Immunomodulators, compositions and methods thereof

Abstract

The present invention relates to a compound represented by formula (III), a method of using the compound as an immunomodulator, and a pharmaceutical composition comprising the compound. The compounds may be used to treat, prevent or ameliorate a disease or condition, such as cancer or infection. # imgabs0 #

Description

[0001] This application is a divisional application of the invention patent application with the application date of January 20, 2020, application number 202080011241.X, and invention name “Immunomodulators, compositions and methods thereof”. Technical Field

[0002] The present invention relates to compounds that are inhibitors of the PD-1 / PD-L1 protein / protein interaction. The present invention also relates to pharmaceutical compositions comprising the compounds, and to the use of the compounds in treating cancer, precancerous syndromes, and other diseases associated with inhibition of the PD-1 / PD-L1 protein / protein interaction. Background Art

[0003] Cancer immunotherapy has been increasingly used to treat advanced malignancies. The immune checkpoint signaling network has garnered widespread attention. Some cancers are extremely refractory to conventional chemotherapy. In certain cases, tumor survival can be assisted by checkpoint immunomodulation, maintaining the imbalance between immune surveillance and cancer cell proliferation. Immune checkpoint inhibitors have revolutionized the treatment options and expectations for cancer patients.

[0004] Programmed cell death-1 (PD-1), also known as CD279, is a cell surface receptor expressed on activated T cells, natural killer T cells, B cells, and macrophages. It functions as an intrinsic negative feedback system that prevents T cell activation, thereby reducing autoimmunity and enhancing self-tolerance. PD-1 is also known to play a crucial role in suppressing antigen-specific T cell responses in diseases such as cancer and viral infections. The interaction between PD-1 and PD-L1 leads to a decrease in tumor-infiltrating lymphocytes, a reduction in T-cell receptor-mediated proliferation, and immune evasion by cancer cells. The immunosuppressive effects can be reversed by inhibiting the local interaction of the immunosuppressive PD-1 and PD-L1, and this effect is additive when the interaction of PD-1 with PD-L2 is also blocked.

[0005] The development of therapeutic approaches aims to block the inhibitory signaling cascade mediated by PD-1 to enhance or "rescue" T cell responses. Currently, most drugs approved in the field of immunotherapy are monoclonal antibodies. These monoclonal antibodies have shown impressive clinical results in the treatment of some types of tumors. However, therapeutic antibodies have several disadvantages, such as limited tissue and tumor penetration, very long half-life, lack of oral bioavailability, immunogenicity, and difficulty and high cost in production.

[0006] Recently, small molecules that bind to PD-L1 have been described in WO2015033299, WO2015033301, WO2015034820, WO2018183171, WO2018119224, and WO2018119266. In addition, small molecule inhibitors that directly target PD-1 or PD-L1 have not yet been approved.

[0007] Therefore, there remains a need for more effective and more easily administered therapeutic agents to counteract the PD-1 / PD-L1 protein / protein interaction. In the present invention, applicants have discovered potent small molecules that are active as inhibitors of the PD-1 and PD-L1 interaction and can therefore be used for therapeutic administration to enhance immunity against cancer and / or infectious diseases. These small molecules are expected to be effective drugs with the desired stability, solubility, bioavailability, therapeutic index, and toxicity profiles, which are crucial for their potential application in promoting human health. Summary of the Invention

[0008] The present invention relates to a compound that is an inhibitor of the functional interaction between PD-L1 and PD-1. The inhibitor of the interaction between PD-L1 and PD-1 can be used to treat cancer and infectious diseases.

[0009] The compound of the present invention has a structure as shown in formula (I).

[0010] The compound represented by formula (I) or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate,

[0011]

[0012] in,

[0013] R1 and R2 are independently selected from halogen, CN, C 1-6 Alkyl or C 1-4 alkyl halide;

[0014] Q is a bond, -NH- or -(CH2) m -O-;

[0015] A ring is C 5-6 Aryl, C 5-6 Heteroaryl, C 4-6 Cycloalkyl or C 4-6 Heterocycloalkyl, wherein C 5-6 Heteroaryl and C 4-6 Heterocycloalkyl optionally contains 1, 2 or 3 heteroatoms independently selected from N, S or O; or

[0016] A ring is C 8-10 fused bicyclic ring;

[0017] R3 is H, halogen, -(CH2) s -NR4R5、C 1-4 Alkyl, C 1-4 Alkoxy, hydroxy, oxy, CN, (CH2) q -CONR4R5,-

[0018] COR4, -NR4R5, -NR4C(=O)NR4R5, -NR4C(=NR4)NR4R5, -S(O)2R4, -S(O)2NR4R5, -S(O)R4, -

[0019] S(O)NR4R5、C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 5-6 Aryl, C 5-6 Heteroaryl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl, wherein C 5-6 Heteroaryl and C 3-6 Heterocycloalkyl optionally contains 1, 2 or 3 heteroatoms independently selected from N, S or O; 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 5-6 Aryl, C 5-6 Heteroaryl, C 3-6 Cycloalkyl and C 3-6 Heterocycloalkyl is optionally substituted with one or more substituents independently selected from R6;

[0020] R4 and R5 are independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocyclic group, the C 1-4 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocyclyl is optionally substituted with one or more substituents independently selected from R6; or

[0021] R4 and R5 together with the atoms to which they are attached form a 4-10 membered heterocyclic ring, said 4-10 membered heterocyclic ring being optionally substituted with one or more substituents independently selected from R6;

[0022] R6 is H, halogen, hydroxy, oxy, CN, -(CH2) k-NR7R8, -COR7, -NR7R8, -NR7C(=O)NR7R8, -NR7C(=NR7)NR7R8, -S(O)2R7, -S(O)2NR7R8, -S(O)R7, -S(O)NR7R8, or R6 is selected from substituted or unsubstituted C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 5-6 Aryl, C 5-6 Heteroaryl, C 3-10 Heterocyclic group, wherein the C 5-6 Heteroaryl and C 3-10 The heterocyclic group optionally contains 1, 2 or 3 heteroatoms independently selected from N, S or O;

[0023] R7 and R8 are independently selected from H, halogen, hydroxy, oxo, CN, -S(O)2-C 1-4 Alkyl, -NH2, -NH-C 1-4 alkyl,-

[0024] (CH2)-N(C 1-4 alkyl)2, or R7 and R8 are independently selected from substituted or unsubstituted C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 5-6 Aryl, C 5-6 Heteroaryl, C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl; wherein the C 5-6 Heteroaryl and C 3-6 The heterocycloalkyl group optionally contains 1, 2 or 3 heteroatoms independently selected from N, S or O;

[0025] m, n, q, k and s are independently selected from 0, 1, 2, 3 or 4.

[0026] In some embodiments, R3 in formula (I) is H, halogen, -(CH2) s -NR4R5、C 1-4 Alkyl, C 1-4 Alkoxy, hydroxy, oxy, CN, (CH2) q -CONR4R5, -NR4R5, -NR4C(=NR4)NR4R5, -S(O)2R4,C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl or C3-6 Heterocycloalkyl, wherein C 3-6 Heterocycloalkyl optionally contains 1, 2 or 3 heteroatoms independently selected from N, S or O; 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl and C 3-6 Heterocycloalkyl is optionally substituted with one or more substituents independently selected from R6.

[0027] In some embodiments, R3 in formula (I) is H, halogen, -(CH2) s -NR4R5、CN、-S(O)2R4、C 1-4 Alkyl, C 1-4 Alkoxy, the -(CH2) s -NR4R5、C 1-4 Alkyl, C 1-4 The alkoxy group is optionally substituted with one or more substituents independently selected from R6.

[0028] In some embodiments, R6 in formula (I) is H, halogen, hydroxyl, oxy, CN, -(CH2) k -NR7R8, -COR7, -NR7R8, -NR7C(=O)NR7R8, -S(O)2R7, or R6 is selected from substituted or unsubstituted C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 5-6 Aryl, C 5-6 Heteroaryl, C 3-10 Heterocyclic group, wherein the C 5-6 Heteroaryl and C 3-10 The heterocyclic group optionally contains 1, 2 or 3 heteroatoms independently selected from N, S or O.

[0029] In some embodiments, R6 in formula (I) is H, halogen, hydroxyl, oxy, CN, -(CH2)-N-(C 1-4 alkyl)2, -(CH2)-NH2, -N-(C 1-4 Alkyl)2, -NH2, -CO-N-(C 1-4 Alkyl)2, -CO-NH2, -S(O)2-C 1-4 Alkyl, C 1-4 Alkyl-OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 5-6 Aryl, C 5-6 Heteroaryl, C 3-10 Heterocyclic group, wherein the C 5-6 Heteroaryl and C 3-10 The heterocyclic group optionally contains 1, 2 or 3 heteroatoms independently selected from N, S or O.

[0030] In some embodiments, R6 in formula (I) is halogen, oxy, -OH, -NH2, -N(CH3)2, -C 1-4 Alkyl-OH, -C 1-4 Alkyl-NH-CH3, -NH-C 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 5-6 Aryl, C 5-6 Heteroaryl, C 3-6 heterocyclic group, guanidino group or sulfone group.

[0031] In some embodiments, in formula (I),

[0032] R1 and R2 are independently selected from halogen, CN, -C 1-6 Alkyl or -C 1-4 alkyl halide;

[0033] Q is a bond, -NH- or -(CH2) m -O-;

[0034] A ring is C 5-6 Aryl or C 5-6 Heteroaryl, the C 5-6 The heteroaryl group optionally contains 1, 2 or 3 heteroatoms independently selected from N, S or O; or

[0035] A ring is C 8-10 fused bicyclic ring;

[0036] R3 is H, halogen, -(CH2) s -NR4R5, -C 1-4 Alkyl, -C 1-4 Alkoxy, the -(CH2) s -NR4R5, -C 1-4 Alkyl, -C 1-4 Alkoxy is optionally substituted by one or more independently selected from halogen, -C 1-4 Alkyl, -C 1-4 Haloalkyl, -C 1-4 Alkoxy, C 5-6 Heteroaryl, C5-6 substituted by an aryl, carboxyl, amino, hydroxyl, guanidino or sulfone substituent;

[0037] R4 and R5 are independently selected from H, -C 1-4 Alkyl or C 3-6 Cycloalkyl, C 3-6 Heterocyclyl, the -C 1-4 Alkyl or C 3-6 Cycloalkyl, C 3-6 The heterocyclic group is optionally substituted by halogen, -OH, N(CH3)2, -C 1-4 Alkyl, -C 1-4 Haloalkyl, -C 3-6 Heterocyclic group, -NH-C 1-4 substituted with an alkyl group or a sulfone; or

[0038] R4 and R5 together with the atoms to which they are attached form a 4-6 membered heterocyclic ring, wherein the 4-6 membered heterocyclic ring is optionally substituted by one or more independently selected from -OH, -N(CH3)2, -NH2, oxo, halogen, -C 1-4 Alkyl, -C 1-4 Alkoxy, -C 1-4 Alkyl-OH, -C 1-4 substituted by an alkyl-NH-CH3 or sulfone substituent;

[0039] m, n and s are independently selected from 0, 1, 2, 3 or 4.

[0040] In some embodiments, Q in formula (I) is selected from a bond, -NH-, or -CH2-O-.

[0041] In some embodiments, Ring A in Formula (I) is selected from

[0042] In some embodiments, Ring A in Formula (I) is selected from

[0043] In some embodiments, Ring A in Formula (I) is selected from

[0044] In some embodiments, the compound is represented by formula (II):

[0045]

[0046] or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein

[0047] Ring B is C 5-6 Cycloalkyl or C5-6 heterocycloalkyl;

[0048] R1, R2, R3 and the subscript n are as defined in any embodiment of formula (I).

[0049] In some embodiments, the compound is represented by formula (III):

[0050]

[0051] or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein

[0052] Ring C is a benzene ring or a heteroaryl group, wherein the heteroaryl group contains 1, 2 or 3 N atoms;

[0053] R1, R2, R3 and the subscript n are as defined in any embodiment of formula (I).

[0054] In some embodiments, the compound is represented by formula (IV):

[0055]

[0056] or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein

[0057] D ring is C 5-6 Aryl, C 5-6 Heteroaryl or C 5-6 Heterocycloalkyl, the C 5-6 Heteroaryl and C 5-6 The heterocycloalkyl group optionally contains 1, 2 or 3 heteroatoms independently selected from N, S or O;

[0058] R1, R2, R3 and the subscript n are as defined in any embodiment of formula (I).

[0059] In some embodiments, the compound is represented by formula (V):

[0060]

[0061] or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein

[0062] R1, R2, R3 and the subscript n are as defined in any embodiment of formula (I).

[0063] In some embodiments, the compound is represented by formula (VI):

[0064]

[0065] or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein

[0066] Ring A, Q, R1, R2, R3 and the subscript n are as defined in any embodiment of formula (I).

[0067] In some embodiments, R1 is selected from F, Cl, -CH3, -CN or -O-CH3.

[0068] In some embodiments, R1 is selected from -CH3, F, or -O-CH3.

[0069] In some embodiments, R2 is selected from -CH3, F, Cl or Br.

[0070] In some embodiments, R2 is -CH3.

[0071] In some embodiments, R3 is selected from H, F, Cl, -CH3, -CF3, -O-CF3, -O-CHF2, -O-CH3, -CN, -NH2,

[0072]

[0073]

[0074] In some embodiments, wherein n is 1, 2 or 3.

[0075] In some embodiments, wherein m is 1.

[0076] In some embodiments, wherein s is 1.

[0077] In some embodiments, wherein q is 1.

[0078] In some embodiments, k is 1.

[0079] In some embodiments, the compound of formula (I) is:

[0080] 1)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((((1R,2S)-2-hydroxycyclopentyl)(methyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0081] 2)(2'S)-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(6-(difluoromethoxy)benzo[d]oxazole-2,5-diyl))bis(methylene))di-L-proline;

[0082] 3)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((S)-2-(methoxycarbonyl)pyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0083] 4)((2-(2'-cyano-3'-(6-(difluoromethoxy)-5-((3,3-dimethylazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0084] 5)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(pyrrolidin-1-ylmethyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0085] 6)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(pyrrolidin-1-ylmethyl)benzo[d]oxazol-2-yl)-2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0086] 7)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((2-hydroxyethyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0087] 8)((2-(3'-(5-(azetidin-1-ylmethyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0088] 9)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-fluoroazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0089] 10)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-fluoropyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0090] 11)((2-(3'-(5-(((S)-2-carbamoylpyrrolidin-1-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0091] 12)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((S)-2-(hydroxymethyl)pyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0092] 13)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(morpholinomethyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0093] 14)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0094] 15)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((methylamino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0095] 16)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((dimethylamino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0096] 17)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((2-hydroxyethyl)(methyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0097] 18)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((3R,4R)-3,4-difluoropyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0098] 19)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((((S)-5-oxopyrrolidin-2-yl)methyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0099] 20)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-hydroxyazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0100] 21)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((ethylamino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0101] 22)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((3,3,3-trifluoro-2-hydroxypropyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0102] 23)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3,4-dimethylpiperazin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0103] 24)((2-(3'-(5-(aminomethyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0104] 25)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((((1R,2S)-2-hydroxycyclopentyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0105] 26)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((((1R,2S)-2-hydroxycyclopentyl)(methyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-D-proline;

[0106] 27)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((((1S,2R)-2-hydroxycyclopentyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0107] 28)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((oxetan-3-ylamino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0108] 29)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((((R)-tetrahydrofuran-2-yl)methyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0109] 30)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((methyl(((R)-tetrahydrofuran-2-yl)methyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0110] 31)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((S)-2-(hydroxymethyl)azetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0111] 32)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((2-(methylsulfonyl)ethyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0112] 33)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-(dimethylamino)azetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0113] 34)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3,3-dimethylazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0114] 35)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((R)-2-(hydroxymethyl)azetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0115] 36)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((2-methylazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0116] 37)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((2-hydroxy-2-methylazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0117] 38)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((2-methylpyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0118] 39)((2-(3'-(5-((6-oxa-1-azaspiro[3.3]hept-1-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0119] 40)((2-(3'-(5-((2-amino-2-methylazetidin-1-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0120] 41)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-(methylsulfonyl)azetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0121] 42)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((R)-2-ethylazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0122] 43)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-methoxyazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0123] 44)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-hydroxy-3-methylazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0124] 45)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-((methylamino)methyl)azetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0125] 46)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-oxoazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0126] 47)((2-(3'-(5-((2-oxa-6-azaspiro[3.3]hept-6-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0127] 48)((2-(3'-(5-((2-azaspiro[3.3]hept-2-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0128] 49)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0129] 50)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0130] 51)((2-(3'-(5-((2,7-diazaspiro[3.5]nonan-2-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0131] 52)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((3-(propylamino)propyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0132] 53)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((methyl(3-(propylamino)propyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0133] 54)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((2,2-dioxo-2-thia-6-azaspiro[3.3]hept-6-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0134] 55)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0135] 56)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-methylazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0136] 57)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((((1R,2R)-2-hydroxycyclopentyl)(methyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0137] 58)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((3-((2-hydroxyethyl)amino)propyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0138] 59)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0139] 60)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((2-methylazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0140] 61)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-methylpyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0141] 62)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((2,2-dimethylpyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0142] 63)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((S)-2-(methoxymethyl)pyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0143] 64)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((((S)-tetrahydrofuran-2-yl)methyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0144] 65)((2-(2'-cyano-3'-(6-(difluoromethoxy)-5-(pyrrolidin-1-yl-methyl)benzo[d]oxazol-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)proline;

[0145] 66)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(pyrrolidin-1-yl-methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-D-proline;

[0146] 67)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3,3-dimethylpyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0147] 68)((2-(3'-(5-((3-(diethylamino)azetidin-1-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0148] 69)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-(2-hydroxypropan-2-yl)azetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0149] 70)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((2,5-dihydro-1H-pyrrol-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0150] 71)((2-(3'-(5-((2-azabicyclo[2.1.1]hexan-2-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0151] 72)((2-(3'-(5-(((1s,4s)-7-azabicyclo[2.2.1]hept-7-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0152] 73)((2-(3'-(5-((((3,3-difluoro-1-(hydroxymethyl)cyclobutyl)methyl)amino)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0153] 74)((2-(3'-(5-((5-azaspiro[2.3]hexan-5-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0154] 75)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-oxo-6-azabicyclo[3.2.1]octan-6-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0155] 76)((2-(3'-(5-((1,1-difluoro-5-azaspiro[2.3]hexan-5-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0156] 77)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-(hydroxymethyl)-3-methylpyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0157] 78)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-(hydroxymethyl)-3-methylazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0158] 79)((2-(3'-(5-((3-cyano-3-methylazetidin-1-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0159] 80)((2-(3'-(5-((3-cyanoazetidin-1-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0160] 81)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-methenylazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0161] 82)((2-(3'-(5-((3-(cyanomethenyl)azetidin-1-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0162] 83)((2-(2,2'-dicyano-3'-(6-(difluoromethoxy)-5-((3,3-dimethylazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0163] 84)((6-(difluoromethoxy)-2-(3'-(5-((3,4-dimethylpyrrolidin-1-yl)methyl)-7-(trifluoromethyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0164] 85)(R)-1-((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3,3-dimethylazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid;

[0165] 86)(S)-1-((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3,3-dimethylazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid;

[0166] 87)((2-(2'-cyano-3'-(6-(difluoromethoxy)-5-((3,3-dimethylazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-D-proline;

[0167] 88)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-((3-methylpyrrolidin-1-yl)methyl)-7-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0168] 89)((2-(3'-(5-((2-azabicyclo[2.1.1]hexan-2-yl)methyl)-7-(trifluoromethyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0169] 90)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-((3-methylpyrrolidin-1-yl)methyl)-7-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-D-proline;

[0170] 91)(3R)-1-((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-((3-methylpyrrolidin-1-yl)methyl)-7-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid;

[0171] 92)(3S)-1-((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-((3-methylpyrrolidin-1-yl)methyl)-7-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid;

[0172] 93)((6-(difluoromethoxy)-2-(3'-(5-((3,3-dimethylazetidin-1-yl)methyl)-7-(trifluoromethyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0173] 94)((2-(3'-(5-(azetidin-1-yl-methyl)-7-methylbenzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0174] 95)((6-(difluoromethoxy)-2-(3'-(7-fluoro-5-(pyrrolidin-1-yl-methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0175] 96)((6-(difluoromethoxy)-2-(3'-(5-((ethylamino)methyl)-6-fluoro-benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0176] 97)((2-(3'-(6-chloro-5-((ethylamino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0177] 98)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(pyrrolidin-1-ylmethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0178] 99)((6-(difluoromethoxy)-2-(3'-(5-((((1R,2S)-2-hydroxycyclopentyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0179] 100)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(pyrrolidin-1-yl-methyl)-7-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0180] 101)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(pyrrolidin-1-yl-methyl)-6-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0181] 102)((2-(3'-(6,7-difluoro-5-(pyrrolidin-1-ylmethyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0182] 103)((2-(3'-(7-cyano-5-((3,3-dimethylazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0183] 104)((6-(difluoromethoxy)-2-(3'-(5-((2-hydroxy-2-methylazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0184] 105)((6-(difluoromethoxy)-2-(3'-(5-((2-(hydroxymethyl)azetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0185] 106)((2-(3'-(5-((6-oxa-1-azaspiro[3.3]hept-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0186] 107)((2-(3'-(5-((1-azaspiro[3.3]hept-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0187] 108)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(6-(pyrrolidin-1-yl-methyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0188] 109)((6-(difluoromethoxy)-2-(3'-(6-((3,3-dimethylazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0189] 110)((2-(2'-chloro-3'-(6-((3,3-dimethylazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0190] 111)((2-(2'-chloro-3'-(6-((3,3-dimethylazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-D-proline;

