Aromatic ethylenic compounds, their production process, intermediates, pharmaceutical compositions and uses thereof

Abstract

Disclosed are aromatic ethylene-based compounds, their preparation methods, intermediates, pharmaceutical compositions, and uses. The aromatic ethylene-based compounds are represented by formula I-0. The aromatic ethylene-based compounds have significant inhibitory effects on PD-1 / PD-L1, as well as higher drug peak concentrations, larger areas under the drug-time curve, and better oral bioavailability. These compounds are highly effective small molecule inhibitors of PD-1 / PD-L1, and can effectively alleviate or treat related diseases such as cancer. [Formula 1] TIFF2023540612000252.tif46170

Description

Detailed Description of the Invention

[0001] This application claims the priority of Chinese patent application No. 2020109394150, filed on September 9, 2020, the priority of Chinese patent application No. 2020114144032, filed on December 2, 2020, the priority of Chinese patent application No. 2021103688808, filed on April 6, 2021, and the priority of Chinese patent application No. 2021109957653, filed on August 27, 2021. This application cites the above Chinese patent applications in their entirety.

[0002] [Technical field] The present invention relates to aromatic ethylenic compounds, their preparation methods, intermediates, pharmaceutical compositions and uses thereof. [Background technology] PD-1 (programmed death receptor 1), or PD-1 receptor, is an important immunosuppressive molecule. It is a member of the CD28 superfamily and was originally cloned from the apoptotic murine T cell hybridoma 2B4.11. Targeting PD-1 for immunomodulation is important for anti-tumor, anti-infection, anti-autoimmune disease, and organ transplant survival. Its ligand, PD-L1, can also be targeted, and the corresponding antibodies can achieve the same effect.

[0003] PD-1 / PD-L1 exerts a negative immunoregulatory role. Binding of cell surface PD-1 to PD-L1 induces phosphorylation of Tyr in the immunoreceptor tyrosine-based switch motif (ITSM) domain in the cytoplasm of T cells. The phosphorylated Tyr recruits the phosphatases protein tyrosinase 2 and protein tyrosinase 1, inhibiting extracellular signal transduction (ESC) activation and blocking the activation of phosphatidylinositol 3-kinase (PI3K) and serine-threonine protein kinase (Akt), ultimately suppressing T cell proliferation and cytokine secretion. PD-1 / PD-L1 signaling suppresses T cell activation and proliferation, while also reducing the secretion of the cytokines interleukin 2 (IL2), interferon-γ, and IL-10 (Eur. J. Immunol., 2002, 32(3), 634-643). Furthermore, PD-1 / PD-L1 signaling also exerts a similar immune function on B cells as it does on T cells. When PD-1 binds to the antigen receptor on B cells, the cytoplasmic domain of PD-1 interacts with tyrosinase, which contains a binding site for protein tyrosinase 2, ultimately inhibiting B cell activation. The role of PD-1 / PD-L1, an immune negative regulatory molecule, in tumor immune evasion has attracted much attention. Extensive research has demonstrated that increased levels of PD-L1 on the surface of tumor cells in the tumor microenvironment simultaneously bind to PD-1 on activated T cells, transmitting negative regulatory signals that lead to apoptosis or immune unresponsiveness of tumor antigen-specific T cells, thereby suppressing the immune response and further promoting tumor cell evasion.

[0004] Currently, PD-1 / PD-L1 antibody inhibitors already on the market include Nivolumab (2014) from BMS, Lambrolizumab (2014) from Merck, and Atezolizumab (2016) from Roche. PD-1 / PD-L1 antibody inhibitors under investigation include Pidilizumab from CureTech, AMP-224 from GSK, and MEDI-4736 from AstraZeneca. All of these are large biological molecules, and small molecule PD-1 / PD-L1 inhibitors are still in the early stages of research and development. Curis' polypeptide PD-L1 small molecule inhibitor AC-170 (WO2012168944, WO2015033299, WO2015033301, WO2015036927, WO201504) is currently being investigated. 4900) has just entered Phase I clinical trials, BMS's benzyl phenyl ether-based small molecule PD-1 / PD-L1 inhibitors (WO2015034820, WO2015160641, WO2017066227, WO2018009505, WO2018044963, WO2018118848) are still in the preclinical research stage, and Incyte's series of small molecule PD-1 / PD-L1 inhibitors (WO2017070089) , WO2017087777, WO2017106634, WO2017112730, WO2017192961, WO2017205464, WO2017222976, WO2018013789, WO2018044783, WO2018119221, WO2018119224, WO2018119263, WO2018219266, WO2018119286) are still in the preclinical research stage. Compared to large biological molecules, small molecules can penetrate cell membranes and act on intracellular targets, offering a wider range of applications. Second, chemical modifications of small molecules often result in superior bioavailability and compliance, effectively preventing enzyme degradation and inactivation in the gastrointestinal tract. Finally, small molecule research is maturing in many aspects, including manufacturing processes, formulation design, and administration modes.

[0005] Currently, there are no reports of biphenyl compounds being marketed as small molecule PD-1 / PD-L1 inhibitors in existing technologies, and a solution to this situation is expected.

[0006] [Summary of the Invention] The technical problem to be solved by the present invention is to provide aromatic ethylene compounds, their preparation methods, intermediates, pharmaceutical compositions and uses thereof, which are completely different from existing technologies. The aromatic ethylene compounds of the present invention have significant inhibitory effects on PD-1 / PD-L1, as well as higher drug peak concentrations, larger areas under the drug-time curve and better oral bioavailability. These are highly effective small molecule inhibitors of PD-1 / PD-L1, and can effectively alleviate or treat related diseases such as cancer.

[0007] The present invention provides an aromatic ethylenic compound represented by formula I-0, a tautomer thereof, a stereoisomer thereof, a racemate thereof or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof (referring to the aromatic ethylenic compound represented by formula I-0, a tautomer thereof, a stereoisomer thereof, a racemate thereof or an isotopic derivative thereof).

[0008] [ka]

[0009] however: R 1 is cyano, C1-C4 alkyl, C1-C4 alkyl substituted with one or more deuterium atoms, halogen, C1-C4 alkyl substituted with one or more halogen atoms, R 3 , R 6 , R 12 , R 13 and R 14 are independently H or deuterium, R 2 is hydroxyl, halogen, C1-C4 alkyl, one or more R A-1 C1-C4 alkyl, C1-C6 alkoxy or one or more R A-2 to and C1-C6 alkoxy substituted by R A-1 and R A-2are independently deuterium, hydroxyl, halogen, cyano, C1-C4 alkoxy, C1-C4 alkoxy substituted with one or more deuterium atoms,

[0010] [ka] and R A-1-1 is C1-C4 alkyl or C1-C4 alkyl substituted with one or more deuterium atoms, and R A-1-2 and R A-1-3 are independently H, deuterium, C1-C4 alkyl, or one or more R A-1-1-1 and R is a C1-C4 alkyl substituted with A-1-1-1 is deuterium, hydroxyl or COOR A-1-1-2 and

[0011] R 4 and R 5 are independently hydroxyl, halogen, C1-C4 alkyl, one or more R B-1 C1-C4 alkyl, C1-C6 alkoxy or one or more R B-2 C1-C6 alkoxy substituted with R B-1 and R B-2 are independently deuterium, hydroxyl, halogen, cyano, C6-C 10 aryl, one or more R B-1-3 C6-C substituted by 10 aryl, 3- to 12-membered heteroaryl, one or more R B-1-4 C1-C4 alkoxy, C1-C4 alkoxy substituted by one or more deuterium atoms,

[0012] [ka] wherein in the heteroaryl, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1 to 4;

[0013] R B-1-3 and R B-1-4 are independently cyano, halogen, C1-C4 alkyl, or C1-C4 alkoxy; R B-1-1 and R B-1-2 are independently H, deuterium, C1-C4 alkyl, or one or more R B-1-1-1 and R is a C1-C4 alkyl substituted with B-1-1-1 is deuterium, hydroxyl or COOR B-1-1-5 and Or R B-1-1 , R B-1-2 together with the nitrogen atom linked thereto form a 5- to 7-membered carbocyclic ring or one or more R B-1-1-2 In the carboheterocycle, heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1 to 4; B-1-1-2 is deuterium, C1-C4 alkyl, C1-C4 alkyl substituted with one or more deuterium atoms, COOR B-1-1-6 or a C1-C4 amide, R A-1-1-2 , R B-1-1-5 and R B-1-1-6 are independently H, deuterium, C1-C4 alkyl, or C1-C4 alkyl substituted with one or more deuterium atoms; R 7 , R 8 , R 9 , R 10 and R 11 are independently H or deuterium, R 15 and R 16 are independently H, deuterium, or halogen.

[0014] In some embodiments, in the aromatic ethylenic compound represented by formula I-0, R B-1 and R B-2 are independently deuterium, hydroxyl, halogen, cyano, C1-C4 alkoxy, C1-C4 alkoxy substituted with one or more deuterium atoms,

[0015] [ka] and other variables are as defined in any embodiment of the invention.

[0016] The present invention provides an aromatic ethylenic compound represented by formula I, a tautomer thereof, a stereoisomer thereof, a racemate thereof or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof (referring to an aromatic ethylenic compound represented by formula I above, a tautomer thereof, a stereoisomer thereof, a racemate thereof or an isotopic derivative thereof).

[0017] [ka]

[0018] however: R 1 is cyano, C1-C4 alkyl, C1-C4 alkyl substituted with one or more deuterium atoms, R 3 , R 6 , R 12 , R 13 and R 14 are independently H or deuterium, R 2 is hydroxyl, halogen, C1-C4 alkyl, one or more R A-1 C1-C4 alkyl, C1-C6 alkoxy or one or more R A-2 C replaced by 1~ C6 alkoxy, R A-1 and R A-2 are independently deuterium, hydroxyl, halogen, cyano, C1-C4 alkoxy, C1-C4 alkoxy substituted with one or more deuterium atoms,

[0019] [ka] and R A-1-1is C1-C4 alkyl or C1-C4 alkyl substituted with one or more deuterium atoms, and R A-1-2 and R A-1-3 are independently H, deuterium, C1-C4 alkyl, or one or more R A-1-1-1 and R is a C1-C4 alkyl substituted with A-1-1-1 is deuterium, hydroxyl or COOR A-1-1-2 and

[0020] R 4 and R 5 are independently hydroxyl, halogen, C1-C4 alkyl, one or more R B-1 C1-C4 alkyl, C1-C6 alkoxy or one or more R B-2 C1-C6 alkoxy substituted with R B-1 and R B-2 are independently deuterium, hydroxyl, halogen, cyano, C1-C4 alkoxy, C1-C4 alkoxy substituted with one or more deuterium atoms,

[0021] [ka] and

[0022] R B-1-1 and R B-1-2 are independently H, deuterium, C1-C4 alkyl, or one or more R B-1-1-1 and R is a C1-C4 alkyl substituted with B-1-1-1 is deuterium, hydroxyl or COOR B-1-1-5 and Or R B-1-1 , R B-1-2 together with the nitrogen atom linked thereto form a 5- to 7-membered carbocyclic ring or one or more R B-1-1-2 In the carboheterocycle, heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1 to 4; B-1-1-2is deuterium, C1-C4 alkyl, C1-C4 alkyl substituted with one or more deuterium atoms, COOR B-1-1-6 or a C1-C4 amide, R A-1-1-2 , R B-1-1-5 and R B-1-1-6 are independently H, deuterium, C1-C4 alkyl, or C1-C4 alkyl substituted with one or more deuterium atoms; R 7 , R 8 , R 9 , R 10 and R 11 are independently H or deuterium.

[0023] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R 1 is C1-C4 alkyl, said C1-C4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example, methyl, and the other variables are as defined in any embodiment of the present invention.

[0024] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R 1 is a C1-C4 alkyl substituted by one or more deuterium atoms, the C1-C4 alkyl substituted by one or more deuterium atoms is a C1-C2 alkyl substituted by one or more deuterium atoms, such as mono-deuterated methyl, di-deuterated methyl, tri-deuterated methyl, mono-deuterated ethyl, di-deuterated ethyl, tri-deuterated ethyl, tetra-deuterated ethyl or penta-deuterated ethyl, and other variables are as defined in any embodiment of the present invention.

[0025] In some embodiments, the aromatic ethylenic compound represented by formula I-0 or I In R 1When is a halogen, said halogen is fluorine, chlorine, bromine or iodine, for example chlorine, and the other variables are as defined in any embodiment of the present invention.

[0026] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R 1 is C1-C4 alkyl substituted with one or more halogens, the halogens are fluorine, chlorine, bromine or iodine, for example, fluorine, and the other variables are as defined in any embodiment of the present invention.

[0027] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R 1 is C1-C4 alkyl substituted with one or more halogens, said C1-C4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example, methyl, and the other variables are as defined in any embodiment of the present invention.

[0028] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R 2 When is a halogen, said halogen is fluorine, chlorine, bromine or iodine, for example chlorine, and the other variables are as defined in any embodiment of the present invention.

[0029] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R 2 is C1-C4 alkyl, said C1-C4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example, methyl, and the other variables are as defined in any embodiment of the present invention.

[0030] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R 2is one or more R A-1 wherein the C1-C4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, for example, methyl, and the other variables are as defined in any embodiment of the present invention.

[0031] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R 2 is one or more R A-1 When R is C1-C4 alkyl substituted with A-1 are the same or different, and the plurality is 2, 3, 4 or 5, and other variables are as defined in any embodiment of the present invention.

[0032] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R 2 is C1-C6 alkoxy, said C1-C6 alkoxy is C1-C4 alkoxy, for example, methoxy, ethoxy, n-propoxy or n-butoxy, also for example, methoxy, and all other variables are as defined in any embodiment of the present invention.

[0033] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R 2 is one or more R A-2 where C1-C6 alkoxy substituted by is C1-C6 alkoxy, said C1-C6 alkoxy is C1-C4 alkoxy, for example, methoxy, ethoxy, n-propoxy, or n-butoxy, and the other variables are as defined in any embodiment of the present invention.

[0034] In some embodiments, the aromatic ethylenic compound represented by formula I-0 or I In R 2 is one or more R A-2 When the alkoxy is C1-C6 substituted with A-2are the same or different, and the plurality is 2, 3, 4 or 5, and other variables are as defined in any embodiment of the present invention.

[0035] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R A-1 and R A-2 is independently a halogen, said halogen is fluorine, chlorine, bromine or iodine, e.g., fluorine, and the other variables are as defined in any embodiment of the present invention.

[0036] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R A-1 and R A-2 is independently C1-C4 alkoxy, the C1-C4 alkoxy is methoxy, ethoxy, n-propoxy or n-butoxy, for example, methoxy, and the other variables are as defined in any embodiment of the present invention.

[0037] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R A-1 and R A-2 is independently a C1-C4 alkoxy substituted by one or more deuteriums, said C1-C4 alkoxy substituted by one or more deuteriums is a C1-C2 alkoxy substituted by one or more deuteriums, for example, monodeuterated methoxy, dideuterated methoxy, trideuterated methoxy, monodeuterated ethoxy, dideuterated ethoxy, trideuterated ethoxy, tetradeuterated ethoxy or pentadeuterated ethoxy, for example, trideuterated methoxy, and all other variables are as defined in any embodiment of the invention.

[0038] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R A-1-1is C1-C4 alkyl, said C1-C4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example, methyl, and the other variables are as defined in any embodiment of the present invention.

[0039] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R A-1-1 is a C1-C4 alkyl substituted by one or more deuterium atoms, the C1-C4 alkyl substituted by one or more deuterium atoms is a C1-C2 alkyl substituted by one or more deuterium atoms, such as mono-deuterated methyl, di-deuterated methyl, tri-deuterated methyl, mono-deuterated ethyl, di-deuterated ethyl, tri-deuterated ethyl, tetra-deuterated ethyl or penta-deuterated ethyl, and other variables are as defined in any embodiment of the present invention.

[0040] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R A-1-2 and R A-1-3 is independently C1-C4 alkyl, said C1-C4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example, methyl, ethyl or isopropyl, and the other variables are as defined in any embodiment of the present invention.

[0041] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R A-1-2 and R A-1-3 may independently be one or more R A-1-1-1 wherein the C1-C4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, for example, methyl, ethyl, or isopropyl, and the other variables are any of the variables of the present invention. As defined in the embodiment.

[0042] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R A-1-2 and R A-1-3 may independently be one or more R A-1-1-1 When R is C1-C4 alkyl substituted with A-1-1-1 are the same or different, and the plurality is 2, 3, 4 or 5, and other variables are as defined in any embodiment of the present invention.

[0043] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R 4 and R 5 is independently a halogen, said halogen is fluorine, chlorine, bromine or iodine, e.g., chlorine, and the other variables are as defined in any embodiment of the present invention.

[0044] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R 4 and R 5 is independently C1-C4 alkyl, said C1-C4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, for example, methyl, and the other variables are as defined in any embodiment of the present invention.

[0045] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R 4 and R 5 may independently be one or more R B-1 wherein the C1-C4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, for example, methyl, and the other variables are as defined in any embodiment of the present invention.

[0046] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R 4 and R 5 may independently be one or more R B-1 When R is C1-C4 alkyl substituted with B-1 are the same or different, and the plurality is 2, 3, 4 or 5, and other variables are as defined in any embodiment of the present invention.

[0047] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R 4 and R 5 is independently C1-C6 alkoxy, said C1-C6 alkoxy is C1-C4 alkoxy, for example, methoxy, ethoxy, n-propoxy, or n-butoxy, also for example, methoxy, and the other variables are as defined in any embodiment of the present invention.

[0048] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R 4 and R 5 may independently be one or more R B-2 where C1-C6 alkoxy substituted by is C1-C6 alkoxy, said C1-C6 alkoxy is C1-C4 alkoxy, for example, methoxy, ethoxy, n-propoxy, or n-butoxy, and the other variables are as defined in any embodiment of the present invention.

[0049] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R 4 and R 5 may independently be one or more R B-2 When the alkoxy is C1-C6 substituted with B-2 are the same or different, and the plurality is 2, 3, 4 or 5, and other variables are as defined in any embodiment of the present invention.

[0050] In some embodiments, the aromatic ethylenic compound represented by formula I-0 or I In R B-1 and R B-2 is independently a halogen, said halogen is fluorine, chlorine, bromine or iodine, e.g., fluorine, and the other variables are as defined in any embodiment of the present invention.

[0051] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R B-1 and R B-2 But independently C6~C 10 When it is aryl, the C6 to C 10 Aryl is phenyl, and the other variables are as defined in any embodiment of the present invention.

[0052] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R B-1 and R B-2 may independently be one or more R B-1-3 C6-C substituted by 10 When it is aryl, the C6 to C 10 Aryl is phenyl, and the other variables are as defined in any embodiment of the present invention.

[0053] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R B-1 and R B-2 may independently be one or more R B-1-3 C6-C substituted by 10 When R is aryl, B-1-3 are the same or different, and the plurality is 2, 3, 4 or 5, and other variables are as defined in any embodiment of the present invention.

[0054] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R B-1 and R B-2is independently a 3- to 12-membered heteroaryl, said 3- to 12-membered heteroaryl is a 5- to 7-membered heteroaryl, and all other variables are as defined in any embodiment of the present invention.

[0055] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R B-1 and R B-2 is independently 3-12 membered heteroaryl, the heteroatoms of said 3-12 membered heteroaryl are selected from N, the number of heteroatoms is 1, and the other variables are as defined in any embodiment of the present invention.

[0056] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R B-1 and R B-2 may independently be one or more R B-1-4 When the 3- to 12-membered heteroaryl is substituted by, said 3- to 12-membered heteroaryl is a 5- to 7-membered heteroaryl, and all other variables are as defined in any embodiment of the present invention.

[0057] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R B-1 and R B-2 may independently be one or more R B-1-4 wherein the heteroatom of said 3-12 membered heteroaryl is selected from N, the number of heteroatoms is 1, and the other variables are as defined in any embodiment of the present invention.

[0058] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R B-1 and R B-2 may independently be one or more R B-1-4 When R is a 3- to 12-membered heteroaryl substituted with B-1-4are the same or different, and the plurality is 2, 3, 4 or 5, and other variables are as defined in any embodiment of the present invention.

[0059] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R B-1-3 and R B-1-4 are independently halogen, Fluorine may be fluorine, chlorine, bromine, or iodine, for example, fluorine or iodine, and other variables are as defined in any embodiment of the present invention.

[0060] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R B-1 and R B-2 is independently C1-C4 alkoxy, said C1-C4 alkoxy is methoxy, ethoxy, n-propoxy or n-butoxy, for example, methoxy, and the other variables are as defined in any embodiment of the present invention.

[0061] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R B-1 and R B-2 is independently a C1-C4 alkoxy substituted by one or more deuteriums, said C1-C4 alkoxy substituted by one or more deuteriums is a C1-C2 alkoxy substituted by one or more deuteriums, for example, monodeuterated methoxy, dideuterated methoxy, trideuterated methoxy, monodeuterated ethoxy, dideuterated ethoxy, trideuterated ethoxy, tetradeuterated ethoxy or pentadeuterated ethoxy, for example, trideuterated methoxy, and all other variables are as defined in any embodiment of the invention.

[0062] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R B-1-1 and R B-1-2is independently C1-C4 alkyl, said C1-C4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example, methyl, ethyl or isopropyl, and the other variables are as defined in any embodiment of the present invention.

[0063] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R B-1-1 and R B-1-2 may independently be one or more R B-1-1-1 wherein the C1-C4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, for example, methyl, ethyl, or isopropyl, and the other variables are as defined in any embodiment of the present invention.

[0064] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R B-1-1 and R B-1-2 may independently be one or more R B-1-1-1 When R is C1-C4 alkyl substituted with B-1-1-1 are the same or different, and the plurality is 2, 3, 4 or 5, and other variables are as defined in any embodiment of the present invention.

[0065] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R B-1-1 , R B-1-2 together with the nitrogen atom to which they are attached form a 5- to 7-membered carboheterocycle, in which the heteroatoms are N and / or O, and the other variables are as defined in any embodiment of the present invention.

[0066] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R B-1-1 , R B-1-2together with the nitrogen atom to which they are attached form a 5- to 7-membered carboheterocycle, the number of heteroatoms in said carboheterocycle is 1 or 2, and the other variables are as defined in any embodiment of the present invention.

[0067] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R B-1-1 , R B-1-2 together with the nitrogen atom to which they are attached, one or more R B-1-1-2 When a heterocarbocycle is formed, the heterocarbocycle may be substituted with wherein the heteroatoms are N and / or O, and other variables are as defined in any embodiment of the invention.

[0068] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R B-1-1 , R B-1-2 together with the nitrogen atom to which they are attached, one or more R B-1-1-2 When forming a carboheterocycle substituted with, the number of heteroatoms in said carboheterocycle is 1 or 2, and the other variables are as defined in any embodiment of the present invention.

[0069] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R B-1-1 , R B-1-2 together with the nitrogen atom to which they are attached, one or more R B-1-1-2 When forming a carboheterocycle substituted by B-1-1-2 are the same or different, and the plurality is 2, 3, 4 or 5, and other variables are as defined in any embodiment of the present invention.

[0070] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R B-1-1-2is C1-C4 alkyl, said C1-C4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example, methyl, and the other variables are as defined in any embodiment of the present invention.

[0071] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R B-1-1-2 is a C1-C4 alkyl substituted by one or more deuterium atoms, said C1-C4 alkyl substituted by one or more deuterium atoms is a C1-C2 alkyl substituted by one or more deuterium atoms, such as mono-deuterated methyl, di-deuterated methyl, tri-deuterated methyl, mono-deuterated ethyl, di-deuterated ethyl, tri-deuterated ethyl, tetra-deuterated ethyl or penta-deuterated ethyl, and other variables are as defined in any embodiment of the present invention.

[0072] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R B-1-1-2 is a C1-C4 amide, the C1-C4 amide is

[0073] [ka] and R B-1-1-3 and R B-1-1-4 are independently H, deuterium, C1-C4 alkyl, or C1-C4 alkyl substituted with one or more deuteriums, wherein the C1-C4 alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, and the C1-C4 alkyl substituted with one or more deuteriums is, for example, trideuteromethyl, and all other variables are as defined in any embodiment of the present invention.

[0074] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, RA-1-1-2 , R B-1-1-5 and R B-1-1-6 But independently C1 -C4 alkyl, the C1-C4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example, methyl, and the other variables are as defined in any embodiment of the present invention.

[0075] In some embodiments, in the aromatic ethylenic compound represented by formula I-0, R 15 and R 16 is independently a halogen, said halogen is fluorine, chlorine, bromine or iodine, e.g., fluorine or bromine, and the other variables are as defined in any embodiment of the present invention.

[0076] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R 3 , R 6 , R 12 , R 13 and R 14 are independently H, and the other variables are as defined in any embodiment of the present invention.

[0077] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R 2 is halogen, C1-C4 alkyl or one or more R A-1 and C1-C4 alkyl substituted with, and other variables are as defined in any embodiment of the invention.

[0078] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R A-1 and R A-2 are independently hydroxyl, halogen, cyano, C1-C4 alkoxy,

[0079] [ka] and other variables are as defined in any embodiment of the present invention.

[0080] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R A-1 is a halogen or

[0081] [ka] and other variables are as defined in any embodiment of the present invention.

[0082] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R A-1 is a halogen, and the other variables are as defined in any embodiment of the present invention. In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R A-1-1 is C1-C4 alkyl, and the other variables are as defined in any embodiment of the present invention.

[0083] In some embodiments, the aromatic ethylenic compound represented by formula I-0 or I In R A-1-2 and R A-1-3 are independently H or one or more R A-1-1-1 and C1-C4 alkyl substituted with, and other variables are as defined in any embodiment of the invention.

[0084] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R A-1-2 and R A-1-3 one of which is H and the other is one or more R A-1-1-1 and C1-C4 alkyl substituted with, and other variables are as defined in any embodiment of the invention.

[0085] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R A-1-1-2 , R B-1-1-5 and R B-1-1-6 are independently H or C1-C4 alkyl, and the other variables are as defined in any embodiment of the present invention.

[0086] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R A-1-1-2 , R B-1-1-5 and R B-1-1-6 are independently H, and the other variables are as defined in any embodiment of the present invention.

[0087] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, the one or more R A-1-1-1 C1-C4 alkyl substituted by

[0088] [ka] and other variables are as defined in any embodiment of the present invention.

[0089] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, the one or more R A-1-1-1 C1-C4 alkyl substituted by

[0090] [ka] and other variables are as defined in any embodiment of the present invention.

[0091] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R 4 and R 5 are independently halogen, C1-C4 alkyl, one or more R B-1C1-C4 alkyl, C1-C6 alkoxy or one or more R B-2 and the other variables are any of the groups of the present invention. As defined in the embodiment.

[0092] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R B-1 and R B-2 are independently deuterium, hydroxyl, cyano, C6-C 10 aryl, one or more R B-1-3 C6-C substituted by 10 aryl, 3- to 12-membered heteroaryl, one or more R B-1-4 C1-C4 alkoxy, C1-C4 alkoxy substituted by one or more deuterium atoms,

[0093] [ka] and other variables are as defined in any embodiment of the present invention.

[0094] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R B-1 and R B-2 are independently deuterium, hydroxyl, cyano, C1-C4 alkoxy, C1-C2 alkoxy substituted with one or more deuterium atoms,

[0095] [ka] and other variables are as defined in any embodiment of the present invention.

[0096] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R B-1is hydroxyl, C1-C4 alkoxy, C1-C2 alkoxy substituted with one or more deuterium atoms, or

[0097] [ka] and other variables are as defined in any embodiment of the present invention.

[0098] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R B-1 is hydroxyl or

[0099] [ka] and other variables are as defined in any embodiment of the present invention.

[0100] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R B-2 Deuterium, cyano, hydroxyl, C6-C 10 aryl, one or more R B-1-3 C6-C substituted by 10 aryl, 3- to 12-membered heteroaryl, one or more R B-1-4 or C1-C4 alkoxy substituted by, and other variables are as defined in any embodiment of the invention.

[0101] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R B-2 is deuterium, cyano, hydroxyl, or C1-C4 alkoxy, and the other variables are as defined in any embodiment of the present invention.

[0102] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R B-1-3 and R B-1-4is independently cyano or halogen, and the other variables are as defined in any embodiment of the present invention.

[0103] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, the one or more R B-1-3 C6-C substituted by 10 The aryl is

[0104] [ka] and other variables are as defined in any embodiment of the present invention.

[0105] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, the 3- to 12-membered heteroaryl is

[0106] [ka] and other variables are as defined in any embodiment of the present invention.

[0107] In some embodiments, the aromatic ethylenic compound represented by formula I-0 or I wherein the one or more R B-1-4 The 3- to 12-membered heteroaryl substituted by

[0108] [ka] and other variables are as defined in any embodiment of the present invention.

[0109] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R B-1-1 and R B-1-2 are independently H or one or more R B-1-1-1or C1-C4 alkyl substituted by R B-1-1 , R B-1-2 together with the nitrogen atom linked thereto, form one or more 5- to 7-membered R B-1-1-2 and forming a carboheterocycle substituted by: and the other variables are as defined in any embodiment of the invention.

[0110] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R B-1-1 and R B-1-2 one of which is H and the other is one or more R B-1-1-1 or C1-C4 alkyl substituted by R B-1-1 , R B-1-2 together with the nitrogen atom linked thereto, form one or more 5- to 7-membered R B-1-1-2 and forming a carboheterocycle substituted by: and the other variables are as defined in any embodiment of the invention.

[0111] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, the one or more R B-1-1-1 C1-C4 alkyl substituted by

[0112] [ka] and other variables are as defined in any embodiment of the present invention.

[0113] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, the one or more R B-1-1-1 C1-C4 alkyl substituted by

[0114] [ka] and other variables are as defined in any embodiment of the present invention.

[0115] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R B-1-1-2 is C1-C4 alkyl, COOR B-1-1-6 or C1-C4 amide, and other variables are as defined in any embodiment of the invention.

[0116] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R B-1-1-2 is methyl, carboxyl, or -CONH2, and the other variables are as defined in any embodiment of the present invention.

[0117] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, the carboheterocycle is

[0118] [ka] and other variables are as defined in any embodiment of the present invention.

[0119] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, the one or more R B-1-1-2 A carboheterocycle substituted by

[0120] [ka] and other variables are as defined in any embodiment of the present invention.

[0121] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, the one or more R B-1-1-2 A carboheterocycle substituted by

[0122] [ka] and other variables are as defined in any embodiment of the present invention.

[0123] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R 4 teeth,

[0124] [ka] and other variables are as defined in any embodiment of the present invention.

[0125] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I, R 5 is a halogen, a C1-C4 alkyl, one or more R B-1 C1-C4 alkyl, C1-C6 alkoxy or one or more R B-2 C1-C6 alkoxy substituted with R B-1 and R B-2 are independently deuterium, hydroxyl, cyano, C1-C4 alkoxy, C1-C2 alkoxy substituted with one or more deuterium atoms, or

[0126] [ka] and other variables are as defined in any embodiment of the present invention.

[0127] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I,

[0128] [ka] and other variables are as defined in any embodiment of the present invention.

[0129] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I,

[0130] [ka] and other variables are as defined in any embodiment of the present invention.

[0131] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I,

[0132] [ka] and other variables are as defined in any embodiment of the present invention.

[0133] In some embodiments, in the aromatic ethylenic compound represented by formula I-0 or I,

[0134] [ka] is.

[0135] In some embodiments, in the aromatic ethylenic compound represented by formula I-0, R 15 and R 16 is H or deuterium, and the other variables are as defined in any embodiment of the present invention.

[0136] In some embodiments, in the aromatic ethylenic compound represented by formula I-0, R 15 is H or deuterium, and R 16 is H, deuterium or halogen, and other variables are as defined in any embodiment of the present invention.

[0137] In some embodiments, in the aromatic ethylenic compound represented by formula I-0, R 1 is halogen, C1-C4 alkyl substituted with one or more halogens, and all other variables are as defined in any embodiment of the present invention.

[0138] In some embodiments, in the aromatic ethylenic compound represented by formula I-0, R 15 is deuterium or halogen, and the other variables are as defined in any embodiment of the present invention.

[0139] In some embodiments, in the aromatic ethylenic compound represented by formula I-0, R 16 is deuterium or halogen, and the other variables are as defined in any embodiment of the present invention.

[0140] In some embodiments, the aromatic ethylenic compound represented by formula I-0 or I is selected from any one of the following schemes: Scheme 1: R 2 teeth,

[0141] [ka] and R 4 and R 5 are independently halogen, C1-C4 alkyl, one or more R B-1 C1-C4 alkyl, C1-C6 alkoxy or one or more R B-2 C1-C6 alkoxy substituted with R B-1 and R B-2 are independently deuterium, hydroxyl, cyano, C1-C4 alkoxy, C1-C2 alkoxy substituted with one or more deuterium atoms, or

[0142] [ka] and R 3 , R6 , R 12 , R 13 and R 14 is H,

[0143] Scheme 2: R 2 is halogen, C1-C4 alkyl or one or more R A-1 and R is a C1-C4 alkyl substituted with A-1 is a halogen and R 4 teeth,

[0144] [ka] and R 5 is a halogen, hydroxyl, C1-C4 alkyl, one or more R B-1 C1-C4 alkyl, C1-C6 alkoxy or one or more R B-2 C1-C6 alkoxy substituted with R B-1 and R B-2 are independently deuterium, hydroxyl, cyano, C1-C4 alkoxy, C1-C2 alkoxy substituted with one or more deuterium atoms, or

[0145] [ka] and R 3 , R 6 , R 12 , R 13 and R 14 is H,

[0146] Scheme 3: R 2 is halogen, C1-C4 alkyl or one or more R A-1 and R is a C1-C4 alkyl substituted with A-1 is a halogen and R 4 is a halogen, a C1-C4 alkyl, one or more R B-1 C1-C4 alkyl, C1-C6 alkoxy or one or more R B-2C1-C6 alkoxy substituted with R B-1 and R B-2 are independently deuterium, hydroxyl, cyano, C1-C4 alkoxy, C1-C2 alkoxy substituted with one or more deuterium atoms, or

[0147] [ka] and R 5 teeth,

[0148] [ka] and R 3 , R 6 , R 12 , R 13 and R 14 is H,

[0149] Scheme 4: R 2 teeth,

[0150] [ka] and R 4 and R 5 are independently halogen, C1-C4 alkyl, one or more R B-1 C1-C4 alkyl, C1-C6 alkoxy or one or more R B-2 C1-C6 alkoxy substituted with R B-1 and R B-2 are independently deuterium, hydroxyl, cyano, C1-C4 alkoxy, C1-C2 alkoxy substituted with one or more deuterium atoms, or

[0151] [ka] and R 3 , R 6 , R 12 , R13 and R 14 is H and R 15 and R 16 at least one of is H or deuterium,

[0152] Scheme 5: R 2 is halogen, C1-C4 alkyl or one or more R A-1 and R is a C1-C4 alkyl substituted with A-1 is a halogen and R 4 teeth,

[0153] [ka] and R 5 is a halogen, hydroxyl, C1-C4 alkyl, one or more R B-1 C1-C4 alkyl, C1-C6 alkoxy or one or more R B-2 C1-C6 alkoxy substituted with R B-1 and R B-2 are independently deuterium, hydroxyl, cyano, C1-C4 alkoxy, C1-C2 alkoxy substituted with one or more deuterium atoms, or

[0154] [ka] and R 3 , R 6 , R 12 , R 13 and R 14 is H and R 15 and R 16 at least one of is H or deuterium,

[0155] Scheme 6: R 2 is halogen, C1-C4 alkyl or one or more R A-1 and R is a C1-C4 alkyl substituted with A-1 is a halogen and R 4is a halogen, a C1-C4 alkyl, one or more R B-1 C1-C4 alkyl, C1-C6 alkoxy or one or more R B-2 C1-C6 alkoxy substituted with R B-1 and R B-2 are independently deuterium, hydroxyl, cyano, C1-C4 alkoxy, C1-C2 alkoxy substituted with one or more deuterium atoms, or

[0156] [ka] and R 5 teeth,

[0157] [ka] and R 3 , R 6 , R 12 , R 13 and R 14 is H and R 15 and R 16 At least one of is H or deuterium.

[0158] In some embodiments, in the aromatic ethylenic compound represented by formula I-0, R 1 is cyano, CH3, CD3, Cl, CH2F, C1-C4 alkyl substituted with one or more halogens, and other variables are as defined in any embodiment of the present invention.

[0159] In some embodiments, in the aromatic ethylenic compound represented by formula I-0,

[0160] [ka]

[0161] [ka]

[0162] [ka]

[0163] [ka] and other variables are as defined in any embodiment of the present invention.

[0164] In some embodiments, in the aromatic ethylenic compound represented by formula I-0, R 15 and R 16 are independently H, deuterium, Br, or F, and other variables are as defined in any embodiment of the present invention.

[0165] In some embodiments, the aromatic ethylenic compound represented by formula I-0 or I is any one of the following compounds:

[0166] [ka]

[0167] [ka]

[0168] [ka]

[0169] [ka]

[0170] [ka]

[0171] [ka]

[0172] [ka]

[0173] [ka]

[0174] The present invention also provides a method for preparing the aromatic ethylene compound represented by Formula I-0, and the method for preparing the aromatic ethylene compound represented by Formula I-0 includes the following Method 1, Method 2, Method 3, Method 4, Method 5, or Method 6.

