R10R13 Rio N R14 R10 (:)-14 (:)----\43 ;
;
RN %
R12 R12 , , S--_./y ,,, % R12 i\l---r/ R13 Rlo /
R10R13 --$___----) - -wo s-----414 ; wo 14 RN
R12 R12 p12 i\i---/A
13 .õ...------.õ..---:-/J,,` s= V.___ 14 N N R
N"----.%\- c_R
\/\*1 _,,,.
n S
R14 R14 R.-A R1_ N
R11 ,, RN RN RN
---, /1 rNi /I
R10-11--- ________ R14 r_.II R9 rN:Z9 Rio N \J _ _Rio N S --\____/------R10 mr\l' R10 o) ; ; ; rµ ; , ,I_79 N \ I I X N --N- --/-, _R10 õ,/_R10 V
\" R8 \S-N
R8 , s-,-- R8 S
. N - N ------<\
: 7-- , N R8---<\S--- N R 8 - R8----1\1--N , R8 N-N , µ0-1\I , N- , or 0-N -, R6 represents ¨C2H5;
and R8, R9, R113, R11, R12, R13, R14, Ra; R13, Rc; Rd; Re ; RN and rt^N1 have the same meanings as defined in claim 1 or a diastereomer, an enantiomer, a mixture of 2489-CIPO-CLAIMS-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 diastereomers, a mixture of enantiomer, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
5. The compound according to Claim 1 or 4 represented by formula (11):
oN
H
o N H 0 (11) H
wherein L2 represents -NIRN1-, and R3 represents 1-adamantyl; or L2 represents -NRN1CH2-, and R3 represents 2-bicyclo[3.1.1]heptyl, and the afore-mentioned 1-adamantyl and 2-bicyclo[3.1.1]heptyl residues optionally contain one or more C=C double bond(s) and/or are optionally substituted by one or more of Ra, Rb, Rc, Rd, and Re;
RN RN RN
IR1II Rii 11R8 -- il R8 .
R2 represents or N i N
N
R1 , / R1 0 , Ra, Rb, Rc, Rd, and Re represent independently of each other -H, -F, -CI, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C2H5, -CON H2, -CON HCH3, -CON (CH3)2, -CONN C2Hs, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2Hs, -CH2CON H2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2Hs, -NHCOCH3, -NHCOC2Hs, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C2Hs, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3;
RN represents -H, -CH3, -C2H5, -C3H7, -CH (CH3)2, -C4H9, -CH2-CH (CH3)2, -CH (CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-CsH9, -CH2-cyclo-C3Hs, -CH2-cyclo-C4H7, -CH2-cyclo-CsH9, -CH2F, -CH F2, -CF3, -CH2C1, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3, -00C2H5, -00C3H7, -COCH(CH3)2, -COC(CH3)3, -CO-cyclo-C3H5, -CO-cyclo-C4H7, -CO-cyclo-05H9, -COOCH 3, 2489-CIPO-CLAIMS-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -SO2CH3, -SO2CF3, -502C2H5, -502C3H7, -SO2CH(CH3)2, or -502C(CH3)3;
RI" represents -H, -CH3, or -CH2CH3;
R8, R", and R" represent independently of each other -H, -F, -CI, -Br, -1, -OH, -CN, -NO2, -CH3, -C2F15, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2F, -CHF2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -OCH3, -0C21-15, -0C3H7, -OCH(CH3)2, -0C(CH3)3, -0C4H9, -OCH F2, -OCF3, -OCH2CF3, -OC2F5, -OCH2OCH3, -0-cyclo-C3F15, -OCH2-cyclo-C3H5, -0-C2H4-cyclo-C3H5, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -CECH, -CEC-CH3, -CH2-CECH, or -Ph, or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomer, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
6. The compound according to any one of claims 1õ wherein the compound has any one of the formula (II-a) - (II-I), (11-bl) - (II-b2), and (III-a) - (III-I):
0 Rd Rc Re 0 0)LN Rb Ra 0 H (rH
N NH
Ra R2 N 1\ N R2 N N
Rb 0 0 HjC
(II-a) (II-b) ON N
NH Ra 2)-rµi NH N H
R2 N Rb R -Rb (11-bl) (II-b2) N ,1-1 Ra 2489-CIPO-CLAIMS-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 0 (II-d) N
H
0 A (;N1 0 Rb H
Ra (11-c) 0AN .-----õ, 0 N
H H
Rb Ra Rb Ra A
0H 0 0 JC H 0 Rc R2 N )-L L2 1 N Rc A N ...---,,,__., L2 H H 0 0 Rd 0 0 Rd (11-e) (11-f) 0 0 Rd Rb Ra 0)-L N ,---.õ
H Rc H Rc (11-g) (11-h) H Rb Ra H
0H 0 Rc 0 JC
H
R2 N 0 0 Rd 1 N R2 N 1 N
(11-i) (lH) 0}-, H H
H
(11-k) (11-1) 2489-CIPO-CLAIMS-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 o Rd Rc Re 0 Rb Ra I:)N
H H
NN KLA NH
NN I N )-LI N NH
1 N Rb o 0 ___N H 0 ,I,,.,,,., j 0 'RN 'RN
(III-a) (III-b) o o oN 0 H H
H
N H
R8 \ 1 rii RB-eXjC
H 0 bjFINA
R1 o (III- R"
c) (11I-d) 0 )-L o '--, N ----'' H 0-LN------õ,, H
S N NI H
R8 1 N N R8 1 ri N If 0 0 o o R10 s R 11 (11I-e) (III-f) N ----''' 0 '--- A N ---''' H H
H H
R ,----,..õ,..,õ N
R8 -- _e N -- 8 0 _e r il . il " '19 N
(11I-g) (11I-h) 0 o N
H ON
R13 0 N ...õ.,--1-{-.. ..---- IR] H
i N N 1 N H
R13 s I H
0 0 1 h'Cr . 11 r\IN
R10 Rl 0 0 (111-i) (III-j) 2489-CIPO-CLAIMS-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 0)-L o N
0.A
H N
H
0 jcH 0 R13 0 N )-L NH H
N N )-LNH
N
I H
Rio Rio Riz R13 12 (11I-k) (III-I) wherein L1; L2, R2; R13, R10, R11 ; R12, R13, R14, RN, Ra; R13, Rc; Rd and K i-ie have the same meanings as defined in claim 1.
7. The compound according to any one of the claims 1 ¨ 5, wherein R3 represents ----- ----.--/j[-, , , .d1--_________________________________ , , _.
-- , 0, , , , , F jZci jZCF3 jZOH jZCO2Me F
F
., ., ., ., Br ; CI OH
., CO2Me ', ', ', 0 '=
CO2H CONH2 ; CONMe2 H
Br OH
CO2H , ' CF3 - - , , - - - - , , , or -8. The compound according to any one of the claims 1, - 7, wherein R2 represents 2489-CIPO-CLAIMS-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 H I H H H
H I
N N N
N N
N
t ---N --,N ,N ,N ,N ,N
N ,N ,N
N , , I I I
I I I
N_-Br N ___ N ___NN
N
_. -----N-- N1 .--, p N Y __ N ) __ N N
--N ___________________________________________ / , , CI CI
I
,-vt )N N, 0 , - ---1\lyNN ----N NN
N
HN
, I NC--Cr _i \\
N
HN HN \ , I H I I
N. I N N, ,N
-- Br 0 ili\I c----..--_ -...,N, N/N (\ ,N r\cLii , N-NN \\ ii N //) , __ / , ! N
NI=1\1 ----CS-CI ---q-Br -- , s CI -----Br 01_0,--' H2N 0 Br, Br , Br , CI
BrSN_Br 0 \ __ --,SyBr CIS cl N Me0 --tN /----\Nj Br 0 ,-, \ , -- Br s--- ' --S.-Br --S..--CF3 BrS -.5 \ Nii.---%,1-3 S - - \ ,rph N
,S -- S --H , N\\ .3N\7. Nis\i_r_H
, - S-N S.õ-- - - /--ll 1\i/ IT N/S - s N
\ N 0 N-N S-N ---N N'N 0 , , ,S --H
1\lis\v. )--,-/ -- cj\__<\NT,- - (111:_ N I (--- --HO 0-N N- 0-N HN-2- \/
, H , NO2 N --,_,,----- --_,-----.:NO2 HN.--- 1\1)-- N_ I I
N-0 - N.-- CO2Me 1\1- 1\1- , -_,CO2H , -I\li\I --./ --.N
' 1 N 1 1\1 1\1-- -N NI , , , 0 0 , , /
-- \ / -- \ \
Br , I , 0 , , 2489-CIPO-CLAIMS-ZED-P04402W027.docx Date Recue/Date Received 2022-06-30 F
\
0 , S
\ --<\
-N"L'S N-L'S H HN
OH
-eN-N
N N N' , or 9. The compound according to claim 1 selected from the group consisting of:
Compound Name 1-1: (S)-N1-ethyl-N6-(1-(2-(1-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-(1-methyl-1H-imidazole-5-carboxamido)-2-oxohexanediamide, 1-2: (S)-N1-ethyl-5-(1H-imidazole-4-carboxamido)-N6-(1-(2-(1-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-oxohexanediamide, 1-3: (S)-N1-ethyl-N6-(1-(2-(1-adamantyl(methyl)amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-(1-methyl-1H-imidazole-5-carboxamido)-2-oxohexanediamide, 1-4: (S)-N1-ethyl-N6-(1-(2-(3,5-dimethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-(1-methyl-1H-imidazole-5-carboxamido)-2-oxohexanediamide, 1-5: (S)-N1-ethyl-N6-(1-(2-(3-ethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-(1-methyl-1H-imidazole-5-carboxamido)-2-oxohexanediamide, 1-6: (S)-N1-ethyl-N6-(1-(2-(3-trifluoromethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-(1-methyl-1H-imidazole-5-carboxamido)-2-oxohexanediamide, 1-7: (S)-N1-ethyl-N6-(1-(2-(3-hydroxyadamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-(1-methyl-1H-imidazole-5-carboxamido)-2-oxohexanediamide, 1-8: (S)-N1-ethyl-N6-(1-(2-(3-fluoroadamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-(1-methyl-1H-imidazole-5-carboxamido)-2-oxohexanediamide, 2489-CIPO-CLAIMS-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 1-9: (S)-N1-ethyl-N6-(1-(2-(3-chloroadamantane-1-amino)-2-oxoethyl)-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-5-carboxamido)-2-oxohexanediamide, 1-10: (S)-N1-ethyl-N6-(1-(2-(3-bromoadamantane-1-amino)-2-oxoethyl)-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-5-carboxamido)-2-oxohexanediamide, 1-11: (S)-N1-ethyl-N6-(1-(2-(3-methyl adamantane-3-carboxylate-1-am ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-5-carboxam ido)-2-oxohexanediam ide, 1-12: (S)-N1-ethyl-N6-(1-(2-(4,4-difluoroadamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-5-carboxamido)-2-oxohexanediamide, 1-13: (S)-N1-(1-(2-(((1S,2R,55)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide, 1-14: (S)-N1-(1-(2-(((1R,2R,5R)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide, 1-15: (S)-N1-ethyl-N6-(1-(2-(3-ethyladamantane-1-amino)-2-oxoethyl)-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-4-carboxamido)-2-oxohexanediamide, 1-16: (S)-N1-ethyl-N6-(1-(2-(3-ethyladamantane-1-amino)-2-oxoethyl)-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-2-carboxamido)-2-oxohexanediamide, 1-17: (S)-2-(1,4-dimethy1-1H-imidazole-5-carboxamido)-N6-ethyl-N1-(1-(2-(3-ethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, 1-18: (S)-N1-ethy1-5-(1-isobuty1-1H-imidazole-4-carboxamido)-N6-(1-(2-(3-ethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxohexanediamide, 1-19: (S)-2-(1-cyclopenty1-1H-imidazole-4-carboxamido)-N6-ethyl-N1-(1-(2-(3-ethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, 1-20: (S)-2-(1-cyclobuty1-1H-imidazole-4-carboxamido)-N6-ethyl-N1-(1-(2-(3-ethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, 1-21: (S)-2-(1,4-dimethy1-1H-imidazole-5-carboxamido)-N6-ethyl-N1-(1-(2-(3,5-dimethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, 2489-CIPO-CLAIMS-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 1-22: (S)-N1-ethyl-N6-(1-(2-(3,5-dimethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-4-carboxamido)-2-oxohexanediamide, 1-23: (S)-N1-ethyl-N6-(1-(2-(3,5-dimethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-2-carboxamido)-2-oxohexanediamide, 1-24: (S)-2-(1,2-dimethy1-1H-imidazole-5-carboxamido)-N6-ethyl-N1-(1-(2-(3,5-dimethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, 1-25: (S)-N1-ethyl-N6-(1-(2-(3-methyladamantane-1-amino)-2-oxoethyl)-oxo-1,2-dihydropyridin-3-y1)-5-(1-methy1-1H-imidazole-5-carboxamido)-2-oxohexanediamide, 1-26: (S)-2-(2-chloro-1-methy1-1H-imidazole-5-carboxamido)-N6-ethyl-(1-(2-(3,5-dimethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, 1-27: (S)-2-(1,2-dimethy1-1H-imidazole-5-carboxamido)-N6-ethyl-N1-(1-(2-(3-methyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, 1-28: (S)-N1-ethyl-N6-(1-(2-(3,5,7-trimethy1-1-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(1-methyl-1H-imidazole-5-carboxamido)-2-oxohexanediamide, 1-29: (S)-2-(2-chloro-1-methy1-1H-imidazole-5-carboxamido)-N6-ethyl-(1-(2-(3,5,7-trimethy1-1-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(benzofuran-2-carboxam ido)-N6-ethyl-N1-(1-(2-(2-1-30 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-N1-ethyl-N6-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-1-31 dihydropyridin-3-y1)-5-(3-methylbenzofuran-2-carboxamido)-2-oxohexanediamide, (S)-2-(3-chlorobenzofuran-2-carboxam ido)-N6-ethyl-N1-(1-(2-(2-1-32 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(4-bromobenzofuran-2-carboxam ido)-N6-ethyl-N1-(1-(2-(2-1-33 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(benzo[b]thiophene-2-carboxam ido)-N6-ethyl-N1-(1-(2-(2-1-34 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, 2489-CIPO-CLAIMS-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 (S)-N1-ethy1-5-(7-fluorobenzo[b]thiophene-2-carboxamido)-N6-(1-(2-1-35 (2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-oxohexanediamide, (S)-2-(4,5-difluoro-1H-indole-2-carboxam ido)-N6-ethyl-N1-(1-(2-(2-1-36 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-N1-ethyl-N6-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-1-37 dihydropyridin-3-y1)-5-(3-methy1-1H-indole-2-carboxamido)-2-oxohexanediamide, (S)-2-(1H-benzo[d]imidazole-2-carboxam ido)-N6-ethyl-N1-(1-(2-(2-1-38 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(2,3-dihydro-1H-indene-2-carboxam ido)-N6-ethyl-N1-(1-(2-(2-1-39 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-N1-ethyl-N6-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-1-40 dihydropyridin-3-y1)-5-(4-methy1-2-(trifluoromethyl)thiazole-5-carboxamido)-2-oxohexanediamide, (S)-2-(4-bromo-2-(trifluoromethyl)thiazole-5-carboxam ido)-N6-ethyl-1-41 N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-N1-ethyl-N6-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-1-42 dihydropyridin-3-y1)-5-(4-methy1-2-phenylthiazole-5-carboxamido)-2-oxohexanediamide, (S)-2-(5-bromo-3-methylthiophene-2-carboxamido)-N6-ethyl-N1-(1-1-43 (2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(3,5-dibromothiophene-2-carboxam ido)-N6-ethyl-N1-(1-(2-(2-1-44 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(5-bromo-3-methylfuran-2-carboxamido)-N6-ethyl-N1-(1-(2-(2-1-45 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(2,5-dichlorothiophene-3-carboxam ido)-N6-ethyl-N1-(1-(2-(2-1-46 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(2,5-dibromothiophene-3-carboxam ido)-N6-ethyl-N1-(1-(2-(2-1-47 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, 2489-CIPO-CLAIMS-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 (S)-2-(2,5-dichlorothiazole-4-carboxamido)-N6-ethyl-N1-(1-(2-(2-1-48 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(2,5-dimethylfuran-3-carboxamido)-N6-ethyl-N1-(1-(2-(2-1-49 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(4-bromothiazole-2-carboxam ido)-N6-ethyl-N1-(1-(2-(2-1-50 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(4-bromothiophene-2-carboxam ido)-N6-ethyl-N1-(1-(2-(2-1-51 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(4-bromo-5-chlorothiophene-2-carboxam ido)-N6-ethyl-N1-(1-1-52 (2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(4,5-dibromothiophene-2-carboxam ido)-N6-ethyl-N1-(1-(2-(2-1-53 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-(4,5-dichlorothiophene-2-carboxam ido)-N6-ethyl-N1-(1-(2-(2-1-54 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-2-((S)-1-acetylpyrrolidine-2-carboxam ido)-N6-ethyl-N1-(1-(2-(2-1-55 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-N1-ethyl-N6-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-1-56 dihydropyridin-3-y1)-5-(1-methy1-1H-1,2,3-triazole-5-carboxamido)-2-oxohexanediamide, (S)-N1-ethyl-N6-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-1-57 dihydropyridin-3-y1)-2-oxo-5-(2H-tetrazole-5-carboxamido)hexanediamide, (S)-N1-ethyl-N6-(1-(2-(5-hydroxyadamantane-2-am ino)-2-oxoethyl)-1-58 2-oxo-1,2-dihydropyridin-3-y1)-2-oxo-5-(pyrazine-2-carboxamido)hexanediamide, (S)-N1-ethyl-N6-(1-(2-(5-fluoroadamantane-2-am ino)-2-oxoethyl)-2-1-59 oxo-1,2-dihydropyridin-3-y1)-2-oxo-5-((S)-pyrrolidine-3-carboxamido)hexanediamide, (S)-N1-ethyl-N6-(1-(2-(5-chloroadamantane-2-am ino)-2-oxoethyl)-2-1-60 oxo-1,2-dihydropyridin-3-y1)-2-oxo-5-((S)-piperidine-2-carboxamido)hexanediamide, 2489-CIPO-CLAIMS-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 (S)-N1-ethyl-N6-(1-(2-(5-bromoadamantane-2-amino)-2-oxoethyl)-2-1-61 oxo-1,2-dihydropyridin-3-y1)-2-oxo-5-((R)-piperidine-3-carboxamido)hexanediamide, (S)-N1-ethyl-N6-(1-(2-(5-methyladamantane-2-amino)-2-oxoethyl)-2-1-62 oxo-1,2-dihydropyridin-3-y1)-5-((R)-morpholine-3-carboxamido)-oxohexanediamide, (S)-N1-ethyl-N6-(1-(2-(2-carbonitrileadamantane-2-am ino)-2-1-63 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxo-54(35,4R)-quinuclidine-3-carboxamido)hexanediamide, (S)-methyl 3-(6-(ethylamino)-1-(1-(2-(methyl 2-aminoadamantane-2-1-64 carboxylate)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-1,5,6-trioxohexan-2-ylcarbamoy1)-5-nitrobenzoate, (S)-N1-(1-(2-(1-adamantylmethylam ino)-2-oxoethyl)-2-oxo-1,2-1-65 dihydropyridin-3-y1)-N6-ethy1-2-(5-nitronicotinamido)-5-oxohexanediamide, 54(25)-1-(1-(2-1-adamantylmethylam ino)-2-oxoethyl)-2-oxo-1,2-1-66 dihydropyridin-3-ylamino)-6-(ethylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinic acid, (S)-N1-ethyl-N6-(1-(2-(2-adamantyl(methyl)am ino)-2-oxoethyl)-2-1-67 oxo-1,2-dihydropyridin-3-y1)-5-(6-methylimidazo[2,1-b]thiazole-carboxamido)-2-oxohexanediamide, (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylam ino)-2-1-68 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide, (S)-N1-ethy1-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-1-69 oxo-1-(2-oxo-2-((1R,25,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-ylamino)ethyl)-1,2-dihydropyridin-3-y1)hexanediamide, (S)-N1-(1-(2-((1R,2R,45)-bicyclo[2.2.1]heptan-2-ylamino)-2-1-70 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide, (S)-N1-(1-(2-((1s,4R)-bicyclo[2.2.1]heptan-1-ylam ino)-2-oxoethyl)-2-1-71 oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-2-(isonicotinamido)-5-oxohexanediamide, (S)-N1-(1-(2-(bicyclo[2.2.1]heptan-7-ylam ino)-2-oxoethyl)-2-oxo-1,2-1-72 dihydropyridin-3-y1)-N6-ethy1-5-oxo-2-(pyridazine-4-carboxamido)hexanediamide, (S)-N1-(1-(2-((1R,2R,4R)-bicyclo[2.2.1]hept-5-en-2-ylamino)-2-1-73 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-5-oxo-2-(pyridazine-3-carboxamido)hexanediamide, 2489-CIPO-CLAIMS-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 (2S)-N1-(1-(2-(bicyclo[2.2.2]octan-2-ylam ino)-2-oxoethyl)-2-oxo-1,2-1-74 dihydropyridin-3-y1)-N6-ethy1-5-oxo-2-(2H-1,2,3-triazole-4-carboxamido)hexanediamide, (S)-N1-ethy1-5-(1-methyl-1H-1,2,3-triazole-4-carboxam ido)-2-oxo-1 75 N6-(2-oxo-1-(2-oxo-2-((1R,2R,4R)-1,7,7--trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-y1)hexanediamide, (S)-N1-ethy1-5-(1-methyl-1H-1,2,4-triazole-3-carboxam ido)-2-oxo-1 76 N6-(2-oxo-1-(2-oxo-2-((1R,2R,3R,5S)-2,6,6--trimethylbicyclo[3.1.1]heptan-3-ylamino)ethyl)-1,2-dihydropyridin-3-y1)hexanediamide, (S)-2-(benzofuran-3-carboxam ido)-N6-ethy1-5-oxo-N1-(2-oxo-1-(2-1-77 oxo-2-((1S,25,35,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)ethyl)-1,2-dihydropyridin-3-y1)hexanediamide, (S)-2-(benzo[b]thiophene-3-carboxam ido)-N6-ethyl-N1-(1-(2-(4-1-78 homoisotwistane-3-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-y1)-5-oxohexanediamide, (S)-N1-ethyl-N6-(1-(2-(diamantane-1-am ino)-2-oxoethyl)-2-oxo-1,2-1-79 dihydropyridin-3-y1)-5-(1-methy1-1H-pyrazole-4-carboxamido)-2-oxohexanediamide, (S)-N1-ethyl-N6-(1-(2-(diamantane-4-am ino)-2-oxoethyl)-2-oxo-1,2-1-80 dihydropyridin-3-y1)-5-(1-methy1-1H-pyrazole-3-carboxamido)-2-oxohexanediamide, 1 81 (S)-N1-(1-(1-adamantylmethyl)-2-oxo-1,2-dihydropyridin-3-y1)--ethy1-2-(1-methy1-1H-pyrazole-5-carboxamido)-5-oxohexanediamide, (S)-N1-(14(3-hydroxy-1-adamantyl)methyl)-2-oxo-1,2-1-82 dihydropyridin-3-y1)-2-(4-cyclopropy1-1,2,3-thiadiazole-5-carboxam ido)-N6-ethy1-5-oxohexanediam ide, (S)-N1-(14(3-bromo-1-adamantyl)methyl)-2-oxo-1,2-dihydropyridin-1-83 3-y1)-N6-ethy1-5-oxo-2-(1,2,5-thiadiazole-3-carboxamido)hexanediamide, (S)-N1-(1-(2-adamantylmethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-1-84 ethy1-2-(4-(hydroxymethyl)-1,2,3-thiadiazole-5-carboxamido)-5-oxohexanediamide, (S)-2-(4-tert-buty1-1H-pyrrole-3-carboxam ido)-N1-(1-(2-(1-1-85 adamantylamino)ethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-oxohexanediamide, 2489-CIPO-CLAIMS-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 (S)-2-(4-cyano-1-methy1-1H-pyrrole-2-carboxam ido)-N1-(1-(1-1-86 adamantylamino)propy1)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-oxohexanediamide, (S)-N1-(1-(3-(2-adamantylam ino)-3-oxopropy1)-2-oxo-1,2-1-87 dihydropyridin-3-y1)-N6-ethy1-2-(5-methoxyoxazole-2-carboxamido)-5-oxohexanediamide, (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-1-88 dihydropyridin-3-y1)-N6-ethy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide, (S)-2-(2-acetyloxazole-4-carboxam ido)-N1-(1-(2-1-89 (bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-5-oxohexanediamide, (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-1-90 dihydropyridin-3-y1)-N6-ethy1-2-(2-isopropyloxazole-5-carboxamido)-5-oxohexanediamide, (25)-N1-(1-(2-(bicyclo[3.2.1]octan-8-ylam ino)-2-oxoethyl)-2-oxo-1,2-1-91 dihydropyridin-3-y1)-2-(3,5-dimethylisoxazole-4-carboxamido)-ethy1-5-oxohexanediamide, (S)-N1-ethyl-N6-(1-(2-(5-carboxy-2-am inoadamantane)-2-oxoethyl)-1-92 2-oxo-1,2-dihydropyridin-3-y1)-5-(4-methylpyrimidine-5-carboxamido)-2-oxohexanediamide, (5S)-N1-ethyl-N6-(1-(2-(4-aminoadamantane-N,N-dimethy1-1-1-93 carboxamide)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxo-(1,2,3,4-tetrahydronaphthalene-2-carboxamido)hexanediamide, (S)-2-((S)-1,4-diazabicyclo[2.2.2]octane-2-carboxam ido)-N6-ethyl-1-94 N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide, (S)-N1-ethy1-5-(1H-indole-3-carboxam ido)-N6-(1-(2-(2-1-95 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxohexanediamide, (S)-N1-ethyl-N6-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-1-96 dihydropyridin-3-y1)-5-(6-methylimidazo[2,1-b]thiazole-3-carboxamido)-2-oxohexanediamide, (S)-2-(benzo[d]thiazole-2-carboxam ido)-N1-(1-(2-((1S,2R,4R)-1-97 bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-5-oxohexanediamide, (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylam ino)-2-1-98 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-2-(imidazo[2,1-b]thiazole-6-carboxamido)-5-oxohexanediamide, 2489-CIPO-CLAIMS-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylam ino)-2-1-99 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-2-(4-hydroxy-(trifluoromethoxy)quinoline-3-carboxamido)-5-oxohexanediamide, (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-1-100 dihydropyridin-3-y1)-2-(cinnoline-3-carboxamido)-N6-ethy1-5-oxohexanediamide, (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-1-101 dihydropyridin-3-y1)-N6-ethy1-2-(3-ethylbenzofuran-2-carboxamido)-5-oxohexanediamide, (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-1-102 dihydropyridin-3-y1)-N6-ethy1-2-(1-ethy1-1H-indole-2-carboxamido)-5-oxohexanediamide, (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-1-103 dihydropyridin-3-y1)-N6-ethy1-2-(2-methy1-1,8-naphthyridine-3-carboxamido)-5-oxohexanediamide, (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-1-104 dihydropyridin-3-y1)-N6-ethy1-5-oxo-2-(1,2,3,4-tetrahydroquinoline-6-carboxamido)hexanediamide, (S)-N1-ethyl-N6-(1-(2-(2-carboxy-2-am ino-5-1 105 (trifluoromethyl)adamantane)-2-oxoethyl)-2-oxo-1,2-dihydropyridin--3-yI)-2-oxo-5-(3-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)hexanediamide, (S)-N1-ethyl-N6-(1-(2-(5-ethyladamantane-2-am ino)-2-oxoethyl)-2-1-106 oxo-1,2-dihydropyridin-3-yI)-5-(1,6-naphthyridine-2-carboxamido)-2-oxohexanediamide, (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-1-107 dihydropyridin-3-y1)-N6-ethy1-2-(2,6-naphthyridine-1-carboxamido)-5-oxohexanediamide, (S)-2-(4-amino-1,2,5-oxadiazole-3-carboxamido)-N1-(1-(2-1-108 (bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-5-oxohexanediamide, (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-1-109 dihydropyridin-3-y1)-2-(6-(dimethylamino)benzofuran-2-carboxamido)-N6-ethy1-5-oxohexanediamide, (S)-2-(2-acetamidothiazole-5-carboxamido)-N1-(1-(2-1-110 (bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-ethy1-5-oxohexanediamide, 2489-CIPO-CLAIMS-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 (S)-N4-(1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1-111 1,2-dihydropyridin-3-ylamino)-6-(ethylamino)-1,5,6-trioxohexan-2-yl)-1H-pyrrole-2,4-dicarboxamide, (S)-N1-ethyl-N6-(1-(2-(1-acetylamino-4-aminoadamantane)-2-1-112 oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-oxo-5-(5-sulfamoylfuran-3-carboxamido)hexanediamide, (S)-2-(benzofuran-5-carboxamido)-N6-ethyl-N1-(1-(2-(1-1-113 acetylamino-4-aminoadamantane)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-oxohexanediamide, (S)-2-(benzofuran-6-carboxamido)-N6-ethyl-N1-(1-(2-(4-1-114 aminoadamantane-1-carboxamide)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-oxohexanediamide, (S)-N1-ethyl-N6-(1-(2-(4-aminoadamantane-1-carboxamide)-2-1-115 oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-(3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamido)-2-oxohexanediamide, (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-1-116 dihydropyridin-3-yl)-N6-ethyl-2-(5-methyl-1,2,4-oxadiazole-3-carboxamido)-5-oxohexanediamide, (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-1-117 dihydropyridin-3-yl)-N6-ethyl-5-oxo-2-(1,2,3-thiadiazole-carboxamido)hexanediamide, (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-1-118 dihydropyridin-3-yl)-N6-ethyl-5-oxo-2-(1,2,4-thiadiazole-carboxamido)hexanediamide, (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-1-119 dihydropyridin-3-yl)-N6-ethyl-5-oxo-2-(1,3,4-thiadiazole-carboxamido)hexanediamide, (S)-N1-ethyl-5-(4-formyl-1,2,3-thiadiazole-5-carboxamido)-N6-(1-(2-1-120 (2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-oxohexanediamide, (S)-N1-ethyl-N6-(1-(2-(3,5-dimethyladamantane-1-amino)-2-1-121 oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-(nicotinamido)-oxohexanediamide or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising a compound of any one of the claims 1 ¨ 9 as an active ingredient, together with at least one pharmaceutically acceptable carrier, excipient and/or diluent.
