Aromatic vinyl compounds, methods of making, intermediates, pharmaceutical compositions, and uses thereof

Abstract

This invention discloses an aromatic ethylene compound, its preparation method, intermediates, pharmaceutical compositions, and applications. The aromatic ethylene compound disclosed in this invention is shown in Formula I-0. The aromatic ethylene compound of this invention exhibits significant inhibitory effects on PD-1 / PD-L1, while also possessing higher peak drug concentrations, larger area under the curve (AUC), and better oral bioavailability. It is a highly effective small molecule inhibitor of PD-1 / PD-L1, capable of effectively alleviating or treating cancer and related diseases.

Description

Technical Field

[0001] This invention relates to an aromatic vinyl compound, its preparation method, intermediates, pharmaceutical compositions, and applications. Background Technology

[0002] PD-1 (programmed death 1) is an important immunosuppressive molecule. A member of the CD28 superfamily, it was originally cloned from apoptotic mouse T-cell hybridoma 2B4.11. Immunomodulation targeting PD-1 plays a significant role in anti-tumor, anti-infection, anti-autoimmune diseases, and organ transplant survival. Its ligand PD-L1 can also serve as a target, and corresponding antibodies can achieve the same effect.

[0003] PD-1 / PD-L1 exerts a negative immunomodulatory effect. When PD-1 and PD-L1 are coupled on the cell surface, it leads to phosphorylation of Tyr in the tyrosine-based switch motif (ITSM) domain of the T cell cytoplasm. Phosphorylated Tyr then recruits phosphatases protein tyrosinase 2 and protein tyrosinase 1, which not only block the activation of extracellular signal-regulated kinases but also block the activation of phosphatidylinositol 3-kinase (PI3K) and serine-threonine protein kinase (Akt), ultimately inhibiting T lymphocyte proliferation and the secretion of related cytokines. PD-1 / PD-L1 signaling can inhibit T cell activation and proliferation, while the secretion of cytokines interleukin-2 (IL2), interferon-γ, and IL-10 is also reduced (Eur. J. Immunol., 2002, 32(3), 634-643.). Furthermore, PD-1 / PD-L1 signaling has a similar effect on B-cell immune function as T cells. When PD-1 cross-links with B-cell antigen receptors, the PD-1 cytoplasmic region interacts with tyrosinases containing protein tyrosinase 2 binding sites, ultimately blocking B-cell activation. The role of the immunomodulatory molecules PD-1 / PD-L1 in tumor immune escape is increasingly attracting attention. Numerous studies have confirmed that tumor cells in the tumor microenvironment exhibit elevated PD-L1 levels on their surface, which binds to PD-1 on activated T cells, transmitting negative regulatory signals that lead to apoptosis or immunodeficiency of tumor antigen-specific T cells, thereby suppressing the immune response and promoting tumor cell escape.

[0004] Currently marketed PD-1 / PD-L1 antibody inhibitors include BMS's Nivolumab (2014), Merck's Lambrulizumab (2014), and Roche's Atezolizumab (2016). PD-1 / PD-L1 antibody inhibitors under development include Cure Tech's Pidilizumab, GSK's AMP-224, and AstraZeneca's MEDI-4736. All of the above are biological macromolecules, while small molecule PD-1 / PD-L1 inhibitors are currently in the early stages of research and development. Curis peptide-based PD-L1 small molecule inhibitors AC-170 (WO2012168944, WO2015033299, WO2015033301, WO2015036927, WO2015044900) have just entered Phase I clinical trials. BMS benzyl phenyl ether-based small molecule PD-1 / PD-L1 inhibitors (WO2015034820, WO2015160641, WO2017066227, WO2018009505, WO2018044963, WO201...) 8118848 is still in the preclinical research stage. Incyte has also developed a series of small molecule PD-1 / PD-L1 inhibitors (WO2017070089, WO2017087777, WO2017106634, WO2017112730, WO2017192961, WO2017205464, WO2017222976, WO2018013789, WO2018044783, WO2018119221, WO2018119224, WO2018119263, WO2018219266, WO2018119286) that are also in preclinical research. Compared to biological macromolecules, small molecule compounds can cross the cell membrane and act on intracellular targets, so their applications are wide-ranging. Secondly, small molecules, after chemical modification, often exhibit good bioavailability and compliance, effectively avoiding the decomposition and inactivation by enzymes in the digestive tract. Finally, research on small molecules is quite mature at various levels, including production processes, dosage form design, and administration methods.

[0005] Currently, there are no reports of biphenyl compounds being successfully marketed as small molecule PD-1 / PD-L1 inhibitors, and this situation urgently needs to be addressed. Summary of the Invention

[0006] The technical problem solved by this invention is to provide an aromatic vinyl compound, its preparation method, intermediates, pharmaceutical composition, and applications that are completely different from existing technologies. The aromatic vinyl compound of this invention exhibits significant inhibitory effects on PD-1 / PD-L1, while also possessing higher peak drug concentrations, larger area under the curve (AUC), and better oral bioavailability. It is a highly effective small-molecule inhibitor of PD-1 / PD-L1, capable of effectively alleviating or treating cancer and related diseases.

[0007] (In the following invention description, we have marked the changes in blue font. Please take note.)

[0008] The present invention provides a pharmaceutically acceptable salt of an aromatic vinyl compound as shown in Formula I-0, its tautomers, its stereoisomers, its racemates or isotopic derivatives thereof, or such salt as the aforementioned aromatic vinyl compound as shown in Formula I-0, its tautomers, its stereoisomers, its racemates or isotopic derivatives thereof.

[0009]

[0010] in:

[0011] R 1 It can be cyano, C1-C4 alkyl, C1-C4 alkyl substituted with one or more deuterium, halogen, or C1-C4 alkyl substituted with one or more halogens;

[0012] R 3 R 6 R 12 R 13 and R 14 Independently, it can be either H or deuterium;

[0013] R 2 It is hydroxyl, halogen, C1-C4 alkyl, or formed by one or more R A-1 Substituted C1-C4 alkyl, C1-C6 alkoxy, or substituted with one or more R A-2 Substituted C1-C6 alkoxy groups;

[0014] R A-1 and R A-2 Independently, it is deuterium, hydroxyl, halogen, cyano, C1-C4 alkoxy, or a C1-C4 alkoxy substituted with one or more deuterium groups. R A-1-1 It is a C1-C4 alkyl group or a C1-C4 alkyl group substituted with one or more deuterium atoms; R A-1-2 and R A-1-3 Independently H, deuterium, C1-C4 alkyl, or by one or more R A-1-1-1 Substituted C1-C4 alkyl groups, wherein RA -1-1-1 For deuterium, hydroxyl, or COOR A-1-1-2 ;

[0015] R 4 and R 5 Independently hydroxyl, halogen, C1-C4 alkyl, or with one or more R B-1 Substituted C1-C4 alkyl, C1-C6 alkoxy, or substituted with one or more R B-2 Substituted C1-C6 alkoxy groups;

[0016] R B-1 and R B-2 Independently deuterium, hydroxyl, halogen, cyano, C6-C 10 aryl, with one or more R B-1-3 Replacement C6-C 10 aryl, 3-12 heteroaryl, with one or more R B-1-4 Substituted 3-12-membered heteroaryl groups, C1-C4 alkoxy groups, C1-C4 alkoxy groups substituted with one or more deuterium groups, In the heteroaryl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-4.

