Biphenyl derivative inhibitors and methods of making and using the same

Abstract

The present invention relates to biphenyl derivative inhibitors, their preparation methods, and uses. In particular, the present invention relates to compounds represented by general formula (I), their preparation methods, and pharmaceutical compositions containing the compounds, as well as their use as inhibitors in the treatment of cancer, infectious diseases, and autoimmune diseases, wherein the substituents in general formula (I) have the same definitions as in the specification.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of drug synthesis, and particularly relates to a biphenyl derivative inhibitor and a preparation method and application thereof. BACKGROUND

[0002] The immune system plays an important role in controlling various diseases such as cancer. However, tumor cells can escape immune attack or inhibit the activation of the immune system through various pathways. Blocking the signal transmission of immune inhibitory checkpoints, such as programmed cell death protein 1 (PD-1), has been proved to be a potential treatment.

[0003] PD-1 is a member of the CD28 superfamily, and is an immunoinhibitory receptor on the surface of immune cells, especially cytotoxic T cells. PD-1 has two ligands, PD-L1 and PD-L2, of which PD-L1, cell programmed death receptor-ligand 1, is expressed in various cells such as macrophages and dendritic cells, and is commonly highly expressed on tumor cells. PD-L1 exerts an immunoinhibitory effect by binding to PD-1 and enables tumor cells to escape T cell killing, inhibits the activation of T cells and the production of corresponding cytokines, weakens infectious immunity and tumor immunity, and promotes the progression of infectious diseases and tumors. Using a PD-L1 inhibitor such as an antibody or a small molecule inhibitor can relieve the immunoinhibitory effect of PD-L1, promote the immune clearance of tumors, and thus achieve a therapeutic effect on tumors.

[0004] PD-1 / PD-L1 is a hot spot in the research of tumor immunotherapy in recent years, and the breadth, depth and persistence of the response of its monoclonal antibody drugs are very rare. At present, several PD-1 / PD-L1 monoclonal antibody drugs have been marketed in the clinic and have achieved great success. PD-L1 inhibitors can be used to treat almost all major cancers including non-small cell lung cancer, liver cancer, gastric cancer, intestinal cancer, kidney cancer, etc., and have great clinical application value.

[0005] PD-L1 inhibitors from macromolecules to small molecules are becoming a new research and development trend and a hot spot. Small molecule inhibitors have many natural advantages in terms of administration mode and production cost, and have the potential to replace antibody macromolecules. Foreign pharmaceutical companies including BMS and Incyte are actively developing PD-L1 small molecule inhibitors.

[0006] The oral small molecule inhibitor developed by BMS is currently in the preclinical research stage, and several patents have been published in succession. The small molecule inhibitor INCB086550 developed by Incyte is in the phase I clinical research stage, and the small molecule inhibitor CA-170 developed by Aurigene / Curis is also in the phase I clinical research stage.

[0007] International applications WO2015034820, WO2015160641, WO2014151634, WO2017066227, WO2017070089, WO2017106634, WO2017112730, WO2017192961, WO2017222976, WO2018013789, WO2018044783, WO2018119224, WO2018119236, WO2018119263, WO2018119266 and WO2018119286, etc. report PD-1 or PD-L1 small molecule compound inhibitors. In addition, international applications WO2014151634, WO2011161699, WO2012168944, WO2013132317, WO2013144704, WO2015033299, WO2015033301, WO2015033303 and WO2015036927 report macrocyclic and peptide compound PD-1 or PD-L1 inhibitors. However, there is still a great demand for PD-L1 small molecule inhibitors that are more effective for the PD-1 / PD-L1 pathway, have better pharmacokinetic properties and drug-likeness.

[0008] PD-L1 small molecule inhibitors have good application prospects in the pharmaceutical industry as drugs. First, PD-L1 small molecule inhibitors can be orally administered, which has the advantage of better compliance than antibody drugs administered intravenously, and can avoid serious side effects such as colitis caused by long-term residence of antibodies in the body. Second, PD-L1 small molecule inhibitors have a unique mechanism of action of binding to PD-L1 and endocytosis, which may exhibit different efficacy in clinical practice than antibodies. Finally, PD-L1 small molecule inhibitors have lower production and quality control costs, and have a price advantage far lower than that of macromolecular drugs, and can be applied to various major tumors like PD-L1 antibody inhibitors, and have great market potential. SUMMARY

[0009] The purpose of the present application is to provide a compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0010]

[0011] wherein:

[0012] L1 is selected from a bond, -(CH2) n1 -(CH2) n1 NR aa C(O)(CR aa R bb ) n2 -(CH2)n1 (CR aa R bb ) n2 -、-(CR aa R bb ) n1 O(CH2) n2 -、-(CH2) n1 O(CR aa R bb ) n2 -、-(CR aa R bb ) n1 S(CH2) n2 -、-(CH2) n1 S(CR aa R bb ) n2 -、-(CR aa R bb ) n1 (CH2) n2 NR cc -、-(CH2) n1 NR aa (CR bb R cc ) n2 -、-(CH2) n1 C(O)(CR aa R bb ) n2 -、-(CH2) n1 P(O)R aa -、-(CH2) n1 S(O) n2 -、-(CH2) n1 S(O) n2 NR aa -、-(CH2) n1 NR aa S(O) n2 -或-(CH2) n1 C(O)NR aa -;

[0013] L2选自键、-(CH2) n3 -、-(CR dd R ee ) n3 -、-(CR dd R ee ) n3 (CH2) n4 NR ff -、-(CH2) n3 NR dd (CR eeR ff ) n4 -, -(CH2) n3 (CR dd R ee ) n4 -, -(CR dd R ee ) n3 O(CH2) n4 -, -(CH2) n3 O(CR dd R ee ) n4 -, -(CR dd R ee ) n3 S(CH2) n4 -, -(CH2) n3 S(CR dd R ee ) n4 -, -(CH2) n3 C(O)(CR dd R ee ) n4 -, -(CH2) n3 NR dd C(O)(CR ee R ff ) n4 -, -(CH2) n3 P(O)R dd -, -(CH2) n3 S(O) n4 -, -(CH2) n3 S(O) n4 NR dd -, -(CH2) n3 NR dd S(O) n4 -, or -(CH2) n3 C(O)NR dd - ;

[0014] Ring A is selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0015] R is selected from hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, halogenated alkyl, alkoxy, alkylthio, halogenated alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, which amino, alkyl, alkenyl, alkynyl, deuterated alkyl, halogenated alkyl, alkoxy, alkylthio, halogenated alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally, can be further substituted;

[0016] R1is selected from hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, oxo, thioxo, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally can be further substituted;

[0017] R2is selected from hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally can be further substituted;

[0018] R3is selected from hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, oxo, thioxo, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally can be further substituted;

[0019] R5is selected from hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, oxo, thioxo, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) n5 R gg , -(CH2) n5 (CR kk R jj ) n6 R gg , -(CH2) n5 NR kk R jj , -(CH2) n5 NR gg CR ii R kk R jj , (CH2) n5 (CR kk R jj ) n6 C(O)OR gg , -(CH2) n5 C(O)O(CR kk R jj )n6 OC(O)R gg -(CH2) n5 CR gg =CR kk R jj -(CH2) n5 OR gg -(CH2) n5 SR gg -(CH2) n5 C(O)R gg -(CH2) n5 C(O)OR gg -(CH2) n5 S(O) n6 R gg -(CH2) n5 NR gg C(O)R kk or-(CH2) n5 C(O)NR kk R jj , said amino, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups, optionally, can be further substituted;

[0020] R aa , R bb and R cc are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thioxo, carboxyl, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups, optionally, can be further substituted;

[0021] alternatively, any two of R aa , R bb and R cc can be linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, said cycloalkyl, heterocyclyl, aryl and heteroaryl groups, optionally, can be further substituted;

[0022] R dd , R ee and R ffeach independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thioxo, carboxyl, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally can be further substituted;

[0023] or, any two of R dd , R ee , R ff and R jj may be linked to form a cycloalkyl, heterocyclyl, aryl, or heteroaryl, said cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally can be further substituted;

[0024] R ii , R gg , R kk and R jj each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thioxo, carboxyl, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally can be further substituted;

[0025] or, any two of R ii , R gg , R kk and R jj may be linked to form a cycloalkyl, heterocyclyl, aryl, or heteroaryl, said cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally can be further substituted;

[0026] x is an integer from 0 to 6;

[0027] z is an integer from 0 to 6;

[0028] n1 is an integer from 0 to 3;

[0029] n2 is an integer from 0 to 3;

[0030] n3 is an integer from 0 to 3;

[0031] n4 is an integer from 0 to 3;

[0032] n5 is an integer from 0 to 3; and

[0033] n6 is an integer from 0 to 3.

[0034] In a preferred embodiment of the present application, the compound according to general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is characterized in that L1is selected from the group consisting of a bond, -(CH2) n1 - -(CH2) n1 NR aa C(O)(CR aa R bb ) n2 - -(CH2) n1 (CR aa R bb ) n2 - -(CR aa R bb ) n1 O(CH2) n2 - -(CH2) n1 O(CR aa R bb ) n2 - -(CR aa R bb ) n1 S(CH2) n2 - -(CH2) n1 S(CR aa R bb ) n2 - -(CH2) n1 NR aa (CR bb R cc ) n2 - -(CR aa R bb ) n1 (CH2) n2 NR cc - -(CH2) n1 C(O)(CR aa R bb ) n2 - or -(CH2) n1 C(O)NR aa -;

[0035] preferably a bond or -NR aa -;

[0036] more preferably a bond or -NH-;

[0037] R aa , R bb and R cc are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 one or more substituents of aryl and 5-14 membered heteroaryl;

[0038] or any two of R aa , R bb and R cc may be linked to form a C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl, said C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, haloC 1-6alkyl, C 1-6 alkyl, C 3-12 alkyl, C 6-14 alkyl, C n3 one or more substituents selected from the group consisting of alkoxy, C

[0039] n1 is an integer from 0 to 3;

[0040] n2 is an integer from 0 to 3.

[0041] In a preferred embodiment of the present application, the compound of general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is characterized in that L2 is selected from a bond, -(CH2) n3 -, -(CH2) dd R ee ) n3 -, -(CH2) dd R ee ) n3 (CH2) n4 NR ff -, -(CH2) n3 NR dd (CR ee R ff ) n4 -, -(CH2) n3 (CR dd R ee ) n4 -, -(CH2) dd R ee ) n3 O(CH2) n4 -, -(CH2) n3 O(CR dd R ee ) n4 -, -(CH2) dd R ee ) n3 S(CH2) n4 -, -(CH2) n3 S(CR dd R ee ) n4 -, -(CH2) n3 C(O)(CR dd R ee ) n4 -, -(CH2) n3 NR dd C(O)(CR ee R ff ) n4 -, -(CH2) n3 S(O) n4 -, -(CH2)n3 S(O) n4 NR dd -、-(CH2) n1 NR dd S(O) n4 -or-(CH2) n3 C(O)NR dd -;

[0042] Preferred is -(CH2) n3 -、-(CR dd R ee ) n3 (CH2) n4 NR ff -or-(CH2) n3 NR dd (CR ee R ff ) n4 -;

[0043] More preferred

[0044] R dd 、R ee and R ff are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0045] Or, R dd 、R ee and R ff Any two of them can be linked to form a C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0046] n3 is an integer from 0 to 3; and

[0047] n4 is an integer from 0 to 3.

[0048] In a preferred embodiment of the present invention, the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof, is characterized in that ring A is selected from C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl;

[0049] Preferably 5-10 membered heteroaryl, 5-6 membered heteroaryl and C 6-10 Aryl or 5-6 membered heteroaryl and 5-6 membered heteroaryl;

[0050] More preferred

[0051] In a preferred embodiment of the present application, the compound of general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is characterized in that R is selected from hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 halogenated alkyl, C 1-6 alkoxy, C 1-6 alkylthio, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 halogenated alkyl, C 1-6 alkoxy, C 1-6 alkylthio, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 halogenated alkyl, C 1-6 alkoxy, C 1-6 alkylthio, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, -(CH2) m1 R a , -(CH2) m1 (CR a R b ) m2 R c , -(CH2) m1 OR a , -(CH2) m1 OC(O)R a , -(CH2) m1 NR a R b , -(CH2)m1 NR a CHR b R c 、-(CH2) m1 C(O)R a 、-(CH2) m1 (CR a R b ) m2 C(O)OR c 、-(CH2) m1 C(O)O(CR a R b ) m2 OC(O)R c 、-(CH2) m1 CR a =CR b R c 、-(CH2) m1 SR a 、-(CH2) m1 S(O) m2 R a 、-(CH2) m1 NR a C(O)R b or -(CH2) m1 C(O)NR a R b is substituted by one or more substituents in;

[0052] Preferably, hydrogen, 3-10 membered heterocyclic group or 5-12 membered heteroaryl, said 3-10 membered heterocyclic group and 5-12 membered heteroaryl, optionally further substituted by hydrogen, halogen, amino, hydroxyl, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 The aryl group and the 5-12 membered heteroaryl group are substituted by one or more substituents.

[0053] More preferred

[0054] R a 、R b and R c are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, carboxyl, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 one or more substituents of aryl and 5-14 membered heteroaryl;

[0055] or any two of R a , R b and R c may be linked to form a C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl, said C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C

[0056] m1 is an integer from 0 to 3; and

[0057] m2 is an integer from 0 to 3.

[0058] In a preferred embodiment of the present application, the compound of general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is characterized in that R1 is selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl;

[0059] preferably hydrogen, halogen, cyano, C 1-3 alkyl, or C 1-3 alkyl;

[0060] more preferably hydrogen, cyano or methoxy.

[0061] In a preferred embodiment of the present application, the compound according to general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, is characterized in that R2is selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 alkyl, or C 2-6 alkenyl, or C 2-6 alkynyl, or C 1-6 deuterated alkyl, or C 1-6 halogenated alkyl, or C 1-6 alkoxy, or C 1-6 alkylthio, halogenated C 1-6 alkoxy, or C 1-6 hydroxyalkyl, or C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, or C 6-14 aryl and 5- to 14-membered heteroaryl, optionally substituted by one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 alkyl, or C 2-6 alkenyl, or C 2-6 alkynyl, or C 1-6 deuterated alkyl, or C 1-6 halogenated alkyl, or C 1-6 alkoxy, or C 1-6 alkylthio, halogenated C 1-6 alkoxy, or C 1-6 hydroxyalkyl, or C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, or C 6-14 aryl and 5- to 14-membered heteroaryl, optionally substituted by one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 alkyl, or C 2-6 alkenyl, or C 2-6 alkynyl, or C 1-6 deuterated alkyl, or C 1-6 halogenated alkyl, or C 1-6 alkoxy, or C 1-6 alkylthio, halogenated C 1-6 alkoxy, or C 1-6 hydroxyalkyl, or C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, or C 6-14 aryl and 5- to 14-membered heteroaryl, optionally substituted by one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C

[0062] preferably hydrogen, halogen or C 1-3 alkyl;

[0063] more preferably chlorine or methyl.

[0064] In a preferred embodiment of the present application, the compound according to formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is characterized in that R3is selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 halogenated alkyl, C 1-6 alkoxy, C 1-6 alkylthio, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-14 aryl and 5- to 14-membered heteroaryl, optionally substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 halogenated alkyl, C 1-6 alkoxy, C 1-6 alkylthio, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-14 aryl and 5- to 14-membered heteroaryl, optionally substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 halogenated alkyl, C 1-6 alkoxy, C 1-6 alkylthio, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-14 aryl and 5- to 14-membered heteroaryl, optionally substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, oxo, thioxo, C

[0065] preferably hydrogen, halogen or C 1-3 alkyl;

[0066] more preferably chlorine or methyl.

[0067] In a preferred embodiment of the present application, the compound according to formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is characterized in that R5is selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, -(CH2) n5 R gg , -(CH2) n5 (CR kk R jj ) n6 R gg , -(CH2) n5 NR kk R jj , -(CH2) n5 NR gg CR ii R kk R jj , (CH2) n5 (CR kk R jj ) n6 C(O)OR gg , -(CH2) n5 C(O)O(CR kk R jj ) n6 OC(O)R gg , -(CH2) n5 CR gg =CR kk R jj , -(CH2) n5 OR gg , -(CH2) n5 SR gg , -(CH2) n5 C(O)R gg , -(CH2) n5 C(O)OR gg , -(CH2) n5 S(O) n6 R gg , -(CH2) n5 NR gg C(O)R kk or -(CH2) n5 C(O)NR kk R jj , said amino, C 1-6 alkyl, C 2-6 alkenyl, C2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl;

[0068] preferably hydrogen, C 3-12 cycloalkyl, C 1-6 alkoxy, -(CH2) n5 R gg or -(CH2) n5 NR kk R jj ;

[0069] more preferably hydrogen, methoxy, C 3-8 cycloalkyl, imidazolinyl,

[0070] R ii , R gg , R kk and R jj are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12cycloalkyl, 3- to 12-membered heterocyclyl, C 6-14 aryl or 5- to 14-membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-14 aryl and 5- to 14-membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, carboxyl, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-14 aryl, 5- to 14-membered heteroaryl, -(CH2) m3 R d , -(CH2) m3 OR d , -(CH2) m3 C(O)R d , -(CH2) m3 C(O)OR d , -(CH2) m3 NR d R e , -(CH2) m3 SR d , -(CH2) m3 S(O) m4 R d , -(CH2) m3 NR d C(O)R e and -(CH2) m3 C(O)NR d R e one or more substituents;

[0071] or, R ii , R gg , R kk and R jjAny two of which are linkable to form a C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl, said C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 one or more substituents of aryl and 5-14 membered heteroaryl;

[0072] R d and R e are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, carboxyl, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0073] n5 is an integer from 0 to 3;

[0074] n6 is an integer from 0 to 2;

[0075] m3 is an integer from 0 to 3; and

[0076] m4 is an integer from 0 to 2.

[0077] In a preferred embodiment of the present invention, the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, is characterized in that the general formula (I) is further represented by the general formula (II):

[0078]

[0079] in:

[0080] Ring B is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl;

[0081] Preferably a 3-10 membered heterocyclic group or a 5-10 membered heteroaryl group;

[0082] The following groups are preferred:

[0083]

[0084] R4 is selected from hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -(CH2) m3 R d 、-(CH2) m3 (CRd R e ) m4 R f , -(CH2) m3 OR d , -(CH2) m3 OC(O)R d , -(CH2) m3 NR d R e , -(CH2) m3 NR d CHR e R f , -(CH2) m3 C(O)R d , -(CH2) m3 (CR d R e ) m4 C(O)OR f , -(CH2) m3 C(O)O(CR d R e ) m4 OC(O)R f , -(CH2) m3 CR d =CR e R f , -(CH2) m3 SR d , -(CH2) m3 S(O) m4 R d , -(CH2) m3 NR d C(O)R e or -(CH2) m3 C(O)NR d R e , said amino, C 1-6 1-6C-alkyl, C 2-6 2-6C-alkenyl, C 2-6 2-6C-alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-14 aryl and 5- to 14-membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0085] Preferably hydrogen, halogen, hydroxyl or C 1-6 alkyl;

[0086] More preferably hydrogen, fluorine, chlorine, bromine, hydroxy, methyl, ethyl or isopropyl;

[0087] R d 、R e and R f are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, carboxyl, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C1-6 alkyl, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C

[0088] y is an integer from 0 to 6;

[0089] m3 is an integer from 0 to 3; and

[0090] m4 is an integer from 0 to 3.

[0091] In a preferred embodiment of the present application, the compound of general formula (I), stereoisomer thereof, or pharmaceutically acceptable salt thereof is characterized in that the general formula (I) is further represented by general formula (III):

[0092]

[0093] wherein:

[0094] R6 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C1-6 alkylthio, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-14 one or more substituents selected from the group consisting of hydrogen, C

[0095] preferably hydrogen, C 3-8 cycloalkyl, or C 1-6 alkoxy;

[0096] more preferably hydrogen, cyclopropyl, methoxy or ethoxy;

[0097] R7is selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-14 aryl, 5- to 14-membered heteroaryl, -(CH2) n5 R gg or -(CH2) n5 NR kk R jj ;

[0098] more preferably more preferably -(CH2) n5 NHR jj ;

[0099] most preferably the following substituents:

[0100]

[0101] R gg , R kk and R jj are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, haloC 1-6 alkoxy, C1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, carboxyl, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, -(CH2) m5 R g , -(CH2) m5 OR g , -(CH2) m5 C(O)R g , -(CH2) m5 C(O)OR g , -(CH2) m5 NR g R k , -(CH2) m5 SR g , -(CH2) m5 S(O) m6 R g , -(CH2) m5 NR g C(O)R k and -(CH2) m5 C(O)NR g R k one or more substituents;

[0102] or, R gg , R kk and Rjj Any two of which are linkable to form a C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, haloC 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C

[0103] Preferably, the 3-12 membered heterocyclyl is selected from 5-6 membered oxygen- or nitrogen-containing heterocyclyl, optionally further substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, haloC 1-6 Alkoxy or C 1-6 Hydroxyalkyl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, haloC 1-3 Alkoxy or C 1-3 Hydroxyalkyl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C

[0104] R g and R k are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, carboxyl, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 one or more substituents of aryl and 5-14 membered heteroaryl;

[0105] n5 is an integer from 0 to 3;

[0106] m5 is an integer from 0 to 3; and

[0107] m6 is an integer from 0 to 2.

[0108] In a preferred embodiment of the present application, the compound according to general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is characterized in that general formula (I) is further represented by general formula (IV):

[0109]

[0110] In a preferred embodiment of the present application, the compound according to general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is characterized in that general formula (I) is further represented by general formula (V):

[0111]

[0112] In a preferred embodiment of the application, ring A is selected from C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-12 membered heteroaryl;

[0113] preferably 5-10 membered heteroaryl, 5-6 membered heteroaryl and C 6-10 aryl or 5-6 membered heteroaryl and 5-6 membered heteroaryl;

[0114] more preferably

[0115] In a preferred embodiment of the application, ring B is selected from C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl; preferably 3-10 membered heterocyclyl or 5-10 membered heteroaryl; more preferably the following groups:

[0116]

[0117] In a preferred embodiment of the application, R4is selected from hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 halogenated alkyl, C 1-6 alkoxy, C 1-6 alkylthio, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, -(CH2) m3 R d , -(CH2) m3 (CR d R e ) m4 R f , -(CH2) m3 OR d , -(CH2) m3 OC(O)R d , -(CH2) m3 NR d R e , -(CH2) m3 NR d CHR e Rf 、-(CH2) m3 C(O)R d 、-(CH2) m3 (CR d R e ) m4 C(O)OR f 、-(CH2) m3 C(O)O(CR d R e ) m4 OC(O)R f 、-(CH2) m3 CR d =CR e R f 、-(CH2) m3 SR d 、-(CH2) m3 S(O) m4 R d 、-(CH2) m3 NR d C(O)R e or -(CH2) m3 C(O)NR d R e , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0118] Preferred are hydrogen, halogen, hydroxy, oxo, C1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, -(CH2) m3 R d , -(CH2) m3 OR d , -(CH2) m3 C(O)R d , -(CH2) m3 OC(O)R d , -(CH2) m3 C(O)O(CR d R e ) m4 OC(O)R f or -(CH2) m3 NR d C(O)R e ;

[0119] more preferably -H, -F, -Cl, -Br, -OH, -CH3, -CH2CH3, -CH(CH3)2, =0, -OCH3, -CH2F, -CH2OH, -CH2CN, -COOH, -C(O)CH3, -OC(O)CH3, -OC(O)CH(CH3)2, -C(O)OCH2OC(O)CH(CH3)2, or -NHC(O)CH3;

[0120] R d , R e and R f are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, or 5-14 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, haloC 1-6 alkoxy, C1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-14 aryl and 5- to 14-membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, carboxyl, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-14 one or more substituents from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, carboxyl, oxo, C

[0121] y is an integer from 0 to 3;

[0122] m3 is an integer from 0 to 2; and

[0123] m4 is an integer from 0 to 2.

[0124] In a preferred embodiment of the present application, R7 is selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-14 aryl, 5- to 14-membered heteroaryl, -(CH2) n5 R gg or -(CH2) n5 NR kk R jj ;

[0125] more preferably

[0126] R gg , R kk and R jjEach independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, carboxyl, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -(CH2) m5 R g 、-(CH2) m5 OR g 、-(CH2) m5 C(O)R g 、-(CH2) m5 C(O)OR g 、-(CH2) m5 C(O)O(CH2) m6 OC(O)R g -(CH2) m5 OC(O)R g 、-(CH2) m5 NR gR k 、-(CH2) m5 SR g 、-(CH2) m5 S(O) m6 R g 、-(CH2) m5 NR g C(O)R k and -(CH2) m5 C(O)NR g R k is substituted by one or more substituents in;

[0127] Or, R gg 、R kk and R jj Any two of them can be linked to form a C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0128] R g and R k are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, carboxyl, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, carboxyl, oxo, C

[0129] n5 is an integer from 0 to 3;

[0130] m5 is an integer from 0 to 3; and

[0131] m6 is an integer from 0 to 2.

[0132] The present application also provides intermediates of the general formula, which are compounds of the structure shown in general formula (VI), (X), (IX), (XI), (XII), (XIII), (XIV):

[0133]

[0134] wherein R6, R7, R2, R1, R3, R4, L1, L2, ring A, ring B, x and y are as previously described;

[0135] Ha is halogen; preferably bromine.

[0136] The present application also provides a method for preparing a compound of general formula (III) as previously described, comprising the following steps:

[0137] condensing a compound of formula (VII) and a compound of formula (VIII) under the action of a reducing agent to obtain a compound of general formula (III),

[0138]

[0139] wherein,

[0140] L1is a bond;

[0141] L2is methylene;

[0142] the reducing agent is sodium borohydride, potassium borohydride, lithium aluminum hydride, sodium cyanoborohydride, potassium cyanoborohydride, sodium bis(2-methoxyethoxy)aluminum dihydride, or stannous chloride;

[0143] or, reacting RggH and a compound of general formula (XI) to obtain a compound of general formula (III),

[0144]

[0145] wherein: R7is -CH2Rgg; Rgg is as defined above;

[0146] or, reacting a compound of general formula (XV) and a compound of general formula (XIV) to obtain a compound of general formula (III),

[0147]

[0148] wherein:

[0149] R8is C 1-6 alkyl, haloC 1-6 alkyl or deuterated C 1-6 alkyl; preferably methyl or ethyl.

[0150] In certain embodiments of the present application, the process for preparing a compound of general formula (III) further comprises the following steps:

[0151] coupling a compound of formula (IX) and a compound of formula (X) in the presence of a catalyst and a base to obtain a compound of formula (VI),

[0152]

[0153] wherein: Ha is halogen, preferably bromine;

[0154] the catalyst is preferably dicyclohexylphosphino ferrocene palladium dichloride, palladium tris(triphenylphosphine), tris(dibenzylideneacetone)dipalladium, palladium acetate, or [1,1' bis(diphenylphosphino) ferrocene] palladium dichloride;

[0155] the base is preferably a carbonate; more preferably cesium carbonate, sodium carbonate, or potassium carbonate;

[0156] or, reacting a compound of general formula (XII) in the presence of an oxidizing agent to obtain a compound of general formula (IX),

[0157]

[0158] The oxidizing agent is preferably selected from the group consisting of potassium permanganate, ozone, periodic acid, potassium dichromate, high-iron salt, nitrobenzenesulfonic acid, potassium osmium acid dihydrate and sodium periodate.

[0159] The present application further relates to a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds of general formula (I), stereoisomers thereof or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0160] The present application further relates to the use of any of the compounds of general formula (I), stereoisomers thereof or pharmaceutically acceptable salts thereof, or the pharmaceutical composition described in the preparation of a PD-1 or PD-L1 inhibitor drug.

[0161] The present application further relates to the use of the compounds of general formula (I), stereoisomers thereof or pharmaceutically acceptable salts thereof, or the pharmaceutical composition thereof in the preparation of a drug for treating cancer, infectious diseases, autoimmune diseases, wherein the cancer is selected from the group consisting of skin cancer, lung cancer, urological tumor, hematological tumor, breast cancer, glioma, digestive system tumor, reproductive system tumor, lymphoma, nervous system tumor, brain tumor, head and neck cancer; the infectious diseases are selected from the group consisting of bacterial infection, viral infection; the autoimmune diseases are selected from the group consisting of organ-specific autoimmune diseases, systemic autoimmune diseases, wherein the organ-specific autoimmune diseases include chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, Goodpasture's syndrome, primary biliary cirrhosis, multiple sclerosis, acute idiopathic polyneuritis, and the systemic autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, autoimmune hemolytic anemia.

[0162] The present application further relates to the use of the compounds of general formula (I), stereoisomers thereof or pharmaceutically acceptable salts thereof, or the pharmaceutical composition thereof in the preparation of a method for treating cancer, infectious diseases, autoimmune diseases.

[0163] The present application further relates to a method for the prophylactic and / or therapeutic treatment of cancer, infectious diseases, autoimmune diseases, comprising administering to a patient a therapeutically effective amount of the compounds of general formula (I), stereoisomers thereof or pharmaceutically acceptable salts thereof, or the pharmaceutical composition thereof.

[0164] The present application also provides methods of using the compounds or pharmaceutical compositions of the present application to treat disease conditions, including but not limited to conditions associated with PD-1 or PD-L1.

[0165] The present application also relates to a method of treating cancer, infectious diseases, autoimmune diseases in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of the present application or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.

[0166] In some embodiments, the present method relates to the treatment of a disorder such as cancer, infectious diseases, autoimmune diseases.

[0167] In some embodiments, the cancer related to the present method is selected from skin cancer, lung cancer, urological tumor, hematological tumor, breast cancer, glioma, digestive system tumor, reproductive system tumor, lymphoma, nervous system tumor, brain tumor, head and neck cancer.

[0168] In some embodiments, the infectious disease related to the present method is selected from bacterial infection, viral infection.

[0169] In some embodiments, the autoimmune disease related to the present method is selected from organ-specific autoimmune disease including chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, Goodpasture's syndrome, primary biliary cirrhosis, multiple sclerosis, Guillain-Barre syndrome, systemic autoimmune disease including rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, autoimmune hemolytic anemia.

[0170] Detailed description of the invention

[0171] Unless otherwise indicated, the terms used in the specification and claims have the following meanings.

[0172] The term "alkyl" refers to saturated aliphatic hydrocarbon groups which are straight-chain or branched-chain groups containing 1 to 20 carbon atoms, preferably alkyl groups containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, most preferably 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof, and the like. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment, and are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate, with methyl, ethyl, i-propyl, t-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl, and hydroxyl-substituted alkyl being preferred.

[0173] The term "alkylene" refers to an alkyl group in which one hydrogen atom is further replaced by a substituent, for example: "methylene" refers to -CH2-, "ethylene" refers to -(CH2)2-, "propylene" refers to -(CH2)3-, "butylene" refers to -(CH2)4-, and the like. The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example ethenyl, 1 -propenyl, 2-propenyl, 1 -, 2- or 3-butenyl, and the like. The alkenyl group can be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio.

[0174] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring comprising 3 to 20 carbon atoms, preferably comprising 3 to 12 carbon atoms, more preferably comprising 3 to 8 carbon atoms, further preferably comprising 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spirocyclic, fused, and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0175] The term "spirocycloalkyl" refers to a polycyclic group sharing one carbon atom between rings (referred to as a spiro atom), which can contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Spirocycloalkyl groups are classified as mono-, bi- or polycycloalkyl groups depending on the number of spiro atoms shared between the rings, preferably mono- and bicycloalkyl groups. More preferably 4 membered / 4 membered, 4 membered / 5 membered, 4 membered / 6 membered, 5 membered / 5 membered, or 5 membered / 6 membered monospirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups include:

[0176]

[0177] Also included are spirocycloalkyl groups sharing a spiro atom between a monocycloalkyl and a heterocycloalkyl group, non-limiting examples include:

[0178]

[0179] The term "fused ring alkyl" refers to a fully carbon polycyclic group of 5 to 20 members, where each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, where one or more rings can contain one or more double bonds, but no ring has a fully conjugated system of π electrons. Preferably, 6 to 14 members, more preferably 7 to 10 members. Depending on the number of rings comprising the group, it can be referred to as a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl, preferably bicyclic or tricyclic, more preferably 5 / 5 or 5 / 6 bicyclic alkyl. Non-limiting examples of fused ring alkyl groups include:

[0180]

[0181] The term "bridged ring alkyl" refers to a fully carbon polycyclic group of 5 to 20 members, where any two rings share two non-adjacent carbon atoms, which can contain one or more double bonds, but no ring has a fully conjugated system of π electrons. Preferably, 6 to 14 members, more preferably 7 to 10 members. Depending on the number of rings comprising the group, it can be referred to as a bicyclic, tricyclic, tetracyclic or polycyclic bridged ring alkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged ring alkyl groups include:

[0182]

[0183] The cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring attached to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl and the like. The cycloalkyl group can be optionally substituted or unsubstituted, when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0184] The term "heterocyclyl" refers to a saturated or partially unsaturated, monocyclic or polycyclic ring system hydrocarbon substituent containing 3 to 20 ring atoms, where one or more of the ring atoms are selected from nitrogen, oxygen or S(O) mheteroatoms, the remaining ring atoms being carbon. Preferably, the ring contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, the ring contains 3 to 10 ring atoms; further preferably, the ring contains 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrazinonyl, pyridinonyl, tetrahydropyrrolyl, azetidinyl, oxetanyl, oxepanyl, imidazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and pyranyl, and the like; preferably, pyrazinonyl, pyridinonyl, tetrahydropyrrolyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrazolidinyl, morpholinyl, piperazinyl, and tetrahydropyranyl; more preferably, tetrahydropyrrolyl, azetidinyl, oxetanyl, piperidinyl, piperazinyl, and tetrahydropyranyl. Polycyclic heterocyclyl groups include spiro, fused, and bridged ring heterocyclyl groups; wherein the spiro, fused, and bridged ring heterocyclyl groups are optionally connected to other groups by a single bond, or further annelated to other cycloalkyl, heterocyclyl, aryl, and heteroaryl groups through any two or more atoms on the ring.

