WO2023110138A1 - Inhibitors of transglutaminases - Google Patents

Inhibitors of transglutaminases Download PDF

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Publication number
WO2023110138A1
WO2023110138A1 PCT/EP2021/086674 EP2021086674W WO2023110138A1 WO 2023110138 A1 WO2023110138 A1 WO 2023110138A1 EP 2021086674 W EP2021086674 W EP 2021086674W WO 2023110138 A1 WO2023110138 A1 WO 2023110138A1
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Prior art keywords
compound
cyclo
preparation
bicyclo
och
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PCT/EP2021/086674
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French (fr)
Inventor
Herr Ralf PASTERNACK
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Zedira Gmbh
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Application filed by Zedira Gmbh filed Critical Zedira Gmbh
Priority to PCT/EP2021/086674 priority Critical patent/WO2023110138A1/en
Priority to EP22741487.7A priority patent/EP4192813A1/en
Priority to KR1020247003531A priority patent/KR20240028466A/en
Priority to KR1020237044976A priority patent/KR20240035404A/en
Priority to IL309474A priority patent/IL309474A/en
Priority to EP22741488.5A priority patent/EP4192814A1/en
Priority to IL309476A priority patent/IL309476A/en
Priority to AU2022305117A priority patent/AU2022305117A1/en
Priority to PCT/EP2022/068216 priority patent/WO2023275336A1/en
Priority to PCT/EP2022/068212 priority patent/WO2023275333A1/en
Priority to EP22741485.1A priority patent/EP4192812A1/en
Priority to AU2022301517A priority patent/AU2022301517A1/en
Priority to CA3166252A priority patent/CA3166252A1/en
Priority to IL309077A priority patent/IL309077A/en
Priority to AU2022303109A priority patent/AU2022303109A1/en
Priority to CA3231322A priority patent/CA3231322A1/en
Priority to PCT/EP2022/068217 priority patent/WO2023275337A1/en
Priority to CA3231327A priority patent/CA3231327A1/en
Priority to KR1020247003631A priority patent/KR20240028473A/en
Publication of WO2023110138A1 publication Critical patent/WO2023110138A1/en
Priority to CONC2024/0000832A priority patent/CO2024000832A2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • Transglutaminases are part of the class of transferases and according to EC nomenclature they are correctly designated as “protein-glutamine: amine ⁇ -glutamyl transferases” (EC 2.3.2.13). They link the ⁇ -amino group of the amino acid lysine and the ⁇ -glutamyl group of the amino acid glutamine forming an isopeptide bond while ammonia is released.
  • 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.
  • 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).
  • 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- 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.
  • the objective of the present invention is to provide novel, most probably reversible or irreversible inhibitors of transglutaminases, in particular transglutaminase 2 and methods for the synthesis of said inhibitors as well as several uses of these inhibitors. 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/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.
  • such chemical warhead moiety is particularly selected from reversible warheads such as ⁇ -ketoaldehydes, ⁇ -ketoketones, ⁇ -ketoacids, ⁇ -ketoesters, ⁇ - ketoamides as well as irreversible warheads such as ⁇ ,ß-unsatureated-ketoester, ⁇ ,ß- unsatureated ketoamide and ⁇ ,ß-unsatureated-sulfone.
  • reversible warheads such as ⁇ -ketoaldehydes, ⁇ -ketoketones, ⁇ -ketoacids, ⁇ -ketoesters, ⁇ - ketoamides as well as irreversible warheads such as ⁇ ,ß-unsatureated-ketoester, ⁇ ,ß- unsatureated ketoamide and ⁇ ,ß-unsatureated-sulfone.
  • the compounds of the present invention act as selective inhibitors of transglutaminase 2.
  • the present invention relates to compounds of the general formula (I): wherein L represents –L1– or L1 represents –CH 2 –, –CH 2 CH 2 –, –CH 2 CH 2 CH 2 –, –CH 2 CO—, –CH 2 CH 2 CO—; L2 represents a bond, –NRN1–, –NRN1CH N1 2–, –NR CH 2 CH 2 –, or –NRN1CH(CH 3 )–, R1 represents R2 represents , , ,
  • 1-adamantyl and “2-bicyclo[3.1.1]heptyl” have the following structures respectively: and Ra, Rb, Rc, Rd and Re have the same meanings as defined herein.
  • 2-bicyclo[3.1.1]heptyl have the following structure: , or , and Ra and Rb, have the same meanings as defined herein. More preferred, the compound has any one of the formula (II-a), (II-b), (II-b1) – (II-b2), and (III-a) – (III-b ):
  • the present invention refers to the compound of the formula (I) , wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 – R13 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.
  • L represents –L1– or –L1-L2–;
  • L1 represents —CH 2 –, –CH 2 CH 2 –, –CH 2 CH 2 CH 2 –, –CH 2 CO–, –CH 2 CH 2 CO—;
  • L2 represents a bond, –NRN1–, –NRN1CH N1 2–, –NR CH 2 CH 2 –, or –NRN1CH(CH 3 )–;
  • the present invention relates to the compound of the formula (I), (I) wherein L represents –L1– or –L1-L2–; L1 represents —CH 2 –, –CH 2 CH 2 –, –CH 2 CH 2 CH 2 –, –CH 2 CO—, –CH 2 CH 2 CO—; L2 represents a bond, –NRN1–, –NRN1CH N1 2–, –NR CH 2 CH 2 –, or –NRN1CH(CH 3 )–; 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-homoiso
  • L1 represents –CH 2 –, or –CH 2 CO—;
  • L2 represents a bond, —NRN1–, –NRN1CH N1 2–, or –NR CH(CH 3 )–;
  • L1 is not –CH 2 CO—, when the compound has the formula (IV-b), wherein L2 is not –NRN1CH 2 –, when the compound has the formula (IV-c), and R2 , R3, R6, R8, R9, R10, R11 , R12 , R13, Ra, Rb, Rc, Rd and L2 have the same meanings as defined herein, preferably as defined in formula (I) or (Ib).
  • Ra, and Rb have the same meanings as defined above, preferred in formula (I), or (Ib); preparably, Ra, and Rb represents independently of each other –H, –F, –Cl, –Br, –OH, –CN, –CH 3 , –C 2 H 5 , or –CO 2 Me.
  • R2 represents
  • the present invention refers to the compound selected from the group consisting of:
  • the compound of the formula (I) has irreversible warheads such as ⁇ ,ß-unsatureated-ketoester, ⁇ ,ß-unsatureated ketoamide and ⁇ ,ß-unsatureated-sulfone.
  • the compounds of the present invention act selective inhibitors of transglutaminase 2.
  • the present invention refers to the compounds of the formula (I) wherein L represents –L1– or –L1–L2– ; L1 represents —CH 2 –, –CH 2 CH 2 –, –CH 2 CH 2 CH 2 –, –CH 2 CO—, –CH 2 CH 2 CO—; L2 represents a bond, –NRN1–, –NRN1CH N1 2–, –NR CH 2 CH 2 –, or
  • L represents –L1– or –L1–L2–;
  • L1 represents —CH 2 –, –CH 2 CH 2 –, –CH 2 CH 2 CH 2 –, –CH 2 CO–, –CH 2 CH 2 CO—;
  • L2 represents a bond, –NRN1–, –NRN1CH N1 2–, –NR CH 2 CH 2 –, or –NRN1CH(CH 3 )–;
  • L1 , L2 , R2 , R3, R5 – R7 , and RN1 have the meanings as defined above.
  • L , R2 , R3, and R5 – R7 have the meanings as defined above.
  • L represents –L1– or –L1–L2–;
  • L1 represents –CH 2 –, –CH 2 CH 2 –, –CH 2 CH 2 CH 2 –, –CH 2 CO–, –CH 2 CH 2 CO—;
  • L2 represents a bond, –NRN1–, –NRN1CH N1 2–, –NR CH 2 CH 2 –, or –NRN1CH(CH 3 )–;
  • L1 , L2 , R5 – R14 , RN and RN1 have the meanings as defined herein.
  • R5 represents –H, –CH 3 , –CH 2 CH 3 , –CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , –CH 2 CH 2 CH 2 CH 3 , –CH 2 CH(CH 3 ) 2 , –C(CH 3 ) 3 , –cyclo-C 3 H 5 , –cyclo-C 4 H 7 , –CH 2 –cyclo-C 3 H 5 , –CH 2 –cyclo-C 4 H 7 ;
  • R6 and R7 represent independently of each other –H, –CH 3 , –CH 2 CH 3 , –CH 2 CH 2 CH 3.
  • R5 represents –H, –CH 3 , –CH 2 CH 3 , –CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , –CH 2 CH 2 CH 2 CH 3 , –CH 2 CH(CH 3 ) 2 , –C(CH 3 ) 3 , –cyclo-C 3 H 5 , –cyclo-C 4 H 7 , –CH 2 –cyclo-C 3 H 5 , –CH 2 –cyclo-C 4 H 7 ; and/or R6 and R7 represent independently of each other –H, –CH 3 , –CH 2 CH 3 , –CH 2 CH 2 CH 3.
  • the present invention refers to the compounds selected from the group consisting of:
  • the present invention relates to a method for the synthesis of a compound of formula (I), especially any compound of any one of the formulae (Ia) – (Ie):
  • a method for producing the compound of the formula (Ia) comprising: Step 1A: providing a compound 4a Step 2A: performing coupling reaction of the compound 4a with a compound 5 to obtain a compound 6a Step 3A: deprotecting an amino protecting group PG3 to obtain a compound 7a
  • Step 4A performing coupling reaction of the compound 7a with a carboxylic acid (R2-CO 2 H 8) to obtain a compound 9a
  • Step 5A performing oxidation reaction of the compound 9a to produce the compound of the formula (Ia) wherein L, R2 , R3,and R6 have the same meanings as defined above in formula (Ia), and PG3 is an amino protecting group.
  • Step 1A ⁇ is carried out before the step 1A: (a) providing a protected aldehyde ; (b) performing a coupling reaction of the aldehyde 1 with an isocyanide (CN-R6) 2a to obtain an intermediate compound 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 wherein R2 , R6 have the same meanings as defined in formula (Ia), PG1 and PG3 are amino protecting groups, PG2 is a carboxyl protecting group.
  • Step 1A (a) providing a protected aldehyde 1 (b) performing a coupling reaction of the aldehyde 1 with an isocyanide (CN-R6) 2a to obtain an intermediate compound 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
  • Step 1A providing a compound 4a
  • Step 2A performing coupling reaction of the compound 4a with a compound 5 to obtain a compound 6a
  • Step 3A deprotecting the amino protecting group PG3 to obtain a compound 7a
  • Step 4A performing coupling reaction of the compound 7a with a carboxylic acid (R2-CO 2 H 8) to obtain a compound 9a
  • Step 5A performing oxidation reaction of the compound 9a to produce the compound of the formula (Ia) wherein L, R2 , R3,and R6 have the same meanings as
  • the present invention relates to a method for producing the compound of formula (Ib) comprising the following steps in the following order: Step 1B: providing a compoun Step 2B: performing coupling reaction of the compound 4b with a compound 5 to obtain a compound Step 3B: deprotecting an amino protecting group PG3 to obtain a compound 7b 7b; Step 4B: performing coupling reaction of the compound 7b with a carboxylic acid (R2-CO 2 H 8) to obtain a compound 9b 9b; Step 5B: performing oxidation reaction of the compound 9b to produce the compound of the formula (Ib) (Ib); wherein L, R2 , R3, R6 and R7 have the same meanings as defined above in the formula (Ib), and PG3 is an amino protecting group.
  • the chemical warhead precursor may be firstly converted to under a basic condition such as treating with K 2 CO 3 , and then is converted to the corresponding chemical warhead by an oxidation 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.
  • DMP Dess-Martin periodinane
  • IBX iodoxybenzoic acid
  • hypochlorite/TEMPO 2,2,6,6-tetramethylpiperidine-1-oxyl
  • the method for producing the compound of the formula (Ic) comprises the following steps in the following order: Step 1C: providing a compound 4c Step 2C: performing coupling reaction of the compound 4c with a compound 5 to obtain a compound Step 3C: deprotecting an amino protecting group PG3 to obtain a compound 7c Step 4C: performing coupling reaction of the compound 7c with a carboxylic acid (R2-CO 2 H 8) to produce the compound of the formula (Ic) wherein L, R2 , R3, R5 have the same meanings as defined above above in formula (Ic), and PG3 is an amino protecting group.
  • Step 1C ⁇ is carried out before the step 1C: (a) providing a protected aldehyde 1 (b) performing a coupling reaction of the aldehyde 1 with a triphenyl phosphonium ylide 2c to obtain an intermediate compound 3c; or alternatively (b ⁇ ) performing a coupling reaction of the aldehyde 1 with a phosphonate 2c ⁇ to obtain an intermediate compound 3c; (c) deprotecting the protecting groups PG1 and PG2 of the compound 3c and introducing an amino protecting group PG3 to obtain a compound 4c.
  • Step 1C ⁇ (a) providing a protected aldehyde 1 (b) performing a coupling reaction of the aldehyde 1 with a triphenyl phosphonium ylide 2c to obtain an intermediate compound 3c;
  • Scheme 3 A further aspect of the present invention relates to the production of compounds of the formula (Id).
  • a method for producing the compound of the formula (Id) comprising: Step 1D: providing a compound 4d 4d; Step 2D: performing coupling reaction of the compound 4d with a compound 5 to obtain a compound Step 3D: deprotecting an amino protecting group PG3 to obtain a compound 7d
  • Step 4D performing coupling reaction of the compound 7d with a carboxylic acid (R2-CO 2 H 8) to produce the compound of the formula (Id) wherein L, R2 , R3, R6, R7 have the same meanings as defined above in formula (Id), and PG3 is an amino protecting group.
  • Step 1D ⁇ is carried out before the step 1D: (a) providing a protected aldehyde 1 (b) performing a coupling reaction of the aldehyde 1 with a phosphonate 2d to obtain an intermediate compound 3d; (c) deprotecting the protecting groups PG1 and PG2 of the compound 3d preferably under acidic condition and introducing an amino protecting group PG3 to obtain a compound 4d .
  • Step 1D ⁇ : (a) providing a protected aldehyde 1 (b) performing a coupling reaction of the aldehyde 1 with a phosphonate 2d to obtain an intermediate compound 3d; (c) deprotecting the compound 3d preferably under acidic condition and introducing an amino protecting group PG3 to obtain a compound 4d; Step 1D: providing a compound 4d Step 2D: performing coupling reaction of the compound 4d with a compound 5 to obtain a compound Step 3D: deprotecting an amino protecting group PG3 to obtain a compound 7d 7d; Step 4D: performing coupling reaction of the compound 7d with a carboxylic acid (R2-CO 2 H 8) to produce the compound of the formula (Id) (Id) ; wherein L, R2 , R3, R6, R7 have the same meanings as defined above in formula (Id), and PG3 is an amino protecting group.
  • a further aspect of the present invention relates to the production of compounds of the formula (Ie).
  • a method for producing the compound of the formula (Ie) comprising: Step 1E: providing a compound Step 2E: performing coupling reaction of the compound 4e with a compound 5 to obtain a compound Step 3E: deprotecting an amino protecting group PG3 to obtain a compound 7e
  • Step 4E performing coupling reaction of the compound 7e with a carboxylic acid (R2-CO 2 H 8) to produce the compound of the formula (Ie) wherein L, R2 , R3, R5 have the same meanings as defined above in formula (Ie), and PG3 is an amino protecting group.
  • Step 1E ⁇ is carried out before the step 1E: (a) providing a protected aldehyde (b) performing a coupling reaction of the aldehyde 1 with a sulfonylmethyl phosphonate 2e to obtain an intermediate compound 3e; (c) deprotecting the protecting groups PG1 and PG2 of the compound 3e preferably under acidic condition and introducing an amino protecting group PG3 to obtain a compound 4e .
  • Step 1E (a) providing a protected aldehyde 1 (b) performing a coupling reaction of the aldehyde 1 with a sulfonylmethyl phosphonate 2e to obtain an intermediate compound 3e; (c) deprotecting the protecting groups PG1 and PG2 of the compound 3e preferably under acidic condition and introducing an amino protecting group PG3 to obtain a compound 4e
  • Step 1E providing a compound Step 2E: performing coupling reaction of the compound 4e with a compound 5 to obtain a compound Step 3E: deprotecting an amino protecting group PG3 to obtain a compound 7e
  • Step 4E performing coupling reaction of the compound 7e with a carboxylic acid (R2-CO 2 H 8) to produce the compound of the formula (Ie) wherein L, R2 , R3, R5 have the same meanings as defined above in formula (Ie), and PG3 is an amino protecting group.
  • protecting groups PG1 and PG2 are simultaneously removed and the protecting group PG3 is selectively introduced.
  • PG1 and PG3 are same.
  • protecting groups 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.
  • 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.
  • activating reagents are commonly used to activating carboxylic acid reminderPeptide 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.
  • 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-1- yloxy)tripyrrolidinophosphonium hexafluorophosphate), TBTU (2-(1H-Benzotriazole-1- yl)-1,1,3,3-tetramethylaminium tetrafluoroborate), EEDQ (N-Ethoxycarbonyl-2-ethoxy- 1,2-dihydroquinoline), Poly
  • 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).
  • TG2 transglutaminsase 2
  • the compounds of formula (I) described herein or according to the present invention may be administered themselves or in form of a pharmacologically acceptalbe salt.
  • the compounds of the present invention may form of a pharmacologically acceptalbe salt with organic or inorganic acids or bases.
  • 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
  • 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.
  • salts could also be formed with inorganic or organic bases. Examples for suitable inorganic or organic bases are, for example, NaOH, KOH, NH 4 OH, 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 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.
  • 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).
  • 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.
  • inventive compounds as reversible and irreversible TG inhibitors effectively inhibit the activity of TGs, especially TG2.
  • 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 descirbed 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.
  • 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 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.
  • 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 compound of the formula (I), or the pharmaceutical composition thereof is useful in the treatment or prophylaxis of celiac disease.
  • 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. 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a pharmaceutically acceptable carrier such as a compressed inert gas, e.g. nitrogen.
  • a low melting wax such as a mixture of fatty acid glycerides, e.g. cocoa butter
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • lubricants 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.
  • 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.
  • 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.
  • Boc tert-butoxycarbonyl
  • BocOSu N-tert-butoxycarbonyloxy-succinimide
  • DCM diichloromethane
  • 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
  • EtOAc ethyl acetate
  • HATU 1- [Bis(dimethylamino)methylene]-1H-1,2,3-
  • Example I Synthetic method I Scheme. I-1 Preparation of compound 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 HCl (32%) were added, and the suspension was stirred for another night at 4°C. The precipitate was filtered and dried.
  • Example B-1 Inhibitory effect of the compounds according to the invention Transglutaminase assay
  • the incorporation of dansylcadaverine into dimethylcasein Zedira product T036, Lorand et al., Anal Biochem, 1971, 44:221-31
  • 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.
  • 15 ⁇ l of inhibitor working dilution are added per well of a 96 well microtiter plate.
  • 15 ⁇ l of a 2% (v/v) DMSO solution prepared using the buffer mentioned above are added per well.
  • a slope of the increase in fluorescence between 20 and 30 min is calculated for determination of the IC 50 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. IC 50 values are calculated by plotting the enzymatic activity (as percentage from control containing 2% DMSO instead of inhibitor) against the inhibitor concentration. IC 50 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 tables 1, 2 and 3 using IC 50 -values. Table 1.
  • efficacy of reversible TG2 inhibitors A: IC 50 ⁇ 150 nM, B: 150 nM ⁇ IC 50 ⁇ 600 nM, C: IC 50 ⁇ 600 nM Table 2.