[0017] R B-1-3 and R B-1-4 It is independently cyano, halogen, C1-C4 alkyl, or C1-C4 alkoxy;

[0018] R B-1-1 and R B-1-2 Independently H, deuterium, C1-C4 alkyl, or by one or more R B-1-1-1 Substituted C1-C4 alkyl groups, wherein R B-1-1-1 For deuterium, hydroxyl, or COOR B-1-1-5 ;

[0019] Or, R B-1-1 R B-1-2 Together with the nitrogen atoms attached to them, they form 5-7 membered carbon heterocycles or are formed by one or more R atoms. B-1-1-2 The substituted carbon heterocycle, wherein the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-4, wherein R B-1-1-2 For deuterium, C1-C4 alkyl, C1-C4 alkyl substituted with one or more deuterium, COOR B-1-1-6 Or C1-C4 amide group;

[0020] R A-1-1-2 R B-1-1-5 and R B-1-1-6 Independently H, deuterium, C1-C4 alkyl, or C1-C4 alkyl substituted with one or more deuterium;

[0021] R 7 R 8 R 9 R 10 and R 11 Independently, it can be either H or deuterium;

[0022] R 15 and R 16 It can be H, deuterium, or halogen independently.

[0023] In some embodiments, in the aromatic vinyl compounds represented by formula I-0, R B-1 and R B-2 Independently, it is deuterium, hydroxyl, halogen, cyano, C1-C4 alkoxy, or a C1-C4 alkoxy substituted with one or more deuterium groups. The definitions of other variables are as described in any embodiment of this invention.

[0024] The present invention provides a pharmaceutically acceptable salt of an aromatic vinyl compound as shown in Formula I, its tautomers, its stereoisomers, its racemates or isotopic derivatives thereof, or such salt as the aforementioned aromatic vinyl compound as shown in Formula I, its tautomers, its stereoisomers, its racemates or isotopic derivatives thereof.

[0025]

[0026] in:

[0027] R 1 It is cyano, C1-C4 alkyl, or C1-C4 alkyl substituted with one or more deuterium groups;

[0028] R 3 R 6 R 12 R 13 and R 14 Independently, it can be either H or deuterium;

[0029] R 2 It is hydroxyl, halogen, C1-C4 alkyl, or formed by one or more R A-1 Substituted C1-C4 alkyl, C1-C6 alkoxy, or substituted with one or more R A-2 Substituted C1-C6 alkoxy groups;

[0030] R A-1 and R A-2 Independently, it is deuterium, hydroxyl, halogen, cyano, C1-C4 alkoxy, or a C1-C4 alkoxy substituted with one or more deuterium groups. R A-1-1 It is a C1-C4 alkyl group or a C1-C4 alkyl group substituted with one or more deuterium atoms; R A-1-2 and RA-1-3 Independently H, deuterium, C1-C4 alkyl, or by one or more R A-1-1-1 Substituted C1-C4 alkyl groups, wherein R A -1-1-1 For deuterium, hydroxyl, or COOR A-1-1-2 ;

[0031] R 4 and R 5 Independently hydroxyl, halogen, C1-C4 alkyl, or with one or more R B-1 Substituted C1-C4 alkyl, C1-C6 alkoxy, or substituted with one or more R B-2 Substituted C1-C6 alkoxy groups;

[0032] R B-1 and R B-2 Independently, it is deuterium, hydroxyl, halogen, cyano, C1-C4 alkoxy, or a C1-C4 alkoxy substituted with one or more deuterium groups.

[0033] R B-1-1 and R B-1-2 Independently H, deuterium, C1-C4 alkyl, or by one or more R B-1-1-1 Substituted C1-C4 alkyl groups, wherein R B-1- 1-1 is deuterium, hydroxyl group or COOR B-1-1-5 ;

[0034] Or, R B-1-1 R B-1-2 Together with the nitrogen atoms attached to them, they form 5-7 membered carbon heterocycles or are formed by one or more R atoms. B-1-1-2 The substituted carbon heterocycle, wherein the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-4, wherein R B-1-1-2 For deuterium, C1-C4 alkyl, C1-C4 alkyl substituted with one or more deuterium, COOR B-1-1-6 Or C1-C4 amide group;

[0035] R A-1-1-2 R B-1-1-5 and R B-1-1-6 Independently H, deuterium, C1-C4 alkyl, or C1-C4 alkyl substituted with one or more deuterium;

[0036] R 7 R 8 R 9 R 10 and R 11 Independently, it is either H or deuterium.

[0037] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R1 When the alkyl group is C1-C4, the C1-C4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, for example, methyl, and the definitions of other variables are as described in any embodiment of the present invention.

[0038] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R 1 When the C1-C4 alkyl group is substituted with one or more deuterium ions, the C1-C4 alkyl group substituted with one or more deuterium ions is a C1-C2 alkyl group substituted with one or more deuterium ions, such as monodeutermethyl, dideutermethyl, trideutermethyl, monodeuterethyl, dideuterethyl, trideuterethyl, tetradeuterethyl, or pentadeuterethyl, for example, trideutermethyl, and other variables are defined as described in any embodiment of the present invention.

[0039] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R 1 When the halogen is halogen, the halogen is fluorine, chlorine, bromine or iodine, such as chlorine, and the definitions of other variables are as described in any embodiment of the present invention.

[0040] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R 1 When the C1-C4 alkyl group is substituted with one or more halogens, the halogens are fluorine, chlorine, bromine, or iodine, such as fluorine, and other variables are defined as described in any embodiment of the invention.

[0041] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R 1 When the C1-C4 alkyl group is substituted with one or more halogens, the C1-C4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, such as methyl, and other variables are defined as described in any embodiment of the invention.

[0042] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R 2 When the halogen is halogen, the halogen is fluorine, chlorine, bromine or iodine, such as chlorine, and the definitions of other variables are as described in any embodiment of the present invention.

[0043] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R 2 When the alkyl group is C1-C4, the C1-C4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, for example, methyl, and the definitions of other variables are as described in any embodiment of the present invention.

[0044] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R2 For one or more R A-1 When the substituted C1-C4 alkyl group is used, the C1-C4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, for example methyl, and other variables are defined as described in any embodiment of the invention.

