CN110730777A - Chemical compounds as inhibitors of the ATF4 pathway - Google Patents

Chemical compounds as inhibitors of the ATF4 pathway Download PDF

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Publication number
CN110730777A
CN110730777A CN201880038106.7A CN201880038106A CN110730777A CN 110730777 A CN110730777 A CN 110730777A CN 201880038106 A CN201880038106 A CN 201880038106A CN 110730777 A CN110730777 A CN 110730777A
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bicyclo
chlorophenoxy
pent
azetidinyl
acetamide
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J.M.阿克斯滕
M.P.德玛蒂诺
K.A.埃文斯
J.M.拉尔夫
B.卡利塔
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GlaxoSmithKline Intellectual Property Development Ltd
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GlaxoSmithKline Intellectual Property Development Ltd
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Priority claimed from PCT/IN2018/050375 external-priority patent/WO2018225093A1/en
Publication of CN110730777A publication Critical patent/CN110730777A/en
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    • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
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    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
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Abstract

The present invention relates to substituted bridged cycloalkane derivatives. In particular, the invention relates to compounds according to formula (IIIQ): wherein X6’、a、b、C8’、D8’、L82’、L83’、R81’、R82’、R83’、R84’、R85’、R86’、z82’、z84’、z85’And z86’As defined herein; or a salt thereof. The compounds of the present invention are inhibitors of the ATF4 pathway. Accordingly, the present invention further relates to pharmaceutical compositions comprising the compounds of the present invention. The invention also relates to methods of inhibiting the ATF4 pathway and treating diseases associated therewith using the compounds of the invention or pharmaceutical compositions comprising the compounds of the invention.

Description

Chemical compounds as inhibitors of the ATF4 pathway
Technical Field
The present invention relates to substituted bridged cycloalkane derivatives which are inhibitors of the ATF4 pathway. The invention also relates to pharmaceutical compositions comprising such compounds and methods of using such compounds for treating diseases/injuries associated with activated unfolded protein response pathways, such as cancer, pre-cancerous syndromes, alzheimer's disease, spinal cord injury, traumatic brain injury, ischemic stroke, diabetes, parkinson's disease, huntington's disease, Creutzfeldt-Jakob disease and related prion diseases, progressive supranuclear palsy, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular diseases, inflammation, fibrosis, chronic and acute liver diseases, chronic and acute lung diseases, chronic and acute kidney diseases, chronic traumatic brain disease (CTE), neurodegeneration, dementia, cognitive impairment, atherosclerosis, eye diseases, neurological disorders, pain, cardiac arrhythmias, for organ transplantation and for transport of organs for transplantation.
Background
In metazoans, different stress signals converge at a single phosphorylation event at serine 51 (translation initiation factor eIF2 α) of a common effector. This step is performed by four eIF2 α kinases in mammalian cells: PERK, which responds to the accumulation of unfolded proteins in the Endoplasmic Reticulum (ER), GCN2 responds to amino acid starvation and UV light, PKR responds to viral infection, and HRI responds to heme deficiency. The collection of these signaling pathways is called "integrated stress response" (ISR) because they are clustered on the same molecular event. eIF2 α phosphorylation leads to translational attenuation, the consequence of which enables cells to respond to varying stresses (1).
eIF2 (containing three subunits α, β, and γ) binds GTP and initiator Met-tRNA to form a ternary complex (eIF2-GTP-Met-tRNAi), which in turn binds to the 40S ribosomal subunit of the 5' UTR of the scanned mRNA to select the initiating AUG codon. Upon phosphorylation of its α -subunit, eIF2 becomes a competitive inhibitor of its GTP-exchange factor (GEF), eIF2B (2). The tight and inefficient binding of phosphorylated eIF2 to eIF2B prevents loading of the eIF2 complex with GTP, preventing formation of the ternary complex and reducing translation initiation (3). Because eIF2B is less abundant than eIF2, phosphorylation of only a small fraction of total eIF2 has a significant effect on eIF2B activity in cells.
Paradoxically, a small group of mrnas containing an upstream open reading frame (uORF) in their 5' UTR is up-regulated in translation under conditions of reduced protein synthesis (4, 5). These include mammalian ATF4(cAMP element binding (CREB) transcription factor) and CHOP (pro-apoptotic transcription factor) (6-8). ATF4 regulates the expression of many genes involved in metabolism and nutrient uptake and additional transcription factors such as CHOP, which are under translational and transcriptional control (9). Thus, phosphorylation of eIF2 α results in preferential translation of key regulatory molecules and directs various changes in the cellular transcriptome during cellular stress.
One of the eIF2 α kinases, PERK, is located at the intersection of the ISR and Unfolded Protein Response (UPR), maintaining a steady state of protein folding rate in the ER (10). Due to an imbalance between protein folding load and protein folding ability (a condition known as "ER stress"), UPRs are activated by unfolded or misfolded proteins that accumulate in the ER lumen. In mammals, the UPR comprises three signaling branches mediated by the ER-localized transmembrane sensor PERK, IRE1, and ATF 6. These sensor proteins detect the accumulation of unfolded proteins in the ER and transmit information across the ER membrane, initiating a unique signaling pathway that converges in the activation of a broad transcriptional response, ultimately leading to ER amplification (11). The luminal stress sensing domains of PERK and IRE1 are homologous and may be activated in a similar manner by direct binding to unfolded peptides (12). This binding event results in oligomerization and trans autophosphorylation of its cytoplasmic kinase domain, and for PERK, phosphorylates its unique known substrate eIF2 α. In this way, PERK activation leads to a rapid reduction in the load of newly synthesized proteins, which translocate into the ER-lumen (13).
Under ER stress, transcription factor XBP 1s produced by the unconventional mRNA splicing reaction initiated by IRE1 and transcription factor ATF6 produced by proteolysis and release from the ER membrane, in concert with ATF4, induce a huge UPR transcription response. Transcriptional targets for UPRs include the ER protein folding mechanism, the ER-associated degradation mechanism, and many other components that play a role in the secretory pathway (14). Although UPR can initially relieve ER stress and thus confer cytoprotection, sustained and severe ER stress leads to activation of apoptosis, thereby eliminating damaged cells (15, 16).
Small molecule therapies that inhibit UPR and/or integrate stress responses can be used in cancer (17,18,19) as a single agent or in combination with other chemotherapies, for enhancing long-term memory (24, 25), for neurodegenerative and prion-related diseases (20), for white matter disease (VWM) (23), and for biotechnological applications that benefit from increased protein translation.
It is an object of the present invention to provide novel compounds which prevent translation of ATF4 or are inhibitors of the ATF4 pathway.
It is another object of the present invention to provide a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (IIIQ).
It is another object of the present invention to provide a method for treating neurodegenerative diseases, cancer, and other diseases/injuries associated with activated unfolded protein response pathways such as: alzheimer's disease, spinal cord injury, traumatic brain injury, ischemic stroke, diabetes, parkinson's disease, huntington's disease, creutzfeldt-jakob disease, and related prion diseases, amyotrophic lateral sclerosis, progressive supranuclear palsy, myocardial infarction, cardiovascular disease, inflammation, fibrosis, chronic and acute liver disease, chronic and acute lung disease, chronic and acute kidney disease, chronic traumatic brain disease (CTE), neurodegeneration, dementia, atherosclerosis, eye diseases, neurological disorders, pain, cardiac arrhythmias, methods for organ transplantation and for transporting organs for transplantation comprising administering a novel inhibitor of the ATF4 pathway.
Disclosure of Invention
The present invention relates to substituted bridged cycloalkane derivatives. In particular, the invention relates to compounds according to formula IIIQ:
Figure BDA0002308602660000031
wherein X6 ', a, b, C8 ', D8 ', L82 ', L83 ' and R81’、R82’、R83’、R84’、R85’、R86', z82 ', z84 ', z85 ' and z86 ' are defined below; or a salt thereof, including pharmaceutically acceptable salts thereof.
The present invention also relates to the discovery that compounds of formula (IIIQ) are effective as inhibitors of the ATF4 pathway.
The present invention also relates to the discovery that compounds of formula (IIIQ) prevent translation of ATF 4.
The invention also relates to a method of treating alzheimer's disease comprising administering to a human in need thereof an effective amount of a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof.
The invention also relates to a method of treating parkinson's disease, comprising administering to a human in need thereof an effective amount of a compound of formula (IIIQ), or a pharmaceutically acceptable salt thereof.
The present invention also relates to a method of treating amyotrophic lateral sclerosis, comprising administering to a human in need thereof an effective amount of a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof.
The invention also relates to a method of treating huntington's disease comprising administering to a human in need thereof an effective amount of a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof.
The invention also relates to a method of treating creutzfeldt-jakob disease comprising administering to a human in need thereof an effective amount of a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof.
The present invention also relates to a method of treating Progressive Supranuclear Palsy (PSP) comprising administering to a human in need thereof an effective amount of a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof.
The invention also relates to a method of treating dementia comprising administering to a human in need thereof an effective amount of a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof.
The present invention also relates to a method of treating spinal cord injury comprising administering to a human in need thereof an effective amount of a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof.
The present invention also relates to a method of treating traumatic brain injury comprising administering to a human in need thereof an effective amount of a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof.
The present invention also relates to a method for treating ischemic stroke comprising administering to a human in need thereof an effective amount of a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof.
The present invention also relates to a method of treating diabetes comprising administering to a human in need thereof an effective amount of a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof.
The present invention also relates to methods of treating a disease state selected from the group consisting of: myocardial infarction, cardiovascular disease, atherosclerosis, ocular diseases, and cardiac arrhythmias comprising administering an effective amount of a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof to a human in need thereof.
The invention also relates to a method of treating an integrated stress related disorder in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof.
The invention also relates to a method of treating a disease associated with phosphorylation of eIF2a in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of formula (IIIQ), or a pharmaceutically acceptable salt thereof.
The invention also relates to a method of treating a disease in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof, wherein the disease is selected from the group consisting of cancer, neurodegenerative diseases, ablative leukoencephalopathy, childhood ataxia with reduced CNS myelination and dysnoesia syndrome.
The invention also relates to a method of improving long term memory in a patient comprising administering to the patient a therapeutically effective amount of a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof.
The invention also relates to a method of increasing protein expression in a cell or in vitro expression system comprising administering to the cell or expression system an effective amount of a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof.
The invention also relates to a method of treating an inflammatory disease in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of a compound of formula (IIIQ), or a pharmaceutically acceptable salt thereof.
The invention also relates to methods of using the compounds of formula (IIIQ) for organ transplantation and for transporting organs for transplantation.
The invention also includes methods of co-administering the compounds of the invention with other active ingredients.
The present invention includes the treatment of neurodegenerative diseases, cancer, and other diseases/injuries associated with activated unfolded protein response pathways such as: alzheimer's disease, spinal cord injury, traumatic brain injury, ischemic stroke, diabetes, parkinson's disease, huntington's disease, creutzfeldt-jakob disease and related prion diseases, amyotrophic lateral sclerosis, progressive supranuclear palsy, myocardial infarction, cardiovascular diseases, inflammation, fibrosis, chronic and acute liver diseases, chronic and acute lung diseases, chronic and acute kidney diseases, chronic traumatic brain disease (CTE), neurodegeneration, dementia, atherosclerosis, eye diseases, cardiac arrhythmias, methods for organ transplantation and for transporting organs for transplantation comprising administering a compound of formula (IIIQ).
The invention also relates to a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof for use in therapy.
The invention also relates to a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof, for use in the treatment of alzheimer's disease.
The invention also relates to a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof, for use in the treatment of parkinson's disease syndrome.
The invention also relates to a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof, for use in the treatment of amyotrophic lateral sclerosis.
The invention also relates to a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof, for use in the treatment of huntington's disease.
The invention also relates to compounds of formula (IIIQ) or pharmaceutically acceptable salts thereof, which are useful for treating creutzfeldt-jakob disease.
The invention also relates to a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof, for use in the treatment of Progressive Supranuclear Palsy (PSP).
The invention also relates to a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof, for use in the treatment of dementia.
The invention also relates to a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof for use in the treatment of spinal cord injury.
The invention also relates to a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof for use in the treatment of traumatic brain injury.
The invention also relates to a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof for use in the treatment of ischemic stroke.
The invention also relates to a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof for use in the treatment of diabetes.
The present invention also relates to compounds of formula (IIIQ) or pharmaceutically acceptable salts thereof, for use in treating a disease state selected from: myocardial infarction, cardiovascular disease, atherosclerosis, ocular disease, and cardiac arrhythmia.
The invention also relates to the use of a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of diseases associated with integrated stress.
The invention also relates to the use of a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease associated with phosphorylation of eIF2 a.
The invention also relates to the use of a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease selected from: cancer, neurodegenerative diseases, ablative leukoencephalopathy, childhood ataxia with reduced CNS myelination and dysnoesia syndrome.
The invention also relates to the use of a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for improving long term memory.
The invention also relates to the use of a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for increasing protein expression in a cell or in an in vitro expression system.
The invention also relates to the use of a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of an inflammatory disease.
The invention also relates to the use of a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for organ transplantation and for transporting organs for transplantation.
The invention also relates to the use of a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease state selected from: neurodegenerative diseases, cancer, and other diseases/injuries associated with activated unfolded protein response pathways such as: alzheimer's disease, spinal cord injury, traumatic brain injury, ischemic stroke, diabetes, parkinson's disease, huntington's disease, creutzfeldt-jakob disease and related prion diseases, amyotrophic lateral sclerosis, progressive supranuclear palsy, myocardial infarction, cardiovascular disease, inflammation, fibrosis, chronic and acute liver disease, chronic and acute lung disease, chronic and acute kidney disease, chronic traumatic brain disease (CTE), neurodegeneration, dementia, atherosclerosis, ocular disease, neurological disorders, pain, arrhythmia, for organ transplantation and for transporting organs for transplantation.
The invention includes pharmaceutical compositions comprising a pharmaceutical excipient and a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof.
The invention also relates to a pharmaceutical composition as defined above for use in therapy.
The present invention also relates to a combination for use in therapy comprising a therapeutically effective amount of (i) a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof; and (ii) other active ingredients.
Detailed Description
Included among the compounds of the present invention and used in the methods of the present invention are compounds of formula (I):
Figure BDA0002308602660000071
wherein:
L2and L3Independently a bond, -NH-, -O-, -S-, -S (O) -, -S (O)2-, substituted or unsubstituted C1-6Alkylene or substituted or unsubstituted C1-6A heteroalkylene group;
R5and R6Each independently of the others is hydrogen, fluorine, chlorine, bromine, iodine, -OCH3、-OCH2Ph、-C(O)Ph、-CH3、-CF3、-CN、-S(O)CH3、-OH、-NH2、-COOH、-CONH2、-NO2、-C(O)CH3、-CH(CH3)2、-CCH、-CH2CCH、-SO3H、-SO2NH2、-NHC(O)NH2、-NHC(O)H、-NHOH、-OCF3、-OCHF2Substituted or unsubstituted C1-6An alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group;
R2and R4Independently is NR8O, CH2, or S;
R8selected from: hydrogen, C1-6Alkyl and C substituted by 1 to 6 fluorine1-6An alkyl group;
a and b are independently 0 or 1;
c and D are independently phenyl or pyridine;
x is C1-3Alkylene or C substituted by 1 to 3 fluorine1-3An alkylene group;
Z2and z4Independently 0 or 1; and is
Z5And z6Independently an integer from 0 to 5;
and salts thereof.
The invention also relates to pharmaceutically acceptable salts of the compounds of formula (I).
Included among the compounds of the present invention and used in the methods of the present invention are compounds of formula (II):
Figure BDA0002308602660000081
wherein:
L12and L13Independently are: -CH2-O-、-O-CH2-、-O-CH2-CH2-and-CH2-CH2-O-；
R15And R16Independently hydrogen or chlorine;
R12and R14Is O;
a1and b1Independently 0 or 1;
C1and D1Independently phenyl or pyridine;
X1is selected from-CH2-and-CH2-CH2-；
z12And z14Independently 0 or 1; and is
z15And z16Independently an integer from 0 to 5;
and salts thereof.
The invention also relates to pharmaceutically acceptable salts of the compounds of formula (II).
Included among the compounds of the present invention and used in the methods of the present invention are compounds of formula (III):
Figure BDA0002308602660000082
wherein:
L2selected from: a bond, -NH-, -O-, -S-, -S (O) -, -S (O)2-, substituted or unsubstituted C1-6Alkylene or substituted or unsubstituted C1-6Heteroalkylene, or L2Further taken together with R3 to form a heterocycloalkyl;
L3selected from: a bond, -NH-, -O-, -S-, -S (O) -, -S (O)2-, takingSubstituted or unsubstituted C1-6Alkylene or substituted or unsubstituted C1-6Heteroalkylene, or L3Further taken together with R1 to form a heterocycloalkyl;
R1selected from: hydrogen, C1-6Alkyl, substituted C1-6Alkyl, heterocycloalkyl, or
R1And L3Together form a heterocycloalkyl group;
R3selected from: hydrogen, C1-6Alkyl, substituted C1-6Alkyl, heterocycloalkyl, or
R3And L2Together form a heterocycloalkyl group;
R5and R6Each independently of the others is hydrogen, fluorine, chlorine, bromine, iodine, -OCH3、-OCH2Ph、-C(O)Ph、-CH3、-CF3、-CN、-S(O)CH3、-OH、-NH2、-COOH、-CONH2、-NO2、-C(O)CH3、-CH(CH3)2、-C≡CH、-CH2C≡CH、-SO3H、-SO2NH2、-NHC(O)NH2、-NHC(O)H、-NHOH、-OCF3、-OCHF2Substituted or unsubstituted C1-6An alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group;
R2and R4Independently is NR8、O、CH2Or S;
R8selected from: hydrogen, C1-6Alkyl and C substituted by 1 to 6 fluorine1-6An alkyl group;
a and b are independently 0 or 1;
c and D are independently phenyl or pyridyl;
x is C1-3Alkylene or C substituted by 1 to 3 fluorine1-3An alkylene group;
z2and z4Independently 0 or 1; and is
z5And z6Independently an integer from 0 to 5;
or a salt thereof, including pharmaceutically acceptable salts thereof.
The invention also relates to pharmaceutically acceptable salts of the compounds of formula (III).
Included among the compounds of the present invention and used in the methods of the present invention are compounds of formula (IV):
Figure BDA0002308602660000091
wherein:
L12selected from: bond, -CH2-、-NH-、CH2-O-、-O-CH2-、-O-CH2-CH2-and-CH2-CH2-O-, or L12Further with R11Together form an imidazolidinyl group;
L13selected from: bond, -CH2-、-NH-、CH2-O-、-O-CH2-、-O-CH2-CH2-and-CH2-CH2-O-, or L13Further with R13Together form an imidazolidinyl group;
R11selected from: hydrogen, C1-6Alkyl, substituted C1-6Alkyl, oxetanyl, or
R11And L12Together form an imidazolidinyl group;
R13selected from: hydrogen, C1-6Alkyl, substituted C1-6Alkyl, oxetanyl, or
R13And L13Together form an imidazolidinyl group;
R15and R16Independently hydrogen, methyl, or chlorine;
R12and R14Is O;
a1and b1Independently 0 or 1;
C1and D1Independently is phenyl or pyridyl;
X1is selected from-CH2-and-CH2-CH2-；
Z12And z14Independently 0 or 1; and is
Z15And z16Independently an integer from 0 to 5;
or a salt thereof, including pharmaceutically acceptable salts thereof.
The invention also relates to pharmaceutically acceptable salts of the compounds of formula (IV).
Included among the compounds of the present invention and used in the methods of the present invention are compounds of formula (IIIX):
Figure BDA0002308602660000101
wherein:
L22selected from: a bond, -NH-, -O-, -S-, -S (O) -, -S (O)2-, substituted or unsubstituted C1-6Alkylene and substituted or unsubstituted C1-6Heteroalkylene, or L22And R23Together form a heterocycloalkyl group;
L23and R21Together form a heterocycloalkyl group;
R23selected from: hydrogen, C1-6Alkyl, substituted C1-6An alkyl group, a heterocycloalkyl group,
or R23And L22Together form a heterocycloalkyl group;
R25and R26Each independently of the others is hydrogen, fluorine, chlorine, bromine, iodine, -OCH3、-OCH2Ph、-C(O)Ph、-CH3、-CF3、-CN、-S(O)CH3、-OH、-NH2、-COOH、-CONH2、-NO2、-C(O)CH3、-CH(CH3)2、-C≡CH、-CH2C≡CH、-SO3H、-SO2NH2、-NHC(O)NH2、-NHC(O)H、-NHOH、-OCF3、-OCHF2Substituted or unsubstituted C1-6An alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group;
R22and R24Independently is NR28、O、CH2Or S;
R28selected from: hydrogen, C1-6Alkyl and C substituted by 1 to 6 fluorine1-6An alkyl group;
a and b are independently 0 or 1;
C2and D2Independently is phenyl or pyridyl;
X2is C1-3Alkylene or C substituted by 1 to 3 fluorine1-3An alkylene group;
z22and z24Independently 0 or 1; and is
z25And z26Independently an integer from 0 to 5;
or a salt thereof, including pharmaceutically acceptable salts thereof.
The invention also relates to pharmaceutically acceptable salts of the compounds of formula (IIIX).
Included among the compounds of the present invention and used in the methods of the present invention are compounds of formula (IVX):
Figure BDA0002308602660000111
wherein:
L32selected from: a bond, -NH-, -O-, -S-, -S (O) -, -S (O)2-, substituted or unsubstituted C1-6Alkylene and substituted or unsubstituted C1-6A heteroalkylene group;
L33and R31Together form a heterocycloalkyl group;
R33selected from: hydrogen, C1-6Alkyl, substituted C1-6Alkyl, and heterocycloalkyl;
R35and R36Each independently of the others is hydrogen, fluorine, chlorine, bromine, iodine, -OCH3、-OCH2Ph、-C(O)Ph、-CH3、-CF3、-CN、-S(O)CH3、-OH、-NH2、-COOH、-CONH2、-NO2、-C(O)CH3、-CH(CH3)2、-C≡CH、-CH2C≡CH、-SO3H、-SO2NH2、-NHC(O)NH2、-NHC(O)H、-NHOH、-OCF3、-OCHF2Substituted or unsubstituted C1-6An alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group;
R32and R34Independently is NR38、O、CH2Or S;
R38selected from: hydrogen, C1-6Alkyl and C substituted by 1 to 6 fluorine1-6An alkyl group;
a and b are independently 0 or 1;
C3and D3Independently is phenyl or pyridyl;
X3is C1-3Alkylene or C substituted by 1 to 3 fluorine1-3An alkylene group;
z32and z34Independently 0 or 1; and is
z35And z36Independently an integer from 0 to 5;
or a salt thereof, including pharmaceutically acceptable salts thereof.
The invention also relates to pharmaceutically acceptable salts of the compounds of formula (IVX).
Included among the compounds of the present invention and used in the methods of the present invention are compounds of formula (VX):
Figure BDA0002308602660000121
wherein:
L42selected from: bond, -CH2-、-NH-、CH2-O-、-O-CH2-、-O-CH2-CH2-and-CH2-CH2-O-, or L42And R41Together form an imidazolidinyl or pyrrolidinyl group;
L43and R43Together form an imidazolidinyl or pyrrolidinyl group;
R41selected from: hydrogen, C1-6Alkyl, substituted C1-6Alkyl, and oxetanyl, or
R41And L42Together form an imidazolidinyl or pyrrolidinyl group;
R45and R46Independently hydrogen, methyl, or chlorine;
R42and R44Is O;
a and b are independently 0 or 1;
C4and D4Independently is phenyl or pyridyl;
X4is selected from-CH2-and-CH2-CH2-；
Z42And z44Independently 0 or 1; and is
Z45And z46Independently an integer from 0 to 5;
or a salt thereof, including pharmaceutically acceptable salts thereof.
The invention also relates to pharmaceutically acceptable salts of compounds of formula (VX).
Included among the compounds of the present invention and used in the methods of the present invention are compounds of formula (VIX):
Figure BDA0002308602660000131
wherein:
L52selected from: bond, -CH2-、-NH-、CH2-O-、-O-CH2-、-O-CH2-CH2-and-CH2-CH2-O-；
L53And R53Together form an imidazolidinyl or pyrrolidinyl group;
R51selected from: hydrogen, C1-6Alkyl, substituted C1-6Alkyl, and oxetanyl;
R55and R56Independently hydrogen, methyl, or chlorine;
R52and R54Is O;
a and b are independently 0 or 1;
C5and D5Independently is phenyl or pyridyl;
X5is selected from-CH2-and-CH2-CH2-；
Z52And z54Independently 0 or 1; and is
Z55And z56Independently an integer from 0 to 5;
or a salt thereof, including pharmaceutically acceptable salts thereof.
The invention also relates to pharmaceutically acceptable salts of the compounds of formula (VIX).
Included among the compounds of the present invention and used in the methods of the present invention are compounds of formula (VIIX):
Figure BDA0002308602660000141
wherein:
L62selected from: bond, -CH2-、-NH-、CH2-O-、-O-CH2-、-O-CH2-CH2-and-CH2-CH2-O-, or L62And R61Together form an imidazolidinyl or pyrrolidinyl group;
L63and R63Together form an imidazolidinyl or pyrrolidinyl group;
R61selected from: hydrogen, C1-6Alkyl, substituted C1-6Alkyl, and oxetanyl, or
R61And L62Together form an imidazolidinyl or pyrrolidinyl group;
R65and R66Independently hydrogen, methyl, or chlorine;
R62and R64Is O;
C6and D6Independently is phenyl or pyridyl;
Z62and z64Independently 0 or 1; and is
Z65And z66Independently isAn integer of 0 to 3;
or a salt thereof, including pharmaceutically acceptable salts thereof.
The invention also relates to pharmaceutically acceptable salts of compounds of formula (VIIX).
Included among the compounds of the present invention and used in the methods of the present invention are compounds of formula (VIIIX):
Figure BDA0002308602660000142
wherein:
L72selected from: bond, -CH2-、-NH-、CH2-O-、-O-CH2-、-O-CH2-CH2-and-CH2-CH2-O-；
L73And R73Together form an imidazolidinyl or pyrrolidinyl group;
R71selected from: hydrogen, C1-6Alkyl, substituted C1-6Alkyl, and oxetanyl;
R75and R76Independently hydrogen, methyl, or chlorine;
R72and R74Is O;
C7and D7Independently is phenyl or pyridyl;
Z72and z74Independently 0 or 1; and is
Z75And z76Independently an integer from 0 to 3;
or a salt thereof, including pharmaceutically acceptable salts thereof.
The invention also relates to pharmaceutically acceptable salts of compounds of formula (VIIIX).
Included among the compounds of the present invention and used in the methods of the present invention are compounds of formula (IIIZ):
Figure BDA0002308602660000151
wherein:
L82selected from: a bond, -NH-, -O-, -S-, -S (O) -, -S (O)2-, cycloalkyl, -O-cycloalkyl, cycloalkyl-O-, -NH-cycloalkyl, cycloalkyl-NH-, azetidinyl, -O-azetidinyl, azetidinyl-O-, -N-azetidinyl, azetidinyl-N-, substituted or unsubstituted C1-6Alkylene and substituted or unsubstituted C1-6Heteroalkylene, or L82And R83Together form: heterocycloalkyl, heterocycloalkyl-O-, heterocycloalkyl-NH-, heterocycloalkyl-CH2-, oxoheterocycloalkyl-O-, oxoheterocycloalkyl-N-, or oxoheterocycloalkyl-CH2-；
L83Selected from: cycloalkyl, -O-cycloalkyl, cycloalkyl-O-, -NH-cycloalkyl, cycloalkyl-NH-, azetidinyl, -O-azetidinyl, azetidinyl-O-, -N-azetidinyl, azetidinyl-N-, or L83And R81Together form: heterocycloalkyl, heterocycloalkyl-O-, heterocycloalkyl-NH-, heterocycloalkyl-CH2-, oxoheterocycloalkyl-O-, oxoheterocycloalkyl-N-, or oxoheterocycloalkyl-CH2-；
R81Selected from: hydrogen, C1-6Alkyl, substituted C1-6Alkyl and heterocycloalkyl, or R81And L83Together form: heterocycloalkyl, heterocycloalkyl-O-, heterocycloalkyl-NH-, heterocycloalkyl-CH2-, oxoheterocycloalkyl-O-, oxoheterocycloalkyl-N-, or oxoheterocycloalkyl-CH2-；
R83Selected from: hydrogen, C1-6Alkyl, substituted C1-6Alkyl and heterocycloalkyl, or R83And L82Together form: heterocycloalkyl, heterocycloalkyl-O-, heterocycloalkyl-NH-, heterocycloalkyl-CH2-, oxoheterocycloalkyl-O-, oxoheterocycloalkyl-N-, or oxoheterocycloalkyl-CH2-；
R85And R86Each independently of the others being fluorine, chlorine, bromine, iodine, -OCH3、-OCH2Ph、-C(O)Ph、-CF3、-CN、-S(O)CH3、-OH、-NH2、-COOH、-CONH2、-NO2、-C(O)CH3、-C≡CH、-CH2C≡CH、-SCH3、-SO3H、-SO2NH2、-NHC(O)NH2、-NHC(O)H、-NHOH、-OCF3、-OCHF2Substituted or unsubstituted C1-6An alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group;
R82and R84Independently is NR88、O、CH2Or S;
R88selected from: hydrogen, C1-6Alkyl and C substituted by 1 to 6 fluorine1-6An alkyl group;
a and b are independently 0 or 1;
C8and D8Independently is phenyl or pyridyl;
X6is C1-3Alkylene or C substituted by 1 to 3 fluorine1-3An alkylene group;
Z82and z84Independently 0 or 1; and is
Z85And z86Independently an integer from 0 to 5;
or a salt thereof, including pharmaceutically acceptable salts thereof.
The invention also relates to pharmaceutically acceptable salts of the compounds of formula (IIIZ).
Included among the compounds of the present invention and used in the methods of the present invention are compounds of formula (IVZ):
Figure BDA0002308602660000161
wherein:
L92selected from: a bond, -NH-, -O-, -S-, -S (O) -, -S (O)2-, substituted or unsubstituted C1-6Alkylene and substituted or unsubstituted C1-6A heteroalkylene group;
L93selected from: cycloalkyl, -O-cycloalkanesAnd cycloalkyl-O-, azetidinyl, -O-azetidinyl, azetidinyl-O-, or L93And R91Together form: heterocycloalkyl, heterocycloalkyl-O-, oxoheterocycloalkyl, or oxoheterocycloalkyl-O-;
R91selected from: hydrogen, C1-6Alkyl, substituted C1-6Alkyl, and heterocycloalkyl, or R91And L93Together form: heterocycloalkyl, heterocycloalkyl-O-, oxoheterocycloalkyl, or oxoheterocycloalkyl-O-;
R93selected from: hydrogen, C1-6Alkyl, substituted C1-6Alkyl, and heterocycloalkyl;
R95and R96Independently selected from: fluorine, chlorine, bromine, iodine, -OCH3、-OCH2Ph、-C(O)Ph、-CF3、-CN、-S(O)CH3、-OH、-NH2、-COOH、-CONH2、-NO2、-C(O)CH3、-C≡CH、-CH2C≡CH、-SCH3、-SO3H、-SO2NH2、-NHC(O)NH2、-NHC(O)H、-NHOH、-OCF3、-OCHF2Substituted or unsubstituted C1-6An alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group;
R92and R94Independently is NR98O, or S;
R98selected from: hydrogen, C1-6Alkyl and C substituted by 1 to 6 fluorine1-6An alkyl group;
a and b are independently 0 or 1;
C9and D9Independently is phenyl or pyridyl;
X7is C1-3Alkylene or C substituted by 1 to 3 fluorine1-3An alkylene group;
Z92and z94Independently 0 or 1; and is
Z95And z96Independently an integer from 0 to 5;
or a salt thereof, including pharmaceutically acceptable salts thereof.
The invention also relates to pharmaceutically acceptable salts of the compounds of formula (IVZ).
Included among the compounds of the present invention and used in the methods of the present invention are compounds of formula (VZ):
wherein:
L102selected from: bond, -CH2-、-NH-、CH2-O-、-O-CH2-, cyclopropyl, -O-cyclopropyl, cyclopropyl-O-, -NH-cyclopropyl, cyclopropyl-NH-, azetidinyl, -O-azetidinyl, azetidinyl-O-, -N-azetidinyl, azetidinyl-N-, -O-CH2-CH2-and-CH2-CH2-O-, or L102And R101Together form: imidazolidinyl, azetidinyl-O-, azetidinyl-N-, azetidinyl-CH2-, piperidinyl-O-, piperidinyl-N-, piperidinyl-CH2-, piperazinyl-O-, piperazinyl-N-, piperazinyl-CH2-, oxopiperazinyl-O-, oxopiperazinyl-N-, oxopiperazinyl-CH2-, pyrrolidinyl-O-, pyrrolidinyl-N-, pyrrolidinyl-CH2-, oxopyrrolidinyl-O-, oxopyrrolidinyl-N-, or oxopyrrolidinyl-CH2-；
L103Selected from: cyclopropyl, azetidinyl, -O-azetidinyl, azetidinyl-O-, -N-azetidinyl, azetidinyl-N-, or L103And R103Together form: imidazolidinyl, azetidinyl-O-, azetidinyl-N-, azetidinyl-CH2-, piperidinyl-O-, piperidinyl-N-, piperidinyl-CH2-, piperazinyl-O-, piperazinyl-N-, piperazinyl-CH2-, oxopiperazinyl, oxopiperazineradical-O-, oxo-piperazinyl-N-, oxo-piperazinyl-CH2-, pyrrolidinyl-O-, pyrrolidinyl-N-, pyrrolidinyl-CH2-, oxopyrrolidinyl-O-, oxopyrrolidinyl-N-, or oxopyrrolidinyl-CH2-；
R101Selected from: hydrogen, C1-6Alkyl, substituted C1-6Alkyl, and oxetanyl, or
R101Together with L102 form: imidazolidinyl, azetidinyl-O-, azetidinyl-N-, azetidinyl-CH2-, piperidinyl-O-, piperidinyl-N-, piperidinyl-CH2-, piperazinyl-O-, piperazinyl-N-, piperazinyl-CH2-, oxopiperazinyl-O-, oxopiperazinyl-N-, oxopiperazinyl-CH2-, pyrrolidinyl-O-, pyrrolidinyl-N-, pyrrolidinyl-CH2-, oxopyrrolidinyl-O-, oxopyrrolidinyl-N-, or oxopyrrolidinyl-CH2-；
R103Selected from: hydrogen, C1-6Alkyl, substituted C1-6Alkyl, and oxetanyl, or
R103And L103Together form: imidazolidinyl, azetidinyl-O-, azetidinyl-N-, azetidinyl-CH2-, piperidinyl-O-, piperidinyl-N-, piperidinyl-CH2-, piperazinyl-O-, piperazinyl-N-, piperazinyl-CH2-, oxopiperazinyl-O-, oxopiperazinyl-N-, oxopiperazinyl-CH2-, pyrrolidinyl-O-, pyrrolidinyl-N-, pyrrolidinyl-CH2-, oxopyrrolidinyl-O-, oxopyrrolidinyl-N-, or oxopyrrolidinyl-CH2-；
R105And R106Each independently selected from: methyl, cyclopropyl, -OCF3Fluorine, chlorine, -SCH3、-OCH3、-OCHF2and-CF3；
R102And R104Is O;
a and b are independently 0 or 1;
C10and D10Independently is phenyl or pyridyl;
X8is selected from-CH2-and-CH2-CH2-；
Z102And z104Independently 0 or 1; and is
Z105And z106Independently an integer from 0 to 5;
or a salt thereof, including pharmaceutically acceptable salts thereof.
The invention also relates to pharmaceutically acceptable salts of the compounds of formula (VZ).
Included among the compounds of the present invention and used in the methods of the present invention are compounds of formula (VIZ):
Figure BDA0002308602660000191
wherein:
L112selected from: bond, -CH2-、-NH-、CH2-O-、-O-CH2-、-O-CH2-CH2-, and-CH2-CH2-O-；
L113Selected from: cyclopropyl, -O-cyclopropyl, cyclopropyl-O-, azetidinyl, -O-azetidinyl, azetidinyl-O-, or L113And R113Together form: imidazolidinyl, azetidinyl-O-, piperidinyl-O-, piperazinyl-O-, oxopiperazinyl-O-, pyrrolidinyl-O-, oxopyrrolidinyl, or oxopyrrolidinyl-O-;
R113selected from: hydrogen, C1-6Alkyl, substituted C1-6Alkyl, and oxetanyl, or
R113And L113Together form: imidazolidinyl, azetidinyl-O-, piperidinyl-O-, piperazinyl-O-Oxopiperazinyl, oxopiperazinyl-O-, pyrrolidinyl-O-, oxopyrrolidinyl, or oxopyrrolidinyl-O-;
R111selected from: hydrogen, C1-6Alkyl, substituted C1-6Alkyl, and oxetanyl;
R115and R116Each independently selected from: methyl, cyclopropyl, -OCF3Fluorine, chlorine, -SCH3、-OCH3、-OCHF2and-CF3；
R112And R114Is O;
a and b are independently 0 or 1;
C11and D11Independently is phenyl or pyridyl;
X9is selected from-CH2-and-CH2-CH2-；
Z112And z114Independently 0 or 1; and is
Z115And z116Independently an integer from 0 to 5;
or a salt thereof, including pharmaceutically acceptable salts thereof.
The invention also relates to pharmaceutically acceptable salts of the compounds of formula (VIZ).
Included among the compounds of the present invention and used in the methods of the present invention are compounds of formula (VIIZ):
Figure BDA0002308602660000201
wherein:
w is selected from the group consisting of dicyclopentanyl and dicyclohexanyl;
L122selected from: bond, -CH2-、-NH-、CH2-O-、-O-CH2-, cyclopropyl, -O-cyclopropyl, cyclopropyl-O-, -NH-cyclopropyl, cyclopropyl-NH-, azetidinyl, -O-azetidinyl, azetidinyl-O-, -N-azetidinyl, azetidinyl-N-, -O-CH2-CH2-and-CH2-CH2-O-, or L122And R121Together form: imidazolidinyl, azetidinyl-O-, azetidinyl-N-, azetidinyl-CH2-, piperidinyl-O-, piperidinyl-N-, piperidinyl-CH2-, piperazinyl-O-, piperazinyl-N-, piperazinyl-CH2-, oxopiperazinyl-O-, oxopiperazinyl-N-, oxopiperazinyl-CH2-, pyrrolidinyl-O-, pyrrolidinyl-N-, pyrrolidinyl-CH2-, oxopyrrolidinyl-O-, oxopyrrolidinyl-N-, or oxopyrrolidinyl-CH2-；
L123Selected from: cyclopropyl, -O-cyclopropyl, cyclopropyl-O-, -NH-cyclopropyl, cyclopropyl-NH-, azetidinyl, -O-azetidinyl, azetidinyl-O-, -N-azetidinyl, azetidinyl-N-, or L123And R123Together form: imidazolidinyl, azetidinyl-O-, azetidinyl-N-, azetidinyl-CH2-, piperidinyl-O-, piperidinyl-N-, piperidinyl-CH2-, piperazinyl-O-, piperazinyl-N-, piperazinyl-CH2-, oxopiperazinyl-O-, oxopiperazinyl-N-, oxopiperazinyl-CH2-, pyrrolidinyl-O-, pyrrolidinyl-N-, pyrrolidinyl-CH2-, oxopyrrolidinyl-O-, oxopyrrolidinyl-N-, or oxopyrrolidinyl-CH2-；
R121Selected from: hydrogen, C1-6Alkyl, substituted C1-6Alkyl, and oxetanyl, or
R121And L122Together form: imidazolidinyl, azetidinyl-O-, azetidinyl-N-, azetidinyl-CH2-, piperidinyl-O-, piperidinyl-N-, piperidinyl-CH2-, piperazinyl-O-, piperazinyl-N-, piperazinyl-CH2-, oxopiperazinyl-O-, oxopiperazinyl-N-, oxopiperazinyl-CH2-, pyrrolidinyl-O-),pyrrolidinyl-N-, pyrrolidinyl-CH2-, oxopyrrolidinyl-O-, oxopyrrolidinyl-N-, or oxopyrrolidinyl-CH2-；
R123Is hydrogen or R123And L123Together form: imidazolidinyl, azetidinyl-O-, azetidinyl-N-, azetidinyl-CH2-, piperidinyl-O-, piperidinyl-N-, piperidinyl-CH2-, piperazinyl-O-, piperazinyl-N-, piperazinyl-CH2-, oxopiperazinyl-O-, oxopiperazinyl-N-, oxopiperazinyl-CH2-, pyrrolidinyl-O-, pyrrolidinyl-N-, pyrrolidinyl-CH2-, oxopyrrolidinyl-O-, oxopyrrolidinyl-N-, or oxopyrrolidinyl-CH2-；
R125And R126Each independently selected from: methyl, cyclopropyl, -OCF3Fluorine, chlorine, -SCH3、-OCH3、-OCHF2and-CF3；
R122And R124Is O;
C12and D12Independently is phenyl or pyridyl;
Z122and z124Independently 0 or 1; and is
Z125And z126Independently an integer from 0 to 3;
or a salt thereof, including pharmaceutically acceptable salts thereof.
The invention also relates to pharmaceutically acceptable salts of compounds of formula (VIIZ).
Included among the compounds of the present invention and used in the methods of the present invention are compounds of formula (VIIIZ):
Figure BDA0002308602660000221
wherein:
W1selected from the group consisting of dicyclopentanyl and dicyclohexanyl;
L132selected from: bond, -CH2-、-NH-、CH2-O-、-O-CH2-、-O-CH2-CH2-and-CH2-CH2-O-；
L133 is selected from: cyclopropyl, -O-cyclopropyl, cyclopropyl-O-, azetidinyl, -O-azetidinyl, azetidinyl-O-, or L133And R133Together form: imidazolidinyl, azetidinyl-O-, piperidinyl-O-, piperazinyl-O-, oxopiperazinyl-O-, pyrrolidinyl-O-, oxopyrrolidinyl, or oxopyrrolidinyl-O-;
R133is hydrogen or R133And L133Together form: imidazolidinyl, azetidinyl-O-, piperidinyl-O-, piperazinyl-O-, oxopiperazinyl-O-, pyrrolidinyl-O-, oxopyrrolidinyl, or oxopyrrolidinyl-O-;
R135and R136Each independently selected from: methyl, cyclopropyl, -OCF3Fluorine, chlorine, -SCH3、-OCH3、-OCHF2and-CF3；
R132And R134Is O;
C13and D13Each independently is phenyl or pyridyl;
Z132and z134Each independently is 0 or 1; and is
Z135And z136Each independently is an integer from 0 to 3;
or a salt thereof, including pharmaceutically acceptable salts thereof.
The invention also relates to pharmaceutically acceptable salts of compounds of formula (VIIIZ).
Included among the compounds of the present invention and used in the methods of the present invention are compounds of formula (IIIQ):
Figure BDA0002308602660000231
wherein:
L82’selected from: a bond, -NH-, -O-, -S-, -S (O) -, -S (O)2-, cycloalkyl, -O-cycloalkyl, cycloalkyl-O-, -NH-cycloalkyl, cycloalkyl-NH-, azetidinyl, -O-azetidinyl, azetidinyl-O-, -N-azetidinyl, azetidinyl-N-, substituted or unsubstituted C1-6Alkylene and substituted or unsubstituted C1-6Heteroalkylene, or L82’And R83’Together form: heterocycloalkyl, heterocycloalkyl-O-, heterocycloalkyl-NH-, heterocycloalkyl-CH2-, oxoheterocycloalkyl-O-, oxoheterocycloalkyl-N-, or oxoheterocycloalkyl-CH2-,
Or the like, or, alternatively,
L82’and is adjacent to L82’To C8’R of the point of attachment of (A)85’The substituents together forming a fused ring to C8’The cycloalkyl, heterocycloalkyl, and/or heteroaryl ring of (a);
L83’selected from: cycloalkyl, -O-cycloalkyl, cycloalkyl-O-, -NH-cycloalkyl, cycloalkyl-NH-, azetidinyl, -O-azetidinyl, azetidinyl-O-, -N-azetidinyl, azetidinyl-N-, or L83’And R81’Together form: heterocycloalkyl, heterocycloalkyl-O-, heterocycloalkyl-NH-, heterocycloalkyl-CH2-, oxoheterocycloalkyl-O-, oxoheterocycloalkyl-N-, or oxoheterocycloalkyl-CH2-,
Or the like, or, alternatively,
L83’and is adjacent to L83’To D8’R of the point of attachment of (A)86’The substituents together form a ring fused to D8’The cycloalkyl, heterocycloalkyl, and/or heteroaryl ring of (a);
R81’selected from: hydrogen, C1-6Alkyl, substituted C1-6Alkyl and heterocycloalkyl, or R81’And L83’Together form: heterocycloalkyl, heterocycloalkyl-O-, heterocycloalkyl-NH-, heterocycloalkyl-CH2-, oxoheterocycloalkyloxo-heterocycloalkyl-O-, oxo-heterocycloalkyl-N-, or oxo-heterocycloalkyl-CH2-；
R83’Selected from: hydrogen, C1-6Alkyl, substituted C1-6Alkyl and heterocycloalkyl, or R83’And L82’Together form: heterocycloalkyl, heterocycloalkyl-O-, heterocycloalkyl-NH-, heterocycloalkyl-CH2-, oxoheterocycloalkyl-O-, oxoheterocycloalkyl-N-, or oxoheterocycloalkyl-CH2-；
R85’Selected from: fluorine, chlorine, bromine, iodine, -OCH3、-OCH2Ph、-C(O)Ph、-CF3、-CN、-S(O)CH3、-OH、-NH2、-COOH、-CONH2、-NO2、-C(O)CH3、-C≡CH、-CH2C≡CH、-SCH3、-SO3H、-SO2NH2、-NHC(O)NH2、-NHC(O)H、-NHOH、-OCF3、-OCHF2Substituted or unsubstituted C1-6An alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group,
or the like, or, alternatively,
two adjacent R85’The substituents may combine to form a fused to C8’A cycloalkyl ring, a heterocycloalkyl ring and/or a heteroaryl ring of (a),
or the like, or, alternatively,
adjacent to L82’To C8’R of the point of attachment of (A)85’The substituents may be substituted with L82’Combined to form a fusion to C8’The cycloalkyl, heterocycloalkyl, and/or heteroaryl ring of (a);
R86’selected from: fluorine, chlorine, bromine, iodine, -OCH3、-OCH2Ph、-C(O)Ph、-CF3、-CN、-S(O)CH3、-OH、-NH2、-COOH、-CONH2、-NO2、-C(O)CH3、-C≡CH、-CH2C≡CH、-SCH3、-SO3H、-SO2NH2、-NHC(O)NH2、-NHC(O)H、-NHOH、-OCF3、-OCHF2Substituted or unsubstituted C1-6An alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group,
or the like, or, alternatively,
two adjacent R86’The substituents may combine to form a cycloalkyl ring, a heterocycloalkyl ring, or be fused to D8’The heteroaryl ring of (a) is a ring,
or the like, or, alternatively,
adjacent to L83’To D8’R of the point of attachment of (A)86’The substituents may be substituted with L83’Combined to form a fusion to D8’The cycloalkyl, heterocycloalkyl, and/or heteroaryl ring of (a);
R82’and R84’Independently is NR88’、O、CH2Or S;
R88’selected from: hydrogen, C1-6Alkyl and C substituted by 1 to 6 fluorine1-6An alkyl group;
a and b are independently 0 or 1;
C8’and D8’Independently is phenyl or pyridyl;
X6’is C1-3Alkylene or C substituted by 1 to 3 fluorine1-3An alkylene group;
Z82’and z84’Independently 0 or 1; and is
Z85’And z86’Independently an integer from 0 to 5;
or a salt thereof, including pharmaceutically acceptable salts thereof.
The invention also relates to pharmaceutically acceptable salts of compounds of formula (IIIQ).
Included among the compounds of the present invention and used in the methods of the present invention are compounds of formula (IVQ):
Figure BDA0002308602660000251
wherein:
L92’selected from: a bond, -NH-, -O-, -S-, -S (O) -, -S (O)2-, substituted or unsubstituted C1-6Alkylene and substituted or unsubstituted C1-6A heteroalkylene group;
L93’selected from: cycloalkyl, -O-cycloalkyl, and cycloalkyl-O-, azetidinyl, -O-azetidinyl, azetidinyl-O-, or L93’And R91’Together form: heterocycloalkyl, heterocycloalkyl-O-, oxoheterocycloalkyl, or oxoheterocycloalkyl-O-,
or the like, or, alternatively,
L93’and is adjacent to L93’R of the point of attachment of (A)96’The substituents together form a cycloalkyl, heterocycloalkyl, or heteroaryl ring;
R91’selected from: hydrogen, C1-6Alkyl, substituted C1-6Alkyl, and heterocycloalkyl, or R91’And L93’Together form: heterocycloalkyl, heterocycloalkyl-O-, oxoheterocycloalkyl, or oxoheterocycloalkyl-O-;
R93’selected from: hydrogen, C1-6Alkyl, substituted C1-6Alkyl, and heterocycloalkyl;
R95’selected from: fluorine, chlorine, bromine, iodine, -OCH3、-OCH2Ph、-C(O)Ph、-CF3、-CN、-S(O)CH3、-OH、-NH2、-COOH、-CONH2、-NO2、-C(O)CH3、-C≡CH、-CH2C≡CH、-SCH3、-SO3H、-SO2NH2、-NHC(O)NH2、-NHC(O)H、-NHOH、-OCF3、-OCHF2Substituted or unsubstituted C1-6An alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group;
R96’selected from: fluorine, chlorine, bromine, iodine, -OCH3、-OCH2Ph、-C(O)Ph、-CF3、-CN、-S(O)CH3、-OH、-NH2、-COOH、-CONH2、-NO2、-C(O)CH3、-C≡CH、-CH2C≡CH、-SCH3、-SO3H、-SO2NH2、-NHC(O)NH2、-NHC(O)H、-NHOH、-OCF3、-OCHF2Substituted or unsubstituted C1-6An alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group,
or the like, or, alternatively,
two adjacent R96’The substituents may combine to form a cycloalkyl ring, a heterocycloalkyl ring, and/or be fused to D9’The heteroaryl ring of (a) is a ring,
or the like, or, alternatively,
adjacent to L93’To D9’R of the point of attachment of (A)96’The substituents may be substituted with L93’Combined to form a cycloalkyl ring, a heterocycloalkyl ring and/or fused to D9’A heteroaryl ring of (a);
R92’and R94’Independently is NR98’O, or S;
R98’selected from: hydrogen, C1-6Alkyl and C substituted by 1 to 6 fluorine1-6An alkyl group;
a and b are independently 0 or 1;
C9’and D9’Independently is phenyl or pyridyl;
X7’is C1-3Alkylene or C substituted by 1 to 3 fluorine1-3An alkylene group;
Z92’and z94’Independently 0 or 1; and is
Z95’And z96’Independently an integer from 0 to 5;
or a salt thereof, including pharmaceutically acceptable salts thereof.
The invention also relates to pharmaceutically acceptable salts of the compounds of formula (IVQ).
Included among the compounds of the present invention and used in the methods of the present invention are compounds of formula (VQ):
Figure BDA0002308602660000271
wherein:
L102’selected from: bond, -CH2-、-NH-、CH2-O-、-O-CH2-, cyclopropyl, -O-cyclopropyl, cyclopropyl-O-, -NH-cyclopropyl, cyclopropyl-NH-, azetidinyl, -O-azetidinyl, azetidinyl-O-, -N-azetidinyl, azetidinyl-N-, -O-CH2-CH2-and-CH2-CH2-O-, or L102’And R101’Together form: imidazolidinyl, azetidinyl-O-, azetidinyl-N-, azetidinyl-CH2-, piperidinyl-O-, piperidinyl-N-, piperidinyl-CH2-, piperazinyl-O-, piperazinyl-N-, piperazinyl-CH2-, oxopiperazinyl-O-, oxopiperazinyl-N-, oxopiperazinyl-CH2-, pyrrolidinyl-O-, pyrrolidinyl-N-, pyrrolidinyl-CH2-, oxopyrrolidinyl-O-, oxopyrrolidinyl-N-, or oxopyrrolidinyl-CH2-,
Or the like, or, alternatively,
L102’and is adjacent to L102’R of the point of attachment of (A)105’The substituents together form a heterocycloalkyl ring;
L103’selected from: cyclopropyl, -O-cyclopropyl, cyclopropyl-O-, -NH-cyclopropyl, cyclopropyl-NH-, azetidinyl, -O-azetidinyl, azetidinyl-O-, -N-azetidinyl, azetidinyl-N-, or L103’And R103’Together form: imidazolidinyl, azetidinyl-O-, azetidinyl-N-, azetidinyl-CH2-, piperidinyl-O-, piperidinyl-N-, piperidinyl-CH2-, piperazinyl-O-, piperazinyl-N-, piperazinyl-CH2-, oxopiperazinyl-O-, oxopiperazinyl-N-, oxopiperazinylradical-CH2-, pyrrolidinyl-O-, pyrrolidinyl-N-, pyrrolidinyl-CH2-, oxopyrrolidinyl-O-, oxopyrrolidinyl-N-, or oxopyrrolidinyl-CH2-,
Or the like, or, alternatively,
L103’and is adjacent to L103’R of the point of attachment of (A)106’The substituents together form a heterocycloalkyl ring;
R101’selected from: hydrogen, C1-6Alkyl, substituted C1-6Alkyl, and oxetanyl, or
R101And L102’Together form: imidazolidinyl, azetidinyl-O-, azetidinyl-N-, azetidinyl-CH2-, piperidinyl-O-, piperidinyl-N-, piperidinyl-CH2-, piperazinyl-O-, piperazinyl-N-, piperazinyl-CH2-, oxopiperazinyl-O-, oxopiperazinyl-N-, oxopiperazinyl-CH2-, pyrrolidinyl-O-, pyrrolidinyl-N-, pyrrolidinyl-CH2-, oxopyrrolidinyl-O-, oxopyrrolidinyl-N-, or oxopyrrolidinyl-CH2-；
R103’Selected from: hydrogen, C1-6Alkyl, substituted C1-6Alkyl, and oxetanyl, or
R103’And L103’Together form: imidazolidinyl, azetidinyl-O-, azetidinyl-N-, azetidinyl-CH2-, piperidinyl-O-, piperidinyl-N-, piperidinyl-CH2-, piperazinyl-O-, piperazinyl-N-, piperazinyl-CH2-, oxopiperazinyl-O-, oxopiperazinyl-N-, oxopiperazinyl-CH2-, pyrrolidinyl-O-, pyrrolidinyl-N-, pyrrolidinyl-CH2-, oxopyrrolidinyl-O-, oxopyrrolidinyl-N-, or oxopyrrolidinyl-CH2-；
R105’Selected from: first of allAlkyl, cyclopropyl, -OCF3Fluorine, chlorine, -SCH3、-OCH3、-OCHF2and-CF3,
Or the like, or, alternatively,
adjacent to L102’To C10’R of the point of attachment of (A)105’The substituents may be substituted with L102’Combined to form a fusion to C10’The heterocycloalkyl ring of (a);
R106’selected from: methyl, cyclopropyl, -OCF3Fluorine, chlorine, -SCH3、-OCH3、-OCHF2and-CF3,
Or the like, or, alternatively,
adjacent to L103’To D10’R of the point of attachment of (A)106’The substituents may be substituted with L103’Combined to form a fusion to D10’The heterocycloalkyl ring of (a);
R102’and R104’Is O;
a and b are independently 0 or 1;
C10’and D10’Independently is phenyl or pyridyl;
X8’is selected from-CH2-and-CH2-CH2-；
Z102’And z104’Independently 0 or 1; and is
Z105’And z106’Independently an integer from 0 to 5;
or a salt thereof, including pharmaceutically acceptable salts thereof.