[0191] 112)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(6-(pyrrolidin-1-ylmethyl)oxazolo[5,4-b]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0192] 113)((6-(difluoromethoxy)-2-(3'-(6-((3,3-dimethylazetidin-1-yl)methyl)oxazolo[5,4-b]pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0193] 114)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(6-(((R)-3-methylpyrrolidin-1-yl)methyl)oxazolo[5,4-b]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0194] 115)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(6-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)oxazolo[5,4-b]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0195] 116)((6-(difluoromethoxy)-2-(3'-(6-((3-(dimethylamino)azetidin-1-yl)methyl)oxazolo[5,4-b]pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0196] 117)((2-(3'-(6,7-difluoro-5-(pyrrolidin-1-ylmethyl)benzo[d]oxazol-2-yl)-2'-methoxy-2-methyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0197] 118)((2-(2'-cyano-3'-(6,7-difluoro-5-(pyrrolidin-1-ylmethyl)benzo[d]oxazol-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0198] 119)((2-(3'-(6-((6-cyanopyridin-3-yl)methoxy)-5-(((2-hydroxyethyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0199] 120)((2-(3'-(6-((5-cyanopyridin-3-yl)methoxy)-5-(((2-hydroxyethyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0200] 121)((6-(difluoromethoxy)-2-(3'-(5-(((2-hydroxyethyl)amino)methyl)-6-((5-(methylsulfonyl)pyridin-3-yl)methoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0201] 122)((6-(difluoromethoxy)-2-(3'-(5-((ethylamino)methyl)-6-((5-(methylsulfonyl)pyridin-3-yl)methoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0202] 123)((6-(difluoromethoxy)-2-(3'-(5-((dimethylamino)methyl)-6-((5-(methylsulfonyl)pyridin-3-yl)methoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0203] 124)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-((methylamino)methyl)-6-((3-(methylsulfonyl)benzyl)oxy)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0204] 125)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-((methylamino)methyl)-6-((4-(methylsulfonyl)benzyl)oxy)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0205] 126)((6-(difluoromethoxy)-2-(3'-(5-((dimethylamino)methyl)-6-((4-(methylsulfonyl)benzyl)oxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0206] 127)((2-(3'-(7-cyano-5-(pyrrolidin-1-yl-methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0207] 128)((2-(2-cyano-3'-(6-(difluoromethoxy)-5-((3,3-dimethylazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0208] 129)((2-(3'-(7-cyano-5-((3-(hydroxymethyl)-3-methylazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0209] 130)((2-(3'-(7-cyano-5-(((S)-3-methylpyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0210] 131)((2-(3'-(7-cyano-5-(((R)-3-methylpyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0211] 132)((2-(3'-(7-cyano-5-(((R)-3-methylpyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-D-proline;

[0212] 133)((2-(3'-(7-cyano-5-(((3-methyloxetan-3-yl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0213] 134)((2-(3'-(7-cyano-5-((3-(dimethylamino)azetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0214] 135)((2-(3'-(7-cyano-5-((2-(2-hydroxyethyl)piperidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0215] 136)((2-(3'-(7-cyano-5-(((cyanomethyl)(methyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0216] 137)((2-(3'-(7-cyano-5-((3-(hydroxymethyl)azetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0217] 138)((2-(3'-(7-cyano-5-(((2-hydroxy-2-methylpropyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0218] 139)((2-(3'-(7-cyano-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0219] 140)((2-(3'-(7-cyano-5-((3,3-dimethylazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-D-proline;

[0220] 141)((2-(3'-(7-cyano-5-((ethyl(2-hydroxyethyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0221] 142)((2-(3'-(7-cyano-5-((3-cyanopyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0222] 143)((2-(3'-(7-cyano-5-((3-cyanopyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-D-proline;

[0223] 144)((2-(3'-(7-cyano-5-((3-ethynyl-3-hydroxyazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0224] 145)((2-(3'-(7-cyano-5-(pyrrolidin-1-ylmethyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-D-proline;

[0225] 146)((2-(3'-(7-cyano-5-((7-oxo-2,6-diazaspiro[3.4]octan-2-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0226] 147)((2-(3'-(5-((bis(1-hydroxypropan-2-yl)amino)methyl)-7-cyanobenzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0227] 148)((2-(3'-(7-cyano-5-((3-morpholinoazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0228] 149)((2-(3'-(7-cyano-5-((3-(methyl(oxetan-3-yl)amino)azetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0229] 150)((2-(3'-(7-cyano-5-((3-hydroxy-3-methyl-[1,3'-diazetidin-1'-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0230] 151)((2-(3'-(7-cyano-5-((6-oxo-2,5-diazaspiro[3.4]octan-2-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0231] 152)((2-(3'-(7-cyano-5-((3-((dimethylamino)methyl)pyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0232] 153)((2-(3'-(7-cyano-5-((1,1-difluoro-5-azaspiro[2.4]hept-5-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0233] 154)((2-(3'-(7-cyano-5-(((R)-3-(hydroxymethyl)pyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0234] 155)((2-(3'-(7-cyano-5-(((3-hydroxycyclobutyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0235] 156)((2-(3'-(5-((3-amino-4-methylpyrrolidin-1-yl)methyl)-7-cyanobenzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0236] 157)((2-(3'-(5-(((azetidin-3-ylmethyl)amino)methyl)-7-cyanobenzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0237] 158)((2-(3'-(7-cyano-5-((3-(dimethylamino)-4-methylpyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0238] 159)((2-(3'-(7-cyano-5-((3-((dimethylamino)methyl)-3-methylazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0239] 160)((2-(3'-(7-cyano-5-((((1-methyl-1H-imidazol-4-yl)methyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0240] 161)((2-(3'-(5-((3-(aminomethyl)-3-methylazetidin-1-yl)methyl)-7-cyanobenzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0241] 162)((2-(3'-(7-cyano-5-((3-fluoropyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0242] 163)((2-(3'-(7-cyano-5-((3-fluoropyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-D-proline;

[0243] 164)((2-(3'-(7-cyano-5-((3,4-difluoropyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0244] 165)((2-(3'-(7-cyano-5-(((R)-3-cyanopyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0245] 166)((6-(difluoromethoxy)-2-(3'-(5-((3-fluoropyrrolidin-1-yl)methyl)-7-(trifluoromethyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0246] 167)((2-(3'-(7-cyano-5-((3-fluoro-3-methylpyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0247] 168)((2-(3'-(7-cyano-5-(((R)-3-(fluoromethyl)pyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0248] 169)(R)-1-((2-(3'-(7-cyano-5-(pyrrolidin-1-ylmethyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid;

[0249] 170)((6-(difluoromethoxy)-2-(3'-(6-((3,3-dimethylazetidin-1-yl)methyl)oxazolo[5,4-b]pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-D-proline;

[0250] 171)S)-1-((8-((3'-(5-(((S)-2-carboxypyrrolidin-1-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)-2-methylpyrrolidine-2-carboxylic acid;

[0251] 172)((2-(3'-((3-((carboxymethyl)amino)methyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0252] 173)(S)-1-((8-((3'-(5-(((S)-2-carboxypyrrolidin-1-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)piperidine-2-carboxylic acid;

[0253] 174)((6-(difluoromethoxy)-2-(3'-((3-((3-fluoropyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0254] 175)((6-(difluoromethoxy)-2-(3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0255] 176)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-((3-(morpholinomethyl)-1,7-naphthyridin-8-yl)amino)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0256] 177)((2-(3'-((3-(azetidin-1-ylmethyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)proline;

[0257] 178)((6-(difluoromethoxy)-2-(3'-((3-((3-hydroxyazetidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)proline;

[0258] 179)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-((3-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)-1,7-naphthyridin-8-yl)amino)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)proline;

[0259] 180)(3S)-1-((6-(difluoromethoxy)-2-(3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid;

[0260] 181)(3R)-1-((6-(difluoromethoxy)-2-(3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid;

[0261] 182)((6-(difluoromethoxy)-2-(3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-D-proline;

[0262] 183)((5-(difluoromethoxy)-2-(2,2'-dimethyl-3'-((4-(pyrrolidin-1-ylmethyl)pyridin-2-yl)amino)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-6-yl)methyl)-L-proline;

[0263] 184)((2-(3'-(5-(carboxymethyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0264] 185)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(2-(methylsulfonyl)ethyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0265] 186)((2-(3'-(5-(1-carboxyethyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0266] 187)((2-(3'-(5-(2-carboxyethyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0267] 188)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0268] 189)((6-(difluoromethoxy)-2-(3'-(5-(2-hydroxyethyl)-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0269] 190)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0270] 191)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)proline;

[0271] 192)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(oxetan-2-ylmethyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)proline;

[0272] 193)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-((5-oxopyrrolidin-2-yl)methyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)proline;

[0273] 194)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(pyridin-3-ylmethyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)proline;

[0274] 195)((2-(3'-(5-(cyanomethyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)proline;

[0275] 196)((2-(3'-(5-(2-amino-2-oxoethyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)proline;

[0276] 197)((6-(difluoromethoxy)-2-(3'-(5-(ethylsulfonyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)proline;

[0277] 198)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)proline;

[0278] 199)((6-(difluoromethoxy)-2-(3'-(5-(3-hydroxypropyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)proline;

[0279] 200)((6-(difluoromethoxy)-2-(3'-(5-(3-fluoropropyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)proline;

[0280] 201)((2-(3'-(5-(2,2-difluoroethyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)proline;

[0281] 202)((6-(difluoromethoxy)-2-(3'-(5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)proline;

[0282] 203)((6-(difluoromethoxy)-2-(3'-(6,7-dihydro-4H-pyrano[3,4-d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)proline;

[0283] 204)((6-(difluoromethoxy)-2-(3'-(5,6-dihydro-4H-cyclopenta[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)proline;

[0284] 205)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(4,5,6,7-tetrahydrobenzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)proline;

[0285] 206)((6-(difluoromethoxy)-2-(3'-(5-(2-hydroxyethyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0286] 207) 2-((2-(2'-cyano-2-methyl-3'-(4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)pyrrolidine-1-carboxylic acid;

[0287] 208)((2-(3'-((2-chloro-5-((5-(difluoromethoxy)pyridin-3-yl)methoxy)-4-(((R)-3-hydroxypyrrolidin-1-yl)methyl)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0288] 209)((2-(3'-((2-chloro-5-((5-(difluoromethoxy)pyridin-3-yl)methoxy)-4-((3-fluoropyrrolidin-1-yl)methyl)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0289] 210)((2-(3'-((4-(((2-acetamidoethyl)amino)methyl)-2-chloro-5-((3-cyanobenzyl)oxy)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0290] 211)((2-(3'-((4-(((S)-2-carboxypyrrolidin-1-yl)methyl)-2-chloro-5-((3-cyanobenzyl)oxy)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0291] 212)((6-(difluoromethoxy)-2-(3'-(((4,6-dimethoxy-5-(pyrrolidin-1-yl-methyl)pyrimidin-2-yl)oxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0292] 213)((6-(difluoromethoxy)-2-(3'-(((5-((3,3-dimethylazetidin-1-yl)methyl)-4,6-dimethoxypyrimidin-2-yl)oxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0293] 214)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-((5-(((((S)-5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)oxy)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0294] 215)((6-(difluoromethoxy)-2-(2′-fluoro-2-methyl-4″-(((((S)-5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0295] 216)((6-(difluoromethoxy)-2-(3″-(difluoromethoxy)-2′-fluoro-2-methyl-4″-(((((S)-5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0296] 217)((6-(difluoromethoxy)-2-(4″-(((2-hydroxyethyl)amino)methyl)-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0297] 218)((6-(difluoromethoxy)-2-(2,2',3"-trimethyl-4"-(pyrrolidin-1-ylmethyl)-[1,1':3',1"-terphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)proline;

[0298] 219)((2-(3″-chloro-2,2′-dimethyl-4″-(pyrrolidin-1-ylmethyl)-[1,1′:3′,1″-terphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)proline;

[0299] 220)((6-(difluoromethoxy)-2-(2″-fluoro-2,2′-dimethyl-4″-(pyrrolidin-1-ylmethyl)-[1,1′:3′,1″-terphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)proline;

[0300] 221)((2-(2'-bromo-2"-fluoro-2-methyl-4"-(pyrrolidin-1-ylmethyl)-[1,1':3',1"-terphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)proline;

[0301] 222)((2-(2'-chloro-2"-fluoro-2-methyl-4"-(pyrrolidin-1-ylmethyl)-[1,1':3',1"-terphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)proline;

[0302] 223)((2-(2'-chloro-2"-fluoro-2-methyl-4"-(pyrrolidin-1-ylmethyl)-[1,1':3',1"-terphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0303] 224)((2-(2'-chloro-2"-fluoro-2-methyl-4"-(pyrrolidin-1-ylmethyl)-[1,1':3',1"-terphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-D-proline;

[0304] 225)((6-(difluoromethoxy)-2-(4″-guanidino-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0305] 226)((6-(difluoromethoxy)-2-(4″-(((3-(dimethylamino)propyl)(methyl)amino)methyl)-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0306] 227)((6-(difluoromethoxy)-2-(4″-((3-methoxypyrrolidin-1-yl)methyl)-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0307] 228)((6-(difluoromethoxy)-2-(4″-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0308] 229)((2-(3″-chloro-2,2′-dimethyl-4″-(pyrrolidin-1-ylmethyl)-[1,1′:3′,1″-terphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0309] 230)((6-(difluoromethoxy)-2-(2,2′,3″-trimethyl-4″-(pyrrolidin-1-ylmethyl)-[1,1′:3′,1″-terphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0310] 231)((2-(2″-chloro-2,2′-dimethyl-4″-(pyrrolidin-1-ylmethyl)-[1,1′:3′,1″-terphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0311] 232)((6-(difluoromethoxy)-2-(2,2'-dimethyl-4"-(pyrrolidin-1-ylmethyl)-3"-(trifluoromethoxy)-[1,1':3',1"-terphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0312] 233)((6-(difluoromethoxy)-2-(2,2'-dimethyl-4"-(pyrrolidin-1-ylmethyl)-3"-(trifluoromethyl)-[1,1':3',1"-terphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0313] 234)((6-(difluoromethoxy)-2-(2,2′,3″,5″-tetramethyl-4″-(pyrrolidin-1-ylmethyl)-[1,1′:3′,1″-terphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0314] 235)((6-(difluoromethoxy)-2-(3″-fluoro-5″-methoxy-2,2′-dimethyl-4″-(pyrrolidin-1-ylmethyl)-[1,1′:3′,1″-terphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0315] 236)((2-(3″-carboxy-2,2′-dimethyl-4″-(pyrrolidin-1-yl-methyl)-[1,1′:3′,1″-terphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0316] 237)((6-(difluoromethoxy)-2-(4″-((3,3-dimethylazetidin-1-yl)methyl)-3″-fluoro-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0317] 238)((6-(difluoromethoxy)-2-(3″-fluoro-2,2′-dimethyl-4″-((3-methylpyrrolidin-1-yl)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0318] 239)((6-(difluoromethoxy)-2-(3″-fluoro-4″-(((2-hydroxyethyl)amino)methyl)-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0319] 240)((2-(3″-cyano-4″-(((S)-3-(hydroxymethyl)pyrrolidin-1-yl)methyl)-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0320] 241)((6-(difluoromethoxy)-2-(3″-fluoro-4″-(isoindolin-2-ylmethyl)-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)proline;

[0321] 242)((6-(difluoromethoxy)-2-(4″-((3-fluoropyrrolidin-1-yl)methyl)-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)proline;

[0322] 243)((6-(difluoromethoxy)-2-(3″-fluoro-2,2′-dimethyl-4″-(pyrrolidin-1-ylmethyl)-[1,1′:3′,1″-terphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0323] 244)((6-(difluoromethoxy)-2-(3″-(difluoromethoxy)-2,2′-dimethyl-4″-(pyrrolidin-1-ylmethyl)-[1,1′:3′,1″-terphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0324] 245)((2-(3″-cyano-2,2′-dimethyl-4″-(pyrrolidin-1-ylmethyl)-[1,1′:3′,1″-terphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0325] 246)((6-(difluoromethoxy)-2-(3'-(6-methoxy-5-(((S)-3-methylpyrrolidin-1-yl)methyl)pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0326] 247)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-4-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0327] 248)((6-(difluoromethoxy)-2-(3″-fluoro-2,2′-dimethyl-4″-(((S)-3-phenylpyrrolidin-1-yl)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)proline;

[0328] 249)((6-(difluoromethoxy)-2-(3″-(4-fluorophenethoxy)-2,2′-dimethyl-4″-(pyrrolidin-1-ylmethyl)-[1,1′:3′,1″-terphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)proline;

[0329] 250)((2-(3″-(cyclopropylmethoxy)-2,2′-dimethyl-4″-(pyrrolidin-1-ylmethyl)-[1,1′:3′,1″-terphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)proline;

[0330] 251)((2-(4″-(((R)-3-(1H-tetrazol-5-yl)pyrrolidin-1-yl)methyl)-3″-fluoro-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)proline;

[0331] 252)((2-(4″-(((S)-3-((benzyloxy)methyl)pyrrolidin-1-yl)methyl)-3″-fluoro-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)proline;

[0332] 253)((6-(difluoromethoxy)-2-(2″-fluoro-2,2′-dimethyl-4″-(pyrrolidin-1-ylmethyl)-[1,1′:3′,1″-terphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0333] 254)((6-(difluoromethoxy)-2-(3″,5″-dimethoxy-2,2′-dimethyl-4″-(pyrrolidin-1-ylmethyl)-[1,1′:3′,1″-terphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline hydrochloride;

[0334] 255)((6-(difluoromethoxy)-2-(2,2'-dimethyl-4"-(pyrrolidin-2-yl)-[1,1':3',1"-terphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0335] 256)((2-(4″-((S)-amino(carboxy)methyl)-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0336] 257)((6-(difluoromethoxy)-2-(4″-(((S)-3-((S)-2-((methoxycarbonyl)amino)-3-methylbutanamide)pyrrolidin-1-yl)methyl)-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0337] 258)((6-(difluoromethoxy)-2-(3″-fluoro-2,2′-dimethyl-4″-((5-ureidoisoindolin-2-yl)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0338] 259)(S)-1-((2-(3'-(7-cyano-5-(((S)-3-methylpyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid;

[0339] 260)((6-(difluoromethoxy)-2-(3″-fluoro-2,2′-dimethyl-4″-((3-ureidopyrrolidin-1-yl)methyl)-[1,1′:3′,1″-terphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0340] 261)((2-(3'-(5-(((S)-3-chloropyrrolidin-1-yl)methyl)-7-cyanobenzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0341] 262)((6-(difluoromethoxy)-2-(3'-(4-fluoro-6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0342] 263)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0343] 264)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(pyrrolidin-1-ylmethyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0344] 265)((6-(difluoromethoxy)-2-(3'-(5-fluoro-6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0345] 266)((6-(difluoromethoxy)-2-(3'-(6-methoxy-5-(pyrrolidin-1-ylmethyl)pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0346] 267)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(6-oxo-5-(pyrrolidin-1-ylmethyl)-1,6-dihydropyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0347] 268)((6-(difluoromethoxy)-2-(2'-(difluoromethyl)-3'-(5-fluoro-6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0348] 269)((6-(difluoromethoxy)-2-(3'-(5-fluoro-6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-2'-(fluoromethyl)-2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0349] 270)((6-(difluoromethoxy)-2-(3'-(2-fluoro-6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0350] 271)((6-(difluoromethoxy)-2-(3'-(5-((3,3-dimethylazetidin-1-yl)methyl)-6-methoxypyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0351] 272)((6-(difluoromethoxy)-2-(3'-(6-methoxy-5-(((R)-3-methylpyrrolidin-1-yl)methyl)pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0352] 273)((6-(difluoromethoxy)-2-(3'-(6-methoxy-5-(((S)-3-methylpyrrolidin-1-yl)methyl)pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-D-proline;

[0353] 274)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(pyrrolidin-1-ylmethyl)-4-vinylpyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0354] 275)((6-(difluoromethoxy)-2-(3'-(5-((3-(difluoromethyl)pyrrolidin-1-yl)methyl)-6-methoxypyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0355] 276)((6-(difluoromethoxy)-2-(3'-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0356] 277)((6-(difluoromethoxy)-2-(3'-(6-methoxy-5-(((S)-2-methylpyrrolidin-1-yl)methyl)pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0357] 278)((2-(3'-(5-(((1s,4s)-7-azabicyclo[2.2.1]hept-7-yl)methyl)-6-methoxypyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0358] 279)((6-(difluoromethoxy)-2-(3'-(6-methoxy-5-(((R)-2-methylpyrrolidin-1-yl)methyl)pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0359] 280)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0360] 281)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(2-(pyrrolidin-1-ylmethyl)pyrimidin-5-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0361] 282)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0362] 283)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(2-(pyrrolidin-1-yl)pyrimidin-5-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0363] 284)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(pyrrolidin-1-ylmethyl)pyrazin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0364] 285)((6-(difluoromethoxy)-2-(3'-(6-methoxy-5-(pyrrolidin-1-ylmethyl)pyrazin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0365] 286)((6-(difluoromethoxy)-2-(3'-(6-methoxy-5-(((R)-3-methylpyrrolidin-1-yl)methyl)pyrazin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0366] 287)((2-(2'-chloro-3'-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyrazin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0367] 288)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(1,2,3,4-tetrahydroisoquinolin-6-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0368] 289)((6-(difluoromethoxy)-2-(3'-(isoindolin-5-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0369] 290)((2-(3'-(2-(2-carboxyethyl)isoindolin-5-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0370] 291)((2-(3'-(2-(carboxymethyl)isoindolin-5-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0371] 292)((2-(3'-(2-(1-carboxyethyl)isoindolin-5-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0372] 293)((2-(3'-(2-amino-1H-benzo[d]imidazol-5-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0373] 294)((6-(difluoromethoxy)-2-(3'-(5-((3,3-dimethylpyrrolidin-1-yl)methyl)-6-methoxypyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0374] 295)((2-(3'-(7-cyano-5-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0375] 296)((2-(3'-(6,7-difluoro-5-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0376] 297)((6-(difluoromethoxy)-2-(3'-(6-fluoro-5-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0377] 298)((2-(3'-(6,7-difluoro-1-methyl-5-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0378] 299)((2-(3'-(6,7-difluoro-5-(pyrrolidin-1-ylmethyl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0379] 300)((2-(3'-(4,5-difluoro-6-(pyrrolidin-1-ylmethyl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0380] 301)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(pyrrolidin-1-ylmethyl)-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0381] 302)((2-(2'-chloro-3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-2-methyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0382] 303)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamido)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0383] 304)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(4-methyl-5-(pyrrolidin-1-ylmethyl)oxazol-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0384] 305)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(6-(pyrrolidin-1-ylmethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0385] 306)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(4-(pyrrolidin-1-yl)piperidin-1-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0386] 307)((6-(difluoromethoxy)-2-(3'-(4-(((1-(hydroxymethyl)cyclopropyl)methyl)amino)piperidin-1-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0387] 308)((6-(difluoromethoxy)-2-(3'-(4-((3,3-dimethylazetidin-1-yl)methyl)piperidin-1-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0388] 309)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(4-(pyrrolidin-1-ylmethyl)piperidin-1-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0389] 310)((6-(difluoromethoxy)-2-(3'-(5-((((1R,2S)-2-hydroxycyclopentyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-D-proline;

[0390] 311)((6-(difluoromethoxy)-2-(3'-(5-((2,2-dimethylpyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0391] 312)((6-(difluoromethoxy)-2-(3'-(5-((3,3-dimethylazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0392] 313)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-((2-methylazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0393] 314)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-methyl-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

[0394] 315)((2-(3'-(5-((3-carbamoylpyrrolidin-1-yl)methyl)-7-cyanobenzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline; or

[0395] 316)((2-(3'-(7-cyano-5-((3-cyano-3-methylpyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline.