[0045] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R 2 For one or more R A-1 When C1-C4 alkyl groups are substituted, each R A-1 Whether the numbers are the same or different, the "multiple" can be 2, 3, 4 or 5, and the definitions of other variables are as described in any embodiment of this invention.

[0046] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R 2 When the alkoxy group is C1-C6, the C1-C6 alkoxy group is a C1-C4 alkoxy group, such as methoxy, ethoxy, n-propoxy, or n-butoxy, or methoxy, and other variables are defined as described in any embodiment of the present invention.

[0047] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R 2 For one or more R A-2 When the C1-C6 alkoxy group is substituted, the C1-C6 alkoxy group is a C1-C4 alkoxy group, such as methoxy, ethoxy, n-propoxy, or n-butoxy, and other variables are defined as described in any embodiment of the present invention.

[0048] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R 2 For one or more R A-2 When C1-C6 alkoxy groups are substituted, each R A-2 Whether the numbers are the same or different, the "multiple" can be 2, 3, 4 or 5, and the definitions of other variables are as described in any embodiment of this invention.

[0049] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R A-1 and R A-2 When the halogen is used independently, it is fluorine, chlorine, bromine, or iodine, for example, fluorine, and other variables are defined as described in any embodiment of the invention.

[0050] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R A-1 and R A-2When independently a C1-C4 alkoxy group, the C1-C4 alkoxy group is methoxy, ethoxy, n-propoxy, or n-butoxy, for example, methoxy, and other variables are defined as described in any embodiment of the invention.

[0051] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R A-1 and R A-2 When independently a C1-C4 alkoxy group is substituted with one or more deuterium ions, the C1-C4 alkoxy group substituted with one or more deuterium ions is a C1-C2 alkoxy group substituted with one or more deuterium ions, such as monodeuterium methoxy, dideuterium methoxy, trideuterium methoxy, monodeuterium ethoxy, dideuterium ethoxy, trideuterium ethoxy, tetradeuterium ethoxy, or pentadeuterium ethoxy, such as trideuterium methoxy, and other variables are defined as described in any embodiment of the invention.

[0052] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R A-1-1 When the alkyl group is C1-C4, the C1-C4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, for example, methyl, and the definitions of other variables are as described in any embodiment of the present invention.

[0053] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R A-1-1 When the C1-C4 alkyl group is substituted with one or more deuterium ions, the C1-C4 alkyl group substituted with one or more deuterium ions is a C1-C2 alkyl group substituted with one or more deuterium ions, such as monodeutermethyl, dideutermethyl, trideutermethyl, monodeuterethyl, dideuterethyl, trideuterethyl, tetradeuterethyl, or pentadeuterethyl, for example, trideutermethyl, and other variables are defined as described in any embodiment of the present invention.

[0054] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R A-1-2 and R A -1-3 When independently a C1-C4 alkyl group, the C1-C4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, for example methyl, ethyl, or isopropyl, and other variables are defined as described in any embodiment of the invention.

[0055] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R A-1-2 and R A -1-3 Independently for one or more R A-1-1-1When the substituted C1-C4 alkyl group is used, the C1-C4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, for example, methyl, ethyl, or isopropyl, and other variables are defined as described in any embodiment of the present invention.

[0056] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R A-1-2 and R A -1-3 Independently for one or more R A-1-1-1 When C1-C4 alkyl groups are substituted, each R A-1-1-1 Whether the numbers are the same or different, the plurality can be 2, 3, 4 or 5, and the definitions of other variables are as described in any embodiment of the present invention.

[0057] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R 4 and R 5 When the halogen is used independently, it is fluorine, chlorine, bromine, or iodine, such as chlorine, and other variables are defined as described in any embodiment of the invention.

[0058] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R 4 and R 5 When independently a C1-C4 alkyl group, the C1-C4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, for example methyl, and other variables are defined as described in any embodiment of the invention.

[0059] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R 4 and R 5 Independently for one or more R B-1 When the substituted C1-C4 alkyl group is used, the C1-C4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, for example methyl, and other variables are defined as described in any embodiment of the invention.

[0060] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R 4 and R 5 Independently for one or more R B-1 When C1-C4 alkyl groups are substituted, each R B-1 The multiple can be 2, 3, 4 or 5, and the definitions of other variables are as described in any embodiment of the present invention.

[0061] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R4 and R 5 When independently a C1-C6 alkoxy group, the C1-C6 alkoxy group is a C1-C4 alkoxy group, such as methoxy, ethoxy, n-propoxy, or n-butoxy, or, for example, methoxy. Other variables are defined as described in any embodiment of the invention.

[0062] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R 4 and R 5 Independently for one or more R B-2 When the C1-C6 alkoxy group is substituted, the C1-C6 alkoxy group is a C1-C4 alkoxy group, such as methoxy, ethoxy, n-propoxy, or n-butoxy, and other variables are defined as described in any embodiment of the present invention.

[0063] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R 4 and R 5 Independently for one or more R B-2 When C1-C6 alkoxy groups are substituted, each R B-2 Whether the numbers are the same or different, the plurality can be 2, 3, 4 or 5, and the definitions of other variables are as described in any embodiment of the present invention.

[0064] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R B-1 and R B-2 When the halogen is independent, it is fluorine, chlorine, bromine, or iodine, for example, fluorine, and other variables are defined as described in any embodiment of the invention.

[0065] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R B-1 and R B-2 For C6-C independently 10 In the aryl case, the C6-C 10 The aryl group is phenyl, and the definitions of other variables are as described in any embodiment of this invention.

[0066] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R B-1 and R B-2 To independently be for one or more R B-1-3 Replacement C6-C 10 In the aryl case, the C6-C 10 The aryl group is phenyl, and the definitions of other variables are as described in any embodiment of this invention.

[0067] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R B-1 and R B-2 To independently be for one or more R B-1-3 Replacement C6-C 10 When aryl, each R B-1-3 Whether the numbers are the same or different, the plurality can be 2, 3, 4 or 5, and the definitions of other variables are as described in any embodiment of the present invention.

[0068] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R B-1 and R B-2 When the 3-12 heteroaryl group is independently defined as a 5-7 heteroaryl group, the other variables are defined as described in any embodiment of the present invention.

[0069] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R B-1 and R B-2 When the heteroaryl group is independently 3-12 nucleotides, the heteroatom of the 3-12 nucleotide is selected from N, the number of heteroatoms is 1, and the definitions of other variables are as described in any embodiment of the present invention.

[0070] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R B-1 and R B-2 To independently be for one or more R B-1-4 When the substituted 3-12 heteroaryl group is replaced, the 3-12 heteroaryl group is a 5-7 heteroaryl group, and the definitions of other variables are as described in any embodiment of the present invention.