[0185] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group sharing one atom (referred to as a spiro atom) between two single rings, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) m heteroatoms, the remaining ring atoms being carbon. It can contain one or more double bonds, but no ring has a completely conjugated pi-electron system. Preferably, it is 6 to 14 membered, more preferably 7 to 10 membered. Spiroheterocyclyl groups are classified as mono-, bi-, or polyspiroheterocyclyl groups, preferably mono- and bi-spiroheterocyclyl groups, depending on the number of spiro atoms between the rings. More preferably, it is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocyclyl group. Non-limiting examples of spiroheterocyclyl groups include:

[0186]

[0187] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members, in which each ring in the system shares an adjacent pair of atoms with another ring in the system, one or more rings can contain one or more double bonds, but no ring has a completely conjugated pi-electon system, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) mheteroatoms, the remaining ring atoms being carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Depending on the number of rings making up the ring system, it can be a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl group, preferably bicyclic or tricyclic, more preferably 5 membered / 5 membered or 5 membered / 6 membered bicyclic fused heterocyclyl group. Non-limiting examples of fused heterocyclyl groups include:

[0188]

[0189] The term "bridged heterocyclyl" refers to a 5 to 14 membered, polycyclic heterocyclic group, sharing two non-adjacent atoms of any two rings, which can contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen or S(O) m heteroatoms, the remaining ring atoms being carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Depending on the number of rings making up the ring system, it can be a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl group, preferably bicyclic or tricyclic, more preferably 5 membered / 5 membered or 5 membered / 6 membered bicyclic fused heterocyclyl group. Non-limiting examples of fused heterocyclyl groups include:

[0190]

[0191] The heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring that is attached to the parent structure is a heterocyclyl ring, non-limiting examples of which include:

[0192]

[0193] The heterocyclyl group can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0194] The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (that is, rings which share adjacent pairs of carbon atoms) ring systems having a completely conjugated pi-electron system, preferably 6 to 10 membered, more preferably 6 to 8 membered, for example, phenyl and naphthyl. More preferably phenyl. The aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring that is attached to the parent structure is an aryl ring, non-limiting examples of which include:

[0195]

[0196] Aryl can be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate.

[0197] The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered, more preferably 5 to 8 membered, most preferably 5 or 6 membered, such as imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, pyridazinyl or pyrazinyl, and the like; preferably triazolyl, thienyl, thiazolyl, pyridyl, imidazolyl, pyrazolyl, pyridazinyl, pyrazinyl or pyrimidinyl; more preferably pyridyl, imidazolyl, pyrazolyl, pyridazinyl, pyrazinyl or pyrimidinyl. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring that is attached to the parent structure is the heteroaryl ring, non-limiting examples of which include:

[0198]

[0199] Heteroaryl can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate.

[0200] The term "fused ring group" refers to a polycyclic group formed by two or more carbon or heterocyclic rings sharing a ring edge, and includes fused cycloalkyl, fused heteroaryl, fused aryl and fused heteroaryl groups, wherein the fused cycloalkyl refers to a polycyclic group formed by a cycloalkyl and a heterocyclyl, aryl, heteroaryl sharing a ring edge; the fused heterocyclyl refers to a polycyclic group formed by a heterocyclyl and a cycloalkyl, aryl, heteroaryl sharing a ring edge; the fused aryl refers to a polycyclic group formed by an aryl and a cycloalkyl, heterocyclyl, heteroaryl sharing a ring edge; and the fused heteroaryl refers to a polycyclic group formed by a heteroaryl and a cycloalkyl, heterocyclyl, heteroaryl sharing a ring edge; for example:

[0201]

[0202] The term "alkoxy" means -O-(alkyl) and -O-(non-substituted cycloalkyl), wherein alkyl is defined as above, preferably alkyl containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, most preferably 1 to 3 carbon atoms. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group can be optionally substituted or non-substituted, when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate.

[0203] The term "alkylthio" means -S-(alkyl) and -S-(non-substituted cycloalkyl), wherein alkyl is defined as above. Non-limiting examples of alkylthio groups include methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio. The alkylthio group can be optionally substituted or non-substituted, when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate.

[0204] "Haloalkyl" means an alkyl group as defined above substituted by one or more halogens.

[0205] "Haloalkoxy" means an alkoxy group as defined above substituted by one or more halogens.

[0206] "Hydroxyalkyl" means an alkyl group as defined above substituted by a hydroxy group.

[0207] "Alkenyl" means alkenyl, also known as olefinic, preferably an alkyl group containing 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, most preferably 2 to 3 carbon atoms. The alkenyl group can be further substituted by other relevant groups such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate.

[0208] "Alkynyl" refers to (CH≡C-), preferably alkyl containing 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, most preferably 2 to 3 carbon atoms. The alkynyl group referred to can be further substituted with other relevant groups, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate.

[0209] "Haloalkyl" refers to an alkyl group as defined above substituted with one or more halogens.

[0210] "Haloalkoxy" refers to an alkoxy group as defined above substituted with one or more halogens.

[0211] "Hydroxyalkyl" refers to an alkyl group as defined above substituted with a hydroxyl group.

[0212] "Hydroxyl" refers to the -OH group.

[0213] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0214] "Amino" refers to -NH2.

[0215] "Cyano" refers to -CN.

[0216] "Nitro" refers to -NO2.

[0217] "Carboxyl" refers to -C(O)OH.

[0218] "THF" refers to tetrahydrofuran.

[0219] "EtOAc" refers to ethyl acetate.

[0220] "MeOH" refers to methanol.

[0221] "DMF" refers to N,N-dimethylformamide.

[0222] "TFA" refers to trifluoroacetic acid.

[0223] "MeCN" refers to acetonitrile.

[0224] "DMA" refers to N,N-dimethylacetamide.

[0225] "Et2O" refers to diethyl ether.

[0226] "DCE" refers to 1,2 dichloroethane.

[0227] "DIPEA" refers to N,N-diisopropylethylamine.

[0228] "NBS" refers to N-bromosuccinimide.

[0229] "NIS" refers to N-iodosuccinimide.

[0230] "Cbz-Cl" refers to benzyl chloroformate.

[0231] "Pd2(dba)3" refers to tris(dibenzylideneacetone)dipalladium.

[0232] "Dppf" refers to 1,1'-bis(diphenylphosphino)ferrocene.

[0233] "HATU" refers to 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0234] "KHMDS" refers to potassium hexamethyldisilazide.

[0235] "LiHMDS" refers to lithium bis(trimethylsilylamide).

[0236] "MeLi" refers to methyllithium.

[0237] "n-BuLi" refers to n-butyllithium.

[0238] "NaBH(OAc)3" refers to sodium triacetoxyborohydride.

[0239] Different expressions such as “X is selected from A, B, or C”, “X is selected from A, B and C”, “X is A, B or C”, and “X is A, B and C” all express the same meaning, that is, X can be any one or more of A, B, and C.

[0240] The hydrogen atoms described in the present invention can all be replaced by their isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by a deuterium atom.

[0241] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0242] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0243] "Pharmaceutical composition" means a mixture of one or more of the compounds described herein or physiologically / pharmaceutically acceptable salts or prodrugs thereof with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to a subject, and to facilitate absorption of the active ingredient.

[0244] "Pharmaceutically acceptable salt" refers to those salts of the compounds of the present application which are safe and effective for use in a mammal, and possess the desired biological activity. DETAILED DESCRIPTION

[0245] The present application is further described in connection with the following examples, which are not meant to limit the scope of the application.

[0246] Examples

[0247] The structure of the compounds of the present application is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements are performed on a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD) and deuterated chloroform (CDCl3) as the solvent and tetramethylsilane (TMS) as the internal standard.

[0248] Liquid chromatography-mass spectrometry (LC-MS) measurements are performed on an Agilent 1200 Infinity Series Mass Spectrometer. HPLC measurements are performed on an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).

[0249] Thin layer chromatography (TLC) silica gel plates are purchased from Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates, with a thickness of 0.15 mm to 0.20 mm. Thin layer chromatography (TLC) silica gel plates are used for product purification, with a thickness of 0.4 mm to 0.5 mm. Column chromatography is generally performed using Yantai Huanghai silica gel with a mesh size of 200 to 300.

[0250] The starting materials in the examples of the present application are known and commercially available, or can be synthesized using or according to methods known in the art.

[0251] Unless otherwise specified, all reactions in the present application are carried out under continuous magnetic stirring, under a dry nitrogen or argon atmosphere, using dry solvents, and the reaction temperature is in degrees Celsius.

[0252] Example 1

[0253] (S)-1-((6-((2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3-yl)methyl)piperidine-2-carboxylic acid

[0254]

[0255] First Step: Preparation of methyl 3-cyano-4-hydroxybenzoate

[0256]

[0257] Methyl 4-hydroxy-3-iodobenzoate (60 g, 0.216 mol), zinc cyanide (38 g, 0.324 mol) and tetrakis triphenylphosphine palladium (12.46 g, 0.011 mol) were suspended in N,N-dimethylformamide (300 mL) under nitrogen atmosphere, heated to 140 °C and stirred overnight. The reaction was cooled, filtered and the filtrate was adjusted to basic by adding saturated potassium carbonate aqueous solution. The reaction mixture was extracted with ethyl acetate (150 mL x 3) to remove impurities. The filtrate was then adjusted to acidic by adding concentrated hydrochloric acid and extracted with dichloromethane (300 mL x 3). The organic phase was washed with saturated sodium chloride aqueous solution (100 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (37.2 g, 97%).

[0258] MS m / z (ESI): 176.1 [M-H] + .

[0259] Second Step: Preparation of methyl 3-cyano-4-hydroxy-5-nitrobenzoate

[0260]

[0261] Methyl 3-cyano-4-hydroxybenzoate (37.2 g, 0.210 mol) was dissolved in glacial acetic acid (200 mL) and nitric acid (32.6 mL, 0.735 mol) was added at room temperature. The reaction mixture was then heated to 70 °C and stirred for 1 hour. The reaction was completed by pouring the reaction mixture into a large amount of ice water and stirring for 30 minutes. The reaction mixture was filtered and the filter cake was dried to obtain the title compound (24.9 g, 53%).

[0262] MS m / z (ESI): 221.1 [M-H] + .

[0263] Third Step: Preparation of methyl 3-amin-4-hydroxy-5-nitrobenzoate

[0264]

[0265] Methyl 3-cyano-4-hydroxy-5-nitrobenzoate (24.9 g, 0.112 mol) and palladium on carbon hydrogenation catalyst (2.5 g) were suspended in methanol (500 mL), hydrogen gas was bubbled through three times, then stirred at room temperature for 4 hours. The reaction was filtered and the filtrate was concentrated under reduced pressure to give the title compound (16.6 g, 77%).

[0266] MS m / z (ESI): 191.1 [M-H] + .

[0267] Fourth Step: Preparation of Methyl 3-(3-bromo-2-methylbenzamido)-5-cyano-4- hydroxybenzoate

[0268]

[0269] Under nitrogen atmosphere, 3-bromo-2-methylbenzoic acid (20.5 g, 0.095 mol), 2-(7- azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (36.1 g, 0.095 mol) and N,N-DIPEA (22.5 mL, 0.130 mol) were dissolved in dry N,N-dimethylformamide (150 mL), stirred at room temperature for 1 hour, then methyl 3-amino-4-hydroxy-5- nitrobenzoate (16.6 g, 0.086 mol) was added and the reaction was continued at room temperature overnight. The reaction was poured into a large amount of ice water, stirred for 30 minutes, then the aqueous phase was filtered and the filter cake was concentrated under reduced pressure, then the filter cake was slurried with petroleum ether: ethyl acetate = 4: 1 (400 mL) for 1 hour, filtered and dried to give the title compound (31.6 g, 94%).

[0270] MS m / z (ESI): 387.1 [M-H] + .

[0271] Fifth Step: Preparation of Methyl 2-(3-bromo-2-methylphenyl)-7-cyanobenzo[d]oxazole- 5-carboxylate

[0272]

[0273] Under nitrogen atmosphere, 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (35.1 g, 0.154 mol) and triphenylphosphine (40.4 g, 0.154 mol) were suspended in dry toluene (600 mL), after stirring at room temperature for 1 hour, 3-(3-bromo-2-methylbenzamido)-5-cyano-4-hydroxybenzoic acid methyl ester (30 g, 0.077 mol) was added and the reaction was stirred at 110 °C overnight. After completion of the reaction, the reaction mixture was concentrated to remove toluene, then saturated aqueous potassium carbonate solution was added to adjust to basicity, after stirring for 30 minutes, the aqueous phase was filtered and the filter cake was concentrated under reduced pressure, then the filter cake was slurried with ethanol for 1 hour, the filter cake was filtered and dried to obtain the title compound (26.8 g, 94%).

[0274] Step 6: Preparation of 2-(3-bromo-2-methylphenyl)-5-(hydroxymethyl)benzo[d]oxazole-7- carbonitrile

[0275]

[0276] Under nitrogen atmosphere, 2-(3-bromo-2-methylphenyl)-7-cyanobenzo[d]oxazole-5- carboxylic acid methyl ester (26.8 g, 0.072 mol) and calcium chloride (16.1 g, 0.144 mol) were suspended in a mixture of tetrahydrofuran (600 mL) and ethanol (300 mL), after stirring at room temperature for 1 hour, sodium borohydride (8.2 g, 0.216 mol) was added and the reaction was stirred at 55 °C for 4 hours. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution, then the reaction mixture was concentrated to precipitate a large amount of solid, which was filtered and concentrated under reduced pressure, then the filter cake was slurried with methanol for 1 hour, filtered and dried to obtain the title compound (20.7 g, 84%).

[0277] MS m / z (ESI): 343.1 [M+H] + .

[0278] Step 7: Preparation of 5-(hydroxymethyl)-2-(2-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)benzo[d]oxazole-7-carbonitrile

[0279]

[0280] Under nitrogen atmosphere, 2-(3-bromo-2-methylphenyl)-5-(hydroxymethyl)benzo[d]oxazole-7-carbonitrile (20 g, 0.06 mol), bis(pinacolato)diboron (30.5 g, 0.12 mol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (4.4 g, 0.006 mol) and potassium acetate (17.6 mg, 0.18 mol) were suspended in dry 1,4-dioxane (600 mL) and heated to 100 °C with stirring overnight. The reaction was filtered and the filtrate was passed through a pad of silica gel to remove the color, then slurried with ethanol for 1 h, filtered and dried to give the title compound (18.7 g, 82%).

[0281] MS m / z (ESI): 391.2 [M+H] + .

[0282] Eighth Step: Preparation of 5-((3-fluoroazetidin-l-yl)methyl)-2-(2-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazole-7-carbonitrile

[0283]

[0284] To a solution of 5-(hydroxymethyl)-2-(2-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazole-7-carbonitrile (2.0 g, 5.13 mmol) in dichloromethane (120 mL) was added DMP (3.26 g, 7.7 mmol) at room temperature with stirring. The reaction was stirred at room temperature for 30 min and concentrated under reduced pressure to remove the solvent. The residue was dispersed in 1,2-dichloroethane (80 mL), and 3-fluoroazetidine hydrochloride (858 mg, 7.7 mmol) and DIPEA (1.27 mL, 7.7 mmol) were added. The reaction was heated to 48 °C with stirring for 2 h, and sodium triacetoxyborohydride (6.52 g, 30.8 mmol) was added. The reaction was stirred at 48 °C for another 1 h. The reaction was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride successively. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel to give the title compound as a white solid (1.71 g, 75%).

[0285] MS m / z (ESI): 448.2 [M+H] + .

[0286] Ninth Step: Preparation of 2-(3'-amino-2'-chloro-2-methyl-[l,l'-biphenyl]-3-yl)-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazole-7-carbonitrile

[0287]

[0288] To a solution of 5-((3-fluoroazetidin-l-yl)methyl)-2-(2-methyl-3-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazole-7-carbonitrile (1.0 g, 2.24 mmol), 3- bromo-2-chloroaniline (385 mg, 1.86 mmol), bis(cyclohexyl)phosphine palladium dichloride (183 mg, 0.224 mmol) and potassium carbonate (1.46 g, 4.48 mmol) in a mixture of tert-butanol (40 mL) and water (4 mL) was heated to 90 °C and stirred for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was taken up in dichloromethane. The organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel to give the title compound (795 mg, 96%).

[0289] MS m / z (ESI): 447.2 [M+H] + .

[0290] Step 10: Preparation of N-(2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol- 2-yl)-2'-methyl-[l,l'-biphenyl]-3-yl)-4-methoxy-5-vinylmethylpyridinamide

[0291]

[0292] To a solution of 2-(3'-amino-2'-chloro-2-methyl-[l,l'-biphenyl]-3-yl)-5-((3-fluoroazetidin-l- yl)methyl)benzo[d]oxazole-7-carbonitrile (500 mg, 1.12 mmol) and methyl 4-methoxy-5- vinylmethylpyridine-4-carboxylate (325 mg, 1.68 mmol) in dry toluene (20 mL) was added LiHMDS in methylcyclohexane (3.4 mL, 3.4 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride successively. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel to give the title compound (364 mg, 54%).

[0293] MS m / z (ESI): 608.1 [M+H] + .

[0294] Tenth Step: Preparation of N-(2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-formyl-4-methoxymethylpyridinamide

[0295]

[0296] N-(2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-4-methoxy-5-vinylmethylpyridinamide (364 mg, 0.6 mmol) was dissolved in a mixture solvent of dioxane (40 mL) and water (16 mL), potassium osmate dihydrate (22 mg, 0.06 mmol) and sodium periodate (642 mg, 3.0 mmol) were added successively, the reaction solution was stirred at room temperature for 2 hours, the solvent was removed by concentration under reduced pressure, the residue was dissolved in ethyl acetate, washed successively with aqueous sodium thiosulfate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by concentration under reduced pressure, the residue was separated by silica gel column chromatography to obtain the title compound (350 mg, 96%).

[0297] MS m / z (ESI): 610.2 [M+H] + .

[0298] Twelfth Step: Preparation of (S)-1-((6-((2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)piperidine-2-carboxylic acid

[0299]

[0300] N-(2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-formyl-4-methoxymethylpyridinamide (70 mg, 0.115 mmol) and (S)-piperidine-2-carboxylic acid (74 mg, 0.574 mmol) were dissolved in anhydrous methanol (5 mL), DIPEA (0.095 mL, 0.574 mmol) was added with stirring at room temperature, the reaction solution was stirred at 40°C for 2 hours, sodium triacetoxyborohydride (122 mg, 0.574 mmol) was added, stirring was continued for 0.5 hours, the solvent was removed by concentration under reduced pressure, and the residue was separated by prep-HPLC to obtain the title compound (11 mg, 13%).

[0301] MS m / z (ESI): 723.2 [M+H] + .

[0302] Example 2

[0303] ((6-((2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3-yl)methyl)-L-proline

[0304]

[0305] N-(2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)-5-formyl-4-methoxymethyl-pyridinamide (30 mg, 0.05 mmol) and L-proline (58 mg, 0.5 mmol) were dissolved in anhydrous methanol (10 mL), DIPEA (0.082 mL, 0.5 mmol) was added with stirring at room temperature, the reaction was stirred at 40 °C for 2 hours, sodium triacetoxyborohydride (106 mg, 0.5 mmol) was added, stirring was continued for 0.5 hours, the solvent was removed by reduced pressure concentration, the residue was separated by prep-HPLC to obtain the title compound (6.5 mg, 18%).

[0306] MS m / z (ESI): 709.1 [M+H] + .

[0307] Example 3

[0308] (S)-l-((6-((2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3-yl)methyl)azetidine-2- carboxylic acid

[0309]

[0310] (S)-l-((6-((2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3-yl)methyl)azetidine-2- carboxylic acid was prepared according to Example 1.

[0311] MS m / z (ESI): 695.2 [M+H] + .

[0312] Example 4

[0313] (S)-4-((6-((2-chloro-3'-(7-cyano-5-((3-fluorooxetan-3-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3-yl)methyl)morpholine-3- carboxylic acid

[0314]

[0315] (S)-4-((6-((2-chloro-3'-(7-cyano-5-((3-fluorooxetan-3-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3-yl)methyl)morpholine-3- carboxylic acid was prepared according to Example 1.

[0316] MS m / z (ESI): 725.2 [M+H] + .

[0317] Example 5

[0318] 2-((6-((2-chloro-3'-(7-cyano-5-((3-fluorooxetan-3-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3-yl)methyl)-2-azabicyclo[2.2.2] octane-4-carboxylic acid

[0319]

[0320] N-(2-chloro-3'-(7-cyano-5-((3-fluorooxetan-3-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)-5-formyl-4-methoxymethyl-pyridinamide (30 mg, 0.05 mmol) and 2-azabicyclo[2.2.2]octane-4-carboxylic acid hydrochloride (16 mg, 0.1 mmol) were dissolved in anhydrous methanol (10 mL), DIPEA (0.082 mL, 0.5 mmol) was added with stirring at room temperature, the reaction was stirred at 40 °C for 2 hours, sodium triacetoxyborohydride (106 mg, 0.5 mmol) was added, stirring was continued for 0.5 hours, the solvent was removed by reduced pressure concentration, the residue was separated by prep-HPLC to give the title compound (5.4 mg, 15%).

[0321] MS m / z (ESI): 749.2 [M+H] + .

[0322] Example 6

[0323] 1-((6-((2-chloro-3'-(7-cyano-5-((3-fluorooxetan-1-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)oxetan-3- carboxylic acid

[0324]

[0325] N-(2-chloro-3'-(7-cyano-5-((3-fluorooxetan-1-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)-5-formyl-4-methoxymethylpyridinamide (70 mg, 0.115 mmol) and oxetan-3-carboxylic acid (58 mg, 0.574 mmol) were dissolved in anhydrous methanol (5 mL), DIPEA (0.095 mL, 0.574 mmol) was added with stirring at room temperature, the reaction was stirred at 40 °C for 2 hours, sodium triacetoxyborohydride (122 mg, 0.574 mmol) was added, stirring was continued for 0.5 hours, the solvent was removed by reduced pressure concentration, the residue was separated by prep-HPLC to give the title compound (28.5 mg, 36%).

[0326] MS m / z (ESI): 695.2 [M+H] + .

[0327] Example 7

[0328] ((6-((2-chloro-3'-(7-cyano-5-((3-fluorooxetan-1-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)glycine

[0329]

[0330] N-(2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)-5-formyl-4-methoxymethylpyridinamide (30 mg, 0.05 mmol) and glycine (38 mg, 0.5 mmol) were dissolved in anhydrous methanol (10 mL), DIPEA (0.082 mL, 0.5 mmol) was added with stirring at room temperature, the reaction was stirred at 40 °C for 2 hours, sodium triacetoxyborohydride (106 mg, 0.5 mmol) was added, and stirring was continued for 0.5 hours. The solvent was removed by concentration under reduced pressure, and the residue was separated by prep-HPLC to obtain the title compound (18.8 mg, 56%).

[0331] MS m / z (ESI): 669.2 [M+H] + .

[0332] Example 8

[0333] ((6-((2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)-L-alanine

[0334]

[0335] N-(2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)-5-formyl-4-methoxymethylpyridinamide (30 mg, 0.05 mmol) and L-alanine (45 mg, 2.445 mmol) were dissolved in anhydrous methanol (10 mL), DIPEA (0.082 mL, 0.5 mmol) was added with stirring at room temperature, the reaction was stirred at 40 °C for 2 hours, sodium triacetoxyborohydride (106 mg, 0.5 mmol) was added, and stirring was continued for 0.5 hours. The solvent was removed by concentration under reduced pressure, and the residue was separated by prep-HPLC to obtain the title compound (17.1 mg, 50%).

[0336] MS m / z (ESI): 683.1 [M+H] + .

[0337] Example 9

[0338] N-((6-((2-chloro-3'-(7-cyano-5-((3-fluorooxetan-1-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3-yl)methyl)-N-methyl-L- alanine

[0339]

[0340]

[0341] N-(2-chloro-3'-(7-cyano-5-((3-fluorooxetan-1-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)-5-formyl-4-methoxymethyl-pyridinamide (30 mg, 0.05 mmol) and methyl-L-alanine (52 mg, 0.5 mmol) were dissolved in anhydrous methanol (10 mL), DIPEA (0.082 mL, 0.5 mmol) was added with stirring at room temperature, the reaction was stirred at 40 °C for 2 hours, sodium triacetoxyborohydride (106 mg, 0.5 mmol) was added, stirring was continued for 0.5 hours, the solvent was removed by reduced pressure concentration, the residue was separated by prep-HPLC to give the title compound (8.2 mg, 24%).

[0342] MS m / z (ESI): 697.1 [M+H] + .

[0343] Example 10

[0344] 1-(((6-((2-chloro-3'-(7-cyano-5-((3-fluorooxetan-1-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3-yl)methyl)amino)cyclopropane- 1-carboxylic acid

[0345]

[0346] N-(2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)-5-formyl-4-methoxymethylpyridinamide (30 mg, 0.05 mmol) and 1-aminocyclopropane-l-carboxylic acid (51 mg, 0.5 mmol) were dissolved in anhydrous methanol (10 mL), DIPEA (0.082 mL, 0.5 mmol) was added with stirring at room temperature, the reaction was stirred at 40 °C for 2 hours, sodium triacetoxyborohydride (106 mg, 0.5 mmol) was added, and stirring was continued for 0.5 hours. The solvent was removed by concentration under reduced pressure, and the residue was separated by prep-HPLC to obtain the title compound (18.8 mg, 54%).

[0347] MS m / z (ESI): 695.1 [M+H] + .

[0348] Example 11

[0349] ((6-((2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)-D-serine

[0350]

[0351] ((6-((2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)-D-serine was prepared according to Example 1.

[0352] MS m / z (ESI): 699.2 [M+H] + .

[0353] Example 12

[0354] (R)-2-(((6-((2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)amino)-3- hydroxy-2-methylpropanoic acid

[0355]

[0356] The preparation of (R)-2-(((6-((2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)amino)-3-hydroxy-2-methylpropanoic acid refers to Example 1.

[0357] MS m / z(ESI):713.2[M+H] + .

[0358] Example 13

[0359] Ethyl ((6-((2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)-L-alaninate

[0360]

[0361] The preparation of ethyl ((6-((2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)-L-alaninate was carried out according to Example 1.

[0362] MS m / z(ESI):711.2[M+H] + .

[0363] Example 14

[0364] Isopropyl ((6-((2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)-L-alaninate

[0365]

[0366] The preparation of isopropyl ((6-((2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)-L-alaninate was carried out according to Example 1.

[0367] MS m / z(ESI):725.2[M+H] + .

[0368] Example 15

[0369] Isopropyl ((6-((2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3-yl)methyl)-D-serinate

[0370]

[0371] Isopropyl ((6-((2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3-yl)methyl)-D-serinate was prepared according to Example 1.

[0372] MS m / z (ESI): 741.2 [M+H] + .

[0373] Example 16

[0374] Isopropyl (R)-2-(((6-((2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3-yl)methyl)amino)-3-hydroxy-2- methyl-propionic acid ester

[0375]

[0376] Isopropyl (R)-2-(((6-((2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3-yl)methyl)amino)-3-hydroxy-2- methyl-propionic acid ester was prepared according to Example 1.

[0377] MS m / z (ESI): 755.2 [M+H] + .

[0378] Example 17

[0379] Methyl (S)-l-((6-((2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3-yl)methyl)piperidine-2-carboxylate

[0380]

[0381] Methyl (S)-1-((6-((2-chloro-3'-(7-cyano-5-((3-fluorooxetan-1-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3-yl)methyl)piperidine-2-carboxylate was prepared according to Example 1.

[0382] MS m / z (ESI): 737.2 [M+H] + .

[0383] Example 18

[0384] Ethyl ((6-((2-chloro-3'-(7-cyano-5-((3-fluorooxetan-1-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3-yl)methyl)-L-proline

[0385]

[0386] Ethyl ((6-((2-chloro-3'-(7-cyano-5-((3-fluorooxetan-1-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3-yl)methyl)-L-proline was prepared according to Example 1.

[0387] MS m / z (ESI): 737.2 [M+H] + .

[0388] Example 19

[0389] (Iso-butoxy)methyl (S)-1-((6-((2-chloro-3'-(7-cyano-5-((3-fluorooxetan-1-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3-yl)methyl)piperidine-2-carboxylate

[0390]

[0391] (Iso-butoxy)methyl (S)-1-((6-((2-chloro-3'-(7-cyano-5-((3-fluorooxetan-1-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3-yl)methyl)piperidine-2-carboxylate was prepared according to Example 1.

[0392] MS m / z (ESI): 823.2 [M+H] + .

[0393] Example 20

[0394] (6-((2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3-yl)-isobutyl ester

[0395]

[0396] (6-((2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3-yl)-isobutyl ester was prepared according to Example 1.

[0397] MS m / z (ESI): 809.2 [M+H] + .

[0398] Example 21

[0399] ((((6-((2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3-yl)methyl)-L-alaninyl)oxy)methyl isobutyrate

[0400]

[0401] ((((6-((2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3-yl)methyl)-L-alaninyl)oxy)methyl isobutyrate was prepared according to Example 1.

[0402] MS m / z (ESI): 783.2 [M+H] + .

[0403] Example 22

[0404] N-(2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)-5-(((2-hydroxypropyl)amino)methyl)-4- methoxymethylpyridine amide

[0405]

[0406] N-(2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)-5-(((2-hydroxypropyl)amino)methyl)-4- methoxymethylpyridine amide was prepared according to the procedure described in Reference Example 1.

[0407] MS m / z (ESI): 685.2 [M+H] + .

[0408] Example 23

[0409] N-(2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)-5-(((2-hydroxypropyl)amino)methyl)-4- methoxymethylpyridine amide

[0410]

[0411] N-(2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)-5-(((2-hydroxypropyl)amino)methyl)-4- methoxymethylpyridine amide (30 mg, 0.05 mmol) and (S)-l-aminopropan-2-ol (37 mg, 0.5 mmol) were dissolved in anhydrous methanol (10 mL), DIPEA (0.082 mL, 0.5 mmol) was added with stirring at room temperature, the reaction was stirred at 40 °C for 2 hours, sodium triacetoxyborohydride (106 mg, 0.5 mmol) was added, stirring was continued for 0.5 hour, the solvent was removed by reduced pressure concentration, the residue was separated by prep-HPLC to give the title compound (16.6 mg, 3%).

[0412] MS m / z (ESI): 669.2 [M+H] + .

[0413] Example 24

[0414] (R)-N-(2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)-5-(((2-hydroxypropyl)amino)methyl)-4- methoxymethylpyridinamide

[0415]

[0416] N-(2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)-5-(((2-hydroxypropyl)amino)methyl)-4- methoxymethylpyridinamide (70 mg, 0.115 mmol) and (R)-l-aminopropan-2-ol (86 mg, 1.15 mmol) were dissolved in anhydrous methanol (10 mL), DIPEA (0.19 mg, 1.15 mmol) was added with stirring at room temperature, the reaction was stirred at 40 °C for 2 hours, sodium triacetoxyborohydride (244 mg, 1.15 mmol) was added, stirring was continued for 0.5 hours, the solvent was removed by reduced pressure concentration, the residue was separated by prep-HPLC to give the title compound (8.0 mg, 10%).

[0417] MS m / z (ESI): 669.2 [M+H] + .

[0418] Example 25

[0419] N-(2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)-5-(((2-hydroxypropyl)amino)methyl)-4- methoxymethylpyridinamide

[0420]

[0421] N-(2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)-5-(((2-hydroxypropyl)amino)methyl)-4- methoxymethylpyridinamide (30 mg, 0.05 mmol) and 2-aminoethanol (31 mg, 0.5 mmol) were dissolved in anhydrous methanol (10 mL), DIPEA (0.082 mL, 0.5 mmol) was added with stirring at room temperature, the reaction was stirred at 40 °C for 2 hours, sodium triacetoxyborohydride (106 mg, 0.5 mmol) was added, stirring was continued for 0.5 hours, the solvent was removed by reduced pressure concentration, the residue was separated by prep-HPLC to give the title compound (16.5 mg, 50%).

[0422] MS m / z (ESI): 655.2 [M+H] + .

[0423] Example 26

[0424] (R)-N-(2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)-5-(((l-hydroxypropan-2-yl)amino)methyl)-4- methoxymethylpyridinamide

[0425]

[0426] The preparation of (R)-N-(2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)-5-(((l-hydroxypropan-2-yl)amino)methyl)-4- methoxymethylpyridinamide refers to Example 1.

[0427] MS m / z (ESI): 669.2 [M+H] + .

[0428] Example 27

[0429] (S)-N-(2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)-5-((2-(hydroxymethyl)piperidin-l-yl)methyl)-4- methoxymethylpyridinamide

[0430]

[0431] The preparation of (S)-N-(2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)-5-((2-(hydroxymethyl)piperidin-l-yl)methyl)-4- methoxymethylpyridinamide refers to Example 1.

[0432] MS m / z (ESI): 709.2 [M+H] + .

[0433] Example 28

[0434] N-(2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)-5-((3-hydroxyazetidin-l-yl)methyl)-4- methoxymethylpyridinamide

[0435]

[0436] N-(2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)-5-((3-hydroxyazetidin-l-yl)methyl)-4- methoxymethylpyridinamide

[0437] MS m / z (ESI): 667.2 [M+H] + .

[0438] Example 29

[0439] N-(2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)-5-((3-hydroxyazetidin-l-yl)methyl)-4- methoxymethylpyridinamide

[0440]

[0441] N-(2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)-5-((3-hydroxyazetidin-l-yl)methyl)-4- methoxymethylpyridinamide

[0442] MS m / z (ESI): 695.2 [M+H] + .

[0443] Example 30

[0444] N-(2-chloro-3'-(7-cyano-5-((3-fluorooxetan-3-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)-5-((((1S,2R)-2-hydroxycyclopentyl)amino)methyl)-4- methoxymethylpyridine amide

[0445]

[0446] N-(2-chloro-3'-(7-cyano-5-((3-fluorooxetan-3-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)-5-((((1S,2R)-2-hydroxycyclopentyl)amino)methyl)-4- methoxymethylpyridine amide was prepared according to Example 1.

[0447] MS m / z (ESI): 695.2 [M+H] + .

[0448] Example 31

[0449] N-(2-chloro-3'-(7-cyano-5-((3-fluorooxetan-3-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)-5-(((trans-2-hydroxycyclopentyl)amino)methyl)-4- methoxymethylpyridine amide

[0450]

[0451] N-(2-chloro-3'-(7-cyano-5-((3-fluorooxetan-3-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)-5-(((trans-2-hydroxycyclopentyl)amino)methyl)-4- methoxymethylpyridine amide was prepared according to Example 1.

[0452] MS m / z (ESI): 697.2 [M+H] + .

[0453] Example 32

[0454] (S)-N-(2-chloro-3'-(7-cyano-5-((3-fluorooxetan-3-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)-4-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl) methylpyridine amide

[0455]

[0456] N-(2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)-5-formyl-4-methoxymethylpyridinamide (30 mg, 0.05 mmol) and (S)-5-(aminomethyl)pyrrolidin-2-one hydrochloride (75 mg, 0.5 mmol) were dissolved in anhydrous methanol (10 mL), DIPEA (0.082 mg, 0.5 mmol) was added with stirring at room temperature, the reaction was stirred at 40 °C for 2 hours, sodium triacetoxyborohydride (106 mg, 0.5 mmol) was added, and stirring was continued for 0.5 hours. The solvent was removed by concentration under reduced pressure, and the residue was separated by prep-HPLC to obtain the title compound (18.7 mg, 53%).