[0396] The present invention also provides a pharmaceutical composition comprising any compound of the present invention and a pharmaceutically acceptable excipient, such as hydroxypropyl methylcellulose. In the composition, the weight ratio of the compound to the excipient is in the range of about 0.0001 to about 10.

[0397] The present invention also provides use of the pharmaceutical composition of formula (I) in preparing a medicament for treating a disease in a subject.

[0398] The present invention further provides a preferred technical solution for the application.

[0399] The present invention also provides use of the compound or its pharmaceutical composition in preparing medicines.

[0400] In some embodiments, the medicament is for treating or preventing cancer.

[0401] In some embodiments, the cancer is colon cancer, stomach cancer, thyroid cancer, lung cancer, leukemia, pancreatic cancer, melanoma, multiple melanomas, brain cancer, kidney cancer, prostate cancer, ovarian cancer, or breast cancer.

[0402] In some embodiments, the drug acts as a PD-1 / PD-L1 interaction inhibitor.

[0403] In some embodiments, the medicament is used to enhance, stimulate and / or increase the immune response of a patient.

[0404] The general chemical terms used in the formula have their usual meanings. For example, unless otherwise indicated, the term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine. Preferred halogen groups include F, Cl and Br.

[0405] Unless otherwise specified, the alkyl group used in the present invention includes a saturated monovalent hydrocarbon group having a straight chain, branched chain or cyclic group. For example, the alkyl group includes methyl, ethyl, propyl, isopropyl, cyclopropyl, n-n-butyl, isobutyl, sec-butyl, t-butyl, cyclobutyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl. Similarly, as in C 1-4 C in the alkyl group 1-4 It refers to a group containing 1, 2, 3 or 4 carbon atoms arranged in a straight chain, branched or cyclic form.

[0406] Alkenyl and alkynyl groups include straight chain, branched or cyclic alkenes and alkynes. Likewise, "C 2-8 Alkenyl" and "C 2-8 "Alkynyl" refers to an alkenyl or alkynyl group containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms arranged in a straight chain, branched or cyclic form.

[0407] The alkoxy group is an oxygen ether formed from the aforementioned linear, branched or cyclic alkyl group.

[0408] As used herein, unless otherwise indicated, the term "aryl" refers to an unsubstituted or substituted monocyclic or polycyclic ring system containing carbon ring atoms. Preferred aryl groups are monocyclic or bicyclic 6-8 membered aromatic ring systems. Preferred aryl groups are benzene or naphthalene rings. Most preferred aryl groups are benzene rings.

[0409] Unless otherwise indicated, the term "heterocyclyl" as used herein represents an unsubstituted or substituted 3 to 10-membered saturated or partially unsaturated monocyclic, spirocyclic, bridged bicyclic or fused bicyclic ring system containing carbon atoms and 1-3 heteroatoms selected from N, O or S, wherein the N or S heteroatom may be optionally oxidized, or the N heteroatom may be optionally quaternized. The heterocyclyl may be attached to any heteroatom or carbon atom that forms a stable structure. Examples of heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, pyridyl, piperazinyl, oxypiperazinyl, oxazepine, azepine, tetrahydrofuranyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone and oxadiazolyl.

[0410] Unless otherwise indicated, the term "heteroaryl" as used herein refers to an unsubstituted or substituted stable 5- or 6-membered monoaromatic ring system, or an unsubstituted or substituted 9- or 10-membered benzo-fused heteroaromatic ring system, or a bicyclic heteroaromatic ring system, wherein the "heteroaryl" comprises carbon atoms and 1 to 4 heteroatoms selected from N, O or S, wherein the N or S atom may be optionally oxo-substituted and the N atom may be optionally quaternized. The heteroaryl group may be attached at any heteroatom or carbon atom that forms a stable structure. Examples of such heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyladeninyl, quinolinyl, or isoquinolinyl.

[0411] The term "alkenyloxy" refers to an -O-alkenyl group, wherein alkenyl is as defined above.

[0412] The term "alkynyloxy" refers to an -O-alkynyl group, wherein alkynyl is as defined above.

[0413] The term "cycloalkyl" refers to a cyclic saturated alkyl chain containing 3 to 12 carbon atoms, for example, cyclopropyl, cyclobutyl.

[0414] The term "substituted" refers to a group in which one or more hydrogen atoms are independently replaced by the same or different substituents. Typical substituents include but are not limited to halogen (F, Cl, Br or I), C 1-8 Alkyl, C 3-12 Cycloalkyl, -OR 1 SR 1 , =O, =S, -C(O)R 1 、-C(S)R 1 、=NR 1 、-C(O)OR 1 、-C(S)OR 1 、-NR 1 R 2 、C(O)NR 1 R 2 , cyano, nitro, -S(O)2R 1 、-OS(O2)OR 1 、-OS(O)2R 1 、-OP(O)(OR 1 )(OR 2 ); where R 1 and R 2Independently selected from -H, lower alkyl, lower haloalkyl. In some embodiments, the substituent is independently selected from -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, isobutoxy, t-butoxy, -SCH , -SC 2 H 5 , formaldehyde, -C (OCH 3 ), cyano, nitro, CF 3 , -OCF 3 , amino, dimethylamino, methylsulfide, sulfonyl and acetyl.

[0415] The term "composition" as used herein is intended to encompass products comprising specified ingredients in specified amounts, as well as any product produced directly or indirectly by the combination of specified ingredients in specified amounts. Therefore, pharmaceutical compositions comprising the compounds of the present invention as active ingredients and methods for preparing the compounds of the present invention are also part of the present invention. In addition, some crystalline forms of the compounds may exist as polymorphs, which are also intended to be included in the present invention. In addition, some compounds may form solvates with water (i.e., hydrates) or common organic solvents, which are also intended to be included within the scope of the present invention.

[0416] Examples of substituted alkyl groups include, but are not limited to, 2-aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, methoxymethyl, pentafluoroethyl, and piperazinylmethyl.

[0417] Examples of substituted alkoxy groups include, but are not limited to, aminomethoxy, trifluoromethoxy, 2-ethoxyaminoethoxy, 2-ethoxycarbonylethoxy, and 3-hydroxypropoxy.

[0418] The compounds of the present invention may also exist in the form of pharmaceutically acceptable salts. For pharmaceutical applications, the salt forms of the compounds of the present invention refer to non-toxic "pharmaceutically acceptable salts." The pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic / anionic or basic / cationic salts. The pharmaceutically acceptable acidic / anionic salts are generally formed in which the basic nitrogen atom is protonated by an inorganic or organic acid. Representative organic or inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, lactic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, oxalic acid, pamoic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, cyclohexanesulfonic acid, salicylic acid, sugar acid, or trifluoroacetic acid. The pharmaceutically acceptable basic / cationic salts include, but are not limited to, aluminum salts, calcium salts, chloroprocaine salts, choline salts, diethanolamine salts, ethylenediamine salts, lithium salts, magnesium salts, potassium salts, sodium salts, and zinc salts.

[0419] Prodrugs of the compounds of the present invention are encompassed within the scope of protection of the present invention. Typically, such prodrugs are functional derivatives that are readily converted into the desired compound in vivo. Therefore, the term "administering" as used in the treatment methods provided herein includes administering a compound disclosed herein, or, although not explicitly disclosed, a compound that, upon administration to a subject, is converted in vivo into a compound disclosed herein to treat the various diseases described. Conventional methods for selecting and preparing suitable prodrug derivatives are described in books such as "Design of Prodrugs" (ed. H. Bundgaard, Elsevier, 1985).

[0420] Obviously, the definition of any substituent or variable at a particular position in one molecule is independent of the definition of any substituent or variable at a particular position in other molecules. It is readily understood that the compounds of the present invention can be prepared by selecting appropriate substituents or substitution patterns according to the prior art in the subject matter to provide compounds that are chemically stable and readily prepared and synthesized using the methods described in the prior art or in the present invention.

[0421] The compounds of the present invention may contain one or more asymmetric centers and may thus produce diastereomers and optical isomers. The present invention includes all possible diastereomers and racemic mixtures thereof, their substantially pure resolved enantiomers, all possible geometric isomers and pharmaceutically acceptable salts thereof.

[0422] The above formula I does not precisely define the stereostructure of a particular position of the compound. The present invention includes all stereoisomers of the compound represented by formula (I) and pharmaceutically acceptable salts thereof. Furthermore, mixtures of stereoisomers and isolated specific stereoisomers are also encompassed by the present invention. During the synthetic process for preparing such compounds, or using racemization or epimerization processes known to those skilled in the art, the resulting product may be a mixture of stereoisomers.

[0423] When the compound represented by formula (I) exists in tautomers, unless otherwise stated, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof.

[0424] When the compound shown in formula (I) and its pharmaceutically acceptable salt exist solvate or polymorph, the present invention includes any possible solvate and polymorph. The type of solvent that forms solvate is not particularly limited, as long as the solvent is pharmacologically acceptable. For example, similar solvents such as water, ethanol, propanol, acetone can be adopted.

[0425] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid. When the compound provided by the present invention is an acid, its corresponding salt can be prepared from a pharmaceutically acceptable non-toxic base, including inorganic bases and organic bases. Salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper (ic and ous), iron, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like. In particular, ammonium, calcium, magnesium, potassium and sodium salts are preferred. Non-toxic organic bases from which pharmaceutically acceptable salts can be derived include primary, secondary and tertiary amines, as well as cyclic amines and substituted amines, such as naturally occurring and synthetic substituted amines. Other pharmaceutically acceptable non-toxic organic bases capable of forming salts include ion exchange resins and arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, halamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0426] When the compound provided by the present invention is a base, its corresponding salt can be prepared from a pharmaceutically acceptable non-toxic acid, including inorganic and organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and the like. Preferably, methanesulfonic acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid. More preferably, phosphoric acid, hydrochloric acid, and malic acid. Since the compound represented by formula (I) is intended for pharmaceutical use, it is preferably used in substantially pure form, for example, at least 60% pure, more preferably at least 75% pure, and particularly preferably at least 98% pure (% by weight).

[0427] The pharmaceutical compositions provided herein include a compound of formula (I) (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable excipient, and other optional therapeutic components or adjuvants. Although the most suitable mode of administration of the active ingredient in any given case depends on the specific subject receiving the administration, the subject's properties, and the severity of the condition, the pharmaceutical compositions of the present invention include pharmaceutical compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous administration, intramuscular injection, and intravenous administration) administration. The pharmaceutical compositions of the present invention can be conveniently present in unit dosage forms known in the art and prepared by any preparation method known in the pharmaceutical field.

[0428] In practice, according to conventional pharmaceutical compounding techniques, the compound represented by formula (I) of the present invention, or a prodrug, metabolite, or pharmaceutically acceptable salt thereof, can be mixed as an active ingredient with a pharmaceutical carrier to form a pharmaceutical composition. The pharmaceutical carrier can take a variety of forms, depending on the desired route of administration, for example, oral or parenteral (including intravenous). Therefore, the pharmaceutical composition of the present invention can be in the form of individual units suitable for oral administration, such as capsules, cachets, or tablets containing a predetermined dose of the active ingredient. Furthermore, the pharmaceutical composition of the present invention can be in the form of a powder, granules, solution, aqueous suspension, non-aqueous liquid, oil-in-water emulsion, or water-in-oil emulsion. In addition to the common dosage forms mentioned above, the compound represented by formula (I) or its pharmaceutically acceptable salt can also be administered via controlled release and / or delivery devices. The pharmaceutical composition of the present invention can be prepared by any pharmaceutical method. Generally, such methods include the step of bringing the active ingredient into association with a carrier that constitutes one or more necessary components. Generally, the pharmaceutical composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely divided solid carrier, or a mixture of the two. In addition, the product can be easily prepared into a desired appearance.

[0429] Therefore, the pharmaceutical composition of the present invention comprises a pharmaceutically acceptable carrier and a compound represented by formula (I), or a pharmaceutically acceptable salt thereof. The combination of the compound represented by formula (I), or a pharmaceutically acceptable salt thereof, with one or more other therapeutically active drugs is also included in the pharmaceutical composition of the present invention.

[0430] The pharmaceutical carrier used in the present invention can be, for example, a solid carrier, a liquid carrier, or a gaseous carrier. Examples of solid carriers include lactose, gypsum, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, and stearic acid. Examples of liquid carriers include syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen. When preparing oral pharmaceutical formulations, any convenient pharmaceutical medium can be used. For example, water, ethylene glycol, oils, alcohols, flavor enhancers, preservatives, colorants, etc. can be used in the preparation of oral liquid formulations such as suspensions, elixirs, and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants, etc. can be used in the preparation of oral solid formulations such as powders, capsules, and tablets. Tablets and capsules are preferred for oral formulations due to ease of administration. Alternatively, tablet coating can be performed using standard aqueous or non-aqueous formulation techniques.

[0431] Tablets containing the compounds or pharmaceutical compositions of the present invention can be prepared by compression or molding, optionally with one or more auxiliary ingredients or adjuvants. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as a powder or granules, mixed with a lubricant, an inert diluent, a surface active agent, or a dispersant, in a suitable machine. Molded tablets can be prepared by moistening the powdered compound or pharmaceutical composition with an inert liquid diluent and then molding it in a suitable machine. Preferably, each tablet contains about 0.05 mg to 5 g of the active ingredient, and each cachet or capsule contains about 0.05 mg to 5 g of the active ingredient. For example, dosage forms intended for oral administration to humans contain about 0.5 mg to about 5 g of the active ingredient, compounded with suitable and conveniently metered auxiliary materials, which may comprise from 5% to 95% of the total pharmaceutical composition. Unit dosage forms generally contain from about 1 mg to about 2 g of the active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

[0432] The pharmaceutical compositions provided herein for parenteral administration can be prepared by adding the active ingredient to water to form an aqueous solution or suspension. Suitable surfactants such as hydroxypropylcellulose may be included. Dispersions can also be prepared using glycerol, liquid polyethylene glycol, or mixtures thereof in oils. Furthermore, preservatives may be included in the pharmaceutical compositions of the present invention to prevent the growth of harmful microorganisms.

[0433] The present invention provides pharmaceutical compositions suitable for injection use, including sterile aqueous solutions or dispersions. Further, the above-mentioned pharmaceutical compositions can be prepared into the form of sterile powders that can be used for immediate preparation of sterile injections. In any case, the final injection form must be sterile and, in order to be easy to inject, must be easy to flow. In addition, the pharmaceutical composition must be stable during preparation and storage. Therefore, it is preferred to preserve the contamination of antimicrobial agents such as bacteria and fungi. The carrier can be a solvent or dispersion medium, for example, water, ethanol, polyols (such as glycerol, propylene glycol, liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0434] The pharmaceutical composition provided by the present invention can be in a form suitable for topical administration, for example, an aerosol, emulsion, ointment, lotion, dusting powder, or other similar dosage forms. Furthermore, the pharmaceutical composition provided by the present invention can be in a form suitable for use with a transdermal drug delivery device. These preparations can be prepared using the compound represented by formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, by conventional processing methods. As an example, the preparation of an emulsion or ointment is by adding a hydrophilic material and water (the total amount of the two is about 5wt% to 10wt% of the compound) to the above-mentioned compound to obtain an emulsion or ointment with the desired consistency.

[0435] The pharmaceutical composition provided by the present invention can be prepared in a form suitable for rectal administration using a solid as a carrier. A unit dose suppository of the mixture is the most preferred dosage form. Suitable adjuvants include cocoa butter and other materials commonly used in the art. Suppositories can be easily prepared by first mixing the pharmaceutical composition with softened or melted adjuvants, then cooling and molding the mixture into a mold.

[0436] In addition to the aforementioned carrier components, the pharmaceutical preparations may also include, where appropriate, one or more additional excipient components, such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants), and the like. Furthermore, other excipients may include penetration enhancers to adjust the osmotic pressure between the drug and blood. Pharmaceutical compositions containing the compound of formula (I), or a pharmaceutically acceptable salt thereof, may also be prepared in the form of a powder or concentrate.

[0437] Generally, for the treatment of the conditions indicated above, the dosage level may be about 0.01 mg / kg to 150 mg / kg of body weight per day, or about 0.5 mg to 7 g per patient per day. For example, for colon cancer, rectal cancer, mantle cell lymphoma, multiple myeloma, breast cancer, prostate cancer, glioblastoma, esophageal squamous cell carcinoma, liposarcoma, T-cell lymphoma, melanoma, pancreatic cancer, glioblastoma, or lung cancer, the effective dosage level may be about 0.01 mg / kg to 50 mg / kg of body weight per day, or about 0.5 mg to 3.5 g per patient per day.

[0438] However, it is understood that doses lower or higher than those recited above may be acceptable. The specific dosage level and dosage regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health, sex, diet, time of administration, route of administration, excretion rate, combination use of drugs, severity and course of the specific disease being treated, the subject's predisposition to the disease, and the judgment of the treating physician.

[0439] These and other aspects will become apparent from the following written description of the invention.

[0440] The following examples are provided to better illustrate the present invention. Unless otherwise expressly stated, all parts and percentages are by weight and all temperatures are in degrees Celsius.

[0441] The present invention is described in more detail by way of specific examples. The following examples are illustrative only and are not intended to limit the present invention in any way. One skilled in the art can readily identify various non-critical parameters that can be changed or modified to achieve essentially the same results. According to at least one assay method described herein, it was found that the compounds disclosed in the examples can inhibit the activity of the PD-1 / PD-L1 protein / protein interaction. Example

[0442] The laboratory preparation method of the compound of the present invention is as follows. Open access preparative LCMS purification of some compounds is performed in a Waters mass directed fractionation system. The basic equipment settings, protocols and control software of these systems have been described in detail in the literature. See, for example, "Two-Pump At Column Dilution Configuration for Preparative LC-MS", K.Blom, J.Combi.Chem., 2002, 4, 295-301; Blom et al., "Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification", J.Combi.Chem., 2003, 5, 670-83; and Blom et al., "Preparative LC-MS Purification: Improved Compound Specific Method Optimization", J.Combi.Chem., 2004, 6, 874-883.

[0443] The compounds described herein can be obtained from commercial sources or synthesized by conventional methods as shown below using commercially available starting materials and reagents. The abbreviations used in the examples are as follows:

[0444] EA: ethyl acetate;

[0445] STAB: sodium triacetoxyborohydride;

[0446] TBAI: tetrabutylammonium iodide;

[0447] DMF: dimethylformamide;

[0448] THF: tetrahydrofuran;

[0449] TEA: triethylamine;

[0450] TLC: preparative thin layer chromatography;

[0451] AcOH or HOAC: acetic acid;

[0452] BSA: bovine serum albumin;

[0453] DCM: dichloromethane;

[0454] DDQ: 2,3-dichloro-5,6-dicyano-p-benzoquinone;

[0455] DMSO: dimethyl sulfoxide;

[0456] EtOAc: ethyl acetate;

[0457] h or hrs: hours;

[0458] HTRF: homogeneous time-resolved fluorescence;

[0459] MeOH: methanol;

[0460] min: minute;

[0461] PE: petroleum ether;

[0462] Pd(dppf)Cl2: 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium;

[0463] rt or RT: room temperature;

[0464] TBAI: tetrabutylammonium iodide;

[0465] THF: tetrahydrofuran;

[0466] Pd2(dba)3: tris(dibenzylideneacetone)dipalladium;

[0467] NBS: N-bromosuccinimide;

[0468] BPO: benzoyl peroxide;

[0469] TLC: preparative thin layer chromatography.

[0470] Preparation of intermediates

[0471] Example A Preparation of Intermediate A

[0472] ((6-(difluoromethoxy)-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

[0473]

[0474] Step 1: Preparation of methyl 2,4-dihydroxy-5-nitrobenzoate

[0475]

[0476] Methyl 2,4-dihydroxybenzoate (850 g) was dissolved in a mixture of glacial AcOH (3.6 L) and Ac2O (900 mL). After the clear solution was cooled to 10°C (ice bath), concentrated HNO3 (65%) dissolved in glacial AcOH (500 mL) was added over 1 hour. The light brown solution was warmed to 15-20°C and stirred for 1 hour. The reaction mixture was poured into H2O (3 L), the precipitate was filtered, and the filter cake was washed with a small amount of H2O. The crude product was then poured into MeOH (2 L) with stirring, the precipitate was filtered, and the filter cake was washed with a small amount of MeOH. After vacuum drying, 480 g of the title product was obtained.