[0071] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R B-1 and R B-2 To independently be for one or more R B-1-4 When the 3-12-membered heteroaryl group is substituted, the heteroatom of the 3-12-membered heteroaryl group is selected from N, the number of heteroatoms is 1, and the definitions of other variables are as described in any embodiment of the present invention.

[0072] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R B-1 and R B-2 To independently be for one or more R B-1-4 When substituted with 3-12 heteroaryl groups, each R B-1-4 Whether the numbers are the same or different, the plurality can be 2, 3, 4 or 5, and the definitions of other variables are as described in any embodiment of the present invention.

[0073] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R B-1-3 and R B -1-4 The variable is independently a halogen, which is fluorine, chlorine, bromine, or iodine, for example, fluorine or iodine, and other variables are defined as described in any embodiment of the invention.

[0074] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R B-1 and R B-2 The C1-C4 alkoxy group is independently defined as methoxy, ethoxy, n-propoxy, or n-butoxy, for example, methoxy, and other variables are defined as described in any embodiment of the invention.

[0075] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R B-1 and R B-2 When independently referred to as a C1-C4 alkoxy group substituted with one or more deuterium ions, the C1-C4 alkoxy group substituted with one or more deuterium ions is a C1-C2 alkoxy group substituted with one or more deuterium ions, such as monodeuterium methoxy, dideuterium methoxy, trideuterium methoxy, monodeuterium ethoxy, dideuterium ethoxy, trideuterium ethoxy, tetradeuterium ethoxy, or pentadeuterium ethoxy, such as trideuterium methoxy, and other variables are defined as described in any embodiment of the invention.

[0076] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R B-1-1 and R B -1-2 When independently a C1-C4 alkyl group, the C1-C4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, for example methyl, ethyl, or isopropyl, and other variables are defined as described in any embodiment of the invention.

[0077] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R B-1-1 and R B -1-2 Independently for one or more R B-1-1-1 When the substituted C1-C4 alkyl group is used, the C1-C4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, for example, methyl, ethyl, or isopropyl, and other variables are defined as described in any embodiment of the present invention.

[0078] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R B-1-1 and R B -1-2Independently for one or more R B-1-1-1 When C1-C4 alkyl groups are substituted, each R B-1-1-1 Whether the numbers are the same or different, the plurality can be 2, 3, 4 or 5, and the definitions of other variables are as described in any embodiment of the present invention.

[0079] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R B-1-1 R B -1-2 When the nitrogen atoms connected to them together form a 5-7 member carbon heterocycle, the heteroatom in the carbon heterocycle is N and / or O, and the definitions of other variables are as described in any embodiment of the present invention.

[0080] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R B-1-1 R B -1-2 When the carbon heterocycles formed together with the nitrogen atoms connected to them form a 5-7 member carbon heterocycle, the number of heteroatoms in the carbon heterocycle is 1 or 2, and the definitions of other variables are as described in any embodiment of the present invention.

[0081] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R B-1-1 R B -1-2 Together with the nitrogen atoms bonded to them, they form a group consisting of one or more R atoms. B-1-1-2 When a substituted carbon heterocycle is used, the heteroatom in the carbon heterocycle is N and / or O, and the definitions of other variables are as described in any embodiment of the present invention.

[0082] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R B-1-1 R B -1-2 Together with the nitrogen atoms bonded to them, they form a group consisting of one or more R atoms. B-1-1-2 When a substituted carbon heterocycle is used, the number of heteroatoms in the carbon heterocycle is 1 or 2, and the definitions of other variables are as described in any embodiment of the present invention.

[0083] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R B-1-1 R B -1-2 Together with the nitrogen atoms bonded to them, they form a group consisting of one or more R atoms. B-1-1-2 When a carbon heterocycle is substituted, each R B-1-1-2 Whether the numbers are the same or different, the plurality can be 2, 3, 4 or 5, and the definitions of other variables are as described in any embodiment of the present invention.

[0084] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when the R B-1 -1 -2 When the alkyl group is C1-C4, the C1-C4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, for example, methyl, and the definitions of other variables are as described in any embodiment of the present invention.

[0085] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when the R B -1-1-2 When the C1-C4 alkyl group is substituted with one or more deuterium ions, the C1-C4 alkyl group substituted with one or more deuterium ions is a C1-C2 alkyl group substituted with one or more deuterium ions, such as monodeutermethyl, dideutermethyl, trideutermethyl, monodeuterethyl, dideuterethyl, trideuterethyl, tetradeuterethyl, or pentadeuterethyl, for example, trideutermethyl, and other variables are defined as described in any embodiment of the present invention.

[0086] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when the R B -1-1-2 When the amide group is C1-C4, the C1-C4 amide group is R B-1-1-3 and R B-1-1-4 Independently, it is H, deuterium, C1-C4 alkyl, or a C1-C4 alkyl substituted with one or more deuterium, 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 deuterium is, for example, trideuterylmethyl, and other variables are defined as described in any embodiment of the invention.

[0087] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, when R A-1-1-2 R B -1-1-5 and R B-1-1-6 When independently a C1-C4 alkyl group, the C1-C4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, for example methyl, and other variables are defined as described in any embodiment of the invention.

[0088] In some embodiments, in the aromatic vinyl compounds represented by formula I-0, when R 15 and R 16 When the halogen is independent, it is fluorine, chlorine, bromine, or iodine, such as fluorine or bromine, and other variables are defined as described in any embodiment of the invention.

[0089] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, R 3 R 6 R 12 R 13 and R 14 H is independent of H, and the definitions of other variables are as described in any embodiment of this invention.

[0090] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, R 2 It is a halogen, C1-C4 alkyl, or formed by one or more R A-1 The substituted C1-C4 alkyl groups, and other variables are defined as described in any embodiment of the invention.

[0091] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, R A-1 and R A-2 Independently hydroxyl, halogen, cyano, C1-C4 alkoxy, The definitions of other variables are as described in any embodiment of this invention.

[0092] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, R A-1 Halogen or The definitions of other variables are as described in any embodiment of this invention.

[0093] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, R A-1 For halogens, the definitions of other variables are as described in any embodiment of this invention.

[0094] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, R A-1-1 It is a C1-C4 alkyl group, and the definitions of other variables are as described in any embodiment of the present invention.

[0095] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, R A-1-2 and R A-1-3 Independently for H or by one or more R A-1 -1-1 substituted C1-C4 alkyl groups, and other variables are defined as described in any embodiment of the invention.

[0096] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, R A-1-2 and R A-1-3 One is H, and the other is one or more R. A-1-1-1The substituted C1-C4 alkyl groups, and other variables are defined as described in any embodiment of the invention.