The invention also relates to pharmaceutically acceptable salts of the compounds of formula (VQ).
Included among the compounds of the present invention and used in the methods of the present invention are compounds of formula (VIQ):
Figure BDA0002308602660000291
wherein:
L112’selected from: bond, -CH2-、-NH-、CH2-O-、-O-CH2-、-O-CH2-CH2-, and-CH2-CH2-O-；
L113’Selected from: cyclopropyl, -O-cyclopropyl, cyclopropyl-O-, azetidinyl, -O-azetidinyl, azetidinyl-O-, or L113’And R113’Together form: imidazolidinyl, azetidinyl-O-, piperidinyl-O-, piperazinyl-O-, oxopiperazinyl-O-, pyrrolidinyl-O-, oxopyrrolidinyl, or oxopyrrolidinyl-O-,
or the like, or, alternatively,
L113’and is adjacent to L113’R of the point of attachment of (A)116’The substituents together form a heterocycloalkyl ring;
R113’selected from: hydrogen, C1-6Alkyl, substituted C1-6Alkyl, and oxetanyl, or
R113’And L113’Together form: imidazolidinyl, azetidinyl-O-, piperidinyl-O-, piperazinyl-O-, oxopiperazinyl-O-, pyrrolidinyl-O-, oxopyrrolidinyl, or oxopyrrolidinyl-O-;
R111’selected from: hydrogen, C1-6Alkyl, substituted C1-6Alkyl, and oxetanyl;
R115’selected from: methyl, cyclopropyl, -OCF3Fluorine, chlorine, -SCH3、-OCH3、-OCHF2and-CF3；
R116’Selected from: methyl, cyclopropyl, -OCF3Fluorine, chlorine, -SCH3、-OCH3、-OCHF2and-CF3,
Or the like, or, alternatively,
adjacent to L113’To D11’R of the point of attachment of (A)116’The substituents may be substituted with L113’Combined to form a fusion to D11’The heterocycloalkyl ring of (a);
R112’and R114’Is O;
a and b are independently 0 or 1;
C11’and D11’Independently is phenyl or pyridyl;
X9’is selected from-CH2-and-CH2-CH2-；
Z112’And z114’Independently 0 or 1; and is
Z115’And z116’Independently an integer from 0 to 5;
or a salt thereof, including pharmaceutically acceptable salts thereof.
The invention also relates to pharmaceutically acceptable salts of the compounds of formula (VIQ).
Included among the compounds of the present invention and used in the methods of the present invention are compounds of formula (VIIQ):
Figure BDA0002308602660000301
wherein:
w is selected from the group consisting of dicyclopentanyl and dicyclohexanyl;
L122’selected from: bond, -CH2-、-NH-、CH2-O-、-O-CH2-, cyclopropyl, -O-cyclopropyl, cyclopropyl-O-, -NH-cyclopropyl, cyclopropyl-NH-, azetidinyl, -O-azetidinyl, azetidinyl-O-, -N-azetidinyl, azetidinyl-N-, -O-CH2-CH2-and-CH2-CH2-O-, or L122’And R121’Together form: imidazolidinyl, azetidinyl-O-, azetidinyl-N-, azetidinyl-CH2-, piperidinyl-O-, piperidinyl-N-, piperidinyl-CH2-, piperazinyl-O-, piperazinyl-N-, piperazinyl-CH2-, oxopiperazinyl-O-, oxopiperazinyl-N-, oxopiperazinyl-CH2-, pyrrolidinyl-O-, pyrrolidinyl-N-, pyrrolidinyl-CH2-, oxopyrrolidinyl-O-, oxopyrrolidinyl-N-, or oxopyrrolidinyl-CH2-,
Or the like, or, alternatively,
L122’and is adjacent to L122’R of the point of attachment of (A)125’The substituents together form a cyclohexyl, cyclobutyl, or tetrahydropyran ring;
L123’selected from: cyclopropyl, azetidinyl, -O-azetidinyl, azetidinyl-O-, -N-azetidinyl, azetidinyl-N-, or L123’And R123’Together form: imidazolidinyl, azetidinyl-O-, azetidinyl-N-, azetidinyl-CH2-, piperidinyl-O-, piperidinyl-N-, piperidinyl-CH2-, piperazinyl-O-, piperazinyl-N-, piperazinyl-CH2-, oxopiperazinyl-O-, oxopiperazinyl-N-, oxopiperazinyl-CH2-, pyrrolidinyl-O-, pyrrolidinyl-N-, pyrrolidinyl-CH2-, oxopyrrolidinyl-O-, oxopyrrolidinyl-N-, or oxopyrrolidinyl-CH2-,
Or the like, or, alternatively,
L123’and is adjacent to L123’R of the point of attachment of (A)126’The substituents together form a cyclohexyl, cyclobutyl, or tetrahydropyran ring;
R121’selected from: hydrogen, C1-6Alkyl, substituted C1-6Alkyl, and oxetanyl, or
R121’And L122’Together form: imidazolidinyl, azetidinyl-O-, azetidinyl-N-, azetidinyl-CH2-, piperidinyl-O-, piperidinyl-N-, piperidinyl-CH2-, piperazinyl-O-, piperazinyl-N-, piperazinyl-CH2-, oxopiperazinyl-O-, oxopiperazinyl-N-, oxopiperazinyl-CH2-, pyrrolidinyl-O-, pyrrolidinyl-N-, pyrrolidinyl-CH2-, oxopyrrolidinyl-O-, oxopyrazolepyrrolidinyl-N-, or oxopyrrolidinyl-CH2-；
R123’Is hydrogen or R123’And L123’Together form: imidazolidinyl, azetidinyl-O-, azetidinyl-N-, azetidinyl-CH2-, piperidinyl-O-, piperidinyl-N-, piperidinyl-CH2-, piperazinyl-O-, piperazinyl-N-, piperazinyl-CH2-, oxopiperazinyl-O-, oxopiperazinyl-N-, oxopiperazinyl-CH2-, pyrrolidinyl-O-, pyrrolidinyl-N-, pyrrolidinyl-CH2-, oxopyrrolidinyl-O-, oxopyrrolidinyl-N-, or oxopyrrolidinyl-CH2-；
R125’Selected from: methyl, cyclopropyl, -OCF3Fluorine, chlorine, -SCH3、-OCH3、-OCHF2and-CF3,
Or the like, or, alternatively,
adjacent to L122’To C12’R of the point of attachment of (A)125’The substituents may be substituted with L122’Combined to form a cyclohexyl ring, a cyclobutyl ring or fused to C12’The tetrahydropyran ring of (a);
R126’selected from: methyl, cyclopropyl, -OCF3Fluorine, chlorine, -SCH3、-OCH3、-OCHF2and-CF3,
Or the like, or, alternatively,
adjacent to L123' to D12’R of the point of attachment of (A)126’The substituents may be substituted with L123’Combined to form a cyclohexyl ring, cyclobutyl ring or fused to D12’The tetrahydropyran ring of (a);
R122’and R124’Is O;
C12’and D12’Independently is phenyl or pyridyl;
Z122’and z124’Independently 0 or 1; and is
Z125’And z126’Independently an integer from 0 to 3;
or a salt thereof, including pharmaceutically acceptable salts thereof.
The invention also relates to pharmaceutically acceptable salts of compounds of formula (VIIQ).
Included among the compounds of the present invention and used in the methods of the present invention are compounds of formula (VIIIQ):
Figure BDA0002308602660000321
wherein:
W1selected from the group consisting of dicyclopentanyl and dicyclohexanyl;
L132’selected from: bond, -CH2-、-NH-、CH2-O-、-O-CH2-、-O-CH2-CH2-and-CH2-CH2-O-；
L133’Selected from: cyclopropyl, -O-cyclopropyl, cyclopropyl-O-, azetidinyl, -O-azetidinyl, azetidinyl-O-, or L133’And R133’Together form: imidazolidinyl, azetidinyl-O-, piperidinyl-O-, piperazinyl-O-, oxopiperazinyl-O-, pyrrolidinyl-O-, oxopyrrolidinyl, or oxopyrrolidinyl-O-,
or the like, or, alternatively,
L133’and is adjacent to L133’R of the point of attachment of (A)136’The substituents together form a cyclohexyl, cyclobutyl, or tetrahydropyran ring;
R133’is hydrogen or R133’And L133’Together form: imidazolidinyl, azetidinyl-O-, piperidinyl-O-, piperazinyl-O-, oxopiperazinyl-O-, pyrrolidinyl-O-, oxopyrrolidinyl, or oxopyrrolidinyl-O-;
R135'selected from: methyl, cyclopropyl, -OCF3Fluorine, chlorine, -SCH3、-OCH3、-OCHF2and-CF3；
R136’Selected from: methyl, cyclopropyl, -OCF3Fluorine, chlorine, -SCH3、-OCH3、-OCHF2and-CF3,
Or the like, or, alternatively,
adjacent to L133’To D13’R of the point of attachment of (A)136’The substituents may be substituted with L133’Combined to form a cyclohexyl ring, cyclobutyl ring or fused to D13’The tetrahydropyran ring of (a);
R132’and R134’Is O;
C13’and D13’Each independently is phenyl or pyridyl;
Z132’and z134’Each independently is 0 or 1; and is
Z135’And z136’Each independently is an integer from 0 to 3;
or a salt thereof, including pharmaceutically acceptable salts thereof.
The invention also relates to pharmaceutically acceptable salts of compounds of formula (VIIIQ).
The compounds of the present invention include:
n, N' - (bicyclo [2.2.2] octane-1, 4-diyl) bis (2- (4-chlorophenoxy) acetamide);
2- (4-chlorophenoxy) -N- (4- (2- ((6-chloropyridin-3-yl) oxy) acetamido) bicyclo [2.2.2] oct-1-yl) acetamide;
n, N' - (bicyclo [2.2.2] octane-1, 4-diyl) bis (2- ((6-chloropyridin-3-yl) oxy) acetamide);
n, N' - (bicyclo [1.1.1] pentane-1, 3-diyl) bis (2- (4-chlorophenoxy) acetamide);
n, N' - (bicyclo [1.1.1] pentane-1, 3-diyl) bis (2-phenoxyacetamide);
2- (4-chlorophenoxy) -N- (3- (2- (4-chlorophenyl) acetamido) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (4-chlorophenoxy) -N- (3- (2- (p-tolyloxy) acetamido) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (4-chlorophenoxy) -N- (3- (2- ((6-chloropyridin-3-yl) oxy) acetamido) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (4-chlorophenoxy) -N- (3- (2- ((6-methylpyridin-3-yl) oxy) acetamido) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (4-chlorophenoxy) -N- (3- (2- ((5-chloropyridin-2-yl) oxy) acetamido) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (4-chlorophenoxy) -N- (3- (2-phenoxyacetamido) bicyclo [1.1.1] pent-1-yl) acetamide;
4-chloro-N- (3- (2- (4-chlorophenoxy) acetamido) bicyclo [1.1.1] pent-1-yl) benzamide;
2- ((3- (2- (4-chlorophenoxy) acetamido) bicyclo [1.1.1] pent-1-yl) (2- (4-chlorophenoxy) ethyl) amino) -N, N-dimethylacetamide;
2- (4-chlorophenoxy) -N- (3- ((2- (4-chlorophenoxy) ethyl) amino) bicyclo [1.1.1] pent-1-yl) acetamide;
n- (3- ((2- (4-chlorophenoxy) ethyl) amino) bicyclo [1.1.1] pent-1-yl) -2- ((5-chloropyridin-2-yl) oxy) acetamide;
n- (3- (2- (4-chlorophenoxy) acetamido) bicyclo [1.1.1] pent-1-yl) -N- (2- (4-chlorophenoxy) ethyl) glycine methyl ester;
ethyl 4- ((3- (2- (4-chlorophenoxy) acetamido) bicyclo [1.1.1] pent-1-yl) (2- (4-chlorophenoxy) ethyl) amino) butyrate;
2- (4-chlorophenoxy) -N- (3- ((2- (4-chlorophenoxy) ethyl) (methyl) amino) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (4-chlorophenoxy) -N- (3- (N- (2- (4-chlorophenoxy) ethyl) acetamido) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (4-chlorophenoxy) -N- (3- ((2- (4-chlorophenoxy) ethyl) (oxetan-3-yl) amino) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (4-chlorophenoxy) -N- (3- ((2- ((4-chlorophenyl) amino) ethyl) amino) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
1- (3- ((2- (4-chlorophenoxy) ethyl) amino) bicyclo [1.1.1] pent-1-yl) -3- (4-chlorophenyl) imidazolidin-2-one;
2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
and
and salts thereof, including pharmaceutically acceptable salts thereof.
The compounds of the present invention include:
2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (4-chlorophenoxy) -N- (3- (3- (4-fluorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
n- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-fluorophenoxy) acetamide;
n- (3- (3- (4-chloro-2-methylphenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-chlorophenoxy) acetamide;
n- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-cyclopropylphenoxy) acetamide;
2- (4-chlorophenoxy) -N- (3- (3- (5-chloropyridin-2-yl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (3-chlorophenoxy) -N- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
n- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4- (trifluoromethoxy) phenoxy) acetamide;
2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (4-chloro-3- (trifluoromethyl) phenoxy) -N- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (4-chlorophenoxy) -N- (3- (3- (3-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
n- (3- (2- (4-chlorophenoxy) acetamido) bicyclo [1.1.1] pent-1-yl) -2- (4-chlorophenyl) cyclopropane-1-carboxamide;
n- (4- (2- (4-chlorophenoxy) acetamido) bicyclo [2.1.1] hex-1-yl) -2- (4-chlorophenyl) cyclopropane-1-carboxamide;
2- (4-chlorophenoxy) -N- (3- (2- (4-chlorophenoxy) acetamido) bicyclo [1.1.1] pent-1-yl) cyclopropane-1-carboxamide;
2- (4-chlorophenoxy) -N- (3- ((1- (4-chlorophenyl) azetidin-3-yl) amino) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenoxy) azetidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (4-chlorophenoxy) -N- (3- (2- ((5,6,7, 8-tetrahydronaphthalen-2-yl) oxy) acetamido) bicyclo [1.1.1] pent-1-yl) acetamide;
5-chloro-N- (3- (2- (4-chlorophenoxy) acetamido) bicyclo [1.1.1] pent-1-yl) -2, 3-dihydrobenzofuran-2-carboxamide;
2- (bicyclo [4.2.0] oct-1 (6),2, 4-trien-3-yloxy) -N- (3- (2- (4-chlorophenoxy) acetamido) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (4-chlorophenoxy) -N- (3- (2- (chroman-6-yloxy) acetamido) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (4-chlorophenoxy) -N- (3- (4- (4-chlorophenyl) piperidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (4-chlorophenoxy) -N- (3- (4- (4-chlorophenyl) piperazin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (bicyclo [4.2.0] oct-1, 3, 5-trien-3-yloxy) -N- (4- (2- (4-chlorophenoxy) acetamido) bicyclo [2.2.1] hept-1-yl) acetamide;
2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
(S) -2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
(R) -2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
n- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-fluorophenoxy) acetamide isomer 1;
n- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-fluorophenoxy) acetamide isomer 2;
2- (4-chlorophenoxy) -N- (3- (3- (4-fluorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
n- (3- (3- (3-chloro-4-fluorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-chlorophenoxy) acetamide isomer 1;
n- (3- (3- (3-chloro-4-fluorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-chlorophenoxy) acetamide isomer 2;
n- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- ((5-chloropyridin-2-yl) oxy) acetamide;
n- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4- (trifluoromethyl) phenoxy) acetamide;
n- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4- (trifluoromethoxy) phenoxy) acetamide;
2- (4-chloro-3- (trifluoromethyl) phenoxy) -N- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (4-chlorophenoxy) -N- (3- (3- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (4-chloro-3-fluorophenoxy) -N- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
n- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-cyclopropylphenoxy) acetamide;
n- (3- (3- (4-chloro-3-fluorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-chlorophenoxy) acetamide isomer 1;
n- (3- (3- (4-chloro-3-fluorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-chlorophenoxy) acetamide isomer 2;
2- (4-chlorophenoxy) -N- (3- (3- (pyridin-4-yloxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
1- (3- ((2- (4-chlorophenoxy) ethyl) amino) bicyclo [1.1.1] pent-1-yl) -3- (4-chlorophenyl) imidazolidin-2-one;
2- (4-chloro-3-fluorophenoxy) -N- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
n- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-methoxyphenoxy) acetamide;
2- (3-chloro-4-fluorophenoxy) -N- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
n- (3- (3- (4-chloro-3- (trifluoromethyl) phenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-chlorophenoxy) acetamide;
2- (4-chlorophenoxy) -N- (3- (3- (4-fluoro-3- (trifluoromethyl) phenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
n- (3- (5-chloroisoindolin-2-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-chlorophenoxy) acetamide;
n- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- ((5-chloropyridin-2-yl) oxy) acetamide;
2- (4-chlorophenoxy) -N- (3- (2-oxo-3- (4- (trifluoromethyl) phenyl) imidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
n- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-fluoro-3- (trifluoromethyl) phenoxy) acetamide;
n- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-fluoro-3- (trifluoromethyl) phenoxy) acetamide;
n- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4- (difluoromethoxy) phenoxy) acetamide;
2- (4-chloro-3-fluorophenoxy) -N- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide isomer 1;
(R) -2- (4-chloro-3-fluorophenoxy) -N- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide isomer 2;
2- (4-chlorophenoxy) -N- (3- (3- ((5-chloropyridin-2-yl) oxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
2- ((5-chloropyridin-2-yl) oxy) -N- (3- (3- ((5-chloropyridin-2-yl) oxy) pyrrolidin-1-yl) bicyclo [1.1.1] pentan-1-yl) acetamide;
2- (4-chlorophenoxy) -N- (3- (3- (4-methoxyphenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
n- (3- (3- (4-chloro-2-fluorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-chlorophenoxy) acetamide;
n- (3- (3- (bicyclo [4.2.0] oct-1, 3, 5-trien-3-yloxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-chlorophenoxy) acetamide;
(S) -2- (4-chlorophenoxy) -N- (3- (4- (4-chlorophenoxy) -2-oxopyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
(S) -2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenoxy) -2-oxopyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
(R) -2- (4-chlorophenoxy) -N- (3- (4- (4-chlorophenoxy) -2-oxopyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
(R) -2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenoxy) -2-oxopyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (4-chlorophenoxy) -N- (3- (3- (4- (methylthio) phenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide; and
2- (4-chlorophenoxy) -N- (3- (4- (4-chlorophenoxy) piperidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
and salts thereof, including pharmaceutically acceptable salts thereof.
The compounds of the present invention include:
2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (4-chlorophenoxy) -N- (3- (3- (4-fluorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
n- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-fluorophenoxy) acetamide;
n- (3- (3- (4-chloro-2-methylphenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-chlorophenoxy) acetamide;
n- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-cyclopropylphenoxy) acetamide;
2- (4-chlorophenoxy) -N- (3- (3- (5-chloropyridin-2-yl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (3-chlorophenoxy) -N- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
n- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4- (trifluoromethoxy) phenoxy) acetamide;
2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (4-chloro-3- (trifluoromethyl) phenoxy) -N- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (4-chlorophenoxy) -N- (3- (3- (3-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
n- (3- (2- (4-chlorophenoxy) acetamido) bicyclo [1.1.1] pent-1-yl) -2- (4-chlorophenyl) cyclopropane-1-carboxamide;
n- (4- (2- (4-chlorophenoxy) acetamido) bicyclo [2.1.1] hex-1-yl) -2- (4-chlorophenyl) cyclopropane-1-carboxamide;
2- (4-chlorophenoxy) -N- (3- (2- (4-chlorophenoxy) acetamido) bicyclo [1.1.1] pent-1-yl) cyclopropane-1-carboxamide;
2- (4-chlorophenoxy) -N- (3- ((1- (4-chlorophenyl) azetidin-3-yl) amino) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenoxy) azetidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (4-chlorophenoxy) -N- (3- (4- (4-chlorophenyl) piperidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (4-chlorophenoxy) -N- (3- (4- (4-chlorophenyl) piperazin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (bicyclo [4.2.0] oct-1, 3, 5-trien-3-yloxy) -N- (4- (2- (4-chlorophenoxy) acetamido) bicyclo [2.2.1] hept-1-yl) acetamide;
2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
(S) -2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
(R) -2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
n- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-fluorophenoxy) acetamide isomer 1;
n- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-fluorophenoxy) acetamide isomer 2;
2- (4-chlorophenoxy) -N- (3- (3- (4-fluorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
n- (3- (3- (3-chloro-4-fluorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-chlorophenoxy) acetamide isomer 1;
n- (3- (3- (3-chloro-4-fluorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-chlorophenoxy) acetamide isomer 2;
n- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- ((5-chloropyridin-2-yl) oxy) acetamide;
n- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4- (trifluoromethyl) phenoxy) acetamide;
n- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4- (trifluoromethoxy) phenoxy) acetamide;
2- (4-chloro-3- (trifluoromethyl) phenoxy) -N- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (4-chlorophenoxy) -N- (3- (3- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (4-chloro-3-fluorophenoxy) -N- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
n- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-cyclopropylphenoxy) acetamide;
n- (3- (3- (4-chloro-3-fluorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-chlorophenoxy) acetamide isomer 1;
n- (3- (3- (4-chloro-3-fluorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-chlorophenoxy) acetamide isomer 2;
2- (4-chlorophenoxy) -N- (3- (3- (pyridin-4-yloxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
1- (3- ((2- (4-chlorophenoxy) ethyl) amino) bicyclo [1.1.1] pent-1-yl) -3- (4-chlorophenyl) imidazolidin-2-one;
2- (4-chloro-3-fluorophenoxy) -N- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
n- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-methoxyphenoxy) acetamide;
2- (3-chloro-4-fluorophenoxy) -N- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
n- (3- (3- (4-chloro-3- (trifluoromethyl) phenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-chlorophenoxy) acetamide;
2- (4-chlorophenoxy) -N- (3- (3- (4-fluoro-3- (trifluoromethyl) phenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
n- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- ((5-chloropyridin-2-yl) oxy) acetamide;
2- (4-chlorophenoxy) -N- (3- (2-oxo-3- (4- (trifluoromethyl) phenyl) imidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
n- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-fluoro-3- (trifluoromethyl) phenoxy) acetamide;
n- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-fluoro-3- (trifluoromethyl) phenoxy) acetamide;
n- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4- (difluoromethoxy) phenoxy) acetamide;
2- (4-chloro-3-fluorophenoxy) -N- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide isomer 1;
(R) -2- (4-chloro-3-fluorophenoxy) -N- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide isomer 2;
2- (4-chlorophenoxy) -N- (3- (3- ((5-chloropyridin-2-yl) oxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
2- ((5-chloropyridin-2-yl) oxy) -N- (3- (3- ((5-chloropyridin-2-yl) oxy) pyrrolidin-1-yl) bicyclo [1.1.1] pentan-1-yl) acetamide;
2- (4-chlorophenoxy) -N- (3- (3- (4-methoxyphenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
n- (3- (3- (4-chloro-2-fluorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-chlorophenoxy) acetamide;
(S) -2- (4-chlorophenoxy) -N- (3- (4- (4-chlorophenoxy) -2-oxopyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
(S) -2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenoxy) -2-oxopyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
(R) -2- (4-chlorophenoxy) -N- (3- (4- (4-chlorophenoxy) -2-oxopyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
(R) -2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenoxy) -2-oxopyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (4-chlorophenoxy) -N- (3- (3- (4- (methylthio) phenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide; and
2- (4-chlorophenoxy) -N- (3- (4- (4-chlorophenoxy) piperidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
and salts thereof, including pharmaceutically acceptable salts thereof.
The compounds of the present invention include:
n- (3- (5-chloroisoindolin-2-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-chlorophenoxy) acetamide; and
n- (3- (3- (bicyclo [4.2.0] oct-1, 3, 5-trien-3-yloxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-chlorophenoxy) acetamide;
and salts thereof, including pharmaceutically acceptable salts thereof.
The compounds of the present invention include:
2- (4-chlorophenoxy) -N- (3- (2- ((5,6,7, 8-tetrahydronaphthalen-2-yl) oxy) acetamido) bicyclo [1.1.1] pent-1-yl) acetamide;
5-chloro-N- (3- (2- (4-chlorophenoxy) acetamido) bicyclo [1.1.1] pent-1-yl) -2, 3-dihydrobenzofuran-2-carboxamide;
2- (bicyclo [4.2.0] oct-1 (6),2, 4-trien-3-yloxy) -N- (3- (2- (4-chlorophenoxy) acetamido) bicyclo [1.1.1] pent-1-yl) acetamide; and
2- (4-chlorophenoxy) -N- (3- (2- (chroman-6-yloxy) acetamido) bicyclo [1.1.1] pent-1-yl) acetamide;
and salts thereof, including pharmaceutically acceptable salts thereof.
For the sake of clarity, in any of the above formulas, when
Figure BDA0002308602660000431
When "z" in a moiety is 0, and adjacent "R" and "L" moieties form a ring, such as a heterocycloalkyl, e.g., pyrrolidinyl, then the "R" and "L" moieties need not be adjacent in the ring.
In any of the above formulae
Figure BDA0002308602660000441
In the section, it is to be understood that "R" is not present whenever "Z" is 0.
In any of the above formulae
Figure BDA0002308602660000442
In the section, it is to be understood that whenever "z" is 0, any substituent that may be an "R" group will be hydrogen.
Further, in the above formula, R85’And R86’Is denoted by "each is independently selected from … …". For the sake of clarity, for R85’And R86’And all corresponding groups in each of the above formulae, when two of the same groups are on the same molecule (e.g., when two R's are on the same molecule)85’When the groups are on the same molecule), each85’May be different substituents. For example, one R85’May be F, another R85’May be Cl.
In embodiments, R5Independently fluorine, chlorine, bromine, iodine, -OCH3、-OCH2Ph、-C(O)Ph、-CF3、-CN、-S(O)CH3、-OH、-NH2、-COOH、-CONH2、-NO2、-C(O)CH3、-C≡CH、-CH2C≡CH、-SO3H、-SO2NH2、-NHC(O)NH2、-NHC(O)H、-NHOH、-OCH3、-OCF3、-OCHF2Substituted or unsubstituted C1-6An alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. In embodiments, R5Independently hydrogen, fluorine, chlorine, bromine, iodine, -OCH3、-OCH2Ph、-CH3、-OH、-CF3、-CN、-S(O)CH3、-NO2、-C(O)CH3、-C(O)Ph、-CH(CH3)2or-C.ident.CH. In embodiments, R5is-F. In embodiments, R5is-Cl. In embodiments, R5is-Br. In embodiments, R5is-I. In embodiments, R5Is substituted or unsubstituted C1-6An alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. In embodiments, R5Is unsubstituted C1-6An alkyl group, an unsubstituted heteroalkyl group, an unsubstituted cycloalkyl group, an unsubstituted heterocycloalkyl group, an unsubstituted aryl group, or an unsubstituted heteroaryl group. In embodiments, R5is-OCH3. In embodiments, R5is-OCH2Ph. In embodiments, R5is-CH3. In embodiments, R5is-OH. In embodiments, R5is-CF3. In embodiments, R5is-CN. In embodiments, R5is-S (O) CH3. In embodiments, R5is-NO2. In embodiments, R5is-C (O) CH3. In embodiments, R5is-C (O) Ph. In embodiments, R5is-CH (CH)3)2. In embodiments, R5is-C ≡ CH. In embodiments, R5is-CH2C ≡ CH. In embodiments, R5is-SO3H. In embodiments, R5is-SO2NH2. In embodiments, R5is-NHC (O) NH2. In embodiments, R5is-NHC (O) H. In embodiments, R5is-NHOH. In embodiments, R5is-OCH3. In embodiments, R is-OCF3. In embodiments, R5is-OCHF2。
In embodiments, R6Independently fluorine, chlorine, bromine, iodine, -OCH3、-OCH2Ph、-C(O)Ph、-CF3、-CN、-S(O)CH3、-OH、-NH2、-COOH、-CONH2、-NO2、-C(O)CH3、-C≡CH、-CH2C≡CH、-SO3H、-SO2NH2、-NHC(O)NH2、-NHC(O)H、-NHOH、-OCH3、-OCF3、-OCHF2Substituted or unsubstituted C1-6An alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. In embodiments, R6Independently hydrogen, fluorine, chlorine, bromine, iodine, -OCH3、-OCH2Ph、-CH3、-OH、-CF3、-CN、-S(O)CH3、-NO2、-C(O)CH3、-C(O)Ph、-CH(CH3)2or-C.ident.CH. In embodiments, R6is-F. In embodiments, R6is-Cl. In embodiments, R6is-Br. In embodiments, R6is-I. In embodiments, R6Is substituted or unsubstituted C1-6An alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. In embodiments, R6Is unsubstituted C1-6An alkyl group, an unsubstituted heteroalkyl group, an unsubstituted cycloalkyl group, an unsubstituted heterocycloalkyl group, an unsubstituted aryl group, or an unsubstituted heteroaryl group. In embodiments, R6is-OCH3. In embodiments, R6is-OCH2Ph. In embodiments, R6is-CH3. In embodiments, R6is-OH. In embodiments, R6is-CF3. In embodiments, R6is-CN. In embodiments, R6is-S (O) CH3. In embodiments, R6is-NO2. In embodiments, R6is-C (O) CH3. In embodiments, R6is-C (O) Ph. In embodiments, R6is-CH (CH)3)2. In embodiments, R6is-C ≡ CH. In embodiments, R6is-CH2C ≡ CH. In embodiments, R6is-SO3H. In embodiments, R6is-SO2NH2. In embodiments, R6is-NHC (O) NH2. In embodiments, R6is-NHC (O)) And H. In embodiments, R6is-NHOH. In embodiments, R6is-OCH3. In embodiments, R6is-OCF3. In embodiments, R6is-OCHF2。
In embodiments, R2Is NR8. In embodiments, R2Is NH. In embodiments, R2Is O. In embodiments, R2Is S. In embodiments, R2Is CH2. In embodiments, R4Is NR8. In embodiments, R4Is NH. In embodiments, R4Is O. In embodiments, R4Is S. In embodiments, R4Is CH2. In embodiments, R2And R4Is NH. In embodiments, R2And R4Is O. In embodiments, R2And R4Is S. In embodiments, R2And R4Is NR8。
In an embodiment, L2Is a bond. In an embodiment, L2Is substituted or unsubstituted C1-6An alkylene group. In an embodiment, L2Is substituted or unsubstituted C1-6A heteroalkylene group. In an embodiment, L2Is L2A-L2B-L2CAnd L is2ABonded to a substituted or unsubstituted phenyl group, which may be substituted with R5。L2AIs a bond, -O-, -S-, -NH-, -S (O) -, or-S (O)2-。L2BIs a bond or substituted or unsubstituted C1-6An alkylene group. L is2CIs a bond, -O-, or-NH-. In an embodiment, L2AIs a bond. In an embodiment, L2Ais-O-. In an embodiment, L2Ais-S-. In an embodiment, L2Ais-NH-. In an embodiment, L2Ais-S (O) -. In an embodiment, L2Ais-S (O)2-. In an embodiment, L2BIs a bond. In an embodiment, L2BIs substituted or unsubstituted C1-6An alkylene group. In an embodiment, L2BIs unsubstituted C1-6Alkylene oxideAnd (4) a base. In an embodiment, L2BIs substituted or unsubstituted C1-C5An alkylene group. In an embodiment, L2BIs unsubstituted C1-C5An alkylene group. In an embodiment, L2BIs substituted or unsubstituted C1-C4An alkylene group. In an embodiment, L2BIs unsubstituted C1-C4An alkylene group. In an embodiment, L2BIs substituted or unsubstituted C1-C3An alkylene group. In an embodiment, L2BIs unsubstituted C1-C3An alkylene group. In an embodiment, L2BIs substituted C1-C5An alkylene group. In an embodiment, L2BIs substituted C1-C6An alkylene group. In an embodiment, L2BIs substituted C1-C5An alkylene group. In an embodiment, L2BIs substituted C1-C4An alkylene group. In an embodiment, L2BIs by-CF3Substituted C1-C6An alkylene group. In an embodiment, L2CIs a bond. In an embodiment, L2Cis-O-. In an embodiment, L2Cis-NH-. In an embodiment, L2AIs a bond; l is2BIs unsubstituted methylene; and L is2Cis-O-.
In an embodiment, L3Is a bond. In an embodiment, L3Is substituted or unsubstituted C1-6An alkylene group. In an embodiment, L3Is substituted or unsubstituted C1-6A heteroalkylene group. In an embodiment, L3Is L3A-L3B-L3CAnd L is3ABonded to a substituted or unsubstituted phenyl group, which may be substituted with R5。L3AIs a bond, -O-, -S-, -NH-, -S (O) -, or-S (O)2-。L3BIs a bond or substituted or unsubstituted C1-6An alkylene group. L is3CIs a bond, -O-, or-NH-. In an embodiment, L3AIs a bond. In an embodiment, L3Ais-O-. In an embodiment, L3Ais-S-. In an embodiment, L3Ais-NH-. In the implementation ofIn scheme, L3Ais-S (O) -. In an embodiment, L3Ais-S (O)2-. In an embodiment, L3BIs a bond. In an embodiment, L3BIs substituted or unsubstituted C1-6An alkylene group. In an embodiment, L3BIs unsubstituted C1-6An alkylene group. In an embodiment, L3BIs substituted or unsubstituted C1-C5An alkylene group. In an embodiment, L3BIs unsubstituted C1-C5An alkylene group. In an embodiment, L3BIs substituted or unsubstituted C1-C4An alkylene group. In an embodiment, L3BIs unsubstituted C1-C4An alkylene group. In an embodiment, L3BIs substituted or unsubstituted C1-C3An alkylene group. In an embodiment, L3BIs unsubstituted C1-C3An alkylene group. In an embodiment, L3BIs substituted C1-C5An alkylene group. In an embodiment, L3BIs substituted C1-C6An alkylene group. In an embodiment, L3BIs substituted C1-C5An alkylene group. In an embodiment, L3BIs substituted C1-C4An alkylene group. In an embodiment, L3BIs by-CF3Substituted C1-C6An alkylene group. In an embodiment, L3CIs a bond. In an embodiment, L3Cis-O-. In an embodiment, L3Cis-NH-. In an embodiment, L3AIs a bond; l is3BIs unsubstituted methylene; and L is3Cis-O-.
In an embodiment, L3And R1Together form a heterocycloalkyl group. Suitably, the heterocycloalkyl group is an imidazolidinyl group or a pyrrolidinyl group. Suitably, the heterocycloalkyl group is imidazolidinyl. Suitably, the heterocycloalkyl group is pyrrolidinyl.
In an embodiment, L2And R3Together form a heterocycloalkyl group. Suitably, the heterocycloalkyl group is an imidazolidinyl group or a pyrrolidinyl group. Suitably, the heterocycloalkyl group is imidazolidinyl. Suitably, the first and second electrodes are arranged such that,the heterocycloalkyl group is a pyrrolidinyl group.
In an embodiment, L22And R23Together form a heterocycloalkyl group. Suitably, the heterocycloalkyl group is an imidazolidinyl group or a pyrrolidinyl group. Suitably, the heterocycloalkyl group is imidazolidinyl. Suitably, the heterocycloalkyl group is pyrrolidinyl.
In an embodiment, L23And R21Together form a heterocycloalkyl group. Suitably, the heterocycloalkyl group is an imidazolidinyl group or a pyrrolidinyl group. Suitably, the heterocycloalkyl group is imidazolidinyl. Suitably, the heterocycloalkyl group is pyrrolidinyl.
In an embodiment, L33And R31Together form a heterocycloalkyl group. Suitably, the heterocycloalkyl group is an imidazolidinyl group or a pyrrolidinyl group. Suitably, the heterocycloalkyl group is imidazolidinyl. Suitably, the heterocycloalkyl group is pyrrolidinyl.
In an embodiment, L42And R41Together form an imidazolidinyl or pyrrolidinyl group. Suitably, L42And R41Together form an imidazolidinyl radical. Suitably, L42And R41Together form a pyrrolidinyl group.
In an embodiment, L43And R43Together form an imidazolidinyl or pyrrolidinyl group. Suitably, L43And R43Together form an imidazolidinyl radical. Suitably, L43And R43Together form a pyrrolidinyl group.
In an embodiment, L53And R53Together form an imidazolidinyl or pyrrolidinyl group. Suitably, L53And R53Together form an imidazolidinyl radical. Suitably, L53And R53Together form a pyrrolidinyl group.
In an embodiment, L62And R61Together form an imidazolidinyl or pyrrolidinyl group. Suitably, L62And R61Together form an imidazolidinyl radical. Suitably, L62And R61Together form a pyrrolidinyl group.
In an embodiment, L63And R63Together form an imidazolidinyl or pyrrolidinyl group. Suitably, the first and second electrodes are arranged such that,L63and R63Together form an imidazolidinyl radical. Suitably, L63And R63Together form a pyrrolidinyl group.
In an embodiment, L73And R73Together form an imidazolidinyl or pyrrolidinyl group. Suitably, L73And R73Together form an imidazolidinyl radical. Suitably, L73And R73Together form a pyrrolidinyl group.
In an embodiment, L83And R81Together form a heterocycloalkyl group. In other words, containing-NR81-(C＝R84)Z84-L83-represents a heterocycloalkyl group. Suitably, the heterocycloalkyl group is an imidazolidinyl group or a pyrrolidinyl group. Suitably, the heterocycloalkyl group is imidazolidinyl. Suitably, the heterocycloalkyl group is pyrrolidinyl. In an embodiment, L83And R81Together form an oxoheterocycloalkyl group. In other words, containing-NR81-(C＝R84)Z84-L83The moiety of (A) represents oxoheterocycloalkyl. Suitably, the oxoheterocycloalkyl is 2-oxoimidazolidinyl. Suitably, the oxoheterocycloalkyl is oxopyrrolidinyl. In an embodiment, L83And R81Together form a heterocycloalkyl-O-. In other words, containing-NR81-(C＝R84)Z84-L83The moiety of-represents a heterocycloalkyl-O-wherein said-O-is the attachment of the heterocycloalkyl to D8To the oxygen atom of (a). Suitably, the heterocycloalkyl-O-is azetidinyl-O-or pyrrolidinyl-O-. Suitably, the heterocycloalkyl-O-is pyrrolidinyl-O-.
In an embodiment, L82And R83Together form a heterocycloalkyl group. Suitably, the heterocycloalkyl group is an imidazolidinyl group or a pyrrolidinyl group. Suitably, the heterocycloalkyl group is imidazolidinyl. Suitably, the heterocycloalkyl group is pyrrolidinyl.
In an embodiment, L93And R91Together form a heterocycloalkyl group. Suitably, the heterocycloalkyl group is an imidazolidinyl group or a pyrrolidinyl group. Suitably, the heterocycloalkyl group is imidazolidinyl. Suitably, the heterocycloalkyl group is pyrrolidinyl. In the implementation ofIn scheme, L93And R91Together form an oxoheterocycloalkyl group. Suitably, the oxoheterocycloalkyl is 2-oxoimidazolidinyl. Suitably, the oxoheterocycloalkyl is oxopyrrolidinyl. In an embodiment, L93And R91Together form a heterocycloalkyl-O-. Suitably, the heterocycloalkyl-O-is azetidinyl-O-or pyrrolidinyl-O-. Suitably, the heterocycloalkyl-O-is pyrrolidinyl-O-.
In an embodiment, L102And R101Together form an imidazolidinyl or pyrrolidinyl group. Suitably, L102And R101Together form an imidazolidinyl radical. Suitably, L102And R101Together form a pyrrolidinyl group. In an embodiment, L102And R101Together form an oxoheterocycloalkyl group. Suitably, the oxoheterocycloalkyl is 2-oxoimidazolidinyl. Suitably, the oxoheterocycloalkyl is oxopyrrolidinyl. In an embodiment, L102And R101Together form a heterocycloalkyl-O-. Suitably, the heterocycloalkyl-O-is azetidinyl-O-or pyrrolidinyl-O-. Suitably, the heterocycloalkyl-O-is pyrrolidinyl-O-.
In an embodiment, L103And R103Together form an imidazolidinyl or pyrrolidinyl group. Suitably, L103And R103Together form an imidazolidinyl radical. Suitably, L103And R103Together form a pyrrolidinyl group. In an embodiment, L103And R103Together form an oxoheterocycloalkyl group. Suitably, the oxoheterocycloalkyl is 2-oxoimidazolidinyl. Suitably, the oxoheterocycloalkyl is oxopyrrolidinyl. In an embodiment, L103And R103Together form a heterocycloalkyl-O-. Suitably, the heterocycloalkyl-O-is azetidinyl-O-or pyrrolidinyl-O-. Suitably, the heterocycloalkyl-O-is pyrrolidinyl-O-.
In an embodiment, L113And R113Together form an imidazolidinyl, pyrrolidinyl, or cyclopropyl group. In an embodiment, L113And R113Together form an imidazolidinyl radical. In an embodiment, L113And R113Together form a pyrrolidinyl group. In an embodiment, L113And R113Together form an oxoheterocycloalkyl group. Suitably, the oxoheterocycloalkyl is 2-oxoimidazolidinyl. Suitably, the oxoheterocycloalkyl is oxopyrrolidinyl. In an embodiment, L113And R113Together form a heterocycloalkyl-O-. Suitably, the heterocycloalkyl-O-is azetidinyl-O-or pyrrolidinyl-O-. Suitably, the heterocycloalkyl-O-is pyrrolidinyl-O-.
In an embodiment, L122And R121Together form an imidazolidinyl or pyrrolidinyl group. Suitably, L122And R121Together form an imidazolidinyl radical. Suitably, L122And R121Together form a pyrrolidinyl group. In an embodiment, L122And R121Together form an oxoheterocycloalkyl group. Suitably, the oxoheterocycloalkyl is 2-oxoimidazolidinyl. Suitably, the oxoheterocycloalkyl is oxopyrrolidinyl. In an embodiment, L122And R121Together form a heterocycloalkyl-O-. Suitably, the heterocycloalkyl-O-is azetidinyl-O-or pyrrolidinyl-O-. Suitably, the heterocycloalkyl-O-is pyrrolidinyl-O-.
In an embodiment, L123And R123Together form an imidazolidinyl or pyrrolidinyl group. Suitably, L123And R123Together form an imidazolidinyl radical. Suitably, L123And R123Together form a pyrrolidinyl group. In an embodiment, L123And R123Together form an oxoheterocycloalkyl group. Suitably, the oxoheterocycloalkyl is 2-oxoimidazolidinyl. Suitably, the oxoheterocycloalkyl is oxopyrrolidinyl. In an embodiment, L123And R123Together form a heterocycloalkyl-O-. Suitably, the heterocycloalkyl-O-is azetidinyl-O-or pyrrolidinyl-O-. Suitably, the heterocycloalkyl-O-is pyrrolidinyl-O-.
In an embodiment, L133And R133Together form an imidazolidinyl or pyrrolidinyl group. Suitably, L133And R133Together form an imidazolidinyl radical. Suitably, L133And R133Together form a pyrrolidinyl group. In an embodiment, L133And R133Together form an oxoheterocycloalkyl group. Suitably, the oxoheterocycloalkyl is 2-oxoimidazolidinyl. Suitably, the oxoheterocycloalkyl is oxopyrrolidinyl. In an embodiment, L133And R133Together form a heterocycloalkyl-O-. Suitably, the heterocycloalkyl-O-is azetidinyl-O-or pyrrolidinyl-O-. Suitably, the heterocycloalkyl-O-is pyrrolidinyl-O-.
In an embodiment, the symbol z2Is 0. In an embodiment, the symbol z2Is 1. In an embodiment, the symbol z4Is 0. In an embodiment, the symbol z4Is 1. In an embodiment, the symbol z2And z4Is 0. In an embodiment, the symbol z2And z4Is 1. In an embodiment, the symbol z5Is 0. In an embodiment, the symbol z5Is 1. In an embodiment, the symbol z5Is 2. In an embodiment, the symbol z5Is 3. In an embodiment, the symbol z5Is 4. In an embodiment, the symbol z6Is 0. In an embodiment, the symbol z6Is 1. In an embodiment, the symbol z6Is 2. In an embodiment, the symbol z6Is 3. In an embodiment, the symbol z6Is 4.
One skilled in the art will appreciate that salts, including pharmaceutically acceptable salts, of compounds according to formula (IIIQ) can be prepared. Indeed, in some embodiments of the invention, salts of compounds according to formula (IIIQ), including pharmaceutically acceptable salts, may be preferred over the respective free or unsalified compounds. Thus, the present invention further relates to salts, including pharmaceutically acceptable salts, of compounds according to formula (IIIQ).
Salts, including pharmaceutically acceptable salts, of the compounds of the present invention can be readily prepared by those skilled in the art.
Typically, the salts of the present invention are pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" embraces salts that refer to non-toxic salts of the compounds of the present invention.
Representative pharmaceutically acceptable acid addition salts include, but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, bisulfate, bitartrate, butyrate, calcium edetate, camphorate, camphorsulfonate (camsylate), caprate (caprate), hexanoate (caprate), octanoate (caprate), cinnamate, citrate, cyclohexylamine sulfonate, digluconate, 2, 5-dihydroxybenzoate, disuccinate, lauryl sulfate (etonate), edetate (edetate), etonate (lauryl sulfate), ethane-1, 2-disulfonate (edisylate), ethanesulfonate (esylate), formate, fumarate, hemi-lactobionate (mucate), Gentisate (2, 5-dihydroxybenzoate), glucoheptanoate (gluceptate), gluconate, glucuronate, glutamate, glutarate, glycerophosphate, glycolate, hexylresorcinate (hexyleresorcinate), hippurate, hydrabamine (N, N' -bis (dehydroabietyl) -ethylenediamine), hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, isobutyrate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, mesylate (mesylate), methylsulfate, mucate, naphthalene-1, 5-disulfonate (napadisylate), naphthalene-2-sulfonate (napsylate), nicotinate, nitrate, oleate, palmitate, p-aminobenzenesulfonate, p-aminosalicylate, pamoate (pamoate), Pantothenate, pectate, persulfate, phenylacetate, phenylethylbarbiturate, phosphate, polygalacturonate, propionate, p-toluenesulfonate (tosylate), pyroglutamate, pyruvate, salicylate, sebacate, stearate, subacetate, succinate, sulfamate, sulfate, tannate, tartrate, theachlorate (teoelolate) (8-chlorotheophylline), thiocyanate, triethyliodide (triethiodide), undecanoate, undecylenate, and valerate.
Representative pharmaceutically acceptable base addition salts include, but are not limited to, aluminum, 2-amino-2- (hydroxymethyl) -1, 3-propanediol (TRIS, tromethamine), arginine, benzphetamine (N-benzylphenethylamine), benzathine (N, N '-dibenzylethylenediamine), bis- (2-hydroxyethyl) amine, bismuth, calcium, chloroprocaine, choline, clemizole (1-p-chlorobenzyl-2-pyrrolidin-1' -ylmethylbenzimidazole), cyclohexylamine, dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lutidine (lepidine), lithium, lysine, magnesium, meglumine (N-methylglucamine), Piperazine, piperidine, potassium, procaine, quinine, quinoline, sodium, strontium, tert-butylamine and zinc.
The compounds of formula (IIIQ) may contain one or more asymmetric centers (also known as chiral centers) and may therefore exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or mixtures thereof. Chiral centers, such as chiral carbon atoms, may be present on substituents such as alkyl groups. Wherein when the stereochemistry of a chiral center present in a compound of formula (IIIQ), or in any of the chemical structures shown herein, is not specified, it is intended to include all individual stereoisomers and all mixtures thereof. Thus, compounds of formula (IIIQ) containing one or more chiral centers may be used in the form of a racemic mixture, an enantiomerically or diastereomerically enriched mixture, or as an enantiomerically or diastereomerically pure individual stereoisomer.
The compounds of formula (IIIQ) and pharmaceutically acceptable salts thereof may contain isotopically labeled compounds, which are identical to those recited in formula (IIIQ) and similar general formulae, but for the replacement by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of such isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as 2H, 3H, 11C, 13C, 14C, 15N, 17O, 18O, 31P, 32P, 35S, 18F, 36Cl, 123I and 125I.
Isotopically labeled compounds, for example, those incorporating a radioactive isotope such as 3H or 14C, are useful in drug and/or substrate tissue distribution assays. Tritium (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and ease of detection. The 11C and 18F isotopes are particularly useful in PET (positron emission tomography) and the 125I isotope is particularly useful in SPECT (single photon emission computed tomography), both of which can be used for brain imaging. Furthermore, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages which may be attributed to greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and hence may be preferred in certain circumstances. Isotopically labeled compounds can generally be prepared by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
The compounds of formula (IIIQ) may also contain double bonds or other centers of geometric asymmetry. Wherein when the stereochemistry of the geometric asymmetric center present in the compound of formula (IIIQ) or in any of the chemical structures shown herein is not indicated, the trans (E) geometric isomer, the cis (Z) geometric isomer, and all mixtures thereof, are intended to be included. Likewise, all tautomeric forms are also included in formula (IIIQ), whether or not such tautomers exist in equilibrium or predominantly in one form.
The compound of formula (IIIQ) or a salt thereof, including pharmaceutically acceptable salts, may be present in solid or liquid form. When present in the solid state, the compounds of the present invention may be present in crystalline or amorphous form or as mixtures thereof. One skilled in the art will appreciate that a compound of the present invention in crystalline form may form a pharmaceutically acceptable solvate, wherein solvent molecules are incorporated into the crystal lattice during crystallization. Solvates in which water is the solvent incorporated into the crystal lattice are commonly referred to as "hydrates". Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water.
It will be further appreciated by those skilled in the art that some of the compounds of formula (IIIQ) or salts thereof (including pharmaceutically acceptable salts thereof) in crystalline form, including various solvates thereof, may exist in polymorphic form (i.e., have the ability to develop different crystalline structures). These different crystalline forms are commonly referred to as "polymorphs". Polymorphs have the same chemical composition, but different stacking, geometric arrangements, and other crystalline solid state characteristics, and thus polymorphs can have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically have different melting points, IR spectra, and X-ray powder diffraction patterns, which can be used for identification. One skilled in the art will appreciate that different polymorphs can be produced in the preparation of a compound by, for example, changing or adjusting the reaction conditions or reagents employed. For example, polymorphs can be produced by varying the temperature, pressure or solvent. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.
Although the definitions for each variable have been listed individually for each variable as described above, the present invention includes compounds wherein several or each definition in formula (IIIQ) is selected from each definition listed above. Accordingly, the present invention is intended to include all combinations of definitions for each variable.
Definition of
"alkyl" and "alkylene" and derivatives thereof, refer to hydrocarbon chains having the indicated number of "member atoms". Alkyl is monovalent and alkylene is divalent. E.g. C1-C6Alkyl refers to alkyl groups having 1 to 6 member atoms. The alkyl and alkylene groups may be saturated, unsaturated, straight or branched. Representative branched alkyl groups have 1,2, or 3 branches. Alkyl and alkylene groups include methyl, ethyl, ethylene, propyl (n-propyl and isopropyl), butene, butyl (n-butyl, isobutyl and tert-butyl), pentyl and hexyl.
"alkoxy" refers to-O-alkyl, wherein "alkyl" is as defined herein. E.g. C1-C4Alkoxy means alkoxy having 1 to 4 member atoms. Representative branched alkoxy groups have 1,2 or 3 branches. Examples of such groups include methoxy, ethoxy, propoxy and butoxy.
"aryl" refers to an aromatic hydrocarbon ring. Aryl is monocyclic, bicyclic and tricyclic ring systems having a total of 5 to 14 ring member atoms, wherein at least one ring system is aromatic and wherein each ring in the system contains 3 to 7 member atoms, such as phenyl, naphthalene, tetrahydronaphthalene and biphenyl. Suitably, aryl is phenyl.
"cycloalkyl", unless otherwise defined, refers to a saturated or unsaturated non-aromatic hydrocarbon ring having from 3 to 7 carbon atoms. Cycloalkyl is a monocyclic ring system. E.g. C3-C7Cycloalkyl refers to cycloalkyl groups having 3 to 7 member atoms. Examples of cycloalkyl groups for use herein include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptyl. Suitably, the cycloalkyl group is selected from: cyclopropyl, cyclobutyl, and cyclohexyl. Suitably, the cycloalkyl group is cyclopropyl.
"halogen" refers to fluorine, chlorine, bromine and iodine.