2489-CIPO-CLAIMS-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 11. Compound according to any one of the claims 1 ¨ 9 for use in medicine.
12. Compound according to any one of the claims 1 ¨ 9 or the pharmaceutical composition according to claim 8 for use in the treatment or prophylaxis of autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, ocular diseases, and skin disorders.
13. Compound for use, or the pharmaceutical composition for use according to claim 12, wherein the autoimmune and inflammatory diseases comprises multiple sclerosis, celiac disease, Duhring-Brocq-disease (dermatitis herpetiformis), gluten ataxia, gluten neuropathy, diabetes, rheumatoid arthritis, Graves' disease, inflammatory bowel disease, systemic lupus erythematosus psoriasis, and gingivitis;
the vascular diseases comprise atherosclerosis, thrombosis, vascular stiffness;
the fibrotic diseases affecting the lung, the kidney, the liver, the skin or the gut like cystic fibrosis, kidney fibrosis and diabetic nephropathy, intestinal fibrosis, idiopathic lung fibrosis, liver fibrosis;
the liver diseases like alcoholic hepatitis, alcoholic steatohepatitis, nonalcoholic steatohepatitis, non-alcoholic fatty liver disease, liver cirrhosis, autoimmune hepatitis or liver inflammation;
the cholestatic liver diseases comprise primary biliary cholangitis and primary sclerosing cholangitis;
the cancer comprises glioblastoma, melanoma, pancreatic cancer, renal cell carcinoma, meningioma, and breast cancer, the neurodegenerative diseases comprise Parkinson's disease, Huntington's disease, or Alzheimer's disease;
the ocular diseases comprise glaucoma, cataracts, macular degeneration, or uveitis;
and the skin disorders comprise acne, psoriasis, scarring, and skin aging.
14. Compound for use, or the pharmaceutical composition for use according to any one of the claims 12 and 13 in the treatment or prophylaxis of celiac disease.
2489-CIPO-CLAIMS-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 15. A method for producing the compound of formula (la) according to claim 1 comprising:
Step 1A: providing a compound 4a Ac0)-L N -R6 H
PGNJ(rOH
H 0 4a;
Step 2A: performing coupling reaction of the compound 4a with a compound 5 i-i2N N)-L A_R
_ , , -to obtain a compound 6a AcO-L N ' R6 H
R-6a;
Step 3A: deprotecting an amino protecting group PG3to obtain a compound 7a Ac0)-L R6 N' H
H
H2N Jc N N, L-R3 7a;
Step 4A: performing coupling reaction of the compound 7a with a carboxylic acid (R2-CO2H 8) to obtain a compound 9a Ac0)-L N -R6 H
0 iC 0 , N 'R-9a;
Step 5A: performing oxidation reaction of the compound 9a to produce the 2489-CIPO-CLAIMS-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 compound of the formula (la) ON.R6 H
A NO-L ,L, , R2 N , N R-(la);
wherein L, R2, R3, and R6 have the same meanings as defined in claim 1, and PG3 is an amino protecting group.
2489-CIPO-CLAIMS-ZED-P04402W027 docx Date Recue/Date Received 2022-06-30 1. A compound of the general formula (I):
H (1) y R3 wherein L represents -L1- or -L1-L2-; preferably -L1-L2-;
Ll represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2C0-, or -CH2CH2C0-;
L2 represents a bond, -NR141-, -NRN1CH2-, -NRN1CH2CH2-, or -NRN1CH(CH3)-;
RI represents '-./R4 ;
R2 represents RN
Rt1 ,C) Ra -__ S Ra Rii \ S Ra -- 11 R8 \ , , ( Rlo R9 ; ' R9 Rlo R9 ; ' R9 Rlo n. rµ9 ;
RN RN RN RN RN
RN
R11 N R8 R11 N, N, R11 N
K ------(\ R 111...õ,1 R8 ) ________________________________________________________ N N
/ R9 Rlo ss , IRn R4 .- IRn Rlo , ' ' RN Rlo Rlo R1.:!._- R1-õ!OR8 - - _OR8 - -q ' ca' R8 Y __________ N ) __ N N )--N N
R10 ' R19 , R10 R8 N¨
' ' RN
RN
, ' R10 n11 S R 8 - - S R8 - ----s", ll'N R11 N, 0------ ----- - rk---- __- -- ----\ 'N
N¨XR8 , Rlo , _________ Rlo __ Rlo N 1 ) N N Y
N N
N Rlo Rio____N ,N _RN
Nr-ii, _ N, mr\I r7.....1 Dp13 R13 ,N - -- N-rk LI _\,,j . = \-) i , , N-Ni ; N=N ; ------- R14 , N R14 , 2489-CIPO-CLAIMS-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 R12 R12 N R12 0 - = - / y, S - = = _ _ / y, ------------- R13 N R13 ri, , ___LR13 __Ri3 ----------------------------------------- ¨R13 -\
\IV \- R14 R14 N R14 NR14 N=R14 R10 R10 RN
N-__/y, N--_/y R12 p12 - - -TR13 '-/r/ 13 õ..------,,,õ--"`
R14 N-----\ -- 1A c____\7R
\-14.
Rlo R." R14 R._ , RN RN RN
9 ,ii, R9 rii-/iR9 N- -/,R9 S rR
_ r /I R10 RIO
0) _ R10 N _________ - Rlo _ \ -,----Dio -R8 R8 ,S-,--R9 ,S -- N II
N--7_, N \ 1 N _ ./ T- -- ,--N
N
to _R10 I s)''-'i \
." R8 \S-N µ1\1:=N , R8 . 5 ,-- N,-- o R ---- 1/ d--- R8--- -1 Ru---- Nji -N-N b-N , NC) - 0-N , --N
, , H
, N
, , ' , N ---eNNH ---eNNH ---( --( N
- N N __ \( S S z S S z N
---eNNH ---eNNH
11 NINN3 N __ ( NJ
N, , _rN N --No -----eNo ----eNo -- iv ____________________ ---(N3 - N -e N
, \( N
N Nj , \
0 0 z N N
H S
N_ s N
-N-___ , --1"Ds H H , N
S
_---------\N
S-I\i/2 , N
S'N ' /2 N
-- o ___--"µ 0,N ____N
__cf\r/
-fr---N \N-1\i'd --c__ H H
2489-CIPO-CLAIMS-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 _ \ F
z N O _ _ , z ,- z - , - _______________ z z- z -___ - z-z- z - z-i / \ //_ 7 / -z 7 -- zõ / z//- r z/, z c i z / \ z/ \
z/ \ / `z / C / z)/ z)/
`z z)/ z/ \ z/ \ z/ z/ `z , -z , z - -/ -/ -z z --/ -- z z v=i , , , /
/
) ____ z (y, , , _ _ N- z z z_z , z z , ,_z - ,, z z 17 / \ / \ z// \ 'z / z/7 'z z//
'z z ' 1 , 'z - / `z / \
z z z)/ \ z/ z)/- z)/
c z)/ \ z)/ \ z?' \ z z / z z/
z- - -/ - - -/ -z _=z --/ - z -/ -/ --z trvz i ,, ,, ,, N O
, e?
, cõ
N
P, RN
C J a) ^ ^
¨ 0 . >
.
Z Z Z Z KZ z Z c) CT) a (.) Z Vk' Z / \ / \ Z Z// - / % C \ / z//
/ / ---Z Z' \ Z// / 2 Z
,r a [t \i\--- Z
oc'' a) / \
w Cy z Z)/ / 0 /
Z)/ \ Z)/ \Z Zi/ Z/ Z/ (Z ^, w a , ¨ ¨/ ¨Z ¨Z z ¨
___________________________ ¨ ¨ --/ --63 :Tz = 1 , , , w 0, , 1 , , , (,) a) o ct ,r a õ
I\IN -.N,N
N
N , 1 1\r' N. -, N-,N TheN
N -,,1\1 ''IrN
, - --''N
N.N
, NN 1\IN NN
, , '--ry N.N
, --r -,,N,N
N,NN N.NN 1 1\IN
H -, HN NH , , , , ., H
N=\ 0 N=N N=\ N---N
\ N
, N- N- N- -N -N
- - \ -- -, -- /, / \ hN
N N , , N ' -N -N -\ - \
- N
( -- - - \
N -- -\ /
\ //N, \ /
N N
______________________ , , - - \ \ iN
-- z\N
1\1 , \ N __ , -- 11 N N
, N N N \\ //
2 , , , 2489-CIPO-CLAIMS-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 N=\ N=\
\ / N / N / N¨N N S
N N N //N
N
N=N N=N N=N N=N N=N
-- \ /N -- __ -- -- z/ ¨___ __ --\ , N N /
N N /
, , ___________________________________ , , , N=\ N=\ N=\ N=\ N---( \ /71, \ S \ _______ I\1 / , N
N N N
, \ --/
N // N¨N \\_N N
, , , __________ , ' , -- /(N
\ /71, \ S \ _______ I\1 , N
N N N
' -- --i --i --i --? /
N¨ N //N N¨N N N __ /
, , , ¨ \ ___\
¨\ ¨\ ¨\
N ; N¨// // N¨N N
Ns, \ N N N N N N /
_______________ , N¨N /
N ; /
¨ or N¨N -N N//
wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 ¨ R14 and R" ; and preferably with 1 to 3 of the substituents R11 ¨
R13;
R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl;
diamantyl;
hexamethylenetetraminyl and the afore-mentioned residues optionally contain one or more C=C double bond(s) and/or are optionally substituted by one or more of Ra; R13, Rc; Rd, and Re;
2489-CIPO-CLAIMS-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 Ra, Rb, Rc, Rd, and Re represent independently of each other -H, -F, -CI, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C21-15, -CONH2, -CONHCH3, -CON(CH3)2, -CONHC2F1s, -CH2CO2H, -CH2CO2CH3, -CH2CO2C21-15, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2Hs, -NHCOCH3, -NHCOC21-15, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C21-15, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3;
R4 represents -NR6R7;
R6 and R7 represent independently of each other -H, -CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, .. -CH2CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CH=CH2, .. -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3, -cyclo-C31-15, -cyclo-C4H7, -cyclo-051-19, -cyclo-C6H11, -CH2-cyclo-C3Hs, -CH2-cyclo-C4H7, -CH2-cyclo-C51-19, -CH2-cyclo-C6H11, -Ph, -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2NHCH3, or -CH2CH2N(CH3)2, or -NR6R7 is -N(C21-15)2, --I\I - -1\I - -NO
or N/ \
\ ___________________________________________________________________________ / =
, R8, R9, R10, R11, R12, R13, and R14 represent independently of each other -H, -F, -CI, -Br, -1, -OH, -CN, -NO2, -CH3, -C21-15, -C3H7, -CH (CH3)2, -C4H9, -CH2-CH (CH3)2, -CH(CH3)-C2Hs, -C(CH3)3, -cyclo-C31-15, -CH2-cyclo-C31-15, -CH2OH, -CH2F, -CH F2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -OCH3, -0C21-15, -0C3H7, -OCH(CH3)2, -0C(CH3)3, -0C4H9, -OCH F2, -OC F3, -OC H2C F3 , -0C2F5, -OCH20C H3, -0-CyCIO-C3H5, -OCH2-CyClo-C3H5, -0-C2H4-CyClO-C3H5, -CHO, -COCH3, -COCF3, -00C21-15, -00C3H7, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2Hs, -COOC3H7, -COOCH (CH3)2, -COOC(CH3)3, -00C-CH3, -00C-CF3, -00C-C2Hs, -00C-C3H7, -00C-CH(CH3)2, -00C-C(CH3)3, -NH2, -NHCH3, -NHC21-15, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C21-15)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC21-15, -NHCOC3H7, -NHCOCH (CH3)2, -NHCOC(CH3)3, -CONH2, -CONHCH3, -CONHC21-15, -CONHC3H7, -CON HCH (CH3)2, -CON H-cyclo-C31-15, -CON
HC(CH3)3, -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -502N H2, -S 02N HC H3, -SO2NHC2H5, -SO2NHC3H7, .. -SO2NHCH(CH3)2, -SO2NH-cyclo-C3Hs, -SO2NHC(CH3)3, -502N(CH3)2, -502N(C2H5)2, 2489-CIPO-CLAIMS-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 -SO2N(C3H7)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C2H5, -NHSO2C3H7, -NHSO2CH (CH3)2, -NHSO2C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -CECH, -CEC-CH3, -CH2-CECH, -Ph, -0-Ph, -0-CH2-Ph, r1\1 = -NO IL:12)1 -Nr-N --r r1\1 r1\1 r / __ \ / __ \ / __ \
N\ /NH N\ N
or N\ /N
or R8 and R9 or R9 and R1 can form together one of the following five-membered or six-membered rings:
__o -_1\1 - I
or or R12 and R13 or R13 and R14 can form together one of the following five-mem bered or six-membered rings:
.0 .0 .0 .0 - .23 ''0 H or I =
RN represents -H, -CH3, -C2F15, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH (CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-051-19, -CH2-cyclo-C3F15, -CH2-cyclo-C4H7, -CH2-cyclo-051-19, -CH2F, -CHF2, -CF3, -CH2C1, -CH2Br, -CH21, -CH2-CH2F, -CH2-CH F2; -CF12-CF3, -CH2-CH2C1, -CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3, -00C21-15, -00C3H7, -COCH (CH3)2, -COC(CH3)3, -CO-cyclo-C3H5, -CO-cyclo-C4H7, -CO-cyclo-051-19, -COOCH 3;
-COOC21-15, -COOC3H7 -COOCH (C H3)2, -COOC(CH3)3, -COOCH2Ph, -502CH3, -502CF3, -502C2H5, -502C3H7, -SO2CH (CH3)2, - 02-CyClo-C3H5, or -502C(CH3)3;
RI" represents -H, -CH3, or -CH2CH3;
2489-CIPO-CLAIMS-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomers, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, wherein R2 represents R1:1S R8 RN
-... 0 r,8 1 __________ rm R11 0 R8 \ , __ S Rs 1 _______________________________________ r , ___ r __ ,, \ , R8 R10 R9 / R9 R10 D9 ' R9 R10 R9 ;
' ; rµ ; ;
RN RN RN RN
R11 II R8 R11 II, R11 II\1 , - _ ii, R1 ________________________________________________________________________ ,,1 ON._ _ - RzcON _Rs 1( 1 iN
, i) ( N N
, Ro R10 ss , R9 R.,,r, 09 R10 /
/
; F\ ; ; ;
R10 nµ
po10 R11 S
' --0,---R8 r.µ):-õ, - ' R8 _________ A- ,x. . $-N __.- RtiSõs _R8 0? Os 1r \ ir-)--N `-', N
N N¨ N
R10 R8 N¨ , R8 Rio ' ,,, ' , , R" RN RN RN
-_ S Rs -___11,k, R11 N, ,N Rlo \ ----- ,N N\-11--- --R10 zN,N_RN
N
) ____________________________________ N -=N -'\ ,N
Rlo Rlo N-N
, , , ppN -----------------R1=3 - 13 N 1, R - R=- r ,r1 ¨R=-----VN, N--" LI.,.,.,.,,,...,R13 -) \N=
-)=
-) N=N , D14 N\ Rl4 N R14 N\ Rl4 N\ R14 , "
RN
0--/y _ S--__//, _ i\l--/y, N--/y,R12 - - -TRIi ---, ¨R13 --- 1 \,+R13 Rlo R14 R14 R14 N----%\- iA
Rio Rio R.-, Ri2 Ri2 ,µ
R r_ 14 ii R9 _I _] ii 7----- 9 r -/, R13 N ."R
_ 1 --.- ______________________________________ S
R14 R..14 R._n N --\___,-------Rlo , , , , m 9 m R9 /S,I, - -_ R10 711-1-= o10 r.1---= 01 0 N µ _,K N-- )----r\ \ - EN N \ I S\
R8 S'N NO , S,-- R8 N1/, II Sõ,- - )õ, . 1\1,-- . N,-- 0 )\--N -R8--- N./ IT R8---- -/ Ru-----R8 , , N-N b-N N-C) , 0-N N
, , H
, N
, ' ' , 2489-CIPO-CLAIMS-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 ---eNNH ---eNNH
"(1\13 N ( ii\ij N N __ \( S S y , N
---eNNH ---eNNH
IIN , NNIN3 N _____________________________________ N __ N ( , --(N3 ______________________________________________________ N
i __ \( ZN , NJ N
o 6 7 N
, ' H S
-----71\r--s H N1--- -- -(-----N&\ -N-S
' H , , , S---__-N _//_-/ N s ___ ---C-\-- N
S'INI
H
N 0--_-N
-N
------Nl-No N -0 ---_--N, ------0"--N&\
H H
/
-"Q
-, I\1 ., i --I I I
N /
/ N
'N
, - 1\1 -.,N
I II
N Th\r N /
-, NõN
I -I
N1,N
, -. N -. -, 'N 'N
N N
N
.. 1\1 I\1 -.,z1\1N
I N I
N N
, , '--N
I I I
1\1 le , , N , 2489-CIPO-CLAIMS-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 '-'N '---N
I
N
, '--- -, N N
-, f N N
Nõ, " NN NN, , , N
NK," NN N
, -.,NN,N
ii 1 -..,...,.----..n, IN , N N , N
, , - N, 'N -,,1\1N -,,N,N
1\1 N , , 1 N f NN, NN N .N
, N , N , NõN -.,N,N
N, 1\1 N
N -,,1\1 -,1\1 NN, NN N N , , -, --N.N
N
' , NN N NN
, , ' ., NN:I\I
, '-' '--I - N, I
N.NN N,NN NN
' _, Icl NH
HN NH , , 2489-CIPO-CLAIMS-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 HN H , NH , ' N=\ 0 N=N N=\ N--\ N
N/ \ '/IV
' N¨ N¨ N¨ ¨N ¨N
¨ ¨ _______ \ ¨ ¨ \ ¨ ¨ \ /iV __ ¨ ¨
¨ ¨ ¨¨ ________________ / N
N N
' , ________ , , _¨N ¨N ¨N \ ¨ __ \
¨ ¨ ¨\ / N N
¨ ¨ ¨ / N ¨- \(1\I
N , N _______________________________________ N , , \
N ¨ \
N , \ ,N \ N
N/ ¨ ¨ =
N N
\\ //
N , N=\ N=\
¨ ¨ ¨ ¨
¨ ¨ /(1\1 ¨ ¨ ¨$, / N
\ / N / N s / N
N¨N S
N
N N N //N
, , , N=N N=N N=N N=N N=N
¨ ¨ \ ;NI ¨ ¨ ¨ ¨ ¨ ¨ ___ ¨ ¨
\ ,N /
, _________ ' , N N N
, , N=\ N=\ N=\ N=\ N-- ¨ /(N ¨ ¨ ¨\ / N ¨ ¨ / N ¨ ¨ ___ 51 ¨ ¨
\ /71 , \ S \ N / N
N, N __ , / _________ N
, , N¨ N¨ N¨ N¨ N-- ¨ ____ ¨ ¨ _________ \
\ ¨ ¨ __ \ N N N ¨ ¨ / N / N /
N/ //, N¨N, ¨N, V I
, , ¨N ¨N Ns ¨N ¨N
¨ ¨ /s(N ¨ ¨ \ /N
¨ ¨ ¨ N , ¨ i / N __ ¨ ¨
N
\ /71 , \ S I\1 , _______________________ N ' N _________________________ N
, , ¨N ¨N /¨N _ _ _¨N ____ ¨N
¨ ¨ ____ ¨ ¨ i ¨ ¨ /
\ N N / N
N ¨// N //N
N¨N N 'I V /
, , , , , 2489-CIPO-CLAIMS-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 /N
\ ,N ( N N N \ S N S
N ; N¨// // N-N N
, , ¨\
--- /N
Nss ____________ , \ ,N N N
/ N N N, /
N N-N ; N sis\l¨ or \N-N ;
, , wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 ¨ R14 and RN ; and preferably with 1 to 3 of the substituents R11 ¨
R13 and the substituents R9 ¨ R14 and RN have the meanings as defined in claim 1.
3. The compound according to claim 1, wherein R2 represents RN
0 m -,o r,8 1 _____________ r R11 0 R8 \ , __ S 1 Rs r Rll S R8 \ / -_ ii \ / R8 R10 N .-,9 / R9 R10 R9 ; / R9 R10 R9 ;
; ; ;
RN RN RN RN RN RN
R11 N R8 R11 N, R11 N, __ N, N
ii _ R=NR 8 K -,(- =\/
N \ i N
/ R9 Rlo ss / R.n R i = -n R.n Rlo , RN Rlo N 8 Rl _ 11 0 8 - - O R8 ---- 1---R i0 - R, R -?
ca' R8 Y __________ N ) __ N N Y __ N N¨
wo R10 R10 R8 N¨ ' ;
RN RN
, , R10 RZyS, - Rii s ,rN8 - _ ,SN ___R8 - -õ.õ,1`1,N Rii N, 0\2 ir" 1 ¨ ir ii 1 ___ 'N
N N N N N
Rio Rio io R
10 R8 , , , , , ,N N"-R10 R10.,,N ,N e. RN
\ r/
,N, õN, oN r1 R13 R=-N-F\
\-, N-N ; N I-C =N ; .--,14 N R14 p12 R12 N R12 O---__' s I , S 13 R13 N Ri3 r Ri3 ---$_& -p13 \N
,,, N R14 N\-) i A
R14 N R14 R10 R." R10 R., RN
N,'µ ,712 s R12 ,õ------.../,:',2 p12 - - N---TR13 - - 1 \ 13 - ji 1 R14 N--%\- 1 A ___\7 R
\/\\--Rlo R." R14 R14 , , , , 2489-CIPO-CLAIMS-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 . ____________ Nv__R RN 14 N R9 r N ,R9 _ Rlo _ r Ii -/R9 R9 R1n N ___________ S
N /_Rio o) _ - (õ;
' \___,"-------0,,lo -, , R8 R8 ,S,- -R9 ,S - - - N, II
N\ N
\ I -s)---)\--N
,, R10 6-\ -N
\" N R8 S µ1\N , R8 , Rd . S,,,-- N,-- N
R ----- 1/ N R8--- -I IRa----- I/
N-N b-N N-0 0-N , , H
\ \ \ N __ \( , N
, , - -- -eNNH ¨ --eN0 S
--\ N - -c-ONJ NNJ
, , , I
I I
N
' -,,I\I N
I I
N.N 1 N N
, N NH
H ., . ., ., .
N fcìIIIIìNH , , H
N----_ or N, wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 - R14 and RN ; and preferably with 1 to 3 of the substituents R13 and the substituents R9 - R14 and RN have the meanings as defined in claim 1.
4. The compound according to claim 1, wherein the compound has the formula (lb) 2489-CIPO-CLAIMS-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 --- -N
i H
N ,L, 3 H
(lb) wherein L represents -L1- or _L1-L2-; preferably -1_1-L2-;
Ll represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2C0-, or -CH2CH2C0-;
L2 represents a bond, -NW"-, -NRN1CH2-, -NRN1CH2CH2-, or -NRN1CH(CH3)-;
R2 represents RN
R11 0 Rs - - S R8 R11 S R8 -- 8 \ - -II(R
R10 R9 ;
- R9 R10 R9 ;
, ; "
, RN RN RN RN
N
R11 N R8 R11 , Rii N, R11 0 _ -Rii 0__--R 8 ) __ N N
1 0 R9 R10 `, - R0 Rio R9 Rio , = , ; Rio Rio - _ 0 mRs N Os ¨ 0? Rio Rii S
0?,õ---x ----- .--- R1-_.1 SR8 ) N , N
R19 NR8 N¨ ' , R8 Rio / ___ N
RN
RN RN RN
-_ S Rs -_,,,N,k.
N Rii N R
, rill 1 __ /N 10___,N,N....RN N,N_____Rio N )¨N1 \¨N ,N
R10 Rlo , ' N¨N
, ' ' , ' , , N, D N
--------------------------- ¨R13 R13 N
- ..." N'" LI.,.,.,.,,;.,,,,\,; j \ II R13 N=N R14 N R14 N R14 N=R14 , RN
N R12 0 ------ /Y,) _ S ----_.// , N--__// RN
r --R,, - - -\TR'i - - -_____ \-) R14 R14 R14 _ r_IR
N=R14 Rlo R10 R10 ;
N---__/y, - S H
N----.%\
N 7'7R R
m) 13 13 N --\" i A
r-, - , , 14 ,-,0 , R14 , 2489-CIPO-CLAIMS-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 RN H
, ri R9 N , , N-R14 rN,R910 _ r /I
inX _____________ R - N S -N -cR 0) , , , 0 õ
- ___ -\_1_11 9 R9 /
\N
" --/_=-= R10 ,1\1\1-1.--, R10 NN
, S -µ.
, N N ,, ks S\, N N) NN \N R8 N_IN NN
, ,S -- R,8 N n ,S,-- ,- n N,,-- n Nõ,------N R`-'---\ 11 1)'-li R --- -! R ----- 1/
R8 IN-N \O-N IN- Or 0-N ;
, , , R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl, diamantyl, hexamethylenetetraminyl, and the afore-mentioned residues optionally contain one or more C=C double bond(s) and/or are substituted by one or more of Ra, Rb, Rc, Rd, and Re;
Ra, Rb, Rc, Rd, and Re represent independently of each other -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C2F-16, -CONH2, -CONHCH3, -CON(CH3)2, -CONHC2H6, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H6, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2H6, -NHCOCH3, -NHCOC2F16, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C21-16, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3;
R4 represents -NR6R7;
R6 and R7 represent independently of each other -H, -CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3, -cyclo-C31-16, -cyclo-C4H7, -cyclo-C61-16, -cyclo-C6H11, -CH2-cyclo-C3H6, -CH2-cyclo-C4H7, -CH2-cyclo-C61-16, -CH2-cyclo-C6H11, -Ph, -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2, or -NR6R7 is -N(C21-16)2, - -1\I -10 - -NO
or N/\ ).
2489-CIPO-CLAIMS-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 RN represents -H, -CH3, -C2E-13, -C3H7, -CH (CH3)2, -C4 H9 , -CH 2-CH (CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H3, -cyclo-C4H7, -cyclo-C31-19, -CH2-cyclo-C3H3, -CH2F, -CH F2 , -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3, -00C21-13, -00C3H7, -COCH (CH3)2, -COC(CH 3)3, -COOC H 3 , -COOC2H 5 , -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -SO2CH3, -SO2CF3, -SO2C2H3, -502C3H7, -SO2CH(CH3)2, or -502C(CH3)3;
RNI represent -H, -CH3, or -CH2CH3;
and R8 - R14 have the meanings as defined in formula (I);
or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomers, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
5. The compound according to any one of claims 1 - 4, wherein Ll represents -CH2-, or -CH2C0-;
L2 represents a bond, -NRNI-, -NRN1CH2-, or -NRNICH(CH3)-;
R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 4-homoisotwistyl, adamantyl, or diamantyl, and the afore-mentioned residues optionally contain one or more C=C double bond(s) and/or are substituted by one or more of Ra, Rb, Rc, Rd , and Re;
and Ra, Rb, Rc, Rd , Re and RNI have the same meanings as defined in claim 1.
6. The compound according to any one of the claims 1 - 5, wherein R2 represents Rlo 0 R8 0 R8 _ S R8 RSr R8 C)\
0\)R
Rii3 R9 R9 Rio R9 R8 N-N
RN RN
µ` R10 R11 5 R11 S 8 S R8 - R8 C)\
) __ N
R- RloI Rlo Rlo Rlo RN RN
RiNN Riz Riz N Rlo \
"
N. EioN pe, 13 N
N--- -------------------------------------------------- u N=N N R14 2489-CIPO-CLAIMS-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 RN
R13 - - TR13 - - -\ TR13 - -¨R13 \
- \R14 N i, N R14 R10 R ., R10 R10 R14 , , _ r / RR91() 111=Z:
RN
N ----/Y,) . . . . / - - - - .....õ - - -----/, µs I
N -%\-R14 A-) 1 n S r_. R9 1311.14 P¨ N - "\____/------- R10 , ' ' , ' ' , , RN o= ) D R8 ri R9 , , , , ,S - -/ - / i ._.11 9 _ N , 1 --/R10 Nz -\N
, 0 , S \S-N
, R8 , , N 1 , S - - - N, - - N
R - - - -,--N -S)- N- Ra -L-i -1 R8----N'N R8 N-N \O-N N "C) or 0-N
;
, , , and R8 ¨ R14 and RN have the meanings as defined in claim 1 or 2.
7. The compound according to any one of the claims 1 ¨ 6, wherein the compound has any one of the formulae (IV-a) ¨ (IV-o) and (V-a) ¨ (V-d):
O. JL -R6 )-L -NH
o NR
" 6 H 0 0 Rc 0 ( H 0 Rb R2j NH 1 NI-1,) N - Li¨ L2 )-L Rb H
0 0 Ra Ra (IV-a) (IV-b) o 0 o , NR6 ())L N. R6 H H Rb Ra 0 0 0 ( H 0 A H
Rc H 0 0 Ra H
0 0 Rd IR' Rb (IV-d) (IV-c) 0 N-R6 0 )-L N- R6 Rb Ra H Rb Ra H Rc 0 H 0 Rc 0 0 A j(H
H
0 0 Rd H
(IV-a) (IV-f) 2489-CIPO-CLAIMS-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 0 Rd o c:1A R6 o R6 N - N -H Rc H Rb Ra 0 0 0 0 Rc A H II
L2 A JC 111N ...-----õ,õ. L2 H
0 0 Rd (IV-g) (IV-h) (DA R6 (DA R6 N - Ra N-H
Rb j H
0 H 0 Rc 0 H 0 H
0 0 Rd H
(IV-i) (IV1) 0 N R6 OA N , R6 7p -H H
0 iCH 0 0 H 0 A N N R2 N ..----õ,_õ L2 A N
(IV-k) (IV-1) o o NHII
0 0 0 ,d 0 (IV-m) (IV-n) o 0 o, . R (DA 6 H
0 I\1)-L 12 ...--,...õ_õ. -__ R2). N Hc NH " - N L2 1 R8 \ I hi 1 N ._ R3 (IV-o) (V-a) 0 o o)- ,R6 N
H H
,------..õ,._ _R3 S:e(:- N /C H
N
R8 \ 1 N N 1 N R8-- I R10H 1 N L2-- R3 (V-C) (V-b) 2489-CIPO-CLAIMS-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 0 )-L N -R6 H
0 iFi 0 N
R12 d I
\
Rlo ¨
(V-d) and R2; R3 ; R6 ; R8 ; R9 ; R1 0 ; R1 1 ; R1 2 ; R1 3 ; Ra ; RI3 ; Rc ; Rd anCI - . L 2 have the same meanings as defined in claim 1.