[0477] Step 2: Preparation of methyl 5-amino-2,4-dihydroxybenzoate

[0478]

[0479] A solution of compound a-2 (77.1 g) and 10% Pd(OH) / C (11.5 g) in methanol (2 L) was stirred at room temperature under a hydrogen pressure of 1.1 atmospheres for 3 hours. The catalyst was removed by filtration, the solid residue was washed with methanol (300 mL), and the solvent was removed under vacuum. 72 g of methyl 5-amino-2,4-dihydroxybenzoate was obtained.

[0480] Step 3: Preparation of methyl 2-(3-bromo-2-methylphenyl)-6-hydroxybenzo[d]oxazole-5-carboxylate

[0481]

[0482] A solution of methyl 5-amino-2,4-dihydroxybenzoate (32.9 g) and 3-bromo-2-methylbenzaldehyde (32.5 g) in MeOH (1 L) was stirred at 80 ° C for 2.5 hours, and the resulting mixture was subsequently concentrated under reduced pressure. DCM (500 ml) was added to the mixture, and DDQ (55.6 g) was added. The resulting mixture was stirred at room temperature for 1 hour. The reaction was diluted with DCM and washed with Na2S2O3 aqueous solution and NaHCO3 solution. The organic layer was dried with MgSO4, filtered, and the filtrate was then concentrated. The crude product was purified by column chromatography (PE: DCM = 1 / 1) to give 45 g of 2- (3-bromo-2-methylphenyl) -6-hydroxybenzo [d] oxazole -5- carboxylic acid methyl ester as a brown solid.

[0483] Step 4: Preparation of methyl 2-(3-bromo-2-methylphenyl)-6-(difluoromethoxy)benzo[d]oxazole-5-carboxylate

[0484]

[0485] 2-(3-bromo-2-methylphenyl)-6-hydroxybenzo[d]oxazole-5-carboxylic acid methyl ester (10.0 g), sodium 2-bromo-2,2-difluoroacetate (5.46 g), Cs2CO3 (27.09 g), KI (4.59 g), and TBAI (10.22 g) were added to DMF (200 mL), and the mixture was stirred at 100°C for 3 hours. The reaction was diluted with DCM and washed with saturated NaCl solution. The crude product was purified by column chromatography (PE:DCM = 1 / 1) to give 5 g of 2-(3-bromo-2-methylphenyl)-6-(difluoromethoxy)benzo[d]oxazole-5-carboxylic acid methyl ester.

[0486] Step 5: Preparation of (2-(3-bromo-2-methylphenyl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methanol

[0487]

[0488] To a THF (50 mL) solution of 2-(3-bromo-2-methylphenyl)-6-(difluoromethoxy)benzo[d]oxazole-5-carboxylic acid methyl ester (1.30 g) was added dropwise LiAlH4 in THF (2.5 M). The mixture was allowed to warm to room temperature. After 1 h, the mixture was quenched with 1 mL H2O and 1 mL 10% NaOH and washed with 1 M HCl, water, and salt water. The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated to give (2-(3-bromo-2-methylphenyl)-6-(difluoromethoxy)benzo[d]oxazole-5-yl)methanol as a yellow solid (1.2 g).

[0489] Step 6: Preparation of 2-(3-bromo-2-methylphenyl)-6-(difluoromethoxy)benzo[d]oxazole-5-carbaldehyde

[0490]

[0491] To a solution of (2-(3-bromo-2-methylphenyl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methanol (1.40 g) in dry THF (15 mL) was added Dess-Martin (2.39 g) in portions at 10° C. The resulting solution was stirred at room temperature for 1 h. The mixture was filtered through celite. The solid was washed with DCM, and the combined filtrate was washed with aqueous sodium bicarbonate, water, and brine, dried, and concentrated. The resulting residue was purified by column chromatography (eluting with a gradient of n-hexane-ethyl acetate 20:1 to 5:1) to give 2-(3-bromo-2-methylphenyl)-6-(difluoromethoxy)benzo[d]oxazole-5-carbaldehyde (1.27 g).

[0492] Step 7: Preparation of ((2-(3-bromo-2-methylphenyl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

[0493]

[0494] A solution of 2-(3-bromo-2-methylphenyl)-6-(difluoromethoxy)benzo[d]oxazole-5-carbaldehyde (1.0 g), L-proline methyl ester (1.7 g), and HOAC (316 mg) in MeOH was stirred at room temperature for 30 mins. NaBH3CN (498 mg) was added to the mixture, heated to 60°C and stirred for 2 hrs. The mixture was cooled, diluted with DCM, and washed with H2O and NaCl solution. The organic phase was dried over MgSO4, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (DCM:MeOH=10:1) to give 671 mg of ((2-(3-bromo-2-methylphenyl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester as a white solid.

[0495] Step 8: Preparation of ((6-(difluoromethoxy)-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

[0496]

[0497] Under N2 protection, to a solution of ((2-(3-bromo-2-methylphenyl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester (680 mg) in 1,4-dioxane (16.0 ml) were added bis-pinacolatodiboron (1.20 g), Pd(dppf)Cl2 .DCM (100 mg) and KOAc (102 mg). The reaction mixture was heated at 100 ° C for 10 hrs. The reaction solution was then diluted with 30 mL of water and extracted with DCM (90 ml × 2). The combined organic phase was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (eluted with a gradient of n-hexane-ethyl acetate from 4:1 to 2:1) to give ((6-(difluoromethoxy)-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester (500 mg). LC-MS (m / z): 543.2 (M+H) + .

[0498] Example B Synthesis of Intermediate B

[0499] ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

[0500]

[0501] Step 1: Preparation of ((2-(3'-bromo-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

[0502]

[0503] Under N₂ protection, to a solution of Intermediate A (21.7 g) and 1-bromo-3-iodo-2-toluene (9.0 g) in toluene (150 mL) was added EtOH (30 mL), 10% Na₂CO₃ aq. (30 mL), and Pd(dppf)Cl₂.DCM (1.0 g). The mixture was stirred at 90°C overnight. The reaction was quenched with H₂O (100 mL) and extracted three times with EtOAc (100 mL). The organic phases were combined and washed with brine. The resulting solution was concentrated and purified by column chromatography to afford ((2-(3'-bromo-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester (18.2 g) as a brown oil.

[0504] Step 2: Preparation of ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

[0505]

[0506] To a solution of compound b-1 (18.2 g) in 1,4-dioxane (120 mL) under N₂ protection was added bis-pinacolatodiboron (12.4 g), Pd(dppf)Cl₂.DCM (1.0 g), and KOAc (9.9 g). The reaction mixture was heated to 100°C for 6 hours. The reaction mixture was quenched with 300 mL of water and extracted three times with EtOAc (150 mL). The combined organic phases were washed with brine, dried over MgSO₄, and concentrated in vacuo. The residue was purified by column chromatography (eluting with a gradient of n-hexane-ethyl acetate from 20:1 to 10:1) to give ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester (15.1 g) as a brown oil. LC-MS (m / z): 633.9 (M+H) + .

[0507] Example 1 Preparation of Compound 1

[0508] ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((((1R,2S)-2-hydroxycyclopentyl)(methyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline

[0509]

[0510] Step 1: Preparation of ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

[0511]

[0512] To a solution of intermediate A (5 g) in 1,4-dioxane (80 mL) / H₂O (16 mL) were added compound a-6 (3.9 g), K₂CO₃ (3.8 g), and Pd(dppf)Cl₂CH₂Cl₂ (732 mg). The mixture was stirred at 80°C under N₂ protection for 12 hours. Once the starting material had reacted almost completely and the reaction had ceased, the mixture was poured into H₂O (300 mL) and extracted three times with DCM (100 mL). The organic phase was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to yield a residue. The residue was further purified on a silica gel column to yield compound 1-1 (3.7 g).

[0513] Step 2: Preparation of ((2-(3'-(5-(chloromethyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)-yl)methyl)-L-proline methyl ester

[0514]

[0515] Compound 1-1 (1.5 g) was dissolved in DCM (20 mL). SOCl2 (495 mg) was added dropwise to the solution and allowed to react at room temperature for 1 h. The reaction was continued until the starting material was almost completely reacted and the reaction ceased. The resulting mixture was concentrated under reduced pressure to yield 1.56 g of compound 1-2 (crude product).

[0516] Step 3: Preparation of ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((((1R,2S)-2-hydroxycyclopentane)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

[0517]

[0518] A solution of compound 1-2 (300 mg), (1S,2R)-2-aminocyclopentan-1-ol (168 mg), KCO (283 mg), and KI (68 mg) in CHCN (10 mL) was stirred at 50°C for 1.5 hr. The reaction mixture was poured into H2O (30 mL) and extracted three times with DCM (15 mL). The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to yield the crude product. The crude product was further purified using a silica gel column (DCM / MeOH) to yield compound 1-3 (240 mg).

[0519] Step 4: Preparation of ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((((1R,2S)-2-hydroxycyclopentyl)(methyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

[0520]

[0521] A solution of compound 1-3 (240 mg), HCHO (45 mg) and CH3COOH (36 mg) in MeOH (5 mL) / DCM (5 mL) was stirred at 30 ° C for 30 mins, then NaBH3CN (57 mg) was added and stirring was continued until the raw materials were almost completely reacted and the reaction stopped. The reaction solution was poured into H2O (30 mL) and extracted three times with DCM (15 mL). The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a crude product. The crude product was further purified using a silica gel column (DCM / MeOH) to give compound 1-4 (200 mg).

[0522] Step 5: Preparation of ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((((1R,2S)-2-hydroxycyclopentyl)(methyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline (Compound 1)

[0523]

[0524] Compound 1-4 (200 mg) and LiOH (51 mg) were dissolved in a mixture of THF (8 mL) / H₂O (2 mL) and stirred at 35°C for 12 hrs. The reaction solution was poured into H₂O (30 mL) and extracted three times with DCM (10 mL) / MeOH (5 mL). The organic phases were combined, dried over anhydrous MgSO₄, filtered, and concentrated under reduced pressure. This afforded 160 mg of ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((((1R,2S)-2-hydroxycyclopentyl)(methyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline (Compound 1). LC-MS (m / z): 803.3 (M+H). + .

[0525] Example 2 Preparation of Compound 2

[0526] (2'S)-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(6-(difluoromethoxy)benzo[d]oxazole-2,5-diyl))bis(methylene))bis-L-proline

[0527]

[0528] Step 1: Preparation of methyl 6-(difluoromethoxy)-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazole-5-carboxylate

[0529]

[0530] To a solution of compound a-5 (880 mg) in 1,4-dioxane (16.0 mL) were added bis-pinacolatodiboron (1.80 g), Pd(dppf)Cl2 . DCM (150 mg) and KOAc (130 mg) were added. The reaction mixture was heated to 100°C for 10 hr. The reaction mixture was diluted with 30 mL and extracted with DCM (90 mL x 2). The combined organic phases were washed with brine, dried over MgSO4, and concentrated under reduced pressure to obtain a residue. The residue was purified on a silica gel column (eluted with a gradient of n-hexane-ethyl acetate (4:1 to 2:1) to obtain compound 2-1 (600 mg).

[0531] Step 2: Preparation of 2,2'-(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(6-(difluoromethoxy)benzo[d]oxazole-5-carboxylic acid methyl ester)

[0532]

[0533] A solution of compound 2-1 (8 g), compound a-5 (8.95 g), K2CO3 (5.25 g), and Pd(dppf)Cl2.DCM (1.65 g) in 1,4-dioxane (160 mL) / H2O (16 mL) was evacuated and filled with nitrogen three times. The mixture was heated to reflux for 2 hrs. 200 mL of H2O was added to the reaction, and the mixture was extracted with EtOAc (2 × 200 mL). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated to a residue. The residue was purified by column chromatography (EA) to afford compound 2-2 (6.3 g).

[0534] Step 3: Preparation of ((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(6-(difluoromethoxy)benzo[d]oxazole-2,5-diyl))dimethanol

[0535]

[0536] LiAlH4 (2.5 M) was added dropwise to a solution of compound 2-2 (6.3 g) in THF (150 mL) at 0°C. The mixture was stirred at 0°C for 30 min. The reaction mixture was quenched with water at 0°C, dried over Na2SO4, filtered, and concentrated to give compound 2-3 (5.7 g).

[0537] Step 4: Preparation of 2,2'-(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(6-(difluoromethoxy)benzo[d]oxazole-5-carbaldehyde)

[0538]

[0539] Dess-Martin (11.95 g) was added to a solution of compound 2-3 (5.70 g) in THF (100 mL). The mixture was stirred at room temperature for 2 hours. The reaction was quenched with NaHCO and NaSO, and extracted with EtOAc (2 x 100 mL). The combined organic phases were washed with brine (100 mL), dried over NaSO, filtered, and concentrated to afford compound 2-4 (5.5 g).

[0540] Step 5: Preparation of (2'S)-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(6-(difluoromethoxy)benzo[d]oxazole-2,5-diyl))bis(methylene))bis-L-proline (Compound 2)

[0541]

[0542] A solution of compound 2-4 (4 g), L-proline (4.58 g) and AcOH (0.82 g) in MeOH (100 mL) was stirred for 30 mins. NaBH3CN was added to the mixture and stirring was continued for 12 hrs. 200 mL of H2O was added to the reaction and extracted with DCM (2×200 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated to give a crude product. The crude product was purified by column chromatography (DCM / MeOH=10:1) to give 2.56 g of (2'S)-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(6-(difluoromethoxy)benzo[d]oxazole-2,5-diyl))bis(methylene))di-L-proline (Compound 2). LC-MS (m / z): 803.3 (M+H) + .

[0543] Example 3 Synthesis of Compound 3

[0544] ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((S)-2-(methoxycarbonyl)pyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline

[0545]

[0546] Step 1 Preparation of ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-formylbenzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

[0547]

[0548] Dess-Martin (11.79 g) was added portionwise to a solution of compound 1-1 (10.00 g) in THF (200 ml). The mixture was stirred at room temperature for 2 h. The reaction was quenched with NaSO and sodium bicarbonate solution and extracted with EtOAc (2 x 150 ml). The combined organic phases were washed with brine (100 ml), dried over NaSO, and concentrated to afford compound 3-1 (9.50 g).

[0549] Step 2: Preparation of ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((S)-2-(methoxycarbonyl)pyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline

[0550]

[0551] A solution of compound 3-1 (5.90 g), L-proline (2.85 g), and AcOH (0.51 g) in MeOH (60 mL) was stirred for 30 minutes, and then NaBH3CN (1.55 g) was added to the mixture. The reaction was stirred for 3 hours. 100 mL of water was added to the reaction, and the mixture was extracted with DCM (2 × 100 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated to a residue. The residue was purified by column chromatography (DCM / MeOH=10:1) to give ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((S)-2-(methoxycarbonyl)pyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline (3.6 g). LC-MS (m / z): 817.3 (M+H) + .

[0552] Example 4 Synthesis of Compound 4

[0553] ((2-(2'-Cyano-3'-(6-(difluoromethoxy)-5-((3,3-dimethylazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline

[0554]

[0555] Step 1: Preparation of 2-bromo-6-vinylcyanobenzene

[0556]

[0557] Under a nitrogen atmosphere, a solution of 2-bromo-6-m-iodobenzocyanide (10 g), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (5 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.5 g), and potassium carbonate (13.4 g) in 1,4-dioxane (100 mL) / H₂O (20 mL) was stirred at 80°C for 12 hours. The reaction solution was poured into H₂O (30 mL) and extracted with DCM (15 mL x 3). The organic phase was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was further purified by silica gel column chromatography to obtain compound 4-1 (5 g).

[0558] Step 2: Preparation of 2-bromo-6-cyanobenzaldehyde

[0559]

[0560] A solution of compound 4-1 (1 g) and sodium periodate (3.67 g) in THF (20 mL) / H₂O (6 mL) was stirred in an ice bath. Potassium osmate (20 mg) was then added to the mixture, and stirring continued at room temperature for 4 hrs. The reaction mixture was poured into H₂O (150 mL) and extracted twice with EA (100 mL). The organic phase was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to afford the title compound 4-2 (800 mg).

[0561] Step 3: Preparation of methyl 2-(3-bromo-2-benzocyano)-6-hydroxybenzo[d]oxazole-5-carboxylate

[0562]

[0563] A solution of compound 4-2 (1 g) and methyl 5-amino-2,4-dihydroxybenzoate (870 mg) in MeOH (150 mL) was stirred at 80°C for 2.5 hours, then the reaction mixture was concentrated under reduced pressure and dissolved in dichloromethane. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (1.3 g) was added to the reaction mixture and stirring continued at room temperature. After 1 hour, the mixture was filtered, the filter cake was washed with dichloromethane, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was suspended in methanol, filtered, and the filter cake was dried in a vacuum oven to obtain the title compound (1.4 g).

[0564] Step 4: Preparation of methyl 2-(3-bromo-2-benzocyanato)-6-(difluoromethoxy)benzo[d]oxazole-5-carboxylate

[0565]

[0566] Sodium difluorochloroacetate (850 mg) and cesium carbonate (2.62 g) were added to a stirred solution of methyl 2-(3-bromo-2-benzocyanate)-6-hydroxybenzo[d]oxazole-5-carboxylate (1 g) in DMF (20 mL) / H2O (0.6 mL). The reaction mixture was heated to 80°C and stirred for 4 hrs. The mixture was then poured into H2O (100 mL) and extracted twice with EA (80 mL). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give a crude product. The crude product was further purified by silica gel column to give title compound 4-4 (800 mg).

[0567] Step 5: Preparation of 2-bromo-6-(6-(difluoromethoxy)-5-(hydroxymethyl)benzo[d]oxazol-2-yl)benzocyanate

[0568]

[0569] This compound was prepared using a method similar to that described in step 5 of Example A, using compound 4-4 instead of compound a-4. The mixture was concentrated under reduced pressure to give the title compound 4-5.

[0570] Step 6: Preparation of 2-bromo-6-(5-(chloromethyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)cyanobenzene

[0571]

[0572] This compound was prepared using a procedure similar to that described in Example 1, Step 2, substituting Compound 4-5 for Compound 1-1. The crude product was used directly in the next step.

[0573] Step 7: Preparation of 2-bromo-6-(6-(difluoromethoxy)-5-((3,3-dimethylazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)benzocyanate

[0574]

[0575] This compound was prepared using a method similar to that described in Step 3 of Example 1, substituting Compound 4-6 for Compound 1-2 and substituting 3,3-dimethylazetidine for (1S,2R)-2-aminocyclopentane-1-ol. The crude product was further purified by silica gel column (PE / EA) to give the title compound (290 mg).

[0576] Step 8: Preparation of ((2-(2'-cyano-3'-(6-(difluoromethoxy)-5-((3,3-dimethylazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

[0577]

[0578] This compound was prepared using a similar method as described in step 1 of example 1, substituting compound 4-7 for compound a-6. The crude product was further purified by silica gel column to afford the title compound.

[0579] Step 9: Preparation of ((2-(2'-cyano-3'-(6-(difluoromethoxy)-5-((3,3-dimethylazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline

[0580]

[0581] This compound was prepared using a method similar to that described in step 5 of Example 1, using compound 4-8 instead of compound 1-4. The mixture was concentrated under reduced pressure to give the title compound. LC-MS (m / z): 784.3 (M+H) + .

[0582] The compounds in Table 1 can be prepared by methods similar to those in Examples 1-4 using different starting materials and suitable reagents.

[0583] Table 1

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592]

[0593]

[0594] Example 100 Synthesis of Compound 100

[0595] ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(pyrrolidin-1-yl-methyl)-7-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline

[0596]

[0597] Step 1: Preparation of 4-hydroxy-3-nitro-5-(trifluoromethyl)benzaldehyde

[0598]

[0599] 4-Hydroxy-3-(trifluoromethyl)benzaldehyde (1 g) was dissolved in concentrated H2SO4 (10 mL). After the mixture was cooled to 5°C (ice bath), concentrated HNO3 (65%) (612 mg) was added dropwise and stirred for 30 minutes. After the starting material was almost completely reacted and the reaction was complete, the mixture was poured into ice water (30 mL) and collected by filtration to obtain compound 100-2 (1 g).

[0600] Step 2: Preparation of 2-nitro-4-(pyrrolidin-1-ylmethyl)-6-(trifluoromethyl)phenol

[0601]

[0602] A solution of compound 100-2 (500 mg), pyrrolidine (454 mg), and CH3COOH (255 mg) in 1,4-dioxane (10 mL) was stirred at 30°C for 30 minutes, followed by the addition of sodium triacetoxyborohydride (1.35 g) and continued stirring. The reaction mixture was poured into H2O (30 mL) and extracted three times with DCM (15 mL). The mixture was washed with brine, dried over anhydrous Na2SO4, filtered, and dried in vacuo. The crude product was further purified by silica gel column chromatography (DCM / MeOH = 20:1) to afford compound 100-3 (420 mg).

[0603] Step 3: Preparation of 2-amino-4-pyrrolidin-1-ylmethyl)-6-(trifluoromethyl)phenol

[0604]

[0605] A solution of compound 100-3 (420 mg) and 10% Pd(OH) / C (150 mg) in methanol (10 mL) was reacted at room temperature under a hydrogen pressure of 1.1 atmospheres for 3 hrs. The catalyst was removed by filtration, and the solid residue was washed with methanol (300 mL). The solvent was removed to obtain 300 mg of compound 100-4.

[0606] Step 4: Preparation of 2-(3-bromo-2-methyl-phenyl)-5-(pyrrolidin-1-ylmethyl)-7-(trifluoromethyl)-1,3-benzoxazole

[0607]

[0608] This compound was prepared using a method similar to that described in Example A, Step 3, substituting compound 100-4 for compound a-3. The crude product was used directly in the next reaction.

[0609] Step 5: Preparation of (2S)-1-[[6-(difluoromethoxy)-2-[2-methyl-3-[2-methyl-3-[5-(pyrrolidin-1-ylmethyl)-7-(trifluoromethyl)-1,3-benzoxazol-2-yl]phenyl]phenyl]-1,3-benzoxazol-5-yl]methyl]pyrrolidine-2-carboxylic acid methyl ester

[0610]

[0611] Intermediate A (345.72 mg), compound 100-5 (280 mg), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (53 mg), and potassium carbonate (88.10 mg) were dissolved in 1,4-dioxane (8 mL) and H₂O (2 mL) and stirred at 80°C for 12 hours under N₂ protection. The reaction solution was poured into H₂O (30 mL) and extracted three times with DCM (15 mL). The organic phase was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was further purified by silica gel column to obtain compound 100-6 (300 mg).