[0457] MS m / z (ESI): 708.2 [M+H] + .

[0458] Example 33

[0459] N-(2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)-5-formyl-4-methoxymethylpyridinamide (30 mg, 0.05 mmol) and (S)-5-(aminomethyl)pyrrolidin-2-one hydrochloride (75 mg, 0.5 mmol) were dissolved in anhydrous methanol (10 mL), DIPEA (0.082 mg, 0.5 mmol) was added with stirring at room temperature, the reaction was stirred at 40 °C for 2 hours, sodium triacetoxyborohydride (106 mg, 0.5 mmol) was added, and stirring was continued for 0.5 hours. The solvent was removed by concentration under reduced pressure, and the residue was separated by prep-HPLC to obtain the title compound (18.7 mg, 53%).

[0460]

[0461] N-(2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)-5-formyl-4-methoxymethylpyridinamide (30 mg, 0.05 mmol) and (S)-5-(aminomethyl)pyrrolidin-2-one hydrochloride (75 mg, 0.5 mmol) were dissolved in anhydrous methanol (10 mL), DIPEA (0.082 mg, 0.5 mmol) was added with stirring at room temperature, the reaction was stirred at 40 °C for 2 hours, sodium triacetoxyborohydride (106 mg, 0.5 mmol) was added, and stirring was continued for 0.5 hours. The solvent was removed by concentration under reduced pressure, and the residue was separated by prep-HPLC to obtain the title compound (18.7 mg, 53%).

[0462] MS m / z (ESI): 708.2 [M+H] + .

[0463] Example 34

[0464] N-(2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-((3-fluoroazetidin-1-yl)methyl)-4-methoxymethylpicolinamide

[0465]

[0466] N-(2-chloro-3'-(7-cyano-5-((3-fluoroazetidine-1-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-formyl-4-methoxymethylpicolinamide (70 mg, 0.115 mmol) and 3-fluoroazetidine (64 mg, 0.574 mmol) were dissolved in anhydrous methanol (5 mL). DIPEA (0.095 mL, 0.574 mmol) was added with stirring at room temperature. The reaction solution was stirred at 40°C for 2 hours. Sodium triacetoxyborocyanide (122 mg, 0.574 mmol) was added and stirring was continued for 0.5 hour. The solvent was removed by concentration under reduced pressure. The residue was separated by prep-HPLC to obtain the title compound (25.6 mg, 33%).

[0467] MS m / z(ESI):669.1[M+H] + .

[0468] Example 35

[0469] 5-((6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-N-(2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-4-methoxymethylpicolinamide

[0470]

[0471] N-(2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)-5-formyl-4-methoxymethylpyridinamide (70 mg, 0.115 mmol) and l-(2,6-diazaspiro[3.3]heptan-2-yl)ethan-l-one hydrochloride (101 mg, 0.574 mmol) were dissolved in anhydrous methanol (5 mL), DIPEA (0.095 mL, 0.574 mmol) was added with stirring at room temperature, the reaction was stirred at 40 °C for 2 hours, sodium triacetoxyborohydride (122 mg, 0.574 mmol) was added, and stirring was continued for 0.5 hours. The solvent was removed by concentration under reduced pressure, and the residue was separated by prep-HPLC to give the title compound (4.1 mg, 5%).

[0472] MS m / z (ESI): 734.2 [M+H] + .

[0473] Example 36

[0474] 5-((5-oxa-2-azaspiro[3.4]octan-2-yl)methyl)-N-(2-chloro-3'-(7-cyano-5-((3- fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[l,l'-biphenyl]-3-yl)-4- methoxymethylpyridinamide

[0475]

[0476] 5-((5-oxa-2-azaspiro[3.4]octan-2-yl)methyl)-N-(2-chloro-3'-(7-cyano-5-((3- fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[l,l'-biphenyl]-3-yl)-4- methoxymethylpyridinamide was prepared according to Example 1.

[0477] MS m / z (ESI): 707.2 [M+H] + .

[0478] Example 37

[0479] (S)-l-((6-((2-chloro-3'-(7-cyano-5-((3-(fluoromethyl)-3-hydroxyazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[l,l'-biphenyl]-3-yl)carbamoyl)-4- methoxypyridin-3-yl)methyl)piperidine-2-carboxylic acid

[0480] (S)-l-((6-((2-chloro-3'-(7-cyano-5-((3-(fluoromethyl)-3-hydroxyazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[l,l'-biphenyl]-3-yl)carbamoyl)-4- methoxypyridin-3-yl)methyl)piperidine-2-carboxylic acid

[0481] (S)-1-((6-((2-chloro-3'-(7-cyano-5-((3-(fluoromethyl)-3-hydroxyazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3-yl)methyl)piperidine-2-carboxylic acid was prepared according to Example 1.

[0482] The compound can be prepared according to the following method:

[0483] Step 1: Preparation of 3-(fluoromethyl)azetidin-3-ol

[0484]

[0485] Tert-butyl-1-oxa-5-azaspiro[2.3]hexane-5-carboxylate (1.5 g, 8.1 mmol) was dissolved in triethylamine trihydrofluoride (5 mL) and stirred at room temperature for 1 hour. The reaction was extracted with ethyl acetate (50 mL x 3), washed with saturated aqueous sodium carbonate (30 mL x 3), washed with saturated aqueous sodium chloride (30 mL x 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The resulting product was dissolved in hydrochloric acid dioxane solution (2 mL) and stirred at room temperature for 1 hour. The reaction was concentrated to obtain the title compound (540 mg, 63%).

[0486] MS m / z (ESI): 106.1 [M+H] + .

[0487] Step 2: Preparation of 5-formyl-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazole-7-carbonitrile

[0488]

[0489] 5-(hydroxymethyl)-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazole-7-carbonitrile (5.0 g, 12.81 mmol) was dispersed in dichloromethane (150 mL) and stirred at room temperature. DMP (8.14 g, 19.2 mmol) was added, and the reaction was stirred at room temperature for 2 hours. The reaction was quenched with saturated aqueous NaHCO3 solution (100 mL) and extracted with DCM (300 mL). The organic layer was washed with saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound as a white solid (4.72 g, 95%).

[0490] MS m / z (ESI): 389.2 [M+H] + .

[0491] Step 3: Preparation of 5-((3-(fluoromethyl)-3-hydroxyazetidin-l-yl)methyl)-2-(2- methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazole-7- carbonitrile

[0492]

[0493] To a solution of 5-formyl-2-(2-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)benzo[d]oxazole-7-carbonitrile (2.2 g, 5.67 mmol) and 3-(fluoromethyl) azetidin-3-ol (3.55 g, 7.37 mmol, as 3.3 trifluoroacetate salt) in 1,2- dichloroethane (50 mL) was added diisopropylethylamine (3.14 g, 24.3 mmol) with stirring at room temperature. The resulting reaction mixture was heated to 50 °C in an oil bath and stirred for 2 h. Sodium triacetoxyborohydride (2.4 g, 11.34 mmol) was added and the resulting reaction mixture was stirred at 50 °C for another 4 h. The reaction mixture was cooled to room temperature, diluted with dichloromethane, washed sequentially with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel to give the title compound (1.5 g, 55%).

[0494] MS m / z (ESI): 478.2 [M+H] + .

[0495] Step 4: Preparation of N-(2-chloro-3'-(7-cyano-5-((3-(fluoromethyl)-3- hydroxyazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[l,l'-biphenyl]-3-yl)-5- formyl-4-methoxymethylpyridinamide

[0496]

[0497] N-(3-bromo-2-chlorophenyl)-5-(hydroxymethyl)-4-methoxymethylpyridinamide (1.75 g, 4.71 mmol) and 5-((3-(fluoromethyl)-3-hydroxyazetidin-l-yl)methyl)-2-(2-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazole-7-carbonitrile (1.5 g, 3.14 mmol) were dispersed in dioxane (100 mL), (bis(dicyclohexylphosphino)ferrocene)palladium dichloride (237 mg, 0.314 mmol) was added, the reaction was protected with nitrogen, cesium carbonate (2.04 g, 6.28 mmol) in water (10 mL) was added with stirring at room temperature, the reaction was replaced with nitrogen once, and transferred to an oil bath to be heated to 90 °C with stirring for 16 hours. The solvent was removed by concentration under reduced pressure, the residue was dissolved in dichloromethane, filtered through celite, the filtrate was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was dissolved in dichloromethane (100 mL), Dess-Martin oxidizing agent (2.12 g, 5 mmol) was added with stirring at room temperature, the reaction was stirred at room temperature for 30 minutes, diluted with dichloromethane, the resulting mixture was washed successively with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was separated by column chromatography on silica gel to give the title compound (654 mg, 33%).

[0498] MS m / z (ESI): 640.2 [M+H] + .

[0499] Fifth Step: Preparation of (S)-l-((6-((2-chloro-3'-(7-cyano-5-((3-(fluoromethyl)-3- hydroxyazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[l,l'-biphenyl]-3-yl)carbamoyl)- 4-methoxypyridin-3-yl)methyl)piperidine-2-carboxylic acid

[0500]

[0501] N-(2-chloro-3'-(7-cyano-5-((3-(fluoromethyl)-3-hydroxyazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[l,l'-biphenyl]-3-yl)-5-formyl-4-methoxymethylpyridine amide (100 mg, 0.156 mmol) and (S)-piperidine-2-carboxylic acid (40 mg, 0.312 mmol) were dissolved in a mixed solvent of N,N-dimethylformamide (3 mL) and methanol (3 mL), 5 drops of acetic acid were added, the reaction was stirred at room temperature for 2 hours, sodium cyanoborohydride (20 mg, 0.312 mmol) was added, the resulting reaction was continued to be stirred at room temperature for 16 hours, the solvent was removed by concentration under reduced pressure, the residue was dissolved in dichloromethane, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, the residue was dissolved in methanol, and the title compound (22.5 mg, 19%) was separated by prep-HPLC.

[0502] 1 H NMR (400 MHz, CD3OD) δ 8.67 (s, 1H), 8.62 (d, J = 8.7 Hz, 1H), 8.26 (d, J = 8.8 Hz, 1H), 8.07 (s, 1H), 7.98 (s, 1H), 7.79 (s, 1H), 7.53 (dt, J = 14.8, 7.2 Hz, 2H), 7.45 (d, J = 8.1 Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H), 4.60 - 4.41 (m, 4H), 4.12 (s, 3H), 3.95 (s, 2H), 3.60 (d, J = 8.9 Hz, 2H), 3.51 (d, J = 10.7 Hz, 1H), 3.42 - 3.36 (m, 1H), 3.24 (d, J = 8.3 Hz, 2H), 3.00 (t, J = 11.3 Hz, 1H), 2.55 (s, 3H), 2.25 (d, J = 12.4 Hz, 1H), 1.88 - 1.68 (m, 4H), 1.53 (d, J = 12.3 Hz, 1H).

[0503] MS m / z (ESI): 753.2 [M+H] + .

[0504] Example 38

[0505] ((6-((2-chloro-3'-(7-cyano-5-((3-(fluoromethyl)-3-hydroxyazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[l,l'-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)-L-proline

[0506]

[0507] ((6-((2-chloro-3'-(7-cyano-5-((3-(fluoromethyl)-3-hydroxyazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[l,l'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3-yl)methyl)-L-proline was prepared according to Example 1.

[0508] MS m / z (ESI): 737.2 [M+H] + .

[0509] Example 39

[0510] N-(2-chloro-3'-(7-cyano-5-((3-(fluoromethyl)-3-hydroxyazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[l,l'-biphenyl]-3-yl)-5-((3-hydroxyazetidin-l-yl)methyl)-4-methoxymethylpyridinamide

[0511]

[0512] N-(2-chloro-3'-(7-cyano-5-((3-(fluoromethyl)-3-hydroxyazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[l,l'-biphenyl]-3-yl)-5-((3-hydroxyazetidin-l-yl)methyl)-4-methoxymethylpyridinamide was prepared according to Example 1.

[0513] MS m / z (ESI): 697.2 [M+H] + .

[0514] Example 40

[0515] (S)-N-(2-chloro-3'-(7-cyano-5-((3-(fluoromethyl)-3-hydroxyazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[l,l'-biphenyl]-3-yl)-5-(((2-hydroxypropyl)amino)methyl)-4-methoxymethylpyridinamide

[0516]

[0517] (S)-N-(2-chloro-3'-(7-cyano-5-((3-(fluoromethyl)-3-hydroxyazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[l,l'-biphenyl]-3-yl)-5-(((2-hydroxypropyl)amino)methyl)-4-methoxymethylpyridinamide was prepared according to Example 1.

[0518] MS m / z (ESI): 699.2 [M+H] + .

[0519] Example 41

[0520] (S)-1-((6-((2-chloro-3'-(7-cyano-5-((3-(fluoromethyl)-3-hydroxyazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3-yl)methyl)piperidin-2-one

[0521]

[0522] (S)-1-((6-((2-chloro-3'-(7-cyano-5-((3-(fluoromethyl)-3-hydroxyazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3-yl)methyl)piperidin-2-one was prepared according to Example 1.

[0523] MS m / z (ESI): 853.2 [M+H] + .

[0524] Example 42

[0525] (S)-1-((6-((2-chloro-3'-(7-cyano-5-((3-(fluoromethyl)-3-hydroxyazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3-yl)methyl)-L-alaninate

[0526]

[0527] (S)-1-((6-((2-chloro-3'-(7-cyano-5-((3-(fluoromethyl)-3-hydroxyazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3-yl)methyl)-L-alaninate was prepared according to Example 1.

[0528] MS m / z (ESI): 755.2 [M+H] + .

[0529] Example 43

[0530] (S)-1-((6-((2-chloro-3'-(7-cyano-5-((((3R,4R)-3-fluorotetrahydro-2H-pyran-4- yl)amino)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4- methoxypyridin-3-yl)methyl)piperidin-2-one

[0531]

[0532] (S)-1-((6-((2-chloro-3'-(7-cyano-5-((((3R,4R)-3-fluorotetrahydro-2H-pyran-4- yl)amino)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4- methoxypyridin-3-yl)methyl)piperidin-2-one was prepared according to Reference Example 1.

[0533] MS m / z (ESI): 767.2 [M+H] + .

[0534] Example 44

[0535] ((6-((2-chloro-3'-(7-cyano-5-((((3R,4R)-3-fluorotetrahydro-2H-pyran-4- yl)amino)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4- methoxypyridin-3-yl)methyl)-L-proline

[0536]

[0537] ((6-((2-chloro-3'-(7-cyano-5-((((3R,4R)-3-fluorotetrahydro-2H-pyran-4- yl)amino)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4- methoxypyridin-3-yl)methyl)-L-proline was prepared according to Reference Example 1.

[0538] MS m / z (ESI): 753.2 [M+H] + .

[0539] Example 45

[0540] N-(2-chloro-3'-(7-cyano-5-((((3R,4R)-3-fluorotetrahydro-2H-pyran-4- yl)amino)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-4-methoxy-5- ((oxetan-3-ylamino)methyl)methylpyridineamide

[0541]

[0542] N-(2-chloro-3'-(7-cyano-5-((((3R,4R)-3-fluorotetrahydro-2H-pyran-4- yl)amino)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((2- fluoroethyl)amino)methyl)-4-methoxymethylpyridine amide was prepared according to Example 1.

[0543] MS m / z (ESI): 701.2 [M+H] + .

[0544] Example 46

[0545] N-(2-chloro-3'-(7-cyano-5-((((3R,4R)-3-fluorotetrahydro-2H-pyran-4- yl)amino)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((2- fluoroethyl)amino)methyl)-4-methoxymethylpyridine amide

[0546]

[0547] N-(2-chloro-3'-(7-cyano-5-((((3R,4R)-3-fluorotetrahydro-2H-pyran-4- yl)amino)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((2- fluoroethyl)amino)methyl)-4-methoxymethylpyridine amide was prepared according to Example 1.

[0548] MS m / z (ESI): 701.2 [M+H] + .

[0549] Example 47

[0550] N-(2-chloro-3'-(7-cyano-5-((((3R,4R)-3-fluorotetrahydro-2H-pyran-4- yl)amino)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((2- fluoroethyl)amino)methyl)-4-methoxymethylpyridine amide

[0551]

[0552] N-(2-chloro-3'-(7-cyano-5-((((3R,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-((((1R,2S)-2-fluorocyclopropyl)amino)methyl)-4-methoxymethylpyridine amide was prepared according to Example 1.

[0553] MS m / z (ESI): 713.2 [M+H] + .

[0554] Example 48

[0555] N-(2-chloro-3'-(7-cyano-5-((((3R,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-((((1R,2S)-2-fluorocyclopropyl)amino)methyl)-4-methoxymethylpyridine amide

[0556]

[0557] N-(2-chloro-3'-(7-cyano-5-((((3R,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-((((1R,2S)-2-fluorocyclopropyl)amino)methyl)-4-methoxymethylpyridine amide was prepared according to Example 1.

[0558] MS m / z (ESI): 713.2 [M+H] + .

[0559] Example 49

[0560] N-(2-chloro-3'-(7-cyano-5-((3-(fluoromethyl)-3-hydroxyazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-((((1R,2S)-2-fluorocyclopropyl)amino)methyl)-4-methoxymethylpyridine amide

[0561]

[0562] N-(2-chloro-3'-(7-cyano-5-((3-hydroxyazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)-5-((((R)-2-hydroxypropyl)amino)methyl)-4- methoxymethylpyridineamide was prepared according to Example 1.

[0563] MS m / z (ESI): 699.2 [M+H] + .

[0564] Example 50

[0565] N-(2-chloro-3'-(7-cyano-5-((3-hydroxyazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)-5-((((R)-2-hydroxypropyl)amino)methyl)-4- methoxymethylpyridineamide

[0566]

[0567] N-(2-chloro-3'-(7-cyano-5-((3-hydroxyazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)-5-((((R)-2-hydroxypropyl)amino)methyl)-4- methoxymethylpyridineamide was prepared according to Example 1.

[0568] MS m / z (ESI): 667.2 [M+H] + .

[0569] Example 51

[0570] N-(2-chloro-3'-(7-cyano-5-((((S)-2-hydroxypropyl)amino)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)-5-((((R)-2-hydroxypropyl)amino)methyl)-4- methoxymethylpyridineamide

[0571]

[0572] N-(2-chloro-3'-(7-cyano-5-((((S)-2-hydroxypropyl)amino)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)-5-((((R)-2-hydroxypropyl)amino)methyl)-4- methoxymethylpyridineamide was prepared according to Example 1.

[0573] MS m / z (ESI): 669.2 [M+H]+ .

[0574] Example 52

[0575] N-(2-chloro-3'-(7-cyano-5-((((3R,4R)-3-hydroxytetrahydro-2H-pyran-4- yl)amino)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-((((1R,2S)-2- fluorocyclopropyl)amino)methyl)-4-methoxymethylpyridineamide

[0576]

[0577] N-(2-chloro-3'-(7-cyano-5-((((3R,4R)-3-hydroxytetrahydro-2H-pyran-4- yl)amino)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-((((1R,2S)-2- fluorocyclopropyl)amino)methyl)-4-methoxymethylpyridineamide was prepared according to Example 1.

[0578] MS m / z (ESI): 711.2 [M+H] + .

[0579] Example 53

[0580] N-(2-chloro-3'-(7-cyano-5-((((3R,4R)-4-hydroxytetrahydrofuran-3-yl)amino)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-((((1R,2S)-2-fluorocyclopropyl)amino)methyl)-4-methoxymethylpyridineamide

[0581]

[0582] N-(2-chloro-3'-(7-cyano-5-((((3R,4R)-4-hydroxytetrahydrofuran-3-yl)amino)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-((((1R,2S)-2-fluorocyclopropyl)amino)methyl)-4-methoxymethylpyridineamide was prepared according to Example 1.

[0583] MS m / z (ESI): 697.2 [M+H] + .

[0584] Example 54

[0585] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]oct-2-yl)methyl)-7-cyano- benzo [d] oxazol-2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-((((1R,2S)-2- fluorocyclopropyl)amino)methyl)-4-methoxymethylpyridinecarboxamide

[0586]

[0587] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]oct-2-yl)methyl)-7-cyano- benzo [d] oxazol-2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-((((1R,2S)-2- fluorocyclopropyl)amino)methyl)-4-methoxymethylpyridinecarboxamide was prepared according to Example 1.

[0588] MS m / z (ESI): 734.2 [M+H] + .

[0589] Example 55

[0590] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]oct-2-yl)methyl)-7-cyano- benzo [d] oxazol-2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-((((1R,2S)-2- fluorocyclopropyl)amino)methyl)-4-methoxymethylpyridinecarboxamide

[0591]

[0592] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]oct-2-yl)methyl)-7-cyano- benzo [d] oxazol-2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-((((1R,2S)-2- fluorocyclopropyl)amino)methyl)-4-methoxymethylpyridinecarboxamide was prepared according to Example 1.

[0593] MS m / z (ESI): 707.2 [M+H] + .

[0594] Example 56

[0595] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]oct-2-yl)methyl)-7-cyano- benzo [d] oxazol-2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-((((1R,2S)-2- fluorocyclopropyl)amino)methyl)-4-methoxymethylpyridinecarboxamide

[0596]

[0597] N-(2-chloro-3'-(7-cyano-5-((6-carbonyl-2,5-diazaspiro[3.4]octan-2-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-((((1R,2S)-2-fluorocyclopropyl)amino)methyl)-4-methoxymethylpyridine amide was prepared according to Example 1.

[0598] MS m / z (ESI): 720.2 [M+H] + .

[0599] Example 57

[0600] N-(2-chloro-3'-(7-cyano-5-((6-carbonyl-2,5-diazaspiro[3.4]octan-2-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-((((1R,2S)-2-fluorocyclopropyl)amino)methyl)-4-methoxymethylpyridine amide

[0601]

[0602] N-(2-chloro-3'-(7-cyano-5-((6-carbonyl-2,5-diazaspiro[3.4]octan-2-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-((((1R,2S)-2-fluorocyclopropyl)amino)methyl)-4-methoxymethylpyridine amide was prepared according to Example 1.

[0603] MS m / z (ESI): 720.2 [M+H] + .

[0604] Example 58

[0605] N-(2-chloro-3'-(7-cyano-5-((6-carbonyl-2,5-diazaspiro[3.4]octan-2-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-((((1R,2S)-2-fluorocyclopropyl)amino)methyl)-4-methoxymethylpyridine amide

[0606]

[0607] N-(2-chloro-3'-(7-cyano-5-(((3-fluoro-2-methylpyridin-4-yl)amino)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-((((1R,2S)-2-fluorocyclopropyl)amino)methyl)-4-methoxymethylpyridinamide was prepared according to Example 1.

[0608] MS m / z (ESI): 720.2 [M+H] + .

[0609] Example 59

[0610] ((2-(2'-chloro-3'-(5-((((1R,2S)-2-fluorocyclopropyl)amino)methyl)-4-methoxymethylpyridinamido)-2-methyl-[1,1'-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)-L-proline

[0611]

[0612] ((2-(2'-chloro-3'-(5-((((1R,2S)-2-fluorocyclopropyl)amino)methyl)-4-methoxymethylpyridinamido)-2-methyl-[1,1'-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)-L-proline was prepared according to Example 1.

[0613] MS m / z (ESI): 709.2 [M+H] + .

[0614] Example 60

[0615] (S)-1-((2-(2'-chloro-3'-(5-((((1R,2S)-2-fluorocyclopropyl)amino)methyl)-4-methoxymethylpyridinamido)-2-methyl-[1,1'-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylic acid

[0616]

[0617] (S)-1-((2-(2'-chloro-3'-(5-((((1R,2S)-2-fluorocyclopropyl)amino)methyl)-4-methoxymethylpyridinamido)-2-methyl-[1,1'-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylic acid was prepared according to Example 1.

[0618] MS m / z (ESI): 723.2 [M+H] + .

[0619] Example 61

[0620] (S)-1-((2-(2'-chloro-3'-(5-(((2-fluoroethyl)amino)methyl)-4- methoxymethylpyridinoylamido)-2-methyl-[1,1'-biphenyl]-3-yl)-7- cyanobenzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylic acid

[0621]

[0622] (S)-1-((2-(2'-chloro-3'-(5-(((2-fluoroethyl)amino)methyl)-4- methoxymethylpyridinoylamido)-2-methyl-[1,1'-biphenyl]-3-yl)-7- cyanobenzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylic acid was prepared according to Reference Example 1.

[0623] MS m / z (ESI): 711.2 [M+H] + .

[0624] Example 62

[0625] (S)-1-((2-(2'-chloro-3'-(4-methoxy-5-((oxetan-3-ylamino)methyl)methylpyridinoylamido)-2-methyl-[1,1'-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylic acid

[0626]

[0627] (S)-1-((2-(2'-chloro-3'-(4-methoxy-5-((oxetan-3-ylamino)methyl)methylpyridinoylamido)-2-methyl-[1,1'-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylic acid was prepared according to Reference Example 1.

[0628] MS m / z (ESI): 721.2 [M+H] + .

[0629] Example 63

[0630] (S)-1-((2-(2'-chloro-3'-(5-((((S)-2-hydroxypropyl)amino)methyl)-4- methoxymethylpyridinoylamido)-2-methyl-[1,1'-biphenyl]-3-yl)-7- cyanobenzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylic acid

[0631]

[0632] (S)-1-((2-(2'-chloro-3'-(5-((((S)-2-hydroxypropyl)amino)methyl)-4- methoxymethylpyridinamido)-2-methyl-[1,1'-biphenyl]-3-yl)-7- cyanobenzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylic acid was prepared according to Example 1.

[0633] MS m / z (ESI): 723.2 [M+H] + .

[0634] Example 64

[0635] 1-((2-(2'-chloro-3'-(4-methoxy-5-((oxetan-3-ylamino)methyl)methylpyridinamido)- 2-methyl-[1,1'-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)azetidine-3- carboxylic acid

[0636]

[0637] 1-((2-(2'-chloro-3'-(4-methoxy-5-((oxetan-3-ylamino)methyl)methylpyridinamido)- 2-methyl-[1,1'-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)azetidine-3- carboxylic acid was prepared according to Example 1.

[0638] MS m / z (ESI): 693.2 [M+H] + .

[0639] Example 65

[0640] ( isobutoxy)methyl (S)-1-((2-(2'-chloro-3'-(5-((((S)-2-hydroxypropyl)amino)methyl)- 4-methoxymethylpyridinamido)-2-methyl-[1,1'-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol- 5-yl)methyl)piperidine-2-carboxylate

[0641]

[0642] ( isobutoxy)methyl (S)-1-((2-(2'-chloro-3'-(5-((((S)-2-hydroxypropyl)amino)methyl)- 4-methoxymethylpyridinamido)-2-methyl-[1,1'-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol- 5-yl)methyl)piperidine-2-carboxylate was prepared according to Example 1.

[0643] MS m / z (ESI): 823.2 [M+H] + .

[0644] Example 66

[0645] (S)-1-((6-((2-chloro-3'-(7-cyano-5-(((3-fluoro-2-methylpyridin-4-yl)amino)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)piperidin-2-one

[0646]

[0647] The preparation of (isobutoxy)methyl ((2-(2'-chloro-3'-(5-((((S)-2-hydroxypropyl)amino)methyl)-4-methoxymethylpyridinoylamino)-2-methyl-[1,1'-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)-L-proline is described in Reference Example 1.

[0648] MS m / z (ESI): 809.2 [M+H] + .

[0649] Example 67

[0650] (S)-1-((6-((2-chloro-3'-(7-cyano-5-(((3-fluoro-2-methylpyridin-4-yl)amino)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)piperidin-2-one

[0651]

[0652] First Step: Preparation of 2-(3'-tert-butoxycarbonylamino-2'-chloro-2-methyl-[1,1'-biphenyl]-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrile

[0653]

[0654] Tert-butyl (3-bromo-2-chlorophenyl)carbamate (2.0 g, 6.53 mmol), 5- (hydroxymethyl)-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazole-7-carbonitrile (2.8 g, 7.18 mmol), bis-cyclohexylphosphine palladium dichloride (530 mg, 0.65 mmol) and potassium carbonate (6.38 g, 19.58 mmol) were added into a mixture solvent of tert-butanol (40 mL) and water (4 mL), the reaction system was protected by nitrogen, heated to 90 °C and stirred for 16 hours. The solvent was removed by concentration under reduced pressure, the residue was dispersed in dichloromethane, the organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was dispersed in dichloromethane (100 mL), sodium bicarbonate (5.5 g, 65.3 mmol) and DMP (3.0 g, 7.2 mmol) were added successively, and the reaction was stirred at room temperature for 30 minutes. The reaction solution was diluted with dichloromethane, washed successively with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography to obtain the title compound (2.03 g, 64%).

[0655] MS m / z (ESI): 488.2 [M+H] + .

[0656] Second Step: Preparation of 2-(3'-amino-2'-chloro-2-methyl-[1,1'-biphenyl]-3-yl)-5-(((3-fluoro-2-methylpyridin-4-yl)amino)methyl)benzo[d]oxazole-7-carbonitrile

[0657]

[0658] To a solution of 2-(3'-tert-butoxycarbonylamino-2'-chloro-2-methyl-[1,1'-biphenyl]-3-yl)-5- formylbenzo[d]oxazole-7-carbonitrile (500 mg, 1.03 mmol) and 3-fluoro-2-methylpyridin-4-amine hydrochloride (332 mg, 2.05 mmol) in 1,2-dichloroethane (20 mL) was added DIPEA (0.68 mL, 4.1 mmol) and tetraethyl orthotitanate (904 mg, 3.08 mmol) sequentially at room temperature. The reaction mixture was heated to 80 °C and stirred for 16 h. Acetic acid (1 mL) and sodium cyanoborohydride (258 mg, 4.1 mmol) were added and the reaction mixture was stirred at 80 °C for another 1 h. The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate and saturated sodium chloride sequentially. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel. The obtained product was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (5 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 30 min. The solvent was removed by concentration under reduced pressure. The residue was dissolved in acetic acid and washed with saturated sodium bicarbonate and saturated sodium chloride sequentially. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (425 mg, 83%) which was used directly in the next step.

[0659] MS m / z (ESI): 498.2 [M+H] + .

[0660] Step 3: Preparation of N-(2-chloro-3'-(7-cyano-5-(((3-fluoro-2-methylpyridin-4-yl)amino)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-4-methoxy-5-vinylmethylpyridinamide

[0661]

[0662] To a solution of 2-(3'-tert-butoxycarbonylamino-2'-chloro-2-methyl-[1,1'-biphenyl]-3-yl)-5- formylbenzo[d]oxazole-7-carbonitrile (500 mg, 1.03 mmol) and 3-fluoro-2-methylpyridin-4-amine hydrochloride (332 mg, 2.05 mmol) in 1,2-dichloroethane (20 mL) was added DIPEA (0.68 mL, 4.1 mmol) and tetraethyl orthotitanate (904 mg, 3.08 mmol) sequentially at room temperature. The reaction mixture was heated to 80 °C and stirred for 16 h. Acetic acid (1 mL) and sodium cyanoborohydride (258 mg, 4.1 mmol) were added and the reaction mixture was stirred at 80 °C for another 1 h. The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate and saturated sodium chloride sequentially. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel. The obtained product was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (5 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 30 min. The solvent was removed by concentration under reduced pressure. The residue was dissolved in acetic acid and washed with saturated sodium bicarbonate and saturated sodium chloride sequentially. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (425 mg, 83%) which was used directly in the next step.

[0663] MS m / z (ESI): 659.2 [M+H] + .

[0664] Fourth Step: Preparation of N-(2-chloro-3'-(7-cyano-5-(((3-fluoro-2-methylpyridin-4- yl)amino)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-formyl-4- methoxymethylpyridinamide

[0665]

[0666] The crude N-(2-chloro-3'-(7-cyano-5-(((3-fluoro-2-methylpyridin-4-yl)amino)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-4-methoxy-5-vinylmethylpyridinamide was dissolved in a mixed solvent of dioxane (40 mL) and water (16 mL), and potassium osmate dihydrate (32 mg, 0.085 mmol) and sodium periodate (1.1 g, 5.12 mmol) were added successively with stirring at room temperature. The reaction solution was stirred at room temperature for 1 hour, most of the solvent was removed by concentration under reduced pressure, and the residue was diluted with ethyl acetate. The ethyl acetate layer was washed successively with saturated aqueous sodium thiosulfate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the residue was separated by silica gel column chromatography to obtain the title compound (136 mg, 24% in total yield for two steps).

[0667] MS m / z (ESI): 661.2 [M+H] + .

[0668] Fifth Step: Preparation of (S)-1-((6-((2-chloro-3'-(7-cyano-5-(((3-fluoro-2-methylpyridin-4- yl)amino)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4- methoxypyridin-3-yl)methyl)piperidine-2-carboxylic acid

[0669]

[0670] N-(2-chloro-3'-(7-cyano-5-(((3-fluoro-2-methylpyridin-4-yl)amino)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-formyl-4-methoxymethylpyridinamide (34 mg, 0.052 mmol) and L-piperidinic acid (66 mg, 0.515 mmol) were dissolved in anhydrous methanol (10 mL), DIPEA (0.085 mL, 0.515 mmol) was added with stirring at room temperature, the reaction was stirred at 40 °C for 2 hours, sodium triacetoxyborohydride (110 mg, 0.515 mmol) was added, and stirring was continued for 0.5 hours. The solvent was removed by concentration under reduced pressure, and the residue was separated by prep-HPLC to obtain the title compound (7.1 mg, 18%).

[0671] MS m / z (ESI): 774.1 [M+H] + .

[0672] Example 68

[0673] ((6-((2-chloro-3'-(7-cyano-5-(((3-fluoro-2-methylpyridin-4-yl)amino)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)-L-proline

[0674]

[0675] ((6-((2-chloro-3'-(7-cyano-5-(((3-fluoro-2-methylpyridin-4-yl)amino)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)-L-proline was prepared according to Example 67.

[0676] MS m / z (ESI): 760.2 [M+H] + .