"heteroaryl" refers to a monocyclic aromatic 4 to 8 membered ring containing 1 to 7 carbon atoms and containing 1 to 4 heteroatoms, with the proviso that when the number of carbon atoms is 3, then the aromatic ring contains at least 2 heteroatoms, or the aromatic ring is fused to one or more rings, such as to a heteroaromatic ring, an aryl ring, a heterocyclic ring, a cycloalkyl ring. Heteroaryl groups comprising more than one heteroatom may comprise different heteroatoms. Heteroaryl groups include, but are not limited to: benzimidazolyl, benzothiazolyl, benzothienyl, benzopyrazinyl, benzotriazolyl, benzo [1,4] dioxanyl, benzofuranyl, 9H-a-carbolinyl, cinnolinyl, furanyl, pyrazolyl, imidazolyl, pyrazinyl, naphthyridinyl, oxazolyl, oxothiadiazolyl, oxadiazolyl, phthalazinyl, pyridyl, pyrrolyl, purinyl, pteridinyl, phenazinyl, pyrazolopyrimidinyl, pyrazolopyridinyl, pyrrolizinyl, pyrimidinyl, isothiazolyl, furazanyl, pyrimidinyl, tetrazinyl, isoxazolyl, quinoxalinyl, quinazolinyl, quinolyl, quinolizinyl, quinolyl, thienyl, thiophenyl, triazolyl, triazinyl, tetrazolopyrimidinyl, triazolopyrimidyl, tetrazolyl, thiazolyl, and thiazolidinyl groups. Suitably, the heteroaryl group is selected from: pyrazolyl, imidazolyl, oxazolyl and thienyl. Suitably, the heteroaryl group is a pyridyl or imidazolyl group. Suitably, the heteroaryl group is a pyridyl group.
"heterocycloalkyl" refers to a saturated or unsaturated non-aromatic ring containing 4 to 12 member atoms, of which 1 to 11 are carbon atoms and 1 to 6 are heteroatoms. Heterocycloalkyl groups containing more than one heteroatom may contain different heteroatoms. Heterocycloalkyl is a monocyclic ring system or a monocyclic ring fused to an aromatic or heteroaromatic ring having from 3 to 6 member atoms. Heterocycloalkyl groups include: pyrrolidinyl, tetrahydrofuryl, dihydrofuranyl, pyranyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothienyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, oxetanyl, thiazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1, 3-dioxolanyl, 1, 3-dioxanyl, 1, 4-dioxanyl, 1, 3-oxathiolanyl, 1, 3-oxathianyl, 1, 3-dithianyl, 1, 3-oxazolidin-2-one, hexahydro-1H-azepanyl, 4,5,6,7, tetrahydro-1H-benzimidazolyl, piperidinyl, 1,2,3, 6-tetrahydro-pyridinyl, and azetidinyl. Suitably, "heterocycloalkyl" includes: piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, imidazolidinyl, oxetanyl and pyrrolidinyl. Suitably, "heterocycloalkyl" is selected from: imidazolidinyl, tetrahydropyranyl and pyrrolidinyl.
"heteroatom" means a nitrogen, sulfur or oxygen atom.
"Heteroalkyl" and "heteroalkylene" by themselves or in combination with another term, unless otherwise stated, refer to a non-cyclic stable straight or branched chain or combination thereof containing at least one carbon atom (and up to the number specified) and at least one heteroatom selected from O, N, P, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. E.g. C1-6The heteroalkyl (ene) group contains at least one and up to 6 carbon atoms in addition to at least one heteroatom. Heteroalkyl is monovalent and heteroalkylene is divalent. The heteroalkyl and heteroalkylene groups may form, together with another substituent, a heterocycloalkyl group. The heteroatom O, N, P, S and Si can be placed at any internal position of the heteroalkyl or heteroalkylene group or at the point where the alkyl group is attached to the rest of the molecule. Examples of heteroalkyl groups include, but are not limited to: -CH2-CH2-O-CH3、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)2、-CH2-S-CH2-CH3、-S(O)-CH3、-CH2-CH2-S(O)2-CH3、-CH＝CH-O-CH3、-Si(CH3)3、-CH2-CH＝N-OCH3、-CH＝CHN(CH3)2、-O-CH3、-O-CH2-CH3-CN. Examples of heteroalkylene groups include, but are not limited to: -CH2-CH2-O-CH2-、-CH2-CH2-NH-CH2-、-CH2-CH2-N(CH3)CH2-、-CH2-S-CH2-CH2-、-S(O)-CH2-、-CH2-CH2-S(O)2-CH2-、-CH＝CH-O-CH2-、-Si(CH3)2CH2-、–N(CH3)CH2–、-O-CH2-CH2-CH2-、-CH2-CH＝N-OCH2-、-CH＝CHN(CH3)CH2-、-O-CH2and-O-CH2-CH2-. Up to two or three heteroatoms may be consecutive, e.g. -CH2-NH-OCH3and-CH2-O-Si(CH3)3。
For the sake of clarity, "2-oxoimidazolidinyl" as used herein refers to a monovalent substituentOr a divalent substituent
Figure BDA0002308602660000542
Depending on its attachment to the rest of the molecule. Similarly, all other ring substituents used herein may be monovalent, divalent, etc., depending on its attachment to the rest of the molecule.
As used herein, "substituted," unless otherwise defined, means that the subject chemical moiety has from 1 to 9 substituents, suitably from 1 to 5 substituents, selected from:
the fluorine is introduced into the reaction mixture containing the fluorine,
the chlorine is added to the reaction mixture in the presence of chlorine,
the bromine is added to the reaction mixture,
the amount of iodine is such that,
C1-6an alkyl group, a carboxyl group,
c substituted with 1 to 6 substituents independently selected from1-6Alkyl groups: fluorine, oxo, -OH, -COOH, -NH2and-CN, wherein the content of the N,
-OC1-6an alkyl group, a carboxyl group,
-OC substituted with 1 to 6 substituents independently selected from the group consisting of1-6Alkyl groups: fluorine, oxo, -OH, -COOH, -NH2and-CN, wherein the content of the N,
a mercapto group,
-SRx，
wherein R isxIs selected from C1-6Alkyl, and C substituted with 1 to 6 substituents independently selected from1-6Alkyl groups: fluorine, oxo, -OH, -COOH, -NH2and-CN, wherein the content of the N,
-S(O)Rx,
wherein R isxIs selected from C1-6Alkyl and C substituted with 1 to 6 substituents independently selected from1-6Alkyl groups: fluorine, oxo, -OH, -COOH, -NH2and-CN, wherein the content of the N,
-S(O)2H,
-S(O)2Rx，
wherein R isxIs selected from C1-6Alkyl and C substituted with 1 to 6 substituents independently selected from1-6Alkyl groups: fluorine, oxo, -OH, -COOH, -NH2and-CN, wherein the content of the N,
an oxo group is present in the amino group,
a hydroxyl group(s),
an amino group, a carboxyl group,
-NHRx，
wherein R isxIs selected from C1-6Alkyl and C substituted with 1 to 6 substituents independently selected from1-6Alkyl groups: fluorine, oxo, -OH, -COOH, -NH2and-CN, wherein the content of the N,
-NRx1Rx2，
wherein R isx1And Rx2Each independently selected from C1-6Alkyl and C substituted with 1 to 6 substituents independently selected from1-6Alkyl groups: fluorine, oxo, -OH, -COOH, -NH2And a group of-CN, guanidino,
-C(O)OH，
-C(O)ORx，
wherein R isxIs selected from C1-6Alkyl and C substituted with 1 to 6 substituents independently selected from1-6Alkyl groups: fluorine, oxo, -OH, -COOH, -NH2and-CN, wherein the content of the N,
-C(O)NH2，
-C(O)NHRx,
wherein R isxIs selected from C1-6Alkyl and C substituted with 1 to 6 substituents independently selected from1-6Alkyl groups: fluorine, oxo, -OH, -COOH, -NH2and-CN, wherein the content of the N,
-C(O)NRx1Rx2，
wherein R isx1And Rx2Each independently selected from C1-6Alkyl and C substituted with 1 to 6 substituents independently selected from1-6Alkyl groups: fluorine, oxo, -OH, -COOH, -NH2and-CN, -S (O)2NH2，
-S(O)2NHRx，
Wherein R isxIs selected from C1-6Alkyl and C substituted with 1 to 6 substituents independently selected from1-6Alkyl groups: fluorine, oxo, -OH, -COOH, -NH2and-CN, wherein the content of the N,
-S(O)2NRx1Rx2，
wherein R isx1And Rx2Each independently selected from C1-6Alkyl and C substituted with 1 to 6 substituents independently selected from1-6Alkyl groups: fluorine, oxo, -OH, -COOH, -NH2and-CN, wherein the content of the N,
-NHS(O)2H，
-NHS(O)2Rx，
wherein R isxIs selected from C1-6Alkyl and C substituted with 1 to 6 substituents independently selected from1-6Alkyl groups: fluorine, oxo, -OH, -COOH, -NH2and-CN, wherein the content of the N,
-NHC(O)H，
-NHC(O)Rx，
wherein R isxIs selected from C1-6Alkyl and C substituted with 1 to 6 substituents independently selected from1-6Alkyl groups: fluorine, oxo, -OH, -COOH, -NH2and-CN, wherein the content of the N,
-NHC(O)NH2，
-NHC(O)NHRx，
wherein R isxIs selected from C1-6Alkyl and C substituted with 1 to 6 substituents independently selected from1-6Alkyl groups: fluorine, oxo, -OH, -COOH, -NH2and-CN, wherein the content of the N,
-NHC(O)NRx1Rx2，
wherein R isx1And Rx2Each independently selected from C1-6Alkyl and substituted with 1 to 6 independent substituents
C of a substituent selected from1-6Alkyl groups: fluorine, oxo, -OH, -COOH, -NH2and-CN, nitro, and
a cyano group.
Suitably, "substituted" means that the bulk chemical moiety has from 1 to 4 substituents selected from:
the fluorine is introduced into the reaction mixture containing the fluorine,
the chlorine is added to the reaction mixture in the presence of chlorine,
the bromine is added to the reaction mixture,
the amount of iodine is such that,
C1-4an alkyl group, a carboxyl group,
c substituted with 1 to 4 substituents independently selected from1-4Alkyl groups: fluorine, oxo, -OH, -COOH, -NH2and-CN, wherein the content of the N,
-OC1-4an alkyl group, a carboxyl group,
-OC substituted with 1 to 4 substituents independently selected from the group consisting of1-4Alkyl groups: fluorine, oxo, -OH, -COOH, -NH2and-CN, wherein the content of the N,
-SH，
-S(O)2H,
an oxo group is present in the amino group,
a hydroxyl group(s),
an amino group, a carboxyl group,
-NHRx，
wherein R isxIs selected from C1-4Alkyl and C substituted 1 to 4 times by fluorine1-6An alkyl group, a carboxyl group,
-NRx1Rx2，
wherein R isx1And Rx2Each independently selected from C1-4Alkyl and C substituted 1 to 4 times by fluorine1-4An alkyl group, a carboxyl group,
a guanidine group of the amino acid or the amino acid,
-C(O)OH，
-C(O)ORx，
wherein R isxIs selected from C1-4Alkyl and C substituted 1 to 4 times by fluorine1-4An alkyl group, a carboxyl group,
-C(O)NH2，
-C(O)NHRx,
wherein R isxIs selected from C1-4Alkyl and C substituted 1 to 4 times by fluorine1-4An alkyl group, a carboxyl group,
-C(O)NRx1Rx2，
wherein R isx1And Rx2Each independently selected from C1-4Alkyl and C substituted 1 to 4 times by fluorine1-4An alkyl group, a carboxyl group,
-S(O)2NH2，
-NHS(O)2H，
-NHC(O)H，
-NHC(O)NH2，
nitro group, and
a cyano group.
Suitably, "substituted" means that the bulk chemical moiety has from 1 to 4 substituents selected from:
the fluorine is introduced into the reaction mixture containing the fluorine,
the chlorine is added to the reaction mixture in the presence of chlorine,
the bromine is added to the reaction mixture,
the amount of iodine is such that,
C1-4an alkyl group, a carboxyl group,
c substituted with 1 to 4 substituents independently selected from1-4Alkyl groups: fluorine, oxo, -OH, -COOH, -NH2、-NHC1-3Alkyl radical、-N(C1-3Alkyl radical)2、–OC1-4An alkyl group and a group-CN,
-OC1-4an alkyl group, a carboxyl group,
-OC substituted with 1 to 4 substituents independently selected from the group consisting of1-4Alkyl groups: fluorine, oxo, -OH, -COOH, -NH2、-NHC1-3Alkyl, -N (C)1-3Alkyl radical)2and-CN, wherein the content of the N,
-SH，
-S(O)2H,
an oxo group is present in the amino group,
a hydroxyl group(s),
an amino group, a carboxyl group,
-NHRx，
wherein R isxIs selected from C1-4Alkyl, and C substituted by 1 to 4 fluorine1-4An alkyl group, a carboxyl group,
-NRx1Rx2，
wherein R isx1And Rx2Each independently selected from C1-4Alkyl, and C substituted by 1 to 4 fluorine1-4An alkyl group, a carboxyl group,
a guanidine group of the amino acid or the amino acid,
-C(O)OH，
-C(O)ORx，
wherein R isxIs selected from C1-4Alkyl, and C substituted by 1 to 4 fluorine1-4An alkyl group, a carboxyl group,
-C(O)NH2，
-C(O)NHRx,
wherein R isxIs selected from C1-4Alkyl, and C substituted by 1 to 4 fluorine1-4An alkyl group, a carboxyl group,
-C(O)NRx1Rx2，
wherein R isx1And Rx2Each independently selected from C1-4Alkyl, and C substituted by 1 to 4 fluorine1-4An alkyl group, a carboxyl group,
-S(O)2NH2，
-NHS(O)2H，
-NHC(O)H，
-NHC(O)NH2，
nitro group, and
a cyano group.
Suitably, "substituted" means that the bulk chemical moiety has from 1 to 4 substituents selected from:
the fluorine is introduced into the reaction mixture containing the fluorine,
the chlorine is added to the reaction mixture in the presence of chlorine,
the bromine is added to the reaction mixture,
the amount of iodine is such that,
C1-4an alkyl group, a carboxyl group,
c substituted with 1 to 4 substituents independently selected from1-4Alkyl groups: fluorine, oxo, -OH, -COOH, -NH2、-NHCH3、-N(CH3)2、-OCH3、-OCH2CH3and-CN, wherein the content of the N,
-OC1-4an alkyl group, a carboxyl group,
-OC substituted with 1 to 4 substituents independently selected from the group consisting of1-4Alkyl groups: fluorine, oxo, -OH, -COOH, -NH2、-NHCH3、-N(CH3)2and-CN, wherein the content of the N,
-SH，
-S(O)2H,
an oxo group is present in the amino group,
a hydroxyl group(s),
an amino group, a carboxyl group,
-NHRx，
wherein R isxIs selected from C1-4Alkyl, and C substituted by 1 to 4 fluorine1-6An alkyl group, a carboxyl group,
-NRx1Rx2，
wherein R isx1And Rx2Each independently selected from C1-4Alkyl, and C substituted by 1 to 4 fluorine1-4An alkyl group, a carboxyl group,
a guanidine group of the amino acid or the amino acid,
-C(O)OH，
-C(O)ORx，
wherein R isxIs selected from C1-4Alkyl, and C substituted by 1 to 4 fluorine1-4An alkyl group, a carboxyl group,
-C(O)NH2，
-C(O)NHRx,
wherein R isxIs selected from C1-4Alkyl, and C substituted by 1 to 4 fluorine1-4An alkyl group, a carboxyl group,
-C(O)NRx1Rx2，
wherein R isx1And Rx2Each independently selected from C1-4Alkyl, and C substituted by 1 to 4 fluorine1-4An alkyl group, a carboxyl group,
-S(O)2NH2，
-NHS(O)2H，
-NHC(O)H，
-NHC(O)NH2，
nitro group, and
a cyano group.
Suitably, "substituted" means that the bulk chemical moiety has 1 to 3 substituents selected from:
the fluorine is introduced into the reaction mixture containing the fluorine,
the chlorine is added to the reaction mixture in the presence of chlorine,
the bromine is added to the reaction mixture,
C1-4an alkyl group, a carboxyl group,
-OC1-4an alkyl group, a carboxyl group,
an oxo group is present in the amino group,
a hydroxyl group(s),
an amino group, a carboxyl group,
-C(O)OH，
-C(O)NH2，
nitro group, and
a cyano group.
As used herein, the symbols and conventions used in the methods, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of biological chemistry. Standard single or three letter abbreviations are commonly used to designate amino acid residues, which are assumed to be in the L-configuration unless otherwise indicated. All starting materials were obtained from commercial suppliers and used without further purification unless otherwise indicated. Specifically, the following abbreviations may be used in the examples and throughout the specification:
ac (acetyl);
ACN (acetonitrile);
BH3.Me2s (borane dimethyl sulfide complex);
bn (benzyl);
boc (tert-butoxycarbonyl);
CAN (cerium ammonium nitrate);
c18 (refers to the 18-carbon alkyl group on silicon in the HPLC stationary phase);
CH3CN (acetonitrile);
DCM (dichloromethane);
DIAD (diisopropyl azodicarboxylate);
dioxane (1, 4-dioxane);
DMF (N, N-dimethylformamide);
DMSO (dimethyl sulfoxide);
Et3n (triethylamine);
EtOAc (ethyl acetate);
Et2o (diethyl ether);
HCl (hydrochloric acid);
HEPES (4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid);
HPLC (high pressure liquid chromatography);
IPA (isopropyl alcohol);
K2CO3(potassium carbonate);
LiOH.H2o (lithium hydroxide monohydrate);
MeOH (methanol);
NaCNBH3(sodium cyanoborohydride);
NaHCO3(sodium bicarbonate);
NaOH (sodium hydroxide);
Na2SO4(sodium sulfate);
NH4cl (ammonium chloride);
rt (room temperature);
TLC (thin layer chromatography);
TEA (triethylamine);
TFA (trifluoroacetic acid);
THF (tetrahydrofuran); and
Figure BDA0002308602660000621
(2,4, 6-tripropyl-1, 3,5,2,4, 6-trioxatriphosphane-2, 4, 6-trioxide).
All references to ether refer to diethyl ether and brine refer to a saturated aqueous solution of NaCl.
Application method
Compounds according to formula (IIIQ) and pharmaceutically acceptable salts thereof are inhibitors of the ATF4 pathway. Compounds that are inhibitors of the ATF4 pathway can be readily identified by showing activity in the following ATF4 cell-based assay. These compounds are useful for treating conditions in which the underlying pathology may be attributable to (but not limited to) modulation of the eIF2a pathway, such as neurodegenerative diseases, cancer, cardiovascular and metabolic diseases. Thus, in another aspect, the invention relates to methods of treating these conditions.
Integration Stress Response (ISR) is a collection of cellular stress response pathways that converge in phosphorylation of the translation initiation factor eIF2 α, resulting in a reduction in overall translation in the cell. Mammalian cells have four eIF2 α kinases that phosphorylate this initiation factor in the same residue (serine 51); PERK is activated by accumulation of unfolded proteins in the Endoplasmic Reticulum (ER), GCN2 is activated by amino acid starvation, PKR is activated by viral infection, and HRI is activated by heme deficiency. Activation of these kinases reduces the synthesis of a large number of proteins, but ultimately also increases the expression of specific mrnas containing the uORF. Two examples of these mrnas are the transcription factor ATF4 and the pro-apoptotic gene CHOP. Depending on the cellular environment and the duration and severity of the stress, phosphorylation of eIF2 α and the concomitant reduction in protein translation under stress has been shown to have both cytoprotective and cytotoxic effects. An integrated stress-related disorder is a disorder characterized by increased activity of an integrated stress response (e.g., increased phosphorylation of eIF2 α by eIF2 α kinase compared to a control (e.g., a subject not suffering from the disorder)). A disease associated with phosphorylation of eIF2 α is a disease characterized by increased phosphorylation of eIF2 α relative to a control (e.g., a subject not suffering from the disease).
Activation of PERK occurs under ER stress and hypoxia, and its activation and action on translation has been demonstrated to have a cytoprotective effect on tumor cells [17 ]. Adaptation to hypoxia in the tumor microenvironment is crucial for survival and metastatic potential. PERK has also been shown to promote cancer proliferation by limiting oxidative DNA damage and death [18,19 ]. Furthermore, newly discovered PERK inhibitors have been demonstrated to have anti-tumor activity in a human pancreatic tumor xenograft model [20 ]. The compounds disclosed herein reduce the viability of cells subjected to ER stress. Thus, pharmacological and acute inhibition of PERK branching with the compounds disclosed herein results in decreased cellular adaptation. The compounds disclosed herein block the cytoprotective effect of eIF2 α phosphorylation after stress during tumor growth and thus prove to be effective antiproliferative agents.
It is known that several eIF2alpha kinases can be activated simultaneously under certain stress conditions. For example, during tumor growth, starved nutrient and hypoxic conditions are known to activate both GCN2 and PERK. Like PERK, GCN2 and its common target ATF4 are also thought to have a cytoprotective effect [21 ]. By blocking the signaling of both kinases, ISRs have the ability to protect cancer cells from the low nutrient and oxygen levels encountered during tumor growth, and the compounds disclosed herein can bypass this ability of ISRs.
Prolonged ER stress results in the accumulation of the pro-apoptotic molecule CHOP. In a prion mouse model, overexpression of eIF2 α phosphatase increased survival in prion-infected mice, while sustained eIF2 α phosphorylation decreased survival [22 ]. Restoration of protein translation rates during prion diseases has been shown to rescue synaptic defects and neuronal loss. The compounds disclosed herein desensitize cells to eIF2 α phosphorylation, thereby maintaining protein translation. By blocking the deleterious effects of prolonged eIF2 α phosphorylation, the compounds disclosed herein have been shown to be effective inhibitors of neuronal cell death in prion diseases. Given the prevalence of protein misfolding and UPR activation in several neurodegenerative diseases, such as Alzheimer's Disease (AD) and Parkinson's Disease (PD), manipulation of the PERK-eIF 2a branch can prevent synaptic failure and neuronal death that are prevalent in these disease profiles.
Another example of a tissue-specific pathology associated with elevated eIF2a phosphorylation is fatal encephalopathy, ablative white matter disease (VWM) or childhood ataxia with reduced CNS myelination (CACH). This disease is associated with mutations in eIF2B, eIF2B being a GTP exchange factor necessary for eIF2 function in translation [23 ]. eIF2 α phosphorylation inhibits the activity of eIF2B, and mutations in this crossover factor decrease its crossover activity, exacerbating the effects of eIF2 α phosphorylation. The serious consequences of CACH mutation reveal the risk of over-activation of UPR, especially because it is associated with oligodendrocytes producing myelin. Small molecules (e.g., the compounds disclosed herein) block signaling via eIF2a phosphorylation, thereby reducing the deleterious effects of its over-activation in VWM.
In another aspect, there is provided a method of improving long term memory in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (IIIQ). In embodiments, the patient is a human. In embodiments, the patient is a mammal.
The compounds of the present invention inhibit the integrated stress response involved in the pathogenesis of neurological disorders. Suitably, the present invention relates to a method of treating or lessening the severity of a neurological disorder. Suitably, diseases that can be treated using the compounds of the invention include: alcoholism, anxiety, depression, schizophrenia, bipolar disorder, obsessive compulsive disorder, panic disorder, chronic pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia, premenstrual syndrome (PMS), adolescent depression, trichotillomania, dysthymia and substance abuse.
In an embodiment, the neurological disorder is treated in a human patient.
The compounds of the present invention inhibit the complex stress response associated with the pathogenesis of pain. Visceral pain is pain associated with the viscera, including internal organs of the body. These organs include, for example, the heart, lungs, reproductive organs, bladder, ureters, digestive organs, liver, pancreas, spleen, and kidneys. Visceral pain can occur in a variety of conditions, such as pancreatitis, childbirth, abdominal surgery associated with ileus, cystitis, menstrual periods, or dysmenorrhea. Likewise, kidney pain, epigastric pain, pleural pain and painful biliary colic, appendicitis pain can all be considered visceral pain. Subphorax pain or pressure from early myocardial infarction is also visceral. Visceral pain can be caused by stomach, duodenum or colon disease. Common diseases of the Gastrointestinal (GI) tract that cause visceral pain include Functional Bowel Disease (FBD) and Inflammatory Bowel Disease (IBD). These gastrointestinal disorders include a variety of disease states that are currently only moderately controlled, including with respect to FBD, gastroesophageal reflux, dyspepsia, Irritable Bowel Syndrome (IBS) and Functional Abdominal Pain Syndrome (FAPS), and with respect to IBD, crohn's disease, ileitis and ulcerative colitis, all of which produce visceral pain on a regular basis.
Suitably, the present invention relates to a method of treating or reducing the severity of pain. The present invention can alleviate pain from a number of causes, including but not limited to impact; amputation of limbs; severe chemical or thermal burns; sprains, ligament tears, fractures, trauma, and other tissue injuries; dental surgery, procedures and diseases (maladies); delivery (baby and childbirth); migraine headache; during the physical therapy period; post-operative pain; radiation poisoning; cancer; acquired immunodeficiency syndrome (AIDS); epidural (epidial or peridial) fibrosis; failure of back surgery and laminectomy; sciatica; sickle cell crisis pain; arthritis; (ii) an autoimmune disease; intractable bladder pain; and so on. The present invention relates to the treatment of intractable pain, regardless of its cause.
In embodiments, the pain is treated in a human patient.
The compounds of the present invention inhibit the unfolded protein response, which is involved in the pathogenesis of disc degeneration. Suitably, the present invention relates to a method for treating or alleviating the severity of intervertebral disc degeneration.
In embodiments, the compounds described herein are provided as a pharmaceutical composition comprising the compound and a pharmaceutically acceptable excipient. In an embodiment of this method, the compound or pharmaceutically acceptable salt thereof is co-administered with a second agent (e.g., a therapeutic agent). In an embodiment of this method, the compound or pharmaceutically acceptable salt thereof is co-administered with a second agent (e.g., a therapeutic agent) which is administered in a therapeutically effective amount. In embodiments, the second agent is an agent for improving memory.
It was demonstrated that the induction of Long Term Memory (LTM) was reduced and impaired due to increased eIF2 α phosphorylation. This data strongly supports the notion that under physiological conditions, a reduction in eIF2 α phosphorylation is a key step in long-term synaptic changes required for memory formation, and ATF4 has been shown to be an important regulator of these processes [24] [25] [26 ]. It is not clear what the different eIF2 α kinases contribute to learning or whether each kinase plays a different role in different parts of the brain. Regardless of the eIF2 α kinase responsible for phosphorylation of eIF2 α in the brain, the compounds disclosed herein that block translation and ATF4 production make them ideal molecules for blocking the effect of this phosphorylation event on memory. Pharmacological treatment with the compounds disclosed herein increases spatial memory and enhances auditory and contextual fear conditioning.
Translation modulators, such as compounds of formula (IIIQ), may be useful as therapeutic agents to improve memory in human diseases associated with memory loss, such as alzheimer's disease and other neurological diseases that activate UPRs in neurons and thus may have negative effects on memory consolidation, such as parkinson's disease, amyotrophic lateral sclerosis, and prion diseases. Furthermore, mutations in eIF2 γ disrupt complex integrity, which links intellectual disability (intellectual impairment syndrome or ID) to impaired translation initiation in humans [27 ]. Thus, the two diseases with impaired elF2 function, ID and VWM show different phenotypes, but both mainly affect the brain and impair learning ability.
The compounds of formula (IIIQ) may also be used in applications where increased protein production is desired, such as in vitro cell-free systems for protein production. In vitro systems have basal levels of eIF2 α phosphorylation, which decreases translation yield [28,29 ]. Similarly, antibody production by hybridomas can also be increased by the addition of compounds disclosed herein.
In another aspect, there is provided a method of increasing protein expression in a cell or in vitro expression system, the method comprising administering to the cell or expression system an effective amount of a compound of formula (IIIQ). In an embodiment, the method is a method of increasing protein expression in a cell, and comprises administering to the cell an effective amount of a compound of formula (IIIQ). In embodiments, the method is a method of increasing protein expression of an in vitro protein expression system, and comprises administering to the in vitro (e.g., cell-free) protein expression system an effective amount of a compound of formula (IIIQ).
In embodiments, the compounds described herein are provided as a pharmaceutical composition comprising the compound and a pharmaceutically acceptable excipient. In an embodiment of the method, the compound or pharmaceutically acceptable salt thereof is co-administered with a second agent. In an embodiment of this method, the compound or pharmaceutically acceptable salt thereof is co-administered with a second agent, which is administered in a therapeutically effective amount. In embodiments, the second agent is an agent for improving protein expression.
Suitably, the present invention relates to a method of treating or lessening the severity of breast cancer, including inflammatory breast cancer, ductal cancer and lobular cancer.
Suitably, the present invention relates to a method of treating or lessening the severity of colon cancer.
Suitably, the present invention relates to methods of treating or lessening the severity of pancreatic cancer, including insulinomas, adenocarcinomas, ductal adenocarcinomas, adenosquamous carcinomas, acinar cell carcinomas, and glucagonoma.
Suitably, the present invention relates to a method of treating or lessening the severity of skin cancer, including melanoma, including metastatic melanoma.
Suitably, the present invention relates to a method of treating or lessening the severity of lung cancer, including small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, adenocarcinoma and large cell carcinoma.
Suitably, the present invention relates to a method of treating or lessening the severity of a cancer selected from: brain cancer (glioma), glioblastoma, astrocytoma, glioblastoma multiforme, Bannayan-Zonana syndrome, cowden disease, Lee-Du's disease, Willemm's tumor, Ewing's sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, head and neck cancer, renal cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate cancer, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid cancer, lymphoblastic T-cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T-cell leukemia, human myelogenous leukemia, chronic myelogenous leukemia, and human myelogenous leukemia, Plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, multiple myeloma, acute megakaryoblastic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, hodgkin's lymphoma, non-hodgkin's lymphoma, lymphoblastic T-cell lymphoma, burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulval cancer, cervical cancer, endometrial cancer, kidney cancer, mesothelioma, esophageal cancer, salivary gland carcinoma, hepatocellular carcinoma, gastric cancer, nasopharyngeal cancer, buccal cancer, oral cancer, GIST (gastrointestinal stromal tumor), neuroendocrine cancer and testicular cancer.
Suitably, the present invention relates to a method of treating or lessening the severity of a pre-cancerous syndrome in a mammal, including a human, wherein said pre-cancerous syndrome is selected from the group consisting of: cervical intraepithelial neoplasia, Monoclonal Gammaglobulin of Unknown Significance (MGUS), myelodysplastic syndrome, aplastic anemia, cervical lesions, cutaneous nevi (premna), Prostatic Intraepithelial Neoplasia (PIN), Ductal Carcinoma In Situ (DCIS), colonic polyps and severe hepatitis or cirrhosis.
Suitably, the present invention relates to a method of treating or lessening the severity of: neurodegenerative diseases/injuries such as alzheimer's disease, spinal cord injury, traumatic brain injury, ischemic stroke, diabetes, parkinson's disease, huntington's disease, creutzfeldt-jakob disease, and related prion diseases, progressive supranuclear palsy, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, inflammation, fibrosis, chronic and acute liver disease, chronic and acute lung disease, chronic and acute kidney disease, chronic traumatic brain disease (CTE), neurodegeneration, dementia, cognitive impairment, atherosclerosis, eye diseases, cardiac arrhythmias, for organ transplantation and for transporting organs for transplantation.
Suitably, the present invention relates to a method of preventing damage to an organ during and after organ transplantation and during transport of the organ for transplantation. A method of preventing organ damage during and after organ transplantation comprising administering a compound of formula (IIIQ) in vivo. A method for preventing organ damage during transport of an organ for transplantation comprising adding a compound of formula (IIIQ) to a solution containing the organ during transport.
Suitably, the present invention relates to a method of treating or reducing the severity of a neurodegenerative eye disease, wherein the disease is retinitis pigmentosa.
Suitably, the present invention relates to a method of treating or reducing the severity of an eye disease, wherein the disease is selected from retinal dystrophy and corneal dystrophy, such as rich's cornual dystrophy.
Suitably, the present invention relates to a method of treating or lessening the severity of ocular disease/angiogenesis. Methods of treating or lessening the severity of ocular disease/angiogenesis would include the in vivo administration of a compound of formula (III). In an embodiment of the method according to the invention, the ocular disorder, including vascular leakage, may be: edema or neovascularization of any occlusive or inflammatory retinal vascular disease, such as rubeosis of the iris, neovascular glaucoma, pterygium, vascularized glaucoma filtering blebs, papillary conjunctiva; choroidal neovascularization, such as neovascular age-related macular degeneration (AMD), myopia, anterior uveitis, trauma, or idiopathic ocular disease; macular edema, such as post-operative macular edema, macular edema secondary to uveitis, including retinal and/or choroidal inflammation, macular edema secondary to diabetes, and macular edema secondary to retinal vascular occlusive diseases (i.e., branch and central retinal vein occlusion); retinal neovascularization due to diabetes, such as retinal vein occlusion, uveitis, ocular ischemic syndrome from carotid artery disease, ocular or retinal artery occlusion, sickle cell retinopathy, other ischemic or occlusive neovascular retinopathy, retinopathy of prematurity, or early disease (Ealedisteae); and genetic diseases such as von hippel-Lindau syndrome (von hippel-Lindau syndrome).
In some embodiments, the neovascular age-related macular degeneration is wet age-related macular degeneration. In other embodiments, the neovascular age-related macular degeneration is dry age-related macular degeneration and the patient is characterized by an increased risk of developing wet age-related macular degeneration.
In embodiments, an eye disease is treated in a human patient.
The treatment methods of the present invention comprise administering to a patient in need thereof an effective amount of a compound according to formula (IIIQ) or a pharmaceutically acceptable salt thereof.
The present invention also provides a compound according to formula (IIIQ), or a pharmaceutically acceptable salt thereof, for use in medical therapy, in particular therapy: cancer, pre-cancerous syndromes, alzheimer's disease, spinal cord injury, traumatic brain injury, ischemic stroke, diabetes, parkinson's disease, huntington's disease, creutzfeldt-jakob disease and related prion diseases, progressive supranuclear palsy, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, inflammation, fibrosis, chronic and acute liver disease, chronic and acute lung disease, chronic and acute kidney disease, chronic traumatic brain disease (CTE), neurodegeneration, dementia, cognitive impairment, atherosclerosis, ocular disease, in organ transplantation and cardiac arrhythmia. The present invention also provides a compound according to formula (IIIQ) or a pharmaceutically acceptable salt thereof for use in preventing organ damage during transport of an organ for transplantation. Thus, in other aspects, the invention relates to the use of a compound according to formula (IIIQ), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease characterized by activation of UPR, such as cancer.
The treatment methods of the present invention comprise administering to a mammal, suitably a human, in need thereof a safe and effective amount of a compound of formula (IIIQ), or a pharmaceutically acceptable salt thereof.
As used herein, "treating" and derivatives thereof, when referring to a condition, means: (1) ameliorating or preventing the disorder and one or more biological manifestations of the disorder, (2) interfering with (a) one or more points in a biological cascade that leads to or is the cause of the disorder, or (b) one or more biological manifestations of the disorder, (3) alleviating one or more symptoms or effects associated with the disorder, or (4) slowing the progression of the disorder or one or more biological manifestations of the disorder.
The term "treatment" and its derivatives refer to therapeutic treatment. Therapeutic treatment is suitable for alleviating symptoms or for treatment when early signs of the disease or its progression are present. Prophylactic treatment is appropriate when the subject has a strong family history of, for example, neurodegenerative disease. Prophylactic treatment is suitable when the subject has, for example, a family history of strong cancer or is considered to have a high risk of developing cancer or the subject has been exposed to a carcinogen.
Those skilled in the art will appreciate that "prevention" is not an absolute term. Medically, "preventing" is understood to mean prophylactically administering an agent to substantially reduce the likelihood or severity of, or delay the onset of, a condition or biological manifestation thereof.
"safe and effective amount" as used with respect to a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof, refers to an amount of the compound that is, within the scope of sound medical judgment, sufficient to treat the condition of the patient, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio). The safe and effective amount of the compound will vary with the particular route of administration chosen; the condition being treated; the severity of the condition being treated; the age, size, weight and physical condition of the patient being treated; a history of the patient being treated; the duration of the treatment; the nature of concurrent therapy; the expected therapeutic effect, and the like, may vary, but can still be routinely determined by those skilled in the art.
As used herein, "patient" and derivatives thereof refer to a human or other mammal, suitably a human.
The compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof may be administered by any suitable route of administration, including systemic administration. Systemic administration includes oral administration and parenteral administration. Parenteral administration refers to routes other than enteral, transdermal or inhalation administration, and is typically by injection or infusion. Parenteral administration includes intravenous, intramuscular and subcutaneous injection or infusion.
The compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof may be administered once or according to a dosing regimen whereby doses are administered at different time intervals over a given period of time. For example, the dose may be administered once, twice, three times or four times daily. The dosage may be continued until the desired therapeutic effect is achieved, or may be administered indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for the compounds of the invention are determined by the pharmacokinetic properties of the compound, such as absorption, distribution and half-life, which can be determined by one skilled in the art. Furthermore, suitable dosing regimens for the compounds of the invention, including the duration of administration of the regimen, will depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient being treated, the nature of concurrent therapy, the intended therapeutic effect, and possible factors within the knowledge and experience of those skilled in the art. One skilled in the art will also appreciate that depending on the appropriate dosing regimen, it may be necessary to adjust to the individual patient's response to the dosing regimen, or to adjust over time to changes in the individual patient's needs.
In addition, the compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof may be administered as a prodrug. As used herein, a "prodrug" of a compound of the invention is a functional derivative of the compound that, upon administration to a patient, ultimately releases the compound of the invention in vivo. Administration of the compounds of the invention in prodrug form may enable one skilled in the art to do one or more of the following: (a) altering the release of the compound in vivo; (b) altering the duration of action of the compound in vivo; (C) altering the delivery or distribution of the compound in vivo; (d) altering the solubility of the compound in vivo; and (e) overcoming side effects or other problems encountered with the compounds. when-COOH or-OH groups are present, pharmaceutically acceptable esters such as methyl esters, ethyl esters, and the like can be used for-COOH, and acetate esters, maleate esters, and the like can be used for-OH, and those esters known in the art for improving solubility or hydrolysis characteristics.
The compounds of formula (IIIQ) and pharmaceutically acceptable salts thereof may be co-administered with at least one other active agent known to be useful in the treatment of cancer or precancerous syndrome.
As used herein, the term "co-administration" refers to the simultaneous administration or separate sequential administration in any manner of an ATF4 pathway inhibiting compound as described herein and another active agent or agents known to be useful in the treatment of cancer, including chemotherapy and radiation therapy. As used herein, the term "additional active agent or agents" includes any compound or therapeutic agent that is known or exhibits a beneficial property when administered to a patient in need of treatment for cancer. Preferably, the compounds are administered at times close to each other, if not simultaneously. Furthermore, it does not matter whether the compounds are administered in the same dosage form, e.g., one compound may be administered by injection and the other compound may be administered orally.
In general, any antineoplastic agent active against a susceptible tumor to be treated can be co-administered in the cancer treatment of the present invention. Examples of such agents can be found in Cancer Principles and Practice of Oncology by v.t.device and s.hellman (ed.), 6 th edition (2.15.2001), Lippincott Williams & Wilkins Publishers. One of ordinary skill in the art will be able to discern which combination of agents is useful based on the particular characteristics of the drug and the cancer involved. Typical anti-tumor agents useful in the present invention include, but are not limited to, anti-microtubule agents such as diterpenoids and vinca alkaloids; a platinum coordination complex; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkyl sulfonates, nitrosoureas, and triazenes; antibiotic drugs such as anthracyclines, actinomycins, and bleomycin; topoisomerase II inhibitors such as epipodophyllotoxin; antimetabolites such as purine and pyrimidine analogs and antifolate compounds; topoisomerase I inhibitors such as camptothecin; hormones and hormone analogs; a signal transduction pathway inhibitor; non-receptor tyrosine kinase angiogenesis inhibitors; an immunotherapeutic agent; a pro-apoptotic agent; inhibitors of cell cycle signaling; a proteasome inhibitor; and cancer metabolism inhibitors.
Examples of other active ingredients (antineoplastic agents) for use in combination or co-administration with the ATF4 pathway inhibiting compounds of the present invention are chemotherapeutic agents.
Suitably, the pharmaceutically active compounds of the present invention are for use in combination with a VEGFR inhibitor, suitably 5- [ [4- [ (2, 3-dimethyl-2H-indazol-6-yl) methylamino ] -2-pyrimidinyl ] amino ] -2-methylbenzenesulfonamide, or a pharmaceutically acceptable salt thereof (suitably the monohydrochloride), disclosed and protected in international application No. PCT/US01/49367, published as 19/12/2001, published as WO02/059110 and published as 1/8/2002, the entire contents of which are incorporated herein by reference, and which is the compound of example 69. 5- [ [4- [ (2, 3-dimethyl-2H-indazol-6-yl) methylamino ] -2-pyrimidinyl ] amino ] -2-methylbenzenesulfonamide can be prepared as described in International application No. PCT/US 01/49367.
In one embodiment, the method of cancer treatment of the present invention comprises co-administering a compound of formula (IIIQ) and/or a pharmaceutically acceptable salt thereof and at least one antineoplastic agent, such as one antineoplastic agent selected from the group consisting of: anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, anti-metabolites, topoisomerase I inhibitors, hormones and hormone analogs, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, pro-apoptotic agents, cell cycle signaling inhibitors; a proteasome inhibitor; and cancer metabolism inhibitors.
"chemotherapy" or "chemotherapeutic agent" is used according to its ordinary meaning and refers to a chemical composition or compound having anti-tumor properties or the ability to inhibit cell growth or proliferation.
In addition, the compounds described herein can be co-administered with conventional immunotherapeutic agents, including, but not limited to, immunostimulants (e.g., Bacillus Calmette-guerin (bcg), levamisole, interleukin-2, interferon-alpha, etc.), monoclonal antibodies (e.g., anti-CD 20, anti-HER 2, anti-CD 52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD 33 monoclonal antibody-calicheamicin conjugate, anti-CD 22 monoclonal antibody-pseudomonas exotoxin conjugate, etc.), and radioimmunotherapy (e.g., conjugated to conventional immunotherapeutics)111In、90Y is or131anti-CD 20 monoclonal antibody of I, etc.).
In another embodiment, the compounds described herein may be co-administered with conventional radiotherapeutic agents, including, but not limited to radionuclides such as radionuclides47Sc、64C、67C、89Sr、86Y、87Y and212bi, optionally conjugated to an antibody directed against a tumor antigen.
Other examples of other active ingredients (antineoplastic agents) for use in combination or co-administration with the ATF4 pathway inhibiting compounds of the invention are anti-PD-L1 agents.
anti-PD-L1 antibodies and methods for their preparation are known in the art.
The antibody to PD-L1 may be polyclonal or monoclonal, and/or recombinant and/or humanized.
Exemplary PD-L1 antibodies are disclosed in:
U.S. patent nos. 8,217,149; 12/633,339, respectively;
U.S. patent nos. 8,383,796; 13/091,936, respectively;
U.S. patent nos. 8,552,154; 13/120,406, respectively;
U.S. patent publication numbers 20110280877; 13/068337, respectively;
U.S. patent publication numbers 20130309250; 13/892671, respectively;
WO2013019906；
WO2013079174；
U.S. application No. 13/511,538 (filed 8/7/2012), which is the U.S. national phase of international application No. PCT/US10/58007 (filed 2010);
and
U.S. application No. 13/478,511 (filed 5/23/2012).
Other exemplary antibodies and methods of use of PD-L1 (also known as CD274 or B7-H1) are disclosed in U.S. patent nos. 7,943,743; US20130034559, WO2014055897, U.S. patent No. 8,168,179; and U.S. patent No. 7,595,048. The PD-L1 antibody is under development as an immunomodulator for the treatment of cancer.
In one embodiment, the antibody to PD-L1 is an antibody disclosed in U.S. patent No. 8,217,149. In another embodiment, the anti-PD-L1 antibody comprises the CDRs of an antibody disclosed in U.S. patent No. 8,217,149.
In another embodiment, the antibody to PD-L1 is an antibody disclosed in U.S. application No. 13/511,538. In another embodiment, the anti-PD-L1 antibody comprises the CDRs of an antibody disclosed in U.S. application No. 13/511,538.
In another embodiment, the antibody to PD-L1 is the antibody disclosed in application No. 13/478,511. In another embodiment, the anti-PD-L1 antibody comprises the CDRs of an antibody disclosed in U.S. application No. 13/478,511.
In one embodiment, the anti-PD-L1 antibody is BMS-936559 (MDX-1105). In another embodiment, the anti-PD-L1 antibody is MPDL3280A (RG 7446). In another embodiment, the anti-PD-L1 antibody is MEDI 4736. In another embodiment, the anti-PD-L1 antibody is atezumab. In another embodiment, the anti-PD-L1 antibody is avizumab. In another embodiment, the anti-PD-L1 antibody is dolvacizumab.
Other examples of other active ingredients (antineoplastic agents) for use in combination or co-administration with the TF4 pathway inhibiting compounds of the invention are PD-1 antagonists.
"PD-1 antagonist" refers to any compound or biomolecule that blocks the binding of PD-L1 expressed on cancer cells to PD-1 expressed on immune cells (T cells, B cells, or NKT cells), and preferably also blocks the binding of PD-L2 expressed on cancer cells to PD-1 expressed on immune cells. Alternative names or synonyms for PD-1 and its ligands include: PDCD1, PD1, CD279, and SLEB2 for PD-1; PDCD1L1, PDL1, B7H1, B7-4, CD274 and B7-H for PD-L1; and PDCD1L2, PDL2, B7-DC, Btdc and CD273 for PD-L2. In any of the embodiments of aspects or embodiments of the invention wherein the human is the individual to be treated, the PD-1 antagonist blocks binding of human PD-L1 to human PD-1, and preferably blocks binding of human PD-L1 and PD-L2 to human PD-1. The human PD-1 amino acid sequence can be numbered at the NCBI locus: NP _ 005009. The human PD-L1 and PD-L2 amino acid sequences can be numbered at the NCBI locus, respectively: NP-054862 and NP-079515.
PD-1 antagonists useful in any aspect of the invention include monoclonal antibodies (mabs) or antigen-binding fragments thereof that specifically bind to PD-1 or PD-L1, and preferably specifically bind to human PD-1 or human PD-L1. The mAb may be a human antibody, a humanized antibody, or a chimeric antibody, and may include human constant regions. In some embodiments, the human constant region is selected from the group consisting of an IgG1, IgG2, IgG3, and IgG4 constant region, and in preferred embodiments, the human constant region is an IgG1 or IgG4 constant region. In some embodiments, the antigen binding fragment is selected from the group consisting of Fab, Fab '-SH, F (ab')2, scFv, and Fv fragments.
Examples of mabs that bind to human PD-1 and that can be used in the various aspects and embodiments of the invention are described in US7488802, US7521051, US8008449, US8354509, US8168757, WO2004/004771, WO2004/072286, WO2004/056875, and US 2011/0271358.
Specific anti-human PD-1 mabs useful as PD-1 antagonists in any aspect or embodiment of the invention include: MK-3475 which is a humanized IgG4mAb having the structure described in WHO Drug Information, Vol.27, No.2, page 161-162 (2013) and comprising the heavy and light chain amino acid sequences set forth in FIG. 6; nivolumab, a human IgG4mAb, having the structure described in whodrum Information, vol.27, No.1, pages 68-69 (2013), and which comprises the heavy and light chain amino acid sequences shown in fig. 7; humanized antibodies h409A11, h409A16 and h409A17 (described in WO 2008/156712) and AMP-514, which are being developed by Medimone.
Other PD-1 antagonists that can be used in any aspect or embodiment of the invention include immunoadhesins that specifically bind to PD-1, and preferably to human PD-1, e.g., fusion proteins comprising the extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region of an immunoglobulin molecule, such as an Fc region. Examples of immunoadhesion molecules that specifically bind to PD-1 are described in WO2010/027827 and WO 2011/066342. Specific fusion proteins useful as PD-1 antagonists in the methods of treatment, medicaments, and uses of the invention include AMP-224 (also known as B7-DCIg), which is a PD-L2-FC fusion protein and binds to human PD-1.
Other examples of mabs that bind to human PD-L1 and that may be used in the methods of treatment, medicaments and uses of the invention are described in WO2013/019906, W02010/077634a1 and US 8383796. Specific anti-human PD-L1 mAbs that may be used as PD-1 antagonists in the methods, medicaments and uses of treatment of the present invention include MPDL3280A, BMS-936559, MEDI4736, MSB 0010718C.
Figure BDA0002308602660000741
Permumab markets an anti-PD-1 antibody for the treatment of lung cancer by Merck. The amino acid sequence and methods of use of pembrolizumab are disclosed in U.S. patent No. 8,168,757.
Figure BDA0002308602660000742
Nastulbumab is a fully human monoclonal antibody marketed by Bristol Myers Squibb against the negatively immunoregulatory human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1/PCD-1) with immunopotentiating activity. Nivolumab binds and blocks the activation of PD-1 (an Ig superfamily transmembrane protein) by its ligands PD-L1 and PD-L2, leading to the activation of T cells and cell-mediated immune responses against tumor cells or pathogens. Activated PD-1 negatively regulates T cell activation and effector function by inhibiting the P13k/Akt pathway activation. Other names for nivolumab include: BMS-936558, MDX-1106 and ONO-4538. The amino acid sequence of nivolumab and methods of use and preparation are disclosed in U.S. patent No. 8,008,449.
Other examples of other active ingredients (antineoplastic agents) for use in combination or co-administration with the ATF4 pathway inhibiting compounds of the present invention are immunomodulators.
As used herein, "immunomodulator" refers to any substance that affects the immune system, including monoclonal antibodies. ICOS binding proteins of the invention may be considered immunomodulatory agents. The immunomodulator can be used as antitumor agent for treating cancer. For example, immunomodulators include, but are not limited to, anti-CTLA-4 antibodies such as lepril mab
Figure BDA0002308602660000743
And anti-PD-1 antibody: (
Figure BDA0002308602660000745
/nivolumab and
Figure BDA0002308602660000747
permumab). Other immunomodulators include, but are not limited to, OX-40 antibodies, PD-L1 antibodies, LAG3 antibodies, TIM-3 antibodies, 41BB antibodies, and GITR antibodies.
(Yiprimab) is a fully human CTLA-4 antibody marketed by Bristol Myers Squibb. The protein structure and methods of use of yiprimab are described in U.S. Pat. Nos.6,984,720 and 7,605,238.
Suitably, the compounds of the invention are in combination with an inhibitor of protein kinase r (pkr) -like ER kinase (PERK) activity.
Suitably, the compounds of the invention are used in combination with an inhibitor of eIF2a kinase protein kinase r (pkr), heme-regulated eIF2a kinase (HRI), or general control non-suppressible 2 protein (GCN 2) activity.
Suitably, the compounds of formula (IIIQ) and pharmaceutically acceptable salts thereof may be co-administered with at least one other active agent known for the treatment of neurodegenerative diseases/injuries.
Suitably, the compounds of formula (IIIQ) and pharmaceutically acceptable salts thereof may be co-administered with at least one other active agent known for the treatment of diabetes.
Suitably, the compounds of formula (IIIQ) and pharmaceutically acceptable salts thereof may be co-administered with at least one other active agent known for the treatment of cardiovascular diseases.
Suitably, the compounds of formula (IIIQ) and pharmaceutically acceptable salts thereof may be co-administered with at least one other active agent known for the treatment of ocular diseases.
The compounds described herein may be used in combination with each other, with other active agents known to be useful in the treatment of cancer (e.g., pancreatic cancer, breast cancer, multiple myeloma or secretory cell cancer), neurodegenerative diseases, ablative leukopathies, childhood ataxia with reduced CNS myelination and/or dysnoesia syndrome (e.g., associated with impaired function of eIF2 or components of signal transduction pathways, including eIF 2), or with auxiliary agents that may not be effective alone but may contribute to the therapeutic efficacy of the active agent.
In embodiments, the compounds described herein are provided as a pharmaceutical composition comprising the compound and a pharmaceutically acceptable excipient. In an embodiment of the method, the compound or pharmaceutically acceptable salt thereof is co-administered with a second agent (e.g., a therapeutic agent). In an embodiment of this method, the compound or pharmaceutically acceptable salt thereof is co-administered with a second agent (e.g., a therapeutic agent), which is administered in a therapeutically effective amount. In embodiments of the method, the second agent is an agent for treating cancer (e.g., pancreatic cancer, breast cancer, multiple myeloma or secretory cell cancer), a neurodegenerative disease, an ablative leukoderma, a childhood ataxia with a reduction in CNS myelination, and/or a mental retardation syndrome (e.g., associated with impaired function of eIF2 or components of signal transduction pathways, including eIF 2) or an inflammatory disease (e.g., POCD or TBI). In embodiments, the second agent is an anti-cancer agent. In embodiments, the second agent is a chemotherapeutic agent. In embodiments, the second agent is an agent for improving memory. In embodiments, the second agent is an agent for treating a neurodegenerative disease. In an embodiment, the second agent is an agent for treating ablative leukopathies. In embodiments, the second agent is an agent for treating childhood ataxia with a reduction in CNS myelination. In embodiments, the second agent is an agent for treating a intellectual impairment syndrome. In embodiments, the second agent is an agent for treating pancreatic cancer. In embodiments, the second agent is an agent for treating breast cancer. In embodiments, the second agent is an agent for treating multiple myeloma. In embodiments, the second agent is an agent for treating myeloma. In embodiments, the second agent is an agent for treating a secretory cell carcinoma. In embodiments, the second agent is an agent for reducing phosphorylation of eIF2 a. In embodiments, the second agent is an agent for inhibiting a pathway activated by eIF2a phosphorylation. In embodiments, the second agent is an agent for inhibiting integrated stress response. In embodiments, the second agent is an anti-inflammatory agent.
The term "eIF 2A" or "eIF 2A" refers to the protein "eukaryotic translation initiation factor 2A". In embodiments, "eIF2alpha" or "eIF2alpha" refers to a human protein. The term "eIF2alpha" or "eIF2alpha" includes both wild-type and mutant forms of the protein. In embodiments, "eIF2alpha" or "eIF 2a" refers to proteins associated with EntrezGene 83939, OMIM 609234, UniProt Q9BY44, and/or RefSeq (protein) NP 114414.
Suitably, the present invention relates to a method of treating an integrated stress-related disorder in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof.
Suitably, the integrated stress-related disease is cancer. Suitably, the integrated stress-related disorder is a neurodegenerative disorder. Suitably, the integrated stress-related disease is an ablative leukosis. Suitably, the integrated stress-related disorder is childhood ataxia with reduced CNS myelination. Suitably, the integrated stress-related disorder is a dysnoesia syndrome.
Suitably, the present invention relates to a method of treating a disease associated with eIF2 α phosphorylation in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (IIIZ) or a pharmaceutically acceptable salt thereof.