[0097] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, R A-1-1-2 R B -1-1-5 and R B-1-1-6 Independently, it is H or C1-C4 alkyl, and other variables are defined as described in any embodiment of the invention.

[0098] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, R A-1-1-2 R B -1-1-5 and R B-1-1-6 H is independent of H, and the definitions of other variables are as described in any embodiment of this invention.

[0099] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, the one or more R A-1-1-1 The substituted C1-C4 alkyl groups are The definitions of other variables are as described in any embodiment of this invention.

[0100] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, the one or more R A-1-1-1 The substituted C1-C4 alkyl groups are The definitions of other variables are as described in any embodiment of this invention.

[0101] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, R 4 and R 5 Independently halogenated, C1-C4 alkyl, and oxidized by one or more R B-1 Substituted C1-C4 alkyl, C1-C6 alkoxy, or substituted with one or more R B-2 The substituted C1-C6 alkoxy groups, and other variables are defined as described in any embodiment of the invention.

[0102] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, R B-1 and R B-2 To be independently deuterium, hydroxyl, cyano, C6-C 10 aryl, with one or more R B-1-3 Replacement C6-C 10 aryl, 3-12 heteroaryl, with one or more R B-1-4 Substituted 3-12-membered heteroaryl groups, C1-C4 alkoxy groups, C1-C4 alkoxy groups substituted with one or more deuterium groups, The definitions of other variables are as described in any embodiment of this invention.

[0103] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, R B-1 and R B-2 Independently, it can be deuterium, hydroxyl, cyano, C1-C4 alkoxy, or C1-C2 alkoxy substituted with one or more deuterium groups. The definitions of other variables are as described in any embodiment of this invention.

[0104] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, R B-1 It is a hydroxyl group, a C1-C4 alkoxy group, a C1-C2 alkoxy group substituted with one or more deuterium groups, or The definitions of other variables are as described in any embodiment of this invention.

[0105] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, R B-1 hydroxyl or The definitions of other variables are as described in any embodiment of this invention.

[0106] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, R B-2 It is deuterium, cyano, hydroxyl, C6-C 10 aryl, with one or more R B-1-3 Replacement C6-C 10 aryl, 3-12 heteroaryl, with one or more R B-1-4 The substituted 3-12 heteroaryl or C1-C4 alkoxy groups, and other variables are defined as described in any embodiment of the present invention.

[0107] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, R B-2 The group is deuterium, cyano, hydroxyl, or C1-C4 alkoxy, and other variables are defined as described in any embodiment of the present invention.

[0108] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, R B-1-3 and R B-1-4 Independently, it can be either cyano or halogen, and other variables are defined as described in any embodiment of the invention.

[0109] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, the one or more R B-1-3 Replacement C6-C 10 Aryl is The definitions of other variables are as described in any embodiment of this invention.

[0110] In some embodiments, in the aromatic ethylene compounds represented by formula I-0 or I, the 3-12 heteroaryl group is... Other variables are defined as described in any embodiment of the invention. In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, the one or more R B-1-4 The substituted 3-12 heteroaryl group is The definitions of other variables are as described in any embodiment of this invention.

[0111] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, R B-1-1 and R B-1-2 Independently for H or by one or more R B-1-1-1 Substituted C1-C4 alkyl; or, R B-1-1 R B-1-2 Together with the nitrogen atoms bonded to them, they form 5-7 nucleotides bounded by one or more R atoms. B-1-1-2 The substituted carbon heterocycle, and other variables are defined as described in any embodiment of the invention.

[0112] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, R B-1-1 and R B-1-2 One is H, and the other is one or more R. B-1-1-1 Substituted C1-C4 alkyl; or, R B-1-1 R B-1-2 Together with the nitrogen atoms bonded to them, they form 5-7 nucleotides bounded by one or more R atoms. B-1-1-2 The substituted carbon heterocycle, and other variables are defined as described in any embodiment of the invention.

[0113] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, the one or more R B-1-1-1 The substituted C1-C4 alkyl groups are The definitions of other variables are as described in any embodiment of this invention.

[0114] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, the one or more R B-1-1-1 The substituted C1-C4 alkyl groups are The definitions of other variables are as described in any embodiment of this invention.

[0115] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, R B-1-1-2C1-C4 alkyl, COOR B-1-1-6 Or C1-C4 amide groups, and the definitions of other variables are as described in any embodiment of the present invention.

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

[0117] In some embodiments, in the aromatic ethylene compounds represented by formula I-0 or I, the carbon heterocycle is The definitions of other variables are as described in any embodiment of this invention.

[0118] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, the one or more R B-1-1-2 The substituted carbon heterocycle is The definitions of other variables are as described in any embodiment of this invention.

[0119] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, the one or more R B-1-1-2 The substituted carbon heterocycle is The definitions of other variables are as described in any embodiment of this invention.

[0120] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, R 4 for The definitions of other variables are as described in any embodiment of this invention.

[0121] In some embodiments, in the aromatic vinyl compounds represented by formula I-0 or I, R 5 Halogen, C1-C4 alkyl, or with one or more R B-1 Substituted C1-C4 alkyl, C1-C6 alkoxy, or substituted with one or more R B-2 Substituted C1-C6 alkoxy groups; R B-1 and R B-2 It can be independently deuterium, hydroxyl, cyano, C1-C4 alkoxy, C1-C2 alkoxy substituted with one or more deuterium groups, or The definitions of other variables are as described in any embodiment of this invention.

[0122] In some embodiments, the aromatic vinyl compounds represented as of formula I-0 or I, for The definitions of other variables are as described in any embodiment of this invention.

[0123] In some embodiments, the aromatic vinyl compounds represented as of formula I-0 or I, for The definitions of other variables are as described in any embodiment of this invention.

[0124] In some embodiments, the aromatic vinyl compounds represented as of formula I-0 or I, for The definitions of other variables are as described in any embodiment of this invention.

[0125] In some embodiments, the aromatic vinyl compounds represented as of formula I-0 or I, for

[0126] In some embodiments, in the aromatic vinyl compounds represented by formula I-0, R 15 and R 16 At least one of them is H or deuterium, and the other variables are defined as described in any embodiment of the present invention.

[0127] In some embodiments, in the aromatic vinyl compounds represented by formula I-0, R 15 For H or deuterium; R 16 The variable is H, deuterium, or halogen, and the other variables are defined as described in any embodiment of the present invention.

[0128] In some embodiments, in the aromatic vinyl compounds represented by formula I-0, R 1 The variable is a halogen, a C1-C4 alkyl group substituted with one or more halogens, and other variables are defined as described in any embodiment of the invention.

[0129] In some embodiments, in the aromatic vinyl compounds represented by formula I-0, R 15 The variable is either deuterium or halogen, and the other variables are defined as described in any embodiment of the present invention.