[0677] Example 69

[0678] ((6-((2-chloro-3'-(7-cyano-5-(((3-fluoro-2-methylpyridin-4-yl)amino)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)-L-proline

[0679]

[0680] N-(2-chloro-3'-(7-cyano-5-(((3-fluoro-2-methylpyridin-4-yl)amino)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-formyl-4-methoxymethylpyridinamide (34 mg, 0.052 mmol) and L-alanine (46 mg, 0.515 mmol) were dissolved in anhydrous methanol (10 mL), DIPEA (0.085 mL, 0.515 mmol) was added with stirring at room temperature, the reaction was stirred at 40 °C for 2 hours, sodium triacetoxyborohydride (110 mg, 0.515 mmol) was added, and stirring was continued for 0.5 hours. The solvent was removed by concentration under reduced pressure, and the residue was separated by prep-HPLC to obtain the title compound (12.9 mg, 34%).

[0681] MS m / z (ESI): 734.2 [M+H] + .

[0682] Example 70

[0683] Isopropyl ((6-((2-chloro-3'-(7-cyano-5-(((3-fluoro-2-methylpyridin-4-yl)amino)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)-L-alaninate

[0684]

[0685] Isopropyl ((6-((2-chloro-3'-(7-cyano-5-(((3-fluoro-2-methylpyridin-4-yl)amino)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)-L-alaninate was prepared according to Example 67.

[0686] MS m / z (ESI): 776.2 [M+H] + .

[0687] Example 71

[0688] 1-((6-((2-chloro-3'-(7-cyano-5-(((3-fluoro-2-methylpyridin-4-yl)amino)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)azetidine-3-carboxylic acid

[0689]

[0690] N-(2-chloro-3'-(7-cyano-5-(((3-fluoro-2-methylpyridin-4-yl)amino)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxypropyl)amino)methyl)-4- methoxymethylpyridine amide

[0691] MS m / z (ESI): 746.1 [M+H] + .

[0692] Example 72

[0693] (R)-N-(2-chloro-3'-(7-cyano-5-(((3-fluoro-2-methylpyridin-4-yl)amino)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxypropyl)amino)methyl)-4- methoxymethylpyridine amide

[0694]

[0695] N-(2-chloro-3'-(7-cyano-5-(((3-fluoro-2-methylpyridin-4-yl)amino)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxypropyl)amino)methyl)-4- methoxymethylpyridine amide

[0696] MS m / z (ESI): 720.2 [M+H] + .

[0697] Example 73

[0698] N-(2-chloro-3'-(7-cyano-5-(((2-methoxypyridin-4-yl)amino)methyl)benzo[d]oxazol- 2-yl)-2'-methyl-[1, 1 '-biphenyl]-3-yl)-4-methoxy-5-(((2-methoxypyridin-4-yl)amino)methyl)methylpyridine amide

[0699]

[0700] N-(2-chloro-3'-(7-cyano-5-(((2-methoxypyridin-4-yl)amino)methyl)benzo[d]oxazol- 2-yl)-2'-methyl-[1, 1 '-biphenyl]-3-yl)-4-methoxy-5-(((2-methoxypyridin-4-yl)amino)methyl)methylpyridine amide was prepared according to Example 67.

[0701] MS m / z (ESI): 767.2 [M+H] + .

[0702] Example 74

[0703] N-(2-chloro-3'-(7-cyano-5-(((2-methoxypyridin-4-yl)amino)methyl)benzo[d]oxazol- 2-yl)-2'-methyl-[1, 1 '-biphenyl]-3-yl)-4-methoxy-5-(((2-methoxypyridin-4-yl)amino)methyl)methylpyridine amide

[0704]

[0705] N-(2-chloro-3'-(7-cyano-5-(((2-methoxypyridin-4-yl)amino)methyl)benzo[d]oxazol- 2-yl)-2'-methyl-[1, 1 '-biphenyl]-3-yl)-4-methoxy-5-(((2-methoxypyridin-4-yl)amino)methyl)methylpyridine amide was prepared according to Example 67.

[0706] MS m / z (ESI): 777.2 [M+H] + .

[0707] Example 75

[0708] ((6-((2-chloro-3'-(7-cyano-5-(((2-methoxypyridin-4-yl)amino)methyl)benzo[d]oxazol- 2-yl)-2'-methyl-[1, 1 '-biphenyl]-3-yl)carbamoyl)-4-cyclopropylpyridin-3-yl)methyl)-D- serine

[0709]

[0710] ((6-((2-chloro-3'-(7-cyano-5-(((2-methoxypyridin-4-yl)amino)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-cyclopropylpyridin-3-yl)methyl)-D-serine was prepared according to Example 67.

[0711] MS m / z (ESI): 758.2 [M+H] + .

[0712] Example 76

[0713] N-(3'-(5-(((5-bromo-2-methoxypyridin-4-yl)amino)methyl)-7-cyanobenzo[d]oxazol-2-yl)-2-chloro-2'- methyl-[1,1'-biphenyl]-3-yl)-4-cyclopropyl-5-(4,5-dihydro-1H-imidazol-2-yl)methylpyridinecarboxamide

[0714]

[0715] N-(3'-(5-(((5-bromo-2-methoxypyridin-4-yl)amino)methyl)-7-cyanobenzo[d]oxazol-2-yl)-2-chloro-2'- methyl-[1,1'-biphenyl]-3-yl)-4-cyclopropyl-5-(4,5-dihydro-1H-imidazol-2-yl)methylpyridinecarboxamide was prepared according to Example 67.

[0716] MS m / z (ESI): 787.2 [M+H] + .

[0717] Example 77

[0718] (S)-1-((6-((2-chloro-3'-(7-cyano-5-(((3-fluoro-2-methylpyridin-4-yl)amino)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-cyclopropylpyridin-3-yl)methyl)piperidine-2-carboxylic acid

[0719]

[0720] (S)-1-((6-((2-chloro-3'-(7-cyano-5-(((3-fluoro-2-methylpyridin-4-yl)amino)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-cyclopropylpyridin-3-yl)methyl)piperidine-2-carboxylic acid was prepared according to Example 67.

[0721] MS m / z (ESI): 784.2 [M+H]+ .

[0722] Example 78

[0723] (S)-1-((2-(2'-chloro-3'-(4-cyclopropyl-5-(((3-fluoro-2-methylpyridin-4-yl)amino)methyl)methylpyridinamido)-2-methyl-[1,1'-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylic acid

[0724]

[0725] (S)-1-((2-(2'-chloro-3'-(4-cyclopropyl-5-(((3-fluoro-2-methylpyridin-4-yl)amino)methyl)methylpyridinamido)-2-methyl-[1,1'-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylic acid was prepared according to Example 1, referring to the preparation of (S)-1-((2-(2'-chloro-3'-(4-cyclopropyl-5-(((3-fluoro-2-methylpyridin-4-yl)amino)methyl)methylpyridinamido)-2-methyl-[1,1'-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylic acid.

[0726] MS m / z (ESI): 786.2 [M+H] + .

[0727] Example 79

[0728] (S)-1-((2-(2'-chloro-3'-(4-cyclopropyl-5-(((3-fluoro-2-methylpyridin-4-yl)amino)methyl)methylpyridinamido)-2-methyl-[1,1'-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylic acid

[0729]

[0730] (S)-1-((2-(2'-chloro-3'-(4-cyclopropyl-5-(((3-fluoro-2-methylpyridin-4-yl)amino)methyl)methylpyridinamido)-2-methyl-[1,1'-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylic acid was prepared according to Example 1, referring to the preparation of (S)-1-((2-(2'-chloro-3'-(4-cyclopropyl-5-(((3-fluoro-2-methylpyridin-4-yl)amino)methyl)methylpyridinamido)-2-methyl-[1,1'-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylic acid.

[0731] MS m / z (ESI): 786.2 [M+H] + .

[0732] Example 80

[0733] (S)-1-((2-(2'-chloro-3'-(4-cyclopropyl-5-(((3-fluoro-2-methylpyridin-4-yl)amino)methyl)methylpyridinamido)-2-methyl-[1,1'-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylic acid

[0734]

[0735] (S)-1-((2-(2'-chloro-3'-(4-cyclopropyl-5-((((S)-2-hydroxypropyl)amino)methyl) methylpyridinamido)-2-methyl-[1,1'-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl) piperidine-2-carboxylate was prepared according to Example 1.

[0736] MS m / z (ESI): 833.2 [M+H] + .

[0737] Example 81

[0738] (S)-1-((6-((2-chloro-3'-(7-cyano-5-((3-(fluoromethyl)-3-hydroxyazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4- cyclopropylpyridin-3-yl)methyl)piperidine-2-carboxylic acid

[0739]

[0740] (S)-1-((6-((2-chloro-3'-(7-cyano-5-((3-(fluoromethyl)-3-hydroxyazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4- cyclopropylpyridin-3-yl)methyl)piperidine-2-carboxylic acid was prepared according to Example 1.

[0741] MS m / z (ESI): 763.2 [M+H] + .

[0742] Example 82

[0743] Isopropyl ((6-((2-chloro-3'-(7-cyano-5-((3-(fluoromethyl)-3-hydroxyazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4- cyclopropylpyridin-3-yl)methyl)-L-alaninate

[0744]

[0745] Isopropyl ((6-((2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-cyclopropylpyridin-3-yl)methyl)-L-alaninate was prepared according to Example 1.

[0746] MS m / z (ESI): 765.2 [M+H] + .

[0747] Example 83

[0748] Isopropyl ((6-((2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-cyclopropylpyridin-3-yl)methyl)-L-alaninate

[0749]

[0750] Isopropyl ((6-((2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-cyclopropylpyridin-3-yl)methyl)-L-alaninate was prepared according to Example 1.

[0751] MS m / z (ESI): 735.2 [M+H] + .

[0752] Example 84

[0753] (S)-1-((6-((2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-cyclopropylpyridin-3-yl)methyl)piperidine-2-carboxylic acid

[0754]

[0755] (S)-1-((6-((2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-cyclopropylpyridin-3-yl)methyl)piperidine-2-carboxylic acid was prepared according to Example 1.

[0756] MS m / z (ESI): 733.2 [M+H] + .

[0757] Example 85

[0758] ((6-((2-chloro-3'-(7-cyano-5-((3-fluorooxetan-1-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-cyclopropylpyridin-3-yl)methyl)-L-proline

[0759]

[0760] ((6-((2-chloro-3'-(7-cyano-5-((3-fluorooxetan-1-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-cyclopropylpyridin-3-yl)methyl)-L-proline was prepared according to Reference Example 1.

[0761] MS m / z (ESI): 719.2 [M+H] + .

[0762] Example 86

[0763] N-(2-chloro-3'-(7-cyano-5-((3-fluorooxetan-1-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)-4-cyclopropyl-5-(((1,3-dihydroxypropan-2-yl)amino)methyl)methyl pyridinamide

[0764]

[0765] N-(2-chloro-3'-(7-cyano-5-((3-fluorooxetan-1-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)-4-cyclopropyl-5-(((1,3-dihydroxypropan-2-yl)amino)methyl)methyl pyridinamide was prepared according to Reference Example 1.

[0766] MS m / z (ESI): 695.2 [M+H] + .

[0767] Example 87

[0768] (S)-N-(2-chloro-3'-(7-cyano-5-((3-fluorooxetan-1-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)-4-cyclopropyl-5-(((2-hydroxypropyl)amino)methyl)methyl pyridinamide

[0769]

[0770] (S)-N-(2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)-4-cyclopropyl-5-(((2-hydroxypropyl)amino)methyl)pyridinecarboxamide was prepared according to Example 1.

[0771] MS m / z (ESI): 679.2 [M+H] + .

[0772] Example 88

[0773] (S)-N-(2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)-4-cyclopropyl-5-(((2-hydroxypropyl)amino)methyl)pyridinecarboxamide was prepared according to Example 1.

[0774]

[0775] (S)-N-(2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)-4-cyclopropyl-5-(((2-hydroxypropyl)amino)methyl)pyridinecarboxamide was prepared according to Example 1.

[0776] MS m / z (ESI): 711.2 [M+H] + .

[0777] Example 89

[0778] (S)-N-(2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)-4-cyclopropyl-5-(((2-hydroxypropyl)amino)methyl)pyridinecarboxamide was prepared according to Example 1.

[0779]

[0780] (S)-N-(2-chloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)-4-cyclopropyl-5-(((2-hydroxypropyl)amino)methyl)pyridinecarboxamide was prepared according to Example 1.

[0781] MS m / z (ESI): 709.2 [M+H] + .

[0782] Example 90

[0783] 1 -((6-((2-chloro-3'-(7-cyano-5-((3-fluorooxetan-3-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3-yl)methyl)oxetan-3-yl acetate

[0784]

[0785] 1 -((6-((2-chloro-3'-(7-cyano-5-((3-fluorooxetan-3-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3-yl)methyl)oxetan-3-yl acetate was prepared according to Reference Example 1.

[0786] MS m / z (ESI): 709.2 [M+H] + .

[0787] Example 91

[0788] 1 -((6-((2-chloro-3'-(7-cyano-5-((3-fluorooxetan-3-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3-yl)methyl)oxetan-3-yl isobutyrate

[0789]

[0790] 1 -((6-((2-chloro-3'-(7-cyano-5-((3-fluorooxetan-3-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3-yl)methyl)oxetan-3-yl isobutyrate was prepared according to Reference Example 1.

[0791] MS m / z (ESI): 737.2 [M+H] + .

[0792] Example 92

[0793] 1 -((7-cyano-2-(2,2'-dichloro-3'-(5-((((1R,2S)-2-fluorocyclopropyl)amino)methyl)- 4-methoxymethylpyridinoylamino)-[1,1 '-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl) azetidin-3-yl acetate

[0794]

[0795] 1 -((7-cyano-2-(2,2'-dichloro-3'-(5-((((1R,2S)-2-fluorocyclopropyl)amino)methyl)- 4-methoxymethylpyridinoylamino)-[1,1 '-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl) azetidin-3-yl acetate was prepared according to Example 1.

[0796] MS m / z (ESI): 729.2 [M+H] + .

[0797] Example 93

[0798] 1 -((7-cyano-2-(2,2'-dichloro-3'-(5-((((1R,2S)-2-fluorocyclopropyl)amino)methyl)- 4-methoxymethylpyridinoylamino)-[1,1 '-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl) azetidin-3-yl isobutyrate

[0799]

[0800] 1 -((7-cyano-2-(2,2'-dichloro-3'-(5-((((1R,2S)-2-fluorocyclopropyl)amino)methyl)- 4-methoxymethylpyridinoylamino)-[1,1 '-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl) azetidin-3-yl isobutyrate was prepared according to Example 1.

[0801] MS m / z (ESI): 757.2 [M+H] + .

[0802] Example 94

[0803] (3R,4R)-4-(((2-(2'-chloro-3'-(5-((((1R,2S)-2-fluorocyclopropyl)amino)methyl)-4- methoxymethylpyridinoylamino)-2-methyl-[1,1 '-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol- 5-yl)methyl)amino)tetrahydro-2H-pyran-3-yl acetate

[0804]

[0805] (3R,4R)-4-(((2-(2'-chloro-3'-(5-((((1R,2S)-2-fluorocyclopropyl)amino)methyl)-4- methoxymethylpyridinoyl amino)-2-methyl-[1, 1 '-biphenyl]-3-yl)-7-cyano benzo[d]oxazol-5- yl)methyl)amino)tetrahydro-2H-pyran-3-yl acetate was prepared according to Example 1.

[0806] MS m / z (ESI): 753.2 [M+H] + .

[0807] Example 95

[0808] (3R,4R)-4-(((2-(2'-chloro-3'-(5-((((1R,2S)-2-fluorocyclopropyl)amino)methyl)-4- methoxymethylpyridinoyl amino)-2-methyl-[1, 1 '-biphenyl]-3-yl)-7-cyano benzo[d]oxazol-5- yl)methyl)amino)tetrahydro-2H-pyran-3-yl acetate

[0809]

[0810] (3R,4R)-4-(((2-(2'-chloro-3'-(5-((((1R,2S)-2-fluorocyclopropyl)amino)methyl)-4- methoxymethylpyridinoyl amino)-2-methyl-[1, 1 '-biphenyl]-3-yl)-7-cyano benzo[d]oxazol-5- yl)methyl)amino)tetrahydro-2H-pyran-3-yl acetate was prepared according to Example 1.

[0811] MS m / z (ESI): 741.2 [M+H] + .

[0812] Example 96

[0813] (3R,4R)-4-(((2-(2'-chloro-3'-(4-methoxy-5-((oxetan-3-ylamino)methyl)methylpyridinoyl amino)-2-methyl-[1, 1 '-biphenyl]-3-yl)-7-cyano benzo[d]oxazol-5-yl)methyl)amino)tetrahydro- 2H-pyran-3-yl acetate

[0814]

[0815] (3R,4R)-4-(((2-(2'-chloro-3'-(4-methoxy-5-((oxetan-3-ylamino)methyl)methylpyridinoyl amino)-2-methyl-[1, 1 '-biphenyl]-3-yl)-7-cyano benzo[d]oxazol-5-yl)methyl)amino)tetrahydro- 2H-pyran-3-yl acetate was prepared according to Example 1.

[0816] MS m / z (ESI): 751.2 [M+H] + .

[0817] Example 97

[0818] (S)-N-(2,2'-Dichloro-3'-(7-cyano-5-((3-fluoroazetidin-l-yl)methyl)benzo[d]oxazol-2-yl)- [1,1'-biphenyl]-3-yl)-5-(((2-hydroxypropyl)amino)methyl)-4-methoxymethylpyridineamide

[0819]

[0820] First Step: Preparation of 3-(3-bromo-2-chlorobenzamido)-5-cyano-4- hydroxybenzoic acid methyl ester

[0821]

[0822] Under nitrogen atmosphere, 3-bromo-2-chlorobenzoic acid (16.17 g, 0.069 mol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (35.34 g, 0.094 mol) and N,N-DIPEA (16.3 mL, 0.094 mol) were dissolved in dry N,N-dimethylformamide (150 mL), after stirring at room temperature for 1 hour, 3-amino-4-hydroxy-5-nitrobenzoic acid methyl ester (12 g, 0.062 mol) was added and the reaction was continued at room temperature overnight. After the reaction was completed, the reaction solution was poured into a large amount of ice water, stirred for 30 minutes, the aqueous phase was filtered and the filter cake was concentrated under reduced pressure, then the filter cake was slurried with petroleum ether: ethyl acetate = 4: 1 (400 mL) for 1 hour, the filter cake was filtered and dried to obtain the title compound (18.5 g, 72%).

[0823] MS m / z (ESI): 409.1 [M-H] + .

[0824] Second Step: Preparation of 2-(3-bromo-2-chlorophenyl)-7-cyanobenzo[d]oxazole-5- carboxylic acid methyl ester

[0825]

[0826] Methyl 2-(3-bromo-2-chlorophenyl)-7-cyanobenzo[d]oxazole-5-carboxylate (2 g, 5.11 mmol) and calcium chloride (1.13 g, 10.22 mmol) were suspended in a mixture of tetrahydrofuran (100 mL) and ethanol (50 mL) at room temperature. After stirring for 1 h at room temperature, sodium borohydride (580 mg, 15.32 mmol) was added and the reaction was stirred at 55 °C for 4 h. Upon completion of the reaction, the reaction was quenched with saturated ammonium chloride solution and the reaction was concentrated to precipitate a solid. The solid was filtered and the filtrate was concentrated and slurry in methanol for 1 h. The solid was filtered and dried to give the title compound (1.42 g, 76%).

[0827] Step 3: Preparation of 2-(3-bromo-2-chlorophenyl)-5-(hydroxymethyl)benzo[d]oxazole-7- carbonitrile

[0828]

[0829] Methyl 2-(3-bromo-2-chlorophenyl)-7-cyanobenzo[d]oxazole-5-carboxylate (2 g, 5.11 mmol) and calcium chloride (1.13 g, 10.22 mmol) were suspended in a mixture of tetrahydrofuran (100 mL) and ethanol (50 mL) at room temperature. After stirring for 1 h at room temperature, sodium borohydride (580 mg, 15.32 mmol) was added and the reaction was stirred at 55 °C for 4 h. Upon completion of the reaction, the reaction was quenched with saturated ammonium chloride solution and the reaction was concentrated to precipitate a solid. The solid was filtered and the filtrate was concentrated and slurry in methanol for 1 h. The solid was filtered and dried to give the title compound (1.42 g, 76%).

[0830] MS m / z (ESI): 363.1 [M+H] + .

[0831] Step 4: Preparation of 2-(2-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-5- (hydroxymethyl)benzo[d]oxazole-7-carbonitrile

[0832]

[0833] A mixture of 2-(3-bromo-2-chlorophenyl)-5-(hydroxymethyl)benzo[d]oxazole-7- carbonitrile (1.42 g, 3.92 mmol), bis(pinacolato)diboron (1.2 g, 4.71 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (286 mg, 0.392 mol) and potassium acetate (768 mg, 7.84 mmol) was suspended in dry 1,4-dioxane (40 mL) and heated to 100 °C overnight under nitrogen. The reaction was filtered and the filtrate was passed through a pad of silica gel and then slurried with ethanol for 1 h, filtered and dried to give the title compound (1.2 g, 74%).

[0834] MS m / z (ESI): 411.2 [M+H] + .

[0835] Fifth Step: Preparation of tert-butyl (2,2'-dichloro-3'-(7-cyano-5- hydroxymethylbenzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)carbamate

[0836]

[0837] To a mixture of tert-butyl (3-bromo-2-chlorophenyl)carbamate (4.26 g, 13.94 mmol), 2-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5- (hydroxymethyl)benzo[d]oxazole-7-carbonitrile (5.19 g, 12.66 mmol), bis(dicyclohexylphosphino)ferrocene palladium dichloride (517 mg, 0.633 mmol) and cesium carbonate (8.23 g, 25.32 mmol) was added to a mixture of tert-butanol (100 mL) and water (10 mL) and the reaction was heated to 90 °C for 9 h under nitrogen. The solvent was removed by concentration under reduced pressure and the residue was taken up in ethyl acetate and washed sequentially with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel to give the title compound (3.68 g, 57%).

[0838] MS m / z (ESI): 510.1 [M+H] + .

[0839] Sixth Step: Preparation of 2-(3'-amino-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-5- ((3-fluoroazetidin-1-yl)methyl)benzo[d]oxazole-7-carbonitrile

[0840]

[0841] To a solution of tert-butyl (2,2'-dichloro-3'-(7-cyano-5- hydroxymethylbenzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)carbamate (1.38 g, 2.7 mmol) in dichloromethane (50 mL) was added DMP (1.72 g, 4.1 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was filtered and concentrated. The residue was re-dispersed in 1,2-dichloroethane (100 mL). 3- fluorocyclobutylamine hydrochloride (453 mg, 4.1 mmol) and DIPEA (0.67 mL, 4.1 mmol) were added. The reaction mixture was heated to 50 °C and stirred for 2 h. Sodium borohydride acetate (2.87 g, 13.52 mmol) was added. The reaction mixture was stirred at 50 °C for 30 min. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution successively. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in dichloromethane (20 mL). Trifluoroacetic acid (10 mL) was added. The reaction mixture was stirred at room temperature for 30 min. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium carbonate solution and saturated aqueous sodium chloride solution successively. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel to give the title compound (728 mg, 58%).

[0842] MS m / z (ESI): 467.1 [M+H] + .

[0843] Step 7: Preparation of N-(2,2'-dichloro-3'-(7-cyano-5-((3-fluoroazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)-4-methoxy-5-vinylmethylpyridinamide

[0844]

[0845] Methyl 4-methoxy-5-vinylmethylpyridine-1-carboxylate (454 mg, 2.34 mmol) and 2-(3'-amino-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-5-((3-fluoroazetidin-1-yl)methyl)benzo[d]oxazole-7-carbonitrile (728 mg, 1.56 mmol) were dispersed in dry toluene (25 mL). The reaction system was protected with dry nitrogen. LiHMDS (6.93 mL, 0.9 mmol / L, 6.24 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 19 h. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution and saturated aqueous sodium bicarbonate solution successively. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel to give the title compound (140 mg, 14%).

[0846] MS m / z (ESI): 628.1 [M+H] + .

[0847] Step 8: Preparation of N-(2,2'-dichloro-3'-(7-cyano-5-((3-fluoroazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)-5-formyl-4-methoxymethylpyridinamide

[0848]

[0849] N-(2,2'-dichloro-3'-(7-cyano-5-((3-fluoroazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)-4-methoxy-5-vinylmethylpyridinamide (140 mg, 0.223 mmol) was dispersed in a mixed solvent of dioxane (20 mL) and water (8 mL), and potassium osmate dihydrate (8.2 mg, 0.0223 mmol) and sodium periodate (239 mg, 1.12 mmol) were added successively with stirring at room temperature. The reaction solution was stirred at room temperature for 1 hour, and the organic solvent was removed by concentration under reduced pressure. The residue was extracted with ethyl acetate, and the organic phase was washed successively with saturated aqueous sodium thiosulfate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by silica gel column chromatography to obtain the title compound (140 mg, 100%).

[0850] MS m / z (ESI): 630.1 [M+H] + .

[0851] Step 9: Preparation of (S)-N-(2,2'-dichloro-3'-(7-cyano-5-((3-fluoroazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxypropyl)amino)methyl)-4-methoxymethylpyridinamide

[0852]

[0853] N-(2,2'-dichloro-3'-(7-cyano-5-((3-fluorooxetan-3-yl)methyl)benzo[d]oxazol-2-yl)- [1,1'-biphenyl]-3-yl)-5-(((1,3-dihydroxypropan-2-yl)amino)methyl)-4- methoxymethylpyridineamide

[0854] MS m / z (ESI): 689.2 [M+H] + .

[0855] Example 98

[0856] N-(2,2'-dichloro-3'-(7-cyano-5-((3-fluorooxetan-3-yl)methyl)benzo[d]oxazol-2-yl)- [1,1'-biphenyl]-3-yl)-5-(((1,3-dihydroxypropan-2-yl)amino)methyl)-4- methoxymethylpyridineamide

[0857]

[0858] N-(2,2'-dichloro-3'-(7-cyano-5-((3-fluorooxetan-3-yl)methyl)benzo[d]oxazol-2-yl)- [1,1'-biphenyl]-3-yl)-5-(((1,3-dihydroxypropan-2-yl)amino)methyl)-4- methoxymethylpyridineamide

[0859] MS m / z (ESI): 705.2 [M+H] + .

[0860] Example 99

[0861] N-(2,2'-dichloro-3'-(7-cyano-5-((3-fluoroazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)- [1,1'-biphenyl]-3-yl)-5-((3-hydroxyazetidin-1-yl)methyl)-4-methoxymethylpyridinecarboxamide

[0862]

[0863] N-(2,2'-dichloro-3'-(7-cyano-5-((3-fluoroazetidin-1-yl)methyl)benzo[d]oxazol-2-yl)- [1,1'-biphenyl]-3-yl)-5-((3-hydroxyazetidin-1-yl)methyl)-4-methoxymethylpyridinecarboxamide was prepared according to Reference Example 1.

[0864] MS m / z (ESI): 687.2 [M+H] + .

[0865] Example 100

[0866] N-(2,2'-dichloro-3'-(7-cyano-5-((((3R,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)methyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)-4- methoxymethylpyridinecarboxamide

[0867]

[0868] N-(2,2'-dichloro-3'-(7-cyano-5-((((3R,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)methyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)-4- methoxymethylpyridinecarboxamide was prepared according to Reference Example 1.

[0869] MS m / z (ESI): 719.2 [M+H] + .

[0870] Example 101

[0871] N-(2,2'-dichloro-3'-(7-cyano-5-((((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)-5-((((1R,2S)-2-fluorocyclopropyl)amino)methyl)-4- methoxymethylpyridinecarboxamide

[0872]

[0873] N-(2,2'-dichloro-3'-(7-cyano-5-((((3R,4R)-3-hydroxytetrahydro-2H-pyran-4- yl)amino)methyl)benzo[d]oxazol-2-yl)-[1,1 '-biphenyl]-3-yl)-5-((((1 R,2S)-2- fluorocyclopropyl)amino)methyl)-4-methoxymethylpyridineamide was prepared according to Example 1.

[0874] MS m / z (ESI): 731.2 [M+H] + .

[0875] Example 102

[0876] (S)-N-(2,2'-dichloro-3'-(7-cyano-5-(((3-fluoro-2-methylpyridin-4-yl)amino)methyl)benzo[d]oxazol-2-yl)-[1,1 '-biphenyl]-3-yl)-5-(((2-hydroxypropyl)amino)methyl)-4- methoxymethylpyridineamide

[0877]

[0878] (S)-N-(2,2'-dichloro-3'-(7-cyano-5-(((3-fluoro-2-methylpyridin-4-yl)amino)methyl)benzo[d]oxazol-2-yl)-[1,1 '-biphenyl]-3-yl)-5-(((2-hydroxypropyl)amino)methyl)-4- methoxymethylpyridineamide was prepared according to Example 1.

[0879] MS m / z (ESI): 740.2 [M+H] + .

[0880] Example 103

[0881] (S)-1-((6-((2,2'-dichloro-3'-(5-((3-fluoroazetidin-1-yl)methyl)-6-methoxypyridin-2-yl)- [1,1 '-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)piperidine-2-carboxylic acid

[0882]

[0883] First step: Preparation of (3-bromo-2-chlorophenyl)boronic acid

[0884]

[0885] 1,3-Dibromo-2-chlorobenzene (2.7 g, 10 mmol) and triisopropyl borate (2.3 g, 12 mmol) were added to a mixture of tetrahydrofuran (7 mL) and toluene (28 mL) under nitrogen protection. 1.6 M n-butyllithium in hexane (7.5 mL, 12 mmol) was added dropwise at -78 °C. The reaction mixture was stirred at this temperature for 2 h, then gradually warmed to room temperature and stirred for another 2 h. The reaction was quenched with 2 M hydrochloric acid solution and stirred at room temperature for 30 min. The mixture was extracted with ethyl acetate and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound as a crude product which was used directly in the next step.

[0886] Second Step: Preparation of 6-(3-bromo-2-chlorophenyl)-2-methoxynicotinaldehyde

[0887]

[0888] 6-Chloro-2-methoxynicotinaldehyde (400 mg, 2.34 mmol), (3-bromo-2-chlorophenyl)boronic acid (600 mg, 2.57 mmol), Pd(PPh3)4(266 mg, 0.23 mmol) and potassium carbonate (646 mg, 4.68 mmol) were dissolved in a mixture of dioxane (20 mL) and water (2 mL) under nitrogen protection. The reaction mixture was heated to 95 °C and stirred overnight. After the reaction was completed, the reaction mixture was cooled, filtered and concentrated. The residue was separated by flash silica gel column chromatography (PE:EA = 4:1) to give the title compound (600 mg, 78%).

[0889] MS m / z (ESI): 326.7 [M+H] + .

[0890] Third Step: Preparation of 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)aniline

[0891]

[0892] 3-Bromo-2-chloroaniline (6.21 g, 30.1 mmol), pinacol diboronic acid (8.04 g, 31.7 mmol), Pd(dppf)Cl2(1.10 g, 1.51 mmol) and AcOK (8.85 g, 90.3 mmol) were added to dioxane (80 mL) under nitrogen protection. The reaction mixture was heated to 100 °C and stirred for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography to give the title compound as a brown solid (7.26 g, 95%).

[0893] MS m / z (ESI): 254.1 [M+H]+ .

[0894] Step 4: Preparation of 6-(3'-amino-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-2- methoxynicotinaldehyde

[0895]

[0896] To a mixture of 6-(3-bromo-2-chlorophenyl)-2-methoxynicotinaldehyde (1 g, 3.05 mmol), 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (925 mg, 3.66 mol), Pd(dppf)Cl2DCM complex (378 mg, 0.46 mmol) and cesium carbonate (1.98 g, 6.1 mmol) in dioxane (20 mL) and water (3 mL) was purged with nitrogen and stirred at 95 °C overnight. After the reaction was completed, the reaction was cooled and concentrated. The residue was separated by flash silica gel column chromatography (PE:EA = 4:1) to give the title compound (710 mg, 62%).

[0897] MS m / z (ESI): 373.3 [M+H] + .

[0898] Step 5: Preparation of 2,2'-dichloro-3'-(5-((3-fluoroazetidin-1-yl)methyl)-6- methoxypyridin-2-yl)-[1,1'-biphenyl]-3-amine

[0899]

[0900] To a mixture of 6-(3'-amino-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde (710 mg, 1.9 mmol) and 3-fluoroazetidine hydrochloride (632 mg, 5.7 mmol) in methanol (10 mL) was added DIPEA to neutralize, and then 5 drops of acetic acid was added, and stirred at room temperature for 2 hours. After the addition of sodium cyanoborohydride (353 mg, 5.7 mmol), it was continuously stirred at room temperature overnight. After the reaction was completed, the reaction was cooled and concentrated. The residue was separated by flash silica gel column chromatography (PE:EA = 3:1) to give the title compound (530 mg, 65%).

[0901] MS m / z (ESI): 432.4 [M+H] + .

[0902] Step 6: Preparation of N-(2,2'-dichloro-3'-(5-((3-fluoroazetidin-l-yl)methyl)-6- methoxypyridin-2-yl)-[l,l'-biphenyl]-3-yl)-4-methoxy-5-vinylmethylpyridine amide

[0903]

[0904] N-(2,2'-dichloro-3'-(5-((3-fluoroazetidin-l-yl)methyl)-6-methoxypyridin-2-yl)- [l,l'-biphenyl]-3-yl)-4-methoxy-5-vinylmethylpyridine amide (380 mg, 0.642 mmol) was dissolved in a mixture solvent of dioxane (10 mL) and water (4 mL), and potassium osmate (26 mg, 0.07 mmol) and sodium periodate (684 mg, 3.21 mmol) were added at room temperature. The reaction solution was stirred at room temperature for one hour, quenched with saturated aqueous sodium bisulfite solution, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (350 mg, 92%).

[0905] MS m / z (ESI): 593.1 [M+H] + .

[0906] Step 7: Preparation of N-(2,2'-dichloro-3'-(5-((3-fluoroazetidin-l-yl)methyl)-6- methoxypyridin-2-yl)-[l,l'-biphenyl]-3-yl)-5-formyl-4-methoxymethylpyridine amide

[0907]

[0908] N-(2,2'-dichloro-3'-(5-((3-fluoroazetidin-l-yl)methyl)-6-methoxypyridin-2-yl)- [l,l'-biphenyl]-3-yl)-4-methoxy-5-vinylmethylpyridine amide (380 mg, 0.642 mmol) was dissolved in a mixture solvent of dioxane (10 mL) and water (4 mL), and potassium osmate (26 mg, 0.07 mmol) and sodium periodate (684 mg, 3.21 mmol) were added at room temperature. The reaction solution was stirred at room temperature for one hour, quenched with saturated aqueous sodium bisulfite solution, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (350 mg, 92%).