[0612] Step 6: Preparation of (2S)-1-[[6-(difluoromethoxy)-2-[2-methyl-3-[2-methyl-3-[5-(pyrrolidin-1-ylmethyl)-7-(trifluoromethyl)-1,3-benzoxazol-2-yl]phenyl]phenyl]-1,3-benzoxazol-5-yl]methyl]pyrrolidine-2-carboxylic acid (Compound 100)

[0613]

[0614] This compound was prepared using a method similar to that described in Step 5 of Example 1, using Compound 100-6 instead of Compound 1-4. Filtered and dried under vacuum to yield (2S)-1-[[6-(difluoromethoxy)-2-[2-methyl-3-[2-methyl-3-[5-(pyrrolidin-1-ylmethyl)-7-(trifluoromethyl)-1,3-benzoxazol-2-yl]phenyl]phenyl]-1,3-benzoxazol-5-yl]methyl]pyrrolidine-2-carboxylic acid (Compound 100). LC-MS (m / z): 761.3 (M+H) + .

[0615] Example 101 Synthesis of Compound 101

[0616] ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(pyrrolidin-1-yl-methyl)-6-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline

[0617]

[0618] Step 1: Preparation of methyl 4-hydroxy-2-(trifluoromethyl)benzoate

[0619]

[0620] To a solution of 4-hydroxy-2-(trifluoromethyl)benzoic acid (18.0 g) in methanol (300 ml) was added concentrated sulfuric acid (10 ml) dropwise, and the mixture was refluxed with stirring for 12 hours. After cooling to room temperature, water (200 ml) was added to the reaction mixture, and after concentrating under reduced pressure to remove methanol, the mixture was extracted twice with ethyl acetate (200 ml). The organic phase was washed with water, saturated aqueous sodium bicarbonate solution, and saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (18 g).

[0621] Step 2: Preparation of methyl 4-hydroxy-5-nitro-2-(trifluoromethyl)benzoate

[0622]

[0623] This compound was prepared using a method similar to that described in Step 1 of Example 100, substituting Compound 101-1 for Compound 100-1. The crude product was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound.

[0624] Step 3: Preparation of methyl 5-amino-4-hydroxy-2-(trifluoromethyl)benzoate

[0625]

[0626] This compound was prepared using a procedure similar to that described in Step 3 of Example 1, substituting Compound 101-2 for Compound 100-3. The filtrate was concentrated under reduced pressure to afford the title compound.

[0627] Step 4: Preparation of methyl 2-(3-bromo-2-methylphenyl)-6-(trifluoromethyl)benzo[d]oxazole-5-carboxylate

[0628]

[0629] This compound was prepared using a procedure similar to that described in Step 3 of Example A, substituting Compound 101-3 for Compound a-3. The crude product was suspended in methanol, filtered, and dried in a vacuum oven to afford the title compound.

[0630] Step 5: Preparation of (2-(3-bromo-2-methylphenyl)-6-(trifluoromethyl)benzo[d]oxazol-5-yl)methanol

[0631]

[0632] This compound was prepared using a procedure similar to that described in step 5 of example A, substituting compound 101-4 for compound a-5. The filtrate was concentrated under reduced pressure to afford the title compound.

[0633] Step 6: Preparation of 2-(3-bromo-2-methylphenyl)-5-(chloromethyl)-6-(trifluoromethyl)benzo[d]oxazole

[0634]

[0635] This compound was prepared using a procedure similar to that described in Example 1, Step 2, substituting Compound 101-5 for Compound 1-1. The crude product was used directly in the next step.

[0636] Step 7: Preparation of 2-(3-bromo-2-methylphenyl)-5-(-ylpyrrolidin-1-ylmethyl)-6-(trifluoromethyl)benzo[d]oxazole

[0637]

[0638] This compound was prepared using a method similar to that described in Step 3 of Example 1, substituting Compound 101-6 for Compound 1-2 and pyrrolidine for (1S,2R)-2-aminocyclopentane-1-ol. The crude product was further purified by silica gel column (PE / EA) to give the title compound.

[0639] Step 8: Preparation of ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(-ylpyrrolidin-1-ylmethyl)-6-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

[0640]

[0641] This compound was prepared using a similar procedure as described in step 1 of example 1, substituting compound 101-7 for compound a-6. The crude product was further purified by silica gel column to afford the title compound.

[0642] Step 9: Preparation of ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(-ylpyrrolidin-1-ylmethyl)-6-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline

[0643]

[0644] This compound was prepared using a method similar to that described in Step 5 of Example 1, using Compound 101-8 instead of Compound 1-4. The mixture was concentrated under reduced pressure to afford the title compound. LC-MS (m / z): 761.3 (M+H) + .

[0645] Example 102 Synthesis of Compound 102

[0646] ((2-(3'-(6,7-difluoro-5-(pyrrolidin-1-ylmethyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline

[0647]

[0648] Step 1: Preparation of methyl 2,3-difluoro-4-hydroxy-5-nitrobenzoate

[0649]

[0650] This compound was prepared using a method similar to that described in Step 1 of Example A, substituting methyl 2,3-difluoro-4-hydroxybenzoate for compound a-1. The crude product was further purified by silica gel column chromatography (n-hexane / ethyl acetate) to afford the title compound.

[0651] Step 2: Preparation of methyl 5-amino-2,3-difluoro-4-hydroxybenzoate

[0652]

[0653] This compound was prepared using a procedure similar to that described in Example A, Step 2, substituting compound 102-1 for compound a-2. The filtrate was concentrated under reduced pressure to afford the title compound.

[0654] Step 3: Preparation of methyl 2-(3-bromo-2-methylphenyl)-6,7-difluorobenzo[d]oxazole-5-carboxylate

[0655]

[0656] This compound was prepared using a method similar to that described in step 3 of Example A, substituting compound 102-2 for compound a-3. The crude product was dissolved in methanol, filtered, and dried in a vacuum oven to afford the title compound.

[0657] Step 4: Preparation of (2-(3-bromo-2-methylphenyl)-6,7-difluorobenzo[d]oxazol-5-yl)methanol

[0658]

[0659] This compound was prepared using a procedure similar to that described in step 5 of example A, substituting compound 102-3 for compound a-5. The filtrate was concentrated under reduced pressure to afford the title compound.

[0660] Step 5: Preparation of ((2-(3'-(6,7-difluoro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

[0661]

[0662] This compound was prepared using a similar method as described in step 1 of example 1, substituting compound 102-4 for compound a-6. The crude product was further purified by silica gel column to afford the title compound.

[0663] Step 6: Preparation of ((2-(3'-(5-(chloromethyl)-6,7-difluorobenzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

[0664]

[0665] This compound was prepared using a procedure similar to that described in Example 1, Step 2, substituting Compound 102-5 for Compound 1-1. The crude product was used directly in the next step.

[0666] Step 7: Preparation of ((2-(3'-(6,7-difluoro-5-(-ylpyrrolidin-1-ylmethyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

[0667]

[0668] This compound was prepared using a method similar to that described in Step 3 of Example 1, substituting Compound 102-6 for Compound 1-2 and pyrrolidine for (1S,2R)-2-aminocyclopentane-1-ol. The crude product was further purified by silica gel column (PE / EA) to afford the title compound.

[0669] Step 8: Preparation of ((2-(3'-(6,7-difluoro-5-(-ylpyrrolidin-1-ylmethyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline

[0670]

[0671] This compound was prepared using a method similar to that described in step 5 of Example 1, using compound 102-7 instead of compound 1-4. The crude product was further purified by silica gel column to give the title compound. LC-MS (m / z): 729.3 (M+H) + . 1 H NMR(500MHz,DMSO-d6)δ8.21(dd,J=7.9,1.4Hz,1H),8.19–8.14(m,2H),8.08( s,1H),7.82(s,1H),7.62-7.54(m,2H),7.51-7.44(m,2H),7.40(t,J=71.9Hz, 1H),4.58(s,2H),4.36-4.20(m,2H),3.91(s,1H),3.46(s,3H),3.20-3.07(m, 2H), 2.96 (s, 1H), 2.45 (d, J = 4.0Hz, 6H), 2.35-2.25 (m, 1H), 2.08-1.76 (m, 8H).

[0672] Example 103 Synthesis of Compound 103

[0673] ((2-(3'-(7-cyano-5-((3,3-dimethylazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline

[0674]

[0675] Step 1: Preparation of methyl 3-cyano-4-hydroxy-5-nitrobenzoate

[0676]

[0677] This compound was prepared using a method similar to that described in Step 1 of Example A, substituting methyl 3-cyano-4-hydroxybenzoate for compound a-1. The crude product was further purified by silica gel column chromatography (n-hexane / ethyl acetate) to afford the title compound.

[0678] Step 2: Preparation of methyl 3-amino-5-cyano-4-hydroxybenzoate

[0679]

[0680] This compound was prepared using a procedure similar to that described in Example A, Step 2, substituting compound 103-1 for compound a-2. The filtrate was concentrated under reduced pressure to afford the title compound.

[0681] Step 3: Preparation of methyl 2-(3-bromo-2-methylphenyl)-7-cyanobenzo[d]oxazole-5-carboxylate

[0682]

[0683] This compound was prepared using a similar method as described in step 3 of Example A, substituting compound 103-2 for compound a-3. The crude product was further purified by silica gel column to afford the title compound.

[0684] Step 4: Preparation of 2-(3-bromo-2-methylphenyl)-5-(hydroxymethyl)benzo[d]oxazole-7-carbonitrile

[0685]

[0686] This compound was prepared using a procedure similar to that described in step 5 of example A, substituting compound 103-3 for compound a-5. The filtrate was concentrated under reduced pressure to afford the title compound.

[0687] Step 5: Preparation of ((2-(3'-(7-cyano-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

[0688]

[0689] This compound was prepared using a similar method as described in step 1 of example 1, substituting compound 103-4 for compound a-6. The crude product was further purified by silica gel column to afford the title compound.

[0690] Step 6: Preparation of ((2-(3'-(5-(chloromethyl)-7-cyanobenzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

[0691]

[0692] This compound was prepared using a procedure similar to that described in Example 1, Step 2, substituting Compound 103-5 for Compound 1-1. The crude product was used directly in the next step.

[0693] Step 7: Preparation of ((2-(3'-(7-cyano-5-((3,3-dimethylazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

[0694]

[0695] This compound was prepared using a method similar to that described in Step 3 of Example 1, substituting Compound 103-6 for Compound 1-2 and substituting 3,3-dimethylazetidine for (1S,2R)-2-aminocyclopentane-1-ol. The crude product was further purified by silica gel column (PE / EA) to afford the title compound.

[0696] Step 8: Preparation of ((2-(3'-(7-cyano-5-((3,3-dimethylazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline

[0697]

[0698] This compound was prepared using a method similar to that described in step 5 of Example 1, using compound 103-7 instead of compound 1-4. The crude product was further purified by silica gel column to give the title compound. LC-MS (m / z): 732.3 (M+H) + . 1 H NMR(500MHz, DMSO-d6)8.20(dd,J=7.9,1.4Hz,1H),8.16(dd,J=7.9,1.5Hz,1H),8.09(s,1H),7.97 (s,1H),7.85(s,1H),7.73(s,1H),7.62–7.51(m,2H),7.50–7.41(m,2H),7.38(t,J=71.9Hz,1H),3 .96(s,2H),3.75(s,2H),3.36(dd,J=9.1,5.4Hz,1H),3.07(td,J=9.4,8.4,3.3Hz,1H),2.99(s,3H ), 2.56 (q, J = 8.5Hz, 1H), 2.44 (d, 6H, J = 2.5Hz), 2.17-2.08 (m, 1H), 1.90–1.68 (m, 4H), 1.20 (s, 6H).

[0699] The compounds in Table 2 can be prepared by methods similar to Examples 100-103 using different starting materials and appropriate reagents.

[0700] Table 2

[0701]

[0702]

[0703]

[0704]

[0705]

[0706]

[0707]

[0708]

[0709]

[0710]

[0711] Example 171 Synthesis of Compound 171

[0712] (S)-1-((8-((3'-(5-(((S)-2-carboxypyrrolidin-1-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)-2-methylpyrrolidine-2-carboxylic acid

[0713]

[0714] Step 1: Preparation of 8-chloro-3-vinyl-1,7-naphthyridine

[0715]

[0716] To a toluene (30 mL) solution of compound 171-1 (2.43 g) was added EtOH (10 mL), 10% Na2CO3 aq. (10 mL) and Pd(dppf)Cl2.DCM (420 mg). 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (3.1 g) was then added dropwise under N2 protection. The mixture was stirred at 100 ° C for 16 hours. The reaction was quenched with H2O (50 mL) and extracted three times with EtOAc. The organic phases were combined and washed with brine. The resulting solution was concentrated and purified on a silica gel column (eluted with a gradient of n-hexane-ethyl acetate 8:1 to 5:1) to give 8-chloro-3-vinyl-1,7-naphthyridine (1.1 g) as a brown solid.

[0717] Step 2: Preparation of (8-chloro-1,7-naphthyridin-3-yl)methanol

[0718]

[0719] To a solution of compound 171-2 (380 mg) in 1,4-dioxane (20 mL) / water (20 mL) was added K2OsO4 (4.0 mg) and stirred at room temperature for 30 min. NaIO4 (1.0 g) was added portionwise at the same temperature. After stirring for 3 hours, the reaction solution was quenched with saturated Na2S2O3 solution and extracted three times with DCM (40 mL). The organic phases were combined, dried over Na2SO4, and the resulting solution was concentrated to give 8-chloro-1,7-naphthyridine-3-carbaldehyde.

[0720] The above 8-chloro-1,7-naphthyridine-3-carboxaldehyde was dissolved in 20 mL of MeOH, and NaBH4 (200 mg) was added all at once. The resulting mixture was stirred at room temperature and quenched with water (30 mL) after two hours. The mixture was extracted three times with DCM (20 mL), and the organic phase was dried over Na2SO4. The resulting solution was concentrated and purified on a silica gel column (eluted with a gradient of n-hexane-ethyl acetate 1:1 to 1:2) to give (8-chloro-1,7-naphthyridine-3-yl)methanol (240 mg) as a white solid.

[0721] Step 3: Preparation of (8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methanol

[0722]

[0723] To a microwave reaction vial were added 3-bromo-2-methylaniline (2.50 g), compound 171-3 (1.86 g), t-BuOH (15 mL), and HCl (4.0 M in 1,4-dioxane, 3 mL). The vial was capped, and the reaction mixture was incubated at 100°C in a microwave oven for 4 h. The reaction mixture was diluted with 20 mL of water and extracted with DCM (50 mL x 2). The combined organic phases were washed with brine, dried over MgSO₄, and concentrated in vacuo. The resulting residue was concentrated and recrystallized from DCM:n-hexane (1:1) to afford (8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methanol (2.0 g) as an off-white solid.

[0724] Step 4: Preparation of ((5-(difluoromethoxy)-2-(3'-((3-(hydroxymethyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-6-yl)methyl)-L-proline methyl ester

[0725]

[0726] Under N2 protection, EtOH (5 mL), 10% Na2CO3 aq. (5 mL) and Pd(dppf)Cl2.DCM (78 mg) were added to a toluene (15 mL) solution of compound 171-4 (0.69 g) and intermediate A (1.5 g). The mixture was stirred at 110 ° C overnight. The reaction was quenched with H2O (20 mL) and extracted three times with EtOAc (50 mL). The organic phases were combined, washed with brine, concentrated, and purified on a silica gel column (eluted with a gradient of n-hexane-ethyl acetate 3:1 to 1:1) to give compound 171-5 (0.88 g) as a brown oil.

[0727] Step 5: Preparation of (S)-1-((8-((3'-(6-(difluoromethoxy)-5-(((S)-2-(methoxycarbonyl)-ylpyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)-2-methylpyrrolidine-2-carboxylic acid methyl ester

[0728]

[0729] To a solution of compound 171-5 (250 mg) and TEA (100 mg) in DCM (5.0 mL) was added MsCl (89 mg) dropwise at 0°C. The reaction was allowed to react at room temperature for 4 hours. The resulting mixture was concentrated in vacuo and dissolved in THF (5 mL). Methyl (S)-2-methylpyrrolidine-2-carboxylate (143 mg) and KI (1 mg) were added to the solution, and the reaction was stirred overnight at room temperature until the mesylate was consumed. The residue was concentrated and purified using an RP-column (mobile phase: MeCN:water = 10:90 containing 0.1% HCl) to give an off-white solid.

[0730] Step 6: Preparation of (S)-1-((8-((3'-(5-(((S)-2-carboxypyrrolidin-1-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)-2-methylpyrrolidine-2-carboxylic acid

[0731]

[0732] To a solution of compound 171-6 (105 mg) in THF / water = 1:1 (4 mL) was added LiOH (40 mg). The resulting mixture was stirred at room temperature for 24 hours. The THF layer was separated and purified by RP-column (mobile phase: MeCN: water (0.1% HCl) gradient of 10:90 to 30:70) to give 78 mg of (S)-1-((8-((3'-(5-(((S)-2-carboxypyrrolidin-1-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)-2-methylpyrrolidine-2-carboxylic acid (compound 171). LC-MS (m / z): 777.3 (M+H) + . 1 H NMR (500MHz, methanol-d4) δ9.23(d,1H,J=2.1Hz),8.60(d,1H,J=2.0Hz),8.20(dd,1H,J=7.9,1.5Hz),8.07(s,1H),7.76(s,1H),7.69–7.63(m,2H) ,7.57(t,1H,J=7.8Hz),7.53(t,1H,J=7.7Hz),7.46(dd,1H,J=7.6,1.5Hz),7.38(dd,1H,J=7.6,1.4Hz),7.35(d,1H,J=6.9Hz),7.12(t,1H,J F-H=72.6Hz), 4.83(d,1H,J=13.2Hz), 4.74(d,1H,J=13.3Hz), 4.62(d,1H,J=13.2Hz), 4.49(d,1H,J=13.2Hz), 4.33(dd,1H,J=9.6,7.2Hz), 3.66-3.6 2(m,1H),3.52–3.37(m,3H),2.63–2.56(m,1H),2.55(s,3H),2.41–2.32 (m,1H),2.29–2.14(m,4H),2.09(s,3H),2.06–1.98(m,2H),1.75(s,3H).

[0733] The compounds in Table 3 can be prepared by a method similar to Example 171 using different starting materials and appropriate reagents.

[0734] Table 3

[0735]

[0736]

[0737] Example 314 Synthesis of Compound 314

[0738] ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-methyl-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline

[0739]

[0740] Step 1: Preparation of benzyl (3S,4S)-3-(3-bromo-2-methylbenzamide)-4-hydroxypiperidine-1-carboxylate

[0741]

[0742] 3-Bromo-2-methylbenzoic acid (800 mg), benzyl (3S,4S)-3-amino-4-hydroxypiperidine-1-carboxylate (931.13 mg), EDCI (1.43 g), HOBT (1.01 g), and TEA (1.13 g) were added sequentially to DCM (50 mL), and the mixture was stirred at room temperature overnight. The reaction solution was diluted with dichloromethane and washed sequentially with saturated aqueous sodium bicarbonate and sodium chloride. The organic phase was dried over Na2SO4 and concentrated to yield an off-white solid, benzyl (3S,4S)-3-(3-bromo-2-methylbenzamide)-4-hydroxypiperidine-1-carboxylate (1.4 g, crude product).

[0743] Step 2: Preparation of benzyl (S)-3-(3-bromo-2-methylbenzamide)-4-oxopiperidine-1-carboxylate

[0744]

[0745] Dess-Martin (2.65 g) was added portionwise to a solution of compound 314-3 (1.4 g) in DCM (30 mL) at room temperature and stirred for 3 hr. LC-MS monitored the reaction completion, and the reaction mixture was quenched with Na2S2O3 solution and extracted three times with EA. The organic phase was washed with NaHCO3 solution, dried over Na2SO4, and concentrated to afford benzyl (S)-3-(3-bromo-2-methylbenzamide)-4-oxopiperidine-1-carboxylate (1.1 g, crude) as a pale yellow solid.

[0746] Step 3: Preparation of benzyl 2-(3-bromo-2-methylphenyl)-6,7-dihydrooxazolo[4,5-c]pyridine-5(4H)-carboxylate

[0747]

[0748] A solution of POCl3 (757.52 mg) in 1,4-dioxane (5 mL) was added dropwise to a solution of compound 314-4 (891 mg) in 1,4-dioxane (15 mL). The temperature was raised to 105°C and stirring was continued for 2 hours. The reaction mixture was slowly added dropwise to ice water and extracted with ethyl acetate. The organic phase was washed with saturated aqueous NaHCO3 and NaCl solution, dried, and concentrated to obtain a residue, which was purified by chromatography (DCM:MeOH = 20:1) to obtain an off-white solid, compound 314-5 (800 mg).

[0749] Step 4: Preparation of benzyl (S)-2-(3'-(6-(difluoromethoxy)-5-((2-(methoxycarbonyl)-ylpyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6,7-dihydrooxazolo[4,5-c]pyridine-5(4H)-carboxylate

[0750]

[0751] Compound 314-5 (800 mg), Intermediate A (1015 mg), Pd(dppf)Cl2 (343 mg), and K2CO3 (129.38 mg) were added to a mixture of 1,4-dioxane (20 mL) and H2O (5 mL). The reaction mixture was evacuated and filled with N2 three times, then heated to 80°C and stirred for 3 hours. LC-MS monitored the reaction for completion. The reaction mixture was concentrated and purified by TCL (PE:EA=1:3) to give benzyl (S)-2-(3'-(6-(difluoromethoxy)-5-((2-(methoxycarbonyl)-ylpyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6,7-dihydrooxazolo[4,5-c]pyridine-5(4H)-carboxylate (800 mg) as an off-white solid.