  • efficacy of reversible TG2 inhibitors A: IC 50 ⁇ 40 nM, B: 40 nM ⁇ IC 50 ⁇ 400 nM, C: IC 50 ⁇ 400 nM

Abstract

The invention relates to the compound of general formula (I) 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

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 ^-glutamyl transferases” (EC 2.3.2.13). They link the ^-amino group of the amino acid lysine and the ^-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- 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. The objective of the present invention is to provide novel, most probably reversible or irreversible inhibitors of transglutaminases, in particular transglutaminase 2 and methods for the synthesis of said inhibitors as well as several uses of these inhibitors. 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/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 reversible warheads such as α-ketoaldehydes, α-ketoketones, α-ketoacids, α-ketoesters, α- ketoamides as well as irreversible warheads such as α,ß-unsatureated-ketoester, α,ß- unsatureated ketoamide and α,ß-unsatureated-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):
Figure imgf000003_0003
wherein L represents –L1– or
Figure imgf000003_0001
L1 represents –CH2–, –CH2CH2–, –CH2CH2CH2–, –CH2CO–, –CH2CH2CO–; L2 represents a bond, –NRN1–, –NRN1CH N1 2–, –NR CH2CH2–, or –NRN1CH(CH3)–, R1 represents
Figure imgf000003_0002
R2 represents
Figure imgf000004_0001
Figure imgf000004_0002
,
Figure imgf000005_0001
,
Figure imgf000006_0001
Figure imgf000007_0001
,
Figure imgf000008_0001
Figure imgf000009_0001
wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 – R13 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-homoisotwistanyl, adamantly, 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, –CO2C2H5, –CONH2, –CONHCH3, –CON(CH3)2, –CONHC2H5, –CH2CO2H, –CH2CO2CH3, –CH2CO2C2H5, –CH2CONH2, –CH2CONHCH3, –CH2CON(CH3)2, –CH2CONHC2H5, –NHCOCH3, –NHCOC2H5, –NHCOCF3, –NHCOCH2CF3, –NHSO2CH3, –NHSO2C2H5, –NHSO2CHF2, –NHSO2CF3, –NHSO2CH2CF3; R4 represents –R5, –OR5 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-C5H9, –cyclo-C6H11, –CH2–cyclo-C3H5, –CH2–cyclo-C4H7, –CH2–cyclo-C5H9, –CH2–cyclo-C6H11, –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-C3H5, –cyclo-C4H7, –cyclo-C5H9, –cyclo-C6H11, –CH2–cyclo-C3H5, –CH2–cyclo-C4H7, –CH2–cyclo- C5H9, –CH2–cyclo-C6H11, –CH2–Ph, –CH2OCH3, –CH2OCH2CH3, –CH2CH2OCH3, –CH2CH2OCH2CH3, –CH2CH2NHCH3, –CH2CH2N(CH3)2, or –NR6R7 represents , , , Or ; 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, ^CHF2, ^CF3, ^CH2Cl, ^CH2Br, ^CH2I, ^CH2 ^CH2F, ^CH2 ^CHF2, ^CH2 ^CF3, ^CH2 ^CH2Cl, ^CH2 ^CH2Br, ^CH2 ^CH2I, –OCH3, –OC2H5, –OC3H7, –OCH(CH3)2, –OC(CH3)3, –OC4H9, –OCHF2, –OCF3, −OCH2CF3, –OC2F5, −OCH2OCH3, –O-cyclo-C3H5, –OCH2-cyclo-C3H5, –O–C2H4-cyclo-C3H5, –CHO, –COCH3, –COCF3, –COC2H5, –COC3H7, –COCH(CH3)2, –COC(CH3)3, –COOH, –COOCH3, –COOC2H5, –COOC3H7, –COOCH(CH3)2, –COOC(CH3)3, –OOC–CH3, –OOC–CF3, –OOC–C2H5, –OOC–C3H7, –OOC–CH(CH3)2, –OOC–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, –NHCOCH(CH3)2, –NHCOC(CH3)3, –CONH2, –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, –NHSO2C(CH3)3, ^CH=CH2, ^CH2 ^CH=CH2, ^C(CH3)=CH2, ^CH=CH ^CH3, ^C≡CH, ^C≡C ^CH3, ^CH2-C≡CH, ^Ph, ^O ^Ph, ^O ^CH2-Ph, , , , , , , , N N , , , , , or ; or R8 and R9 or R9 and R10 can form together one of the following five- membered or six-membered rings: , , , , , , , , N , , , , or ; or R12 and R13 or R13 and R14 can form together one of the following five- membered or six-membered rings; , , , , , , , , or ; 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-C5H9, ^CH2 ^cyclo ^C3H5, ^CH2 ^cyclo-C4H7, ^CH2 ^cyclo-C5H9, ^CH2F, ^CHF2, ^CF3, ^CH2Cl, ^CH2Br, ^CH2I, ^CH2 ^CH2F, ^CH2 ^CHF2, ^CH2 ^CF3, ^CH2 ^CH2Cl, ^CH2 ^CH2Br, ^CH2 ^CH2I, ^CH2 ^CH=CH2, ^CH2-C≡CH, –CHO, –COCH3, –COC2H5, –COC3H7, –COCH(CH3)2, –COC(CH3)3, ^CO ^cyclo ^C3H5, ^CO ^cyclo-C4H7, ^CO ^cyclo-C5H9, –COOCH3, –COOC2H5, –COOC3H7, –COOCH(CH3)2, –COOC(CH3)3, –COOCH2Ph, –SO2CH3, –SO2CF3, –SO2C2H5, –SO2C3H7, –SO2CH(CH3)2, –SO2 ^cyclo ^C3H5, or –SO2C(CH3)3; RN1 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 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-homoisotwistanyl, adamantly, diamantyl, and hexamethylenetetraminyl used herein, have the following parent structures respectively:
Figure imgf000012_0002
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. Preferred are the compounds of any one of the formulae (Ia), (Ib) and (Ic):
Figure imgf000012_0001
Figure imgf000013_0001
and L, R2 , R3, R5, R6, R7 have the same meanings as defined in the formula (I) In some embodiments, the present invention relates to the comopund of the formula (I)
Figure imgf000013_0002
wherein L represents –L1–L2– ; L1 represents –CH2CO–, L2 represents –NRN1–, and R3 represents 1-adamantyl; or L2 represents –NRN1CH 3 2–, and R represents 2-bicyclo[3.3.1]heptyl, and the afore-mentioned 1-adamantly and 2-bicyclo[3.1.1]heptyl residues are optionally contain one or more C=C double bond and/or are substituted one or more of Ra, Rb, R1 represents
Figure imgf000013_0003
R2 represents
Figure imgf000013_0004
R6 represents ^C2H5; and R8, R10, R11 , Ra, Rb, Rc, Rd, Re , RN and RN1 have the same meanings as defined in formula (I). In some embodiments, the present invention relates to the compound of the formula (Ia):
Figure imgf000014_0001
wherein L represents –L1–L2– ; L1 represents –CH2CO–, L2 represents –NRN1–, and R3 represents 1-adamantyl; or L2 represents –NRN1CH –, and 3 2 R represents 2-bicyclo[3.3.1]heptyl, and the afore-mentioned 1-adamantly and 2-bicyclo[3.1.1]heptyl residues are optionally contain one or more C=C double bond and/or are substituted one or more of Ra, Rb, Rc, Rd, and Re; R2 represents
Figure imgf000014_0002
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, –CO2C2H5, –CONH2, –CONHCH3, –CON(CH3)2, –CONHC2H5, –CH2CO2H, –CH2CO2CH3, –CH2CO2C2H5, –CH2CONH2, –CH2CONHCH3, –CH2CON(CH3)2, –CH2CONHC2H5, –NHCOCH3, –NHCOC2H5, –NHCOCF3, –NHCOCH2CF3, –NHSO2CH3, –NHSO2C2H5, –NHSO2CHF2, –NHSO2CF3, –NHSO2CH2CF3; R8, 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, ^CHF2, ^CF3, ^CH2Cl, ^CH2Br, ^CH2I, ^CH2 ^CH2F, ^CH2 ^CHF2, ^CH2 ^CF3, ^CH2 ^CH2Cl, ^CH2 ^CH2Br, ^CH2 ^CH2I, –OCH3, –OC2H5, –OC3H7, –OCH(CH3)2, –OC(CH3)3, –OC4H9, –OCHF2, –OCF3, −OCH2CF3, –OC2F5, −OCH2OCH3, –O-cyclo-C3H5, –OCH2-cyclo-C3H5, –O–C2H4-cyclo-C3H5, –CHO, –COCH3, –COCF3, –COC2H5, –COC3H7, –COCH(CH3)2, –COC(CH3)3, –COOH, –COOCH3, –COOC2H5, –COOC3H7, –COOCH(CH3)2, –COOC(CH3)3, –OOC–CH3, –OOC–CF3, –OOC–C2H5, –OOC–C3H7, –OOC–CH(CH3)2, –OOC–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, –NHCOCH(CH3)2, –NHCOC(CH3)3, –CONH2, –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, –NHSO2C(CH3)3, ^CH=CH2, ^CH2 ^CH=CH2, ^C(CH3)=CH2, ^CH=CH ^CH3, ^C≡CH, ^C≡C ^CH3, ^CH2-C≡CH, ^Ph, ^O ^Ph, ^O ^CH2-Ph, , , , , , , , N N , , , , , or ; 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-C5H9, ^CH2 ^cyclo ^C3H5, ^CH2 ^cyclo-C4H7, ^CH2 ^cyclo-C5H9, ^CH2F, ^CHF2, ^CF3, ^CH2Cl, ^CH2Br, ^CH2I, ^CH2 ^CH2F, ^CH2 ^CHF2, ^CH2 ^CF3, ^CH2 ^CH2Cl, ^CH2 ^CH2Br, ^CH2 ^CH2I, ^CH2 ^CH=CH2, ^CH2-C≡CH, –CHO, –COCH3, –COC2H5, –COC3H7, –COCH(CH3)2, –COC(CH3)3, ^CO ^cyclo ^C3H5, ^CO ^cyclo-C4H7, ^CO ^cyclo-C5H9, –COOCH3, –COOC2H5, –COOC3H7, –COOCH(CH3)2, –COOC(CH3)3, –COOCH2Ph, –SO2CH3, –SO2CF3, –SO2C2H5, –SO2C3H7, –SO2CH(CH3)2, –SO2 ^cyclo ^C3H5, or –SO2C(CH3)3; RN1 represents –H, ^CH3, or ^C2H5; 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): (II) wherein L2 represents –NRN1–, and R3 represents 1-adamantyl; or L2 represents –NRN1CH 3 2–, and R represents 2-bicyclo[3.3.1]heptyl, and the afore-mentioned adamantly and bicyclo[3.1.1]heptyl residues are optionally contain one or more C=C double bond and/or are substituted one or more of Ra, Rb, Rc, Rd, and Re; R2 represents RN R11 N 10 N R , , ; 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, –CO2C2H5, –CONH2, –CONHCH3, –CON(CH3)2, –CONHC2H5, –CH2CO2H, –CH2CO2CH3, –CH2CO2C2H5, –CH2CONH2, –CH2CONHCH3, –CH2CON(CH3)2, –CH2CONHC2H5, –NHCOCH3, –NHCOC2H5, –NHCOCF3, –NHCOCH2CF3, –NHSO2CH3, –NHSO2C2H5, –NHSO2CHF2, –NHSO2CF3, –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-C5H9, ^CH2 ^cyclo ^C3H5, ^CH2 ^cyclo-C4H7, ^CH2 ^cyclo-C5H9, ^CH2F, ^CHF2, ^CF3, ^CH2Cl, ^CH2Br, ^CH2I, ^CH2 ^CH2F, ^CH2 ^CHF2, ^CH2 ^CF3, ^CH2 ^CH2Cl, ^CH2 ^CH2Br, ^CH2 ^CH2I, ^CH2 ^CH=CH2, ^CH2-C≡CH, –CHO, –COCH3, –COC2H5, –COC3H7, –COCH(CH3)2, –COC(CH3)3, ^CO ^cyclo ^C3H5, ^CO ^cyclo-C4H7, ^CO ^cyclo-C5H9, –COOCH3, –COOC2H5, –COOC3H7, –COOCH(CH3)2, –COOC(CH3)3, –COOCH2Ph, –SO2CH3, –SO2CF3, –SO2C2H5, –SO2C3H7, –SO2CH(CH3)2, or –SO2C(CH3)3; RN1 represent –H, –CH3, or –CH2CH3; R8, 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, ^cyclo-C3H5, ^CH2 ^cyclo ^C3H5, ^CH2F, ^CHF2, ^CF3, ^CH2Cl, ^CH2Br, ^CH2I, ^CH2 ^CH2F, ^CH2 ^CHF2, ^CH2 ^CF3, ^CH2 ^CH2Cl, ^CH2 ^CH2Br, ^CH2 ^CH2I, –OCH3, –OC2H5, –OC3H7, –OCH(CH3)2, –OC(CH3)3, –OC4H9, –OCHF2, –OCF3, −OCH2CF3, –OC2F5, −OCH2OCH3, –O-cyclo-C3H5, –OCH2-cyclo-C3H5, –O–C2H4-cyclo-C3H5, ^CH=CH2, ^CH2 ^CH=CH2, ^C(CH3)=CH2, ^CH=CH ^CH3, ^C≡CH, ^C≡C ^CH3, ^CH2-C≡CH, ^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:
Figure imgf000017_0001
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: , or , and Ra and Rb, have the same meanings as defined herein. More preferred, the compound has any one of the formula (II-a), (II-b), (II-b1) – (II-b2), and (III-a) – (III-b ):
Figure imgf000017_0002
Figure imgf000018_0003
wherein R2 , RN , Ra, Rb, Rc, Rd and Re have the same meanings as defined herein, preferred in the formula (Ia) , more preferred in the formula (II). In a preferred embodmiment, the invention refers to the compound of the formula (I), (Ia) and (II), wherein R3 represents
Figure imgf000018_0001
In a preferred embodmiment, the invention refers to the compound of the formula (I), (Ia) and (II), wherein R2 represents
Figure imgf000018_0002
Most preferred are the following compounds of formula (I):
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0002
In another aspect of the present invention, the present invention refers to the compound of the formula (I)
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
,
Figure imgf000028_0001
wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 – R13 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-homoisotwistanyl, adamantly, 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; and when R3 is 2-bicyclo[3.1.1]heptyl, L is not –CH N1 3 2CONR CH2–, and when R is 1-adamantyl, then L is not –CH N1 2CONR –; 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, –CO2C2H5, –CONH2, –CONHCH3, –CON(CH3)2, –CONHC2H5, –CH2CO2H, –CH2CO2CH3, –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-C5H9, –cyclo-C6H11, –CH2–cyclo-C3H5, –CH2–cyclo-C4H7, –CH2–cyclo- C5H9, –CH2–cyclo-C6H11, –CH2–Ph, –CH2OCH3, –CH2OCH2CH3, –CH2CH2OCH3, –CH2CH2OCH2CH3, –CH2CH2NHCH3, –CH2CH2N(CH3)2, or –NR6R7 represents , , , or ; R8 – R14 have the meanings and preferred meanings as disclosed herein; 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-C5H9, ^CH2 ^cyclo ^C3H5, ^CH2F, ^CHF2, ^CF3, ^CH2Cl, ^CH2Br, ^CH2I, ^CH2 ^CH2F, ^CH2 ^CHF2, ^CH2 ^CF3, ^CH2 ^CH2Cl, ^CH2 ^CH2Br, ^CH2 ^CH2I, ^CH2 ^CH=CH2, ^CH2-C≡CH, –CHO, –COCH3, –COC2H5, –COC3H7, –COCH(CH3)2, –COC(CH3)3, –COOCH3, –COOC2H5, –COOC3H7, –COOCH(CH3)2, –COOC(CH3)3, –COOCH2Ph, –SO2CH3, –SO2CF3, –SO2C2H5, –SO2C3H7, –SO2CH(CH3)2, or –SO2C(CH3)3; RN1 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. Also preferred are the compounds of the formula (Ib):
Figure imgf000030_0001
wherein L represents –L1– or –L1-L2–; L1 represents –CH2–, –CH2CH2–, –CH2CH2CH2–, –CH2CO–, –CH2CH2CO–; L2 represents a bond, –NRN1–, –NRN1CH N1 2–, –NR CH2CH2–, or –NRN1CH(CH3)–;
Figure imgf000030_0002
,
Figure imgf000031_0001
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-homoisotwistanyl, adamantly, 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; and when R3 is 2-bicyclo[3.1.1]heptyl, L is not –CH N1 3 2CONR CH2–, and when R is 1-adamantyl, then L is not –CH N1 2CONR –; 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, –CO2C2H5, –CONH2, –CONHCH3, –CON(CH3)2, –CONHC2H5, –CH2CO2H, –CH2CO2CH3, –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-C5H9, –cyclo-C6H11, –CH2–cyclo-C3H5, –CH2–cyclo-C4H7, –CH2–cyclo- C5H9, –CH2–cyclo-C6H11, –CH2–Ph, –CH2OCH3, –CH2OCH2CH3, –CH2CH2OCH3, –CH2CH2OCH2CH3, –CH2CH2NHCH3, –CH2CH2N(CH3)2, or –NR6R7 represents , , , or ; 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-C5H9, ^CH2 ^cyclo ^C3H5, ^CH2F, ^CHF2, ^CF3, ^CH2Cl, ^CH2Br, ^CH2I, ^CH2 ^CH2F, ^CH2 ^CHF2, ^CH2 ^CF3, ^CH2 ^CH2Cl, ^CH2 ^CH2Br, ^CH2 ^CH2I, ^CH2 ^CH=CH2, ^CH2-C≡CH, –CHO, –COCH3, –COC2H5, –COC3H7, –COCH(CH3)2, –COC(CH3)3, –COOCH3, –COOC2H5, –COOC3H7, –COOCH(CH3)2, –COOC(CH3)3, –COOCH2Ph, –SO2CH3, –SO2CF3, –SO2C2H5, –SO2C3H7, –SO2CH(CH3)2, or –SO2C(CH3)3; RN1 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 enantiomer, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof. Preferably, -NR6R7 of the formula (Ib) represents –NH2, –NHCH3, –N(CH3)2, –NHCH(CH3)2, –NHCH2CH2CH3, –NH–CH2CH=CH2, –NHCH2CH2CH2CH3, –NHCH2CH(CH3)2, –NHC(CH3)3, –NHCH2CH2CH2CH2CH3, –NH–cyclo-C3H5, –NH–cyclo-C4H7, –NH–cyclo-C5H9, –NH–cyclo-C6H11, –NHCH2–cyclo-C3H5, –NHCH2–cyclo-C4H7, –NHCH2–cyclo-C5H9, –NHCH2–cyclo-C6H11, –NHCH2–Ph, –NHCH2OCH3, –NHCH2OCH2CH3, –NHCH2CH2OCH3, –NHCH2CH2NHCH3, –NHCH2CH2N(CH3)2, , , , or . In some embodiments, the present invention relates to the compound of the formula (I), (I) wherein L represents –L1– or –L1-L2–; L1 represents –CH2–, –CH2CH2–, –CH2CH2CH2–, –CH2CO–, –CH2CH2CO–; L2 represents a bond, –NRN1–, –NRN1CH N1 2–, –NR CH2CH2–, or –NRN1CH(CH3)–;
Figure imgf000033_0001
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-homoisotwistanyl, adamantly, 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; and when R3 is 2-bicyclo[3.1.1]heptyl, L is not –CH N1 3 2CONR CH2–, and when R is 1-adamantyl, then L is not –CH N1 2CONR –; R6 represents –H, –CH3, –CH2CH=CH2, –cyclo-C3H5, –CH2CH2CH2CH2CH3 ; and R8 – R14 , Ra, Rb, Rc, Rd, Re, RN , and RN1 have the meanings and preferred meanings as defined herein. Also preferred are compounds of the formula (I) or (Ib), wherein L1 represents –CH2–, or –CH2CO–; L2 represents a bond, –NRN1–, –NRN1CH N1 2–, or –NR CH(CH3)–; R3 represents bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 4-homoisotwistanyl, adamantly, or diamantyl,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; and and when R3 is 2-bicyclo[3.1.1]heptyl, –L1-L2– is not –CH N1 3 2CONR CH2–, and R is 1-adamantyl then –L1-L2– is not –CH N1 2CONR –; and Ra, Rb, Rc, Rd, Re and RN1 have the same meanings as defined herein. Preferably, R2 of the formula (I) or (Ib) represents
Figure imgf000034_0001
Preferred are compounds having any one of the formulae (IV-a) – (IV-l) and (V-a) – (V-d):
Figure imgf000035_0001
Figure imgf000036_0002
wherein L1 is not –CH2CO–, when the compound has the formula (IV-b), wherein L2 is not –NRN1CH2–, when the compound has the formula (IV-c), and R2 , R3, R6, R8, R9, R10, R11 , R12 , R13, Ra, Rb, Rc, Rd and L2 have the same meanings as defined herein, preferably as defined in formula (I) or (Ib). Also preferred are the compounds of any of the formula (IVa-1),
Figure imgf000036_0001
wherein R6 represents –H, –CH3, –CH2CH3, –CH(CH3)2, –CH2CH2CH3, –CH2CH=CH2, –CH2CH2CH2CH3, –CH2CH(CH3)2, –C(CH3)3, –CH2CH2CH2CH2CH3, –cyclo-C3H5, or –CH2–cyclo-C3H5. and R2 , Ra, and Rb have the same meanings as defined above, preferred in formula (I), or (Ib); preparably, Ra, and Rb represents independently of each other –H, –F, –Cl, –Br, –OH, –CN, –CH3, –C2H5, or –CO2Me. Preferably, in any of the formula (I), (Ib), (IV-a) – (IV-l), or (IVa-1): R2 represents
Figure imgf000037_0001
R6 represents –H, –CH3, –CH2CH3, –CH(CH3)2, –CH2CH2CH3, –CH2CH=CH2, –CH2CH2CH2CH3, –CH2CH(CH3)2, –C(CH3)3, –CH2CH2CH2CH2CH3, –cyclo-C3H5, or –CH2–cyclo-C3H5. 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), (Ib), (IV-a) – (IV-l), and (V-a) – (V-d), wherein R3 represents
Figure imgf000038_0001
Suprisingly, 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 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:
Figure imgf000038_0002
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0002
or a pharmaceutically acceptable salt thereof. In another aspect of the present invention, the compound of the formula (I) has irreversible warheads such as α,ß-unsatureated-ketoester, α,ß-unsatureated ketoamide and α,ß-unsatureated-sulfone. The compounds of the present invention act selective inhibitors of transglutaminase 2. Thus, in some embodiments the present invention refers to the compounds of the formula (I)
Figure imgf000053_0001
wherein L represents –L1– or –L1–L2– ; L1 represents –CH2–, –CH2CH2–, –CH2CH2CH2–, –CH2CO–, –CH2CH2CO–; L2 represents a bond, –NRN1–, –NRN1CH N1 2–, –NR CH2CH2–, or
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 – R13 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-homoisotwistanyl, adamantly, 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, –CO2C2H5, –CONH2, –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 –R5, –OR5 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-C5H9, –cyclo-C6H11, –CH2–cyclo-C3H5, –CH2–cyclo-C4H7, –CH2–cyclo-C5H9, –CH2–cyclo-C6H11, –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-C3H5, –cyclo-C4H7, –cyclo-C5H9, –cyclo-C6H11, –CH2–cyclo-C3H5, –CH2–cyclo-C4H7, –CH2–cyclo- C5H9, –CH2–cyclo-C6H11, –CH2–Ph, –CH2OCH3, –CH2OCH2CH3, –CH2CH2OCH3, –CH2CH2OCH2CH3, –CH2CH2NHCH3, –CH2CH2N(CH3)2, or –NR6R7 represents , , , or ; 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, ^CHF2, ^CF3, ^CH2Cl, ^CH2Br, ^CH2I, ^CH2 ^CH2F, ^CH2 ^CHF2, ^CH2 ^CF3, ^CH2 ^CH2Cl, ^CH2 ^CH2Br, ^CH2 ^CH2I, –OCH3, –OC2H5, –OC3H7, –OCH(CH3)2, –OC(CH3)3, –OC4H9, –OCHF2, –OCF3, −OCH2CF3, –OC2F5, −OCH2OCH3, –O-cyclo-C3H5, –OCH2-cyclo-C3H5, –O–C2H4-cyclo-C3H5, –CHO, –COCH3, –COCF3, –COC2H5, –COC3H7, –COCH(CH3)2, –COC(CH3)3, –COOH, –COOCH3, –COOC2H5, –COOC3H7, –COOCH(CH3)2, –COOC(CH3)3, –OOC–CH3, –OOC–CF3, –OOC–C2H5, –OOC–C3H7, –OOC–CH(CH3)2, –OOC–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, –NHCOCH(CH3)2, –NHCOC(CH3)3, –CONH2, –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, –NHSO2C(CH3)3, ^CH=CH2, ^CH2 ^CH=CH2, ^C(CH3)=CH2, ^CH=CH ^CH3, ^C≡CH, ^C≡C ^CH3, ^CH2-C≡CH, ^Ph, ^O ^Ph, ^O ^CH2-Ph, , , , , , , , N N , , , , , or ; or R8 and R9 or R9 and R10 can form together one of the following five- membered or six-membered rings: , , , , , , , , N , , , , or ; or R12 and R13 or R13 and R14 can form together one of the following five- membered or six-membered rings; , , , , , , , , or ; 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-C5H9, ^CH2 ^cyclo ^C3H5, ^CH2 ^cyclo-C4H7, ^CH2 ^cyclo-C5H9, ^CH2F, ^CHF2, ^CF3, ^CH2Cl, ^CH2Br, ^CH2I, ^CH2 ^CH2F, ^CH2 ^CHF2, ^CH2 ^CF3, ^CH2 ^CH2Cl, ^CH2 ^CH2Br, ^CH2 ^CH2I, ^CH2 ^CH=CH2, ^CH2-C≡CH, –CHO, –COCH3, –COC2H5, –COC3H7, –COCH(CH3)2, –COC(CH3)3, ^CO ^cyclo ^C3H5, ^CO ^cyclo-C4H7, ^CO ^cyclo-C5H9, –COOCH3, –COOC2H5, –COOC3H7, –COOCH(CH3)2, –COOC(CH3)3, –COOCH2Ph, –SO2CH3, –SO2CF3, –SO2C2H5, –SO2C3H7, –SO2CH(CH3)2, –SO2 ^cyclo ^C3H5, or –SO2C(CH3)3; RN1 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. Preferred, are the compounds of the formula (I),
Figure imgf000062_0002
wherein L represents –L1– or –L1–L2–; L1 represents –CH2–, –CH2CH2–, –CH2CH2CH2–, –CH2CO–, –CH2CH2CO–; L2 represents a bond, –NRN1–, –NRN1CH N1 2–, –NR CH2CH2–, or –NRN1CH(CH3)–;
Figure imgf000062_0003
, , and L1 , L2 , R2 , R3, R5 – R7 , and RN1 have the meanings as defined above.