[0130] In some embodiments, in the aromatic vinyl compounds represented by formula I-0, R 16 The variable is either deuterium or halogen, and the other variables are defined as described in any embodiment of the present invention.

[0131] In some embodiments, the aromatic vinyl compound represented by formula I-0 or I is selected from any of the following schemes, Scheme 1: R 2 for R 4 and R 5 Independently halogenated, C1-C4 alkyl, and oxidized by one or more R B-1Substituted C1-C4 alkyl, C1-C6 alkoxy, or substituted with one or more R B-2 Substituted C1-C6 alkoxy groups; R B-1 and R B-2 It can be independently deuterium, hydroxyl, cyano, C1-C4 alkoxy, C1-C2 alkoxy substituted with one or more deuterium groups, or R 3 R 6 R 12 R 13 and R 14 For H;

[0132] Option 2: R 2 It is a halogen, C1-C4 alkyl, or formed by one or more R A-1 Substituted C1-C4 alkyl; R A-1 It is a halogen; R 4 for R 5 Halogen, hydroxyl, C1-C4 alkyl, or with one or more R B-1 Substituted C1-C4 alkyl, C1-C6 alkoxy, or substituted with one or more R B-2 Substituted C1-C6 alkoxy groups; R B-1 and R B-2 It can be independently deuterium, hydroxyl, cyano, C1-C4 alkoxy, C1-C2 alkoxy substituted with one or more deuterium groups, or R 3 R 6 R 12 R 13 and R 14 For H;

[0133] Option 3: R 2 It is a halogen, C1-C4 alkyl, or formed by one or more R A-1 Substituted C1-C4 alkyl; R A-1 It is a halogen; R 4 Halogen, C1-C4 alkyl, or with one or more R B-1 Substituted C1-C4 alkyl, C1-C6 alkoxy, or substituted with one or more R B-2 Substituted C1-C6 alkoxy groups; R B-1 and R B-2 It can be independently deuterium, hydroxyl, cyano, C1-C4 alkoxy, C1-C2 alkoxy substituted with one or more deuterium groups, or R 5 for R 3 R 6 R 12 R 13 and R 14 For H;

[0134] Option 4: R 2 for R 4 and R 5 Independently halogenated, C1-C4 alkyl, and oxidized by one or more R B-1 Substituted C1-C4 alkyl, C1-C6 alkoxy, or substituted with one or more R B-2 Substituted C1-C6 alkoxy groups; R B-1 and R B-2 It can be independently deuterium, hydroxyl, cyano, C1-C4 alkoxy, C1-C2 alkoxy substituted with one or more deuterium groups, or R 3 R 6 R 12 R 13 and R 14 For H; R 15 and R 16 At least one of them is H or deuterium;

[0135] Option 5: R 2 It is a halogen, C1-C4 alkyl, or formed by one or more R A-1 Substituted C1-C4 alkyl; R A-1 It is a halogen; R 4 for R 5 Halogen, hydroxyl, C1-C4 alkyl, or with one or more R B-1 Substituted C1-C4 alkyl, C1-C6 alkoxy, or substituted with one or more R B-2 Substituted C1-C6 alkoxy groups; R B-1 and R B-2 It can be independently deuterium, hydroxyl, cyano, C1-C4 alkoxy, C1-C2 alkoxy substituted with one or more deuterium groups, or R 3 R 6 R 12 R 13 and R 14 For H; R 15 and R 16 At least one of them is H or deuterium;

[0136] Option Six: R 2 It is a halogen, C1-C4 alkyl, or formed by one or more R A-1 Substituted C1-C4 alkyl; R A-1 It is a halogen; R 4 Halogen, C1-C4 alkyl, or with one or more R B-1 Substituted C1-C4 alkyl, C1-C6 alkoxy, or substituted with one or more R B-2Substituted C1-C6 alkoxy groups; R B-1 and R B-2 It can be independently deuterium, hydroxyl, cyano, C1-C4 alkoxy, C1-C2 alkoxy substituted with one or more deuterium groups, or R 5 for R 3 R 6 R 12 R 13 and R 14 For H; R 15 and R 16 At least one of them is H or deuterium.

[0137] In some embodiments, in the aromatic vinyl compounds represented by formula I-0, R 1 The alkyl group is cyano, CH3, CD3, Cl, CH2F, or a C1-C4 alkyl group substituted with one or more halogens. Other variables are defined as described in any embodiment of the present invention.

[0138] In some embodiments, the aromatic vinyl compounds represented as of Formula I-0, for

[0139]

[0140]

[0141] The definitions of other variables are as described in any embodiment of this invention.

[0142] In some embodiments, in the aromatic vinyl compounds represented by formula I-0, R 15 and R 16 The variables are independently H, deuterium, Br, or F, and the other variables are defined as described in any embodiment of the present invention.

[0143] In some embodiments, the aromatic vinyl compound represented by formula I-0 or I is any of the following compounds:

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151] The present invention also provides a method for preparing the aromatic ethylene compound shown in Formula I-0, wherein the method for preparing the aromatic ethylene compound shown in Formula I-0 includes the following methods 1, 2, 3, 4, 5, or 6:

[0152] Method 1 includes the following steps: In a solvent, under the action of a reducing agent, the compound shown in Formula II-a-0 and the compound shown in Formula III-a undergo a reductive amination reaction as shown below to obtain an aromatic vinyl compound shown in Formula I-0.

[0153]

[0154] In Method 1, R 4 for 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 is as stated above;

[0155] Method 2 includes the following steps: In a solvent, under the action of a base, the compound shown in Formula II-b-0 and the compound shown in Formula III-a undergo the following substitution reaction to obtain the aromatic ethylene compound shown in Formula I-0.

[0156]

[0157] In Method 2, R 4 for R 1 R 2 R 3 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R12 R 13 R 14 R 15 R 16 R B-1-1 and R B-1-2 As defined above, X 1 It is a halogen;

[0158] Method 3 includes the following steps: In a solvent, under the action of a reducing agent, the compound shown in Formula II-c-0 and the compound shown in Formula III-a undergo a reductive amination reaction as shown below to obtain an aromatic vinyl compound shown in Formula I-0.

[0159]

[0160] In method 3, R 5 for 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 is as stated above;

[0161] Method 4 includes the following steps: In a solvent, under the action of a base, the compound shown in Formula II-d-0 and the compound shown in Formula III-a undergo the following substitution reaction to obtain the aromatic ethylene compound shown in Formula I-0.

[0162]

[0163] In method 4, R 5 for 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 R15 R 16 R B-1-1 and R B-1-2 As defined above, X 2 It is a halogen;

[0164] Method 5 includes the following steps: In a solvent, under the action of a reducing agent, the compound shown as shown in Formula II-e-0 and the compound shown as shown in Formula III-b undergo a reductive amination reaction as shown below to obtain an aromatic vinyl compound shown as shown in Formula I-0.