[0175] Method 1 includes the following steps of reductive amination of a compound represented by formula II-a-0 and a compound represented by formula III-a in a solvent under the action of a reducing agent to obtain an aromatic ethylenic compound represented by formula I-0:

[0176] [ka]

[0177] In Method 1, R 4 teeth,

[0178] [ka] and R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R14 , R 15 , R 16 , R B-1-1 and R B-1-2 The definition of is the same as above,

[0179] Method 2 includes the following steps: in a solvent, under the action of a base, a compound represented by formula II-b-0 and a compound represented by formula III-a are subjected to a substitution reaction to obtain an aromatic ethylenic compound represented by formula I-0:

[0180] [ka]

[0181] In Method 2, R 4 teeth,

[0182] [ka] and R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R B-1-1 and R B-1-2 The definition of is the same as above, and X 1 is a halogen,

[0183] Method 3 includes the following steps: in a solvent, a compound represented by Formula II-c-0 and a compound represented by Formula III-a are subjected to a reductive amination reaction under the action of a reducing agent to obtain an aromatic ethylenic compound represented by Formula I-0:

[0184] [ka]

[0185] In Method 3, R 5 teeth,

[0186] [ka] and R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R B-1-1 and R B-1-2 The definition of is the same as above,

[0187] Method 4 includes the following steps of: subjecting a compound represented by formula II-d-0 and a compound represented by formula III-a to a substitution reaction in a solvent under the action of a base to obtain an aromatic ethylenic compound represented by formula I-0:

[0188] [ka]

[0189] In Method 4, R 5 teeth,

[0190] [ka] and R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R B-1-1 and R B-1-2 The definition of is the same as above, and X 2 is a halogen,

[0191] Method 5 includes the following steps: in a solvent, under the action of a reducing agent, a compound represented by II-e-0 and a compound represented by formula III-b are subjected to a reductive amination reaction to obtain an aromatic ethylenic compound represented by formula I-0:

[0192] [ka]

[0193] In Method 5, R 2 teeth,

[0194] [ka] and R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R A-1-1 and R A-1-2 The definition of is the same as above,

[0195] Method 6 includes the steps of: subjecting a compound represented by formula II-f-0 and a compound represented by formula III-b to a substitution reaction in a solvent under the action of a base to obtain an aromatic ethylenic compound represented by formula I-0,

[0196] [ka]

[0197] In Method 6, R 2 teeth,

[0198] [ka] and R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R A-1-1 and R A-1-2 The definition of is the same as above, and X 3 is a halogen.

[0199] The present invention also provides a method for preparing the aromatic ethylenic compound represented by Formula I, which includes the following Method 1, Method 2, Method 3, Method 4, Method 5, or Method 6:

[0200] Method 1 includes the steps of: subjecting a compound represented by Formula II-a and a compound represented by Formula III-a to a reductive amination reaction in a solvent under the action of a reducing agent to obtain an aromatic ethylenic compound represented by Formula I, as follows:

[0201] [ka]

[0202] In Method 1, R 4 teeth,

[0203] [ka] and R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R B-1-1 and R B-1-2 The definition of is the same as above,

[0204] Method 2 includes the following steps: in a solvent, under the action of a base, a compound represented by formula II-b and a compound represented by formula III-a are subjected to a substitution reaction to obtain an aromatic ethylenic compound represented by formula I:

[0205] [ka]

[0206] In Method 2, R 4 teeth,

[0207] [ka] and R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R B-1-1 and R B-1-2 The definition of is the same as above, and X 1 is a halogen,

[0208] Method 3 includes the following steps: in a solvent, under the action of a reducing agent, a compound represented by Formula II-c and a compound represented by Formula III-a are subjected to a reductive amination reaction to obtain an aromatic ethylenic compound represented by Formula I:

[0209] [ka]

[0210] In method 3, R 5 teeth,

[0211] [ka] and R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R B-1-1 and R B-1-2 The definition of is the same as above,

[0212] Method 4 includes the following steps: in a solvent, under the action of a base, a compound represented by formula II-d and a compound represented by formula III-a are subjected to a substitution reaction to obtain an aromatic ethylenic compound represented by formula I:

[0213] [ka]

[0214] In Method 4, R 5 teeth,

[0215] [ka] and R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R B-1-1 and R B-1-2 The definition of is the same as above, and X 2 is a halogen,

[0216] Method 5 includes the following steps: in a solvent, under the action of a reducing agent, a compound represented by Formula II-e and a compound represented by Formula III-b are subjected to a reductive amination reaction to obtain an aromatic ethylenic compound represented by Formula I:

[0217] [ka]

[0218] In Method 5, R 2 teeth,

[0219] [ka] and R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R A-1-1 and R A-1-2 The definition of is the same as above,

[0220] Method 6 includes the following steps: in a solvent, under the action of a base, a compound represented by formula II-f and a compound represented by formula III-b are subjected to a substitution reaction to obtain an aromatic ethylenic compound represented by formula I:

[0221] [ka]

[0222] In Method 6, R 2 teeth,

[0223] [ka] and R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R A-1-1 and R A-1-2 The definition of is the same as above, and X 3 is a halogen.

[0224] In Method 1, Method 3, Method 5, Method 1, Method 3 or Method 5, the method and conditions for said reductive amination reaction may be conventional methods and conditions for such reactions in the art. In Method 2, Method 4, Method 6, Method 2, Method 4 or Method 6, the method and conditions for said substitution reaction may be conventional methods and conditions for such reactions in the art.

[0225] The present invention also provides compounds represented by II-a-0, II-b-0, II-c-0, II-d-0, II-e-0, or II-f-0.

[0226] [ka]

[0227] In the compound of the above general formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 The definition of is the same as above, and X 1 , X 2 and X 3 are independently halogen.

[0228] The present invention also provides compounds represented by II-a, II-b, II-c, II-d, II-e, or II-f.

[0229] [ka]

[0230] In the compound of the above general formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 The definition of is the same as above, and X 1 , X 2 and X 3 are independently halogen.

[0231] In some embodiments, the compound represented by II-a-0 or II-a is any one of the following compounds:

[0232] [ka]

[0233] [ka]

[0234] [ka]

[0235] [ka]

[0236] In some embodiments, the compound represented by II-b is the following compound:

[0237] [ka]

[0238] In some embodiments, the compound represented by II-c is any one of the following compounds:

[0239] [ka]

[0240] In some embodiments, the compound represented by II-e is any one of the following compounds:

[0241] [ka]

[0242] The present invention also relates to any one of the following aromatic ethylene compounds, their tautomers, their stereoisomers, their racemates or their isotope derivatives, or a derivative thereof (the above-mentioned any one of the following aromatic ethylene compounds, their tautomers, their stereoisomers, their racemates or their isotope derivatives) The present invention provides pharmaceutically acceptable salts of the compounds (which refer to derivatives thereof).

[0243] [ka]

[0244] The present invention also provides a pharmaceutical composition, which comprises the above-mentioned aromatic ethylenic compound, a tautomer thereof, a stereoisomer thereof, a racemate thereof or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof (referring to the above-mentioned aromatic ethylenic compound, a tautomer thereof, a stereoisomer thereof, a racemate thereof or an isotopic derivative thereof), and a pharmaceutically acceptable excipient.

[0245] The present invention also provides a pharmaceutical composition comprising the aromatic ethylenic compound, its tautomer, its stereoisomer, its racemate, or its isotopic derivative, or a pharmaceutically acceptable salt thereof (referring to the aromatic ethylenic compound, its tautomer, its stereoisomer, its racemate, or its isotopic derivative), and at least one other drug, wherein the other drug is a chemotherapeutic drug or a targeted drug. The targeted drug is preferably one or more of a COX-2 inhibitor, a DPP4 inhibitor, a CSF-1α inhibitor, and an A2a antagonist.

[0246] In the pharmaceutical composition, the aromatic ethylenic compound, its tautomer, its stereoisomer, The amount of the aromatic ethylenic compound, its tautomer, its stereoisomer, its racemate or its isotopic derivative, or a pharmaceutically acceptable salt thereof (referring to the aromatic ethylenic compound, its tautomer, its stereoisomer, its racemate or its isotopic derivative) used may be a therapeutically effective amount.

[0247] The pharmaceutically acceptable additives may be additives commonly used in the field of pharmaceutical manufacturing. Additives are primarily used to provide a safe, stable, and functional pharmaceutical composition, and may also provide a method for enabling the active ingredient to dissolve at a desired rate after administration to a subject, or for promoting effective absorption of the active ingredient after administration of the composition to a subject. The pharmaceutically acceptable additives may be inert fillers, or may serve a specific function, such as stabilizing the overall pH of the composition or preventing the active ingredient of the composition from decomposing. The pharmaceutically acceptable additives may include one or more of the following additives: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adherents, glidants, wetting agents, gelling agents, absorption retarders, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

[0248] The pharmaceutical compositions of the present invention can be manufactured in accordance with the present disclosure using any method known to one of ordinary skill in the art, for example, conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, entrapping, or lyophilizing processes. The pharmaceutical compositions described herein can be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ophthalmic, rectal, topical, or parenteral (infusion, injection, implant, subcutaneous, intravenous, intraarterial, intramuscular) administration. The pharmaceutical compositions of the present invention may also be in controlled-release or delayed-release dosage forms (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, caplets, softgels, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum formulations. Examples of formulations for parenteral administration include, but are not limited to, injectable solutions, dry formulations that can be dissolved or suspended in a pharmaceutically acceptable carrier, injectable suspensions, and injectable emulsions. Examples of other suitable formulations of the pharmaceutical compositions include, but are not limited to, eye drops and other ophthalmic formulations, aerosols, nasal sprays or inhalants, liquid dosage forms suitable for parenteral administration, suppositories, and tablets.

[0249] The present invention also provides use of the above-mentioned aromatic ethylene compound, its tautomer, its stereoisomer, its racemate or its isotopic derivative, or a pharmaceutically acceptable salt thereof (referring to the above-mentioned aromatic ethylene compound, its tautomer, its stereoisomer, its racemate or its isotopic derivative), or the above-mentioned pharmaceutical composition, in the manufacture of a PD-1 inhibitor and / or a PD-L1 inhibitor.

[0250] In the above uses, the PD-1 inhibitor or PD-L1 inhibitor can be used inside a mammalian organism, or can be used outside the organism, mainly for experimental purposes, such as to provide a standard or control sample for comparison, or to be prepared into a kit according to methods routine in the art for rapid detection of the inhibitory effects of PD-1 or PD-L1.

[0251] The present invention also provides use of the above-mentioned aromatic ethylene compound, its tautomer, its stereoisomer, its racemate, or its isotopic derivative, or a pharmaceutically acceptable salt thereof (referring to the above-mentioned aromatic ethylene compound, its tautomer, its stereoisomer, its racemate, or its isotopic derivative), or the above-mentioned pharmaceutical composition, in the manufacture of a medicament for the prevention and / or treatment of a disease associated with the PD-1 / PD-L1 signaling pathway.

[0252] The disease associated with the PD-1 / PD-L1 signal pathway is selected from cancer, infectious diseases, autoimmune diseases, and diseases related thereto. The cancer is preferably one or more of lung cancer, esophageal cancer, gastric cancer, colon cancer, hematological tumors, lymphoma, head and neck cancer, liver cancer, nasopharyngeal cancer, brain tumor, breast cancer, cervical cancer, blood cancer and bone cancer.

[0253] The infection is preferably a bacterial infection and / or a viral infection. The autoimmune disease is preferably one or more of rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, systemic vasculitis and relapsing polychondritis.

[0254] Unless otherwise specified, the terms used in this invention have the following meanings: The term "pharmaceutically acceptable" refers to salts, solvents, additives, etc. that are generally non-toxic, safe, and suitable for patients. The "patient" is preferably a mammal, more preferably a human.

[0255] The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of a pharmaceutically acceptable base in a separate solution or in a suitable inert solvent. Such pharmaceutically acceptable base addition salts include, but are not limited to, lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, diethanolamine salts, etc. When the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a separate solution or in a suitable inert solvent. The pharmaceutically acceptable acids include inorganic acids, such as, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like. The pharmaceutically acceptable acids include organic acids, such as, but not limited to, acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isopropyl alcohol, methyl methyl ester ... Examples of suitable salts include, but are not limited to, sonicotinic acid, acidic citric acid, oleic acid, tannic acid, pantothenic acid, bitartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, saccharic acid, formic acid, ethanesulfonic acid, pamoic acid (i.e., 4,4'-methylenebis(3-hydroxy-2-naphthoic acid)), amino acids (glutamic acid, arginine, etc.). When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts. For example, see Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science 66: 1-19 (1977), or Handbook of Pharmaceutical Salts: See Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0256] The terms "compound," "tautomer," "stereoisomer," "racemate," "isotopic derivative," and their "pharmaceutically acceptable salts" may exist in crystalline or amorphous form. The term "crystal" refers to a state in which ions or molecules are arranged in a strictly periodic, regular manner in three-dimensional space, with a periodic repeating pattern at regular intervals. This periodic arrangement can result in the existence of multiple crystals, i.e., crystalline polymorphism. The term "amorphous" refers to a state in which ions or molecules are distributed randomly, i.e., there is no periodic arrangement between ions or molecules.

[0257] The term "stereoisomer" refers to cis-trans isomers or optical isomers. Isomers can be separated, purified, and enriched by asymmetric synthesis or chiral separation techniques (including, but not limited to, thin layer chromatography, rotary chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.), or can be obtained by chiral resolution by bond formation (e.g., chemical bond) or salt formation (e.g., physical bond) with other chiral compounds.

[0258] The term "isotopic derivative" refers to the fact that the atoms of the "compounds," "tautomers," "stereoisomers," "racemates," and "pharmaceutically acceptable salts" thereof may exist in their natural abundance or non-natural abundance forms. For example, the natural abundance form of a hydrogen atom means that about 99.985% of it is protium and about 0.015% is deuterium, while the non-natural abundance form means that 95% of it is deuterium. That is, one or more atoms of the terms "compounds," "tautomers," "stereoisomers," "racemates," and "pharmaceutically acceptable salts" thereof may exist in non-natural abundance forms.

[0259] In the definition of a compound, any variable (e.g., R A-1 When R occurs more than once, the definition of that variable at each occurrence is independent of its definition at any other occurrence, and the definitions are independent of and do not influence each other. Thus, when a particular group occurs at one, two, three, four, or five R A-1 When substituted by a group, i.e., when the group is substituted by up to five R A-1 and R at that position may be substituted. A-1 Definition of R in the remaining positions A-1 The definitions of are independent of each other and may be different or the same. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0260] The term "alkyl" refers to straight or branched chain alkyls containing the specified number of carbon atoms. The term "alkoxy" refers to an -OR X refers to the group, where R X is alkyl as defined above. The term "pharmaceutically acceptable excipients" refers to additives and additives used in the manufacture and formulation of pharmaceuticals, including all substances contained in drug formulations except for active ingredients. For details, please refer to Part 4 of the Pharmacopoeia of the People's Republic of China (2015 Edition) or the Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).

[0261] The term "prevention" refers to reducing the risk of developing a disease or disorder. The term "treatment" refers to therapeutic therapy. With respect to a particular disease, treatment refers to (1) alleviating one or more biological manifestations of the disease or condition, (2) interfering with (a) one or more points in the biological cascade leading to or causing the disease or (b) one or more biological manifestations of the disease, (3) ameliorating one or more symptoms, effects, or side effects associated with the disease or one or more symptoms, effects, or side effects associated with the disease or its treatment, or (4) reducing the disease or one or more biological manifestations of the disease.

[0262] The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., most preferably humans.

[0263] The above preferred conditions can be combined in any way to obtain each preferred embodiment of the present invention, without violating the common knowledge of the art. All of the reagents and raw materials used in the present invention are commercially available.

[0264] The positive effect of the present invention is that the aromatic ethylene compound or its pharmaceutically acceptable salt of the present invention has a significant inhibitory effect on PD-1 and PD-L1, and at the same time, has a better It has a drug peak concentration, area under the drug-time curve and oral bioavailability, and can effectively alleviate or treat related diseases such as cancer. DETAILED DESCRIPTION OF THE INVENTION

[0265] The present invention will be further described below with reference to examples, but the present invention is not limited to the scope of the examples. In the following examples, experimental methods for which specific conditions are not described are selected according to conventional methods and conditions or product instructions.

[0266] In the following examples, room temperature refers to 10°C to 30°C, and overnight refers to 8 to 24 hours, preferably 12 to 18 hours. The structures of the compounds were identified by nuclear magnetic resonance (NMR) or mass spectrometry (MS). Nuclear magnetic resonance spectra were obtained using a Bruker Avance-500 instrument, with deuterated dimethyl sulfoxide, deuterated chloroform, and deuterated methanol as solvents, and tetramethylsilane (TMS) as the internal standard. Mass spectra were obtained using an Agilent Technologies 6110 liquid chromatography-mass spectrometry (LC-MS) instrument, with an ESI ion source.

[0267] The microwave reaction was carried out in an Explorer automatic microwave synthesizer manufactured by CEM, USA, with a magnetron frequency of 2450 MHz and a microwave continuous power of 300 W. The instrument used for preparative high-performance liquid chromatography was a Waters 2767, and the preparative column used was an XBrige C18, 19 x 150 mm x 5 μm. The acidic mobile phase was 1% formic acid (A) + acetonitrile (B); the basic mobile phase was 5 mmol / L aqueous ammonium bicarbonate. The flow rate was 15 mmL / min. The gradient was 20% to 70% (the initial mobile phase was 80% water / 20% acetonitrile, and the final mobile phase was 30% water / 70% acetonitrile, where % refers to volume percentage). The detection wavelengths were 214 nm and 254 nm.

[0268] Example 1 (S,E)-1-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-3-trifluoromethylbenzyl)piperidine-2-carboxylic acid (Compound 1)

[0269] [ka]

[0270] Synthesis of compound 1-c To a solution of 2-bromo-6-chlorobenzonitrile (2.16 g, 10.0 mmol) and phenylboronic acid (1.33 g, 11.0 mmol) in 1,4-dioxane (40 mL), water (4 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (365 mg, 0.5 mmol), and sodium carbonate (2.65 g, 25.0 mmol) were added. The reaction mixture was heated to 80 °C and stirred under nitrogen for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 6:1) to give compound 1-c (1.55 g, yield: 72%).

[0271] Synthesis of compound 1-b To a solution of compound 1-c (1.50 g, 7.0 mmol) and vinyl pinacol borate (2.13 g, 8.4 mmol) in 1,4-dioxane (80 mL), water (8 mL), palladium acetate (78 mg, 0.35 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (333 mg, 0.70 mmol), cesium fluoride (2.10 g, 14.0 mmol), and potassium phosphate (2.97 g, 14.0 mmol) were added. The reaction mixture was heated to 80 °C and stirred under nitrogen for 6 h. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 6:1) to give compound 1-b (1.17 g, 82% yield).

[0272] 1 H NMR (400 MHz,CD3Cl): δ 7.67 (dd,J=1.2 Hz, 7.6 Hz,1H), 7.59 (t,J=8.0 Hz,1H), 7.53-7.56 (m, 2H), 7.44-7.50 (m, 3H), 7.37 (dd,J=1.2 Hz, 7.6 Hz,1H), 7.20 (dd,J=10.8 Hz, 17.6 Hz,1H), 5.96 (d,J=17.6 Hz,1H), 5.57 (d,J=10.8Hz,1H) ppm

[0273] Synthesis of compound 1-a Compound 1-b (100 mg, 0.487 mmol) and 4-bromo-3-trifluoromethyl-benzaldehyde (123 mg, 0.487 mmol) were dissolved in toluene (20 mL), and N,N'-diisopropylethylamine (504 mg, 3.896 mmol) and bis(tri-tert-butylphosphine)palladium (18 mg, 0.034 mmol) were added. The reaction solution was purged with nitrogen gas three times at room temperature, heated to 80 °C, and stirred for 16 h. The reaction solution was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed sequentially with water (100 mL × 3) and saturated brine (100 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1 to 5:1) to give compound 1-a (62 mg, yield: 33.7%).

[0274] 1 H NMR (400 MHz, CDCl3): δ 10.01 (s, 1H), 8.15 (s, 1H), 8.05-8.00 (m, 2H), 7.77-7.75 (d, J= 8.0 Hz, 1H), 7.67-7.60 (m, 3H), 7.51-7.39 (m, 6H) ppm

[0275] Synthesis of Compound 1 Compound 1-a (62 mg, 0.164 mmol) was suspended in methanol (10 mL), and (S)-piperidine-2-carboxylic acid (43 mg, 0.329 mmol) and sodium cyanoborohydride (21 mg, 0.329 mmol) were added. The reaction solution was heated to 70°C and stirred for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to obtain compound 1 (15 mg, yield: 18.8%). Got it.

[0276] LC-MS (ESI): m / z = 491.0 [M+H] + . 1H NMR (400 MHz, CD3OD): δ 8.08-8.06 (d, J= 8.0 Hz, 1H), 8.03 (s, 1H), 7.93-7.88 (m, 2H), 7.81-7.77 (t, J= 8.0 Hz, 1H), 7.76-7.71 (m, 1H), 7.66-7.59 (m, 3H), 7.56-7.50 (m, 4H), 4.73-4.70 (d, J = 12.8 Hz, 1H), 4.21-4.17 (m, 1H), 3.53-3.50 (m, 1H), 3.39-3.36 (m, 1H), 3.02-2.97 (m, 1H), 2.32-2.29 (m, 1H), 1.88-1.84 (m, 3H), 1.74-1.68 (m, 1H), 1.62-1.56 (m, 1H) ppm.

[0277] Example 2 (S,E)-1-(3-chloro-4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)benzyl)piperidine-2-carboxylic acid (compound 2)

[0278] [ka]

[0279] Synthesis of compound 2-a Compound 1-b (205.0 mg, 1.0 mmol) and 4-bromo-3-chlorobenzaldehyde (240.9 mg, 1.1 mmol) were dissolved in toluene (30 mL), and N,N'-diisopropylethylamine (387 mg, 3.0 mmol) and bis(tri-tert-butylphosphine)palladium (51.1 mg, 0.1 mmol) were added. The reaction solution was purged with nitrogen gas three times at room temperature, heated to 90 °C, and stirred for 10 h. The reaction solution was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed sequentially with water (100 mL × 3) and saturated brine (100 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1 to 5:1) to give compound 2-a (270 mg, yield: 78%).

[0280] Synthesis of compound 2 Compound 2-a (172 mg, 0.5 mmol) was suspended in methanol (30 mL), and (S)-piperidine-2-carboxylic acid (43 mg, 0.329 mmol) and sodium cyanoborohydride (63.0 mg, 1.0 mmol) were added. The reaction solution was heated to 60°C and stirred for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give a white solid 2 (75 mg, yield: 32%).

[0281] LC-MS (ESI): m / z = 457.3 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ 7.97 (d, J = 7.2 Hz, 1H), 7.93 (t, J = 8.0 Hz, 1H), 7.82-7.75 (m, 3H), 7.66-7.47 (m, 3H), 4.62 (d, J = 12.8 Hz, 1H), 4.13 -4.08 (m, 1H), 3.50-3.40 (m, 2H), 3.00-2.94 (m, 1H), 2.32-2.28 (m, 1H), 1.87-1.54 (m, 5H) ppm.

[0282] Example 3 (S,E)-1-(3-chloro-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)benzyl)piperidine-2-carboxylic acid (compound 3)

[0283] [ka]

[0284] Synthesis of compound 3-c Phenylboronic acid (1.626 g, 13.34 mmol) and 2,6-dibromotoluene (5.0 g, 20.0 mmol) were dissolved in a mixture of 1,4-dioxane (60 mL) and water (3 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.154 g, 1.334 mmol) and sodium carbonate (3.535 g, 33.35 mmol) were added. The reaction mixture was purged with nitrogen gas three times, heated to 80 °C, and stirred for 16 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed sequentially with water (100 mL × 3) and saturated brine (100 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether) to give compound 3-c (1.9 g, yield: 57.2%).

[0285] 1 H NMR (400 MHz, CDCl3): δ 7.56-7.54 (m, 1H), 7.44-7.35 (m, 3H), 7.28-7.25 (m, 2H), 7.17-7.15 (m, 1H), 7.08 (t, J = 8Hz, 1H), 2.31 (s, 3H)ppm

[0286] Synthesis of compound 3-b Compound 3-c (1.071 g, 4.33 mmol) and vinylboronic acid pinacol ester (800.9 mg, 5.20 mmol) were dissolved in toluene (50 mL), and bis(tri-tert-butylphosphine)palladium (154.8 mg, 0.303 mmol) and triethylamine (3.51 g, 34.64 mmol) were added. The reaction system was heated under nitrogen. The mixture was purged with nitrogen gas three times, then heated to 80°C and stirred for 16 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed successively with water (50 mL x 3) and saturated brine (50 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether) to give compound 3-b (0.89 g, yield: 64.1%).

[0287] 1 H NMR (400 MHz, CDCl3): δ 7.75-7.71 (d, J = 18Hz, 1H), 7.56-7.54 (m, 1H), 7.41-7.39 (m, 2H), 7.36-7.34 (m, 1H), 7.30-7.28 (m, 2H), 7.23-7.17 (m, 2H), 6.12-6.07 (d, J = 18Hz, 1H), 2.82 (s, 3H), 1.32 (s, 12H) ppm

[0288] Synthesis of compound 3-a Compound 3-b (349 mg, 1.09 mmol) and 3-chloro-4-bromobenzaldehyde (200 mg, 0.911 mmol) were dissolved in ethylene glycol dimethyl ether (20 mL), and cesium fluoride (277 mg, 1.82 mmol), sodium carbonate (242 mg, 2.28 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (79 mg, 0.091 mmol) were added. The reaction solution was purged with nitrogen gas three times at room temperature. The mixture was heated to 80 °C and stirred for 16 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed with water (100 mL x 3) and saturated brine (100 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1 to 5:1) to obtain compound 3-a (175 mg, yield: 57.8%).

[0289] 1 H NMR (400 MHz, CDCl3): δ 9.90 (s, 1H), 7.85-7.79 (m, 2H), 7.72-7.70 (d, J= 8.0 Hz, 1H), 7.60-7.57 (m, 1H), 7.52-7.48 (m, 1H), 7.38-7.34 (m, 3H), 7.31-7.21 (m, 5H), 2.26 (s, 3H) ppm

[0290] Synthesis of compound 3 Compound 3-a (175 mg, 0.526 mmol) was suspended in methanol (15 mL), and (S)-piperidine-2-carboxylic acid (136 mg, 1.052 mmol) and sodium cyanoborohydride (66 mg, 1.052 mmol) were added. The reaction solution was heated to 70°C and stirred for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 3 (43 mg, yield: 18.3%).

[0291] LC-MS (ESI): m / z = 446.0 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ 7.82-7.80 (d, J= 8.0 Hz, 1H), 7.58 (s, 1H), 7.52-7.48 (m, 2H), 7.41-7.39 (d, J= 7.2 Hz, 1H), 7.34-7.25 (m, 4H), 7.20-7.16 (m, 3H), 7.07-7.06 (d, J= 6.8 Hz,1H), 4.50-4.47 (d, J= 12.4 Hz,1H), 3.99-3.94 (m, 1H), 3.37-3.34 (d, J= 10.4 Hz,1H), 3.28-3.25 (m, 1H), 2.88-2.82 (t, J= 12.4 Hz,1H), 2.19 (s, 3H), 2.16 (s, 1H), 1.75-1.72 (m, 3H ), 1.63-1.60 (m, 1H), 1.48-1.41 (m, 1H) ppm.

[0292] Example 4 (S,E)-1-(4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-3-trifluoromethylbenzyl)piperidine-2-carboxylic acid (compound 4)

[0293] [ka]

[0294] Synthesis of compound 4-a Compound 3-b (304 mg, 0.949 mmol) and 3-trifluoromethyl-4-bromobenzaldehyde (200 mg, 0.791 mmol) were dissolved in ethylene glycol dimethyl ether (20 mL), and cesium fluoride (241 mg, 1.582 mmol), sodium carbonate (210 mg, 1.98 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (69 mg, 0.079 mmol) were added. The reaction solution was purged with nitrogen gas three times at room temperature. The mixture was heated to 80 °C and stirred for 16 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (100 mL), and then washed with water (100 mL × 3) and saturated brine (100 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1 to 5:1) to obtain compound 4-a (132 mg, yield: 45.7%).

[0295] 1 H NMR (400 MHz, CDCl3): δ 9.98 (s, 1H), 8.12 (s, 1H), 8.01-7.98 (d, J= 8.4 Hz,1H), 7.92-7.90 (d, J= 8.4 Hz, 1H), 7.54-7.48 (m, 2H), 7.38-7.22 (m, 8H), 2.26 (s, 3H) ppm

[0296] Synthesis of compound 4 Compound 4-a (132 mg, 0.36 mmol) was suspended in methanol (15 mL), and (S)-piperidine-2-carboxylic acid (93 mg, 0.72 mmol) and sodium cyanoborohydride (46 mg, 0.72 mmol) were added. The reaction solution was heated to 70°C and stirred for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 4 (39 mg, yield: 22.7%).

[0297] LC-MS (ESI): m / z = 480.0 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ 7.99-7.97 (d, J= 8.0 Hz, 1H), 7.88 (s, 1H), 7.75-7.73 (d, J= 8.0 Hz, 1H), 7.56-7.52 (d, J= 16.0 Hz, 1H), 7.49-7.47 (d, J= 8.0 Hz, 1H ), 7.37-7.34 (t, J= 7.2 Hz, 2H), 7.30-7.19 (m, 5H), 7.12-7.10 (d, J= 7.2 Hz, 1H), 4.63-4.59 (d, J= 12.8 Hz, 1H), 4.10-4.07 (m, 1H), 3.41-3.39 (d, J= 10.4 Hz, 1H), 2.93-2.87 (t, J= 10.8 Hz, 1H), 2.22 (s, 3H), 2.20 (m, 1H), 1.78-1.76 (m, 3H), 1.65-1.62 (m, 1H), 1.52-1.46 (m, 1H) ppm.

[0298] Example 5 (S,E)-1-(-5-chloro-2-methyl-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)benzyl)piperidine-2-carboxylic acid (Compound 5)

[0299] [ka]

[0300] Synthesis of compound 5-c 5-Chloro-2-methylphenol (2.85 g, 20.0 mmol) was dissolved in anhydrous dichloromethane (100 mL), titanium tetrachloride (11.38 g, 60.0 mmol) was added, and the reaction solution was cooled to 0 °C. Under nitrogen gas protection, dichloromethoxymethane (6.90 g, 60.0 mmol) was added dropwise. After the addition was complete, the reaction solution was warmed to room temperature and stirred for 2 h. The reaction was then quenched by pouring the reaction solution onto crushed ice and extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed sequentially with water (100 mL) and saturated brine (100 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 3:1) to obtain compound 5-c (1.569 g, yield: 45.9%). LC-MS (ESI): m / z = 171.0 [M+H] + .

[0301] Synthesis of compound 5-b Compound 5-c (1.05 g, 6.16 mmol) was dissolved in anhydrous dichloromethane (100 mL), and triethylamine (1.25 g, 12.32 mmol) was added. The reaction solution was cooled to -78°C under nitrogen gas protection, and trifluoromethanesulfonic anhydride (2.61 g, 9.23 mmol) was added dropwise. After the dropwise addition was completed, the reaction solution was warmed to room temperature and stirred for 2 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed with water (100 mL) and saturated brine (100 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. The residue was purified by filtration (petroleum ether:ethyl acetate=50:1 to 10:1) to give compound 5-b (1.50 g, yield: 80.2%).

[0302] Synthesis of compound 5-a Compound 3-b (634.7 mg, 1.982 mmol) and compound 5-b (500 mg, 1.652 mmol) were dissolved in toluene (20 mL) at room temperature, and potassium phosphate (701.4 mg, 3.304 mmol), cesium fluoride (501.9 mg, 3.304 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (142.7 mg, 0.165 mmol) were added. The reaction solution was heated to 80 °C and stirred under nitrogen gas protection for 16 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed with water (100 mL) and saturated brine (100 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50:1 to 20:1) to obtain compound 5-a (501 mg, yield: 87.6%).

[0303] Synthesis of compound 5 To a solution of compound 5-a (70 mg, 0.20 mmol) and L-piperidine-2-carboxylic acid (52 mg, 0.40 mmol) in methanol (10 mL) was added dichloromethane (10 mL). The mixture was stirred at room temperature for 1 hour, and then sodium cyanoborohydride (32 mg, 0.50 mmol) was added. After stirring at room temperature for 16 hours, the reaction solution was concentrated under reduced pressure, and the residue was washed with water (100 mL), filtered, and purified by preparative high-performance liquid chromatography to give a white solid 5 (34 mg, yield: 37%).

[0304] LC-MS (ESI): m / z = 460 [M+H] + . 1 H NMR (400 MHz, CD3Cl): δ 7.77 (s, 1H), 7.70 (s, 1H), 7.62~7.63 (m, 1H), 7.60 (d, J=18.0Hz, 1H), 7.43~7.47 (m, 2H), 7.34~7.39 (m, 2H), 7.27~7.32 (m, 3H), 7.17~7.19 (m, 1H), 4.88 (d, J=12.8Hz, 1H), 4.67 (d, J=12.8Hz, 1H), 4.05~4.09 (m, 1H), 3.53~3.57 (m, 1H), 3.01~3.06 (m, 1H), 2.53 (s, 3H), 2.32 (s, 3H), 2.27~2.31 (m, 1H), 1.82~1.89 (m, 3H), 1.72~1.75 (m, 1H), 1.57~1.64 (m, 1H) ppm.

[0305] Example 6 (S,E)-1-(2-methoxy-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-5-trifluoromethylbenzyl)piperidine-2-carboxylic acid (Compound 6)

[0306] [ka]

[0307] Synthesis of compound 6-b Titanium tetrachloride (2.84 g, 15.0 mmol) was added to a solution of 2-bromo-4-methoxy-1-(trifluoromethyl)benzene (1.28 g, 5.0 mmol) in dry dichloromethane (30 mL) at 0 °C. 1,1'-Dichloromethyl ether (1.15 g, 10.0 mmol) was slowly added dropwise to the mixture while stirring at 0 °C. After the addition was completed, the reaction was continued at 0 °C for 3 h. The reaction was quenched by slowly adding ice water (30 mL). The mixture was extracted with ethyl acetate (30 mL × 3) and washed with water (30 mL × 2) and saturated brine (30 mL × 2), successively. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to give compound 6-b (254 mg, yield: 18%).

[0308] 1 H NMR (400 MHz, CD3Cl): δ 10.40 (s, 1H), 8.14 (s, 1H), 7.35 (s, 1H),4.01 (s, 3H) ppm

[0309] Synthesis of compound 6-a To a mixture of compound 6-b (141 mg, 0.50 mmol), compound 3-b (200 mg, 0.62 mmol), and toluene (25 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (48 mg, 0.12 mmol), potassium phosphate (212 mg, 1.0 mmol), and cesium fluoride (150 mg, 1.0 mmol) were added and stirred at 80 °C for 16 h under a nitrogen atmosphere. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 6:1 to 4:1) to give compound 6-a (107 mg, 54% yield). LC-MS (ESI): m / z = 397 [M+H] + .

[0310] Synthesis of compound 6 To a solution of compound 6-a (80 mg, 0.20 mmol) and L-piperidine-2-carboxylic acid (52 mg, 0.40 mmol) in methanol (10 mL) was added dichloromethane (10 mL). The mixture was stirred at room temperature for 1 hour, and then sodium cyanoborohydride (32 mg, 0.50 mmol) was added. The mixture was stirred at room temperature for 16 hours, then concentrated under reduced pressure. The residue was washed with water (30 mL × 3), filtered, concentrated under reduced pressure, and purified by preparative high-performance liquid chromatography to give the white solid product 6 (41 mg, yield: 40%).

[0311] LC-MS (ESI): m / z = 510 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ 7.81 (s, 1H), 7.54 (d, J=16.0Hz, 1H), 7.45 (d, J=16.0Hz, 1H), 7.44 (s, 1H), 7.32~7.35 (m, 2H), 7.24~7.28 (m, 2H), 7.17~7.21 (m, 3H), 7.09 (d, J=7.6Hz, 1H), 4.45 (d, J=12.8Hz, 1H), 4.31 (d, J=12.8Hz, 1H), 3.98 (s, ppm.

[0312] Example 7 (S,E)-1-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-methoxy-5-trifluoromethylbenzyl)piperidine-2-carboxylic acid (Compound 7)

[0313] [ka]

[0314] Synthesis of compound 7-a Compound 1-b (100 mg, 0.487 mmol) and 4-bromo-2-methoxy-5-trifluoromethylbenzaldehyde (138 mg, 0.487 mmol) were dissolved in toluene (20 mL), and N,N'-diisopropylethylamine (504 mg, 3.896 mmol) and bis(tri-tert-butylphosphine)palladium (25 mg, 0.049 mmol) were added. The reaction solution was purged with nitrogen gas at room temperature for 1 minute, heated to 110 °C under microwave conditions, and stirred for 30 minutes. The reaction solution was cooled to room temperature, diluted with ethyl acetate (100 mL), and then washed successively with water (100 mL × 3) and saturated brine (100 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1 to 5:1) to give compound 7-a (17 mg, yield: 8.6%). LC-MS (ESI): m / z = 408.0 [M+H] + .

[0315] Synthesis of compound 7 Compound 7-a (17 mg, 0.042 mmol) was suspended in methanol (5 mL), and (S)-piperidine-2-carboxylic acid (11 mg, 0.084 mmol) and sodium cyanoborohydride (6.0 mg, 0.084 mmol) were added. The reaction solution was heated to 70°C and stirred for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 7 (3.7 mg, yield: 7.0%).