Figure imgf000062_0001
L , R2 , R3, and R5 – R7 have the meanings as defined above. Also preferred are the compounds of the formula (I)
Figure imgf000063_0002
wherein L represents –L1– or –L1–L2–; L1 represents –CH2–, –CH2CH2–, –CH2CH2CH2–, –CH2CO–, –CH2CH2CO–; L2 represents a bond, –NRN1–, –NRN1CH N1 2–, –NR CH2CH2–, or –NRN1CH(CH3)–;
Figure imgf000063_0001
,
Figure imgf000064_0001
and L1 , L2 , R5 – R14 , RN and RN1 have the meanings as defined herein. Also preferred are the compounds of any one of the formulae (Ic) – (Ie)
Figure imgf000064_0002
Figure imgf000065_0001
More preferred, are the compound of the formula (I), wherein
Figure imgf000065_0002
L2 represents a bond, –NRN1–, –NRN1CH2–, or –NRN1CH(CH3)–; R3 represents bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 4- homoisotwistanyl, adamantly, or diamantyl 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; and R5, R6, R7 , Ra, Rb, Rc, Rd, Re and RN1 have the same meanings as defined above. Also preferred, are the compound of any one of the formulae (Ic) – (Ie),
Figure imgf000066_0001
,
Figure imgf000067_0001
R3 represents bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 4- homoisotwistanyl, adamantly, or diamantyl 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; and R5 – R14 , Ra, Rb, Rc, Rd, Re, RN and RN1 have the same meanings as defined above. More preferred are compounds of any one the formulae (VI-a) – (Vl-l), (VII-a) – (VII-l), (VIII-a) – (VIIl-l), (IX-a) – (IX-d), (X-a) – (X-d), and (XI-a) – (XI-d):
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
same meanings as defined above Preferred are the compounds of any one of the formule (I), (Ic) – (Ie), (VI-a) – (Vl-l), (VII-a) – (VII-l), (VIII-a) – (VIIl-l), wherein R2 represents
Figure imgf000073_0001
, , , , R5 represents –H, –CH3, –CH2CH3, –CH2CH2CH3, –CH(CH3)2, –CH2CH2CH2CH3, –CH2CH(CH3)2, –C(CH3)3, –cyclo-C3H5, –cyclo-C4H7, –CH2–cyclo-C3H5, –CH2–cyclo-C4H7; R6 and R7 represent independently of each other –H, –CH3, –CH2CH3, –CH2CH2CH3. Preferred, are the compounds of any one of the formule (IX-a) – (IX-d), (X-a) – (X-d), and (XI-a) – (XI-d), wherein R5 represents –H, –CH3, –CH2CH3, –CH2CH2CH3, –CH(CH3)2, –CH2CH2CH2CH3, –CH2CH(CH3)2, –C(CH3)3, –cyclo-C3H5, –cyclo-C4H7, –CH2–cyclo-C3H5, –CH2–cyclo-C4H7; and/or R6 and R7 represent independently of each other –H, –CH3, –CH2CH3, –CH2CH2CH3. Preferred, are the compound of any of the formulae (I), (Ic) – (Ie), (VI-a) – (Vl-l), (VII-a) – (VII-l), (VIII-a) – (VIIl-l), (IX-a) – (IX-d), (X-a) – (X-d), and (XI-a) – (XI-d), wherein
Figure imgf000074_0001
In very preferred embodiment the present invention refers to the compounds selected from the group consisting of:
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
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 any one of the formulae (Ia) – (Ie):
Figure imgf000089_0002
As shown in Scheme 1, a method for producing the compound of the formula (Ia) comprising: Step 1A: providing a compound 4a
Figure imgf000090_0001
Step 2A: performing coupling reaction of the compound 4a with a compound 5
Figure imgf000090_0002
to obtain a compound 6a
Figure imgf000090_0003
Step 3A: deprotecting an amino protecting group PG3 to obtain a compound 7a
Figure imgf000090_0004
Step 4A: performing coupling reaction of the compound 7a with a carboxylic acid (R2-CO2H 8) to obtain a compound 9a
Figure imgf000090_0005
Step 5A: performing oxidation reaction of the compound 9a to produce the compound of the formula (Ia)
Figure imgf000091_0001
wherein L, R2 , R3,and R6 have the same meanings as defined above in formula (Ia), and PG3 is an amino protecting group. Scheme 1
Figure imgf000091_0002
Figure imgf000091_0003
Optionally, Step 1A´ is carried out before the step 1A: (a) providing a protected aldehyde
Figure imgf000092_0001
; (b) performing a coupling reaction of the aldehyde 1 with an isocyanide (CN-R6) 2a to obtain an intermediate compound 3a
Figure imgf000092_0002
(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
Figure imgf000092_0003
wherein R2 , R6 have the same meanings as defined in formula (Ia), 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 (Ia) is preferred: Step 1A´: (a) providing a protected aldehyde 1
Figure imgf000092_0004
(b) performing a coupling reaction of the aldehyde 1 with an isocyanide (CN-R6) 2a to obtain an intermediate compound 3a
Figure imgf000093_0001
(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
Figure imgf000093_0002
Step 1A: providing a compound 4a
Figure imgf000093_0003
Step 2A: performing coupling reaction of the compound 4a with a compound 5
Figure imgf000093_0004
to obtain a compound 6a
Figure imgf000093_0005
Step 3A: deprotecting the amino protecting group PG3 to obtain a compound 7a
Figure imgf000093_0006
Step 4A: performing coupling reaction of the compound 7a with a carboxylic acid (R2-CO2H 8) to obtain a compound 9a
Figure imgf000094_0001
Step 5A: performing oxidation reaction of the compound 9a to produce the compound of the formula (Ia)
Figure imgf000094_0002
wherein L, R2 , R3,and R6 have the same meanings as defined above in the formula (Ia), and PG1 and PG3 are amino protecting groups, PG2 is a carboxyl protecting group. In a similar manner, the compound of the formula (Ib) can be produced and thus, the present invention relates to a method for producing the compound of formula (Ib) comprising the following steps in the following order: Step 1B: providing a compoun
Figure imgf000094_0003
Step 2B: performing coupling reaction of the compound 4b with a compound 5
Figure imgf000094_0004
to obtain a compound
Figure imgf000094_0005
Step 3B: deprotecting an amino protecting group PG3 to obtain a compound 7b 7b; Step 4B: performing coupling reaction of the compound 7b with a carboxylic acid (R2-CO2H 8) to obtain a compound 9b 9b; Step 5B: performing oxidation reaction of the compound 9b to produce the compound of the formula (Ib) (Ib); wherein L, R2 , R3, R6 and R7 have the same meanings as defined above in the formula (Ib), and PG3 is an amino protecting group. In the step 5A and/or 5B the chemical warhead precursor may be firstly converted to under a basic condition such as treating with K2CO3, and then is converted to the corresponding chemical warhead by an oxidation 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. A further aspect of the present invention relates to the production of compounds of the formula (Ic). As shown in Scheme 2, the method for producing the compound of the formula (Ic): comprises the following steps in the following order: Step 1C: providing a compound 4c
Figure imgf000096_0001
Step 2C: performing coupling reaction of the compound 4c with a compound 5
Figure imgf000096_0002
to obtain a compound
Figure imgf000096_0003
Step 3C: deprotecting an amino protecting group PG3 to obtain a compound 7c
Figure imgf000096_0004
Step 4C: performing coupling reaction of the compound 7c with a carboxylic acid (R2-CO2H 8) to produce the compound of the formula (Ic)
Figure imgf000096_0005
wherein L, R2 , R3, R5 have the same meanings as defined above above in formula (Ic), and PG3 is an amino protecting group. Scheme 2
Figure imgf000097_0004
Figure imgf000097_0001
Figure imgf000097_0002
Optionally, Step 1C´ is carried out before the step 1C: (a) providing a protected aldehyde 1
Figure imgf000097_0003
(b) performing a coupling reaction of the aldehyde 1 with a triphenyl phosphonium ylide 2c to obtain an intermediate compound 3c;
Figure imgf000098_0001
or alternatively (b´) performing a coupling reaction of the aldehyde 1 with a phosphonate 2c´ to obtain an intermediate compound 3c;
Figure imgf000098_0002
(c) deprotecting the protecting groups PG1 and PG2 of the compound 3c and introducing an amino protecting group PG3 to obtain a compound 4c. Therefore, the following method for the production of compounds of the formula (Ic) is preferred: Step 1C´: (a) providing a protected aldehyde 1
Figure imgf000098_0003
(b) performing a coupling reaction of the aldehyde 1 with a triphenyl phosphonium ylide 2c to obtain an intermediate compound 3c;
Figure imgf000099_0001
or alternatively (b´) performing a coupling reaction of the aldehyde 1 with a phosphonate 2c´ to obtain an intermediate compound 3c;
Figure imgf000099_0002
(c) deprotecting the protecting groups PG1 and PG2 of the compound 3c preferably under acidic condition and introducing an amino protecting group PG3 to obtain a compound 4c
Figure imgf000099_0003
Step 1C: providing a compound 4c
Figure imgf000099_0004
Step 2C: performing coupling reaction of the compound 4c with a compound 5
Figure imgf000100_0001
to obtain a compound 6c
Figure imgf000100_0002
Step 3C: deprotecting an amino protecting group PG3 to obtain a compound 7c
Figure imgf000100_0003
Step 4C: performing coupling reaction of the compound 7c with a carboxylic acid (R2-CO2H 8) to produce the compound of the formula (Ic)
Figure imgf000100_0004
wherein L, R2 , R3, R5 have the same meanings as defined above in formula (Ic), and PG1 and PG3 are amino protecting groups, PG2 is a carboxyl protecting group. Scheme 3
Figure imgf000101_0002
Figure imgf000101_0001
A further aspect of the present invention relates to the production of compounds of the formula (Id). As shown in Scheme 3, a method for producing the compound of the formula (Id): comprising: Step 1D: providing a compound 4d
Figure imgf000102_0001
4d; Step 2D: performing coupling reaction of the compound 4d with a compound 5
Figure imgf000102_0002
to obtain a compound
Figure imgf000102_0003
Step 3D: deprotecting an amino protecting group PG3 to obtain a compound 7d
Figure imgf000102_0004
Step 4D: performing coupling reaction of the compound 7d with a carboxylic acid (R2-CO2H 8) to produce the compound of the formula (Id)
Figure imgf000102_0005
wherein L, R2 , R3, R6, R7 have the same meanings as defined above in formula (Id), and PG3 is an amino protecting group. Optionally, Step 1D´ is carried out before the step 1D: (a) providing a protected aldehyde 1
Figure imgf000103_0001
(b) performing a coupling reaction of the aldehyde 1 with a phosphonate 2d to obtain an intermediate compound 3d;
Figure imgf000103_0002
(c) deprotecting the protecting groups PG1 and PG2 of the compound 3d preferably under acidic condition and introducing an amino protecting group PG3 to obtain a compound 4d
Figure imgf000103_0003
. Therefore, the following method for the production of compounds of the formula (Id) is preferred: Step 1D´: (a) providing a protected aldehyde 1
Figure imgf000103_0004
(b) performing a coupling reaction of the aldehyde 1 with a phosphonate 2d to obtain an intermediate compound 3d; (c) deprotecting the
Figure imgf000104_0001
compound 3d preferably under acidic condition and introducing an amino protecting group PG3 to obtain a compound
Figure imgf000104_0002
4d; Step 1D: providing a compound 4d
Figure imgf000104_0003
Step 2D: performing coupling reaction of the compound 4d with a compound 5
Figure imgf000104_0004
to obtain a compound
Figure imgf000104_0005
Step 3D: deprotecting an amino protecting group PG3 to obtain a compound 7d
Figure imgf000105_0001
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) (Id) ; wherein L, R2 , R3, R6, R7 have the same meanings as defined above in formula (Id), and PG3 is an amino protecting group. A further aspect of the present invention relates to the production of compounds of the formula (Ie).