[0752] Step 5: Preparation of ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

[0753]

[0754] Pd / C (200 mg) was added to a solution of compound 314-7 (800 mg) in MeOH (50 mL). The mixture was stirred at room temperature under a H2 atmosphere for 5 hours. The reaction mixture was filtered and concentrated to afford ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester (500 mg, crude) as an off-white solid.

[0755] Step 6: Preparation of ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-methyl-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

[0756]

[0757] will(CHO) n(72 mg) was added to a mixed solution of compound 314-8 (500 mg) in DCM (30 mL) and MeOH (10 mL). After the mixture was stirred for 30 min, NaBH3CN (150 mg) was added portionwise to the reaction solution and stirred at room temperature overnight. The reaction was concentrated and purified by TLC (DCM:MeOH = 20:1) to give ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-methyl-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester (400 mg) as an off-white solid.

[0758] Step 7: Preparation of ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-methyl-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline

[0759]

[0760] This compound was prepared using a method similar to that described in Step 5 of Example 1, using Compound 314-9 instead of Compound 1-4. The crude product was purified by TLC (DCM:MeOH=4:1) to give 210 mg of ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-methyl-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline (Compound 314) as an off-white solid. LC-MS (m / z): 629.3 (M+H) + .

[0761] The compounds in Table 4 can be prepared by a method similar to Example 314 using different starting materials and appropriate reagents.

[0762] Table 4

[0763]

[0764]

[0765]

[0766]

[0767] Example 208 Preparation of Compound 208

[0768] ((2-(3'-((2-chloro-5-((5-(difluoromethoxy)pyridin-3-yl)methoxy)-4-(((R)-3-hydroxypyrrolidin-1-yl)methyl)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline

[0769]

[0770] Step 1: Preparation of 1-bromo-3-(chloromethyl)-2-toluene

[0771]

[0772] (3-Bromo-2-methylphenyl)methanol (20 g) was dissolved in DCM (200 ml) and stirred at room temperature, then 20 ml of SOCl2 was slowly added. The mixture was stirred for 2 hrs and concentrated to give 1-bromo-3-(chloromethyl)-2-toluene (23.1 g).

[0773] Step 2: Preparation of 4-((3-bromo-2-methylbenzyl)oxy)-5-chloro-2-hydroxybenzaldehyde

[0774]

[0775] A solution of 1-bromo-3-(chloromethyl)-2-toluene (2.0 g), 5-chloro-2,4-dihydroxybenzaldehyde (2.34 g), potassium carbonate (3.78 g), and KI (1.51 g) in acetonitrile (20 mL) was stirred at 80°C overnight. After completion of the reaction, 20 mL of water was added, and the mixture was concentrated, filtered, and dried to give 4-((3-bromo-2-methylbenzyl)oxy)-5-chloro-2-hydroxybenzaldehyde (2.8 g).

[0776] Step 3: Preparation of 4-((3-bromo-2-methylbenzyl)oxy)-5-chloro-2-((5-(difluoromethoxy)pyridin-3-yl))methoxy)benzaldehyde

[0777]

[0778] Compound 208-3 (500 mg), (5-(difluoromethoxy)pyridin-3-yl)methanol (408 mg), potassium carbonate (585 mg), and KI (195 mg) were added to acetonitrile (10 mL), and the reaction mixture was stirred at 80° C. overnight. After adding 20 mL of water, the mixture was concentrated, filtered, and dried to obtain 4-((3-bromo-2-methylbenzyl)oxy)-5-chloro-2-((5-(difluoromethoxy)pyridin-3-yl)-yl)methoxy)benzaldehyde (478 mg).

[0779] Step 4: Preparation of ((2-(3'-((2-chloro-5-((5-(difluoromethoxy)pyridin-3-yl))methoxy)-4-formylphenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

[0780]

[0781] Compound 208-4 (470 mg), Intermediate A (597 mg), and potassium carbonate (236 mg) were added to a mixture of 1,4-dioxane (12 mL) and water (3 mL) with stirring. Pd(dppf)Cl2 was then added to the mixture under an N2 atmosphere. The reaction mixture was heated to 80°C and stirred overnight. The mixture was quenched with water (30 mL) and extracted with DCM (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (DCM / MeOH: 15 / 1) to give compound 208-5 (550 mg).

[0782] Step 5: Preparation of ((2-(3'-((2-chloro-5-((5-(difluoromethoxy)pyridin-3-yl))methoxy)-4-(((R)-3-hydroxy-pyrrolidin-1-yl)methyl)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

[0783]

[0784] Compound 208-5 (270 mg), (R)-pyrrolidin-3-ol (80 mg), and glacial acetic acid (40 mg) were added to 10 mL of methanol with stirring. The mixture was heated to 50°C and stirred for 1 hour. After the mixture cooled to room temperature, sodium cyanoborohydride was added, and the mixture was stirred at room temperature for 2 hours. The mixture was then diluted with water (10 mL) and extracted with DCM (15 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified on a silica gel column (DCM / MeOH = 15 / 1) to give compound 208-6 (110 mg).

[0785] Step 6: Preparation of ((2-(3'-((2-chloro-5-((5-(difluoromethoxy)pyridin-3-yl))methoxy)-4-(((R)-3-hydroxy-pyrrolidin-1-yl)methyl)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline (Compound 208)

[0786]

[0787] Compound 208-6 (110 mg) was added to 5 mL of methanol with stirring, and 8 mg of LiOH was weighed and dissolved in 1 mL of water, then added to the mixture. The reaction mixture was heated to 35°C and stirred overnight. 10 mL of water was added to the mixture and extracted with DCM (15 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 105 mg of ((2-(3'-((2-chloro-5-((5-(difluoromethoxy)pyridin-3-yl))methoxy)-4-(((R)-3-hydroxy-pyrrolidin-1-yl)methyl)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline (Compound 208). LC-MS (m / z): 905.3 (M+H) + .

[0788] The compounds in Table 5 can be prepared by a method similar to Example 208 using different starting materials and appropriate reagents.

[0789] Table 5

[0790]

[0791]

[0792] Example 242 Preparation of Compound 242

[0793] ((6-(difluoromethoxy)-2-(4″-((3-fluoropyrrolidin-1-yl)methyl)-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)proline

[0794]

[0795] Step 1: Preparation of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde

[0796]

[0797] To a solution of 4-bromobenzaldehyde (9.25 g) in 1,4-dioxane (120 mL) were added bis-pinacolatodiboron (15.8 g), Pd(dppf)Cl2.DCM (0.48 g), and KOAc (20.0 g). The reaction was heated to 100°C for 4 hours. The mixture was diluted with 150 mL of water and extracted with ethyl acetate (150 mL x 2). The combined organic phases were washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified on a silica gel column (eluted with a gradient of n-hexane-ethyl acetate (20:1 to 10:1) to afford 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (11.2 g) as a white solid.

[0798] Step 2: Preparation of 3'-bromo-2'-methyl-[1,1'-biphenyl]-4-carbaldehyde

[0799]

[0800] To a solution of compound 242-2 (60 mL) in EtOH (20 mL) was added 10% Na2CO3 aq. (20 mL) and Pd(dppf)Cl2.DCM (420 mg), and then 1-bromo-3-iodo-2-toluene (9.0 g) was added dropwise under N2 protection. The mixture was stirred at 100 ° C for 16 hours. The reaction was then quenched with water (50 mL) and extracted three times with ethyl acetate (100 mL). The organic phases were combined and washed with brine. The resulting solution was concentrated and purified by silica gel column (eluted with a gradient of n-hexane-ethyl acetate 20: 1 to 10: 1) to give 3'-bromo-2'-methyl-[1,1'-biphenyl]-4-carboxaldehyde (3.2 g) as a light yellow solid.

[0801] Step 3: Preparation of 1-((3'-bromo-2'-methyl-[1,1'-biphenyl]-4-yl)methyl)-3-fluoropyrrolidine

[0802]

[0803] 3'-Bromo-2'-methyl-[1,1'-biphenyl]-4-carboxaldehyde (275 mg) was dissolved in 5 mL of DCM. 3-Fluoropyrrolidine (120 mg) and HOAC were added in one go. The resulting mixture was stirred at room temperature for 1 hour, and then STAB (420 mg) was added in one go at the same temperature. The reaction was stirred at room temperature for 3 hours. The resulting mixture was quenched with saturated Na2CO3, extracted 3 times with ethyl acetate (20 mL), and the organic phase was dried over Na2SO4. The resulting solution was concentrated to give 1-((3'-bromo-2'-methyl-[1,1'-biphenyl]-4-yl)methyl)-3-fluoropyrrolidine (320 mg) as a colorless oil.

[0804] Step 4: Preparation of ((6-(difluoromethoxy)-2-(4″-((3-fluoro-pyrrolidin-1-yl)methyl)-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)proline methyl ester

[0805]

[0806] This compound was prepared using a method similar to that described in step 4 of Example 171, using compound 242-4 instead of compound 171-4. The resulting mixture was purified by RP-column (mobile phase: MeCN: water (0.1% HCl) gradient elution 40:60 to 50:50) to give compound 242-5 (288 mg).

[0807] Step 5: Preparation of ((6-(difluoromethoxy)-2-(4″-((3-fluoro-pyrrolidin-1-yl)methyl)-2,2′-dimethyl-[1,1′:3′,1″-triphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)proline

[0808]

[0809] This compound was prepared using a method similar to that described in step 6 of Example 171, substituting compound 242-5 for compound 171-6. The crude product was purified by RP-column (mobile phase: MeCN:water (0.1% HCl) gradient elution 40:60 to 50:50) to give ((6-(difluoromethoxy)-2-(4″-((3-fluoro-pyrrolidin-1-yl)methyl)-2,2′-dimethyl-[1,1′:3′,1″-triphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)proline (168 mg) as a white solid (Compound 242). LC-MS (m / z): 670.3 (M+H) + .

[0810] Example 243 Preparation of Compound 243

[0811] ((6-(difluoromethoxy)-2-(3″-fluoro-2,2′-dimethyl-4″-(pyrrolidin-1-ylmethyl)-[1,1′:3′,1″-terphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline

[0812]

[0813] Step 1: Preparation of ((6-(difluoromethoxy)-2-(3″-fluoro-4″-formyl-2,2′-dimethyl-[1,1′:3′,1″-triphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

[0814]

[0815] This compound was prepared using a method similar to that described in Example 1, Step 1, replacing compound a-6 with 4-bromo-2-fluorobenzaldehyde and intermediate B with intermediate A. The resulting solution was concentrated and purified using a silica gel column (using n-hexane-ethyl acetate 5:1) to give the title compound as a yellow oil.

[0816] Step 2: Preparation of ((6-(difluoromethoxy)-2-(4″-((3-fluoro-pyrrolidin-1-yl)methyl)-2,2′-dimethyl-[1,1′:3′,1″-terphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

[0817]

[0818] This compound was prepared using a procedure similar to that described in Example 2, Step 5, substituting Compound 243-1 for Compound 2-4 and pyrrolidine for L-proline. The resulting solution was concentrated to afford the title compound as a colorless oil.

[0819] Step 5: Preparation of ((6-(difluoromethoxy)-2-(3″-fluoro-2,2′-dimethyl-4″-(-ylpyrrolidin-1-ylmethyl)-[1,1′:3′,1″-triphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline

[0820]

[0821] This compound was prepared using a method similar to that described in Step 5 of Example 1, using Compound 243-2 instead of Compound 1-4. The crude product was purified by RP-column (mobile phase: MeCN: water (0.1% HCl) gradient elution 10:90 to 30:70) to give the title compound. LC-MS (m / z): 670.3 (M+H) + . 1H NMR (500MHz, methanol-d4) δ: 8.16 (dd, 1H, J=7.9, 1.5Hz), 8.07 (s, 1H), 7.76 (s, 1H), 7.70 (t, 1H, J= 7.7Hz),7.50(t,1H,J=7.7Hz),7.43–7.27(m,5H),7.20(dd,1H,J=7.5,1.4Hz),7.12(t,1H,J F-H =72.6Hz),4.75(d,1H,J=13.1Hz),4.54(d,1H,J=13.1Hz),4.54(s,2H),4.37(dd,1H,J=9.5,7.4Hz),3.66-3.60(m,3H),3 .45-3.40(m,1H),3.29-3.23(m,2H),2.65-2.57(m,1H),2.49(s,3H),2.28–2.14(m,4H),2.10-2.00(m,3H),1.96(s,3H).

[0822] Example 244 Preparation of Compound 244

[0823] ((6-(difluoromethoxy)-2-(3″-(difluoromethoxy)-2,2′-dimethyl-4″-(pyrrolidin-1-ylmethyl)-[1,1′:3′,1″-terphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline

[0824]

[0825] Step 1: Preparation of 4-bromo-2-(difluoromethoxy)benzaldehyde

[0826]

[0827] To a solution of 4-bromo-2-hydroxybenzaldehyde (4.0 g) in DMF (50 mL) was added Cs2CO3 (9.8 g) and KI (400 mg). The mixture was stirred at room temperature for 30 minutes, and then sodium 2-bromo-2,2-difluoroacetate (6.0 g) was added in small batches. The mixed solution was stirred at 75 ° C overnight. The mixture was diluted with 100 mL of water and extracted three times with ethyl acetate (100 mL). The combined organic phases were washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column (eluted with a gradient of n-hexane-ethyl acetate 8: 1 to 5: 1) to give 4-bromo-2-(difluoromethoxy)benzaldehyde (2.8 g) as a brown oil.

[0828] Step 2: Preparation of 5-bromo-2-(pyrrolidin-1-ylmethyl)benzonitrile

[0829]

[0830] This compound was prepared using a method similar to that described in Step 5 of Example 2, substituting Compound 244-1 for Compound 2-4 and pyrrolidine for L-proline. The crude product was purified by silica gel column (eluting with a DCM-MeOH gradient from 20:1 to 10:1) to give the title compound.

[0831] Step 3: Preparation of ((6-(difluoromethoxy)-2-(3″-(difluoromethoxy)-2,2′-dimethyl-4″-(-ylpyrrolidin-1-ylmethyl)-[1,1′:3′,1″-terphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

[0832]

[0833] This compound was prepared using a method similar to that described in Step 1 of Example 1, substituting Compound 244-2 for Compound a-6 and Intermediate B for Intermediate A. The resulting solution was concentrated and purified using a silica gel column (eluted with a gradient of n-hexane-ethyl acetate 5:1 to 1:1) to give the title compound.

[0834] Step 4: Preparation of ((6-(difluoromethoxy)-2-(3″-(difluoromethoxy)-2,2′-dimethyl-4″-(-ylpyrrolidin-1-ylmethyl)-[1,1′:3′,1″-terphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline

[0835]

[0836] This compound was prepared using a method similar to that described in step 5 of Example 1, using compound 244-3 instead of compound 1-4. The crude product was purified by RP-column purification (mobile phase: MeCN: water (0.1% HCl) gradient 10:90 to 35:65) to give the title compound. LC-

[0837] MS (m / z): 718.3 (M+H) + . 1 H NMR (500 MHz, methanol-d4), δ: 8.16 (dd, 1H, J = 7.9, 1.5 Hz), 8.07 (s, 1H), 7.76

[0838] (s,1H),7.73(d,1H,J=7.9Hz),7.50(t,1H,J=7.7Hz),7.42–7.36(m,3H),7.34(d,1H,J=1.4Hz),7.30(d d,1H,J=7.7,1.4Hz),7.21(dd,1H,J=7.4,1.4Hz),7.13(td,2H,J=72.8,2.4Hz),4.73(d,1H,J=13.2Hz), 4.61(d,1H,J=13.2Hz),4.53(s,2H),4.30(dd,1H,J=9.7,7.1Hz),3.69–3.56(m,3H),3.44-3.38(m,1H) ,3.31-3.28(m,2H),2.62-2.55(m,1H),2.50(s,3H),2.23-2.15(m,4H),2.12–2.00(m,3H),1.96(s,3H).

[0839] Example 245 Preparation of Compound 245

[0840] ((2-(3″-cyano-2,2′-dimethyl-4″-(pyrrolidin-1-ylmethyl)-[1,1′:3′,1″-terphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline

[0841]

[0842] Step 1: Preparation of 5-bromo-2-(bromomethyl)benzenecyanate

[0843]

[0844] Under N2 protection, BPO (2.4 g) was added to a solution of 5-bromo-2-methylbenzenecyanate (20.0 g) and NBS (19.6 g) in CCl4 (300 mL). The mixture was stirred at 70°C overnight. The reaction was quenched with saturated NaHCO3 solution (200 mL). The organic phases were combined and washed with brine. The resulting solution was concentrated and purified by silica gel column (eluted with a gradient of n-hexane-ethyl acetate 20:1 to 1:1) to give the crude product 5-bromo-2-(bromomethyl)benzenecyanate as a yellow solid.

[0845] Step 2: Preparation of 5-bromo-2-(-ylpyrrolidin-1-ylmethyl)benzene

[0846]

[0847] To a solution of compound 245-1 (5.4 g) in THF (60 mL) was added pyrrolidine (2.85 g) dropwise at 0°C. The reaction mixture was heated to 40°C for 5 hours. The reaction mixture was diluted with 200 mL of water and then extracted three times with ethyl acetate (150 mL). The combined organic phases were washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column (eluted with a gradient of n-hexane-ethyl acetate from 2:1 to 1:2) to give 5-bromo-2-(-ylpyrrolidin-1-ylmethyl)benzenecyanate (3.8 g) as a brown oil.

[0848] Step 3: Preparation of ((2-(3″-cyano-2,2′-dimethyl-4″-(-ylpyrrolidin-1-ylmethyl)-[1,1′:3′,1″-triphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

[0849]

[0850] This compound was prepared using a method similar to that described in Example 1, Step 1, substituting Compound 245-2 for Compound a-6 and Intermediate B for Intermediate A. The crude product was purified by silica gel column (eluting with a gradient of n-hexane-ethyl acetate 5:1 to 1:1) to give the title compound.

[0851] Step 4: Preparation of ((2-(3″-cyano-2,2′-dimethyl-4″-(-ylpyrrolidin-1-ylmethyl)-[1,1′:3′,1″-triphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline

[0852]

[0853] This compound was prepared using a method similar to that described in Step 5 of Example 1, using Compound 245-3 instead of Compound 1-4. The crude product was purified by RP-column purification (mobile phase: MeCN:water (0.1% HCl) gradient elution 10:90 to 35:65) to give the title compound. LC-MS (m / z): 677.3 (M+H) + . 1 H NMR (500MHz, methanol-d4) δ: 8.21 (dd, 1H, J=7.9, 1.5Hz), 8.10 (s, 1H), 7.76 (s, 1H), 7.70 (t, 1H, J= 7.7Hz),7.50(t,1H,J=7.7Hz),7.49-7.28(m,5H),7.20(dd,1H,J=7.5,1.4Hz),7.12(t,1H,J F-H=72.6Hz),4.73(d,1H,J=13.1Hz),4.51(d,1H,J=13.1Hz),4.51(s,2H),4.37(dd,1H,J=9.5,7.4Hz),3.69-3.51(m,3H),3 .47-3.42(m,1H),3.25-3.20(m,2H),2.65-2.57(m,1H),2.49(s,3H),2.28-2.12(m,4H),2.10-2.00(m,3H),1.96(s,3H).

[0854] Example 246 Preparation of Compound 246

[0855] ((6-(difluoromethoxy)-2-(3'-(6-methoxy-5-(((S)-3-methylpyrrolidin-1-yl)methyl)pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline

[0856]

[0857] Step 1: Preparation of ((6-(difluoromethoxy)-2-(3'-(5-formyl-6-methoxypyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

[0858]

[0859] This compound was prepared using a method similar to that described in Step 1 of Example 1, substituting 6-chloro-2-methoxypicolinaldehyde for compound a-6 and intermediate B for intermediate A. The crude product was purified by silica gel column purification (n-hexane-ethyl acetate = 3:1) to give the title compound.

[0860] Step 2: ((6-(difluoromethoxy)-2-(3'-(6-methoxy-5-(((S)-3-methyl-pyrrolidin-1-yl)methyl)pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

[0861]

[0862] This compound was prepared using a procedure similar to that described in Step 5 of Example 2, substituting Compound 246-1 for Compound 2-4 and (S)-3-methylpyrrolidine for L-proline. The resulting solution was concentrated to afford the title compound.

[0863] Step 3: ((6-(difluoromethoxy)-2-(3'-(6-methoxy-5-(((S)-3-methyl-pyrrolidin-1-yl)methyl)pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline

[0864]

[0865] This compound was prepared using a method similar to that described in Step 5 of Example 1, replacing Compound 1-4 with Compound 246-2. The organic phase was separated and purified using an RP-column (mobile phase: MeCN:water (0.1% HCl) gradient elution from 15:85 to 30:70) to afford ((6-(difluoromethoxy)-2-(3'-(6-methoxy-5-(((S)-3-methylpyrrolidin-1-yl)methyl)pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline (30.8 mg) as a white solid. LC-MS (m / z): 697.3 (M+H) + . 1 H NMR(500MHz,DMSO-d6)δ8.11(dd,1H,J=7.9,1.5Hz),7.96(s,1H),7.77(d,1H,J=7.5Hz),7.72(s,1H),7.54 -7.37(m,5H),7.24-7.19(m,1H),7.16(d,1H,J=7.5Hz),3.95(s,2H),3.89(s,3H),3.58(s,2H),3.11-3.03 (m,1H),2.78(t,1H,J=2.8Hz),2.68–2.60(m,1H),2.60-2.52(m,3H),2.45(s,3H),2.22-2.16(m,1H),2.15 -2.07(m,2H),2.05(s,3H),2.02-1.93(m,1H),1.88-1.70(m,3H),1.34-1.27(m,1H),1.00(d,J=6.7Hz,3H).