[0316] LC-MS (ESI): m / z = 521.0 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ 7.86 (s, 1H), 7.80 (d, J= 7.6 Hz, 1H), 7.70-7.66 (t, J= 8.0 Hz, 1H), 7.62-7.52 (m, 2H), 7.50-7.47 (m, 2H), 7.44-7.37 (m, 5H), 4.46-4.43 (d, J= 13.2 Hz, 2H), 4.32-4.29 (d, J= 12.8 ppm.

[0317] Example 8 (S,E)-1-(5-chloro-4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-methylbenzyl)piperidine-2-carboxylic acid (compound 8)

[0318] [ka]

[0319] Synthesis of compound 8-c Method one: Biphenyl-2-carboxylic acid (5 g, 25.22 mmol) was dissolved in anhydrous tetrahydrofuran (180 mL), stirred under nitrogen gas protection, and cooled to -78 °C in an ice-acetone bath. Under nitrogen gas protection, 1.3 M s-butyllithium solution in n-hexane (44 mL, 57.2 mmol) was added dropwise to the mixture within 30 minutes. After the addition was complete, stirring was continued for 2.5 hours under nitrogen gas at -78 °C. 1,2-Dibromotetrachloroethane (24.6 g, 75.6 mmol) was added to the resulting orange-red solution. The dry ice-acetone bath was removed, and the reaction was allowed to warm to room temperature and stirred for 16 hours. Water (30 mL) was added to the reaction solution, which was then separated. The aqueous phase was washed with ether (40 mL), and the pH was adjusted to 1 with 4 N hydrochloric acid. Extraction with ether (20 mL × 4) was performed, and the combined organic phase was washed with brine (20 mL), concentrated under reduced pressure, and the residue was recrystallized from petroleum ether / ethyl acetate to give compound 8-e (4.9 g, yield: 71%). LC-MS (ESI): m / z = 276 [M−H] + .

[0320] Compound 8-e (2.75 g, 10 mmol) was dissolved in dichloromethane (50 mL) and two drops of N,N'-dimethylformamide were added as a catalyst. Oxalyl chloride (5.54 g, 20 mmol) was added dropwise to the solution while stirring. After the addition was completed, the mixture was stirred for 1 hour. The mixture was then spin-dried to obtain the crude chloride. The chloride was dissolved in dichloromethane (50 mL) and the solution was slowly added dropwise to concentrated aqueous ammonia (50 mL) with stirring. After the addition was completed, the mixture was stirred for 1 hour and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL) and concentrated under reduced pressure to obtain compound 8-d (2.56 g, 93% yield), which was directly used in the next step. LC-MS (ESI): m / z = 277 [M+H] + . Compound 8-d (2.50 g, 9.1 mmol) was dissolved in dichloromethane (50 mL) and triethylamine (2.30 g, 23 mmol) was added. Trifluoroacetic anhydride (2.5 g, 11.8 mmol) was added dropwise at 0 °C and stirred for 2 h. The reaction solution was diluted with ethyl acetate (200 mL), washed with brine (20 mL × 3), and concentrated under reduced pressure to give white solid 8-c (2.10 g, 92% yield), which was used directly in the next step.

[0321] Method 2 Phenylboronic acid (3.06 g, 10 mmol) and 2-bromo-6-iodobenzonitrile (3.0 g, 12 mmol) were dissolved in a mixture of 1,4-dioxane (40 mL) and water (4 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (731 mg, 1.0 mmol) and sodium carbonate (4.08 g, 30 mmol) were added. The reaction mixture was purged with nitrogen gas three times, then heated to 40 °C and stirred for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:dichloromethane = 7:1) to give compound 8-c (1.65 g, yield: 67.5%).

[0322] Synthesis of compound 8-b Compound 8-c (516 mg, 2 mmol) and vinylboronic acid pinacol ester (462 mg, 3 mmol) were dissolved in toluene (20 mL), and bis(tri-tert-butylphosphine)palladium (102 mg, 0.2 mmol) and triethylamine (2.02 g, 20 mmol) were added. The reaction mixture was purged with nitrogen gas three times, then heated to 80 °C and stirred for 12 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 8-b (364 mg, yield: 55%).

[0323] 1H NMR (400 MHz, DMSO-d6): δ 8.01 (d, J=7.6Hz, 1H), 7.79-7.75 (m, 1H), 7.60-7.50 (m, 7H), 6.50 (d, J=18Hz, 1H), 2.28 (s, 3H), 1.27 (s, 12H)ppm

[0324] Synthesis of compound 8-a Compound 8-b (110 mg, 0.332 mmol) and compound 8-f (84 mg, 0.277 mmol) were dissolved in toluene (20 mL), and potassium phosphate (118 mg, 0.554 mmol), cesium fluoride (84 mg, 0.554 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (24 mg, 0.028 mmol) were added. The reaction solution was purged with nitrogen gas three times, heated to 90 °C, and stirred for 16 h. The reaction solution was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed sequentially with water (100 mL) and saturated brine (100 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1 to 5:1) to give compound 8-a (56 mg, yield: 56.6%).

[0325] Synthesis of compound 8 Compound 8-a (56 mg, 0.156 mmol) was suspended in methanol (10 mL), and (S)-piperidine-2-carboxylic acid (41 mg, 0.313 mmol) and sodium cyanoborohydride (20 mg, 0.313 mmol) were added. The reaction solution was heated to 70°C and stirred for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 8 (21.9 mg, yield: 29.7%).

[0326] LC-MS (ESI): m / z = 471.0 [M+H] + . 1H NMR (400 MHz, CD3OD): δ 7.85-7.84 (d, J= 7.6 Hz, 1H), 7.67-7.61 (m, 4H), 7.52-7.46 (m, 3H), 7.42-7.38 (m, 4H), 4.57-4.47 (m, 2H), 3.99-3.96 (m, 1H), 3.47-3.44 (m, 1H), 2.95-2.88 (m, 1H), 2.42 (s, 3H), 2.20-2.15 (m, 1H), 1.77-1.61 (m, 4H), 1.52-1.46 (m, 1H) ppm.

[0327] Example 9 (S,E)-4-(5-chloro-4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-methylbenzyl)morpholine-3-carboxylic acid (Compound 9)

[0328] [ka]

[0329] Synthesis of compound 9 Compound 8-a (100 mg, 0.279 mmol) and (S)-morpholine-3-carboxylic acid (73 mg, 0.559 mmol) were suspended in methanol (10 mL), and sodium cyanoborohydride (36 mg, 0.559 mmol) was added. The reaction solution was heated to 70 °C and stirred for 16 hours. After completion of the reaction, the solution was spin-dried, and the resulting white residue was dissolved in ethyl acetate and washed once with water and once with saturated brine. The reaction solution was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed sequentially with water (100 mL) and once with saturated brine (100 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 9 (7.3 mg, yield: 5.5%).

[0330] LC-MS (ESI): m / z = 473.0 [M+H] + . 1H NMR (400 MHz, CD3OD): δ 7.81-7.79 (d, J =7.6Hz, 1H), 7.62-7.57 (m, 2H), 7.53 (s, 1H), 7.45-7.33 (m, 8H), 4.18-4.14 (d, J =13.2Hz, 1H), 3.92-3.89 (dd, J =3.6 Hz, J =11.6Hz, 1H), 3.73-3.64 (m, 3H), 3.60-3.55 (m, 1H), 3.35-3.33 (m, 1H), 2.98-2.93 (m, 1H), 2.60-2.56 (m, 1H), 2.33 (s, 3H) ppm.

[0331] Example 10 (S,E)-1-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2,5-dimethylbenzyl)piperidine-3-carboxylic acid (compound 10)

[0332] [ka]

[0333] Synthesis of compound 10-b 1,4-Dibromo-2,5-dimethylbenzene (2.64 g, 10.0 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL). The solution was cooled to -78 °C and stirred under nitrogen gas protection. 2.4 M n-butyllithium solution (5.0 mL, 12.0 mmol) was slowly added dropwise. After the addition was complete, the reaction solution was slowly warmed to -20 °C. After 10 minutes, the solution was cooled again to -78 °C and anhydrous N,N'-dimethylformamide (876 mg, 12.0 mmol) was added dropwise. After stirring for 30 minutes, the ice-water bath was removed and the reaction mixture was allowed to warm to room temperature and continue stirring for 10 hours. The reaction mixture was quenched by pouring it into ice water, and then extracted with ethyl acetate (200 mL). The organic phase was washed with water (200 mL) and saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to give compound 10-b (1.2 g, yield: 56%).

[0334] 1 H NMR: (400 MHz DMSO-d6): δ 10.17(s, 3H), 7.75 (s, 1H), 7.62 (s, 1H), 2.56 (s, 3H), 2.38 (s, 3H) ppm

[0335] Synthesis of compound 10-a Compound 10-b (106.5 mg, 0.5 mmol) and compound 8-b (198.6 mg, 0.6 mmol) were dissolved in anhydrous toluene (30 mL). To the mixture was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (73.1 mg, 0.1 mmol), potassium phosphate (424 mg, 2.0 mmol), and cesium fluoride (304 mg, 2.0 mmol). The reaction mixture was stirred at 100 °C for 16 h under nitrogen gas protection. The reaction solution was cooled to room temperature and concentrated under reduced pressure to give a residue. The product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=15:1 to 5:1) to give a yellow solid 10-a (80 mg, yield: 48%).

[0336] Synthesis of compound 10 Compound 10-a (80.0 mg, 0.237 mmol) and (S)-piperidine-2-carboxylic acid (61.2 mg, 0.474 mmol) were dissolved in methanol (20 mL), sodium cyanoborohydride (37.3 mg, 0.59 mmol) was added, and the mixture was heated to 60° C. and stirred for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give white solid 10 (36.1 mg, yield: 34%).

[0337] LC-MS (ESI): m / z = 451.3 [M+H] + . 1 H NMR (400 MHz CD3OD): δ 7.96 (d, J = 8.0 Hz, 1H), 7.74 (t, J = 8.0 Hz, 1H), 7.67 (d, J = 16.0 Hz, 1H), 7.59-7.45 (m, 9H), 4.67 (d, J = 12.8 Hz, 1H), 4.06 (d, J = 12.8 Hz, 1H), 3.56-3.53 (m, 1H), 3.33-3.32 (m, 1H), 3.01-2.98 (m, 1H), 2.50 (s, 3H), 2.49 (s, 3H), 2.31-2.27 (m, 1H), 1.88-1.60 (m, 5H) ppm.

[0338] Example 11 (S,E)-4-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2,5-dimethylbenzyl)morpholine-3-carboxylic acid (Compound 11)

[0339] [ka]

[0340] Synthesis of compound 11 Compound 10-a (80.0 mg, 0.237 mmol) and (S)-morpholine-3-carboxylic acid (62 mg, 0.474 mmol) were dissolved in methanol (25 mL), sodium cyanoborohydride (37.3 mg, 0.59 mmol) was added, and the mixture was heated to 60°C and stirred for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give white solid 11 (50 mg, yield: 46%).

[0341] LC-MS (ESI): m / z = 453.3 [M+H] + . 1 H NMR (400 MHz CD3OD): δ 7.95 (d, J = 7.6 Hz, 1H), 7.73 (t, J = 8.0 Hz, 1H), 7.66 (d, J = 16.4 Hz, 1H), 7.59-7.47 (m, 7H), 7.44 (d, J = 7.2 Hz, 1H), 7.38 (s, 1H), 4.55 (d, J = 12.8 Hz, 1H), 4.16 (dd , J1= 3.6 Hz, J2= 12.0 Hz, 1H), 3.94 (d, J = 12.8 Hz, 1H), 3.90-3.85 (m, 1H), 3.79-3.61 (m, 3H), 3.13-3.10 (m, 1H), 3.00-2.94 (m, 1H), 2.50 (s, 3H), 2.48 (s, 3H) ppm.

[0342] Example 12 (S,E)-2-((4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2,5-dimethylbenzyl)amino)-3-hydroxyl-2-methylpropionic acid (compound 12)

[0343] [ka]

[0344] Synthesis of compound 12 Methylserine (127 mg, 1.06 mmol) was dissolved in methanol (10 mL), and 0.53 M aqueous sodium hydroxide (2 mL, 1.06 mmol) was added dropwise with stirring for 10 minutes. The reaction solution was cooled to 0 °C, and a solution of compound 10-a (120.0 mg, 0.35 mmol) in tetrahydrofuran (6 mL) was slowly added dropwise. The reaction solution was warmed to room temperature and stirred for 16 hours. Sodium borohydride (27.0 mg, 0.71 mmol) was added to the reaction solution, and stirring was continued for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography to give a white solid 12 (12 mg, yield: 7%).

[0345] LC-MS (ESI): m / z = 441.4 [M+H] + . 1 H NMR (400 MHz DMSO-d6): δ 8.07 (d, J = 7.6 Hz, 1H), 7.77 (t, J = 8.0 Hz, 1H), 7.68 (d, J = 16.0 Hz, 1H), 7.61-7.47 (m, 6H), 7.43 (s, 2H), 7.32 (d, J = 16.0 Hz, 1H), 7.32 (s, 1H), 6.09 (bs, 1H), 3.63 (s, 2H), 3.44-3.38 (m, 2H), 2.40 (s, 3H), 2.32 (s, 3H), 1.15 (s, 3H) ppm.

[0346] Example 13 (S,E)-1-(5-chloro-4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-methylbenzyl)piperazine-2-carboxylic acid (Compound 13)

[0347] [ka]

[0348] Synthesis of compound 13-a Compound 8-a (100 mg, 0.279 mmol) and (S)-4-Boc-piperazine-2-carboxylic acid (129 mg, 0.559 mmol) were dissolved in methanol (20 mL), sodium cyanoborohydride (36 mg, 0.559 mmol) was added, and the mixture was heated to 70 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and washed sequentially with water (100 mL) and saturated brine (100 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 13-a (28 mg, yield: 17.5%). LC-MS (ESI): m / z = 572.0 [M+H] + .

[0349] Synthesis of compound 13 Compound 13-a (28 mg, 0.049 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (2 mL) was added, and the reaction solution was stirred at room temperature for 2 hours, concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography to obtain compound 13 (10.9 mg, yield: 47.4%).

[0350] LC-MS (ESI): m / z = 472.0 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ 7.93-7.91 (d, J =8.0Hz, 1H), 7.74-7.70 (m, 2H), 7.61-7.55 (m, 4H), 7.51-7.46 (m, 5H), 4.59 (s, 1H), 3.79 (s, 2H), 3.41-3.37 (m, 1H), 3.24-3.20 (m, 2H), 3.13-3.04 (m, 2H), 2.63-2.59 (m, 1H), 2.41 (s, 3H) ppm.

[0351] Example 14 (S,E)-1-(5-chloro-4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-methylbenzyl)-4-methylpiperazine-2-carboxylic acid (Compound 14)

[0352] [ka]

[0353] Synthesis of compound 14-c (S)-1-Boc-piperazine-2-carboxylic acid methyl ester (200 mg, 0.819 mmol) was dissolved in methanol (20 mL) and 37% aqueous formaldehyde (0.5 mL, 4.10 mmol), glacial acetic acid (99 mg, 1.64 mmol), and 10% Pd-C (50 mg) were added. The reaction solution was stirred under hydrogen gas at room temperature for 16 hours. The reaction solution was filtered through diatomaceous earth and washed with methanol (30 mL x 3). The combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to give compound 14-c (204 mg, yield: 96.7%). LC-MS (ESI): m / z = 159.0 [M-Boc+H] + .

[0354] Synthesis of compound 14-b Compound 14-c (204 mg, 0.79 mmol) was dissolved in dichloromethane (30 mL) and trifluoroacetic acid (6 mL) was added. The reaction solution was stirred at room temperature for 2 hours, concentrated under reduced pressure, and the residue was added with dichloromethane (30 mL) and concentrated under reduced pressure once. Toluene (30 mL) was added to the residue and concentrated under reduced pressure once. The residue was dried under vacuum to give compound 14-b (123 mg, yield: 99.0%), which was used directly in the next step. LC-MS (ESI): m / z = 159.0 [M+H] + .

[0355] Synthesis of compound 14-a Compound 8-a (136 mg, 0.38 mmol) and compound 14-b (195 mg, 0.76 mmol) were dissolved in a methanol solution (20 mL), and sodium cyanoborohydride (48 mg, 0.76 mmol) and sodium acetate (155 mg, 1.14 mmol) were added. The reaction solution was heated to 70 °C and stirred for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane (100 mL) and washed sequentially with water (100 mL) and saturated brine (100 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 14-a (30 mg, yield: 15.8%). LC-MS (ESI): m / z = 500.0 [M+H] + .

[0356] Synthesis of compound 14 Compound 14-a (70 mg, 0.185 mmol) was dissolved in methanol (5 mL). To a mixture of tetrahydrofuran (5 mL) and water (1 mL), sodium hydroxide (23 mg, 0.371 mmol) was added. The reaction solution was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was diluted with water (50 mL). The pH of the solution was adjusted to 3-5 with dilute hydrochloric acid to precipitate a white solid. After filtration, the cake was purified by preparative high-performance liquid chromatography to obtain compound 14 (11.0 mg, yield: 37.9%).

[0357] LC-MS (ESI): m / z = 486.0 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ 7.92-7.90 (d, J =8.0Hz, 1H), 7.74-7.69 (m, 2H), 7.60-7.55 (m, 3H), 7.54-7.52 (m, 1H), 7.51-7.41 (m, 5H), 3.82 (s, 2H), 3.40 (s, 2H), 3.22-3.20 (d, J =8.4Hz, 2H), 3.07-3.05 (d, J =9.2Hz, 1H), 2.79 (s, 3H), 2.69-2.65 (m, 1H), 2.40 (s, 3H) ppm.

[0358] Example 15 (S,E)-1-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-(4-cyanobutoxy)-5-methylbenzyl)piperidine-2-carboxylic acid (Compound 15)

[0359] [ka]

[0360] Synthesis of compound 15-c A mixture of 3-bromo-4-methylphenol (374 mg, 1.0 mmol), 5-bromovaleronitrile (486 mg, 3.0 mmol), potassium carbonate (553 mg, 4 mmol), and N,N'-dimethylformamide (5 mL) was heated to 60°C and stirred for 16 hours. The reaction solution was cooled to room temperature and diluted with water (20 mL). The resulting mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined and washed with saturated brine (20 mL). The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1) to give a white solid 15-c (536 mg, yield: 100%).

[0361] 1 H NMR (400 MHz, CDCl3): δ 7.12 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 2.6 Hz, 1H), 6.74 (dd, J = 8.4, 2.6 Hz, 1H), 3.96 (t, J = 5.7 Hz, 2H), 2.44 (t, J = 6.8 Hz, 2H), 2.32 (s, 3H), 1.97 - 1.82 (m, 4H) ppm

[0362] Synthesis of compounds 15-b-1 and 15-b-2 Compound 15-c (268 mg, 1 mmol) and 1,2-dichloromethyl methyl ether (138 mg, 1.2 mmol) were dissolved in dichloromethane (5 mL). Titanium tetrachloride (569 mg, 3.0 mmol) was added dropwise at 0 °C and stirred for 2 h. The reaction solution was quenched with ice water (20 mL), and the resulting mixture was extracted with dichloromethane (20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to give white solid 15-b-1 (141 mg, yield: 48%) and pale yellow solid 15-b-2 (100 mg, yield: 34%).

[0363] Compound 15-b-1: 1 H NMR (400 MHz, CDCl3): δ 10.39 (s, 1H), 7.67 (s, 1H), 7.18 (s,1H), 4.11 (t, J = 5.9 Hz, 2H),2.47 (t, J = 6.9 Hz, 2H), 2.36 (s, 3H), 2.03 (dt, J = 8.8, 5.8 Hz, 2H), 1.96 - 1.84 (m, 2H) ppm

[0364] Compound 15-b-2: 1 H NMR (400 MHz, CDCl3): δ 10.41 (s, 1H), 7.34 (d, J = 8.5 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H), 4.07 (t, J = 5.7 Hz, 2H), 2.48 (t, J = 6.8 Hz, 2H), 2.08 - 1.85 (m, 4H) ppm

[0365] Synthesis of compound 15-a A mixture of compound 15-b-2 (135 mg, 0.46 mmol), compound 8-b (181 mg, 0.55 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (37 mg, 0.05 mmol), potassium carbonate (126 mg, 0.91 mmol), 1,4-dioxane (2 mL), and water (0.2 mL) was stirred at 90 °C under nitrogen gas protection for 16 h. The reaction solution was cooled to room temperature and diluted with saturated brine (20 mL). The resulting mixture was extracted with dichloromethane (50 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to give compound 15-a (130 mg, yield: 68%).

[0366] LC-MS (ESI): m / z = 421.4 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 10.45 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.70 - 7.63 (m, 2H), 7.60 - 7.42 (m, 8H), 7.21 (s, 1H), 4.22 (t, J = 5.9 Hz, 2H), 2.48 (t, J = 7.0 Hz, 2H), 2.42 (s, 3H), 2.12 - 2.02 (m, 2H), 2.00 - 1.89 (m, 2H) ppm

[0367] Synthesis of compound 15 To a mixture of compound 15-a (50 mg, 0.12 mmol), (S)-piperidine-2-carboxylic acid (31 mg, 0.24 mmol), methanol (1 mL), and tetrahydrofuran (1 mL) was added sodium cyanoborohydride (15 mg, 0.24 mmol). The reaction mixture was heated to 70°C and stirred for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give white solid 15 (32 mg, yield: 50%).

[0368] LC-MS (ESI): m / z = 534.5 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ 7.96 (d, J = 7.8 Hz, 1H), 7.73 (t, J = 7.9 Hz, 1H), 7.67 (d, J = 16.1 Hz, 1H), 7.60 - 7.54 (m, 2H), 7.54 - 7.44 (m, 5H), 7.40 (s, 1H), 7.33 (s, 1H), 4.50 (d, J = 12.9 Hz, 1H), 4.34 (d, J = 12.7 Hz, 1H), 4.22 (t, J = 6.1 Hz, 2H), 3.53 (d, J = 7.5 Hz, 1H), 3.32 (s, 1H), 2.99 (t, J = 12.3 Hz, 1H), 2.57 (t, J = 7.0 Hz, 2H), 2.45 (s, 3H), 2.29 - 2.16 (m, 1H), 2.09 - 1.99 (m, 2H), 1.95 - 1.65 (m, 6H), 1.63 - 1.50 (m, 1H) ppm.

[0369] Example 16 (E)-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-(4-cyanobutoxy)-5-methylbenzyl)glycine (Compound 16)

[0370] [ka]

[0371] Synthesis of compound 16 To a mixture of compound 15-a (80 mg, 0.19 mmol), glycine (57 mg, 0.76 mmol), methanol (1 mL), and tetrahydrofuran (1 mL) was added sodium cyanoborohydride (60 mg, 0.95 mmol). The reaction mixture was heated to 70 °C and stirred for 1 h. Sodium cyanoborohydride (60 mg, 0.95 mmol) was then added, and stirring was continued for 1 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give 16 (19.6 mg, 21% yield) as a white solid.

[0372] LC-MS (ESI): m / z = 480.5 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.05 (d, J = 7.9 Hz, 1H), 7.79 (t, J = 7.9 Hz, 1H), 7.67 (d, J = 16.0 Hz, 1H), 7.62 - 7.47 (m, 6H), 7.40 (d, J = 16.0 Hz, 1H), 7.26 (d, J = 5.6 Hz, 2H), 4.12 (t, J = 6.0 Hz, 2H), 3.94 (s, 2H), 3.13 (s, 2H), 2.60 (t, J = 7.0 Hz, 2H), 2.38 (s, 3H), 1.93 - 1.84 (m, 2H), 1.83 - 1.74 (m, 2H) ppm.

[0373] Example 17 (S,E)-4-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-(4-cyanobutoxy)-5-methylbenzyl)morpholine-3-carboxylic acid (Compound 17)

[0374] [ka]

[0375] Synthesis of compound 17 To a mixture of compound 15-a (63 mg, 0.15 mmol), (S)-morpholine-3-carboxylic acid (39 mg, 0.30 mmol), methanol (1 mL), and tetrahydrofuran (1 mL) was added sodium cyanoborohydride (38 mg, 0.60 mmol). The reaction mixture was heated to 65°C and stirred for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give white solid 17 (46.1 mg, yield: 57%).

[0376] LC-MS (ESI): m / z = 536.4 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ 7.95 (d, J = 7.9 Hz, 1H), 7.72 (t, J = 7.9 Hz, 1H), 7.66 (d, J = 16.1 Hz, 1H), 7.59 - 7.54 (m, 2H), 7.54 - 7.43 (m, 5H), 7.40 (s, 1H), 7.32 (s, 1H), 4.50 (d, J = 12.8 Hz, 1H), 4.33 (d, J = 12.7 Hz, 1H), 4.26 - 4.13 (m, 3H), 3.93 (d, J = 12.8 Hz, 1H), 3.82 - 3.64 (m, 3H), 3.25 (d, J = 12.6 Hz, 1H), 3.09 (t, J = 9.8 Hz, 1H), 2.57 (t, J = 7.0 Hz, 2H), 2.44 (s, 3H), 2.09 - 1.98 (m, 2H), 1.95 - 1.83 (m, 2H) ppm.

[0377] Example 18 (S,E)-1-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-(4-cyanobutoxy)-5-methylbenzyl)piperazine-2-carbo acid (compound 18)

[0378] [ka]

[0379] Synthesis of compound 18 To a mixture of compound 15-a (63 mg, 0.15 mmol), (S)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (69 mg, 0.30 mmol), methanol (1 mL), and tetrahydrofuran (1 mL) was added sodium cyanoborohydride (38 mg, 0.60 mmol). The reaction mixture was heated to 60 °C and stirred for 1 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (1 mL) and stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography to give 18 (36.5 mg, 45% yield) as a white solid.

[0380] LC-MS (ESI): m / z = 535.5 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ 7.94 (d, J = 8.0 Hz, 1H), 7.71 (t, J = 7.9 Hz, 1H), 7.65 (d, J = 16.0 Hz, 1H), 7.59 - 7.39 (m, 7H), 7.31 (s, 1H), 7.22 (s, 1H), 4.12 (t, J = 5.8 Hz, 2H), 3.92 (s, 2H), 3.42 (t, J = 4.9 Hz, 1H), 3.29 (s, 1H), 3.19 - 3.05 (m, 3H), 2.69 (m, 1H), 2.56 (t, J = 6.9 Hz, 2H), 2.42 (s, 3H), 2.03 - 1.83 (m, 4H) ppm.

[0381] Example 19 (E)-(5-chloro-4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-methylbenzyl)glycine (Compound 19)

[0382] [ka]

[0383] Synthesis of compound 19-c Compound 8-a (260 mg, 0.727 mmol) was dissolved in a mixture of methanol (5 mL) and tetrahydrofuran (5 mL). Sodium borohydride (55 mg, 1.454 mmol) was added and stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 mL). It was washed sequentially with water (50 mL) and saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1 to 3:1) to give compound 19-c (218 mg, yield: 83.8%).

[0384] Synthesis of compound 19-b Compound 19-c (116 mg, 0.322 mmol) was dissolved in dichloromethane (10 mL), and one drop of N,N'-dimethylformamide was added. Then, thionyl chloride (0.5 mL) was added dropwise. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and dichloromethane (50 mL x 2) was added to the residue, followed by concentration under reduced pressure. The residue was dried in vacuo to give compound 19-b (122 mg, yield: 99.0%), which was used directly in the next step.

[0385] Synthesis of compound 19-a Methyl serine hydrochloride (41 mg, 0.322 mmol) and compound 19-b (122 mg, 0.322 mmol) were dissolved in acetonitrile (20 mL), and potassium carbonate (223 mg, 1.61 mmol) and sodium iodide (10 mg, 0.065 mmol) were added. The reaction solution was heated to 80 °C and stirred for 16 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane (50 mL) and washed sequentially with water (50 mL) and saturated brine (50 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:2) to give compound 19-a (63 mg, yield: 45.5%). LC-MS (ESI): m / z = 431.0 [M+H] + .

[0386] Synthesis of compound 19 Compound 19-a (63 mg, 0.146 mmol) was dissolved in a mixture of methanol (5 mL), tetrahydrofuran (5 mL), and water (1 mL). Sodium hydroxide (12 mg, 0.292 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was diluted with water (50 mL), and the pH of the solution was adjusted to 3-5 with dilute hydrochloric acid. A white solid precipitated, filtered, and the cake was purified by preparative high-performance liquid chromatography to give compound 19 (10.0 mg, yield: 16.4%).

[0387] LC-MS (ESI): m / z = 417.0 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ 7.97-7.95 (d, J =8.0Hz, 1H), 7.79-7.72 (m, 3H), 7.64-7.57 (m, 4H), 7.52-7.47 (m, 4H), 4.35 (s, 2H), 4.05 (s, 2H), 2.52 (s, 3H) ppm.

[0388] Example 20 (S,E)-1-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-hydroxymethyl-5-trifluoromethylbenzyl)piperidine-2-carboxylic acid (Compound 20)

[0389] [ka]

[0390] Synthesis of compound 20-h 5-Bromophthalein (6.3 g, 30 mmol) was dissolved in trifluoromethanesulfonic acid (60 mL) and cooled to 0 °C with stirring. N-iodosuccinimide (16.8 g, 75 mmol) powder was slowly added to the reaction mixture. The ice bath was then removed, and the mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was poured into ice water (200 mL) to precipitate a large amount of yellow solid. The solid was filtered and washed with water (500 mL × 3). The solid was then dissolved in dichloromethane (500 mL) and washed with saturated sodium thiosulfate solution (100 mL × 2). The organic phase was washed again with water (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a deep yellow solid 20-h (9.0 g, yield: 89.1%). The product was used directly in the next step without further purification.

[0391] Synthesis of compound 20-g Compound 20-h (6.7 g, 20 mmol), methyl fluorosulfonyldifluoroacetate (19 g, 100 mmol), and cuprous iodide (760 mg, 2 mmol) were mixed in N,N-dimethylformamide (50 mL), and the reaction mixture was stirred at 90 °C for 16 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered. Ethyl acetate (300 mL) was added to the filtrate, which was washed sequentially with water (50 mL × 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give white solid 20-g (900 mg, yield: 16.0%). LC-MS (ESI): m / z = 282 [M+H] + .

[0392] Synthesis of compound 20-f Compound 20-g (800 mg, 2.8 mmol) was dissolved in a mixed solvent of tetrahydrofuran (18 mL) and water (2 mL). Lithium hydroxide monohydrate (420 mg, 10 mmol) was added and stirred at room temperature for 16 hours. The pH was adjusted to 1 with 1N hydrochloric acid, concentrated under reduced pressure, and purified by reverse-phase chromatography (Biotage Flash) to give white solid 20-f (650 mg, yield: 75.6%). LC-MS (ESI): m / z = 299 [MH] + .

[0393] Synthesis of compound 20-e Compound 20-f (600 mg, 2 mmol) was dissolved in N,N-dimethylformamide (10 mL), and imidazole (260 mg, 4 mmol) and tert-butyldimethylchlorosilane (450 mg, 3 mmol) were added. The mixture was stirred at room temperature for 16 hours. Ethyl acetate (100 mL) was added to the reaction solution, which was then washed with water (20 mL × 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 20-e (600 mg, yield: 72.6%).

[0394] 1 H NMR (400 MHz, DMSO-d6): δ 8.19 (s, 1H), 8.11 (s, 1H), 5.10 (s, 2H), 5.10 (s, 9H), 0.11 (s, 6H) ppm

[0395] Synthesis of compound 20-d Compound 20-e (413 mg, 1 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and a solution of borane in tetrahydrofuran (5 mL, 5 mmol) was added dropwise at 0°C under nitrogen gas protection. After the addition was completed, the mixture was refluxed for 16 hours. The reaction solution was cooled to room temperature, and methanol (10 mL) was slowly added dropwise. After the addition was completed, the mixture was refluxed for 1 hour. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1) to obtain compound 20-d (260 mg, yield: 65.0%) was obtained. LC-MS (ESI): m / z = 399 [MH] + .

[0396] Synthesis of compound 20-c Compound 20-d (210 mg, 0.52 mmol) was dissolved in dichloromethane (10 mL) and manganese dioxide (450 mg, 5.2 mmol) was added. The reaction was stirred at room temperature for 16 hours. It was filtered and washed with dichloromethane (10 mL × 3). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 20-c (150 mg, yield: 71.5%). The product was not further purified.

[0397] Synthesis of compound 20-b A mixture of compound 20-c (120 mg, 0.42 mmol), compound 8-b (141 mg, 0.42 mmol), sodium carbonate (132 mg, 1.26 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (31 mg, 0.042 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was stirred at 80 °C under nitrogen gas protection for 16 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 20-b (65 mg, yield: 29.8%). LC-MS (ESI): m / z = 522 [M+H] + .

[0398] Synthesis of compound 20-a A mixture of compound 20-b (50 mg, 0.096 mmol), L-piperidine-2-carboxylic acid (24 mg, 0.19 mmol), sodium cyanoborohydride (12 mg, 0.19 mmol), and methanol (3 mL) was stirred at 80 °C under nitrogen gas protection for 3 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography (Biotage Flash) to give compound 20-a (35 mg, yield: 57.6%). LC-MS (ESI): m / z = 635 [M+H] + .

[0399] Synthesis of compound 20 Compound 20-a (30 mg, 0.047 mmol) was dissolved in tetrahydrofuran (5 mL), and 1.0 M tetrabutylammonium fluoride solution (0.5 mL, 0.5 mmol) was added thereto. The reaction solution was stirred at room temperature for 16 hours, then concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography to obtain compound 20 (8 mg, yield: 33.3%).

[0400] LC-MS (ESI): m / z = 521 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ 8.04 (s, 1H), 7.93 (s, 1H), 7.89 (d, J=8.0Hz, 1H), 7.77 (t, J=8.0Hz, 1H), 7.72-7.62 (m, 2H), 7.59-7.46 (m, 6H), 5.04 (d, J=12.4Hz, 1H), 4.92-4.91 (m, 1H), 4.81-4.80 (m, 1H), 4.21 (d, J=12.8Hz, 1H), 3.56-3.53 (m, 1H), 3.21-3.18 (m, 1H), 2.95-2.89 (m, 1H), 2.26-2.23 (m, 1H), 1.94-1.76 (m, 3H), 1.63-1.58 (m, 2H) ppm.

[0401] Example 21 (S,E)-4-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl) (vinyl)-2-hydroxymethyl-5-trifluoromethylbenzyl)morpholine-3-carboxylic acid (compound 21)

[0402] [ka]

[0403] Synthesis of compound 21-a A mixture of compound 20-b (50 mg, 0.096 mmol), L-morpholine-3-carboxylic acid (24 mg, 0.19 mmol), sodium cyanoborohydride (12 mg, 0.19 mmol), and methanol (3 mL) was stirred at 80 °C under nitrogen gas protection for 3 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography (Biotage Flash) to give compound 21-a (35 mg, 57.6% yield). LC-MS (ESI): m / z = 635 [M+H] + .

[0404] Synthesis of compound 21 Compound 21-a (30 mg, 0.047 mmol) was dissolved in tetrahydrofuran (5 mL), to which 1.0 M tetrabutylammonium fluoride solution (0.5 mL, 0.5 mmol) was added. The reaction was stirred at room temperature for 16 h, then concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography to give compound 21 (8 mg, yield: 33.3%).

[0405] LC-MS (ESI): m / z = 523 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ 8.03(s, 1H), 7.87 (d, J=8.0Hz, 1H), 7.81 (s, 1H), 7.75(t, J=8.0Hz, 1H), 7.67-7.47 (m, 8H), 4.98 (d, J=13.2Hz, 1H), 4.81-4.80 (m, 1H), 4.51 (d. 1H) ppm.

[0406] Example 22 (S,E)-4-(5-chloro-2-methyl-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)benzyl)morpholine-3-carboxylic acid (Compound 22)

[0407] [ka]

[0408] Synthesis of compound 22 Compound 5-a (100 mg, 0.288 mmol) and (S)-morpholine-3-carboxylic acid (75.7 mg, 0.577 mmol) were dissolved in methanol (10 mL), sodium cyanoborohydride (36.3 mg, 0.577 mmol) was added, and the reaction solution was heated to 70 °C and stirred for 16 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give white solid 22 (37.2 mg, yield: 27.8%).

[0409] LC-MS (ESI): m / z = 462.0 [M+H] + . 1H NMR (400 MHz, CD3OD): δ 7.69 (s, 1H), 7.60-7.52 (m, 3H), 7.44-7.40 (m, 2H), 7.36-7.24 (m, 5H), 7.16-7.14 (d, J = 7.6Hz, 2H), 4.44-4.40 (d, J = 13.2Hz, 2H), 4.11-4.07 (dd, J = 4.0Hz, J = 12.4Hz, 1H), 3.93-3.90 (d, J = 13.2Hz, 1H), 3.86-3.79 (m, 2H), 3.74-3.68 (m, 1H), 3.61-3.58 (m, 1H), 3.15-3.12 (m, 1H), 2.91-2.86 (m, 1H), 2.48 (s, 3H), 2.29 (s, 3H) ppm.

[0410] Example 23 (S,E)-1-(5-chloro-2-methyl-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)benzyl)piperazine-2-carboxylic acid (Compound 23)

[0411] [ka]

[0412] Synthesis of compound 23-a Compound 5-a (100 mg, 0.288 mmol) and (S)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (133 mg, 0.577 mmol) were dissolved in methanol (10 mL), sodium cyanoborohydride (36 mg, 0.577 mmol) was added, and the reaction solution was heated to 70 °C and stirred for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to obtain the product. Compound 23-a (76 mg, yield: 46.9%) was obtained. LC-MS (ESI): m / z = 561.0 [M+H] + .

[0413] Synthesis of compound 23 Compound 23-a (76 mg, 0.135 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography to give compound 23 (29.4 mg, yield: 46.8%).