Figure imgf000105_0002
As shown in Scheme 4, a method for producing the compound of the formula (Ie): comprising: Step 1E: providing a compound
Figure imgf000105_0003
Step 2E: performing coupling reaction of the compound 4e with a compound 5
Figure imgf000106_0001
to obtain a compound
Figure imgf000106_0002
Step 3E: deprotecting an amino protecting group PG3 to obtain a compound 7e
Figure imgf000106_0003
Step 4E: performing coupling reaction of the compound 7e with a carboxylic acid (R2-CO2H 8) to produce the compound of the formula (Ie)
Figure imgf000106_0004
wherein L, R2 , R3, R5 have the same meanings as defined above in formula (Ie), and PG3 is an amino protecting group. Scheme 4 EA )
Figure imgf000107_0004
Figure imgf000107_0001
Figure imgf000107_0002
Ie Optionally, Step 1E´ is carried out before the step 1E: (a) providing a protected aldehyde
Figure imgf000107_0003
(b) performing a coupling reaction of the aldehyde 1 with a sulfonylmethyl phosphonate 2e to obtain an intermediate compound 3e;
Figure imgf000108_0001
(c) deprotecting the protecting groups PG1 and PG2 of the compound 3e preferably under acidic condition and introducing an amino protecting group PG3 to obtain a compound 4e
Figure imgf000108_0002
. Therefore, the following method for the production of compounds of the formula (Ie) is preferred: Step 1E´: (a) providing a protected aldehyde 1
Figure imgf000108_0003
(b) performing a coupling reaction of the aldehyde 1 with a sulfonylmethyl phosphonate 2e to obtain an intermediate compound 3e;
Figure imgf000108_0004
(c) deprotecting the protecting groups PG1 and PG2 of the compound 3e preferably under acidic condition and introducing an amino protecting group PG3 to obtain a compound 4e
Figure imgf000109_0001
Step 1E: providing a compound
Figure imgf000109_0002
Step 2E: performing coupling reaction of the compound 4e with a compound 5
Figure imgf000109_0003
to obtain a compound
Figure imgf000109_0004
Step 3E: deprotecting an amino protecting group PG3 to obtain a compound 7e
Figure imgf000109_0005
Step 4E: performing coupling reaction of the compound 7e with a carboxylic acid (R2-CO2H 8) to produce the compound of the formula (Ie)
Figure imgf000110_0001
wherein L, R2 , R3, R5 have the same meanings as defined above in formula (Ie), and PG3 is an amino protecting group. In an alternative route first all protecting groups PG1 and PG2 are simultaneously removed and the protecting group PG3 is selectively introduced. Prefearbly, 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 Steps 2A, 2B, 2C, 2D, 2E, 4A, 4B, 4C, 4D, and 4E, to promote the coupling reaction with amino group of intermediate compound, activating reagents are commonly used to activating carboxylic acid („Peptide 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-1- yloxy)tripyrrolidinophosphonium hexafluorophosphate), TBTU (2-(1H-Benzotriazole-1- yl)-1,1,3,3-tetramethylaminium tetrafluoroborate), EEDQ (N-Ethoxycarbonyl-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), HBTU (O-Benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate), HOBt (1-Hydroxybenzotriazole), HOAt (1-Hydroxy-7- azabenzotriazole), DCC (N,N′-Dicyclohexylcarbodiimide), EDC (or EDAC or EDCI, 1- Ethyl-3-(3-dimethylaminopropyl)carbodiimide), BOP-Cl (Bis(2-oxo-3- oxazolidinyl)phosphinic chloride), TFFH (Tetramethylfluoroformamidinium hexafluorophosphate), BroP (Bromo tris(dimethylamino) phosphonium hexafluorophosphate), PyBroP (Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate) and CIP (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 acceptalbe salt. The compounds of the present invention may form of a pharmacologically acceptalbe 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 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 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 descirbed 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. 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. 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. 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. 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 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 for a given pharmaceutically active ingredient is part of the ordinary skills of the one skilled in the art. Examples Following abbreviations used in the examples have the following meaning. Boc (tert-butoxycarbonyl), BocOSu (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-(3ʹ-dimethylaminopropyl)carbodiimide), TFA (trifluoroacetic acid), THF (tetrahydrofuran), EtOAc (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 I. Synthetic method I Scheme. I-1
Figure imgf000118_0001
Preparation of compound
Figure imgf000119_0001
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 HCl (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
Figure imgf000119_0002
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) DIPEA. 7.45 g (1.1 eq) of 1-ethyl-3-(3ʹ-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
Figure imgf000119_0003
10.3 g (31.0 mmol) of ZED3912 were suspended in 200 mL MeOH 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. I-2
Figure imgf000120_0001
Preparation of compound
Figure imgf000121_0001
(S)-1-tert-butyl 5-methyl 2-(tert-butoxycarbonylamino)pentanedioate Chemical Formula: C15H27NO6 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 with 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
Figure imgf000121_0002
13.4 g of ZED788 ( ^39,6 mmol) and 986 mg of N,N-dimethyl-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 with 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
Figure imgf000122_0001
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
Figure imgf000122_0002
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) methyl 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]+ Preparation of compound
Figure imgf000123_0001
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 EtOAc 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-1b
Figure imgf000123_0002
600 mg (0.95 mmol) of I-1a 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 µl (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 EtOAc 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]+ Preparation of compound I-1c
Figure imgf000124_0001
527 mg (0.83 mmol) of I-1b were dissolved in 7 ml MeOH.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]+
Figure imgf000124_0002
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, δ [ppm]: 1.27 (t, 3H, ethyl-CH3), 1.74 (m, 6H, adamantyl-C4-H2), 1.97 // 2.15 (m // m, 1H // 1H, β-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, γ-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-C5-H), 7.31 (d, 1H, pyridinone-C6-H), 7.69 (s, 1H, imidazole-CH), 7.77 (s, 1H, imidazole-CH), 8.04 (d, 1H, adamantyl-NH), 8.17 (d, 1H, pyridinone-C4-H), 8.44 (q, 1H, ethylamide-NH), 8.56 (d, 1H, α-NH), 9.16 (s, 1H, pyridinone-NH). 13C-NMR (DMSO-D6, 500 MHz, δ [ppm]: 15.14 (ethyl-CH3), 24.54 (β-CH2), 29.19 (adamantyl-C3-H), 33.54 (imidazole-N-CH3), 33.71 (γ-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 (α-CH2), 104.66 (pyridinone-C5-H), 122.39 (pyridinone-C4-H), 125.22 (imidazole- Cq), 127.92 (pyridinone-N-Cq), 132.85 (imidazole-CH), 133.27 (pyridinone-C6-H), 142.23 (imidazole-CH), 156.63 (pyridinone-C=O), 160.32 (imidazole-C=O), 161.10 (C=O-NH-CH2CH3), 165.75 (C=O-adamantylamide), 170.56 (C=O-NH-pyridinone), 198.43 (C=O-ethylamide).
Figure imgf000125_0001
The synthesis of compound I-2 was performed according to compound I-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]+
Figure imgf000125_0002
The synthesis of compound I-3 was performed according to compound I-1, using N- methyl-1-adamantanamine instead of 1-adamantanamine in step 2 (preparation of compound ZED3912). Yield: 26 mg, 52% (last step) ESI-MS: 608.5 [M+H]+ Preparation of compound I-4
Figure imgf000126_0001
To the ^-hydroxyester precursor of compound I-4 (382 mg, 0.61 mmol, prepared by using 3,5-dimethyl-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 I-5
Figure imgf000126_0002
(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 Chemical Formula: C32H43N7O6 Exact Mass: 621.33 Molecular Weight: 621.73 To the ^-hydroxyester precursor of compound I-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 suspension was extracted with EtOAc. 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 I-6
Figure imgf000127_0001
The synthesis of compound I-6 was performed according to compound I-1, using 3- trifluoromethyl-1-adamantanamine instead of 1-adamantanamine in step 2 (preparation of compound ZED3912). Yield: 36 mg, 51% (last step) ESI-MS: 662.4 [M+H]+ Preparation of compound I-7
Figure imgf000127_0002
The synthesis of compound I-7 was performed according to compound I-1, using 3- hydroxy-1-adamantanamine instead of 1-adamantanamine in step 2 (preparation of compound ZED3912). Yield: 21 mg, 45% (last step) ESI-MS: 610.5 [M+H]+ Preparation of compound I-8
Figure imgf000128_0001
The synthesis of compound I-8 was performed according to compound I-1, using 3- fluoro-1-adamantanamine instead of 1-adamantanamine in step 2 (preparation of compound ZED3912). Yield: 52 mg, 61% (last step) ESI-MS: 612.5 [M+H]+ Preparation of compound I-9
Figure imgf000128_0002
(S)-N1-ethyl-N6-(1-(2-(3-chloroadamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin- 3-yl)-5-(1-methyl-1H-imidazole-5-carboxamido)-2-oxohexanediamide Chemical Formula: C30H38ClN7O6 Exact Mass: 627.26 Molecular Weight: 628.12 The synthesis of compound I-9 was performed according to compound I-1, using 3- chloro-1-adamantanamine instead of 1-adamantanamine in step 2 (preparation of compound ZED3912). Yield: 49 mg, 68% (last step) ESI-MS: 628.3 / 630.3 [M+H]+
Figure imgf000128_0003
The synthesis of compound I-10 was performed according to compound I-1, using 3- bromo-1-adamantanamine instead of 1-adamantanamine in step 2 (preparation of compound ZED3912). Yield: 59 mg, 71% (last step) ESI-MS: 672.3 / 674.3 [M+H]+ Preparation of compound I-11
Figure imgf000129_0001
The synthesis of compound I-11 was performed according to compound I-1, using methyl 3-aminoadamantane-1-carboxylate instead of 1-adamantanamine in step 2 (preparation of compound ZED3912). Yield: 85 mg, 74% (last step) ESI-MS: 652.5 [M+H]+ Preparation of compound I-12
Figure imgf000129_0002
The synthesis of compound I-3 was performed according to compound I-12, using 4,4- difluoro-1-adamantanamine instead of 1-adamantanamine in step 2 (preparation of compound ZED3912). Yield: 23 mg, 47% (last step) ESI-MS: 630.4 [M+H]+
Figure imgf000130_0001
The synthesis of compound I-3 was performed according to compound I-13, using (−)- cis-myrtanylamine instead of 1-adamantanamine in step 2 (preparation of compound ZED3912). Yield: 74 mg, 68% (last step) ESI-MS: 596.5 [M+H]+ Preparation of compound I-14
Figure imgf000130_0002
The synthesis of compound I-3 was performed according to compound I-14, using (−)- cis-(pinan-2-ylmethyl)amine instead of 1-adamantanamine in step 2 (preparation of compound ZED3912). Yield: 52 mg, 63% (last step) ESI-MS: 596.5 [M+H]+ Preparation of compound I-15
Figure imgf000130_0003
The synthesis of compound I-15 was performed according to compound I-5, using 1- methyl-1H-imidazole-4-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b). Yield: 26 mg, 67% (last step) ESI-MS: 622.5 [M+H]+ Preparation of compound I-16
Figure imgf000131_0001
The synthesis of compound I-16 was performed according to compound I-5, using 1- methyl-1H-imidazole-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b). Yield: 46 mg, 71% (last step) ESI-MS: 622.5 [M+H]+ Preparation of compound I-17
Figure imgf000131_0002
The synthesis of compound I-17 was performed according to compound I-5, using 1,4- dimethyl-1H-imidazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b). Yield: 69 mg, 75% (last step) ESI-MS: 636.5 [M+H]+ Preparation of compound I-18
Figure imgf000132_0001
The synthesis of compound I-18 was performed according to compound I-5, using 1- isobutyl-1H-imidazole-4-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b). Yield: 38 mg, 62% (last step) ESI-MS: 664.5 [M+H]+ Preparation of compound I-19
Figure imgf000132_0002
The synthesis of compound I-19 was performed according to compound I-5, using 1- cyclopentyl-1H-imidazole-4-carboxylic acid instead of 1-methyl-1H-imidazole-5- carboxylic acid in step 6 (according to compound I-1b). Yield: 24 mg, 57% (last step) ESI-MS: 676.5 [M+H]+ Preparation of compound I-20
Figure imgf000132_0003
The synthesis of compound I-20 was performed according to compound I-5, using 1- cyclobutyl-1H-imidazole-4-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b). Yield: 32 mg, 66% (last step) ESI-MS: 662.5 [M+H]+ Preparation of compound I-21
Figure imgf000133_0001
The synthesis of compound I-21 was performed according to compound I-4, using 1,4- dimethyl-1H-imidazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b). Yield: 25 mg, 56% (last step) ESI-MS: 636.5 [M+H]+ Preparation of compound I-22
Figure imgf000133_0002
The synthesis of compound I-22 was performed according to compound I-4, using 1- methyl-1H-imidazole-4-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b). Yield: 45 mg, 77% (last step) ESI-MS: 622.5 [M+H]+ Preparation of compound I-23
Figure imgf000134_0001
The synthesis of compound I-23 was performed according to compound I-4, using 1- methyl-1H-imidazole-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b). Yield: 18 mg, 50% (last step) ESI-MS: 622.5 [M+H]+ Preparation of compound I-24
Figure imgf000134_0002
Chemical Formula: C33H45N7O6 Exact Mass: 635.34 Molecular Weight: 635.75 (S)-2-(1,2-dimethyl-1H-imidazole-5-carboxamido)-N6-ethyl-N1-(1-(2-(3,5-dimethyladamantane- 1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-oxohexanediamide The synthesis of compound I-24 was performed according to compound I-4, using 1,2- dimethyl-1H-imidazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b). Yield: 44 mg, 72% (last step) ESI-MS: 636.5 [M+H]+ Preparation of compound I-25
Figure imgf000135_0001
The synthesis of compound I-25 was performed according to compound I-1, using 3- methyl-1-adamantanamine instead of 1-adamantanamine in step 2 (preparation of compound ZED3912). Yield: 37 mg, 59% (last step) ESI-MS: 608.5 [M+H]+ Preparation of compound I-26
Figure imgf000135_0002
The synthesis of compound I-26 was performed according to compound I-4, using 2- chloro-1-methyl-1H-imidazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5- carboxylic acid in step 6 (according to compound I-1b). Yield: 57 mg, 71% (last step) ESI-MS: 656.5 / 658.5 [M+H]+ Preparation of compound I-27
Figure imgf000135_0003
The synthesis of compound I-27 was performed according to compound I-25, using 1,2- dimethyl-1H-imidazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b). Yield: 29 mg, 52% (last step) ESI-MS: 622.5 [M+H]+ Preparation of compound I-28
Figure imgf000136_0001
The synthesis of compound I-28 was performed according to compound I-1, using 3,5,7-trimethyl-1-adamantanamineinstead of 1-adamantanamine in step 2 (preparation of compound ZED3912). Yield: 48 mg, 63% (last step) ESI-MS: 636.5 [M+H]+ Preparation of compound I-29
Figure imgf000136_0002
The synthesis of compound I-29 was performed according to compound I-28, using 2- chloro-1-methyl-1H-imidazole-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: 670.5 / 672.5 [M+H]+ Example II. Synthetic method Scheme II-1
Figure imgf000137_0001
Figure imgf000137_0002
1 Preparation of compound
Figure imgf000137_0003
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 HCl (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
Figure imgf000137_0004
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-(3ʹ-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 200 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 4 Preparation of compound ZED3906
Figure imgf000138_0001
24.2 g (73.0 mmol) of ZED3905 were suspended in 600 mL MeOH 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]+ Scheme II-2
Figure imgf000138_0002
Preparation of compound ZED788
Figure imgf000139_0001
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 with 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
Figure imgf000139_0002
13.4 g of ZED788 ( ^39,6 mmol) and 986 mg of N,N-dimethyl-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 with 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
Figure imgf000140_0001
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]+ 5 Preparation of compound
Figure imgf000140_0002
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]+ 6 Preparation of compound ZED3907
Figure imgf000141_0001
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 EtOAc 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. Yield: 27.4 g, 75% ESI-MS: 616.4 [M+H]+
Figure imgf000141_0002
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 µl (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 EtOAc 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]+ 8 Preparation of compound ZED3266
Figure imgf000142_0001
409 mg (0.61 mmol) of ZED3907 were dissolved in 5 ml MeOH. 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]+ 9 Preparation of compound II-3
Figure imgf000142_0002
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, ^ [ppm]: 1.46 // 1.98 (d // d, 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-C5-H), 2.05 // 2.16 (m // m, 1H // 1H, ^- CH2), 2.53 (s, 3H, benzofuran-CH3), 2.64 (d, 3H, amide-N-CH3), 2.96 (t, 2H, ^-CH2), 3.82 (m, 1H, adamantyl-C2-H), 4.64 (s, 2H, N-CH2), 4.70 (ddd, 1H, ^-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, ^ ^-NH), 9.36 (s, 1H, pyridinone-NH). 13C-NMR (DMSO-D6, 500 MHz, ^ [ppm]: 8.62 (benzofuran-CH3), 24.50 ( ^-CH2), 25.37 (amide-N-CH3), 26.57 // 26.62 (adamantyl-C5-H), 30.83 (adamantyl-C4-H2), 31.35 (adamantyl-C1-H), 33.61 ( ^-CH2), 36.66 (adamantyl-C4’-H2), 37.01 (adamantyl-C6-H2), 51.64 (N-CH2), 52.80 ( ^-CH2), 53.24 (adamantyl-C2-H), 104.51 (pyridinone-C5-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=O), 159.59 (benzofuran-C=O), 161.32 (C=O-NH-CH3), 165.65 (C=O-adamantylamide), 170.42 (C=O-NH-pyridinone), 198.06 (C=O-methylamide). 10 Preparation of compound II-2
Figure imgf000143_0001
To the ^-hydroxyester precursor of compound II-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]+ 11 Preparation of compound II-4
Figure imgf000144_0001
To the ^-hydroxyester precursor of compound II-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 EtOAc. 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]+ 12 Preparation of compound II-5
Figure imgf000144_0002
The synthesis of compound II-5 was performed according to compound II-3, using 4- bromo-1-benzofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 69 mg, 72% (last step) ESI-MS: 694.3 / 696.3 [M+H]+ 13 Preparation of
Figure imgf000145_0001
The synthesis of compound II-6 was performed according to compound II-3, using benzo[b]thiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 287 mg, 76% (last step) ESI-MS: 632.3 [M+H]+ 14 Preparation of compound II-7
Figure imgf000145_0002
The synthesis of compound II-7 was performed according to compound II-3, using 5- bromobenzo[b]thiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2- carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 145 mg, 59% (last step) ESI-MS: 710.2 / 712.2 [M+H]+ 15 Preparation of compound II-8
Figure imgf000146_0001
The synthesis of compound II-8 was performed according to compound II-3, using 7- fluorobenzo[b]thiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2- carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 78 mg, 71% (last step) ESI-MS: 650.3 [M+H]+ 16 Preparation of compound II-9
Figure imgf000146_0002
The synthesis of compound II-9 was performed according to compound II-3, using 1H- indole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 57 mg, 69% (last step) ESI-MS: 615.4 [M+H]+ 17 Preparation of compound II-10
Figure imgf000147_0001
The synthesis of compound II-10 was performed according to compound II-3, using 4,5- difluoro-1H-indole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 47 mg, 65% (last step) ESI-MS: 651.3 [M+H]+ 18 Preparation of compound II-11
Figure imgf000147_0002
The synthesis of compound II-11 was performed according to compound II-3, using 3- methyl-1H-indole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 58 mg, 72% (last step) ESI-MS: 629.4 [M+H]+ 19 Preparation of compound II-12
Figure imgf000148_0001
The synthesis of compound II-12 was performed according to compound II-3, using 1H- benzo[d]imidazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 27 mg, 48% (last step) ESI-MS: 616.4 [M+H]+ 20 Preparation of compound II-13
Figure imgf000148_0002
The synthesis of compound II-13 was performed according to compound II-3, using 2,3- dihydro-1H-indene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 38 mg, 61% (last step) ESI-MS: 616.4 [M+H]+ 21 Preparation of compound II-14
Figure imgf000149_0001
The synthesis of compound II-14 was performed according to compound II-3, using 2- bromo-4-methylthiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 98 mg, 70% (last step) ESI-MS: 675.2 / 677.2 [M+H]+ 22 Preparation of compound II-15
Figure imgf000149_0002
The synthesis of compound II-15 was performed according to compound II-3, using 4- methyl-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2- carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 67 mg, 51% (last step) ESI-MS: 665.4 [M+H]+ 23 Preparation of compound II-16
Figure imgf000149_0003
The synthesis of compound II-16 was performed according to compound II-3, using 4- bromo-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2- carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 136 mg, 63% (last step) ESI-MS: 729.3 / 731.3 [M+H]+ 24 Preparation of compound II-17
Figure imgf000150_0001
The synthesis of compound II-17 was performed according to compound II-3, using 2,4- dichlorothiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 102 mg, 71% (last step) ESI-MS: 651.2 / 653.2 [M+H]+ 25 Preparation of compound II-18
Figure imgf000150_0002
The synthesis of compound II-18 was performed according to compound II-3, using 2- methoxy-4-methylthiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2- carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 56 mg, 63% (last step) ESI-MS: 627.3 [M+H]+ 26 Preparation of compound II-19
Figure imgf000151_0001
The synthesis of compound II-19 was performed according to compound II-3, using 4- methyl-2-phenylthiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 46 mg, 67% (last step) ESI-MS: 673.4 [M+H]+ 27 Preparation of compound II-20
Figure imgf000151_0002
The synthesis of compound II-20 was performed according to compound II-3, using 2,4- dimethylthiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 216 mg, 77% (last step) ESI-MS: 611.4 [M+H]+ 28 Preparation of compound II-21