[0165]

[0166] In Method 5, R 2 for 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 is as stated above;

[0167] Method 6 includes the following steps: In a solvent, under the action of a base, the compound shown in Formula II-f-0 and the compound shown in Formula III-b are subjected to the following substitution reaction to obtain the aromatic ethylene compound shown in Formula I-0.

[0168]

[0169] In Method 6, R 2 for 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 RA -1-1 and R A-1-2 As defined above, X 3 It is a halogen.

[0170] The present invention also provides a method for preparing the aromatic ethylene compound as shown in Formula I, wherein the method for preparing the aromatic ethylene compound as shown in Formula I includes the following methods: Method 1, Method 2, Method 3, Method 4, Method 5, or Method 6:

[0171] Method 1 includes the following steps: In a solvent, under the action of a reducing agent, the compound shown in Formula II-a and the compound shown in Formula III-a undergo a reductive amination reaction as shown below to obtain an aromatic vinyl compound shown in Formula I.

[0172]

[0173] In Method 1, R 4 for 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 is as stated above;

[0174] Method 2 includes the following steps: In a solvent, under the action of a base, the compound shown in Formula II-b and the compound shown in Formula III-a undergo the following substitution reaction to obtain the aromatic ethylene compound shown in Formula I.

[0175]

[0176] In Method 2, R 4 for 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 B-1-1 and R B-1-2 As defined above, X 1 It is a halogen;

[0177] Method 3 includes the following steps: In a solvent, under the action of a reducing agent, the compound shown in Formula II-c and the compound shown in Formula III-a undergo a reductive amination reaction as shown below to obtain an aromatic vinyl compound shown in Formula I.

[0178]

[0179] In Method 3, R 5 for 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 is as stated above;

[0180] Method 4 includes the following steps: In a solvent, under the action of a base, the compound shown in Formula II-d and the compound shown in Formula III-a undergo the following substitution reaction to obtain the aromatic ethylene compound shown in Formula I.

[0181]

[0182] In Method 4, R 5 for 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 As defined above, X 2 It is a halogen;

[0183] Method 5 includes the following steps: In a solvent, under the action of a reducing agent, the compound shown in Formula II-e and the compound shown in Formula III-b undergo a reductive amination reaction as shown below to obtain an aromatic vinyl compound shown in Formula I.

[0184]

[0185] In Method 5, R 2 for 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 is as stated above;

[0186] Method six includes the following steps: In a solvent, under the action of a base, the compound shown in formula II-f and the compound shown in formula III-b undergo the following substitution reaction to obtain the aromatic ethylene compound shown in formula I.

[0187]

[0188] In Method Six, R 2 for 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 As defined above, X 3 It is a halogen.

[0189] In Method 1, Method 3, Method 5, Method 1, Method 3, or Method 5, the methods and conditions for the reductive amination reaction can be conventional methods and conditions for such reactions in the art.

[0190] In Method 2, Method 4, Method 6, Method 2, Method 4, or Method 6, the substitution reaction methods and conditions described can be conventional methods and conditions for such reactions in the art.

[0191] The present invention also provides compounds such as II-a-O, II-b-O, II-c-O, II-d-O, II-e-O, or II-f-O.

[0192]

[0193] In the above general formula compounds, 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 As defined above, X 1 X 2 and X 3 Halogens are independent of each other.

[0194] The present invention also provides compounds such as II-a, II-b, II-c, II-d, II-e, or II-f.

[0195]

[0196]

[0197] In the above general formula compounds, 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 As defined above, X 1 X 2 and X 3 Halogens are independent of each other.

[0198] In some embodiments, the compound represented as II-a-0 or II-a is any of the following compounds:

[0199]

[0200]

[0201]

[0202]

[0203] In some embodiments, the compound shown as II-b is a compound that is:

[0204]

[0205] In some embodiments, the compound shown as II-c is any of the following compounds:

[0206]

[0207] In some embodiments, the compound shown as II-e is any of the following compounds:

[0208]

[0209] The present invention also provides pharmaceutically acceptable salts of any of the following aromatic vinyl compounds, their tautomers, their stereoisomers, their racemates or their isotopic derivatives, or any of them (referring to any of the aforementioned aromatic vinyl compounds, their tautomers, their stereoisomers, their racemates or their isotopic derivatives).

[0210]

[0211] The present invention also provides a pharmaceutical composition comprising the above-mentioned aromatic vinyl compounds, their tautomers, their stereoisomers, their racemates or their isotopic derivatives, or pharmaceutically acceptable salts thereof (referring to the aforementioned aromatic vinyl compounds, their tautomers, their stereoisomers, their racemates or their isotopic derivatives), and pharmaceutical excipients.

[0212] The present invention also provides a pharmaceutical composition comprising the aforementioned aromatic vinyl compounds, their tautomers, their stereoisomers, their racemates or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof (referring to the aforementioned aromatic vinyl compounds, their tautomers, their stereoisomers, their racemates or isotopic derivatives thereof), 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.

[0213] In the pharmaceutical composition described herein, the amount of the aromatic vinyl compound, its tautomer, its stereoisomer, its racemate or its isotopic derivative, or a pharmaceutically acceptable salt thereof (referring to the aforementioned aromatic vinyl compound, its tautomer, its stereoisomer, its racemate or its isotopic derivative) may be a therapeutically effective amount.

[0214] The pharmaceutical excipients may be those widely used in the pharmaceutical manufacturing industry. Excipients primarily serve to provide a safe, stable, and functional pharmaceutical composition, and may also provide methods to enable the active ingredient to dissolve at a desired rate after administration to a subject, or to promote the effective absorption of the active ingredient after administration to a subject. The pharmaceutical excipients may be inert fillers, or provide a function such as stabilizing the overall pH of the composition or preventing the degradation of the active ingredient. The pharmaceutical excipients may include one or more of the following: binders, suspending agents, emulsifiers, diluents, fillers, granulators, adhesives, disintegrants, lubricants, anti-adhesion agents, flow aids, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

[0215] The pharmaceutical compositions of the present invention can be prepared using any method known to those skilled in the art, based on the disclosure. For example, conventional mixing, dissolving, granulation, emulsification, grinding, encapsulation, embedding, or lyophilization processes.

[0216] The pharmaceutical compositions of this invention can be administered in any form, including by injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ocular, rectal, topical, or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intra-arterial, intramuscular) administration. The pharmaceutical compositions of this invention can also be 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, tablets, soft capsules, 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 preparations. Examples of parenteral formulations include, but are not limited to, solutions for injection, dry formulations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic preparations; aerosols, such as nasal sprays or inhalers; liquid dosage forms suitable for parenteral administration; suppositories; and tablets.