[0414] LC-MS (ESI): m / z = 461.0 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ 7.63 (s, 1H), 7.59-7.57 (d, J = 7.6Hz, 1H), 7.51-7.47 (d, J = 16.0Hz, 1H), 7.44-7.41 (m, 3H), 7.37-7.24 (m, 5H), 7.15-7.13 (d, J = 7.2Hz, 1H), 3.96-3.85 (q, J = 13.6Hz, J = 16.4Hz, 2H), 3.75-3.73 (t, J = 4.0Hz, 1H), 3.59-3.55 (dd, J = 4.4Hz, J = 13.2Hz, 1H), 3.38-3.34 (dd, J = 4.0Hz, J = 12.8Hz, 1H), 3.25-3.19 (m, 2H), 3.12-3.06 (m, 1H), 2.84-2.80(m, 1H), 2.41 (s, 3H), 2.29 (s, 3H) ppm.

[0415] Example 24 (S,E)-1-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-(2-methoxyethoxy)-5-methylbenzyl)piperidine-2-carboxylic acid (Compound 24)

[0416] [ka]

[0417] Synthesis of compound 24-c 3-Bromo-4-methylphenol (3.74 g, 20 mmol), paraformaldehyde (4.41 g, 152 mmol), magnesium chloride (2.86 g, 30 mmol), triethylamine (7.56 g, 75 mmol), and acetonitrile (150 mL) The mixture was heated to reflux for 4 hours. The reaction solution was cooled to room temperature, diluted with water (500 mL), and then the pH was adjusted to 2-3 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate (500 mL × 2). The organic phases were combined, washed with saturated brine (200 mL), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 50:1) to give a white solid 24-c (2.45 g, yield: 57%).

[0418] Synthesis of compound 24-b A mixture of compound 24-c (645 mg, 3.0 mmol), 1-bromo-2-methoxyethane (625 mg, 4.5 mmol), potassium carbonate (829 mg, 6.0 mmol), and N,N'-dimethylformamide (5 mL) was heated to 60 °C and stirred for 4 h. The reaction solution was cooled to room temperature and diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (50 mL). The organic phase was washed with water (50 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give white solid 24-b (624 mg, yield: 76%).

[0419] 1 H NMR (400 MHz, CDCl3): δ 10.43 (s, 1H), 7.67 (s, 1H), 7.21 (s, 1H), 4.21 (t, J = 6.0, 2H), 3.79 (t, J = 4.0, 2H), 3.45 (s, 3H), 2.36 (s, 3H)ppm

[0420] Synthesis of compound 24-a A mixture of compound 24-b (273 mg, 1.0 mmol), compound 8-b (397 mg, 1.2 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (73 mg, 0.1 mmol), potassium carbonate (276 mg, 2.0 mmol), 1,4-dioxane (5 mL), and water (0.5 mL) was stirred at 90 °C for 16 h under nitrogen gas protection. The reaction solution was cooled to room temperature and diluted with saturated brine (20 mL). The resulting mixture was extracted with ethyl acetate (40 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was washed with ethyl acetate (50 mL) to give pale green solid 24-a (330 mg, 83% yield). LC-MS (ESI): m / z = 398.4 [M+H] + .

[0421] Synthesis of compound 24 To a mixture of compound 24-a (60 mg, 0.15 mmol), (S)-piperidine-2-carboxylic acid (39 mg, 0.30 mmol), methanol (1 mL), and tetrahydrofuran (1 mL) was added sodium cyanoborohydride (38 mg, 0.60 mmol), and the reaction mixture was heated to 65° C. and stirred for 1 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give 24 (35.2 mg, 46% yield) as a white solid.

[0422] LC-MS (ESI): m / z = 511.5 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ 7.96 (d, J = 7.9 Hz, 1H), 7.73 (t, J = 7.9 Hz, 1H), 7.66 (d, J = 16.1 Hz, 1H), 7.60 - 7.54 (m, 2H), 7.54 - 7.44 (m, 5H), 7.34 (s, 2H), 4.82 - 4.77 (m, 1H), 4.60 (d, J = 12.8 Hz, 1H), 4.36 - 4.26 (m, 2H), 4.22 (d, J = 13.1 Hz, 1H), 3.94 - 3.74 (m, 2H), 3.57 - 3.48 (m, 1H), 3.45 (s, 3H), 2.95 (t, J = 12.0 Hz, 1H), 2.44 (s, 3H), 2.34 - 2.20 (m, J = 15.8 Hz, 1H), 1.94 - 1.76 (m, 3H), 1.74 - 1.62 (m, 1H), 1.61 - 1.47 (m, 1H) ppm.

[0423] Example 25 (S,E)-4-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-(2-methoxyethoxy)-5-methylbenzyl)morpholine-3-carboxylic acid (Compound 25)

[0424] [ka]

[0425] Synthesis of compound 25 To a mixture of compound 24-a (60 mg, 0.15 mmol), (S)-morpholine-3-carboxylic acid (39 mg, 0.30 mmol), methanol (1 mL), and tetrahydrofuran (1 mL) was added sodium cyanoborohydride (38 mg, 0.60 mmol), and the reaction solution was heated to 65° C. and stirred for 1 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give white solid 25 (41.0 mg, yield: 53%).

[0426] LC-MS (ESI): m / z = 513.5 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ 7.96 (d, J = 7.9 Hz, 1H), 7.73 (t, J = 7.9 Hz, 1H), 7.66 (d, J = 16.1 Hz, 1H), 7.59 - 7.54 (m, J = 8.0, 1.6 Hz, 2H), 7.54 - 7.44 (m, 5H), 7.36 (s, 1H), 7.34 (s, 1H), 4.65 (d, J = 12.7 Hz, 1H), 4.36 - 4.20 (m, 4H), 3.98 - 3.86 (m, 2H), 3.85 - 3.77 (m, 1H), 3.77 - 3.64 (m, 3H), 3.46 (s, 3H), 3.26 - 3.10 (m, 2H), 2.44 (s, 3H) ppm.

[0427] Example 26 (S,E)-4-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-(2-hydroxylethoxyl)-5-methylbenzyl)piperidine-2-carboxylic acid (Compound 26)

[0428] [ka]

[0429] Synthesis of compound 26-b A mixture of compound 24-c (645 mg, 3.0 mmol), (2-bromoethoxy)(tert-butyl)dimethylsilane (1.08 g, 4.5 mmol), potassium carbonate (829 mg, 6.0 mmol), and N,N'-dimethylformamide (5 mL) was heated to 60 °C and stirred for 16 h. The reaction solution was cooled to room temperature and diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (50 mL). The organic phase was washed with water (50 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to give white solid 26-b (767 mg, yield: 68%).

[0430] Synthesis of compound 26-a A mixture of compound 26-b (373 mg, 1.0 mmol), compound 8-b (397 mg, 1.2 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (73 mg, 0.1 mmol), potassium carbonate (276 mg, 2.0 mmol), 1,4-dioxane (5 mL), and water (0.5 mL) was stirred at 90 °C for 16 h under nitrogen gas protection. The reaction solution was cooled to room temperature and diluted with saturated brine (20 mL). The resulting mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give yellow solid 26-a (355 mg, yield: 71%). LC-MS (ESI): m / z = 498.5 [M+H] + .

[0431] Synthesis of compound 26 To a mixture of compound 26-a (75 mg, 0.15 mmol), (S)-piperidine-2-carboxylic acid (39 mg, 0.30 mmol), methanol (1 mL), and tetrahydrofuran (1 mL) was added sodium cyanoborohydride (38 mg, 0.60 mmol). The reaction mixture was heated to 60 °C and stirred for 1 h. The mixture was then concentrated under reduced pressure. Tetrahydrofuran (1 mL), water (one drop), and trifluoroacetic acid (0.5 mL) were added to the resulting residue, and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography to give 26 (48.3 mg, 53% yield) as a white solid.

[0432] LC-MS (ESI): m / z = 497.5 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.05 (d, J = 8.0 Hz, 1H), 7.79 (t, J = 7.9 Hz, 1H), 7.67 (d, J = 16.0 Hz, 1H), 7.63 - 7.47 (m, 6H), 7.40 (d, J = 16.0 Hz, 1H), 7.27 (s, 2H), 7.07 (s, 1H), 4.13 - 3.90 (m, 5H), 3.75 (t, J = 4.6 Hz, 2H), 3.28 - 3.21 (m, 1H), 3.08 - 3.00 (m, 1H), 2.38 (s, 3H), 1.97 - 1.86 (m, 1H), 1.78 - 1.66 (m, 1H), 1.63 - 1.48 (m, 3H), 1.45 - 1.31 (m, 1H) ppm.

[0433] Example 27 (S,E)-1-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-(2-methoxyethoxy)-5-methylbenzyl)piperazine-2-carboxylic acid (Compound 27)

[0434] [ka]

[0435] Synthesis of compound 27 To a mixture of compound 24-a (60 mg, 0.15 mmol), (S)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (69 mg, 0.30 mmol), methanol (1 mL), and tetrahydrofuran (1 mL) was added sodium cyanoborohydride (38 mg, 0.60 mmol). The reaction mixture was heated to 60 °C and stirred for 1 h. The mixture was then cooled to room temperature and concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (1.5 mL) and trifluoroacetic acid (0.5 mL) and stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give 27 (66.7 mg, 87% yield) as a white solid.

[0436] LC-MS (ESI): m / z = 512.4 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ 7.95 (d, J = 7.9 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H), 7.65 (d, J = 16.1 Hz, 1H), 7.59 - 7.54 (m, J = 8.0, 1.5 Hz, 2H), 7.53 - 7.41 (m, 5H), 7.30 (s, 1H), 7.27 (s, 1H), 4.22 (t, J = 4.4 Hz, 2H), 4.06 (d, J = 13.1 Hz, 1H), 3.97 (d, J = 13.4 Hz, 1H), 3.85 - 3.75 (m, 2H), 3.49 (dd, J = 7.0, 3.5 Hz, 1H), 3.44 (s, 3H), 3.35 (dd, J = 12.9, 3.5 Hz, 1H), 3.25 (dd, J = 13.1, 6.9 Hz, 1H), 3.18 - 3.08 (m, 3H), 2.79 - 2.71 (m, 1H), 2.42 (s, 3H) ppm.

[0437] Example 28 (S,E)-1-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-hydroxymethyl-5-trifluoromethylbenzyl)piperazine-2-carboxylic acid (Compound 28)

[0438] [ka]

[0439] Synthesis of compound 28-a A mixture of compound 20-b (50 mg, 0.096 mmol), (S)-4-tert-butoxycarbonyl-2-piperazinecarboxylic acid (44 mg, 0.19 mmol), sodium cyanoborohydride (12 mg, 0.19 mmol), and methanol (3 mL) was stirred at 80 °C under nitrogen gas protection for 3 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography (Biotage Flash) to give compound 28-a (42 mg, 60% yield). LC-MS (ESI): m / z = 736 [M+H] + .

[0440] Synthesis of compound 28 Compound 28-a (34 mg, 0.047 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the reaction mixture was stirred overnight at room temperature. After concentration under reduced pressure, the residue was purified by preparative high-performance liquid chromatography to give compound 28 (11 mg, yield: 45%).

[0441] LC-MS (ESI): m / z = 522 [M+H] + . 1H NMR (400 MHz, DMSO-d6): δ 8.01(s, 1H), 7.98 (d, J=8.0Hz, 1H), 7.82 (t, J=8.0Hz, 1H), 7.77 (s, 1H), 7.67-7.47 (m, 8H), 4.75 (dd, J=36.8Hz, 14.8Hz, 2H), 3.81 (dd, J=38.4 Hz, 13.6Hz, 2H), 3.16-3.12 (m, 2H), 3.01-2.98 (m, 2H), 2.93-2.90 (m, 1H), 2.86-2.84 (m, 2H) ppm.

[0442] Example 29 (S,E)-4-Carbamoyl-1-(5-chloro-4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-methylbenzyl)piperazine-2-carboxylic acid (Compound 29)

[0443] [ka]

[0444] Synthesis of compound 29-c (S)-1-Boc-piperazine-2-carboxylic acid methyl ester (733 mg, 3.0 mmol) and triethylamine (3.036 g, 30.0 mmol) were dissolved in tetrahydrofuran (50 mL) and cooled to 0 °C in an ice bath. Trimethylsilyl isocyanate (3.456 g, 30.0 mmol) was added dropwise. After the addition was complete, the reaction solution was stirred at room temperature for 2 h. After the reaction was complete, the mixture was diluted with ethyl acetate (50 mL) and washed sequentially with water (50 mL) and saturated brine (50 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1000:3) to give compound 29-c (663 mg, yield: 76.9%). LC-MS (ESI): m / z = 288.0 [M+H] + .

[0445] Synthesis of compound 29-b Compound 29-c (663 mg, 2.308 mmol) was dissolved in dichloromethane (15 mL), trifluoroacetic acid (3 mL) was added, and the reaction solution was stirred at room temperature for 2 h. After concentration under reduced pressure, toluene (20 mL) was added to the residue, and the mixture was concentrated under reduced pressure. Toluene (20 mL) was added to the residue, and the mixture was concentrated under reduced pressure. The residue was again added to the residue, and the mixture was concentrated under reduced pressure. The residue was dried in vacuo to give compound 29-b (1.132 g, 99% yield), which was used directly in the next step.

[0446] Synthesis of compound 29-a Compound 29-b (79 mg, 0.208 mmol) and compound 19-b (59 mg, 0.208 mmol) were dissolved in acetonitrile (20 mL), and potassium carbonate (144 g, 1.04 mmol) and sodium iodide (7 mg, 0.042 mmol) were added. The reaction solution was heated to 80°C and stirred for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL) and washed successively with water (50 mL) and saturated brine (50 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography to give compound 29-a (56 mg, yield: 50.9%). LC-MS (ESI): m / z = 529.0 [M+H] + .

[0447] Synthesis of compound 29 Compound 29-a (56 mg, 0.106 mmol) was dissolved in methanol (5 mL), tetrahydrofuran (5 mL), and water (1 mL). Sodium hydroxide (9 mg, 0.212 mmol) was added and the mixture was stirred at room temperature for 3 hours. The pH was adjusted to 4-5 with 1N hydrochloric acid, and the reaction solution was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 29 (14.9 mg, yield: 27.3%).

[0448] LC-MS (ESI): m / z = 515.0 [M+H] + . 1H NMR (400 MHz, CD3OD): δ 7.95-7.93 (d, J = 8.0Hz, 1H), 7.76-7.72 (m, 2H), 7.66 (s, 1H), 7.59-7.46 (m, 8H), 4.21-4.17 (d, J = 13.2Hz, 1H), 3.83-3.76 (m, 2H), 3.70-3.64 (m, 1H), 3.59-3.55 (m, 1H), 3.42-3.37 (m, 2H), 3.13-3.06 (m, 1H), 2.62-2.57 (m, 1H), 2.45 (s, 3H) ppm.

[0449] Example 30 (S,E)-4-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-(2-hydroxylethoxyl)-5-methylbenzyl)morpholine-3-carboxylic acid (compound 30)

[0450] [ka]

[0451] Synthesis of compound 30 To a mixture of compound 26-a (75 mg, 0.15 mmol), (S)-morpholine-3-carboxylic acid (39 mg, 0.30 mmol), methanol (1 mL), and tetrahydrofuran (1 mL) was added sodium cyanoborohydride (38 mg, 0.60 mmol). The reaction mixture was heated to 65 °C and stirred for 1 h. After cooling to room temperature, it was concentrated under reduced pressure. Tetrahydrofuran (1.0 mL), water (0.5 mL), and trifluoroacetic acid (0.5 mL) were added to the resulting residue, and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography to give 30 (66 mg, 88% yield) as a white solid.

[0452] LC-MS (ESI): m / z = 499.5 [M+H] + . 1H NMR (400 MHz, DMSO-d6): δ 8.05 (d, J = 7.8 Hz, 1H), 7.78 (t, J = 7.9 Hz, 1H), 7.66 (d, J = 16.0 Hz, 1H), 7.63 - 7.47 (m, 6H), 7.37 (d, J = 16.0 Hz, 1H), 7.23 (s, 1H), 7.20 (s, 1H), 4.06 (t, J = 5.1 Hz, 2H), 3.85 (d, J = 13.9 Hz, 1H), 3.81 - 3.67 (m, 5H), 3.59 (bs, 2H), 3.24 (t, J = 4.6 Hz, 1H), 3.02 - 2.94 (m, 1H), 2.38 (s, 3H), 2.36 - 2.31 (m, 1H) ppm.

[0453] Example 31 (S,E)-1-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-hydroxyl-5-methylbenzyl)piperidine-2-carboxylic acid (compound 31)

[0454] [ka]

[0455] Synthesis of compound 31-a A mixture of compound 24-c (215 mg, 1.0 mmol), compound 8-b (397 mg, 1.2 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (73 mg, 0.1 mmol), potassium carbonate (276 mg, 2.0 mmol), 1,4-dioxane (5 mL), and water (1 mL) was stirred at 90 °C for 16 h under nitrogen gas protection. The reaction solution was cooled to room temperature, diluted with saturated brine (20 mL), and the pH was adjusted to approximately 3 with 1 M dilute hydrochloric acid. The resulting mixture was extracted with dichloromethane (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was washed with ethyl acetate (50 mL) to give brown solid 31-a (210 mg, yield: 62%). LC-MS (ESI): m / z = 340.3 [M+H] + .

[0456] Synthesis of compound 31 To a mixture of compound 31-a (51 mg, 0.15 mmol), (S)-piperidine-2-carboxylic acid (39 mg, 0.30 mmol), methanol (1 mL), and tetrahydrofuran (1 mL) was added sodium cyanoborohydride (38 mg, 0.60 mmol). The reaction mixture was heated to 65°C and stirred for 1 h. The mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give 31 (21.6 mg, 32% yield) as a white solid.

[0457] LC-MS (ESI): m / z = 453.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.08 (d, J = 8.0 Hz, 1H), 7.78 (t, J = 7.9 Hz, 1H), 7.64 (d, J = 16.0 Hz, 1H), 7.61 - 7.47 (m, 6H), 7.30 (d, J = 16.0 Hz, 1H), 7.06 (s, 1H), 7.02 (s, 1H), 4.01 (d, J = 13.6 Hz, 1H), 3.48 (d, J = 13.5 Hz, 1H), 3 .09 (d, J = 6.1 Hz, 1H), 2.93 (d, J = 11.8 Hz, 1H), 2.33 (s, 3H), 2.28 (t, J = 9.6 Hz, 1H), 1.96 - 1.85 (m, 1H), 1.73 - 1.51 (m, 3H), 1.51 - 1.30 (m, 2H) ppm.

[0458] Example 32 (S,E)-4-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-hydroxyl-5-methylbenzyl)morpholine-3-carboxylic acid (compound 32)

[0459] [ka]

[0460] Synthesis of compound 32 To a mixture of compound 31-a (75 mg, 0.15 mmol), (S)-morpholine-3-carboxylic acid (39 mg, 0.30 mmol), methanol (1 mL), and tetrahydrofuran (1 mL) was added sodium cyanoborohydride (38 mg, 0.60 mmol). The reaction mixture was heated to 65°C and stirred for 1 h. The mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give 32 (19.8 mg, 29% yield) as a white solid.

[0461] LC-MS (ESI): m / z = 455.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.09 (d, J = 8.0 Hz, 1H), 7.77 (t, J = 7.8 Hz, 1H), 7.65 (d, J = 16.0 Hz, 1H), 7.62 - 7.46 (m, 6H), 7.29 (d, J = 16.0 Hz, 1H), 7.09 (s, 1H), 7.04 (s, 1H), 3.93 (d, J = 13.9 Hz, 1H), 3.83 (dd, J = 11.2, 3.5 Hz, 1H), 3.70 (dd, J = 11.2, 6.6 Hz, 1H), 3.66 - 3.53 (m, 3H), 3.29 - 3.27 (m, 1H), 2.96 - 2.87 (m, 1H), 2.38 - 2.29 (m, 4H) ppm.

[0462] Example 33 (S,E)-1-(5-chloro-2-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-4-(2-methoxyethoxy)benzyl)piperidine-2-carboxylic acid (compound 33)

[0463] [ka]

[0464] Synthesis of compound 33-c To a solution of 2,4-dihydroxy-5-chlorobenzaldehyde (1.73 g, 10.0 mmol) in N,N-dimethylformamide (16 mL) was added potassium carbonate (1.66 g, 12.0 mmol). The mixture was stirred at 0 °C for 15 minutes. After cooling to -10 °C, a solution of N-phenyl(bistrifluoromethanesulfonyl)imide (3.56 g, 10.0 mmol) in N,N-dimethylformamide (20 mL) was added dropwise. After the addition was complete, the mixture was allowed to react at -10 °C for 2 hours. 100 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with water (30 mL x 1) and saturated brine (30 mL x 1), successively. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to give compound 33-c (2.51 g, yield: 82%).

[0465] 1 H NMR (400 MHz, CD3Cl): δ 10.07 (s, 1H), 7.99 (s, 1H), 7.07 (s, 1H) ppm

[0466] Synthesis of compound 33-b To a mixture of compound 33-c (524 mg, 1.73 mmol) and compound 8-b (662 mg, 2.00 mmol) in toluene (25 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (88 mg, 0.12 mmol), potassium phosphate (733 mg, 3.46 mmol), and cesium fluoride (519 mg, 3.46 mmol) were added and stirred at 80 °C for 16 h under a nitrogen atmosphere. After concentration under reduced pressure, the residue was diluted with water, adjusted to a pH of less than 3 with 1 M hydrochloric acid, and extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 1). After concentration under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to give compound 33-b (447 mg, yield: 72%). LC-MS (ESI): m / z = 358 [MH] - .

[0467] Synthesis of compound 33-a To a solution of compound 33-b (358 mg, 1.00 mmol) in N,N-dimethylformamide (15 mL), potassium carbonate (276 mg, 2.00 mmol) and 2-bromoethyl methyl ether (210 mg, 1.50 mmol) were added. The mixture was stirred at 60° C. for 6 hours. The mixture was stirred. After cooling to room temperature, it was diluted with water (100 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined and washed with water (30 mL × 2) and saturated brine (30 mL). After concentration under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to give compound 33-a (347 mg, yield: 83%). LC-MS (ESI): m / z = 418 [M+H] + .

[0468] Synthesis of compound 33 To a solution of compound 33-a (84 mg, 0.20 mmol) in dichloromethane (10 mL), (S)-piperidine-2-carboxylic acid (39 mg, 0.30 mmol) and methanol (10 mL) were added. The mixture was stirred at room temperature for 1 hour, followed by the addition of sodium cyanoborohydride (32 mg, 0.50 mmol). After the addition was complete, the mixture was stirred at room temperature for 16 hours. After concentration under reduced pressure, the residue was purified by preparative high-performance liquid chromatography to give compound 33 (35 mg, yield: 28%).

[0469] LC-MS (ESI): m / z = 531 [M+H] + . 1 H NMR (400 MHz, CD3Cl): δ 8.30 (d, J=8.0Hz, 1H), 8.05 (d, J=16.0Hz, 1H), 7.77(t, J=8.0Hz, 1H), 7.66 (s, 1H), 7.56~7.60 (m, 3H), 7.47~7.53 (m, 5H), 4.32~4.34 (m, 2H), 4.06~4.11 (m, 1H), 3.81~3.84 (m, 2H), 3.54~3.57 (m, 1H), 3.44~3.46 (m, ppm.

[0470] Example 34 (S,E)-4-(5-chloro-2-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-4-(2-methoxyethoxy)benzyl)morpholine-3-carboxylic acid (Compound 34)

[0471] [ka]

[0472] Synthesis of compound 34 To a solution of compound 33-a (84 mg, 0.20 mmol) in dichloromethane (10 mL) was added (S)-morpholine-3-carboxylic acid (39 mg, 0.30 mmol) and methanol (10 mL). The mixture was stirred at room temperature for 1 hour, followed by the addition of sodium cyanoborohydride (32 mg, 0.50 mmol). After the addition was complete, the mixture was stirred at room temperature for 16 hours. After concentration under reduced pressure, the residue was purified by preparative high-performance liquid chromatography to give compound 34 (36 mg, 28% yield).

[0473] LC-MS (ESI): m / z = 533 [M+H] + . 1H NMR (400 MHz, DMSO-d6): δ 8.09 (d, J=7.6Hz, 1H), 8.05 (d, J=18.0Hz, 1H), 7.78(t, J=8.0Hz, 1H), 7.58~7.61 (m, 2H), 7.49~7.55 (m, 4H), 7.46(s, 1H), 7.43 (d, J=18.0Hz, 1H), 7.39 (s, 1H), 4.29 (t, J=4.8Hz, 2H), 4.02 (d, J=12.6Hz, 1H), 3.71~3.73 (m, 4H), 3.50~3.57 (m, 3H), 3.35 (s, 3H), 3.19 (t, J=4.8Hz, 1H), 2.73~2.80 (m, 1H), 2.23~2.28 (m, 1H) ppm.

[0474] Example 35 (S,E)-2-((5-chloro-2-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-4-(2-methoxyethoxy)benzyl)amino)-3-hydroxyl-2-methylpropionic acid (compound 35)

[0475] [ka]

[0476] Synthesis of compound 35 To a suspension of (S)-methylserine (60 mg, 0.50 mmol) in methanol (10 mL), 1 M aqueous sodium hydroxide (1 mL, 1.0 mmol) was added and stirred to dissolve the solid. A solution of compound 33-a (63 mg, 0.15 mmol) in tetrahydrofuran (5 mL) was added to the mixture, and after the addition was complete, the mixture was stirred for 16 hours. Sodium borohydride (19 mg, 0.50 mmol) was added, and stirring was continued for 1 hour. After concentration under reduced pressure, the residue was washed with water, extracted with ethyl acetate, and concentrated under reduced pressure. The resulting residue was purified by preparative liquid chromatography to give compound 35 (21 mg, yield: 27%).

[0477] LC-MS (ESI): m / z = 521 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.21 (d, J=7.6Hz, 1H), 8.06 (d, J=16.0Hz, 1H), 7.79(t, J=8.0Hz, 1H), 7.56~7.61 (m, 3H), 7.52~7.55 (m, 3H), 7.51(s, 1H), 7.47 (d, J=16.0Hz, 1H), 7.47 (s, 1H) , 4.30~4.32 (m, 2H), 4.00 (dd, J=24.0 Hz ,12.6Hz, 2H), 3.72~3.79 (m, 2H), 3.66 (d, J=10.8Hz, 1H), 3.57(d, J=10.8Hz, 1H), 3.35(s, 3H), 1.32 (s, 3H) ppm.

[0478] Example 36 (S,E)-1-(5-chloro-2-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-4-(3-methylsulfonyl)propoxy)benzyl)piperidine-2-carboxylic acid (Compound 36)

[0479] [ka]

[0480] Synthesis of compound 36-b A 100 mL flask was charged with 3-methylsulfonyl-1-propanol (1.38 g, 10 mmol), 1,4-diazabicyclo[2.2.2]octane (1.68 g, 15 mmol), and dry dichloromethane (40 mL). To the mixture was added p-toluenesulfonyl chloride (2.29 g, 12 mmol) in batches at 0 °C. After the addition was complete, the mixture was stirred at room temperature for 16 hours. Water (60 mL) was added to the mixture, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (40 mL × 2). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to give compound 36-b (2.69 g, yield: 92%).

[0481] Synthesis of compound 36-a Compound 33-b (80.0 mg, 0.22 mol) and compound 33-b (92.9 mg, 0.33 mol) were dissolved in anhydrous N,N-dimethylformamide (20 mL), and potassium carbonate (91.0 mg, 0.66 mmol) was added to the solution. The reaction mixture was stirred under nitrogen gas protection at 50 °C for 16 h, then cooled to room temperature. Water (100 mL) was added to form a suspension, and 4 N dilute hydrochloric acid was added dropwise to adjust the suspension to pH 7. The mixture was extracted with ethyl acetate (150 mL). The organic phase was washed with water (60 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10 to 3:1) to give yellow solid 36-a (80 mg, yield: 77%). LC-MS (ESI): m / z = 480.1 [M+H] + .

[0482] Synthesis of compound 36 Compound 36-a (80.0 mg, 0.17 mmol) and (S)-piperidine-2-carboxylic acid (56.7 mg, 0.44 mmol) were dissolved in methanol (20 mL), sodium cyanoborohydride (27.7 mg, 0.44 mmol) was added, and the mixture was heated to 60 °C and stirred for 2 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give white solid 36 (28.1 mg, yield: 28%). Ta.

[0483] LC-MS (ESI): m / z = 593.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.17-7.81 (m, 2H), 7.79 (t, J = 8.0 Hz, 1H), 7.62-7.50 (m, 6H), 7.45 (s, 1H), 7.44-7.41 (m, 2H), 4.30 (t, J = 6.4 Hz, 2H), 4.02 (d, J = 12.8 Hz, 1H), 3.34-3.30 (m, 3H), 3.10-3.06 (bs, 1H), 3.05 (s, 3H), 2.79-2.74 (m, 1H), 2.26-2.21 (m, 3H), 1.81-1.47 (m, 4H), 1.38-1.36 (m, 2H) ppm.

[0484] Example 37 (S,E)-4-(5-chloro-2-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-4-(3-methylsulfonyl)propoxy)benzyl)morpholine-3-carboxylic acid (Compound 37)

[0485] [ka]

[0486] Synthesis of compound 37 Compound 36-a (150 mg, 0.31 mmol) and (S)-morpholine-3-carboxylic acid (131 mg, 1.0 mmol) were dissolved in methanol (20 mL), sodium cyanoborohydride (63.0 mg, 1.0 mmol) was added, and the mixture was heated to 60°C and stirred for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give white solid 37 (15.0 mg, yield: 5.0%).

[0487] LC-MS (ESI): m / z = 595.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.10 (d, J = 8.0 Hz, 1H), 8.06 (d, J = 16.0 Hz, 1H), 7.80 (t, J = 8.0 Hz, 1H), 7.62-7.51 (m, 6H), 7.46-7.42 (m, 3H), 4.29 (t, J = 6.0 Hz, 2H), 4.03 (d, J = 12.8 Hz, 1H), 3.75-3.72 (m, 2H), 3.59-3.52 (m, 3H), 3.31-3.28 (m, 3H), 3.22-3.20 (m, 1H), 3.05 (s, 3H), 2.82-2.78 (m, 1H), 2.29-2.20 (m, 3H) ppm.

[0488] Example 38 (S,E)-2-((5-chloro-2-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-4-(3-methylsulfonyl)propoxy)benzyl)amino)-3-hydroxyl-2-methylpropionic acid (compound 38)

[0489] [ka]

[0490] Synthesis of compound 38 (S)-Methylserine (74.5 mg, 0.626 mmol) was dissolved in methanol (8 mL) and 0.313 M aqueous sodium hydroxide (2 mL, 0.626 mmol) was added dropwise with stirring. After the addition was complete, the mixture was stirred at room temperature for 10 minutes. The reaction solution was cooled to 0°C, and a solution of compound 36-a (120.0 mg, 0.35 mmol) in tetrahydrofuran (6 mL) was slowly added dropwise. After the addition was complete, the mixture was warmed to room temperature and stirred for 16 hours. Sodium borohydride (27.0 mg, 0.71 mmol) was added to the reaction solution and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography to give 38 (27.0 mg, 22% yield) as a white solid.

[0491] LC-MS (ESI): m / z = 441.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.21 (d, J = 8.0 Hz, 1H), 8.05 (d, J = 6.0 Hz, 1H), 7.77 (t, J = 8.0 Hz, 1H), 7.60-7.44 (m, 9H), 4.30 (t, J = 6.4 Hz, 2H), 4.05-4.00 (m, 2H), 3.70-3.58 (m, 2H), 3.31-3.29 (m, 3H), 3.03 (s, 3H), 2.25-2.20 (m, 2H), 1.32 (s, 3H) ppm.

[0492] Example 39 (S,E)-1-(5-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-(4-cyanobutoxy)-4-methylbenzyl)piperidine-2-carboxylic acid (compound 39)

[0493] [ka]

[0494] Synthesis of compound 39-c A mixture of 4-bromo-3-methylphenol (1.87 g, 10.0 mmol), paraformaldehyde (2.21 g, 76.2 mmol), magnesium chloride (1.43 g, 15.0 mmol), triethylamine (3.78 g, 37.4 mmol), and acetonitrile (70 mL) was heated to reflux for 3 h. The reaction solution was cooled to room temperature, diluted with water (100 mL), and then adjusted to pH 3 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with water (100 mL) and saturated brine (50 mL), respectively, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 50:1) to give a white solid 39-c (1.4 g, yield: 66%).

[0495] Synthesis of compound 39-b A mixture of compound 39-c (500 mg, 2.33 mmol), 5-bromovaleronitrile (452 ​​mg, 2.79 mmol), potassium carbonate (482 mg, 3.49 mmol), and N,N-dimethylformamide (5 mL) was heated at 60 °C for 16 h. The reaction solution was cooled to room temperature and diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (50 mL). The organic phase was washed with water (50 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give white solid 39-b (550 mg, yield: 80%).

[0496] 1 H NMR (400 MHz, CDCl3): δ 10.33 (s, 1H), 7.95 (s, 1H), 6.86 (s, 1H), 4.12 (t, J = 5.9 Hz, 2H), 2.47 (t, J = 6.9 Hz, 2H), 2.44 (s, 3H), 2.09 - 2.00 (m, 2H), 1.96 - 1.86 (m, 2H) ppm

[0497] Synthesis of compound 39-a A mixture of compound 39-b (296 mg, 1.0 mmol), compound 8-b (397 mg, 1.2 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (73 mg, 0.1 mmol), potassium carbonate (276 mg, 2.0 mmol), 1,4-dioxane (5 mL), and water (0.5 mL) was stirred at 90 °C under nitrogen gas protection for 16 hours. The reaction solution was diluted with saturated brine (20 mL). The resulting mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined and washed with anhydrous sodium sulfate. The mixture was dried over silica gel, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=2:1) ​​to give compound 39-a (260 mg, yield: 62%). LC-MS (ESI): m / z = 421.3 [M+H] + .

[0498] Synthesis of compound 39 To a mixture of compound 39-a (50 mg, 0.12 mmol), (S)-piperidine-2-carboxylic acid (31 mg, 0.24 mmol), methanol (1 mL), and tetrahydrofuran (1 mL) was added sodium cyanoborohydride (30 mg, 0.24 mmol). The reaction solution was stirred at 65 °C for 1 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give white solid 39 (37.7 mg, yield: 56%).

[0499] LC-MS (ESI): m / z = 534.6 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ 7.88 (d, J = 7.9 Hz, 1H), 7.82 (s, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.61 (d, J = 16.1 Hz, 1H), 7.58 - 7.45 (m, 5H), 7.43 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 16.1 Hz, 1H), 7.00 (s, 1H), 4.57 (d, J = 12.8 Hz, 1H), 4.37 (d, J = 12.7 Hz, 1H), 4.17 (t, J = 6.1 Hz, 2H), 3.56 (d, J = 6.5 Hz, 1H), 3.32 (s, 1H), 3.03 (t, J = 10.3 Hz, 1H), 2.58 (t, J = 7.0 Hz, 2H), 2.50 (s, 3H), 2.23 (d, J = 13.3 Hz, 1H), 2.09 - 1.98 (m, 2H), 1.98 - 1.81 (m, 4H), 1.80 - 1.51 (m, 3H) ppm.

[0500] Example 40 (S,E)-4-(5-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-(4-cyanobutoxy)-4-methylbenzyl)morpholine-3-carboxylic acid (compound 40)

[0501] [ka]

[0502] Synthesis of compound 40 To a mixture of compound 39-a (50 mg, 0.12 mmol), (S)-morpholine-3-carboxylic acid (31 mg, 0.24 mmol), methanol (1 mL), and tetrahydrofuran (1 mL) was added sodium cyanoborohydride (30 mg, 0.24 mmol). The reaction solution was stirred at 65° C. for 1 hour. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give a white solid 40 (39 mg, yield: 61%).

[0503] LC-MS (ESI): m / z = 536.5 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.08 (d, J = 8.0 Hz, 1H), 7.76 (t, J = 7.9 Hz, 1H), 7.71 (s, 1H), 7.68 (d, J = 16.0 Hz, 1H), 7.63 - 7.48 (m, 5H), 7.46 (d, J = 7.7 Hz, 1H), 7.28 (d, J = 16.0 Hz, 1H), 6.88 (s, 1H), 4.05 (t, J = 5.9 Hz, 2H), 3.91 - 3.81 (m, 2H), 3.77 - 3.62 (m, 3H), 3.61 - 3.54 (m, 1H), 3.29 (t, J = 3.8 Hz, ppm.

[0504] Example 41 (S,E)-1-(5-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-(2-hydroxylethoxyl)-4-methylbenzyl)piperidine-2-carboxylic acid (compound 41)

[0505] [ka]

[0506] Synthesis of compound 41-b A mixture of compound 39-c (400 mg, 1.86 mmol), (2-bromoethoxy)(tert-butyl)dimethylsilane (534 mg, 2.23 mmol), potassium carbonate (514 mg, 3.72 mmol), and N,N-dimethylformamide (4 mL) was heated at 60 °C for 16 h. The reaction solution was cooled to room temperature and diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with water (50 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 30:1) to give white solid 41-b (526 mg, yield: 76%).