Figure imgf000152_0001
The synthesis of compound II-21 was performed according to compound II-3, using 5- bromo-3-methylthiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2- carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 178 mg, 79% (last step) ESI-MS: 674.2 / 676.2.4 [M+H]+ 29 Preparation of compound II-22
Figure imgf000152_0002
The synthesis of compound II-22 was performed according to compound II-3, using 3,5- dibromothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 89 mg, 67% (last step) ESI-MS: 738.2 / 740.2 / 742.2 [M+H]+ 30 Preparation of compound II-23
Figure imgf000153_0001
The synthesis of compound II-23 was performed according to compound II-3, using 5- bromothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 141 mg, 72% (last step) ESI-MS: 660.2 / 662.2 [M+H]+ 31 Preparation of compound II-24
Figure imgf000153_0002
The synthesis of compound II-24 was performed according to compound II-3, using 5- chlorothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 117 mg, 78% (last step) ESI-MS: 616.3 / 618.3 [M+H]+ 32 Preparation of compound II-25
Figure imgf000154_0001
The synthesis of compound II-25 was performed according to compound II-3, using 5- bromo-3-methylfuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 173 mg, 72% (last step) ESI-MS: 658.2 / 660.2 [M+H]+ 33 Preparation of compound II-26
Figure imgf000154_0002
The synthesis of compound II-26 was performed according to compound II-3, using 5- chlorofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 127 mg, 56% (last step) ESI-MS: 600.3 / 602.3 [M+H]+ 34 Preparation of compound II-27
Figure imgf000155_0001
The synthesis of compound II-27 was performed according to compound II-3, using 5- chlorothiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 112 mg, 65% (last step) ESI-MS: 616.3 / 618.3 [M+H]+ 35 Preparation of compound II-28
Figure imgf000155_0002
The synthesis of compound II-28 was performed according to compound II-3, using 2,5- dichlorothiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 319 mg, 77% (last step) ESI-MS: 650.3 / 652.3 / 654.3 [M+H]+ 36 Preparation of compound II-29
Figure imgf000156_0001
The synthesis of compound II-29 was performed according to compound II-3, using 2,5- dibromothiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 98 mg, 52% (last step) ESI-MS: 738.2 / 740.2 / 742.2 [M+H]+ 37 Preparation of compound II-30
Figure imgf000156_0002
The synthesis of compound II-30 was performed according to compound II-3, using 5- bromothiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 171 mg, 73% (last step) ESI-MS: 660.2 / 662.2 [M+H]+ 38 Preparation of compound II-31
Figure imgf000157_0001
The synthesis of compound II-31 was performed according to compound II-3, using 2- chloro-5-methylthiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 32 mg, 41% (last step) ESI-MS: 631.3 / 633.3 [M+H]+ 39 Preparation of compound II-32
Figure imgf000157_0002
The synthesis of compound II-32 was performed according to compound II-3, using 2,5- dichlorothiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 41 mg, 35% (last step) ESI-MS: 651.2 / 653.2 / 655.2 [M+H]+ 40 Preparation of compound II-33
Figure imgf000158_0001
The synthesis of compound II-33 was performed according to compound II-3, using 2,5- dibromothiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 21 mg, 32% (last step) ESI-MS: 739.2 / 741.2 / 743.2 [M+H]+
Figure imgf000158_0002
The synthesis of compound II-34 was performed according to compound II-3, using 2- bromo-5-methylthiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 42 mg, 57% (last step) ESI-MS: 675.2 / 677.2 [M+H]+
Figure imgf000159_0001
The synthesis of compound II-35 was performed according to compound II-3, using 2- bromothiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 66 mg, 46% (last step) ESI-MS: 661.2 / 663.2 [M+H]+ 43 Preparation of compound II-36
Figure imgf000159_0002
The synthesis of compound II-36 was performed according to compound II-3, using 2- chlorothiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 74 mg, 58% (last step) ESI-MS: 617.3 / 619.3 [M+H]+ 44 Preparation of compound II-37
Figure imgf000160_0001
The synthesis of compound II-37 was performed according to compound II-3, using 2,5- dimethylfuran-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 152 mg, 73% (last step) ESI-MS: 594.4 [M+H]+ 45 Preparation of compound II-38
Figure imgf000160_0002
The synthesis of compound II-38 was performed according to compound II-3, using 4,5- dimethylthiazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 46 mg, 38% (last step) ESI-MS: 611.4 [M+H]+ 46 Preparation of compound II-39
Figure imgf000161_0001
The synthesis of compound II-39 was performed according to compound II-3, using 4- bromothiazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 84 mg, 68% (last step) ESI-MS: 661.2 / 663.2 [M+H]+ 47 Preparation of c
Figure imgf000161_0002
The synthesis of compound II-40 was performed according to compound II-3, using 4- bromothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 163 mg, 73% (last step) ESI-MS: 660.2 / 662.2 [M+H]+ 48 Preparation of compound II-41
Figure imgf000162_0001
The synthesis of compound II-41 was performed according to compound II-3, using 4- bromo-3-methylthiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2- carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 114 mg, 68% (last step) ESI-MS: 674.2 / 676.2 [M+H]+
Figure imgf000162_0002
The synthesis of compound II-42 was performed according to compound II-3, using 3- bromothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 149 mg, 76% (last step) ESI-MS: 660.2 / 662.2 [M+H]+ 50 Preparation of compound II-43
Figure imgf000163_0001
The synthesis of compound II-43 was performed according to compound II-3, using 3- chloro-4-methylthiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2- carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 110 mg, 64% (last step) ESI-MS: 630.3 / 632.3 [M+H]+ 51 Preparation of compound II-44
Figure imgf000163_0002
The synthesis of compound II-44 was performed according to compound II-3, using 4- bromo-5-chlorothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2- carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 126 mg, 59% (last step) ESI-MS: 694.2 / 696.2 / 698.2 [M+H]+ 52 Preparation of compound II-45
Figure imgf000164_0001
The synthesis of compound II-45 was performed according to compound II-3, using 4,5- dibromothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 89 mg, 51% (last step) ESI-MS: 738.2 / 740.2 / 742.2 [M+H]+ 53 Preparation of compound II-46
Figure imgf000164_0002
The synthesis of compound II-46 was performed according to compound II-3, using 4,5- dibromo-3-methoxythiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2- carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 59 mg, 40% (last step) ESI-MS: 768.2 / 770.2 / 772.2 [M+H]+
Figure imgf000165_0001
The synthesis of compound II-47 was performed according to compound II-3, using 4- bromofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 90 mg, 69% (last step) ESI-MS: 644.3 / 646.3 [M+H]+ 55 Preparation of compound II-48
Figure imgf000165_0002
The synthesis of compound II-48 was performed according to compound II-3, using 4,5- dibromofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 72 mg, 56% (last step) ESI-MS: 722.2 / 724.2 / 726.2 [M+H]+ 56 Preparation of compound II-49
Figure imgf000166_0001
The synthesis of compound II-49 was performed according to compound II-3, using 4,5- dichlorothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 55 mg, 48% (last step) ESI-MS: 650.3 / 652.3 / 654.3 [M+H]+
Figure imgf000166_0002
(S)-2-((S)-1-acetylpyrrolidine-2-carboxamido)-N1-(1-(2-(2-adamantylamino)- 2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-5-oxohexanediamide Chemical Formula: C31H42N6O7 Exact Mass: 610.31 Molecular Weight: 610.70 The synthesis of compound II-50 was performed according to compound II-3, using (S)- 1-acetylpyrrolidine-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 190 mg, 78% (last step) ESI-MS: 611.4 [M+H]+ 58 Preparation of compound II-51
Figure imgf000167_0001
The synthesis of compound II-51 was performed according to compound II-3, using 1- methyl-1H-1,2,3-triazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 28 mg, 35% (last step) ESI-MS: 581.4 [M+H]+ 59 Preparation of compound II-52
Figure imgf000167_0002
The synthesis of compound II-52 was performed according to compound II-3, using 2H- tetrazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 23 mg, 31% (last step) ESI-MS: 568.4 [M+H]+ 60 Preparation of compound II-53
Figure imgf000168_0001
The synthesis of compound II-53 was performed according to compound II-3, using pyrazine-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 79 mg, 74% (last step) ESI-MS: 578.3 [M+H]+ 61 Preparation of compound II-54
Figure imgf000168_0002
The synthesis of compound II-54 was performed according to compound II-3, using (S)- 1-methylpyrrolidine-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 68 mg, 82% (last step) ESI-MS: 583.4 [M+H]+ 62 Preparation of compound II-55
Figure imgf000169_0001
The synthesis of compound II-55 was performed according to compound II-3, using (S)- 1-Boc-pyrrolidine-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound 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]+
Figure imgf000169_0002
The synthesis of compound II-56 was performed according to compound II-3, using (2S,4S)-1-Boc-4-bromopyrrolidine-2-carboxylic acid instead of 3-methylbenzo[b]furan-2- carboxylic acid in step 6 (preparation of compound 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]+ 64 Preparation of compound II-58
Figure imgf000170_0001
The synthesis of compound II-58 was performed according to compound II-3, using (S)- 1-Boc-piperidine-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound 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]+ 65 Preparation of compound II-59
Figure imgf000170_0002
The synthesis of compound II-59 was performed according to compound II-3, using (R)- 1-Boc-piperidine-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound 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]+ 66 Preparation of compound II-60
Figure imgf000171_0001
The synthesis of compound II-60 was performed according to compound II-3, using (R)- 4-Boc-morpholine-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound 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]+ 67 Preparation of compound II-61
Figure imgf000171_0002
The synthesis of compound II-61 was performed according to compound II-3, using quinuclidine-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 24 mg, 54% (last step) ESI-MS: 609.4 [M+H]+ 68 Preparation of compound II-62
Figure imgf000172_0001
(S)-methyl 3-(1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin- 3-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)-5-nitrobenzoate Chemical Formula: C33H38N6O10 Exact Mass: 678.26 Molecular Weight: 678.69 The synthesis of compound II-62 was performed according to compound II-3, using mono-methyl 5-nitroisophthalate instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 57 mg, 66% (last step) ESI-MS: 679.3 [M+H]+ 69 Preparation of compound II-63
Figure imgf000172_0002
The synthesis of compound II-63 was performed according to compound II-3, using 5- nitronicotinic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 76 mg, 65% (last step) ESI-MS: 622.3 [M+H]+ 70 Preparation of compound II-64
Figure imgf000173_0001
(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: C31H36N6O8 Exact Mass: 620.26 Molecular Weight: 620.65 The synthesis of compound II-64 was performed according to compound II-3, using 3,5- pyridinedicarboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 16 mg, 52% (last step) ESI-MS: 621.3 [M+H]+ 71 Preparation of compound II-65
Figure imgf000173_0002
The synthesis of compound II-65 was performed according to compound II-3, using 5- (methoxycarbonyl)nicotinic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 34 mg, 62% (last step) ESI-MS: 635.3 [M+H]+ 72 Preparation of compound II-66
Figure imgf000174_0001
The synthesis of compound II-66 was performed according to compound II-3, using 6- methylimidazo[2,1-b]thiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2- carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 45 mg, 37% (last step) ESI-MS: 636.4 [M+H]+ 73 Preparation of compound II-67
Figure imgf000174_0002
The synthesis of compound II-67 was performed according to compound II-3, using N-methyl-2-adamantanamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 66 mg, 45% (last step) ESI-MS: 644.4 [M+H]+ 74 Preparation of compound II-68
Figure imgf000175_0001
The synthesis of compound II-68 was performed according to compound II-3, using 5- hydroxy-2-adamantanamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 21 mg, 34% (last step) ESI-MS: 646.4 [M+H]+ 75 Preparation of compound II-69
Figure imgf000175_0002
The synthesis of compound II-69 was performed according to compound II-3, using 5- fluoro-2-adamantanamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 48 mg, 57% (last step) ESI-MS: 648.4 [M+H]+ 76 Preparation of compound II-70
Figure imgf000176_0001
The synthesis of compound II-70 was performed according to compound II-3, using 5- chloro-2-adamantanamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 45 mg, 35% (last step) ESI-MS: 664.3 / 666.3 [M+H]+ 77 Preparation of compound II-71
Figure imgf000176_0002
The synthesis of compound II-71 was performed according to compound II-3, using 5- bromo-2-adamantanamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 31 mg, 34% (last step) ESI-MS: 708.3 / 710.3 [M+H]+ 78 Preparation of compound II-72
Figure imgf000177_0001
The synthesis of compound II-72 was performed according to compound II-3, using 5- methyl-2-adamantanamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 68 mg, 54% (last step) ESI-MS: 644.4 [M+H]+ 79 Preparation of compound II-73
Figure imgf000177_0002
The synthesis of compound II-73 was performed according to compound II-3, using 2- aminoadamantane-2-carbonitrile instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 26 mg, 46% (last step) ESI-MS: 655.4 [M+H]+ 80 Preparation of compound II-74
Figure imgf000178_0001
The synthesis of compound II-74 was performed according to compound II-3, using 2- methyl 2-aminoadamantane-2-carboxylate instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 38 mg, 61% (last step) ESI-MS: 688.4 [M+H]+ 81 Preparation of compound II-87
Figure imgf000178_0002
The synthesis of compound II-87 was performed according to compound II-3, using 1- adamantanemethylamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 43 mg, 53% (last step) ESI-MS: 644.4 [M+H]+ 82 Preparation of compound II-88
Figure imgf000179_0001
The synthesis of compound II-88 was performed according to compound II-2, using 1- rimantadine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 31 mg, 41% (last step) ESI-MS: 644.4 [M+H]+ 83 Preparation of compound II-90
Figure imgf000179_0002
The synthesis of compound II-90 was performed according to compound II-3, using (±)- endo-2-norbornylamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 67 mg, 65% (last step) ESI-MS: 590.4 [M+H]+ 84 Preparation of compound II-92
Figure imgf000180_0001
The synthesis of compound II-92 was performed according to compound II-3, using (R)- (+)-bornylamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 52 mg, 66% (last step) ESI-MS: 632.5 [M+H]+ 85 Preparation of compound II-94
Figure imgf000180_0002
The synthesis of compound II-94 was performed according to compound II-3, using exo- 2-aminonorbornane instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 62 mg, 68% (last step) ESI-MS: 590.4 [M+H]+ 86 Preparation of compound II-95
Figure imgf000181_0001
The synthesis of compound II-95 was performed according to compound II-3, using bicyclo[2.2.1]heptan-1-ylamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 14 mg, 32% (last step) ESI-MS: 590.4 [M+H]+ 87 Preparation of compound II-96
Figure imgf000181_0002
The synthesis of compound II-96 was performed according to compound II-3, using bicyclo[2.2.1]heptan-7-ylamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 36 mg, 53% (last step) ESI-MS: 590.4 [M+H]+
Figure imgf000182_0001
The synthesis of compound II-97 was performed according to compound II-3, using bicyclo[2.2.1]hept-5-en-2-amine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 21 mg, 44% (last step) ESI-MS: 588.4 [M+H]+ 89 Preparation of compound II-98
Figure imgf000182_0002
The synthesis of compound II-98 was performed according to compound II-3, using bicyclo[2.2.2]oct-2-ylamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 25 mg, 41% (last step) ESI-MS: 604.4 [M+H]+ 90 Preparation of compound II-99
Figure imgf000183_0001
The synthesis of compound II-99 was performed according to compound II-3, using (R)- (−)-isobornylamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 27 mg, 48% (last step) ESI-MS: 632.5 [M+H]+ 91 Preparation of compound II-100
Figure imgf000183_0002
(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-yl)hexanediamide Chemical Formula: C34H41N5O7 Exact Mass: 631.30 Molecular Weight: 631.72 The synthesis of compound II-100 was performed according to compound II-3, using (1R,2R,3R,5S)-(−)-isopinocampheylamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 17 mg, 39% (last step) ESI-MS: 632.5 [M+H]+ 92 Preparation of compound II-101
Figure imgf000184_0001
The synthesis of compound II-101 was performed according to compound II-3, using (1S,2S,3S,5R)-(+)-isopinocampheylamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 25 mg, 41% (last step) ESI-MS: 632.5 [M+H]+ 93 Preparation of compound II-103
Figure imgf000184_0002
The synthesis of compound II-103 was performed according to compound II-3, using 3- amino-4-homoisotwistane instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 12 mg, 28% (last step) ESI-MS: 644.5 [M+H]+ 94 Preparation of compound II-104
Figure imgf000185_0001
(S)-N1-(1-(2-(diamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)- N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C38H43N5O7 Exact Mass: 681.32 Molecular Weight: 681.78 The synthesis of compound II-104 was performed according to compound II-3, using 1- aminodiamantane instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 17 mg, 35% (last step) ESI-MS: 682.5 [M+H]+ 95 Preparation of compound II-105
Figure imgf000185_0002
(S)-N1-(1-(2-(diamantane-4-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)- N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide Chemical Formula: C38H43N5O7 Exact Mass: 681.32 Molecular Weight: 681.78 The synthesis of compound II-105 was performed according to compound II-3, using 4- aminodiamantane instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 8 mg, 26% (last step) ESI-MS: 682.5 [M+H]+ Scheme II-3 New Building Block
Figure imgf000186_0001
Figure imgf000186_0002
Figure imgf000186_0003
96 Preparation of compound ZED4893
Figure imgf000186_0004
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 EtOAc 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]+ 97 Preparation of compound ZED4894
Figure imgf000186_0005
484 mg (1.68 mmol) of ZED4893 were suspended in 30 mL MeOH 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]+ 98 Preparation of compound II-107
Figure imgf000187_0001
The synthesis of compound II-107 was performed according to compound II-3, using ZED4894 instead of ZED3906 in step 5 (according to ZED3907). Yield: 41 mg, 49% (last step) ESI-MS: 587.4 [M+H]+ 99 Preparation of compound II-108
Figure imgf000187_0002
The synthesis of compound II-108 was performed according to compound II-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]+ 100 Preparation of compound II-109
Figure imgf000188_0001
The synthesis of compound II-109 was performed according to compound II-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]+ 101 Preparation of compound II-110
Figure imgf000188_0002
The synthesis of compound II-110 was performed according to compound II-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]+ 102 Preparation of compound II-111
Figure imgf000189_0001
The synthesis of compound II-111 was performed according to compound II-3, using nicotinic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 65 mg, 46% (last step) ESI-MS: 577.4 [M+H]+ 103 Preparation of compound II-112
Figure imgf000189_0002
The synthesis of compound II-112 was performed according to compound II-3, using isonicotinic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 47 mg, 52% (last step) ESI-MS: 577.4 [M+H]+ 104 Preparation of compound II-113
Figure imgf000190_0001
The synthesis of compound II-113 was performed according to compound II-3, using pyridazine-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 34 mg, 46% (last step) ESI-MS: 578.4 [M+H]+ 105 Preparation of compound II-114
Figure imgf000190_0002
The synthesis of compound II-114 was performed according to compound II-3, using pyridazine-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (preparation of compound ZED3264). Yield: 43 mg, 56% (last step) ESI-MS: 578.4 [M+H]+ 106 Preparation of compound II-115
Figure imgf000191_0001
The synthesis of compound II-115 was performed according to compound II-1, using cyclopropyl isocyanide instead of methyl isocyanide in step 4 (preparation of compound ZED3632). Yield: 47 mg, 64% (last step) ESI-MS: 656.5 [M+H]+ 107 Preparation of compound II-116
Figure imgf000191_0002
The synthesis of compound II-116 was performed according to compound II-1, using pentyl isocyanide instead of methyl isocyanide in step 4 (preparation of compound ZED3632). Yield: 87 mg, 71% (last step) ESI-MS: 686.5 [M+H]+ 108 Preparation of compound II-117
Figure imgf000192_0001
The synthesis of compound II-117 was performed according to compound II-1, using allyl isocyanide instead of methyl isocyanide in step 4 (preparation of compound ZED3632). Yield: 42 mg, 63% (last step) ESI-MS: 656.5 [M+H]+ Scheme II-4
Figure imgf000192_0005
Figure imgf000192_0002
2) 3-Methylbenzo[b]- furan-2-carboxylic acid
Figure imgf000192_0003
HATU, DIPEA, DMF
Figure imgf000192_0004
Preparation of compound 10
Figure imgf000193_0001
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
Figure imgf000193_0002
16.2 g ( ^38.6 mmol) of cyanohydrin 10 were dissolved in 95 ml MeOH 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]+ Preparation of compound 15
Figure imgf000194_0001
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
Figure imgf000194_0002
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 EtOAc. 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]+ 109 Preparation of compound II-118