8. The compound according to any one of the claims 1 ¨ 7, wherein R2 represents o 0 -- -(:)¨ Br -._ (:) q Br ____O______ 0- " 0 -S-*
0 \\-4 -Br, ; Br ;
s B r \_-S --- S - -\ // \ / y __ , _.-- -----u-C1 Br S
Br Br, ; Br) ; Br , S ---1Sr CI - - -CSBr -- -- --Sz-a --- S Br Br, ; CI , Br ; Br ; CI ; WO Br ;
--"' l CI
s S Br ci S Br C --1 5___ Br HN
NC ___ 0---, \
, , ------0 \ N ,--S
N
H2N N meo - - - <72 1N1 - - - '\- - - - - (/ 3 ,)-----(/
,--- ) 0 µ __ ,- __ 1 H ; 0 0--J N - N---NBr , , S,/ Br s__-C1 -------s__-Br -------s_-C1 Br-----.5 Br - - 1 N N ) __ N N N
N---N , , CI 5 __---C1 -JS-CF3 __ - --)S Br N N N ) __ N ) __ N
CI ; Br -- --)s,_-0Me -js_.- Ph \ //----SN__--CI ' C- \---NH
N N N N N // <=
N-N
N
I
Icl Icl NI, ,H 1 _NI
,N--- 1 -,,N,N N\"/N ',N ,N
N\ N\
1 HN/"'----1 \\ , __ > / >\ __ N )\ N N N
N ,/
N N , 2489-CIPO-CLAIMS-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 , J\i, . -....---,,,..,No2 -....---,,,,..õ. ,co2H -____---,..,.,,,. ,CO2nne N=Nj 002Me , N , The H
C) N --- / N,N'-.1\1 1 _-_ --I I
N r\j-N re N \= - __ \ 1\1 Br''' , - H
1\1 - \ \ , (---- 1-11--- HN--HN-- N S-' \/ 0 \_--------\--- \¨N-__\
, , , , ---N--- 0 -- \ -- \ -- \
s- ___________ N -- \
, , CI , Br , , I , S
-- \
, 0 ; o.--- s , , , ;
F H
S H \ N
S N N
-- \
Br H
N
F
H S
..--___ -----(\
F N N
OH ;
.--,_ , r3k;0 HN
H\ --- ---N N-- NN
, , :
, I\L -NI S.,õir -- ,S
--1 ----- e'N 'il"------ S
N N) .-\s_i\I s.N-----1N- N----1TN ' ' <\I Ki-- N\\ _IN
N
; ;
N \ N \ N \ _.. \I\ N ( \1_7.___ Ni\\
H
\N \N \N N - - N ---, 0 ; HO \/ \N-0 0-N , or NI--0-N and R6 represents -H, -CH3, -CH(CH3)2, -CH2CH2CH3, -CH2CH=CH2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CH2CH2CH2CH3, -cyclo-C3H3, -cyclo-C3119, -cyclo-C6H11 or -CH2-cyclo-C3H3.
2489-CIPO-CLAIMS-ZED-P04403W024.docx Date Recue/Date Received 2022-06-30 9. The compound according to claim 1 selected from the group consisting of:
Compound Name 11-2: (S)-2-(benzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-5-oxohexanediamide 11-3: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-4: (S)-2-(3-chlorobenzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-5-oxohexanediamide 11-5: (S)-2-(4-bromobenzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-5-oxohexanediamide 11-6: (S)-2-(4-bromobenzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-5-oxohexanediamide 11-7: (S)-2-(benzo[b]thiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-5-oxohexanediamide 11-8: (S)-2-(5-bromobenzo[b]thiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-5-oxohexanediamide 11-9: (S)-2-(1H-indole-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-5-oxohexanediamide 0-1 0: (S)-2-(4,5-difluoro-1H-indole-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-5-oxohexanediamide 0-11: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(3-methyl-1H-indole-2-carboxamido)-5-oxohexanediamide 0-1 2: (S)-2-(1H-benzo[d]imidazole-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-5-oxohexanediamide 0-1 3: (S)-2-(2,3-dihydro-1H-indene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-5-oxohexanediamide 11-1 4: (S)--(2-bromo-4-methylthiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-2489-CIPO-CLAIMS-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 methy1-5-oxohexanediamide 11-1 5: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(4-methy1-2-(trifluoromethyl)thiazole-5-carboxamido)-5-oxohexanediamide 11-1 6: (S)-2-(4-bromo-2-(trifluoromethyl)thiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-1 7: (S)-2-(2,4-dichlorothiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-1 8: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(2-methoxy-4-methylthiazole-5-carboxamido)-N6-methy1-5-oxohexanediamide 11-1 9: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(4-methy1-2-phenylthiazole-5-carboxamido)-5-oxohexanediamide 11-20: (S)-2-(2,4-dimethylthiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-21: (S)-2-(5-bromo-3-methylthiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-22: (S)-2-(3,5-dibromothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-23: (S)-2-(5-bromothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-24: (S)-2-(5-chlorothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-25: (S)-2-(5-bromo-3-methylfuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-26: (S)-2-(5-chlorofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-27: (S)-2-(5-chlorothiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-2489-CIPO-CLAIMS-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 methy1-5-oxohexanediamide 11-28: (S)-2-(2,5-dichlorothiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-29: (S)-2-(2,5-dibromothiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-30: (S)-2-(5-bromothiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-31: (S)-2-(2-chloro-5-methylthiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-32: (S)-2-(2,5-dichlorothiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-33: (S)-2-(2,5-dibromothiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-34: (S)-2-(2-bromo-5-methylthiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-35: (S)-2-(2-bromothiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-36: (S)-2-(2-chlorothiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-37: (S)-2-(2,5-dimethylfuran-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-38: (S)-2-(4,5-dimethylthiazole-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-39: (S)-2-(4-bromothiazole-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-40: (S)-2-(4-bromothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-2489-CIPO-CLAIMS-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 methy1-5-oxohexanediamide 11-41: (S)-2-(4-bromo-3-methylthiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-42: (S)-2-(3-bromothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-43: (S)-2-(3-chloro-4-methylthiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-44: (S)-2-(4-bromo-5-chlorothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-45: (S)-2-(4,5-dibromothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-46: (S)-2-(4,5-dibromo-3-methoxythiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-47: (S)-2-(4-bromofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-48: (S)-2-(4,5-dibromofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-49: (S)-2-(4,5-dichlorothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-50: (S)-2-((S)-1-acetylpyrrolidine-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-51: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-1,2,3-triazole-5-carboxamido)-5-oxohexanediamide 11-52: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(2H-tetrazole-5-carboxamido)hexanediamide 2489-CIPO-CLAIMS-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-53: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(pyrazine-2-carboxamido)hexanediamide 11-54: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-24(S)-1-methylpyrrolidine-2-carboxamido)-5-oxohexanediamide 11-55: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-24(S)-pyrrolidine-3-carboxamido)hexanediamide 11-56: (S)-24(25,45)-4-bromopyrrolidine-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-58: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-24(S)-piperidine-2-carboxamido)hexanediamide 11-59: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-24(R)-piperidine-3-carboxamido)hexanediamide 11-60: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-24(R)-morpholine-3-carboxamido)-5-oxohexanediamide 11-61: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(quinuclidine-3-carboxamido)hexanediamide 11-62: (S)-methyl 3-(1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-ylcarbamoy1)-5-nitrobenzoate 11-63: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(5-nitronicotinamido)-5-oxohexanediamide 11-64: (S)-5-(1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinic acid 11-65: (S)-methyl 5-(1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinate 11-66: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(6-methylimidazo[2,1-b]thiazole-5-carboxamido)-5-oxohexanediamide 2489-CIPO-CLAIMS-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-67: (S)-N1-(1-(2-(2-adamantyl(methyl)amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-68: (S)-N1-(1-(2-(5-hydroxyadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-69: (S)-N1-(1-(2-(5-fluoroadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-70: (S)-N1-(1-(2-(5-chloroadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-71: (S)-N1-(1-(2-(5-bromoadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-72: (S)-N1-(1-(2-(5-methyladamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-73: (S)-N1-(1-(2-(2-carbonitrileadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-74: (S)-N1-(1-(2-(2-methyl adamantane-2-carboxylate-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-87: (S)-N1-(1-(2-(1-adamantylmethylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-88: (S)-N1-(1-(2-(1-(1-adamantyl)ethanamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-90: (S)-N1-(1-(2-((1R,25,45)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methyl benzofuran-2-carboxamido)-5-oxohexanediam ide 11-92: (S)-N1-methy1-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1S,25,4R)-1,7,7-trimethylbicyclo[2.2.11heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-y1)hexanediamide 11-94: (S)-N1-(1-(2-((1R,2R,45)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 2489-CIPO-CLAIMS-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-95: (S)-N1-(1-(2-(bicyclo[2.2.1]heptan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-dihyd ropyridin-3-y1)-N6-methy1-2-(3-methylbenzofu ran-2-carboxam ido)-5-oxohexanediam ide 11-96: (S)-N1-(1-(2-(bicyclo[2.2.1]heptan-7-ylam ino)-2-oxoethyl)-2-oxo-1,2-dihyd ropyridin-3-y1)-N6-methy1-2-(3-methylbenzofu ran-2-carboxam ido)-5-oxohexanediam ide 11-97: (S)-N1-(1-(2-(bicyclo[2.2.1]hept-5-en-2-ylam ino)-2-oxoethyl)-2-oxo-1,2-di hyd ropyrid in-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxam ido)-5-oxohexanediam ide 11-98: (25)-N 1-(1-(2-(bicyclo[2.2.2]octan-2-ylam ino)-2-oxoethyl )-2-oxo-1,2-dihyd ropyridin-3-y1)-N6-methy1-2-(3-methylbenzofu ran-2-carboxam ido)-5-oxohexanediam ide 11-99: (S)-N1-methy1-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediam ide 11-100: (S)-N1-methy1-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylam ino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide 11-101: (S)-N1-methy1-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1S,25,35,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylam ino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide 11-103: (S)-N1-(1-(2-(4-homoisotwistane-3-amino)-2-oxoethyl )-2-oxo-1,2-dihyd ropyridin-3-y1)-N6-methy1-2-(3-methylbenzofu ran-2-carboxam ido)-5-oxohexanediam ide 11-104: (S)-N1-(1-(2-(diamantane-1-am i no)-2-oxoethyl)-2-oxo-1,2-dihyd ropyridin-3-y1)-N6-methy1-2-(3-methylbenzofu ran-2-carboxam ido)-5-oxohexanediam ide 11-105: (S)-N1-(1-(2-(diamantane-4-am i no)-2-oxoethyl)-2-oxo-1,2-dihyd ropyridin-3-y1)-N6-methy1-2-(3-methylbenzofu ran-2-carboxam ido)-5-oxohexanediam ide 11-107: (S)-N1-(1-(1-adamantylmethyl)-2-oxo-1,2-d ihydropyrid in-3-y1)-methy1-2-(3-methyl benzofu ran-2-carboxam ido)-5-oxohexaned i am ide 11-108: (25)-N 1-(14(3-hydroxy-1-adamantyl)methyl)-2-oxo-1,2-dihyd ropyridin-3-y1)-N6-methy1-2-(3-methylbenzofu ran-2-carboxam ido)-5-oxohexanediam ide 11-109: (25)-N 1-(14(3-bromo-1-adam antyl )methyl)-2-oxo-1,2-dihyd ropyridi n-3-y1)-N6-methy1-2-(3-m ethyl be nzofu ra n-2-carboxam ido)-5-oxohexanediamide 11-110: (S)-N1-(1-(2-adamantylmethyl)-2-oxo-1,2-d ihydropyrid in-3-y1)-methy1-2-(3-methyl benzofu ran-2-carboxam ido)-5-oxohexaned i am ide 2489-CIPO-CLAIMS-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 11-111: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(nicotinamido)-5-oxohexanediamide 11-112: (S)-2-(isonicotinamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 0-113: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(pyridazine-4-carboxamido)hexanediamide 11-114: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(pyridazine-3-carboxamido)hexanediamide 11-115: (S)-N1-cyclopropyl-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(3-methylbenzofuran-2-carboxamido)-2-oxohexanediamide 11-116: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(3-methylbenzofuran-2-carboxamido)-5-oxo-N6-pentylhexanediamide 11-117: (S)-N1-allyl-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(3-methylbenzofuran-2-carboxamido)-2-oxohexanediamide 11-115: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-119: (S)-N1-ally1-5-(benzofuran-2-carboxamido)-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxohexanediamide 11-120: (S)-2-(benzofuran-2-carboxamido)-N6-isopropyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide 11-121: (S)-2-(benzofuran-2-carboxamido)-N6-cyclopropyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide 11-122: (S)-2-(benzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxo-N6-phenylhexanediamide 11-123: (S)-2-(benzofuran-2-carboxamido)-N6-benzyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide 11-124: (S)-2-(benzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide 2489-CIPO-CLAIMS-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 8-125: (S)-2-(2,5-dichlorothiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide 11-126: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(4-methy1-2-(trifluoromethyl)thiazole-5-carboxamido)-5-oxohexanediamide 8-127: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(1-methy1-1H-1,2,3-triazole-5-carboxamido)-5-oxohexanediamide 8-128: (25)-N1-(1-(24(1R,2R,45)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(2,5-dichlorothiophene-3-carboxamido)-N6-methyl-5-oxohexanediamide 11-129: (25)-N1-(1-(24(1R,2R,45)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(4-methyl-2-(trifluoromethyl)thiazole-5-carboxamido)-5-oxohexanediamide 8-130: (25)-N1-(1-(24(1R,2R,45)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(1-methyl-1H-1,2,3-triazole-5-carboxamido)-5-oxohexanediamide 8-131: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(2H-1,2,3-triazole-4-carboxamido)hexanediamide 11-132: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1H-1,2,3-triazole-4-carboxamido)hexanediamide 8-133: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-1,2,3-triazole-4-carboxamido)-5-oxohexanediamide 8-134: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1H-1,2,4-triazole-3-carboxamido)hexanediamide 8-135: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-1,2,4-triazole-3-carboxamido)-5-oxohexanediamide 8-136: (S)-2-(benzofuran-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 8-137: (S)-2-(benzo[b]thiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 2489-CIPO-CLAIMS-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 (S)-N1-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-11-138 dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-pyrazole-3-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-11-139 dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-pyrazole-4-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-11-140 dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-pyrazole-5-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-11-141 dihydropyridin-3-y1)-N6-methy1-2-(4-methy1-1,2,3-thiadiazole-5-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-11-142 dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1,2,5-thiadiazole-3-carboxamido)hexanediamide (S)-2-(4-iodo-1-methy1-1H-pyrazole-5-carboxam ido)-N1-(1-(2-(2-11-143 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide (S)-N1-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-11-144 dihydropyridin-3-y1)-2-(1-methy1-1H-pyrazole-5-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-11-145 dihydropyridin-3-y1)-2-(4-methy1-1,2,3-thiadiazole-5-carboxamido)-5-oxohexanediamide (S)-2-(benzofuran-2-carboxam ido)-N1-(1-(2-((1R,2R,4S)-11-146 bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide (S)-N1-(1-(2-((1R,2R,45)-bicyclo[2.2.1]heptan-2-ylamino)-2-11-147 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(3-methylbenzofuran-carboxamido)-5-oxohexanediamide (S)-2-(benzofuran-2-carboxam ido)-N1-(1-(2-((1S,2R,4R)-11-148 bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylam ino)-2-II-149 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(3-methylbenzofuran-carboxamido)-5-oxohexanediamide (S)-2-(benzofuran-2-carboxam ido)-5-oxo-N1-(2-oxo-1-(2-oxo-2-11-150 ((1R,25,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide 2489-CIPO-CLAIMS-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 (S)-2-(3-methylbenzofuran-2-carboxamido)-5-oxo-N1-(2-oxo-1-(2-11-151 oxo-2-((1R,25,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-y1)hexanediamide (S)-N1-(1-(2-((1R,2R,45)-bicyclo[2.2.1]heptan-2-ylamino)-2-11-152 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(4-methy1-1,2,3-thiadiazole-5-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-((1R,2R,45)-bicyclo[2.2.1]heptan-2-ylamino)-2-11-153 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-pyrazole-5-carboxamido)-5-oxohexanediamide (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylam ino)-2-11-154 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(4-methy1-(trifluoromethyl)thiazole-5-carboxamido)-5-oxohexanediamide (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylam ino)-2-11-155 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(2,5-dichlorothiophene-3-carboxamido)-N6-methy1-5-oxohexanediamide (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylam ino)-2-11-156 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(4-methy1-1,2,3-thiadiazole-5-carboxamido)-5-oxohexanediamide (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylam ino)-2-11-157 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1,2,3-triazole-5-carboxamido)-5-oxohexanediamide (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylam ino)-2-11-158 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-pyrazole-5-carboxamido)-5-oxohexanediamide (S)-N1-methy1-5-(4-methy1-2-(trifluoromethyl)thiazole-5-11 159 carboxam ido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1R,25,4R)-1,7,7--trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide (S)-2-(2,5-dichlorothiophene-3-carboxam ido)-N6-methy1-5-oxo-N1-11-160 (2-oxo-1-(2-oxo-2-((1R,25,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide (S)-N1-methy1-5-(4-methy1-1,2,3-thiadiazole-5-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1R,25,4R)-1,7,7-11-161 trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide (S)-N1-methy1-5-(1-methy1-1H-1,2,3-triazole-5-carboxam ido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1R,25,4R)-1,7,7-11-162 trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide (S)-N1-methy1-5-(1-methy1-1H-pyrazole-5-carboxam ido)-2-oxo-N6-11-163 (2-oxo-1-(2-oxo-2-((1R,25,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide 2489-CIPO-CLAIMS-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 (2S)-2-(4-tert-buty1-1H-pyrrole-3-carboxam ido)-N6-methyl-N1-(1-(2-11-164 (1-adamantylamino)ethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide (25)-2-(4-cyano-1-methy1-1H-pyrrole-2-carboxam ido)-N6-methyl-N1-11-165 (1-(3-(1-adamantylamino)propy1)-2-oxo-1,2-dihydropyridin-3-y1)-oxohexanediamide (S)-N1-(1-(3-(2-adamantylam ino)-3-oxopropy1)-2-oxo-1,2-11-166 dihydropyridin-3-y1)-2-(5-methoxyoxazole-2-carboxamido)-N6-methy1-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-167 dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide (S)-2-(2-acetyloxazole-4-carboxam ido)-N1-(1-(2-11-168 (bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-169 dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-170 dihydropyridin-3-y1)-2-(2-isopropyloxazole-5-carboxamido)-N6-methy1-5-oxohexanediamide (25)-2-(benzofuran-2-carboxamido)-N1-(1-(2-(bicyclo[3.2.1]octan-8-11-171 ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-oxohexanediamide (25)-N1-(1-(2-(bicyclo[3.2.1]octan-8-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-172 dihydropyridin-3-y1)-2-(3,5-dimethylisoxazole-4-carboxamido)-methy1-5-oxohexanediamide (S)-N1-(1-(2-(5-carboxy-2-am inoadamantane)-2-oxoethyl)-2-oxo-11-173 1,2-dihydropyridin-3-y1)-N6-methy1-2-(4-methylpyrimidine-5-carboxamido)-5-oxohexanediamide (25)-N1-(1-(2-(4-aminoadamantane-N,N-dimethy1-1-carboxamide)-2-11-174 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1,2,3,4-tetrahydronaphthalene-2-carboxamido)hexanediamide (S)-2-((S)-1,4-diazabicyclo[2.2.2]octane-2-carboxam ido)-N6-tert-11-176 butyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide (S)-N1-tert-buty1-5-(1H-indole-3-carboxamido)-N6-(1-(2-(2-11-176 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxohexanediamide 2489-CIPO-CLAIMS-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 (S)-N1-tert-butyl-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-11-177 1,2-dihydropyridin-3-y1)-5-(6-methylimidazo[2,1-b]thiazole-3-carboxamido)-2-oxohexanediamide (S)-2-(benzo[d]thiazole-2-carboxam ido)-N1-(1-(2-((1S,2R,4R)-11-178 bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-cyclopenty1-5-oxohexanediamide (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylam ino)-2-11-179 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-cyclopenty1-2-(imidazo[2,1-b]thiazole-6-carboxamido)-5-oxohexanediamide (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylam ino)-2-11 180 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-cyclopenty1-2-(4--hydroxy-6-(trifluoromethoxy)quinoline-3-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-181 dihydropyridin-3-y1)-2-(cinnoline-3-carboxamido)-N6-cyclohexy1-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-182 dihydropyridin-3-y1)-N6-cyclohexy1-2-(3-ethylbenzofuran-2-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-183 dihydropyridin-3-y1)-N6-cyclohexy1-2-(1-ethy1-1H-indole-2-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-184 dihydropyridin-3-y1)-N6-cyclohexy1-2-(2-methy1-1,8-naphthyridine-3-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-185 dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1,2,3,4-tetrahydroquinoline-6-carboxamido)hexanediamide (S)-N1-(1-(2-(2-carboxy-2-am ino-5-(trifluoromethyl)adamantane)-2-11-186 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(3-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)hexanediamide (S)-N1-(1-(2-(5-ethyladamantane-2-am ino)-2-oxoethyl)-2-oxo-1,2-11-187 dihydropyridin-3-y1)-N6-methy1-2-(1,6-naphthyridine-2-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-188 dihydropyridin-3-y1)-N6-methy1-2-(2,6-naphthyridine-1-carboxamido)-5-oxohexanediamide (S)-2-(4-amino-1,2,5-oxadiazole-3-carboxamido)-N1-(1-(2-11-189 (bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 2489-CIPO-CLAIMS-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-190 dihydropyridin-3-y1)-2-(6-(dimethylamino)benzofuran-2-carboxamido)-N6-methy1-5-oxohexanediamide (S)-2-(2-acetamidothiazole-5-carboxamido)-N1-(1-(2-11-191 (bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide (S)-N4-(1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-11-192 1,2-dihydropyridin-3-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-y1)-1H-pyrrole-2,4-dicarboxamide (S)-N1-(1-(2-(1-acetylamino-4-am inoadamantane)-2-oxoethyl)-2-11-193 oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(5-sulfamoylfuran-3-carboxamido)hexanediamide (S)-2-(benzofuran-5-carboxam ido)-N1-(1-(2-(1-acetylam ino-4-11-194 am inoadamantane)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-methy1-5-oxohexanediam ide (S)-2-(benzofuran-6-carboxam ido)-N1-(1-(2-(4-aminoadamantane-1-11-195 carboxamide)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide (S)-N1-(1-(2-(4-am inoadamantane-1-carboxamide)-2-oxoethyl)-2-11-196 oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-(1-methylcyclopropy1)-1,2,4-oxadiazole-5-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-197 dihydropyridin-3-y1)-N6-methy1-2-(5-methy1-1,2,4-oxadiazole-3-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-198 dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1,2,3-thiadiazole-4-carboxamido)hexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-199 dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1,2,4-thiadiazole-5-carboxamido)hexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-200 dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1,3,4-thiadiazole-2-carboxamido)hexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-201 dihydropyridin-3-y1)-2-(4-cyclopropy1-1,2,3-thiadiazole-5-carboxam ido)-N6-methy1-5-oxohexanediamide (S)-2-(4-cyclopropy1-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-11-202 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 2489-CIPO-CLAIMS-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 (S)-2-(4-isopropyl-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-11-203 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-5-oxohexanediamide (S)-2-(4-ethyl-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-11-204 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-5-oxohexanediamide (S)-2-(4-formyl-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-11-205 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-5-oxohexanediamide (S)-2-(4-(hydroxymethyl)-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-11-206 (2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-5-oxohexanediamide (S)-N1-(1-(2-(1-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-11-207 y1)-N6-methy1-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(((1S,2R,55)-6,6-dimethylbicyclo[3.1.1Theptan-2-11-208 yl)methylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(1-methyl-1H-imidazole-2-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(((1R,2R,5R)-6,6-dimethylbicyclo[3.1.1Theptan-2-11-209 yl)methylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(1H-imidazole-4-carboxamido)-N6-methyl-5-oxohexanediamide (S)-N1-(1-(2-(3,5-dimethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-11-210 dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-imidazole-5-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(3,5,7-trimethy1-1-adamantylamino)-2-oxoethyl)-2-oxo-1,2-11-211 dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-imidazole-5-carboxamido)-5-oxohexanediamide or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising a compound of any one of the claims 1 ¨ 9 as an active ingredient, together with at least one pharmaceutically acceptable carrier, excipient and/or diluent.
11. Compound according to any one of the claims 1 ¨ 9 for use in medicine.
12. Compound according to any one of the claims 1 ¨ 9 or the pharmaceutical composition according to claim 9 for use in the treatment or prophylaxis of autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, ocular diseases, and skin disorders.
2489-CIPO-CLAIMS-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 13. Compound for use, or the pharmaceutical composition for use according to claim 12, wherein the autoimmune and inflammatory diseases comprise multiple sclerosis, celiac disease, Duhring-Brocq-disease (dermatitis herpetiformis), gluten ataxia, gluten neuropathy, diabetes, rheumatoid arthritis, Graves' disease, inflammatory bowel disease, systemic lupus erythematosus psoriasis, and gingivitis; wherein the vascular diseases comprise atherosclerosis, thrombosis, vascular stiffness;
wherein the fibrotic diseases affect the lung, the kidney, the liver, the skin or the gut like cystic fibrosis, kidney fibrosis and diabetic nephropathy, intestinal fibrosis, idiopathic lung fibrosis, liver fibrosis; wherein the liver diseases comprise alcoholic hepatitis, alcoholic steatohepatitis, nonalcoholic steatohepatitis, non-alcoholic fatty liver disease, liver cirrhosis, autoimmune hepatitis or liver inflammation; wherein the cholestatic liver diseases comprise primary biliary cholangitis and primary sclerosing cholangitis; wherein the cancer comprises glioblastoma, melanoma, pancreatic cancer, renal cell carcinoma, meningioma, and breast cancer, wherein the neurodegenerative diseases comprise Parkinson's disease, Huntington's disease, or Alzheimer's disease, wherein the ocular diseases comprise glaucoma, cataracts, macular degeneration, or uveitis; and wherein the skin disorders comprise acne, psoriasis, scarring, and skin aging.
14. Compound for use, or the pharmaceutical composition for use according to any one of the claims 12 and 13 in the treatment or prophylaxis of celiac disease.
15. A method for producing the compound of formula (lb) according to claim 1 or 3 comprising:
Step 1B: providing a compound 4b AcO)-LN.R6 ' H 0 4b;
Step 2B: performing coupling reaction of the compound 4b with a compound 5 H2N)-L L
, N- 'R3 to obtain a compound 6b 2489-CIPO-CLAIMS-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30 Ac0 , R6 PG3Ni\O- _L.
N R-6b;
Step 3B: deprotecting an amino protecting group PG3to obtain a compound 7b Ac0)-L , R6 'R-7b;
Step 4B: performing coupling reaction of the compound 7b with a carboxylic acid (R2-CO2H 8) to obtain a compound 9b Ac0 , R6 N R-9b;
Step 5B: performing oxidation reaction of the compound 9b to produce the compound of the formula (lb) N
(lb);
wherein L, R2, R3, R6and R7 have the same meanings as defined in claim 1, and PG3 is an amino protecting group.