[0507] Synthesis of compound 41-a A mixture of compound 41-b (373 mg, 1.0 mmol), compound 8-b (397 mg, 1.2 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (73 mg, 0.1 mmol), potassium carbonate (276 mg, 2.0 mmol), 1,4-dioxane (5 mL), and water (0.5 mL) was stirred at 90 °C for 16 h under nitrogen gas protection. The reaction solution was cooled to room temperature and diluted with saturated brine (20 mL). The resulting mixture was extracted with dichloromethane (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give yellow solid 41-a (420 mg, 84% yield). LC-MS (ESI): m / z = 498.5 [M+H] + .

[0508] Synthesis of compound 41 To a mixture of compound 41-a (75 mg, 0.15 mmol), (S)-piperidine-2-carboxylic acid (39 mg, 0.30 mmol), methanol (1 mL), and tetrahydrofuran (1 mL) was added sodium cyanoborohydride (38 mg, 0.60 mmol). The reaction solution was stirred at 65 °C for 1 hour. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Tetrahydrofuran (1 mL), water (0.5 mL), and trifluoroacetic acid (0.5 mL) were added to the residue, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by preparative high-performance liquid chromatography to give white solid 41 (40.2 mg, yield: 54%).

[0509] LC-MS (ESI): m / z = 495.5 [MH] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.06 (d, J = 7.9 Hz, 1H), 7.76 (t, J = 7.9 Hz, 1H), 7.74 (s, 1H), 7.66 (d, J = 16.0 Hz, 1H), 7.62 - 7.58 (m, 2H), 7.57 - 7.48 (m, 3H), 7.47 (d, J = 7.6 Hz, 1H), 7.27 (d, J = 16.0 Hz, 1H), 6.91 (s, 1H), 4.10 - 3.97 (m, 4H), 3.81 (d, J = 13.7 Hz, 1H), 3.73 (t, J = 4.6 Hz, 2H), 3.12 (dd, J = 8.2, 3.9 Hz, 1H), 3.07 - 3.00 (m, 1H), 2.45 (s, 3H), 2.42 - 2.31 (m, 1H), 1.90 - 1.80 (m, 1H), 1.77 - 1.65 (m 1H), 1.61 - 1.45 (m, 3H), 1.43 - 1.22 (m, 1H) ppm.

[0510] Example 42 (S,E)-4-(5-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-(2-hydroxylethoxyl)-4-methylbenzyl)morpholine-3-carboxylic acid (compound 42)

[0511] [ka]

[0512] Synthesis of compound 42 To a mixture of compound 41-a (75 mg, 0.15 mmol), (S)-morpholine-3-carboxylic acid (39 mg, 0.30 mmol), methanol (1 mL), and tetrahydrofuran (1 mL) was added sodium cyanoborohydride (38 mg, 0.60 mmol). The reaction solution was stirred at 65 °C for 1 hour. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Tetrahydrofuran (1 mL), water (0.5 mL), and trifluoroacetic acid (0.5 mL) were added to the residue, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by preparative high-performance liquid chromatography to give white solid 42 (53.3 mg, yield: 58%).

[0513] LC-MS (ESI): m / z = 499.5 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.08 (d, J = 7.9 Hz, 1H), 7.76 (t, J = 7.9 Hz, 1H), 7.72 (s, 1H), 7.68 (d, J = 16.0 Hz, 1H), 7.63 - 7.50 (m, 5H), 7.46 (d, J = 7.7 Hz, 1H), 7.28 (d, J = 16.0 Hz, 1H), 6.88 (s, 1H), 4.03 (t, J = 4.1 Hz, 2H), 3.92 (d, J = 14.4 Hz, 1H), 3.80 - 3.71 (m, 4H), 3.67 (d, J = 14.5 Hz, 1H), 3.61 (t, J = 4.7 Hz, 2H), 3.22 (t, J = 4.5 Hz, 1H), 3.02 - 2.95 (m, 1H), 2.44 (s, 3H), 2.37 - 2.28 (m, 1H) ppm.

[0514] Example 43 (S,E)-1-(5-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-(2-methoxyethoxy)-4-methylbenzyl)piperidine-2-carboxylic acid (compound 43)

[0515] [ka]

[0516] Synthesis of compound 43-b A mixture of compound 39-c (400 mg, 1.86 mmol), 1-bromo-2-methoxyethane (310 mg, 2.23 mmol), potassium carbonate (514 mg, 3.72 mmol), and N,N-dimethylformamide (4 mL) was heated at 60°C for 20 hours. The reaction solution was cooled to room temperature and diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (50 mL x 2). The organic phases were combined and washed with water (50 mL) and saturated brine ( 20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=3:1) to give a white solid 43-b (433 mg, yield: 85%).

[0517] Synthesis of compound 43-a A mixture of compound 43-b (273 mg, 1.0 mmol), compound 8-b (397 mg, 1.2 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (73 mg, 0.1 mmol), potassium carbonate (276 mg, 2.0 mmol), 1,4-dioxane (5 mL), and water (0.5 mL) was stirred at 90 °C under nitrogen gas protection for 16 h. The reaction solution was diluted with saturated brine (20 mL). The resulting mixture was extracted with dichloromethane (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was washed with ethyl acetate (20 mL) to give an off-white solid 43-a (284 mg, 71% yield). LC-MS (ESI): m / z = 398.4 [M+H] + .

[0518] Synthesis of compound 43 To a mixture of compound 43-a (40 mg, 0.1 mmol), (S)-piperidine-2-carboxylic acid (26 mg, 0.2 mmol), methanol (1 mL), and tetrahydrofuran (1 mL) was added sodium cyanoborohydride (25 mg, 0.4 mmol). The reaction solution was stirred at 65° C. for 1 hour. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by preparative high-performance liquid chromatography to give white solid 43 (33.2 mg, 65% yield).

[0519] LC-MS (ESI): m / z = 511.4 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ 7.89 (d, J = 8.0 Hz, 1H), 7.76 (s, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.61 (d, J = 16.1 Hz, 1H), 7.58 - 7.45 (m, 5H), 7.43 (d, J = 7.6 Hz, 1H), 7.38 (d, J = 16.1 Hz, 1H), 6.99 (s, 1H), 4.68 (d, J = 12.7 Hz, 1H), 4.35 - 4.16 (m, 3H), 3.97 - 3.86 (m, 1H), 3.84 - 3.73 (m, 1H), 3.56 (d, 1H), 3.45 (s, 3H), 3.29 - 3.21 (m, 1H), 3.00 (t, J = 11.6 Hz, 1H), 2.50 (s, 3H), 2.25 (s, 1H), 1.99 - 1.49 (m, 5H) ppm.

[0520] Example 44 (S,E)-4-(5-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-(2-methoxyethoxy)-4-methylbenzyl)morpholine-3-carboxylic acid (Compound 44)

[0521] [ka]

[0522] Synthesis of compound 44 To a mixture of compound 43-a (40 mg, 0.1 mmol), (S)-morpholine-3-carboxylic acid (26 mg, 0.2 mmol), methanol (1 mL), and tetrahydrofuran (1 mL) was added sodium cyanoborohydride (25 mg, 0.4 mmol). The reaction solution was stirred at 65°C for 1 hour. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by preparative high-performance liquid chromatography to give white solid 44 (26 mg, yield: 51%).

[0523] LC-MS (ESI): m / z = 513.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.08 (d, J = 8.0 Hz, 1H), 7.76 (t, J = 7.8 Hz, 1H), 7.74 (s, 1H), 7.68 (d, J = 16.0 Hz, 1H), 7.64 - 7.48 (m, 5H), 7.46 (d, J = 7.6 Hz, 1H), 7.29 (d, J = 16.1 Hz, 1H), 6.89 (s, 1H), 4.18 - 4.10 (m, 2H), 3.90 - 3.81 (m, 2H), 3.78 - 3.55 (m, 7H), 3.33 (s, 3H), 3.06 (t, J = 10.8 Hz, 1H), 2.44 (s, 3H), 2.36 (d, J = 12.0 Hz, 1H) ppm.

[0524] Example 45 (S,E)-1-(2-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-6-(4-cyanobutoxy)-3-methylbenzyl)piperidine-2-carboxylic acid (compound 45)

[0525] [ka]

[0526] Synthesis of compound 45-a Compound 15-b-1 (250 mg, 0.84 mmol), compound 8-b (334 mg, 1.01 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloro A mixture of palladium(II) (58 mg, 0.08 mmol), potassium carbonate (232 mg, 1.68 mmol), 1,4-dioxane (5 mL), and water (0.5 mL) was stirred at 90 °C for 16 h under nitrogen gas protection. The reaction solution was cooled to room temperature and diluted with saturated brine (20 mL). The resulting mixture was extracted with dichloromethane (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was washed with acetonitrile (20 mL) and a mixture of dioxane and water (5:1) (20 mL) to give an off-white solid 45-a (280 mg, yield: 79%). LC-MS (ESI): m / z = 421.4 [M+H] + .

[0527] Synthesis of compound 45 To a mixture of compound 45-a (42 mg, 0.1 mmol), (S)-piperidine-2-carboxylic acid (26 mg, 0.2 mmol), methanol (1 mL), and tetrahydrofuran (1 mL) was added sodium cyanoborohydride (25 mg, 0.4 mmol). The reaction solution was stirred at 65°C for 1 hour. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by preparative high-performance liquid chromatography to give white solid 45 (30.8 mg, yield: 58%).

[0528] LC-MS (ESI): m / z = 534.5 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ 8.11 (d, J = 7.9 Hz, 1H), 7.79 (t, J = 7.9 Hz, 1H), 7.62 (d, J = 16.8 Hz, 1H), 7.59-7.45 (m, 6H), 7.39 (d, J = 8.5 Hz, 1H), 7.06 (d, J = 6.8 Hz, 1H), 7.03 (d, J = 14.9 Hz, 1H), 4.76 (d, 1H), 4.59 (d, J = 13.9 Hz, 1H), 4.27-4.14 (m, 2H), 3.63 (s, 1H), 3.28 - 3.22 (m, 1H), 3.18-3.04 (m, 1H), 2.58 (t, J = 7.0 Hz, 2H), 2.39 (s, 3H), 2.17-1.99 (m, J = 9.0, 5.9 Hz, 4H), 1.94-1.85 (m, 2H), 1.85-1.75 (m, 1H), 1.75-1.54 (m, 3H) ppm.

[0529] Example 46 (S,E)-4-(2-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-6-(4-cyanobutoxy)-3-methylbenzyl)morpholine-3-carboxylic acid (Compound 46)

[0530] [ka]

[0531] Synthesis of compound 46 Compound 45-a (42 mg, 0.1 mmol), (S)-morpholine-3-carboxylic acid To a mixture of 46 (26 mg, 0.2 mmol), methanol (1 mL), and tetrahydrofuran (1 mL) was added sodium cyanoborohydride (25 mg, 0.4 mmol). The reaction solution was stirred at 65 °C for 1 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by preparative high-performance liquid chromatography to give 46 (25.3 mg, yield: 47%) as a white solid.

[0532] LC-MS (ESI): m / z = 536.5 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ 8.18 (d, J = 7.9 Hz, 1H), 7.78 (t, J = 7.9 Hz, 1H), 7.71 (d, J = 16.5 Hz, 1H), 7.60-7.54 (m, 2H), 7.54-7.44 (m, 4H), 7.37 (d, J = 8.6 Hz, 1H), 7.06 (d, J = 16.9 Hz, 1H), 7.02 (d, J = 9.2 Hz, 1H), 4.71 (d, J = 13.0 Hz, 1H), 4.55 (d, J = 13.2 Hz, 1H), 4.22-4.13 (m, 2H), 4.10 (dd, J = 12.6, 3.8 Hz, 1H), 3.97-3.83 (m, 2H), 3.80-3.66 (m, 2H), 3.29-3.22 (m, 1H), 3.15-3.02 (m, 1H), 2.58 (t, J = 7.0 Hz, 2H), 2.40 (s, 3H), 2.10-1.98 (m, 2H), 1.94-1.82 (m, 2H) ppm

[0533] Example 47 (S,E)-1-(5-chloro-2-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-4-(cyanomethoxy)benzyl)piperidine-2-carboxylic acid (Compound 47)

[0534] [ka]

[0535] Synthesis of compound 47-a Compound 33-b (155 mg, 0.43 mol) and bromoacetonitrile (102.7 mg, 0.86 mol) were dissolved in anhydrous N,N-dimethylformamide (15 mL), and potassium carbonate (178 mg, 1.29 mmol) was added to the solution. The reaction mixture was stirred at 30 °C under nitrogen gas protection for approximately 5 h and then cooled to room temperature. Water (100 mL) was added to form a suspension, and the pH was adjusted to 7 with 4 N hydrochloric acid. The mixture was extracted with ethyl acetate (150 mL), washed with water (60 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10 to 3:1) to give compound 47-a (70 mg, yield: 41%). LC-MS (ESI): m / z = 399.1 [M+H] + .

[0536] Synthesis of compound 47 Compound 47-a (70.0 mg, 0.175 mmol) and the starting material (S)-piperidine-2-carboxylic acid (45.3 mg, 0.35 mmol) were dissolved in methanol (12 mL), sodium cyanoborohydride (22.1 mg, 0.35 mmol) was added, and the mixture was heated to 60°C and stirred for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give white solid 47 (25.0 mg, yield: 28%).

[0537] LC-MS (ESI): m / z = 512.3 [M+H] + . 1 H NMR: (400 MHz DMSO-d6): δ 8.14 (s, 1H), 8.11 (d, J = 9.6 Hz, 1H), 7.79 (t, J = 8.0 Hz, 1H), 7.61-7.44 (m, 9H), 5.40 (s, 2H), 7.44-7.41 (m, 2H), 3.98 (d, J = 13.2 Hz, 1H), 3.43 (d, J = 13.2 Hz, 1H), 3.08-3.05 (m, 1H), 2.76-2.73 (m, 1H), 2.15-2.11 (m, 1H), 1.78-1.68 (m, 2H), 1.54-1.36 (m, 4H) ppm.

[0538] Example 48 (S,E)-1-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-(cyanomethoxy)-5-methylbenzyl)piperidine-2-carboxylic acid (Compound 48)

[0539] [ka]

[0540] Synthesis of compound 48-b A mixture of compound 24-c (215 mg, 1.0 mmol), bromoacetonitrile (120 mg, 1.2 mmol), potassium carbonate (276 mg, 2.0 mmol), and N,N-dimethylformamide (3 mL) was stirred at room temperature for 16 hours. The reaction solution was diluted with water (20 mL). The precipitated solid was filtered and dried to give white solid 48-b (213 mg, 84% yield).

[0541] Synthesis of compound 48-a Compound 48-b (210 mg, 0.826 mmol), compound 8-b (328 mg, 0.992 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloro A mixture of palladium(II) (61 mg, 0.083 mmol), potassium carbonate (228 mg, 1.65 mmol), 1,4-dioxane (5 mL), and water (0.5 mL) was stirred at 90 °C for 16 hours under nitrogen gas protection. The reaction solution was cooled to room temperature and diluted with saturated brine (20 mL). The resulting mixture was extracted with dichloromethane (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was washed with ethyl acetate (20 mL × 2) to give a pale green solid 48-a (300 mg, yield: 96%). LC-MS (ESI): m / z = 379.3 [M+H] + .

[0542] Synthesis of compound 48 To a mixture of compound 48-a (57 mg, 0.15 mmol), (S)-piperidine-2-carboxylic acid (39 mg, 0.30 mmol), methanol (1 mL), and tetrahydrofuran (1 mL) was added sodium cyanoborohydride (38 mg, 0.60 mmol). The reaction solution was stirred at 65 °C for 1 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give white solid 48 (14.7 mg, yield: 20%).

[0543] LC-MS (ESI): m / z = 492.4 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ 7.97 (d, J = 8.0 Hz, 1H), 7.75 (t, J = 7.9 Hz, 1H), 7.69 (d, J = 16.1 Hz, 1H), 7.62-7.44 (m, 9H), 5.20 (s, 2H), 4.49 (d, J = 12.9 Hz, 1H), 4.34 (d, J = 12.8 Hz, 1H), 3.50 (d, J = 8.4 Hz,1H), 3.42-3.33 (m, 1H), 2.97 (t, J = 10.5 Hz, 1H), 2.49 (s, 3H), 2.26 (d, J = 12.2 Hz, 1H), 1.95-1.66 (m,4H), 1.63-1.46 (m, 1H) ppm.

[0544] Example 49 (S,E)-1-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-(methoxymethyl)-5-trifluoromethylbenzyl)piperidine-2-carboxylic acid (Compound 49)

[0545] [ka]

[0546] Synthesis of compound 49-d Compound 20-f (600 mg, 2 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL) and sodium hydride (80 mg, 4 mmol) was added at 0 °C under nitrogen gas protection. After the addition was complete, the mixture was warmed to room temperature and stirred for 30 min. Iodomethane (570 mg, 4 mmol) was added and the mixture was stirred at room temperature for 3 h. Water (1 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL). The mixture was washed with water (20 mL × 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 49-d (292 mg, yield: 45.0%).

[0547] 1 H NMR (400 MHz, DMSO-d6): δ 8.22 (s, 1H), 8.09 (s, 1H), 4.87 (s, 2H), 3.92 (s, 3H), 3.46 (s, 3H) ppm.

[0548] Synthesis of compound 49-c Compound 49-d (290 mg, 0.88 mmol) was dissolved in anhydrous methanol (10 mL) and sodium borohydride (100 mg, 2.66 mmol) was added under nitrogen gas protection at 0 °C. After the addition was completed, the mixture was refluxed for 16 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 49-c (170 mg, yield: 65.0%). LC-MS (ESI): m / z = 299 [MH] + .

[0549] Synthesis of compound 49-b Compound 49-c (170 mg, 0.56 mmol) was dissolved in dichloromethane (10 mL) and manganese dioxide (493 mg, 5.6 mmol) was added. The reaction solution was stirred at room temperature for 16 hours. After filtration, the cake was washed with dichloromethane (20 mL × 3). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 49-b (114 mg, yield: 68%).

[0550] Synthesis of compound 49-a Compound 49-b (110 mg, 0.36 mmol), compound 8-b (141 mg, 0.42 mmol), sodium carbonate (132 mg, 1.26 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (31 mg, 0.042 mmol) were added to a mixture of 1,4-dioxane (5 mL) and water (0.5 mL), and the mixture was stirred at 80 °C under nitrogen gas protection for 16 h. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 49-a (65 mg, yield: 43.0%). LC-MS (ESI): m / z = 422 [M+H] + .

[0551] Synthesis of compound 49 A mixture of compound 49-a (30 mg, 0.07 mmol), (S)-piperidine-2-carboxylic acid (24 mg, 0.19 mmol), sodium cyanoborohydride (12 mg, 0.19 mmol), and methanol (3 mL) was stirred at 80° C. under nitrogen gas protection for 3 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 49 (10 mg, yield: 26.3%).

[0552] LC-MS (ESI): m / z = 535 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 7.97 (d, J=8.0 Hz, 1H), 7.93(s, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.80 (s,1H), 7.66-7.46 (m,8H), 4.67 (s, 2H), 3.87(d, J=14.4 Hz, 1H), 3.57 (d, J=14.4 Hz, 1H), 3.38 (s, 3H), 3.17 (t, J=5.6 Hz, 1H), 2.81-2.78 (m, 1H), 2.20-2.19 (m, 1H), 1.78-1.76 (m, 2H), 1.45-1.37 (m, 4H) ppm.

[0553] Example 50 (S,E)-4-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-(methoxymethyl)-5-trifluoromethylbenzyl)morpholine-3-carboxylic acid (Compound 50)

[0554] [ka]

[0555] Synthesis of compound 50 A mixture of compound 49-a (30 mg, 0.07 mmol), (S)-morpholine-3-carboxylic acid (24 mg, 0.19 mmol), sodium cyanoborohydride (12 mg, 0.19 mmol), and methanol (3 mL) was stirred at 80 °C under nitrogen gas protection for 3 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 50 (10 mg, yield: 33.3%).

[0556] LC-MS (ESI): m / z = 537 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 7.90 (d, J=8.0Hz,1H), 7.87(s,1H), 7.83 (t, J=8.0 Hz, 1H), 7.69 (s,1H), 7.59-7.39 (m,8H), 4.61 (s, 2H), 3.91 (d, J=14.4 Hz, 1H), 3.80-3.76 (m, 1H), 3.69-3.64 (m, 2H), 3.56-3.52 (m, 1H), 3.48-3.42 (m, 2H), 3.32 (s, 3H), 2.87-2.83 (m, 1H), 2.21-2.18 (m, 1H) ppm.

[0557] Example 51 (S,E)-1-(2-methoxy-4-(2-(2-methyl-d3)-[1,1'-biphenyl]-3-yl)vinyl)-5-trifluoromethylbenzyl)piperidine-2-carboxylic acid (Compound 51)

[0558] [ka]

[0559] Synthesis of compound 51-c Potassium tert-butoxide (84 mg, 0.75 mmol) was added to a mixture of compound 3-c (618 mg, 2.5 mmol) and deuterated dimethyl sulfoxide (3 mL). The reaction solution was stirred at room temperature for 20 hours and then diluted with water (20 mL). The mixture was extracted with petroleum ether (50 mL). The resulting organic phase was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether) to give compound 51-c (550 mg, yield: 88%).

[0560] 1 H NMR (400 MHz, DMSO-d6): δ 7.67-7.59 (m, 1H), 7.49 - 7.37 (m, 3H), 7.35 -7.28 (m, 2H), 7.23-7.17 (m, 2H) ppm

[0561] Synthesis of compound 51-b A mixture of compound 51-c (500 mg, 2.0 mmol), vinylboronic acid pinacol ester (462 mg, 3.0 mmol), bis(tri-tert-butylphosphine)palladium (102 mg, 0.2 mmol), triethylamine (2.02 g, 20 mmol), and toluene (10 mL) was stirred at 80 °C under nitrogen gas protection for 16 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 50:1) to give compound 51-b (450 mg, yield: 70%).

[0562] Synthesis of compound 51-a A mixture of compound 6-b (113 mg, 0.4 mmol), compound 51-b (155 mg, 0.48 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (29 mg, 0.04 mmol), potassium carbonate (110 mg, 0.8 mmol), 1,4-dioxane (3 mL), and water (0.5 mL) was stirred at 90 °C under nitrogen gas protection for 5 h. The reaction solution was cooled to room temperature and diluted with saturated brine (20 mL). The resulting mixture was extracted with dichloromethane (40 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 50:1). The resulting product was washed with methanol (1.5 mL × 2) to give white solid 51-a (75 mg, yield: 47%).

[0563] LC-MS (ESI): m / z = 400.4 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 10.44 (s, 1H), 8.16 (s, 1H), 7.59 (dd, J = 7.6, 1.0 Hz, 1H), 7.51-7.28 (m, 10H), 7.25-7.23 (m, 1H), 4.07 (s, 3H)ppm

[0564] Synthesis of compound 51 To a mixture of compound 51-a (40 mg, 0.1 mmol), (S)-piperidine-2-carboxylic acid (26 mg, 0.2 mmol), methanol (1 mL), and tetrahydrofuran (1 mL) was added sodium cyanoborohydride (25 mg, 0.4 mmol). The reaction solution was stirred at 65 °C for 1 hour. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give white solid 51 (16.2 mg, yield: 32%).

[0565] LC-MS (ESI): m / z = 513.5 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ 7.89 (s, 1H), 7.62 (d, J = 15.8 Hz, 1H), 7.56 - 7.51 (m, 2H), 7.42 (t, J = 7.3 Hz, 2H), 7.37-7.24 (m, 5H), 7.20-7.15 (m, 1H), 4.53 (d, J = 12.9 Hz, 1H), 4.40 (d, J = 12.9 Hz,1H), 4.06 (s, 3H), 3.57-3.46 (m, 1H), 3.31 (s, 1H), 3.00 (t, J = 10.7 Hz, 1H), 2.24 (d, J = 14.8 Hz, 1H), 1.97-1.64 (m, 4H), 1.63-1.48 (m, 1H) ppm

[0566] Example 52 (S,E)-1-(5-chloro-2-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-4-(methoxy-d3)benzyl)piperidine-2-carboxylic acid (compound 52)

[0567] [ka]

[0568] Synthesis of compound 52-a Compound 33-b (140 mg, 0.39 mol) and deuterated iodomethane (565.5 mg, 3.9 mol) were dissolved in anhydrous N,N-dimethylformamide (15 mL), and then potassium carbonate (269.1 mg, 1.95 mmol) was added. The reaction mixture was stirred for 12 hours under nitrogen gas protection at 30°C, and then allowed to return to room temperature. Water (100 mL) was added to form a suspension, and 4N hydrochloric acid solution was added dropwise to adjust the suspension to neutral. The mixture was extracted with ethyl acetate (150 mL x 3), and the organic phase was washed with water (60 mL) and saturated brine (50 mL). L), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=20 to 10:1) to give a white solid 52-a (110 mg, yield: 75%). LC-MS (ESI): m / z = 377.4 [M+H] + .

[0569] Synthesis of compound 52 Compound 52-a (110.0 mg, 0.292 mmol) and (S)-piperidine-2-carboxylic acid (75.3 mg, 0.58 mmol) were dissolved in methanol (20 mL), sodium cyanoborohydride (36.8 mg, 0.58 mmol) was added, and the mixture was heated to 60° C. and stirred for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give white solid 52 (19.0 mg, yield: 13%).

[0570] LC-MS (ESI): m / z = 490.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.17-8.13 (m, 2H), 7.78 (t, J = 8.0 Hz, 1H), 7.62-7.41 (m, 9H), 4.00 (d, J = 12.4 Hz, 1H), 3.41 (d, J = 12.8 Hz, 1H), 3.12-3.03 (m, 1H), 2.78-2.74 (m, 1H), 2.16-2.12 (m, 1H), 1.82-1.36 (m, 6H) ppm.

[0571] Example 53 (S,E)-1-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-((methoxy-d3)methyl)-5-trifluoromethylbenzyl)piperidine-2-carboxylic acid (compound 53)

[0572] [ka]

[0573] Synthesis of compound 53-d Compound 20-f (600 mg, 2 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL), cooled in an ice bath, and added with sodium hydride (80 mg, 4 mmol) under nitrogen gas protection. After the addition was complete, the mixture was allowed to return to room temperature and stirred for 30 minutes. Deuterated iodomethane (570 mg, 4 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. Water (1 mL) was added to quench the reaction, and ethyl acetate (100 mL) was added. The mixture was washed with water (20 mL × 3) and saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. The residue was purified by HPLC (petroleum ether:ethyl acetate=10:1) to give compound 53-d (292 mg, yield: 45.0%).

[0574] Synthesis of compound 53-c Compound 53-d (290 mg, 0.88 mmol) was dissolved in anhydrous methanol (10 mL), and sodium borohydride (100 mg, 2.66 mmol) was added under nitrogen gas protection at 0 °C. The reaction mixture was refluxed for 16 h. After cooling to room temperature, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 53-c (170 mg, yield: 65.0%). LC-MS (ESI): m / z = 301 [MH] + .

[0575] Synthesis of compound 53-b Compound 53-c (170 mg, 0.56 mmol) was dissolved in dichloromethane (10 mL), manganese dioxide (493 mg, 5.6 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. After filtration, the manganese dioxide was washed with dichloromethane. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 53-b (114 mg, yield: 68%).

[0576] 1 H NMR (400 MHz, DMSO-d6): δ 10.17 (s, 1H), 8.31 (s, 1H), 8.08 (s, 1H), 4.88 (s, 2H) ppm

[0577] Synthesis of compound 53-a A mixture of compound 53-b (110 mg, 0.36 mmol), compound 8-b (141 mg, 0.42 mmol), sodium carbonate (132 mg, 1.26 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (31 mg, 0.042 mmol), 1,4-dioxane (5 mL), and water (0.5 mL) was stirred at 80 °C under nitrogen gas protection for 16 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 53-a (65 mg, yield: 43.0%). LC-MS (ESI): m / z = 425 [M+H] + .

[0578] Synthesis of compound 53 A mixture of compound 53-a (30 mg, 0.07 mmol), (S)-piperidine-2-carboxylic acid (24 mg, 0.19 mmol), sodium cyanoborohydride (12 mg, 0.19 mmol), and methanol (3 mL) was stirred at 80° C. under nitrogen gas protection for 3 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 53 (10 mg, yield: 26.3%).

[0579] LC-MS (ESI): m / z = 538 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 7.97 (d, J=8.0 Hz, 1H), 7.94 (s,1H), 7.82 (t, J=8.0 Hz, 1H), 7.80 (s,1H), 7.66-7.46 (m, 8H), 4.66 (s, 2H), 3.91(d, J=14.0 Hz,1H), 3.61 (d, J=14.4Hz, 1H), 3.23-3.21 (m, 1H), 2.83-2.80 (m, 1H), 2.26-2.23 (m, 1H), 1.81-1.78 (m, 2H), 1.54-1.40 (m, 4H) ppm

[0580] Example 54 (S,E)-4-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-((methoxy-d3)methyl)-5-trifluoromethylbenzyl)morpholine-3-carboxylic acid (Compound 54)

[0581] [ka]

[0582] Synthesis of compound 54 A mixture of compound 53-a (30 mg, 0.07 mmol), (S)-morpholine-3-carboxylic acid (24 mg, 0.19 mmol), sodium cyanoborohydride (12 mg, 0.19 mmol), and methanol (3 mL) was stirred at 80 °C under nitrogen gas protection for 3 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 54 (10 mg, yield: 33.3%).

[0583] LC-MS (ESI): m / z = 540 [M+H] + . 1H NMR (400 MHz, DMSO-d6): δ 7.97 (d, J=8.0 Hz, 1H), 7.93 (s,1H), 7.82 (t, J=8.0 Hz, 1H), 7.79 (s, 1H), 7.61-7.49 (m, 8H), 4.71 (s, 2H), 4.06 (d, J=14.0 Hz, 1H), 3.74-3.73 (m, 2H), 3.58-3.52 (m, 3H), 3.06 (d, J=14.4 Hz, 1H), 2.82-2.79 (m, 1H), 2.20-2.15 (m, 1H) ppm

[0584] Example 55 (S,E)-3-Hydroxy-2-methyl-((3-(2-(2-methyl-d3)-[1,1'-biphenyl]-3-yl)ethenyl)-4-trifluoromethylbenzyl)amino)propionic acid (Compound 55)

[0585] [ka]

[0586] Synthesis of compound 55-a A mixture of compound 51-c (125 mg, 0.5 mmol), 4-(trifluoromethyl)-3-vinylbenzaldehyde (150 mg, 0.75 mmol), bis(tri-tert-butylphosphine)palladium (26 mg, 0.05 mmol), triethylamine (506 mg, 5.0 mmol), and toluene (2 mL) was stirred at 80 °C under nitrogen gas protection for 16 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 0 to 0.04:1) to give compound 55-a (92 mg, 50% yield).

[0587] Synthesis of compound 55 To a mixture of compound 55-a (37 mg, 0.1 mmol), (S)-2-amino-3-hydroxyl-2-methylpropionic acid (24 mg, 0.2 mmol), methanol (1 mL), and tetrahydrofuran (1 mL) was added sodium cyanoborohydride (25 mg, 0.4 mmol). The reaction mixture was heated to 65°C and stirred for 1 hour. After cooling to room temperature, it was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give 55 (18.4 mg, 39% yield) as a white solid.

[0588] LC-MS (ESI): m / z = 473.5 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ 8.15 (s, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.67 - 7.59 (m, 2H), 7.55 (dd, J = 7.7 Hz, 1H), 7.46 - 7.39 (m, 2H), 7.39 - 7.25 (m, 5H), 7.18 (dd, J = 7.6, 1.2 Hz, 1H), 4.35 (q, J = 12.5 Hz, 2H), 4.06 (d, J = 12.2 Hz, 1H), 3.86 (d, J = 12.1 Hz, 1H), 1.60 (s, 3H) ppm

[0589] Example 56 (S,E)-3-Hydroxy-2-methyl-2-(((3-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-4-trifluoromethylphenyl)methylene-d2)amino)propionic acid (Compound 56)

[0590] [ka]

[0591] Synthesis of compound 56-d To a solution of 3-bromo-4-trifluoromethylbenzaldehyde (253 mg, 0.79 mmol) and 3-b (300 mg, 0.79 mmol) in 1,4-dioxane (20 mL) and water (2 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (57.8 mg, 0.079 mmol) and sodium carbonate (216.2 g, 2.4 mmol) at room temperature. The reaction mixture was heated to 80 °C and stirred under nitrogen for 16 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to give compound 56-d (136 mg, yield: 47%).

[0592] Synthesis of compound 56-c Sodium hydroxide (360.0 mg, 9.0 mmol) was added to silver oxide (510.4 mg, 2.2 mmol), water (20 mL), and dioxane (50 mL) at room temperature, and compound 56-d (732.0 mg, 2.0 mmol) was added in batches. The reaction mixture was heated to 70 °C and stirred for 12 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in water (40 mL) and adjusted to pH 4-5 with 4 M hydrochloric acid solution. A large amount of white solid precipitated, which was suction filtered and dried to give white solid 56-c (740 mg, 96% yield). This product was not further purified.

[0593] 1 H NMR: (400 MHz, DMSO-d6): δ 13.34 (s, 1H), 8.44 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.66-7.59 (m, 2H), 7.50-7.46 (m, 2H), 7.42-7.25 (m, 5H), 7.22 (d, J = 6.8 Hz, 1H), 2.30 (s, 3H) ppm

[0594] Synthesis of compound 56-b Compound 56-c (740 mg, 1.93 mol) was dissolved in anhydrous tetrahydrofuran (40 mL). N,N-carbonyldiimidazole (333.5 mg, 2.03 mmol) was added at room temperature, and the mixture was stirred under nitrogen gas protection at room temperature for 16 h. A solution of sodium deuterated borohydride (203.3 mg, 4.84 mmol) in heavy water (8 mL) was slowly added dropwise to the reaction mixture, and stirring was continued at room temperature for 16 h. The mixture was concentrated under reduced pressure, and the residue was added to water (50 mL) and adjusted to neutrality with 4 M hydrochloric acid solution. Extraction was performed with ethyl acetate (150 mL × 3). The organic phase was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10 to 2:1) to give white solid 56-b (630 mg, yield: 88%).

[0595] 1 H NMR (400 MHz, DMSO-d6): δ 7.95 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 2.8 Hz, 1H), 7.56 (d, J = 11.6 Hz, 1H),7.49-7.45 (m, 3H), 7.40-7.24 (m, 5H), 7.19 (d, J = 7.2 Hz, 1H), 5.40 (s, 1H), 2.28 (s, 3H)ppm

[0596] Synthesis of compound 56-a Compound 56-b (630 mg, 1.70 mmol) was dissolved in anhydrous dichloromethane (50 mL), thionyl chloride (2.02 g, 17.0 mmol) and anhydrous N,N-dimethylformamide (0.5 mL) were added, and the mixture was heated to 70 °C and stirred for 6 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 30:10 to 1) to give compound 56-a (600 mg, yield: 90%).

[0597] 1H NMR (400 MHz, DMSO-d6): δ 8.15 (s, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.65-7.59 (m, 3H), 7.50-7.23 (m, 7H), 7.21 (d, J = 7.2 Hz, 1H), 2.31 (s, 3H) ppm

[0598] Synthesis of compound 56 Compound 56-a (116.4 mg, 0.30 mmol) and the starting (S)-2-methylserine methyl ester hydrochloride (183.0 mg, 0.60 mmol) were dissolved in acetonitrile (20 mL), potassium carbonate (207 mg, 1.5 mmol) and sodium iodide (45.0 mg, 0.30 mmol) were added, and the mixture was heated to 80 °C and stirred for 5 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 56 (13.5 mg, yield: 9.5%).

[0599] LC-MS (ESI): m / z = 572.5 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.05 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.65-7.58 (m, 2H), 7.52-7.46 (m, 3H), 7.42-7.32 (m, 4H), 7.29-7.24 (m, 1H), 7.21 (d, J = 6.8 Hz, 1H), 5.06 (t, J = 6.0 Hz, 1H), 3.61-3.57 (dd, J1= 5.6 Hz, J2= 10.0 Hz, 1H), 3.41 3.37 (dd, J1= 5.2 Hz, J2= 10.0 Hz, 1H), 2.29 (s, 3H), 1.94 (bs, 1H), 1.20 (s, 3H) ppm

[0600] Example 57 (S,E)-1-(5-chloro-4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-methoxybenzyl)piperidine-2-carboxylic acid (Compound 57)

[0601] [ka]

[0602] Synthesis of compound 57-c To a mixture of 3-bromo-4-chlorophenol (2.07 g, 10.0 mmol) and methanesulfonic acid (15 mL), urotropine (1.54 g, 11.0 mmol) was slowly added in batches. The mixture was stirred at 105 °C for 1 hour. The reaction solution was cooled to room temperature, and an ice-water mixture (100 mL) was added. Extraction was performed with ethyl acetate (30 mL × 3), and the combined organic phase was washed with water (30 mL) and saturated brine (30 mL) successively. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 57-c (750 mg, yield: 32%).

[0603] 1 H NMR (400 MHz, CDCl3): δ 10.90 (brs, 1H),9.83 (s, 1H),7.62 (s, 1H),7.34 (s, 1H) ppm

[0604] Synthesis of compound 57-b To a mixture of compound 57-c (200 mg, 0.85 mmol), cesium carbonate (552 mg, 1.70 mmol), and N,N-dimethylformamide (10 mL), iodomethane (362 mg, 2.55 mmol) was added and stirred at room temperature for 4 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with water (30 mL) and saturated brine (30 mL) sequentially. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 57-b (170 mg, yield: 80%).