Figure imgf000195_0001
The synthesis of compound II-118 was performed according to compound II-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]+ 110 Preparation of compound II-119
Figure imgf000195_0002
The synthesis of compound II-119 was performed according to compound II-2, using allyl isocyanide instead of methyl isocyanide in step 4 (preparation of compound ZED3632). Yield: 56 mg, 71% (last step) ESI-MS: 642.4 [M+H]+ 111 Preparation of compound II-120
Figure imgf000196_0001
The synthesis of compound II-120 was performed according to compound II-2, using isopropyl isocyanide instead of methyl isocyanide in step 4 (preparation of compound ZED3632). Yield: 62 mg, 65% (last step) ESI-MS: 644.5 [M+H]+ 112 Preparation of compound II-121
Figure imgf000196_0002
The synthesis of compound II-121 was performed according to compound II-2, using cyclopropyl isocyanide instead of methyl isocyanide in step 4 (preparation of compound ZED3632). Yield: 44 mg, 51% (last step) ESI-MS: 642.4 [M+H]+ 113 Preparation of compound II-122
Figure imgf000197_0001
The synthesis of compound II-122 was performed according to compound II-2, using phenyl isocyanide instead of methyl isocyanide in step 4 (preparation of compound ZED3632). Yield: 37 mg, 56% (last step) ESI-MS: 678.4 [M+H]+ 114 Preparation of compound II-123
Figure imgf000197_0002
The synthesis of compound II-123 was performed according to compound II-2, using benzyl isocyanide instead of methyl isocyanide in step 4 (preparation of compound ZED3632). Yield: 46 mg, 52% (last step) ESI-MS: 692.5 [M+H]+ 115 Preparation of compound II-124
Figure imgf000198_0001
Chemical Formula: C32H35N5O7 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-yl)-5-oxohexanediamide The synthesis of compound II-124 was performed according to compound II-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]+ 116 Preparation of compound II-125
Figure imgf000198_0002
The synthesis of compound II-125 was performed according to compound II-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]+ 117 Preparation of compound II-126
Figure imgf000199_0001
The synthesis of compound II-126 was performed according to compound II-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]+ 118 Preparation of compound II-127
Figure imgf000199_0002
The synthesis of compound II-127 was performed according to compound II-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]+ 119 Preparation of compound II-128
Figure imgf000200_0001
Chemical Formula: C26H29Cl2N5O6S Exact Mass: 609.12 Molecular Weight: 610.51 (2S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2- dihydropyridin-3-yl)-2-(2,5-dichlorothiophene-3-carboxamido)-N6-methyl-5-oxohexanediamide The synthesis of compound II-128 was performed according to compound II-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]+ 120 Preparation of compound II-129
Figure imgf000200_0002
The synthesis of compound II-129 was performed according to compound II-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]+ 121 Preparation of compound II-130
Figure imgf000201_0001
The synthesis of compound II-130 was performed according to compound II-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]+ Example III. Synthetic method III Scheme III-1
Figure imgf000201_0002
Figure imgf000201_0003
1 Preparation of compound
Figure imgf000201_0004
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 HCl (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
Figure imgf000202_0001
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-(3ʹ-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 200 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
Figure imgf000202_0002
24.2 g (73.0 mmol) of ZED3905 were suspended in 600 mL MeOH 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]+ Scheme III-2
Figure imgf000203_0001
Scheme III-3
Figure imgf000204_0001
Preparation of compound ZED788
Figure imgf000204_0002
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 with 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
Figure imgf000205_0001
13.4 g of ZED788 ( ^39,6 mmol) and 986 mg of N,N-dimethyl-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 with 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
Figure imgf000205_0002
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
Figure imgf000206_0001
13.3 g of ZED721 ( ^32.8 mmol) were dissolved in 60 ml of benzene and 11.2 g of (carbomethoxymethylene)triphenylphosphorane (1 eq) was added portionwise. After stirring overnight, the solvent was evaporated. The residue was purified by flash chromatography. Yield: 12.0 g, 83% ESI-MS: 444.3 [M+H]+ Preparation of compound Ib
Figure imgf000206_0002
12.0 g of ZED755 (27.1 mmol) are dissolved in 100 ml DCM/TFA (1:1) and stirred at room temperature for 1 h. The solvent was evaporated, and the residue was dissolved in 100 ml DMF and 9.23 ml DIPEA (2 eq). 7.15 g of N-(tert- butoxycarbonyloxy)succinimide were added and the reaction was stirred at room temperature overnight. The solvent was evaporated, and the residue was dissolved in ethyl acetate and washed with 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: 5.89 g, 76% ESI-MS: 288.3 [M+H]+ 5 4 Preparation of compound ZED4198
Figure imgf000207_0001
1.67 g (5.80 mmol) of (S,E)-2-(tert-butoxycarbonylamino)-7-methoxy-7-oxohept-5-enoic acid, 2.21 g (1 eq) HATU and 1.75 g (1 eq) ZED3906 were dissolved in 25 mL DMF and 1.97 mL DIPEA (2 eq) and stirred at 45°C overnight. The solvent was evaporated; the residue was dissolved in 100 mL EtOAc and washed twice with each 30 mL citric acid solution (10%), NaHCO3 solution (10%) and brine. The organic phase was dried over Na2SO4, filtered and the solvent was evaporated. Yield: 1.65 g, 50% ESI-MS: 571.4 [M+H]+ 5 Preparation of compound III-1
Figure imgf000207_0002
200 mg (0.35 mmol) of ZED4198 were dissolved in 6 ml DCM/TFA (1:1) and stirred at room temperature for 1 h. The solvent was evaporated, and the residue was dissolved in 9 ml DMF. 44.2 mg (1 eq) 1-methyl-1H-imidazole-5-carboxylic acid, 133 mg (1 eq) HATU and 119 µl (2 eq) DIPEA were added, and the reaction was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by HPLC. Yield: 165 mg, 81% ESI-MS: 579.4 [M+H]+ 1H-NMR (DMSO-D6, 500 MHz, ^ [ppm]: 1.50 // 2.00 (d // d, 2H // 2H, adamantyl- C4-H2), 1.70 // 1.80 (m, 4H, adamantyl-C4-H2), 1.78 (m, 2H, adamantyl-C1-H), 1.78 (m, 2H, adamantyl-C6-H2), 1.80 (m, 2H, adamantyl-C5-H), 1.90 // 2.03 (m // m, 1H // 1H, ^-CH2), 2.32 (m, 2H, ^-CH2), 3.62 (s, 3H, O-CH3), 3.79 (s, 3H, imidazole-N-CH3), 3.83 (m, 1H, adamantyl-C2-H), 4.58 (ddd, 1H, ^-CH2), 4.66 (s, 2H, N-CH2), 5.85 (m, 1H, =CH-), 6.25 (t, 1H, pyridinone-C5-H), 6.92 (m, 1H, =CH-), 7.33 (d, 1H, pyridinone-C6-H), 7.72 (s, 1H, imidazole-CH), 7.77 (s, 1H, imidazole-CH), 8.09 (d, 1H, adamantyl-NH), 8.21 (d, 1H, pyridinone-C4-H), 8.61 (d, 1H, ^ ^-NH), 9.25 (s, 1H, pyridinone-NH). 13C-NMR (DMSO-D6, 500 MHz, ^ [ppm]: 26.70 // 26.64 (adamantyl-C5-H), 28.44 ( ^ -CH2), 29.10 ( ^-CH2), 30.92 (adamantyl-C4-H2), 31.44 (adamantyl-C1-H), 33.46 (imidazole-N-CH3), 36.74 (adamantyl-C4’-H2), 37.09 (adamantyl-C6-H2), 51.14 (O-CH3), 51.62 (N-CH2), 53.07 ( ^ -CH2), 53.32 (adamantyl-C2-H), 104.59 (pyridinone-C5-H), 121.04 (=CH-), 122.30 (pyridinone-C4-H), 125.06 (imidazole- Cq), 127.90 (pyridinone-N-Cq), 132.78 (imidazole-CH), 133.26 (pyridinone-C6- H), 142.18 (imidazole-CH), 148.54 (=CH-), 156.60 (pyridinone-C=O), 160.24 (imidazole-C=O), 165.71 (C=O-adamantylamide), 165.98 (Cq methyl ester), 170.69 (C=O-NH-pyridinone). 6 Preparation of compound III-2
Figure imgf000208_0001
The synthesis of compound III-2 was performed according to compound III-1, using 3- methylbenzo[b]furan-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 101 mg, 75% (last step) ESI-MS: 629.4 [M+H]+ 7 Preparation of compound III-3
Figure imgf000209_0001
(S,E)-methyl 6-(3-chlorobenzofuran-2-carboxamido)-7-(1-(2-(2-adamantylamino)- 2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxohept-2-enoate Chemical Formula: C34H37ClN4O7 Exact Mass: 648.24 Molecular Weight: 649.13 The synthesis of compound III-3 was performed according to compound III-1, using 3- chlorobenzofuran-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 214 mg, 82% (last step) ESI-MS: 649.3 / 651.3 [M+H]+ 8 Preparation of compound III-4
Figure imgf000209_0002
The synthesis of compound III-4 was performed according to compound III-1, using 4- bromo-1-benzofuran-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 104 mg, 76% (last step) ESI-MS: 693.3 / 695.3 [M+H]+ 9 Preparation of compound III-5
Figure imgf000210_0001
The synthesis of compound III-5 was performed according to compound III-1, using benzo[b]thiophene-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 356 mg, 85% (last step) ESI-MS: 631.3 [M+H]+ 10 Preparation of compound III-6
Figure imgf000210_0002
The synthesis of compound III-6 was performed according to compound III-1, using 5- bromobenzo[b]thiophene-2-carboxylic acid instead of 1-methyl-1H-imidazole-5- carboxylic acid in the final step. Yield: 102 mg, 70% (last step) ESI-MS: 709.2 / 711.2 [M+H]+ 11 Preparation of compound III-7
Figure imgf000211_0001
The synthesis of compound III-7 was performed according to compound III-1, using 7- fluorobenzo[b]thiophene-2-carboxylic acid instead of 1-methyl-1H-imidazole-5- carboxylic acid in the final step. Yield: 56 mg, 68% (last step) ESI-MS: 649.3 [M+H]+ 12 Preparation of compound III-8
Figure imgf000211_0002
The synthesis of compound III-8 was performed according to compound III-1, using 1H- indole-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 79 mg, 76% (last step) ESI-MS: 614.4 [M+H]+ 13 Preparation of compound III-9
Figure imgf000212_0001
The synthesis of compound III-9 was performed according to compound III-1, using 4,5- difluoro-1H-indole-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 43 mg, 76% (last step) ESI-MS: 650.3 [M+H]+ 14 Preparation of compound III-10
Figure imgf000212_0002
The synthesis of compound III-10 was performed according to compound III-1, using 3- methyl-1H-indole-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 73 mg, 82% (last step) ESI-MS: 628.4 [M+H]+ 15 Preparation of compound III-11
Figure imgf000213_0001
The synthesis of compound III-11 was performed according to compound III-1, using 1H-benzo[d]imidazole-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 22 mg, 41% (last step) ESI-MS: 615.4 [M+H]+ 16 Preparation of compound III-12
Figure imgf000213_0002
The synthesis of compound III-12 was performed according to compound III-1, using 2,3-dihydro-1H-indene-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 51 mg, 75% (last step) ESI-MS: 615.4 [M+H]+ 17 Preparation of compound III-13
Figure imgf000214_0001
The synthesis of compound III-13 was performed according to compound III-1, using 2,5-dichlorothiophene-3-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 78 mg, 71% (last step) ESI-MS: 649.3 / 651.3 [M+H]+ 18 Preparation of compound III-14
Figure imgf000214_0002
The synthesis of compound III-14 was performed according to compound III-1, using 4- methyl-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5- carboxylic acid in the final step. Yield: 52 mg, 67% (last step) ESI-MS: 664.4 [M+H]+ 19 Preparation of compound III-15
Figure imgf000215_0001
The synthesis of compound III-15 was performed according to compound III-1, using 3,5-dibromothiophene-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 143 mg, 86% (last step) ESI-MS: 737.2 / 739.2 / 741.2 [M+H]+ 20 Preparation of compound III-16
Figure imgf000215_0002
The synthesis of compound III-16 was performed according to compound III-1, using 2,5-dibromothiophene-3-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 107 mg, 65% (last step) ESI-MS: 737.2 / 739.2 / 741.2 [M+H]+ 21 Preparation of compound III-17
Figure imgf000216_0001
The synthesis of compound III-17 was performed according to compound III-1, using 5- bromothiophene-3-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 89 mg, 80% (last step) ESI-MS: 659.2 / 661.2 [M+H]+ 22 Preparation of compound III-18
Figure imgf000216_0002
(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 Chemical Formula: C30H35BrN4O6S Exact Mass: 658.15 Molecular Weight: 659.59 The synthesis of compound III-18 was performed according to compound III-1, using 4- bromothiophene-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 143 mg, 76% (last step) ESI-MS: 659.2 / 661.2 [M+H]+ 23 Preparation of compound III-19
Figure imgf000217_0001
The synthesis of compound III-19 was performed according to compound III-1, using 4,5-dibromothiophene-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 57 mg, 64% (last step) ESI-MS: 737.2 / 739.2 / 741.2 [M+H]+ 24 Preparation of compound III-20
Figure imgf000217_0002
The synthesis of compound III-20 was performed according to compound III-1, using 4,5-dichlorothiophene-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 78 mg, 73% (last step) ESI-MS: 649.3 / 651.3 / 653.3 [M+H]+ 25 Preparation of compound III-21
Figure imgf000218_0001
The synthesis of compound III-21 was performed according to compound III-1, using (S)-1-acetylpyrrolidine-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 114 mg, 86% (last step) ESI-MS: 610.4 [M+H]+ 26 Preparation of compound III-22
Figure imgf000218_0002
(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 Chemical Formula: C29H37N7O6 Exact Mass: 579.28 Molecular Weight: 579.65 The synthesis of compound III-22 was performed according to compound III-1, using 1- methyl-1H-1,2,3-triazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5- carboxylic acid in the final step. Yield: 45 mg, 59% (last step) ESI-MS: 580.4 [M+H]+ 27 Preparation of compound III-23
Figure imgf000219_0001
(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 Chemical Formula: C27H34N8O6 Exact Mass: 566.26 Molecular Weight: 566.61 The synthesis of compound III-23 was performed according to compound III-1, using 2H-tetrazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 42 mg, 57% (last step) ESI-MS: 567.4 [M+H]+ 28 Preparation of compound III-24
Figure imgf000219_0002
(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 Chemical Formula: C30H36N6O6 Exact Mass: 576.27 Molecular Weight: 576.64 The synthesis of compound III-24 was performed according to compound III-1, using pyrazine-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 54 mg, 68% (last step) ESI-MS: 577.3 [M+H]+ 29 Preparation of compound III-25
Figure imgf000220_0001
(S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin- 3-ylamino)-6-((S)-1-methylpyrrolidine-2-carboxamido)-7-oxohept-2-enoate Chemical Formula: C31H43N5O6 Exact Mass: 581.32 Molecular Weight: 581.70 The synthesis of compound III-25 was performed according to compound III-1, using (S)-1-methylpyrrolidine-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 85 mg, 79% (last step) ESI-MS: 582.4 [M+H]+ 30 Preparation of compound III-26
Figure imgf000220_0002
(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 Chemical Formula: C30H41N5O6 Exact Mass: 567.31 Molecular Weight: 567.68 The synthesis of compound III-26 was performed according to compound III-1, using (S)-1-Boc-pyrrolidine-3-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: 78 mg, 93% (last step) ESI-MS: 568.4 [M+H]+ 31 Preparation of compound III-27
Figure imgf000221_0001
(S,E)-methyl 6-((2S,4S)-4-bromopyrrolidine-2-carboxamido)-7-(1-(2-(2-adamantylamino)- 2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-7-oxohept-2-enoate Chemical Formula: C30H40BrN5O6 Exact Mass: 645.22 Molecular Weight: 646.57 The synthesis of compound III-27 was performed according to compound III-1, using (2S,4S)-1-Boc-4-bromopyrrolidine-2-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: 56 mg, 89% (last step) ESI-MS: 646.3 / 648.3 [M+H]+ 32 Preparation of compound III-28
Figure imgf000221_0002
The synthesis of compound III-28 was performed according to compound III-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, 86% (last step) ESI-MS: 565.3 [M+H]+ 33 Preparation of compound III-29
Figure imgf000222_0001
The synthesis of compound III-29 was performed according to compound III-1, using (S)-1-Boc-piperidine-2-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: 108 mg, 94% (last step) ESI-MS: 582.4 [M+H]+ 34 Preparation of compound III-30
Figure imgf000222_0002
(S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin- 3-ylamino)-7-oxo-6-((R)-piperidine-3-carboxamido)hept-2-enoate Chemical Formula: C31H43N5O6 Exact Mass: 581.32 Molecular Weight: 581.70 The synthesis of compound III-30 was performed according to compound III-1, using (R)-1-Boc-piperidine-3-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: 68 mg, 87% (last step) ESI-MS: 582.4 [M+H]+ 35 Preparation of compound III-31
Figure imgf000223_0001
(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 Chemical Formula: C30H41N5O7 Exact Mass: 583.30 Molecular Weight: 583.68 The synthesis of compound III-31 was performed according to compound III-1, using (R)-4-Boc-morpholine-3-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: 73 mg, 90% (last step) ESI-MS: 584.4 [M+H]+ 36 Preparation of compound III-32
Figure imgf000223_0002
(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 Chemical Formula: C33H45N5O6 Exact Mass: 607.34 Molecular Weight: 607.74 The synthesis of compound III-32 was performed according to compound III-1, using quinuclidine-3-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 23 mg, 71% (last step) ESI-MS: 608.4 [M+H]+ 37 Preparation of compound III-33
Figure imgf000224_0001
The synthesis of compound III-33 was performed according to compound III-1, using mono-methyl 5-nitroisophthalate instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 68 mg, 86% (last step) ESI-MS: 678.3 [M+H]+ 38 Preparation of compound III-34
Figure imgf000224_0002
(S,E)-methyl 7-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin- 3-ylamino)-6-(5-nitronicotinamido)-7-oxohept-2-enoate Chemical Formula: C31H36N6O8 Exact Mass: 620.26 Molecular Weight: 620.65 The synthesis of compound III-34 was performed according to compound III-1, using 5- nitronicotinic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 54 mg, 75% (last step) ESI-MS: 621.3 [M+H]+
Figure imgf000225_0001
The synthesis of compound III-35 was performed according to compound III-1, using 3,5-pyridinedicarboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 28 mg, 63% (last step) ESI-MS: 620.3 [M+H]+ 40 Preparation of compound III-36
Figure imgf000225_0002
The synthesis of compound III-36 was performed according to compound III-1, using 5- (methoxycarbonyl)nicotinic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 48 mg, 77% (last step) ESI-MS: 634.3 [M+H]+ 41 Preparation of compound III-37
Figure imgf000226_0001
The synthesis of compound III-37 was performed according to compound III-2, using N-methyl-2-adamantanamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 42 mg, 47% (last step) ESI-MS: 643.4 [M+H]+ 42 Preparation of compound III-38
Figure imgf000226_0002
The synthesis of compound III-38 was performed according to compound III-2, using 5- hydroxy-2-adamantanamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 35 mg, 24% (last step) ESI-MS: 645.4 [M+H]+ 43 Preparation of compound III-39
Figure imgf000227_0001
The synthesis of compound IIII-39 was performed according to compound IIII-2, using 5-fluoro-2-adamantanamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 64 mg, 68% (last step) ESI-MS: 647.4 [M+H]+ 44 Preparation of compound III-40
Figure imgf000227_0002
The synthesis of compound III-40 was performed according to compound III-2, using 5- chloro-2-adamantanamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 32 mg, 27% (last step) ESI-MS: 663.3 / 665.3 [M+H]+ 45 Preparation of compound III-41
Figure imgf000228_0001
The synthesis of compound III-41 was performed according to compound III-2, using 5- bromo-2-adamantanamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 41 mg, 57% (last step) ESI-MS: 707.3 / 709.3 [M+H]+ 46 Preparation of compound III-42
Figure imgf000228_0002
The synthesis of compound III-42 was performed according to compound III-2, using 5- methyl-2-adamantanamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 51 mg, 47% (last step) ESI-MS: 643.4 [M+H]+ 47 Preparation of compound III-43
Figure imgf000229_0001
The synthesis of compound III-43 was performed according to compound III-2, using 2- aminoadamantane-2-carbonitrile instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 36 mg, 52% (last step) ESI-MS: 654.4 [M+H]+ 48 Preparation of compound III-44
Figure imgf000229_0002
The synthesis of compound III-44 was performed according to compound III-2, using 2- methyl 2-aminoadamantane-2-carboxylate instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 49 mg, 68% (last step) ESI-MS: 687.4 [M+H]+ 49 Preparation of compound III-45
Figure imgf000230_0001
The synthesis of compound III-45 was performed according to compound III-2, using 1- adamantanamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 214 mg, 77% (last step) ESI-MS: 629.4 [M+H]+ 50 Preparation of compound III-46
Figure imgf000230_0002
The synthesis of compound III-46 was performed according to compound III-2, using 3,5-dimethyl-1-adamantanamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 67 mg, 77% (last step) ESI-MS: 657.4 [M+H]+ 51 Preparation of compound III-47
Figure imgf000231_0001
The synthesis of compound III-47 was performed according to compound III-2, using N- methyl-1-adamantanamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 36 mg, 41% (last step) ESI-MS: 643.4 [M+H]+ 52 Preparation of compound III-48
Figure imgf000231_0002
The synthesis of compound III-48 was performed according to compound III-2, using 3- ethyl-1-adamantanamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 78 mg, 54% (last step) ESI-MS: 657.4 [M+H]+
Figure imgf000232_0001
The synthesis of compound III-49 was performed according to compound III-2, using 3- trifluoromethyl-1-adamantanamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 29 mg, 45% (last step) ESI-MS: 697.4 [M+H]+ 54 Preparation of compound III-50
Figure imgf000232_0002
The synthesis of compound III-50 was performed according to compound III-2, using 3- hydroxy-1-adamantanamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 23 mg, 37% (last step) ESI-MS: 645.4 [M+H]+ 55 Preparation of compound III-51
Figure imgf000233_0001
The synthesis of compound III-51 was performed according to compound III-2, using 3- fluoro-1-adamantanamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 56 mg, 62% (last step) ESI-MS: 647.4 [M+H]+ 56 Preparation of compound III-52
Figure imgf000233_0002