2489-CIPO-CLAIMS-ZED-P04403W024 docx Date Recue/Date Received 2022-06-30
1. A compound of the general formula (I):
0 (0 H (1) R2 N N ,,N yL R3 wherein L represents ¨L1¨ or ¨L1-L2¨; and preferably ¨L1-L2¨;
Ll represents ¨CH2¨, ¨CH2CH2¨, ¨CH2CH2CH2¨, ¨CH2C0¨, or ¨CH2CH2C0¨;
L2 represents a bond, ¨NR141¨, ¨NRN1CH2¨, ¨NRN1CH2CH2¨, or ¨NRN1CH(CH3)¨;
0 0 õp RI represents or 1 0 R2 represents Rii \ s R8 RN
0 m O r-t8 1 __________ r R11 0 R8 __ S Rs \ / / _ _ N
\ / R8 , \ /
'' ' R9 R10 R9 ; R9 R10 R9 ;
' , ' RN RN RN RN RN
RN
R11 N R8 R11 N, Ri 1 N, R11 N
N_ - - R11 N
ns8 -I4N 1 iN
I --i' =ii.-1-µ
, 4 K n N
, __ N
, R9 R10 `, / R9 R .- w R1c) , ' , RN R1c) R10 Rt0, 1.1 /7- / RtLa,, R8 - __<0., Rs - -ir 0.) R8 N N N Y __ N N
R19 R19 R19 R8 N- , , , , ' RN RN
R10 Rii S 1 S 8 - - -- - N. 11 N
0 ---- Ri ---IR S R8 R' :1\1 2 ______________________ N ) __ N 2 __ N 2 __ N
) _________________________________________________________________________ N
N-----\R8 , FN 010 , , R10 R10 , ' , RN
, N R10 R10 oN
, _ _ r, , N, N ri R9 p 1 3 N ;,--- --Ni 1 ---1,1,TR -(--\_j----R10 N-N ; LC--"\--Djp, 1¶4 \-N
i ; , , -, R12 R12 R12 N R12 0---__ R13 /') R13 ------------------------- N
R13 r ---TR13 Ri3 -\ 4,, ----------- \-) \N=\-) R ,-, N=R14 N R14 N R14 N=R14 R10 2489-CIPO-CLAIMS-ZED-P04404W026.docx Date Recue/Date Received 2022-06-30 RN
R12 S R12 R N i \ i ----, ./Y R12 , 13 i \ 1 /Y,) --TR
c_\7R
R14 R14 N-----.%\- iA
_ _II '/ :IR9 10 :____s 14 ii y, R9 R9 / ______ N N R
-2- 1 R13 _ . f R 1 0 N - --/_,--)14. _R1 0 R._ R10 N--- 0 , 9 R R8 R8 ,S,r - R8 r\-/-.: 1 n N'\\ -.SX- mi -- 0 0)----NI).-\ /NI - R8õ,_<\s'ii". Ni7/ 1 --(-: ki _R .,., \ , ,.." N R8 \ s-N N-_---N R8 N-N , 6-N
N, - N, - 0 R8-- -] - R8---- /1 -N- , , 0-N N
, , H
N 0 $ S
ij , N
, , , , , _7 ---eNNH ' --eNNH
N
-- A - -(3 N _______ ( Nj N
- N
N N __ \( S , S y N
---eNNH ---eNNH
IIN , NiNj N __ ( v(D ONJ
, _7N N
-- A - - -(3 - - -eN0 - - -eN0 N N N
/ \( Z NiNj N , ' H S
N _<7 n -----('-----N\
N N-N'S
H H , , , , N ---___.--0 H
N
A-NI S-N-N/
' 0 , ._--N-_._ H H , , , /
----1\----1----, 1\1 '-N
N, ' 2489-CIPO-CLAIMS-ZED-P04404W026.docx Date Recue/Date Received 2022-06-30 r 6 X 0 CD 6 , , , , , , , , ) , ,, , , , , ,, ,, , / / , ,, , z_ /
, , c > / , CD K Z=
0 W Z/ Z/ Z=z Z_ Z_ z/_ ¨z CD rili / 1/ \ /K \ /( \ $ / /
L / \ Z
rD' 0 \ /
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N) g o x N) ri) CD
e..) Z= /¨ /¨ Z= __ / Z= Z / -- / /
__ / /Z Z\ /Z Z\ /Z Z Z Z , z , /Z \ /Z
\ /K \ /( , /( \ /K
\ / / K Z \ /
Z
Z
Z Z Z Z
--NI
z / \ z, , j \ \ //Z Z / Z Z //Z Z //Z \ z/ \z / Z_ / \ //Z \ / \ z, Z \ / Cil Z-Z Z
---_ -/
/_ /_ Z= Z= Z= ________________________________________ /¨ Z= Z¨ /¨ /-- --Z=-Z \ Z \ Z\ /Z /Z /Z /Z /Z Z \ /Z /Z / Z
/ Z \ /
( ( ( Z Z \ J \ \ Z Z \ z Z
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/ \ ___ //Z z Z
Z Z I Z Z-Z // Z
Z¨// Z¨// Z Z Z Z
-- - --- -N ---NN, Nle , NõN
, N '-'' I I I
N1, 1\1N1 NN
, , õ
1 ir 1\1N--N N-,1\1 , N
, , - - N, N
N.NN N.NN I
1\1N
H õ
HN NH
' , , , õ
N NH, H
, N=\ 0 N=N N=\ N---N
\ N
N/ \ ' ,,N
, N- N- N- -1\1µ -N
--- _____________________________________________________ -- / -- N
__________________________________ / //1\1 N N ' , / ______________________ N ' , -N -N -\ ___\
-- ________________________ -- \ -- /N --tsN
-- ( N \ /il , N , N N
, \
=
N -\
, --\ N --\ N
N --I\1 N N
// , N=\ N=\
--- /(1\1 --- /N
\ / N / N / N N N S
N N-N // N
, , , , N=N N=N N=N N=N N=N
---, \ /71 /
N N
, 2489-CIPO-CLAIMS-ZED-P04404W026.docx Date Recue/Date Received 2022-06-30 ( \
\ /71; " N N \ IV
/ \ __ N N , , --- \
N/ //N N-N N NsN /
, , , , , __Ns- /N ---/N -- /N -- \ /N
( \ N \ /71; \ ______ \ N, N ___ \ ' , .. N
, --i --i \ N N N / N / N
N-// // N-N N sN __ /
, , , , _______ , /( \
N N , N/ //N' N-N N
, --\
II
N /
Ns, \ N N N N N i\I-N
N // -N , N- , , \1 N 1,/ , or wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 -R14, RN; and preferably with 1 to 3 of the substituents R11 -R13;
R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl, diamantyl, hexamethylenetetraminyl and the afore-mentioned residues optionally contain one or more C=C double bond(s) and/or are substituted by one or more of Ra, Rb, Rc, Rd, and Re;
Ra, Rb, Rc, Rd, and Re represent independently of each other -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C2F-15, -CONH2, -CONHCH3, -CON(CH3)2, -CONHC2F15, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H5, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2F15, -NHCOCH3, -NHCOC2F15, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C21-15, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3;
2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 R4 represents -R5, -0R5 or -NR6R7;
R5 represents -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CH2CH2CH2CH3, -CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-051-19, -cyclo-C6H11, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-051-19, -CH2-cyclo-C6H11, -Ph, -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, or -CH2CH2OCH2CH3;
R6 and R7 represent independently of each other -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3, -cyclo-C3F15, -cyclo-C4H7, -cyclo-051-19, -cyclo-C6H11, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-051-19, -CH2-cyclo-C6H11, -Ph, -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2NHCH3, or -CH2CH2N(CH3)2, / - -N -N O N\
/ \
or -NR6R7 represents - -< - or R6, R5, R10, R11, R12, R13, and R14 represent independently of each other -H, -F, -C1, -Br, -1, -OH, -CN, -NO2, -CH3, -C2F15, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3F15, -CH2-cyclo-C3F15, -CH2OH, -CH2F, -CHF2, -CF3, -CH2C1, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2C1, -CH2-CH2Br, -CH2-CH21, -OCH3, -0C21-15, -0C3H7, -OCH(CH3)2, -0C(CH3)3, -0C4H9, -OCHF2, -OCF3, -OCH2CF3, -OC2F5, -OCH2OCH3, -0-CyClo-C3F15, -OCH2-CyClo-C3H5, -0-C2H4-CyClo-C3H5, -CHO, -COCH3, -COCF3, -00C21-15, -00C3H7, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -00C-CH3, -00C-CF3, -00C-C2H5, -00C-C3H7, -00C-CH(CH3)2, -00C-C(CH3)3, -NH2, -NHCH3, -NHC2F15, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC21-15, -NHCOC3H7, -NHCOCH(CH3)2, -NHCOC(CH3)3, -CONH2, -CONHCH3, -CONHC2F15, -CONHC3H7, -CONHCH(CH3)2, -CONH-cyclo-C3F15, -CONHC(CH3)3, -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -SO2NHCH(CH3)2, -SO2NH-cyclo-C3H5, -SO2NHC(CH3)3, -502N(CH3)2, -502N(C2H5)2, 2489-CIPO-CLAIMS-ZED-P04404W026.docx Date Recue/Date Received 2022-06-30 -SO2N(C3H7)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C2H5, -NHSO2C3H7, -NHSO2CH (CH3)2, -NHSO2C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -CECH, -CEC-CH3, -CH2-CECH, -Ph, -0-Ph, -0-CH2-Ph, r1\1 -Nr-N -- r r1\1 r1\1 r / __ \ / __ \ / __ \
N\ /NH N\ N
Or N\ /N
or R9 and R9 or R9 and R1 can form together one of the following five-membered or six-membered rings:
.0 - - -1\1 --_1, _1\1 -or or R12 and R13 or R13 and R14 can form together one of the following five-mem bered or six-membered rings:
.0 .0 .0 .0 0 H or I
RN represents -H, -CH3, -C2F15, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH (CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-051-19, -CH2-cyclo-C3F15, -CH2-cyclo-C4H7, -CH2-cyclo-051-19, -CH2F, -CHF2, -CF3, -CH2C1, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2C1, -CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3, -00C21-15, -00C3H7, -COCH (CH3)2, -COC(CH3)3, -CO-cyclo-C3H5, -CO-cyclo-C4H7, -CO-cyclo-051-19, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -502CH3, -502CF3, -502C2H5, -502C3H7, -SO2CH (CH3)2, -502-cyclo-C3H5, or -502C(CH3)3;
RI" represents -H, -CH3, or -CH2CH3;
2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomers, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
0 (0 H (1) R2 N N ,,N yL R3 wherein L represents ¨L1¨ or ¨L1-L2¨; and preferably ¨L1-L2¨;
Ll represents ¨CH2¨, ¨CH2CH2¨, ¨CH2CH2CH2¨, ¨CH2C0¨, or ¨CH2CH2C0¨;
L2 represents a bond, ¨NR141¨, ¨NRN1CH2¨, ¨NRN1CH2CH2¨, or ¨NRN1CH(CH3)¨;
0 0 õp RI represents or 1 0 R2 represents Rii \ s R8 RN
0 m O r-t8 1 __________ r R11 0 R8 __ S Rs \ / / _ _ N
\ / R8 , \ /
'' ' R9 R10 R9 ; R9 R10 R9 ;
' , ' RN RN RN RN RN
RN
R11 N R8 R11 N, Ri 1 N, R11 N
N_ - - R11 N
ns8 -I4N 1 iN
I --i' =ii.-1-µ
, 4 K n N
, __ N
, R9 R10 `, / R9 R .- w R1c) , ' , RN R1c) R10 Rt0, 1.1 /7- / RtLa,, R8 - __<0., Rs - -ir 0.) R8 N N N Y __ N N
R19 R19 R19 R8 N- , , , , ' RN RN
R10 Rii S 1 S 8 - - -- - N. 11 N
0 ---- Ri ---IR S R8 R' :1\1 2 ______________________ N ) __ N 2 __ N 2 __ N
) _________________________________________________________________________ N
N-----\R8 , FN 010 , , R10 R10 , ' , RN
, N R10 R10 oN
, _ _ r, , N, N ri R9 p 1 3 N ;,--- --Ni 1 ---1,1,TR -(--\_j----R10 N-N ; LC--"\--Djp, 1¶4 \-N
i ; , , -, R12 R12 R12 N R12 0---__ R13 /') R13 ------------------------- N
R13 r ---TR13 Ri3 -\ 4,, ----------- \-) \N=\-) R ,-, N=R14 N R14 N R14 N=R14 R10 2489-CIPO-CLAIMS-ZED-P04404W026.docx Date Recue/Date Received 2022-06-30 RN
R12 S R12 R N i \ i ----, ./Y R12 , 13 i \ 1 /Y,) --TR
c_\7R
R14 R14 N-----.%\- iA
_ _II '/ :IR9 10 :____s 14 ii y, R9 R9 / ______ N N R
-2- 1 R13 _ . f R 1 0 N - --/_,--)14. _R1 0 R._ R10 N--- 0 , 9 R R8 R8 ,S,r - R8 r\-/-.: 1 n N'\\ -.SX- mi -- 0 0)----NI).-\ /NI - R8õ,_<\s'ii". Ni7/ 1 --(-: ki _R .,., \ , ,.." N R8 \ s-N N-_---N R8 N-N , 6-N
N, - N, - 0 R8-- -] - R8---- /1 -N- , , 0-N N
, , H
N 0 $ S
ij , N
, , , , , _7 ---eNNH ' --eNNH
N
-- A - -(3 N _______ ( Nj N
- N
N N __ \( S , S y N
---eNNH ---eNNH
IIN , NiNj N __ ( v(D ONJ
, _7N N
-- A - - -(3 - - -eN0 - - -eN0 N N N
/ \( Z NiNj N , ' H S
N _<7 n -----('-----N\
N N-N'S
H H , , , , N ---___.--0 H
N
A-NI S-N-N/
' 0 , ._--N-_._ H H , , , /
----1\----1----, 1\1 '-N
N, ' 2489-CIPO-CLAIMS-ZED-P04404W026.docx Date Recue/Date Received 2022-06-30 r 6 X 0 CD 6 , , , , , , , , ) , ,, , , , , ,, ,, , / / , ,, , z_ /
, , c > / , CD K Z=
0 W Z/ Z/ Z=z Z_ Z_ z/_ ¨z CD rili / 1/ \ /K \ /( \ $ / /
L / \ Z
rD' 0 \ /
'a X .
/ zµµ / z\ / \ //z \ F z, z z s\
//z z ,(, z 0 .
i z / \\¨z \ z z / ..
...
0 .. ... .. ...
.. ...
...
..
.. CD
N) g o x N) ri) CD
e..) Z= /¨ /¨ Z= __ / Z= Z / -- / /
__ / /Z Z\ /Z Z\ /Z Z Z Z , z , /Z \ /Z
\ /K \ /( , /( \ /K
\ / / K Z \ /
Z
Z
Z Z Z Z
--NI
z / \ z, , j \ \ //Z Z / Z Z //Z Z //Z \ z/ \z / Z_ / \ //Z \ / \ z, Z \ / Cil Z-Z Z
---_ -/
/_ /_ Z= Z= Z= ________________________________________ /¨ Z= Z¨ /¨ /-- --Z=-Z \ Z \ Z\ /Z /Z /Z /Z /Z Z \ /Z /Z / Z
/ Z \ /
( ( ( Z Z \ J \ \ Z Z \ z Z
\ \ \
/
/ \ ___ //Z z Z
Z Z I Z Z-Z // Z
Z¨// Z¨// Z Z Z Z
-- - --- -N ---NN, Nle , NõN
, N '-'' I I I
N1, 1\1N1 NN
, , õ
1 ir 1\1N--N N-,1\1 , N
, , - - N, N
N.NN N.NN I
1\1N
H õ
HN NH
' , , , õ
N NH, H
, N=\ 0 N=N N=\ N---N
\ N
N/ \ ' ,,N
, N- N- N- -1\1µ -N
--- _____________________________________________________ -- / -- N
__________________________________ / //1\1 N N ' , / ______________________ N ' , -N -N -\ ___\
-- ________________________ -- \ -- /N --tsN
-- ( N \ /il , N , N N
, \
=
N -\
, --\ N --\ N
N --I\1 N N
// , N=\ N=\
--- /(1\1 --- /N
\ / N / N / N N N S
N N-N // N
, , , , N=N N=N N=N N=N N=N
---, \ /71 /
N N
, 2489-CIPO-CLAIMS-ZED-P04404W026.docx Date Recue/Date Received 2022-06-30 ( \
\ /71; " N N \ IV
/ \ __ N N , , --- \
N/ //N N-N N NsN /
, , , , , __Ns- /N ---/N -- /N -- \ /N
( \ N \ /71; \ ______ \ N, N ___ \ ' , .. N
, --i --i \ N N N / N / N
N-// // N-N N sN __ /
, , , , _______ , /( \
N N , N/ //N' N-N N
, --\
II
N /
Ns, \ N N N N N i\I-N
N // -N , N- , , \1 N 1,/ , or wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 -R14, RN; and preferably with 1 to 3 of the substituents R11 -R13;
R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl, diamantyl, hexamethylenetetraminyl and the afore-mentioned residues optionally contain one or more C=C double bond(s) and/or are substituted by one or more of Ra, Rb, Rc, Rd, and Re;
Ra, Rb, Rc, Rd, and Re represent independently of each other -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C2F-15, -CONH2, -CONHCH3, -CON(CH3)2, -CONHC2F15, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H5, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2F15, -NHCOCH3, -NHCOC2F15, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C21-15, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3;
2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 R4 represents -R5, -0R5 or -NR6R7;
R5 represents -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CH2CH2CH2CH3, -CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-051-19, -cyclo-C6H11, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-051-19, -CH2-cyclo-C6H11, -Ph, -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, or -CH2CH2OCH2CH3;
R6 and R7 represent independently of each other -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3, -cyclo-C3F15, -cyclo-C4H7, -cyclo-051-19, -cyclo-C6H11, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-051-19, -CH2-cyclo-C6H11, -Ph, -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2NHCH3, or -CH2CH2N(CH3)2, / - -N -N O N\
/ \
or -NR6R7 represents - -< - or R6, R5, R10, R11, R12, R13, and R14 represent independently of each other -H, -F, -C1, -Br, -1, -OH, -CN, -NO2, -CH3, -C2F15, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3F15, -CH2-cyclo-C3F15, -CH2OH, -CH2F, -CHF2, -CF3, -CH2C1, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2C1, -CH2-CH2Br, -CH2-CH21, -OCH3, -0C21-15, -0C3H7, -OCH(CH3)2, -0C(CH3)3, -0C4H9, -OCHF2, -OCF3, -OCH2CF3, -OC2F5, -OCH2OCH3, -0-CyClo-C3F15, -OCH2-CyClo-C3H5, -0-C2H4-CyClo-C3H5, -CHO, -COCH3, -COCF3, -00C21-15, -00C3H7, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -00C-CH3, -00C-CF3, -00C-C2H5, -00C-C3H7, -00C-CH(CH3)2, -00C-C(CH3)3, -NH2, -NHCH3, -NHC2F15, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC21-15, -NHCOC3H7, -NHCOCH(CH3)2, -NHCOC(CH3)3, -CONH2, -CONHCH3, -CONHC2F15, -CONHC3H7, -CONHCH(CH3)2, -CONH-cyclo-C3F15, -CONHC(CH3)3, -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -SO2NHCH(CH3)2, -SO2NH-cyclo-C3H5, -SO2NHC(CH3)3, -502N(CH3)2, -502N(C2H5)2, 2489-CIPO-CLAIMS-ZED-P04404W026.docx Date Recue/Date Received 2022-06-30 -SO2N(C3H7)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C2H5, -NHSO2C3H7, -NHSO2CH (CH3)2, -NHSO2C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -CECH, -CEC-CH3, -CH2-CECH, -Ph, -0-Ph, -0-CH2-Ph, r1\1 -Nr-N -- r r1\1 r1\1 r / __ \ / __ \ / __ \
N\ /NH N\ N
Or N\ /N
or R9 and R9 or R9 and R1 can form together one of the following five-membered or six-membered rings:
.0 - - -1\1 --_1, _1\1 -or or R12 and R13 or R13 and R14 can form together one of the following five-mem bered or six-membered rings:
.0 .0 .0 .0 0 H or I
RN represents -H, -CH3, -C2F15, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH (CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-051-19, -CH2-cyclo-C3F15, -CH2-cyclo-C4H7, -CH2-cyclo-051-19, -CH2F, -CHF2, -CF3, -CH2C1, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2C1, -CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3, -00C21-15, -00C3H7, -COCH (CH3)2, -COC(CH3)3, -CO-cyclo-C3H5, -CO-cyclo-C4H7, -CO-cyclo-051-19, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -502CH3, -502CF3, -502C2H5, -502C3H7, -SO2CH (CH3)2, -502-cyclo-C3H5, or -502C(CH3)3;
RI" represents -H, -CH3, or -CH2CH3;
2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomers, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, wherein the compound has the formula (I):
H (1) N I-H I
wherein L represents ¨L1¨ or -¨L1¨L2¨; and preferably ¨L1-L2¨;
Ll represents ¨CH2¨, ¨CH2CH2¨, ¨CH2CH2CH2¨, ¨CH2C0¨, or ¨CH2CH2C0¨;
L2 represents a bond, ¨NRI41_, ¨NRN1CH2¨, ¨NRN1CH2CH2¨, or ¨NRN1CH(CH3)¨;
0 0, /0 RI represents or ,\S/
R2 represents RN
-__ 0 R8 R11 0 R8 -... S Rs Rii S Rs --ri R8 R10 R10 R9 , ' R9 R10 mg , , rµ , RN RN RN RN RN RN
R11 N R8 R11 N, Ri-1 i N, \1 N R11 N
_ 21( - - 1,(N
RyN_ii R8 , ) __ N N
/ R9 R10 `, ,/ R9 R10 R9 R10 ' , , RN
..._=}IN __R8 Ri_1C1 _ _ R11 0 R8 __________ - - \ .õs--ON. _R8 R1-1.) ax, _..- R11 S
Rs -\ ir \ ir N N 1 --- ir- _____________ \ ir N N N N
R10 , R10 , , " D10 , R10 RN RN
- RN
SR8 N, Ri _--1 --- __ 'N I ,N
- -1 ', N, o'N
---- N
N N N N
R10 R10 N¨N , N=N
, , , , , LI
R13 N' r R13 R13 N \' R14 N R14 N\ R14 N R14 N R14 , , 2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 RN
0----/Y,) 13 s----i\i----/%
-\R14 - - -\TR13 -- 4 1 \ ,tR13 R14 R14 N----%\' iA
Rio Rio R10 R., , , , , R12 p12 RN
,,...-----` `µ 1. õNr ..._ ), _____________________________________________ N, N R14 ii 1)P9 R -r r __ /, R10 _ D14 D._14. R10 N S --------R10 F` , F` , , , RN
ril/IR9 F\
_R10 V " . ---/-= M 1 0 .. R9 , ---/- \ M 1 0 - -¨ \ 1\1____i-x - N
, , H
, , N
, ' , , N ..N
---eNNH ---eNNH --- - i N ______ ( Nj N __ \ - N N __ \( N---S
H N"N's H .. , , , S-..._¨N N S ___________________ \-- N
---N-..._ ------N&\ --t ---- N
S-1\1//
N-..._-0 H
N
\S-N-N/
O N
0,....,____N
-N-N-N---- N
H H , , , ---N --c-----N&\ ---c-\ -;\-1---) -, I\1 , --I I I
N
N
N
I II
N 1\r N
, '- -, N,N
I -I
N,N , N
-, N -. -, N N
N N N
, 2489-CIPO-CLAIMS-ZED-P04404W026.docx Date Recue/Date Received 2022-06-30 _ - , ,, N I\1 - N, '- 'N
N:N 1 -.,N -.,1\1 -_,1\1 N Th\l , , ---, N N I \1 N N
'-'N '-'N
I
N N NN, , ., -.,N N - N N
II , f -Nie NN N N , , rNõN
NK, Ne -_,NN,N
N N
, 1 f -.,NN
N N, 1 -.,1\IN -_,I\IN -_,I\IN
1\1 N
1 1 f e Th\IINI N N , --,1\1 -.1\1 -_,N
NN N.N , -. -,N,N
N , N
-, N. -, 1\1 -_,1\1 ' y -1 N ,,;, N:NI
N
, , , -_,1\1 'r 1 N N , NN NN
, , -, --N-N
N:N
N
, ., NN NN NN
N.N ---. :----.. : N:1\1 N NN N
, 2489-CIPO-CLAIMS-ZED-P04404W026.docx Date Recue/Date Received 2022-06-30 0C-90-ZZOZ panpoa alea/an5a alea xooP 9Z0M40440d-03Z-SVVIV10-0d10-684Z
g ' i __ N ' N¨\\ g ' N-N // / N
si\I N N N N
_ _--, __ ¨N , ¨N , ¨N , ¨N ¨N
N __ \ N N , __ N/ I\I / / NI//
---)/ \
N ' ---N \=N \=N \=N \=N
, N // __ \
1\1 " ) N `
-e \ __ N
, N=N N=N N=N N=N N=N
N¨\\ // N N¨\\ N-N
SN N N / \ NI / N / \
NN -- -- -- - -\=N \=N
, __ //
NN
N \ 14/ \
cNi-v?
---\¨ __ , ' N ________ ' /, ______ , N ' N
1\1 3 \
e , _____________ \ - $___ NI/ __ __ ' - \
\ N
\¨ \¨ N¨ , N¨- , N¨
, __ N N
NI// 1\1 N\/ \ -- / _-- \___ N¨ N¨ ¨N , ¨N ¨N
, , / N
N N
\ __ N/ \ -- N - ) 0--i ¨N \=N N=N 0 \=N
, ' HN ' NH
' H
H N N
., ' , HN NH
H N
H
-- __ , , N N
NN,N
NNN
I
, , __i_NzµN
---\ /( ---/N -- /N
\ /71, \ \ N , N , \ N
Nz N
, , /-N
--i --i N/ //N N-N \\_N __ 'IV
, , , , ________ , \ S
N NI, N/ , //N' N-N N
, , --\
---i /N
. =
N /
Nss \ ,N N N N, N is\I-N
_______________ , N-N, N, l\1 // -N s- , or "
R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl, diamantyl, or hexamethylenetetraminyl and the afore-mentioned residues optionally contain one or more C=C double bond(s) and/or are optionally substituted by one or more of Ra, Rb, Rc, Rd, and Re;
Ra, Rb, Rc, Rd, and Re represent independently of each other -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C21-16, -CONH2, -CONHCH3, -CON(CH3)2, -CONHC2F16, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H6, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2F16, -NHCOCH3, -NHCOC21-16, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NNSO2C21-16, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3;
R4 represents -R5, -0R5 or -NR6R7;
R5 represents -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CH2CH2CH2CH3, -CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3, -cyclo-C3F-16, -cyclo-C4H7, -cyclo-C61-16, -cyclo-C6H11, -CH2-cyclo-C3F-16, -CH2-cyclo-C4H7, -CH2-cyclo-C6H6, -CH2-cyclo-C6H11, -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, or -CH2CH2OCH2CH3;
2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 R6 and R7 represent independently of each other -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3, -cyclo-C3F15, -cyclo-C4H7, -cyclo-051-19, -cyclo-C6H11, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-C51-19, -CH2-cyclo-C6H11, -Ph, -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2NHCH3, or -CH2CH2N(CH3)2, or -NR6R7 represents - -< -10 - -NO
or i\i/ \
\ _________________________________________________________________________ /
=
R6, R6, R10, R11, R12, R13, and R14 represent independently of each other -H, -F, -C1, -Br, -1, -OH, -CN, -NO2, -CH3, -C2F15, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3F15, -CH2-cyclo-C3F15, -CH2F, -CH F2, -CF3, -CH2C1, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2C1, -CH2-CH2Br, -CH2-CH21, -OCH3, -0C21-15, -0C3H7, -OCH(CH3)2, -0C(CH3)3, -0C4H9, -OCH F2, -0CF3, -OCH 2C F3 , -0C2F5, -OCH20C H3, -0-CyCIO-C3H5, -OCH2-CyCIO-C3H5, -0-C2H4-CyCIO-C3H5, -CHO, -COCH3, -COCF3, -00C21-15, -00C3H7, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -00C-CH3, -00C-CF3, -00C-C2H5, -00C-C3H7, -00C-CH(CH3)2, -00C-C(CH3)3, -NH2, -NHCH3, -NHC2F15, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC21-15, -NHCOC3H7, -NHCOCH(CH3)2, -NHCOC(CH3)3, -CONH2, -CONHCH3, -CONHC2F15, -CONHC3H7, -CON HCH (CH3)2, -CON H-cyclo-C3F15, -CON HC(CH3)3, -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -SO2NHCH(CH3)2, -SO2NH-cyclo-C3H5, -SO2NHC(CH3)3, -502N(CH3)2, -502N(C2H5)2, -502N(C3H7)2, -502N[CH(CH3)2]2, -502N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C21-15, -NHSO2C3H7, -NHSO2CH(CH3)2, -NHSO2C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -CECH, -CEC-CH3, -CH2-CECH, -Ph, -0-Ph, -0-CH2-Ph, - -NO N
rTh N
- N/Th\1 r __rN1 __---J rN N
r N N N
r r r / __ \ / __ \ / __ \
---cc, (2, 0 N\ /NH N\ ,N-; Or N\ 71 \.
___________________________________________________ /
2489-CIPO-CLAIMS-ZED-P04404W026.docx Date Recue/Date Received 2022-06-30 or R8 and R9 or R9 and R1 can form together one of the following five-membered or six-membered rings:
- o-N
1\1 -N or or R12 and R13 or R13 and R14 can form together one of the following five-membered or six-membered rings:
,0 ,,0 ,,0 'N
H or I =
R" represents -H, -CH3, -C2E-13, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H3, -cyclo-C4H7, -cyclo-C31-19, -CH2-cyclo-C3H3, -CH2F, -CH F2; -CF3, -CH2C1 -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3, -00C21-13, -00C3H7, -COCH (CH3)2, -COC(CH3)3, -COOC H3 -COOC21-15, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -SO2CH3, -SO2CF3, -SO2C21-13, -502C3H7, -SO2CH(CH3)2, or -502C(CH3)3;
RN1 represents -H, -CH3, or -CH2CH3;
or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomer, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
H (1) N I-H I
wherein L represents ¨L1¨ or -¨L1¨L2¨; and preferably ¨L1-L2¨;
Ll represents ¨CH2¨, ¨CH2CH2¨, ¨CH2CH2CH2¨, ¨CH2C0¨, or ¨CH2CH2C0¨;
L2 represents a bond, ¨NRI41_, ¨NRN1CH2¨, ¨NRN1CH2CH2¨, or ¨NRN1CH(CH3)¨;
0 0, /0 RI represents or ,\S/
R2 represents RN
-__ 0 R8 R11 0 R8 -... S Rs Rii S Rs --ri R8 R10 R10 R9 , ' R9 R10 mg , , rµ , RN RN RN RN RN RN
R11 N R8 R11 N, Ri-1 i N, \1 N R11 N
_ 21( - - 1,(N
RyN_ii R8 , ) __ N N
/ R9 R10 `, ,/ R9 R10 R9 R10 ' , , RN
..._=}IN __R8 Ri_1C1 _ _ R11 0 R8 __________ - - \ .õs--ON. _R8 R1-1.) ax, _..- R11 S
Rs -\ ir \ ir N N 1 --- ir- _____________ \ ir N N N N
R10 , R10 , , " D10 , R10 RN RN
- RN
SR8 N, Ri _--1 --- __ 'N I ,N
- -1 ', N, o'N
---- N
N N N N
R10 R10 N¨N , N=N
, , , , , LI
R13 N' r R13 R13 N \' R14 N R14 N\ R14 N R14 N R14 , , 2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 RN
0----/Y,) 13 s----i\i----/%
-\R14 - - -\TR13 -- 4 1 \ ,tR13 R14 R14 N----%\' iA
Rio Rio R10 R., , , , , R12 p12 RN
,,...-----` `µ 1. õNr ..._ ), _____________________________________________ N, N R14 ii 1)P9 R -r r __ /, R10 _ D14 D._14. R10 N S --------R10 F` , F` , , , RN
ril/IR9 F\
_R10 V " . ---/-= M 1 0 .. R9 , ---/- \ M 1 0 - -¨ \ 1\1____i-x - N
, , H
, , N
, ' , , N ..N
---eNNH ---eNNH --- - i N ______ ( Nj N __ \ - N N __ \( N---S
H N"N's H .. , , , S-..._¨N N S ___________________ \-- N
---N-..._ ------N&\ --t ---- N
S-1\1//
N-..._-0 H
N
\S-N-N/
O N
0,....,____N
-N-N-N---- N
H H , , , ---N --c-----N&\ ---c-\ -;\-1---) -, I\1 , --I I I
N
N
N
I II
N 1\r N
, '- -, N,N
I -I
N,N , N
-, N -. -, N N
N N N
, 2489-CIPO-CLAIMS-ZED-P04404W026.docx Date Recue/Date Received 2022-06-30 _ - , ,, N I\1 - N, '- 'N
N:N 1 -.,N -.,1\1 -_,1\1 N Th\l , , ---, N N I \1 N N
'-'N '-'N
I
N N NN, , ., -.,N N - N N
II , f -Nie NN N N , , rNõN
NK, Ne -_,NN,N
N N
, 1 f -.,NN
N N, 1 -.,1\IN -_,I\IN -_,I\IN
1\1 N
1 1 f e Th\IINI N N , --,1\1 -.1\1 -_,N
NN N.N , -. -,N,N
N , N
-, N. -, 1\1 -_,1\1 ' y -1 N ,,;, N:NI
N
, , , -_,1\1 'r 1 N N , NN NN
, , -, --N-N
N:N
N
, ., NN NN NN
N.N ---. :----.. : N:1\1 N NN N
, 2489-CIPO-CLAIMS-ZED-P04404W026.docx Date Recue/Date Received 2022-06-30 0C-90-ZZOZ panpoa alea/an5a alea xooP 9Z0M40440d-03Z-SVVIV10-0d10-684Z
g ' i __ N ' N¨\\ g ' N-N // / N
si\I N N N N
_ _--, __ ¨N , ¨N , ¨N , ¨N ¨N
N __ \ N N , __ N/ I\I / / NI//
---)/ \
N ' ---N \=N \=N \=N \=N
, N // __ \
1\1 " ) N `
-e \ __ N
, N=N N=N N=N N=N N=N
N¨\\ // N N¨\\ N-N
SN N N / \ NI / N / \
NN -- -- -- - -\=N \=N
, __ //
NN
N \ 14/ \
cNi-v?