[0909] MS m / z (ESI): 595.1 [M+H] + .

[0910] Eighth Step: Preparation of (S)-1-((6-((2,2'-dichloro-3'-(5-((3-fluoroazetidin-1-yl)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)piperidine-2-carboxylic acid

[0911]

[0912] N-(2,2'-dichloro-3'-(5-((3-fluoroazetidin-1-yl)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-5-formyl-4-methoxymethylpyridine amide (100 mg, 0.168 mmol) and (S)-piperidine-2-carboxylic acid (33 mg, 0.253 mmol) were dissolved in a mixed solvent of methanol (2 mL) and DMF (2 mL), 2 drops of acetic acid were added, and stirring was performed at room temperature for 3 hours. After sodium cyanoborohydride (31 mg, 0.504 mmol) was added, stirring was continued overnight at room temperature. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by prep-HPLC to obtain the title compound (17.3 mg, 15%).

[0913] MS m / z (ESI): 708.3 [M+H] + .

[0914] Example 104

[0915] ((6-((2,2'-dichloro-3'-(5-((3-fluoroazetidin-1-yl)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)-L-proline

[0916]

[0917] ((6-((2,2'-dichloro-3'-(5-((3-fluoroazetidin-1-yl)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)-L-proline was prepared according to Example 103.

[0918] MS m / z (ESI): 694.2 [M+H] + .

[0919] Example 105

[0920] (Iso-butoxy)methyl (S)-1-((6-((2,2'-dichloro-3'-(5-((3-fluoroazetidin-1-yl)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)piperidine-2-carboxylate

[0921]

[0922] (Iso-butoxy)methyl (S)-1-((6-((2,2'-dichloro-3'-(5-((3-fluoroazetidin-1-yl)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)piperidine-2-carboxylate was prepared according to Reference Example 103.

[0923] MS m / z (ESI): 808.2 [M+H] + .

[0924] Example 106

[0925] Iso-propyl ((6-((2,2'-dichloro-3'-(5-((3-fluoroazetidin-1-yl)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)-L-alaninate

[0926]

[0927] Iso-propyl ((6-((2,2'-dichloro-3'-(5-((3-fluoroazetidin-1-yl)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)-L-alaninate was prepared according to Reference Example 103.

[0928] MS m / z (ESI): 710.2 [M+H] + .

[0929] Example 107

[0930] (S)-N-(2,2'-dichloro-3'-(5-((3-fluoroazetidin-1-yl)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxypropyl)amino)methyl)-4-methoxymethylpyridinecarboxamide

[0931]

[0932] The preparation of (S)-N-(2,2'-dichloro-3'-(5-((3-fluoroazetidin-l-yl)methyl)-6- methoxypyridin-2-yl)-[l,l'-biphenyl]-3-yl)-5-(((2-hydroxypropyl)amino)methyl)-4- methoxymethylpyridineamide was performed according to Example 103.

[0933] MS m / z (ESI): 654.2 [M+H] + .

[0934] Example 108

[0935] N-(2,2'-dichloro-3'-(5-((3-fluoroazetidin-l-yl)methyl)-6-methoxypyridin-2-yl)-[l,l'- biphenyl]-3-yl)-5-(((l,3-dihydroxypropan-2-yl)amino)methyl)-4-methoxymethylpyridineamide

[0936]

[0937] First Step: Preparation of 2,2'-dichloro-3'-(5-((3-fluoroazetidin-l-yl)methyl)-6- methoxypyridin-2-yl)-[l,l'-biphenyl]-3-amine

[0938]

[0939] 6-(3'-amino-2,2'-dichloro-[l,l'-biphenyl]-3-yl)-2-methoxynicotinaldehyde (710 mg, 1.90 mmol) and 3-fluoroazetidine hydrochloride (632 mg, 5.7 mmol) were dissolved in methanol (10 mL), neutralized with DIPEA, and 5 drops of acetic acid were added, and stirred at room temperature for 2 hours. After the addition of sodium cyanoborohydride (353 mg, 5.70 mmol), stirring was continued overnight at room temperature. After the reaction was completed, the reaction solution was concentrated. The residue was separated by flash silica gel column chromatography (PE:EA = 3: 1) to obtain the title compound (530 mg, 86%).

[0940] MS m / z (ESI): 432.3 [M+H] + .

[0941] Second Step: Preparation of N-(2,2'-dichloro-3'-(5-((3-fluoroazetidin-l-yl)methyl)-6- methoxypyridin-2-yl)-[l,l'-biphenyl]-3-yl)-4-methoxy-5-vinylmethylpyridineamide

[0942]

[0943] Dissolve 2,2'-dichloro-3'-(5-((3-fluoroazetidin-l-yl)methyl)-6-methoxypyridin-2-yl)- [1,1'-biphenyl]-3-amine (300 mg, 0.693 mmol) and methyl 4-methoxy-5-vinylmethylpyridine- carboxylate (174 mg, 0.900 mmol) in tetrahydrofuran (10 mL) and add 1.3 M LiHMDS in tetrahydrofuran (2.1 mL, 2.77 mmol) at room temperature. Stir the reaction at room temperature overnight. Quench the reaction with methanol, concentrate and separate the residue by flash column chromatography on silica gel (DCM:MeOH = 10:1) to give the title compound (380 mg, 93%).

[0944] MS m / z (ESI): 593.3 [M+H] + .

[0945] Step 3: Preparation of N-(2,2'-dichloro-3'-(5-((3-fluoroazetidin-l-yl)methyl)-6- methoxypyridin-2-yl)-[l,l'-biphenyl]-3-yl)-5-formyl-4-methoxymethylpyridinamide

[0946]

[0947] Dissolve N-(2,2'-dichloro-3'-(5-((3-fluoroazetidin-l-yl)methyl)-6-methoxypyridin-2-yl)- [1,1'-biphenyl]-3-yl)-4-methoxy-5-vinylmethylpyridinamide (380 mg, 0.642 mmol) in a mixture of dioxane (10 mL) and water (4 mL) and add potassium osmate (26 mg, 0.07 mmol) and sodium periodate (684 mg, 3.21 mmol) sequentially at room temperature. Stir the reaction at room temperature for 1 h, then quench with saturated aqueous sodium sulfite. Extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate the filtrate to give the title compound (350 mg, 92%).

[0948] MS m / z (ESI): 595.4 [M+H] + .

[0949] Step 4: Preparation of N-(2,2'-dichloro-3'-(5-((3-fluoroazetidin-l-yl)methyl)-6- methoxypyridin-2-yl)-[l,l'-biphenyl]-3-yl)-5-(((l,3-dihydroxypropan-2-yl)amino)methyl)- 4-methoxymethylpyridinamide

[0950]

[0951] N-(2,2'-dichloro-3'-(5-((3-fluoroazetidin-l-yl)methyl)-6-methoxypyridin-2-yl)- [1,1'-biphenyl]-3-yl)-5-formyl-4-methoxymethylpyridine amide (80 mg, 0.135 mmol) and 2-aminopropane-l,3-diol (37 mg, 0.404 mmol) were dissolved in methanol (5 mL), 3 drops of acetic acid were added and stirred at room temperature for 2 hours. After the addition of sodium cyanoborohydride (25 mg, 0.404 mmol), stirring was continued overnight at room temperature. After the reaction was complete, the reaction was concentrated and the residue was purified by reverse phase column chromatography to give the title compound (6.0 mg, 7%).

[0952] MS m / z (ESI): 670.2 [M+H] + .

[0953] Example 109

[0954] (S)-l-((6-((3'-(5-((6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-6-methoxypyridin-2- yl)-2,2'-dichloro-[l,r-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)piperidine- 2-carboxylic acid

[0955]

[0956] First Step: Preparation of N-(3-bromo-2-chlorophenyl)-4-methoxy-5-vinylmethylpyridine amide

[0957]

[0958] Methyl 4-methoxy-5-vinylmethylpyridine carboxylate (3.88 g, 20 mmol) and 3-bromo-2-chloroaniline (4.12 g, 20 mmol) were dissolved in dry tetrahydrofuran (20 mL), the reaction system was protected with dry nitrogen, potassium tert-butoxide tetrahydrofuran solution (1 M / L, 50 mmol, 50 mL) was added under stirring, the reaction was stirred at room temperature for 2 hours, the solvent was removed by reduced pressure concentration, the residue was dispersed in water, ultrasonic, filtered, the filter residue was collected and dried under reduced pressure to give the title compound (6.63 g, 90%).

[0959] MS m / z (ESI): 367.0 [M+H] + .

[0960] Second Step: Preparation of N-(3-bromo-2-chlorophenyl)-5-(hydroxymethyl)-4- methoxymethylpyridine amide

[0961]

[0962] N-(3-bromo-2-chlorophenyl)-4-methoxy-5-vinylmethylpyridinamide (6.63 g, 18.03 mmol) was dissolved in a mixture of dioxane (600 mL) and water (200 mL) and stirred at room temperature. Potassium osmate dihydrate (133 mg, 0.36 mmol) and sodium periodate (19.3 g, 90.17 mmol) were added sequentially and the reaction was stirred at room temperature for 2 hours. The solvent was removed by concentration under reduced pressure and the residue was dissolved in water. Saturated aqueous sodium thiosulfate was added and the mixture was stirred at room temperature for 30 minutes. The mixture was filtered and the filter cake was washed with saturated aqueous sodium thiosulfate, saturated aqueous sodium chloride, and water. The filter cake was collected and dried under reduced pressure. The crude product was dissolved in a mixture of tetrahydrofuran (200 mL) and methanol (100 mL) and cooled to 0 °C in an ice water bath. Sodium borohydride (685 mg, 18.03 mmol) was added and the reaction was stirred at 0 °C for 2 hours. The solvent was removed by concentration under reduced pressure and the residue was slurried in water. The mixture was filtered and the filter cake was dried under reduced pressure. The crude product was purified by column chromatography on silica gel to give the title compound (6.6 g, 98%).

[0963] MS m / z (ESI): 371.0 [M+H] + .

[0964] Step 3: Preparation of N-(2,2'-dichloro-3'-(5-formyl-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-5-(hydroxymethyl)-4-methoxymethylpyridinamide

[0965]

[0966] N-(3-bromo-2-chlorophenyl)-5-(hydroxymethyl)-4-methoxymethylpyridinamide (210 mg, 0.566 mmol), 6-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methoxynicotinaldehyde (254 mg, 0.679 mol), Pd(dppf)Cl2DCM complex (50 mg, 0.06 mmol), and cesium carbonate (460 mg, 1.42 mmol) were dissolved in a mixture of dioxane (10 mL) and water (1 mL) and stirred at 95 °C under a nitrogen atmosphere overnight. After the reaction was complete, the reaction was cooled and concentrated. The residue was purified by column chromatography on silica gel (PE:EA = 3:2) to give the title compound (200 mg, 66%).

[0967] MS m / z (ESI): 538.3 [M+H] + .

[0968] Step 4: Preparation of N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-6- methoxypyridin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-5-(hydroxymethyl)-4- methoxymethylpyridinamide

[0969]

[0970] N-(2,2'-dichloro-3'-(5-formyl-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-5- (hydroxymethyl)-4-methoxymethylpyridinamide (200 mg, 0.372 mmol) and 1-(2,6- diazaspiro[3.3]heptan-2-yl)ethan-1-one trifluoroacetate (716 mg, 1.48 mmol) were dissolved in methanol (10 mL), after neutralization with DIPEA, 8 drops of acetic acid were added, and stirred at room temperature for 5 hours. After the addition of sodium cyanoborohydride (70 mg, 1.12 mmol), it was continuously stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated, and the residue was separated by flash silica gel column chromatography (DCM:MeOH = 10:1) to obtain the title compound (180 mg, 73%).

[0971] MS m / z (ESI): 662.8 [M+H] + .

[0972] Step 5: Preparation of N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-6- methoxypyridin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-5-formyl-4-methoxymethylpyridinamide

[0973]

[0974] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-6-methoxypyridin-2-yl)- 2,2'-dichloro-[1,1'-biphenyl]-3-yl)-5-(hydroxymethyl)-4-methoxymethylpyridinamide (180 mg, 0.271 mmol) was dissolved in dichloromethane (10 mL), and sodium bicarbonate (227 mg, 2.71 mmol) and DMP (173 mg, 0.407 mmol) were sequentially added at room temperature. The resulting reaction solution was stirred at room temperature for 2 hours. After diluting the reaction solution with dichloromethane, the organic phase was sequentially washed with saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the title compound (140 mg, 78%).

[0975] MS m / z (ESI): 660.7 [M+H] + .

[0976] Step 6: Preparation of (S)-1-((6-((3'-(5-((6-acetyl-2,6-diazaspiro[3.3]heptan-2- yl)methyl)-6-methoxypyridin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)-4- methoxypyridin-3-yl)methyl)piperidine-2-carboxylic acid

[0977]

[0978] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-6-methoxypyridin-2-yl)- 2,2'-dichloro-[1,1'-biphenyl]-3-yl)-5-formyl-4-methoxymethylpyridine amide (66 mg, 0.10 mmol) and (S)-piperidine-2-carboxylic acid (38.7 mg, 0.3 mmol) were dissolved in a mixed solvent of methanol (2.4 mL) and DMF (2.4 mL), after adding 2 drops of acetic acid, stirred at room temperature for 4 hours. After adding sodium cyanoborohydride (18 mg, 0.03 mmol), continue to stir overnight at room temperature. After the reaction was complete, the reaction was concentrated, and the residue was subjected to prep-HPLC to obtain the title compound (6.6 mg, 9%).

[0979] MS m / z (ESI): 773.2 [M+H] + .

[0980] Example 110

[0981] ((6-((3'-(5-((6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-6-methoxypyridin-2-yl)- 2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)-L-proline

[0982]

[0983] ((6-((3'-(5-((6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-6-methoxypyridin-2-yl)- 2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)-L-proline was prepared according to Example 103.

[0984] MS m / z (ESI): 759.2 [M+H] + . MS m / z (ESI): 759.2 [M+H]

[0985] Example 111

[0986] (tert-butoxy)methyl (S)-1-((6-((3'-(5-((6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-6- methoxypyridin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3- yl)methyl)piperidin-2-one

[0987]

[0988] (tert-butoxy)methyl (S)-1-((6-((3'-(5-((6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-6- methoxypyridin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3- yl)methyl)piperidin-2-one was prepared according to Example 103.

[0989] MS m / z (ESI): 873.2 [M+H] + .

[0990] Example 112

[0991] Isopropyl ((6-((3'-(5-((6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-6-methoxypyridin-2- yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3-yl)methyl)-L-alaninate

[0992]

[0993] Isopropyl ((6-((3'-(5-((6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-6-methoxypyridin-2- yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3-yl)methyl)-L-alaninate was prepared according to Example 103.

[0994] MS m / z (ESI): 775.2 [M+H] + .

[0995] Example 113

[0996] (S)-N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy pyridin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxypropyl)amino)methyl)-4- methoxymethylpyridine amide

[0997]

[0998] (S)-N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy pyridin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxypropyl)amino)methyl)-4- methoxymethylpyridine amide was prepared according to Reference Example 103.

[0999] MS m / z (ESI): 719.2 [M+H] + .

[1000] Example 114

[1001] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy pyridin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-5-(((1,3-dihydroxypropan-2-yl)amino)methyl)-4- methoxymethylpyridine amide

[1002]

[1003] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy pyridin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxypropyl)amino)methyl)-4- methoxymethylpyridine amide (70 mg, 0.106 mmol) and 2-aminopropane-1,3-diol (30 mg, 0.318 mmol) were dissolved in methanol (7 mL), 3 drops of acetic acid were added and stirred at room temperature for 3 hours. After the addition of sodium cyanoborohydride (20 mg, 0.318 mmol), stirring was continued at room temperature overnight. After the completion of the reaction, the reaction was concentrated and the residue was purified by reverse phase column chromatography to give the title compound (0.8 mg, 1%).

[1004] MS m / z (ESI): 735.2 [M+H] + .

[1005] Example 115

[1006] (S)-1-((6-((2,2'-dichloro-3'-(5-((3-(fluoromethyl)-3-hydroxyazetidin-1-yl)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)piperidine-2-carboxylic acid

[1007]

[1008] (S)-1-((6-((2,2'-dichloro-3'-(5-((3-(fluoromethyl)-3-hydroxyazetidin-1-yl)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)piperidine-2-carboxylic acid was prepared according to Reference Example 103.

[1009] MS m / z (ESI): 738.2 [M+H] + .

[1010] Example 116

[1011] ((6-((2,2'-dichloro-3'-(5-((3-(fluoromethyl)-3-hydroxyazetidin-1-yl)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)-L-proline

[1012]

[1013] ((6-((2,2'-dichloro-3'-(5-((3-(fluoromethyl)-3-hydroxyazetidin-1-yl)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)-L-proline was prepared according to Reference Example 103.

[1014] MS m / z (ESI): 724.2 [M+H] + .

[1015] Example 117

[1016] isopropyl ((6-((2,2'-dichloro-3'-(5-((3-(fluoromethyl)-3-hydroxyazetidin-1-yl)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)-L-alaninate

[1017]

[1018] Preparation of (S)-N-(2,2'-dichloro-3'-(5-((3-(fluoromethyl)-3- hydroxyazetidin-1-yl)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-5-(((2- hydroxypropyl)amino)methyl)-4-methoxymethylpyridineamide refers to Example 103.

[1019] MS m / z (ESI): 740.2 [M+H] + .

[1020] Example 118

[1021] (S)-N-(2,2'-dichloro-3'-(5-((3-(fluoromethyl)-3- hydroxyazetidin-1-yl)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-5-(((2- hydroxypropyl)amino)methyl)-4-methoxymethylpyridineamide

[1022]

[1023] (S)-N-(2,2'-dichloro-3'-(5-((3-(fluoromethyl)-3- hydroxyazetidin-1-yl)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-5-(((2- hydroxypropyl)amino)methyl)-4-methoxymethylpyridineamide refers to Example 103.

[1024] MS m / z (ESI): 684.2 [M+H] + .

[1025] Example 119

[1026] N-(2,2'-dichloro-3'-(5-((3-(fluoromethyl)-3- hydroxyazetidin-1-yl)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-5-(((2- fluoroehtyl)amino)methyl)-4-methoxymethylpyridineamide

[1027]

[1028] N-(2,2'-dichloro-3'-(5-((3-(fluoromethyl)-3- hydroxyazetidin-1-yl)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-5-(((2- fluoroehtyl)amino)methyl)-4-methoxymethylpyridineamide refers to Example 103.

[1029] MS m / z (ESI): 672.2 [M+H] + .

[1030] Example 120

[1031] N-(2,2'-dichloro-3'-(5-((3-(fluoromethyl)-3-hydroxyazetidin-l-yl)methyl)-6- methoxypyridin-2-yl)-[l,l'-biphenyl]-3-yl)-5-((((lR,2S)-2-fluorocyclopropyl)amino)methyl)- 4-methoxymethylpyridinecarboxamide

[1032]

[1033] The preparation of N-(2,2'-dichloro-3'-(5-((3-(fluoromethyl)-3-hydroxyazetidin-l- yl)methyl)-6-methoxypyridin-2-yl)-[l,l'-biphenyl]-3-yl)-5-((((lR,2S)-2- fluorocyclopropyl)amino)methyl)-4-methoxymethylpyridinecarboxamide refers to Example 103.

[1034] MS m / z (ESI): 684.2 [M+H] + .

[1035] Example 121

[1036] ((6-(2,2'-dichloro-3'-(4-methoxy-5-((oxetan-3-ylamino)methyl)methylpyridinecarboxamido)- [l,l'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-L-proline

[1037]

[1038] The preparation of ((6-(2,2'-dichloro-3'-(4-methoxy-5-((oxetan-3-ylamino)methyl)methylpyridinecarboxamido)-[l,l'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-L-proline refers to Example 103.

[1039] MS m / z (ESI): 692.2 [M+H] + .

[1040] Example 122

[1041] (S)-l-((6-(2,2'-dichloro-3'-(4-methoxy-5-((oxetan-3-ylamino)methyl)methylpyridinecarboxamido)- [l,l'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)piperidine-2-carboxylic acid

[1042]

[1043] The preparation of (S)-1-((6-(2,2'-dichloro-3'-(4-methoxy-5-((oxetan-3- ylamino)methyl)pyridinoylamino)-[1, 1 '-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl) piperidine-2-carboxylic acid is described in Reference Example 103.

[1044] MS m / z (ESI): 706.2 [M+H] + .

[1045] Example 123

[1046] N-(2,2'-dichloro-3'-(6-methoxy-5-((oxetan-3-ylamino)methyl)pyridin-2-yl)- [1, 1 '-biphenyl]-3-yl)-4-methoxy-5-((oxetan-3-ylamino)methyl)pyridinecarboxamide

[1047]

[1048] The preparation of N-(2,2'-dichloro-3'-(6-methoxy-5-((oxetan-3- ylamino)methyl)pyridin-2-yl)-[1, 1 '-biphenyl]-3-yl)-4-methoxy-5-((oxetan-3- ylamino)methyl)pyridinecarboxamide is described in Reference Example 103.

[1049] MS m / z (ESI): 650.2 [M+H] + .

[1050] Example 124

[1051] N-(2,2'-dichloro-3'-(5-(((1,3-dihydroxypropan-2-yl)amino)methyl)-6- methoxypyridin-2-yl)-[1, 1 '-biphenyl]-3-yl)-4-methoxy-5-((oxetan-3- ylamino)methyl)pyridinecarboxamide

[1052]

[1053] The preparation of N-(2,2'-dichloro-3'-(5-(((1,3-dihydroxypropan-2-yl)amino)methyl)-6- methoxypyridin-2-yl)-[1, 1 '-biphenyl]-3-yl)-4-methoxy-5-((oxetan-3- ylamino)methyl)pyridinecarboxamide is described in Reference Example 103.

[1054] MS m / z (ESI): 668.2 [M+H] + .

[1055] Example 125

[1056] (S)-N-(2,2'-dichloro-3'-(5-(((2-hydroxypropyl)amino)methyl)-6-methoxy pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-4-methoxy-5-((oxetan-3-ylamino)methyl)methyl pyridine amide

[1057]

[1058] (S)-N-(2,2'-dichloro-3'-(5-(((2-hydroxypropyl)amino)methyl)-6-methoxy pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-4-methoxy-5-((oxetan-3-ylamino)methyl)methyl pyridine amide was prepared according to Reference Example 103.

[1059] MS m / z (ESI): 652.2 [M+H] + .

[1060] Example 126

[1061] N-(2,2'-dichloro-3'-(5-((((S)-2-hydroxypropyl)amino)methyl)-6-methoxy pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-5-((((S)-2-hydroxypropyl)amino)methyl)-4-methoxymethyl pyridine amide

[1062]

[1063] N-(2,2'-dichloro-3'-(5-((((S)-2-hydroxypropyl)amino)methyl)-6-methoxy pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-5-((((S)-2-hydroxypropyl)amino)methyl)-4-methoxymethyl pyridine amide was prepared according to Reference Example 103.

[1064] MS m / z (ESI): 654.2 [M+H] + .

[1065] Example 127

[1066] N-(2,2'-dichloro-3'-(5-((((S)-2-hydroxypropyl)amino)methyl)-6-methoxy pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-5-((((1R,2S)-2-fluorocyclopropyl)amino)methyl)-4-methoxymethyl pyridine amide

[1067]

[1068] N-(2,2'-dichloro-3'-(5-((((S)-2-hydroxypropyl)amino)methyl)-6- methoxypyridin-2-yl)-[1,1 '-biphenyl]-3-yl)-5-((((1R,2S)-2-fluorocyclopropyl)amino)methyl)- 4-methoxymethylpyridineamide was prepared according to Example 103.

[1069] MS m / z (ESI): 654.2 [M+H] + .

[1070] Example 128

[1071] N-(2,2'-dichloro-3'-(5-((((S)-2-hydroxypropyl)amino)methyl)-6- methoxypyridin-2-yl)-[1,1 '-biphenyl]-3-yl)-5-((((1R,2S)-2-fluorocyclopropyl)amino)methyl)- 4-methoxymethylpyridineamide

[1072]

[1073] N-(2,2'-dichloro-3'-(5-((((S)-2-hydroxypropyl)amino)methyl)-6- methoxypyridin-2-yl)-[1,1 '-biphenyl]-3-yl)-5-((((1R,2S)-2-fluorocyclopropyl)amino)methyl)- 4-methoxymethylpyridineamide was prepared according to Example 103.

[1074] MS m / z (ESI): 654.2 [M+H] + .

[1075] Example 129

[1076] N-(2,2'-dichloro-3'-(5-((((R)-2-hydroxypropyl)amino)methyl)-6- methoxypyridin-2-yl)-[1,1 '-biphenyl]-3-yl)-5-((((1R,2S)-2-fluorocyclopropyl)amino)methyl)- 4-methoxymethylpyridineamide

[1077]

[1078] N-(2,2'-dichloro-3'-(5-((((R)-2-hydroxypropyl)amino)methyl)-6- methoxypyridin-2-yl)-[1,1 '-biphenyl]-3-yl)-5-((((1R,2S)-2-fluorocyclopropyl)amino)methyl)- 4-methoxymethylpyridineamide was prepared according to Example 103.

[1079] MS m / z (ESI): 654.2 [M+H] + .

[1080] Example 130

[1081] N-(2,2'-dichloro-3'-(5-((3-hydroxyazetidin-l-yl)methyl)-6-methoxypyridin-2-yl)- [1,1'-biphenyl]-3-yl)-5-((((1R,2S)-2-fluorocyclopropyl)amino)methyl)-4- methoxymethylpyridi namide

[1082]

[1083] The preparation of N-(2,2'-dichloro-3'-(5-((3-hydroxyazetidin-l-yl)methyl)-6- methoxypyridin-2-yl)-[l,l'-biphenyl]-3-yl)-5-((((1R,2S)-2-fluorocyclopropyl)amino)methyl)- 4-methoxymethylpyridinamide refers to Example 103.

[1084] MS m / z (ESI): 652.2 [M+H] + .

[1085] Example 131

[1086] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxypyridin-2-yl)-2,2'- dichloro-[l,l'-biphenyl]-3-yl)-5-((((1R,2S)-2-fluorocyclopropyl)amino)methyl)-4- methoxymethylpyridinamide

[1087]

[1088] The preparation of N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6- methoxypyridin-2-yl)-2,2'-dichloro-[l,l'-biphenyl]-3-yl)-5-((((1R,2S)-2- fluorocyclopropyl)amino)methyl)-4-methoxymethylpyridinamide refers to Example 103.

[1089] MS m / z (ESI): 719.2 [M+H] + .

[1090] Example 132

[1091] N-(2,2'-dichloro-3'-(5-(((1,3-dihydroxypropan-2-yl)amino)methyl)-6-methoxypyridin-2- yl)-[l,l'-biphenyl]-3-yl)-5-((((1R,2S)-2-fluorocyclopropyl)amino)methyl)-4- methoxymethylpyridinamide

[1092]

[1093] The preparation of N-(2,2'-dichloro-3'-(5-(((1,3-dihydroxypropan-2-yl)amino)methyl)- 6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-5-((((1R,2S)-2-fluorocyclopropyl)amino)methyl)- 4-methoxymethylpyridine amide is described in Reference Example 103.

[1094] MS m / z (ESI): 670.2 [M+H] + .

[1095] Example 133

[1096] (S)-N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxypyridin-2-yl)-2- chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((2-hydroxypropyl)amino)methyl)-4- methoxymethylpyridine amide

[1097]

[1098] First Step: Preparation of 3'-bromo-2-chloro-2'-methyl-[1,1'-biphenyl]-3-amine

[1099]

[1100] 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.0 g, 7.91 mmol), 2,6-dibromotoluene (3.92 g, 15.8 mmol), Pd(dppf)Cl2(289 mg, 0.396 mmol), K2CO3(2.18 g, 15.8 mmol) were added into a mixed solvent of 1,4-epoxyhexane (70 mL) and water (7 mL) respectively, and stirred at 85 °C under nitrogen protection for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the title compound as a colorless oil (1.36 g, 58%).

[1101] MS m / z (ESI): 296.0 [M+H] + .

[1102] Second Step: Preparation of 2-chloro-2'-methyl-3'-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-[1,1'-biphenyl]-3-amine

[1103]

[1104] To a solution of 3'-bromo-2-chloro-2'-methyl-[1,1'-biphenyl]-3-amine (1.36 g, 4.61 mmol), bis(pinacolato)diboron (1.03 g, 4.06 mmol), Pd(dppf)Cl2(168 mg, 0.231 mmol), AcOK (1.36 g, 13.8 mmol) in 1,4-dioxane (20 mL) was added under nitrogen protection and heated to 100 °C for 1 h. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel to give the title compound as a brown oil (1.58 g, 100%).

[1105] MS m / z (ESI): 344.2 [M+H] + .

[1106] Step 3: Preparation of 1-(6-((6-chloro-2-methoxypyridin-3-yl)methyl)-2,6- diazaspiro[3.3]heptan-2-yl)ethanone

[1107]

[1108] To a solution of 6-chloro-2-methoxynicotinaldehyde (200 mg, 1.16 mmol) and 1-{2,6- diazaspiro[3.3]heptan-2-yl}ethan-1-one trifluoromethanesulfonate (878 mg, 1.74 mmol) in dichloroethane (6 mL) was added DIPEA (720 mg, 5.58 mmol) and stirred at room temperature for 10 min, then sodium borohydride in acetic acid (734 mg, 3.48 mmol) was added and stirred at room temperature for 1 h. The reaction mixture was diluted with DCM (10 mL) and washed with saturated aqueous sodium bicarbonate solution (5 mL). The organic layer was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel to give the title compound as a white solid (158 mg, 46%).

[1109] MS m / z (ESI): 296.1 [M+H] + .

[1110] Step 4: Preparation of 1-(6-((6-(3'-amino-2'-chloro-2-methyl-[1,1'-biphenyl]-3-yl)-2- methoxypyridin-3-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethanone

[1111]

[1112] To a solution of methyl 5-formyl-4-methoxymethylpyridinate (100 mg, 0.510 mmol) in dichloroethane (2 mL) was added (S)-(+)-1 -amino-2-propanol (115 mg, 1.53 mmol) and stirred at room temperature for 30 min. Sodium borohydride in acetic acid (323 mg, 1.53 mmol) was added and stirred at room temperature for 16 h. The reaction was quenched with saturated aqueous sodium bicarbonate (5 mL) and extracted with dichloromethane (10 mL). The organic layer was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel to give the title compound as a colorless oil (16 mg, 3%).

[1113] MS m / z (ESI): 477.2 [M+H] + .

[1114] Fifth step: Preparation of (S)-methyl 5-(((2-hydroxypropyl)amino)methyl)-4- methoxymethylpyridinate

[1115]

[1116] To a solution of methyl 5-formyl-4-methoxymethylpyridinate (100 mg, 0.510 mmol) in dichloroethane (2 mL) was added (S)-(+)-1 -amino-2-propanol (115 mg, 1.53 mmol) and stirred at room temperature for 30 min. Sodium borohydride in acetic acid (323 mg, 1.53 mmol) was added and stirred at room temperature for 16 h. The reaction was quenched with saturated aqueous sodium bicarbonate (5 mL) and extracted with dichloromethane (10 mL). The organic layer was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel to give the title compound as a colorless oil (16 mg, 3%).

[1117] MS m / z (ESI): 477.2 [M+H] + .

[1118] Sixth step: Preparation of (S)-N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-6- methoxypyridin-2-yl)-2-chloro-2'-methyl-[1,1 '-biphenyl]-3-yl)-5-(((2-hydroxypropyl)amino)methyl)- 4-methoxymethylpyridinamide

[1119]

[1120] LiHMDS (0.285 mL, 1.0 M in THF) was added dropwise to a solution of (S)-methyl 5-(((2-hydroxypropyl)amino)methyl)-4-methoxymethylpyridine-2-carboxylate (14 mg, 0.057 mmol) and l-(6-((6-(3'-amino-2'-chloro-2-methyl-[l,l'-biphenyl]-3-yl)-2- methoxypyridin-3-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethanone (27 mg, 0.057 mmol) in tetrahydrofuran (1 mL) at room temperature and stirred for 5 minutes at room temperature. The reaction was quenched with half-saturated aqueous ammonium chloride solution (2 mL) and extracted with dichloromethane (10 mL). The organic phase was concentrated under reduced pressure and purified by prep-HPLC to give the title compound as a white solid (5 mg, 13%).

[1121] MS m / z (ESI): 699.3 [M+H] + .

[1122] Example 134

[1123] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-6-methoxypyridin-2-yl)-2- chloro-2'-methyl-[l,l'-biphenyl]-3-yl)-4-methoxy-5-((oxetan-3-ylamino)methyl)methylpyridine amide

[1124]

[1125] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-6-methoxypyridin-2-yl)-2- chloro-2'-methyl-[l,l'-biphenyl]-3-yl)-4-methoxy-5-((oxetan-3-ylamino)methyl)methylpyridine amide was prepared according to Example 133.

[1126] MS m / z (ESI): 697.2 [M+H] + .

[1127] Example 135

[1128] ((6-((3'-(5-((6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-6-methoxypyridin-2-yl)-2- chloro-2'-methyl-[l,l'-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)-L-proline

[1129]

[1130] ((6-((3'-(5-((6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-6-methoxy pyridin-2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4- methoxy pyridin-3-yl)methyl)-L-proline was prepared according to Example 133.

[1131] MS m / z (ESI): 739.2 [M+H] + .

[1132] Example 136

[1133] (S)-1-((6-((3'-(5-((6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-6-methoxy pyridin-2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4- methoxy pyridin-3-yl)methyl) piperidine-2-carboxylic acid

[1134]

[1135] (S)-1-((6-((3'-(5-((6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-6-methoxy pyridin-2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4- methoxy pyridin-3-yl)methyl) piperidine-2-carboxylic acid was prepared according to Example 133.

[1136] MS m / z (ESI): 753.2 [M+H] + .

[1137] Example 137

[1138] (S)-1-((6-((2-chloro-3'-(6-methoxy-5-((oxetan-3-ylamino)methyl)pyridin-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxy pyridin-3-yl)methyl) piperidine-2- carboxylic acid

[1139]

[1140] (S)-1-((6-((2-chloro-3'-(6-methoxy-5-((oxetan-3-ylamino)methyl)pyridin-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxy pyridin-3-yl)methyl) piperidine-2- carboxylic acid was prepared according to Example 133.

[1141] MS m / z (ESI): 686.2 [M+H]+ .

[1142] Example 138

[1143] ((6-((2-chloro-3'-(6-methoxy-5-((oxetan-3-ylamino)methyl)pyridin-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3-yl)methyl)-L-proline

[1144]

[1145] ((6-((2-chloro-3'-(6-methoxy-5-((oxetan-3-ylamino)methyl)pyridin-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3-yl)methyl)-L-proline was prepared according to Example 133.