The synthesis of compound III-52 was performed according to compound III-2, using 3- chloro-1-adamantanamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 24 mg, 32% (last step) ESI-MS: 663.3 / 665.3 [M+H]+ 57 Preparation of compound III-53
Figure imgf000234_0001
The synthesis of compound III-53 was performed according to compound III-2, using 3- bromo-1-adamantanamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 25 mg, 42% (last step) ESI-MS: 707.3 / 709.3 [M+H]+ 58 Preparation of compound III-54
Figure imgf000234_0002
The synthesis of compound III-54 was performed according to compound III-2, using methyl 3-aminoadamantane-1-carboxylate instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 38 mg, 52% (last step) ESI-MS: 687.4 [M+H]+ 59 Preparation of compound III-55
Figure imgf000235_0001
The synthesis of compound III-55 was performed according to compound III-2, using 4,4-difluoro-1-adamantanamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 11 mg, 36% (last step) ESI-MS: 665.4 [M+H]+ 60 Preparation of compound III-56
Figure imgf000235_0002
The synthesis of compound III-56 was performed according to compound III-2, using 1- adamantanemethylamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 47 mg, 68% (last step) ESI-MS: 643.4 [M+H]+ 61 Preparation of compound III-57
Figure imgf000236_0001
The synthesis of compound III-57 was performed according to compound III-2, using 1- rimantadine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 23 mg, 35% (last step) ESI-MS: 644.4 [M+H]+ 62 Preparation of compound III-58
Figure imgf000236_0002
The synthesis of compound III-58 was performed according to compound III-1, using (±)-endo-2-norbornylamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 36 mg, 53% (last step) ESI-MS: 539.4 [M+H]+ 63 Preparation of compound III-59
Figure imgf000237_0001
The synthesis of compound III-59 was performed according to compound III-2, using (±)-endo-2-norbornylamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 56 mg, 69% (last step) ESI-MS: 589.4 [M+H]+ 64 Preparation of compound III-60
Figure imgf000237_0002
The synthesis of compound III-60 was performed according to compound III-1, using (R)-(+)-bornylamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 25 mg, 49% (last step) ESI-MS: 581.5 [M+H]+ 65 Preparation of compound III-61
Figure imgf000238_0001
The synthesis of compound III-61 was performed according to compound III-2, using (R)-(+)-bornylamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 42 mg, 63% (last step) ESI-MS: 631.5 [M+H]+ 66 Preparation of compound III-62
Figure imgf000238_0002
The synthesis of compound III-62 was performed according to compound III-1, using exo-2-aminonorbornane instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 56 mg, 64% (last step) ESI-MS: 539.4 [M+H]+ 67 Preparation of compound III-63
Figure imgf000239_0001
(S,E)-methyl 7-(1-(2-((1R,2R,4S)-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 Chemical Formula: C32H36N4O7 Exact Mass: 588.26 Molecular Weight: 588.65 The synthesis of compound III-63 was performed according to compound III-2, using exo-2-aminonorbornane instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 78 mg, 71% (last step) ESI-MS: 589.4 [M+H]+ 68 Preparation of compound III-64
Figure imgf000239_0002
The synthesis of compound III-64 was performed according to compound III-2, using bicyclo[2.2.1]heptan-1-ylamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 27 mg, 52% (last step) ESI-MS: 589.4 [M+H]+ 69 Preparation of compound III-65
Figure imgf000240_0001
The synthesis of compound III-65 was performed according to compound III-2, using bicyclo[2.2.1]heptan-7-ylamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 52 mg, 75% (last step) ESI-MS: 589.4 [M+H]+ 70 Preparation of compound III-66
Figure imgf000240_0002
The synthesis of compound III-66 was performed according to compound III-2, using bicyclo[2.2.1]hept-5-en-2-amine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 36 mg, 54% (last step) ESI-MS: 587.4 [M+H]+ 71 Preparation of compound III-67
Figure imgf000241_0001
The synthesis of compound III-67 was performed according to compound III-2, using bicyclo[2.2.2]oct-2-ylamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 42 mg, 51% (last step) ESI-MS: 603.4 [M+H]+ 72 Preparation of compound III-68
Figure imgf000241_0002
The synthesis of compound III-68 was performed according to compound III-2, using (R)-(−)-isobornylamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 26 mg, 56% (last step) ESI-MS: 631.5 [M+H]+ 73 Preparation of compound III-69
Figure imgf000242_0001
(S,E)-methyl 6-(3-methylbenzofuran-2-carboxamido)-7-oxo-7-(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-ylamino)hept-2-enoate Chemical Formula: C35H42N4O7 Exact Mass: 630.31 Molecular Weight: 630.73 The synthesis of compound III-69 was performed according to compound III-2, using (1R,2R,3R,5S)-(−)-isopinocampheylamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 15 mg, 48% (last step) ESI-MS: 631.5 [M+H]+ 74 Preparation of compound III-70
Figure imgf000242_0002
The synthesis of compound III-70 was performed according to compound III-2, using (1S,2S,3S,5R)-(+)-isopinocampheylamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 21 mg, 58% (last step) ESI-MS: 631.5 [M+H]+ 75 Preparation of compound III-71
Figure imgf000243_0001
The synthesis of compound III-71 was performed according to compound III-2, using (−)-cis-myrtanylamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 12 mg, 45% (last step) ESI-MS: 631.5 [M+H]+ 76 Preparation of compound III-72
Figure imgf000243_0002
The synthesis of compound III-72 was performed according to compound III-2, using 3- amino-4-homoisotwistane instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 23 mg, 59% (last step) ESI-MS: 643.5 [M+H]+ 77 Preparation of compound III-73
Figure imgf000244_0001
The synthesis of compound III-73 was performed according to compound III-2, using 1- aminodiamantane instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 26 mg, 62% (last step) ESI-MS: 681.5 [M+H]+ 78 Preparation of compound III-74
Figure imgf000244_0002
The synthesis of compound III-74 was performed according to compound III-2, using 4- aminodiamantane instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 17 mg, 53% (last step) ESI-MS: 681.5 [M+H]+ Scheme III-4
Figure imgf000245_0001
Figure imgf000245_0003
79 Preparation of ZED4684
Figure imgf000245_0002
2.5 mL (24.3 mmol) of 2-chloro-N,N-dimethylacetamide and 4.2 mL (1 eq) of triethyl phosphite were stirred at 160°C for 8 h. The mixture was purified by HPLC. Yield: 2.50 g, 46% ESI-MS: 224.4 [M+H]+ 80 Preparation of ZED4688
Figure imgf000246_0001
500 mg (2.24 mmol) of ZED4684 were dissolved in 16 mL THF. At 0°C, 251 mg (2.24 mmol) of potassium tert-butoxide were added. After 30 min, 723 mg (1.87 mmol) of the aldehyde (S)-tert-butyl 2-(bis(tert-butoxycarbonyl)amino)-5-oxopentanoate (ZED721) in 16 mL THF were added and the mixture was stirred at 0°C for 1.5 h before being quenched with water (16 mL, 0°C). After extraction with EtOAc (2 x 32 mL), the combined organic phases were washed with brine (15 mL), dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by HPLC. Yield: 659 mg, 77% ESI-MS: 457.5 [M+H]+ 81 Preparation of ZED4690
Figure imgf000246_0002
659 mg of ZED4688 (1.44 mmol) were dissolved in 20 ml DCM/TFA (1:1) and stirred at room temperature for 1 h. The solvent was evaporated, and the residue was dissolved in 10 ml DMF and 245 µl DIPEA (2 eq). 310 mg (1 eq) of N-(tert- butoxycarbonyloxy)succinimide were added and the reaction was stirred at room temperature overnight. The solvent was evaporated and the residue was dissolved in ethyl acetate and washed with 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 HPLC. Yield: 242 mg, 56% ESI-MS: 301.5 [M+H]+ 82 Preparation
Figure imgf000247_0001
242 mg (0.81 mmol) of ZED4688, 308 mg (1 eq) HATU and 244 mg (1 eq) ZED3906 were dissolved in 10 mL DMF and 276 µL DIPEA (2 eq) and stirred at 45°C overnight. The solvent was evaporated; the residue was dissolved in 50 mL EtOAc and washed twice 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. The residue was purified by HPLC. Yield: 288 mg, 61% ESI-MS: 584.4 [M+H]+ 83 Preparation of compound III-75
Figure imgf000247_0002
100 mg (0.17 mmol) of ZED4692 were dissolved in 6 ml DCM/TFA (1:1) and stirred at room temperature for 1 h. The solvent was evaporated, and the residue was dissolved in 15 ml DMF and 58 µl DIPEA (2 eq). 30 mg (1 eq) of 3-methylbenzo[b]furan-2- carboxylic acid and 65 mg (1 eq) of HATU were added, and the reaction was stirred at room temperature overnight. The solvent was evaporated; the residue was purified by HPLC. Yield: 78 mg, 71% ESI-MS: 642.5 [M+H]+ 84 Preparation of compound III-76
Figure imgf000248_0001
The synthesis of compound III-76 was performed according to compound III-75, using 1-methyl-1H-imidazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in the final step. Yield: 70 mg, 69% (last step) ESI-MS: 592.5 [M+H]+ 85 Preparation of compound III-77
Figure imgf000248_0002
The synthesis of compound III-77 was performed according to compound III-75, using 3,5-dimethyl-1-adamantanamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 45 mg, 57% (last step) ESI-MS: 670.5 [M+H]+
Figure imgf000249_0001
86 Preparation of compound ZED4893
Figure imgf000249_0002
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 EtOAc 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]+ 87 Preparation of compound ZED4894
Figure imgf000249_0003
484 mg (1.68 mmol) of ZED4893 were suspended in 30 mL MeOH 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]+ 88 Preparation of compound III-78
Figure imgf000250_0001
The synthesis of compound III-78 was performed according to compound III-1, using ZED4894 instead of ZED3906 in step 5 (according to ZED3907). Yield: 43 mg, 59% (last step) ESI-MS: 536.4 [M+H]+ 89 Preparation of compound III-79
Figure imgf000250_0002
The synthesis of compound III-79 was performed according to compound III-2, using ZED4894 instead of ZED3906 in step 5 (according to ZED3907). Yield: 56 mg, 69% (last step) ESI-MS: 586.4 [M+H]+ 90 Preparation of compound III-80
Figure imgf000251_0001
The synthesis of compound III-80 was performed according to compound III-79, using 3-(bromomethyl)-1-adamantanol instead of 1-(bromomethyl)adamantane (according to ZED4893). Yield: 29 mg, 51% (last step) ESI-MS: 602.4 [M+H]+ 91 Preparation of compound III-81
Figure imgf000251_0002
(6S,E)-methyl 7-(1-((3-bromo-1-adamantyl)methyl)-2-oxo-1,2-dihydropyridin- 3-ylamino)-6-(3-methylbenzofuran-2-carboxamido)-7-oxohept-2-enoate Chemical Formula: C34H38BrN3O6 Exact Mass: 663.19 Molecular Weight: 664.59 The synthesis of compound III-81 was performed according to compound III-79, using 1-bromo-3-(bromomethyl)adamantane instead of 1-(bromomethyl)adamantane (according to ZED4893). Yield: 37 mg, 61% (last step) ESI-MS: 664.3 / 666.3 [M+H]+ 92 Preparation of compound III-82
Figure imgf000252_0001
The synthesis of compound III-82 was performed according to compound III-79, using 2-(bromomethyl)adamantane instead of 1-(bromomethyl)adamantane (according to ZED4893). Yield: 58 mg, 77% (last step) ESI-MS: 586.4 [M+H]+ 93 Preparation of compound III-83
Figure imgf000252_0002
The synthesis of compound III-83 was performed according to compound III-1, using nicotinic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in the final step. Yield: 59 mg, 79% (last step) ESI-MS: 576.4 [M+H]+ 94 Preparation of compound III-84
Figure imgf000253_0001
The synthesis of compound III-84 was performed according to compound III-1, using isonicotinic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in the final step. Yield: 73 mg, 85% (last step) ESI-MS: 576.4 [M+H]+ 95 Preparation of compound III-85
Figure imgf000253_0002
The synthesis of compound III-85 was performed according to compound III-1, using pyridazine-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in the final step. Yield: 54 mg, 78% (last step) ESI-MS: 577.4 [M+H]+ 96 Preparation of compound III-86
Figure imgf000254_0001
The synthesis of compound III-86 was performed according to compound III-1, using pyridazine-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in the final step. Yield: 47 mg, 82% (last step) ESI-MS: 577.4 [M+H]+ 97 Preparation of compound III-87
Figure imgf000254_0002
The synthesis of compound III-87 was performed according to compound III-1, using 1- adamantanamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 117 mg, 78% (last step) ESI-MS: 579.5 [M+H]+ 98 Preparation of compound III-88
Figure imgf000255_0001
The synthesis of compound III-88 was performed according to compound III-1, using 3,5-dimethyl-1-adamantanamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 132 mg, 83% (last step) ESI-MS: 607.5 [M+H]+ 99 Preparation of compound III-89
Figure imgf000255_0002
The synthesis of compound III-89 was performed according to compound III-2, using (carbethoxyethylidene)triphenylphosphorane instead of (carbomethoxymethylene) triphenylphosphorane (according to ZED755). Yield: 57 mg, 85% (last step) ESI-MS: 643.5 [M+H]+ 100 Preparation of compound III-90
Figure imgf000256_0001
The synthesis of compound III-90 was performed according to compound III-2, using diethyl (methanesulfonylmethyl)phosphonate instead of (carbomethoxymethylene)triphenylphosphorane (according to ZED755). Yield: 79 mg, 72% (last step) ESI-MS: 649.4 [M+H]+ 101 Preparation of compound III-91
Figure imgf000256_0002
The synthesis of compound III-91 was performed according to compound III-1, using 3,5,7-trimethyl-1-adamantanamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 41 mg, 69% (last step) ESI-MS: 621.5 [M+H]+ 102 Preparation of compound III-92
Figure imgf000257_0001
The synthesis of compound III-92 was performed according to compound III-2, using 3,5,7-trimethyl-1-adamantanamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 67 mg, 75% (last step) ESI-MS: 671.5 [M+H]+ 103 Preparation of compound III-93
Figure imgf000257_0002
The synthesis of compound III-93 was performed according to compound III-22, using 3,5,7-trimethyl-1-adamantanamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 34 mg, 68% (last step) ESI-MS: 622.5 [M+H]+ 104 Preparation of compound III-94
Figure imgf000258_0001
The synthesis of compound III-94 was performed according to compound III-13, using 3,5,7-trimethyl-1-adamantanamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 69 mg, 88% (last step) ESI-MS: 691.3 / 693.3 [M+H]+ 105 Preparation of compound III-95
Figure imgf000258_0002
The synthesis of compound III-95 was performed according to compound III-14, using 3,5,7-trimethyl-1-adamantanamine instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 35 mg, 64% (last step) ESI-MS: 706.4 [M+H]+ 106 Preparation of compound III-96
Figure imgf000259_0001
The synthesis of compound III-96 was performed according to compound III-22, using exo-2-aminonorbornane instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 24 mg, 64% (last step) ESI-MS: 540.4 [M+H]+ 107 Preparation of compound III-97
Figure imgf000259_0002
The synthesis of compound III-97 was performed according to compound III-13, using exo-2-aminonorbornane instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 78 mg, 84% (last step) ESI-MS: 609.3 / 611.3 [M+H]+ 108 Preparation of compound III-98
Figure imgf000260_0001
The synthesis of compound III-98 was performed according to compound III-14, using exo-2-aminonorbornane instead of 2-adamantanamine in step 2 (preparation of compound ZED3905). Yield: 48 mg, 68% (last step) ESI-MS: 624.3 [M+H]+ 109 Preparation of compound III-99
Figure imgf000260_0002
The synthesis of compound III-99 was performed according to compound III-89, using 1-methyl-1H-imidazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in the final step. Yield: 68 mg, 79% (last step) ESI-MS: 593.5 [M+H]+ 110 Preparation of compound III-100
Figure imgf000261_0001
The synthesis of compound III-100 was performed according to compound III-90, using 1-methyl-1H-imidazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in the final step. Yield: 46 mg, 73% (last step) ESI-MS: 599.4 [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 al., 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-HCl, 7.5 mM CaCl2, 150 mM NaCl, 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-HCl, 7.5 mM CaCl2, 150 mM NaCl, pH = 7.4) to yield the final working dilutions containing 2% (v/v) DMSO. 15 µl of inhibitor working dilution are added per well of a 96 well microtiter plate. As control, 15 µl of a 2% (v/v) DMSO solution prepared using the buffer mentioned above are added per well. Immediately before starting the assay, 600 µl transglutaminase working solution are added to 11.4 ml assay buffer (50 mM Tris-HCl, 10 mM CaCl2, 10 mM glutathione, 2.5% glycerol, 16.7 µM dansylcadaverine, 4 µM N,N-dimethylcasein, 200 mM NaCl, pH = 8.0).285 µl of this reaction mix are added per well containing the inhibitor. Increase in fluorescence is measured using λex = 330 nm and λem = 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 IC50 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. IC50 values are calculated by plotting the enzymatic activity (as percentage from control containing 2% DMSO instead of inhibitor) against the inhibitor concentration. IC50 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 tables 1, 2 and 3 using IC50-values. Table 1. efficacy of reversible TG2 inhibitors A: IC50 < 150 nM, B: 150 nM ≤ IC50 < 600 nM, C: IC50 ≥ 600 nM
Figure imgf000263_0001
Table 2. efficacy of reversible TG2 inhibitors A: IC50 < 40 nM, B: 40 nM ≤ IC50 < 400 nM, C: IC50 ≥ 400 nM
Figure imgf000264_0001
Figure imgf000265_0001
Figure imgf000266_0001
Figure imgf000267_0002
Figure imgf000267_0001
Table 3. efficacy of irreversible TG2 inhibitors A: IC50 < 25 nM, B: 25 nM < IC50 < 250 nM, C: IC50 ≥ 250 nM
Figure imgf000268_0001
Figure imgf000269_0001
Figure imgf000270_0002
Figure imgf000270_0001
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. 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. Table 4. logD values of reversible TG2 inhibitors A: logD < 1, B: 1 ≤ logD < 3, C: logD ≥ 3
Figure imgf000271_0001
Figure imgf000272_0001
Table 5. logD values of reversible TG2 inhibitors A: logD < 1, B: 1 ≤ logD < 3, C: logD ≥ 3
Figure imgf000272_0002
Figure imgf000273_0001
Figure imgf000274_0001
Figure imgf000275_0001
Table 6. logD values of irreversible TG2 inhibitors A: logD < 1, B: 1 ≤ logD < 3, C: logD ≥ 3
Figure imgf000275_0002
Figure imgf000276_0001
Figure imgf000277_0001
Figure imgf000278_0001
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 P values ab -6 app ove 1x10 cm/s are classified as permeable whereas compounds bearing P valu -6 app es below 1x10 cm/s are classified as not permeable. Table 7. Caco2 peremability assay of reversible TG2 inhibitors A: P < 1x10-6 cm/s, B: -6 app Papp ≥ 1x10 cm/s
Figure imgf000279_0001
Figure imgf000280_0001
Table 8. Caco2 peremability assay of reversible TG2 inhibitors A: P < 1x10-6 c -6 app m/s, B: Papp ≥ 1x10 cm/s
Figure imgf000280_0002
Figure imgf000281_0001
Figure imgf000282_0001
Figure imgf000283_0001
Table 9. Caco2 peremability assay of irreversible TG2 inhibitors A: P < 1x10-6 -6 app cm/s, B: Papp ≥ 1x10 cm/s
Figure imgf000283_0002
Figure imgf000284_0001
Figure imgf000285_0001
Figure imgf000286_0001

Claims

CLAIMS 1. A compound of the general formula (I):
Figure imgf000287_0002
wherein L represents –L1– or –L1-L2–; L1 represents –CH2–, –CH2CH2–, –CH2CH2CH2–, –CH2CO–, –CH2CH2CO–; L2 represents a bond, –NRN1–, –NRN1CH N1 2–, –NR CH2CH2–, or –NRN1CH(CH3)–;
Figure imgf000287_0003
, R2 represents
Figure imgf000287_0001
,
Figure imgf000288_0001
Figure imgf000289_0001
Figure imgf000290_0001
Figure imgf000291_0001
,
Figure imgf000292_0001
,
Figure imgf000293_0001
wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 – R13 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-homoisotwistanyl, adamantly, 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, –CO2C2H5, –CONH2, –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 –R5, –OR5 or –NR6R7; R5 represents –H, –CH3, –CH2CH3, –CH2CH2CH3, –CH(CH3)2,
Figure imgf000293_0002
–cyclo-C3H5, –cyclo-C4H7, –cyclo-C5H9, –cyclo-C6H11, –CH2–cyclo-C3H5, –CH2–cyclo-C4H7, –CH2–cyclo-C5H9, –CH2–cyclo-C6H11, –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-C3H5, –cyclo-C4H7, –cyclo-C5H9, –cyclo-C6H11, –CH2–cyclo-C3H5, –CH2–cyclo-C4H7, –CH2–cyclo- C5H9, –CH2–cyclo-C6H11, –CH2–Ph, –CH2OCH3, –CH2OCH2CH3, –CH2CH2OCH3, –CH2CH2OCH2CH3, –CH2CH2NHCH3, or –CH2CH2N(CH3)2, or –NR6R7 represents ,
Figure imgf000294_0001
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, ^CHF2, ^CF3, ^CH2Cl, ^CH2Br, ^CH2I, ^CH2 ^CH2F, ^CH2 ^CHF2, ^CH2 ^CF3, ^CH2 ^CH2Cl, ^CH2 ^CH2Br, ^CH2 ^CH2I, –OCH3, –OC2H5, –OC3H7, –OCH(CH3)2, –OC(CH3)3, –OC4H9, –OCHF2, –OCF3, −OCH2CF3, –OC2F5, −OCH2OCH3, –O-cyclo-C3H5, –OCH2-cyclo-C3H5, –O–C2H4-cyclo-C3H5, –CHO, –COCH3, –COCF3, –COC2H5, –COC3H7, –COCH(CH3)2, –COC(CH3)3, –COOH, –COOCH3, –COOC2H5, –COOC3H7, –COOCH(CH3)2, –COOC(CH3)3, –OOC–CH3, –OOC–CF3, –OOC–C2H5, –OOC–C3H7, –OOC–CH(CH3)2, –OOC–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, –NHCOCH(CH3)2, –NHCOC(CH3)3, –CONH2, –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,
Figure imgf000294_0002
or R8 and R9 or R9 and R10 can form together one of the following five- membered or six-membered rings: ,
Figure imgf000294_0003
or R12 and R13 or R13 and R14 can form together one of the following five- membered or six-membered rings;
Figure imgf000295_0001
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-C5H9, ^CH2 ^cyclo ^C3H5, ^CH2 ^cyclo-C4H7, ^CH2 ^cyclo-C5H9, ^CH2F, 3, ^CH2Cl, ^CH2Br, ^CH2I, ^CH2 ^CH2F, ^CH2 ^CHF2, CH2 ^CH2Cl, ^CH2 ^CH2Br, ^CH2 ^CH2I, ^CH2 ^CH=CH2, –CHO, –COCH3, –COC2H5, –COC3H7, –COCH(CH3)2, ^CO ^cyclo ^C3H5, ^CO ^cyclo-C4H7, ^CO ^cyclo-C5H9, –COOCH3, –COOC3H7, –COOCH(CH3)2, –COOC(CH3)3, –COOCH2Ph,
Figure imgf000295_0002
–SO2CF3, –SO2C2H5, –SO2C3H7, –SO2CH(CH3)2, –SO2 ^cyclo ^C3H5, or –SO2C(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
Figure imgf000295_0003
wherein L represents –L1–L2– ; L1 represents –CH2CO–, L2 represents –NRN1–, and R3 represents 1-adamantyl; or L2 represents –NRN1CH 3 2–, and R represents 2-bicyclo[3.3.1]heptyl, and the afore-mentioned 1-adamantly and 2-bicyclo[3.1.1]heptyl 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; ;
Figure imgf000296_0001
R6 represents ^C2H5; and R8, R10, R11 , Ra, Rb, Rc, Rd, Re , RN and RN1 have the same meanings as defined in claim 1. 3. The compound according to Claim 1 or 2 represented by formula (II):
Figure imgf000296_0002
wherein L2 represents –NRN1–, and R3 represents 1-adamantyl; or L2 represents –NRN1CH 3 2–, and R represents 2-bicyclo[3.