---\¨ __ , ' N ________ ' /, ______ , N ' N
1\1 3 \
e , _____________ \ - $___ NI/ __ __ ' - \
\ N
\¨ \¨ N¨ , N¨- , N¨
, __ N N
NI// 1\1 N\/ \ -- / _-- \___ N¨ N¨ ¨N , ¨N ¨N
, , / N
N N
\ __ N/ \ -- N - ) 0--i ¨N \=N N=N 0 \=N
, ' HN ' NH
' H
H N N
., ' , HN NH
H N
H
-- __ , , N N
NN,N
NNN
I
, , __i_NzµN
---\ /( ---/N -- /N
\ /71, \ \ N , N , \ N
Nz N
, , /-N
--i --i N/ //N N-N \\_N __ 'IV
, , , , ________ , \ S
N NI, N/ , //N' N-N N
, , --\
---i /N
. =
N /
Nss \ ,N N N N, N is\I-N
_______________ , N-N, N, l\1 // -N s- , or "
R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl, diamantyl, or hexamethylenetetraminyl and the afore-mentioned residues optionally contain one or more C=C double bond(s) and/or are optionally substituted by one or more of Ra, Rb, Rc, Rd, and Re;
Ra, Rb, Rc, Rd, and Re represent independently of each other -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C21-16, -CONH2, -CONHCH3, -CON(CH3)2, -CONHC2F16, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H6, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2F16, -NHCOCH3, -NHCOC21-16, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NNSO2C21-16, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3;
R4 represents -R5, -0R5 or -NR6R7;
R5 represents -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CH2CH2CH2CH3, -CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3, -cyclo-C3F-16, -cyclo-C4H7, -cyclo-C61-16, -cyclo-C6H11, -CH2-cyclo-C3F-16, -CH2-cyclo-C4H7, -CH2-cyclo-C6H6, -CH2-cyclo-C6H11, -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, or -CH2CH2OCH2CH3;
2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 R6 and R7 represent independently of each other -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3, -cyclo-C3F15, -cyclo-C4H7, -cyclo-051-19, -cyclo-C6H11, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-C51-19, -CH2-cyclo-C6H11, -Ph, -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2NHCH3, or -CH2CH2N(CH3)2, or -NR6R7 represents - -< -10 - -NO
or i\i/ \
\ _________________________________________________________________________ /
=
R6, R6, R10, R11, R12, R13, and R14 represent independently of each other -H, -F, -C1, -Br, -1, -OH, -CN, -NO2, -CH3, -C2F15, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3F15, -CH2-cyclo-C3F15, -CH2F, -CH F2, -CF3, -CH2C1, -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2C1, -CH2-CH2Br, -CH2-CH21, -OCH3, -0C21-15, -0C3H7, -OCH(CH3)2, -0C(CH3)3, -0C4H9, -OCH F2, -0CF3, -OCH 2C F3 , -0C2F5, -OCH20C H3, -0-CyCIO-C3H5, -OCH2-CyCIO-C3H5, -0-C2H4-CyCIO-C3H5, -CHO, -COCH3, -COCF3, -00C21-15, -00C3H7, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -00C-CH3, -00C-CF3, -00C-C2H5, -00C-C3H7, -00C-CH(CH3)2, -00C-C(CH3)3, -NH2, -NHCH3, -NHC2F15, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC21-15, -NHCOC3H7, -NHCOCH(CH3)2, -NHCOC(CH3)3, -CONH2, -CONHCH3, -CONHC2F15, -CONHC3H7, -CON HCH (CH3)2, -CON H-cyclo-C3F15, -CON HC(CH3)3, -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -SO2NHCH(CH3)2, -SO2NH-cyclo-C3H5, -SO2NHC(CH3)3, -502N(CH3)2, -502N(C2H5)2, -502N(C3H7)2, -502N[CH(CH3)2]2, -502N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C21-15, -NHSO2C3H7, -NHSO2CH(CH3)2, -NHSO2C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -CECH, -CEC-CH3, -CH2-CECH, -Ph, -0-Ph, -0-CH2-Ph, - -NO N
rTh N
- N/Th\1 r __rN1 __---J rN N
r N N N
r r r / __ \ / __ \ / __ \
---cc, (2, 0 N\ /NH N\ ,N-; Or N\ 71 \.
___________________________________________________ /
2489-CIPO-CLAIMS-ZED-P04404W026.docx Date Recue/Date Received 2022-06-30 or R8 and R9 or R9 and R1 can form together one of the following five-membered or six-membered rings:
- o-N
1\1 -N or or R12 and R13 or R13 and R14 can form together one of the following five-membered or six-membered rings:
,0 ,,0 ,,0 'N
H or I =
R" represents -H, -CH3, -C2E-13, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H3, -cyclo-C4H7, -cyclo-C31-19, -CH2-cyclo-C3H3, -CH2F, -CH F2; -CF3, -CH2C1 -CH2Br, -CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3, -00C21-13, -00C3H7, -COCH (CH3)2, -COC(CH3)3, -COOC H3 -COOC21-15, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -SO2CH3, -SO2CF3, -SO2C21-13, -502C3H7, -SO2CH(CH3)2, or -502C(CH3)3;
RN1 represents -H, -CH3, or -CH2CH3;
or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomer, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
3. The compound according to Claim 1, wherein 0, R1 represents N R6 -31- R5 R7 R5 , or R2 represents 2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 RN
- _ 0 Rs R11 0 Ra - _ S D m8 R11 S R8 -1 ____________ r i _____________ r ( R10 R9 ; __ / R9 Rlo R9 ' R9 R113 D
rµ9 ;
RN RN RN RN RN RN
R11 1\1 R8 R11 1\1, R11 1\1, -_ 1\1, D11 1\1 R
11 1\1 R8 "-"-r\ , e ) __ N
R9 R10 sµ / R.o R10 R9 Rlo __ , N
/ , RN Rlo Rlo ri D8 R11 0 - _ R1)0____R8 1 - - R8 8 --- ----rµ -,.... _- õ)- -Y __ N ) __ N N Y __ N-- u=N____ ? R R
R10 , R10 , ' , rµ o10 , R- N =
= , , RN RN
'' R10 R11 S 11 S 8 - - S R8 - - li-__ 11 __ 1\1 RI R 1 ,N RI N
N N N N
N--"N N
RR ; 1-N - D10 ; R10 R10 ; ;
;
RN RN ;
N ---R10 D10 N N, _DN ___1=00 ., ---(2' N " IV, _ , _NI , pp \-) \¨NN---, N-N ; N =IV , o r`14 ,' , ' , , , , R13 ------------------- I R13 N R 1 , -\ N
N R14 N R14 NI- R14 NI' R14 R R1410 ;
RN
S 13 i\i-/-:., RN N--/y (ri R9 N 1 \ TRU S
FN-- - -Rlo R1 9 \___,------- 010 o14 N
, F` , , R12 R12 H .
\ _____________________________________________________________ N --1...).___ R13 N -- rµ ), N,5 r`
\7R
/\\-) 1 n ____ S
o,, r`14 oi, A - Dii._ N
--.-N
, RN RN
T ri R9 _ _r_ Fz 1 0 H
m R9 _ _r_ R1 0 \ -/ / IN. 10 ¨R
o) S -, , N-- - \
,r\,,Nr \N1 N /
,-\"
, , N , 2489-CIPO-CLAIMS-ZED-P04404W026.docx Date Recue/Date Received 2022-06-30 R8 R8 ,S - ' R8 N II S --1 N \ .Z N-- s)-- ,_-N R8 ____ ..-fi' r\i N---)T - -\
N N R8 \S-N 1\l'N R8 ; N-N ; 6-N ;
R
. R N,-- . N,--1\1- , or 0-N ;
wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R5 ¨R14, and RN; and preferably with 1 to 3 of the substituents R11 _ rc ^13, and R5 ¨ R14 and RN have the meanings as defined in claim 1.
- _ 0 Rs R11 0 Ra - _ S D m8 R11 S R8 -1 ____________ r i _____________ r ( R10 R9 ; __ / R9 Rlo R9 ' R9 R113 D
rµ9 ;
RN RN RN RN RN RN
R11 1\1 R8 R11 1\1, R11 1\1, -_ 1\1, D11 1\1 R
11 1\1 R8 "-"-r\ , e ) __ N
R9 R10 sµ / R.o R10 R9 Rlo __ , N
/ , RN Rlo Rlo ri D8 R11 0 - _ R1)0____R8 1 - - R8 8 --- ----rµ -,.... _- õ)- -Y __ N ) __ N N Y __ N-- u=N____ ? R R
R10 , R10 , ' , rµ o10 , R- N =
= , , RN RN
'' R10 R11 S 11 S 8 - - S R8 - - li-__ 11 __ 1\1 RI R 1 ,N RI N
N N N N
N--"N N
RR ; 1-N - D10 ; R10 R10 ; ;
;
RN RN ;
N ---R10 D10 N N, _DN ___1=00 ., ---(2' N " IV, _ , _NI , pp \-) \¨NN---, N-N ; N =IV , o r`14 ,' , ' , , , , R13 ------------------- I R13 N R 1 , -\ N
N R14 N R14 NI- R14 NI' R14 R R1410 ;
RN
S 13 i\i-/-:., RN N--/y (ri R9 N 1 \ TRU S
FN-- - -Rlo R1 9 \___,------- 010 o14 N
, F` , , R12 R12 H .
\ _____________________________________________________________ N --1...).___ R13 N -- rµ ), N,5 r`
\7R
/\\-) 1 n ____ S
o,, r`14 oi, A - Dii._ N
--.-N
, RN RN
T ri R9 _ _r_ Fz 1 0 H
m R9 _ _r_ R1 0 \ -/ / IN. 10 ¨R
o) S -, , N-- - \
,r\,,Nr \N1 N /
,-\"
, , N , 2489-CIPO-CLAIMS-ZED-P04404W026.docx Date Recue/Date Received 2022-06-30 R8 R8 ,S - ' R8 N II S --1 N \ .Z N-- s)-- ,_-N R8 ____ ..-fi' r\i N---)T - -\
N N R8 \S-N 1\l'N R8 ; N-N ; 6-N ;
R
. R N,-- . N,--1\1- , or 0-N ;
wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R5 ¨R14, and RN; and preferably with 1 to 3 of the substituents R11 _ rc ^13, and R5 ¨ R14 and RN have the meanings as defined in claim 1.
4. The compound according to Claim 1, wherein R2 represents RN
-_, 0 Ra R11 0 Ra - õ S Ra RzS Rs -- 11 \ / 1 __ r , , , __ r ( R10 R9 ; / R9 R10 R9 ; / R9 R10 R9 ;
RN RN RN RN RN
R11 N R8 R11 N, R11 N, __ N, R11 N RN
_in K n 1 I
/ R9 R10 sµ / IRn K . - R., R10 __ ;
N
' ' RN
R11 0 _ R11 0 R8 - -0_-- R8 -- '¨R
N N
--N Y __ N N
Rlo R10 R10 ; R10 ; ; ; ;
RN RN RN
Rii S R8 --___õ-SN _R8 --õ--N." D. 11 N, , N R10 R10N,N_RN
.,1 N N N ' ' ,N NL\i--=1\j ) ______________________________________________ N
Rlo Rlo , , / , =
, , , , RN
,N 10 N
N r_,R -_ ,I1, - N, pp r iR
Q.,,.,,,,,, R=-' , --\- N---, N-N ; N=N - \_,--------,-,10 R14 N
, rc , , , N R12 0 -/,) 13 S ---/
- - - -\-) Rõ., N Ria N R14 N=R14 R10 R10 R14 i\l---/') 13 N -/Y
. -1 13 .,, . = - - - --- - - - ..., , _ , . = - - - -:-. 7 R14 N--%\- iA ___\7R
Rlo R., R14 , 2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 RN
. ii R9 \ __________ __________ 7._it 17)1 S rN IR9 _ R10 r /1 R10 1 1 . --/_-- \ R1 0 R10 N C:1) , k , Rio - -H
N
, , , , , , _7N _7N
- - -eNNH - - --eNNH
- - A -- A3 ----eNS
N ______ ( ii\ij N N N __ \( -eNNH - - -eNNH
ZN
, N
- -N Nj / \( li , N
, 7C) , 0 7 N
N
, H __________________________________________ S
N-,...___--S N
N" 'S
H H , , ' /S , NN S - _ _e----F¨\--N
----\--N N
, , , ' N,0 H
N
S'N'N
- N , , 0,N
H H , , , , 0,N , I I I
N /
/ N
-. N -- --' N
, , I II
N 1\r N
, ., -, N. N -, 1\1 2489-CIPO-CLAIMS-ZED-P04404W026.docx Date Recue/Date Received 2022-06-30 , z z , ____ k õ ________________ , __ z ¨ /¨, z ¨ /¨, z ¨ k \\ - Z Z - Z
, ¨ z , _____ ,_ z_z 3 zõ õ _______ , z, _______ , z, , zõ µsz , ,- c, __ -, z// õ /
, ____________ \ \z , __ c , ____________________ , z)/ , z)/ , z)/ , ________________________ \ , 0 , _, _, _z õz ,_/ _ ,_ õz õz õ, ,_ ,_ ,_z ,_/ ,_z , , ______________________________________________________ 0., z_z , / ____ z z ,_z_ ,/ ,_ z ___ _ ________________ z_ / ,_ z_õ _ ,z_ ,/ ,_ z_z z_õ
, / \ z ___ \ ,z / , / \ z// ____ ,zzõ
,z ,/ \ z, _______ \ ,- c, ______ ,,z ,,,, , z, ,,z / ,,z / ,, cz)/ \ z/ __ , , , _________ \ z)/ z)/
z z)/ \ z)/ \ , \zz/ ,zz/ , µz _ _ _z ,,z _/ ,_ õz ,_, ,_, õz , , , __ , , , , , , , cs) N
P, RN
'cl -ca3 _ _ ____________ - z - - z - z ___ z - - zz ________ z z - - = c) z// z z z / 'µz ( z// / Z Zz' \ z// ¨z ( 'µz z Z' \ Z' ¨) z//¨ , z/ , a ,P
a) ,r a [t r O a) Zi/ \ / / Zi/ Z)/ \ Z)/ d Zi/ Z// c ^, w w a 0 ¨
¨/ ¨Z ¨Z Z ¨ ¨/ ¨ ¨ ¨/ , ¨Z , ¨Z , ¨Z , ¨Z "a3 , , , , Q a) o ct a q a) .
(0 ,r a ' ry - -N.N- NN-.N NN:N
, I -,,NN
N.NN N,NN
Th\1N
H ., NH
HN NH , , ., H
, N=\ 0 N=N N=\ N--- /(N
¨ N
\ N \ N hN " , , ' N¨ N¨ N¨ ¨N ¨N
¨ -- \ /N -- \
--- / ¨N* __ / [1\1 N N / , / ______________________ N ; ' ¨N ¨N ¨\
-- \ -- \ /N ¨ ¨ \ N
---\\ ( -- N ¨\ hN
N ______________________________ N * / ' , ¨-i\\ /
____________________________________________________________ 1 , , -- \ /\N
\ ) ¨ \
--i /N
1\1 , --\ ',\I --\ N -- let N N N/ N* //N
, N=\ N=\
-- /(N
\ / N / N, / N N N
N N¨N N * // N
, , , N=N N=N N=N N=N N=N
\ hN N /
N N * /
, _____________________ ' , , , , N=\ N=\ N=\ N=\ N--- ¨\ /(N ---/N1 -- /N -- /N -- \
N
* N N , , N¨ N¨ N¨ N¨ N¨_ -- -- -- -- ___ ¨ ¨ /
N N N N / Ns, /
N/ * // N¨N N N
, , , , , 2489-CIPO-CLAIMS-ZED-P04404W026.docx Date Recue/Date Received 2022-06-30 -- /(N
\ /71; \ \ N N \ ,N
* N , N ;
--¨ --i ---¨N
-- /
N/ //N N¨N N __ sN ;
, , , ______________________________________ \ ' ¨\ ¨\
Z( Z( _________ Z( N
\ ,,N1 ; N=/ * __ // N¨N N
, , , , ¨ ¨ --¨i /N
-- . -- .
Ns, \ N N N
N N 'N¨N ;
N ; N¨N, N, sis\l/ , or wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 ¨ R14, RN=
, and preferably with 1 to 3 of the substituents R11 ¨ R13 and the substituents R9 ¨R14, and R" have the meanings as defined in claim 1.
-_, 0 Ra R11 0 Ra - õ S Ra RzS Rs -- 11 \ / 1 __ r , , , __ r ( R10 R9 ; / R9 R10 R9 ; / R9 R10 R9 ;
RN RN RN RN RN
R11 N R8 R11 N, R11 N, __ N, R11 N RN
_in K n 1 I
/ R9 R10 sµ / IRn K . - R., R10 __ ;
N
' ' RN
R11 0 _ R11 0 R8 - -0_-- R8 -- '¨R
N N
--N Y __ N N
Rlo R10 R10 ; R10 ; ; ; ;
RN RN RN
Rii S R8 --___õ-SN _R8 --õ--N." D. 11 N, , N R10 R10N,N_RN
.,1 N N N ' ' ,N NL\i--=1\j ) ______________________________________________ N
Rlo Rlo , , / , =
, , , , RN
,N 10 N
N r_,R -_ ,I1, - N, pp r iR
Q.,,.,,,,,, R=-' , --\- N---, N-N ; N=N - \_,--------,-,10 R14 N
, rc , , , N R12 0 -/,) 13 S ---/
- - - -\-) Rõ., N Ria N R14 N=R14 R10 R10 R14 i\l---/') 13 N -/Y
. -1 13 .,, . = - - - --- - - - ..., , _ , . = - - - -:-. 7 R14 N--%\- iA ___\7R
Rlo R., R14 , 2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 RN
. ii R9 \ __________ __________ 7._it 17)1 S rN IR9 _ R10 r /1 R10 1 1 . --/_-- \ R1 0 R10 N C:1) , k , Rio - -H
N
, , , , , , _7N _7N
- - -eNNH - - --eNNH
- - A -- A3 ----eNS
N ______ ( ii\ij N N N __ \( -eNNH - - -eNNH
ZN
, N
- -N Nj / \( li , N
, 7C) , 0 7 N
N
, H __________________________________________ S
N-,...___--S N
N" 'S
H H , , ' /S , NN S - _ _e----F¨\--N
----\--N N
, , , ' N,0 H
N
S'N'N
- N , , 0,N
H H , , , , 0,N , I I I
N /
/ N
-. N -- --' N
, , I II
N 1\r N
, ., -, N. N -, 1\1 2489-CIPO-CLAIMS-ZED-P04404W026.docx Date Recue/Date Received 2022-06-30 , z z , ____ k õ ________________ , __ z ¨ /¨, z ¨ /¨, z ¨ k \\ - Z Z - Z
, ¨ z , _____ ,_ z_z 3 zõ õ _______ , z, _______ , z, , zõ µsz , ,- c, __ -, z// õ /
, ____________ \ \z , __ c , ____________________ , z)/ , z)/ , z)/ , ________________________ \ , 0 , _, _, _z õz ,_/ _ ,_ õz õz õ, ,_ ,_ ,_z ,_/ ,_z , , ______________________________________________________ 0., z_z , / ____ z z ,_z_ ,/ ,_ z ___ _ ________________ z_ / ,_ z_õ _ ,z_ ,/ ,_ z_z z_õ
, / \ z ___ \ ,z / , / \ z// ____ ,zzõ
,z ,/ \ z, _______ \ ,- c, ______ ,,z ,,,, , z, ,,z / ,,z / ,, cz)/ \ z/ __ , , , _________ \ z)/ z)/
z z)/ \ z)/ \ , \zz/ ,zz/ , µz _ _ _z ,,z _/ ,_ õz ,_, ,_, õz , , , __ , , , , , , , cs) N
P, RN
'cl -ca3 _ _ ____________ - z - - z - z ___ z - - zz ________ z z - - = c) z// z z z / 'µz ( z// / Z Zz' \ z// ¨z ( 'µz z Z' \ Z' ¨) z//¨ , z/ , a ,P
a) ,r a [t r O a) Zi/ \ / / Zi/ Z)/ \ Z)/ d Zi/ Z// c ^, w w a 0 ¨
¨/ ¨Z ¨Z Z ¨ ¨/ ¨ ¨ ¨/ , ¨Z , ¨Z , ¨Z , ¨Z "a3 , , , , Q a) o ct a q a) .
(0 ,r a ' ry - -N.N- NN-.N NN:N
, I -,,NN
N.NN N,NN
Th\1N
H ., NH
HN NH , , ., H
, N=\ 0 N=N N=\ N--- /(N
¨ N
\ N \ N hN " , , ' N¨ N¨ N¨ ¨N ¨N
¨ -- \ /N -- \
--- / ¨N* __ / [1\1 N N / , / ______________________ N ; ' ¨N ¨N ¨\
-- \ -- \ /N ¨ ¨ \ N
---\\ ( -- N ¨\ hN
N ______________________________ N * / ' , ¨-i\\ /
____________________________________________________________ 1 , , -- \ /\N
\ ) ¨ \
--i /N
1\1 , --\ ',\I --\ N -- let N N N/ N* //N
, N=\ N=\
-- /(N
\ / N / N, / N N N
N N¨N N * // N
, , , N=N N=N N=N N=N N=N
\ hN N /
N N * /
, _____________________ ' , , , , N=\ N=\ N=\ N=\ N--- ¨\ /(N ---/N1 -- /N -- /N -- \
N
* N N , , N¨ N¨ N¨ N¨ N¨_ -- -- -- -- ___ ¨ ¨ /
N N N N / Ns, /
N/ * // N¨N N N
, , , , , 2489-CIPO-CLAIMS-ZED-P04404W026.docx Date Recue/Date Received 2022-06-30 -- /(N
\ /71; \ \ N N \ ,N
* N , N ;
--¨ --i ---¨N
-- /
N/ //N N¨N N __ sN ;
, , , ______________________________________ \ ' ¨\ ¨\
Z( Z( _________ Z( N
\ ,,N1 ; N=/ * __ // N¨N N
, , , , ¨ ¨ --¨i /N
-- . -- .
Ns, \ N N N
N N 'N¨N ;
N ; N¨N, N, sis\l/ , or wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 ¨ R14, RN=
, and preferably with 1 to 3 of the substituents R11 ¨ R13 and the substituents R9 ¨R14, and R" have the meanings as defined in claim 1.
5. The compound according to any one of claims 1, 3 and 4, wherein 0 R6 0\ 9 R1 represents -"N" -.,R5 , or , L1 represents ¨CH2¨, or ¨CH2C0¨;
L2 represents a bond, ¨NRI41¨, ¨NRN1CH2¨, or ¨NRN1CH(CH3)¨;
R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, 4-homoisotwistyl, adamantyl, or diamantyl and the afore-mentioned residues optionally contain one or more C=C double bond(s) and/or are substituted by one or more of Ra, Rb, Rc, Rd, and Re;
and R6, R6, R7, Ra, Rb, Rc, Rd, Re and RN1 have the same meanings as defined in claim 1.
L2 represents a bond, ¨NRI41¨, ¨NRN1CH2¨, or ¨NRN1CH(CH3)¨;
R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, 4-homoisotwistyl, adamantyl, or diamantyl and the afore-mentioned residues optionally contain one or more C=C double bond(s) and/or are substituted by one or more of Ra, Rb, Rc, Rd, and Re;
and R6, R6, R7, Ra, Rb, Rc, Rd, Re and RN1 have the same meanings as defined in claim 1.
6. The compound according to any one of the claims 1, and 3 ¨ 5, wherein the compound has any one of the formulae (VI-a) ¨ (VI-1), (Vika) ¨ (VII-1), (VW-a) ¨ (VIII-1), (IX-a) ¨ (IX-d), (X-a)¨ (X-d), and (Xl-a)¨ (Xl-d):
2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 oo.R5 'R
%
0H 0 0 0 b A N )-L N ,L Rc 2 1 NH Ll L2 R R2 N
R- NH 1 1-1\1' H
O Ra Ra (VI-a) (VI-b) O0.R5 (D'o,R5 Rb Ra A N L2 A N L2 IR' R2 N 1 N Ra R2 H 1 N
H
0 0Rc Rb 0 0 Rd (VI-d) (VI-c) O0,R5 0 0, Rb Ra Rb Ra Rc 0H 0 Rc 0 0 A N L2 _.--,,.. L2 R2 N 1 N R2)- N 1 N
H
0 0 Rd H
(VI-a) (VI-f) (D'o,R5 R5 Rd IR Rb Ra 0H 0 0 icH 0 Rc H
0 0 H 0 Rd (VI-g) (VI-h) 00, 5 0 0, R5 R
NH L2 Rc a R2 A N kii ' -i\J(L2 0 d R H
R
Rb (VH) (VI-i) 2489-CIPO-CLAIMS-ZED-P04404W026.docx Date Recue/Date Received 2022-06-30 O0,R5 oo,R5 A 1\1 \ A
NL
_ J1 2 R N N
H H
(VI-k) (VI-1) c:iii, R7 0 N , JCILH 0 0H 0 N L2 Rb )-L N Rc R2 0 N, L1 H H
Ra Ra (Vika) (VII-b) cp,ii, R7 c:1' N , 127 Rb Ra Rb Ra 0H 0 Rc j:) JC H 9 N L2 N IR' H
0 0 Rd H
0 0 Rd (VII-c) (VII-d) o iiR7 , 0ii,R7 Rb Ra Rb Ra Rc 0H 0 Rc 1) JC H ?
)-L N N L2 H
0 0 Rd H
(VII-e) (V114) o ii, 0-'ii,IR7 R7 Rd Rc Rb Ra 0H 0 0H 0 Rc )-L N )-L L2 )-L N L2 H
0 0 Rd (VII-g) (VII-h) 2489-CIPO-CLAIMS-ZED-P04404W026.docx Date Recue/Date Received 2022-06-30 N c:,'N,127 (:)' ' R7 % Ra %
Rb O H 0 Rc 0 0 AN .õ..-1-1., -----..õ.õõ L2 EN1 )-L L2 H
0 0 Rd H
(VII-i) (VII-j) ON. R7 c:1 N , R7 O iC H 0 0 JC
N..õ,)-1-.. ..--,..._,.._ A N )-L L2 H
(VII-k) (VII-1) o 0, `, 6R
o=s- 0=S-R5 o H 0 0H 0 A Rc N L2 Rb N
1 N A N, L1 Ra Ra (VIII-a) (VIII-b) q 0 µ \ R5 0= s-Rb Ra A N N L2 A õ , Rc N 1 N R a R2 H
0 0Rc Rb 0 0 Rd (VIII-d) (VIII-c) (:), o=s o=S-R5 Rb Ra Ra Rb RC
0 A F j Rc 0 0 H
)-L
R2 il N
, il 1\1 L 2 R2A N N jc 1 N L2 H Rd H
(VIII-e) (VI114) 2489-CIPO-CLAIMS-ZED-P04404W026.docx Date Recue/Date Received 2022-06-30 o o \\ R5 o=S-R5 Rd 0=S' Rc Rb Ra 0 jC H 0 0 A A Rc N L2 0 _ il r\'(1_2 R
H
0 0 d (VIII-g) (VIII-h) o P\ _R5 o=s Ra Rb 0 (rH 0 Rc 0 H 0 A R2 N L2 A N )-L L2 Rd N
_ J1 I\I R2 N 1 N
H H
(VIII-i) (VIII-j) o o oA-R5 oA-R5 [ffF 7Q
o H 0 0 JC H 0 H
(VIII-k) (VIII-1) 0 N )-L L2 N L2 R3 R8 \ I H 1 N
0 N 0 '- R3 R8 \S I HN 0 0 (IX-a) (IX-b) 0 O. oo,R5 R5 o H 0 0 JCH0 L
/71 \ I H 0 R --UFI R12N N 0 0 K' \ N 0 '- R3 ¨
(I X-C) (IX-d) 2489-CIPO-CLAIMS-ZED-P04404W026.docx Date Recue/Date Received 2022-06-30 O'il-R7 0N-R7 O H 0 0 ( H 011 0 N )-L L2_ R3 R8 S
R8 \ 1 rii 1 N 'r N
\ I H
(X-a) (X-b) O N ' R7 0 N' R7 O ( H 0u 0 rH 0id N L2 0 N L2 =
N ¨ R3 R11 N
R8-- 1 ril R12 1 rii-N 0 0 K/ \ 0 0 R1 3 ¨
(X-c) (X-d) 0 D5 0\ R5 \\ ix 0=S 0 'S' OH 0 0 ( H OR
0 N L2., 3 S
i N N
O 0 \ I H
(Xl-a) (Xl-b) \ R6 cl\ R6 0=\S- 0=\s-O H 0u 0 H 011 S__fL R11 0 N L2 R3 R8--- 1 rii R12 /71 1 hi 1 N
N R10 0 0 Ki \ 0 0 ¨
(Xl-c) (Xl-d) and R2, R3; R5, R6, R7, R8, R9, R1 0, R11, R12, R1 3, Ra; R13, Rc; Rd L
anCI - . 2 have the same meanings as defined in claim 1.