[1146] MS m / z (ESI): 672.2 [M+H] + .

[1147] Example 139

[1148] ((6-(2'-chloro-3'-(5-((((S)-2-hydroxypropyl)amino)methyl)-4-methoxymethyl- pyridinoylamido)-2-methyl-[1,1'-biphenyl]-3-yl)-2-methoxy-pyridin-3-yl)methyl)-L- proline

[1149]

[1150] ((6-(2'-chloro-3'-(5-((((S)-2-hydroxypropyl)amino)methyl)-4-methoxymethyl- pyridinoylamido)-2-methyl-[1,1'-biphenyl]-3-yl)-2-methoxy-pyridin-3-yl)methyl)-L- proline was prepared according to Example 133.

[1151] MS m / z (ESI): 674.2 [M+H] + .

[1152] Example 140

[1153] ((6-(2'-chloro-3'-(4-methoxy-5-((oxetan-3-ylamino)methyl)pyridinoylamido)-2- methyl-[1,1'-biphenyl]-3-yl)-2-methoxy-pyridin-3-yl)methyl)-L-proline

[1154]

[1155] ((6-(2'-chloro-3'-(4-methoxy-5-((oxetan-3-ylamino)methyl)pyridinoyl- amino)-2-methyl-[1,1'-biphenyl]-3-yl)-2-methoxy-pyridin-3-yl)methyl)-L-proline was prepared according to Example 133.

[1156] MS m / z (ESI): 672.2 [M+H] + .

[1157] Example 141

[1158] ((6-(2'-chloro-3'-(5-((((1R,2S)-2-fluorocyclopropyl)amino)methyl)-4- methoxymethylpyridinoyl-amino)-2-methyl-[1,1'-biphenyl]-3-yl)-2-methoxy-pyridin-3- yl)methyl)-L-proline

[1159]

[1160] ((6-(2'-chloro-3'-(5-((((1R,2S)-2-fluorocyclopropyl)amino)methyl)-4- methoxymethylpyridinoyl-amino)-2-methyl-[1,1'-biphenyl]-3-yl)-2-methoxy-pyridin-3- yl)methyl)-L-proline was prepared according to Example 133.

[1161] MS m / z (ESI): 674.2 [M+H] + .

[1162] Example 142

[1163] (S)-1-((6-((2-chloro-3'-(5-((3-fluoroazetidin-1-yl)methyl)-6-methoxypyridin-2-yl)- 2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)piperidine-2- carboxylic acid

[1164]

[1165] (S)-1-((6-((2-chloro-3'-(5-((3-fluoroazetidin-1-yl)methyl)-6-methoxypyridin-2-yl)- 2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)piperidine-2- carboxylic acid was prepared according to Example 133.

[1166] MS m / z (ESI): 688.2 [M+H] + .

[1167] Example 143

[1168] ((6-((2-chloro-3'-(5-((3-fluoroazetidin-l-yl)methyl)-6-methoxypyridin-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3-yl)methyl)-L-proline

[1169]

[1170] ((6-((2-chloro-3'-(5-((3-fluoroazetidin-l-yl)methyl)-6-methoxypyridin-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)carbamoyl)-4-methoxy-pyridin-3-yl)methyl)-L-proline was prepared according to Reference Example 133.

[1171] MS m / z (ESI): 674.2 [M+H] + .

[1172] Example 144

[1173] (S)-N-(2-chloro-3'-(5-((3-fluoroazetidin-l-yl)methyl)-6-methoxypyridin-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)-5-(((2-hydroxypropyl)amino)methyl)-4- methoxymethylpyridine amide

[1174]

[1175] (S)-N-(2-chloro-3'-(5-((3-fluoroazetidin-l-yl)methyl)-6-methoxypyridin-2-yl)-2'- methyl-[l,l'-biphenyl]-3-yl)-5-(((2-hydroxypropyl)amino)methyl)-4- methoxymethylpyridine amide was prepared according to Reference Example 133.

[1176] MS m / z (ESI): 634.2 [M+H] + .

[1177] Example 145

[1178] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-6-methoxypyridin-2-yl)- 2,2'-dichloro-[l,l'-biphenyl]-3-yl)-4-cyclopropyl-5-(((2-hydroxyethyl)amino)methyl) methylpyridine amide

[1179]

[1180] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy-pyridin-2-yl)-2,2'- dichloro-[1,1'-biphenyl]-3-yl)-4-cyclopropyl-5-(((2-hydroxyethyl)amino)methyl)methyl- pyridinamide was prepared according to Example 103.

[1181] MS m / z (ESI): 715.2 [M+H] + .

[1182] Example 146

[1183] (S)-N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy-pyridin-2-yl)-2,2'- dichloro-[1,1'-biphenyl]-3-yl)-4-cyclopropyl-5-(((2-hydroxyethyl)amino)methyl)methyl- pyridinamide

[1184]

[1185] (S)-N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy-pyridin-2-yl)-2,2'- dichloro-[1,1'-biphenyl]-3-yl)-4-cyclopropyl-5-(((2-hydroxyethyl)amino)methyl)methyl- pyridinamide was prepared according to Example 103.

[1186] MS m / z (ESI): 729.2 [M+H] + .

[1187] Example 147

[1188] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy-pyridin-2-yl)-2,2'- dichloro-[1,1'-biphenyl]-3-yl)-4-cyclopropyl-5-(((1,3-dihydroxypropan-2-yl)amino)methyl)- methylpyridinamide

[1189]

[1190] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy-pyridin-2-yl)-2,2'- dichloro-[1,1'-biphenyl]-3-yl)-4-cyclopropyl-5-(((1,3-dihydroxypropan-2-yl)amino)methyl)- methylpyridinamide was prepared according to Example 103.

[1191] MS m / z (ESI): 745.2 [M+H] + .

[1192] Example 148

[1193] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy pyridin-2-yl)-2,2'- dichloro-[1,1'-biphenyl]-3-yl)-4-cyclopropyl-5-((oxetan-3-ylamino)methyl)methyl pyridine amide

[1194]

[1195] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy pyridin-2-yl)-2,2'- dichloro-[1,1'-biphenyl]-3-yl)-4-cyclopropyl-5-((oxetan-3-ylamino)methyl)methyl pyridine amide was prepared according to Example 103.

[1196] MS m / z (ESI): 727.2 [M+H] + .

[1197] Example 149

[1198] (S)-4-cyclopropyl-N-(2,2'-dichloro-3'-(5-(((2-hydroxypropyl)amino)methyl)-6-methoxy pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-5-((oxetan-3-ylamino)methyl)methyl pyridine amide

[1199]

[1200] (S)-4-cyclopropyl-N-(2,2'-dichloro-3'-(5-(((2-hydroxypropyl)amino)methyl)-6-methoxy pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-5-((oxetan-3-ylamino)methyl)methyl pyridine amide was prepared according to Example 103.

[1201] MS m / z (ESI): 662.2 [M+H] + .

[1202] Example 150

[1203] 4-cyclopropyl-N-(2,2'-dichloro-3'-(5-((((S)-2-hydroxypropyl)amino)methyl)-6-methoxy pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-5-((((1R,2S)-2-fluorocyclopropyl)amino)methyl)methyl pyridine amide

[1204]

[1205] 4-cyclopropyl-N-(2,2'-dichloro-3'-(5-((((S)-2-hydroxypropyl)amino)methyl)-6- methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-5-((((1R,2S)-2-fluorocyclopropyl)amino)methyl) methylpyridine amide was prepared according to Example 103.

[1206] MS m / z (ESI): 664.2 [M+H] + .

[1207] Example 151

[1208] N-(2,2'-dichloro-3'-(5-((3-fluoroazetidin-1-yl)methyl)-6-methoxypyrazin-2-yl)-[1,1'- biphenyl]-3-yl)-5-(((1,3-dihydroxypropan-2-yl)amino)methyl)-4-methoxymethylpyridine amide

[1209]

[1210] First Step: Preparation of 3'-bromo-2,2'-dichloro-[1,1'-biphenyl]-3-amine

[1211]

[1212] 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.0 g, 7.91 mmol), 1,3-dibromo-2-chlorobenzene (4.27 g, 15.8 mmol), Pd(dppf)Cl2(578 mg, 0.791 mmol), K2CO3(2.62 g, 19.0 mmol) were added into a mixture solvent of 1,4-epoxyhexane (70 mL) and water (7 mL) respectively, and stirred at 95 °C for 3 hours under nitrogen protection. After the reaction solution was cooled, it was separated, the organic layer was concentrated under reduced pressure, the residue was diluted with DCM (50 mL), washed with water (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to give the title compound as a white solid (1.14 g, 45%).

[1213] MS m / z (ESI): 316.1 [M+H] + .

[1214] Second Step: Preparation of N-(3'-bromo-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-4-methoxy-5- vinylmethylpyridine amide

[1215]

[1216] KHMDS (3.2 mL, 1.0 M in THF) was added dropwise to a solution of 3'-bromo-2,2'- dichloro-[1,1 '-biphenyl]-3-amine (506 mg, 1.16 mmol) and methyl 4-methoxy-5- vinylmethylpyridine-2-carboxylate (310 mg, 1.16 mmol) in tetrahydrofuran (6 mL) at room temperature and stirred at room temperature for 10 minutes. The reaction was quenched with saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (20 mL). The organic phase was washed with saturated aqueous sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (770 mg, 99%).

[1217] MS m / z (ESI): 477.0 [M+H] + .

[1218] Third step: Preparation of N-(3'-bromo-2,2'-dichloro-[1,1 '-biphenyl]-3-yl)-5- formyl-4-methoxymethylpyridinamide

[1219]

[1220] NaIO4(1.53 g, 7.15 mmol) was added portionwise to a solution of N-(3'-bromo-2,2'- dichloro-[1,1 '-biphenyl]-3-yl)-4-methoxy-5-vinylmethylpyridinamide (770 mg, 1.61 mmol) and K2OsO4.2H2O (30 mg, 81 μmol) in a mixture of 1,4-dioxane (15 mL) and H2O (5 mL) at room temperature and stirred at room temperature for 5 hours. The reaction was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with DCM (20 mL), washed with saturated aqueous sodium bicarbonate solution (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 3:1 to 2:1 ) to give the title compound as a grey solid (325 mg, 42%).

[1221] MS m / z (ESI): 479.0 [M+H] + .

[1222] Fourth step: Preparation of N-(2,2'-dichloro-3'-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-[1,1 '-biphenyl]-3-yl)-5-formyl-4-methoxymethylpyridinamide

[1223]

[1224] To a solution of N-(3'-bromo-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-5-formyl-4- methoxymethylpyridinamide (325 mg, 0.680 mmol), pinacol diborane (212 mg, 0.748 mmol), Pd(dppf)Cl2(50 mg, 0.068 mmol), AcOK (200 mg, 2.04 mmol) in 1,4- dioxane (3 mL) was heated to 100 °C under nitrogen for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (PE:EA = 10:1 to 1:1) to give the title compound as a gray solid (180 mg, 50%).

[1225] MS m / z (ESI): 527.2 [M+H] + .

[1226] Fifth step: Preparation of 5-bromo-2-((3-fluoroazetidin-1-yl)methyl)-3- methoxypyrazine

[1227]

[1228] To a solution of 5-bromo-3-methoxypyrazine-2-carbaldehyde (50 mg, 0.230 mmol) and 3-fluoroazetidine hydrochloride (51 mg, 0.460 mmol) in dichloroethane (2 mL) was added DIPEA (59 mg, 0.460 mmol) and stirred at room temperature for 1 h, then sodium borohydride acetate (146 mg, 0.69 mmol) was added and stirred at room temperature for 16 h. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate (5 mL) and DCM (10 mL), and the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE:EA = 2:1 to 0:1) to give the title compound as a colorless oil (64 mg, 100%).

[1229] MS m / z (ESI): 276.1 [M+H] + .

[1230] Sixth step: Preparation of N-(2,2'-dichloro-3'-(5-((3-fluoroazetidin-1-yl)methyl)-6- methoxypyrazin-2-yl)-[1,1'-biphenyl]-3-yl)-5-formyl-4-methoxymethylpyridinamide

[1231]

[1232] To a mixture of 5-bromo-2-((3-fluoroazetidin-l-yl)methyl)-3-methoxy- pyrazine (64 mg, 0.233 mmol), N-(2,2'-dichloro-3'-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-[l,l'-biphenyl]-3-yl)-5-formyl-4-methoxymethylpyridinamide (90 mg, 0.171 mmol), tetrakis(triphenylphosphine)palladium (20 mg, 0.0171 mmol), potassium carbonate (47 mg, 0.344 mmol) in 1,4-dioxane (2.0 mL) and water (0.4 mL) was purged with nitrogen and heated to 100 °C for 2 h. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 10:1) to give the title compound as a brown oil (66 mg, 65%).

[1233] MS m / z (ESI): 596.1 [M+H] + .

[1234] Step 7: Preparation of N-(2,2'-dichloro-3'-(5-((3-fluoroazetidin-l-yl)methyl)-6- methoxypyrazin-2-yl)-[l,l'-biphenyl]-3-yl)-5-(((l,3-dihydroxypropan-2-yl)amino)methyl)- 4-methoxymethylpyridinamide

[1235]

[1236] To a mixture of N-(2,2'-dichloro-3'-(5-((3-fluoroazetidin-l-yl)methyl)-6- methoxypyrazin-2-yl)-[l,l'-biphenyl]-3-yl)-5-formyl-4-methoxymethylpyridinamide (66 mg, 0.111 mmol), serinol (20 mg, 0.222 mmol) in methanol (0.5 mL) and dichloroethane (0.5 mL) was stirred at room temperature for 0.5 h, then sodium cyanoborohydride (69 mg, 1.11 mmol) was added and stirred at room temperature for 2 h. The reaction was concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound as a white solid (12.7 mg, 16%).

[1237] MS m / z (ESI): 671.2 [M+H] + .

[1238] Example 152

[1239] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-6-methoxypyrazin-2-yl)-2,2'- dichloro-[1,1'-biphenyl]-3-yl)-5-(((1,3-dihydroxypropan-2-yl)amino)methyl)-4- methoxymethylpyridineamide

[1240]

[1241] First Step: Preparation of 1-(6-((5-bromo-3-methoxypyrazin-2-yl)methyl)-2,6- diazaspiro[3.3]heptan-2-yl)ethanone

[1242]

[1243] DIPEA (190 mg, 14.7 mmol) was added to a solution of 5-bromo-3-methoxypyrazine-2- carboxaldehyde (50 mg, 0.230 mmol) and 1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone hydrochloride (233 mg, 0.460 mmol) in dichloroethane (2 mL), stirred at room temperature for 1 hour, then sodium borohydride in acetic acid (146 mg, 0.690 mmol) was added, stirred at room temperature for 16 hours. The reaction was partitioned between saturated aqueous sodium bicarbonate solution (5 mL) and DCM (10 mL), the organic layer was concentrated under reduced pressure, the residue was separated and purified by column chromatography on silica gel (DCM:MeOH = 100:1 ~ 10:1) to give the title compound as a colorless oil (53 mg, 68%).

[1244] MS m / z (ESI): 341.1 [M+H] + .

[1245] Second Step: Preparation of N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-6- methoxypyrazin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-5-formyl-4-methoxymethylpyridineamide

[1246]

[1247] To a mixture of 1-(6-((5-bromo-3-methoxypyrazin-2-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethanone (53 mg, 0.156 mmol), N-(2,2'-dichloro-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-yl)-5-formyl-4- methoxymethylpyridinamide (90 mg, 0.171 mmol), tetrakis(triphenylphosphine)palladium (18 mg, 0.0156 mmol), potassium carbonate (43 mg, 0.312 mmol) in 1,4- dioxane (2.0 mL) and water (0.4 mL) was purged with nitrogen and heated to 100 °C for 2 h. The reaction was diluted with water (5 mL) and extracted with dichloromethane (10 mL x 2). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 10:1) to give the title compound as a brown oil (40 mg, 39%).

[1248] MS m / z (ESI): 661.2 [M+H] + .

[1249] Step 3: Preparation of N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-6- methoxypyrazin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-5-(((1,3-dihydroxypropan-2-yl)amino)methyl)-4- methoxymethylpyridinamide

[1250]

[1251] To a mixture of N-(3'-(5-((6-acetyl-2-azaspiro[3.3]heptan-2-yl)methyl)-6-methoxypyrazin-2-yl)-2,2'- dichloro-[1,1'-biphenyl]-3-yl)-5-formyl-4-methoxymethylpyridinamide (40 mg, 0.0605 mmol), serinol (11 mg, 0.121 mmol) in methanol (0.5 mL) and dichloroethane (0.5 mL) was stirred at room temperature for 1 h, then sodium cyanoborohydride (19 mg, 0.306 mmol) was added and stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound as a white solid (4.9 mg, 11%).

[1252] MS m / z (ESI): 736.2 [M+H] + .

[1253] Example 153

[1254] N-(3'-(5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-6-methoxypyrazin-2-yl)-2,2'- dichloro-[1,1'-biphenyl]-3-yl)-5-(((1,3-dihydroxypropan-2-yl)amino)methyl)-4- methoxymethylpyridinecarboxamide

[1255]

[1256] First Step: Preparation of 2,2'-dichloro-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- [1,1'-biphenyl]-3-amine

[1257]

[1258] To a solution of 3'-bromo-2,2'-dichloro-[1,1'-biphenyl]-3-amine (431 mg, 1.37 mmol), pinacol diboronic acid (384 mg, 1.51 mmol), Pd(dppf)Cl2(100 mg, 0.137 mmol), AcOK (403 mg, 4.11 mmol) in 1,4-dioxane (5 mL) was heated to 100 °C under nitrogen protection for 5 h. The reaction was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE:EA = 5:1 ~ 2:1) to give the title compound as a gray solid (380 mg, 76%).

[1259] MS m / z (ESI): 364.1 [M+H] + .

[1260] Second Step: Preparation of (2,2'-dichloro-3'-(4-methoxy-5-vinylmethylpyridineamido)- [1,1'-biphenyl]-3-yl)boronic acid

[1261]

[1262] KHMDS (2.1 mL, 1.0 THF solution) was added dropwise to a solution of 2,2'-dichloro-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1 '-biphenyl]-3-amine (380 mg, 1.05 mmol) and methyl 4-methoxy-5-vinylmethylpyridine-2-carboxylate (202 mg, 1.05 mmol) in tetrahydrofuran (5 mL) at room temperature and stirred at room temperature for 10 minutes. The reaction was quenched with half-saturated aqueous ammonium chloride solution (3 mL) and extracted with ethyl acetate (10 mL). The organic phase was washed with saturated aqueous sodium chloride (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (463 mg, 99%).

[1263] MS m / z (ESI): 443.1 [M+H] + .

[1264] Step 3: Preparation of N-(2,2'-dichloro-3'-(5-formyl-6-methoxypyrazin-2-yl)-[1,1 '- biphenyl]-3-yl)-4-methoxy-5-vinylmethylpyridine-2-carboxamide

[1265]

[1266] To a solution of 5-bromo-3-methoxypyrazine-2-carboxaldehyde (184 mg, 0.850 mmol), (2,2'-dichloro-3'-(4-methoxy-5-vinylmethylpyridine-2-carboxamido)-[1,1 '- biphenyl]-3-yl)boronic acid (413 mg, 0.932 mmol), tetrakis(triphenylphosphine)palladium (97 mg, 0.0840 mmol), potassium carbonate (233 mg, 1.69 mmol) in 1,4-dioxane (6 mL) and water (1.2 mL) was heated to 100 °C under nitrogen for 3 hours. The reaction was concentrated under reduced pressure, the residue was diluted with water (10 mL) and then extracted with dichloromethane (20 mL x 2), the organic phases were combined, washed with saturated aqueous sodium chloride (20 mL) and then dried over anhydrous sodium sulfate, filtered and the organic solvent was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE:EA = 10:1 to 2:1 ) to give the title compound as a brown oil (212 mg, 47%).

[1267] MS m / z (ESI): 535.1 [M+H] + .

[1268] Step 4: Preparation of N-(3'-(5-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)-6- methoxypyrazin-2-yl)-2,2'-dichloro-[1,1 '-biphenyl]-3-yl)-4-methoxy-5- vinylmethylpyridine-2-carboxamide

[1269]

[1270] To a solution of N-(2,2'-dichloro-3'-(5-formyl-6-methoxypyrazin-2-yl)-[1,1'-biphenyl]-3-yl)-4-methoxy-5-vinylmethylpyridinecarboxamide (106 mg, 0.199 mmol) and 2-oxa-6-azaspiro[3.3]heptane (24 mg, 0.238 mmol) in dichloroethane (2 mL) was stirred at room temperature for 0.5 h, then sodium borohydride in acetic acid (125 mg, 0.588 mmol) was added and stirred at room temperature for 1 h. The reaction was partitioned between saturated aqueous sodium bicarbonate (5 mL) and dichloromethane (10 mL), and the organic layer was concentrated under reduced pressure to give the title compound as a brown solid (121 mg, 99%).

[1271] MS m / z (ESI): 618.2 [M+H] + .

[1272] Fifth Step: Preparation of N-(3'-(5-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)-6-methoxypyrazin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-5-formyl-4-methoxymethylpyridinecarboxamide

[1273]

[1274] NaIO4(209 mg, 0.978 mmol) was added portionwise to a solution of N-(3'-(5-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)-6-methoxypyrazin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-4-methoxy-5-vinylmethylpyridinecarboxamide (121 mg, 0.196 mmol) and K2OsO4.2H2O (3.6 mg, 9.79 μmol) in 1,4-dioxane (3 mL) and H2O (1 mL) at room temperature, and stirred at room temperature for 1 h. The reaction was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with DCM (20 mL), washed with saturated aqueous sodium bicarbonate (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a light brown solid (118 mg, 97%).

[1275] MS m / z (ESI): 620.2 [M+H] + .

[1276] Step 6: Preparation of N-(3'-(5-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)-6- methoxypyrazin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-5-(((1,3-dihydroxypropan-2- yl)amino)methyl)-4-methoxymethylpyridine amide

[1277]

[1278] To a mixture of N-(3'-(5-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)-6- methoxypyrazin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-5-formyl-4- methoxymethylpyridine amide (118 mg, 0.190 mmol) and serinol (35 mg, 0.380 mmol) in methanol (1 mL) and dichloroethane (1 mL) was added sodium cyanoborohydride (119 mg, 1.90 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound as a white solid (23 mg, 17%).

[1279] MS m / z (ESI): 695.2 [M+H] + .

[1280] Example 154

[1281] 4-cyclopropyl-N-(2,2'-dichloro-3'-(5-((3-fluoroazetidin-1-yl)methyl)-6- methoxypyrazin-2-yl)-[1,1'-biphenyl]-3-yl)-5-(((1,3-dihydroxypropan-2-yl)amino)methyl) methylpyridine amide

[1282]

[1283] 4-cyclopropyl-N-(2,2'-dichloro-3'-(5-((3-fluoroazetidin-1-yl)methyl)-6- methoxypyrazin-2-yl)-[1,1'-biphenyl]-3-yl)-5-(((1,3-dihydroxypropan-2-yl)amino)methyl) methylpyridine amide was prepared according to Reference Example 103.

[1284] MS m / z (ESI): 681.2 [M+H] + .

[1285] Example 155

[1286] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-6-methoxypyrazin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-4-cyclopropyl-5-(((1,3-dihydroxypropan-2-yl)amino)methyl)methylpicolinamide

[1287]

[1288] Refer to Example 103 for the preparation of N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]heptane-2-yl)methyl)-6-methoxypyrazin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-4-cyclopropyl-5-(((1,3-dihydroxypropan-2-yl)amino)methyl)methylpicolinamide.

[1289] MS m / z(ESI):746.2[M+H] + .

[1290] Example 156

[1291] N-(3'-(5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-6-methoxypyrazin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-4-cyclopropyl-5-(((1,3-dihydroxypropan-2-yl)amino)methyl)methylpicolinamide

[1292]

[1293] Refer to Example 103 for the preparation of N-(3'-(5-((2-oxa-6-azaspiro[3.3]heptane-6-yl)methyl)-6-methoxypyrazin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-4-cyclopropyl-5-(((1,3-dihydroxypropan-2-yl)amino)methyl)methylpicolinamide.

[1294] MS m / z(ESI):704.2[M+H] + .

[1295] Example 157

[1296] N-(2,2'-dichloro-3'-(5-((3-fluoroazetidin-1-yl)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-3-methoxy-5-((oxetan-3-ylamino)methyl)methylpicolinamide

[1297]

[1298] N-(2,2'-dichloro-3'-(5-((3-fluoroazetidin-l-yl)methyl)-6-methoxypyridin-2-yl)- [1,1'-biphenyl]-3-yl)-3-methoxy-5-((oxetan-3-ylamino)methyl)methylpyridine amide was prepared according to Example 1.

[1299] MS m / z (ESI): 652.2 [M+H] + .

[1300] Example 158

[1301] N-(2'-chloro-3'-(5-((3-fluoroazetidin-l-yl)methyl)-6-methoxypyridin-2-yl)-2-methyl- [1,1'-biphenyl]-3-yl)-5-((3-fluoroazetidin-l-yl)methyl)-4-methoxymethylpyridine amide

[1302]

[1303] First step: 6-(3'-amino-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde

[1304]

[1305] 3-bromo-2-methylaniline (200 mg, 0.535 mmol), 6-(2-chloro-3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)-2-methoxynicotinaldehyde (100 mg, 0.535 mol), Pd(dppf)Cl2DCM complex (88 mg, 0.107 mmol) and cesium carbonate (436 mg, 1.34 mmol) were dissolved in a mixed solvent of dioxane (10 mL) and water (1 mL), and degassed, and stirred at 95 °C under nitrogen protection overnight. After the reaction was completed, the reaction solution was cooled and concentrated. The residue was separated by flash silica gel column chromatography (PE:EA = 3:1) to obtain the title compound (50 mg, 26%).

[1306] MS m / z (ESI): 353.2 [M+H] + .

[1307] Second step: 2'-chloro-3'-(5-((3-fluoroazetidin-l-yl)methyl)-6-methoxypyridin-2-yl)- 2-methyl-[1,1'-biphenyl]-3-amine

[1308]

[1309] Dissolve 6-(3'-amino-2-chloro-2'-methyl-[l,l'-biphenyl]-3-yl)-2- methoxynicotinaldehyde (50 mg, 0.141 mmol) and 3-fluoroazetidine hydrochloride (47 mg, 0.424 mmol) in methanol (7 mL), after neutralization with DIPEA, add 3 drops of acetic acid, stir at room temperature for 3 hours. After the addition of sodium cyanoborohydride (22 mg, 0.352 mmol), continue to stir at room temperature overnight. After the reaction is complete, cool the reaction, concentrate. The residue is separated by flash silica gel column chromatography (PE:EA = 3: 1) to obtain the title compound (50 mg, 86%).

[1310] MS m / z (ESI): 412.3 [M+H] + .

[1311] Third step: methyl 5-((3-fluoroazetidin-l-yl)methyl)-4- methoxymethylpyridine-2-carboxylate

[1312]

[1313] Dissolve methyl 5-formyl-4-methoxymethylpyridine-2-carboxylate (300 mg, 1.53 mmol) and 3-fluoroazetidine hydrochloride (427 mg, 3.85 mmol) in methanol (13 mL), after neutralization with DIPEA, add 6 drops of acetic acid, stir at room temperature for 3 hours. After the addition of sodium cyanoborohydride (190 mg, 3.06 mmol), continue to stir at room temperature overnight. After the reaction is complete, cool the reaction, concentrate. The residue is separated by flash silica gel column chromatography (DCM:MeOH = 10: 1) to obtain the title compound (340 mg, 87%).

[1314] MS m / z (ESI): 255.2 [M+H] + .

[1315] Fourth step: N-(2'-chloro-3'-(5-((3-fluoroazetidin-l-yl)methyl)-6- methoxypyridin-2-yl)-2-methyl-[l,l'-biphenyl]-3-yl)-5-((3-fluoroazetidin-l-yl)methyl)- 4-methoxymethylpyridine-2-carboxamide

[1316]

[1317] Dissolve 2'-chloro-3'-(5-((3-fluoroazetidin-l-yl)methyl)-6-methoxypyridin-2-yl)-2- methyl-[l,l'-biphenyl]-3-amine (50 mg, 0.121 mmol) and methyl 5-((3-fluoroazetidin-l- yl)methyl)-4-methoxymethylpyridine carboxylate (30 mg, 0.121 mmol) in tetrahydrofuran (4 mL), add 1 M LiHMDS in tetrahydrofuran (0.43 mL, 0.43 mmol) at room temperature. Stir the reaction at room temperature overnight. Quench the reaction with methanol, concentrate, and purify the residue by reverse phase column chromatography to give the title compound (7.1 mg, 9%).

[1318] MS m / z (ESI): 634.3 [M+H] + .

[1319] Example 159

[1320] N-(2'-chloro-3'-((3-((3-fluoroazetidin-l-yl)methyl)-l,7-naphthyridin-8-yl)amino)-2- methyl-[l,l'-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)-4- methoxymethylpyridine amide

[1321]

[1322] First Step: Preparation of N-(3-bromo-2-chlorophenyl)-3-((3-fluoroazetidin-l-yl)methyl)- 1,7-naphthyridin-8-amine

[1323]

[1324] Dissolve (8-((3-bromo-2-chlorophenyl)amino)-l,7-naphthyridin-3-yl)methanol (1.58 g, 4.32 mmol) in DMF (50 mL), add DMP (2.75 g, 6.48 mmol) with stirring at room temperature, stir the reaction at room temperature for 0.5 hours, concentrate under reduced pressure to remove the solvent, disperse the residue in tetrahydrofuran (100 mL), add 3-fluoroazetidine hydrochloride (964 mg, 8.64 mmol) and DIPEA (1.43 mL, 8.64 mmol) in sequence, stir the reaction at room temperature for 1 hour, add sodium triacetoxyborohydride (3.66 g, 17.28 mmol), continue to stir the reaction at room temperature for 16 hours, concentrate under reduced pressure to remove the solvent, disperse the residue in ethyl acetate, wash with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dry over anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography to give the title compound (1.02 g, 56%).

[1325] MS m / z (ESI): 421.2 [M+H] + .

[1326] Second Step: Preparation of 2-chloro-N3-(3-((3-fluoroazetidin-l-yl)methyl)-l,7- naphthyridin-8-yl)-2'-methyl-[l,l'-biphenyl]-3,3'-diamine

[1327]

[1328] N-(3-bromo-2-chlorophenyl)-3-((3-fluoroazetidin-l-yl)methyl)-l,7-naphthyridin-8- amine (300 mg, 0.71 mmol), 2-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)aniline (250 mg, 1.07 mmol), dichlorobis(cyclohexyl) palladium (58 mg, 0.071 mmol) and potassium carbonate (463 mg, 1.42 mmol) were added into a mixture solvent of tert-butanol (20 mL) and water (2 mL), the reaction system was protected by nitrogen, heated to 90 °C and stirred for 16 hours. The solvent was removed by concentration under reduced pressure, the residue was dispersed in dichloromethane, the organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by silica gel column chromatography to obtain the title compound (147 mg, 46%).

[1329] MS m / z (ESI): 448.1 [M+H] +

[1330] Third Step: Preparation of methyl 5-(((tert-butoxycarbonyl)(2-((tert- butyldimethylsilyl)oxy)ethyl)amino)methyl)-4-methoxymethylpyridinate

[1331]

[1332] Methyl 5-formyl-4-methoxymethylpyridine carboxylate (250 mg, 1.275 mmol) and 2-aminoethanol (117 mg, 1.91 mmol) were dissolved in methanol (10 mL), 5 drops of acetic acid were added, sodium cyanoborohydride was added with stirring at room temperature, the reaction was stirred at room temperature for 30 minutes, DIPEA (0.5 mL) was added, di-tert-butyl dicarbonate (500 mg, 2.3 mmol) was added with stirring at room temperature, the reaction was stirred at room temperature for 30 minutes, the solvent was removed by concentration under reduced pressure, the residue was dispersed in ethyl acetate, and sequentially washed with saturated sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated, the residue was dissolved in tetrahydrofuran (10 mL), imidazole (174 mg, 2.55 mmol) and TBSCl (384 mg, 2.55 mmol) were added sequentially with stirring at room temperature, the reaction was stirred at room temperature for 2 hours, the solvent was removed by concentration under reduced pressure, the residue was dispersed in ethyl acetate, and sequentially washed with saturated sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was separated by column chromatography on silica gel to obtain the title compound (425 mg, 73%).

[1333] MS m / z (ESI): 455.2 [M+H] +

[1334] Fourth Step: Preparation of N-(2'-chloro-3'-((3-((3-fluoroazetidin-l-yl)methyl)-l,7- naphthyridin-8-yl)amino)-2-methyl-[l,r-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)- 4-methoxymethylpyridine amide

[1335]

[1336] To a solution of 2-chloro-N3-(3-((3-fluoroazetidin-l-yl)methyl)-l,7- naphthyridin-8-yl)-2'-methyl-[l,l'-biphenyl]-3,3'-diamine (100 mg, 0.223 mmol) and methyl 5-(((tert-butoxycarbonyl)(2-((tert-butyldimethylsilyl)oxy)ethyl)amino)methyl)- 4-methoxymethylpyridine-1-carboxylate (122 mg, 0.268 mmol) in dry toluene (5 mL) under nitrogen was added LiHMDS (1.03 mL, 1.34 mmol) and the reaction was stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate and washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL) was added. The reaction was stirred at room temperature for 3 h. The solvent was removed under reduced pressure and the residue was purified by prep-HPLC to give the title compound (7.5 mg, 5%).

[1337] MS m / z (ESI): 656.2 [M+H] + .

[1338] Example 160

[1339] (R)-N-(2'-chloro-3'-((3-((3-fluoropyrrolidin-l-yl)methyl)-l,7-naphthyridin-8-yl)amino)- 2-methyl-[l,l'-biphenyl]-3-yl)-4-methoxy-5-((oxetan-3-ylamino)methyl)methylpyridinecarboxamide

[1340]

[1341] (R)-N-(2'-chloro-3'-((3-((3-fluoropyrrolidin-l-yl)methyl)-l,7-naphthyridin-8-yl)amino)- 2-methyl-[l,l'-biphenyl]-3-yl)-4-methoxy-5-((oxetan-3-ylamino)methyl)methylpyridinecarboxamide was prepared according to Example 159.

[1342] MS m / z (ESI): 682.2 [M+H] + .