Suitably, the disease associated with phosphorylation of eIF2 α is cancer. Suitably, the disease associated with phosphorylation of eIF2 α is a neurodegenerative disease. Suitably, the disease associated with eIF2 α phosphorylation is ablative leukosis. Suitably, the disease associated with phosphorylation of eIF2 α is childhood ataxia with reduced CNS myelination. Suitably, the disease associated with eIF2 α phosphorylation is dysnoesia syndrome.
Suitably, the present invention relates to a method of treating a disease selected from: cancer, neurodegenerative diseases, ablative white matter disease, childhood ataxia with reduced CNS myelination and dysnoesia syndrome.
Suitably, the present invention relates to a method of treating an inflammatory disease in a patient in need of such treatment, which comprises administering to the patient a therapeutically effective amount of a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof.
Suitably, the inflammatory disease is associated with neurogenic inflammation. Suitably, the inflammatory disease is post-operative cognitive dysfunction. Suitably, the inflammatory disease is traumatic brain injury or Chronic Traumatic Encephalopathy (CTE).
In an embodiment of the method of treating a disease, the disease is selected from cancer, neurodegenerative diseases, ablative white matter disease, childhood ataxia with reduced CNS myelination and dysnoesia syndrome. In an embodiment of the method of treating a disease, the disease is cancer. In an embodiment of the method of treating a disease, the disease is a neurodegenerative disease. In an embodiment of the method of treating a disease, the disease is an ablative leukosis. In an embodiment of the method of treating a disease, the disease is childhood ataxia with reduced CNS myelination. In an embodiment of the method of treating a disease, the disease is a mental retardation syndrome. In an embodiment of the method of treating a disease, the disease is associated with phosphorylation of eIF2 α. In embodiments of the method of treating a disease, the disease is associated with the eIF2a signaling pathway. In an embodiment of the method of treating a disease, the disease is a cancer of the secretory cell type. In an embodiment of the method of treating a disease, the disease is pancreatic cancer. In an embodiment of the method of treating a disease, the disease is breast cancer. In an embodiment of the method of treating a disease, the disease is multiple myeloma. In an embodiment of the method of treating a disease, the disease is lymphoma. In an embodiment of the method of treating a disease, the disease is leukemia. In an embodiment of the method of treating a disease, the disease is a hematopoietic cancer.
In an embodiment of the method of treating a disease, the disease is alzheimer's disease. In an embodiment of the method of treating a disease, the disease is amyotrophic lateral sclerosis. In an embodiment of the method of treating a disease, the disease is creutzfeldt-jakob disease. In an embodiment of the method of treating a disease, the disease is frontotemporal dementia. In an embodiment of the method of treating a disease, the disease is Gerstmann-Straussler-Scheinker syndrome. In an embodiment of the method of treating a disease, the disease is huntington's disease. In an embodiment of the method of treating a disease, the disease is HIV-associated dementia. In an embodiment of the method of treating a disease, the disease is Kuru disease (Kuru). In an embodiment of the method of treating a disease, the disease is dementia with lewy bodies. In an embodiment of the method of treating a disease, the disease is multiple sclerosis. In an embodiment of the method of treating a disease, the disease is parkinson's disease. In an embodiment of the method of treating a disease, the disease is a prion disease.
In an embodiment of the method of treating a disease, the disease is an inflammatory disease. In embodiments, the inflammatory disease is post-operative cognitive dysfunction. In embodiments, the inflammatory disease is traumatic brain injury. In embodiments, the inflammatory disease is arthritis. In embodiments, the inflammatory disease is rheumatoid arthritis. In embodiments, the inflammatory disease is psoriatic arthritis. In embodiments, the inflammatory disease is juvenile idiopathic arthritis. In embodiments, the inflammatory disease is multiple sclerosis. In embodiments, the inflammatory disease is Systemic Lupus Erythematosus (SLE). In embodiments, the inflammatory disease is myasthenia gravis. In embodiments, the inflammatory disease is juvenile onset diabetes. In embodiments, the inflammatory disease is type 1 diabetes. In embodiments, the inflammatory disease is Guillain-Barre syndrome (Guillain-Barre syndrome). In embodiments, the inflammatory disease is Hashimoto encephalitis. In embodiments, the inflammatory disease is hashimoto's thyroiditis (hashimoto thyroiditis). In embodiments, the inflammatory disease is ankylosing spondylitis. In embodiments, the inflammatory disease is psoriasis. In embodiments, the inflammatory disease is Sjogren's syndrome. In embodiments, the inflammatory disease is vasculitis. In embodiments, the inflammatory disease is glomerulonephritis. In embodiments, the inflammatory disease is autoimmune thyroiditis. In embodiments, the inflammatory disease is Behcet's disease. In embodiments, the inflammatory disease is crohn's disease. In embodiments, the inflammatory disease is ulcerative colitis. In embodiments, the inflammatory disease is bullous pemphigoid. In embodiments, the inflammatory disease is sarcoidosis. In embodiments, the inflammatory disease is ichthyosis. In embodiments, the inflammatory disease is Graves ophthalmopathy. In embodiments, the inflammatory disease is inflammatory bowel disease. In embodiments, the inflammatory disease is Addison disease. In embodiments, the inflammatory disease is vitiligo. In embodiments, the inflammatory disease is asthma. In embodiments, the inflammatory disease is allergic asthma. In embodiments, the inflammatory disease is acne vulgaris. In embodiments, the inflammatory disease is coeliac disease. In embodiments, the inflammatory disease is chronic prostatitis. In embodiments, the inflammatory disease is inflammatory bowel disease. In embodiments, the inflammatory disease is a pelvic inflammatory disease. In embodiments, the inflammatory disease is reperfusion injury. In embodiments, the inflammatory disease is sarcoidosis. In embodiments, the inflammatory disease is transplant rejection. In an embodiment, the inflammatory disease is interstitial cystitis. In embodiments, the inflammatory disease is atherosclerosis. In embodiments, the inflammatory disease is atopic dermatitis.
In embodiments, the method of treatment is a prophylactic method. For example, a method of treating post-operative cognitive dysfunction may comprise preventing or reducing the severity of post-operative cognitive dysfunction or symptoms of post-operative cognitive dysfunction by administering a compound described herein prior to surgery.
In one embodiment, the present invention provides a compound of formula (IIIQ), or a pharmaceutically acceptable salt thereof, for use in treating a disease selected from: cancer, neurodegenerative diseases, ablative white matter disease, childhood ataxia with reduced CNS myelination and dysnoesia syndrome.
In one embodiment, the present invention provides a compound of formula (IIIQ), or a pharmaceutically acceptable salt thereof, for use in treating an integration stress related disease.
In one embodiment, the present invention provides a compound of formula (IIIQ), or a pharmaceutically acceptable salt thereof, for use in treating a disease associated with phosphorylation of eIF2 α.
In one embodiment, the present invention provides the use of a compound of formula (IIIQ), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease selected from: cancer, neurodegenerative diseases, ablative white matter disease, childhood ataxia with reduced CNS myelination and dysnoesia syndrome.
In one embodiment, the present invention provides the use of a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of an integration stress related disease.
In one embodiment, the invention provides the use of a compound of formula (IIIQ), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease associated with phosphorylation of eIF2 α.
Composition comprising a metal oxide and a metal oxide
The pharmaceutically active compounds within the scope of the present invention are useful as inhibitors of the ATF4 pathway in mammals, particularly humans, in need thereof.
Accordingly, the present invention provides methods of treating cancer, neurodegeneration, and other conditions requiring inhibition of the ATF4 pathway comprising administering an effective amount of a compound of formula (IIIQ), or a pharmaceutically acceptable salt thereof. The compounds of formula (IIIQ) also provide a method of treating the above conditions because they exhibit the ability to act as inhibitors of the ATF4 pathway. The medicament may be administered to a patient in need thereof by any conventional route of administration, including but not limited to intravenous, intramuscular, oral, topical, subcutaneous, intradermal, intraocular, and parenteral. Suitably, the ATF4 pathway inhibitor may be delivered directly to the brain by intrathecal or intraventricular routes, or the H-PGDS inhibitor may be placed in a device or pump that continuously releases ATF4 pathway inhibiting drug and implanted into the appropriate anatomical location.
The pharmaceutically active compounds of the present invention may be incorporated into convenient dosage forms such as capsules, tablets, or injectable formulations. Solid or liquid pharmaceutical carriers are used. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Liquid carriers include syrup, peanut oil, olive oil, saline and water. Similarly, the carrier or diluent may include any extended release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies widely, but preferably is from about 25mg to about 1g per dosage unit. When a liquid carrier is used, the preparation is in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or non-aqueous liquid suspension.
The pharmaceutical compositions may be prepared according to conventional techniques well known to the pharmaceutical chemist and include mixing, granulating and compressing as necessary to form tablets, or mixing, filling and dissolving the ingredients as necessary to provide the desired oral or parenteral product.
The dose of the pharmaceutically active compound of the invention in the pharmaceutical dosage unit as described above will be an effective non-toxic amount, preferably selected from the range of 0.001-100mg/kg of active compound, preferably 0.001-50 mg/kg. When treating human patients in need of an ATF4 pathway inhibitor, the selected dose is preferably administered orally or parenterally 1-6 times daily. Preferred forms of parenteral administration include topical, rectal, transdermal, injection and continuous infusion. Oral dosage units for human administration preferably contain 0.05 to 3500mg of active compound. Oral administration using lower doses is preferred. However, high dose parenteral administration can also be used with safety and convenience to the patient.
The optimal dosage to be administered can be readily determined by one skilled in the art and will vary with the particular ATF4 pathway inhibitor used, the strength of the formulation, the mode of administration, and the advancement of the disease condition. Other factors depending on the particular patient being treated will result in the need to adjust the dosage, including the patient's age, weight, diet and time of administration.
When administered in transporting an organ for transplantation to prevent organ damage, the compound of formula (IIIQ) is added to a solution, suitably a buffer solution, containing the organ during transportation.
The method of the present invention for inducing ATF4 pathway inhibitory activity in mammals, including humans, comprises administering to a subject in need of such activity an effective ATF4 pathway inhibitory amount of a pharmaceutically active compound of the present invention.
The invention also provides the use of a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting the ATF4 pathway.
The present invention also provides the use of a compound of formula (IIIQ), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for: treating cancer, pre-cancerous syndromes, alzheimer's disease, spinal cord injury, traumatic brain injury, ischemic stroke, diabetes, parkinson's disease, huntington's disease, creutzfeldt-jakob disease and related prion diseases, progressive supranuclear palsy, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, inflammation, fibrosis, chronic and acute liver disease, chronic and acute lung disease, chronic and acute kidney disease, chronic traumatic brain disease (CTE), neurodegeneration, dementia, cognitive impairment, atherosclerosis, ocular diseases, cardiac arrhythmias; for organ transplantation and for transporting organs for transplantation.
The invention also provides the use of a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for preventing organ damage during transport of an organ for transplantation.
The present invention also provides a pharmaceutical composition comprising a compound of formula (IIIQ), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier for use as an ATF4 pathway inhibitor.
The present invention also provides a pharmaceutical composition for treating cancer comprising a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
In addition, the pharmaceutically active compounds of the present invention may be co-administered with additional active ingredients, such as other compounds known to treat cancer, or compounds known to be effective when used in combination with ATF4 pathway inhibitors.
The invention also provides novel processes and novel intermediates useful in the preparation of the compounds of the invention.
The invention also provides a pharmaceutical composition comprising from 0.5mg to 1000mg of a compound of formula (IIIQ) or a pharmaceutically acceptable salt thereof and from 0.5mg to 1000mg of a pharmaceutically acceptable excipient.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Accordingly, the following examples are to be construed as merely illustrative, and not limitative of the scope of the invention in any way whatsoever.
Examples
The following examples illustrate the invention. These examples are not intended to limit the scope of the invention but rather to provide guidance to those skilled in the art in making and using the compounds, compositions, and methods of the invention. While particular embodiments of the present invention have been described, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention.
Example I
N, N' - (bicyclo [ 2.2.2)]Octane-1, 4-diyl) bis (2- (4-chlorophenoxy) acetamide)
Figure BDA0002308602660000811
Figure BDA0002308602660000821
Step 1: to a solution of 4-chlorophenol (15g, 116.67mmol, 1 eq) in DMF (100mL) at room temperature was added anhydrous potassium carbonate (24.15g, 175.01mmol, 1.5 eq) in portions. After stirring for 2 min, methyl 2-bromoacetate (13.3mL, 140.01mmol, 1.2 equiv.) was added. The reaction mixture was heated at 80 ℃ for 4 h. After consumption of the starting material (TLC, 5% EtOAc in hexanes), the reaction mixture was cooled to room temperature, diluted with water (100mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine solution (50mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product. The crude product was purified by flash column chromatography
Figure BDA0002308602660000822
Purify using silica gel column and elute product in 15% ethyl acetate in hexanes. The product-containing fractions were concentrated to give methyl 2- (4-chlorophenoxy) acetate (22.5g, 96.5% yield) as a light yellow liquid. LCMS (ES) M/z 200.0[ M + H ]]+。1H NMR(400MHz，CDCl3)：δppm 3.67(s，3H)，4.78(s，2H)，6.91–6.95(m，2H)，7.28–7.32(m，2H)。
Step 2: to a solution of methyl 2- (4-chlorophenoxy) acetate (22.5g, 112.15mmol, 1 equiv) in ethanol (100mL) was added a solution of sodium hydroxide (5.38g, 134.58mmol, 1.2 equiv) in water (100mL) at 0 ℃. After stirring at 0 ℃ for 5 minutes, the reaction mixture was warmed to room temperature and then refluxed for 2.5h, during which the starting material was completely consumed. The heating was removed and the reaction mixture was cooled to room temperature. The ethanol was removed in vacuo and the reaction mixture was diluted with water (50mL) and then Et2O (50 mL). The aqueous layer was acidified to pH 3 with 1N HCl and the precipitated product was filtered through a sintered funnel, washed with ice-cold water (10mL) and dried under high vacuum to give 2- (4-chlorophenoxy) acetic acid (20g, 95.6% yield) as a white solid. LCMS (ES) M/z 186.1[ M + H ]]+。1H NMR(400MHz，DMSO-d6)δppm 4.65(s，2H)，6.91(d，J＝9.2Hz，2H)，7.29(d，J＝8.8Hz，2H)，12.98(bs，1H)。
And step 3: bicyclo [2.2.2] in DCM (10mL) at 0 deg.C]Octane-1, 4-diamine dihydrochloride (0.200g, 0.938mmol, 1 equiv.) Triethylamine (0.660mL, 4.69mmol, 5 equiv.) and 2- (4-chlorophenoxy) acetic acid (0.437g, 2.34mmol, 2.5 equiv.) were added. After stirring at 0 ℃ for 5 minutes, add
Figure BDA0002308602660000832
(50 wt.% in ethyl acetate) (1.79mL, 2.81mmol, 3 equivalents) and the reaction mixture was stirred at room temperature for 16h, at which time the starting material was completely consumed. The reaction mixture was diluted with water (5mL) and extracted with DCM (2 × 10 mL). The combined organic extracts were extracted with saturated NaHCO3Aqueous solution (8mL) and water (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude material was purified by flash column chromatography using silica gel column, with the product eluted in 4-5% methanol in DCM. The product-containing fractions were concentrated under reduced pressure to give N, N' - (bicyclo [ 2.2.2)]Octane-1, 4-diyl) bis (2- (4-chlorophenoxy) acetamide) (0.040g, 8.94% yield) as a white solid. LCMS (ES) M/z 477.1[ M + H]+。1H NMR(400MHz，DMSO-d6)δppm 1.87(s，12H)，4.35(s，4H)，6.9(d，J＝9.2Hz，4H)，7.30(d，J＝8.8Hz，4H)，7.37(s，2H)。
Example II
N, N' - (bicyclo [ 1.1.1)]Pentane-1, 3-diyl) bis (2- (4-chlorophenoxy) acetamide)
Figure BDA0002308602660000831
Step 1: bis in DCM (10mL) at 0 deg.CRing [1.1.1]To pentane-1, 3-diamine dihydrochloride (0.200g, 1.169mmol, 1 equiv.) was added triethylamine (0.820mL, 5.845mmol, 5 equiv.) and 2- (4-chlorophenoxy) acetic acid (0.479g, 2.572mmol, 2.2 equiv.). After stirring at 0 ℃ for 5 minutes, add
Figure BDA0002308602660000833
(50 wt.% in ethyl acetate) (2.22mL, 3.507mmol, 3 equiv.) and the reaction mixture was stirred at room temperature for 16h when the starting material was completely consumed. The reaction mixture was diluted with water (5mL) and extracted with DCM (2 × 15 mL). The combined organic extracts were extracted with saturated NaHCO3Aqueous solution (8mL) and water (5 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude material was purified by flash column chromatography using silica gel column, with the product eluting with 1-3% methanol in DCM as eluent. The product-containing fractions were concentrated under reduced pressure to give N, N' - (bicyclo [ 1.1.1)]Pentane-1, 3-diyl) bis (2- (4-chlorophenoxy) acetamide) (0.260g, 51.38% yield) as a white solid. LCMS (ES) M/z 435[ M + H ═ M]+。1H NMR(400MHz，DMSO-d6)δppm 2.23(s，6H)，4.40(s，4H)，6.94(d，J＝8.8Hz，4H)，7.31(d，J＝8.8Hz，4H)，8.65(s，2H)。
Examples III and IV
The compounds of examples III and IV are generally prepared according to the procedures described above for examples I and II.
Table I.
Figure BDA0002308602660000841
Figure BDA0002308602660000851
Example V
N, N' - (bicyclo [ 1.1.1)]Pentane-1, 3-diyl) bis (2-phenoxyacetamide)
Figure BDA0002308602660000852
Step 1: at 0 deg.C to (3-aminobicyclo [ 1.1.1)]Pent-1-yl) carbamic acid tert-butyl ester (0.1g, 0.50mmol, 1.0 equiv) to a stirred solution in DCM (3.0mL) was added dropwise a solution of 4M HCl in dioxane (1.0mL) and the reaction mixture stirred at rt for 3 h. After consumption of starting material (TLC, 5% MeOH in DCM), the reaction mixture was concentrated under reduced pressure and the resulting solid was washed with n-pentane (2 × 10mL) and dried under high vacuum to give bicyclo [1.1.1]Pentane-1, 3-diamine dihydrochloride (0.08g, 93% yield) as an off-white solid.1H NMR(400MHz，DMSO-d6)δppm 2.19(s，6H)，9.04(s，6H)。
Step 2: bicyclo [1.1.1] at 0 deg.C]To a solution of pentane-1, 3-diamine dihydrochloride (0.08g, 0.46mmol, 1.0 equiv.) in DCM (8.0mL) was added triethylamine (0.33mL, 2.35mmol, 5.0 equiv.). The reaction was stirred for 10 minutes, then 2, 2-phenoxyacetic acid (0.17g, 1.17mmol, 2.5 equivalents) and
Figure BDA0002308602660000853
(50 wt.% in ethyl acetate) (0.56mL, 0.94mmol, 2.0 equiv.) was added to the reaction mixture. The reaction mixture was stirred at room temperature (25 ℃) for 3 h. After consumption of starting material (TLC, 5% MeOH in DCM), the solvent was concentrated under reduced pressure and saturated sodium bicarbonate solution (20mL) was added to the crude material. The mixture was stirred for 20 minutes and the solid was filtered, washed with water (10mL) and N-pentane (20mL), and dried under high vacuum to give N, N' - (bicyclo [ 1.1.1)]Pentane-1, 3-diyl) bis (2-phenoxyacetamide) (0.135g, 78.9% yield) as an off-white solid. LCMS (ES) M/z 367.2[ M + H]+。1H NMR(400MHz，DMSO-d6)δppm 2.25(s，6H)，4.39(s，4H)，6.94(t，J＝8.0Hz，6H)，7.27(t，J＝8.0Hz，4H)，8.63(s，2H)。
TABLE II
Example VI
2- (4-chlorophenoxy) -N- (3- (2- (4-chlorophenyl) acetyl)Amino) bicyclo [1.1.1]Pent-1-yl) acetamides
Step 1: to N- (3-aminobicyclo [1.1.1] at 0 DEG C]To a solution of pentan-1-yl) -2- (4-chlorophenoxy) acetamide hydrochloride (0.08g, 0.26mmol, 1 eq) in DCM (15.0mL) was added triethylamine (0.11mL, 0.79mmol, 3 eq). The reaction was stirred for 10 min, then 2- (4-chlorophenyl) acetic acid (0.049g, 0.31mmol, 1.2 eq.) and(50 wt.% in ethyl acetate) (0.33mL, 0.52mmol, 2 equivalents) was added to the reaction mixture. The reaction mixture was then stirred at room temperature (25 ℃) for 16 h. After consumption of starting material, the reaction mixture was diluted with water (5mL) and extracted with DCM (2 × 10 mL). The combined organic extracts were extracted with saturated NaHCO3The aqueous solution (8mL) was washed, then water (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude material was purified by flash column chromatography using silica gel column, with the product eluted with 2-3% methanol in DCM. The product-containing fractions were concentrated under reduced pressure to give 2- (4-chlorophenoxy) -N- (3- (2- (4-chlorophenyl) acetamido) bicyclo [1.1.1]Pent-1-yl) acetamide (0.053g, 48% yield) as an off-white solid. LCMS (ES) M/z 419.1[ M + H]+。1H NMR(400MHz，DMSO-d6)：δppm2.18(s，6H)，3.34(s，2H)，4.39(s，2H)，6.93-6.95(m.2H)，7.21-7.23(m，2H)，7.30-7.33(m，4H)，8.62-8.63(m，2H)。
The compounds of examples VII through XII are generally prepared according to the procedure of example VI above.
TABLE III
Figure BDA0002308602660000871
Figure BDA0002308602660000891
Example XIII
2- ((3- (2- (4-chlorophenoxy) acetamido) bicyclo [1.1.1]Pent-1-yl) (2- (4-chlorophenoxy) ethyl) Amino) -N, N-dimethylacetamide
Figure BDA0002308602660000901
Step 1: to N- (3-aminobicyclo [ 1.1.1)]To a solution of pentan-1-yl) -2- (4-chlorophenoxy) acetamide hydrochloride (0.3g, 0.99mmol, 1 equiv) in TEA (0.55mL, 3.96mmol, 4 equiv) was added 1- (2-bromoethoxy) -4-chlorobenzene (0.27g, 1.18mmol, 1.2 equiv) and the reaction mixture was stirred at room temperature for 10 min. The reaction mixture was then heated at 100 ℃ for 1h. After consumption of starting material (TLC, 5% DCM in methanol), the reaction mixture was cooled to rt, diluted with water (10mL) and extracted with EtOAc (2X10 mL). The combined organic layers were washed with brine solution (50mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography
Figure BDA0002308602660000902
Purify using silica gel column and elute product with 2% methanol in DCM. The product-containing fractions were concentrated to give 2- (4-chlorophenoxy) -N- (3- ((2- (4-chlorophenoxy) ethyl) amino) bicyclo [1.1.1]Pent-1-yl) acetamide (0.15g, 36% yield) as a light brown liquid. LCMS (ES) M/z 421.1[ M + H]+。1H NMR(400MHz，DMSO-d6)δppm 1.95(bs，6H)，2.81(bs，2H)，3.92-3.95(m，2H)，4.39(s，2H)，6.92-6.95(m，4H)，7.30(t，J＝8.0Hz，4H)，8.55(bs，1H)。
Step 2: to 2- (4-chlorophenoxy) -N- (3- ((4-chlorophenoxy) ethyl) amino) bicyclo [1.1.1]To a solution of pentan-1-yl) acetamide (004g, 009mmol 1 eq) in TEA (005mL, 036mmol, 4 eq) was added 2-chloro-N, N-dimethylacetoacetylAmine (0.043g, 0.36mmol, 4 equivalents) and the reaction mixture was heated at 80 ℃ for 1h. After consumption of the starting material (TLC, 5% methanol in DCM), the reaction mixture was cooled to rt, diluted with water (10mL) and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine solution (20mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography
Figure BDA0002308602660000912
Purify using silica gel column and elute product as 5% ethyl methyl alcohol in DCM. The product-containing fractions were concentrated to give 2- ((3- (2- (4-chlorophenoxy) acetamido) bicyclo [1.1.1]Pent-1-yl) (2- (4-chlorophenoxy) ethyl) amino) -N, N-dimethylacetamide (0.02g, 41% yield) as an off-white solid. LCMS (ES) M/z 506.2[ M + H]+。1H NMR(400MHz，DMSO-d6)δppm 1.99(s，6H)，2.74(s，3H)，2.90-2.91(m，2H)，2.93-2.95(m，3H)，3.37(s，2H)，3.93-3.96(m，2H)，4.39(s，2H)，6.89-6.95(m，4H)，7.31(t，J＝8.0Hz，4H)，8.57(s,1H)。
The compounds of examples XIV and XV are generally prepared according to the procedure described above for example XIII.
TABLE XIV
Figure BDA0002308602660000911
Figure BDA0002308602660000921
Example XVI
N- (3- (2- (4-chlorophenoxy) acetamido) bicyclo [1.1.1]Pent-1-yl) -N- (2- (4-chlorophenoxy) ethyl Yl) Glycine methyl ester
Figure BDA0002308602660000922
Figure BDA0002308602660000931
Step 1: to 2- (4-chlorophenoxy) -N- (3- ((2- (4-chlorophenoxy) ethyl) amino) bicyclo [1.1.1 at room temperature]To a solution of pentan-1-yl) acetamide (0.06g, 0.14mmol, 1 eq) in DMF (15mL) was added potassium carbonate (0.029g, 0.21mmol, 1.5 eq) in portions. After stirring for 2 min, methyl 2-bromoacetate (0.016g, 0.16mmol, 1.2 eq) was added. The reaction mixture was heated at 80 ℃ for 6 h. After consumption of the starting material (TLC, 15% EtOAc in hexanes), the reaction mixture was cooled to room temperature, diluted with water (10mL) and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine solution (20mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography using silica gel column and the product was eluted with 40% ethyl acetate in hexane. The product-containing fractions were concentrated to give N- (3- (2- (4-chlorophenoxy) acetamido) bicyclo [1.1.1]Pent-1-yl) -N- (2- (4-chlorophenoxy) ethyl) glycine methyl ester (0.006g, 8% yield) as a colourless gum. LCMS (ES) M/z 493.1[ M + H]+。1H NMR(400MHz，DMSO-d6)δppm 1.98(s，6H)，2.99–3.02(m，2H)，3.47(s，2H)，3.56(s，3H)，3.95–3.98(m，2H)，4.39(s，2H)，6.95–6.89(m，4H)，7.31(t，J＝8.0Hz，4H)，8.58(s，1H)。
TABLE V
Figure BDA0002308602660000932
Example XVII
4- ((3- (2- (4-chlorophenoxy) acetamido) bicyclo [1.1.1]Pent-1-yl) (2- (4-chlorophenoxy) ethyl) Amino) butyric acid ethyl ester
Figure BDA0002308602660000941
Step 1: to 2- (4-chlorophenoxy) -N- (3- ((4-chlorophenoxy) ethyl) amino) bicyclo [1.1.1]To a solution of pentan-1-yl) acetamide (0.09g, 0.21mmol, 1 eq) in TEA (0.086mL, 0.84mmol, 4 eq) was added ethyl 4-bromobutyrate (0.053mL, 0.31mmol, 1.5 eq)And the reaction mixture was heated at 100 ℃ for 1h. After consumption of starting material (TLC, 5% methanol in DCM), the reaction mixture was cooled to rt, diluted with water (10mL) and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine solution (20mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography using silica gel column and the product was eluted with 2.5% methanol in DCM. The product-containing fractions were concentrated to provide 4- ((3- (2- (4-chlorophenoxy) acetamido) bicyclo [1.1.1]Pent-1-yl) (2- (4-chlorophenoxy) ethyl) amino) butyric acid ethyl ester (0.04g, 35% yield) as a pale yellow gum. LCMS (ES) M/z 535.2[ M + H]+。1HNMR(400MHz，DMSO-d6δppm 1.12-1.22(m，3H)，1.59-1.63(m，2H)，1.98(s，6H)，2.26-2.30(m，2H)，2.48(bs，2H)，2.80-2.83(m，2H)，3.90-3.93(m，2H)，3.98-4.03(m，2H)，4.40(s，2H)，6.90-6.95(m，4H)，7.30(t，J＝8.0Hz，4H)，8.58(s，1H)。
TABLE VI
Example XVIII
2- (4-chlorophenoxy) -N- (3- ((2- (4-chlorophenoxy) ethyl) (methyl) amino) bicyclo [1.1.1]Penta-1- Yl) acetamide
Figure BDA0002308602660000952
Step 1: to 2- (4-chlorophenoxy) -N- (3- ((2- (4-chlorophenoxy) ethyl) amino) bicyclo [1.1.1] at 0 deg.C]To a solution of pentan-1-yl) acetamide (0.050g, 0.118mmol, 1 equiv) in tetrahydrofuran (5mL) were added aqueous formaldehyde (0.2mL) and acetic acid (0.050 mL). After stirring at room temperature for 1h, sodium triacetoxyborohydride (0.037g, 0.178mmol, 1.5 equiv.) was added at 0 ℃. After stirring for 5 minutes, the reaction mixture was stirred at room temperatureAnd 14 h. The reaction mixture was then quenched with saturated sodium bicarbonate (1mL) and extracted with ethyl acetate (2 × 15 mL). The combined organic layers were washed with water (2.0mL), brine (3mL), and then dried over anhydrous sodium sulfate. The organic layer was filtered and concentrated under reduced pressure to give the crude product, which was purified by preparative TLC using 3% methanol in DCM as mobile phase. The product was concentrated under reduced pressure and dried under high vacuum to afford 2- (4-chlorophenoxy) -N- (3- ((2- (4-chlorophenoxy) ethyl) (methyl) amino) bicyclo [1.1.1]Pent-1-yl) acetamide (0.027g, 52.94% yield) as a white solid. LCMS (ES) M/z 435.1[ M + H [ ]]+。1H NMR(400MHz，DMSO-d6)：δppm1.96(s，6H)，2.20(s，3H)，2.70(t，J＝5.6Hz，2H)，3.99(t，J＝5.6Hz，2H)，4.40(s，2H)，6.92–6.95(m，4H)，7.28–7.33(m，4H)，8.60(s，1H)。
TABLE VII
Figure BDA0002308602660000961
Example XIX
2- (4-chlorophenoxy) -N- (3- (N- (2- (4-chlorophenoxy) ethyl) acetamido) bicyclo [1.1.1]Penta-1- Yl) acetamide
Figure BDA0002308602660000962
Step 1: to 2- (4-chlorophenoxy) -N- (3- ((2- (4-chlorophenoxy) ethyl) amino) bicyclo [1.1.1] at 0 deg.C]To a solution of pentan-1-yl) acetamide (0.050g, 0.118mmol, 1 equiv) in DMF (5mL) was added triethylamine (0.066mL, 0.47mmol, 4 equiv.) and acetic acid (0.009mL, 0.166mmol, 1.4 equiv.). After stirring for 5 minutes, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (0.034g, 0.178mmol, 1.5 equivalents) and hydroxybenzotriazole (0.027g, 0.178mmol, 1.5 equivalents) were added. The reaction mixture was then stirred at room temperature for 14 h. The reaction mixture was diluted with water (5mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic extracts were extracted with saturated NaHCO3Aqueous solution (3mL), water (10mL) and dried over anhydrous sodium sulfate. The organic layer was filtered and concentrated under reduced pressure to giveTo the crude product, it was purified by the following preparative HPLC method.
Column: intersil ODS 3V (250mmx4.6mmx5mic)
Mobile phase (a): 0.1% aqueous ammonia solution
Mobile phase (B): ACN
Flow rate: 1.0mL/min
T/％B:0/20，10/80，25/90，27/20，30/20
Yield: 0.029g, white solid, 53.70%
LCMS(ES)m/z＝463.1[M+H]+。1H NMR(400MHz，DMSO-d6)：δppm2.05(s，3H)，2.30(s，6H)，3.62(t，J＝5.6Hz，2H)，4.03(t，J＝5.2Hz，2H)，4.41(s，2H)，6.93–6.97(m，4H)，7.27–7.31(m，4H)，8.41(s，1H)。
TABLE VIII
Figure BDA0002308602660000971
Example XX
2- (4-chlorophenoxy) -N- (3- ((2- (4-chlorophenoxy) ethyl) (oxetan-3-yl) amino) bicyclo [1.1.1]Pent-1-yl) acetamides
Figure BDA0002308602660000981
Step 1: to 2- (4-chlorophenoxy) -N- (3- ((2- (4-chlorophenoxy) ethyl) amino) bicyclo [1.1.1]To a solution of pentan-1-yl) acetamide (0.060g, 0.142mmol, 1 equiv) in methanol (5mL) were added oxetan-3-one (0.012mL, 0.213mmol, 1.5 equiv) and ZnCl2(0.5M in THF, 1.13mL, 0.569mmol, 4 equiv.). The reaction mixture was then cooled with an ice bath and sodium cyanoborohydride (0.026g, 0.427mmol, 3 equiv.) was added at 0 ℃. The reaction mixture was then stirred at 50 ℃ for 5h, then cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (5mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with water (5mL), brine (5mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product,it was purified by preparative TLC using 3% methanol in DCM as mobile phase. The product containing fractions were concentrated under reduced pressure and dried under high vacuum to afford 2- (4-chlorophenoxy) -N- (3- ((2- (4-chlorophenoxy) ethyl) (oxetan-3-yl) amino) bicyclo [1.1.1]Pent-1-yl) acetamide (0.024g, 35.82% yield) as a white solid. LCMS (ES) M/z 477.1[ M + H]+。1H NMR(400MHz，DMSO-d6)：δppm 1.96(s，6H)，2.82–2.84(m，2H)，3.89–3.96(m，3H)，4.39–4.43(m，4H)，4.52–4.55(m，2H)，6.93(d，J＝8.8Hz，4H)，7.29–7.32(m，4H)，8.60(s，1H)。
TABLE IX
Figure BDA0002308602660000982
Figure BDA0002308602660000991
Example XXI
2- (4-chlorophenoxy) -N- (3- ((2- ((4-chlorophenyl) amino) ethyl) amino) bicyclo [1.1.1]Penta-1-yl) Acetamide
Figure BDA0002308602660000992
Step 1: n- (3-Aminobicyclo [1.1.1] pent-1-yl) -2- (4-chlorophenoxy) acetamide hydrochloride (0.300g, 0.989mmol, 1 equiv.), triethylamine (0.556mL, 3.95mmol, 4 equiv.), and N- (2-bromoethyl) -4-chloroaniline (0.278g, 1.18mmol, 1.2 equiv.) were added to a closed tube. The reaction mixture was then sealed and heated at 100 ℃ for 1h, at which time it was cooled to room temperature, diluted with water (5mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with water (10mL) then saturated brine solution (8mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography using silica gel column and a mixture of methanol in DCM as eluent and the product eluted with 4-5% methanol in DCM. The product-containing fractions were concentrated to give 2- (4-chlorophenoxy) -N- (3- ((2- ((4-chlorophenyl) amino) ethyl) amino) bicyclo [1.1.1] pent-1-yl) acetamide (0.130g, 31.32% yield) as an off-white solid. Lcms (es) M/z 420.1[ M + H ] +, 1H NMR (400MHz, DMSO-d6) δ ppm 1.93(s, 6H), 2.61-2.64 (M, 2H), 2.99-3.03 (M, 2H), 4.39(s, 2H), 5.63-5.66 (M, 1H), 6.53(d, J ═ 8.8Hz, 2H), 6.94(d, J ═ 8.8Hz, 2H), 7.05(d, J ═ 8.8Hz, 2H), 7.31(d, J ═ 8.8Hz, 2H), 8.54(s, 1H).
Table X
Figure BDA0002308602660001001
Example XXII
2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1]Penta-1- Yl) acetamide
Figure BDA0002308602660001002
Figure BDA0002308602660001011
Step 1: to 2- (4-chlorophenoxy) -N- (3- ((2- ((4-chlorophenyl) amino) ethyl) amino) bicyclo [1.1.1] at 0 deg.C]To a solution of pentan-1-yl) acetamide (0.090g, 0.21mmol, 1 equiv.) in DCM (5mL) was added triethylamine (0.150mL, 1.07mmol, 5 equiv.) and triphosgene (0.038g, 0.128mmol, 0.6 equiv.). After stirring for 5 minutes, the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was then quenched with saturated sodium bicarbonate solution and extracted with DCM (2 × 10 mL). The combined organic extracts were washed with cold water (8mL) then saturated brine solution (6mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography using silica gel column and a mixture of ethyl acetate in hexane as eluent, the product was eluted with 35-40% ethyl acetate in hexane to afford 2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) acetamide (0.044g, 46.31% yield) It is a white solid. LCMS (ES) M/z 446.1[ M + H]+。1H NMR(400MHz，DMSO-d6)δppm 2.29(s，6H)，3.42(t，J＝8.4Hz，2H)，3.75(t，J＝6.8Hz，2H)，4.42(s，2H)，6.96(d，J＝9.2Hz，2H)，7.32(d，J＝8.8Hz，4H)，7.55(d，J＝8.8Hz，2H)，8.71(s，1H)。
TABLE XI
Figure BDA0002308602660001012
Example XXIII
1- (3- ((2- (4-chlorophenoxy) ethyl) amino) bicyclo [1.1.1]Pent-1-yl) -3- (4-chlorophenyl) imidazole Alk-2-ones
Figure BDA0002308602660001021
Step 1: to a closed tube were added tert-butyl (3-aminobicyclo [1.1.1] pent-1-yl) carbamate (0.400g, 2.01mmol, 1 eq), triethylamine (0.709mL, 5.04mmol, 2.5 eq) and N- (2-bromoethyl) -4-chloroaniline (0.567g, 2.42mmol, 1.2 eq). The reaction mixture was sealed and heated at 100 ℃ for 1h. The reaction mixture was cooled to room temperature, diluted with water (5mL) and extracted with EtOAc (2 × 15 mL). The combined organic extracts were washed with cold water (5mL) then saturated brine solution (5mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography using silica gel column and a mixture of methanol in DCM as eluent, the product eluted with 4-5% methanol in DCM. The product-containing fractions were concentrated to give tert-butyl (3- ((2- ((4-chlorophenyl) amino) ethyl) amino) bicyclo [1.1.1] pent-1-yl) carbamate (0.305g, 43.01% yield) as a pale yellow gum. Lcms (es) M/z 352.3[ M + H ] +, 1H NMR (400MHz, DMSO-d6) δ ppm 1.34(s, 9H), 1.80(s, 6H), 2.58-2.60 (M, 2H), 2.98-3.02 (M, 2H), 5.64(bs, 1H), 6.53(d, J8.8 Hz, 2H), 7.04(d, J8.8 Hz, 2H), 7.35(bs, 1H).
Step 2: to (3- ((2- ((4-chlorophenyl) amino) at 0 deg.C) Ethyl) amino) bicyclo [1.1.1]To a solution of t-butyl pent-1-yl) carbamate (0.305g, 0.86mmol, 1 eq) in DCM (10mL) was added triethylamine (0.609mL, 4.33mmol, 5 eq) and triphosgene (0.154g, 0.520mmol, 0.6 eq). After stirring for 5 minutes, the reaction mixture was stirred at room temperature for 2.5 h. The reaction mixture was then quenched with saturated sodium bicarbonate solution and extracted with DCM (2 × 10 mL). The combined organic extracts were washed with water (10mL), then saturated brine solution (5mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography using a silica gel column and a mixture of ethyl acetate in hexane as eluent, the product eluted with 80-90% ethyl acetate in hexane. The product-containing fractions were concentrated to give (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) carbamic acid tert-butyl ester (0.240g, 73.39% yield) as a white solid. LCMS (ES) M/z 378.1[ M + H]+。1H NMR(400MHz，DMSO-d6)δppm1.36(s，9H)，2.16(s，6H)，3.40(t，J＝8.0Hz，2H)，3.74(t，J＝6.8Hz，2H)，7.32(d，J＝8.8Hz，2H)，7.53–7.55(m，3H)。
And step 3: to (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] at 0 ℃]Pent-1-yl) carbamic acid tert-butyl ester (0.240g, 0.635mmol, 1 eq) to a solution in DCM (8mL) was added a solution of 4M HCl in 1, 4-dioxane (5 mL). The reaction mixture was then stirred at room temperature (25 ℃) for 2.5 h. The solvent was then evaporated under reduced pressure. The resulting crude material was washed with n-pentane (10 mL). The pentane was then decanted and the solid dried to give 1- (3-aminobicyclo [1.1.1]Pentan-1-yl) -3- (4-chlorophenyl) imidazolidin-2-one hydrochloride (0.185g, white solid, crude material). LCMS (ES) M/z 278.1[ M + H]+。1H NMR(400MHz，DMSO-d6)δppm 2.27(s，6H)，3.43(t，J＝8.0Hz，2H)，3.77(t，J＝7.6Hz，2H)，7.34(d，J＝8.8Hz，2H)，7.54(d，J＝9.2Hz，2H)，8.74(s，3H)。
And 4, step 4: 1- (3-amino-bicyclo [1.1.1]]Pent-1-yl) -3- (4-chlorophenyl) imidazolidin-2-one hydrochloride (0.120g, 0.381mmol, 1 eq), triethylamine (0.214mL, 1.52mmol, 4 eq), and 1- (2-bromoethoxy) -4-chlorobenzene (0.107g, 0.458mmol,1.2 equivalents) was added to the closed tube. The reaction mixture was sealed and heated at 100 ℃ for 1h. The reaction mixture was cooled to room temperature, diluted with water (5mL) and extracted with EtOAc (2 × 15 mL). The combined organic extracts were washed with cold water (5mL) then saturated brine solution (5mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was purified by preparative TLC using 2.5% methanol in DCM as the mobile phase. The mixture was concentrated under reduced pressure and dried under high vacuum to afford 1- (3- ((2- (4-chlorophenoxy) ethyl) amino) bicyclo [1.1.1]Pent-1-yl) -3- (4-chlorophenyl) imidazolidin-2-one (0.028g, 16.96% yield) as an off-white solid. LCMS (ES) M/z 432.1[ M + H]+。1H NMR(400MHz，DMSO-d6)：δppm 2.00(s，6H)，2.60(bs，1H)，2.82-2.84(m，2H)，3.40(t，J＝8.4Hz，2H)，3.74(t，J＝7.2Hz，2H)，3.96(t，J＝5.6Hz，2H)，6.94(d，J＝8.0Hz，2H)，7.28–7.33(m，4H)，7.54(d，J＝9.2Hz，2H)。
TABLE XII
Example XXIV and example 6a
2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1]Pentan-1-yl) ethyl Amides of carboxylic acids
Figure BDA0002308602660001042
Step 1: to a solution of methyl 2, 4-dibromobutyrate (1.2g, 1 eq) in DMF (15mL) at room temperature was added 4-chlorophenol (0.59g, 1 eq), followed by K2CO3(0.636g, 1 eq.) and the reaction was stirred at 60 ℃ for 3 h. The reaction mixture was then allowed to return to room temperature. Water (5mL) was added and the mixture was extracted with EtOAc (3X50 mL). The combined EtOAc extracts were extracted with anhydrous Na2SO4Dried, filtered and distilled under vacuum. The crude material was purified by flash column chromatography, the product eluted with 10% EtOAc in hexanes. The product-containing fractions were combined and the solvent was evaporated to afford 4-bromo-methyl 2- (4-chlorophenoxy) butanoate as gum (1 g).1H NMR(400MHz，CDCl3)δppm 2.3–2.5(m，2H)，3.55–3.64(m，2H)，3.76(s，3H)，4.83–4.85(m，1H)，6.86(d，J＝3.2Hz，2H)，7.23–7.25(m，2H)。
Step 2: methyl 4-bromo-2- (4-chlorophenoxy) butyrate (0.3g, 1.01mmol, 1 eq.) and (3-aminobicyclo [ 1.1.1)]Pent-1-yl) carbamic acid tert-butyl ester (0.2g, 1.01mmol, 1 eq) was filled into the closed tube and Et was added3N (0.6 mL). The mixture was then heated at 100 ℃ for 1h using an oil bath. The reaction mixture was diluted with water (50mL) and extracted with EtOAc (2X50 mL). The combined EtOAc extracts were extracted with anhydrous Na2SO4Dried, filtered and evaporated in vacuo. The crude material was purified by column chromatography using 45% EtOAc in hexanes as eluent to give the desired product (3- (3- (4-chlorophenoxy) -2-oxopyrrolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) carbamic acid tert-butyl ester as an off-white solid (0.1g, 25.6%). LCMS (ES) M/z 337.1[ M + H ]]+(loss of the tert-butyl group).
1H NMR(400MHz，DMSO-d6)δppm 1.44(s，9H)，2.04–2.18(m，1H)，2.39(s，6H)，2.46–2.54(m，1H)，3.29–3.35(m，1H)，3.42–3.47(m，1H)，4.77(t，J＝7.2Hz，1H)，4.94(bs，1H)，6.98(d，J＝9.2Hz，2H)，7.21(d，J＝8.8Hz，2H)。
And step 3: to (3- (3- (4-chlorophenoxy) -2-oxopyrrolidin-1-yl) bicyclo [1.1.1] at 0 deg.C]Pent-1-yl) carbamic acid tert-butyl ester (0.1g, 0.25mmol) to a solution in DCM (5mL) was added 2mL of a 4M solution of HCl in 1, 4-dioxane and the mixture was stirred at rt for 16 h. The reaction mixture was concentrated to give 1- (3-aminobicyclo [1.1.1]Pent-1-yl) -3- (4-chlorophenoxy) pyrrolidin-2-one hydrochloride (crude yield 0.08g, 96.3%) was carried to the next step without further purification. LCMS (ES) M/z 293[ M + H]+。1H NMR(400MHz，DMSO-d6)δppm 1.89–1.90(m，1H)，2.18–2.19(m，1H)，2.28–2.33(m，6H)，4.98(t，J＝7.2Hz，1H)，7.02(d，J＝8.8Hz，2H)，7.3(d，J＝9.6Hz，1H)，8.79(s，3H)。
And 4, step 4: to 1- (3-Ammonia) at 0 deg.CBicyclo [1.1.1] radicals]Pent-1-yl) -3- (4-chlorophenoxy) pyrrolidin-2-one hydrochloride (0.08g, 0.24mmol, 1 eq) to a solution in THF (5mL) was added BH3.Me2S (0.06mL, 0.61mmol, 2,5 equiv.). The reaction mixture was then stirred at room temperature for 16 h. The reaction mixture was then quenched with MeOH (1mL) at 0 ℃ and stirred for 30 minutes, and concentrated under reduced pressure on a rotary evaporator to give the crude product. The crude material was then dissolved in DCM (50mL) and saturated Na2HCO3And (4) washing the solution. Anhydrous Na for organic phase2SO4Dried, filtered and evaporated in vacuo to give 3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1]Pent-1-amine (0.06g, crude yield) was used in the next step without further purification. LCMS (ES) M/z 279[ M + H ]]+。
And 5: to a solution of 2- (4-chlorophenoxy) acetic acid (0.06g, 0.23mmol, 1.5 equiv.) in DCM (5mL) at 0 deg.C was added triethylamine (0.15mL, 1.07mmol, 5 equiv.), followed by
Figure BDA0002308602660001062
(50 wt% in EtOAc) (0.25mL, 0.43mmol, 2 equiv.). The mixture was stirred at 0 ℃ for 10 minutes, at which time it was added at 0 ℃
Figure BDA0002308602660001063
(50 wt.% in ethyl acetate) (1.12g, 1.768mmol, 2 equiv.) in dichloromethane (10mL) and stirred for 10 min. To the reaction mixture was slowly added 3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1]A solution of pentan-1-amine (0.06g) in DCM (1mL) and the reaction was stirred at room temperature for 16 h. The reaction mixture was diluted with water (50mL) and extracted with DCM (2 × 50 mL). The combined organic layers were washed with saturated NaHCO3Washed with aqueous solution (50mL) and then with anhydrous Na2SO4Dried, filtered and evaporated under reduced pressure in vacuo. The crude product was purified by preparative TLC using 40% EtOAc in hexane. Finally, after drying, the desired product 2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) acetamide as a white solid (0.0108g, 11.2%). LCMS (ES) M/z 447.3[ M + H ]]+。1H NMR(400MHz，DMSO-d6)δppm 1.76–1.77(m，1.5H)，1.95(s，6H)，2.2–2.27(m，1.5H)，2.58–2.61(m，1H)，2.65– 2.69(m，1H)，2.84(m，1H)，4.4(s，2H)，4.85(bs，1H)，6.88(d，J＝8.8Hz，2H)，6.94(d，J＝8.8Hz，2H)，7.28(d，J＝8.4Hz，2H)，7.32(d，J＝8.8Hz，2H)，8.61(s，1H)。
TABLE XIII
Figure BDA0002308602660001071
Example XXIV A and B
The following two structural compounds can be readily prepared by one skilled in the art generally in accordance with the above examples.
Figure BDA0002308602660001072
Examples 1a and XXII
2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1]Penta-1- Yl) acetamide
Figure BDA0002308602660001073
Figure BDA0002308602660001081
Step 1: to a solution of 4-chloroaniline (5g, 39.37mmol, 1 eq) in acetonitrile (30mL) was added 1, 2-dibromoethane (6.7mL, 78.74mmol, 2 eq) at room temperature. After stirring at 85 ℃ for 16h, the reaction mixture was brought to room temperature and concentrated in vacuo. The crude material was purified by flash column chromatography (6% EtOAc in hexanes). The product-containing fractions were combined and concentrated to give N- (2-bromoethyl) -4-chloroaniline as a brown liquid (1g, 11%).1H NMR(400MHz，DMSO–d6)δppm 3.29–3.43(m，2H)，3.52–3.55(m，2H)，6.05(bs，1H)，6.59(d，J＝8.8Hz，2H)，7.08(d，J＝8.8Hz，2H)。
Step 2: [ note: the reaction is carried out in two batches, each having 0.25g, i.e. 0.25X2 ═ 0.5g ]
Adding N- (3-amino bicyclo [1.1.1] in a closed tube]Pent-1-yl) -2- (4-chlorophenoxy) acetamide (0.25g, 0.93mmol, 1 eq) and then triethylamine (0.6mL, 4.68mmol) and N- (2-bromoethyl) -4-chloroaniline (0.26g, 1.12mmol, 1.2 eq) were added. The reaction mixture was sealed and heated at 100 ℃ for 1h using an oil bath. The reaction mixture was cooled to room temperature, diluted with water (50mL), and extracted with EtOAc (2X15 mL). The combined EtOAc extracts were extracted with anhydrous Na2SO4Dried, filtered and evaporated in vacuo. The resulting crude material was purified by flash column chromatography (5% MeOH in DCM) to give the desired product 2- (4-chlorophenoxy) -N- (3- ((2- ((4-chlorophenyl) amino) ethyl) amino) bicyclo [1.1.1]Pent-1-yl) acetamide (0.4g, 78%). LCMS (ES) M/z 420.1[ M + H]+。
And step 3: to 2- (4-chlorophenoxy) -N- (3- ((2- ((4-chlorophenyl) amino) ethyl) amino) bicyclo [1.1.1] at 0 deg.C]To a solution of pentan-1-yl) acetamide (0.3g, 0.71mmol, 1 equiv) in DCM (15mL) was added triethylamine (0.5mL, 3.57mmol, 5 equiv.), followed by triphosgene (0.21g, 0.71mmol, 1 equiv.). After stirring the reaction at room temperature for 12h, the reaction mixture was stirred with saturated NaHCO at 0 deg.C3Aqueous solution (5mL) was quenched and extracted with DCM (2 × 15 mL). The combined organic phases were washed with anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure to give the crude product (0.08g) which was purified by preparative HPLC to give the product 2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) acetamide (0.04g) as an off-white solid. LCMS (ES) M/z 446.3[ M + H]+。1H NMR(400MHz，DMSOd6)δppm 2.29(s，6H)，3.43(t，J＝8Hz，2H)，3.75(t，J＝8Hz，2H)，4.43(s，2H)，6.96(d，J＝8.4Hz，2H)，7.33(d，J＝8.4Hz，4H)，7.55(d，J＝8.4Hz，2H)，8.73(s，1H)。
The compounds of examples 1b to 1c were generally prepared according to the procedure of example 1a above.