2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 oo.R5 'R
%
0H 0 0 0 b A N )-L N ,L Rc 2 1 NH Ll L2 R R2 N
R- NH 1 1-1\1' H
O Ra Ra (VI-a) (VI-b) O0.R5 (D'o,R5 Rb Ra A N L2 A N L2 IR' R2 N 1 N Ra R2 H 1 N
H
0 0Rc Rb 0 0 Rd (VI-d) (VI-c) O0,R5 0 0, Rb Ra Rb Ra Rc 0H 0 Rc 0 0 A N L2 _.--,,.. L2 R2 N 1 N R2)- N 1 N
H
0 0 Rd H
(VI-a) (VI-f) (D'o,R5 R5 Rd IR Rb Ra 0H 0 0 icH 0 Rc H
0 0 H 0 Rd (VI-g) (VI-h) 00, 5 0 0, R5 R
NH L2 Rc a R2 A N kii ' -i\J(L2 0 d R H
R
Rb (VH) (VI-i) 2489-CIPO-CLAIMS-ZED-P04404W026.docx Date Recue/Date Received 2022-06-30 O0,R5 oo,R5 A 1\1 \ A
NL
_ J1 2 R N N
H H
(VI-k) (VI-1) c:iii, R7 0 N , JCILH 0 0H 0 N L2 Rb )-L N Rc R2 0 N, L1 H H
Ra Ra (Vika) (VII-b) cp,ii, R7 c:1' N , 127 Rb Ra Rb Ra 0H 0 Rc j:) JC H 9 N L2 N IR' H
0 0 Rd H
0 0 Rd (VII-c) (VII-d) o iiR7 , 0ii,R7 Rb Ra Rb Ra Rc 0H 0 Rc 1) JC H ?
)-L N N L2 H
0 0 Rd H
(VII-e) (V114) o ii, 0-'ii,IR7 R7 Rd Rc Rb Ra 0H 0 0H 0 Rc )-L N )-L L2 )-L N L2 H
0 0 Rd (VII-g) (VII-h) 2489-CIPO-CLAIMS-ZED-P04404W026.docx Date Recue/Date Received 2022-06-30 N c:,'N,127 (:)' ' R7 % Ra %
Rb O H 0 Rc 0 0 AN .õ..-1-1., -----..õ.õõ L2 EN1 )-L L2 H
0 0 Rd H
(VII-i) (VII-j) ON. R7 c:1 N , R7 O iC H 0 0 JC
N..õ,)-1-.. ..--,..._,.._ A N )-L L2 H
(VII-k) (VII-1) o 0, `, 6R
o=s- 0=S-R5 o H 0 0H 0 A Rc N L2 Rb N
1 N A N, L1 Ra Ra (VIII-a) (VIII-b) q 0 µ \ R5 0= s-Rb Ra A N N L2 A õ , Rc N 1 N R a R2 H
0 0Rc Rb 0 0 Rd (VIII-d) (VIII-c) (:), o=s o=S-R5 Rb Ra Ra Rb RC
0 A F j Rc 0 0 H
)-L
R2 il N
, il 1\1 L 2 R2A N N jc 1 N L2 H Rd H
(VIII-e) (VI114) 2489-CIPO-CLAIMS-ZED-P04404W026.docx Date Recue/Date Received 2022-06-30 o o \\ R5 o=S-R5 Rd 0=S' Rc Rb Ra 0 jC H 0 0 A A Rc N L2 0 _ il r\'(1_2 R
H
0 0 d (VIII-g) (VIII-h) o P\ _R5 o=s Ra Rb 0 (rH 0 Rc 0 H 0 A R2 N L2 A N )-L L2 Rd N
_ J1 I\I R2 N 1 N
H H
(VIII-i) (VIII-j) o o oA-R5 oA-R5 [ffF 7Q
o H 0 0 JC H 0 H
(VIII-k) (VIII-1) 0 N )-L L2 N L2 R3 R8 \ I H 1 N
0 N 0 '- R3 R8 \S I HN 0 0 (IX-a) (IX-b) 0 O. oo,R5 R5 o H 0 0 JCH0 L
/71 \ I H 0 R --UFI R12N N 0 0 K' \ N 0 '- R3 ¨
(I X-C) (IX-d) 2489-CIPO-CLAIMS-ZED-P04404W026.docx Date Recue/Date Received 2022-06-30 O'il-R7 0N-R7 O H 0 0 ( H 011 0 N )-L L2_ R3 R8 S
R8 \ 1 rii 1 N 'r N
\ I H
(X-a) (X-b) O N ' R7 0 N' R7 O ( H 0u 0 rH 0id N L2 0 N L2 =
N ¨ R3 R11 N
R8-- 1 ril R12 1 rii-N 0 0 K/ \ 0 0 R1 3 ¨
(X-c) (X-d) 0 D5 0\ R5 \\ ix 0=S 0 'S' OH 0 0 ( H OR
0 N L2., 3 S
i N N
O 0 \ I H
(Xl-a) (Xl-b) \ R6 cl\ R6 0=\S- 0=\s-O H 0u 0 H 011 S__fL R11 0 N L2 R3 R8--- 1 rii R12 /71 1 hi 1 N
N R10 0 0 Ki \ 0 0 ¨
(Xl-c) (Xl-d) and R2, R3; R5, R6, R7, R8, R9, R1 0, R11, R12, R1 3, Ra; R13, Rc; Rd L
anCI - . 2 have the same meanings as defined in claim 1.
7. The compound according to any one of the claims 1 and 3 ¨ 6, wherein R2 represents 2489-CIPO-CLAIMS-ZED-P04404W026.docx Date Recue/Date Received 2022-06-30 Br -._ CI Br 0 ,-Br / 1 Br, , Br , 0 , , p 0 H2N 0 -Br ---SN-CI
\\ // Br, , Br , _ SN _Br --1_5-Br -- \ s/ S ----CS-C1 ---c7zBr //- \ /
Br Br , CI Br , Br , S S
-- CI -- Br S S
CI Br--__-Br 0--Br -Cl CI--..õ,a_S
CI , Me() Br , /
S-___ --- S---_./
-- l ______ sBr s___-CI -----s_.--Br l - -----s-C1 N---NBr N N N ) __ N
N---N /
' , Br--_Br Cl--1 5N-C1 --CF3 --Br --ys__--cl \ /i \
, N , __ N N N N
CI
, , ---S-CF3 __ SN __ \ IV __________ --s.--lph ir )S__-CI
N N N N
Br --- -' H HN _ N (?-\ - -N--- Me0---_ll - 1--- 3 .\----3 \ N 0 \ N N N
, , , H
I
-- NC /"--r--,_. -' N
, N
-0\-1 \\ .1, H2N HN N N-"\ / N , N
' ' H
ICI N I
N. - _I-I NO
N I
,N 2 N- 'NI ',N (\ , N N:7-.---_:--' N N _ _NI
N
, // Y __ N \-N )LN
µ1\1-1\IN ,/ / NI=N CO2Me , --_,..-----, -,,---õ-:õ_,,, ,NO2 -.---...-CO2H -,,----...õ-0O2Me _.,,,,___õõ,,, , 1\1 , 1\1 N
(Nr,, ___ 1 r NN__-- ,,,.
-- k --, Br HN--- \/
, , H , , 1\1- \ N
r -\N- õ___\L_I") __ \
0 \-----3- - \--NI----- S-----1----N N S
, , , , ' , 0 I CI
Br , 2489-CIPO-CLAIMS-ZED-P04404W026.docx Date Recue/Date Received 2022-06-30 F
/ , 0 / /
\
0 , S , , , H
H N
c N
-- -- \ \ F
Br F , H
N H H
\
--4 --- __ N N
, , OH i , E3%, ,....,,0 --F
I 1 - - r\j--- N --, N--N NI N) NN\
N
----N N N--:- N\ 3y N\
" II /S--- S--- N/\ N \N
,=== , , Nsis\i_r_H Nis\v, N.õ,,-- , -or O¨N
, .
\\ // Br, , Br , _ SN _Br --1_5-Br -- \ s/ S ----CS-C1 ---c7zBr //- \ /
Br Br , CI Br , Br , S S
-- CI -- Br S S
CI Br--__-Br 0--Br -Cl CI--..õ,a_S
CI , Me() Br , /
S-___ --- S---_./
-- l ______ sBr s___-CI -----s_.--Br l - -----s-C1 N---NBr N N N ) __ N
N---N /
' , Br--_Br Cl--1 5N-C1 --CF3 --Br --ys__--cl \ /i \
, N , __ N N N N
CI
, , ---S-CF3 __ SN __ \ IV __________ --s.--lph ir )S__-CI
N N N N
Br --- -' H HN _ N (?-\ - -N--- Me0---_ll - 1--- 3 .\----3 \ N 0 \ N N N
, , , H
I
-- NC /"--r--,_. -' N
, N
-0\-1 \\ .1, H2N HN N N-"\ / N , N
' ' H
ICI N I
N. - _I-I NO
N I
,N 2 N- 'NI ',N (\ , N N:7-.---_:--' N N _ _NI
N
, // Y __ N \-N )LN
µ1\1-1\IN ,/ / NI=N CO2Me , --_,..-----, -,,---õ-:õ_,,, ,NO2 -.---...-CO2H -,,----...õ-0O2Me _.,,,,___õõ,,, , 1\1 , 1\1 N
(Nr,, ___ 1 r NN__-- ,,,.
-- k --, Br HN--- \/
, , H , , 1\1- \ N
r -\N- õ___\L_I") __ \
0 \-----3- - \--NI----- S-----1----N N S
, , , , ' , 0 I CI
Br , 2489-CIPO-CLAIMS-ZED-P04404W026.docx Date Recue/Date Received 2022-06-30 F
/ , 0 / /
\
0 , S , , , H
H N
c N
-- -- \ \ F
Br F , H
N H H
\
--4 --- __ N N
, , OH i , E3%, ,....,,0 --F
I 1 - - r\j--- N --, N--N NI N) NN\
N
----N N N--:- N\ 3y N\
" II /S--- S--- N/\ N \N
,=== , , Nsis\i_r_H Nis\v, N.õ,,-- , -or O¨N
, .
8. The compound according to any one of the claims 1 and 3 ¨ 7, wherein R3 represents , , , ------. ----- '' i ' , , , , . , , .
F , Br , CI, OH, . CN
., CO2H, CONH2, CONMe2, N)-H
OH
CO2Me \, CO2H Br 2489-CIPO-CLAIMS-ZED-P04404W026.docx Date Recue/Date Received 2022-06-30 F jZci jZcF3 jZoH jZCO2Me F
F
,
F , Br , CI, OH, . CN
., CO2H, CONH2, CONMe2, N)-H
OH
CO2Me \, CO2H Br 2489-CIPO-CLAIMS-ZED-P04404W026.docx Date Recue/Date Received 2022-06-30 F jZci jZcF3 jZoH jZCO2Me F
F
,
9. The compound according to claim 1 selected from the group consisting of:
Compound Name 111-1 : (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylam ino)-6-(1-methyl-1H-im idazole-5-carboxamido)-7-oxohept-2-enoate 111-2: (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylam ino)-6-(3-methylbenzofuran-2-carboxam ido)-7-oxo he pt-2-enoate 111-3: (S,E)-methyl 6-(3-ch loro be nzofu ran-2-carboxam ido)-7-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylam ino)-7-oxo he pt-2-enoate 111-4: (S,E)-methyl 6-(4-bromobenzofuran-2-carboxam ido)-7-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylam ino)-7-oxo he pt-2-enoate 111-5: (S,E)-methyl 6-(benzo[b]thiophene-2-carboxam ido)-7-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylam ino)-7-oxo he pt-2-enoate 111-6: (S,E)-methyl 6-(5-bromobenzo[b]thiophene-2-carboxamido)-7-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-dihyd ropyridi n-3-ylam i no)-7-oxo he pt-2-enoate 111-7: (S,E)-methyl 6-(7-fluorobenzo[b]thiophene-2-carboxamido)-7-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-dihyd ropyridi n-3-ylam i no)-7-oxo he pt-2-enoate 111-8: (S,E)-methyl 6-(1H-indole-2-carboxam ido)-7-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylam ino)-7-oxo he pt-2-enoate 111-9: (S,E)-methyl 6-(4, 5-d ifluoro-1H-indole-2-carboxam ido)-7-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylam ino)-7-oxo he pt-2-enoate 111-1 0: (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylam ino)-6-(3-methyl-1H-indole-2-carboxam ido)-7-oxo he pt-2-enoate 2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 111-1 1: (S,E)-methyl 6-(1H-benzo[d]imidazole-2-carboxamido)-7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxohept-2-enoate 111-1 2: (S,E)-methyl 6-(2,3-dihydro-1H-indene-2-carboxamido)-7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxohept-2-enoate 111-1 3: (S,E)-methyl 6-(2,5-dichlorothiophene-3-carboxamido)-7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxohept-2-enoate 111-1 4: (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(4-methyl-2-(trifluoromethyl)thiazole-5-carboxamido)-7-oxohept-2-enoate 111-1 5: (S,E)-methyl 6-(3,5-dibromothiophene-2-carboxamido)-7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxohept-2-enoate 111-1 6: (S,E)-methyl 6-(2,5-dibromothiophene-3-carboxamido)-7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxohept-2-enoate 111-1 7: (S,E)-methyl 6-(5-bromothiophene-3-carboxamido)-7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxohept-2-enoate 111-1 8: (S,E)-methyl 6-(4-bromothiophene-2-carboxamido)-7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxohept-2-enoate 111-1 0: (S,E)-methyl 6-(4,5-dibromothiophene-2-carboxamido)-7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxohept-2-enoate 111-20: (S,E)-methyl 6-(4,5-dichlorothiophene-2-carboxamido)-7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxohept-2-enoate 111-21: (S,E)-methyl 64(S)-1-acetylpyrrolidine-2-carboxamido)-7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxohept-2-enoate 111-22: (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-1H-1,2,3-triazole-5-carboxamido)-7-oxohept-2-enoate 111-23: (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxo-6-(2H-tetrazole-5-carboxamido)hept-2-enoate 2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 111-24: (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxo-6-(pyrazine-2-carboxamido)hept-2-enoate 111-25: (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-64(S)-1-methylpyrrolidine-2-carboxamido)-7-oxohept-2-enoate 111-26: (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxo-6-((S)-pyrrolidine-3-carboxamido)hept-2-enoate 111-27: (S,E)-methyl 64(25,45)-4-bromopyrrolidine-2-carboxamido)-7-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1 ,2-dihyd ropyridi n-3-ylamino)-7-oxohept-2-enoate 111-28: (S,E)-methyl 6-(1H-imidazole-4-carboxamido)-7-(1-(2-(2-adamantylam ino)-2-oxoethyl )-2-oxo-1 ,2-dihydropyridin-3-ylam ino)-7-oxohept-2-enoate 111-29: (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxo-6-((S)-piperidine-2-carboxamido)hept-2-enoate 111-30: (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylam ino)-7-oxo-6-((R)-piperidine-3-carboxamido)hept-2-enoate 111-31 : (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-((R)-morpholine-3-carboxamido)-7-oxohept-2-enoate 111-32: (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxo-6-(quinuclidine-3-carboxamido)hept-2-enoate 111-33: (S,E)-methyl 3-(1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-methoxy-1,7-dioxohept-5-en-2-ylcarbamoy1)-5-nitrobenzoate 111-34: (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(5-nitronicotinamido)-7-oxohept-2-enoate 111-35: (S,E)-5-(1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-methoxy-1,7-dioxohept-5-en-2-ylcarbamoyl)nicotinic acid 111-36: (S,E)-methyl 5-(1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-methoxy-1,7-dioxohept-5-en-2-ylcarbamoyl)nicotinate 2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 111-37: (S,E)-methyl 7-(1-(2-(2-adam antyl (methyl )am i no )-2-oxoethyl )-2-oxo-1,2-d i hyd ropyrid in-3-ylam i no)-6-(3-methyl benzofura n-2-carboxam ido)-7-oxohept-2-enoate 111-38: (S,E)-methyl 7-(1-(2-(5-hyd roxyadamantane-2-am i no )-2-oxoethyl )-2-oxo-1 ,2-d i hyd ropyrid i n-3-y1 am i no )-6-(3-methyl benzofu ra n-2-carboxam ido)-7-oxohept-2-enoate 111-39: (S,E)-methyl 741424541 uo roadam antane-2-am i no )-2-oxoethyl )-2-oxo-1 ,2-d i hyd ropyrid i n-3-y1 am i no )-6-(3-methyl benzofu ra n-2-carboxam ido)-7-oxohept-2-enoate 111-40: (S,E)-methyl 7-(1-(2-(5-chloroadamantane-2-am i no )-2-oxoethyl )-2-oxo-1 ,2-d i hyd ropyrid i n-3-y1 am i no )-6-(3-methyl benzofu ra n-2-carboxam ido)-7-oxohept-2-enoate 111-41 : (S,E)-methyl 7-(1-(2-(5-bromoadamantane-2-am i no )-2-oxoethyl )-2-oxo-1 ,2-d i hyd ropyrid i n-3-y1 am i no )-6-(3-methyl benzofu ra n-2-carboxam ido)-7-oxohept-2-enoate 111-42: (S,E)-methyl 7-(1-(2-(5-methyladamantane-2-am i no )-2-oxoethyl )-2-oxo-1 ,2-d i hyd ropyrid i n-3-y1 am i no )-6-(3-methyl benzofu ra n-2-carboxam ido)-7-oxohept-2-enoate 111-43: (S,E)-methyl 7-(1-(2-(2-ca rbo nitri lead am antane-2-am i no)-2-oxoethyl )-2-oxo-1,2-d i hyd ro pyrid i n-3-y1 am i no)-6-(3-methylbenzofuran-2-carboxamido)-7-oxohept-2-enoate 111-44: (S,E)-methyl 7-(1-(2-(2-methyl adamantane-2-carboxylate-2-am ino)-2-oxoethyl )-2-oxo-1 ,2-d i hyd ropyridin-3-ylam ino)-6-(3-methylbenzofuran-2-carboxamido)-7-oxohept-2-enoate 111-45: (S,E)-methyl 7-(1-(2-(1-adama ntylam i no)-2-oxoethyl )-2-oxo-1, 2-d i hyd ropyridin-3-ylam ino )-6-(3-m ethyl benzofuran-2-carboxam ido)-7-oxohept-2-enoate 111-46: (S,E)-methyl 7-(1-(2-(3,5-d imethyladamantane-1-am i no)-2-oxoethyl )-2-oxo-1,2-d ihydropyridin-3-ylam i no )-6-(3-m ethyl benzofu ran-2-carboxam ido)-7-oxohept-2-enoate 111-47: (S,E)-methyl 7-(1-(2-(1-adam antyl (methyl )am i no )-2-oxoethyl )-2-oxo-1,2-d i hyd ropyrid in-3-ylam i no)-6-(3-methyl benzofura n-2-carboxam ido)-7-oxohept-2-enoate 111-48: (S,E)-methyl 7-(1-(2-(3-ethyladamantane-1-am i no )-2-oxoethyl )-2-oxo-1 ,2-d i hyd ropyrid i n-3-y1 am i no )-6-(3-methyl benzofu ra n-2-carboxam ido)-7-oxohept-2-enoate 111-49: (S,E)-methyl 7-(1-(2-(3-trifl uo rom ethylad am antane-1-am i no)-2-oxoethyl )-2-oxo-1,2-d i hyd ro pyrid i n-3-y1 am i no)-6-(3-methylbenzofuran-2-carboxamido)-7-oxohept-2-enoate 2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 111-50: (S,E)-methyl 7-(1-(2-(3-hydroxyadamantane-1-amino)-2-oxoethyl)-oxo-1,2-dihydropyridin-3-ylam ino)-6-(3-methylbenzofu ran-2-carboxam ido)-7-oxohept-2-enoate 111-51 : (S,E)-methyl 7-(1-(2-(3-fluoroadamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylam ino)-6-(3-methylbenzofu ran-2-carboxam ido)-7-oxohept-2-enoate 111-52: (S,E)-methyl 7-(1-(2-(3-chloroadamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylam ino)-6-(3-methylbenzofu ran-2-carboxam ido)-7-oxohept-2-enoate 111-53: (S,E)-methyl 7-(1-(2-(3-bromoadamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylam ino)-6-(3-methylbenzofu ran-2-carboxam ido)-7-oxohept-2-enoate 111-54: (S,E)-methyl 7-(1-(2-(3-methyl adamantane-3-carboxylate-1-am ino)-2-oxoethyl)-2-oxo-1,2-di hyd ropyridin-3-ylam ino)-6-(3-methyl benzofu ra n-2-carboxam i do)-7-oxohe pt-2-enoate 111-55: (S,E)-methyl 7-(1-(2-(4,4-difluoroadamantane-1-am ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylam ino)-6-(3-methyl benzofu ran-2-carboxam ido)-7-oxohept-2-enoate 111-56: (S,E)-methyl 7-(1-(2-(1-adamantylmethylam ino)-2-oxoethyl)-2-oxo-1,2-di hyd ropyrid in-3-ylam ino)-6-(3-methylbenzofuran-2-carboxam ido)-7-oxohept-2-enoate 111-57: (S,E)-methyl 7-(1-(2-(1-(1-adamantyl)ethanamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylam ino)-6-(3-methylbenzofu ran-2-carboxam ido)-7-oxohept-2-enoate 111-58: (S,E)-methyl 7-(1-(2-((1R,25,45)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxam ido)-7-oxohept-2-enoate 111-59: (S,E)-methyl 7-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl )-2-oxo-1,2-dihydropyridi n-3-ylami no)-6-(3-methyl benzofu ra n-2-carboxam i do)-7-oxohe pt-2-enoate 111-60: (S,E)-methyl 6-(1-methy1-1H-im idazole-5-carboxam ido)-7-oxo-7-(2-oxo-1-(2-oxo-2-((1S ,25,4R)-1,7, 7-trimethyl bicyclo[2 .2 .1] heptan-2-ylam ino)ethyl)-1,2-di hydropyrid in-3-ylam ino)hept-2-enoate 111-61 : (S,E)-methyl 6-(3-m ethyl be nzofu ra n-2-carboxam ido )-7-oxo-7-(2-oxo-1-(2-oxo-2-((1S,25,4R)-1,7 ,7-trimethylbicyclo[2.2 .1]heptan-2-ylam ino)ethyl)-1,2-di hydropyrid in-3-ylam ino)hept-2-enoate 111-62: (S,E)-methyl 7-(1-(2-((1R,2R,45)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxam ido)-7-oxohept-2-enoate 2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 111-63: (S,E)-methyl 7-(1-(2-((1R,2R,45)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(3-methylbenzofuran-2-carboxamido)-7-oxohept-2-enoate 111-64: (S,E)-methyl 7-(1-(2-(bicyclo[2.2.1]heptan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(3-methylbenzofuran-2-carboxamido)-7-oxohept-2-enoate 111-65: (S,E)-methyl 7-(1-(2-(bicyclo[2.2.1]heptan-7-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(3-methylbenzofuran-2-carboxamido)-7-oxohept-2-enoate 111-66: (S,E)-methyl 7-(1-(2-(bicyclo[2.2.1]hept-5-en-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(3-methylbenzofuran-2-carboxamido)-7-oxohept-2-enoate 111-67: (6S,E)-methyl 7-(1-(2-(bicyclo[2.2.2]octan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(3-methylbenzofuran-2-carboxamido)-7-oxohept-2-enoate 111-68: (S,E)-methyl 6-(3-methylbenzofuran-2-carboxamido)-7-oxo-7-(2-oxo-1-(2-oxo-2-((1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-ylamino)hept-2-enoate 111-69: (S,E)-methyl 6-(3-methylbenzofuran-2-carboxamido)-7-oxo-7-(2-oxo-1-(2-oxo-2-((1R,2R,3R,55)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)ethyl)-1,2-dihydropyridin-3-ylamino)hept-2-enoate 111-70: (S,E)-methyl 6-(3-methylbenzofuran-2-carboxamido)-7-oxo-7-(2-oxo-1-(2-oxo-2-((1S,25,35,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)ethyl)-1,2-dihydropyridin-3-ylamino)hept-2-enoate 111-71: (S,E)-methyl 7-(1-(2-(((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(3-methylbenzofuran-2-carboxamido)-7-oxohept-2-enoate 111-72: (S,E)-methyl 7-(1-(2-(4-homoisotwistane-3-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(3-methylbenzofuran-2-carboxamido)-7-oxohept-2-enoate 111-73: (S,E)-methyl 7-(1-(2-(diamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(3-methylbenzofuran-2-carboxamido)-7-oxohept-2-enoate 111-74: (S,E)-methyl 7-(1-(2-(diamantane-4-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(3-methylbenzofuran-2-carboxamido)-7-oxohept-2-enoate 111-75: (S,E)-N7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N1,N1-dimethy1-6-(3-methylbenzofuran-2-carboxamido)hept-2-enediamide 2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 111-76: (S,E)-N7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N1,N1-dimethy1-6-(1-methy1-1H-imidazole-5-carboxamido)hept-2-enediamide 111-77: (S,E)-N7-(1-(2-(3,5-dimethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N1,N1-dimethyl-6-(3-methylbenzofuran-2-carboxamido)hept-2-enediamide 111-78: (S,E)-methyl 7-(1-(1-adamantylmethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate 111-79: (S,E)-methyl 7-(1-(1-adamantylmethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(3-methylbenzofuran-2-carboxamido)-7-oxohept-2-enoate 111-80: (6S,E)-methyl 7-(14(3-hydroxy-1-adamantyl)methyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(3-methylbenzofuran-2-carboxamido)-7-oxohept-2-enoate 111-81: (6S,E)-methyl 7-(14(3-bromo-1-adamantyl)methyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(3-methylbenzofuran-2-carboxamido)-7-oxohept-2-enoate 111-82: (S,E)-methyl 7-(1-(2-adamantylmethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(3-methylbenzofuran-2-carboxamido)-7-oxohept-2-enoate 111-83: (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(nicotinamido)-7-oxohept-2-enoate 111-84: (S,E)-methyl 6-(isonicotinamido)-7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxohept-2-enoate 111-85: (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxo-6-(pyridazine-4-carboxamido)hept-2-enoate 111-86: (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxo-6-(pyridazine-3-carboxamido)hept-2-enoate 111-87: (S,E)-methyl 7-(1-(2-(1-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazole-2-carboxamido)-7-oxohept-2-enoate 111-88: (S,E)-methyl 7-(1-(2-(3,5-dimethyladamantane)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate 111-89: (S,E)-ethyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(3-methylbenzofuran-2-carboxamido)-7-oxohept-2-enoate 2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 111-90: (S, E)-N-(1-(1-(2-(2-adamantylam ino)-2-oxoethyl )-2-oxo-1,2-dihyd ropyridin-3-ylam ino)-6-(methylsulfony1)-1-oxohex-5-en-2-y1)-3-methylbenzofuran-2-carboxamide 111-91 : (S,E)-methyl 7414243,5 ,7-trimethy1-1-adam antylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylam ino)-6-(1-methy1-1H-im idazole-5-carboxam ido)-7-oxohept-2-enoate (S,E)-methyl 7414243,5 ,7-trimethy1-1-adam antylam ino)-2-oxoethyly 111-92: 2-oxo-1,2-dihydropyridin-3-ylam ino)-6-(3-methyl benzofu ran-2-carboxam ido)-7-oxohept-2-enoate (S,E)-methyl 7414243,5 ,7-trimethy1-1-adam antylam ino)-2-oxoethyly 111-93: 2-oxo-1,2-dihydropyridin-3-ylam ino)-6-(1-methy1-1H-1,2,3-triazole-5-carboxam ido)-7-oxohept-2-enoate (S,E)-methyl 6-(2, 5-d ichlorothiophene-3-carboxam ido)-7-(1-(2-111-94: (3,5 ,7-trimethy1-1-adamantylam i no)-2-oxoethyl)-2-oxo-1,2-dihyd ropyridin-3-ylam ino)-7-oxohept-2-enoate (S,E)-methyl 7414243,5 ,7-trimethy1-1-adam antylam ino)-2-oxoethyly 111-95: 2-oxo-1,2-dihydropyridin-3-ylam ino)-6-(4-methy1-2-(trifluoromethyl)thiazole-5-carboxam ido)-7-oxohept-2-enoate (6S,E)-methyl 7-(1-(2-((1R,2R,45)-bicyclo[2.2.1]heptan-2-ylam ino)-111-96: 2-oxoethyl)-2-oxo-1,2-di hyd ropyridin-3-ylam ino)-6-(1-methy1-1,2 ,3-triazo le-5-carboxam ido)-7-oxohept-2-enoate (65,E)-methyl 7-(1-(2-((1R,2R,45)-bicyclo[2.2.1]heptan-2-ylam ino)-111-97: 2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(2,5-dichlorothiophene-3-carboxamido)-7-oxohept-2-enoate (65,E)-methyl 7-(1-(2-((1R,2R,45)-bicyclo[2.2.1]heptan-2-ylam ino)-111-98: 2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(4-methy1-2-(trifluoromethyl)thiazole-5-carboxam ido)-7-oxohept-2-enoate (S,E)-ethyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-111-99: dihydropyridin-3-ylam ino)-6-(1-methy1-1H-im idazole-5-carboxamido)-7-oxohept-2-enoate (S, E)-N-(1-(1-(2-(2-adamantylam ino)-2-oxoethyl )-2-oxo-1,2-111-100 : dihydropyridin-3-ylam ino)-6-(methylsulfony1)-1-oxohex-5-en-2-y1)-1-methy1-1H-imidazole-5-carboxamide (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-111A 01 : dihydropyridin-3-ylamino)-7-oxo-6-(2H-1,2,3-triazole-4-carboxam ido)hept-2-enoate (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-111A 02: dihydropyridin-3-ylam ino)-7-oxo-6-(1H-1,2,3-triazole-4-carboxam ido)hept-2-enoate (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-111-1 03: dihydropyridin-3-ylam ino)-6-(1-methy1-1H-1,2,3-triazole-4-carboxam ido)-7-oxohept-2-enoate 2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-111-1 04: dihydropyridin-3-ylam ino)-7-oxo-6-(1H-1,2,4-triazole-3-carboxam ido)hept-2-enoate (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-111-1 05: dihydropyridin-3-ylam ino)-6-(1-methy1-1H-1,2,4-triazole-3-carboxam ido)-7-oxohept-2-enoate (S,E)-methyl 6-(benzofuran-3-carboxam ido)-7-(1-(2-(2-111-1 06: adamantylam ino)-2-oxoethyl )-2-oxo-1,2-di hyd ropyridi n-3-ylam ino)-7-oxohept-2-enoate (S,E)-methyl 6-(benzo[b]thiophene-3-carboxam ido)-7-(1-(2-(2-111-1 07: adamantylam ino)-2-oxoethyl )-2-oxo-1,2-di hyd ropyridi n-3-ylam ino)-7-oxohept-2-enoate (S,E)-methyl 7414243,5 ,7-trimethy1-1-adam antylam ino)-2-oxoethyly 111-1 08 2-oxo-1,2-dihydropyridin-3-ylam ino)-6-(4-methy1-1,2,3-thiadiazole-5-carboxam ido)-7-oxohept-2-enoate (S,E)-methyl 7414243,5 ,7-trimethy1-1-adam antylam ino)-2-oxoethyly 111-1 09 2-oxo-1,2-dihydropyridin-3-ylam ino)-6-(1-methy1-1H-pyrazole-5-carboxam ido)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(2-((1R,2R,45)-bicyclo[2.2.1]heptan-2-ylamino)-2-111-1 1 0 oxoethyl )-2-oxo-1,2-dihydropyridi n-3-ylami no)-6-(4-methy1-1,2,3-thiadiazole-5-carboxam ido)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(2-((1R,2R,45)-bicyclo[2.2.1]heptan-2-ylamino)-2-111-1 1 1 oxoethyl )-2-oxo-1,2-dihydropyridi n-3-ylami no)-6-(1-methy1-pyrazole-5-carboxam ido)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(2-(3,5-dimethyladamantane-1-am ino)-2-oxoethyl)-111-1 1 2 2-oxo-1,2-dihydropyridin-3-ylamino)-6-(4-methy1-1,2,3-thiadiazole-5-carboxam ido)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(2-(3,5-dimethyladamantane-1-am ino)-2-oxoethyl)-111-1 1 3 2-oxo-1,2-dihydropyridin-3-ylam ino)-6-(1-methy1-1H-pyrazole-5-carboxam ido)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(2-(3,5-dimethyladamantane-1-am ino)-2-oxoethyl)-111-1 1 4 2-oxo-1,2-dihydropyridin-3-ylam ino)-6-(1-methy1-1H-1,2,3-triazole-5-carboxam ido)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-111-1 1 5 oxoethyl )-2-oxo-1,2-dihydropyridi n-3-ylami no)-6-(4-methy1-1,2,3-thiadiazole-5-carboxam ido)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-111-1 1 6 oxoethyl )-2-oxo-1,2-dihydropyridi n-3-ylami no)-6-(1-methy1-1H-1,2,3-triazo le-5-carboxam ido)-7-oxohept-2-enoate 2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 (S,E)-methyl 7-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-111-1 1 7 oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methy1-1H-pyrazole-5-carboxamido)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-111-1 1 8 dihydropyridin-3-ylamino)-6-(4-methy1-1,2,3-thiadiazole-5-carboxamido)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-111-1 1 9 dihydropyridin-3-ylam ino)-6-(1-methy1-1H-pyrazole-5-carboxamido)-7-oxohept-2-enoate (S,E)-methyl 6-(4-methy1-1,2,3-thiadiazole-5-carboxamido)-7-oxo-7-111-1 20 (2-oxo-1-(2-oxo-2-((1R,25,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-ylamino)hept-2-enoate (S,E)-methyl 6-(1-methy1-1H-1,2,3-triazole-5-ca rboxam ido)-7-oxo-7-111-1 21 (2-oxo-1-(2-oxo-2-((1R,25,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-ylamino)hept-2-enoate (S,E)-methyl 6-(1-methy1-1H-pyrazole-5-carboxamido)-7-oxo-7-(2-111-1 22 oxo-1-(2-oxo-2-((1R,25,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-ylamino)ethyl)-1,2-dihydropyridin-3-ylamino)hept-2-enoate (S,E)-methyl 7-(1-(2-(3,5-dimethyladamantane-1-am ino)-2-oxoethyl)-111-1 23 2-oxo-1,2-dihydropyridin-3-ylamino)-6-(4-methy1-2-(trifluoromethyl)thiazole-5-carboxamido)-7-oxohept-2-enoate (S,E)-methyl 6-(2,5-dichlorothiophene-3-carboxamido)-7-(1-(2-(3,5-111-1 24 dimethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-111-1 25 oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(4-methy1-2-(trifluoromethyl)thiazole-5-carboxamido)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-111-1 26 oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(2,5-dichlorothiophene-3-carboxamido)-7-oxohept-2-enoate (S,E)-methyl 6-(4-methy1-2-(trifluoromethyl)thiazole-5-carboxamido)-7-oxo-7-(2-oxo-1-(2-oxo-2-((1R,25,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-ylamino)hept-2-enoate (S,E)-methyl 6-(2,5-dichlorothiophene-3-carboxamido)-7-oxo-7-(2-111-1 28 oxo-1-(2-oxo-2-((1R,25,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-ylamino)ethyl)-1,2-dihydropyridin-3-ylamino)hept-2-enoate 2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-111-1 29 dihydropyridin-3-ylamino)-6-(1-methy1-1H-pyrazole-3-carboxamido)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-111-1 30 dihydropyridin-3-ylamino)-6-(1-methy1-1H-pyrazole-4-carboxamido)-7-oxohept-2-enoate (S,E)-methyl 6-(4-tert-buty1-1H-pyrrole-3-carboxam ido)-7-(1-(2-(1-III-1 31 adamantylamino)ethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxohept-2-enoate (S,E)-methyl 6-(4-cyano-1-methy1-1H-pyrrole-2-carboxamido)-7-(1-III-1 32 (3-(1-adamantylamino)propy1)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(3-(2-adamantylam ino)-3-oxopropy1)-2-oxo-1,2-111-1 33 dihydropyridin-3-ylamino)-6-(5-methoxyoxazole-2-carboxamido)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(2-(bicyclo[2.1.1]hexan-1-ylamino)-2-oxoethyl)-2-111-1 34 oxo-1,2-dihydropyridin-3-ylamino)-6-(2-isopropyloxazole-5-carboxamido)-7-oxohept-2-enoate (6S,E)-methyl 7-(1-(2-(bicyclo[3.2.1]octan-8-ylamino)-2-oxoethyl)-2-111-1 35 oxo-1,2-dihydropyridin-3-ylamino)-6-(3,5-dimethylisoxazole-4-carboxamido)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(2-(5-carboxy-2-aminoadamantane)-2-oxoethyl)-2-111-1 36 oxo-1,2-dihydropyridin-3-ylamino)-6-(4-methylpyrimidine-5-carboxamido)-7-oxohept-2-enoate (65,E)-methyl 7-(1-(2-(4-aminoadamantane-N,N-dimethyl-1-111-1 37 carboxamide)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxo-6-(1,2,3,4-tetrahydronaphthalene-2-carboxamido)hept-2-enoate (S,E)-6-(2-acetyloxazole-4-carboxamido)-N7-(1-(2-111-1 38 (bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N1,N1-diethylhept-2-enediamide (S,E)-N7-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-111-1 39 1,2-dihydropyridin-3-y1)-6-((S)-1,4-diazabicyclo[2.2.2]octane-carboxamido)-N1,N1-diethylhept-2-enediamide (S,E)-N7-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-111-1 40 1,2-dihydropyridin-3-y1)-6-(1H-indole-3-carboxamido)-N1-isopropylhept-2-enediamide (S,E)-N7-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-111-1 41 1,2-dihydropyridin-3-y1)-N1-isopropy1-6-(6-methylimidazo[2,1-b]thiazole-3-carboxamido)hept-2-enediamide 2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 (S,E)-6-(benzo[d]thiazole-2-carboxamido)-N7-(1-(2-111-1 42 (bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N1-pentylhept-2-enediamide (S,E)-N7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-111-1 43 1,2-dihydropyridin-3-y1)-6-(imidazo[2,1-b]thiazole-6-carboxamido)-N1-pentylhept-2-enediamide (S,E)-N7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-111-1 44 1,2-dihydropyridin-3-y1)-N1-cyclopropy1-6-(4-hydroxy-6-(trifluoromethoxy)quinoline-3-carboxamido)hept-2-enediamide (S,E)-N7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-111-1 45 1,2-dihydropyridin-3-y1)-6-(cinnoline-3-carboxamido)-N1-cyclopropylhept-2-enediamide (S,E)-N7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-111-1 46 1,2-dihydropyridin-3-y1)-N1-cyclopenty1-6-(2-methyl-1,8-naphthyridine-3-carboxamido)hept-2-enediamide (S,E)-N7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-111-1 47 1,2-dihydropyridin-3-y1)-N1-cyclopenty1-6-(3-ethylbenzofuran-2-carboxamido)hept-2-enediamide (S,E)-N7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-111-1 48 1,2-dihydropyridin-3-y1)-N1-cyclohexy1-6-(1-ethy1-1H-indole-2-carboxamido)hept-2-enediamide (S,E)-N7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-111-1 49 1,2-dihydropyridin-3-y1)-N1-cyclohexy1-6-(1,2,3,4-tetrahydroquinoline-7-carboxamido)hept-2-enediamide (S,E)-N1-allyl-N7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-111-1 50 2-oxo-1,2-dihydropyridin-3-y1)-6-(1,6-naphthyridine-2-carboxamido)hept-2-enediamide (S,E)-N1-allyl-N7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-111-1 51 2-oxo-1,2-dihydropyridin-3-y1)-6-(2,6-naphthyridine-1-carboxamido)hept-2-enediamide (S,E)-N7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-111-1 52 1,2-dihydropyridin-3-y1)-6-(5-bromo-2-methylfuran-3-carboxamido)-N1-phenylhept-2-enediamide (S,E)-N7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-111-1 53 1,2-dihydropyridin-3-y1)-6-(2,5-dimethylfuran-3-carboxamido)-phenylhept-2-enediamide (S,E)-N1-benzyl-N7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-111-1 54 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-6-(2,5-dichlorothiazole-4-carboxamido)hept-2-enediamide 2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 (S,E)-N1-benzyl-N7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-111-1 55 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-6-(4-bromothiazole-2-carboxamido)hept-2-enediamide (S,E)-benzyl 7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-111-1 56 oxo-1,2-dihydropyridin-3-ylamino)-6-(4-methy1-2-phenylthiazole-carboxamido)-7-oxohept-2-enoate (S,E)-N-(1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-111-1 57 1,2-dihydropyridin-3-ylamino)-1,7-dioxo-7-phenylhept-5-en-2-y1)-1-methy1-1H-imidazole-2-carboxamide (S,E)-isopropyl 7-(1-(2-(bicyclo[2.1.1]hexan-1-ylamino)-2-oxoethyly 111-1 58 2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxo-6-(2H-1,2,3-triazole-carboxamido)hept-2-enoate N4(25,E)-1-(1-(2-(bicyclo[3.2.1]octan-8-ylamino)-2-oxoethyl)-2-oxo-111-1 59 1,2-dihydropyridin-3-ylamino)-1,7-dioxooct-5-en-2-y1)-1-methy1-1,2,4-triazole-3-carboxamide (S,E)-methyl 6-(4-amino-1,2,5-oxadiazole-3-carboxamido)-7-(1-(2-111-1 60 (bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-111-1 61 oxo-1,2-dihydropyridin-3-ylamino)-6-(6-(dimethylamino)benzofuran-2-carboxamido)-7-oxohept-2-enoate (S,E)-methyl 6-(2-acetamidothiazole-5-carboxamido)-7-(1-(2-111-1 62 (bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-111-1 63 oxo-1,2-dihydropyridin-3-ylamino)-6-(5-carbamoy1-1H-pyrrole-3-carboxamido)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(2-(1-acetylamino-4-aminoadamantane)-2-111-1 64 oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxo-6-(5-sulfamoylfuran-3-carboxamido)hept-2-enoate (S,E)-methyl 6-(benzofuran-5-carboxamido)-7-(1-(2-(1-acetylamino-111-1 65 4-aminoadamantane)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxohept-2-enoate (S,E)-methyl 6-(benzofuran-6-carboxam ido)-7-(1-(2-(4-111-1 66 am inoadamantane-1-carboxamide)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylam ino)-7-oxohept-2-enoate 111 1 67 (S,E)-methyl 7-(1-(2-(4-aminoadamantane-1-carboxamide)-2--oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(3-(1-2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamido)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-111-1 68 oxo-1,2-dihydropyridin-3-ylamino)-6-(5-methyl-1,2,4-oxadiazole-3-carboxamido)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-111-1 69 oxo-1,2-dihydropyridin-3-ylamino)-7-oxo-6-(1,2,3-thiadiazole-4-carboxamido)hept-2-enoate (S,E)-methyl 7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-111-1 70 oxo-1,2-dihydropyridin-3-ylamino)-7-oxo-6-(1,2,4-thiadiazole-5-carboxamido)hept-2-enoate (S,E)-methyl 7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-111-1 71 oxo-1,2-dihydropyridin-3-ylamino)-7-oxo-6-(1,3,4-thiadiazole-2-carboxamido)hept-2-enoate (S,E)-methyl 7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-111-1 72 oxo-1,2-dihydropyridin-3-ylamino)-6-(4-cyclopropyl-1,2,3-thiadiazole-5-carboxamido)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-111-1 73 oxo-1,2-dihydropyridin-3-ylamino)-7-oxo-6-(1,2,5-thiadiazole-3-carboxamido)hept-2-enoate (S,E)-methyl 6-(4-formyl-1,2,3-thiadiazole-5-carboxamido)-7-(1-(2-111-1 74 (2-carboxy-2-amino-5-(trifluoromethyl)adamantane)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxohept-2-enoate (S,E)-methyl 6-(4-(hydroxymethyl)-1,2,3-thiadiazole-5-carboxam ido)-111-1 75 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxohept-2-enoate or a pharmaceutically acceptable salt thereof.
Compound Name 111-1 : (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylam ino)-6-(1-methyl-1H-im idazole-5-carboxamido)-7-oxohept-2-enoate 111-2: (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylam ino)-6-(3-methylbenzofuran-2-carboxam ido)-7-oxo he pt-2-enoate 111-3: (S,E)-methyl 6-(3-ch loro be nzofu ran-2-carboxam ido)-7-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylam ino)-7-oxo he pt-2-enoate 111-4: (S,E)-methyl 6-(4-bromobenzofuran-2-carboxam ido)-7-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylam ino)-7-oxo he pt-2-enoate 111-5: (S,E)-methyl 6-(benzo[b]thiophene-2-carboxam ido)-7-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylam ino)-7-oxo he pt-2-enoate 111-6: (S,E)-methyl 6-(5-bromobenzo[b]thiophene-2-carboxamido)-7-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-dihyd ropyridi n-3-ylam i no)-7-oxo he pt-2-enoate 111-7: (S,E)-methyl 6-(7-fluorobenzo[b]thiophene-2-carboxamido)-7-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-dihyd ropyridi n-3-ylam i no)-7-oxo he pt-2-enoate 111-8: (S,E)-methyl 6-(1H-indole-2-carboxam ido)-7-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylam ino)-7-oxo he pt-2-enoate 111-9: (S,E)-methyl 6-(4, 5-d ifluoro-1H-indole-2-carboxam ido)-7-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylam ino)-7-oxo he pt-2-enoate 111-1 0: (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylam ino)-6-(3-methyl-1H-indole-2-carboxam ido)-7-oxo he pt-2-enoate 2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 111-1 1: (S,E)-methyl 6-(1H-benzo[d]imidazole-2-carboxamido)-7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxohept-2-enoate 111-1 2: (S,E)-methyl 6-(2,3-dihydro-1H-indene-2-carboxamido)-7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxohept-2-enoate 111-1 3: (S,E)-methyl 6-(2,5-dichlorothiophene-3-carboxamido)-7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxohept-2-enoate 111-1 4: (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(4-methyl-2-(trifluoromethyl)thiazole-5-carboxamido)-7-oxohept-2-enoate 111-1 5: (S,E)-methyl 6-(3,5-dibromothiophene-2-carboxamido)-7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxohept-2-enoate 111-1 6: (S,E)-methyl 6-(2,5-dibromothiophene-3-carboxamido)-7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxohept-2-enoate 111-1 7: (S,E)-methyl 6-(5-bromothiophene-3-carboxamido)-7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxohept-2-enoate 111-1 8: (S,E)-methyl 6-(4-bromothiophene-2-carboxamido)-7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxohept-2-enoate 111-1 0: (S,E)-methyl 6-(4,5-dibromothiophene-2-carboxamido)-7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxohept-2-enoate 111-20: (S,E)-methyl 6-(4,5-dichlorothiophene-2-carboxamido)-7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxohept-2-enoate 111-21: (S,E)-methyl 64(S)-1-acetylpyrrolidine-2-carboxamido)-7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxohept-2-enoate 111-22: (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-1H-1,2,3-triazole-5-carboxamido)-7-oxohept-2-enoate 111-23: (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxo-6-(2H-tetrazole-5-carboxamido)hept-2-enoate 2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 111-24: (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxo-6-(pyrazine-2-carboxamido)hept-2-enoate 111-25: (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-64(S)-1-methylpyrrolidine-2-carboxamido)-7-oxohept-2-enoate 111-26: (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxo-6-((S)-pyrrolidine-3-carboxamido)hept-2-enoate 111-27: (S,E)-methyl 64(25,45)-4-bromopyrrolidine-2-carboxamido)-7-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1 ,2-dihyd ropyridi n-3-ylamino)-7-oxohept-2-enoate 111-28: (S,E)-methyl 6-(1H-imidazole-4-carboxamido)-7-(1-(2-(2-adamantylam ino)-2-oxoethyl )-2-oxo-1 ,2-dihydropyridin-3-ylam ino)-7-oxohept-2-enoate 111-29: (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxo-6-((S)-piperidine-2-carboxamido)hept-2-enoate 111-30: (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylam ino)-7-oxo-6-((R)-piperidine-3-carboxamido)hept-2-enoate 111-31 : (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-((R)-morpholine-3-carboxamido)-7-oxohept-2-enoate 111-32: (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxo-6-(quinuclidine-3-carboxamido)hept-2-enoate 111-33: (S,E)-methyl 3-(1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-methoxy-1,7-dioxohept-5-en-2-ylcarbamoy1)-5-nitrobenzoate 111-34: (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(5-nitronicotinamido)-7-oxohept-2-enoate 111-35: (S,E)-5-(1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-methoxy-1,7-dioxohept-5-en-2-ylcarbamoyl)nicotinic acid 111-36: (S,E)-methyl 5-(1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-methoxy-1,7-dioxohept-5-en-2-ylcarbamoyl)nicotinate 2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 111-37: (S,E)-methyl 7-(1-(2-(2-adam antyl (methyl )am i no )-2-oxoethyl )-2-oxo-1,2-d i hyd ropyrid in-3-ylam i no)-6-(3-methyl benzofura n-2-carboxam ido)-7-oxohept-2-enoate 111-38: (S,E)-methyl 7-(1-(2-(5-hyd roxyadamantane-2-am i no )-2-oxoethyl )-2-oxo-1 ,2-d i hyd ropyrid i n-3-y1 am i no )-6-(3-methyl benzofu ra n-2-carboxam ido)-7-oxohept-2-enoate 111-39: (S,E)-methyl 741424541 uo roadam antane-2-am i no )-2-oxoethyl )-2-oxo-1 ,2-d i hyd ropyrid i n-3-y1 am i no )-6-(3-methyl benzofu ra n-2-carboxam ido)-7-oxohept-2-enoate 111-40: (S,E)-methyl 7-(1-(2-(5-chloroadamantane-2-am i no )-2-oxoethyl )-2-oxo-1 ,2-d i hyd ropyrid i n-3-y1 am i no )-6-(3-methyl benzofu ra n-2-carboxam ido)-7-oxohept-2-enoate 111-41 : (S,E)-methyl 7-(1-(2-(5-bromoadamantane-2-am i no )-2-oxoethyl )-2-oxo-1 ,2-d i hyd ropyrid i n-3-y1 am i no )-6-(3-methyl benzofu ra n-2-carboxam ido)-7-oxohept-2-enoate 111-42: (S,E)-methyl 7-(1-(2-(5-methyladamantane-2-am i no )-2-oxoethyl )-2-oxo-1 ,2-d i hyd ropyrid i n-3-y1 am i no )-6-(3-methyl benzofu ra n-2-carboxam ido)-7-oxohept-2-enoate 111-43: (S,E)-methyl 7-(1-(2-(2-ca rbo nitri lead am antane-2-am i no)-2-oxoethyl )-2-oxo-1,2-d i hyd ro pyrid i n-3-y1 am i no)-6-(3-methylbenzofuran-2-carboxamido)-7-oxohept-2-enoate 111-44: (S,E)-methyl 7-(1-(2-(2-methyl adamantane-2-carboxylate-2-am ino)-2-oxoethyl )-2-oxo-1 ,2-d i hyd ropyridin-3-ylam ino)-6-(3-methylbenzofuran-2-carboxamido)-7-oxohept-2-enoate 111-45: (S,E)-methyl 7-(1-(2-(1-adama ntylam i no)-2-oxoethyl )-2-oxo-1, 2-d i hyd ropyridin-3-ylam ino )-6-(3-m ethyl benzofuran-2-carboxam ido)-7-oxohept-2-enoate 111-46: (S,E)-methyl 7-(1-(2-(3,5-d imethyladamantane-1-am i no)-2-oxoethyl )-2-oxo-1,2-d ihydropyridin-3-ylam i no )-6-(3-m ethyl benzofu ran-2-carboxam ido)-7-oxohept-2-enoate 111-47: (S,E)-methyl 7-(1-(2-(1-adam antyl (methyl )am i no )-2-oxoethyl )-2-oxo-1,2-d i hyd ropyrid in-3-ylam i no)-6-(3-methyl benzofura n-2-carboxam ido)-7-oxohept-2-enoate 111-48: (S,E)-methyl 7-(1-(2-(3-ethyladamantane-1-am i no )-2-oxoethyl )-2-oxo-1 ,2-d i hyd ropyrid i n-3-y1 am i no )-6-(3-methyl benzofu ra n-2-carboxam ido)-7-oxohept-2-enoate 111-49: (S,E)-methyl 7-(1-(2-(3-trifl uo rom ethylad am antane-1-am i no)-2-oxoethyl )-2-oxo-1,2-d i hyd ro pyrid i n-3-y1 am i no)-6-(3-methylbenzofuran-2-carboxamido)-7-oxohept-2-enoate 2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 111-50: (S,E)-methyl 7-(1-(2-(3-hydroxyadamantane-1-amino)-2-oxoethyl)-oxo-1,2-dihydropyridin-3-ylam ino)-6-(3-methylbenzofu ran-2-carboxam ido)-7-oxohept-2-enoate 111-51 : (S,E)-methyl 7-(1-(2-(3-fluoroadamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylam ino)-6-(3-methylbenzofu ran-2-carboxam ido)-7-oxohept-2-enoate 111-52: (S,E)-methyl 7-(1-(2-(3-chloroadamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylam ino)-6-(3-methylbenzofu ran-2-carboxam ido)-7-oxohept-2-enoate 111-53: (S,E)-methyl 7-(1-(2-(3-bromoadamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylam ino)-6-(3-methylbenzofu ran-2-carboxam ido)-7-oxohept-2-enoate 111-54: (S,E)-methyl 7-(1-(2-(3-methyl adamantane-3-carboxylate-1-am ino)-2-oxoethyl)-2-oxo-1,2-di hyd ropyridin-3-ylam ino)-6-(3-methyl benzofu ra n-2-carboxam i do)-7-oxohe pt-2-enoate 111-55: (S,E)-methyl 7-(1-(2-(4,4-difluoroadamantane-1-am ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylam ino)-6-(3-methyl benzofu ran-2-carboxam ido)-7-oxohept-2-enoate 111-56: (S,E)-methyl 7-(1-(2-(1-adamantylmethylam ino)-2-oxoethyl)-2-oxo-1,2-di hyd ropyrid in-3-ylam ino)-6-(3-methylbenzofuran-2-carboxam ido)-7-oxohept-2-enoate 111-57: (S,E)-methyl 7-(1-(2-(1-(1-adamantyl)ethanamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylam ino)-6-(3-methylbenzofu ran-2-carboxam ido)-7-oxohept-2-enoate 111-58: (S,E)-methyl 7-(1-(2-((1R,25,45)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxam ido)-7-oxohept-2-enoate 111-59: (S,E)-methyl 7-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl )-2-oxo-1,2-dihydropyridi n-3-ylami no)-6-(3-methyl benzofu ra n-2-carboxam i do)-7-oxohe pt-2-enoate 111-60: (S,E)-methyl 6-(1-methy1-1H-im idazole-5-carboxam ido)-7-oxo-7-(2-oxo-1-(2-oxo-2-((1S ,25,4R)-1,7, 7-trimethyl bicyclo[2 .2 .1] heptan-2-ylam ino)ethyl)-1,2-di hydropyrid in-3-ylam ino)hept-2-enoate 111-61 : (S,E)-methyl 6-(3-m ethyl be nzofu ra n-2-carboxam ido )-7-oxo-7-(2-oxo-1-(2-oxo-2-((1S,25,4R)-1,7 ,7-trimethylbicyclo[2.2 .1]heptan-2-ylam ino)ethyl)-1,2-di hydropyrid in-3-ylam ino)hept-2-enoate 111-62: (S,E)-methyl 7-(1-(2-((1R,2R,45)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxam ido)-7-oxohept-2-enoate 2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 111-63: (S,E)-methyl 7-(1-(2-((1R,2R,45)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(3-methylbenzofuran-2-carboxamido)-7-oxohept-2-enoate 111-64: (S,E)-methyl 7-(1-(2-(bicyclo[2.2.1]heptan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(3-methylbenzofuran-2-carboxamido)-7-oxohept-2-enoate 111-65: (S,E)-methyl 7-(1-(2-(bicyclo[2.2.1]heptan-7-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(3-methylbenzofuran-2-carboxamido)-7-oxohept-2-enoate 111-66: (S,E)-methyl 7-(1-(2-(bicyclo[2.2.1]hept-5-en-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(3-methylbenzofuran-2-carboxamido)-7-oxohept-2-enoate 111-67: (6S,E)-methyl 7-(1-(2-(bicyclo[2.2.2]octan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(3-methylbenzofuran-2-carboxamido)-7-oxohept-2-enoate 111-68: (S,E)-methyl 6-(3-methylbenzofuran-2-carboxamido)-7-oxo-7-(2-oxo-1-(2-oxo-2-((1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-ylamino)hept-2-enoate 111-69: (S,E)-methyl 6-(3-methylbenzofuran-2-carboxamido)-7-oxo-7-(2-oxo-1-(2-oxo-2-((1R,2R,3R,55)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)ethyl)-1,2-dihydropyridin-3-ylamino)hept-2-enoate 111-70: (S,E)-methyl 6-(3-methylbenzofuran-2-carboxamido)-7-oxo-7-(2-oxo-1-(2-oxo-2-((1S,25,35,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)ethyl)-1,2-dihydropyridin-3-ylamino)hept-2-enoate 111-71: (S,E)-methyl 7-(1-(2-(((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(3-methylbenzofuran-2-carboxamido)-7-oxohept-2-enoate 111-72: (S,E)-methyl 7-(1-(2-(4-homoisotwistane-3-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(3-methylbenzofuran-2-carboxamido)-7-oxohept-2-enoate 111-73: (S,E)-methyl 7-(1-(2-(diamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(3-methylbenzofuran-2-carboxamido)-7-oxohept-2-enoate 111-74: (S,E)-methyl 7-(1-(2-(diamantane-4-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(3-methylbenzofuran-2-carboxamido)-7-oxohept-2-enoate 111-75: (S,E)-N7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N1,N1-dimethy1-6-(3-methylbenzofuran-2-carboxamido)hept-2-enediamide 2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 111-76: (S,E)-N7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N1,N1-dimethy1-6-(1-methy1-1H-imidazole-5-carboxamido)hept-2-enediamide 111-77: (S,E)-N7-(1-(2-(3,5-dimethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N1,N1-dimethyl-6-(3-methylbenzofuran-2-carboxamido)hept-2-enediamide 111-78: (S,E)-methyl 7-(1-(1-adamantylmethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate 111-79: (S,E)-methyl 7-(1-(1-adamantylmethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(3-methylbenzofuran-2-carboxamido)-7-oxohept-2-enoate 111-80: (6S,E)-methyl 7-(14(3-hydroxy-1-adamantyl)methyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(3-methylbenzofuran-2-carboxamido)-7-oxohept-2-enoate 111-81: (6S,E)-methyl 7-(14(3-bromo-1-adamantyl)methyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(3-methylbenzofuran-2-carboxamido)-7-oxohept-2-enoate 111-82: (S,E)-methyl 7-(1-(2-adamantylmethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(3-methylbenzofuran-2-carboxamido)-7-oxohept-2-enoate 111-83: (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(nicotinamido)-7-oxohept-2-enoate 111-84: (S,E)-methyl 6-(isonicotinamido)-7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxohept-2-enoate 111-85: (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxo-6-(pyridazine-4-carboxamido)hept-2-enoate 111-86: (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxo-6-(pyridazine-3-carboxamido)hept-2-enoate 111-87: (S,E)-methyl 7-(1-(2-(1-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazole-2-carboxamido)-7-oxohept-2-enoate 111-88: (S,E)-methyl 7-(1-(2-(3,5-dimethyladamantane)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate 111-89: (S,E)-ethyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(3-methylbenzofuran-2-carboxamido)-7-oxohept-2-enoate 2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 111-90: (S, E)-N-(1-(1-(2-(2-adamantylam ino)-2-oxoethyl )-2-oxo-1,2-dihyd ropyridin-3-ylam ino)-6-(methylsulfony1)-1-oxohex-5-en-2-y1)-3-methylbenzofuran-2-carboxamide 111-91 : (S,E)-methyl 7414243,5 ,7-trimethy1-1-adam antylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylam ino)-6-(1-methy1-1H-im idazole-5-carboxam ido)-7-oxohept-2-enoate (S,E)-methyl 7414243,5 ,7-trimethy1-1-adam antylam ino)-2-oxoethyly 111-92: 2-oxo-1,2-dihydropyridin-3-ylam ino)-6-(3-methyl benzofu ran-2-carboxam ido)-7-oxohept-2-enoate (S,E)-methyl 7414243,5 ,7-trimethy1-1-adam antylam ino)-2-oxoethyly 111-93: 2-oxo-1,2-dihydropyridin-3-ylam ino)-6-(1-methy1-1H-1,2,3-triazole-5-carboxam ido)-7-oxohept-2-enoate (S,E)-methyl 6-(2, 5-d ichlorothiophene-3-carboxam ido)-7-(1-(2-111-94: (3,5 ,7-trimethy1-1-adamantylam i no)-2-oxoethyl)-2-oxo-1,2-dihyd ropyridin-3-ylam ino)-7-oxohept-2-enoate (S,E)-methyl 