[0866] Example 247 Preparation of Compound 247

[0867] ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-4-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline

[0868]

[0869] Step 1: Preparation of tert-butyl (S)-2-(4-(3'-(6-(difluoromethoxy)-5-(((S)-2-(methoxycarbonyl)-ylpyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

[0870]

[0871] This compound was prepared using a method similar to that described in Step 1 of Example 1, replacing Compound a-6 with tert-butyl (S)-2-(4-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate, and replacing Intermediate A with Intermediate B. The resulting solution was concentrated and purified on a silica gel column (eluted with a gradient of n-hexane-ethyl acetate from 5:1 to 1:1) to give tert-butyl (S)-2-(4-(3'-(6-(difluoromethoxy)-5-(((S)-2-(methoxycarbonyl)-ylpyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (98 mg) as a yellow oil.

[0872] Step 2: Preparation of ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-4-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

[0873]

[0874] A mixture of compound 247-1 (76.0 mg) in DCM / TFA = 7:1 (4 mL) was stirred at room temperature for 4 hrs. The resulting solution was concentrated under high vacuum to give compound 247-2 (60 mg) as a yellow semi-solid.

[0875] Step 3: Preparation of ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-4-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline

[0876]

[0877] This compound was prepared using a method similar to that described in Step 5 of Example 1, using Compound 247-2 instead of Compound 1-4. The crude product was purified by RP-column (mobile phase: MeCN:water (0.1% HCl) gradient from 10:90 to 35:65) to give ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-4-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline (70.6 mg) as a white solid. LC-MS (m / z): 628.3 (M+H) + . 1 H NMR (500MHz, methanol-d4), δ: 8.19 (dd, 1H, J = 8.0, 1.5Hz), 8.07 (s, 1H), 7.76 (d, 1H, J = 10.8Hz), 7.61 (dd, 1H, J = 7.8, 1.3Hz) ,7.52(t,1H,J=7.8Hz),7.46(t,1H,J=7.6Hz),7.38(dd,1H,J=7.6,1.4Hz),7.32(dd,1H,J=7.6,1.4Hz),7.13(t,1H,J F-H =72.6Hz),5.16(t,1H,J=9.3,7.7Hz),4.79(d,1H,J=13.2),4.62(d,1H,J=13.3),4.48(t,1H,J=9.3Hz),3.67 -3.55(m,3H),3.50-3.42(m,1H),2.75-2.60(m,2H),2.58-2.50(m,1H),2.49(s,3H),2.43-2.34(m,1H),2.29 -2.17(m,3H),2.15(s,3H),2.11-1.99(m,1H).

[0878] The compounds in Table 6 can be prepared by methods similar to Examples 242-247 using different starting materials and appropriate reagents.

[0879] Table 6

[0880]

[0881]

[0882]

[0883]

[0884]

[0885]

[0886]

[0887] Example 295 Preparation of Compound 295

[0888] ((2-(3'-(7-cyano-5-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline

[0889]

[0890] Step 1: Preparation of methyl 4-amino-3-iodo-5-nitrobenzoate

[0891]

[0892] Methyl 4-amino-3-nitro-benzoic acid (5 g) was added to a mixture of AgSO (7.93 g) and I (6.47 g) in EtOH (20 mL) at room temperature. The resulting mixture was stirred overnight at room temperature. The mixture was diluted with water (20 mL) and extracted with ethyl acetate. The organic phase was washed with a NaSO aqueous solution, dried over MgSO, and concentrated to dryness. The resulting residue was purified by silica gel column chromatography to obtain the desired compound, 4-amino-3-iodo-5-nitro-benzoic acid methyl ester (7 g), as a yellow solid.

[0893] Step 2: Preparation of 3,4-diamino-5-iodo-benzoic acid methyl ester

[0894]

[0895] To a solution of compound 295-1 (3 g) in EA (30 mL) was added SnCl₂ (8.42 g). The reaction mixture was stirred at 70°C for 16 hours. EA (50 mL) was added to the reaction mixture, and the organic layer was washed with aqueous NaHCO₃, dried over MgSO₄, and concentrated to dryness. The resulting residue was purified by silica gel column chromatography to yield the desired compound, 3,4-diamino-5-iodo-benzoic acid methyl ester (2.6 g), as a yellow solid.

[0896] Step 3: Preparation of methyl 2-(3-bromo-2-methylphenyl)-7-iodo-1H-benzo[d]imidazole-5-carboxylate

[0897]

[0898] A mixture of compound 295-2 (2.6 g), 3-bromo-2-methyl-benzaldehyde (1.77 g), and AcOH (30 mL) was stirred at 80° C. for 16 hrs. EA (50 mL) was added to the reaction mixture, and the organic phase was washed with water, dried over MgSO₄, and concentrated to dryness. The resulting residue was purified by silica gel column chromatography to afford the desired compound, methyl 2-(3-bromo-2-methylphenyl)-7-iodo-1H-benzo[d]imidazole-5-carboxylate, as a yellow solid.

[0899] Step 4: Preparation of 2-(3-bromo-2-methylphenyl)-7-iodo-1H-benzo[d]imidazole-5-carboxylic acid

[0900]

[0901] To a solution of compound 295-3 (2 g) in MeOH (20 mL) was added a solution of NaOH (849.10 mg) in H2O (6 mL). The reaction mixture was stirred at 50 ° C overnight. The mixture was concentrated. Water was added to the mixture and the pH was adjusted to 5 with 2N HCl. The precipitate was filtered and the filter cake was washed with water. The product was dried in a vacuum oven (45 ° C, 3 hours) to give the title compound 2-(3-bromo-2-methylphenyl)-7-iodo-1H-benzo[d]imidazole-5-carboxylic acid as an off-white solid.

[0902] Step 5: Preparation of (2-(3-bromo-2-methylphenyl)-7-iodo-1H-benzo[d]imidazol-5-yl)methanol

[0903]

[0904] Borane tetrahydrofuran complex (20 mL) was added to a solution of compound 295-4 (1.8 g) in THF (20 mL) at -30°C. The reaction mixture was stirred at 60°C for 16 hours. After the mixture cooled to room temperature, 2N HCl (20 mL) was added. After 10 minutes, the mixture was diluted with ethyl acetate and washed with water. The organic phase was dried over MgSO4 and concentrated to dryness. The residue was purified by silica gel column chromatography to give the desired compound (2-(3-bromo-2-methylphenyl)-7-iodo-1H-benzo[d]imidazol-5-yl)methanol (1 g) as a white solid.

[0905] Step 6: Preparation of 2-(3-bromo-2-methylphenyl)-5-(hydroxymethyl)-1H-benzo[d]imidazole-7-carbonitrile

[0906]

[0907] A solution of compound 295-5 (500 mg), Zn(CN) (66.02 mg), and Pd(PPh) (130.34 mg) in DMF (10 mL) was stirred at 90°C for 3 hrs under N2 protection. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate. The organic phase was then washed with aqueous NaCl, dried over MgSO4, and concentrated to dryness. The residue was purified by silica gel column chromatography to yield the desired compound, 2-(3-bromo-2-methylphenyl)-5-(hydroxymethyl)-1H-benzo[d]imidazole-7-carbonitrile (150 mg), as a yellow oil.

[0908] Step 7: Preparation of 2-(3-bromo-2-methylphenyl)-5-(chloromethyl)-1H-benzo[d]imidazole-7-carbonitrile

[0909]

[0910] This compound was prepared using a procedure similar to that described in Example 1, Step 2, substituting compound 295-6 for compound 1-1. The mixture was concentrated to afford the title compound.

[0911] Step 8: Preparation of 2-(3-bromo-2-methylphenyl)-5-(-ylpyrrolidin-1-ylmethyl)-1H-benzo[d]imidazole-7-carbonitrile

[0912]

[0913] This compound was prepared using a method similar to that described in Step 3 of Example 1, substituting Compound 295-7 for Compound 1-2 and pyrrolidine for (1S,2R)-2-aminocyclopentane-1-ol. The crude product was purified by silica gel column chromatography to afford the title compound.

[0914] Step 9: Preparation of ((2-(3'-(7-cyano-5-(-ylpyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

[0915]

[0916] This compound was prepared using a procedure similar to that described in step 1 of example 1, substituting compound 295-8 for compound a-6. The crude product was purified by silica gel column chromatography to afford the title compound.

[0917] Step 10: Preparation of ((2-(3'-(7-cyano-5-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline

[0918]

[0919] This compound was prepared using a method similar to that described in Step 5 of Example 1, using Compound 295-9 instead of Compound 1-4. The crude product was purified by pre-HPLC to give the desired product ((2-(3'-(7-cyano-5-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline. LC-MS (m / z): 717.3 (M+H) + .

[0920] The compounds in Table 7 can be prepared by a method similar to Example 295 using different starting materials and appropriate reagents.

[0921] Table 7

[0922]

[0923] Example 304 Preparation of Compound 304

[0924] ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(4-methyl-5-(pyrrolidin-1-ylmethyl)oxazol-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline

[0925]

[0926] Step 1: 2-Bromo-4-methyl-oxazole-5-carboxylic acid methyl ester

[0927]

[0928] Tert-butyl nitrite (2.24 g) was added to a suspension of 2-amino-4-methyl-oxazole-5-carboxylic acid methyl ester (1.7 g) and CuBr2 (7.28 g) in acetonitrile (20 mL). The mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate. The organic phase was then washed with a NaCl aqueous solution, dried over MgSO4, and concentrated to dryness. The residue was purified by silica gel chromatography to obtain the desired product, 2-bromo-4-methyl-oxazole-5-carboxylic acid methyl ester (800 mg), as a white solid.

[0929] Step 2: Preparation of 2-(3-bromo-2-methyl-phenyl)-4-methyl-oxazole-5-carboxylic acid methyl ester

[0930]

[0931] This compound was prepared using a procedure similar to that described in Example 1, Step 1, and the crude product was purified by silica gel column chromatography to provide the title compound.

[0932] Step 3: Preparation of [2-(3-bromo-2-methyl-phenyl)-4-methyl-oxazol-5-yl]methanol

[0933]

[0934] This compound was prepared using a method similar to that described in step 5 of example A, substituting compound 304-2 for compound a-4. The crude product was purified by silica gel column chromatography to afford the title compound.

[0935] Step 4: Preparation of 2-(3-bromo-2-methyl-phenyl)-5-(chloromethyl)-4-methyl-oxazole

[0936]

[0937] This compound was prepared using a method similar to that described in Step 2 of Example 1, substituting Compound 304-3 for Compound 1-1. The mixture was concentrated to afford the title compound.

[0938] Step 5: Preparation of 2-(3-bromo-2-methyl-phenyl)-4-methyl-5-(-ylpyrrolidin-1-ylmethyl)oxazole

[0939]

[0940] This compound was prepared using a method similar to that described in Step 3 of Example 1, substituting Compound 304-4 for Compound 1-2 and pyrrolidine for (1S,2R)-2-aminocyclopentane-1-ol. The crude product was purified by silica gel column chromatography to afford the title compound.

[0941] Step 6: Preparation of (2S)-1-[[6-(difluoromethoxy)-2-[2-methyl-3-[2-methyl-3-[4-methyl-5-(-ylpyrrolidin-1-ylmethyl)oxazol-2-yl]phenyl]phenyl]-1,3-benzoxazol-5-yl]methyl]pyrrolidine-2-carboxylic acid methyl ester

[0942]

[0943] This compound was prepared using a method similar to that described in step 1 of example 1, substituting compound 304-5 for compound a-6. The crude product was purified by silica gel column chromatography to afford the title compound.

[0944] Step 7: Preparation of ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(4-methyl-5-(-ylpyrrolidin-1-ylmethyl)oxazol-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline

[0945]

[0946] This compound was prepared using a method similar to that described in step 5 of Example 1, using compound 304-6 instead of compound 1-4. The crude product was purified by pre-HPLC to give the title compound. LC-MS (m / z): 657.3 (M+H) + .

[0947] Example 305 Synthesis of Compound 305

[0948] ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(6-(pyrrolidin-1-ylmethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline

[0949]

[0950] Step 1: Preparation of ethyl N-[[5-(hydroxymethyl)-2-pyridyl]aminomethylthio]carbamate

[0951]

[0952] To a solution of (6-aminopyridin-3-yl)methanol (5 g) in 1,4-dioxane (25 mL) was added ethyl N-(thiomethylidene)carbamate (7.92 g). The reaction mixture was stirred at 50°C for 3 hours. The mixture was concentrated to a residue, which was used directly in the next step.

[0953] Step 2: Preparation of (2-amino-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methanol

[0954]

[0955] Hydroxylamine hydrochloride (5.13 g) was added to a solution of compound 305-1 (9.5 g) in methanol (15 mL) / ethanol (15 mL), followed by N,N-diisopropylethylamine (9.62 g). The reaction mixture was stirred at 50°C for 3 hours. The crude product was cooled, and the precipitate was filtered to obtain the desired product (5.0 g) as a green oil.

[0956] Step 3: Preparation of (2-bromo-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methanol

[0957]

[0958] Tert-butyl nitrite (5.6 g) was added to a suspension of compound 305-2 (5 g) and copper bromide (1.22 g) in acetonitrile (50 mL). The mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with DCM and washed with water. The organic phase was dried, filtered, and concentrated to near dryness. The residue was purified by silica gel column chromatography to give the desired product (3.2 g) as a white solid.

[0959] Step 4: Preparation of [2-(3-bromo-2-methyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]methanol

[0960]

[0961] This compound was prepared using a procedure similar to that described in Example 1, Step 1. The residue was purified by silica gel column chromatography to provide the title compound.

[0962] Step 5: Preparation of 2-(3-bromo-2-methyl-phenyl)-6-(chloromethyl)-[1,2,4]triazolo[1,5-a]pyridine

[0963]

[0964] This compound was prepared using a procedure similar to that described in Example 1, Step 2, substituting compound 305-4 for compound 1-1. The crude product was used directly in the next step.

[0965] Step 6: Preparation of 2-(3-bromo-2-methyl-phenyl)-6-(-ylpyrrolidin-1-ylmethyl)-[1,2,4]triazolo[1,5-a]pyridine

[0966]

[0967] This compound was prepared using a method similar to that described in Step 3 of Example 1, substituting Compound 305-5 for Compound 1-2 and pyrrolidine for (1S,2R)-2-aminocyclopentane-1-ol. The crude product was purified by silica gel column chromatography to afford the title compound.

[0968] Step 7: Preparation of (2S)-1-[[6-(difluoromethoxy)-2-[2-methyl-3-[2-methyl-3-[6-(-ylpyrrolidin-1-ylmethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]phenyl]phenyl]-1,3-benzoxazol-5-yl]methyl]pyrrolidine-2-carboxylic acid methyl ester

[0969]

[0970] This compound was prepared using a procedure similar to that described in Example 1, Step 1, substituting compound 305-6 for compound a-6. The crude product was purified by silica gel column chromatography to afford the title compound.

[0971] Step 8: Preparation of ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(6-(-ylpyrrolidin-1-ylmethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline

[0972]

[0973] This compound was prepared using a method similar to that described in step 5 of Example 1, using compound 305-7 instead of compound 1-4. The crude product was purified by pre-HPLC to give the title compound. LC-MS (m / z): 693.3 (M+H) + .

[0974] Example 306 Preparation of Compound 306

[0975] ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(4-(pyrrolidin-1-yl)piperidin-1-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline

[0976]

[0977] Step 1: Preparation of 1-(3-bromo-2-methyl-phenyl)-4-ylpyrrolidin-1-yl-piperidine

[0978]

[0979] Under N2 atmosphere, a mixture of 1,3-dibromo-2-methyl-benzene (1g), 4-pyrrolidin-1-yl-piperidine (617.18mg), Cs2CO3 (3.91g), Pd2(dba)3 (366.10mg) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (462.53mg) in toluene (20mL) was stirred at 100°C overnight. The mixed solution was concentrated to obtain a residue. The residue was purified by silica gel column chromatography to obtain the desired product, 1-(3-bromo-2-methyl-phenyl)-4-pyrrolidin-1-yl-piperidine (450mg), as a red oil.

[0980] Step 2: Preparation of (2S)-1-[[6-(difluoromethoxy)-2-[2-methyl-3-[2-methyl-3-(4-pyrrolidin-1-yl-1-piperidinyl)phenyl]phenyl]-1,3-benzoxazol-5-yl]methyl]pyrrolidine-2-carboxylic acid methyl ester

[0981]

[0982] This compound was prepared using a similar method as described in Example 1, Step 1, substituting compound 306-1 for compound a-6. The crude product was purified by silica gel column chromatography to give the title compound.

[0983] Step 3: Preparation of ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(4-(-ylpyrrolidin-1-yl)piperidin-1-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline

[0984]

[0985] This compound was prepared using a method similar to that described in step 5 of Example 1, using compound 306-2 instead of compound 1-4. The crude product was purified by pre-HPLC to give the title compound. LC-MS (m / z): 645.3 (M+H) + .

[0986] The compounds in Table 8 can be prepared by methods similar to Examples 304-306 using different starting materials and appropriate reagents.

[0987] Table 8

[0988]

[0989]

[0990] Compounds 34, 61, 85, 88, 93, 113, 127, 130, 131, 135, 142 and 146 1 The HNMR data are shown below:

[0991] 1 H NMR (500 MHz, DMSO-d6) δ 8.24 (s, 1H), 8.17 (dd, J = 8.0, 2.2 Hz, 2H), 8.08 (s, 1H), 7.88 (s, 1H), 7.81 (s, 1H), 7.64–7.51 (m, 2H), 7.49–7.20 (m, 4H), 4.52 (s, 2H), 4.38–4.12 (m, 2H), 3.94–3.84 (m, 4H), 3.26–2.86 (m, 3H), 2.45 (s, 6H), 2.37–1.71 (m, 4H), 1.31 (d, J = 43.4 Hz, 6H). (Compound 34)

[0992] 1 H NMR (500 MHz, chloroform-d) δ 8.30–8.03 (m, 4H), 7.66–7.54 (m, 2H), 7.49–7.41 (m, 2H), 7.40–7.35 (m, 2H), 7.10–6.77 (m, 2H), 4.86–4.18 (m, 5H), 3.94–3.57 (m, 3H), 3.43–3.25 (m, 2H), 2.71–2.55 (m, 2H), 2.48 (d, J = 3.7 Hz, 6H), 2.37–1.58 (m, 6H), 1.27–1.08 (m, 3H). (Compound 61)

[0993] 1 H NMR (500MHz, chloroform-d) δ8.13(dd,J=7.8,6.1Hz,2H),7.99(d,J=9.8Hz,2H),7.52(d,J=17.9 Hz,2H),7.48–7.42(m,2H),7.37–7.34(m,2H),6.83(t,J=71.9Hz,1H),6.80(t,J=71.9H z, 1H), 4.29 (d, J = 25.2 Hz, 4H), 3.70 (s, 4H), 3.42 (dd, J = 10.6, 4.4 Hz, 1H), 3.21 (q, J = 8.3 Hz, 2H), 3.09 (d, J = 22.7 Hz, 2H), 2.46 (d, J = 7.9 Hz, 6H), 2.34–2.22 (m, 2H), 1.35 (s, 6H). (Compound 85)

[0994] 1H NMR (500 MHz, chloroform-d) δ 8.36 (s, 1H), 8.22 (dd, J = 7.9, 1.5 Hz, 1H), 8.17–8.07 (m, 2H), 7.99 (s,

[0995] 1H),7.59(s,1H),7.46(dt,J=12.7,7.7Hz,2H),7.42–7.34(m,2H),6.93(t,J =72.1Hz,1H),4.78–4.62(m,2H),4.52(t,J=12.8Hz,2H),4.21(t,J=8.0Hz,1H ),3.87–3.58(m,3H),3.21-3.00(m,2H),2.75–2.53(m,3H),2.47(d,J=15.4Hz ,6H),2.39-2.23(m,2H),2.16(t,J=7.9Hz,2H),1.78(d,J=62.1Hz,1H),1.21–

[0996] 1.10 (m, 3H). (Compound 88)

[0997] 1 H NMR (500 MHz, chloroform-d) δ 8.18 (d, J = 7.9 Hz, 1H), 8.06 (d, J = 7.9 Hz, 1H), 7.93–7.76 (m, 2H), 7.55 (s, 1H), 7.49–7.26 (m, 5H), 6.76 (t, J = 72.9 Hz, 1H), 4.29–3.39 (m, 6H), 3.23–2.91 (m, 6H), 2.38–2.47 (d, J = 25.5 Hz, 6H), 2.09–1.60 (m, 3H), 1.23 (s, 6H). (Compound 93)

[0998] 11H NMR (500 MHz, DMSO-d6) δ 8.38 (s, 1H), 8.26 (s, 1H), 8.20 (dd, J = 7.9, 1.4 Hz, 1H), 8.13 (ddd, J = 23.5, 7.9, 1.5 Hz, 1H), 7.96 (d, J = 10.1 Hz, 1H), 7.72 (d, J = 13.9 Hz, 1H), 7.61–7.49 (m, 2H), 7.45 (ddd, J = 13.6, 7.6, 1.5 Hz, 2H), 7.38 (d, J = 71.9 Hz, 1H), 3.96 (s, 2H), 3.44 - 3.22 (m, 5H), 3.11 - 2.99 (m, 2H), 2.57 (q, J = 8.5 Hz, 1H), 2.45 (d, J = 5.8 Hz, 6H), 2.19 - 2.06 (m, 1H), 1.93–1.64 (m, 4H), 1.22 (d, J = 7.5 Hz, 6H). (Compound 113)

[0999] 1 1H NMR (500 MHz, chloroform-d) δ 8.24 (dd, J = 7.9, 1.4 Hz, 1H), 8.17–8.07 (m, 2H), 8.03 (s, 1H), 7.79 (s,

[1000] 1H), 7.60 (s, 1H), 7.48 (dt, J = 15.0, 7.7 Hz, 2H), 7.43–7.35 (m, 2H), 6.94 (t, J = 71.9 Hz, 1H), 4.60 (d, J = 13.1 Hz, 1H), 4.50 (d, J = 13.2 Hz, 1H), 3.97 (s, 3H), 3.71–3.60 (m, 1H), 3.15 (q, J = 9.9 Hz, 1H), 2.76 (s, 4H), 2.47 (s, 6H), 2.33 - 2.24 (m, 1H), 2.15 - 2.06 (m, 1H), 2.06–1.97 (m, 2H), 1.91 (q, J = 3.5, 3.0 Hz, 4H).