TABLE 1
Figure BDA0002308602660001091
Figure BDA0002308602660001101
Example 1d
N- (3- (3- (4-chloro-2-methylphenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) -2- (4- Chlorophenoxy) acetamide
Figure BDA0002308602660001102
Step 1: to a solution of 4-chloro-2-methyl-1-nitrobenzene (5.0g, 29.14mmol, 1.0 equiv.) in methanol (250mL) was added ammonium chloride (8.57g, 160.27mmol, 5.5 equiv.) at 0 deg.C, stirred for 5 minutes, then zinc powder (28.58g, 437.1mmol, 15.0 equiv.) was added and the reaction mixture stirred at room temperature for 3 h. After consumption of starting material (TLC, 10% ethyl acetate in hexane), the reaction mixture was passed through
Figure BDA0002308602660001111
Bed filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (8-10% EtOAc in hexanes) to give the desired product 4-chloro-2-methylaniline as a brown liquid (3.0g, 73.2% yield). LCMS (ES) M/z 142.1[ M + H]+。1H NMR(400MHz，DMSO-d6)δppm 2.01(s，3H)，4.94(s，2H)，6.56(d，J＝8.0Hz，1H)，6.87(d，J＝8.4Hz，1H)，6.92(s，1H)。
Step 2: to a solution of 4-chloro-2-methylaniline (0.5g, 3.53mmol, 1.0 equiv.) in methanol (20mL) was added 2-chloroacetaldehyde (55% in water) (0.76mL, 5.29mmol, 1.5 equiv.) at room temperature, followed by a catalytic amount of acetic acid (5-6 drops with syringe). After the reaction mixture was stirred for 30 minutes, it was cooled to 0 ℃ and sodium cyanoborohydride (0.44) was addedg, 7.06mmol, 2.0 equiv). The reaction mixture was stirred at rt for 16 h. After consumption of starting material (TLC, 10% ethyl acetate in hexane), the reaction mixture was concentrated under reduced pressure. The crude material was dissolved in ethyl acetate (200mL) and washed with water (2 × 50 mL). The combined organic layers were washed with anhydrous Na2SO4Dry, filter and concentrate under reduced pressure. The crude material was purified by column chromatography (5% EtOAc in hexanes) to give the desired product 4-chloro-N- (2-chloroethyl) -2-methylaniline as a yellow liquid (0.34g, 47.3% yield). LCMS (ES) M/z 204.0[ M + H ]]+。1H NMR(400MHz，DMSO-d6)δppm 2.05(s，3H)，3.42(d，J＝6.0Hz，2H)，3.68–3.71(m，2H)，5.19(s，1H)，6.51–6.56(m，1H)，7.01(s，2H)。
And step 3: at room temperature to (3-aminobicyclo [ 1.1.1)]To a solution of t-butyl pent-1-yl) carbamate (0.3g, 1.51mmol, 1.0 equiv.) in triethylamine (0.85mL, 6.04mmol, 4.0 equiv.) was added 4-chloro-N- (2-chloroethyl) -2-methylaniline (0.37g, 1.81mmol, 1.2 equiv.). After the reaction mixture was stirred at 100 ℃ for 16h and starting material was consumed (TLC, 50% ethyl acetate in hexanes), the reaction mixture was diluted with ethyl acetate (100mL) and washed with water (2 × 10 mL). The combined organic layers were washed with anhydrous Na2SO4Dried, filtered and evaporated under reduced pressure. The crude material was purified by column chromatography (50-60% EtOAc in hexanes) to give the desired product (3- ((2- ((4-chloro-2-methylphenyl) amino) ethyl) amino) bicyclo [1.1.1]Pent-1-yl) carbamic acid tert-butyl ester as a light yellow liquid (0.28g, 50.9% yield). LCMS (ES) 366.1[ M + H ] M/z]+
And 4, step 4: to (3- ((2- ((4-chloro-2-methylphenyl) amino) ethyl) amino) bicyclo [1.1.1 ℃ at 0 DEG C]Pent-1-yl) carbamic acid tert-butyl ester (0.26g, 0.71mmol, 1.0 equiv) to a solution in DCM (20mL) was added triethylamine (0.5mL, 3.55mmol, 5.0 equiv), stirred for 10 min, then triphosgene (0.21g, 0.71mmol, 1.0 equiv) was added at 0 ℃ and the reaction mixture stirred at rt for 3 h. After consumption of the starting material (TLC, 50% ethyl acetate in hexane), the reaction mixture was quenched with sodium bicarbonate solution at 0 ℃ and extracted with ethyl acetate (2 × 70 mL). The combined organic layers were washed with anhydrous Na2SO4Dried, filtered and evaporated under reduced pressure. The crude material was purified by column chromatography (50-60% EtOAc in hexanes) to give the desired product (3- (3- (4-chloro-2-methylphenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) carbamic acid tert-butyl ester as a light yellow liquid (0.09g, 32.1% yield). LCMS (ES) M/z 392.1[ M + H]+。1H NMR(400MHz，DMSO-d6)δppm 1.36(s，9H)，2.13–2.15(m，9H)，3.39(t，J＝7.6Hz，2H)，3.60(t，J＝7.8Hz，2H)，7.19–7.21(m，2H)，7.32(s，1H)，7.52(bs，1H)。
And 5: to (3- (3- (4-chloro-2-methylphenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] at 0 DEG C]Pent-1-yl) carbamic acid tert-butyl ester (0.09g, 0.23mmol, 1.0 equiv) to a solution in DCM (5.0mL) was added 2.0mL of a 4MHCl in 1, 4-dioxane and the mixture was stirred at rt for 16 h. After consumption of starting material (TLC, 5% MeOH in DCM), the reaction mixture was concentrated and the crude material was triturated with n-pentane (2X5mL) and dried under high vacuum to give 1- (3-aminobicyclo [ 1.1.1)]Pent-1-yl) -3- (4-chloro-2-methylphenyl) imidazolidin-2-one hydrochloride (crude yield 0.07g, 93.4% yield) was carried to the next step without further purification. LCMS (ES) M/z 292.1[ M + H]+。1H NMR(400MHz，DMSO-d6)δppm 2.15(s，3H)，2.25(s，6H)，3.43–3.45(m，2H)，3.61–3.63(m，2H)，7.19–7.23(m，2H)，7.33(s，1H)，8.89(bs，3H)。
Step 6: to a solution of 2- (4-chlorophenoxy) acetic acid (0.05g, 0.26mmol, 1.2 equiv.) in DCM (8mL) at 0 deg.C was added triethylamine (0.12mL, 0.84mmol, 4.0 equiv.), stirred for 10 min and added
Figure BDA0002308602660001121
(50 wt% in EtOAc) (0.25mL, 0.42mmol, 2.0 equiv). The reaction mixture was stirred at 0 ℃ for 10 minutes, and 1- (3-aminobicyclo [1.1.1] was added at 0 DEG C]Pent-1-yl) -3- (4-chloro-2-methylphenyl) imidazolidin-2-one hydrochloride ((0.07g, 0.21mmol, 1.0 eq.) was neutralized with triethylamine in 0.2mL DCM and the reaction was stirred at rt for 16 h. After consumption of starting material (TLC, 70% EtOAc in hexanes), the reaction mixture was diluted with DCM (100mL)And with saturated NaHCO3Aqueous solution (2x10mL) and water (2x10 mL). The combined organic layers were washed with anhydrous Na2SO4Dry, filter and concentrate under reduced pressure. The crude product was purified by silica gel column chromatography (50-60% EtOAc in hexanes). It was again purified by preparative HPLC (analytical conditions: Inertsil ODS 3V (250mmx4.6mmx5mic), mobile phase (A): 0.1% aqueous ammonia solution, mobile phase (B): acetonitrile; flow rate: 1.0mL/min) to give the desired product N- (3- (3- (4-chloro-2-methylphenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) -2- (4-chlorophenoxy) acetamide as an off-white solid (0.025g, 25.5% yield). LCMS (ES) M/z 460.3[ M + H]+。1H NMR(400MHz，DMSO-d6)δppm 2.16(s，3H)，2.26(s，6H)，3.42(t，J＝7.4Hz，2H)，3.62(t，J＝7.4Hz，2H)，4.42(s，2H)，6.96(d，J＝8.4Hz，2H)，7.22(s，2H)，7.32(s，3H)，8.70(s，1H)。
The compounds of examples 1e to 1k were generally prepared according to the procedure of example 1d above.
TABLE 2
Figure BDA0002308602660001131
Figure BDA0002308602660001141
Figure BDA0002308602660001151
Figure BDA0002308602660001161
Example 1l
2- (4-chloro-3- (trifluoromethyl) phenoxy) -N- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) acetamides
Figure BDA0002308602660001162
Step 1: to a solution of 4-chloro-3- (trifluoromethyl) phenol (1.5g, 7.63mmol, 1 eq) in acetone (30mL) was added K2CO3(3.15g, 22.82mmol, 3 equiv.) and then ethyl 2-bromoacetate (1.52g, 9.10mmol, 1.2 equiv.) is added dropwise at 0 ℃. The reaction mixture was stirred at 60 ℃ for 4 h. After consumption of the starting material (TLC, 5% EtOAc in hexanes), the reaction mixture was filtered through a buchner funnel and concentrated under reduced pressure. The crude product was purified by flash column chromatography using silica gel column
Figure BDA0002308602660001171
And the product was eluted with 5% ethyl acetate in hexane as an eluent to give the title compound ethyl 2- (4-chloro-3- (trifluoromethyl) phenoxy) acetate (1.3g) as a colorless liquid. LCMS (ES) M/z 282.0[ M + H]+。1HNMR(400MHz，DMSO-d6)δppm 1.18(t，J＝7.2Hz，3H)，4.13-4.18(m，2H)，4.91(s，2H)，7.25-7.28(m，1H)，7.34(d，J＝2.8Hz，1H)，7.61(d，J＝9.2Hz，1H)。
Step 2: to a solution of ethyl 2- (4-chloro-3- (trifluoromethyl) phenoxy) acetate (1.3g, 4.59mmol, 1 eq) in a mixture of THF (20mL) and water (20mL) at 0 ℃ was added lioh2O (0.27g, 11.45mmol, 2.5 equiv.) and the resulting mixture stirred at room temperature for 3 h. After consumption of starting material (TLC, 5% methanol in DCM), THF was removed under reduced pressure. The residue was diluted with water (20mL) and Et2O (2X15mL) to remove unreacted ethyl 2-bromoacetate. The aqueous layer was acidified to pH 2 with 1N HCl at 0 ℃ and extracted with EtOAc (2X30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound 2- (4-chloro-3- (trifluoromethyl) phenoxy) acetic acid (1.05g, 90% yield) as a white solid. LCMS (ES) M/z 253.0[ M-H]-。1H NMR(400MHz，DMSO-d6)δppm 4.81(s，2H)，7.24(d，J＝8.8Hz，1H)，7.32(d，J＝2.4Hz，1H)，7.61(d，J＝8.8Hz，1H)，13.10(s，1H)。
And step 3: at 0 deg.C to (3-aminobicyclo [ 1.1.1)]Pent-1-yl) carbamic acid tert-butyl ester (5g, 25.21mmol, 1.0mAmount) in CHCl3To the solution in (50mL) was added 1-chloro-2-isocyanatoethane (3.22mL, 37.82mmol, 1.5 equiv.) and heated to 60 ℃ for 1h. After completion of the reaction, (TLC in 5% methanol in DCM), the reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude product. To the crude material above, n-pentane (150mL) was added and stirred at room temperature for 0.5 h. A solid formed and was filtered and washed with n-pentane to give (3- (3- (2-chloroethyl) ureido) bicyclo [1.1.1]Pent-1-yl) carbamic acid tert-butyl ester as a white solid (7g, 91% yield). LCMS (ES) M/z 304.1[ M + H]+。1H NMR(400MHz，DMSO-d6)δppm 1.34(s，9H)，2.00(s，6H)，3.24–3.25(m，2H)，3.52(t，J＝6.0Hz，2H)，5.93(s，1H)，6.66(s，1H)，7.41(bs，1H)。
And 4, step 4: to (3- (3- (2-chloroethyl) ureido) bicyclo [ 1.1.1) at room temperature]To a solution of t-butyl pent-1-yl) carbamate (7g, 23.04mmol, 1.0 equiv.) in acetonitrile (70mL) was added cesium carbonate (15g, 46.08mmol, 2.0 equiv.). The reaction was gradually heated to 100 ℃ and stirred for 12 h. After completion of the reaction, (TLC in 5% methanol in DCM), the reaction mixture was cooled to rt, diluted with water (150mL) and extracted with EtOAc (3X100 mL). The combined EtOAc extracts were extracted with anhydrous Na2SO4Dried, filtered and concentrated in vacuo to give the crude product. To the above crude material, diethyl ether (100mL) was added and stirred at room temperature for 0.5 h. A solid was formed and filtered and washed with diethyl ether to give (3- (2-oxoimidazolidin-1-yl) bicyclo [1.1.1 ]Pent-1-yl) carbamic acid tert-butyl ester as a white solid (4g, 65% yield). LCMS (ES) M/z 268.1[ M + H ═]+。1H NMR(400MHz，DMSO-d6)δppm 1.35(s，9H)，2.06(s，6H)，3.15–3.17(m，2H)，3.21–3.23(m，2H)，6.31(s，1H)，7.47(bs，1H)。
And 5: to (3- (2-oxoimidazolidin-1-yl) bicyclo [1.1.1]Pent-butyl-1-yl) carbamate (2.0g, 7.49mmol, 1.0 equiv.) in DMSO (20mL) was added K3PO4(3.18g, 14.98mmol, 2.0 equiv.), DMDAA (0.16mL, 1.498mmol, 0.2 equiv.), and CuI (0.142g, 0.749mmol, 0.1 equiv.) and stirred at room temperature for 10-15 min. 1-chloro-4-iodo was added dropwise to the reaction mixtureBenzene (2.14g, 8.98mmol, 1.2 eq) and stirred at room temperature for 12 h. After completion of the reaction (TLC in 40% ethyl acetate in hexanes), the reaction mixture was diluted with water (30mL) and extracted with EtOAc (3X30 mL). The combined EtOAc extracts were extracted with anhydrous Na2SO4Dried, filtered and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography (60% ethyl acetate in hexane) to give (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [ 1.1.1)]Pent-1-yl) carbamic acid tert-butyl ester (0.8g, 30% yield) as a brown solid. LCMS (ES) M/z 378.1[ M + H]+。1H NMR(400MHz，CDCl3)δppm 1.45(s，9H)，2.36(s，6H)，3.46(t，J＝8.4Hz，2H)，5.00(bs，1H)，7.25–7.27(m，2H)，7.47(d，J＝8.8Hz，2H)。
Step 6: to (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] at 0 ℃]Pent-1-yl) carbamic acid tert-butyl ester (0.8g, 2.11mmol, 1 eq) to a solution in DCM (8mL) was added a solution of 4M HCl in 1, 4-dioxane (8mL) and the reaction mixture was stirred at rt for 6h. After completion of the reaction, the reaction mixture was evaporated in vacuo to give crude 1- (3-aminobicyclo [ 1.1.1)]Pent-1-yl) -3- (4-chlorophenyl) imidazolidin-2-one hydrochloride (0.587g, 100%) as an off-white solid. LCMS (ES) M/z 278.1[ M + H]+。1H NMR(400MHz，DMSO-d6)δppm 2.27(s，6H)，3.43-3.45(m，2H)，3.75-3.77(m，2H)，7.34(d，J＝8.4Hz，2H)，7.54(d，J＝8.4Hz，2H)，8.80(bs，3H)。
And 7: to a solution of 2- (4-chloro-3- (trifluoromethyl) phenoxy) acetic acid (0.078g, 0.30mmol, 1.2 equiv.) in dichloromethane (2mL) was added triethylamine (0.05g, 0.5mmol, 2.0 equiv.) at room temperature. After stirring for 5 minutes, the mixture is cooled to room temperature
Figure BDA0002308602660001192
(50 wt.% in ethyl acetate) (0.12g, 0.37mmol, 1.5 equiv.) was added to the reaction mass and stirred for 10 minutes, then 1- (3-aminobicyclo [ 1.1.1) was added]Pentan-1-yl) -3- (4-chlorophenyl) imidazolidin-2-one hydrochloride (0.08g, 0.25mmol, 1.0 equiv.) and triethylamine (0.05g, 0.5mmol, 2.0 equiv.) in DCM (2 mL). Mixing the reaction mixtureStir at rt for 16h. After completion of the reaction, the reaction mixture was diluted with water (10mL) and extracted with DCM (2 × 25 mL). The combined organic extracts were extracted with saturated NaHCO3Aqueous solution (10mL), brine solution (7mL) were washed, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude material was purified by flash column chromatography using silica gel column, with the product and very close impurities eluting with 3% methanol in DCM. Finally, the crude product was purified by preparative HPLC to give 2- (4-chloro-3- (trifluoromethyl) phenoxy) -N- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) acetamide (0.04g, 17.5% yield) as a white solid. LCMS (ES) M/z 514.4[ M + H ]]+。1HNMR(400MHz，DMSO-d6)δppm 2.29(s，6H)，3.43(t，J＝8.0Hz，2H)，3.75(t，J＝8.0Hz，2H)，4.55(s，2H)，7.26(d，J＝8.4Hz，1H)，7.33(d，J＝8.8Hz，2H)，7.40(d，J＝2.4Hz，1H)，7.55(d，J＝9.2Hz，2H)，7.63(d，J＝8.8Hz，1H)，8.77(s，1H)。
Example 1m
2- (4-chloro-3-fluorophenoxy) -N- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] Pent-1-yl) acetamides
Figure BDA0002308602660001191
Step 1: at 0 deg.C to (3-aminobicyclo [ 1.1.1)]Pent-1-yl) carbamic acid tert-butyl ester (5.0g, 25.21mmol, 1.0 equiv.) in CHCl3(50mL) to a stirred solution was added 1-chloro-2-isocyanatoethane (3.22mL, 37.82mmol, 1.5 equiv.) and the reaction mixture was stirred at 60 ℃ for 1 h. After consumption of starting material (TLC, 5% MeOH in DCM), the reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude product. N-pentane (150mL) was added thereto, stirred at room temperature for 0.5h, and then filtered. The compound was washed with n-pentane to give (3- (3- (2-chloroethyl) ureido) bicyclo [1.1.1]Pent-1-yl) carbamic acid tert-butyl ester (7.0g, 91% yield) as a white solid. LCMS (ES) M/z 304.1[ M + H]+.1H NMR(400MHz，DMSO-d6)δppm 1.34(s，9H),2.00(s，6H)，3.24–3.25(m，2H)，3.52(t，J＝6.0Hz，2H)，5.93(s，1H)，6.66(s，1H)，7.41(bs，1H)。
Step 2: to (3- (3- (2-chloroethyl) ureido) bicyclo [ 1.1.1) at room temperature]Pent-1-yl) carbamic acid tert-butyl ester (7.0g, 23.04mmol, 1.0 eq) in CH3Adding Cs to a stirred solution in CN (70mL)2CO3(15g, 46.08mmol, 2.0 equiv.). The reaction was then heated to 100 ℃ for 12 h. After consumption of starting material (TLC, 5% MeOH in DCM), the reaction mixture was taken up with H2O (200mL) was diluted and extracted with EtOAc (3X100 mL). The combined organics were treated with anhydrous Na2SO4Dried, filtered and concentrated to give crude compound. Diethyl ether (100mL) was added to the crude material, stirred at room temperature for 0.5h, then filtered. The product was washed with diethyl ether to give (3- (2-oxoimidazolidin-1-yl) bicyclo [ 1.1.1)]Pent-1-yl) carbamic acid tert-butyl ester (4.0g, 65% yield) as a white solid. LCMS (ES) M/z 268.1[ M + H ═]+。1H NMR(400MHz，DMSO-d6)δppm 1.35(s，9H)，2.06(s，6H)，3.15–3.17(m，2H)，3.21–3.23(m，2H)，6.31(s，1H)，7.47(bs，1H)。
And step 3: (3- (2-oxoimidazolidin-1-yl) bicyclo [1.1.1] bicyclo [1.1 ] was added to the closed tube at room temperature]Pent-1-yl) carbamic acid tert-butyl ester (2.0g, 7.49mmol, 1.0 eq), 1-chloro-4-iodobenzene (2.14g, 8.98mmol, 1.2 eq), copper iodide (0.142g, 0.749mmol, 0.1 eq), DMDAA (0.16mL, 1.498mmol, 0.2 eq), K3PO4(3.18g, 14.98mmol, 2.0 equiv.) and DMSO (20 mL). The resulting reaction mixture was stirred at room temperature for 12 h. After consumption of the starting material (TLC, 40% EtOAc in hexane), the reaction mixture was passed throughThe bed was filtered and washed with EtOAc (50 mL). Filtered organic matter H2O (100mL) was diluted and extracted to EtOAc (3X100 mL). The combined organics were washed with water (50mL), brine (50mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product. The crude product was purified by flash column chromatography using silica gel column(60% ethyl acetate in hexane) to give (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) carbamic acid tert-butyl ester (0.8g, 30% yield) as a brown solid. LCMS (ES) M/z 378.1[ M + H]+。1H NMR(400MHz，CDCl3)δppm 1.45(s，9H)，2.36(s，6H)，3.46(t，J＝8.4Hz，2H)，5.00(bs，1H)，7.25–7.27(m，2H)，7.47(d，J＝8.8Hz，2H)。
And 4, step 4: a solution of 4M HCl in dioxane (8mL) was added to (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] at 0 ℃]Pent-1-yl) carbamic acid tert-butyl ester (0.8g, 2.11mmol, 1 eq) in DCM (8mL) was added to a stirred solution. The resulting mixture was warmed to 27 ℃ and stirred for 6h. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was concentrated under reduced pressure to give 1- (3-aminobicyclo [ 1.1.1)]Pent-1-yl) -3- (4-chlorophenyl) imidazolidin-2-one hydrochloride (0.587g, 100%) as an off-white solid. LCMS (ES) M/z 278.1[ M + H]+。1H NMR(400MHz，DMSO-d6)δppm 2.27(s，6H)，3.43-3.45(m，2H)，3.75-3.77(m，2H)，7.34(d，J＝8.4Hz，2H)，7.54(d，J＝8.4Hz，2H)，8.80(bs，3H)。
And 5: to 1- (3-aminobicyclo [1.1.1] at 0 DEG C]Pentan-1-yl) -3- (4-chlorophenyl) imidazolidin-2-one hydrochloride (0.075g, 0.238mmol, 1 equiv.), 2- (4-chloro-3-fluorophenoxy) acetic acid (0.058g, 0.285mmol, 1.2 equiv.), and triethylamine (0.166mL, 1.19mmol, 5.0 equiv.) in dichloromethane (5mL) were added
Figure BDA0002308602660001211
(50 wt.% in ethyl acetate) (0.3g, 0.476mmol, 2.0 equiv.). The reaction mixture was warmed to 27 ℃ and stirred for 16h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with dichloromethane (10mL), washed with 10% sodium bicarbonate solution (10mL), water (5mL), brine (5mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography using silica gel column
Figure BDA0002308602660001212
(2% methanol in DCM) to give the title compound as 99% pure but containing a small amount of impurities. Again purified by preparative HPLC [ analytical conditions: column: inertsil ODS 3V (250mmX4.6mmX5um), mobile phase (A): 0.1% ammonia/water, mobile phase (B): ACN; flow rate: 1.0mL/min, time% B: 0/10, 10/80, 25/90, 27/10, 30/10]. The pure fractions were concentrated under reduced pressure and lyophilized to give 2- (4-chloro-3-fluorophenoxy) -N- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) acetamide (0.03g, 27%) as a white solid. LCMS (ES) M/z 464.3[ M + H]+。1H NMR(400MHz，DMSO-d6)δppm 2.29(s，6H)，3.42(t，J＝8.0Hz，2H)，3.75(t，J＝8.4Hz，2H)，4.47(s，2H)，6.82–6.85(m，1H)，7.04–7.07(m，1H)，7.33(d，J＝8.8Hz，2H)，7.48(t，J＝8.8Hz，1H)，7.55(d，J＝9.2Hz，2H)，8.73(s，1H)。
The compounds of examples 1n-1u are generally prepared according to the procedures described above for examples 1l and 1 m.
The compounds of examples 1n to 1u are generally prepared according to the procedure of examples 1l and 1m described above.
TABLE 2b
Figure BDA0002308602660001221
Figure BDA0002308602660001241
Figure BDA0002308602660001251
Example 1v
N- (3- (3- (4-chloro-2-fluorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) -2- (4-chloro-4 Phenoxy) acetamide
Figure BDA0002308602660001252
Figure BDA0002308602660001261
Step 1: at 0 deg.C to (3-aminobicyclo [ 1.1.1)]Pent-1-yl) carbamic acid tert-butyl ester (2g, 10.08mmol, 1.0 equiv.) to a stirred solution in chloroform (20mL) was added 1-chloro-2-isocyanatoethane (1.29mL, 15.13mmol, 1.5 equiv.) and the mixture was heated to 60 ℃ for 1 h. After completion of the reaction (TLC in 5% methanol in DCM), the reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude product. The resulting crude material was triturated with n-pentane (50mL) and stirred at room temperature for 0.5 h. The solid compound was filtered and washed with n-pentane to give (3- (3- (2-chloroethyl) ureido) bicyclo [1.1.1]Pent-1-yl) carbamic acid tert-butyl ester (2.5g, 83% yield) as a white solid. LCMS (ES) M/z 304.1[ M + H]+；1H NMR(400MHz，DMSO-d6)δppm 1.35(s，9H)，2.01(s，6H)，3.25–3.24(m，2H)，3.52–3.53(m，2H)，5.93(s，1H)，6.66(s，1H)，7.41(bs，1H)。
Step 2: to (3- (3- (2-chloroethyl) ureido) bicyclo [ 1.1.1) at room temperature]To a stirred solution of t-butyl pent-1-yl) carbamate (2.5g, 8.22mmol, 1.0 equiv) in acetonitrile (25mL) was added cesium carbonate (4.64g, 14.24mmol, 2.0 equiv) and the mixture was heated to 80 ℃ and stirred for 12 h. After completion of the reaction (TLC in 5% methanol in DCM), the reaction mixture was cooled to room temperature, diluted with water (100mL) and extracted with ethyl acetate (2X50 mL). The combined ethyl acetate extracts were extracted with anhydrous Na2SO4Drying, filtering and concentrating under reduced pressure to give a crude product, which is purified by silica gel column chromatography
Figure BDA0002308602660001262
Using 10% MeOH in dichloromethane as eluent to give (3- (2-oxoimidazolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) carbamic acid tert-butyl ester (0.4g, 18% yield) as a white solid.1H NMR(400MHz，DMSO-d6)δppm 1.35(s，9H)，2.06(s，6H)，3.15–3.17(m，2H)，3.22–3.24(m，2H)，6.31(s，1H)，7.47(bs，1H)。
And step 3: in a closed tube to (3- (2-oxoimidazolidin-1-yl) bicyclo [1.1.1]To a stirred solution of t-butyl pent-1-yl) carbamate (0.25g, 0.935mmol, 1.0 equiv.) in 1, 4-dioxane (5mL) was added 1-bromo-4-chloro-2-fluorobenzene (0.19g, 0.935mmol, 1.0 equiv.). The mixture was degassed by purging with argon for 5 minutes. Then Pd was added under argon atmosphere2(dba)3(0.085g, 0.093mmol, 0.1 equiv.), xanthhphos (0.1g, 0.187mmol, 0.2 equiv.), and Cs2CO3(1.21g, 3.74mmol, 4.0 equiv.) was added to the reaction mixture, the tube was capped and the mixture was stirred at 80 ℃ for 16h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (20mL), and filtered through
Figure BDA0002308602660001271
Bed filtration, and
Figure BDA0002308602660001272
the bed was washed with excess ethyl acetate. The filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography
Figure BDA0002308602660001273
Using 50% ethyl acetate in hexane as eluent to give 3- (3- (4-chloro-2-fluorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) carbamic acid tert-butyl ester (0.17g, 65% yield) as an off-white solid. LCMS (ES) M/z 396.1[ M + H]+。
And 4, step 4: to (3- (3- (4-chloro-2-fluorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] at 0 DEG C]To a stirred solution of t-butyl pent-1-yl) carbamate (0.17g, 0.42mmol, 1.0 equiv) in dichloromethane (2mL) was added a solution of 4m hcl solution in 1, 4-dioxane (1.5 mL). The resulting mixture was warmed to room temperature and stirred for 3 h. The progress of the reaction was monitored by TLC (30% ethyl acetate in hexane). After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained residue was taken up in n-pentaneAnd (6) grinding. The product is dried under high vacuum to give 1- (3-aminobicyclo [ 1.1.1)]Pent-1-yl) -3- (4-chloro-2-fluorophenyl) imidazolidin-2-one hydrochloride (0.09g, crude material) as a light brown solid. Used without further purification. LCMS (ES) M/z 296.1[ M + H]+。
And 5: to a stirred solution of 2- (4-chlorophenoxy) acetic acid (0.05g, 0.27mmol, 1 eq) and triethylamine (0.076mL, 0.54mmol, 2 eq) in dichloromethane (10mL) at 0 deg.C was added
Figure BDA0002308602660001274
(50% wt. in ethyl acetate). The resulting mixture was warmed to room temperature and stirred for 20 minutes. After 20 minutes, the reaction mixture was cooled to 0 ℃ and 1- (3-aminobicyclo [1.1.1] was added at 0 ℃]Solution of pent-1-yl) -3- (4-chloro-2-fluorophenyl) imidazolidin-2-one hydrochloride (0.09g of crude material, 0.27mmol, 1.0 equiv.) and triethylamine (0.11mL, 0.81mmol, 3 equiv.) in dichloromethane (10 mL). The resulting mixture was warmed to room temperature and stirred for 3 h. The progress of the reaction was monitored by TLC (5% methanol in DCM). After completion of the reaction, the reaction mixture was diluted with dichloromethane (100mL), washed with a saturated aqueous sodium bicarbonate solution (50mL), water (30mL) and brine (30mL), finally dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography
Figure BDA0002308602660001283
A solution of 4% methanol in dichloromethane was used as eluent to give the title compound N- (3- (3- (4-chloro-2-fluorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) -2- (4-chlorophenoxy) acetamide (0.08g) as a white solid. LCMS (ES) M/z 464.0[ M + H ]]+；1H NMR(400MHz，DMSO-d6)δppm2.27(s，6H)，3.44(t，J＝7.6Hz，2H)，3.73(t，J＝7.2Hz，2H)，4.42(s，2H)，6.96(d，J＝8.8Hz，2H)，7.25(d，J＝7.2Hz，1H)，7.32(d，J＝8.8Hz，2H)，7.45– 7.52(m，2H)，8.70(s，1H)。
TABLE 3
Figure BDA0002308602660001281
Example 2a
N- (4- (2- (4-chlorophenoxy) acetamido) bicyclo [2.1.1]Hex-1-yl) -2- (4-chlorophenyl) cyclopropane- 1-carboxamides
Figure BDA0002308602660001282
Step 1: to a solution of 2- (4-chlorophenyl) cyclopropane-1-carboxylic acid (0.06g, 0.29mmol, 1.2 equivalents) in DCM (5mL) was added triethylamine (0.14mL, 1.00mmol, 4.0 equivalents) at 0 deg.C and stirred for 10 minutes then added
Figure BDA0002308602660001293
(50 wt% in EtOAc) (0.3mL, 0.50mmol, 2.0 equiv). The reaction mixture was stirred at 0 ℃ for 10 minutes, then N- (4-aminobicyclo [2.1.1] was added at 0 DEG C]Hex-1-yl) -2- (4-chlorophenoxy) acetamide (0.07g, 0.25mmol, 1.0 equiv.) and the reaction stirred at room temperature for 16h. After consumption of starting material (TLC, 5% MeOH in DCM), the reaction mixture was diluted with DCM (50mL) and saturated NaHCO3Aqueous solution (2x10mL) and water (2x10 mL). The combined organic layers were washed with anhydrous Na2SO4Dried, filtered and evaporated under reduced pressure to give the crude material. The crude product was purified by silica gel column chromatography using 1-2% MeOH in DCM as eluent to give the title compound, which was then triturated with n-pentane (2 × 5 mL). The solid was dried under high vacuum to give the desired product N- (4- (2- (4-chlorophenoxy) acetamido) bicyclo [2.1.1]Hex-1-yl) -2- (4-chlorophenyl) cyclopropane-1-carboxamide, which is an off-white solid (0.07g, 61.4%). LCMS (ES) M/z 459.3[ M + H]+。1H NMR(400MHz，DMSO-d6)δppm 1.11–1.15(m，1H)，1.28–1.33(m，1H)，1.72–1.75(m，6H)，1.79–1.83(m，1H)，2.06(s，2H)，2.19–2.23(m，1H)，4.40(s，2H)，6.95(d，J＝8.8Hz，2H)，7.13(d，J＝8.0Hz，2H)，7.31(t，J＝9.2Hz，4H)，8.40(s，1H)，8.48(s，1H)。
The compound of example 2b was prepared generally according to the procedure described above for example 2 a.
TABLE 4
Figure BDA0002308602660001301
Examples 2c and XXIVA
2- (4-chlorophenoxy) -N- (3- (2- (4-chlorophenoxy) acetamido) bicyclo [1.1.1]Pent-1-yl) cyclopropane Alkane-1-carboxamides
Figure BDA0002308602660001302
Figure BDA0002308602660001311
Step 1: to a stirred solution of 4-chlorophenol (0.5g, 3.90mmol, 1 eq) in DMF (15mL) at room temperature was added cesium carbonate (1.98g, 5.85mmol, 1.5 eq) and 1-bromocyclopropane-1-carbonitrile (0.57g, 3.90mmol, 1 eq). The resulting mixture was heated to 90 ℃ and stirred for 16h. The progress of the reaction was monitored by TLC. After consumption of the starting material, the reaction mixture was cooled to room temperature, diluted with water (50mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (50mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography using a silica gel column (10% ethyl acetate in hexanes) to give 2- (4-chlorophenoxy) cyclopropane-1-carbonitrile (0.15g, 20% yield) as an off-white solid.1H NMR(400MHz，DMSO-d6)：δppm 1.47–1.49(m，1H)，1.54–1.59(m，1H)，2.13–2.16(m，1H)，4.40–4.49(s，1H)，7.04(d，J＝8.8Hz，2H)，7.4(d，J＝8.8Hz，2H)。13CNMR(100MHz，DMSO-d6)：δppm 4.47，14.40，55.86，117.19，120.17，126.29，129.93，156.63。
Step 2: to a stirred solution of 2- (4-chlorophenoxy) cyclopropane-1-carbonitrile (0.15g, 0.773mmol, 1 equiv) in water (5mL) was added a 10% aqueous solution of NaOH (5mL) and the resulting mixture was heated to 70 ℃ for 12 h. The progress of the reaction was monitored by TLC. After consumption of the starting material the reaction mixture was cooled to room temperature and acidified to pH-2 with 1N HCl. The product was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine solution (50mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2- (4-chlorophenoxy) cyclopropane-1-carboxylic acid (0.085g, 50% yield) as a viscous solid. LCMS (ES) M/z 212.2[ M-H [ ]]+。1H NMR(400MHz，DMSO-d6)：δppm 1.32–1.36(m，1H)，1.36–1.41(m，1H)，1.92–1.97(m，1H)，4.09–4.11(m，1H)，7.03(d，J＝8.4Hz，2H)，7.32(d，J＝8.4Hz，2H)，12.03(bs，1H)。
And step 3: to a stirred solution of 2- (4-chlorophenoxy) cyclopropane-1-carboxylic acid (0.083g, 0.393mmol, 1.5 equiv.) and triethylamine (0.15mL, 1.04mmol, 4.0 equiv.) in dichloromethane (5mL) was added at 0 deg.C
Figure BDA0002308602660001322
(50 wt.% in ethyl acetate) (0.25mL, 0.393mmol, 1.5 equiv.) and the mixture was stirred for 10 minutes. Then N- (3-amino-bicyclo [ 1.1.1)]Pent-1-yl) -2- (4-chlorophenoxy) acetamide (0.07g, 0.262mmol, 1 eq) was added to the reaction mixture. The resulting mixture was stirred for 16h, during which time it was warmed to room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was diluted with dichloromethane (50mL), washed with water (2 × 30mL), brine (30mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography on silica gel using 4% methanol in dichloromethane as eluent. The resulting product was repurified by preparative HPLC [ analytical conditions: column: ZORBAX (150mmX4.6mmX5mic), mobile phase (A): 0.1% ammonia in water, mobile phase (B): CH (CH)3CN, flow rate: 1.0mL/min of the reaction solution,gradient: 0/10,10/60, 25/90, 27/10, 30/10]To give the title compound 2- (4-chlorophenoxy) -N- (3- (2- (4-chlorophenoxy) acetamido) bicyclo [1.1.1]Pent-1-yl) cyclopropane-1-carboxamide (0.03g, 25% yield) which is a white solid. LCMS (ES) M/z 461.3[ M + H]+。1H NMR(400MHz，DMSO-d6)：δppm 1.10–1.13(m，1H)，1.39– 1.40 9m，1H)，1.84–1.88(m，1H)，1.94–2.00(m，6H)，3.98–3.99(m，1H)，4.37(s，2H)，6.92–7.00(m，4H)，7.25–7.32(m，4H)，8.45(s，1H)，8.56(s，1H)。13C NMR(100MHz，DMSO-d6): delta ppm 10.88, 22.47, 44.59, 44.96, 54.74, 55.61, 67.47, 116.95, 117.26, 125.11, 125.27, 129.24, 129.62, 157.08, 157.49, 167.27, 168.07, HPLC purity 99.79% at 225 nm.
TABLE 5
Figure BDA0002308602660001321
Figure BDA0002308602660001331
Example 3a
2- (4-chlorophenoxy) -N- (3- ((1- (4-chlorophenyl) azetidin-3-yl) amino) bicyclo [1.1.1]Wu-Jia-Zi 1-yl) acetamides
Figure BDA0002308602660001332
Figure BDA0002308602660001341
Step 1: tert-butyl 3-oxoazetidine-1-carboxylate (4.0g, 23.364mmol, 1 eq.) was treated with TFA (8mL) at 0 ℃. After stirring the reaction mixture at 0 ℃ for 4h, the reaction mixture was concentrated to give crude azetidin-3-one 2,2, 2-trifluoroacetate salt (5.1g, crude material) as a light yellow gum. LCMS (ES) M/z 72.0[ M + H ]]+。1HNMR(400MHz，DMSO-d6)：δppm 5.01(s，4H)，9.49(s，2H)。
Step 2: to a stirred solution of azetidin-3-one 2,2, 2-trifluoroacetate (3.0g, 16.189mmol, 1 eq., this 3g was done as 5X0.600 g batches) in DCM (30mL) was added triethylamine (9.10mL, 64.75mmol, 4.0 eq.) followed by copper (II) acetate (5.88g 32.37mmol, 2 eq.) and flushed with air for 45 min. Then (4-chlorophenyl) boronic acid was added and again air purged for 10 minutes. The reaction mixture was stirred at rt for 5 h. After the reaction is complete, the reaction mixture is passed through
Figure BDA0002308602660001342
The bed was filtered and washed with DCM. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (20% ethyl acetate in n-hexane) to give the title compound 1- (4-chlorophenyl) azetidin-3-one (0.042g, 1.43% yield) as an off-white solid. LCMS (ES) M/z 181.9[ M + H]+.1H NMR(400MHz，CDCl3)：δppm 4.65(s，4H)，6.51(d，J＝8.4Hz，2H)，7.23–7.25(m，2H)。
And step 3: to a solution of 4-chlorophenol (117g, 914.06mmol, 1 eq) in water (1200mL) at 0 ℃ was added a solution of sodium hydroxide (146.25g, 3656.25mmol, 4 eq) and stirred at 0 ℃ for 15 min. 4-chloroacetic acid (120.9g, 1279.68mmol, 1.4 equiv.) is then added in portions at 0 ℃ and stirred at the same temperature for 10 min. The reaction mixture was then heated at 100 ℃ for 12 h. After consumption of the starting material (TLC, 5% methanol in DCM), the reaction mixture was cooled to room temperature. The reaction mixture was diluted with water (200mL) and the aqueous layer was washed with ethyl acetate (2X150 mL). The aqueous layer was acidified to pH 1 with concentrated HCl and the precipitated product was filtered through a sintered funnel, washed with ice-cold water (100mL), n-hexane (300mL), and dried under high vacuum to give 2- (4-chlorophenoxy) acetic acid (68.0g, 40% yield) as a white solid. LCMS (ES) M/z 185[ M + H]+。1HNMR(400MHz，DMSO-d6)δppm 4.65(s，2H)，6.91(d，J＝8.8Hz，2H)，7.30(d，J＝8.8Hz，2H)，12.99(bs，1H)。
And 4, step 4: to 2- (4-chlorophenoxy) acetic acid (3) at 0 deg.C3.87g, 181.57mmol, 1.2 equiv.) in DCM (300mL) was added triethylamine (63.35mL, 453.93mmol, 3 equiv.) and stirred at 0 ℃ for 5 min. Adding
Figure BDA0002308602660001351
(50 wt.% in ethyl acetate) (135.1mL, 226.96mmol, 1.5 equiv.) and the reaction mixture was stirred at 0 ℃ for 10 min. Then (3-amino-bicyclo [ 1.1.1)]Pent-1-yl) carbamic acid tert-butyl ester (30.0g, 151.31mmol, 1 eq) was added to the reaction mixture and the reaction mixture was stirred at room temperature for 16h. After completion of the reaction, the reaction mixture was diluted with water (200mL) and extracted with DCM (2 × 300 mL). The combined organic layers were washed with saturated sodium bicarbonate solution (200mL), filtered and concentrated under reduced pressure to give the product. By the same procedure (3-aminobicyclo [ 1.1.1)]Another 30g batch of t-butyl pent-1-yl) carbamate was reacted to give a final combined yield of 108g of (3- (2- (4-chlorophenoxy) acetamido) bicyclo [1.1.1]Pent-1-yl) carbamic acid tert-butyl ester (97.24% yield) as an off-white solid. LCMS (ES) M/z 311.1[ M + H]+(tert-butyl cleavage mass was observed).1H NMR(400MHz，DMSO-d6)δppm 1.35(s，9H)，2.11(s，6H)，4.39(s，2H)，6.94(d，J＝8.8Hz，2H)，7.31(d，J＝8.8Hz，2H)，7.46(bs，1H)，8.60(s，1H)。
And 5: to (3- (2- (4-chlorophenoxy) acetamido) bicyclo [1.1.1] at 0 DEG C]Pentan-1-yl) carbamic acid tert-butyl ester (27g, 73.57mmol, 1 eq) to a solution in DCM (400mL) was added a solution of 4M HCl in 1, 4-dioxane (90mL) and the reaction mixture was stirred at rt for 12 h. After consumption of starting material (TLC, 5% methanol in DCM), DCM was evaporated under reduced pressure and the resulting solid was triturated with ether (300mL) and dried under high vacuum to give N- (3-aminobicyclo [ 1.1.1)]Pent-1-yl) -2- (4-chlorophenoxy) acetamide hydrochloride. Another 3 batches were carried out following the same procedure to obtain a total of 84g (94.52% yield) of N- (3-aminobicyclo [ 1.1.1)]Pent-1-yl) -2- (4-chlorophenoxy) acetamide hydrochloride as an off-white solid. Accordingly, 29.7g was combined with 105.6g, which was prepared by following a similar procedure, by dissolving in 500mL DCM and finally concentrating under reduced pressure to give the product as off-whiteSolid (135.3g crude). LCMS (ES) m/z unionized.1HNMR(400MHz，DMSO-d6)δppm 2.22(s，6H)，4.44(s，2H)，6.95(d，J＝8.8Hz，2H)，7.32(d，J＝9.2Hz，2H)，8.87(s，1H)，9.0(bs，3H)。
Step 6: to N- (3-aminobicyclo [1.1.1] at room temperature]To a stirred solution of pentan-1-yl) -2- (4-chlorophenoxy) acetamide hydrochloride (15.0g, 49.66mmol, 1 eq) in ethyl acetate (200mL) was added saturated sodium bicarbonate (300 mL). After 30 min at room temperature, the reaction mixture was extracted with ethyl acetate (2 × 250 mL). The combined organic extracts were washed with water (100mL) and brine (50mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude N- (3-aminobicyclo [ 1.1.1)]Pent-1-yl) -2- (4-chlorophenoxy) acetamide (13g, crude material) as a brown gum. 5g of the crude material was further purified by purification using reverse phase HPLC [ column: c18, mobile phase (a): 0.1% ammonia in water, mobile phase (B): acetonitrile]. The resulting material was stirred in n-pentane (40mL) at room temperature for 1 h. The solid was then filtered and dried to give N- (3-aminobicyclo [ 1.1.1)]Pent-1-yl) -2- (4-chlorophenoxy) acetamide (3.0g, 60% yield) as a white solid. LCMS (ES) M/z 267.1[ M + H]+。1H NMR(400MHz，DMSO-d6)δppm 1.90(s，6H)，2.11(s，2H)，4.37(s，2H)，6.93(d，J＝8.8Hz，2H)，7.30-7.32(m，2H)，8.47(s，1H)。
And 7: to N- (3-aminobicyclo [1.1.1] at room temperature]To a stirred solution of pentan-1-yl) -2- (4-chlorophenoxy) acetamide (0.070g, 0.262mmol, 1 eq) in methanol (3mL) was added 1- (4-chlorophenyl) azetidin-3-one (0.052g, 0.288mmol, 1.1 eq) and acetic acid (0.05 mL). After stirring at room temperature for 45 min, the reaction mixture was cooled to 0 ℃ and sodium cyanoborohydride (0.032g, 0.524mmol, 2 eq) was added. After stirring the reaction at room temperature for 4h, the solvent was evaporated under reduced pressure. The resulting crude material was diluted with water (5mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic extracts were washed with water (10mL) and brine (5 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude material is purified by flash column chromatography using a silica gel column, wherein the product is purified with polar impuritiesEluted with 2-3% methanol in DCM. The mixture was further purified by using preparative TLC (2.5% methanol in DCM) to give 2- (4-chlorophenoxy) -N- (3- ((1- (4-chlorophenyl) azetidin-3-yl) amino) bicyclo [1.1.1]Pent-1-yl) acetamide (0.028g, 24.77% yield) as an off-white solid. LCMS (ES) M/z 432.3[ M + H [ ]]+。1H NMR(400MHz，DMSO-d6)δppm 1.93(s，6H)，3.12(d，J＝10.0Hz，1H)，3.37(t，J＝6.8Hz，2H)，3.62–3.68(m，1H)，4.01(t，J＝6.8Hz，2H)，4.44(s，2H)，6.38(d，J＝8.8Hz，2H)，6.94(d，J＝8.8Hz，2H)，7.14(d，J＝8.4Hz，2H)，7.32(d，J＝8.8Hz，2H)，8.56(s，1H)。
TABLE 6
Figure BDA0002308602660001371
Example 3b
2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenoxy) azetidin-1-yl) bicyclo [1.1.1]Penta-1- Yl) acetamide
Figure BDA0002308602660001372
Step 1: at 0 deg.C to (3-aminobicyclo [ 1.1.1)]Pent-1-yl) carbamic acid tert-butyl ester (3.0g, 15.15mmol, 1 eq) to a solution of IPA (30mL) was added 2- (chloromethyl) oxirane (1.4g, 15.15mmol, 1 eq) and the reaction mixture was stirred at room temperature for 48 h. After this time, the solvent was evaporated under reduced pressure to give (3- ((3-chloro-2-hydroxypropyl) amino) bicyclo [1.1.1]Pent-1-yl) carbamic acid tert-butyl ester (crude yield 4.4g, 100%) which was carried to the next step without further purification. LCMS (ES) M/z 291[ M + H ]]+。
Step 2: to (3- ((3-chloro-2-hydroxypropyl) amino) bicyclo [1.1.1] at 0 DEG C]To a solution of t-butyl pent-1-yl) carbamate (4.4g, 15.20mmol, 1 eq) in diethyl ether (45mL) was added potassium hydroxide (1.7g, 30.40mmol, 2 eq). After stirring the reaction mixture at room temperature for 16h, the solvent was evaporated under reduced pressure to give the crude product. The crude product obtained isFor treating
Figure BDA0002308602660001381
Purification using 40g silica gel column, gradient elution with 0% MeOH to 5% MeOH in DCM over a 30 minute period to give (3- ((oxetan-2-ylmethyl) amino) bicyclo [1.1.1]Pent-1-yl) carbamic acid tert-butyl ester (colourless syrup, 1.27g, 33%). LCMS (ES) M/z 255[ M + H]+。1H NMR(400MHz，CDCl3)δppm 1.43(s，9H)，2.02(s，6H)，2.58–2.63(m，2H)，2.76–2.78(m，1H)，2.89–2.93(m，1H)，3.05–3.08(m，1H)，4.88(bs，1H)。
And step 3: to (3- ((oxetan-2-ylmethyl) amino) bicyclo [1.1.1] at room temperature]To a solution of t-butyl pent-1-yl) carbamate (4.4g, 15.20mmol, 1 eq) in 1, 4-dioxane (45mL) was added magnesium bromide (1.7g, 30.40mmol, 2 eq). After stirring the reaction mixture at 90 ℃ for 16h, the solvent was evaporated under reduced pressure to give the crude product. The crude product obtained is passed
Figure BDA0002308602660001382
Purification using a 24g silica gel column, gradient elution with 0% MeOH to 5% MeOH in DCM/DCM over a 30 minute period to give (3- (3-hydroxyazetidin-1-yl) bicyclo [ 1.1.1)]Pent-1-yl) carbamic acid tert-butyl ester (colourless syrup, 0.42g, 32%). LCMS (ES) M/z 255[ M + H]+。1H NMR(400MHz，CDCl3)δppm 1.43(s，9H)，1.95(s，6H)，2.99–3.02(m，2H)，3.54–3.57(m，2H)，4.40–4.54(m，1H)，4.89(bs，1H)。
And 4, step 4: to (3- (3-hydroxyazetidin-1-yl) bicyclo [ 1.1.1)]Pent-1-yl) carbamic acid tert-butyl ester (0.4g, 1.57mmol, 1 equiv.) and 4-chlorophenol (0.22g, 1.73mmol, 1.1 equiv.) in DCM (10mL) was added triphenylphosphine (0.61g, 2.35mmol, 1.5 equiv.) followed by DIAD (0.47g, 2.35mmol, 1.5 equiv.) at 0 ℃. After the reaction mixture was stirred at room temperature for 16h, the solvent was evaporated under reduced pressure to give the crude product. The crude product obtained is passed
Figure BDA0002308602660001383
Purification using a 24g silica gel column, gradient elution with 0% MeOH to 5% MeOH in DCM over a 30 minute period to give (3- (3- (4-chlorophenoxy) azetidin-1-yl) bicyclo [ 1.1.1)]Pent-1-yl) carbamic acid tert-butyl ester (0.4 g). LCMS (ES) M/z 365[ M + H]+。1H NMR(400MHz，DMSO-d6)δppm 1.34(s，9H)，1.78(s，6H)，3.01–3.04(m，2H)，3.58–3.63(m，2H)，4.72–4.75(m，1H)，6.82(d，J＝8.8Hz，2H)，7.28(d，J＝8.4Hz，2H)。
And 5: to (3- (3- (4-chlorophenoxy) azetidin-1-yl) bicyclo [1.1.1] at 0 DEG C]To a solution of t-butyl pent-1-yl) carbamate (0.4g, 1.09mmol, 1 eq) in DCM (4mL) was added 2,2, 2-trifluoroacetic acid (2 mL). After the reaction mixture was stirred at room temperature for 16h, the solvent was evaporated under reduced pressure to give the crude product. The crude product was triturated with diethyl ether (3X25mL) to give 3- (3- (4-chlorophenoxy) azetidin-1-yl) bicyclo [1.1.1]Pentan-1-amine 2,2, 2-trifluoroacetate salt (0.21 g). LCMS (ES) M/z 265.1[ M + H]+。1H NMR(400MHz，DMSO-d6)δppm 2.05(s，6H)，3.49(bs，2H)，3.99(bs，2H)，4.87(bs，1H)，6.85(d，J＝8.4Hz，2H)，7.32(d，J＝8.8Hz，2H)，8.69(bs，3H)。
Step 6: to a solution of 2- (4-chlorophenoxy) acetic acid (0.12g, 0.63mmol, 1.2 equiv.) in dichloromethane (4mL) was added triethylamine (0.11g, 1.04mmol, 2.0 equiv.) at room temperature. After stirring for 5 minutes, the mixture is cooled to room temperature
Figure BDA0002308602660001392
(50 wt.% in ethyl acetate) (0.24g, 0.78mmol, 1.5 equiv.) was added to the reaction mixture and stirred for 10 minutes, then 3- (3- (4-chlorophenoxy) azetidin-1-yl) bicyclo [1.1.1]A solution of pentan-1-amine 2,2, 2-trifluoroacetate (0.2g, 0.52mmol, 1.0 equiv.) and triethylamine (0.1g, 1.04mmol, 2.0 equiv.) in DCM (3 mL). After stirring the reaction mixture at room temperature for 16h, the reaction mixture was diluted with water (10mL) and extracted with DCM (2X25 mL). The combined organic extracts were extracted with saturated NaHCO3Aqueous solution (10mL), brine solution (7mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to giveTo a crude product. The crude material was purified by flash column chromatography using a silica gel column, where the product was eluted with very close impurities as a solution of 2-3% methanol in DCM. Finally, the crude product was purified by preparative HPLC to give 2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenoxy) azetidin-1-yl) bicyclo [1.1.1]Pent-1-yl) acetamide (0.04g, 17.5% yield) as a white solid. LCMS (ES) M/z 433.3[ M + H ]]+。1H NMR(400MHz，DMSO-d6)δppm 1.91(s，6H)，3.04–3.08(m，2H)，3.62–3.63(m，2H)，4.40(s，2H)，4.74–4.76(m，1H)，6.83(d，J＝8.4Hz，2H)，6.94(d，J＝8.4Hz，2H)，7.28–7.32(m，4H)，8.64(s，1H)。
TABLE 7
Figure BDA0002308602660001391
Figure BDA0002308602660001401
Example 4a
2- (4-chlorophenoxy) -N- (3- (2- ((5,6,7, 8-tetrahydronaphthalen-2-yl) oxy) acetamido) bicyclo [1.1.1]Pent-1-yl) acetamides
Figure BDA0002308602660001402
Step 1: to a solution of 5,6,7, 8-tetrahydronaphthalen-2-ol (0.5g, 3.373mmol 1 eq.) in DMF (8mL) was added K2CO3(0.69g, 5.059mmol, 1.5 equiv.) then ethyl bromoacetate (0.44mL, 4.048mmol, 1.2 equiv.) is added dropwise at 0 ℃. The reaction mixture was stirred at 80 ℃ for 4 h. After consumption of the starting material (TLC, 5% EtOAc in hexanes), the reaction mixture was cooled to room temperature, diluted with water (20mL) and extracted with EtOAc (2 × 25 mL). The combined organic layers were washed with water (2 × 10mL), brine (20mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography using silica gel column (9.8% ethyl acetate in hexanes) to giveThe title compound ethyl 2- ((5,6,7, 8-tetrahydronaphthalen-2-yl) oxy) acetate (0.35g, 44% yield) as a gum.1H NMR(400MHz，CDCl3)δppm 1.31–1.26(m，3H)，1.76(s，4H)，2.70(d，J＝13.6Hz，4H)，4.26–4.24(m，2H)，4.57(s，2H)，6.61(s，1H)。6.67(d，J＝8.4Hz，1H)，6.96(d，J＝8Hz，1H)。
Step 2: to a solution of ethyl 2- ((5,6,7, 8-tetrahydronaphthalen-2-yl) oxy) acetate (0.35g 1.495mmol, 1 eq) in a mixture of THF (4mL) and water (1mL) at 0 deg.C was added LiOH2O (0.154g, 3.739mmol 2.5 equiv.). The resulting mixture was stirred at room temperature for 1 h. THF was removed under reduced pressure and the residue was diluted with water (10mL) and Et2O (20mL) wash. The aqueous layer was acidified to pH-2 with 1N HCl at 0 ℃ and then extracted with EtOAc (2 × 15 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound 2- ((5,6,7, 8-tetrahydronaphthalen-2-yl) oxy) acetic acid (0.237g, 79% yield) as a white solid. LCMS (ES) M/z 205.1[ M-H ═]+.1H NMR(400MHz，DMSO-d6) δ ppm 1.67(s, 4H), 2.64-2.60 (m, 4H), 4.56(s, 2H), 6.55(s, 1H), 6.60(d, J ═ 8Hz 1H), 6.91(s, J ═ 8.4Hz, 1H), 12.85(s, 1H). The compound was carried directly to the next step without further purification.