7414243,5 ,7-trimethy1-1-adam antylam ino)-2-oxoethyly 111-95: 2-oxo-1,2-dihydropyridin-3-ylam ino)-6-(4-methy1-2-(trifluoromethyl)thiazole-5-carboxam ido)-7-oxohept-2-enoate (6S,E)-methyl 7-(1-(2-((1R,2R,45)-bicyclo[2.2.1]heptan-2-ylam ino)-111-96: 2-oxoethyl)-2-oxo-1,2-di hyd ropyridin-3-ylam ino)-6-(1-methy1-1,2 ,3-triazo le-5-carboxam ido)-7-oxohept-2-enoate (65,E)-methyl 7-(1-(2-((1R,2R,45)-bicyclo[2.2.1]heptan-2-ylam ino)-111-97: 2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(2,5-dichlorothiophene-3-carboxamido)-7-oxohept-2-enoate (65,E)-methyl 7-(1-(2-((1R,2R,45)-bicyclo[2.2.1]heptan-2-ylam ino)-111-98: 2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(4-methy1-2-(trifluoromethyl)thiazole-5-carboxam ido)-7-oxohept-2-enoate (S,E)-ethyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-111-99: dihydropyridin-3-ylam ino)-6-(1-methy1-1H-im idazole-5-carboxamido)-7-oxohept-2-enoate (S, E)-N-(1-(1-(2-(2-adamantylam ino)-2-oxoethyl )-2-oxo-1,2-111-100 : dihydropyridin-3-ylam ino)-6-(methylsulfony1)-1-oxohex-5-en-2-y1)-1-methy1-1H-imidazole-5-carboxamide (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-111A 01 : dihydropyridin-3-ylamino)-7-oxo-6-(2H-1,2,3-triazole-4-carboxam ido)hept-2-enoate (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-111A 02: dihydropyridin-3-ylam ino)-7-oxo-6-(1H-1,2,3-triazole-4-carboxam ido)hept-2-enoate (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-111-1 03: dihydropyridin-3-ylam ino)-6-(1-methy1-1H-1,2,3-triazole-4-carboxam ido)-7-oxohept-2-enoate 2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-111-1 04: dihydropyridin-3-ylam ino)-7-oxo-6-(1H-1,2,4-triazole-3-carboxam ido)hept-2-enoate (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-111-1 05: dihydropyridin-3-ylam ino)-6-(1-methy1-1H-1,2,4-triazole-3-carboxam ido)-7-oxohept-2-enoate (S,E)-methyl 6-(benzofuran-3-carboxam ido)-7-(1-(2-(2-111-1 06: adamantylam ino)-2-oxoethyl )-2-oxo-1,2-di hyd ropyridi n-3-ylam ino)-7-oxohept-2-enoate (S,E)-methyl 6-(benzo[b]thiophene-3-carboxam ido)-7-(1-(2-(2-111-1 07: adamantylam ino)-2-oxoethyl )-2-oxo-1,2-di hyd ropyridi n-3-ylam ino)-7-oxohept-2-enoate (S,E)-methyl 7414243,5 ,7-trimethy1-1-adam antylam ino)-2-oxoethyly 111-1 08 2-oxo-1,2-dihydropyridin-3-ylam ino)-6-(4-methy1-1,2,3-thiadiazole-5-carboxam ido)-7-oxohept-2-enoate (S,E)-methyl 7414243,5 ,7-trimethy1-1-adam antylam ino)-2-oxoethyly 111-1 09 2-oxo-1,2-dihydropyridin-3-ylam ino)-6-(1-methy1-1H-pyrazole-5-carboxam ido)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(2-((1R,2R,45)-bicyclo[2.2.1]heptan-2-ylamino)-2-111-1 1 0 oxoethyl )-2-oxo-1,2-dihydropyridi n-3-ylami no)-6-(4-methy1-1,2,3-thiadiazole-5-carboxam ido)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(2-((1R,2R,45)-bicyclo[2.2.1]heptan-2-ylamino)-2-111-1 1 1 oxoethyl )-2-oxo-1,2-dihydropyridi n-3-ylami no)-6-(1-methy1-pyrazole-5-carboxam ido)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(2-(3,5-dimethyladamantane-1-am ino)-2-oxoethyl)-111-1 1 2 2-oxo-1,2-dihydropyridin-3-ylamino)-6-(4-methy1-1,2,3-thiadiazole-5-carboxam ido)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(2-(3,5-dimethyladamantane-1-am ino)-2-oxoethyl)-111-1 1 3 2-oxo-1,2-dihydropyridin-3-ylam ino)-6-(1-methy1-1H-pyrazole-5-carboxam ido)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(2-(3,5-dimethyladamantane-1-am ino)-2-oxoethyl)-111-1 1 4 2-oxo-1,2-dihydropyridin-3-ylam ino)-6-(1-methy1-1H-1,2,3-triazole-5-carboxam ido)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-111-1 1 5 oxoethyl )-2-oxo-1,2-dihydropyridi n-3-ylami no)-6-(4-methy1-1,2,3-thiadiazole-5-carboxam ido)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-111-1 1 6 oxoethyl )-2-oxo-1,2-dihydropyridi n-3-ylami no)-6-(1-methy1-1H-1,2,3-triazo le-5-carboxam ido)-7-oxohept-2-enoate 2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 (S,E)-methyl 7-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-111-1 1 7 oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methy1-1H-pyrazole-5-carboxamido)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-111-1 1 8 dihydropyridin-3-ylamino)-6-(4-methy1-1,2,3-thiadiazole-5-carboxamido)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-111-1 1 9 dihydropyridin-3-ylam ino)-6-(1-methy1-1H-pyrazole-5-carboxamido)-7-oxohept-2-enoate (S,E)-methyl 6-(4-methy1-1,2,3-thiadiazole-5-carboxamido)-7-oxo-7-111-1 20 (2-oxo-1-(2-oxo-2-((1R,25,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-ylamino)hept-2-enoate (S,E)-methyl 6-(1-methy1-1H-1,2,3-triazole-5-ca rboxam ido)-7-oxo-7-111-1 21 (2-oxo-1-(2-oxo-2-((1R,25,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-ylamino)hept-2-enoate (S,E)-methyl 6-(1-methy1-1H-pyrazole-5-carboxamido)-7-oxo-7-(2-111-1 22 oxo-1-(2-oxo-2-((1R,25,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-ylamino)ethyl)-1,2-dihydropyridin-3-ylamino)hept-2-enoate (S,E)-methyl 7-(1-(2-(3,5-dimethyladamantane-1-am ino)-2-oxoethyl)-111-1 23 2-oxo-1,2-dihydropyridin-3-ylamino)-6-(4-methy1-2-(trifluoromethyl)thiazole-5-carboxamido)-7-oxohept-2-enoate (S,E)-methyl 6-(2,5-dichlorothiophene-3-carboxamido)-7-(1-(2-(3,5-111-1 24 dimethyladamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-111-1 25 oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(4-methy1-2-(trifluoromethyl)thiazole-5-carboxamido)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-111-1 26 oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(2,5-dichlorothiophene-3-carboxamido)-7-oxohept-2-enoate (S,E)-methyl 6-(4-methy1-2-(trifluoromethyl)thiazole-5-carboxamido)-7-oxo-7-(2-oxo-1-(2-oxo-2-((1R,25,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-ylamino)hept-2-enoate (S,E)-methyl 6-(2,5-dichlorothiophene-3-carboxamido)-7-oxo-7-(2-111-1 28 oxo-1-(2-oxo-2-((1R,25,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-ylamino)ethyl)-1,2-dihydropyridin-3-ylamino)hept-2-enoate 2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-111-1 29 dihydropyridin-3-ylamino)-6-(1-methy1-1H-pyrazole-3-carboxamido)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-111-1 30 dihydropyridin-3-ylamino)-6-(1-methy1-1H-pyrazole-4-carboxamido)-7-oxohept-2-enoate (S,E)-methyl 6-(4-tert-buty1-1H-pyrrole-3-carboxam ido)-7-(1-(2-(1-III-1 31 adamantylamino)ethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxohept-2-enoate (S,E)-methyl 6-(4-cyano-1-methy1-1H-pyrrole-2-carboxamido)-7-(1-III-1 32 (3-(1-adamantylamino)propy1)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(3-(2-adamantylam ino)-3-oxopropy1)-2-oxo-1,2-111-1 33 dihydropyridin-3-ylamino)-6-(5-methoxyoxazole-2-carboxamido)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(2-(bicyclo[2.1.1]hexan-1-ylamino)-2-oxoethyl)-2-111-1 34 oxo-1,2-dihydropyridin-3-ylamino)-6-(2-isopropyloxazole-5-carboxamido)-7-oxohept-2-enoate (6S,E)-methyl 7-(1-(2-(bicyclo[3.2.1]octan-8-ylamino)-2-oxoethyl)-2-111-1 35 oxo-1,2-dihydropyridin-3-ylamino)-6-(3,5-dimethylisoxazole-4-carboxamido)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(2-(5-carboxy-2-aminoadamantane)-2-oxoethyl)-2-111-1 36 oxo-1,2-dihydropyridin-3-ylamino)-6-(4-methylpyrimidine-5-carboxamido)-7-oxohept-2-enoate (65,E)-methyl 7-(1-(2-(4-aminoadamantane-N,N-dimethyl-1-111-1 37 carboxamide)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxo-6-(1,2,3,4-tetrahydronaphthalene-2-carboxamido)hept-2-enoate (S,E)-6-(2-acetyloxazole-4-carboxamido)-N7-(1-(2-111-1 38 (bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N1,N1-diethylhept-2-enediamide (S,E)-N7-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-111-1 39 1,2-dihydropyridin-3-y1)-6-((S)-1,4-diazabicyclo[2.2.2]octane-carboxamido)-N1,N1-diethylhept-2-enediamide (S,E)-N7-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-111-1 40 1,2-dihydropyridin-3-y1)-6-(1H-indole-3-carboxamido)-N1-isopropylhept-2-enediamide (S,E)-N7-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-111-1 41 1,2-dihydropyridin-3-y1)-N1-isopropy1-6-(6-methylimidazo[2,1-b]thiazole-3-carboxamido)hept-2-enediamide 2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 (S,E)-6-(benzo[d]thiazole-2-carboxamido)-N7-(1-(2-111-1 42 (bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N1-pentylhept-2-enediamide (S,E)-N7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-111-1 43 1,2-dihydropyridin-3-y1)-6-(imidazo[2,1-b]thiazole-6-carboxamido)-N1-pentylhept-2-enediamide (S,E)-N7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-111-1 44 1,2-dihydropyridin-3-y1)-N1-cyclopropy1-6-(4-hydroxy-6-(trifluoromethoxy)quinoline-3-carboxamido)hept-2-enediamide (S,E)-N7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-111-1 45 1,2-dihydropyridin-3-y1)-6-(cinnoline-3-carboxamido)-N1-cyclopropylhept-2-enediamide (S,E)-N7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-111-1 46 1,2-dihydropyridin-3-y1)-N1-cyclopenty1-6-(2-methyl-1,8-naphthyridine-3-carboxamido)hept-2-enediamide (S,E)-N7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-111-1 47 1,2-dihydropyridin-3-y1)-N1-cyclopenty1-6-(3-ethylbenzofuran-2-carboxamido)hept-2-enediamide (S,E)-N7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-111-1 48 1,2-dihydropyridin-3-y1)-N1-cyclohexy1-6-(1-ethy1-1H-indole-2-carboxamido)hept-2-enediamide (S,E)-N7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-111-1 49 1,2-dihydropyridin-3-y1)-N1-cyclohexy1-6-(1,2,3,4-tetrahydroquinoline-7-carboxamido)hept-2-enediamide (S,E)-N1-allyl-N7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-111-1 50 2-oxo-1,2-dihydropyridin-3-y1)-6-(1,6-naphthyridine-2-carboxamido)hept-2-enediamide (S,E)-N1-allyl-N7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-111-1 51 2-oxo-1,2-dihydropyridin-3-y1)-6-(2,6-naphthyridine-1-carboxamido)hept-2-enediamide (S,E)-N7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-111-1 52 1,2-dihydropyridin-3-y1)-6-(5-bromo-2-methylfuran-3-carboxamido)-N1-phenylhept-2-enediamide (S,E)-N7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-111-1 53 1,2-dihydropyridin-3-y1)-6-(2,5-dimethylfuran-3-carboxamido)-phenylhept-2-enediamide (S,E)-N1-benzyl-N7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-111-1 54 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-6-(2,5-dichlorothiazole-4-carboxamido)hept-2-enediamide 2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 (S,E)-N1-benzyl-N7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-111-1 55 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-6-(4-bromothiazole-2-carboxamido)hept-2-enediamide (S,E)-benzyl 7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-111-1 56 oxo-1,2-dihydropyridin-3-ylamino)-6-(4-methy1-2-phenylthiazole-carboxamido)-7-oxohept-2-enoate (S,E)-N-(1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-111-1 57 1,2-dihydropyridin-3-ylamino)-1,7-dioxo-7-phenylhept-5-en-2-y1)-1-methy1-1H-imidazole-2-carboxamide (S,E)-isopropyl 7-(1-(2-(bicyclo[2.1.1]hexan-1-ylamino)-2-oxoethyly 111-1 58 2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxo-6-(2H-1,2,3-triazole-carboxamido)hept-2-enoate N4(25,E)-1-(1-(2-(bicyclo[3.2.1]octan-8-ylamino)-2-oxoethyl)-2-oxo-111-1 59 1,2-dihydropyridin-3-ylamino)-1,7-dioxooct-5-en-2-y1)-1-methy1-1,2,4-triazole-3-carboxamide (S,E)-methyl 6-(4-amino-1,2,5-oxadiazole-3-carboxamido)-7-(1-(2-111-1 60 (bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-111-1 61 oxo-1,2-dihydropyridin-3-ylamino)-6-(6-(dimethylamino)benzofuran-2-carboxamido)-7-oxohept-2-enoate (S,E)-methyl 6-(2-acetamidothiazole-5-carboxamido)-7-(1-(2-111-1 62 (bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-111-1 63 oxo-1,2-dihydropyridin-3-ylamino)-6-(5-carbamoy1-1H-pyrrole-3-carboxamido)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(2-(1-acetylamino-4-aminoadamantane)-2-111-1 64 oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxo-6-(5-sulfamoylfuran-3-carboxamido)hept-2-enoate (S,E)-methyl 6-(benzofuran-5-carboxamido)-7-(1-(2-(1-acetylamino-111-1 65 4-aminoadamantane)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxohept-2-enoate (S,E)-methyl 6-(benzofuran-6-carboxam ido)-7-(1-(2-(4-111-1 66 am inoadamantane-1-carboxamide)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylam ino)-7-oxohept-2-enoate 111 1 67 (S,E)-methyl 7-(1-(2-(4-aminoadamantane-1-carboxamide)-2--oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(3-(1-2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamido)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-111-1 68 oxo-1,2-dihydropyridin-3-ylamino)-6-(5-methyl-1,2,4-oxadiazole-3-carboxamido)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-111-1 69 oxo-1,2-dihydropyridin-3-ylamino)-7-oxo-6-(1,2,3-thiadiazole-4-carboxamido)hept-2-enoate (S,E)-methyl 7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-111-1 70 oxo-1,2-dihydropyridin-3-ylamino)-7-oxo-6-(1,2,4-thiadiazole-5-carboxamido)hept-2-enoate (S,E)-methyl 7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-111-1 71 oxo-1,2-dihydropyridin-3-ylamino)-7-oxo-6-(1,3,4-thiadiazole-2-carboxamido)hept-2-enoate (S,E)-methyl 7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-111-1 72 oxo-1,2-dihydropyridin-3-ylamino)-6-(4-cyclopropyl-1,2,3-thiadiazole-5-carboxamido)-7-oxohept-2-enoate (S,E)-methyl 7-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-111-1 73 oxo-1,2-dihydropyridin-3-ylamino)-7-oxo-6-(1,2,5-thiadiazole-3-carboxamido)hept-2-enoate (S,E)-methyl 6-(4-formyl-1,2,3-thiadiazole-5-carboxamido)-7-(1-(2-111-1 74 (2-carboxy-2-amino-5-(trifluoromethyl)adamantane)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxohept-2-enoate (S,E)-methyl 6-(4-(hydroxymethyl)-1,2,3-thiadiazole-5-carboxam ido)-111-1 75 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxohept-2-enoate or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising a compound of any one of the claims 1 ¨ 9 as an active ingredient, together with at least one pharmaceutically acceptable carrier, excipient and/or diluent.
11. Compound according to any one of the claims 1 ¨ 9 for use in medicine.
12. Compound according to any one of the claims 1 ¨ 9 or the pharmaceutical composition according to claim 10 for use in the treatment or prophylaxis of autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, ocular diseases, and skin disorders.
2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30
2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30
13. Compound for use, or the pharmaceutical composition for use according to claim 12, wherein the autoimmune and inflammatory diseases comprise multiple sclerosis, celiac disease, Duhring-Brocq-disease (dermatitis herpetiformis), gluten ataxia, gluten neuropathy, diabetes, rheumatoid arthritis, Graves' disease, inflammatory bowel disease, systemic lupus erythematosus psoriasis, and gingivitis; wherein the vascular diseases comprise atherosclerosis, thrombosis, vascular stiffness;
wherein the fibrotic diseases affect the lung, the kidney, the liver, the skin or the gut like cystic fibrosis, kidney fibrosis and diabetic nephropathy, intestinal fibrosis, idiopathic lung fibrosis, liver fibrosis; wherein the liver diseases comprise alcoholic hepatitis, alcoholic steatohepatitis, nonalcoholic steatohepatitis, non-alcoholic fatty liver disease, liver cirrhosis, autoimmune hepatitis or liver inflammation; wherein the cholestatic liver diseases comprise primary biliary cholangitis and primary sclerosing cholangitis; wherein the cancer comprises glioblastoma, melanoma, pancreatic cancer, renal cell carcinoma, meningioma, and breast cancer, wherein the neurodegenerative diseases comprise Parkinson's disease, Huntington's disease, or Alzheimer's disease, wherein the ocular diseases comprise glaucoma, cataracts, macular degeneration, or uveitis; and wherein the skin disorders comprise acne, psoriasis, scarring, and skin aging.
wherein the fibrotic diseases affect the lung, the kidney, the liver, the skin or the gut like cystic fibrosis, kidney fibrosis and diabetic nephropathy, intestinal fibrosis, idiopathic lung fibrosis, liver fibrosis; wherein the liver diseases comprise alcoholic hepatitis, alcoholic steatohepatitis, nonalcoholic steatohepatitis, non-alcoholic fatty liver disease, liver cirrhosis, autoimmune hepatitis or liver inflammation; wherein the cholestatic liver diseases comprise primary biliary cholangitis and primary sclerosing cholangitis; wherein the cancer comprises glioblastoma, melanoma, pancreatic cancer, renal cell carcinoma, meningioma, and breast cancer, wherein the neurodegenerative diseases comprise Parkinson's disease, Huntington's disease, or Alzheimer's disease, wherein the ocular diseases comprise glaucoma, cataracts, macular degeneration, or uveitis; and wherein the skin disorders comprise acne, psoriasis, scarring, and skin aging.
14. Compound for use or the pharmaceutical composition for use according to any one of the claims 12 and 13 in the treatment or prophylaxis of celiac disease.
15. A method for producing the compound of formula (lc) according to claim 1 comprising:
Step 1C: providing a compound 4c 00,R5 %
PG3N crOH
' H 0 4c;
Step 2C: performing coupling reaction of the compound 4c with a compound 5 , N" 'R3 to obtain a compound 6c 2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 00. R5 PG , , N R-6c;
Step 3C: deprotecting an amino protecting group PG3to obtain a compound 7c o0,R5 H2Njco N 'R3 7c;
Step 4C: performing coupling reaction of the compound 7c with a carboxylic acid (R2-CO2H 8) to produce the compound of the formula (lc) 0 0, R2 1\0- N ,L, , R-H
(lc), wherein L, R2, R3, R5 have the same meanings as defined in claim 1, and PG3 is an amino protecting group;
or a method for producing the compound of the formula (ld) according to claim 1 comprising:
Step 1D: providing a compound 4d 0 N, PG,N (rOH
0 4d;
2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 Step 2D: performing coupling reaction of the compound 4d with a compound 5 H2N N LR , 1 '-to obtain a compound 6d CD,N ,R7 %
, 0 PGNJCI\I N R
L, 1 1 " ¨
6d;
Step 3D: deprotecting an amino protecting group PG3to obtain a compound 7d O. N _ %
j - L 3 H2N 1 N 'R
0 7d;
Step 4D: performing coupling reaction of the compound 7d with a carboxylic acid (R2-CO2H 8) to produce the compound of the formula (Id) 0N .R7 %
0 r H 0 R2 N 'AI NL " 'R-, (id) ;
wherein L, R2, R3, R6, R7 have the same meanings as defined above in formula (Id), and PG3 is an amino protecting group;
or a method for producing the compound of the formula (le) according to claim 1 comprising:
Step 1E: providing a compound 4e 2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 0 c OS=S
PGNJ(rON
H 0 4e;
Step 2E: performing coupling reaction of the compound 4e with a compound 5 HN L , , N R3 to obtain a compound 6e o , \ R-0= \S"
pG3, jCi\i,A L , N , N" 'R-H
0 6e;
Step 3E: deprotecting an amino protecting group PG3to obtain a compound 7e 0 , 0=S
FNi j , L
HN 1 N 'R3 0 7e;
Step 4E: performing coupling reaction of the compound 7e with a carboxylic acid (R2-CO2H 8) to produce the compound of the formula (le) P\ 5 0=S¨R
)0 H 0 L NI , , R2 N 1 N 'R-H 0 (le) 2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 wherein L, R2, R3, R5 have the same meanings as defined above in formula (le), and PG3 is an amino protecting group.
2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30
Step 1C: providing a compound 4c 00,R5 %
PG3N crOH
' H 0 4c;
Step 2C: performing coupling reaction of the compound 4c with a compound 5 , N" 'R3 to obtain a compound 6c 2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 00. R5 PG , , N R-6c;
Step 3C: deprotecting an amino protecting group PG3to obtain a compound 7c o0,R5 H2Njco N 'R3 7c;
Step 4C: performing coupling reaction of the compound 7c with a carboxylic acid (R2-CO2H 8) to produce the compound of the formula (lc) 0 0, R2 1\0- N ,L, , R-H
(lc), wherein L, R2, R3, R5 have the same meanings as defined in claim 1, and PG3 is an amino protecting group;
or a method for producing the compound of the formula (ld) according to claim 1 comprising:
Step 1D: providing a compound 4d 0 N, PG,N (rOH
0 4d;
2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 Step 2D: performing coupling reaction of the compound 4d with a compound 5 H2N N LR , 1 '-to obtain a compound 6d CD,N ,R7 %
, 0 PGNJCI\I N R
L, 1 1 " ¨
6d;
Step 3D: deprotecting an amino protecting group PG3to obtain a compound 7d O. N _ %
j - L 3 H2N 1 N 'R
0 7d;
Step 4D: performing coupling reaction of the compound 7d with a carboxylic acid (R2-CO2H 8) to produce the compound of the formula (Id) 0N .R7 %
0 r H 0 R2 N 'AI NL " 'R-, (id) ;
wherein L, R2, R3, R6, R7 have the same meanings as defined above in formula (Id), and PG3 is an amino protecting group;
or a method for producing the compound of the formula (le) according to claim 1 comprising:
Step 1E: providing a compound 4e 2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 0 c OS=S
PGNJ(rON
H 0 4e;
Step 2E: performing coupling reaction of the compound 4e with a compound 5 HN L , , N R3 to obtain a compound 6e o , \ R-0= \S"
pG3, jCi\i,A L , N , N" 'R-H
0 6e;
Step 3E: deprotecting an amino protecting group PG3to obtain a compound 7e 0 , 0=S
FNi j , L
HN 1 N 'R3 0 7e;
Step 4E: performing coupling reaction of the compound 7e with a carboxylic acid (R2-CO2H 8) to produce the compound of the formula (le) P\ 5 0=S¨R
)0 H 0 L NI , , R2 N 1 N 'R-H 0 (le) 2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30 wherein L, R2, R3, R5 have the same meanings as defined above in formula (le), and PG3 is an amino protecting group.
2489-CIPO-CLAIMS-ZED-P04404W026 docx Date Recue/Date Received 2022-06-30
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA3231327A CA3231327A1 (en) | 2021-06-30 | 2022-06-30 | Inhibitors of transglutaminases |
| CA3231322A CA3231322A1 (en) | 2021-06-30 | 2022-06-30 | Inhibitors of transglutaminases |
Applications Claiming Priority (18)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP21182956 | 2021-06-30 | ||
| EP21182956.9 | 2021-06-30 | ||
| EP21183316.5 | 2021-07-01 | ||
| EP21183316 | 2021-07-01 | ||
| PCT/EP2021/086674 WO2023110138A1 (en) | 2021-12-17 | 2021-12-17 | Inhibitors of transglutaminases |
| EPPCT/EP2021/086674 | 2021-12-17 | ||
| EPPCT/EP2022/065435 | 2022-06-07 | ||
| EP2022065437 | 2022-06-07 | ||
| EPPCT/EP2022/065437 | 2022-06-07 | ||
| EP2022065435 | 2022-06-07 | ||
| EPPCT/EP2022/065430 | 2022-06-07 | ||
| EP2022065430 | 2022-06-07 | ||
| EPPCT/EP2022/068216 | 2022-06-30 | ||
| EPPCT/EP2022/068217 | 2022-06-30 | ||
| PCT/EP2022/068216 WO2023275336A1 (en) | 2021-06-30 | 2022-06-30 | Inhibitors of transglutaminases |
| PCT/EP2022/068212 WO2023275333A1 (en) | 2021-06-30 | 2022-06-30 | Inhibitors of transglutaminases |
| EPPCT/EP2022/068212 | 2022-06-30 | ||
| PCT/EP2022/068217 WO2023275337A1 (en) | 2021-06-30 | 2022-06-30 | Inhibitors of transglutaminases |
Related Child Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA3231327A Division CA3231327A1 (en) | 2021-06-30 | 2022-06-30 | Inhibitors of transglutaminases |
| CA3231322A Division CA3231322A1 (en) | 2021-06-30 | 2022-06-30 | Inhibitors of transglutaminases |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA3166252A1 true CA3166252A1 (en) | 2022-12-30 |
Family
ID=84818789
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA3231322A Pending CA3231322A1 (en) | 2021-06-30 | 2022-06-30 | Inhibitors of transglutaminases |
| CA3166252A Pending CA3166252A1 (en) | 2021-06-30 | 2022-06-30 | Inhibitors of transglutaminases |
| CA3231327A Pending CA3231327A1 (en) | 2021-06-30 | 2022-06-30 | Inhibitors of transglutaminases |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA3231322A Pending CA3231322A1 (en) | 2021-06-30 | 2022-06-30 | Inhibitors of transglutaminases |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA3231327A Pending CA3231327A1 (en) | 2021-06-30 | 2022-06-30 | Inhibitors of transglutaminases |
Country Status (1)
| Country | Link |
|---|---|
| CA (3) | CA3231322A1 (en) |
-
2022
- 2022-06-30 CA CA3231322A patent/CA3231322A1/en active Pending
- 2022-06-30 CA CA3166252A patent/CA3166252A1/en active Pending
- 2022-06-30 CA CA3231327A patent/CA3231327A1/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| CA3231322A1 (en) | 2022-12-30 |
| CA3231327A1 (en) | 2022-12-30 |
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