[1001] (Compound 127)

[1002] 11H NMR (500 MHz, DMSO-d6) δ 8.20 (dd, J = 7.9, 1.4 Hz, 1H), 8.16 (dd, J = 7.9, 1.4 Hz, 1H), 8.11 (d, J = 1.5 Hz, 1H), 7.97 (s, 1H), 7.88 (d, J = 1.5 Hz, 1H), 7.73 (s, 1H), 7.63–7.51 (m, 2H), 7.48 (dd, J = 7.6, 1.4 Hz, 1H), 7.44 (dd, J = 7.6, 1.4 Hz, 1H), 7.38 (t, J = 73.7 Hz, 1H), 3.96 (s, 2H), 3.79–3.68 (m, 2H), 3.38–3.31 (m, 1H), 3.09–3.03 (m, 1H), 2.74–2.48 (m, 5H), 2.44 (d, J = 2.9 Hz, 6H), 2.26–1.68 (m, 6H), 1.36–1.20 (m, 1H), 0.99 (d, J = 6.7 Hz, 3H). (Compound 130)

[1003] 1 1H NMR (500 MHz, DMSO-d6) δ 8.21 (dd, J = 7.9, 1.4 Hz, 1H), 8.19 (s, 1H), 8.15 (dd, J = 7.9, 1.4 Hz, 1H), 7.97 (s, 1H), 7.95 (s, 1H), 7.73 (s, 1H), 7.63–7.51 (m, 2H), 7.48 (dd, J = 7.6, 1.4 Hz, 1H), 7.44 (dd, J = 7.5, 1.4 Hz, 1H), 7.38 (t, J = 73.7 Hz, 1H), 3.97 (s, 2H), 3.92–3.86 (m, 2H), 3.38–3.31 (m, 1H), 3.11–3.05 (m, 1H), 2.83–2.51 (m, 5H), 2.44 (d, J = 4.1 Hz, 6H), 2.31–1.70 (m, 6H), 1.46–1.14 (m, 1H), 1.00 (d, J = 6.3 Hz, 3H). (Compound 131)

[1004] 1H NMR (500 MHz, chloroform-d) δ 8.25 (d, J = 7.8 Hz, 1H), 8.14 (dd, J = 7.9, 1.3 Hz, 1H), 8.10 (s, 1H), 7.94 (s, 1H), 7.77 (s, 1H), 7.61 (s, 1H), 7.48 (dt, J = 15.2, 7.7 Hz, 2H), 7.42–7.34 (m, 2H), 6 .93 (t, J = 71.9 Hz, 1H), 4.55 (d, J = 13.0 Hz, 1H), 4.37 (d, J = 13.1 Hz, 2H), 3.94–3.35 (m, 5H), 3.17–2.82 (m, 4H), 2.51 (s, 3H), 2.47 (s, 3H), 2.47–2.29 (m, 2H), 2.16–1.46 (m, 10H). (Compound 135)

[1005] 1 H NMR(500MHz,DMSO-d6)δ8.35–8.30(m,1H),8.23(dd,J=8.0,1.5Hz,1H),8.18(dt,J=7 .9,1.3Hz,1H),8.12(d,J=1.4Hz,1H),8.08(s,1H),7.89(s,1H),7.61(dt,J=13.6,7. 7 Hz, 2H), 7.57–7.45 (m, 2H), 7.40 (t, J = 73.2 Hz, 1H), 4.62–4.25 (m, 4H), 3.58–3.07 (m, 5H), 2.52–2.50 (m, 1H), 2.49–2.48 (m, 4H), 2.45 (d, J = 5.5 Hz, 6H), 2.26–1.80 (m, 4H). (Compound 142)

[1006] 1 H NMR(500MHz,DMSO-d6)δ8.35(s,1H),8.23(d,J=7.9Hz,1H),8.18(d,J=7.8Hz,1H),8.1 3–8.07(m,2H),7.87(s,1H),7.70(s,1H),7.60(dt,J=14.9,7.7Hz,2H),7.56–7.44(m, 2H), 7.32 (t, J = 73.2 Hz, 1H), 4.56–4.01 (m, 7H), 3.50 (s, 2H), 3.45–3.12 (m, 2H), 2.56 (s, 2H), 2.50–2.48 (m, 2H), 2.45 (d, J = 5.5 Hz, 6H), 2.43–2.33 (m, 1H) 2.08–1.79 (m, 3H). (Compound 146)

[1007] Comparative Example

[1008] The following control examples (as shown in Table 9) were prepared substantially according to the method described in Example 7 of WO2018119266.

[1009] Table 9

[1010]

[1011] PD-1 / PD-L1 binding assay (Alphascreen)

[1012] The test was performed in a standard black 384-well polystyrene plate with a final volume of 20 μL. The inhibitor was first serially diluted in DMSO and then added to the plate wells before adding other reaction components. The final DMSO concentration tested was 1%. 100 nL / well of compound was added to a 384 reaction plate (6008280, PerkinElmer) and centrifuged at 1000 rpm for 1 minute. 5 μL / well of 4X PD-L1 solution was added to the 384 reaction plate, centrifuged at 1000 rpm for 1 minute, then 5 μL / well of 4X PD-1 solution was added, centrifuged at 1000 rpm for 1 minute, and then incubated at 25°C for 15 minutes. The compound concentrations were 300, 100, 33.33, 11.11, 3.70, 1.23, 0.41, 0.137, 0.046, 0.015, and 0 nM, respectively. 10 μL / well of a 2X anti-6xHis AlphaLISA acceptor bead and streptavidin donor bead solution (PerkinElmer-AL356F) was added to the above 384-well reaction plate, centrifuged at 1000 rpm for 1 minute, and incubated in the dark at 25°C for 120 minutes. AlphaLISA signal values were read using an Envision reader. IC50 values were determined by fitting a curve of percent control activity versus the logarithm of inhibitor concentration using GraphPad Prism 8.0 software.

[1013] As shown in the examples, the compounds of the present invention, IC 50 Values are in the following range: * represents 0.1 nM <IC 50 ≤5nM"; "**" represents "5nM <IC 50 ≤50nM”; “***” represents “IC 50 >50nM".

[1014] The data of the example compounds obtained using the above-mentioned PD-1 / PD-L1 binding assay (Alphascreen) are shown in Table 10.

[1015] Table 10

[1016]

[1017]

[1018]

[1019] Pharmacokinetic studies

[1020] Adult female C57 mice received a single dose of 10% DMSO, 10% Kolliphor @ The test compound, with HS15 and 80% saline as excipients, was orally administered (orally) to mice (n=9) at a dose of 100 mg / kg. Blood collection time: 15 min, 30 min, 1 h, 2 h, 4 h, 7 h, 24 h. Approximately 0.1 mL of whole blood was collected from the retroorbital venous plexus of 3 mice at each blood collection point and placed in a test tube containing K2-EDTA as an anticoagulant. The whole blood was centrifuged at 4°C and 4000 rpm for 10 min. The plasma was transferred to a centrifuge tube and stored at -20°C until analysis. The concentration of the test compound in the plasma samples was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS / MS). The plasma concentration-time data of each animal were analyzed by Microsoft Excel 2010. A non-compartmental model was introduced in the concentration analysis. The pharmacokinetic parameters of the test compound were collected by WinNonlin (version 4.1; Pharsight) software, and the data are shown in Table 11.

[1021] Adult female C57 mice received a single dose of 15% DMSO, 10% Kolliphor @ The test compound, containing HS15 and 75% saline as excipients, was orally administered (orally) to mice (n=3) at a dose of 5 mg / kg. Blood collection time: 30 min, 2 h, and 4 h. Approximately 0.1 mL of whole blood was collected from the retroorbital venous plexus and placed in a test tube containing K2-EDTA as an anticoagulant. The whole blood was centrifuged at 4°C and 4000 rpm for 10 min. The plasma was transferred to a centrifuge tube and stored at -20°C until analysis. The concentration of the test compound in the plasma sample was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS / MS). The plasma concentration-time data of each animal were analyzed by Microsoft Excel 2010, and the data are shown in Table 12.

[1022] Table 11

[1023]

[1024]

[1025] Table 12

[1026]

[1027]

[1028]

[1029] NA = Not Applicable

[1030] As shown in Tables 11 and 12, we can see that the exemplary compounds of the present invention exhibit unexpectedly superior pharmacokinetic properties to those of the known compound of Comparative Example 1.

[1031] NFAT test

[1032] The PD-1 / PD-L1 Blockade Bioassay involves two cell lines: PD-1 effector cells (Jurkat T cells expressing hPD-1 and a luciferase reporter gene); and PD-L1 aAPC / CHO-K1 cells (CHO-K1 cells expressing hPD-L1 and a cell surface protein that activates the TCR). Antibodies or small molecule compounds are co-incubated with these two cell lines for a period of time. The amount of product is measured using the Bio-Glo luciferase reagent and chemiluminescence to reflect the effect of the antibody or small molecule compound on the PD-1 / PD-L1 interaction.

[1033] Assay buffer: 49.5 mL RPMI-1640; 0.5 mL FBS

[1034] Cell culture medium: 36 mL Ham's F-12; 4 mL FBS

[1035] Reaction steps:

[1036] 1) On the first day, PD-L1 aAPC / CHO-K1 cells were revived and counted using cell recovery medium. Diluted to 2.65*10 5 / ml. Cells were seeded into 384-well plates at a density of 6000 cells / well and cultured for 16-24 hours;

[1037] 2) Dilute the compound to 5 mM with DMSO, using 5 mM as the first concentration. Perform a 3-fold serial dilution for a total of 9 concentration gradients, with the 10th concentration serving as the DMSO control.

[1038] 3) Dilute the positive control antibody to 4 μg / ml with assay buffer. 4 μg / ml is used as the first concentration. Perform 2.5-fold dilutions for a total of 9 concentration gradients. The 10th concentration is the assay buffer control.

[1039] 4) Aspirate the cell culture medium in the 384-well plate, add 10 μL / well of the compound to the 384-well plate and incubate for 2 hours;

[1040] 5) Resuscitate PD-1 effector cells, suspend and count with assay buffer. Dilute cells to 8.75*10 5 / ml. Cells were seeded into the 384-well plate prepared in step 4 at a density of 8,000 cells / well and incubated for 17 hours.

[1041] 6) Add 20 μL / well of Bio-Glo luciferase reagent to the 384-well reaction plate from step 5 and incubate at 25°C for 5-30 minutes.

[1042] 7) Read the RLU (Relative Luminescence Unit) values using an Envision multi-function plate reader. Plot the experimental data using compound concentration as the X value and RLU as the Y value.

[1043] The results are expressed as EC 50 The values are shown in Table 13.

[1044] Table 13

[1045] Example No. <![CDATA[EC 50 (nM)]]> 5 317 103 254 317 4697 318 3225

Claims

1. A compound represented by formula (III), or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, in, R1 and R2 are independently selected from halogen, CN, C 1-6 Alkyl or C 1-4 alkyl halide; Ring C is a benzene ring or a heteroaryl group, wherein the heteroaryl group contains 1, 2 or 3 N atoms; R3 is H, halogen, -(CH2) s -NR4R5、C 1-4 Alkyl, C 1-4 Alkoxy, hydroxy, oxy, CN, (CH2) q -CONR4R5, -COR4, -NR4R5, -NR4C(=O)NR4R5, -NR4C(=NR4)NR4R5, -S(O)2R4, -S(O)2NR4R5, -S(O)R4, -S(O)NR4R5, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 5-6 Aryl, C 5-6 Heteroaryl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl, wherein C 5-6 Heteroaryl and C 3-6 Heterocycloalkyl optionally contains 1, 2 or 3 heteroatoms independently selected from N, S or O; 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 5-6 Aryl, C 5-6 Heteroaryl, C 3-6 Cycloalkyl and C 3-6 Heterocycloalkyl is optionally substituted with one or more substituents independently selected from R6; R4 and R5 are independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocyclic group, the C 1-4 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocyclyl is optionally substituted with one or more substituents independently selected from R6; or R4 and R5 together with the atoms to which they are attached form a 4-10 membered heterocyclic ring, said 4-10 membered heterocyclic ring being optionally substituted with one or more substituents independently selected from R6; R6 is H, halogen, hydroxy, oxy, CN, -(CH2) k -NR7R8, -COR7, -NR7R8, -NR7C(=O)NR7R8, -NR7C(=NR7)NR7R8, -S(O)2R7, -S(O)2NR7R8, -S(O)R7, -S(O)NR7R8, or R6 is selected from substituted or unsubstituted C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 5-6 Aryl, C 5-6 Heteroaryl, C 3-10 Heterocyclic group, wherein the C 5-6 Heteroaryl and C 3-10 The heterocyclic group optionally contains 1, 2 or 3 heteroatoms independently selected from N, S or O; R7 and R8 are independently selected from H, halogen, hydroxy, oxo, CN, -S(O)2-C 1-4 Alkyl, -NH2, -NH-C 1-4 Alkyl, -(CH2)-N(C 1-4 alkyl)2, or R7 and R8 are independently selected from substituted or unsubstituted C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 5-6 Aryl, C 5-6 Heteroaryl, C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl; wherein the C 5-6 Heteroaryl and C 3-6 The heterocycloalkyl group optionally contains 1, 2 or 3 heteroatoms independently selected from N, S or O; n, q, k and s are independently selected from 0, 1, 2, 3 or 4.

2. A compound represented by formula (IV), or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, in, R1 and R2 are independently selected from halogen, CN, C 1-6 Alkyl or C 1-4 alkyl halide; D ring is C 5-6 Aryl, C 5-6 Heteroaryl or C 5-6 Heterocycloalkyl, the C 5-6 Heteroaryl and C 5-6 The heterocycloalkyl group optionally contains 1, 2 or 3 heteroatoms independently selected from N, S or O; R3 is H, halogen, -(CH2) s -NR4R5、C 1-4 Alkyl, C 1-4 Alkoxy, hydroxy, oxy, CN, (CH2) q -CONR4R5, -COR4, -NR4R5, -NR4C(=O)NR4R5, -NR4C(=NR4)NR4R5, -S(O)2R4, -S(O)2NR4R5, -S(O)R4, -S(O)NR4R5, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 5-6 Aryl, C 5-6 Heteroaryl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl, wherein C 5-6 Heteroaryl and C 3-6 Heterocycloalkyl optionally contains 1, 2 or 3 heteroatoms independently selected from N, S or O; 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 5-6 Aryl, C 5-6 Heteroaryl, C 3-6 Cycloalkyl and C 3-6 Heterocycloalkyl is optionally substituted with one or more substituents independently selected from R6; R4 and R5 are independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocyclic group, the C 1-4 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocyclyl is optionally substituted with one or more substituents independently selected from R6; or R4 and R5 together with the atoms to which they are attached form a 4-10 membered heterocyclic ring, said 4-10 membered heterocyclic ring being optionally substituted with one or more substituents independently selected from R6; R6 is H, halogen, hydroxy, oxy, CN, -(CH2) k -NR7R8, -COR7, -NR7R8, -NR7C(=O)NR7R8, -NR7C(=NR7)NR7R8, -S(O)2R7, -S(O)2NR7R8, -S(O)R7, -S(O)NR7R8, or R6 is selected from substituted or unsubstituted C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 5-6 Aryl, C 5-6 Heteroaryl, C 3-10 Heterocyclic group, wherein the C 5-6 Heteroaryl and C 3-10 The heterocyclic group optionally contains 1, 2 or 3 heteroatoms independently selected from N, S or O; R7 and R8 are independently selected from H, halogen, hydroxy, oxo, CN, -S(O)2-C 1-4 Alkyl, -NH2, -NH-C 1-4 Alkyl, -(CH2)-N(C 1-4 alkyl)2, or R7 and R8 are independently selected from substituted or unsubstituted C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 5-6 Aryl, C 5-6 Heteroaryl, C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl; wherein the C 5-6 Heteroaryl and C 3-6 The heterocycloalkyl group optionally contains 1, 2 or 3 heteroatoms independently selected from N, S or O; n, q, k and s are independently selected from 0, 1, 2, 3 or 4.

3. A compound represented by formula (IV), or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein: in, R1 and R2 are independently selected from halogen, CN, C 1-6 Alkyl or C 1-4 alkyl halide; R3 is H, halogen, -(CH2) s -NR4R5、C 1-4 Alkyl, C 1-4 Alkoxy, hydroxy, oxy, CN, (CH2) q -CONR4R5, -COR4, -NR4R5, -NR4C(=O)NR4R5, -NR4C(=NR4)NR4R5, -S(O)2R4, -S(O)2NR4R5, -S(O)R4, -S(O)NR4R5, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 5-6 Aryl, C 5-6 Heteroaryl, C 3-6 Cycloalkyl or C 3-6 Heterocycloalkyl, wherein C 5-6 Heteroaryl and C 3-6 Heterocycloalkyl optionally contains 1, 2 or 3 heteroatoms independently selected from N, S or O; 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 5-6 Aryl, C 5-6 Heteroaryl, C 3-6 Cycloalkyl and C 3-6 Heterocycloalkyl is optionally substituted with one or more substituents independently selected from R6; R4 and R5 are independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocyclic group, the C 1-4 Alkyl, C 3-6 Cycloalkyl or C 3-6 Heterocyclyl is optionally substituted with one or more substituents independently selected from R6; or R4 and R5 together with the atoms to which they are attached form a 4-10 membered heterocyclic ring, said 4-10 membered heterocyclic ring being optionally substituted with one or more substituents independently selected from R6; R6 is H, halogen, hydroxy, oxy, CN, -(CH2) k -NR7R8, -COR7, -NR7R8, -NR7C(=O)NR7R8, -NR7C(=NR7)NR7R8, -S(O)2R7, -S(O)2NR7R8, -S(O)R7, -S(O)NR7R8, or R6 is selected from substituted or unsubstituted C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 5-6 Aryl, C 5-6 Heteroaryl, C 3-10 Heterocyclic group, wherein the C 5-6 Heteroaryl and C 3-10 The heterocyclic group optionally contains 1, 2 or 3 heteroatoms independently selected from N, S or O; R7 and R8 are independently selected from H, halogen, hydroxy, oxo, CN, -S(O)2-C 1-4 Alkyl, -NH2, -NH-C 1-4 Alkyl, -(CH2)-N(C 1-4 alkyl)2, or R7 and R8 are independently selected from substituted or unsubstituted C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 5-6 Aryl, C 5-6 Heteroaryl, C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl; wherein the C 5-6 Heteroaryl and C 3-6 The heterocycloalkyl group optionally contains 1, 2 or 3 heteroatoms independently selected from N, S or O; n, q, k and s are independently selected from 0, 1, 2, 3 or 4.

4. The compound according to any one of claims 1 to 3, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein: R3 is H, halogen, -(CH2) s -NR4R5、C 1-4 Alkyl, C 1-4 Alkoxy, hydroxy, oxy, CN, (CH2) q -CONR4R5, -NR4R5, -NR4C(=NR4)NR4R5, -S(O)2R4,C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl or C 3-6 Heterocycloalkyl, wherein C 3-6 Heterocycloalkyl optionally contains 1, 2 or 3 heteroatoms independently selected from N, S or O; 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl and C 3-6 Heterocycloalkyl is optionally substituted by one or more substituents independently selected from R6; preferably, R3 is H, halogen, -(CH2) s -NR4R5、CN、-S(O)2R4、C 1-4 Alkyl, C 1-4 Alkoxy, the -(CH2) s -NR4R5、C 1-4 Alkyl, C 1-4 The alkoxy group is optionally substituted with one or more substituents independently selected from R6.

5. The compound of claim 1, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein: R6 is H, halogen, hydroxy, oxy, CN, -(CH2) k -NR7R8, -COR7, -NR7R8, -NR7C(=O)NR7R8, -S(O)2R7, or R6 is selected from substituted or unsubstituted C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 5-6 Aryl, C 5-6 Heteroaryl, C 3-10 Heterocyclic group, wherein the C 5-6 Heteroaryl and C 3-10 The heterocyclic group optionally contains 1, 2 or 3 heteroatoms independently selected from N, S or O; preferably, R6 is H, halogen, hydroxyl, oxy, CN, -(CH2)-N-(C 1-4 alkyl)2, -(CH2)-NH2, -N-(C 1-4 Alkyl)2, -NH2, -CO-N-(C 1-4 Alkyl)2, -CO-NH2, -S(O)2-C 1-4 Alkyl, C 1-4 Alkyl-OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 5-6 Aryl, C 5-6 Heteroaryl, C 3-10 Heterocyclic group, wherein the C 5-6 Heteroaryl and C 3-10 The heterocyclic group optionally contains 1, 2 or 3 heteroatoms independently selected from N, S or O; further preferably, R6 is halogen, oxy, -OH, -NH2, -N(CH3)2, -C 1-4 Alkyl-OH, -C 1-4 Alkyl-NH-CH3, -NH-C 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 5-6 Aryl, C 5-6 Heteroaryl, C 3-6 heterocyclic group, guanidino group or sulfone group.

6. The compound of any one of claims 1 to 5, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein R1 is selected from F, Cl, -CH3, -CN or -O-CH3; preferably, R1 is selected from -CH3, F or -O-CH3.

7. The compound according to any one of claims 1 to 6, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein R2 is selected from -CH3, F, Cl or Br; preferably, R2 is -CH3.

8. The compound of any one of claims 1 to 7, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein R3 is selected from H, F, Cl, -CH3, -CF3, -O-CF3, -O-CHF2, -O-CH3, -CN, -NH2, 9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof and at least one pharmaceutically acceptable excipient.

10. Use of the pharmaceutical composition of claim 9 or the compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt or stereoisomer thereof, in the preparation of a medicament for a PD-1 / PD-L1 interaction inhibitor, wherein the medicament is used to treat or prevent cancer, or to enhance, stimulate and / or increase a patient's immune response; preferably, the cancer is colon cancer, gastric cancer, thyroid cancer, lung cancer, leukemia, pancreatic cancer, melanoma, multiple melanomas, brain cancer, kidney cancer, prostate cancer, ovarian cancer or breast cancer.

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