And step 3: to a stirred solution of 2- ((5,6,7, 8-tetrahydronaphthalen-2-yl) oxy) acetic acid (0.11g, 0.563mmol, 1.5 equiv.) and triethylamine (0.20mL, 1.5mmol, 4.0 equiv.) in dichloromethane (4mL) at 0 deg.C was added a solution of propylphosphonic anhydride ((II) (N50 wt.% in ethyl acetate) (0.477mL, 0.75mmol, 2 equivalents) and stirred for 10 min. Then N- (3-aminobicyclo [1.1.1] is reacted at 0 DEG C]A solution of pent-1-yl) -2- (4-chlorophenoxy) acetamide (0.1g, 0.375mmol, 1.0 equiv.) in dichloromethane (5mL) was added to the reaction mixture. The reaction mixture was then stirred at room temperature for 16h. After consumption of starting material (TLC, 5% MeOH in DCM), the reaction mixture was diluted with DCM (100mL), washed with saturated aqueous sodium bicarbonate solution (2x20mL) and water (2x20mL), brine (20mL), and dried over anhydrous sulfurThe sodium salt was dried, filtered and concentrated under reduced pressure to give the crude product. The resulting crude material was purified by flash column chromatography (2-3% methanol in dichloromethane) to give the title compound 2- (4-chlorophenoxy) -N- (3- (2- ((5,6,7, 8-tetrahydronaphthalen-2-yl) oxy) acetamido) bicyclo [1.1.1]Pent-1-yl) acetamide (0.032g, 18% yield) as an off-white solid. LCMS (ES) M/z 455.4[ M + H]+。1H NMR(400MHz，DMSO-d6)δppm 1.68(s，4H)，2.24(s，6H)，2.65–2.61(m，4H)，4.32(s，2H)，4.41(s，2H)，6.66–6.62(m，2H)，6.96–6.92(m，3H)，7.32(d，J＝8.8Hz，2H)，8.58(s，1H)，8.65(s，1H)。
The compounds of examples 4b to 4d were generally prepared according to the procedure of example 4a above.
TABLE 8
Figure BDA0002308602660001421
Figure BDA0002308602660001431
Example 4e
N- (3- (5-chloroisoindolin-2-yl) bicyclo [1.1.1]Pent-1-yl) -2- (4-chlorophenoxy) acetamide
Figure BDA0002308602660001432
Step 1: in a closed tube at room temperature to N- (3-aminobicyclo [1.1.1]]To a stirred solution of pentan-1-yl) -2- (4-chlorophenoxy) acetamide (0.15g, 0.56mmol, 1.0 equiv.) in acetonitrile (3mL) was added triethylamine (0.31mL) and 1, 2-bis (bromomethyl) -4-chlorobenzene (0.167g, 0.56 mmol). The reaction mixture was heated at 100 ℃ for 1 h. The reaction mixture was evaporated by using high vacuum to give the crude product. The crude product was purified by flash column chromatography using silica gel column
Figure BDA0002308602660001433
(2% methanol in DCM) to give the product as a white solidAnd (3) a body. The solid was washed with MeOH (2mL) and LCMS was performed. According to LCMS data, the desired product was 98% pure and 2% dechlorinated product was observed. To remove impurities, the crude product was purified by preparative HPLC [ column: X-Bridge C18(100mmx4.6mmx3.5mic), mobile phase (a): 0.1% ammonia in water, mobile phase (B): ACN, flow rate: 1.0mL/min, T/% B: 0/20,7/60, 13/20, 15/20]. The product-containing fractions were concentrated under reduced pressure to give the title compound N- (3- (5-chloroisoindolin-2-yl) bicyclo [1.1.1]Pent-1-yl) -2- (4-chlorophenoxy) acetamide (0.08g, 35% yield) as a white solid. LCMS (ES) M/z 403.3[ M + H]+。1H NMR(400MHz，DMSO-d6)δppm 2.04(s，6H)，3.85–3.87(m，4H)，4.41(s，2H)，6.95(d，J＝8.8Hz，2H)，7.22(s，2H)，7.32(d，J＝8.8Hz，3H)，8.64(s，1H)。
TABLE 8A
Figure BDA0002308602660001441
Example 5a
2- (4-chlorophenoxy) -N- (3- (4- (4-chlorophenyl) piperidin-1-yl) bicyclo [1.1.1]Pent-1-yl) acetamides
Figure BDA0002308602660001442
Step 1: to a solution of (E) -3- (4-chlorophenyl) acrylic acid (2.0g, 1 eq) in MeOH (20mL) was added thionyl chloride (3.16mL, 4 eq) at room temperature. The resulting solution was stirred at room temperature for 18h and then evaporated to dryness. The crude compound was diluted with EtOAc (50mL) and washed with saturated sodium bicarbonate solution (25mL) and brine (15 mL). Anhydrous Na for organic matter2SO4Drying, filtration and vacuum distillation afforded methyl (E) -3- (4-chlorophenyl) acrylate (2.0g, 93%) as a white solid.1HNMR(400MHz，CDCl3)δppm 3.80(s，3H)，6.41(d，J＝16.0Hz，1H)，7.35(d，J＝8.0Hz，2H)，7.45(d，J＝8.4Hz，2H)，7.63(d，J＝15.6Hz，1H)。
Step 2: to a solution of sodium methoxide in MeOH (prepared by dissolving sodium metal (0.31g, 13.41mmol, 1.2 equivalents) in 15mL of anhydrous MeOH at 0 ℃) was added a solution of dimethyl malonate (1.54mL, 13.41mmol, 1.2 equivalents) in MeOH (1.0mL) at 0 ℃ under a dry atmosphere and stirred for 0.5h at 0 ℃. Finally methyl (E) -3- (4-chlorophenyl) acrylate (2.2g, 11.18mmol, 1 eq) was added to the reaction mixture and the reaction was gradually warmed to room temperature and then heated at reflux (80 ℃). The reaction mixture was evaporated and the residue was dissolved in EtOAc (50mL) and washed with water (25mL) and brine (15 mL). Anhydrous Na for organic phase2SO4Dried, filtered and evaporated under reduced pressure. The crude material was purified by flash column chromatography (20% EtOAc in hexanes) to give the desired product trimethyl 2- (4-chlorophenyl) propane-1, 1, 3-tricarboxylate as a semi-solid (2.6g, 70%). LCMS (ES) M/z 329.0[ M + H]+。1H NMR(400MHz，CDCl3)δppm 2.58–2.75(m，2H)，2.81–2.86(m，1H)，3.51–3.54(m，6H)，3.75(s，3H)，3.89–3.93(m，1H)，7.18(d，J＝8.8Hz，2H)，7.25(d，J＝8.4Hz，2H)。
And step 3: a suspension of trimethyl 2- (4-chlorophenyl) propane-1, 1, 3-tricarboxylate (3.0g, 9.12mmol) in 2N NaOH (8mL) was refluxed slightly at 90 ℃ for 12 h. The reaction mixture was cooled to room temperature and acidified with concentrated HCl to pH-0-1, then heated to 100 ℃ for 12 h. The aqueous solution was distilled to remove most of the water, then extracted with EtOAc (2 × 30mL) with anhydrous Na2SO4Drying, filtration and evaporation under reduced pressure gave 3- (4-chlorophenyl) glutaric acid as an off-white solid (2g, 90%). LCMS (ES) M/z 240.9[ M-H ═]+。1H NMR(400MHz，DMSO-d6)δppm2.68–2.92(m，4H)，3.58–3.77(m，1H)，7.17(d，J＝8.0Hz，2H)，7.31(d，J＝8.4Hz，1H)，10.39(s，2H)。
And 4, step 4: to a solution of 3- (4-chlorophenyl) glutaric acid (1.0g, 4.12mmol, 1 eq) in THF (10mL) at 0 deg.C was added BH3.Me2S (1.17mL, 12.36mmol, 3.0 equiv.). Then the reaction is carried outThe mixture was stirred at room temperature for 12 h. The reaction mixture was then quenched with MeOH (1mL) at 0 ℃ and stirred for 30 minutes, and concentrated under reduced pressure to give the crude product. The crude material was purified by column chromatography (50% EtOAc in hexanes) to give 3- (4-chlorophenyl) pentane-1, 5-diol (0.7g, 80%) as an oily compound. LCMS (ES) M/z 215.1[ M + H]+.1H NMR(400MHz，CDCl3)δppm 1.68–1.83(m，2H)，1.92–2.08(m，2H)，2.88–2.97(m，1H)，3.42–3.48(m，2H)，3.53–3.79(m，2H)，7.13(d，J＝8.0Hz，2H)，7.25–7.28(m，2H)。
And 5: to a stirred solution of 3- (4-chlorophenyl) pentane-1, 5-diol (0.2g, 0.93mmol, 1.0 eq) in DCM (10mL) at 0 deg.C was added methanesulfonyl chloride (0.22mL, 3.0 eq) followed by dropwise addition of Et3N (0.51mL, 3.72mmol, 4.00 equiv). After stirring at 0 ℃ for 0.5h, the reaction mixture was slowly brought to room temperature and stirred at room temperature for 2 h. Adding NH to the reaction mixture4Aqueous Cl (5mL) and aqueous phase extracted with EtOAc (2 × 25 mL). The combined organic phases were washed with anhydrous Na2SO4Dried, filtered and evaporated under reduced pressure to give 3- (4-chlorophenyl) pentane-1, 5-diyl dimesylate (0.25g, crude material) as a semi-solid, which was used directly in the next step without further purification.1H NMR(400MHz，CDCl3)δppm 1.91–2.00(m，2H)，2.15–2.34(m，2H)，2.93(s，6h)，3.13–3.22(m，1H)，3.84–4.06(m，2H)，4.10–4.28(m，2H)，7.13(d，J＝8.0Hz，2H)，7.32(d，J＝8.0Hz，2H)。
Step 6: 3- (4-chlorophenyl) pentane-1, 5-diyl dimethylsulfonate (0.2g, 0.539mmol, 1 equivalent) and N- (3-aminobicyclo [ 1.1.1)]Pent-1-yl) -2- (4-chlorophenoxy) acetamide (0.14g, 0.539mmol, 1 eq) was filled into a closed tube and Et was added3N (0.37mL, 2.69mmol, 5 equiv)). The mixture was then heated at 90 ℃ for 1h using an oil bath. The reaction mixture was evaporated under reduced pressure to give crude compound. The crude material was purified by column chromatography using an eluent of 50% EtOAc in hexane. The product was further repurified by preparative TLC using 50% EtOAc in hexane as mobile phase. After preparative TLC purification, the compound was dissolved in 0.5mL CH3And (C) CN. To which 5mL of n-pentane was addedAlkyl, stirring for 0.5h, then filtering to give 2- (4-chlorophenoxy) -N- (3- (4- (4-chlorophenyl) piperidin-1-yl) bicyclo [1.1.1]Pent-1-yl) acetamide (0.003g, 1.2%) as an off-white solid. LCMS (ES) M/z 445.4[ M + H ]]+。1H NMR(400MHz，DMSO-d6)δppm 1.55–1.58(m，2H)，1.69(s，2H)，1.95–2.03(m，9H)，2.86–2.88(m，2H)，4.40(m，2H)，6.95(d，J＝7.6Hz，2H)，7.25–7.30(m，6H)，8.61(s，1H)。
TABLE 9
Figure BDA0002308602660001471
Example 5b
2- (4-chlorophenoxy) -N- (3- (4- (4-chlorophenyl) piperazin-1-yl) bicyclo [1.1.1]Pent-1-yl) acetamides
Figure BDA0002308602660001481
Step 1: to a solution of 2- (4-chlorophenoxy) acetic acid (25.32g, 136.17mmol, 1.2 equiv.) in DCM (250mL) was added triethylamine (63mL, 453.92mmol, 4 equiv.) at 0 deg.C and stirred for 5 min at 0 deg.C. Adding
Figure BDA0002308602660001482
(50 wt.% in ethyl acetate) (108.4mL, 170.22mmol, 1.5 equiv.) and the reaction mixture was stirred at 0 ° for 10 min. Then, (3-aminobicyclo [1.1.1]]Pent-1-yl) carbamic acid tert-butyl ester (22.5g, 113.48mmol, 1 eq) was added to the reaction mixture and the reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give the crude product, which was obtained by addition of saturated NaHCO3Aqueous solution (50mL) and water (50 mL). The resulting light brown solid was filtered through a sintered funnel and dried. The resulting solid was dissolved in DCM and washed with water. Anhydrous Na for organic layer2SO4Dried, filtered and concentrated under reduced pressure to give (3- (2- (4-chlorophenoxy) acetamido) bicyclo [1.1.1]Pent-1-yl) carbamic acid tert-butyl ester (39g, 93% yield) as a light brown solid. LCMS (ES) M/z 311.1[ M + H]+(tert-butyl cleavage mass was observed).1H NMR(400MHz，DMSO-d6)δppm 1.35(s，9H)，2.11(s，6H)，4.39(s，2H)，6.94(d，J＝8.8Hz，2H)，7.31(d，J＝8.8Hz，2H)，7.46(bs，1H)，8.60(s，1H)。
Step 2: to (3- (2- (4-chlorophenoxy) acetamido) bicyclo [1.1.1] at 0 DEG C]Pentan-1-yl) carbamic acid tert-butyl ester (20g, 54.49mmol, 1 eq) to a solution in DCM (225mL) was added a solution of 4M HCl in 1, 4-dioxane (60 mL). The reaction mixture was stirred at room temperature for 12 h. After consumption of starting material (TLC, 5% methanol in DCM), DCM was evaporated under reduced pressure and the resulting solid was triturated with N-pentane (100mL) and diethyl ether (100mL) and dried under high vacuum to give N- (3-aminobicyclo [ 1.1.1)]Pent-1-yl) -2- (4-chlorophenoxy) acetamide hydrochloride (14g, 84%) as a light brown solid. LCMS (ES) M/z 267.1[ M + H]+. (mass of free amine observed).1H NMR(400MHz，DMSO-d6)δppm 2.22(s，6H)，4.43(s，2H)，6.95(d，J＝9.2Hz，2H)，7.32(d，J＝8.8Hz，2H)，8.65(s，3H)，8.81(s，1H)。
And step 3: to N- (3-aminobicyclo [1.1.1] at room temperature]To a stirred solution of pent-1-yl) -2- (4-chlorophenoxy) acetamide hydrochloride (15.0g, 49.66mmol, 1 eq) in ethyl acetate (200mL) was added saturated sodium bicarbonate. After stirring at room temperature for 30 minutes, it was extracted with ethyl acetate (2 × 250 mL). The combined organic extracts were washed with water (100mL) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give N- (3-aminobicyclo [ 1.1.1)]Pent-1-yl) -2- (4-chlorophenoxy) acetamide (13g, crude material) as a brown gum. The crude material was purified by reverse phase HPLC: [ column: c18, mobile phase (a): 0.1% ammonia in water, mobile phase (B): acetonitrile]. The product containing fractions were concentrated under reduced pressure and the resulting material was stirred in n-pentane (40mL) at room temperature for 1 h. The solid was then filtered and dried to give N- (3-aminobicyclo [ 1.1.1)]Pent-1-yl) -2- (4-Chlorophenoxy) acetamide (6.6g, 50.7% yield) as a white solid. LCMS (ES) M/z 267.1[ M + H]+。1H NMR(400MHz，DMSO-d6)δppm 1.90(s，6H)，2.11(s，2H)，4.37(s，2H)，6.93(d，J＝8.8Hz，2H)，7.30-7.32(m，2H)，8.47(s，1H)。
And 4, step 4: in a closed tube at room temperature to N- (3-aminobicyclo [1.1.1]]To a solution of pentan-1-yl) -2- (4-chlorophenoxy) acetamide (0.2g, 0.74mmol, 1.0 equiv.) in triethylamine (0.52mL, 3.7mmol, 5.0 equiv.) was added N- (2-bromoethyl) -4-chloroaniline (0.21g, 0.89mmol, 1.2 equiv.). The reaction mixture was kept at 100 ℃ for 2 h. The reaction mixture was diluted with DCM (400mL) and the combined organic layers were washed with cold water (2 × 50mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude material was purified by flash chromatography using 0.1% to 10% methanol in DCM as eluent to give 2- (4-chlorophenoxy) -N- (3- ((2- ((4-chlorophenyl) amino) ethyl) amino) bicyclo [1.1.1]Pent-1-yl) acetamide (0.5g, 41.66% yield, 0.2g scale reaction with 4 batches (0.8g)) as an off-white solid. LCMS (ES) M/z 420.0[ M + H ]]+。1H NMR(400MHz，DMSO-d6) δ ppm 1.94(s, 6H), 2.64(d, J ═ 8.0Hz, 2H), 2.99-3.04 (m, 2H), 4.39(s, 2H), 5.66(bs, 1H), 6.54(d, J ═ 8.8Hz, 2H),6.94(d, J ═ 8.8Hz, 2H), 7.05(d, J ═ 8.4Hz, 2H), 7.32(d, J ═ 8.4Hz, 2H), 8.56(s, 1H). No NH protons were observed.
And 5: to 2- (4-chlorophenoxy) -N- (3- ((2- ((4-chlorophenyl) amino) ethyl) amino) bicyclo [1.1.1 at room temperature]To a solution of pentan-1-yl) acetamide (0.2g, 0.47mmol, 1.0 equiv.) in DMF (5mL) was added 1, 2-dibromoethane (0.041mL, 0.47mmol, 1.0 equiv.) and K2CO3(0.32g, 2.3mmol, 5.0 equiv.). After the reaction mixture was held at 100 ℃ for 2h, it was cooled to room temperature and quenched with crushed ice (25mL) and extracted with DCM (2X50 mL). The combined organic layers were washed with cold water (2 × 25mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude material was purified by flash chromatography using 0.5% to 70% ethyl acetate in n-hexane as eluent and repurification by preparative HPLC[ analysis conditions: column: inertsil ODS 3V (250 mm. times.4.6 mm. times.5 μm). Mobile phase (a): 0.1% ammonia in water, mobile phase (B): acetonitrile, flow rate: 1.0mL/min, compound RT: 20.99 minutes]To obtain 2- (4-chlorophenoxy) -N- (3- (4- (4-chlorophenyl) piperazin-1-yl) bicyclo [1.1.1]Pent-1-yl) acetamide (0.045g, 21.5% yield) as a white solid. LCMS (ES) M/z 446.3[ M + H]+。1H NMR(400MHz，DMSO-d6)δppm 1.97(s，6H)，2.48(s，4H)，3.41(s，4H)，4.41(s，2H)，6.91–6.96(m，4H)，7.20(d，J＝8.0Hz，2H)，7.32(d，J＝8.4Hz，2H)，8.63(s，1H)。
Watch 10
Figure BDA0002308602660001501
Example 5c
2- (bicyclo [4.2.0]]Octane-1, 3, 5-trien-3-yloxy) -N- (4- (2- (4-chlorophenoxy) acetamido) bis Ring [2.2.1]Hept-1-yl) acetamide
Figure BDA0002308602660001511
Step 1: to a stirred solution of 4-chloroaniline (2.0g, 15.75mmol, 1.0 equiv.) in acetone (50mL) was added K2CO3(3.04g, 22.05mmol, 1.4 equiv.) then ethyl 2-bromoacetate (1.91mL, 17.32mmol, 1.1 equiv.) is added and the reaction mixture is heated to reflux for 16h. After completion of the reaction, the reaction mixture was used through a buchner funnel
Figure BDA0002308602660001512
And (4) bed filtration.
Figure BDA0002308602660001513
The bed was washed with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure to give the crude product. The crude material was purified by silica gel column chromatography using 15% ethyl acetate in n-hexane as eluent to give (4-chlorophenyl) glycine ethyl ester (1.3g, 38.92%) as an off-white solid.LCMS(ES)m/z＝214.1[M+H]+。1H-NMR(400MHz，DMSO-d6)：1.17(t，J＝7.0Hz，3H)，3.86(d，J＝6.0Hz，2H)，4.09(q，J＝6.9Hz，2H)，6.15(s，1H)，6.54(d，J＝8.4Hz，2H)，7.07(d，J＝8.4Hz，2H)。
Step 2: to a solution of (4-chlorophenyl) glycine ethyl ester (1.0g, 4.67mmol, 1 eq) in methanol (20mL) was added 2-chloroacetaldehyde (6.7mL, 46.73mmol, 10 eq), then acetic acid (0.5mL) was added and stirred at room temperature for 15 min. Addition of NaCNBH at 0 deg.C3(1.17g, 18.69mmol, 4 equiv.) then the reaction mixture was stirred at room temperature for 16h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in ethyl acetate (200mL) and washed with water (100mL) and brine solution (100m L), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography using 8% ethyl acetate in N-hexane as eluent to give N- (2-chloroethyl) -N- (4-chlorophenyl) glycine ethyl ester (0.9g, 70.31%) as a light yellow liquid. LCMS (ES) M/z 276.0[ M + H]+。1H-NMR(400MHz，DMSO-d6)：1.17(t，J＝7.0Hz，3H)，3.67–3.71(m，4H)，4.09(q，J＝7.0Hz，2H)，4.21(s，2H)，6.63(d，J＝8.8Hz，2H)，7.17(d，J＝9.2Hz，2H)。
And step 3: n- (2-chloroethyl) -N- (4-chlorophenyl) glycine ethyl ester (0.35g, 1.26mmol, 1 eq.) and (3-aminobicyclo [ 1.1.1)]Pent-1-yl) carbamic acid tert-butyl ester (0.25g, 1.26mmol, 1 eq) was filled into a closed tube and diisopropylethylamine (0.87mL, 5.05mmol, 4 eq) was added. The mixture was then heated at 100 ℃ for 16h. The reaction mixture was then concentrated under reduced pressure to give the crude product. The crude material was purified by silica gel column chromatography using 35% ethyl acetate in n-hexane as eluent to give (3- (4- (4-chlorophenyl) -2-oxopiperazin-1-yl) bicyclo [1.1.1]Pent-1-yl) carbamic acid tert-butyl ester (0.16g, 16.33%) as a light yellow solid. LCMS (ES) M/z 392.1[ M + H]+。1H-NMR(400MHz，DMSO-d6)：1.36(s，9H)，2.21(s，6H)，3.35(s，2H)，3.42(s，2H)，3.7(s，2H)，6.9(d，J＝8.4Hz，2H)，7.22(d，J＝8.4Hz，2H)，7.5(s，1H)。
And 4, step 4: to (3- (4- (4-chlorophenyl) -2-oxopiperazin-1-yl) bicyclo [1.1.1] at 0 deg.C]Pent-1-yl) carbamic acid tert-butyl ester (0.16g, 0.41mmol, 1 eq) to a solution in DCM (5mL) was added 3mL of a 4M solution of HCl in 1, 4-dioxane and the mixture was stirred at rt for 4 h. The reaction mixture was concentrated to give the crude product. The crude product was washed with anhydrous n-pentane (50mL) and dried under high vacuum to give 1- (3-aminobicyclo [ 1.1.1)]Pent-1-yl) -4- (4-chlorophenyl) piperazin-2-one hydrochloride (0.133g crude material), which was carried to the next step without further purification. LCMS (ES) M/z 292.1[ M + H]+。
And 5: to a solution of 2- (4-chlorophenoxy) acetic acid (0.11g, 0.59mmol, 1.5 equiv.) in DCM (5mL) at 0 deg.C was added triethylamine (0.22mL, 1.58mmol, 4 equiv.), followed by
Figure BDA0002308602660001521
(50 wt% in EtOAc) (0.47mL, 0.79mmol, 2 equiv.) and the mixture is stirred at 0 ℃ for 10 min. To the reaction mixture was slowly added 1- (3-aminobicyclo [1.1.1] at 0 deg.C]A solution of pentan-1-yl) -4- (4-chlorophenyl) piperazin-2-one hydrochloride (0.13g, 0.39mmol, 1 eq) in DCM (2mL) and triethylamine (0.055mL, 0.39mmol, 1 eq) and the reaction was stirred at rt for 16h. The reaction mixture was diluted with water (50mL) and extracted with DCM (2 × 50 mL). The combined organic layers were washed with saturated NaHCO3Washed with aqueous solution (50mL) and then with anhydrous Na2SO4Dried, filtered and evaporated in vacuo. The crude material was purified twice by column chromatography using 50% EtOAc in hexane eluent and again by preparative HPLC (analytical conditions: column: InertsilODS 3V (250mm X4.6mmX5mic), mobile phase (A): 0.1% aqueous ammonia solution; mobile phase (B): CAN; flow rate: 1.0mL/min (40:60)) to give 2- (4-chlorophenoxy) -N- (3- (4- (4-chlorophenyl) -2-oxopiperazin-1-yl) bicyclo [1.1.1] bicyclo [ 1.1.1: (M-x-yK) ]]Pent-1-yl) acetamide (0.017g, 9.4%) as a white solid. LCMS (ES) M/z 460.3[ M + H]+。1H-NMR(400MHz，DMSO-d6)：2.34(s，6H)，3.37–3.43(m，4H)，3.71(s，2H)，4.42(s，2H)，6.91(d，J＝9.2Hz，2H)，6.95(d，J＝9.2Hz，2H)，7.22(d，J＝8.8Hz，2H)，7.32(d，J＝8.8Hz，2H)，8.71(s，1H)。
TABLE 11
Figure BDA0002308602660001531
Example 6a and example XXIV
2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1]Pentan-1-yl) ethyl Amides of carboxylic acids
Figure BDA0002308602660001532
Figure BDA0002308602660001541
Step 1: to a solution of methyl 2, 4-dibromobutyrate (1.2g, 1 eq) in DMF (15mL) at room temperature was added 4-chlorophenol (0.59g, 1 eq), followed by K2CO3(0.636g, 1 eq.) and the reaction was stirred at 60 ℃ for 3 h. The reaction mixture was then warmed to room temperature. Water (5mL) was added and the mixture was extracted with EtOAc (3X50 mL). The combined EtOAc extracts were extracted with anhydrous Na2SO4Dried, filtered and distilled under vacuum. The crude material was purified by flash column chromatography, the product eluted with 10% EtOAc in hexanes to afford methyl 4-bromo-2- (4-chlorophenoxy) butanoate as a gum (1 g).1H NMR(400MHz，CDCl3)δppm 2.3–2.5(m，2H)，3.55–3.64(m，2H)，3.76(s，3H)，4.83–4.85(m，1H)，6.86(d，J＝3.2Hz，2H)，7.23–7.25(m，2H)。
Step 2: methyl 4-bromo-2- (4-chlorophenoxy) butyrate (0.3g, 1.01mmol, 1 eq.) and (3-aminobicyclo [ 1.1.1)]Pent-1-yl) carbamic acid tert-butyl ester (0.2g, 1.01mmol, 1 eq) was filled into the closed tube and Et was added3N (0.6 mL). The mixture was then heated at 100 ℃ for 1h using an oil bath. The reaction mixture was diluted with water (50mL) and extracted with EtOAc (2X50 mL). The combined EtOAc extracts were extracted with anhydrous Na2SO4Dried, filtered and evaporated in vacuo. The crude material was purified by column chromatography using 45% EtOAc in hexanes as eluent to give the desired product (3- (3- (4-chlorophenoxy) -2-oxopyrrolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) carbamic acid tert-butyl ester as an off-white solid (0.1g, 25.6%). LCMS (ES) M/z 337.1[ M + H ]]+(loss of the tert-butyl group).1H NMR(400MHz，DMSO-d6)δppm 1.44(s，9H)，2.04–2.18(m，1H)，2.39(s，6H)，2.46–2.54(m，1H)，3.29–3.35(m，1H)，3.42–3.47(m，1H)，4.77(t，J＝7.2Hz，1H)，4.94(bs，1H)，6.98(d，J＝9.2Hz，2H)，7.21(d，J＝8.8Hz，2H)。
And step 3: to (3- (3- (4-chlorophenoxy) -2-oxopyrrolidin-1-yl) bicyclo [1.1.1] at 0 deg.C]Pent-1-yl) carbamic acid tert-butyl ester (0.1g, 0.25mmol) to a solution in DCM (5mL) was added 2mL of a 4M solution of HCl in 1, 4-dioxane and the mixture was stirred at rt for 16h. The reaction mixture was concentrated to give 1- (3-aminobicyclo [1.1.1]Pent-1-yl) -3- (4-chlorophenoxy) pyrrolidin-2-one hydrochloride (crude yield 0.08g, 96.3%) was carried to the next step without further purification. LCMS (ES) M/z 293[ M + H]+。1H NMR(400MHz，DMSO-d6)δppm 1.89–1.90(m，1H)，2.18–2.19(m，1H)，2.28–2.33(m，6H)，4.98(t，J＝7.2Hz，1H)，7.02(d，J＝8.8Hz，2H)，7.3(d，J＝9.6Hz，1H)，8.79(s，3H)。
And 4, step 4: to 1- (3-aminobicyclo [1.1.1] at 0 DEG C]Pent-1-yl) -3- (4-chlorophenoxy) pyrrolidin-2-one hydrochloride (0.08g, 0.24mmol, 1 eq) to a solution in THF (5mL) was added BH3.Me2S (0.06mL, 0.61mmol, 2,5 equiv.). The reaction mixture was then stirred at room temperature for 16h. The reaction mixture was quenched with MeOH (1mL) at 0 ℃ and stirred for 30 minutes, and concentrated under reduced pressure to give the crude product. The crude material was then dissolved in DCM (50mL) and saturated Na2HCO3And (4) washing the solution. Anhydrous Na for organic phase2SO4Dried, filtered and evaporated in vacuo to give 3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1]Pent-1-amine (0.06g, crude yield) was used in the next step without further purification. LCMS (ES) M/z 279[ M + H ]]+。
And 5: to a solution of 2- (4-chlorophenoxy) acetic acid (0.06g, 0.23mmol, 1.5 equiv.) in DCM (5mL) at 0 deg.C was added triethylamine (0.15mL, 1.07mmol, 5 equiv.), followed by
Figure BDA0002308602660001551
(50 wt% in EtOAc) (0.25mL, 0.43mmol, 2 equiv.). The mixture was stirred at 0 ℃ for 10 minutes, at which time it was added at 0 ℃(50 wt.% in ethyl acetate) (1.12g, 1.768mmol, 2 equiv.) in dichloromethane (10mL) and stirred for 10 min. To the reaction mixture was slowly added 3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1]Pentan-1-amine (0.06g) in DCM (1mL) and the reaction stirred at room temperature for 16h. The reaction mixture was diluted with water (50mL) and extracted with DCM (2 × 50 mL). The combined organic layers were washed with saturated NaHCO3Washed with aqueous solution (50mL) and then with anhydrous Na2SO4Dried, filtered and evaporated under reduced pressure. The crude product was purified by preparative TLC using 40% EtOAc in hexane. Finally drying to obtain the required product 2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenoxy) pyrrolidine-1-yl) bicyclo [1.1.1]Pentan-1-yl) acetamide as a white solid (0.0108g, 11.2%). LCMS (ES) M/z 447.3[ M + H ]]+。1H NMR(400MHz，DMSO-d6)δppm 1.76–1.77(m，1.5H)，1.95(s，6H)，2.2–2.27(m，1.5H)，2.58–2.61(m，1H)，2.65–2.69(m，1H)，2.84(m，1H)，4.4(s，2H)，4.85(bs，1H)，6.88(d，J＝8.8Hz，2H)，6.94(d，J＝8.8Hz，2H)，7.28(d，J＝8.4Hz，2H)，7.32(d，J＝8.8Hz，2H)，8.61(s，1H)。
Example 6b
(S) -2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1]Penta-1- Yl) acetamide
Example 6c
(R) -2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1]Penta-1- Yl) acetamide
Separation of the enantiomers of examples 6b and 6c by chiral preparative HPLC purification:
Example 6a was subjected to chiral preparative HPLC to give example 6b and example 6c by using the following conditions: column: CHIRALPAK 1C (100mmx4.6mmx3mic), mobile phase: hexane: IPA (85:15) with 0.1% DEA.
Figure BDA0002308602660001561
The observed VCD and IR spectra of example 6b were compared to the calculated spectra of the simulated (R) -structure, and the absolute configuration of example 6b was designated as (S) -. The observed VCD and IR spectra of example 6c were compared to the calculated spectra of the simulated (R) -structure, and the absolute configuration of example 6c was designated as (R) -.
The compounds of examples 6d to 6e were prepared generally according to the procedure described above for examples 6a to 6 c.
TABLE 12
Figure BDA0002308602660001562
Figure BDA0002308602660001571
Figure BDA0002308602660001591
Examples 6f and 6g
N- (3- (3- (3-chloro-4-fluorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) -2- (4-chlorophenoxy) Yl) acetamide
Figure BDA0002308602660001592
Figure BDA0002308602660001601
Step 1: to a solution of methyl 3-chloro-4-fluorophenol (2.0g, 13.65mmol, 1.0 equiv.) in DMF (50mL) at 0 deg.C was added K2CO3(1.88g, 13.65mmol, 1.0 equiv.) is stirred for 10 minutes, then methyl 2, 4-dibromobutyrate (1.9mL, 13.65mmol, 1.0 equiv.) is added and the reaction stirred at 60 ℃ for 3 h. After consumption of starting material (TLC, 10% ethyl acetate in hexanes), the reaction mixture was diluted with ice-cold water (100mL) and extracted with EtOAc (2X100 mL). The combined EtOAc extracts were extracted with anhydrous Na2SO4Dried, filtered and distilled under vacuum. The crude material was purified by flash column chromatography, the product eluted with 2-5% EtOAc in hexanes to give methyl 4-bromo-2- (3-chloro-4-fluorophenoxy) butanoate as a pale pink liquid (2.76g, 62.0% yield).1H NMR(400MHz，DMSO-d6)δppm 2.34–2.43(m，2H)，3.58–3.68(m，5H)，4.98–5.04(m，1H)，6.92–6.96(m，1H)，7.18–7.21(m，1H)，7.29–7.40(m，1H)。
Step 2: in a closed tube at 0 deg.C to (3-aminobicyclo [ 1.1.1)]Pent-1-yl) carbamic acid tert-butyl ester (0.8g, 4.03mmol, 1.0 eq) in Et3To a solution in N (2.27mL, 16.12mmol, 4.0 equivalents) was added methyl 4-bromo-2- (3-chloro-4-fluorophenoxy) butanoate (1.57g, 4.84mmol, 1.2 equivalents), and the mixture was heated at 100 ℃ for 1h using an oil bath. (Note: the reaction was carried out by dividing 0.8g into 4 batches). After consumption of starting material (TLC, 50% ethyl acetate in hexane), the reaction mixture was diluted with ethyl acetate (200mL) and washed with water (2X20 mL). The combined EtOAc extracts were extracted with anhydrous Na2SO4Dried, filtered and evaporated in vacuo. The crude material was purified by column chromatography using 60% EtOAc in hexanes as eluent to give the desired product (3- (3- (3-chloro-4-fluorophenoxy) -2-oxopyrrolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) carbamic acid tert-butyl ester as a colorless liquid (0.91g, 55.1%). LCMS (ES) M/z 411[ M + H ]]+，355.0[M+H]+(loss of the tert-butyl group).1H NMR(400MHz，DMSO-d6)δppm 1.44(s，9H)，2.09–2.18(m，1H)，2.39(s，6H)，2.46–2.54(m，1H)，3.29–3.35(m，1H)，3.42–3.47(m，1H)，4.73(t，J＝7.4Hz，1H)，4.96(bs，1H)，6.92–6.95(m，1H)，7.00–7.04(m，1H)，7.10–7.12(m，1H)。
And step 3: to (3- (3- (3-chloro-4-fluorophenoxy) -2-oxopyrrolidin-1-yl) bicyclo [1.1.1] at 0 deg.C]Pent-1-yl) carbamic acid tert-butyl ester (0.91g, 2.21mmol, 1.0 equiv) to a solution in DCM (20mL) was added 10mL of a 4MHCl in 1, 4-dioxane and the mixture was stirred at rt for 3 h. After consumption of starting material (TLC, 5% MeOH in DCM), the reaction mixture was concentrated and the crude material was triturated with n-pentane (2X10mL) and dried under high vacuum to give 1- (3-aminobicyclo [ 1.1.1)]Pent-1-yl) -3- (3-chloro-4-fluorophenoxy) pyrrolidin-2-one hydrochloride (crude yield 0.58g, 85.2%) was carried to the next step without further purification. LCMS (ES) M/z 311.1[ M + H]+。1H NMR(400MHz，DMSO-d6)δppm 1.87–1.96(m，1H)，2.30(q，J＝7.0Hz，6H)，2.55–2.58(m，1H)，3.25–3.31(m，1H)，3.39(t，J＝8.0Hz，1H)，5.02(t，J＝7.6Hz，1H)，6.99–7.01(m，1H)，7.26–7.34(m，2H)，8.79(bs，3H)。
And 4, step 4: to 1- (3-aminobicyclo [1.1.1] at 0 DEG C]Pent-1-yl) -3- (3-chloro-4-fluorophenoxy) pyrrolidin-2-one hydrochloride (0.75g, 2.16mmol, 1.0 equiv.) to a solution in THF (10mL) was added BH3.Me2S (0.63mL, 6.69mmol, 3.1 equiv.) and the reaction stirred for 40 h. (Note: 0.75g was divided into 2 batches and reacted.1.5 equivalents of BH was added3.Me2S, stirring for 16h, monitoring the reaction progress, and adding 0.8 equivalent of BH again3.Me2S, stirred for 8h and 0.8 eq BH added again3.Me2S and the reaction stirred for 16 h). The reaction mixture was then cooled to 0 ℃, quenched with MeOH (5mL), stirred for 30 minutes, and concentrated under reduced pressure to give the crude product. The crude material was triturated with n-pentane (50mL) and dried under high vacuum to give 3- (3- (3-chloro-4-fluorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1]Pentan-1-amine, which is an off-white solid (0.56g, crude yield), was used for the next step without further purification. LCMS (ES) M/z 297.1[ M + H ]]+。
And 5: to a solution of 2- (4-chlorophenoxy) acetic acid (0.42g, 0.23mmol, 1.2 equiv.) in DCM (5mL) was added triethylamine (1.06mL, 7.52mmol, 4.0 equiv.) at 0 deg.C, stirred for 10 min, then added
Figure BDA0002308602660001611
(50 wt% in EtOAc) (2.25mL, 3.76mmol, 2 equiv.). The mixture was stirred at 0 ℃ for 10 minutes, then 3- (3- (3-chloro-4-fluorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] was slowly added at 0 ℃]A solution of pentan-1-amine (0.56g, 1.88mmol, 1.0 equiv.) in DCM (5mL) and the reaction was stirred at room temperature for 16h. After consumption of starting material (TLC, 70% ethyl acetate in hexane), the reaction mixture was diluted with DCM (150mL) and saturated NaHCO3(2x10mL) and water (2x10 mL). The combined organic layers were washed with anhydrous Na2SO4Dried, filtered and evaporated under reduced pressure. The crude material was purified by column chromatography using 70-80% EtOAc in hexanes to give the desired product N- (3- (3- (3-chloro-4-fluorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) -2- (4-chlorophenoxy) acetamide as a white solid (0.21g, 24.1%). The racemic product was further subjected to chiral preparative HPLC to separate the isomers using the following analytical conditions: [ column: CHIRALPAK IC (100 mmx4.6mmx3mic); flow rate: 1.0 mL/min; mobile phase: n-Hexane IPA 0.1% DEA (85:15)]. The product-containing fractions were evaporated separately under reduced pressure, washed with n-pentane (10mL) and dried under high vacuum.
Isomer 1(6f, single unknown stereochemistry):
and (3) recovering: 0.055g (as an off-white solid). LCMS (ES) M/z 465.3[ M + H]+。1H NMR(400MHz，DMSO-d6) δ ppm 1.76(bs, 1H), 1.95(s, 6H), 2.21-2.23 (m, 1H), 2.58-2.68 (m, 3H), 2.82-2.88 (m, 1H), 4.40(s, 2H), 4.87(bs, 1H), 6.88(s, 1H), 6.94(d, J ═ 8.4Hz, 2H), 7.08(s, 1H), 7.27-7.32 (m, 3H), 8.62(s, 1H). Chiral HPLC purity: 100.0% at 220 nm; % ee: 100.0 percent
Isomer 2(6g, single unknown stereochemistry):
recovering: 0.025g (as an off-white solid). LCMS (ES) M/z 465.3[ M + H]+。1H NMR(400MHz，DMSO-d6) δ ppm 1.74(bs, 1H), 1.95(s, 6H), 2.21-2.22 (m, 1H), 2.58-2.68 (m, 3H), 2.82-2.88 (m, 1H), 4.39(s, 2H), 4.86(bs, 1H), 6.87(s, 1H), 6.94(d, J ═ 7.6Hz, 2H), 7.07(s, 1H), 7.26-7.32 (m, 3H), 8.60(s, 1H). Chiral HPLC purity: 100.0% at 225 nm; % ee: 100.0 percent.
Watch 13
Figure BDA0002308602660001621
Figure BDA0002308602660001631
Example 6h
N- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) -2- ((5-chloropyridine-2- Yl) oxy) acetamide
Figure BDA0002308602660001632
Figure BDA0002308602660001641
Step 1: to a solution of 4-chlorophenol (3.9g, 30.46mmol, 1.0 equiv.) in DMF (180mL) was added K2CO3(4.2g, 30.46mmol, 1.0 equiv.) methyl 2, 4-dibromobutyrate (4.26mL, 30.46mmol, 1.0 equiv.) is then added at room temperature and the reaction is stirred at 60 ℃ for 3h (note: the reaction is carried out by dividing 3.9g into 3 batches). After completion of the reaction (TLC, 10% EtOAc in hexanes), the reaction mixture was then returned to room temperature. Water (200mL) was added and the mixture was extracted with EtOAc (3X100 mL). The combined EtOAc extracts were extracted with anhydrous Na2SO4Dried, filtered and distilled under vacuum. The crude material was purified by flash column chromatography, the product eluted with 5% EtOAc in hexanes to afford methyl 4-bromo-2- (4-chlorophenoxy) butyrate as a colorless liquid: (5.8g, 62.0% yield).1H NMR(400MHz，CDCl3)δppm 2.42–2.52(m，2H)，3.52–3.60(m，2H)，3.76(s，3H)，4.82–4.85(m，1H)，6.85(d，J＝8.4Hz，2H)，7.26(d，J＝8.0Hz，2H)。
Step 2: in a closed tube to (3-aminobicyclo [1.1.1]]Pent-1-yl) carbamic acid tert-butyl ester (3.64g, 18.38mmol, 1.0 eq) in Et3To a solution in N (10.5mL, 73.52mmol, 4.0 equiv) was added methyl 4-bromo-2- (4-chlorophenoxy) butanoate (5.67g, 18.38mmol, 1.0 equiv) and the mixture was heated at 100 ℃ for 1 h. (Note: the reaction is carried out in multiple batches, e.g., 0.52gX 7). After completion of the reaction (TLC, 50% EtOAc in hexanes), the reaction mixture was diluted with water (100mL) and extracted with DCM (2X100 mL). The combined EtOAc extracts were extracted with anhydrous Na2SO4Dried, filtered and evaporated in vacuo. The crude material was purified by column chromatography using 35% EtOAc in hexanes to give the desired product (3- (3- (4-chlorophenoxy) -2-oxopyrrolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) carbamic acid tert-butyl ester as an off-white solid (3.0g, 42.0% yield). LCMS (ES) M/z 393.1[ M + H]+。1H NMR(400MHz，DMSO-d6)δppm 1.44(s，9H)，2.11–2.18(m，1H)，2.39(s，6H)，2.48–2.51(m，1H)，3.32–3.35(m，1H)，3.43–3.47(m，1H)，4.77(t，J＝7.0Hz，1H)，4.95(s，1H)，6.98(d，J＝6.8Hz，2H)，7.21(d，J＝7.2Hz，2H)。
And step 3: to (3- (3- (4-chlorophenoxy) -2-oxopyrrolidin-1-yl) bicyclo [1.1.1] at 0 deg.C]Pent-1-yl) carbamic acid tert-butyl ester (1.8g, 4.58mmol, 1.0 equiv.) to a solution in THF (30mL) was added BH3.Me2S (0.87mL, 9.16mmol, 3 equiv.). (Note: 1.8g was divided into 2 batches and the reaction was carried out). After completion of the reaction (TLC, 50% EtOAc in hexanes), the reaction mixture was quenched with methanol at 0 ℃ and stirred for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was diluted with water (200mL) and extracted with DCM (3 × 100 mL). The combined organic layers were washed with brine solution (100mL) and dried over anhydrous Na2SO4Dried, filtered and concentrated to give the crude product. The crude material was purified by silica gel column chromatography using 55% EtOAc in hexanes as the washDealkylation to give (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) carbamic acid tert-butyl ester as an off-white solid (0.8g, 46.24% yield). LCMS (ES) M/z 379.1[ M + H]+。1H NMR(400MHz，DMSO-d6)δppm 1.44(s，9H)，1.91(bs，1H)，2.03(s，6H)，2.17–2.32(m，1H)，2.60–2.61(m，1H)，2.76–2.84(m，2H)，2.95(bs，1H)，4.78(s，1H)，4.89(s，1H)，6.76(d，J＝8.8Hz，2H)，7.21(d，J＝8.8Hz，2H)。
And 4, step 4: to (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] at 0 deg.C]Pent-1-yl) carbamic acid tert-butyl ester (0.8g, 2.11mmol, 1.0 equiv) to a solution in DCM (10mL) was added 5mL of a 4M solution of HCl in 1, 4-dioxane and the mixture was stirred at rt for 16h. After completion of the reaction (TLC, 5% MeOH in DCM), the reaction mixture was concentrated to give 3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1]Pent-1-amine hydrochloride (crude yield 0.65g, 98.48% yield) was carried to the next step without further purification. LCMS (ES) M/z 279.1[ M + H ]]+。1H NMR(400MHz，DMSO-d6)δppm 2.09(bs，1H)，2.24(s，6H)，3.30–3.67(m，5H)，5.10(s，1H)，6.96(d，J＝8.8Hz，2H)，7.34(d，J＝8.8Hz，2H)，9.10(s，3H)。
And 5: to a solution of 5-chloropyridin-2-ol (2.0g, 15.44mmol, 1.0 equiv.) in DMF (20mL) was added silver carbonate (5.96g, 21.61mmol, 1.4 equiv.) at 0 deg.C, stirred for 10 min, then ethyl 2-bromoacetate (2.56mL, 23.16mmol, 1.5 equiv.) was added and the mixture heated at 80 deg.C for 2 h. After completion of the reaction (TLC, 20% EtOAc in hexane), the reaction mixture was passed through
Figure BDA0002308602660001651
The bed was filtered and washed with ethyl acetate (100mL)
Figure BDA0002308602660001652
A bed. The filtrate was evaporated in vacuo. The crude material was purified by column chromatography using 10-15% EtOAc in hexanes to give the desired product ethyl 2- ((5-chloropyridin-2-yl) oxy) acetate as a colorless liquid (0.67g, 20.0% yield). LCMS (ES) M/z 216.1[ M + H]+ 1H NMR(400MHz，DMSO-d6)δppm1.15(t，J＝7.0Hz，3H)，4.10(q，J＝6.9Hz，2H)，4.87(s，2H)，6.97(d，J＝8.8Hz，1H)，7.83(d，J＝8.4Hz，1H)，8.16(s，1H)。
Step 6: to a solution of ethyl 2- ((5-chloropyridin-2-yl) oxy) acetate (0.67g, 3.11mmol, 1.0 eq) in THF (4mL) and water (4mL) was added lithium hydroxide monohydrate (1.3g, 31.1mmol, 10.0 eq) at 0 ℃ and the mixture was stirred at rt for 6h. After completion of the reaction (TLC, 5% MeOH in DCM), the reaction mixture was evaporated in vacuo and the aqueous layer was extracted with ethyl acetate (2 × 10 mL). The aqueous layer was then cooled to 0 ℃ and acidified with concentrated HCl (pH adjusted to 1) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with anhydrous Na2SO4Dried, filtered and concentrated. The crude material was triturated with n-pentane (2x5mL) and dried under high vacuum to give the desired product 2- ((5-chloropyridin-2-yl) oxy) acetic acid as an off-white solid (0.43g, 73.9% yield). LCMS (ES) M/z 188.0[ M + H ]]+。1H NMR(400MHz，DMSO-d6)δppm 4.79(s，2H)，6.94(d，J＝8.8Hz，1H)，7.82(dd，J＝8.8Hz，2.4Hz，1H)，8.162–8.168(m，1H)，12.85(bs，1H)。
And 7: to a solution of 2- ((5-chloropyridin-2-yl) oxy) acetic acid (0.054g, 0.28mmol, 1.5 equiv.) in DCM (6mL) was added triethylamine (0.11mL, 0.76mmol, 4.0 equiv.) at 0 deg.C, stirred for 10 min and added
Figure BDA0002308602660001661
(50 wt% in EtOAc) (0.23mL, 0.38mmol, 2.0 equiv). The reaction mixture was stirred at 0 ℃ for 10 minutes, then 3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] was added at 0 DEG C]Pent-1-amine hydrochloride (0.06g, 0.19mmol, 1.0 equiv) (which was neutralized with triethylamine in DCM) and the reaction was stirred at rt for 2 h. After consumption of starting material (TLC, 5% MeOH in DCM), the reaction mixture was diluted with DCM (100mL) and saturated NaHCO3Aqueous solution (2x10mL) and water (2x10 mL). The combined organic layers were washed with anhydrous Na2SO4Drying, filtering and evaporating under reduced pressure to obtain crudeA substance. The crude product was purified by column chromatography on silica gel using 6-7% MeOH in DCM as eluent to give the desired product N- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) -2- ((5-chloropyridin-2-yl) oxy) acetamide as an off-white solid (0.06g, 70.6% yield).
LCMS(ES)m/z＝448.3[M+H]+。1H NMR(400MHz，DMSO-d6)δppm1.73–1.76(m，1H)，1.95(s，6H)，2.17–2.26(m，1H)，2.56–2.69(m，3H)，2.82–2.86(m，1H)，4.63(s，2H)，4.82–4.84(m，1H)，6.86–6.93(s，3H)，7.28(d，J＝9.2Hz，2H)，7.81(dd，J＝8.8Hz，6.4Hz，1H)，8.14(d，J＝2.0Hz，1H)，8.55(s，1H)。
Example 6i
N- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) -2- (4- (trifluoromethyl) benzene Oxy) acetamide
Figure BDA0002308602660001671
Step 1: to a solution of methyl 2, 4-dibromobutyrate (2g, 7.69mmol, 1 eq) in DMF (60mL) at room temperature was added 4-chlorophenol (0.98g, 7.69mmol, 1 eq), followed by K2CO3(1.06g, 7.69mmol, 1 eq.) and the reaction was stirred at 60 ℃ for 3 h. The reaction mixture was then brought to room temperature, ice-cold water (100mL) was added and the mixture was extracted with EtOAc (2X100 mL). The combined EtOAc extracts were extracted with anhydrous Na2SO4Dried, filtered and distilled under vacuum. The crude material was purified by flash column chromatography, the product eluted with 3.7% EtOAc in hexanes to give methyl 4-bromo-2- (4-chlorophenoxy) butanoate as a gum (1.3g, 56%). LCMS (ES) M/z 308[ M + H]+，1H NMR(400MHz，CDCl3)δppm 2.44–2.52(m，2H)，3.48–3.58(m，2H)，3.76(s，3H)，4.83–4.85(m，1H)，6.84–6.86(m，2H)，7.23–7.25(m，2H)。
Step 2: note: the reaction was carried out in two batches, each having 0.4g, i.e. 2x0.4g ═ 0.8g]. 4-bromo-2- (4-chlorophenoxy) butyric acid methyl esterEster (0.62g, 2.02mmol, 1 eq.) and (3-aminobicyclo [ 1.1.1)]Pent-1-yl) carbamic acid tert-butyl ester (0.4g, 2.02mmol, 1 eq) was filled into the closed tube and Et was added3N (1.1mL, 8.08mmol, 4 equiv.). The reaction mixture was then heated at 100 ℃ for 1.5h using an oil bath. Upon completion, the reaction mixture was cooled to room temperature, diluted with water (15mL) and extracted with EtOAc (2X50 mL). The combined EtOAc extracts were extracted with anhydrous Na2SO4Dried, filtered and evaporated in vacuo. The crude material was purified by column chromatography using 35% EtOAc in hexanes to give the desired product (3- (3- (4-chlorophenoxy) -2-oxopyrrolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) carbamic acid tert-butyl ester as an off-white solid (0.7g, 70%). LCMS (ES) M/z 393.1[ M + H]+.1H NMR(400MHz，CDCl3-d6)δppm 1.44(s，9H)，2.13–2.16(m，1H)，2.39(s，6H)，2.45–2.50(m，1H)，3.31–3.33(m，1H)，3.43–3.45(m，1H)，4.76–4.79(m，1H)，6.82(bs，1H)，6.98(d，J＝8.8Hz，2H)，7.21(d，J＝8.4Hz，2H)。
And step 3: to (3- (3- (4-chlorophenoxy) -2-oxopyrrolidin-1-yl) bicyclo [1.1.1] at 0 deg.C]Pent-1-yl) carbamic acid tert-butyl ester (0.7g, 1.78mmol, 1 eq) to a solution in DCM (15mL) was added 10mL of a 4M solution of HCl in 1, 4-dioxane and the mixture was stirred at rt for 12 h. The reaction mixture was concentrated to give 1- (3-aminobicyclo [1.1.1]Pent-1-yl) -3- (4-chlorophenoxy) pyrrolidin-2-one hydrochloride (0.5g, crude material) was carried to the next step without further purification. LCMS (ES) M/z 293.1[ M + H]+。1H NMR(400MHz，DMSO-d6)δppm 1.89–1.92(m，2H)，2.31(s，6H)，3.28–3.30(m，1H)，3.36–3.39(m，1H)，4.96–5.00(m，1H)，7.02(d，J＝8.8Hz，2H)，7.31(d，J＝8.4Hz，2H)，8.71–8.87(s，3H)。
And 4, step 4: to 1- (3-aminobicyclo [1.1.1] at 0 DEG C]Pent-1-yl) -3- (4-chlorophenoxy) pyrrolidin-2-one hydrochloride (0.5g, 1.52mmol, 1 equiv.) to a solution in THF (10mL) was added BH3.Me2S (0.4mL, 4.5mmol, 3 equiv.). (Note: BH3.Me2S was added at 3 spaced time points. First 1.5 equivalents were added and stirred for 16h and againAdd 0.75 eq and stir for 8h. The reaction progress was then monitored by LCMS, which showed the presence of starting material and 0.75 eq was added again and stirred for 8 h). After completion of the reaction, the reaction mixture was quenched with MeOH (3mL) at 0 ℃, stirred for 30 minutes, and concentrated under reduced pressure to give the crude product. The crude material was washed with n-pentane (15mL) and dried in vacuo to give 3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1]Pent-1-amine (0.6g, crude material) was used in the next step without further purification. LCMS (ES) M/z 279[ M + H ]]+。
And 5: to a solution of 2- (4- (trifluoromethyl) phenoxy) acetic acid (0.56g, 2.58mmol, 1.2 equiv.) in DCM (10mL) at 0 deg.C was added triethylamine (1.2mL, 8.60mmol, 4 equiv.) followed by
Figure BDA0002308602660001681
(50 wt% in EtOAc) (2.5mL, 4.30mmol, 2 equiv.). The mixture was stirred at 0 ℃ for 10 minutes, at which time the reaction mixture was slowly added at 0 ℃: 3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1]A solution of pentan-1-amine (0.6g, 2.15mmol, 1 eq.) in DCM (10mL) and the reaction was stirred at room temperature for 12 h. The reaction mixture was diluted with water (10mL) and extracted with DCM (2 × 20 mL). The combined organic layers were washed with saturated NaHCO3Washed with aqueous solution (15mL) and then with anhydrous Na2SO4Dried, filtered and evaporated under reduced pressure. The crude product was purified by preparative TLC using 50% EtOAc in hexane. Finally drying to obtain the required product N- (3- (3- (4-chlorophenoxy) pyrrolidine-1-yl) bicyclo [1.1.1]Pent-1-yl) -2- (4- (trifluoromethyl) phenoxy) acetamide as a white solid (0.097g, 19%). LCMS (ES) M/z 481.4[ M + H]+。1H NMR(400MHz，DMSO-d6)δppm 1.73–1.77(m，1H)，1.95(s，6H)，2.12–2.26(m，1H)，2.58–2.70(m，3H)，2.84–2.88(m，1H)，4.51(s，2H)，4.83–4.86(m，1H)，6.88(d，J＝8.8Hz，2H)，7.09(d，J＝8.8Hz，2H)，7.28(d，J＝8.8Hz，2H)，7.64(d，J＝8.4Hz，2H)，8.67(s，1H)。
The compounds of examples 6j-6o were prepared generally according to the procedure described above for examples 6h and 6 i.