3.1]heptyl, and the afore-mentioned 1-adamantly and 2-bicyclo[3.1.1]heptyl 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; ;
Figure imgf000296_0003
, , 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, –CO2C2H5, –CONH2, –CONHCH3, –CON(CH3)2, –CONHC2H5, –CH2CO2H, –CH2CO2CH3, –CH2CO2C2H5, –CH2CONH2, –CH2CONHCH3, –CH2CON(CH3)2, –CH2CONHC2H5, –NHCOCH3, –NHCOC2H5, –NHCOCF3, –NHCOCH2CF3, –NHSO2CH3, –NHSO2C2H5, –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-C5H9, ^CH2 ^cyclo ^C3H5, ^CH2 ^cyclo-C4H7, ^CH2 ^cyclo-C5H9, ^CH2F, ^CHF2, ^CF3, ^CH2Cl, ^CH2Br, ^CH2I, ^CH2 ^CH2F, ^CH2 ^CHF2, ^CH2 ^CF3, ^CH2 ^CH2Cl, ^CH2 ^CH2Br, ^CH2 ^CH2I, ^CH2 ^CH=CH2, ^CH2-C≡CH, –CHO, –COCH3, –COC2H5, –COC3H7, –COCH(CH3)2, –COC(CH3)3, ^CO ^cyclo ^C3H5, ^CO ^cyclo-C4H7, ^CO ^cyclo-C5H9, –COOCH3, –COOC2H5, –COOC3H7, –COOCH(CH3)2, –COOC(CH3)3, –COOCH2Ph, –SO2CH3, –SO2CF3, –SO2C2H5, –SO2C3H7, –SO2CH(CH3)2, or –SO2C(CH3)3; RN1 represents –H, –CH3, or –CH2CH3; R8, 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, ^cyclo-C3H5, ^CH2 ^cyclo ^C3H5, ^CH2F, ^CHF2, ^CF3, ^CH2Cl, ^CH2Br, ^CH2I, ^CH2 ^CH2F, ^CH2 ^CHF2, ^CH2 ^CF3, ^CH2 ^CH2Cl, ^CH2 ^CH2Br, ^CH2 ^CH2I, –OCH3, –OC2H5, –OC3H7, –OCH(CH3)2, –OC(CH3)3, –OC4H9, –OCHF2, –OCF3, −OCH2CF3, –OC2F5, −OCH2OCH3, –O-cyclo-C3H5, –OCH2-cyclo-C3H5, –O–C2H4-cyclo- ^C(CH3)=CH2, ^CH=CH ^CH3,
Figure imgf000297_0001
^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.
4. The compound according to any one of claims 1 to 3, wherein the compound has any one of the formula (II-a), (II-b), (II-b1) – (II-b2), and (III-a) – (III-b ):
Figure imgf000297_0002
Figure imgf000298_0001
(III-a) (III-b) wherein R2 , RN , Ra, Rb, Rc, Rd and Re have the same meanings as defined in claim 2.
5. The compound according to any one of the claims 1 – 3, wherein R3 represents
Figure imgf000298_0002
.
6. The compound according to any one of the claims 1 – 4, wherein R2 represents
Figure imgf000298_0003
7. The compound according to claim 1, represented by the formula (I):
Figure imgf000299_0001
wherein L represents –L1– or –L1–L2– ; L1 represents –CH2–, –CH2CH2–, –CH2CH2CH2–, –CH2CO–, –CH2CH2CO–; L2 represents a bond, –NRN1–, –NRN1CH N1 2–, –NR CH2CH2–, or –NRN1CH(CH3)–; R1 represents ;
Figure imgf000299_0002
R2 represents
Figure imgf000299_0003
,
Figure imgf000300_0001
Figure imgf000301_0001
Figure imgf000302_0001
Figure imgf000303_0001
,
Figure imgf000304_0001
wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 – R13 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-homoisotwistanyl, adamantly, 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, and when R3 is 2-bicyclo[3.1.1]heptyl, L is not –CH N1 2CONR CH2–, and when R3 is 1-adamantyl, then L is not –CH N1 2CONR –; 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, –CO2C2H5, –CONH2, –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 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-C5H9, –cyclo-C6H11, –CH2–cyclo-C3H5, –CH2–cyclo-C4H7, –CH2–cyclo- C5H9, –CH2–cyclo-C6H11, –CH2–Ph, –CH2OCH3, –CH2OCH2CH3, –CH2CH2OCH3, –CH2CH2OCH2CH3, –CH2CH2NHCH3, –CH2CH2N(CH3)2, or –NR6R7 represents , , , or ; R5 and R8 – R14 have the meanings as defined in claim 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-C5H9, ^CH2 ^cyclo ^C3H5, ^CH2F, ^CHF2, ^CF3, ^CH2Cl, ^CH2Br, ^CH2I, ^CH2 ^CH2F, ^CH2 ^CHF2, ^CH2 ^CF3, ^CH2 ^CH2Cl, ^CH2 ^CH2Br, ^CH2 ^CH2I, ^CH2 ^CH=CH2, ^CH2-C≡CH, –CHO, –COCH3, –COC2H5, –COC3H7, –COCH(CH3)2, –COC(CH3)3, –COOCH3, –COOC2H5, –COOC3H7, –COOCH(CH3)2, –COOC(CH3)3, –COOCH2Ph, –SO2CH3, –SO2CF3, –SO2C2H5, –SO2C3H7, –SO2CH(CH3)2, or –SO2C(CH3)3; RN1 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.
8. The compound according to claim 1 or 7, wherein
Figure imgf000306_0001
R8 – R14 and RN have the meanings as defined in claim 7.
9. The compound according to claim 7 or 8, wherein L1 represents –CH2–, or –CH2CO–; L2 represents a bond, –NRN1–, –NRN1CH N1 2–, or –NR CH(CH3)–; R3 represents bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 4- homoisotwistanyl, adamantly, 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 when R3 is 2-bicyclo[3.1.1]heptyl, –L1-L2– is not –CH N1 2CONR CH2–, and when R3 is 1-adamantyl, then –L1-L2– is not –CH N1 2CONR –; and Ra, Rb, Rc, Rd, Re and RN1 have the same meanings as defined in claim 7.
10. The compound according to any one of the claims 7 – 9, wherein the compound has any one of the formulae (IV-a) – (IV-l) and (V-a) – (V-d): R
Figure imgf000307_0001
Figure imgf000308_0001
wherein L1 is not –CH2CO–, when the compound has the formula (IV-b), wherein L2 is not –NRN1CH2–, when the compound has the formula (IV-c), and R2 , R3, R6, R8, R9, R10, R11 , R12 , R13, Ra, Rb, Rc, Rd and L2 have the same meanings as defined in claim 7.
11. The compound according to any one of the claims 7 – 10, wherein R2 represents
Figure imgf000308_0002
,
Figure imgf000309_0001
R6 represents –H, –CH3, –CH2CH3, –CH(CH3)2, –CH2CH2CH3, –CH2CH=CH2, –CH2CH2CH2CH3, –CH2CH(CH3)2, –C(CH3)3, –CH2CH2CH2CH2CH3, –cyclo-C3H5, or –CH2–cyclo-C3H5.
12. The compound according to claim 1, wherein the compound has the formula (I):
Figure imgf000309_0002
wherein L represents –L1– or –L1–L2–; L1 represents –CH2–, –CH2CH2–, –CH2CH2CH2–, –CH2CO–, –CH2CH2CO–; L2 represents a bond, –NRN1–, –NRN1CH2–, –NRN1CH2CH2–, or –NRN1CH(CH3)–; R1 represents ;
Figure imgf000310_0001
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-homoisotwistanyl, adamantly, 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, –CO2C2H5, –CONH2, –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 –R5, –OR5 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-C5H9, –cyclo-C6H11, –CH2–cyclo-C3H5, –CH2–cyclo-C4H7, –CH2–cyclo-C5H9, –CH2–cyclo-C6H11, –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-C3H5, –cyclo-C4H7, –cyclo-C5H9, –cyclo-C6H11, –CH2–cyclo-C3H5, –CH2–cyclo-C4H7, –CH2–cyclo- C5H9, –CH2–cyclo-C6H11, –CH2–Ph, –CH2OCH3, –CH2OCH2CH3, –CH2CH2OCH3, –CH2CH2OCH2CH3, –CH2CH2NHCH3, –CH2CH2N(CH3)2,
Figure imgf000311_0001
RN1 represents –H, –CH3, or –CH2CH3; and R2 has the same meanings as defined in claim 1; 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.
13. The compound according to any one of the Claim 1 or 12, wherein
Figure imgf000311_0002
,
Figure imgf000312_0001
14. The compound according to claim 12 or 13, wherein
Figure imgf000312_0003
, , L1 represents –CH2–, or –CH2CO–; L2 represents a bond, –NRN1–, –NRN1CH –, or N1 2 –NR CH(CH3)–; R3 represents bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 4- homoisotwistanyl, adamantly, 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 R5, R6, R7 , Ra, Rb, Rc, Rd, Re and RN1 have the same meanings as defined in claim 12.
15. The compound according to any one of the claims 12 – 14, wherein the compound has any one of the formulae (VI-a) – (Vl-l), (VII-a) – (VII-l), (VIII-a) – (VIIl-l), (IX-a) – (IX-d), (X-a) – (X-d), and (XI-a) – (XI-d):
Figure imgf000312_0002
Figure imgf000313_0001
Figure imgf000314_0001
Figure imgf000315_0001
(VIII-a)
Figure imgf000315_0002
(VIII-g) (VIII-h)
Figure imgf000316_0001
Figure imgf000317_0001
same meanings as defined in claim 1 or in claim 12.
16. The compound according to any one of the claims 11 – 14, wherein R2 represents
Figure imgf000317_0002
,
Figure imgf000318_0001
17. The compound according to any one of the claims 7 – 16, wherein R3 represents
Figure imgf000318_0002
,
Figure imgf000319_0001
18. The compound according to claim 1 selected from the group consisting of:
Figure imgf000319_0002
Figure imgf000320_0001
Figure imgf000321_0001
Figure imgf000322_0001
Figure imgf000323_0001
Figure imgf000324_0001
Figure imgf000325_0001
Figure imgf000326_0001
Figure imgf000327_0001
Figure imgf000328_0001
Figure imgf000329_0001
Figure imgf000330_0001
Figure imgf000331_0001
Figure imgf000332_0001
Figure imgf000333_0001
Figure imgf000334_0001
Figure imgf000335_0001
Figure imgf000336_0001
or a pharmaceutically acceptable salt thereof.
19. A pharmaceutical composition comprising a compound of any one of the claims 1 – 18 as an active ingredient, together with at least one pharmaceutically acceptable carrier, excipient and/or diluent.
20. Compound according to any one of the claims 1 – 18 for use in medicine.
21. Compound according to any one of the claims 1 – 18 or the pharmaceutical composition according to claim 19 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.
22. Compound for use, or the pharmaceutical composition for use according to claim 21, 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; the skin disorders comprise acne, psoriasis, scarring, and skin aging.
23. Compound for use, or the pharmaceutical composition for use according to any one of the claims 21 or 22 in the treatment or prophylaxis of celiac disease.
24. A method for producing the compound of formula (Ia) according to claim 1 comprising: Step 1A: providing a compound 4a
Figure imgf000338_0001
Step 2A: performing coupling reaction of the compound 4a with a compound 5
Figure imgf000338_0002
to obtain a compound 6a
Figure imgf000338_0003
Step 3A: deprotecting an amino protecting group PG3 to obtain a compound 7a
Figure imgf000338_0004
Step 4A: performing coupling reaction of the compound 7a with a carboxylic acid (R2-CO2H 8) to obtain a compound 9a
Figure imgf000338_0005
Step 5A: performing oxidation reaction of the compound 9a to produce the compound of the formula (Ia)
Figure imgf000339_0001
wherein L, R2 , R3,and R6 have the same meanings as defined in claim 1, and PG3 is an amino protecting group; or a method for producing the compound of formula (Ib) according to claim 1 comprising: Step 1B: providing a compound 4b
Figure imgf000339_0002
Step 2B: performing coupling reaction of the compound 4b with a compound 5
Figure imgf000339_0003
to obtain a compound
Figure imgf000339_0004
Step 3B: deprotecting an amino protecting group PG3 to obtain a compound 7b
Figure imgf000339_0005
Step 4B: performing coupling reaction of the compound 7b with a carboxylic acid (R2-CO2H 8) to obtain a compound 9b
Figure imgf000340_0001
Step 5B: performing oxidation reaction of the compound 9b to produce the compound of the formula (Ib)
Figure imgf000340_0002
wherein L, R2 , R3, R6 and R7 have the same meanings as defined in claim 1, and PG3 is an amino protecting group; or a method for producing the compound of formula (Ic) according to claim 1 comprising: Step 1C: providing a compound 4c
Figure imgf000340_0003
Step 2C: performing coupling reaction of the compound 4c with a compound 5
Figure imgf000340_0004
to obtain a compound
Figure imgf000340_0005
Step 3C: deprotecting an amino protecting group PG3 to obtain a compound 7c
Figure imgf000341_0001
Step 4C: performing coupling reaction of the compound 7c with a carboxylic acid (R2-CO2H 8) to produce the compound of the formula (Ic)
Figure imgf000341_0002
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 (Id) according to claim 1 comprising: Step 1D: providing a compound 4d
Figure imgf000341_0003
Step 2D: performing coupling reaction of the compound 4d with a compound 5
Figure imgf000341_0004
to obtain a compound 6d
Figure imgf000342_0001
6d; Step 3D: deprotecting an amino protecting group PG3 to obtain a compound 7d
Figure imgf000342_0002
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)
Figure imgf000342_0003
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 (Ie) according to claim 1 comprising: Step 1E: providing a compound
Figure imgf000342_0004
Step 2E: performing coupling reaction of the compound 4e with a compound 5
Figure imgf000343_0001
to obtain a compound
Figure imgf000343_0002
Step 3E: deprotecting an amino protecting group PG3 to obtain a compound 7e
Figure imgf000343_0003
Step 4E: performing coupling reaction of the compound 7e with a carboxylic acid (R2-CO2H 8) to produce the compound of the formula (Ie)
Figure imgf000343_0004
wherein L, R2 , R3, R5 have the same meanings as defined above in formula (Ie), and PG3 is an amino protecting group.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9434763B2 (en) * 2012-07-17 2016-09-06 Zedira Gmbh Derivatives of pyridinone as inhibitors for tissue transglutaminase
US11072634B2 (en) * 2016-12-27 2021-07-27 Zedira Gmbh Inhibitors of transglutaminases

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9434763B2 (en) * 2012-07-17 2016-09-06 Zedira Gmbh Derivatives of pyridinone as inhibitors for tissue transglutaminase
US11072634B2 (en) * 2016-12-27 2021-07-27 Zedira Gmbh Inhibitors of transglutaminases

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
AYMAN EL-FAHAMFERNANDO ALBERICIO: "Peptide Coupling Reagents, More than a Letter Soup", CHEMICAL REVIEWS, vol. 111, no. 11, 2011, pages 6557 - 6602, XP055708830, DOI: 10.1021/cr100048w
J.M. WODZINSKA, MINI-REVIEWS IN MEDICAL CHEMISTRY, vol. 5, 2005, pages 279 - 292
LORAND ET AL., ANAL BIOCHEM, vol. 44, 1971, pages 221 - 31
SUBBAIAH MURUGAIAH A. M. ET AL: "Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design", JOURNAL OF MEDICINAL CHEMISTRY, vol. 64, no. 19, 30 September 2021 (2021-09-30), US, pages 14046 - 14128, XP055933218, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.1c01215 *
TSE EDWIN G. ET AL: "Nonclassical Phenyl Bioisosteres as Effective Replacements in a Series of Novel Open-Source Antimalarials", JOURNAL OF MEDICINAL CHEMISTRY, vol. 63, no. 20, 17 July 2020 (2020-07-17), US, pages 11585 - 11601, XP055933193, ISSN: 0022-2623, Retrieved from the Internet <URL:http://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.0c00746> DOI: 10.1021/acs.jmedchem.0c00746 *

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