[1343] Example 161

[1344] (R)-N-(2'-chloro-3'-((3-((3-hydroxypyrrolidin-l-yl)methyl)-l,7-naphthyridin-8-yl)amino)- 2-methyl-[l,l'-biphenyl]-3-yl)-4-methoxy-5-(((2-methoxypyridin-4-yl)amino)methyl) methylpyridinecarboxamide

[1345]

[1346] (R)-N-(2'-chloro-3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2-methyl-[1,1'-biphenyl]-3-yl)-4-methoxy-5-(((2-methoxypyridin-4-yl)amino)methyl)pyridinecarboxamide was prepared according to Example 159.

[1347] MS m / z (ESI): 731.2 [M+H] + .

[1348] Example 162

[1349] 1-((6-((2'-chloro-3'-((3-((((3R,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)methyl)-1,7-naphthyridin-8-yl)amino)-2-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)azetidine-3-

[1350] carboxylic acid

[1351]

[1352] 1-((6-((2'-chloro-3'-((3-((((3R,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)methyl)-1,7-naphthyridin-8-yl)amino)-2-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-methoxypyridin-3-yl)methyl)azetidine-3-carboxylic acid was prepared according to Example 159.

[1353] MS m / z (ESI): 740.2 [M+H] + .

[1354] Example 163

[1355] N-(2'-chloro-3'-((3-(((R)-3-fluoropyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2-methyl-[1,1'-biphenyl]-3-yl)-5-(((R)-3-fluoropyrrolidin-1-yl)methyl)methylpyridinecarboxamide

[1356]

[1357] N-(2'-chloro-3'-((3-(((R)-3-fluoropyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2- methyl-[1,1'-biphenyl]-3-yl)-5-(((R)-3-fluoropyrrolidin-1-yl)methyl)methylpyridinecarboxamide was prepared according to Example 159.

[1358] MS m / z (ESI): 668.2 [M+H] + .

[1359] Example 164

[1360] (R)-N-(2'-chloro-3'-((3-((3-fluoropyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2- methyl-[1,1'-biphenyl]-3-yl)-5-(((3-fluoro-2-methylpyridin-4-yl)amino)methyl)methylpyridinecarboxamide

[1361]

[1362] (R)-N-(2'-chloro-3'-((3-((3-fluoropyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2- methyl-[1,1'-biphenyl]-3-yl)-5-(((3-fluoro-2-methylpyridin-4-yl)amino)methyl)methylpyridinecarboxamide was prepared according to Example 159.

[1363] MS m / z (ESI): 705.2 [M+H] + .

[1364] Example 165

[1365] N-(3'-((3-((6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2'- dichloro-[1,1'-biphenyl]-3-yl)-5-(((((3R,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)methyl)- 4-methoxypyridinecarboxamide

[1366]

[1367] N-(3'-((3-((6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2'- dichloro-[1,1'-biphenyl]-3-yl)-5-(((((3R,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)methyl)- 4-methoxypyridinecarboxamide was prepared according to Example 159.

[1368] MS m / z (ESI): 799.2 [M+H] + .

[1369] Example 166

[1370] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-6-methoxy pyridin-2-yl)-2,2'- dichloro-[1,1'-biphenyl]-3-yl)-5-((((3R,4R)-3-fluorotetrahydrofuran-2H-pyran-4-yl)amino)methyl)- 4-methoxypyridineamide

[1371]

[1372] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-6-methoxy pyridin-2-yl)-2,2'- dichloro-[1,1'-biphenyl]-3-yl)-5-((((3R,4R)-3-fluorotetrahydrofuran-2H-pyran-4-yl)amino)methyl)- 4-methoxypyridineamide

[1373] MS m / z (ESI): 763.7 [M+H] + .

[1374] Example 167

[1375] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-6-methoxy pyridin-2-yl)-2,2'- dichloro-[1,1'-biphenyl]-3-yl)-5-((((3R,4R)-3-fluorotetrahydrofuran-2H-pyran-4-yl)amino)methyl)- 4-methoxypyridineamide

[1376]

[1377] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy-pyridin-2-yl)-2,2'- dichloro-[1,1 '-biphenyl]-3-yl)-5-((((1 R,2S)-2-hydroxycyclohexyl)amino)methyl)-4- methoxypyridine amide

[1378] MS m / z (ESI): 761.2 [M+H] + .

[1379] Example 168

[1380] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy-pyridin-2-yl)-2,2'- dichloro-[1,1 '-biphenyl]-3-yl)-5-((((1 R,2S)-2-hydroxycyclohexyl)amino)methyl)-4- methoxypyridine amide

[1381]

[1382] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy-pyridin-2-yl)-2,2'- dichloro-[1,1 '-biphenyl]-3-yl)-5-((((1 R,2S)-2-hydroxycyclohexyl)amino)methyl)-4- methoxypyridine amide

[1383] MS m / z (ESI): 761.2 [M+H] + .

[1384] Example 169

[1385] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy-pyridin-2-yl)-2,2'- dichloro-[1,1 '-biphenyl]-3-yl)-5-((((1 R,2S)-2-hydroxycyclohexyl)amino)methyl)-4- methoxypyridine amide

[1386]

[1387] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy- pyridin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-5-((((cis)-3- hydroxycyclobutyl)amino)methyl)-4-methoxypyridinecarboxamide

[1388] MS m / z (ESI): 731.2 [M+H] + .

[1389] Example 170

[1390] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy- pyridin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-5-((((cis)-3- hydroxycyclobutyl)amino)methyl)-4-methoxypyridinecarboxamide

[1391]

[1392] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy- pyridin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-5-((((cis)-3- hydroxycyclobutyl)amino)methyl)-4-methoxypyridinecarboxamide

[1393] MS m / z (ESI): 731.2 [M+H] + .

[1394] Example 171

[1395] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy- pyridin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-5-((((cis)-3- hydroxycyclobutyl)amino)methyl)-4-methoxypyridinecarboxamide

[1396]

[1397] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy- pyridin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-5-formyl-4-methoxymethylpyridine- amide (70 mg, 0.106 mmol) and (S)-5-(aminomethyl)pyrrolidin-2-one hydrochloride (45 mg, 0.318 mmol) were dissolved in methanol (4 mL), 3 drops of DIPEA was added to neutralize, then 4 drops of acetic acid was added, stirred at room temperature for 2 hours. After sodium cyanoborohydride (20 mg, 0.318 mmol) was added, continue to stir at room temperature overnight. After the reaction was complete, the reaction was concentrated, the residue was purified by reverse phase column chromatography to obtain the title compound (30.2 mg, 38%).

[1398] MS m / z (ESI): 749.9 [M+H] + .

[1399] Example 172

[1400] (S)-N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy- pyridin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-4-methoxy-5-((((5- carbonylpyrrolidin-2-yl)methyl)amino)methyl)methylpyridineamide

[1401]

[1402] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy- pyridin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-5-formyl-4-methoxymethylpyridine- amide (70 mg, 0.106 mmol) and (S)-5-(aminomethyl)pyrrolidin-2-one hydrochloride (45 mg, 0.318 mmol) were dissolved in methanol (4 mL), 3 drops of DIPEA was added to neutralize, then 4 drops of acetic acid was added, stirred at room temperature for 2 hours. After sodium cyanoborohydride (20 mg, 0.318 mmol) was added, continue to stir at room temperature overnight. After the reaction was complete, the reaction was concentrated, the residue was purified by reverse phase column chromatography to obtain the title compound (30.2 mg, 38%).

[1403] MS m / z (ESI): 758.9 [M+H] + .

[1404] Example 173

[1405] (R)-N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy-pyridin-2-yl)-2,2'- dichloro-[1,1'-biphenyl]-3-yl)-4-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)- pyridine amide

[1406]

[1407] (R)-N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy-pyridin-2-yl)-2,2'- dichloro-[1,1'-biphenyl]-3-yl)-4-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)- pyridine amide was prepared according to Reference Example 109.

[1408] MS m / z (ESI): 758.2 [M+H] + .

[1409] Example 174

[1410] (S)-N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy-pyridin-2-yl)-2,2'- dichloro-[1,1'-biphenyl]-3-yl)-4-methoxy-5-(((6-oxopiperidin-3-yl)amino)methyl)methyl)- pyridine amide

[1411]

[1412] (S)-N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy-pyridin-2-yl)-2,2'- dichloro-[1,1'-biphenyl]-3-yl)-4-methoxy-5-(((6-oxopiperidin-3-yl)amino)methyl)methyl)- pyridine amide was prepared according to Reference Example 109.

[1413] MS m / z (ESI): 758.2 [M+H] + .

[1414] Example 175

[1415] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy-pyridin-2-yl)-2,2'- dichloro-[1,1'-biphenyl]-3-yl)-5-((1-acetyazetidin-3-yl)amino)methyl)-4-methoxy-pyridine amide

[1416]

[1417] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy-pyridin-2-yl)-2,2'- dichloro-[1,1 '-biphenyl]-3-yl)-5-((1 -acetylazetidin-3-yl)amino)methyl)-4- methoxypyridine amide was prepared according to Example 109.

[1418] MS m / z (ESI): 758.2 [M+H] + .

[1419] Example 176

[1420] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy-pyridin-2-yl)-2,2'- dichloro-[1,1 '-biphenyl]-3-yl)-5-((1 -acetylazetidin-3-yl)amino)methyl)-4- methoxypyridine amide was prepared according to Example 109.

[1421]

[1422] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy-pyridin-2-yl)-2,2'- dichloro-[1,1 '-biphenyl]-3-yl)-5-((1 -acetylazetidin-3-yl)amino)methyl)-4- methoxypyridine amide was prepared according to Example 109.

[1423] MS m / z (ESI): 707.2 [M+H] + .

[1424] Example 177

[1425] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy-pyridin-2-yl)-2,2'- dichloro-[1,1 '-biphenyl]-3-yl)-5-((1 -acetylazetidin-3-yl)amino)methyl)-4- methoxypyridine amide was prepared according to Example 109.

[1426]

[1427] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy-pyridin-2-yl)-2,2'- dichloro-[1,1 '-biphenyl]-3-yl)-5-((1 -acetylazetidin-3-yl)amino)methyl)-4- methoxypyridine amide was prepared according to Example 109.

[1428] MS m / z (ESI): 747.2 [M+H] + .

[1429] Example 178

[1430] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy-pyridin-2-yl)-2,2'- dichloro-[1,1'-biphenyl]-3-yl)-5-((4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)methyl)-4- methoxy-pyridine amide

[1431]

[1432] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy-pyridin-2-yl)-2,2'- dichloro-[1,1'-biphenyl]-3-yl)-5-((4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)methyl)-4- methoxy-pyridine amide was prepared according to Example 109.

[1433] MS m / z (ESI): 777.2 [M+H] + .

[1434] Example 179

[1435] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy-pyridin-2-yl)-2,2'- dichloro-[1,1'-biphenyl]-3-yl)-5-((4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)methyl)-4- methoxy-pyridine amide

[1436]

[1437] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy-pyridin-2-yl)-2,2'- dichloro-[1,1'-biphenyl]-3-yl)-5-((4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)methyl)-4- methoxy-pyridine amide was prepared according to Example 109.

[1438] MS m / z (ESI): 813.2 [M+H] + .

[1439] Example 180

[1440] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy-pyridin-2-yl)-2,2'- dichloro-[1,1'-biphenyl]-3-yl)-5-((4-acetylpiperazin-1-yl)methyl)-4-methoxypyridine amide

[1441]

[1442] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy-pyridin-2-yl)-2,2'- dichloro-[1,1'-biphenyl]-3-yl)-5-((4-acetylpiperazin-1-yl)methyl)-4-methoxypyridine amide was prepared according to Reference Example 109.

[1443] MS m / z (ESI): 772.2 [M+H] + .

[1444] Example 181

[1445] 5-((3-acetylaminoazetidin-1-yl)methyl)-N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2- yl)methyl)-6-methoxy-pyridin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-4- methoxymethylpyridine amide

[1446]

[1447] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy-pyridin-2-yl)-2,2'- dichloro-[1,1'-biphenyl]-3-yl)-5-((4-acetylpiperazin-1-yl)methyl)-4-methoxypyridine amide (70 mg, 0.106 mmol) and N-(azetidin-3-yl)acetamide hydrochloride (47 mg, 0.318 mmol) were dissolved in methanol (4 mL), 2 drops of DIPEA was added to neutralize, 3 drops of acetic acid was added, stirred at room temperature for 2 hours. After the addition of sodium cyanoborohydride (20 mg, 0.318 mmol), continue to stir overnight at room temperature. After the reaction was complete, the reaction was concentrated, the residue was purified by reverse phase column chromatography to obtain the title compound (25.5 mg, 32%).

[1448] MS m / z (ESI): 758.9 [M+H] + .

[1449] Example 182

[1450] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy pyridin-2-yl)-2,2'- dichloro-[1,1'-biphenyl]-3-yl)-5-((3-(hydroxymethyl)azetidin-1-yl)methyl)-4- methoxymethylpyridine amide

[1451]

[1452] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy pyridin-2-yl)-2,2'- dichloro-[1,1'-biphenyl]-3-yl)-5-((3-(hydroxymethyl)azetidin-1-yl)methyl)-4- methoxymethylpyridine amide (35 mg, 0.053 mmol) and azetidin-3-ylmethanol hydrochloride (20 mg, 0.159 mmol) were dissolved in methanol (4 mL), after neutralization with 2 drops of DIPEA, 3 drops of acetic acid were added, and stirred at room temperature for 2 hours. After the addition of sodium cyanoborohydride (10 mg, 0.159 mmol), stirring was continued overnight at room temperature. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by reverse phase column chromatography to obtain the title compound (1 mg, 3%).

[1453] MS m / z (ESI): 731.7 [M+H] + .

[1454] Example 183

[1455] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy pyridin-2-yl)-2,2'- dichloro-[1,1'-biphenyl]-3-yl)-5-((3-(hydroxymethyl)azetidin-1-yl)methyl)-4- methoxymethylpyridine amide

[1456]

[1457] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-6-methoxy pyridin-2-yl)-2,2'- dichloro-[1,1'-biphenyl]-3-yl)-5-((3-(hydroxymethyl)azetidin-1-yl)methyl)-4- methoxymethylpyridine amide was prepared according to Example 109.

[1458] MS m / z (ESI): 743.2 [M+H] + .

[1459] Example 184

[1460] N-(3'-(5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-6-methoxypyridin-2-yl)-2,2'- dichloro-[1,1'-biphenyl]-3-yl)-5-(((1,3-dihydroxypropan-2-yl)amino)methyl)-4- methoxymethylpyridinamide

[1461]

[1462] First Step: Preparation of 3'-(5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-6- methoxypyridin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-amine

[1463]

[1464] Dissolve 6-(3'-amino-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde (550 mg, 1.47 mmol) and 2-oxa-6-azaspiro[3.3]heptane (365 mg, 3.69 mmol) in methanol (10 mL), add 5 drops of acetic acid, and stir at room temperature for 2 hours. After adding sodium cyanoborohydride (273 mg, 4.41 mmol), continue stirring at room temperature overnight. After the reaction is complete, concentrate the reaction. Isolate the residue by flash column chromatography on silica gel (DCM:MeOH = 10:1) to obtain the title compound (460 mg, 68%).

[1465] MS m / z (ESI): 456.3 [M+H] + .

[1466] Second Step: Preparation of N-(3'-(5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-6- methoxypyridin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-4-methoxy-5-vinylmethylpyridinamide

[1467]

[1468] Dissolve 3'-(5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-6-methoxypyridin-2-yl)-2,2'- dichloro-[1,1'-biphenyl]-3-amine (456 mg, 1.00 mmol) and methyl 4-methoxy-5- vinylmethylpyridine carboxylate (212 mg, 1.10 mmol) in tetrahydrofuran (10 mL), add 0.9 M LiHMDS in tetrahydrofuran (3.3 mL, 2.97 mmol) at room temperature. Stir the reaction at room temperature overnight. Quench the reaction with methanol, concentrate, and separate the residue by flash silica gel column chromatography (DCM:MeOH = 10:1) to give the title compound (400 mg, 65%).

[1469] MS m / z (ESI): 617.3 [M+H] + .

[1470] Third Step: Preparation of N-(3'-(5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-6- methoxypyridin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-5-formyl-4-methoxymethylpyridine amide

[1471]

[1472] Dissolve N-(3'-(5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-6-methoxypyridin-2-yl)-2,2'- dichloro-[1,1'-biphenyl]-3-yl)-4-methoxy-5-vinylmethylpyridine amide (400 mg, 0.649 mmol) in a mixed solvent of dioxane (10 mL) and water (4 mL), add potassium osmate (26 mg, 0.07 mmol) and sodium periodate (691 mg, 3.25 mmol) sequentially at room temperature. Stir the reaction at room temperature for 2 hours, then quench with saturated aqueous sodium sulfite solution. Extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to give the title compound (350 mg, 87%).

[1473] MS m / z (ESI): 619.8 [M+H] + .

[1474] Fourth Step: Preparation of N-(3'-(5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-6- methoxypyridin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-5-(((1,3-dihydroxypropan-2-yl)amino)methyl)-4-methoxymethylpyridine amide

[1475]

[1476] N-(3'-(5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-6-methoxypyridin-2-yl)-2,2'- dichloro-[1,1'-biphenyl]-3-yl)-5-formyl-4-methoxymethylpyridine amide (110 mg, 0.178 mmol) and 2-aminopropane-1,3-diol (50 mg, 0.533 mmol) were dissolved in methanol (15 mL), 3 drops of acetic acid were added and stirred at room temperature for 2 hours. After the addition of sodium cyanoborohydride (33 mg, 0.533 mmol), stirring was continued at room temperature overnight. After the reaction was complete, the reaction was concentrated and the residue was purified by reverse phase column chromatography to give the title compound (43.4 mg, 35%).

[1477] MS m / z (ESI): 694.8 [M+H] + .

[1478] Example 185

[1479] (S)-N-(2,2'-dichloro-3'-(6-methoxy-5-((oxetan-3-ylamino)methyl)pyridin-2-yl)-[1,1'- biphenyl]-3-yl)-5-(((2-hydroxypropyl)amino)methyl)-4-methoxymethylpyridine amide

[1480]

[1481] First Step: Preparation of methyl (S)-5-(((2-hydroxypropyl)amino)methyl)-4- methoxymethylpyridine carboxylate

[1482]

[1483] Methyl 5-formyl-4-methoxymethylpyridine carboxylate (300 mg, 1.53 mmol) and 3-fluoroazetidine hydrochloride (344 mg, 4.59 mmol) were dissolved in methanol (15 mL), 6 drops of acetic acid were added and stirred at room temperature for 3 hours. After the addition of sodium cyanoborohydride (284 mg, 4.59 mmol), stirring was continued at room temperature overnight. After the reaction was complete, the reaction was cooled and concentrated. The residue was separated by flash silica gel column chromatography (PE:EA = 2:1) to give the title compound (291 mg, 75%).

[1484] MS m / z (ESI): 255.2 [M+H] + .

[1485] Second Step: N-((6-(3'-amino-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-2- methoxypyridin-3-yl)methyl)oxetan-3-amine

[1486]

[1487] Dissolve 6-(3'-amino-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde (373 mg, 1.00 mmol) and oxetan-3-amine (216 mg, 3.00 mmol) in methanol (10 mL), add 8 drops of acetic acid, stir at room temperature for 2 hours. After adding sodium cyanoborohydride (155 mg, 2.50 mmol), continue stirring at room temperature overnight. After the reaction is complete, concentrate the reaction. Isolate the residue by flash column chromatography on silica gel (DCM:MeOH = 10:1) to obtain the title compound (350 mg, 81%).

[1488] MS m / z (ESI): 430.4 [M+H] + .

[1489] Third Step: (S)-N-(2,2'-dichloro-3'-(6-methoxy-5-((oxetan-3-ylamino)methyl)pyridin-2-yl)- [1,1'-biphenyl]-3-yl)-5-(((2-hydroxypropyl)amino)methyl)-4-methoxymethylpyridine amide

[1490]

[1491] Dissolve N-((6-(3'-amino-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)oxetan-3-amine (84 mg, 0.195 mmol) and methyl (S)-5-(((2-hydroxypropyl)amino)methyl)-4- methoxymethylpyridine carboxylate (50 mg, 0.195 mmol) in tetrahydrofuran (3 mL), add 1.3 M LiHMDS in tetrahydrofuran (0.9 mL, 1.17 mmol) at room temperature. Stir the reaction at room temperature for 10 minutes. After quenching the reaction with water, extract with ethyl acetate, concentrate the organic phase, and purify the residue by reverse phase column chromatography to obtain the title compound (3.3 mg, 3%).

[1492] MS m / z (ESI): 652.7 [M+H] + .

[1493] Example 18

[1494] N-(2,2'-dichloro-3'-(6-methoxy-5-((oxetan-3-ylamino)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-5-(((trans-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-4-methoxypicolinamide

[1495]

[1496] Refer to Example 185 for the preparation of N-(2,2'-dichloro-3'-(6-methoxy-5-((oxetan-3-ylamino)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-5-(((trans-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-4-methoxypicolinamide.

[1497] MS m / z(ESI):694.2[M+H] + .

[1498] Example 187

[1499] trans-N-(3'-(5-((3-acetylaminoazetidin-1-yl)methyl)-6-methoxypyridin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-5-(((3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-4-methoxymethylpicolinamide

[1500]

[1501] Step 1: Preparation of N-(3'-(5-((3-acetylaminoazetidin-1-yl)methyl)-6-methoxypyridin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-5-(hydroxymethyl)-4-methoxymethylpicolinamide

[1502]

[1503] N-(2,2'-dichloro-3'-(5-formyl-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-5-(hydroxymethyl)-4-methoxymethylpicolinamide (250 mg, 0.464 mmol) and N-(azetidin-3-yl)acetamide hydrochloric acid (208 mg, 1.39 mmol) were dissolved in methanol (10 mL). After neutralization with DIPEA, 8 drops of acetic acid were added and the mixture was stirred at room temperature for 2 hours. Sodium cyanoborohydride (86 mg, 1.39 mmol) was added and stirring continued at room temperature overnight. After completion of the reaction, the reaction mixture was concentrated and the residue was isolated by flash silica gel column chromatography (DCM:MeOH = 10:1) to obtain the title compound (150 mg, 25%).

[1504] MS m / z (ESI): 636.8 [M+H] + .

[1505] Step 2: Preparation of N-(3'-(5-((3-acetylaminoazetidin-l-yl)methyl)-6- methoxypyridin-2-yl)-2,2'-dichloro-[l,l'-biphenyl]-3-yl)-5-formyl-4- methoxymethylpyridinamide

[1506]

[1507] N-(3'-(5-((3-acetylaminoazetidin-l-yl)methyl)-6-methoxypyridin-2-yl)-2,2'- dichloro-[l,l'-biphenyl]-3-yl)-5-(hydroxymethyl)-4-methoxymethylpyridinamide (150 mg, 0.236 mmol) was dissolved in dichloromethane (10 mL), sodium bicarbonate (198 mg, 2.36 mmol) and DMP (150 mg, 0.354 mmol) were added sequentially at room temperature. The resulting reaction was stirred at room temperature for 2 hours. The reaction was diluted with dichloromethane, the organic phase was washed sequentially with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the title compound (150 mg, 99%).

[1508] MS m / z (ESI): 634.7 [M+H] + .

[1509] Step 3: Preparation of trans-N-(3'-(5-((3-acetylaminoazetidin-l-yl)methyl)-6- methoxypyridin-2-yl)-2,2'-dichloro-[l,l'-biphenyl]-3-yl)-5-(((3- hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-4-methoxymethylpyridinamide

[1510]

[1511] N-(3'-(5-((3-acetylazetidin-1-yl)methyl)-6-methoxypyridin-2-yl)-2,2'- dichloro-[1,1'-biphenyl]-3-yl)-5-((((3S,4R)-1-acetyl-3-fluoropiperidin-4-yl)amino)methyl)- 4-methoxymethylpyridinecarboxamide

[1512] MS m / z (ESI): 735.7 [M+H] + .

[1513] Example 188

[1514] N-(3'-(5-((3-acetylazetidin-1-yl)methyl)-6-methoxypyridin-2-yl)-2,2'- dichloro-[1,1'-biphenyl]-3-yl)-5-((((3S,4R)-1-acetyl-3-fluoropiperidin-4-yl)amino)methyl)- 4-methoxymethylpyridinecarboxamide

[1515]

[1516] N-(3'-(5-((3-acetylazetidin-1-yl)methyl)-6-methoxypyridin-2-yl)-2,2'- dichloro-[1,1'-biphenyl]-3-yl)-5-((((3S,4R)-1-acetyl-3-fluoropiperidin-4-yl)amino)methyl)- 4-methoxymethylpyridinecarboxamide

[1517] MS m / z (ESI): 778.9 [M+H] + .

[1518] Example 189

[1519] (S)-N-(3'-(5-((3-acetylazetidin-1-yl)methyl)-6-methoxy-pyridin-2-yl)-2,2'- dichloro-[1,1'-biphenyl]-3-yl)-4-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl) pyridine amide

[1520]

[1521] (S)-N-(3'-(5-((3-acetylazetidin-1-yl)methyl)-6-methoxy-pyridin-2-yl)-2,2'- dichloro-[1,1'-biphenyl]-3-yl)-4-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl) pyridine amide was prepared according to Reference Example 187.

[1522] MS m / z (ESI): 732.2 [M+H] + .

[1523] Example 190

[1524] trans-N-(2,2'-dichloro-3'-(5-((3-(cyanomethyl)azetidin-1-yl)methyl)-6-methoxy-pyridin-2-yl)- [1,1'-biphenyl]-3-yl)-5-(((3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-4- methoxymethylpyridine amide

[1525]

[1526] First step: N-(2,2'-dichloro-3'-(5-((3-(cyanomethyl)azetidin-1-yl)methyl)-6-methoxy-pyridin-2-yl)- [1,1'-biphenyl]-3-yl)-5-(hydroxymethyl)-4-methoxymethylpyridine amide

[1527]

[1528] N-(2,2'-dichloro-3'-(5-formyl-6-methoxy-pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-5- (hydroxymethyl)-4-methoxymethylpyridine amide (250 mg, 0.464 mmol) and 2-(azetidin-3- yl)acetonitrile hydrochloride (183 mg, 1.39 mmol) were dissolved in methanol (10 mL), after neutralization with DIPEA, 8 drops of acetic acid were added, and stirred at room temperature for 2 hours. After the addition of sodium cyanoborohydride (86 mg, 1.39 mmol), stirring was continued overnight at room temperature. After the completion of the reaction, the reaction solution was concentrated, and the residue was separated by flash silica gel column chromatography (DCM:MeOH = 10:1) to obtain the title compound (170 mg, 60%).

[1529] MS m / z (ESI): 618.8 [M+H] + .

[1530] Step 2: Preparation of N-(2,2'-dichloro-3'-(5-((3-(cyanomethyl)azetidin-1-yl)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-5-formyl-4-methoxymethylpyridinamide

[1531]

[1532] N-(2,2'-dichloro-3'-(5-((3-(cyanomethyl)azetidin-1-yl)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-5-(hydroxymethyl)-4-methoxymethylpyridinamide (170 mg, 0.275 mmol) was dissolved in dichloromethane (10 mL), sodium bicarbonate (231 mg, 2.75 mmol) and DMP (174 mg, 0.413 mmol) were added sequentially at room temperature. The resulting reaction was stirred at room temperature for 2 hours. The reaction was diluted with dichloromethane, the organic phase was washed sequentially with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the title compound (168 mg, 99%).

[1533] MS m / z (ESI): 616.7 [M+H] + .

[1534] Step 3: Preparation of trans-N-(2,2'-dichloro-3'-(5-((3-(cyanomethyl)azetidin-1-yl)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-5-(((3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-4-methoxymethylpyridinamide

[1535]

[1536] N-(2,2'-dichloro-3'-(5-((3-(cyanomethyl)azetidin-l-yl)methyl)-6-methoxypyridin-2-yl)- [1,1'-biphenyl]-3-yl)-5-formyl-4-methoxymethylpyridine amide (90 mg, 0.146 mmol) and trans-4-aminotetrahydro-2H-pyran-3-ol (52 mg, 0.468 mmol) were dissolved in methanol (4 mL), 3 drops of acetic acid were added and stirred at room temperature for 2 hours. After the addition of sodium cyanoborohydride (27 mg, 0.437 mmol), stirring was continued overnight at room temperature. After the reaction was complete, the reaction was concentrated and the residue was purified by reverse phase column chromatography to give the title compound (15.7 mg, 14%).

[1537] MS m / z (ESI): 717.7 [M+H] + .

[1538] Example 191

[1539] (S)-N-(2,2'-dichloro-3'-(5-((3-(cyanomethyl)azetidin-l-yl)methyl)-6-methoxypyridin-2-yl)- [1,1'-biphenyl]-3-yl)-4-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridine amide

[1540]

[1541] (S)-N-(2,2'-dichloro-3'-(5-((3-(cyanomethyl)azetidin-l-yl)methyl)-6-methoxypyridin-2-yl)- [1,1'-biphenyl]-3-yl)-4-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridine amide was prepared according to Example 190.

[1542] MS m / z (ESI): 714.2 [M+H] + .

[1543] Example 192

[1544] N-(3'-(5-((3-acetylaminoazetidin-l-yl)methyl)-6-methoxypyridin-2-yl)-2,2'-dichloro- [1,1'-biphenyl]-3-yl)-5-(((((3S,4R)-l-acetyl-3-fluoropiperidin-4-yl)amino)methyl)-4- methoxypyridine amide

[1545]

[1546] N-(3'-(5-((3-acetylazetidin-1-yl)methyl)-6-methoxy-pyridin-2-yl)-2,2'- dichloro-[1,1'-biphenyl]-3-yl)-5-(((((3S,4R)-1-acetyl-3-fluoro-piperidin-4-yl)amino)- methyl)-4-methoxy-picolinamide was prepared according to Example 187.

[1547] MS m / z (ESI): 778.2 [M+H] + .

[1548] Example 193

[1549] trans-N-(2,2'-Dichloro-3'-(5-(((3-hydroxy-tetrahydro-2H-pyran-4-yl)amino)- methyl)-6-methoxy-pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-4-methoxy-5-(((2-(methylamino)- 2-oxo-ethyl)amino)methyl)methyl-picolinamide

[1550]

[1551] First step: trans-N-(2,2'-Dichloro-3'-(5-(((3-hydroxy-tetrahydro-2H-pyran-4-yl)amino)- methyl)-6-methoxy-pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-5-(hydroxymethyl)-4- methoxymethyl-picolinamide

[1552]

[1553] N-(2,2'-Dichloro-3'-(5-formyl-6-methoxy-pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-5- (hydroxymethyl)-4-methoxymethyl-picolinamide (250 mg, 0.464 mmol) and trans-4- aminotetrahydro-2H-pyran-3-ol (163 mg, 1.39 mmol) were dissolved in methanol (10 mL), 5 drops of acetic acid were added and stirred at room temperature for 2 hours. After the addition of sodium cyanoborohydride (84.7 mg, 1.39 mmol), stirring was continued overnight at room temperature. After the reaction was complete, the reaction was concentrated and the residue was separated by flash column chromatography on silica gel (DCM:MeOH = 10:1) to give the title compound (230 mg, 77%).

[1554] MS m / z (ESI): 639.5 [M+H] + .

[1555] Step 2: trans-N-(2,2'-dichloro-3'-(5-(((3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)- 6-methoxypyridin-2-yl)-[1,1 '-biphenyl]-3-yl)-5-formyl-4-methoxymethylpyridinamide

[1556]

[1557] trans-N-(2,2'-dichloro-3'-(5-(((3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)- 6-methoxypyridin-2-yl)-[1,1 '-biphenyl]-3-yl)-5-(hydroxymethyl)-4-methoxymethylpyridinamide (230 mg, 0.359 mmol) was dissolved in dichloromethane (20 mL) and manganese dioxide (625 mg, 7.19 mmol) was added at room temperature. The reaction was refluxed at 50 °C for 48 h. The reaction was cooled, filtered and the filtrate was concentrated to give the title compound (160 mg, 69%).

[1558] MS m / z (ESI): 637.7 [M+H] + .

[1559] Step 3: trans-N-(2,2'-dichloro-3'-(5-(((3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)- 6-methoxypyridin-2-yl)-[1,1 '-biphenyl]-3-yl)-4-methoxy-5-(((2-(methylamino)-2- oxoethyl)amino)methyl)methylpyridinamide

[1560]

[1561] trans-N-(2,2'-dichloro-3'-(5-(((3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)- 6-methoxypyridin-2-yl)-[1,1 '-biphenyl]-3-yl)-5-formyl-4-methoxymethylpyridinamide (50 mg, 0.079 mmol) and 2-amino-N-methyl-acetamide (21 mg, 0.235 mmol) were dissolved in methanol (4 mL) and 3 drops of acetic acid were added. The reaction was stirred at room temperature for 2 h. Sodium cyanoborohydride (15 mg, 0.237 mmol) was added and the reaction was stirred at room temperature overnight. The reaction was complete and the reaction was concentrated. The residue was purified by reverse phase column chromatography to give the title compound (14.7 mg, 25%).

[1562] MS m / z (ESI): 709.4 [M+H] + .

[1563] Example 19

[1564] N-(2,2'-dichloro-3'-(5-((((trans-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-6- methoxypyridin-2-yl)-[1,1 '-biphenyl]-3-yl)-4-methoxy-5-((oxetan-3-ylamino)methyl)picolinamide

[1565]

[1566] N-(2,2'-dichloro-3'-(5-((((trans-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-6- methoxypyridin-2-yl)-[1,1 '-biphenyl]-3-yl)-4-methoxy-5-((oxetan-3-ylamino)methyl)picolinamide

[1567] MS m / z (ESI): 694.2 [M+H] + .

[1568] Example 195

[1569] 5-((((1-cyanocyclopropyl)methyl)amino)methyl)-N-(2,2'-dichloro-3'-(5-(((((trans-3- hydroxytetrahydrofuran-2H-pyran-4-yl)amino)methyl)-6-methoxypyridin-2-yl)-[1,1 '- biphenyl]-3-yl)-4-methoxypyridinamide

[1570]

[1571] 5-((((1-cyanocyclopropyl)methyl)amino)methyl)-N-(2,2'-dichloro-3'-(5-(((((trans-3- hydroxytetrahydrofuran-2H-pyran-4-yl)amino)methyl)-6-methoxypyridin-2-yl)-[1,1 '- biphenyl]-3-yl)-4-methoxypyridinamide

[1572] MS m / z (ESI): 717.2 [M+H] + .