[0605] Synthesis of compound 57-a A mixture of compound 57-b (150 mg, 0.60 mmol) and compound 8-b (260 mg, 0.78 mmol) in toluene (25 mL) was added to [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (44 mg, 0.06 mmol), potassium phosphate (318 mg, 1.5 mmol), cesium fluoride (225 mg, 1.5 mmol), and methyl ... mol) was added and stirred under nitrogen atmosphere at 90° C. for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=5:1) to give compound 57-a (210 mg, yield: 94%).

[0606] 1 H NMR (400 MHz, CDCl3): δ 10.41 (s, 1H),7.88 (d, J=7.6Hz, 1H), 7.87 (s, 1H),7.65~7.68 (m, 3H),7.45~7.58 (m, 6H),7.34 (s, 1H), 4.03 (s, 3H)ppm

[0607] Synthesis of compound 57 To a solution of 57-a (112 mg, 0.30 mmol) in dichloromethane (10 mL), (S)-piperidine-2-carboxylic acid (59 mg, 0.46 mmol) and methanol (10 mL) were added. The mixture was stirred at room temperature for 1 hour, and then sodium cyanoborohydride (32 mg, 0.50 mmol) was added and stirred at room temperature for 16 hours. After concentration under reduced pressure, the residue was purified by preparative high-performance liquid chromatography to give compound 57 (56 mg, yield: 38%).

[0608] LC-MS (ESI): m / z = 487 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ 7.96 (d, J=7.6Hz, 1H),7.77 (t, J=8.0Hz, 1H),7.74 (d, J=16.0Hz, 1H),7.66 (s, 1H),7.65 (d, J=16.0Hz, 1H),7.56-7.58 (m, 2H),7.46-7.53 (m, 5H),4.47 (d, J=12.8Hz, 1H),4.34 (d, J=12.8Hz, 1H),4.00 (s, 3H) ,3.48-3.53 (m, 1H),2.96-3.03 (m, 1H),2.22-2.26 (m, 1H),1.73-1.85 (m, 5H),1.54-1.59 (m, 1H) ppm

[0609] Example 58 (S,E)-1-(5-chloro-2-methoxy-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)benzyl)piperidine-2-carboxylic acid (compound 58)

[0610] [ka]

[0611] Synthesis of compound 58-a A mixture of compound 57-b (250 mg, 1.00 mmol) and compound 3-b (400 mg, 1.25 mmol) in toluene (20 mL) was diluted with [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (73 mg, 0.10 mmol), potassium phosphate (424 mg, 2.0 mmol), and cesium fluoride (300 mg, 2.0 mmol). ol) was added and stirred under nitrogen atmosphere at 90° C. for 16 hours. The reaction mixture was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=5:1) to give compound 58-a (272 mg, yield: 75%).

[0612] 1H NMR (400 MHz, CDCl3): δ 10.39 (s, 1H), 7.85 (s, 1H), 7.63 (d, J=8.0Hz, 1H), 7.49 (d, J=16.0Hz, 1H), 7.36-7.45 (m, 4H), 7.28-7.31 (m, 3H), 7.23-7.25 (m, 2H), 4.01 (s, 3H), 2.33 (s, 3H) ppm

[0613] Synthesis of compound 58 To a solution of compound 58-a (109 mg, 0.30 mmol) in dichloromethane (10 mL), (S)-piperidine-2-carboxylic acid (59 mg, 0.46 mmol) and methanol (10 mL) were added. The mixture was stirred at room temperature for 1 hour, followed by the addition of sodium cyanoborohydride (32 mg, 0.50 mmol), and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography to give compound 58 (66 mg, yield: 46%).

[0614] LC-MS (ESI): m / z = 476 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ 7.59-7.65 (m, 3H), 7.40-7.44 (m, 3H), 7.33-7.37 (m, 2H), 7.25-7.30 (m, 3H), 7.16 (d, J=7.2Hz, 1H), 4.46 (d, J=12.8Hz, 1H), 4.34 (d, J=12.8Hz, 1H), 4.00 (s, 3H), 3.48-3.53 (m, 1H), 2.96-3.03 (m, 1H), 2.30 (s, 1H), 2.22-2.26 (m, 1H), 1.76-1.86 (m, 5H), 1.54-1.59 (m, 1H) ppm

[0615] Example 59 (S,E)-1-(5-chloro-2-(methoxy-d3)-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)benzyl)piperidine-2-carboxylic acid (Compound 59)

[0616] [ka]

[0617] Synthesis of compound 59-b To a mixture of compound 57-c (150 mg, 0.60 mmol), cesium carbonate (390 mg, 1.20 mmol), and N,N-dimethylformamide (8 mL), deuterated iodomethane (362 mg, 2.55 mmol) was added and stirred at room temperature for 16 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with water (30 mL) and saturated brine (30 mL) sequentially. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 59-b (136 mg, 85% yield).

[0618] 1 H NMR (400 MHz, CDCl3): δ 10.35 (s, 1H), 7.87 (s, 1H), 7.28 (s, 1H) ppm

[0619] Synthesis of compound 59-a To a mixture of compound 59-b (133 mg, 0.50 mmol) and compound 3-b (200 mg, 0.62 mmol) in toluene (20 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (65 mg, 0.089 mmol), potassium phosphate (212 mg, 1.0 mmol), and cesium fluoride (150 mg, 1.0 mmol) were added and stirred at 90 °C for 16 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 7:1) to give compound 59-a (123 mg, 67% yield).

[0620] 1 H NMR (400 MHz, CDCl3): δ 10.39 (s, 1H), 7.85 (s, 1H), 7.63 (d, J=8.0Hz, 1H), 7.49 (d, J=16.0Hz, 1H), 7.35-7.43 (m, 4H), 7.28-7.30 (m, 3H), 7.23-7.25 (m, 2H), 4.01 (s, 3H), 2.33 (s, 3H) ppm

[0621] Synthesis of compound 59 To a solution of compound 59-a (120 mg, 0.33 mmol) in dichloromethane (10 mL), (S)-piperidine-2-carboxylic acid (109 mg, 0.78 mmol) and methanol (10 mL) were added. The mixture was stirred at room temperature for 1 hour, followed by the addition of sodium cyanoborohydride (100 mg, 1.58 mmol), and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography to give compound 59 (62 mg, yield: 43%).

[0622] LC-MS (ESI): m / z = 479 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ 7.59-7.65 (m, 3H), 7.40-7.44 (m, 3H), 7.33-7.37 (m, 2H), 7.25-7.30 (m, 3H), 7.16 (d, J=7.2Hz, 1H), 4.46 (d, J=12.8Hz, 1H), 4.34 (d, J=12.8Hz, 1H), 3.50-3.53 (m, 1H), 2.96-3.02 (m, 1H), 2.30(s, 1H),2.22-2.26 (m, 1H), 1.76-1.86 (m, 5H), 1.54-1.60 (m, 1H) ppm.

[0623] Example 60 (S,E)-1-(2-(methoxy-d3)-4-(2-(2-methyl-[1,1'- Biphenyl]-3-yl)vinyl)-5-trifluoromethylbenzyl)piperidine-2-carboxylic acid (Compound 60)

[0624] [ka]

[0625] Synthesis of compound 60-c To a solution of 4-bromo-2-methoxy-5-trifluoromethyl-benzaldehyde (283 mg, 1.0 mmol) in dichloromethane (10 mL) was slowly added dropwise 1.0 M boron tribromide in dichloromethane (2.5 mL, 2.5 mmol) at 0 °C. After the addition was completed, the ice bath was removed and the mixture was stirred at room temperature for 16 hours. 50 mL of saturated aqueous sodium bicarbonate solution was slowly added to the mixture, which was then extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with water (30 mL) and saturated brine (30 mL) successively. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 60-c (142 mg, yield: 53%). LC-MS (ESI): m / z = 267 [MH] - .

[0626] Synthesis of compound 60-b Deuterated iodomethane (290 mg, 2.00 mmol) was added to a mixture of compound 60-c (130 mg, 0.48 mmol), cesium carbonate (500 mg, 1.54 mmol), and N,N-dimethylformamide (8 mL) and stirred at room temperature for 16 h. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with water (30 mL) and saturated brine (30 mL) successively. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 60-b (106 mg, yield: 78%).

[0627] Synthesis of compound 60-a To a mixture of compound 60-b (100 mg, 0.35 mmol) and compound 3-b (145 mg, 0.45 mmol) in toluene (15 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (25 mg, 0.035 mmol), potassium phosphate (148 mg, 0.7 mmol), and cesium fluoride (105 mg, 0.7 mmol) were added and stirred at 90 °C for 16 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 6:1) to give compound 60-a (95 mg, 68% yield). MS (ESI): m / z = 400 [M+H] + .

[0628] Synthesis of compound 60 To a solution of compound 60-a (40 mg, 0.10 mmol) in dichloromethane (10 mL), L-piperidine-2-carboxylic acid (39 mg, 0.3 mmol) and methanol (10 mL) were added. The mixture was stirred at room temperature for 1 hour, followed by the addition of sodium cyanoborohydride (16 mg, 0.25 mmol). After the addition was complete, the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography to give compound 60 (20 mg, 39% yield).

[0629] LC-MS (ESI): m / z = 513 [M+H] + . 1H NMR (400 MHz, CD3OD): δ 7.90 (s, 1H), 7.63 (d, J=16.0Hz, 1H), 7.54 (d, J=8.0Hz, 1H), 7.53 (s, 1H), 7.41~7.44 (m, 2H), 7.35 (d, J=8.0Hz, 1H), 7.26~7.33 (m, 4H), 7.18 (d, J=7.6Hz, 1H), 4.53 (d, J=12.8Hz, 1H), 4.40 (d, J=12.8Hz, 1H), 3.49~3.52 (m, 1H), 2.93~3.03 (m, 1H), 2.30 (s, 3H), 2.22~2.26 (m, 1H), 1.67~1.85 (m, 5H), 1.54~1.59 (m, 1H) ppm.

[0630] Example 61 (S,E)-1-(2-methoxy-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl-2',3',4',5',6'-d5)vinyl)-5-trifluoromethylbenzyl)piperidine-2-carboxylic acid (Compound 61)

[0631] [ka]

[0632] Synthesis of compound 61-d To a solution of 1-bromo-3-chloro-2-methylbenzene (2.05 g, 10.0 mmol) and vinylboronic acid pinacol ester (2.00 g, 13.0 mmol) in toluene (40 mL), bis(tri-tert-butylphosphine)palladium (400 mg, 0.8 mmol) and triethylamine (3.03 g, 30.0 mmol) were added and the mixture was stirred at 80 °C for 16 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 61-d (2.36 g, 85% yield).

[0633] Synthesis of compound 61-c To a mixture of compound 61-d (279 mg, 1.00 mmol) and 4-bromo-2-methoxy-5-trifluoromethylbenzaldehyde (300 mg, 1.06 mmol) in toluene (15 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (73 mg, 0.10 mmol), potassium phosphate (424 mg, 2.0 mmol), and cesium fluoride (300 mg, 2.0 mmol) were added and stirred at 90 °C for 16 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1) to give compound 61-c (205 mg, 58% yield).

[0634] Synthesis of compound 61-b To a mixture of compound 61-c (200 mg, 0.56 mmol) and bis(pinacolato)diboron (200 mg, 0.78 mmol) in toluene (15 mL), tris(dibenzylideneacetone)dipalladium (37 mg, 0.04 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (76 mg, 0.16 mmol), and potassium acetate (165 mg, 1.68 mmol) were added. The mixture was stirred at 90 °C for 16 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 7:1) to give compound 61-b (103 mg, 41% yield).

[0635] 1 H NMR (400 MHz, CD3Cl): δ 10.44 (s, 1H), 8.15 (s, 1H), 7.77 (d, J=7.6Hz, 1H), 7.62 (d, J=7.6Hz, 1H), 7.46 (d, J=16.0Hz, 1H), 7.23~7.30 (m, 3H), 4.07(s, 3H), 2.64 (s, 3H), 1.37 (s, 12H) ppm

[0636] Synthesis of compound 61-a To a solution of compound 61-b (100 mg, 0.22 mmol) and pentadeuterobromobenzene (54 mg, 0.33 mmol) in toluene (10 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (32 mg, 0.044 mmol), potassium phosphate (93 mg, 0.44 mmol), and cesium fluoride (66 mg, 0.44 mmol) were added and stirred at 90 °C for 16 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give compound 61-a (60 mg, 68% yield).

[0637] 1 H NMR (400 MHz, CD3Cl): δ 10.44 (s, 1H), 8.16 (s, 1H), 7.59 (d, J=7.6Hz, 1H), 7.48 (d, J=16.0Hz, 1H), 7.33~7.38 (m, 3H), 7.24~7.28 (m, 1H), 4.07(s, 3H), 2.33 (s, 3H) ppm

[0638] Synthesis of compound 61 To a solution of compound 61-a (60 mg, 0.15 mmol) in dichloromethane (10 mL), L-piperidine-2-carboxylic acid (40 mg, 0.3 mmol) and methanol (10 mL) were added. The mixture was stirred at room temperature for 1 hour, followed by the addition of sodium cyanoborohydride (28 mg, 0.45 mmol). After the addition was complete, the mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography to give compound 61 (21 mg, 27% yield).

[0639] LC-MS (ESI): m / z = 515 [M+H] + . 1H NMR (400 MHz, CD3OD): δ 7.90 (s, 1H), 7.63 (d, J=16.0Hz, 1H), 7.54 (d, J=8.0Hz, 1H), 7.53 (s, 1H), 7.26~7.33 (m, 2H), 7.18 (d, J=7.6Hz, 1H), 4.53 (d, J=12.8Hz, 1H), 4.40 (d, J=12.8Hz, 1H), 4.07 (s, 3H), 3.49~3.52 (m, 1H), 2.97~3.03 (m, 1H), 2.30(s, 3H), 2.23~2.27 (m, 1H), 1.67~1.85 (m, 5H), 1.54–1.59 (m, 1H) ppm.

[0640] Example 62 (R,E)-1-(2-methoxy-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-5-trifluoromethylbenzyl)piperidine-2-carboxylic acid (Compound 62)

[0641] [ka]

[0642] Synthesis of compound 62 To a solution of compound 6-a (198 mg, 0.5 mmol) and D-piperidine-2-carboxylic acid (161.2 mg, 1.25 mmol) in methanol (30 mL) was added sodium cyanoborohydride (63 mg, 1.0 mmol). The mixture was heated to 60°C and stirred for 2 h. After cooling to room temperature, it was concentrated under reduced pressure. The residue was washed with water (30 mL x 3), filtered, concentrated under reduced pressure, and purified by preparative high-performance liquid chromatography to give product 62 (110 mg, 43% yield) as a white solid.

[0643] LC-MS (ESI): m / z = 510.5 [M+H] + . 1H NMR: (400 MHz DMSO-d6): δ 7.78 (s, 1H), 7.65 (d, J = 16.0 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.50-7.46 (m, 3H), 7.42-7.32 (m, 4H), 7.25-7.19 (m, 2H), 3.97 (s, 3H), 3.82-3.67 (m, 2H), 2.94-2.90 (m, 1H), 2.30 (s, 3H), 2.29-2.27 (m, 1H), 1.85-1.78 (m, 2H), 1.52-1.41 (m, 4H) ppm.

[0644] Example 63 (S,E)-1-(2,5-dimethoxy-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)benzyl)piperidine-2-carboxylic acid (Compound 63)

[0645] [ka]

[0646] Synthesis of compound 63-a To a mixture of compound 3-b (160 mg, 0.5 mmol) and 4-bromo-2,5-dimethoxybenzaldehyde (122.5 mg, 0.5 mmol) in toluene (25 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (36.6 mg, 0.05 mmol), potassium phosphate (318 mg, 1.5 mmol), and cesium fluoride (231 mg, 1.5 mmol) were added and stirred at 110 °C for 12 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20 to 3:1) to give compound 63-a (140 mg, 78% yield). LC-MS (ESI): m / z = 359.2 [M+H] + .

[0647] Synthesis of compound 63 To a solution of compound 63-a (140.0 mg, 0.39 mmol) in methanol (20 mL) were added (S)-piperidine-2-carboxylic acid (126.1 mg, 0.97 mmol) and sodium cyanoborohydride (49.1 mg, 0.78 mmol), and the mixture was heated to 60° C. and stirred for 2 h. After cooling to room temperature, the mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography to give compound 63 (110 mg, yield: 59%).

[0648] LC-MS (ESI): m / z = 472.3 [M+H]+. 1 H NMR (400 MHz, CD3OD): δ 7.60 (d, J = 12.0 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.43-7.40 (m, 2H), 7.39-7.21 (m, 6H), 7.11 (d, J = 7.2 Hz, 1H), 4.47 (d, J = 12.4 Hz, 1H), 4.36 (d, J = 12.4 Hz, 1H), 3 .97 (s, 3H), 3.91 (s, 3H), 3.50-3.47 (m, 1H), 3.38-3.30 (m, 1H), 2.95-2.90 (m, 1H), 2.27 (s, 3H), 2.26-2.23 (m, 1H), 1.90-1.53 ​​(m, 5H)ppm

[0649] Example 64 (S,Z)-1-(4-(1-fluoro-2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)2-methoxy-5-trifluoromethylbenzyl)piperidine-2-carboxylic acid (Compound 64)

[0650] [ka]

[0651] Synthesis of compound 64-d The compound (2-methyl-[1,1'-biphenyl]-3-yl)methanol (1.98 g, 10.0 mmol) was dissolved in dichloromethane (100 mL), and manganese dioxide (2.64 g, 30.0 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 16 h, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10 to 5:1) to give colorless crystals 64-d (1.9 g, yield: 96.9%). LC-MS (ESI): m / z = 197.2 [M+H] + .

[0652] Synthesis of compound 64-c Compound 64-d (3.92 g, 20 mmol) was dissolved in N,N-dimethylformamide (39 mL), triphenylphosphine (6.1 g, 23.28 mmol) was added, and the mixture was heated to 100 °C. Then, a 2.0 M solution of sodium chlorodifluoroacetate (4.4 g, 29.1 mmol) in N,N-dimethylformamide was added dropwise, and the reaction was continued with stirring at 100 °C for 1 hour. The mixture was poured into water (200 mL) and extracted with ethyl acetate (100 mL × 2). The organic phase was washed successively with water (100 mL) and saturated brine (100 mL), and then dehydrated. After drying over sodium sulfate, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to give compound 64-c (2.67 g, yield: 58.1%).

[0653] Synthesis of compound 64-b Compound 64-c (2.3 g, 10 mmol) was dissolved in tetrahydrofuran (30 mL) and bis(pinacolato)diboron (4.04 g, 15.9 mmol), cuprous chloride (10.5 mg, 0.106 mmol), tricyclohexylphosphine (59.4 mg, 0.212 mmol), and potassium acetate (1.25 g, 12.72 mmol) were added. The reaction mixture was stirred at 40 °C for 16 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 9:1) to give compound 64-b (3.0 g, yield: 90%).

[0654] Synthesis of compound 64-a Compound 64-b (200 mg, 0.59 mmol), 4-bromo-2-methoxy-5-trifluoromethylbenzaldehyde (168 mg, 0.59 mmol), potassium carbonate (163 mg, 1.18 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (43 mg, 0.059 mmol) in a mixture of 1,4-dioxane (5 mL) and water (0.5 mL) was stirred at 80 °C under nitrogen gas protection for 16 h and then cooled to room temperature. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 64-a (154 mg, yield: 63.0%). LC-MS (ESI): m / z = 415 [M+H] + .

[0655] Synthesis of compound 64 A mixture of compound 64-a (29 mg, 0.07 mmol), (S)-piperidine-2-carboxylic acid (24 mg, 0.19 mmol), sodium cyanoborohydride (12 mg, 0.19 mmol), and methanol (3 mL) was stirred at 80 °C under nitrogen gas protection for 3 h and then cooled to room temperature. After concentration under reduced pressure, the residue was purified by preparative high-performance liquid chromatography to give compound 64 (15 mg, yield: 40.6%).

[0656] LC-MS (ESI): m / z = 528 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 7.87(s, 1H), 7.62 (d, J=7.6Hz, 1H), 7.46 (d, J=7.6 Hz, 2H), 7.39 (t, J=7.2Hz, 1H), 7.35-7.31 (m, 4H), 7.18 (d, J=7.6Hz,1H), 6.50 (d, J=36.8 Hz, 1H), 3.95 (s, 3H), 3.81-3.67 (m, 2H), 3.24-3.22 (m, 1H), 2.90-2.88 (m, 1H), 2.28-2.25 (m, 1H), 2.21 (s, 3H), 1.88- 1.73 (m, 2H), 1.50 - 1.41 (m, 4H) ppm

[0657] Example 65 (Z)-2-((4-(1-fluoro-2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-2-methoxy-5-trifluoromethylbenzyl)amino)-1-ethanol (Compound 65)

[0658] [ka]

[0659] Synthesis of compound 65 A mixture of compound 64-a (29 mg, 0.07 mmol), ethanolamine (11 mg, 0.19 mmol), sodium cyanoborohydride (12 mg, 0.19 mmol), and methanol (3 mL) was stirred at 80 °C under nitrogen gas protection for 3 h, then cooled to room temperature. After concentration under reduced pressure, the residue was purified by preparative high-performance liquid chromatography to give compound 64 (18 mg, yield: 50.1%).

[0660] LC-MS (ESI): m / z = 460 [M+H] + . 1H NMR (400 MHz, DMSO-d6): δ 7.83 (s, 1H), 7.62 (d, J=7.6 Hz,1H), 7.46 (d, J=7.6 Hz, 2H), 7.39 (t, J=7.2 Hz, 1H), 7.35-7.31 (m, 4H), 7.17 (d, J=7.6 Hz, 1H), 6.50 (d, J=36.8 Hz, 1H), 4.51 (t, J=5.2Hz, 1H), 3.96 (s, 3H), 3.77 (s, 3H), 3.49 (q, J=5.6 Hz, 2H), 2.60 (t, J=5.6Hz, 2H), 2.20 (s, 3H) ppm

[0661] Example 66 (Z)-2-((4-(1-bromo-2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-2-methoxy-5-trifluoromethylbenzyl)amino)-1-ethanol (Compound 66)

[0662] [ka]

[0663] Synthesis of compound 66-c Compound 6-b (1.42 g, 5.0 mmol) and compound bis(pinacolato)diboron (1.90 g, 7.5 mmol) were dissolved in toluene (60 mL). To the solution was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (366 mg, 0.5 mmol) and potassium acetate (1.47 g, 15.0 mmol). The reaction solution was heated to 100 °C, stirred for 6 h, and then cooled to room temperature. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 15 to 3:1) to give pale yellow solid 66-c (1.5 g, yield: 90%).

[0664] Synthesis of compound 66-b Compound 64-d (588 mg, 3.0 mmol) was dissolved in anhydrous dichloromethane (40 mL), and carbon tetrabromide (1.48 g, 4.5 mmol) was added. The mixture was then cooled to 0 °C. A solution of triphenylphosphine (1.56 g, 6.0 mmol) in dichloromethane (10 mL) was slowly added dropwise to the reaction mixture. The mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was filtered, and the filtrate was washed with saturated sodium bicarbonate solution (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100 to 20:1) to give colorless oil 66-b (1.05 g, yield: 99%).

[0665] 1 H NMR (400 MHz, CDCl3): δ 7.52 (s, 1H), 7.43-7.34 (m, 4H), 7.30-7.27 (m, 2H), 7.23-7.21 (m, 2H), 2.14 (s, 3H) ppm

[0666] Synthesis of compound 66-a Compound 66-b (220 mg, 0.625 mmol) and compound 66-c (247.5 mg, 0.75 mmol) were dissolved in a mixture of dioxane (30 mL) and water (10 mL), and the solution was added with bis(dibenzylideneacetone)palladium (28.6 mg, 0.03 mmol), tris(2-furyl)phosphine (43.5 mg, 0.187 mmol), and Cesium fluoride (406.2 mg, 1.25 mmol) was added, and the reaction solution was stirred at 65° C. for 16 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give white solid 66-a (80 mg, yield: 27%).

[0667] Synthesis of compound 66 Compound 66-a (80 mg, 0.169 mmol) was dissolved in a mixture of dichloromethane (15 mL) and methanol (5 mL), and ethanolamine (51.5 mg, 0.845 mmol) and one drop of glacial acetic acid were added. The reaction solution was stirred at room temperature for 2 h, followed by the addition of sodium cyanoborohydride (21.4 mg, 0.34 mmol), and stirring was continued for 16 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography to give white solid 66 (30.9 mg, 35% yield).

[0668] LC-MS (ESI): m / z = 520.1 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ 7.71 (s, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.48-7.43 (m, 2H), 7.39-7.37 (m, 1H), 7.34-7.30 (m, 3H), 7.22 (d, J = 6.8 Hz, 1H), 7.17 (s, 1H), 7.08 (s, 1H), 4.04 (s, 3H), 3.90 (s, 2H), 3.71 (t, J = 6.0 Hz, 2H), 2.76 (t, J = 6.0 Hz, 2H), 2.20 (s, 3H)ppm

[0669] Example 67 (S,Z)-1-(4-(1-bromo-2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-2-methoxy-5-trifluoromethylbenzyl)piperidine-2-carboxylic acid (Compound 67)

[0670] [ka]

[0671] Synthesis of compound 67 A mixture of compound 66-a (110 mg, 0.23 mmol), (S)-piperidine-2-carboxylic acid (89 mg, 0.69 mmol), sodium cyanoborohydride (28.9 mg, 0.46 mmol), and methanol (20 mL) was stirred at 60 °C for 2 h and then cooled to room temperature. After concentration under reduced pressure, the residue was purified by preparative high-performance liquid chromatography to give compound 67 (46 mg, yield: 34%).

[0672] LC-MS (ESI): m / z = 588.2 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ 8.00 (s, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.48-7.43 (m, 2H), 7.38 (d, J = 7.2 Hz, 1H), 7.34-7.30 (m, 4H), 7.23 (d, J = 7.2 Hz, 1H), 7. 12 (s, 1H), 4.59 (d, J = 13.2 Hz, 1H), 4.45 (d, J = 12.4 Hz, 1H), 4.05 (s, 3H), 3.57-3.53 (m, 1H), 3.43-3.39 (m, 1H), 3.07-3.01 (m, 1H), 2.33-2.26 (m, 1H), 2.20 (s, 3H), 1.93-1.58 (m, 5H) ppm

[0673] Example 68 (S,Z)-1-(4-(2-bromo-2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-2-methoxy-5-methylbenzyl)piperidine-2-carboxylic acid (Compound 68)

[0674] [ka]

[0675] Synthesis of compound 68-f A mixture of 3-bromo-2-methyl-1,1'-biphenyl (989 mg, 4.0 mmol), bis(pinacolato)diboron (1.52 g, 6.0 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (293 mg, 0.4 mmol), potassium acetate (1.18 g, 1.2 mmol), and 1,4-dioxane (10 mL) was stirred at 90 °C under nitrogen gas protection for 16 h. After cooling to room temperature and concentration under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to give colorless liquid 68-f (1.0 g, yield: 85%).

[0676] 1 H NMR (400 MHz, CD3OD): δ 7.76 (dd, J = 7.2, 1.3 Hz, 1H), 7.43 - 7.36 (m, 2H), 7.36 - 7.26 (m, 4H), 7.24 - 7.19 (m, 1H) ), 2.41 (s, 3H), 1.36 (s, 12H) ppm

[0677] Synthesis of compound 68-e A mixture of 4-bromo-2-hydroxy-5-methylbenzaldehyde (6.45 g, 30.0 mmol), iodomethane (5.11 g, 36.0 mmol), potassium carbonate (8.29 g, 60.0 mmol), and N,N'-dimethylformamide (30 mL) was stirred at room temperature for 16 hours. The reaction solution was diluted with water (150 mL). The precipitated solid was filtered, dried, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give white solid 68-e (5.59 g, 81% yield).

[0678] Synthesis of compound 68-d A mixture of compound 68-e (5.10 g, 22.3 mmol), triethyl orthoformate (6.60 g, 44.5 mmol), ammonium chloride (119 mg, 2.2 mmol), and ethanol (3.08 g, 66.8 mmol) was refluxed for 1 h. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and dried in vacuo. The resulting product 68-d (6.75 g) was used directly in the next step.

[0679] Synthesis of compound 68-c Compound 68-d (1.52 g, 5.0 mmol) was dissolved in dry tetrahydrofuran (15 mL). n-Butyllithium (2.2 mL, 2.5 M n-hexane solution) was slowly added dropwise at −78°C. After the addition was completed, the mixture was stirred at −78°C for 0.5 h, and then N,N'-dimethylformamide (431 mg, 10 mmol) was added dropwise. After the addition was completed, the mixture was stirred at −78°C for 2 h. After warming to room temperature, the reaction solution was quenched with saturated sodium bicarbonate solution (10 mL). The resulting mixture was extracted with ethyl acetate (50 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give pale yellow liquid 68-c (1.07 g, yield: 85%).

[0680] 1 H NMR (400 MHz, DMSO-d6): δ 10.24 (s, 1H), 7.41 (s, 1H), 7.36 (s, 1H), 5.67 (s, 1H), 3.85 (s, 3H), 3.61 - 3.47 (m, 4H), 2.56 (s, 3H), 1.12 (t, J = 7.0 Hz, 6H) ppm

[0681] Synthesis of compound 68-b A solution of carbon tetrabromide (1.72 g) in dichloromethane (5 mL) was added dropwise to a mixture of triphenylphosphine (2.73 g, 10.4 mmol) and dichloromethane (10 mL) at 0 °C. After the addition was complete, stirring was continued at 0 °C for 10 min. Next, a solution of compound 68-c (1.01 g, 4.0 mmol) and triethylamine (1.21 g) in dichloromethane (5 mL) was added dropwise. After the addition was complete, the reaction solution was warmed to room temperature and stirred for 4 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to give white solid 68-b (700 mg, yield: 52%).

[0682] 1 H NMR (400 MHz, DMSO-d6): δ 10.31 (s, 1H), 7.83 (s, 1H), 7.55 (s, 1H), 7.21 (s, 1H), 3.91 (s, 3H), 2.20 (s, 3H) ppm

[0683] Synthesis of compound 68-a Compound 68-b (586 mg, 1.75 mmol), compound 68-f (397 mg, 1.35 mmol), bis(dibenzylideneacetone)palladium (62 mg, 0.068 mmol), A mixture of 68-a (68 mmol), tris(2-furyl)phosphine (94 mg, 0.40 mmol), sodium carbonate solution (2.7 mL, 1 M), and dioxane (7 mL) was reacted at 60 °C for 5 hours under nitrogen gas. After cooling to room temperature, the reaction solution was diluted with water (10 mL), and the resulting mixture was extracted with dichloromethane (30 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography to give compound 68-a (88 mg, 10% yield). LC-MS (ESI): m / z = 421.2 [M+H] + .

[0684] Synthesis of compound 68 To a mixture of compound 68-a (42 mg, 0.10 mmol), (S)-piperidine-2-carboxylic acid (26 mg, 0.20 mmol), methanol (1 mL), and tetrahydrofuran (1 mL) was added sodium cyanoborohydride (25 mg, 0.40 mmol). The reaction mixture was stirred at 60°C for 1 h, cooled to room temperature, concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography to give white solid 68 (21 mg, 39% yield).

[0685] LC-MS (ESI): m / z = 534.2 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ 7.47 - 7.25 (m, 9H), 7.22 (dd, J = 7.5, 1.4 Hz, 1H), 7.03 (s, 1H), 4.47 (d, J = 12.7 Hz, 1H), 4.34 (d, J = 12.8 Hz, 1H), 3.94 (s, 3H), 3.50 (d, J = 11.3 Hz, 1H), 3.32 (s, 1H), 2.97 (t, J = 11.9 Hz, 1H), 2.32 (s, 3H), 2.31 (s, 3H), 2.23 (d, J = 10.5 Hz, 1H), 1.98 - 1.63 (m, 4H), 1.61 - 1.46 (m, 1H) ppm

[0686] Example 69 (Z)-2-((4-(2-bromo-2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-2-methoxy-5-methylbenzyl)amino)-1-ethanol (Compound 69)

[0687] [ka]

[0688] Synthesis of compound 69 To a mixture of compound 68-a (29 mg, 0.07 mmol), ethanolamine (9 mg, 0.15 mmol), methanol (1 mL), and tetrahydrofuran (1 mL) was added sodium cyanoborohydride (18 mg, 0.28 mmol). The reaction mixture was stirred at 60 °C for 1 h, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give white solid 69 (17 mg, 52% yield).

[0689] LC-MS (ESI): m / z = 466.2, 468.2 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ 8.53 (s, 1H), 7.47 - 7.20 (m, 10H), 7.03 (s, 1H), 4.20 (s, 2H), 3.96 (s, 3H), 3.84 - 3.77 (m, 2H), 3.13 - 3.06 (m, 2H), 2.32 (s, 3H), 2.31 (s, 3H) ppm

[0690] Example 70 (S,E)-1-(2-methoxy-5-methyl-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)benzyl)piperidine-2-carboxylic acid (Compound 70)

[0691] [ka]

[0692] Synthesis of compound 70-a A mixture of 4-bromo-2-methoxy-5-methylbenzaldehyde (115 mg, 0.5 mmol), compound 3-b (192 mg, 0.6 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (37 mg, 0.05 mmol), potassium carbonate (138 mg, 1.0 mmol), 1,4-dioxane (2 mL), and water (0.4 mL) was stirred at 90 °C for 16 h under nitrogen gas protection. The reaction solution was cooled to room temperature and diluted with saturated brine (10 mL). The resulting mixture was extracted with dichloromethane (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give yellow solid 70-a (135 mg, yield: 79%).

[0693] Synthesis of compound 70 To a mixture of compound 70-a (51 mg, 0.15 mmol), (S)-piperidine-2-carboxylic acid (38 mg, 0.30 mmol), methanol (1 mL), and tetrahydrofuran (1 mL) was added sodium cyanoborohydride (37 mg, 0.60 mmol). The reaction mixture was stirred at 60° C. for 1 hour, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give white solid 70 (26 mg, 38% yield).

[0694] LC-MS (ESI): m / z = 456.3 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ 7.60 (d, J = 7.5 Hz, 1H), 7.48 - 7.19 (m, 10H), 7.14 (d, J = 7.4 Hz, 1H), 4.46 (d, J = 12.7 Hz, 1H), 4.33 (d, J = 12.7 Hz, 1H), 3.96 (s, 3H), 3.48 (d, J = 7.1 Hz, 1H), 3.38 - 3.32 (m, 1H), 2.96 (t, J = 11.7 Hz, 1H), 2.40 (s, 3H), 2.29 (s, 3H), 2.23 (d, J = 13.4 Hz, 1H), 1.97 - 1.43 (m, 5H) ppm

[0695] Example 71 (S,E)-1-(4-(2-(2-chloro-[1,1'-biphenyl]-3-yl)vinyl)-2-methoxy-5-trifluoromethylbenzyl)piperidine-2-carboxylic acid (Compound 71)

[0696] [ka]

[0697] Synthesis of compound 71-c A mixture of 3-bromo-2-chlorobenzaldehyde (878 mg, 4.0 mmol), phenylboronic acid (536 mg, 4.4 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (146 mg, 0.2 mmol), potassium carbonate (1.11 g, 8.0 mmol), 1,4-dioxane (12 mL), and water (4.0 mL) was stirred at 90 °C for 16 h under nitrogen gas protection. The reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with dichloromethane (40 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 30:1) to give colorless liquid 71-c (764 mg, yield: 88%).

[0698] Synthesis of compound 71-b A mixture of methyltriphenylphosphonium bromide (2.51 g, 7.02 mmol) and tetrahydrofuran (20 mL) was added to potassium tert-butoxide (787 mg, 4.02 mmol) at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction solution was cooled to -78°C. After that, compound 71-c (760 mg, 3.51 mmol) was added, and the reaction solution was then warmed to room temperature and stirred for 16 hours. The reaction solution was quenched with saturated ammonium chloride solution (30 mL). The resulting mixture was extracted with ethyl acetate (40 mL × 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether) to give colorless liquid compound 71-b (360 mg, yield: 48%).

[0699] Synthesis of compound 71-a A mixture of compound 71-b (107 mg, 0.50 mmol), 4-bromo-2-methoxy-5-(trifluoromethyl)benzaldehyde (212 mg, 0.75 mmol), bis(tri-tert-butylphosphine)palladium (26 mg, 0.05 mmol), triethylamine (506 mg, 5.0 mmol), and toluene (2 mL) was reacted under nitrogen gas protection at 80 °C for 16 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give yellow solid 71-a (60 mg, yield: 29%). LC-MS (ESI): m / z = 417.2 [M+H] + .

[0700] Synthesis of compound 71 To a mixture of compound 71-a (60 mg, 0.144 mmol), (S)-piperidine-2-carboxylic acid (37 mg, 0.288 mmol), methanol (1 mL), and tetrahydrofuran (1 mL) was added sodium cyanoborohydride (36 mg, 0.576 mmol). The reaction solution was stirred at 60° C. for 1 hour, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give white solid 71 (19 mg, yield: 25%).

[0701] LC-MS (ESI): m / z = 530.2 [M+H] + . 1H NMR (400 MHz, CD3OD): δ 7.93 (s, 1H), 7.75 - 7.66 (m, 2H), 7.52 - 7.35 (m, 8H), 7.33 (dd, J = 7.5, 1.3 Hz, 1H), 4.45 (d, J = 13.0 Hz, 1H), 4.30 (d, J = 13.1 Hz, 1H), 4.05 (s, 3H), 3.43 (dd, J = 10.5, 3.3 Hz, 1H), 3.30 - 3.24 (m, 1H), 2.88 (t, J = 10.6 Hz, 1H), 2.21 (d, J = 11.9 Hz, 1H), 1.94 - 1.44 (m, 5H)ppm

[0702] Example 72 (S,E)-1-(2-methoxy-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl-1,2-d2)-5-trifluoromethylbenzyl)piperidine-2-carboxylic acid (Compound 72)

[0703] [ka]

[0704] Synthesis of compound 72-d Compound 3-c (1.0 g, 4.05 mmol) and trimethylsilylacetylene (596.2 mg, 6.07 mmol) were dissolved in N,N-dimethylformamide (15 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (142.5 mg, 0.203 mmol) and triethylamine (3.279 g, 32.4 mmol) were added. The reaction solution was heated to 70 °C under nitrogen gas protection and stirred for 16 h. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate (15 mL), and washed once with water (50 mL) and once with saturated brine (50 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether) to give compound 72-d (551 mg, yield: 51.5%).