TABLE 14
Figure BDA0002308602660001691
Figure BDA0002308602660001701
Figure BDA0002308602660001711
Example 6p
2- (4-chlorophenoxy) -N- (3- (3- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) bicyclo [1.1.1]Wu-Jia-Zi 1-yl) acetamides
Figure BDA0002308602660001732
Step 1: to a solution of methyl 2, 4-dibromobutyrate (1g, 3.84mmol, 1 eq) in DMF (30mL) at room temperature was added 4- (trifluoromethyl) phenol (0.49g, 3.84mmol, 1 eq) followed by K2CO3(0.53g, 3.84mmol, 1 eq.) and the reaction was stirred at 60 ℃ for 3 h. The reaction mixture was then allowed to return to room temperature. Ice-cold water (100mL) was added and the mixture was extracted with EtOAc (2X100 mL). The combined EtOAc extracts were extracted with anhydrous Na2SO4Dried, filtered and distilled under vacuum. The crude material was purified by flash column chromatography, the product eluted with 3.9% EtOAc in hexanes to afford methyl 4-bromo-2- (4- (trifluoromethyl) phenoxy) butanoate as a gum (0.8g, 61%). LCMS (ES) M/z 342.9[ M + H ]]+，1H NMR(400MHz，CDCl3)δppm 2.36–2.44(m，2H)，3.59–3.68(m，2H)，3.69(s，3H)，5.08–5.11(m，1H)，7.10(d，J＝8.4Hz，2H)，7.65(d，J＝8.4Hz，2H)。
Step 2: [ note: the reaction is carried out in two batches, each having 0.23g, i.e. 2x0.23g ═ 0.46g]To a closed tube was charged methyl 4-bromo-2- (4- (trifluoromethyl) phenoxy) butanoate (0.39g, 1.16mmol, 1 eq.) and (3-aminobicyclo [ 1.1.1)]To a solution of t-butyl pent-1-yl) carbamate (0.23g, 1.16mmol, 1 eq.) was added Et3N (0.64mL, 4.64mmol, 4 equiv.). The mixture was then heated at 100 ℃ for 1.5h using an oil bath. Upon completion, the reaction mixture was cooled to room temperature, diluted with water (15mL) and extracted with EtOAc (2X50 mL). The combined EtOAc extracts were extracted with anhydrous Na2SO4Dried, filtered and evaporated in vacuo. The crude material was purified by column chromatography using 36% EtOAc in hexanes to give the desired product (3- (2-oxo-3- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) carbamic acid tert-butyl ester as an off-white solid (0.5g, 55%). LCMS (ES) M/z 371.1[ M + H]+(loss of the tert-butyl group).1HNMR(400MHz，CDCl3-d6)δppm 1.26–1.28(m，1H)，1.44(s，9H)，2.16–2.20(m，1H)，2.40(s，6H)，2.53(bs，1H)，3.34–3.36(m，1H)，3.47–3.52(m，1H)，4.88–4.90(m，1H)，7.11(d，J＝7.6Hz，2H)，7.53(d，J＝8.4Hz，2H)。
And step 3: to (3- (2-oxo-3- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] at 0 deg.C]Pent-1-yl) carbamic acid tert-butyl ester (0.5g, 1.17mmol, 1 eq) to a solution in DCM (15mL) was added 10mL of a 4MHCl in 1, 4-dioxane and the mixture was stirred at rt for 12 h. The reaction mixture was concentrated to give 1- (3-aminobicyclo [1.1.1]Pent-1-yl) -3- (4- (trifluoromethyl) phenoxy) pyrrolidin-2-one hydrochloride (0.4g, crude material) was carried to the next step without further purification. LCMS (ES) M/z 327.1[ M + H]+。1H NMR(400MHz，DMSO-d6)δppm 2.34(m，6H)，3.30–3.41(m，4H)，5.13–5.16(m，1H)，7.18(d，J＝8.4Hz，2H)，7.63(d，J＝8Hz，2H)，8.74–8.86(s，3H)。
And 4, step 4: to 1- (3-aminobicyclo [1.1.1] at 0 DEG C]Pent-1-yl) -3- (4- (trifluoro)Methyl) phenoxy) pyrrolidin-2-one hydrochloride (0.4g, 1.10mmol, 1 equiv.) to a solution in THF (10mL) was added BH3.Me2S (0.31mL, 3.30mmol, 3 equiv.). (Note: BH3.Me2S was added at 3 interval time points: first 1.5 equivalents were added and stirred for 16h and again 0.75 equivalents were added and stirred for 8h. Then, the progress of the reaction was monitored by LCMS, which showed the presence of starting material and 0.75 eq was added again and stirred for 8 h). After completion of the reaction, the reaction mixture was quenched with MeOH (3mL) at 0 ℃, stirred for 30 minutes, and concentrated under reduced pressure to give the crude product. The crude material was washed with n-pentane (15mL) and dried in vacuo to give 3- (3- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) bicyclo [1.1.1]Pent-1-amine (0.27g, crude material) was used in the next step without further purification. LCMS (ES) M/z 313.1[ M + H [ ]]+。
And 5: to a solution of 2- (4-chlorophenoxy) acetic acid (0.19g, 1.03mmol, 1.2 equiv) in DCM (10mL) at 0 deg.C was added triethylamine (0.36mL, 2.59mmol, 3 equiv.), followed by
Figure BDA0002308602660001752
(50 wt% in EtOAc) (1.03mL, 1.72mmol, 2 equiv.). The mixture was stirred at 0 ℃ for 10 minutes, at which time the reaction mixture was slowly added at 0 ℃: 3- (3- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) bicyclo [1.1.1]A solution of pentan-1-amine (0.27g, 0.86mmol, 1 eq.) in DCM (10mL) and the reaction was stirred at room temperature for 12 h. The reaction mixture was diluted with water (10mL) and extracted with DCM (2 × 20 mL). The combined organic layers were washed with saturated NaHCO3Washed with aqueous solution (15mL) and then with anhydrous Na2SO4Dried, filtered and evaporated under reduced pressure. The crude product was purified by preparative TLC using 50% EtOAc in hexanes. Finally drying to obtain the required product 2- (4-chlorophenoxy) -N- (3- (3- (4- (trifluoromethyl) phenoxy) pyrrolidine-1-yl) bicyclo [1.1.1]Pent-1-yl) acetamide as a white solid (0.087g, 21%). LCMS (ES) M/z 481.4[ M + H]+。1HNMR(400MHz，CD3OD)δppm 1.93–2.02(m，1H)，2.13(s，6H)，2.31–2.39(m，1H)，2.64–2.68(m，1H)，2.85–2.92(m，2H)，2.98–3.02(m，1H)，4.48(s，2H)，4.97–5.00(m，1H)，6.95(d，J＝9.2Hz，2H)，7.01(d，J＝8.4Hz，2H)，7.27(d，J＝9.2Hz，2H)，7.56(d，J＝8.4Hz，2H)。
Watch 15
Example 6q
2- (4-chloro-3-fluorophenoxy) -N- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1]Penta-1- Yl) acetamide
Figure BDA0002308602660001762
Figure BDA0002308602660001771
Step 1: to a solution of 4-chloro-3-fluorophenol (3g, 20.47mmol, 1 eq) in DMF (20mL) at 0 deg.C was added K2CO3(8.47g, 61.41mmol, 3 equiv.) and then ethyl 2-bromoacetate (6.83g, 40.94mmol, 2 equiv.) are added dropwise. The reaction mixture was stirred at 80 ℃ for 16h. The resulting mixture was warmed to 25 ℃ (room temperature). After consumption of the starting material (TLC, 10% EtOAc in hexanes), the reaction mixture was filtered through a buchner funnel and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography using silica gel column
Figure BDA0002308602660001772
(5% ethyl acetate in hexanes) to give the title compound ethyl 2- (4-chloro-3-fluorophenoxy) acetate (3.8g, as a colorless liquid lcms (es) 232[ M + H) M/z]+。1H NMR(400MHz，CDCl3)δppm 1.30–1.27(m，3H)，4.29–4.23(m，2H)，4.60(s，2H)，6.65–6.63(m，1H)，6.73–6.70(m，1H)，7.29–7.25(m，1H)。
Step 2: to a solution of ethyl 2- (4-chloro-3-fluorophenoxy) acetate (3.8g 16.334mmol, 1 eq) in a mixture of THF (15mL) and water (15mL) at 0 deg.C was added LiOH2O (6.85g, 41.95mmol, 10 equiv.) and the resulting mixture stirred at room temperature for 3 h. After consumption of starting material (TLC, 5% methanol in DCM), THF was removed under reduced pressure and the residue was diluted with water (20mL) and Et2O (2 × 15mL) to remove unreacted ethyl 2-bromoacetate. The aqueous layer was acidified to pH-2 with 1N HCl at 0 ℃. The product was extracted with EtOAc (2 × 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound 2- (4-chloro-3-fluorophenoxy) acetic acid (0.720g, 21% yield) as a white solid. LCMS (ES) M/z 203.0[ M + H ]]+.1H NMR(400MHz，DMSO-d6)δppm 4.71(s，2H)，6.81–6.78(m，1H)，7.07–7.03(m，1H)，7.47–7.43(t，J＝9.2Hz，1H)，13.06(s，1H)。
And step 3: to a solution of methyl 2, 4-dibromobutyrate (4.01g, 0.015mmol, 1 eq) in DMF (50mL) at room temperature was added 4-chlorophenol (2.0g, 0.015mmol, 1 eq), followed by K2CO3(2.1g, 0.015mmol, 1 eq.) and the reaction was stirred at 60 ℃ for 3 h. The reaction mixture was then allowed to return to room temperature. Water (5mL) was added and the mixture was extracted with EtOAc (3X100 mL). The combined EtOAc extracts were extracted with anhydrous Na2SO4Dried, filtered and distilled under vacuum. The crude material was purified by flash column chromatography (10% EtOAc in hexanes) to give methyl 4-bromo-2- (4-chlorophenoxy) butanoate as a colourless liquid (2.6 g).1H NMR(400MHz，CDCl3)δppm 2.42–2.51(m，2H)，3.58–3.62(m，2H)，3.76(s，3H)，4.82–4.85(m，1H)，6.85(d，J＝8.8Hz，2H)，7.26(d，J＝7.2Hz，2H)。
And 4, step 4: methyl 4-bromo-2- (4-chlorophenoxy) butyrate (0.4g, 1.31mmol, 1 eq.) and (3-aminobicyclo [1.1.1]]Pent-1-yl) carbamic acid tert-butyl ester (0.26g, 1.31mmol, 1 eq) was filled into the closed tube and Et was added3N (0.73 mL). The mixture was then heated at 100 ℃ for 1 h. The reaction mixture was diluted with cold water (150mL) and extracted with EtOAc (2X200 mL). Merged EtOAc extract with anhydrous Na2SO4Dried, filtered and evaporated in vacuo. The crude material was purified by column chromatography using 50% EtOAc in hexanes to give the desired product (3- (3- (4-chlorophenoxy) -2-oxopyrrolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) carbamic acid tert-butyl ester as an off-white solid (2.2g, 47.41%) (the reaction was carried out in multiple batches: 0.26gx 9). LCMS (ES) M/z 337.1[ M + H ]]+(loss of the tert-butyl group).1H NMR(400MHz，DMSO-d6) δ ppm 1.36(s, 9H), 1.83-1.92 (m, 1H), 2.16-2.22 (m, 6H), 3.23-3.25 (m, 1H), 3.32-3.37 (m, 1H), 4.96(t, J ═ 8.0Hz, 1H), 7.02(d, J ═ 9.2Hz, 2H), 7.3(d, J ═ 8.8Hz, 2H), 7.55(s, 1H). Note: one proton is combined with the solvent peak.
And 5: to (3- (3- (4-chlorophenoxy) -2-oxopyrrolidin-1-yl) bicyclo [1.1.1] at 0 deg.C]To a solution of t-butyl pent-1-yl) carbamate (2.6g, 5.59mmol) in DCM (30mL) was added 25mL of a 4M HCl in 1, 4-dioxane and the mixture was stirred at rt for 16h. The reaction mixture was concentrated to give 1- (3-aminobicyclo [1.1.1]Pent-1-yl) -3- (4-chlorophenoxy) pyrrolidin-2-one hydrochloride (crude yield 1.8g, 82.9%) was carried to the next step without further purification. LCMS (ES) M/z 293[ M + H]+。1H NMR(400MHz，DMSO-d6) δ ppm 1.87-1.94 (m, 1H), 2.28-2.33 (m, 6H), 3.32-3.38 (m, 2H), 4.99(t, J ═ 7.6Hz, 1H), 7.02(d, J ═ 8.8Hz, 2H), 7.31(d, J ═ 8.4Hz, 2H), 8.76(bs, 3H). Note: one proton is combined with the solvent peak.
Step 6: to 1- (3-aminobicyclo [1.1.1] at 0 DEG C]To a solution of pent-1-yl) -3- (4-chlorophenoxy) pyrrolidin-2-one hydrochloride (0.34g, 1.036mmol, 1 eq) in THF (4mL) was added BH3.Me2S (0.3mL, 0.61mmol, 3 equiv.). (Note: BH3.Me2S was added at 3 interval time points: first 1.5 equivalents were added and stirred for 16h and again 0.75 equivalents were added and stirred for 8h. The reaction progress was then monitored by LCMS, which showed the presence of starting material and 0.75 eq was added again and stirred for 8 h). After completion, the reaction mixture was quenched with methanol at 0 ℃, stirred for 30 minutes, and then evaporated under reduced pressure to giveThe crude product, which was washed with anhydrous n-pentane (50mL) and dried to give 3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1]Pent-1-amine (crude yield 1.4g, 87%) (the reaction was carried out in multiple batches: 0.34gx5) was used for the next step without further purification. LCMS (ES) M/z 279[ M + H ]]+。
And 7: to a solution of 2- (4-chloro-3-fluorophenoxy) acetic acid (0.062g, 0.303mmol, 1.2 equiv.) in DCM (20mL) at 0 deg.C was added triethylamine (0.1mL, 0.718mmol, 3 equiv.), followed by addition
Figure BDA0002308602660001792
(50 wt% in EtOAc) (0.2mL, 0.380mmol, 1.5 equiv.) and the mixture is stirred at 0 ℃ for 10 min. To the reaction mixture was slowly added 3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1]A solution of pentan-1-amine (0.08g, 0.253mmol, 1 eq.) in DCM (10mL) and the reaction was stirred at room temperature for 16h. The reaction mixture was diluted with water (20mL) and extracted with DCM (2 × 20 mL). The combined organic layers were washed with saturated NaHCO3Washed with aqueous solution (10mL) and then with anhydrous Na2SO4Dried, filtered and evaporated under reduced pressure. The crude material was purified by column chromatography twice using 3% MeOH in DCM as eluent to give 2- (4-chloro-3-fluorophenoxy) -N- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) acetamide (0.025g, 18.79%) as a white solid. LCMS (ES) M/z 465.3[ M + H]+。1H NMR(400MHz，DMSO-d6)δppm 1.73-1.77(m，1H),1.95(s，6H)，2.21-2.30(m，1H)，2.58-2.68(m，3H)，2.84-2.88(m，1H)，4.44(s，2H)，4.84(s，1H)，6.82(d，J＝9.2Hz，1H)，6.88(d，J＝8.8Hz，2H)，7.02-7.05(m，1H)，7.28(d，J＝8.8Hz，2H)，7.46(t，J＝8.8Hz，1H)，8.62(s，1H)。
The compound of example 6r was prepared generally according to the procedure described above for example 6 q.
TABLE 16
Figure BDA0002308602660001791
Figure BDA0002308602660001801
Example 6s
2- (4-chlorophenoxy) -N- (3- (3- (pyridin-4-yloxy) pyrrolidin-1-yl) bicyclo [1.1.1]Penta-1-yl) Acetamide
Figure BDA0002308602660001811
Step 1: to a solution of pyridin-4-ol (2.0g, 21.03mmol, 1.0 equiv.) in DMF (30mL) at 0 deg.C was added Ag2CO3(8.7g, 31.54mmol, 1.5 equiv.) and stirred for 5 min, then 3-bromodihydrofuran-2 (3H) -one (2.3mL, 25.23mmol, 1.2 equiv.) is added and the reaction stirred at 60 ℃ for 2H. After consumption of starting material (TLC, 5% MeOH in DCM), the reaction mixture was passed through
Figure BDA0002308602660001812
The bed was filtered and washed with EtOAc (200 mL). The organic layer was washed with ice cold water (2 × 20mL) and anhydrous Na2SO4Dried, filtered and distilled under vacuum. The crude material was purified by flash column chromatography (5-6% MeOH in DCM) to give 3- (pyridin-4-yloxy) dihydrofuran-2 (3H) -one as a brown liquid (1.18g, 31.4% yield). LCMS (ES) M/z 180.0[ M + H ]]+，1H NMR(400MHz，CDCl3)δppm 2.45–2.55(m，1H)，2.72–2.80(m，1H)，4.33–4.42(m，1H)，4.52–4.57(m，1H)，5.05(t，J＝7.8Hz，1H)，6.95–6.97(m，2H)，8.47–8.49(m，2H)。
Step 2: to a solution of 3- (pyridin-4-yloxy) dihydrofuran-2 (3H) -one (0.99g, 5.54mmol, 1.0 equiv.) in toluene (15.0mL) at room temperature was added (3-aminobicyclo [ 1.1.1)]Pent-1-yl) carbamic acid tert-butyl ester (1.1g, 5.54mmol, 1.0 eq), then the mixture was heated to 110 ℃ using an oil bath for 16h. After consumption of starting material (TLC, 5% MeOH in DCM), the reaction mixture was concentrated in vacuo. The crude material was purified by column chromatography using an eluent of 5-7% MeOH in DCM to give the desired product (3- (4-hydroxy-2- (pyridone)Pyridin-4-yloxy) butanamido) bicyclo [1.1.1]Pent-1-yl) carbamic acid tert-butyl ester as a light yellow liquid (1.2g, 57.4% yield). LCMS (ES) M/z 378.1[ M + H]+。1HNMR(400MHz，DMSO-d6)δppm 1.34(s，9H)，1.88–1.89(m，2H)，2.06(s，6H)，3.46–3.48(m，2H)，4.60(bs，1H)，4.71(bs，1H)，6.46(s，2H)，7.44(bs，1H)，8.36(s，2H)，8.73(s，1H)。
And step 3: to (3- (4-hydroxy-2- (pyridin-4-yloxy) butanamido) bicyclo [1.1.1] at 0 deg.C]Pent-1-yl) carbamic acid tert-butyl ester (1.2g, 3.17mmol, 1.0 equiv) to a solution in DCM (20mL) was added triethylamine (1.33mL, 9.51mmol, 3.0 equiv), stirred for 10 min, then methanesulfonyl chloride (0.5mL, 6.36mmol, 2.0 equiv) was added and the mixture stirred at rt for 3 h. After consumption of starting material (TLC, 5% MeOH in DCM), the reaction mixture was cooled to 0 ℃ and quenched with ice. It was extracted with DCM (2 × 80 mL). The combined organic layers were washed with anhydrous Na2SO4Drying, filtration and vacuum distillation to give 4- ((3- ((tert-butoxycarbonyl) amino) bicyclo [ 1.1.1) methane sulfonic acid]Pent-1-yl) amino) -4-oxo-3- (pyridin-4-yloxy) butyl ester (1.6g, crude material) which was carried to the next step without further purification. LCMS (ES) M/z 456.1[ M + H]+。
And 4, step 4: to methanesulfonic acid 4- ((3- ((tert-butoxycarbonyl) amino) bicyclo [1.1.1 ℃ C.)]Pent-1-yl) amino) -4-oxo-3- (pyridin-4-yloxy) butyl ester (1.6g, 3.51mmol, 1.0 eq) to a solution in THF (20mL) was added 60% sodium hydride in mineral oil (0.17g, 4.21mmol, 1.2 eq) and the reaction was stirred at rt for 16h. After consumption of starting material (TLC, 5% MeOH in DCM), the reaction mixture was cooled to 0 ℃, quenched with ice and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with anhydrous Na2SO4Dried, filtered and distilled under reduced pressure to give the crude product. The crude material was purified by column chromatography using 5-7% MeOH in DCM as eluent to give (3- (2-oxo-3- (pyridin-4-yloxy) pyrrolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) carbamic acid tert-butyl ester as an off-white solid (0.73g, 45.3% yield). LCMS (ES) M/z 360.1[ M + H ═]+。1H NMR(400MHz，CDCl3)δppm 1.44(s，9H)，2.16–2.22(m，1H)，2.39(s，6H)，2.54–2.56(m，1H)，3.33–3.39(m，1H)，3.45–3.48(m，1H)，4.91–4.95(m，2H)，6.95–6.96(m，2H)，8.42–8.43(m，2H)。
And 5: to (3- (2-oxo-3- (pyridin-4-yloxy) pyrrolidin-1-yl) bicyclo [1.1.1] at 0 deg.C]Pent-1-yl) carbamic acid tert-butyl ester (0.73g, 2.03mmol, 1.0 equiv.) to a solution in THF (15mL) was added borane dimethylsulfide complex (0.39mL, 4.06mmol, 2.0 equiv.) and the reaction was stirred at room temperature for 16h. After consumption of starting material (TLC, 5% MeOH in DCM), the reaction mixture was cooled to 0 ℃, quenched with methanol, stirred for 1h and distilled under reduced pressure to give the crude product. The crude material was purified by column chromatography using an eluent of 5-7% MeOH in DCM to give (3- (3- (pyridin-4-yloxy) pyrrolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) carbamic acid tert-butyl ester as a pale yellow sticky solid (0.1g, 14.2% yield). LCMS (ES) M/z 346.2[ M + H]+。
Step 6: to (3- (3- (pyridin-4-yloxy) pyrrolidin-1-yl) bicyclo [1.1.1] at 0 deg.C]To a solution of t-butyl pent-1-yl) carbamate (0.1g, 0.29mmol, 1.0 equiv) in DCM (5mL) was added a solution of 4M HCl in 1, 4-dioxane (2.0mL) and the reaction was stirred at rt for 24 h. After consumption of starting material (TLC, 10% MeOH in DCM), the reaction mixture was concentrated under reduced pressure to give the crude product. The crude material was triturated with n-pentane (2x5mL) to give 3- (3- (pyridin-4-yloxy) pyrrolidin-1-yl) bicyclo [1.1.1]Pentan-1-amine dihydrochloride as an off-white solid (0.09g, crude material). LCMS (ES) M/z 246.3[ M + H]+。
And 7: to a solution of 2- (4-chlorophenoxy) acetic acid (0.079g, 0.42mmol, 1.5 equiv.) in DCM (8mL) was added triethylamine (0.19mL, 1.40mmol, 5.0 equiv.) at 0 deg.C, stirred for 10 min, then added
Figure BDA0002308602660001831
(50 wt% in EtOAc) (0.5mL, 0.85mmol, 3.0 equiv). The mixture was stirred at 0 ℃ for 10 minutes, then 3- (3- (pyridin-4-yloxy) pyrrolidin-1-yl) bicyclo [1.1.1] was slowly added at 0 ℃]Penta-1-amine dihydrochloride (0.09g, 0.28mmol, 1.0 mm)Amount) (which was neutralized with triethylamine (3mL) in DCM) and the reaction was stirred at rt for 16h. After consumption of starting material (TLC, 5% MeOH in DCM), the reaction mixture was diluted with DCM (100mL) and saturated NaHCO3(2x5mL) and water (2x5 mL). The combined organic layers were washed with anhydrous Na2SO4Dried, filtered and evaporated under reduced pressure. The crude material was purified by column chromatography using an eluent of 5-7% MeOH in DCM to give the desired product. It was further purified by preparative HPLC [ (analytical conditions: column: Inertsil ODS 3V (250 mmx4.6mmx5mic); mobile phase (A): 0.1% aqueous ammonia solution; mobile phase (B): acetonitrile; flow rate: 1.0mL/min) ]]To obtain the desired product 2- (4-chlorophenoxy) -N- (3- (3- (pyridin-4-yloxy) pyrrolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) acetamide as an off-white solid (0.033g, 28.2% yield). LCMS (ES) M/z 414.38[ M + H]+。1H NMR(400MHz，DMSO-d6)δppm 1.76–1.79(m，1H)，1.96(s，6H)，2.23–2.30(m，1H)，2.48(s，1H)，2.61–2.72(m，2H)，2.86–2.90(m，1H)，4.40(s，2H)，4.96(bs，1H)，6.88(d，J＝4.8Hz，2H)，6.94(d，J＝8.0Hz，2H)，7.31(d，J＝8.4Hz，2H)，8.34(d，J＝5.6Hz，2H)，8.61(s，1H)。
Examples 6t and 6u were generally prepared according to the procedure described above for example 6 s.
Watch 18
Figure BDA0002308602660001841
Figure BDA0002308602660001851
Examples 6v and 6w
N- (3- (3- (4-chloro-3-fluorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) -2- (4-chlorophenoxy) Yl) acetamide
Figure BDA0002308602660001852
Step 1: 4-chloro-3-fluorophenol at 0 DEG C(1.0g, 6.82mmol, 1.0 equiv.) in DMF (20mL) was added K2CO3(0.94g, 6.82mmol, 1.0 equiv.) is stirred for 10 minutes, then methyl 2, 4-dibromobutyrate (0.96mL, 6.82mmol, 1.0 equiv.) is added and the reaction stirred at 60 ℃ for 3 h. After consumption of starting material (TLC, 10% ethyl acetate in hexanes), the reaction mixture was diluted with ice-cold water (50mL) and extracted with EtOAc (2X100 mL). The combined EtOAc extracts were extracted with anhydrous Na2SO4Dried, filtered and distilled under vacuum. The crude material was purified by flash column chromatography (2-5% EtOAc in hexanes) to give methyl 4-bromo-2- (4-chloro-3-fluorophenoxy) butanoate as a colorless liquid (1.18g, crude material). LCMS (ES) M/z 324.0[ M + H]+，
Step 2: in a closed tube at room temperature to (3-aminobicyclo [1.1.1]]Pent-1-yl) carbamic acid tert-butyl ester (0.6g, 3.03mmol, 1.0 eq) in Et3To a solution in N (1.7mL, 12.12mmol, 4.0 equivalents) was added methyl 4-bromo-2- (4-chloro-3-fluorophenoxy) butanoate (1.18g, 3.63mmol, 1.2 equivalents), and the mixture was heated at 100 ℃ for 1h using an oil bath. (Note: the reaction was carried out by dividing 0.6g into 3 batches). After consumption of starting material (TLC, 70% ethyl acetate in hexane), the reaction mixture was diluted with ethyl acetate (100mL) and washed with water (2X20 mL). The combined EtOAc extracts were extracted with anhydrous Na2SO4Dried, filtered and evaporated in vacuo. The crude material was purified by column chromatography using 60-70% EtOAc in hexanes to give the desired product (3- (3- (4-chloro-3-fluorophenoxy) -2-oxopyrrolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) carbamic acid tert-butyl ester as an off-white solid (0.48g, 40.0%). LCMS (ES) M/z 411.3[ M + H]+
And step 3: to (3- (3- (4-chloro-3-fluorophenoxy) -2-oxopyrrolidin-1-yl) bicyclo [1.1.1] at 0 deg.C]Pent-1-yl) carbamic acid tert-butyl ester (0.48g, 1.17mmol, 1.0 equiv) to a solution in DCM (10mL) was added 5mL of a 4MHCl in 1, 4-dioxane and the mixture was stirred at rt for 16h. After consumption of starting material (TLC, 70% ethyl acetate in hexane), the reaction mixture was concentrated and the crude material was triturated with n-pentane (2X10mL) and dried under high vacuum to give 1- (3-aminobicyclo [ 1.1.1)]Pent-1-yl) -3- (4-chloro-3-fluorobenzeneOxy) pyrrolidin-2-one hydrochloride (0.37g, 91.3% yield), which was carried to the next step without further purification. LCMS (ES) M/z 311.1[ M + H]+。1H NMR(400MHz，DMSO-d6)δppm 1.91(bs，1H)，2.31(s，6H)，2.50–2.60(m，3H)，5.05(t，J＝7.6Hz，1H)，6.88(d，J＝8.8Hz，1H)，7.14(d，J＝10.8Hz，1H)，7.41–7.50(m，1H)，8.81–8.98(m，3H)。
And 4, step 4: to 1- (3-aminobicyclo [1.1.1] at 0 DEG C]Pent-1-yl) -3- (4-chloro-3-fluorophenoxy) pyrrolidin-2-one hydrochloride (0.37g, 1.06mmol, 1.0 equiv.) to a solution in THF (10mL) was added BH3.Me2S (0.31mL, 3.30mmol, 3.1 equiv.) and the reaction stirred for 40 h. (Note: initial addition of 1.5 equivalents BH3.Me2S complex, stirred for 16h, the progress of the reaction monitored by LCMS, 0.8 eq BH added again3.Me2S, stirring for 8h, monitoring the progress of the reaction by LCMS and adding 0.8 eq BH again3.Me2S and the reaction stirred for 16 h). After consumption of starting material (TLC, 5% MeOH in DCM), the reaction mixture was cooled to 0 ℃, quenched with MeOH (5mL), stirred for 30 min, and concentrated under reduced pressure to give the crude product. The crude material was triturated with n-pentane (2x5mL) and dried under high vacuum to give 3- (3- (4-chloro-3-fluorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1]Pentan-1-amine, which is an off-white solid (0.4g, crude yield), was used for the next step without further purification. LCMS (ES) M/z 297.1[ M + H ]]+
And 5: to a solution of 2- (4-chlorophenoxy) acetic acid (0.30g, 1.62mmol, 1.2 equiv.) in DCM (10mL) was added triethylamine (0.75mL, 5.40mmol, 4.0 equiv.) at 0 deg.C, stirred for 10 min, then added
Figure BDA0002308602660001871
(50 wt.% in EtOAc) (1.62mL, 2.70mmol, 2 equiv). The mixture was stirred at 0 ℃ for 10 minutes, then 3- (3- (4-chloro-3-fluorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] was slowly added at 0 ℃]A solution of pentan-1-amine (0.4g, 1.35mmol, 1.0 equiv.) in DCM (5mL) and the reaction was stirred at room temperature for 16h. After consumption of starting material (TLC, 70% ethyl acetate in hexane), the reaction was carried outThe mixture was diluted with DCM (200mL) and saturated NaHCO3(2x20mL) and water (2x20 mL). The combined organic layers were washed with anhydrous Na2SO4Dried, filtered and evaporated under reduced pressure. The crude material was purified by column chromatography using 65-80% EtOAc in hexanes to give the desired product N- (3- (3- (4-chloro-3-fluorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) -2- (4-chlorophenoxy) acetamide as an off-white solid (0.16g, 25.4%).
The racemic compound product of step 5 was subjected to chiral preparative HPLC to separate the isomers using the following analytical conditions: [ column: CHIRALPAK IC (100 mmx4.6mmx3mic); flow rate: 1.0 mL/min; mobile phase: n-Hexane IPA with 0.1% DEA (65:35) ]. The fractions containing both isomers were evaporated separately under reduced pressure, triturated with n-pentane (10mL, HPLCgrade) and dried under high vacuum.
Example 6 v: isomer 1 (single unknown stereochemistry):
and (3) recovering: 0.021g (jelly). LCMS (ES) M/z 465.3[ M + H]+。1H NMR(400MHz，DMSO-d6) δ ppm 1.74-1.77 (m, 1H), 1.95(s, 6H), 2.22-2.30 (m, 1H), 2.59-2.69 (m, 3H), 2.84-2.88 (m, 1H), 4.40(s, 2H), 4.88(bs, 1H), 6.76(d, J ═ 9.2Hz, 1H), 6.94-7.00 (m, 3H), 7.31(d, J ═ 7.6Hz, 2H), 7.42(t, J ═ 8.8Hz, 1H), 8.61(s, 1H). Chiral HPLC purity: 100.0% at 225 nm; % ee: 100.0 percent
Example 6 w: isomer 2 (single unknown stereochemistry):
and (3) recovering: 0.025g (gum). LCMS (ES) M/z 465.3[ M + H]+。1H NMR(400MHz，DMSO-d6) δ ppm 1.76-1.77 (m, 1H), 1.95(s, 6H), 2.24-2.25 (m, 1H), 2.59-2.69 (m, 3H), 2.85-2.90 (m, 1H), 4.40(s, 2H), 4.89(bs, 1H), 6.76(d, J ═ 9.2Hz, 1H), 6.94-7.00 (m, 3H), 7.31(d, J ═ 7.6Hz, 2H), 7.42(t, J ═ 8.6Hz, 1H), 8.61(s, 1H). Chiral HPLC purity: 100.0% at 225 nm; % ee: 100.0 percent.
TABLE 17
Figure BDA0002308602660001881
Example 6x
N- (3- (3- (bicyclo [4.2.0 ]))]Octane-1, 3, 5-trien-3-yloxy) pyrrolidin-1-yl) bicyclo [1.1.1]Wu-Jia-Zi 1-yl) -2- (4-chlorophenoxy) acetamide
Figure BDA0002308602660001891
Step 1: to N- (3-aminobicyclo [1.1.1] at room temperature]To a solution of pentan-1-yl) -2- (4-chlorophenoxy) acetamide (3.0g, 11mmol, 1.0 equiv.) in dimethylacetamide (30mL) was added N, N-diisopropylethylamine (9.6mL, 55mmol, 5.0 equiv.) and 1, 4-dibromobutan-2-ol (2.61mL, 22mmol, 2.0 equiv.). The reaction mixture was kept at 80 ℃ for 1 h. The reaction mixture was then cooled to room temperature, quenched with crushed ice (150mL), and extracted with EtOAc (3X150 mL). The combined organic layers were washed with cold water (100mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (neutral alumina column) using 0.1% to 5% methanol in DCM as eluent to give 2- (4-chlorophenoxy) -N- (3- (3-hydroxypyrrolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) acetamide (1.5g, 13.2% yield, 3.0g scale reaction using 3 batches (9.0g)) as a viscous oil. LCMS (ES) M/z 337.1[ M + H ]]+。1H NMR(400MHz，DMSO-d6)δppm 1.49–1.52(m，1H)，1.88–1.96(m，7H)，2.27–2.31(m，1H)，2.38–2.48(m，1H)，2.54–2.59(m，1H)，2.64–2.68(m，1H)，4.15–4.16(m，1H)，4.39(s，2H)，4.63(d，J＝4.4Hz，1H)，6.94(d，J＝8.8Hz，2H)，7.31(d，J＝8.8Hz，2H)，8.58(s，1H)。
Step 2: to 2- (4-chlorophenoxy) -N- (3- (3-hydroxypyrrolidin-1-yl) bicyclo [1.1.1] at 0 deg.C]To a solution of pentan-1-yl) acetamide (0.20g, 0.59mmol, 1.0 equiv) in DCM (50mL) was added TEA (0.24mL, 1.7mmol, 3.0 equiv). After 10 min at the same temperature methanesulfonyl chloride (0.055mL, 0.71mmol, 1.2 equiv.) was added at 0 ℃ and the reaction mixture was kept at room temperature for 2 h. The reaction mixture was washed with DCM (1)50mL) and diluted with 10% aq3Aqueous (2X50mL) and then water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give methanesulfonic acid 1- (3- (2- (4-chlorophenoxy) acetamido) bicyclo [1.1.1]Pent-1-yl) pyrrolidin-3-yl ester (0.22g, crude material) as a yellow solid. It was used for the next step without further purification. LCMS (ES) M/z 415.0[ M + H]+。1H NMR(400MHz，DMSO-d6)δppm 1.87–1.93(m，1H)，1.96(s，6H)，2.15–2.23(m，1H)，2.39–2.48(m，1H)，2.70–2.78(m，3H)，3.15(s，3H)，4.40(s，2H)，5.11–5.14(m，1H)，6.95(d，J＝9.2Hz，2H)，7.32(d，J＝9.2Hz，2H)，8.62(s，1H)。
And step 3: bicyclo [4.2.0] at room temperature]To a solution of octa-1, 3, 5-trien-3-ol (0.07g, 0.57mmol, 1.2 equiv.) in acetonitrile (10mL) was added Cs2CO3(0.4g, 1.2mmol, 2.5 equiv.) and methanesulfonic acid 1- (3- (2- (4-chlorophenoxy) acetamido) bicyclo [1.1.1]Pent-1-yl) pyrrolidin-3-yl ester (0.2g, 0.48mmol, 1.0 equiv.). The reaction mixture was kept at 85 ℃ for 2h under microwave irradiation. The reaction mixture was then cooled to room temperature, diluted with EtOAc (150mL), washed with cold water (2X50mL), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude material was purified by flash column chromatography using 0.1% to 5% methanol in DCM as eluent and further repurified by preparative HPLC [ analytical conditions: column: inertsil ODS 3V (250 mm. times.4.6mmx5mic). Mobile phase (a): 0.1% ammonia in water, mobile phase (B): acetonitrile, T/% B: 0/10, 2/10, 8/80, 13/80, 14/80, 15/10, flow rate: 1.0mL/min (35: 65), compound RT: 16.15 minutes]To obtain N- (3- (3- (bicyclo [4.2.0 ])]Octane-1, 3, 5-trien-3-yloxy) pyrrolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) -2- (4-chlorophenoxy) acetamide (0.06g, 28.4% yield) as a white solid. LCMS (ES) 439[ M + H ] M/z]+。1H NMR(400MHz，DMSO-d6)δppm 1.73–1.76(m，1H)，1.94(s，6H)，2.14–2.22(m，1H)，2.55–2.68(m，3H)，2.82–2.86(m，1H)，3.02(d，J＝5.2Hz，4H)，4.39(s，2H)，4.78(s，1H)，6.64(d，J＝7.2Hz，2H)，6.93(t，J＝8.8Hz，3H)，7.31(d，J＝8.0Hz，2H)，8.60(s，1H)。
TABLE 18B
Examples 7a and 7b
(S) -2- (4-chlorophenoxy) -N- (3- (4- (4-chlorophenoxy) -2-oxopyrrolidin-1-yl) bicyclo [1.1.1] Pent-1-yl) acetamide and (S) -2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenoxy) -2-oxopyrrolidin-1-yl) bis Ring [1.1.1]Pent-1-yl) acetamides
Figure BDA0002308602660001912
Figure BDA0002308602660001921
Step 1: to a solution of chlorophenol (10.0g, 78.12mmol, 1.0 equiv.) in DMF (160mL) at 0 deg.C was added K2CO3(10.8g, 78.12mmol, 1.0 equiv.) then methyl 2, 4-dibromobutyrate (11.0mL, 78.12mmol, 1.0 equiv.) is added and the reaction stirred at 60 ℃ for 2 h. After completion of the reaction (TLC, 10% EtOAc in hexanes), the reaction mixture was brought to room temperature and diluted with ice-cold water (300mL) and the mixture was extracted with EtOAc (3X150 mL). The combined EtOAc extracts were extracted with anhydrous Na2SO4The crude material was purified by flash column chromatography, the product eluted with 5% EtOAc in hexane to give methyl 4-bromo-2- (4-chlorophenoxy) butanoate as a colourless liquid (12.9g, 53.75% yield).1HNMR(400MHz，CDCl3)δppm 2.42–2.48(m，2H)，3.59–3.60(m，2H)，3.76(s，3H)，4.82–4.84(m，1H)，6.85(d，J＝6.8Hz，2H)，7.24(d，J＝9.2Hz，2H)。
Step 2: to (3-aminobicyclo [ 1.1.1)]Pent-1-yl) carbamic acid tert-butyl ester (6.2g, 31.31mmol, 1.0 eq) in Et3To a solution of N (17.46mL, 125.25mmol, 4.0 equiv.) was added 4-bromo-2- (4-chloro)Phenoxy) butyric acid methyl ester (9.6g, 31.31mmol, 1.0 equiv). The mixture was heated at 100 ℃ for 2 h. After completion of the reaction (TLC, 50% EtOAc in hexanes), the reaction mixture was diluted with water (100mL) and extracted with DCM (2X300 mL). The combined extracts were extracted with anhydrous Na2SO4Dried, filtered and evaporated in vacuo. The crude material was purified by column chromatography using 45% EtOAc in hexanes as eluent to give the desired product (3- (3- (4-chlorophenoxy) -2-oxopyrrolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) carbamic acid tert-butyl ester as an off-white solid (6.0g, 48.78% yield).1H NMR(400MHz，DMSO-d6)δppm 1.44(s，9H)，2.11–2.15(m，1H)，2.39(s，6H)，2.49(bs，1H)，3.31–3.33(m，1H)，3.42–3.44(m，1H)，4.77(t，J＝6.6Hz，1H)，4.94(s，1H)，6.96(d，J＝7.6Hz，2H)，7.21(d，J＝7.6Hz，2H)。
And step 3: to (3- (3- (4-chlorophenoxy) -2-oxopyrrolidin-1-yl) bicyclo [1.1.1] at 0 deg.C]Pent-1-yl) carbamic acid tert-butyl ester (6.0g, 15.26mmol, 1.0 equiv.) to a solution in THF (20mL) was added BH3S(CH3)2(2.9mL, 30.53mmol, 2.0 equiv.). (Note: 6.0g was divided into 2 batches and the reaction was carried out). The reaction was stirred at rt for 24 h. After completion of the reaction (TLC, 50% EtOAc in hexanes), the reaction mixture was quenched with methanol at 0 ℃ and stirred for 2 h. The reaction mixture was then evaporated under reduced pressure to give the crude product, which was diluted with water (200mL) and extracted with DCM (3X100 mL). The combined organic layers were washed with brine solution (100mL) and dried over anhydrous Na2SO4Drying, filtering and concentrating to give a crude material which is purified by silica gel column chromatography using 55-60% EtOAc in hexanes as the eluent to give (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [ 1.1.1)]Pent-1-yl) carbamic acid tert-butyl ester as an off-white solid (3.0g, 52.0% yield). LCMS (ES) M/z 379.1[ M + H]+。1H NMR(400MHz，DMSO-d6)δppm 1.43(s，9H)，2.02(s，7H)，2.26–2.32(m，1H)，2.60(s，1H)，2.76–2.82(m，2H)，2.90(s，1H)，4.78(s，1H)，4.91(s，1H)，6.76(d，J＝6.8Hz，2H)，7.20(d，J＝7.2Hz，2H)。
And 4, step 4: at 0 deg.C to3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) carbamic acid tert-butyl ester (3.0g, 7.91mmol, 1.0 equiv) to a solution in DCM (20mL) was added 15mL of a 4M HCl solution in 1, 4-dioxane and the mixture was stirred at rt for 16h. After completion of the reaction (TLC, 50% EtOAc in hexanes), the reaction mixture was concentrated to give the crude product. It was triturated with anhydrous ether (2x30mL) and the solid dried under high vacuum to give 3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1]Pent-1-amine hydrochloride (2.2g, crude material), which was carried to the next step without further purification. LCMS (ES) M/z 279.0[ M + H ]]+。1H NMR(400MHz，DMSO-d6)δppm 2.08(s，1H)，2.24(s，6H)，3.40–3.50(m，5H)，5.10(s，1H)，6.97(d，J＝8.4Hz，2H)，7.34(d，J＝8.4Hz，2H)，9.07(s，3H)。
And 5: to a solution of 2- (4-chlorophenoxy) acetic acid (1.18g, 6.35mmol, 2.0 equiv.) in DCM (20mL) at 0 deg.C was added triethylamine (2.21mL, 15387mmol, 5.0 equiv.), followed by
Figure BDA0002308602660001931
(50 wt% in EtOAc, 3.78mL, 6.35mmol, 2.0 equiv.). The reaction mixture was stirred at 0 ℃ for 5 minutes, then 3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] was added at 0 DEG C]Pent-1-amine hydrochloride (1.0g, 3.17mmol, 1.0 equiv) which was neutralized with triethylamine (1.0 equiv) in DCM and the reaction was stirred at rt for 16h. After consumption of starting material (TLC, 50% EtOAc in hexanes), the reaction mixture was diluted with water (100mL) and extracted with DCM (2 × 100 mL). The combined organic layers were washed with saturated NaHCO3Aqueous (100mL) wash. The combined organic layers were washed with anhydrous Na2SO4Dried, filtered and evaporated under reduced pressure to give the crude material. The crude product was purified by silica gel column chromatography using 65% EtOAc in hexanes as eluent to give the desired product 2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) acetamide (1.1g, 71.0% yield) as an off-white solid. LCMS (ES) M/z 447.4[ M + H]+。1H NMR(400MHz，DMSO-d6)δppm 1.74–1.77(m，1H)，1.95(s，6H)，2.18–2.30(m，1H)，2.48–2.70(m，3H)，2.84–2.86(m，1H)，4.40(s，2H)，4.83–4.84(m，1H)，6.88(d，J＝8.8Hz，2H)，6.94(d，J＝9.2Hz，2H)，7.28(d，J＝8.8Hz，2H)，7.31(d，J＝9.2Hz，2H)，8.60(s，1H)。
The racemic product of step 5 was used continuously for isomer separation by chiral preparative HPLC. [ analysis conditions: column: CHIRALPAK IC (100 mmx4.6mmx3mic); mobile phase: n-Hexane IPA with 0.1% DEA (85: 15); flow rate: 1.0mL/min) ]. The fractions containing the separated isomers were concentrated under reduced pressure. The resulting solid was triturated with HPLC grade n-hexane (200mL) and dried under high vacuum.
Based on VCD analysis, isomer 1 was designated (S) -2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pentan-1-yl) acetamide, and isomer 2 was designated (R) -2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pentan-1-yl) acetamide.
(S) -2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pentan-1-yl) acetamide.
And (3) recovering: 0.34g (off-white solid). LCMS (ES) M/z 447.0[ M + H]+。1H NMR(400MHz，DMSO-d6) δ ppm 1.74-1.77 (m, 1H), 1.95(s, 6H), 2.18-2.30 (m, 1H), 2.48-2.70 (m, 3H), 2.84-2.86 (m, 1H), 4.40(s, 2H), 4.83-4.84 (m, 1H), 6.88(d, J ═ 8.8Hz, 2H),6.94(d, J ═ 9.2Hz, 2H), 7.28(d, J ═ 8.8Hz, 2H), 7.31(d, J ═ 9.2Hz, 2H), 8.60(s, 1H). Chiral HPLC purity: 100% at room temperature 12.719 min. % ee: 100 percent
(R) -2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pentan-1-yl) acetamide.
And (3) recovering: 0.37g (off-white solid). LCMS (ES) M/z 447.0[ M + H]+。1H NMR(400MHz，DMSO-d6)δppm 1.73–1.77(m，1H)，1.95(s，6H)，2.12–2.26(m，1H)，2.65–2.70(m，3H)，2.84–2.88(m，1H)，4.40(s，2H)，4.84(bs，1H)，6.88(d，J＝8.8Hz，2H)，6.94(d，J＝8.8Hz，2H)，7.28(d，J＝8.8Hz，2H)，7.31(d，J＝8.8Hz，2H) 8.60(s, 1H). Chiral hplc. purity: 100% at room temperature for 15.67 min; % ee: 100 percent.
Step 6: to (S) -2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] at 0 deg.C]Pentan-1-yl) acetamide (0.07g, 0.15mmol, 1.0 equiv) to a solution in ethyl acetate (5.0mL) was added ruthenium (IV) oxide monohydrate (0.012g, 0.078mmol, 0.5 equiv), then 10% aqueous sodium periodate solution (0.16g, 0.78mmol, 5.0 equiv) and the reaction was stirred at room temperature for 2 h. After consumption of starting material (TLC, 50% ethyl acetate in hexanes), the reaction mixture was diluted with EtOAc (100mL) and washed with water (2 × 10 mL). The combined EtOAc extracts were extracted with anhydrous Na2SO4Dried, filtered and distilled under reduced pressure. The crude material was purified by preparative TLC using 40% EtOAc in hexane (twice elution) as eluent. The two products were separated to give (S) -2- (4-chlorophenoxy) -N- (3- (4- (4-chlorophenoxy) -2-oxopyrrolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) acetamide (Compound 7a, (0.032g, 44.4% yield) and (S) -2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenoxy) -2-oxopyrrolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) acetamide (compound 7b, 0.035g, 48.6% yield) as an off-white solid.
(S) -2- (4-chlorophenoxy) -N- (3- (4- (4-chlorophenoxy) -2-oxopyrrolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) acetamide 7 a: LCMS (ES) M/z 461.0[ M + H]+。1H NMR(400MHz，DMSO-d6) δ ppm 2.29(s, 6H), 2.81-2.87 (m, 2H), 3.33(d, J ═ 11.2Hz, 1H), 3.75-3.80 (m, 1H), 4.41(s, 2H), 4.99(bs, 1H), 6.94(t, J ═ 7.8Hz, 4H), 7.31(d, J ═ 8.4Hz, 4H), 8.70(s, 1H). Chiral HPLC purity: 99.77% at 280 nm. % ee: 99.54 percent.
(S) -2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenoxy) -2-oxopyrrolidin-1-yl) bicyclo [1.1.1]Pent-1-yl) acetamide 7 b: LCMS (ES) M/z 461.0[ M + H]+。1H NMR(400MHz，DMSO-d6) δ ppm 1.85-1.90 (m, 2H), 2.31(s, 6H), 3.34-3.36 (m, 2H), 4.42(s, 2H), 4.95-4.96 (m, 1H), 6.95(d, J ═ 8.8Hz, 2H), 7.01(d, J ═ 8.8Hz, 2H), 7.31(t, J ═ 9.2Hz, 4H), 8.72(s, 1H). Chiral HPLC purityDegree: 100.0% at 280 nm. % ee: 100.0 percent
Ruthenium (IV) oxide oxidation was performed as described above using (R) -2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pentan-1-yl) acetamide, and products 7c and 7d were isolated by preparative TLC purification.
The compounds of examples 7c to 7d were generally prepared according to the procedure of examples 7a and 7b described above.