[1573] Example 196

[1574] N-(2,2'-dichloro-3'-(5-((3-(hydroxymethyl)azetidin-1-yl)methyl)-4-methoxy- pyrimidin-2-yl]-[1,1 '-biphenyl]-3-yl)-5-((((trans-3-hydroxytetrahydro-2H-pyran-4- yl)amino)methyl)-4-methoxypyridinamide

[1575]

[1576] First Step: Preparation of 2-chloro-4-methoxy-5-vinylpyrimidine

[1577]

[1578] To a solution of 5-bromo-2-chloro-4-methoxy-pyrimidine (10 g, 44.75 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (8.27 g, 53.70 mmol), palladium acetate (1.00 g, 4.48 mmol), triphenylphosphine (2.35 g, 8.95 mmol) and potassium carbonate (12.37 g, 89.50 mmol) in a mixture of acetonitrile (40 mL) and methanol (20 mL) was added, the reaction system was protected by dry nitrogen, heated to 40 °C and stirred for 3.5 hours. Silica gel was added and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to give the title compound (5.37 g, 70%).

[1579] MS m / z (ESI): 171.1 [M+H] + .

[1580] Second Step: Preparation of 2-chloro-4-methoxypyrimidine-5-carbaldehyde

[1581]

[1582] To a solution of 2-chloro-4-methoxy-5-vinylpyrimidine (5.37 g, 31.48 mmol) in a mixture of dioxane (300 mL) and water (120 mL) was added potassium osmate dihydrate (116 mg, 314.78 umol) and sodium periodate (40.4 g, 188.87 mmol) under stirring at room temperature. The reaction solution was stirred at room temperature for 1.5 hours. Most of the organic solvent was removed by concentration under reduced pressure. The residue was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated aqueous sodium thiosulfate solution and saturated aqueous sodium chloride solution, respectively, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to give the title compound (3.27 g, 60%).

[1583] MS m / z (ESI): 173.1 [M+H] + .

[1584] Third Step: Preparation of 2-(3-bromo-2-chlorophenyl)-4-methoxypyrimidine-5- carbaldehyde

[1585]

[1586] (3-bromo-2-chloro-phenyl)boronic acid (2.08 g, 8.84 mmol), 2-chloro-4-methoxy- pyrimidine-5-carbaldehyde (1.98 g, 11.49 mmol), Pd(PPh3)4(1.02 g, 884.09 umol) and K2CO3(2.44 g, 17.68 mmol) were added into a mixture solvent of dioxane (40 mL) and water (4 mL), the reaction was saturated with nitrogen, and heated to 100 °C in a microwave synthesis instrument for 5.5 h. The solvent was removed by concentration under reduced pressure, the residue was dispersed in ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography to give (2.0 g, 69%).

[1587] MS m / z (ESI): 327.0 [M+H] + .

[1588] Fourth Step: Preparation of 2-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)- 4-methoxypyrimidine-5-carbaldehyde

[1589]

[1590] 2-(3-bromo-2-chloro-phenyl)-4-methoxy-pyrimidine-5-carbaldehyde (2.59 g, 7.89 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (3.01 g, 11.84 mmol), Pd(dppf)Cl2(644.46 mg, 789.17 umol) and potassium acetate (1.55 g, 15.78 mmol) were added into dioxane (100 mL), the reaction system was protected with dry nitrogen, and heated to 100 °C for stirring reaction for 4 h. The solvent was removed by concentration under reduced pressure, and the residue was separated by silica gel column chromatography to give the title compound (1.55 g, 52%).

[1591] MS m / z (ESI): 375.2 [M+H] + .

[1592] Third Step: Preparation of N-(2,2'-dichloro-3'-(5-formyl-4-methoxypyrimidin-2-yl)-[1,1'- biphenyl]-3-yl)-5-(hydroxymethyl)-4-methoxymethylpyridinamide

[1593]

[1594] N-(3-bromo-2-chlorophenyl)-5-(hydroxymethyl)-4-methoxymethylpyridinamide (210 mg, 0.566 mmol), 2-(2-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-4- methoxypyrimidine-5-carbaldehyde (254 mg, 0.679 mol), Pd(dppf)Cl2dichloromethane complex (50 mg, 0.06 mmol) and cesium carbonate (460 mg, 1.42 mmol) were dissolved in a mixed solvent of dioxane (10 mL) and water (1 mL), and degassed with nitrogen. The reaction was stirred at 95 °C overnight. After the reaction was completed, the reaction solution was cooled and concentrated. The residue was separated by flash silica gel column chromatography to obtain the title compound (200 mg, 66%).

[1595] MS m / z (ESI): 539.1 [M+H] + .

[1596] Fourth Step: Preparation of N-(2,2'-dichloro-3'-(5-((3-(hydroxymethyl)azetidin-l- yl)methyl)-4-methoxypyrimidin-2-yl)-[l,l'-biphenyl]-3-yl)-5-(hydroxymethyl)-4- methoxymethylpyridinamide

[1597]

[1598] N-(2,2'-dichloro-3'-(5-formyl-4-methoxypyrimidin-2-yl)-[l,l'-biphenyl]-3-yl)-5- (hydroxymethyl)-4-methoxymethylpyridinamide (200 mg, 0.372 mmol) and azetidin-3- ylmethanol hydrochloride (183 mg, 1.48 mmol) were dissolved in a mixed solvent of 1,2- dichloroethane (10 mL) and methanol (10 mL), and DIPEA (191 mg, 1.48 mmol) was added. The reaction was stirred at 40 °C for 2 hours. After sodium boron acetate (788 mg, 3.72 mmol) was added, the reaction was stirred at 40 °C overnight. After the reaction was completed, the reaction solution was concentrated, and the residue was separated by silica gel column chromatography to obtain the title compound (166 mg, 73%).

[1599] MS m / z (ESI): 610.2 [M+H] + .

[1600] Fifth Step: Preparation of N-(2,2'-dichloro-3'-(5-((3-(hydroxymethyl)azetidin-l- yl)methyl)-4-methoxypyrimidin-2-yl)-[l,l'-biphenyl]-3-yl)-5-formyl-4- methoxymethylpyridinamide

[1601]

[1602] N-(2,2'-dichloro-3'-(5-((3-(hydroxymethyl)azetidin-l-yl)methyl)-4- methoxypyrimidin-2-yl)-[l,l'-biphenyl]-3-yl)-5-(hydroxymethyl)-4- methoxymethylpyridine amide (166 mg, 0.271 mmol) was dissolved in 1,2- dichloroethane (10 mL), and activated manganese dioxide (707 mg, 8.13 mmol) was added sequentially at room temperature, and the reaction was heated to 50 °C and stirred for 3 h. It was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (91 mg, 55%).

[1603] MS m / z (ESI): 608.1 [M+H] + .

[1604] Sixth Step: Preparation of N-(2,2'-dichloro-3'-(5-((3-(hydroxymethyl)azetidin-l-yl)methyl)-4- methoxypyrimidin-2-yl)-[l,l'-biphenyl]-3-yl)-5-(((trans-3-hydroxytetrahydro-2H- pyran-4-yl)amino)methyl)-4-methoxymethylpyridine amide

[1605]

[1606] N-(2,2'-dichloro-3'-(5-((3-(hydroxymethyl)azetidin-l-yl)methyl)-4- methoxypyrimidin-2-yl)-[l,l'-biphenyl]-3-yl)-5-(((trans-3-hydroxytetrahydro-2H- pyran-4-yl)amino)methyl)-4-methoxymethylpyridine amide (91 mg, 0.15 mmol) and trans-4-aminotetrahydropyran-3-ol (35 mg, 0.3 mmol) were dissolved in methanol (4 mL), and after the addition of DIPEA (39 mg, 0.3 mmol), it was stirred at room temperature for 2 h. After the addition of sodium borohydride in acetic acid (318 mg, 1.5 mmol), it was stirred for another 30 min. After the reaction was completed, the reaction was concentrated, and the residue was subjected to prep-HPLC to give the title compound (6.6 mg, 6%).

[1607] MS m / z (ESI): 709.2 [M+H] + .

[1608] Example 197

[1609] 5-((((3S,4R)-l-acetyl-3-fluoropiperidin-4-yl)amino)methyl)-N-(2,2'-dichloro-3'-(5- ((3-(hydroxymethyl)azetidin-l-yl)methyl)-4-methoxypyrimidin-2-yl)-[l,l'-biphenyl]- 3-yl)-4-methoxypyridine amide

[1610]

[1611] 5-((((3S,4R)-1-acetyl-3-fluoropiperidin-4-yl)amino)methyl)-N-(2,2'- dichloro-3'-(5-((3-(hydroxymethyl)azetidin-1-yl)methyl)-4-methoxy pyrimidin-2-yl)-[1,1'-biphenyl]-3-yl)-4-methoxypyridine amide was prepared according to Example 196.

[1612] MS m / z (ESI): 752.2 [M+H] + .

[1613] Example 198

[1614] 5-((3-acetylaminoazetidin-1-yl)methyl)-N-(2,2'-dichloro-3'-(5-((3- (hydroxymethyl)azetidin-1-yl)methyl)-4-methoxypyrimidin-2-yl)-[1,1'-biphenyl]-3-yl)- 4-methoxypyridine amide

[1615]

[1616] 5-((3-acetylaminoazetidin-1-yl)methyl)-N-(2,2'-dichloro-3'-(5-((3- (hydroxymethyl)azetidin-1-yl)methyl)-4-methoxypyrimidin-2-yl)-[1,1'-biphenyl]-3-yl)- 4-methoxypyridine amide was prepared according to Example 196.

[1617] MS m / z (ESI): 706.2 [M+H] + .

[1618] Example 199

[1619] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-4-methoxypyrimidin-2- yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-5-(((((3S,4R)-1-acetyl-3-fluoropiperidin-4- yl)amino)methyl)-4-methoxypyridine amide

[1620]

[1621] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]oct-2-yl)methyl)-4-methoxy- pyrimidin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-5-(((((3S,4R)-1-acetyl-3- fluoropiperidin-4-yl)amino)methyl)-4-methoxy-pyridine amide was prepared according to Example 196.

[1622] MS m / z (ESI): 805.2 [M+H] + .

[1623] Example 200

[1624] N-(2,2'-dichloro-3'-(5-((((trans-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)- 4-methoxy-pyrimidin-2-yl)-[1,1'-biphenyl]-3-yl)-4-methoxy-5-((2-(methylamino)-2- oxo-ethyl)amino)methyl)methyl)pyridine amide

[1625]

[1626] N-(2,2'-dichloro-3'-(5-((((trans-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)- 4-methoxy-pyrimidin-2-yl)-[1,1'-biphenyl]-3-yl)-4-methoxy-5-((2-(methylamino)-2- oxo-ethyl)amino)methyl)methyl)pyridine amide was prepared according to Example 196.

[1627] MS m / z (ESI): 710.2 [M+H] + .

[1628] Example 201

[1629] 5-((3-acetylaminoazetidin-1-yl)methyl)-N-(2,2'-dichloro-3'-(5-((((trans-3- hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-4-methoxy-pyrimidin-2-yl)-[1,1'- biphenyl]-3-yl)-4-methoxy-pyridine amide

[1630]

[1631] 5-((3-acetylaminoazetidin-1-yl)methyl)-N-(2,2'-dichloro-3'-(5-((((trans-3- hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-4-methoxy-pyrimidin-2-yl)-[1,1'- biphenyl]-3-yl)-4-methoxy-pyridine amide was prepared according to Example 196.

[1632] MS m / z (ESI): 736.2 [M+H] + .

[1633] Example 202

[1634] N-(2-chloro-3'-(7-cyano-5-(((1,3-dihydroxypropan-2-yl)amino)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((1,3-dihydroxypropan-2-yl)amino)methyl)-4-methoxymethylpyridine amide

[1635]

[1636] First Step: Preparation of N-(2-chloro-3'-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(hydroxymethyl)-4-methoxymethylpyridine amide

[1637]

[1638] N-(3-bromo-2-chloro-phenyl)-5-(hydroxymethyl)-4-methoxy-pyridine-2-carboxamide (1.25 g, 3.36 mmol), 5-formyl-2-[2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazole-7-carbonitrile (2.61 g, 6.73 mmol), cesium carbonate (3.29 g, 10.09 mmol) and X-Phos PdG2 (264.66 mg, 336.37 umol) were added to a reaction flask, dioxane (50 mL) and water (10 mL) were added, the reaction system was vacuumed and protected by nitrogen, heated to 100 °C and stirred for 6 hours, then 5-formyl-2-[2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazole-7-carbonitrile (1.3 g, 3.36 mmol) and X-Phos PdG2 (264.66 mg, 336.37 umol) were added, the reaction was continued to be stirred at 100 °C for 17 hours, cooled to room temperature, the solvent was removed by concentration under reduced pressure, the residue was diluted with water, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by silica gel column chromatography to obtain the title compound (0.82 g, 44%).

[1639] MS m / z (ESI): 736.2 [M+H] + .

[1640] Step 2: Preparation of N-(2-chloro-3'-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)-5-formyl-4-methoxymethylpyridinamide

[1641]

[1642] N-(2-chloro-3'-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)- 5-(hydroxymethyl)-4-methoxymethylpyridinamide (100 mg, 0.18 mmol) was dissolved in dichloromethane (10 mL) and DMP (116 mg, 0.27 mmol) was added with stirring at room temperature. The reaction was stirred at room temperature for 20 minutes, diluted with dichloromethane, washed sequentially with saturated aqueous sodium thiosulfate, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was used directly in the next step.

[1643] MS m / z (ESI): 551.1 [M+H] + .

[1644] Step 3: Preparation of N-(2-chloro-3'-(7-cyano-5-(((1,3-dihydroxypropan-2-yl)amino)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((1,3-dihydroxypropan-2-yl)amino)methyl)-4-methoxymethylpyridinamide

[1645]

[1646] N-(2-chloro-3'-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)- 5-formyl-4-methoxymethylpyridinamide crude (0.18 mmol) was dispersed in methanol (10 mL), and serinol (49 mg, 0.54 mmol) and DIPEA (0.285 mL, 1.8 mmol) were added. The reaction was heated to 40 °C and stirred for 2 hours. Sodium borohydride acetate (381 mg, 1.8 mmol) was added and the reaction was stirred at 40 °C for an additional 30 minutes. The solvent was removed under reduced pressure and the residue was separated by prep-HPLC to give the title product (10.8 mg, 9%). MS m / z (ESI): 701.2 [M+H] + .

[1647] Example 20

[1648] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-7-cyano- benzo[d]oxazol-2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((1,3- dihydroxypropan-2-yl)amino)methyl)-4-methoxymethylpyridazineamide

[1649]

[1650] First Step: Preparation of 5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-2-(3- bromo-2-methylphenyl)benzo[d]oxazole-7-carbonitrile

[1651]

[1652] To a solution of 2-(3-bromo-2-methylphenyl)-5-formylbenzo[d]oxazole-7- carbonitrile (1 g, 2.93 mmol), 1-(2,6-diazaspiro[3.3]octan-2-yl)ethan-1-one (616 mg, 4.4 mmol) and acetic acid (176 mg, 2.93 mmol) in dichloromethane (40 mL) was stirred at room temperature for 1 h. Then sodium cyanoborohydride (369 mg, 5.86 mmol) was added and the reaction was continued at room temperature overnight. The reaction was extracted with dichloromethane (25 mL x 3) and washed with saturated aqueous sodium chloride solution (20 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (DCM:MeOH = 95:5) to give the title compound (1.3 g, 95%).

[1653] MS m / z (ESI): 465.1 [M+H] + .

[1654] Second Step: Preparation of 5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-2-(2- methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazole-7- carbonitrile

[1655]

[1656] A mixture of 5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-2-(3-bromo-2- methylphenyl)benzo[d]oxazole-7-carbonitrile (1.3 g, 2.79 mol), bis(pinacolato)diboron (1.42 g, 5.58 mol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (204 mg, 0.279 mol) and potassium acetate (821 mg, 8.38 mol) was suspended in dry 1,4-dioxane (40 mL) and heated at 110 °C with stirring overnight under nitrogen. The reaction was extracted with dichloromethane (25 mL x 3) and washed with saturated aqueous sodium chloride (20 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting product was purified by column chromatography on silica gel (DCM:MeOH = 95:5) to give the title compound (700 mg, 49%).

[1657] MS m / z (ESI): 512.2 [M+H] + .

[1658] Step 3: Preparation of N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-7- cyano benzo[d]oxazol-2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5- (hydroxymethyl)-4-methoxymethylpyridinamide

[1659]

[1660] A mixture of N-(3-bromo-2-chlorophenyl)-5-(hydroxymethyl)-4- methoxymethylpyridinamide (419 mg, 1.13 mmol), 5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazole-7-carbonitrile (700 mg, 1.36 mmol), [1,1'-bis(dicyclohexylphosphino)ferrocene]dichloropalladium (86 mg, 0.113 mmol) and cesium carbonate (737 mg, 2.26 mmol) was suspended in tert-butanol (20 mL) and water (4 mL), replaced with nitrogen three times, and heated at 100 °C with stirring overnight. The reaction was extracted with dichloromethane (15 mL x 3) and washed with saturated aqueous sodium chloride (10 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting product was purified by column chromatography on silica gel (DCM:MeOH = 95:5) to give the title compound (412 mg, 54%).

[1661] MS m / z (ESI): 677.1 [M+H] + .

[1662] Fourth Step: Preparation of N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-7- cyano-benzo[d]oxazol-2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5- formyl-4-methoxymethyl-pyridinamide

[1663]

[1664] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-7-cyano-benzo[d]oxazol-2-yl)- 2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(hydroxymethyl)-4-methoxymethyl-pyridinamide (400 mg, 0.59 mmol) and Dess-Martin Oxidizing Reagent (376 mg, 0.89 mmol) were suspended in dichloromethane (10 mL), the reaction was stirred at room temperature for 1 hour. The reaction was extracted with dichloromethane (15 mL x 3) after reaction was finished, washed with saturated aqueous sodium chloride solution (10 mL x 3), the organic phase was collected and dried over anhydrous sodium sulfate, filtered and the organic phase was concentrated under reduced pressure, the obtained product was separated and purified by silica gel column chromatography (DCM:MeOH = 95:5) to give the title compound (375 mg, 94%).

[1665] MS m / z (ESI): 675.1 [M+H] + .

[1666] Fifth Step: Preparation of N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-7- cyano-benzo[d]oxazol-2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((1,3- dihydroxypropan-2-yl)amino)methyl)-4-methoxymethyl-pyridinamide

[1667]

[1668] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-7-cyano- benzo[d]oxazol-2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((trans-3- hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-4-methoxymethylpyridinecarboxamide

[1669] MS m / z (ESI): 750.2 [M+H] + .

[1670] Example 204

[1671] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-7-cyano- benzo[d]oxazol-2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((trans-3- hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-4-methoxymethylpyridinecarboxamide

[1672]

[1673] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-7-cyano- benzo[d]oxazol-2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((trans-3- hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-4-methoxymethylpyridinecarboxamide

[1674] MS m / z (ESI): 776.2 [M+H] + .

[1675] Example 205

[1676] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-7- cyanobenzo[d]oxazol-2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((((1R,2S)- 2-hydroxycyclohexyl)amino)methyl)-4-methoxypyridine amide

[1677]

[1678] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-7- cyanobenzo[d]oxazol-2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((((1R,2S)- 2-hydroxycyclohexyl)amino)methyl)-4-methoxypyridine amide was prepared according to Example 203.

[1679] MS m / z (ESI): 774.2 [M+H] + .

[1680] Example 206

[1681] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-7- cyanobenzo[d]oxazol-2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((trans-3- hydroxycyclobutyl)amino)methyl)-4-methoxymethylpyridine amide

[1682]

[1683] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-7-cyano- benzo[d]oxazol-2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((((cis)-3- hydroxycyclobutyl)amino)methyl)-4-methoxypyridinecarboxamide

[1684] MS m / z (ESI): 746.1 [M+H] + .

[1685] Example 207

[1686] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-7-cyano- benzo[d]oxazol-2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((((cis)-3- hydroxycyclobutyl)amino)methyl)-4-methoxypyridinecarboxamide

[1687]

[1688] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-7-cyano- benzo[d]oxazol-2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((((cis)-3- hydroxycyclobutyl)amino)methyl)-4-methoxypyridinecarboxamide

[1689] MS m / z (ESI): 746.2 [M+H] + .

[1690] Example 208

[1691] (R)-N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-7- cyanobenzo[d]oxazol-2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-4- methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridinecarboxamide

[1692]

[1693] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-7-cyanobenzo[d]oxazol- 2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-formyl-4-methoxymethylpyridinecarboxamide (30 mg, 0.044 mmol), (R)-5-(aminomethyl)pyrrolidin-2-one (10 mg, 0.088 mmol) and one drop of acetic acid were dissolved in N,N-dimethylformamide (5 mL) and stirred at room temperature for 1 hour. Then sodium cyanoborohydride (6.3 mg, 0.1 mmol) was added and the reaction was continued at room temperature overnight. The reaction was completed by extracting the reaction mixture with dichloromethane (15 mL x 3), washing with saturated aqueous sodium chloride solution (10 mL x 3), collecting the organic phase, drying over anhydrous sodium sulfate, filtering and concentrating the organic phase under reduced pressure. The resulting product was subjected to prep-HPLC to obtain the title compound (15.3 mg, 45%).

[1694] MS m / z (ESI): 773.1 [M+H] + .

[1695] Example 209

[1696] (S)-N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-7-cyanobenzo[d]oxazol- 2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-4-methoxy-5-((((5-oxopyrrolidin-2- yl)methyl)amino)methyl)pyridinecarboxamide

[1697]

[1698] (S)-N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-7-cyanobenzo[d]oxazol- 2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-4-methoxy-5-((((5-oxopyrrolidin-2- yl)methyl)amino)methyl)pyridinecarboxamide was prepared according to Example 203.

[1699] MS m / z (ESI): 773.2 [M+H] + .

[1700] Example 210

[1701] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-7- cyano benzo [d] oxazol-2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((2- cyanoethyl)amino)methyl)-4-methoxy-pyridine amide

[1702]

[1703] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-7- cyano benzo [d] oxazol-2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((2- cyanoethyl)amino)methyl)-4-methoxy-pyridine amide was prepared according to Example 203.

[1704] MS m / z (ESI): 729.2 [M+H] + .

[1705] Example 211

[1706] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-7- cyano benzo [d] oxazol-2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((((1- cyano cyclopropyl)methyl)amino)methyl)-4-methoxy-pyridine amide

[1707]

[1708] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-7- cyano benzo [d] oxazol-2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-(((((1- cyano cyclopropyl)methyl)amino)methyl)-4-methoxy-pyridine amide was prepared according to Example 203.

[1709] MS m / z (ESI): 755.2 [M+H] + .

[1710] Example 212

[1711] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-7-cyano- benzo [d] oxazol-2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-((2,2- dimethylpyrrolidin-1-yl)methyl)-4-methoxy-pyridine amide

[1712]

[1713] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-7-cyano- benzo [d] oxazol-2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-((2,2- dimethylpyrrolidin-1-yl)methyl)-4-methoxy-pyridine amide was prepared according to Reference Example 203.

[1714] MS m / z (ESI): 758.2 [M+H] + .

[1715] Example 213

[1716] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-7-cyano- benzo [d] oxazol-2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-((4-(fluoromethyl)- 4-hydroxypiperidin-1-yl)methyl)-4-methoxy-pyridine amide

[1717]

[1718] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-7-cyano- benzo [d] oxazol-2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-((4-(fluoromethyl)- 4-hydroxypiperidin-1-yl)methyl)-4-methoxy-pyridine amide was prepared according to Reference Example 203.

[1719] MS m / z (ESI): 792.2 [M+H] + .

[1720] Example 214

[1721] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-7-cyano- benzo [d] oxazol-2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-((4-fluoro-4- (hydroxymethyl)piperidin-1-yl)methyl)-4-methoxy-pyridine amide

[1722]

[1723] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-7- cyanobenzo[d]oxazol-2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-((4- fluoropiperidin-1-yl)methyl)-4-methoxy-pyridine amide was prepared according to Example 203.

[1724] MS m / z (ESI): 792.2 [M+H] + .

[1725] Example 215

[1726] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-7- cyanobenzo[d]oxazol-2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-((4- fluoropiperidin-1-yl)methyl)-4-methoxy-pyridine amide

[1727]

[1728] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-7- cyanobenzo[d]oxazol-2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-((4- fluoropiperidin-1-yl)methyl)-4-methoxy-pyridine amide was prepared according to Example 203.

[1729] MS m / z (ESI): 762.2 [M+H] + .

[1730] Example 216

[1731] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-7- cyanobenzo[d]oxazol-2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-((4- fluoropiperidin-1-yl)methyl)-4-methoxy-pyridine amide

[1732]

[1733] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-7- cyanobenzo[d]oxazol-2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-((4- hydroxy-4-(trifluoromethyl)piperidin-1-yl)methyl)-4-methoxy-pyridine amide was prepared according to Example 203.

[1734] MS m / z (ESI): 828.2 [M+H] + .

[1735] Example 217

[1736] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-7- cyanobenzo[d]oxazol-2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-((4- hydroxy-4-(trifluoromethyl)piperidin-1-yl)methyl)-4-methoxy-pyridine amide was prepared according to Example 203.

[1737]

[1738] First Step: Preparation of N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-7- cyanobenzo[d]oxazol-2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-((4- hydroxy-4-(trifluoromethyl)piperidin-1-yl)methyl)-4-methoxy-pyridine amide

[1739]

[1740] N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]octan-2-yl)methyl)-7- cyanobenzo[d]oxazol-2-yl)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-5-((4- hydroxy-4-(trifluoromethyl)piperidin-1-yl)methyl)-4-methoxy-pyridine amide was prepared according to Example 203.

[1741] MS m / z (ESI): 828.2 [M+H] + .

[1742] Step 2: Preparation of N-(2-chloro-3'-(7-cyano-5-((3-(cyanomethyl)azetidin-l- yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[l,l'-biphenyl]-3-yl)-5-(hydroxymethyl)-4- methoxymethylpyridinamide

[1743]

[1744] N-(2-chloro-3'-(7-cyano-5-((3-(cyanomethyl)azetidin-l-yl)methyl)benzo[d]oxazol-2- yl)-2'-methyl-[l,l'-biphenyl]-3-yl)-5-(hydroxymethyl)-4-methoxymethylpyridinamide (431 mg, 680.78 umol) was dissolved in dichloromethane (30 mL), DMP (433 mg, 1.02 mmol) was added, the reaction was stirred at room temperature for 20 minutes, the reaction was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution successively, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by silica gel column chromatography to give the title compound (400 mg, 93%).

[1745] MS m / z (ESI): 631.2 [M+H] + .

[1746] Step 3: Preparation of N-(2-chloro-3'-(7-cyano-5-((3-(cyanomethyl)azetidin-l- yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[l,l'-biphenyl]-3-yl)-5-(((trans-3- hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-4-methoxymethylpyridinamide

[1747]

[1748] N-(2-chloro-3'-(7-cyano-5-((3-(cyanomethyl)azetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)-5-formyl-4-methoxymethylpyridinamide (50 mg, 79.23 umol) trans-4- aminotetrahydropyran-3-ol (18.6 mg, 158.46 umol) were dissolved in a mixed solvent of methanol (3 mL) and 1,2-dichloroethane (1 mL), DIPEA (20.5 mg, 158.46 umol, 28 uL) was added, the reaction solution was stirred at room temperature overnight, sodium borohydride (168 mg, 792.3 umol) was added, the reaction solution was continued to stir at room temperature for 1 hour, the solvent was removed by reduced pressure concentration, the residue was dispersed in dichloromethane, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution successively, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by preparative TLC and prep-HPLC successively to give the title product (25.1 mg, 40%).

[1749] MS m / z (ESI): 732.2 [M+H] + .

[1750] Example 218

[1751] (S)-N-(2-chloro-3'-(7-cyano-5-((3-(cyanomethyl)azetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)-4-methoxy-5-((((5-carbonylpyrrolidin-2-yl)methyl)amino)methyl)pyridinamide

[1752]

[1753] (S)-N-(2-chloro-3'-(7-cyano-5-((3-(cyanomethyl)azetidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2'- methyl-[1,1'-biphenyl]-3-yl)-4-methoxy-5-((((5-carbonylpyrrolidin-2-yl)methyl)amino)methyl)pyridinamide was prepared according to Example 217.

[1754] MS m / z (ESI): 729.2 [M+H] + .

[1755] Example 219

[1756] (R)-N-(2-chloro-3'-(7-cyano-5-((3-(cyanomethyl)azetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[l,l'-biphenyl]-3-yl)-4-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridinamide

[1757]

[1758] (R)-N-(2-chloro-3'-(7-cyano-5-((3-(cyanomethyl)azetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[l,l'-biphenyl]-3-yl)-4-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridinamide was prepared according to Reference Example 217.

[1759] MS m / z (ESI): 729.2 [M+H] + .

[1760] Example 220

[1761] N-(2-chloro-3'-(7-cyano-5-((3-(cyanomethyl)azetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[l,l'-biphenyl]-3-yl)-5-((2-hydroxyethyl)amino)methyl)-4-methoxypyridinamide

[1762]

[1763] N-(2-chloro-3'-(7-cyano-5-((3-(cyanomethyl)azetidin-l-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[l,l'-biphenyl]-3-yl)-5-((2-hydroxyethyl)amino)methyl)-4-methoxypyridinamide was prepared according to Reference Example 217.

[1764] MS m / z (ESI): 676.2 [M+H] + .

[1765] Example 221

[1766] N-(3'-(5-((3-acetylaminoazetidin-l-yl)methyl)-7-cyanobenzo[d]oxazol-2-yl)-2-chloro-2'-methyl-[l,l'-biphenyl]-3-yl)-5-(((trans-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-4-methoxymethylpyridinamide

[1767]

[1768] Step 1: Preparation of N-(l-((7-cyano-2-(2-methyl-3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methyl)azetidin-3-yl)acetamide

[1769]

[1770] To a solution of 5-formyl-2-(2-methyl-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)benzo[d]oxazole-7-carbonitrile (1 g, 2.58 mmol), N-(azetidin-3-yl)acetamide (441 mg, 3.86 mmol) and N,N-DIPEA (333 mg, 2.58 mmol) in dichloromethane (40 mL) was stirred at room temperature for 1 h. Then sodium borohydride (1.09 g, 5.15 mmol) was added and the reaction was continued at room temperature overnight. The reaction was extracted with dichloromethane (25 mL x 3) and ...

Claims

1. A compound represented by general formula (IV), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: in: L2 is selected from -(CH2) n3 -; Ring B is selected from R1 is selected from hydrogen, halogen, cyano, C 1-3 Alkoxy or C 1-3 alkyl; R2 is selected from hydrogen, halogen or C 1-3 alkyl; R3 is selected from hydrogen, halogen or C 1-3 alkyl; R4 is selected from -H, -F, -Cl, -Br, -OH, -CH3, -CH2CH3; R6 is selected from methoxy; R7 is selected from x is an integer from 0 to 6; y is an integer from 0 to 3; and n3 is 1.

2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R1 is selected from cyano.

3. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R2 is selected from chlorine.

4. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R3 is selected from methyl.

5. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R7 is selected from 6. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R4 is selected from -F.

7. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R7 is selected from 8. A compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that: The structure of the specific compound is as follows:

9. A compound having a structure represented by the general formula (XI): in, L1 is selected from a bond; Ring A is selected from R6, R2, R1, R3, R4, L2, ring B, x and y are the same as those described in claim 1.

10. A compound as shown below:

11. A method for preparing a compound of general formula (III), characterized in that: Under the action of a reducing agent, the compound of formula (VII) and the compound of formula (VIII) are subjected to a condensation reaction to obtain a compound of general formula (III). in: L1 is the key; L2 is a methylene group; The reducing agent is sodium borohydride, potassium borohydride, lithium aluminum hydride, sodium cyanoborohydride, potassium cyanoborohydride, sodium dihydrobis(2-methoxyethoxy)aluminate or stannous chloride; Alternatively, RggH is reacted with a compound represented by the general formula (XI) to obtain a compound represented by the general formula (III), Wherein: R7 is -CH2Rgg; Rgg is selected from amino; wherein the amino group is optionally further C 1-6 Hydroxyalkyl, C 1-6 Alkyl and C 1-6 one or more substitutions in haloalkyl; Or, reacting the compound represented by general formula (XV) with the compound represented by general formula (XIV) to obtain the compound represented by general formula (III), in: R8 is C 1-6 Alkyl, halogenated C 1-6 Alkyl or deuterated C 1-6 alkyl; Ring A is selected from Ring B is selected from R1 is selected from hydrogen, halogen, cyano, C 1-3 Alkoxy or C 1-3 alkyl; R2 is selected from hydrogen, halogen or C 1-3 alkyl; R3 is selected from hydrogen, halogen or C 1-3 alkyl; R4 is selected from -H, -F, -Cl, -Br, -OH, -CH3, -CH2CH3; R6 is selected from methoxy; x is an integer from 0 to 6; and y is an integer from 0 to 3.

12. The method for preparing the compound of general formula (III) according to claim 11, characterized in that: In the presence of a catalyst and a base, the compound of formula (IX) and the compound of formula (X) are subjected to a coupling reaction to obtain a compound of formula (VI). Wherein: Ha is a halogen; The catalyst is biscyclohexylphosphinoferrocene palladium dichloride, tetrakistriphenylphosphine palladium, tris(dibenzylideneacetone)dipalladium, palladium acetate or [1,1'bis(diphenylphosphino)ferrocene]palladium dichloride; The base is cesium carbonate, sodium carbonate or potassium carbonate; Or, under the action of an oxidant, the compound of general formula (XII) is reacted to obtain a compound of general formula (XI), The oxidant is selected from potassium permanganate, ozone, periodic acid, potassium dichromate, ferric salt, nitrobenzenesulfonic acid, potassium osmate dihydrate and sodium periodate.

13. A pharmaceutical composition comprising a therapeutically effective dose of the compound according to any one of claims 1 to 8, its stereoisomers or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers or excipients.

14. Use of the compound according to any one of claims 1 to 8, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 13 in the preparation of a medicament for treating a PD-1 / PD-L1-related disease; the disease is selected from cancer, infectious disease, and autoimmune disease; The cancer is selected from the group consisting of skin cancer, lung cancer, urinary system tumors, blood tumors, breast cancer, glioma, digestive system tumors, reproductive system tumors, lymphoma, nervous system tumors, brain tumors, and head and neck cancer; The infectious disease is selected from bacterial infection and viral infection; The autoimmune disease is selected from organ-specific autoimmune disease and systemic autoimmune disease, wherein: The organ-specific autoimmune diseases include chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, Goodpasture's syndrome, primary biliary cirrhosis, multiple sclerosis, and acute idiopathic polyneuritis; the systemic autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, and autoimmune hemolytic anemia.

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