[0705] 1 H NMR (400 MHz, CDCl3): δ 7.56-7.54 (d, J = 7.6Hz, 1H), 7.44-7.34 (m, 3H), 7.28-7.26 (m, 2H), 7.17-7.15 (d, J = 7.6Hz, 1H), 7.10-7.06 (t, J = 7.6Hz, 1H), 2.31 (s, 3H) ppm

[0706] Synthesis of compound 72-c Compound 72-d (551 mg, 2.084 mmol) was dissolved in methanol (15 mL) and potassium carbonate (863.9 mg, 6.251 mmol) was added. The reaction solution was stirred at room temperature for 0.5 h. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 mL) and washed sequentially with water (50 mL) and saturated brine (50 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether) to give target compound 72-c (361 mg, yield: 90.3%).

[0707] 1H NMR (400 MHz, CDCl3): δ 7.50-7.48 (m, 1H), 7.43-7.35 (m, 3H), 7.30-7.28 (m, 2H), 7.23-7.19 (m, 2H), 3.29 (s, 1H), 2.37 (s, 3H) ppm

[0708] Synthesis of compound 72-b Compound 72-c (100 mg, 0.52 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and the reaction solution was cooled to −50°C in an ice-salt bath. A 1.56 M solution of n-butyllithium in n-hexane (0.4 mL, 0.624 mmol) was added dropwise. After the addition was complete, the reaction solution was stirred at −50°C for 0.5 h.

[0709] Solid dry ice was added to the above reaction solution and stirred for 0.5 hours. The reaction solution was then warmed to room temperature and stirred for 1 hour. Water (10 mL) was added to quench the reaction, and the solution was then adjusted to pH 1-2 with dilute hydrochloric acid (1N). The mixture was extracted with ethyl acetate (50 mL x 2), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was slurried with petroleum ether to give compound 72-b (83 mg, yield: 67.5%).

[0710] 1 H NMR (400 MHz, DMSO-d6): δ 7.62-7.58 (m, 1H), 7.49-7.45 (m, 2H), 7.42-7.39 (m, 1H), 7.37-7.33 (m, 4H), 2.33 (s, 3H) ppm

[0711] Synthesis of compound 72-a Compound 72-b (83 mg, 0.351 mmol) and bis(pinacolato)diboron (107.2 mg, 0.422 mmol) were dissolved in 1,4-dioxane (10 mL), and cuprous oxide (5 mg, 0.035 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (20.3 mg, 0.035 mmol), and deuterium oxide (42 mg, 2.106 mmol) were added. The mixture was stirred overnight at room temperature under nitrogen gas protection.

[0712] Compound 6-b (99 mg, 0.351 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (30.3 mg, 0.035 mmol), sodium carbonate (93 mg, 0.878 mmol), and heavy water (0.5 mL, 0.106 mmol) were added to the above reaction solution. The reaction solution was heated to 80 °C and stirred overnight under nitrogen gas protection. The reaction solution was cooled to room temperature, diluted with ethyl acetate (20 mL), and washed with water (20 mL × 2) and saturated brine (20 mL × 2), successively. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether) to give compound 72-a (41 mg, yield: 29.5%).

[0713] 1 H NMR (400 MHz, CDCl3): δ 10.442 (s, 1H), 8.16 (s, 1H), 7.60-7.58 (m, 1H), 7.45-7.35 (m, 4H), 7.32-7.28 (m, 4H), 4.07 (s, 3H), 2.33 (s, 3H)ppm

[0714] Synthesis of compound 72 Compound 72-a (56 mg, 0.106 mmol) was dissolved in a mixture of methanol (5.5 mL) and dichloromethane (5.5 mL), and glacial acetic acid (9 mg, 0.212 mmol) was added. The reaction solution was stirred at room temperature for 1 hour, and then sodium cyanoborohydride (56 mg, 0.106 mmol) was added and stirring was continued for 16 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (20 mL) and washed successively with water (20 mL) and saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give compound 72 (11.6 mg, yield: 25.4%).

[0715] LC-MS (ESI): m / z = 444 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ 7.62 (s, 1H), 7.54-7.52 (d, J = 7.6Hz, 1H), 7.43-7.40 (m, 3H), 7.36-7.25 (m, 4H), 7.17-7.15 (m, 1H), 4.01 (s, 3H), 3.85 (s, 2H), 3.69-3.67 (m, 2H), 2.74-2.72 (m, 2H), 2.30 (s, 3H) ppm

[0716] Example 73 (S,E)-1-(4-(2-(2-fluoromethyl-[1,1'-biphenyl]-3-yl)vinyl)-2-methoxy-5-trifluoromethylbenzyl)piperidine-2-carboxylic acid (Compound 73)

[0717] [ka]

[0718] Synthesis of compound 73-c To a solution of 2,6-dibromo-benzyl alcohol (2.40 g, 9.06 mmol) in dry dichloromethane (60 mL) was slowly added dropwise (diethylamino)sulfur trifluoride (1.90 g, 11.8 mmol) at -78°C. After the addition was completed, stirring was continued at -78°C for 30 minutes. The cooling bath was removed, and the mixture was allowed to warm to room temperature naturally, and stirring was continued at room temperature for 1 hour. The reaction mixture was quenched by slowly adding saturated aqueous sodium bicarbonate solution (50 mL). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (30 mL x 2). The organic phases were combined, washed successively with water (30 mL) and saturated brine (30 mL), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether). Purification gave compound 73-c (1.86 g, yield: 78%).

[0719] Synthesis of compound 73-b To a mixture of compound 6-b (1.40 g, 5.0 mmol), vinylboronic acid pinacol ester (1.15 g, 7.5 mmol), triethylamine (1.51 g, 15.0 mmol), and toluene (20 mL) was added bis(tri-tert-butylphosphine)palladium (255 mg, 0.50 mmol). The reaction mixture was stirred at 80 °C for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 6:1) to give compound 73-b (1.08 g, yield: 61%). LC-MS (ESI): m / z = 357 [M+H] + .

[0720] Synthesis of compound 73-a To a mixture of compound 73-b (391 mg, 1.1 mmol) and compound 73-c (268 mg, 1.0 mmol) in toluene (15 mL) was added phenylboronic acid (134 mg, 1.1 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (146 mg, 0.2 mmol), potassium phosphate (848 mg, 4.0 mmol), and cesium fluoride (600 mg, 4.0 mmol). The reaction mixture was stirred at 100 °C for 16 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1) to give compound 73-a (150 mg, 36% yield). LC-MS (ESI): m / z = 415 [M+H] + .

[0721] Synthesis of compound 73 To a solution of compound 73-a (41 mg, 0.10 mmol) in dichloromethane (10 mL) was added (S)-piperidine-2-carboxylic acid (39 mg, 0.3 mmol) and methanol (10 mL). The mixture was stirred at room temperature for 1 hour, followed by the addition of sodium cyanoborohydride (16 mg, 0.25 mmol). After the addition was complete, the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography to give compound 73 (22 mg, 42% yield).

[0722] LC-MS (ESI): m / z = 528 [M+H] + . 1H NMR (400 MHz, CD3OD): δ 7.92 (s, 1H), 7.70~7.73 (m, 2H), 7.50~7.55 (m, 2H), 7.41~7.48 (m, 4H), 7.38~7.40 (m, 2H), 7.33~7.35 (m, 1H), 5.50 (s, 1H), 5.38 (s, 1H), 4.53 (d, J=12.8Hz, 1H), 4.39 (d, J=12.8Hz, 1H), 3.49~3.51 (m, 1H), 2.95~3.01 (m, 1H), 2.30 (s, 3H), 2.22~2.26 (m, 1H), 1.70~1.89 (m, 5H), 1.54~1.58 (m, 1H) ppm

[0723] Example 74 (E)-2-((4-(2-(2-fluoromethyl-[1,1'-biphenyl]-3-yl)vinyl)-2-methoxy-5-trifluoromethylbenzyl)amino)-1-ethanol (Compound 74)

[0724] [ka]

[0725] Synthesis of compound 74 To a solution of 73-a (41 mg, 0.10 mmol) in dichloromethane (10 mL) was added ethanolamine (31 mg, 0.5 mmol) and methanol (10 mL). The mixture was stirred at room temperature for 1 hour, followed by the addition of sodium cyanoborohydride (20 mg, 0.31 mmol). After the addition was complete, the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography to give compound 74 (23 mg, 50% yield).

[0726] LC-MS (ESI): m / z = 460 [M+H] + . 1H NMR (400 MHz, CD3OD): δ 7.69 (d, J=7.6Hz, 1H), 7.64 (s, 1H), 7.62~7.66 (m, 1H), 7.51~7.53 (m, 1H), 7.42~7.46 (m, 4H), 7.38~7.41 (m, 3H), 7.31 (d, J=8.0Hz, 1H), 5.48 (s, 1H), 5.36 (s, 1H), 4.01 (s, 3H), 3.84 (s, 2H), 3.68 (t, J=4.2Hz, 2H), 2.72 (t, J=4.2Hz, 2H) ppm.

[0727] Example 75 (S,E)-1-(2-((3-iodobenzyloxy)-5-methyl-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)benzyl)piperidine-2-carboxylic acid (Compound 75)

[0728] [ka]

[0729] Synthesis of compound 75-b Compound 24-c (280 mg, 1.30 mmol) and 3-b (500 mg, 1.56 mmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (48 mg, 0.065 mmol) and potassium carbonate (359 mg, 2.6 mmol) were added. The reaction solution was purged with nitrogen gas three times to remove oxygen from the reaction system, and then heated and stirred at 90 °C for 16 h. The reaction solution was cooled to room temperature, and water (20 mL) was added. The mixture was extracted with dichloromethane (40 mL × 2). The resulting organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was slurried with ethyl acetate, washed, and filtered to give brown solid 75-b (189 mg, yield: 44%). LC-MS (ESI): m / z = 329.27 (M+H) + .

[0730] Synthesis of compound 75-a Compound 75-b (33 mg, 0.10 mmol), 3-iodobenzyl bromide (36 mg, 0.12 mmol), and cesium carbonate (65 mg, 0.20 mmol) were dissolved in 1,4-dioxane (0.5 mL). The reaction solution was heated and stirred at 50 °C for 16 h. The reaction solution was cooled to room temperature and directly separated by reverse-phase chromatography (mobile phase: 0.1% aqueous formic acid: acetonitrile = 0% to 100%) to give pale yellow solid 75-a (33 mg, yield: 61%). LC-MS (ESI): m / z = 545.09 (M+H) + .

[0731] Synthesis of compound 75 Compound 75-a (33 mg, 0.061 mmol) and (S)-piperidine-2-carboxylic acid (16 mg, 0.12 mmol) were dissolved in methanol (1 mL) and tetrahydrofuran (1 mL), and sodium cyanoborohydride (15 mg, 0.24 mmol) was added. The reaction solution was heated and stirred at 60°C for 1 hour. The reaction solution was cooled to room temperature and purified by preparative high-performance liquid chromatography (mobile phase: 1% aqueous formic acid: acetonitrile = 20% to 70%) to give white solid 75 (12 mg, yield: 30%). LC-MS (ESI): m / z = 658.36 (M+H) + .

[0732] 1H-NMR (400 MHz, MeOD) δ:7.90 (s, 1H), 7.69 (d, J = 7.9Hz, 1H), 7.59 (d, J = 7.7Hz, 1H), 7.54 (d, J = 7.5Hz, 1H), 7.46-7.39 (m, 2H), 7.36-7.26 (m, 6H), 7.25-7.12 (m, 4H), 5.25 (s, 2H), 4.47 (d, J = 12.6Hz, 1H), 4.36 (d, J = 12.8Hz, 1H), 3.71-3.53 (m, 1H), 3.45-3.34 (m, 1H), 3.05-2.90 (m, 1H), 2.39 (s, 3H), 2.29-2.19 (m, 4H), 1.98-1.63 (m, 4H), 1.6 -1.47 (m, 1H) ppm

[0733] Example 76 (S,E)-1-(2-((2-iodobenzyloxy)-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-5-(trifluoromethyl)benzyl)piperidine-2-carboxylic acid (Compound 76)

[0734] [ka]

[0735] Synthesis of compound 76-a Compound 4-a (38 mg, 0.10 mmol) and 2-iodobenzyl bromide (36 mg, 0.12 mmol) were dissolved in N,N-dimethylformamide (0.5 mL), and cesium carbonate (65 mg, 0.20 mmol) was added. The reaction solution was heated and stirred at 50 °C for 1 h. The reaction solution was cooled to room temperature and directly separated by reverse-phase chromatography (mobile phase: 0.1% aqueous formic acid: acetonitrile = 0% to 100%) to give pale yellow solid 76-a (40 mg, yield: 67%).

[0736] Synthesis of compound 76 Compound 76-a (40 mg, 0.067 mmol) and (S)-piperidine-2-carboxylic acid (17 mg, 0.13 mmol) were dissolved in methanol (1 mL) and tetrahydrofuran (1 mL), and sodium cyanoborohydride (17 mg, 0.27 mmol) was added. The reaction solution was heated and stirred at 60 °C for 1 h. The reaction solution was cooled to room temperature and directly purified by preparative high-performance liquid chromatography (mobile phase: 0.1% aqueous formic acid: acetonitrile = 20% to 70%) to give white solid 76 (13 mg, yield: 27%). LC-MS (ESI): m / z = 712.4 (M+H). + .

[0737] 1 H-NMR (400 MHz, MeOD) δ:8.00-7.91 (m, 2H), 7.61-7.49 (m, 4H), 7.48-7.39 (m, 3H), 7.39-7.23 (m, 5H), 7.18 (d, J = 6.8Hz, 1H), 7.12 (td, J = 7.7, 1.6Hz, 1H), 5.50-5.37 (m, 2H), 4.56 (d, J = 12.9Hz, 1H), 4.41 (d, J = 13.0Hz, 1H), 3.61 (d, J = 8.7Hz, 1H), 3.47-3.36 (m, 1H), 2.98 (t, J = 10.6Hz, 1H), 2.28 (s, 3H), 2.26-2.16 (m, 1H), 1.90-1.48 (m, 5H) ppm

[0738] Example 77 (S,E)-1-(2-((3-iodobenzyloxy)-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-5-(trifluoromethyl)benzyl)piperidine-2-carboxylic acid (Compound 77)

[0739] [ka]

[0740] Synthesis of compound 77-a Compound 4-a (38 mg, 0.10 mmol) and 3-iodobenzyl bromide (36 mg, 0.12 mmol) were dissolved in N,N-dimethylformamide (0.5 mL), and cesium carbonate (65 mg, 0.20 mmol) was added. The reaction solution was heated and stirred at 50°C for 1 hour. The reaction solution was cooled to room temperature and directly separated by reverse-phase chromatography (mobile phase: 0.1% aqueous formic acid: acetonitrile = 0-100%) to give pale yellow solid 77-a (50 mg, yield: 84%).

[0741] Synthesis of compound 77 Compound 77-a (40 mg, 0.067 mmol) and (S)-piperidine-2-carboxylic acid (17 mg, 0.13 mmol) were dissolved in methanol (1 mL) and tetrahydrofuran (1 mL), and sodium cyanoborohydride (17 mg, 0.27 mmol) was added. The reaction solution was heated and stirred at 60 °C for 1 h. The reaction solution was cooled to room temperature and directly purified by preparative high-performance liquid chromatography (mobile phase: 0.1% aqueous formic acid: acetonitrile = 20% to 70%) to give white solid 377 (18 mg, yield: 38%). LC-MS (ESI): m / z = 712.4 (M+H). + .

[0742] 1 H-NMR (400 MHz, MeOD) δ:7.94 (s, 2H), 7.73 (d, J = 7.9Hz, 1H), 7.60-7.33 (m, 7H), 7.33-7.24 (m, 4H), 7.23-7.15 (m, 2H), 5.38 (s, 2H), 4.55 (d, J = 13.0Hz, 1H), 4.42 (d, J = 13.0Hz, 1H), 3.64 (d, J = 8.0Hz, 1H), 3.45-3.34 (m, 1H), 3.01 (t, J = 10.4Hz, 1H), 2.29 (s, 3H), 2.28-2.22 (m, 1H), 1.95-1.49 (m, 5H) ppm

[0743] Example 78 (S,E)-1-(2-((4-iodobenzyloxy)-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-5-(trifluoromethyl)benzyl)piperidine-2-carboxylic acid (Compound 78)

[0744] [ka]

[0745] Synthesis of compound 78-a Compound 4-a (38 mg, 0.10 mmol) and 4-iodobenzyl bromide (36 mg, 0.12 mmol) were dissolved in N,N-dimethylformamide (0.5 mL), and cesium carbonate (65 mg, 0.20 mmol) was added. The reaction solution was heated and stirred at 50 °C for 1 h. The reaction solution was cooled to room temperature and directly separated by reverse-phase chromatography (mobile phase: 0.1% aqueous formic acid: acetonitrile = 0-100%) to give pale yellow solid 78-a (50 mg, yield: 84%).

[0746] Synthesis of compound 78 To a mixture of compound 78-a (40 mg, 0.067 mmol), (S)-piperidine-2-carboxylic acid (17 mg, 0.13 mmol), methanol (1 mL), and tetrahydrofuran (1 mL) was added sodium cyanoborohydride (17 mg, 0.27 mmol). The reaction solution was stirred at 60 °C for 1 h. The reaction solution was cooled to room temperature, and the resulting mixture was purified by preparative high-performance liquid chromatography (mobile phase: 0.1% aqueous formic acid: acetonitrile = 20% to 70%) to give white solid 78 (20 mg, yield: 42%). LC-MS (ESI): m / z = 712.4 (M+H). + .

[0747] 1H-NMR (400 MHz, MeOD) δ:7.93 (s, 1H), 7.82-7.75 (m, 2H), 7.55 (s, 1H), 7.53 (d, J = 7.7Hz, 1H), 7.49-7.39 (m, 3H), 7.39-7.23 (m, 7H), 7.18 (d, J = 7.5Hz, 1H), 5.38 (s, 2H), 4.55 (d, J = 13.0Hz, 1H), 4.42 (d, J = 13.0Hz, 1H), 3.66 (d, J = 8.3Hz, 1H), 3.45-3.34 (m, 1H), 3.07-2.92 (m, 1H), 2.26 (s, 3H), 2.26-2.20 (m, 1H), 1.98-1.47 (m, 5H) ppm

[0748] Example 79 (S,E)-1-(2-((4-iodo-pyridin-2-yl)methoxy)-5-methyl-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)benzyl)piperidine-2-carboxylic acid (Compound 79)

[0749] [ka]

[0750] Synthesis of compound 79-c 4-Iodopyridine acid (500 mg, 2 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) and a solution of borane in tetrahydrofuran (4 mL, 4 mmol) was added. The reaction solution was stirred at room temperature for 16 hours. The reaction solution was cooled to 0°C, and methanol (10 mL) was added dropwise to the reaction solution. The reaction solution was then heated to 70°C and stirred for 1 hour. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to give 79-c (300 mg, yield 63.6%). LC-MS (ESI): m / z = 236 (M+H) + .

[0751] Synthesis of compound 79-b Compound 79-c (300 mg, 1.2 mmol) was dissolved in dichloromethane (10 mL). To the resulting solution, thionyl chloride (400 mg, 3.6 mmol) was slowly added. The reaction solution was stirred at room temperature for 2 hours. After concentration under reduced pressure, 79-b (355 mg, yield: 96.2%) was obtained, which was used directly in the next step without further purification. LC-MS (ESI): m / z = 254 (M+H) + .

[0752] Synthesis of compound 79-a Compound 79-b (57 mg, 0.2 mmol) and compound 75-b (50 mg, 0.13 mmol) were dissolved in N,N-dimethylformamide (5 mL), potassium carbonate (54 mg, 0.39 mmol) and potassium iodide (214 mg, 1.3 mmol) were added, and the reaction solution was heated and stirred at 50 °C for 30 min. The reaction solution was cooled to room temperature and directly purified by preparative high-performance liquid chromatography to give 79-a (30 mg, 38.4% yield). LC-MS (ESI): m / z = 546 (M+H). + .

[0753] Synthesis of compound 79 Compound 79-a (20 mg, 0.037 mmol) and s-piperidine-2-carboxylic acid (7 mg, 0.054 mmol) were dissolved in methanol (3 mL), sodium cyanoborohydride (5 mg, 0.075 mmol) was added, and the reaction solution was purged with nitrogen gas three times to remove oxygen from the reaction system, then heated at 60 °C for 30 min. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography to give 79 (6 mg, 29.7% yield). LC-MS (ESI): m / z = 659 (M+H). + .

[0754] 1H-NMR (400 MHz, MeOD) δ: 8.33(d, J=5.2Hz,1H), 7.99( s,1H), 7.59-7.27(m, 2H), 7.43-7.31(m, 5H),7.28-7.21 (m, 5H), 7.12(d, 2.39 (s, 3H), 2.24(s, 3H), 2.20-2.16(m, 1H), 1.92-1.68(m, 4H), 1.52-1.50(m, 1H), 1.32- 1.28(m, 1H) ppm

[0755] Example 80 (S,E)-1-(2-((4-iodopyridin-2-yl)methoxy)-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-5-(trifluoromethyl)benzyl)piperidine-2-carboxylic acid (Compound 80)

[0756] [ka]

[0757] Synthesis of compound 80-a Compound 79-b (57 mg, 0.2 mmol) and compound 4-a (50 mg, 0.13 mmol) were dissolved in N,N-dimethylformamide (5 mL), and potassium carbonate (54 HCl (214 mg, 0.39 mmol) and potassium iodide (214 mg, 1.3 mmol) were added, and the reaction solution was heated and stirred at 50°C for 30 minutes. The reaction solution was cooled to room temperature and directly purified by preparative high performance liquid chromatography to give 80-a (30 mg, yield: 38.4%). LC-MS (ESI): m / z = 600 (M+H) + .

[0758] Synthesis of Compound 80 Compound 80-a (20 mg, 0.037 mmol) and s-piperidine-2-carboxylic acid (7 mg, 0.054 mmol) were dissolved in methanol (3 mL), sodium cyanoborohydride (5 mg, 0.075 mmol) was added, and the reaction solution was purged with nitrogen gas three times to remove oxygen from the reaction system, followed by heating at 60 °C for 30 min. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give 80 (8 mg, yield: 30.7%). LC-MS (ESI): m / z = 713 (M+H). + .

[0759] 1 H-NMR (400 MHz, MeOD) δ: 8.27( d, J=5.6Hz,1H), 8.09( s,1H), 7.91( s,1H), 7.81( d, J=6.8Hz,1H),7.55-7.41( m, 5H ), 7.37-7.25( m, 5H ), 7.28(d, J=7.2Hz,1H), 5.48(s, 2H), 4.72-4.64 ( m, 1H ), 4.56 ( s,2H),4.40-4.37(m, 1H), 3.61-3.57(m, 1H), 3.04-3.02(m, 1H), 2.28 (s, 3H), 1.88- 1.76(m,4H), 1.59- 1.57(m,1H) ppm

[0760] Example 81 (S,E)-1-(2-((2-iodopyridin-4-yl)methoxy)-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-5-(trifluoromethyl)benzyl)piperidine-2-carboxylic acid (Compound 81)

[0761] [ka]

[0762] Synthesis of compound 81-c 2-Iodoisonicotinic acid (500 mg, 2 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and a solution of borane in tetrahydrofuran (4 mL, 4 mmol) was added dropwise thereto. The reaction solution was stirred at room temperature for 16 hours. The reaction solution was cooled to 0°C, and methanol (10 mL) was added dropwise thereto. The reaction solution was then heated and stirred at 70°C for 1 hour. The reaction solution was then cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to give 81-c (280 mg, yield: 53.9%). LC-MS (ESI): m / z = 236 (M+H). + .

[0763] Synthesis of compound 81-b Compound 81-c (280 mg, 1.1 mmol) was dissolved in dichloromethane (10 mL) and thionyl chloride (400 mg, 3.6 mmol) was slowly added thereto. The reaction solution was stirred at room temperature for 2 hours. After concentration under reduced pressure, 81-b (342 mg, yield: 97.0%) was obtained, which was used directly in the next step without further purification. LC-MS (ESI): m / z = 254 (M+H). + .

[0764] Synthesis of compound 81-a Compound 81-b (57 mg, 0.2 mmol) and compound 4-a (50 mg, 0.13 mmol) were dissolved in N,N-dimethylformamide (5 mL), potassium carbonate (54 mg, 0.39 mmol) and potassium iodide (214 mg, 1.3 mmol) were added, and the reaction solution was heated and stirred at 50 °C for 30 min. The reaction solution was cooled to room temperature and directly purified by preparative high-performance liquid chromatography to give 81-a (30 mg, yield: 38.4%). LC-MS (ESI): m / z = 600 (M+H) + .

[0765] Synthesis of compound 81 Compound 81-a (20 mg, 0.037 mmol) and s-piperidine-2-carboxylic acid (7 mg, 0.054 mmol) were dissolved in methanol (3 mL), sodium cyanoborohydride (5 mg, 0.075 mmol) was added, and the reaction solution was purged with nitrogen gas three times to remove oxygen from the reaction system, then heated at 60 °C for 30 min. The reaction was allowed to cool to room temperature. After concentration under reduced pressure, the residue was purified by preparative high-performance liquid chromatography to give 81 (9 mg, yield: 34.6%). LC-MS (ESI): m / z = 713 (M+H). + .

[0766] 1 H-NMR (400 MHz, MeOD) δ: 8.37 (d, J=4.8Hz,1H), 8.03 (s,1H), 7.98 (s,1H), 7.61(d, J=4.8Hz,1H),7.55-7.41 (m, 5H ), 7.37-7.25 (m, 5H ), 7.18 (d, J=7.2Hz,1H), 5.43 (s, 2H), 4.62-4.56 (m, 3H ), 4.45-4.42(m, 1H), 3.61-3.54(m, 1H), 3.01-2.97(m, 1H), 2.28 (s, 3H), 1.89- 1.71(m,4H), 1.65- 1.55(m,1H) ppm

[0767] Example 82 (S,E)-1-(2-((5-iodopyridin-3-yl)methoxy)-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-5-(trifluoromethyl)benzyl)piperidine-2-carboxylic acid (Compound 82)

[0768] [ka]

[0769] Synthesis of compound 82-c 5-Iodonicotinic acid (250 mg, 1 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and a solution of borane in tetrahydrofuran (3 mL, 3 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was cooled to 0°C, and methanol (10 mL) was added dropwise. The reaction mixture was then heated and stirred at 70°C for 1 hour. The reaction mixture was then cooled to room temperature, concentrated under reduced pressure, and diluted with ethyl acetate (10 mL). The organic phase was washed sequentially with water (10 mL x 3) and saturated brine (10 mL x 1). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, compound 82-c (141 mg, yield: 59.7%), which was used directly in the next step without further purification. LC-MS (ESI): m / z = 236.0 [M+H] + .

[0770] Synthesis of compound 82-b Compound 82-c (141 mg, 0.6 mmol) was dissolved in dichloromethane (5 mL) and thionyl chloride (214 mg, 1.8 mmol) was slowly added thereto. The reaction solution was stirred at room temperature for 2 hours. After concentration under reduced pressure, 82-b (146 mg, 96.2%) was obtained, which was used directly in the next step without further purification.

[0771] Synthesis of compound 82-a Compound 82-b (43 mg, 0.170 mmol) and compound 4-a (50 mg, 0.131 mmol) were dissolved in N,N-dimethylformamide (2 mL). Sodium carbonate (41.7 mg, 0.393 mmol) and potassium iodide (65.2 mg, 0.393 mmol) were added, and the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (10 mL). The organic phase was washed with water (10 mL × 3) and saturated brine (10 mL × 1). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether = 100%) to give 82-a (48.8 mg, yield: 62.2%). LC-MS (ESI): m / z = 600.0 [M+H] + .

[0772] Synthesis of compound 82 Compound 82-a (48.8 mg, 0.082 mmol) and s-piperidine-2-carboxylic acid (21.2 mg, 0.164 mmol) were dissolved in a mixture of methanol and tetrahydrofuran (10 mL, 1:1 in v:v), and glacial acetic acid (9.8 mg, 0.164 mmol) and sodium cyanoborohydride (25.8 mg, 0.41 mmol) were added. The reaction solution was purged with nitrogen gas three times to remove oxygen from the reaction system, and then the mixture was heated at 60°C for 30 minutes. The reaction was allowed to cool to room temperature. It was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to give 82 (16.4 mg, yield: 28.2%). LC-MS (ESI): m / z = 713.0 [M+H] + ;

[0773] 1 H-NMR (400 MHz, CD3OD) δ: 8.81 (s, 1H), 8.73 (s, 1H), 8.44 (s, 1H), 7.97 (s, 1H), 7.62-7.53 (m, 3H), 7.45-7.41 (m, 2H), 7.37-7.26 (m, 5H), 7.20 (m, 1H), 5.43 (s, 2H), 4.56-4.53 (d, J = 12.8Hz, 1H), 4.42-4.39 (d, J = 12.8Hz, 1H), 3.60 (m, 1H), 3.01-2.95 (m, 1H), 2.31 (s, 3H), 2.27-2.19 (m, 1H), 1.87-1.28 (m, 6H) ppm

[0774] Example 83 (S,E)-1-(2-(4-fluorobutoxy)-5-methyl-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)benzyl)piperidine 2-carboxylic acid (Compound 83)

[0775] [ka]

[0776] Synthesis of compound 83-a Compound 75-b (200 mg, 0.609 mmol) and 1-bromo-4-fluorobutane (141.7 mg, 0.914 mmol) were dissolved in N,N'-dimethylformamide (5 mL), and potassium carbonate (252.5 mg, 1.827 mmol) was added. The reaction solution was stirred at 60 °C for 16 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (3 mL), and washed successively with water (3 mL × 3) and saturated brine (3 mL). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give 83-a (180 mg, yield: 73.5%). LC-MS (ESI): m / z = 403.0 [M+H] + .

[0777] Synthesis of compound 83 Compound 83-a (180 mg, 0.447 mmol) and s-piperidine-2-carboxylic acid (115.5 mg, 0.894 mmol) were dissolved in a mixture of methanol (5 mL) and tetrahydrofuran (5 mL). Glacial acetic acid (53.7 mg, 0.894 mmol) was added, and the reaction mixture was heated and stirred at 60 °C for 3 hours. Sodium cyanoborohydride (140.5 mg, 2.235 mmol) was then added and stirred for 0.5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give 83 (61.9 mg, yield: 26.9%). LC-MS (ESI): m / z = 516.0 [M+H] + ;

[0778] 1 H-NMR (400 MHz, CD3OD) δ: 7.61-7.59 (d , J = 7.6Hz, 1H), 7.46-7.40 (m, 3H), 7.36-7.21 (m, 7H), 7.15-7.13 (d, J = 7.2Hz, 1H), 4.61-4.58 (t, J = 5.6Hz, 1H), 4.49-4.46 (t, J = 5.6Hz, 2H), 4.34-4.31 (d, J = 12.4Hz, 1H), 4.22-4.19 (t, J = 5.6Hz, 2H), 3.56-3.54 (m, 1H), 3.37-3.35 (m, 1H), 3.01-2.96 (m, 1H), 2.40 (s, 3H), 2.28 (s, 3H), 2.25-2.19 (m, 1H), 2.04-1.55 (m, 9H) ppm.

[0779] Example 84 (S,E)-1-(2-(3-fluoropropoxy)-5-methyl-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)benzyl)piperidine 2-carboxylic acid (Compound 84)

[0780] [ka]

[0781] Synthesis of compound 84-a Compound 75-b (200 mg, 0.609 mmol) and 1-bromo-3-fluorobutane (128.9 mg, 0.914 mmol) were dissolved in N,N'-dimethylformamide (5 mL), and potassium carbonate (252.5 mg, 1.827 mmol) was added. The reaction solution was heated and stirred at 60 °C for 16 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (3 mL), and washed successively with water (3 mL × 3) and saturated brine (3 mL). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified using a silica gel column (petroleum ether:ethyl acetate = 5:1) to give 84-a (200 mg, yield: 84.7%). LC-MS (ESI): m / z = 389.0 [M+H] + ;

[0782] Synthesis of compound 84 Compound 84-a (200 mg, 0.515 mmol) and s-piperidine-2-carboxylic acid (133 mg, 1.03 mmol) were dissolved in a mixture of methanol (5 mL) and tetrahydrofuran (5 mL). Glacial acetic acid (61.9 mg, 1.03 mmol) was added, and the mixture was heated and stirred at 60 °C for 3 hours. Sodium cyanoborohydride (161.8 mg, 2.575 mmol) was then added and stirred for 0.5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give 84 (60.5 mg, yield: 23.4%). LC-MS (ESI): m / z = 502.0 [M+H] + ;

[0783] 1 H-NMR (400 MHz, CD3OD) δ: 7.61-7.60 (d, J = 7.6Hz, 1H), 7.47-7.40 (m, 3H), 7.36-7.21 (m, 7H), 7.15-7.13 (d, J = 7.2Hz, 1H), 4.77-4.74 (t, J = 5.6Hz, 1H), 4.65 -4.62 (t, J = 5.6Hz, 2H), 4.52-4.49 (d, J = 12.8Hz, 1H), 4.32-4.27 (m, 3H), 3.54-3.52 (m, 1H), 3.00-2.95 (m, 1H), 2.41 (s, 3H), 2.33-2.30 (m, 1H), 2.28 (s, 3H), 2.26-2.22 (m, 2H), 1.94-1.55 (m, 5H) ppm.

[0784] Example 85 (S,E)-1-(2-(4-fluorobutoxy)-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-5-(trifluoromethyl)benzyl)piperidine-2-carboxylic acid (Compound 85)

[0785] [ka]

[0786] Synthesis of compound 85-a tert-Butyl (S,E)-1-(2-hydroxyl-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-5-(trifluoromethyl)benzyl)piperidine-2-carboxylate (50 mg, 0.091 mmol) and 1-bromo-4-fluorobutane (21 mg, 0.136 mmol) were dissolved in N,N-dimethylformamide (3 mL), potassium carbonate (37.3 mg, 0.273 mmol) was added, and the reaction solution was stirred at 60 °C for 16 hours. The reaction was cooled to room temperature, diluted with ethyl acetate (3 mL), and washed sequentially with water (3 mL × 3) and saturated brine (3 mL). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified using a silica gel column (petroleum ether:ethyl acetate = 5:1) to give 85-a (37 mg, yield: 65.1%). LC-MS (ESI): m / z = 626.0 [M+H] + .

[0787] Synthesis of compound 85 Compound 85-a (37 mg, 0.059 mmol) was dissolved in a solution of hydrochloric acid / dioxane (4.0 M, 10 mL). The reaction solution was stirred at room temperature for 16 hours, concentrated under reduced pressure, and the residue was purified by prep-HPLC to give 85 (17.1 mg, yield: 51.5%). LC-MS (ESI): m / z = 570.0 [M+H] + ;

[0788] 1 H-NMR (400 MHz, CD3OD) δ: 7.94 (s, 1H), 7.64-7.60 (d, J=16.0Hz, 1H), 7.55-7.53 (m, 2H), 7.44-7.41 (m, 2H), 7.37-7.26 (m, 5H), 7.19-7.17 (d, J=7.6Hz, 1H), 4.62-4.59 (t, J=5.6Hz, 1H), 4.57-4.54 (d, J=13.2Hz, 1H), 4.50-4.47 (t, J=5.6Hz, 1H), 4.40-4.32 (m, 3H), 3.58-3.56 (m, 1H), 3.05-2.99 (m, 1H), 2.30 (s, 3H), 2.24-2.23 (m, 1H), 2.07-1.57 (m, 9H) ppm.

[0789] Example 86 (S,E)-1-(2-(3-fluoropropoxy)-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-5-(trifluoromethyl)benzyl)piperidine-2-carboxylic acid (Compound 86)

[0790] [ka]

[0791] Synthesis of compound 86-a tert-Butyl (S,E)-1-(2-hydroxy-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-5-(trifluoromethyl)benzyl)piperidine-2-carboxylate (50 mg, 0.091 mmol) and 1-bromo-3-fluoropropane (19.2 mg, 0.136 mmol) were dissolved in N,N-dimethylformamide (3 mL), potassium carbonate (37.3 mg, 0.273 mmol) was added, and the reaction solution was stirred at 60 °C for 16 hours. The reaction solution was diluted with ethyl acetate (3 mL) and washed successively with water (3 mL × 3) and saturated brine (3 mL). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give 86-a (47 mg, yield: 84.7%). LC-MS (ESI): m / z = 612.0 [M+H]+ .