Watch 19
Figure BDA0002308602660001961
Figure BDA0002308602660001971
Example 8a
2- (4-chlorophenoxy) -N- (3- (4- (4-chlorophenoxy) piperidin-1-yl) bicyclo [1.1.1]Pent-1-yl) acetyl Amines as pesticides
Figure BDA0002308602660001972
Figure BDA0002308602660001981
Step 1: to a solution of 2- (4-chlorophenoxy) acetic acid (33.87g, 181.57mmol, 1.2 equiv.) in DCM (300mL) at 0 deg.C were added triethylamine (63.35mL, 453.93mmol, 3 equiv.) and(50 wt.% in ethyl acetate) (135.1mL, 226.96mmol, 1.5 equiv.) and stirred at 0 ℃ for 10 min. Then (3-amino-bicyclo [ 1.1.1)]Pent-1-yl) carbamic acid tert-butyl ester (30.0g, 151.31mmol, 1 eq) was added to the reaction mixture and the reaction mixture was stirred at room temperature for 16h. Upon completion (monitored by TLC), the reaction mixture was diluted with water (200mL) and extracted with DCM (2 × 300 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (200mL), and the organic phase was washed with brineThe layer was filtered and concentrated under reduced pressure to give the crude product. According to the same procedure, a further 30g of (3-aminobicyclo [ 1.1.1)]Batch reaction of t-butyl pent-1-yl) carbamate to give a final combined yield of 108g of (3- (2- (4-chlorophenoxy) acetamido) bicyclo [1.1.1]Pent-1-yl) carbamic acid tert-butyl ester (97.24% yield) as an off-white solid. LCMS (ES) M/z 311.1[ M + H]+(tert-butyl cleavage mass was observed).1H NMR(400MHz，DMSO-d6)δppm 1.35(s，9H)，2.11(s，6H)，4.39(s，2H)，6.94(d，J＝8.8Hz，2H)，7.31(d，J＝8.8Hz，2H)，7.46(bs，1H)，8.60(s，1H)。
Step 2: to (3- (2- (4-chlorophenoxy) acetamido) bicyclo [1.1.1] at 0 DEG C]To a solution of t-butyl pent-1-yl) carbamate (27g, 73.57mmol, 1 eq) in DCM (400mL) was added a solution of 4M HCl in 1, 4-dioxane (90 mL). The reaction mixture was warmed and stirred at rt for 12 h. After consumption of starting material (TLC, 5% methanol in DCM), DCM was evaporated under reduced pressure. The resulting solid was triturated with ether (300mL) and dried under high vacuum to give N- (3-aminobicyclo [ 1.1.1)]Pent-1-yl) -2- (4-chlorophenoxy) acetamide hydrochloride. Following the same procedure, 3 more batches were carried out to give a total of 84g (94.52% yield) of N- (3-aminobicyclo [ 1.1.1)]Pent-1-yl) -2- (4-chlorophenoxy) acetamide hydrochloride as an off-white solid.1H NMR(400MHz，DMSO-d6)δppm 2.22(s，6H)，4.44(s，2H)，6.95(d，J＝8.8Hz，2H)，7.32(d，J＝9.2Hz，2H)，8.87(s，1H)，9.0(bs，3H)。
And step 3: reacting N- (3-aminobicyclo [1.1.1 [)]Pent-1-yl) -2- (4-chlorophenoxy) acetamide hydrochloride (10.0g, 33.16mmol, 1 eq) was added to aqueous sodium bicarbonate (5.57g, 66.30mmol, 2 eq in 100mL water) and stirred at room temperature for 1 h. The reaction mixture was extracted with DCM (2 × 250 mL). The combined organic extracts were washed with water (100mL) and brine solution (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude N- (3-aminobicyclo [1.1.1]Pent-1-yl) -2- (4-chlorophenoxy) acetamide (18g, crude, 10.0g scale reaction was carried out in 2 batches (20.0 g)). 8g of crude material was further purified by reverse phase purification: [ column: c18, mobile phase (a): 0.1% ammoniaAqueous solution, mobile phase (B): acetonitrile]To give N- (3-aminobicyclo [ 1.1.1)]Pent-1-yl) -2- (4-chlorophenoxy) acetamide (6.6g, 50.7% yield) as a white solid. LCMS (ES) M/z 250.2[ M + H]+(loss of–NH2)。1H NMR(400MHz，DMSO-d6)δppm 1.91(s，6H)，2.10(s，2H)，4.38(s，2H)，6.94(d，J＝8.8Hz，2H)，7.31(d，J＝8.8Hz，2H)，8.47(s，1H)。
And 4, step 4: to a solution of diethyl 3-oxoglutarate (5.0g, 24mmol, 1.0 equiv.) in ethanol (50mL) at 0 deg.C was added sodium borohydride (0.93g, 24mmol, 1.0 equiv.) in portions over 15 minutes and the reaction mixture was held at room temperature for 10 minutes. The reaction mixture is reacted with NH at 0 DEG C4Saturated aqueous Cl (30mL) was quenched, extracted with DCM (2X250mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give diethyl 3-hydroxyglutarate (3.5g, crude material) as a viscous liquid. LCMS (ES) M/z 205.0[ M + H ]]+。1H NMR(400MHz，DMSO-d6)δppm 1.16(t，J＝7.0Hz，6H)，2.31–2.38(m，2H)，2.43–2.48(m，2H)，4.03(q，J＝7.2Hz，4H)，4.20–4.25(m，1H)，5.01(d，J＝6.4Hz，1H)。
And 5: in N2To a solution of diethyl 3-hydroxyglutarate (3.0g, 14mmol, 1.0 eq.) in anhydrous THF (100mL) at 0 deg.C was added slowly and dropwise over 30 minutes a solution of 1M lithium aluminum hydride in THF (58.7mL, 58mmol, 4.0 eq.) under an atmosphere. The reaction mixture was stirred at rt for 16h. The reaction was quenched with 1N aqueous NaOH (20mL) at 0 deg.C, diluted with DCM (150mL), and passed throughAnd (4) bed filtration.
Figure BDA0002308602660002002
The bed was washed with a solution of 10% methanol in DCM (2X100 mL). The filtrate was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give pentane-1, 3, 5-triol (1.4g, 86.5% yield) as a viscous liquid.1H NMR(400MHz，DMSO-d6)δppm 1.40–1.49(m，4H)，3.35(s，1H)，3.40–3.48(m，4H)。
Step 6: to a solution of pentane-1, 3, 5-triol (1.4g, 11mmol, 1.0 equiv.) in pyridine (6mL) at 0 deg.C was added methanesulfonyl chloride (1.89mL, 24mmol, 2.1 equiv.) over 30 minutes. The reaction mixture was stirred at rt for 2 h. The reaction was quenched with 2N aqueous HCl (50mL) at 0 ℃ and extracted with DCM (2X100 mL). The organic layer was washed with 2N aqueous HCl solution (2X50mL), water (50mL), 10% NaHCO3The aqueous solution (50mL) was washed, dried over anhydrous sodium sulfate, filtered and concentrated to give 3-hydroxypentane-1, 5-diyl dimesylate (1.2g, crude material) as a viscous liquid. LCMS (ES) M/z 277.0[ M + H ]]+。
And 7: to N- (3-aminobicyclo [1.1.1] at room temperature]To a solution of pentan-1-yl) -2- (4-chlorophenoxy) acetamide (0.5g, 1.8mmol, 1.0 equiv.) in dimethylacetamide (10mL) was added N, N-diisopropylethylamine (1.57mL, 9mmol, 5.0 equiv.) and 3-hydroxypentane-1, 5-diyl dimesylate (1.0g, 3.6mmol, 2.0 equiv.). The reaction mixture was kept at 80 ℃ for 1.5h under microwave irradiation. It was then cooled to room temperature and quenched with crushed ice (100mL) and extracted with DCM (2X100 mL). The combined organic extracts were washed with cold water (25mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (neutral alumina column) using 0.1% to 10% methanol in DCM as eluent to give 2- (4-chlorophenoxy) -N- (3- (4-hydroxypiperidin-1-yl) bicyclo [1.1.1]Pent-1-yl) acetamide (0.3g, 47.6% yield) as gum. LCMS (ES) M/z 351.0[ M + H ]]+。
And 8: to 2- (4-chlorophenoxy) -N- (3- (4-hydroxypiperidin-1-yl) bicyclo [1.1.1] at 0 deg.C]To a solution of pentan-1-yl) acetamide (0.20g, 0.57mmol, 1.0 equiv) in DCM (30mL) was added TEA (0.24mL, 1.7mmol, 3.0 equiv) and stirred at the same temperature for 30 min. Methanesulfonyl chloride (0.052mL, 0.68mmol, 1.2 equiv.) is then added at 0 ℃ and the reaction mixture is stirred at room temperature for 3 h. The reaction mixture was diluted with DCM (100mL) and 10% NaHCO3Aqueous solution (2X25mL) and water (2X25 mL). The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give methanesulfonic acid 1- (3- (2- (4-chlorophenoxy) acetamido) bicyclo [1.1.1]Pent-1-yl) piperidin-4-yl esters(0.22g, crude material) as a gum. LCMS (ES) M/z 429.1[ M + H ]]+. It was carried to the next step without further purification.
And step 9: to a solution of 4-chlorophenol (0.05g, 0.39mmol, 1.0 equiv.) in DMF (10mL) at room temperature was added K2CO3(0.16g, 1.1mmol, 3.0 equiv.) and methanesulfonic acid 1- (3- (2- (4-chlorophenoxy) acetamido) bicyclo [1.1.1]Pent-1-yl) piperidin-4-yl ester (0.2g, 0.46mmol, 1.2 equiv.). The reaction mixture was stirred at 80 ℃ for 16h, then the reaction mixture was cooled to room temperature and quenched with crushed ice (50 mL). The aqueous material was extracted with DCM (2X100mL) and the combined organic layers were washed with cold water (25mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. It was purified by flash chromatography using 0.1% to 10% methanol in DCM as eluent and further repurified by preparative HPLC [ analytical conditions: column: mobile phase (a): 0.1% ammonia in water, mobile phase (B): acetonitrile, T/% B: 0/10, 2/10, 8/80, 13/80, 14/80, 15/10, compound RT: 9.60 minutes]To obtain 2- (4-chlorophenoxy) -N- (3- (4- (4-chlorophenoxy) piperidin-1-yl) bicyclo [1.1.1]Pent-1-yl) acetamide (8.0mg, 4.4% yield) as a white solid. LCMS (ES) M/z 461[ M + H]+。1H NMR(400MHz，DMSO-d6)δppm 1.55–1.60(m，2H)，1.88–1.91(m，2H)，1.94(s，6H)，2.22(t，J＝9.4Hz，2H)，2.64(bs，2H)，4.32(bs，1H)，4.40(s，2H)，6.94(d，J＝8.8Hz，4H)，7.27(d，J＝8.8Hz，2H)，7.31(d，J＝8.8Hz，2H)，8.60(s，1H)。
Watch 20
Figure BDA0002308602660002011
Figure BDA0002308602660002021
Test example 1: ATF4 cell-based assays
ATF4 report assay measures Thapsigargin (Thapsigargin) -induced cellular stress on ATF4 expressionThe influence of (c). For the reporter assay, the fusion of 5' -UTR with ATF4 was performed under the control of the CMV promoter
Figure BDA0002308602660002022
Plasmids of the luciferase gene were transfected into SH-SY5Y cells, resulting in stable cell lines. ATF 45' -UTR contains two open reading frames that mediate cell stress-dependent translation of a reporter gene. Clones of stably expressing reporter constructs were isolated and selected based on the luminescent response to thapsigargin and the inhibition of this signal by test compounds. Briefly, SH-SY5Y-ATF4-NanoLuc cells were challenged with thapsigargin for 14-18 hours to determine the effect of stress with or without test compounds.
Cells were propagated in growth medium consisting of 90% DMEM F12(InVitrogen # 11320-. Cells for the assay were prepared by: all media was removed from the cells, the plated cells were washed with phosphate buffered saline and isolated by addition of a solution containing 10% Tryple expression solution (InVitrogen12604-021) and 90% of the enzyme-free cell dissociation buffer HANKS base (Gibco 13150-. Trypsin was inactivated by addition of assay medium comprising 90% phenol-free DMEM F12(InVitrogen, 11039), 10% fetal bovine serum (Gibco # 10438-. The suspended cells were centrifuged rapidly at 300g for 5 minutes, the supernatant was removed and the cell pellet was suspended in warm (30-37 ℃) medium containing the above material but without 10% fetal calf serum to a concentration of 1e6 cells/ml.
Assay plates were prepared by adding 250 μ L of compound stock solution in 100% DMSO to each well, then dispensing 20 μ L/well of cell suspension to deliver 15-20k cells/well. Cells were incubated at 37 ℃ for 1 hour. Then, 5. mu.L of 1.5. mu.M or 1. mu.M thapsigargin (final concentration: 200-300nM) was added to each well of the cells. The assay plates containing the cells were incubated at 37 ℃ for 14-18 hours.
Luciferase produced from the ATF4 construct was measured as follows. Aliquots of Nano-Glo reagent(s) ((ii))
Figure BDA0002308602660002032
Luciferase assay substrate, Promega, N113,
Figure BDA0002308602660002034
luciferase assay buffer, Promega, N112: (
Figure BDA0002308602660002033
Part of the luciferase assay system, N1150)) was adjusted to room temperature and the substrate and buffer were mixed according to the manufacturer's instructions. The cell plate was equilibrated to room temperature. 25 μ l/well of mixed Nano-Glo reagent was dispensed into assay wells and pulsed to pellet the contents and sealed with a thin film plate. Plates were incubated for 1 hour at room temperature and then at
Figure BDA0002308602660002035
And detecting luminescence on the plate reader.
Formulation example 1 Capsule composition
The oral dosage forms for administration of the present invention were prepared by filling standard two-piece hard gelatin capsules wherein the proportions of the ingredients are as shown in formulation table 21 below.
Preparation table 21
Figure BDA0002308602660002031
Formulation example 2 injectable parenteral composition
The injectable form for administering the invention is prepared by stirring 1.7% by weight of N- (3- (2- (4-chlorophenoxy) acetamido) bicyclo [1.1.1] pent-1-yl) -2- (4-chlorophenyl) cyclopropane-1-carboxamide (compound of example 2 b) in 10% by volume of aqueous propylene glycol solution.
Formulation example 3 tablet composition
Sucrose, calcium sulfate dihydrate and TF4 pathway inhibitor shown in the following formulation table 22 were mixed with a 10% gelatin solution in the proportions shown and granulated. The wet granulation is sieved, dried, mixed with starch, talc and stearic acid, sieved and compressed into tablets.
Preparation table 22
Figure BDA0002308602660002041
Biological activity
The compounds of the invention were tested for their activity against the translation of ATF4 in the above assay.
The compounds of examples I to IV were tested generally according to the ATF4 cell-based assay described above, and experiments performed in groups of two or more experiments showed that the average TF4 pathway inhibitory activity (IC)50)<125nM。
The compounds of examples I to XXIII are generally tested according to the ATF4 cell-based assay described above, and experiments performed in groups of two or more experiments show that the average TF4 pathway inhibitory activity (IC)50)<325nM。
The compound of example III was tested generally according to the ATF4 cell-based assay described above, and experiments performed in groups of two or more experiments showed that the average ATF4 pathway inhibitory activity (IC)50) It was 8.89 nM.
The compounds of example VI were tested generally according to the ATF4 cell-based assay described above, and experiments performed in groups of two or more experiments showed that the average ATF4 pathway inhibitory activity (IC)50) It was 4.1 nM.
The compound of example IX was tested generally according to the ATF4 cell-based assay described above, and experiments performed in groups of two or more experiments showed that the average ATF4 pathway inhibitory activity (IC)50) It was 300.05 nM.
The compound of example XII was tested generally according to the ATF4 cell-based assay described above, and experiments performed in groups of two or more experiments showed that the average ATF4 pathway inhibitory activity (IC)50) It was 25.2 nM.
The compound of example XVI is generally according toThe experiments described above based on the assay test of ATF4 cells, and performed as a set of two or more experiments, showed that the average ATF4 pathway inhibitory activity (IC)50) Was 13 nM.
The compound of example XXI is tested generally according to the ATF4 cell-based assay described above, and experiments performed in groups of two or more experiments show that the average ATF4 pathway inhibitory activity (IC)50) Was 33 nM.
The compound of example XXII is tested generally according to the ATF4 cell-based assay described above, and experiments performed in groups of two or more experiments show that the average ATF4 pathway inhibitory activity (IC)50) Was 1.3 nM.
The compounds of examples XXIV and 6a are generally tested according to the ATF4 cell-based assay described above, and experiments performed in groups of two or more experiments show that the average ATF4 pathway inhibitory activity (IC)50) It was 7.3 nM.
The compounds of examples 1a to 1v were generally tested according to the ATF4 cell-based assay described above, and experiments performed in at least one set of two or more experiments showed that the average ATF4 pathway inhibitory activity (IC)50) From 0.6 to 384 nM.
The compound of example 1a was tested generally according to the ATF4 cell-based assay described above, and experiments performed in at least one set of two or more experiments showed that the average ATF4 pathway inhibitory activity (IC)50) It was 2.1 nM.
The compound of example 1g was tested generally according to the ATF4 cell-based assay described above, and experiments performed in at least one set of two or more experiments showed that the average ATF4 pathway inhibitory activity (IC)50) Was 17 nM.
The compound of example 1k was tested generally according to the ATF4 cell-based assay described above, and experiments performed in at least one set of two or more experiments showed that the average ATF4 pathway inhibitory activity (IC)50) Was 34 nM.
The compound of example 1l was tested generally according to the ATF4 cell-based assay described above, and experiments performed in at least one set of two or more experiments showed that the average ATF4 pathway inhibitory activity (IC)50) It was 1.6 nM.
The compound of example 1m was tested generally according to the ATF4 cell-based assay described above, and experiments performed in at least one set of two or more experiments showed that the average ATF4 pathway inhibitory activity (IC)50) It was 0.6 nM.
The compound of example 1o was tested generally according to the ATF4 cell-based assay described above, and experiments performed in at least one set of two or more experiments showed that the average ATF4 pathway inhibitory activity (IC)50) Was 10.3 nM.
The compound of example 1r was tested generally according to the ATF4 cell-based assay described above, and experiments performed in at least one set of two or more experiments showed that the average ATF4 pathway inhibitory activity (IC)50) It was 1.8 nM.
The compound of example 1t was tested generally according to the ATF4 cell-based assay described above, and experiments performed in at least one set of two or more experiments showed that the average ATF4 pathway inhibitory activity (IC)50) It was 51.7 nM.
The compound of example 1v was tested generally according to the ATF4 cell-based assay described above, and experiments performed in at least one set of two or more experiments showed that the average ATF4 pathway inhibitory activity (IC)50) It was 23.2 nM.
The compounds of examples 2a to 2c were tested generally according to the ATF4 cell-based assay described above, and experiments performed in at least one set of two or more experiments showed that the average ATF4 pathway inhibitory activity (IC)50) From 12.3 to 27.4 nM.
The compounds of examples 3a and 3b were generally tested according to the ATF4 cell-based assay described above, and experiments performed in at least one set of two or more experiments showed that the average ATF4 pathway inhibitory activity (IC)50) 3.6 to 13.6 nM.
The compounds of examples 4a to 4e were generally tested according to the ATF4 cell-based assay described above, and experiments performed in at least one set of two or more experiments showed that the average ATF4 pathway inhibitory activity (IC)50) From 4.7 to 326 nM.
The compound of example 4d was tested generally according to the ATF4 cell-based assay described above, and in two runsExperiments performed in at least one group for one or more experiments showed that the average ATF4 pathway inhibitory activity (IC)50) Was 12.2 nM.
The compounds of examples 5a to 5c were generally tested according to the ATF4 cell-based assay described above, and experiments performed in at least one set of two or more experiments showed that the average ATF4 pathway inhibitory activity (IC)50) 36 to 2097 nM.
The compounds of examples 6a to 6x were generally tested according to the ATF4 cell-based assay described above, and experiments performed in at least one set of two or more experiments showed that the average ATF4 pathway inhibitory activity (IC)50) From 1.11 to 210 nM.
The compound of example 6c was tested generally according to the ATF4 cell-based assay described above, and experiments performed in at least one set of two or more experiments showed that the average ATF4 pathway inhibitory activity (IC)50) It was 6.7 nM.
The compound of example 6e was tested generally according to the ATF4 cell-based assay described above, and experiments performed in at least one set of two or more experiments showed that the average ATF4 pathway inhibitory activity (IC)50) Was 20 nM.
The compound of example 6i was tested generally according to the ATF4 cell-based assay described above, and experiments performed in at least one set of two or more experiments showed that the average ATF4 pathway inhibitory activity (IC)50) It was 6.9 nM.
The compound of example 6k was tested generally according to the ATF4 cell-based assay described above, and experiments performed in at least one set of two or more experiments showed that the average ATF4 pathway inhibitory activity (IC)50) It was 24.57 nM.
The compound of example 6o was tested generally according to the ATF4 cell-based assay described above, and experiments performed in at least one set of two or more experiments showed that the average ATF4 pathway inhibitory activity (IC)50) Was 5.7 nM.
The compound of example 6q was tested generally according to the ATF4 cell-based assay described above, and experiments performed in at least one set of two or more experiments showed that the average ATF4 pathway inhibitory activity (IC)50) It was 1.1 nM.
The compound of example 6v was tested generally according to the ATF4 cell-based assay described above, and experiments performed in at least one set of two or more experiments showed that the average ATF4 pathway inhibitory activity (IC)50) It was 9.9 nM.
The compounds of examples 7a to 7c were generally tested according to the ATF4 cell-based assay described above, and experiments performed in at least one set of two or more experiments showed that the average ATF4 pathway inhibitory activity (IC)50) 1.2 to 65.8 nM.
The compound of example 8a was tested generally according to the ATF4 cell-based assay described above, and experiments performed in at least one set of two or more experiments showed that the average ATF4 pathway inhibitory activity (IC)50) Was 5.1 nM.
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While the preferred embodiments of the invention have been illustrated by the foregoing, it is to be understood that the invention is not limited to the precise arrangements disclosed herein and that the right is reserved for all modifications which fall within the scope of the appended claims.

Claims (39)

1. A compound represented by the following formula (IIIQ):
Figure FDA0002308602650000011
wherein:
L82’selected from: a bond, -NH-, -O-, -S-, -S (O) -, -S (O)2-, cycloalkyl, -O-cycloalkyl, cycloalkyl-O-, -NH-cycloalkyl, cycloalkyl-NH-, azetidinyl, -O-azetidinyl, azetidinyl-O-, -N-azetidinyl, azetidinyl-N-, substituted or unsubstituted C1-6Alkylene and substituted or unsubstituted C1-6Heteroalkylene, or L82’And R83’Together form: heterocycloalkyl, heterocycloalkyl-O-, heterocycloalkyl-NH-, heterocycloalkyl-CH2-, oxoheterocycloalkyl-O-, oxoheterocycloalkyl-N-, or oxoheterocycloalkyl-CH2-,
Or the like, or, alternatively,
L82’and is adjacent to L82’To C8’R of the point of attachment of (A)85’The substituents together forming a fused ring to C8’The cycloalkyl, heterocycloalkyl, and/or heteroaryl ring of (a);
L83’selected from: cycloalkyl, -O-cycloalkyl, cycloalkyl-O-, -NH-cycloalkyl, cycloalkyl-NH-, azetidinyl, -O-azetidinyl, azetidinyl-O-, -N-azetidinyl, azetidinyl-N-, or L83’And R81’Together form: heterocycloalkyl, heterocycloalkyl-O-, heterocycloalkyl-NH-, heterocycloalkyl-CH2-, oxoheterocycloalkyl-O-, oxoheterocycloalkyl-N-, or oxoheterocycloalkyl-CH2-,
Or the like, or, alternatively,
L83’and is adjacent to L83’To D8’R of the point of attachment of (A)86’The substituents together form a ring fused to D8’The cycloalkyl, heterocycloalkyl, and/or heteroaryl ring of (a);
R81’selected from: hydrogen, C1-6Alkyl, substituted C1-6Alkyl and heterocycloalkyl, or R81’And L83’Together form: heterocycloalkyl, heterocycloalkyl-O-, heterocycloalkyl-NH-, heterocycloalkyl-CH2-, oxoheterocycloalkyl-O-, oxoheterocycloalkyl-N-, or oxoheterocycloalkyl-CH2-；
R83’Selected from: hydrogen, C1-6Alkyl, substituted C1-6Alkyl and heterocycloalkyl, or R83’And L82’Together form: heterocycloalkyl, heterocycloalkyl-O-, heterocycloalkyl-NH-, heterocycloalkyl-CH2-, oxoheterocycloalkyl-O-, oxoheterocycloalkyl-N-, or oxoheterocycloalkyl-CH2-；
R85’Selected from: fluorine, chlorine, bromine, iodine, -OCH3、-OCH2Ph、-C(O)Ph、-CF3、-CN、-S(O)CH3、-OH、-NH2、-COOH、-CONH2、-NO2、-C(O)CH3、-C≡CH、-CH2C≡CH、-SCH3、-SO3H、-SO2NH2、-NHC(O)NH2、-NHC(O)H、-NHOH、-OCF3、-OCHF2Substituted or unsubstituted C1-6An alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group,
or the like, or, alternatively,
two adjacent R85’The substituents may combine to form a fused to C8’A cycloalkyl ring, a heterocycloalkyl ring and/or a heteroaryl ring of (a),
or the like, or, alternatively,
adjacent to L82’To C8’R of the point of attachment of (A)85’The substituents may be substituted with L82’Combined to form a fusion to C8’The cycloalkyl, heterocycloalkyl, and/or heteroaryl ring of (a);
R86’selected from: fluorine, chlorine, bromine, iodine, -OCH3、-OCH2Ph、-C(O)Ph、-CF3、-CN、-S(O)CH3、-OH、-NH2、-COOH、-CONH2、-NO2、-C(O)CH3、-C≡CH、-CH2C≡CH、-SCH3、-SO3H、-SO2NH2、-NHC(O)NH2、-NHC(O)H、-NHOH、-OCF3、-OCHF2Substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstitutedHeterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,
or the like, or, alternatively,
two adjacent R86’The substituents may combine to form a cycloalkyl ring, a heterocycloalkyl ring, or be fused to D8’The heteroaryl ring of (a) is a ring,
or the like, or, alternatively,
adjacent to L83’To D8’R of the point of attachment of (A)86’The substituents may be substituted with L83’Combined to form a fusion to D8’The cycloalkyl, heterocycloalkyl, and/or heteroaryl ring of (a);
R82’and R84’Independently is NR88’、O、CH2Or S;
R88’selected from: hydrogen, C1-6Alkyl and C substituted by 1 to 6 fluorine1-6An alkyl group;
a and b are independently 0 or 1;
C8’and D8’Independently is phenyl or pyridyl;
X6’is C1-3Alkylene or C substituted by 1 to 3 fluorine1-3An alkylene group;
Z82’and z84’Independently 0 or 1; and is
Z85’And z86’Independently an integer from 0 to 5;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, represented by formula (IVQ):
Figure FDA0002308602650000031
wherein:
L92’selected from: a bond, -NH-, -O-, -S-, -S (O) -, -S (O)2-, substituted or unsubstituted C1-6Alkylene and substituted or unsubstituted C1-6A heteroalkylene group;
L93’selected from: cycloalkyl, -O-cycloalkanesAnd cycloalkyl-O-, azetidinyl, -O-azetidinyl, azetidinyl-O-, or L93’And R91’Together form: heterocycloalkyl, heterocycloalkyl-O-, oxoheterocycloalkyl, or oxoheterocycloalkyl-O-,
or the like, or, alternatively,
L93’and is adjacent to L93’R of the point of attachment of (A)96’The substituents together form a cycloalkyl, heterocycloalkyl, or heteroaryl ring;
R91’selected from: hydrogen, C1-6Alkyl, substituted C1-6Alkyl, and heterocycloalkyl, or R91’And L93’Together form: heterocycloalkyl, heterocycloalkyl-O-, oxoheterocycloalkyl, or oxoheterocycloalkyl-O-;
R93’selected from: hydrogen, C1-6Alkyl, substituted C1-6Alkyl, and heterocycloalkyl;
R95’selected from: fluorine, chlorine, bromine, iodine, -OCH3、-OCH2Ph、-C(O)Ph、-CF3、-CN、-S(O)CH3、-OH、-NH2、-COOH、-CONH2、-NO2、-C(O)CH3、-C≡CH、-CH2C≡CH、-SCH3、-SO3H、-SO2NH2、-NHC(O)NH2、-NHC(O)H、-NHOH、-OCF3、-OCHF2Substituted or unsubstituted C1-6An alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group;
R96’selected from: fluorine, chlorine, bromine, iodine, -OCH3、-OCH2Ph、-C(O)Ph、-CF3、-CN、-S(O)CH3、-OH、-NH2、-COOH、-CONH2、-NO2、-C(O)CH3、-C≡CH、-CH2C≡CH、-SCH3、-SO3H、-SO2NH2、-NHC(O)NH2、-NHC(O)H、-NHOH、-OCF3、-OCHF2Substituted or unsubstituted C1-6Alkyl, substitutedOr unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,
or the like, or, alternatively,
two adjacent R96’The substituents may combine to form a cycloalkyl ring, a heterocycloalkyl ring, and/or be fused to D9’The heteroaryl ring of (a) is a ring,
or the like, or, alternatively,
adjacent to L93’To D9’R of the point of attachment of (A)96’The substituents may be substituted with L93’Combined to form a cycloalkyl ring, a heterocycloalkyl ring and/or fused to D9’A heteroaryl ring of (a);
R92’and R94’Independently is NR98’O, or S;
R98’selected from: hydrogen, C1-6Alkyl and C substituted by 1 to 6 fluorine1-6An alkyl group;
a and b are independently 0 or 1;
C9’and D9’Independently is phenyl or pyridyl;
X7’is C1-3Alkylene or C substituted by 1 to 3 fluorine1-3An alkylene group;
Z92’and z94’Independently 0 or 1; and is
Z95’And z96’Independently an integer from 0 to 5;
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1, represented by formula (VQ):
Figure FDA0002308602650000041
wherein:
L102’selected from: bond, -CH2-、-NH-、CH2-O-、-O-CH2-, cyclopropyl, -O-cyclopropyl, cyclopropyl-O-, -NH-cyclopropyl, cyclopropyl-NH-, azetidinyl, -O-Azetidinyl, azetidinyl-O-, -N-azetidinyl, azetidinyl-N-, -O-CH2-CH2-and-CH2-CH2-O-, or L102’And R101’Together form: imidazolidinyl, azetidinyl-O-, azetidinyl-N-, azetidinyl-CH2-, piperidinyl-O-, piperidinyl-N-, piperidinyl-CH2-, piperazinyl-O-, piperazinyl-N-, piperazinyl-CH2-, oxopiperazinyl-O-, oxopiperazinyl-N-, oxopiperazinyl-CH2-, pyrrolidinyl-O-, pyrrolidinyl-N-, pyrrolidinyl-CH2-, oxopyrrolidinyl-O-, oxopyrrolidinyl-N-, or oxopyrrolidinyl-CH2-,
Or the like, or, alternatively,
L102’and is adjacent to L102’R of the point of attachment of (A)105’The substituents together form a heterocycloalkyl ring;
L103’selected from: cyclopropyl, -O-cyclopropyl, cyclopropyl-O-, -NH-cyclopropyl, cyclopropyl-NH-, azetidinyl, -O-azetidinyl, azetidinyl-O-, -N-azetidinyl, azetidinyl-N-, or L103’And R103’Together form: imidazolidinyl, azetidinyl-O-, azetidinyl-N-, azetidinyl-CH2-, piperidinyl-O-, piperidinyl-N-, piperidinyl-CH2-, piperazinyl-O-, piperazinyl-N-, piperazinyl-CH2-, oxopiperazinyl-O-, oxopiperazinyl-N-, oxopiperazinyl-CH2-, pyrrolidinyl-O-, pyrrolidinyl-N-, pyrrolidinyl-CH2-, oxopyrrolidinyl-O-, oxopyrrolidinyl-N-, or oxopyrrolidinyl-CH2-,
Or the like, or, alternatively,
L103’and is adjacent to L103’R of the point of attachment of (A)106’The substituents together form a heterocycloalkyl ring;
R101’selected from: hydrogen, C1-6Alkyl, substituted C1-6Alkyl, and oxetanyl, or
R101And L102’Together form: imidazolidinyl, azetidinyl-O-, azetidinyl-N-, azetidinyl-CH2-, piperidinyl-O-, piperidinyl-N-, piperidinyl-CH2-, piperazinyl-O-, piperazinyl-N-, piperazinyl-CH2-, oxopiperazinyl-O-, oxopiperazinyl-N-, oxopiperazinyl-CH2-, pyrrolidinyl-O-, pyrrolidinyl-N-, pyrrolidinyl-CH2-, oxopyrrolidinyl-O-, oxopyrrolidinyl-N-, or oxopyrrolidinyl-CH2-；
R103’Selected from: hydrogen, C1-6Alkyl, substituted C1-6Alkyl, and oxetanyl, or
R103’And L103’Together form: imidazolidinyl, azetidinyl-O-, azetidinyl-N-, azetidinyl-CH2-, piperidinyl-O-, piperidinyl-N-, piperidinyl-CH2-, piperazinyl-O-, piperazinyl-N-, piperazinyl-CH2-, oxopiperazinyl-O-, oxopiperazinyl-N-, oxopiperazinyl-CH2-, pyrrolidinyl-O-, pyrrolidinyl-N-, pyrrolidinyl-CH2-, oxopyrrolidinyl-O-, oxopyrrolidinyl-N-, or oxopyrrolidinyl-CH2-；
R105’Selected from: methyl, cyclopropyl, -OCF3Fluorine, chlorine, -SCH3、-OCH3、-OCHF2and-CF3,
Or the like, or, alternatively,
adjacent to L102’To C10’R of the point of attachment of (A)105’The substituents may be substituted with L102’Combined to form a fusion to C10’The heterocycloalkyl ring of (a);
R106’selected from: methyl, cyclopropyl, -OCF3Fluorine, chlorine, -SCH3、-OCH3、-OCHF2and-CF3,
Or the like, or, alternatively,
adjacent to L103’To D10’R of the point of attachment of (A)106’The substituents may be substituted with L103’Combined to form a fusion to D10’The heterocycloalkyl ring of (a);
R102’and R104’Is O;
a and b are independently 0 or 1;
C10’and D10’Independently is phenyl or pyridyl;
X8’is selected from-CH2-and-CH2-CH2-；
Z102’And z104’Independently 0 or 1; and is
Z105’And z106’Independently an integer from 0 to 5;
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1, represented by formula (VIQ):
Figure FDA0002308602650000061
wherein:
L112’selected from: bond, -CH2-、-NH-、CH2-O-、-O-CH2-、-O-CH2-CH2-, and-CH2-CH2-O-；
L113’Selected from: cyclopropyl, -O-cyclopropyl, cyclopropyl-O-, azetidinyl, -O-azetidinyl, azetidinyl-O-, or L113’And R113’Together form: imidazolidinyl, azetidinyl-O-, piperidinyl-O-, piperazinyl-O-, oxopiperazinyl-O-, pyrrolidinyl-O-, oxopyrrolidinyl, or oxopyrrolidinyl-O-,
or the like, or, alternatively,
L113’and is adjacent to L113’R of the point of attachment of (A)116’The substituents together form a heterocycloalkyl ring;
R113’selected from: hydrogen, C1-6Alkyl, substituted C1-6Alkyl, and oxetanyl, or
R113’And L113’Together form: imidazolidinyl, azetidinyl-O-, piperidinyl-O-, piperazinyl-O-, oxopiperazinyl-O-, pyrrolidinyl-O-, oxopyrrolidinyl, or oxopyrrolidinyl-O-;
R111’selected from: hydrogen, C1-6Alkyl, substituted C1-6Alkyl, and oxetanyl;
R115’selected from: methyl, cyclopropyl, -OCF3Fluorine, chlorine, -SCH3、-OCH3、-OCHF2and-CF3；
R116’Selected from: methyl, cyclopropyl, -OCF3Fluorine, chlorine, -SCH3、-OCH3、-OCHF2and-CF3,
Or the like, or, alternatively,
adjacent to L113’To D11’R of the point of attachment of (A)116’The substituents may be substituted with L113’Combined to form a fusion to D11’The heterocycloalkyl ring of (a);
R112’and R114’Is O;
a and b are independently 0 or 1;
C11’and D11’Independently is phenyl or pyridyl;
X9’is selected from-CH2-and-CH2-CH2-；
Z112’And z114’Independently 0 or 1; and is
Z115’And z116’Independently an integer from 0 to 5;
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1, represented by formula (VIIQ):
Figure FDA0002308602650000071
wherein:
w is selected from the group consisting of dicyclopentanyl and dicyclohexanyl;
L122’selected from: bond, -CH2-、-NH-、CH2-O-、-O-CH2-, cyclopropyl, -O-cyclopropyl, cyclopropyl-O-, -NH-cyclopropyl, cyclopropyl-NH-, azetidinyl, -O-azetidinyl, azetidinyl-O-, -N-azetidinyl, azetidinyl-N-, -O-CH2-CH2-and-CH2-CH2-O-, or L122’And R121’Together form: imidazolidinyl, azetidinyl-O-, azetidinyl-N-, azetidinyl-CH2-, piperidinyl-O-, piperidinyl-N-, piperidinyl-CH2-, piperazinyl-O-, piperazinyl-N-, piperazinyl-CH2-, oxopiperazinyl-O-, oxopiperazinyl-N-, oxopiperazinyl-CH2-, pyrrolidinyl-O-, pyrrolidinyl-N-, pyrrolidinyl-CH2-, oxopyrrolidinyl-O-, oxopyrrolidinyl-N-, or oxopyrrolidinyl-CH2-,
Or the like, or, alternatively,
L122’and is adjacent to L122’R of the point of attachment of (A)125’The substituents together form a cyclohexyl, cyclobutyl, or tetrahydropyran ring;
L123’selected from: cyclopropyl, azetidinyl, -O-azetidinyl, azetidinyl-O-, -N-azetidinyl, azetidinyl-N-, or L123’And R123’Together to form: imidazolidinyl, azetidinyl-O-, azetidinyl-N-, azetidinyl-CH2-, piperidinyl-O-, piperidinyl-N-),piperidinyl-CH2-, piperazinyl-O-, piperazinyl-N-, piperazinyl-CH2-, oxopiperazinyl-O-, oxopiperazinyl-N-, oxopiperazinyl-CH2-, pyrrolidinyl-O-, pyrrolidinyl-N-, pyrrolidinyl-CH2-, oxopyrrolidinyl-O-, oxopyrrolidinyl-N-, or oxopyrrolidinyl-CH2-,
Or the like, or, alternatively,
L123’and is adjacent to L123’R of the point of attachment of (A)126’The substituents together form a cyclohexyl, cyclobutyl, or tetrahydropyran ring;
R121’selected from: hydrogen, C1-6Alkyl, substituted C1-6Alkyl, and oxetanyl, or
R121’And L122’Together form: imidazolidinyl, azetidinyl-O-, azetidinyl-N-, azetidinyl-CH2-, piperidinyl-O-, piperidinyl-N-, piperidinyl-CH2-, piperazinyl-O-, piperazinyl-N-, piperazinyl-CH2-, oxopiperazinyl-O-, oxopiperazinyl-N-, oxopiperazinyl-CH2-, pyrrolidinyl-O-, pyrrolidinyl-N-, pyrrolidinyl-CH2-, oxopyrrolidinyl-O-, oxopyrrolidinyl-N-, or oxopyrrolidinyl-CH2-；
R123’Is hydrogen or R123’And L123’Together form: imidazolidinyl, azetidinyl-O-, azetidinyl-N-, azetidinyl-CH2-, piperidinyl-O-, piperidinyl-N-, piperidinyl-CH2-, piperazinyl-O-, piperazinyl-N-, piperazinyl-CH2-, oxopiperazinyl-O-, oxopiperazinyl-N-, oxopiperazinyl-CH2-, pyrrolidinyl-O-, pyrrolidinyl-N-, pyrrolidinyl-CH2-, oxopyrrolidinyl-O-, oxopyrrolidinyl-N-, or oxopyrrolidinyl-CH2-；
R125’Selected from: methyl, cyclopropyl, -OCF3Fluorine, chlorine, -SCH3、-OCH3、-OCHF2and-CF3,
Or the like, or, alternatively,
adjacent to L122’To C12’R of the point of attachment of (A)125’The substituents may be substituted with L122’Combined to form a cyclohexyl ring, a cyclobutyl ring or fused to C12’The tetrahydropyran ring of (a);
R126’selected from: methyl, cyclopropyl, -OCF3Fluorine, chlorine, -SCH3、-OCH3、-OCHF2and-CF3,
Or the like, or, alternatively,
adjacent to L123’To D12’R of the point of attachment of (A)126’The substituents may be substituted with L123’Combined to form a cyclohexyl ring, cyclobutyl ring or fused to D12’The tetrahydropyran ring of (a);
R122’and R124’Is O;
C12’and D12’Independently is phenyl or pyridyl;
Z122’and z124’Independently 0 or 1; and is
Z125’And z126’Independently an integer from 0 to 3;
or a salt thereof, including pharmaceutically acceptable salts thereof.
6. The compound of claim 1, represented by formula (VIIIQ):
wherein:
W1selected from the group consisting of dicyclopentanyl and dicyclohexanyl;
L132’selected from: bond, -CH2-、-NH-、CH2-O-、-O-CH2-、-O-CH2-CH2-and-CH2-CH2-O-；
L133’Selected from: cyclopropyl, -O-cyclopropyl, cyclopropyl-O-, azetidinyl, -O-azetidinyl, azetidinyl-O-, or L133’And R133’Together form: imidazolidinyl, azetidinyl-O-, piperidinyl-O-, piperazinyl-O-, oxopiperazinyl-O-, pyrrolidinyl-O-, oxopyrrolidinyl, or oxopyrrolidinyl-O-,
or the like, or, alternatively,
L133’and is adjacent to L133’R of the point of attachment of (A)136’The substituents together form a cyclohexyl, cyclobutyl, or tetrahydropyran ring;
R133’is hydrogen or R133’And L133’Together form: imidazolidinyl, azetidinyl-O-, piperidinyl-O-, piperazinyl-O-, oxopiperazinyl-O-, pyrrolidinyl-O-, oxopyrrolidinyl, or oxopyrrolidinyl-O-;
R135'selected from: methyl, cyclopropyl, -OCF3Fluorine, chlorine, -SCH3、-OCH3、-OCHF2and-CF3；
R136’Selected from: methyl, cyclopropyl, -OCF3Fluorine, chlorine, -SCH3、-OCH3、-OCHF2and-CF3,
Or the like, or, alternatively,
adjacent to L133’To D13’R of the point of attachment of (A)136’The substituents may be substituted with L133’Combined to form a cyclohexyl ring, cyclobutyl ring or fused to D13’The tetrahydropyran ring of (a);
R132’and R134’Is O;
C13’and D13’Each independently is phenyl or pyridyl;
Z132’and z134’Each independently is 0 or 1; and is
Z135’And z136’Each independently is an integer from 0 to 3;
or a salt thereof, including pharmaceutically acceptable salts thereof.
7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (4-chlorophenoxy) -N- (3- (3- (4-fluorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
n- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-fluorophenoxy) acetamide;
n- (3- (3- (4-chloro-2-methylphenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-chlorophenoxy) acetamide;
n- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-cyclopropylphenoxy) acetamide;
2- (4-chlorophenoxy) -N- (3- (3- (5-chloropyridin-2-yl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (3-chlorophenoxy) -N- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
n- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4- (trifluoromethoxy) phenoxy) acetamide;
2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (4-chloro-3- (trifluoromethyl) phenoxy) -N- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (4-chlorophenoxy) -N- (3- (3- (3-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
n- (3- (2- (4-chlorophenoxy) acetamido) bicyclo [1.1.1] pent-1-yl) -2- (4-chlorophenyl) cyclopropane-1-carboxamide;
n- (4- (2- (4-chlorophenoxy) acetamido) bicyclo [2.1.1] hex-1-yl) -2- (4-chlorophenyl) cyclopropane-1-carboxamide;
2- (4-chlorophenoxy) -N- (3- (2- (4-chlorophenoxy) acetamido) bicyclo [1.1.1] pent-1-yl) cyclopropane-1-carboxamide;
2- (4-chlorophenoxy) -N- (3- ((1- (4-chlorophenyl) azetidin-3-yl) amino) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenoxy) azetidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (4-chlorophenoxy) -N- (3- (2- ((5,6,7, 8-tetrahydronaphthalen-2-yl) oxy) acetamido) bicyclo [1.1.1] pent-1-yl) acetamide;
5-chloro-N- (3- (2- (4-chlorophenoxy) acetamido) bicyclo [1.1.1] pent-1-yl) -2, 3-dihydrobenzofuran-2-carboxamide;
2- (bicyclo [4.2.0] oct-1 (6),2, 4-trien-3-yloxy) -N- (3- (2- (4-chlorophenoxy) acetamido) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (4-chlorophenoxy) -N- (3- (2- (chroman-6-yloxy) acetamido) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (4-chlorophenoxy) -N- (3- (4- (4-chlorophenyl) piperidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (4-chlorophenoxy) -N- (3- (4- (4-chlorophenyl) piperazin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (bicyclo [4.2.0] oct-1, 3, 5-trien-3-yloxy) -N- (4- (2- (4-chlorophenoxy) acetamido) bicyclo [2.2.1] hept-1-yl) acetamide;
2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
(S) -2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
(R) -2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
n- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-fluorophenoxy) acetamide isomer 1;
n- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-fluorophenoxy) acetamide isomer 2;
2- (4-chlorophenoxy) -N- (3- (3- (4-fluorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
n- (3- (3- (3-chloro-4-fluorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-chlorophenoxy) acetamide isomer 1;
n- (3- (3- (3-chloro-4-fluorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-chlorophenoxy) acetamide isomer 2;
n- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- ((5-chloropyridin-2-yl) oxy) acetamide;
n- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4- (trifluoromethyl) phenoxy) acetamide;
n- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4- (trifluoromethoxy) phenoxy) acetamide;
2- (4-chloro-3- (trifluoromethyl) phenoxy) -N- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (4-chlorophenoxy) -N- (3- (3- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (4-chloro-3-fluorophenoxy) -N- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
n- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-cyclopropylphenoxy) acetamide;
n- (3- (3- (4-chloro-3-fluorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-chlorophenoxy) acetamide isomer 1;
n- (3- (3- (4-chloro-3-fluorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-chlorophenoxy) acetamide isomer 2;
2- (4-chlorophenoxy) -N- (3- (3- (pyridin-4-yloxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
1- (3- ((2- (4-chlorophenoxy) ethyl) amino) bicyclo [1.1.1] pent-1-yl) -3- (4-chlorophenyl) imidazolidin-2-one;
2- (4-chloro-3-fluorophenoxy) -N- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
n- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-methoxyphenoxy) acetamide;
2- (3-chloro-4-fluorophenoxy) -N- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
n- (3- (3- (4-chloro-3- (trifluoromethyl) phenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-chlorophenoxy) acetamide;
2- (4-chlorophenoxy) -N- (3- (3- (4-fluoro-3- (trifluoromethyl) phenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
n- (3- (5-chloroisoindolin-2-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-chlorophenoxy) acetamide;
n- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- ((5-chloropyridin-2-yl) oxy) acetamide;
2- (4-chlorophenoxy) -N- (3- (2-oxo-3- (4- (trifluoromethyl) phenyl) imidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
n- (3- (3- (4-chlorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-fluoro-3- (trifluoromethyl) phenoxy) acetamide;
n- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-fluoro-3- (trifluoromethyl) phenoxy) acetamide;
n- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4- (difluoromethoxy) phenoxy) acetamide;
2- (4-chloro-3-fluorophenoxy) -N- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide isomer 1;
(R) -2- (4-chloro-3-fluorophenoxy) -N- (3- (3- (4-chlorophenoxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide isomer 2;
2- (4-chlorophenoxy) -N- (3- (3- ((5-chloropyridin-2-yl) oxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
2- ((5-chloropyridin-2-yl) oxy) -N- (3- (3- ((5-chloropyridin-2-yl) oxy) pyrrolidin-1-yl) bicyclo [1.1.1] pentan-1-yl) acetamide;
2- (4-chlorophenoxy) -N- (3- (3- (4-methoxyphenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
n- (3- (3- (4-chloro-2-fluorophenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-chlorophenoxy) acetamide;
n- (3- (3- (bicyclo [4.2.0] oct-1, 3, 5-trien-3-yloxy) pyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) -2- (4-chlorophenoxy) acetamide;
(S) -2- (4-chlorophenoxy) -N- (3- (4- (4-chlorophenoxy) -2-oxopyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
(S) -2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenoxy) -2-oxopyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
(R) -2- (4-chlorophenoxy) -N- (3- (4- (4-chlorophenoxy) -2-oxopyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
(R) -2- (4-chlorophenoxy) -N- (3- (3- (4-chlorophenoxy) -2-oxopyrrolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide;
2- (4-chlorophenoxy) -N- (3- (3- (4- (methylthio) phenyl) -2-oxoimidazolidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide; and
2- (4-chlorophenoxy) -N- (3- (4- (4-chlorophenoxy) piperidin-1-yl) bicyclo [1.1.1] pent-1-yl) acetamide.
8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
9. A method of treating a disease selected from the group consisting of: cancer, pre-cancerous syndromes, alzheimer's disease, spinal cord injury, traumatic brain injury, ischemic stroke, diabetes, parkinson's disease, huntington's disease, creutzfeldt-jakob disease, prion disease, progressive supranuclear palsy, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular diseases, inflammation, fibrosis, chronic and acute liver diseases, chronic and acute lung diseases, chronic and acute kidney diseases, chronic traumatic brain disease (CTE), neurodegeneration, dementia, cognitive impairment, atherosclerosis, eye diseases, neurological disorders, pain, organ transplantation, and cardiac arrhythmias, comprising administering to the mammal a therapeutically effective amount of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.
10.The method of claim 9, wherein the mammal is a human.
11. A method of treating a disease selected from the group consisting of: cancer, pre-cancerous syndromes, alzheimer's disease, spinal cord injury, traumatic brain injury, ischemic stroke, diabetes, parkinson's disease, huntington's disease, creutzfeldt-jakob disease and related prion diseases, progressive supranuclear palsy, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular diseases, inflammation, fibrosis, chronic and acute liver diseases, chronic and acute lung diseases, chronic and acute kidney diseases, chronic traumatic brain disease (CTE), neurodegeneration, dementia, cognitive impairment, atherosclerosis, ocular diseases, neurological disorders, pain, organ transplantation, and cardiac arrhythmias, comprising administering to the mammal a therapeutically effective amount of a compound of claim 7, or a pharmaceutically acceptable salt thereof.
12. The method of claim 11, wherein the mammal is a human.
13. The method according to claim 9, wherein the cancer is selected from the group consisting of: brain cancer (glioma), glioblastoma, astrocytoma, glioblastoma multiforme, Bannayan-Zonana syndrome, cowden disease, leyde disease, breast cancer, colon cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate cancer, sarcoma, and thyroid cancer.
14. The method according to claim 11, wherein the cancer is selected from the group consisting of: brain cancer (glioma), glioblastoma, astrocytoma, glioblastoma multiforme, Bannayan-Zonana syndrome, cowden disease, leyde disease, breast cancer, colon cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate cancer, sarcoma, and thyroid cancer.
15. Use of a compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.
16. A method of inhibiting the ATF4 pathway in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.
17. The method of claim 16, wherein the mammal is a human.
18. A method of treating cancer in a mammal in need thereof, comprising: administering to the mammal a therapeutically effective amount of:
a) a compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof; and
b) at least one antineoplastic agent.
19. The method of claim 18, wherein the at least one anti-neoplastic agent is selected from the group consisting of: anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, anti-metabolites, topoisomerase I inhibitors, hormones and hormone analogs, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, pro-apoptotic agents, cell cycle signaling inhibitors, proteasome inhibitors, and cancer metabolism inhibitors.
20.A pharmaceutical combination comprising:
a) a compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof; and
b) at least one antineoplastic agent.
21. The pharmaceutical combination of claim 20 for use in the treatment of cancer.
22. The method of claim 9, wherein the cancer is selected from the group consisting of: breast cancer, inflammatory breast cancer, ductal carcinoma, lobular carcinoma, colon cancer, pancreatic cancer, insulinoma, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, skin cancer, melanoma, metastatic melanoma, lung cancer, small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, adenocarcinoma, large cell carcinoma, brain cancer (glioma), glioblastoma, astrocytoma, glioblastoma multiforme, Bannayan-Zonana syndrome, cowden disease, lewy-du disease, wilms 'tumor, ewing's sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, insulin head and neck cancer, kidney cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, prostate cancer, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid cancer, adenosquamous cell carcinoma, non-cell carcinoma, Lymphoblastic T cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, multiple myeloma, acute megakaryoblastic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulval cancer, cervical cancer, endometrial cancer, kidney cancer, mesothelioma, esophageal cancer, salivary gland cancer, prostate, Hepatocellular carcinoma, gastric cancer, nasopharyngeal carcinoma, buccal carcinoma, oral cancer, GIST (gastrointestinal stromal tumor), neuroendocrine cancer, and testicular cancer.
23. The method of claim 22, wherein the mammal is a human.
24. A process for preparing a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, which process comprises bringing the compound, or a pharmaceutically acceptable salt thereof, into association with a pharmaceutically acceptable excipient.
25. The method of claim 9 or 10, wherein the pre-cancerous syndrome is selected from the group consisting of: cervical intraepithelial neoplasia, Monoclonal Gammaglobulin of Unknown Significance (MGUS), myelodysplastic syndrome, aplastic anemia, cervical lesions, cutaneous nevi (premna), Prostatic Intraepithelial Neoplasia (PIN), Ductal Carcinoma In Situ (DCIS), colonic polyps and severe hepatitis or cirrhosis.
26. The method of claim 18, wherein the at least one anti-neoplastic agent is pazopanib.
27. A method of treating an ocular disease in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.
28. The method of claim 27, wherein the ocular disease is selected from the group consisting of: redness of the iris; neovascular glaucoma; pterygium; vascularized glaucoma filtration blebs; conjunctival papilloma; choroidal neovascularization, myopia, anterior uveitis, trauma, or idiopathic ocular disease associated with age-related macular degeneration (AMD); macular edema; retinal neovascularization due to diabetes; age-related macular degeneration (AMD); macular Degeneration (AMD); ocular ischemic syndrome derived from carotid artery disease; ocular or retinal artery occlusion; sickle cell retinopathy; retinopathy of prematurity; early stage of the disease; and von hippel-lindau syndrome.
29. The method of claim 27, wherein the ocular disease is selected from the group consisting of: age-related macular degeneration (AMD) and macular degeneration.
30. A method of treating neurodegeneration in a human in need thereof, comprising administering to said human a therapeutically effective amount of a compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.
31. A method for preventing organ damage during transport of an organ for transplantation, comprising adding a compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, to a solution containing the organ during transport.
32. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for use in therapy.
33. Use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease state selected from: cancer, pre-cancerous syndromes, alzheimer's disease, spinal cord injury, traumatic brain injury, ischemic stroke, diabetes, parkinson's disease, huntington's disease, creutzfeldt-jakob disease and related prion diseases, progressive supranuclear palsy, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, inflammation, fibrosis, chronic and acute liver disease, chronic and acute lung disease, chronic and acute kidney disease, chronic traumatic brain disease (CTE), neurodegeneration, dementia, cognitive impairment, atherosclerosis, ocular diseases, neurological disorders, pain, organ transplantation, and cardiac arrhythmias.
34. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition selected from: cancer, pre-cancerous syndromes, alzheimer's disease, spinal cord injury, traumatic brain injury, ischemic stroke, diabetes, parkinson's disease, huntington's disease, creutzfeldt-jakob disease and related prion diseases, progressive supranuclear palsy, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, inflammation, fibrosis, chronic and acute liver disease, chronic and acute lung disease, chronic and acute kidney disease, chronic traumatic brain disease (CTE), neurodegeneration, dementia, cognitive impairment, atherosclerosis, ocular diseases, organ transplantation, and cardiac arrhythmia.
35. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for use in the treatment of diseases associated with integration stress.
36. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease associated with phosphorylation of eIF2 α.
37. Use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or lessening the severity of an integrative stress-related disease.
38. Use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease associated with eIF2 α phosphorylation.
39. A pharmaceutical composition comprising from 0.5 to 1000mg of a compound as defined in any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, and from 0.5 to 1000mg of a pharmaceutically acceptable excipient.
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