[0792] Synthesis of Compound 86 Compound 86-a (47 mg, 0.077 mmol) was dissolved in a solution of hydrochloric acid / dioxane (4.0 M, 10 mL). The reaction solution was stirred at room temperature for 16 hours, concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography to give 86 (19.2 mg, yield: 45.2%). LC-MS (ESI): m / z = 556.0 [M+H] + ;

[0793] 1 H-NMR (400 MHz, CD3OD) δ: 7.92 (s, 1H), 7.65-7.61 (d, J=16.4Hz, 1H), 7.56-7.53 (m, 2H), 7.44-7.41 (m, 2H), 7.37-7.26 (m, 5H), 7.19-7.17 (d, J=7.6Hz, 1H), 4.78-4.75 (t, J=5.6Hz, 1H), 4.66-4.64 (t, J=5.2Hz, 1H), 4.60-4.57 (d, J=12.8Hz, 1H), 4.44-4.35 (m, 3H), 3.56-3.52 (m, 1H), 3.04-2.99 (m, 1H), 2.36-2.34 (m, 1H), 2.30 (s, 3H), 2.28-2.24 (m, 2H), 1.89-1.56 (m, 5H) ppm.

[0794] Example 87 (S,E)-1-(2-(2-fluoroethoxy)-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-5-(trifluoromethyl)benzyl)piperidine-2-carboxylic acid (Compound 87)

[0795] [ka]

[0796] Synthesis of compound 87-a tert-Butyl (S,E)-1-(2-hydroxy-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-5-(trifluoromethyl)benzyl)piperidine-2-carboxylate (50 mg, 0.091 mmol) and 1-bromo-2-fluoroethane (17.3 mg, 0.136 mmol) were dissolved in N,N-dimethylformamide (3 mL), potassium carbonate (37.3 mg, 0.273 mmol) was added, and the reaction solution was stirred at 60 °C for 16 hours. The reaction solution was diluted with ethyl acetate (3 mL) and washed sequentially with water (3 mL × 3) and saturated brine (3 mL). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give 87-a (27 mg, yield: 50.0%). LC-MS (ESI): m / z = 598.0 [M+H] + .

[0797] Synthesis of compound 87 Compound 87-a (47 mg, 0.077 mmol) was dissolved in a solution of hydrochloric acid / dioxane (4.0 M, 10 mL). The reaction solution was stirred at room temperature for 16 hours, concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography to give 87 (14.7 mg, yield: 60.0%). LC-MS (ESI): m / z = 542.0 [M+H] + ;

[0798] 1 H-NMR (400 MHz, DMSO-d6) δ: 7.79 (s, 1H), 7.66-7.62 (d, J=16.0Hz, 1H), 7.57-7.52 (m, 2H), 7.48-7.45 (m, 2H), 7.40-7.31 (m, 4H), 7.23-7.18 (m, 2H), 4.88-4.86 (s, 1H), 4.76-4.74 (s, 1H), 4.54-4.53 (s, 1H), 4.47-4.46 (s, 1H), 3.82-3.79 (d, J=14.8Hz, 1H), 3.71-3.67 (d, J = 14.8 Hz, 1H), 3.22-3.20 (m, 1H), 2.93-2.91 (s, 1H), 2.29 (s, 4H), 1.81-1.77 (m, 2H), 1.50-1.41 (m, 4H) ppm.

[0799] Example 88 (S,E)-1-(2-((5-fluoropyridin-3-yl)methoxy)-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-5-(trifluoro Methyl)benzyl)piperidine-2-carboxylic acid (Compound 88)

[0800] [ka]

[0801] Synthesis of compound 88-a tert-Butyl (S,E)-1-(2-hydroxy-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-5-(trifluoromethyl)benzyl)piperidine-2-carboxylate (100 mg, 0.181 mmol) and 3-(bromomethyl)-5-fluoropyridine hydrochloride (34.44 mg, 0.181 mmol) were dissolved in N,N-dimethylformamide (3 mL), potassium carbonate (75.16 mg, 0.544 mmol) was added, and the reaction solution was stirred at 60 °C for 12 hours. The reaction solution was diluted with ethyl acetate (3 mL) and washed sequentially with water (3 mL × 3) and saturated brine (3 mL). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give 88-a (119 mg, yield: 99.35%). LC-MS (ESI): m / z = 661.0 [M+H] + .

[0802] Synthesis of compound 88 Compound 88-a (119 mg, 0.180 mmol) was dissolved in a solution of hydrochloric acid / dioxane (4.0 M, 10 mL). The reaction solution was stirred at room temperature for 12 hours, concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography to give 88 (43.89 mg, yield: 40.31%). LC-MS (ESI): m / z = 605.0 [M+H] + .

[0803] Example 89 (S,E)-1-(2-((4-fluorobenzyl)oxy)-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-5-(trifluoromethyl))benzyl)piperidine-2-carboxylic acid (Compound 89)

[0804] [ka]

[0805] Synthesis of compound 89-a tert-Butyl (S,E)-1-(2-hydroxy-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-5-(trifluoromethyl)benzyl)piperidine-2-carboxylate (100 mg, 0.181 mmol) and 1-(bromo Methyl-4-fluorobenzene (34.21 mg, 0.181 mmol) was dissolved in N,N-dimethylformamide (3 mL), potassium carbonate (75.16 mg, 0.544 mmol) was added, and the reaction solution was stirred at 60°C for 12 hours. The reaction solution was diluted with ethyl acetate (3 mL) and washed successively with water (3 mL x 3) and saturated brine (3 mL). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give 89-a (118 mg, yield: 98.81%). LC-MS (ESI): m / z = 660.0 [M+H] + .

[0806] Synthesis of compound 89 Compound 89-a (118 mg, 0.179 mmol) was dissolved in a solution of hydrochloric acid / dioxane (4.0 M, 10 mL). The reaction solution was stirred at room temperature for 12 hours, concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography to give 89 (45.48 mg, yield: 42.12%). LC-MS (ESI): m / z = 604.0 [M+H] + .

[0807] Example 90 (S,E)-1-(4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-2-(pyridin-3-ylmethoxy)-5-(trifluoromethyl)benzyl)piperidine-2-carboxylic acid (Compound 90)

[0808] [ka]

[0809] Synthesis of compound 90-a tert-Butyl (S,E)-1-(2-hydroxyl-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-5-(trifluoromethyl)benzyl)piperidine-2-carboxylate (55.1 mg, 0.1 mmol) and 3-(chloromethyl)pyridine (25.51 mg, 0.2 mmol) were dissolved in N,N-dimethylformamide (3 mL), potassium carbonate (69.0 mg, 0.5 mmol) was added, and the reaction solution was stirred at 50 °C for 5 hours. The reaction solution was diluted with ethyl acetate (3 mL) and washed sequentially with water (3 mL × 3) and saturated brine (3 mL). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give 90-a (50 mg, yield: 77.01%). LC-MS (ESI): m / z = 642.2 [M+H] + .

[0810] Synthesis of Compound 90 The compound tert-butyl (S,E)-1-(4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-2-(pyridin-3-ylmethoxy)-5-(trifluoromethyl)benzyl)piperidine-2-carboxylate (50 mg, 0.078 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (5.0 mL) was added, the reaction solution was stirred at room temperature for 12 hours, concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography to give 90 (45.64 mg, yield: 48.20%). LC-MS (ESI): m / z = 587.3 [M+H] + .

[0811] 1 H-NMR(CD3OD-d4) δ:8.77(s, 1H), 8.59(s, 1H), 8.11(d, J=8.0 Hz,1H), 8.00(s, 1H), 7.66(s, 1H), 7.61-7.55(m, 3H), 7.61-7.55(m, 3H), 7.47-7.44(m, 2H), 7.40-7.29(m, 5H), 7.21(d, J=7.2 Hz,1H),5.52(s, 2H),4.58(d, J=12.8 Hz, 1H),4.42(d, J=12.8 Hz,1H), 3.58-3.55(m, 1H),3.43-3.38(m, 3H),3.01-2.95(m, 1H),2.32(s, 3H),2.30-2.24(m, 1H), 1.81-1.54(m, 5H) ppm.

[0812] Example 91 (S,E)-1-(2-((5-cyanopyridin-3-yl)methoxy)-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-5-(trifluoromethyl)benzyl)piperidine-2-carboxylic acid (Compound 91)

[0813] [ka]

[0814] Synthesis of compound 91-a tert-Butyl (S,E)-1-(2-hydroxy-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-5-(trifluoromethyl)benzyl)piperidine-2-carboxylate (55.1 mg, 0.1 mmol) and 5-(chloromethyl)nicotinonitrile hydrogen chloride (37.81 mg, 0.2 mmol) were dissolved in N,N-dimethylformamide (3 mL), potassium carbonate (69 mg, 0.5 mmol) was added, and the reaction solution was stirred at 50 °C for 12 hours. The reaction solution was diluted with ethyl acetate (3 mL) and washed sequentially with water (3 mL × 3) and saturated brine (3 mL). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give 91-a (110 mg, yield: 82.36%). LC-MS (ESI): m / z = 667.2 [M+H] + .

[0815] Synthesis of Compound 91 The compound tert-butyl (S,E)-1-(2-((5-cyanopyridin-3-yl)methoxy)-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-5-(trifluoromethyl)benzyl)piperidine-2-carboxylate (110 mg, 0.165 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (5.0 mL) was added, the reaction solution was stirred at room temperature for 12 hours, concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography to give 91 (58.7 mg, yield: 58.26%). LC-MS (ESI): m / z = 612.4 [M+H] + .

[0816] 1 H-NMR(CD3OD-d4) δ: 9.04(s, 1H), 8.95(s , 1H), 8.48(s, 1H), 8.02(s, 1H),7.67(s, 1H), 7.65-7.56(m, 2H), 7.47-7.44(m, 2H), 7.40-7.29(m, 5H), 7.21(d,J=8.0 Hz, 1H), 5.55(s, 2H), 4.60(d, J=12.8 Hz, 1H),4.44(d, J=12.8 Hz, 1H),3.58-3.55(m, 1H),3.35-3.30(m, 1H),3.02-2.96(m, 1H), 2.32(s, 3H), 2.28-2.24(m, 1H), 1.89-1.54(m, 5H) ppm.

[0817] Effect Example 1 Homogeneous time-resolved fluorescence method The binding ability of the compounds of the present invention to PD-1 / PD-L1 was detected by homogenous time-resolved fluorescence (HTRF) binding assay.

[0818] The purchased kit (CisBio, #64CUS000C-1) contained the necessary reagents for the experiment, such as PD-1, PD-L1, anti-tag1-Eu, anti-tag2-XL665, dilute buffer, and detection buffer.

[0819] Experimental steps 1. Compounds were prepared in 100% DMSO at 10 concentrations with a 3-fold gradient. 2. A DMSO solution of the compound was added to a dilute buffer solution, mixed uniformly, and then transferred to a 96-well plate. 3. PD-L1 was diluted with dilute buffer and then added to the 96-well plate. 4. PD-1 was diluted with dilute buffer, then placed in the 96-well plate and incubated at room temperature for 30 minutes. 5. One anti-tag1-Eu and one anti-tag2-XL665 were added to the detection buffer, mixed evenly, and then transferred to the 96-well plate. 6. The mixture in the 96-well plate was incubated at room temperature for 1 to 24 hours. 7. HTRF readings were taken using Envision.

[0820] Experimental results The biological activities of the compounds of the present invention were determined by the above tests, and the results obtained are shown in Table 1 below:

[0821] [Table 1-1]

[0822] [Table 1-2]

[0823] Effect Example 2 Pharmacokinetics experiment in mice Reagents: Acetonitrile, formic acid, and methanol (HPLC grade) were all purchased from Sigma-Aldrich (USA), and pure water was purchased from Hangzhou Wahaha Group Co., Ltd. (Hangzhou, China). All other chemical reagents were of analytical purity.

[0824] Test equipment: Liquid mass spectrometer (UPLC-MS / MS, AB SCIEX TRIPLE The system consisted of a QUAD 6500 triple quadrupole mass spectrometer, a Shimadzu high-performance liquid chromatography system, and the Analyst 1.6.2 data acquisition and processing system.

[0825] Other equipment: Mettler electronic balance Mettler-ToledoXP26 and XS60025 (USA); Thermo Fisher -70℃ ultra-low temperature refrigerator (USA); Thermo HERAEUS Multifuge X3R low-temperature refrigerated centrifuge (Germany); IKA VIBRAX VXR basic shaker (Germany); IKA disperser (Germany); Xinzhi SCIENTZ-48L refrigerated high-throughput tissue grinder (Ningbo, China), etc.

[0826] Test animals: Six CD1 male mice, weighing 29-30 g before administration, were purchased from Shanghai Jihui Experimental Animal Breeding Co., Ltd., with the animal certificate number SCXK(SH) 2017-0012. The animals should be kept for at least 3 days before testing. The animals were allowed to eat and drink ad libitum throughout the study.

[0827] Experimental steps: 1) Preparation of mother liquor: A certain amount of test drug was weighed into a clean sample vial, dimethyl sulfoxide was added, the mixture was vortexed thoroughly for 1 minute, and sonicated for 5 minutes to obtain a 4 mg / mL solution. Preparation of intravenous drug: A predetermined amount of the above solution was drawn into a clean sample vial, polyethylene glycol-15 hydroxystearate was added, and the mixture was thoroughly vortexed for 1 minute. Normal saline was added, and the mixture was continued to be vortexed for 1 minute to obtain 4 mg / mL of solution A. Preparation of oral medication: A predetermined amount of test drug was weighed into a clean sample vial, and the previously prepared solvent "10% (w / v) polyoxyethylene 40 hydrogenated castor oil + 20% (w / v) sulfobutyl ether β-cyclodextrin + 70% water" was added. The mixture was vortexed thoroughly for 1 minute, magnetically stirred for 20-25 minutes, and sonicated for 10 minutes to obtain 1 mg / mL solution B.

[0828] 2) Intravenous administration: Three mice were injected with 2 mg / kg (5 mL / kg) of Solution A through the tail vein. Oral administration: Three mice were intragastrically administered 10 mg / kg (10 mL / kg) of Solution B.

[0829] 3) Plasma sample collection and storage: Blood samples were collected from the retro-orbital venous plexus of mice at scheduled time points (5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, and 24 h). 25 L of blood was placed in an EDTA-K2 anticoagulant tube (placed on wet ice), and 20 L of blood was immediately diluted with 60 L of water and vortexed thoroughly until homogenous. Plasma was stored long-term in a -70°C refrigerator until sample analysis.

[0830] 4) Plasma sample analysis: 200 μL of acetonitrile (containing 100 ng / mL of internal standard) was added to 25 μL of plasma sample, vortexed for 10 minutes, and centrifuged at 5800 rpm for 10 minutes. 70 μL of the supernatant was transferred to a 96-well injection plate. 1 μL of the plasma sample was used for LC-MS / MS detection.

[0831] 5) Pharmacokinetic parameters were calculated based on the detection results.

[0832] Experimental results Some compounds of the present invention and their control compounds can obtain specific pharmacokinetic parameters through the above tests, and the results are shown in Table 2 below:

[0833] [Table 2]

[0834] As can be seen from Table 2: compared with the control compound, the compounds of the present invention have significantly higher drug peak concentrations, larger areas under the drug-time curve and better oral bioavailability in pharmacokinetic experiments in mice.

Claims

1. An aromatic ethylenic compound represented by formula I-0, a tautomer thereof, a stereoisomer thereof, a racemate thereof or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 (however: R １ is cyano, C １ ~C ４ Alkyl, C substituted with one or more deuterium atoms １ ~C ４ Alkyl, halogen, C substituted with one or more halogens １ ~C ４ is alkyl, R ３ , R ６ , R １２ , R １３ and R １４ are independently H or deuterium, R ２ is a halogen, C １ ~C ４ alkyl, or one or more R Ａ－１ C substituted by １ ~C ４ is alkyl, RA-1 is independently deuterium or halogen; R 4 is 【Chemistry 2】 and R ５ is a halogen, C １ ~C ４ alkyl, one or more R Ｂ－１ C substituted by １ ~C ４ Alkyl, C １ ~C ６ Alkoxy or one or more R Ｂ－２ C substituted by １ ~C ６ is an alkoxy; R Ｂ－１ and R Ｂ－２ are independently deuterium, hydroxyl, halogen, cyano, 3- to 12-membered heteroaryl, one or more R Ｂ－１－４ 3-12 membered heteroaryl substituted by １ ~C ４ Alkoxy or C substituted with one or more deuterium atoms １ ~C ４ alkoxy, wherein the heteroaryl has one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 1 to 4; R Ｂ－１－４ are independently cyano, halogen, C １ ~C ４ Alkyl or C １ ~C ４ is an alkoxy; R B-1-1 is H, deuterium, or C 1 -C 4 alkyl; R Ｂ－１－２ is one or more R Ｂ－１－１－１ C substituted by １ ~C ４ alkyl, and the R Ｂ－１－１－１ is deuterium, hydroxyl or COOR Ｂ－１－１－５ and Or, R Ｂ－１－１ , R Ｂ－１－２ together with the nitrogen atom linked thereto, form one or more R Ｂ－１－１－２ In the carboheterocycle, the number of heteroatoms is 1, and the R Ｂ－１－１－２ is deuterium, C １ ~C ４ Alkyl, C substituted with one or more deuterium atoms １ ~C ４ Alkyl, COOR Ｂ－１－１－６ or C １ ~C ４ is an amide, R Ｂ－１－１－５ and R Ｂ－１－１－６ are independently H, deuterium, and C １ ~C ４ Alkyl or C substituted with one or more deuterium atoms １ ~C ４ is alkyl, R ７ , R ８ , R ９ , R １０ and R １１ are independently H or deuterium, R １５ and R １６ are independently H or deuterium.

2. R Ｂ－１ and R Ｂ－２ are independently deuterium, hydroxyl, halogen, cyano, C １ ~C ４ Alkoxy or C substituted with one or more deuterium atoms １ ~C ４ An aromatic ethylene compound represented by formula I-0 according to claim 1, which is an alkoxy, a tautomer thereof, a stereoisomer thereof, a racemate thereof, an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof.

3. The aromatic ethylene compound represented by formula I-0 according to claim 1, characterized in that the aromatic ethylene compound represented by formula I-0 is an aromatic ethylene compound represented by formula I, a tautomer thereof, a stereoisomer thereof, a racemate thereof, an isotope derivative thereof, or a pharmaceutically acceptable salt thereof. 【Transformation 3】 (however: R １ is cyano, C １ ~C ４ Alkyl, C substituted with one or more deuterium atoms １ ~C ４ is alkyl, R ３ , R ６ , R １２ , R １３ and R １４ are independently H or deuterium, R ２ is a halogen, C １ ~C ４ alkyl, or one or more R Ａ－１ C substituted by １ ~C ４ is alkyl, RA-1 is independently deuterium or halogen; R 4 is 【Chemistry 4】 and R ５ is a halogen, C １ ~C ４ alkyl, one or more R Ｂ－１ C substituted by １ ~C ４ Alkyl, C １ ~C ６ Alkoxy or one or more R Ｂ－２ C substituted by １ ~C ６ is an alkoxy; R Ｂ－１ and R Ｂ－２ are independently deuterium, hydroxyl, halogen, cyano, C １ ~C ４ Alkoxy or C substituted with one or more deuterium atoms １ ~C ４ is an alkoxy; R B-1-1 is H, deuterium, or C 1 -C 4 alkyl; R Ｂ－１－２ is one or more R Ｂ－１－１－１ C substituted by １ ~C ４ alkyl, and the R Ｂ－１－１－１ is deuterium, hydroxyl or COOR Ｂ－１－１－５ and Or, R Ｂ－１－１ , R Ｂ－１－２ together with the nitrogen atom linked thereto, form one or more R Ｂ－１－１－２ In the carboheterocycle, the number of heteroatoms is 1, and the R Ｂ－１－１－２ is deuterium, C １ ~C ４ Alkyl, C substituted with one or more deuterium atoms １ ~C ４ Alkyl, COOR Ｂ－１－１－６ or C １ ~C ４ is an amide, R Ｂ－１－１－５ and R Ｂ－１－１－６ are independently H, deuterium, and C １ ~C ４ Alkyl or C substituted with one or more deuterium atoms １ ~C ４ is alkyl, R ７ , R ８ , R ９ , R １０ and R １１ are independently H or deuterium.

4. R １ is C １ ~C ４ When it is alkyl, １ ~C ４ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; and / or R １ C is substituted with one or more deuterium atoms １ ~C ４ When it is alkyl, C substituted with one or more deuterium atoms １ ~C ４ Alkyl is a C substituted with one or more deuterium atoms. １ ~C ２ is alkyl, and / or R １ is a halogen, said halogen is fluorine, chlorine, bromine or iodine; and / or R １ C substituted with one or more halogens １ ~C ４ When alkyl, the halogen is fluorine, chlorine, bromine or iodine; and / or R １ C substituted with one or more halogens １ ~C ４ When it is alkyl, １ ~C ４ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; and / or R ２ is a halogen, said halogen is fluorine, chlorine, bromine or iodine; and / or R ２ is C １ ~C ４ When it is alkyl, １ ~C ４ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; and / or R ２ is one or more R Ａ－１ C substituted by １ ~C ４ When it is alkyl, １ ~C ４ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; and / or R ２ is one or more R Ａ－１ C substituted by １ ~C ４ When R is alkyl, each R Ａ－１ are the same or different, and the plurality is 2, 3, 4, or 5; and / or, when RA-1 is independently a halogen, said halogen is fluorine, chlorine, bromine or iodine; and / or R ５ is a halogen, said halogen is fluorine, chlorine, bromine or iodine; and / or R ５ is C １ ~C ４ When it is alkyl, １ ~C ４ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; and / or R ５ is one or more R Ｂ－１ C substituted by １ ~C ４ When it is alkyl, １ ~C ４ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; and / or R ５ is one or more R Ｂ－１ C substituted by １ ~C ４ When R is alkyl, each R Ｂ－１ are the same or different, and the plurality is 2, 3, 4, or 5; and / or R ５ is C １ ~C ６ When it is alkoxy, １ ~C ６ Alkoxy is C １ ~C ４ is an alkoxy; and / or R ５ is one or more R Ｂ－２ C substituted by １ ~C ６ When it is alkoxy, １ ~C ６ Alkoxy is C １ ~C ４ is an alkoxy; and / or R ５ is one or more R Ｂ－２ C substituted by １ ~C ６ When R is alkoxy, each R Ｂ－２ are the same or different, and the plurality is 2, 3, 4, or 5; and / or R Ｂ－１ and R Ｂ－２ is independently a halogen, said halogen is fluorine, chlorine, bromine or iodine; and / or R Ｂ－１ and R Ｂ－２ is independently a 3- to 12-membered heteroaryl, said 3- to 12-membered heteroaryl is a 5- to 7-membered heteroaryl; and / or R Ｂ－１ and R Ｂ－２ is independently 3- to 12-membered heteroaryl, the heteroatom of said 3- to 12-membered heteroaryl is selected from N, the number of heteroatoms is 1; and / or R Ｂ－１ and R Ｂ－２ independently represent one or more R Ｂ－１－４ When the 3- to 12-membered heteroaryl is substituted by is a membered heteroaryl; and / or R Ｂ－１ and R Ｂ－２ independently represent one or more R Ｂ－１－４ wherein the heteroatom of said 3- to 12-membered heteroaryl is selected from N, and the number of heteroatoms is 1; and / or R Ｂ－１ and R Ｂ－２ independently represent one or more R Ｂ－１－４ When R is a 3- to 12-membered heteroaryl substituted by Ｂ－１－４ are the same or different, and the plurality is 2, 3, 4, or 5; and / or R Ｂ－１－４ is independently a halogen, said halogen is fluorine, chlorine, bromine or iodine; and / or R Ｂ－１ and R Ｂ－２ However, independently C １ ~C ４ When it is alkoxy, １ ~C ４ Alkoxy is methoxy, ethoxy, n-propoxy or n-butoxy; and / or R Ｂ－１ and R Ｂ－２ are independently substituted by one or more deuterium atoms; １ ~C ４ When it is alkoxy, C substituted with one or more deuterium atoms １ ~C ４ Alkoxy is a C substituted with one or more deuterium atoms. １ ~C ２ is an alkoxy; and / or RB-1-1 is independently C １ ~C ４ When it is alkyl, １ ~C ４ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; and / or R Ｂ－１－２ independently represent one or more R Ｂ－１－１－１ C substituted by １ ~C ４ When it is alkyl, １ ~C ４ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; and / or R Ｂ－１－２ independently represent one or more R Ｂ－１－１－１ C substituted by １ ~C ４ When R is alkyl, each R Ｂ－１－１－１ are the same or different, and the plurality is 2, 3, 4, or 5; and / or R Ｂ－１－１ , R Ｂ－１－２ together with the nitrogen atom to which they are attached, one or more R Ｂ－１－１－２ When forming a carboheterocycle substituted by Ｂ－１－１－２ are the same or different, and the plurality is 2, 3, 4, or 5; and / or the R Ｂ－１－１－２ is C １ ~C ４ When it is alkyl, １ ~C ４ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; and / or the R Ｂ－１－１－２ C is substituted with one or more deuterium atoms １ ~C ４ When it is alkyl, C substituted with one or more deuterium atoms １ ~C ４ Alkyl is a C substituted with one or more deuterium atoms. １ ~C ２ is alkyl, and / or the R Ｂ－１－１－２ is C １ ~C ４ When it is an amide, １ ~C ４ The amide is 【Transformation 5】 and R Ｂ－１－１－３ and R Ｂ－１－１－４ are independently H, deuterium, and C １ ~C ４ Alkyl or C substituted with one or more deuterium atoms １ ~C ４ is alkyl, and / or R Ｂ－１－１－５ and R Ｂ－１－１－６ became independent and became C １ ~C ４ When it is alkyl, １ ~C ４ The aromatic ethylene compound represented by formula I-0 according to claim 1, wherein alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, a tautomer thereof, a stereoisomer thereof, a racemate thereof, an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof.

5. R １ is C １ ~C ４ When it is alkyl, １ ~C ４ Alkyl is methyl, and / or R １ C is substituted with one or more deuterium atoms １ ~C ４ When it is alkyl, C substituted with one or more deuterium atoms １ ~C ４ alkyl is mono-, di-, tri-, mono-, di-, tri-, tetra-, or penta-deuteroethyl; and / or R １ is a halogen, said halogen is chlorine; and / or R １ C substituted with one or more halogens １ ~C ４ When it is alkyl, the halogen is fluorine; R １ C substituted with one or more halogens １ ~C ４ When it is alkyl, １ ~C ４ Alkyl is methyl, and / or R ２ is a halogen, said halogen is chlorine; and / or R ２ is C １ ~C ４ When it is alkyl, １ ~C ４ Alkyl is methyl, and / or R ２ is one or more R Ａ－１ C substituted by １ ~C ４ When it is alkyl, １ ~C ４ Alkyl is methyl, and / or, when RA-1 is independently a halogen, said halogen is fluorine; and / or R ５ is a halogen, said halogen is chlorine; and / or R ５ is C １ ~C ４ When it is alkyl, １ ~C ４ Alkyl is methyl, and / or R ５ is one or more R Ｂ－１ C substituted by １ ~C ４ When it is alkyl, １ ~C ４ Alkyl is methyl, and / or R ５ is C １ ~C ６ When it is alkoxy, １ ~C ６ Alkoxy is methoxy, ethoxy, n-propoxy or n-butoxy; and / or R ５ is one or more R Ｂ－２ C substituted by １ ~C ６ When it is alkoxy, １ ~C ６ Alkoxy is methoxy, ethoxy, n-propoxy or n-butoxy; and / or R Ｂ－１ and R Ｂ－２ is independently a halogen, said halogen is fluorine; and / or R Ｂ－１－４ is independently a halogen, said halogen is fluorine or iodine; and / or R Ｂ－１ and R Ｂ－２ became independent and became C １ ~C ４ When it is alkoxy, １ ~C ４ Alkoxy is methoxy; and / or R Ｂ－１ and R Ｂ－２ are independently substituted by one or more deuterium atoms; １ ~C ４ When it is alkoxy, the C substituted with one or more deuterium atoms １ ~C ４ Alkoxy is monodeuteromethoxy, dideuteromethoxy, trideuteromethoxy, monodeuteroethoxy, dideuteroethoxy, trideuteroethoxy, tetradeuteroethoxy or pentadeuteroethoxy; and / or RB-1-1 is independently C １ ~C ４ When it is alkyl, １ ~C ４ alkyl is methyl, ethyl or isopropyl; and / or R Ｂ－１－２ independently represent one or more R Ｂ－１－１－１ C substituted by １ ~C ４ When it is alkyl, １ ~C ４ alkyl is methyl, ethyl or isopropyl; and / or the R Ｂ－１－１－２ is C １ ~C ４ When it is alkyl, １ ~C ４ Alkyl is methyl, and / or the R Ｂ－１－１－２ C is substituted with one or more deuterium atoms １ ~C ４ When it is alkyl, C substituted with one or more deuterium atoms １ ~C ４ alkyl is mono-, di-, tri-, mono-, di-, tri-, tetra-, or penta-deuteroethyl; and / or the R Ｂ－１－１－２ is C １ ~C ４ When it is an amide, １ ~C ４ The amide is 【Transformation 6】 and R Ｂ－１－１－３ and R Ｂ－１－１－４ are independently H, deuterium, and C １ ~C ４ Alkyl or C substituted with one or more deuterium atoms １ ~C ４ alkyl, １ ~C ４ Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, and the C substituted with one or more deuterium atoms. １ ~C ４ alkyl is trideuteromethyl; and / or R Ｂ－１－１－５ and R Ｂ－１－１－６ became independent and became C １ ~C ４ When it is alkyl, １ ~C ４ The aromatic ethylene compound represented by formula I-0 according to claim 4, wherein alkyl is methyl, a tautomer thereof, a stereoisomer thereof, a racemate thereof, an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof.

6. R ３ , R ６ , R １２ , R １３ and R １４ are independently H, and / or R A-1 is independently halogen; and / or R Ｂ－１－１－５ and R Ｂ－１－１－６ are independently H or C １ ~C ４ is alkyl, and / or R Ｂ－１ and R Ｂ－２ are independently deuterium, hydroxyl, cyano, 3- to 12-membered heteroaryl, one or more R Ｂ－１－４ 3-12 membered heteroaryl substituted by １ ~C ４ Alkoxy or C substituted with one or more deuterium atoms １ ~C ４ is an alkoxy, and / or R Ｂ－１－４ are independently cyano or halogen; and / or R B-1-1 is H and R Ｂ－１－２ is one or more R Ｂ－１－１－１ C substituted by １ ~C ４ alkyl, or R Ｂ－１－１ , R Ｂ－１－２ together with the nitrogen atom linked thereto, form one or more 5- to 7-membered R Ｂ－１－１－２ forming a carboheterocycle substituted by and / or said one or more R Ｂ－１－１－１ C substituted by １ ~C ４ Alkyl is 【Transformation 7】 and and / or R Ｂ－１－１－２ is C １ ~C ４ Alkyl, COOR Ｂ－１－１－６ or C １ ~C ４ is an amide, and / or the carboheterocycle is 【Transformation 8】 The aromatic ethylene compound represented by formula I-0 according to claim 1, a tautomer thereof, a stereoisomer thereof, a racemate thereof, an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof,

7. R ２ is a halogen or C １ ~C ４ is alkyl, and / or R Ａ－１ is a halogen, and / or R Ｂ－１－１－５ and R Ｂ－１－１－６ are independently H, and / or R Ｂ－１ is hydroxyl, C １ ~C ４ Alkoxy or C substituted with one or more deuterium atoms １ ~C ２ is an alkoxy, and / or R Ｂ－２ is deuterium, cyano, hydroxyl, 3- to 12-membered heteroaryl, one or more R Ｂ－１－４ 3-12 membered heteroaryl substituted by １ ~C ４ is an alkoxy, and / or said 3- to 12-membered heteroaryl is 【Chemistry 9】 and and / or said one or more R Ｂ－１－４ 3-12 membered heteroaryl substituted by 【Chemistry 10】 and and / or R Ｂ－１－１－２ is methyl, carboxyl or -CONH ２ and and / or said one or more R Ｂ－１－１－２ A carboheterocycle substituted by 【Chemistry 11】 and and / or R ５ is a halogen, C １ ~C ４ alkyl, one or more R Ｂ－１ C substituted by １ ~C ４ Alkyl, C １ ~C ６ Alkoxy or one or more R Ｂ－２ C substituted by １ ~C ６ is alkoxy, and R Ｂ－１ and R Ｂ－２ are independently deuterium, hydroxyl, cyano, C １ ~C ４ Alkoxy or C substituted with one or more deuterium atoms １ ~C ２ An aromatic ethylenic compound represented by formula I-0 according to claim 6, which is an alkoxy, a tautomer thereof, a stereoisomer thereof, a racemate thereof, an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof.

8. R Ｂ－１ is hydroxyl, and / or 【Chemistry 12】 teeth 【Chemistry 13】 The aromatic ethylene compound represented by formula I-0 according to claim 7, a tautomer thereof, a stereoisomer thereof, a racemate thereof, an isotope derivative thereof, or a pharmaceutically acceptable salt thereof,

9. R １ is a halogen, C substituted with one or more halogens １ ~C ４ is alkyl, and / or R １５ is deuterium, and / or R １６ is deuterium, an aromatic ethylene compound represented by formula I-0 according to claim 1, a tautomer thereof, a stereoisomer thereof, a racemic mixture thereof, an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof.

10. R ２ is a halogen, C １ ~C ４ alkyl or one or more R Ａ－１ C substituted by １ ~C ４ alkyl, and R Ａ－１ is a halogen, and R ４ teeth, 【Chemistry 14】 and R ５ is a halogen, C １ ~C ４ alkyl, one or more R Ｂ－１ C substituted by １ ~C ４ Alkyl, C １ ~C ６ Alkoxy or one or more R Ｂ－２ C substituted by １ ~C ６ is alkoxy, and R Ｂ－１ and R Ｂ－２ are independently deuterium, hydroxyl, cyano, C １ ~C ４ Alkoxy or C substituted with one or more deuterium atoms １ ~C ２ is alkoxy, and R ３ , R ６ , R １２ , R １３ and R １４ is H, or a tautomer, a stereoisomer, a racemate, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof.

11. R １ is cyano, CH ３ , CDs ３ , Cl, CH ２ F, C substituted with one or more halogens １ ~C ４ is alkyl, and / or 【Chemistry 15】 【Chemistry 16】 【change】 The aromatic ethylene compound represented by formula I-0 according to claim 1, a tautomer thereof, a stereoisomer thereof, a racemate thereof, an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof,

12. Any one of the following aromatic ethylenic compounds, their tautomers, their stereoisomers, their racemates or their isotopic derivatives, or pharmaceutically acceptable salts thereof: 【Chemistry 17】 【change】 【change】 【change】 【change】

13. A method for producing an aromatic ethylenic compound according to any one of claims 1 to 12, comprising the following method 1 or method 2: (Method 1 includes the following steps of subjecting a compound represented by formula II-a-0 and a compound represented by formula III-a to a reductive amination reaction in a solvent under the action of a reducing agent to obtain an aromatic ethylene compound represented by formula I-0: [Chemistry 18] In Method 1, R ４ teeth, 【Chemistry 19】 and R １ , R ２ , R ３ , R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , R １１ , R １２ , R １３ , R １４ , R １５ , R １６ , R Ｂ－１－１ and R Ｂ－１－２ are defined as in any one of claims 1 to 12, Method 2 includes the steps of: subjecting a compound represented by formula II-b-0 and a compound represented by formula III-a to a substitution reaction in a solvent under the action of a base to obtain an aromatic ethylenic compound represented by formula I-0, 【Chemistry 20】 In Method 2, R ４ teeth, 【Chemistry 21】 and R １ , R ２ , R ３ , R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , R １１ , R １２ , R １３ , R １４ , R １５ , R １６ , R Ｂ－１－１ and R Ｂ－１－２ is defined as in any one of claims 1 to 12, and X １ is a halogen.)

14. A compound represented by formula II-a-0 or II-b-0. 【Chemistry 22】 (In the above general formula compound, R １ , R ２ , R ３ , R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , R １１ , R １２ , R １３ , R １４ , R １５ and R １６ are defined as in any one of claims 1 to 12, and X1 is halogen.

15. A compound of any one of the following formulas: 【Chemistry 23】 【change】 【change】

16. The aromatic ethylenic compound according to any one of claims 1 to 12, a tautomer thereof, a stereoisomer thereof, a racemate thereof, an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, And / or a pharmaceutical composition comprising the aromatic ethylenic compound according to any one of claims 1 to 12, a tautomer thereof, a stereoisomer thereof, a racemate thereof or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, and at least one other medicament, wherein the other medicament is a chemotherapeutic drug or a targeted drug.

17. 17. The pharmaceutical composition of claim 16, wherein the targeted drug is one or more of a COX-2 inhibitor, a DPP4 inhibitor, a CSF-1α inhibitor, and an A2a antagonist.

18. Use of the aromatic ethylene-based compound according to any one of claims 1 to 12, a tautomer thereof, a stereoisomer thereof, a racemate thereof, an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a PD-1 inhibitor and / or a PD-L1 inhibitor.

19. Use of the aromatic ethylene-based compound according to any one of claims 1 to 12, a tautomer thereof, a stereoisomer thereof, a racemate thereof, or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention and / or treatment of a disease associated with the PD-1 / PD-L1 signal pathway.

20. The use according to claim 19, wherein the disease associated with the PD-1 / PD-L1 signal pathway is cancer, an infectious disease, an autoimmune disease, or a disease related thereto.

21. the cancer is one or more of lung cancer, esophageal cancer, gastric cancer, colon cancer, hematological tumors, lymphoma, head and neck cancer, liver cancer, nasopharyngeal cancer, brain tumor, breast cancer, cervical cancer, blood cancer, and bone cancer; and / or the infection is a bacterial infection and / or a viral infection, and / or the autoimmune disease is one or more of rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, systemic vasculitis and relapsing polychondritis.

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