[0217] The present invention also provides the use of the above-mentioned aromatic vinyl compounds, their tautomers, their stereoisomers, their racemates or their isotopic derivatives, or pharmaceutically acceptable salts thereof (referring to the above-mentioned aromatic vinyl compounds, their tautomers, their stereoisomers, their racemates or their isotopic derivatives), and the above-mentioned pharmaceutical compositions in the preparation of PD-1 inhibitors and / or PD-L1 inhibitors.

[0218] In the aforementioned applications, the PD-1 inhibitor or PD-L1 inhibitor can be used in mammalian organisms; it can also be used in vitro, primarily for experimental purposes, such as providing a standard or control sample for comparison, or preparing a kit according to conventional methods in the art to provide rapid detection of PD-1 or PD-L1 inhibition effects.

[0219] The present invention also provides the use of the above-mentioned aromatic vinyl compounds, their tautomers, their stereoisomers, their racemates or their isotopic derivatives, or pharmaceutically acceptable salts thereof (referring to the aforementioned aromatic vinyl compounds, their tautomers, their stereoisomers, their racemates or their isotopic derivatives), and the above-mentioned pharmaceutical compositions in the preparation of medicaments for the prevention and / or treatment of diseases related to the PD-1 / PD-L1 signaling pathway.

[0220] The diseases related to the PD-1 / PD-L1 signaling pathway are selected from cancer, infectious diseases, autoimmune diseases, or related diseases.

[0221] The cancer is preferably one or more of the following: lung cancer, esophageal cancer, gastric cancer, colorectal cancer, hematologic malignancy, lymphoma, head and neck cancer, liver cancer, nasopharyngeal carcinoma, brain tumor, breast cancer, cervical cancer, leukemia, and bone cancer.

[0222] The infectious diseases are preferably bacterial and / or viral infections.

[0223] The autoimmune disease is preferably one or more of the following: rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, systemic vasculitis, and relapsing polychondritis.

[0224] Unless otherwise specified, the terms used in this invention have the following meanings:

[0225] The term "pharmaceutically acceptable" means that the salts, solvents, excipients, etc., are generally non-toxic, safe, and suitable for patient use. The term "patient" preferably refers to a mammal, and more preferably a human.

[0226] The term "pharmaceutically acceptable salt" refers to a salt prepared from the compounds of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting a sufficient amount of a pharmaceutically acceptable base with the neutral form of such compounds in a pure solution or a suitable inert solvent. 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, and diethanolamine salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting a sufficient amount of a pharmaceutically acceptable acid with the neutral form of such compounds in a pure solution or a suitable inert solvent. Pharmaceutically acceptable acids include inorganic acids, including but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, and sulfuric acid. The pharmaceutically acceptable acids include organic acids, including but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acidic citric acid, oleic acid, tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentian acid, fumaric acid, gluconic acid, succinic acid, formic acid, ethanesulfonic acid, dihydroxynaphthyl acid (i.e., 4,4'-methylene-bis(3-hydroxy-2-naphthylcarboxylic acid)), amino acids (e.g., 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 details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0227] The terms "compound," "tautomer," "stereoisomer," "racemate," "isotope derivative," and their "pharmaceutically acceptable salts" can exist in crystalline or amorphous forms. The term "crystalline form" refers to a state in which the ions or molecules are arranged in a strictly periodic manner in three-dimensional space, exhibiting a regular repetition at certain intervals; due to different periodsic arrangements, multiple crystalline forms can exist, a phenomenon known as polymorphism. The term "amorphous" refers to a state in which the ions or molecules are distributed randomly, meaning that there is no periodic arrangement between the ions and molecules.

[0228] The term "stereoisomer" refers to cis-trans isomers or optical isomers. These stereoisomers can be separated, purified, and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin-layer chromatography, rotational chromatography, column chromatography, gas chromatography, high-performance liquid chromatography, etc.). They can also be obtained by chiral resolution through bonding (chemical bonding, etc.) or salt formation (physical bonding, etc.) with other chiral compounds.

[0229] The term "isotope derivative" refers to atoms in a "compound," "tautomer," "stereoisomer," "racemate," and their "pharmaceutically acceptable salts" that can exist in either their natural or non-natural abundance. For example, the natural abundance of hydrogen atoms means that approximately 99.985% is protium and approximately 0.015% is deuterium; its non-natural abundance means that approximately 95% is deuterium. That is, one or more atoms in the terms "compound," "tautomer," "stereoisomer," "racemate," and their "pharmaceutically acceptable salts" can be atoms existing in a non-natural abundance.

[0230] When any variable (e.g., R) A-1 When a variable appears multiple times in the definition of a compound, the definition at each position is independent of the definitions at the other positions; their meanings are independent and do not affect each other. Therefore, if a group is surrounded by 1, 2, 3, 4, or 5 R... A-1 Group substitution, meaning that the group can be replaced by up to 5 R groups. A-1 Replace, the position R A-1 Definition and other positions R A-1 The definitions of substituents and / or variables are independent and can be either different or the same. Furthermore, combinations of substituents and / or variables are only permitted if the combination produces a stable compound.

[0231] The term "alkyl" refers to a straight-chain or branched alkyl group having a specified number of carbon atoms.

[0232] The term "alkoxy group" refers to the group -OR X , where R X It is an alkyl group as defined above.

[0233] The term "pharmaceutical excipients" refers to the excipients and additives used in the production of pharmaceuticals and the dispensing of prescriptions. It includes all substances contained in pharmaceutical preparations, excluding the active ingredient. See the Pharmacopoeia of the People's Republic of China (2015 Edition), Volume IV, or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009 Sixth Edition).

[0234] The term "prevention" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0235] The term “treatment” refers to a therapeutic approach. When a specific condition is involved, treatment means: (1) alleviating one or more biological manifestations of the disease or condition; (2) interfering with (a) one or more points in a biological cascade that causes or precipitates the condition or (b) one or more biological manifestations of the condition; (3) improving one or more symptoms, effects or side effects associated with the condition, or one or more symptoms, effects or side effects associated with the condition or its treatment; or (4) slowing the development of the condition or one or more biological manifestations of the condition.

[0236] 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, and humans, with humans being the most preferred.

[0237] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0238] The reagents and raw materials used in this invention are all commercially available.

[0239] The positive and progressive effects of this invention are as follows: the aromatic ethylene compounds of this invention or their pharmaceutically acceptable salts have significant inhibitory effects on PD-1 and PD-L1, and at the same time have better peak drug concentration, area under the curve and oral bioavailability, which can effectively alleviate or treat cancer and other related diseases. Detailed Implementation

[0240] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0241] In the following embodiments, room temperature refers to 10°C-30°C; overnight refers to 8-24 hours, preferably 12-18 hours.

[0242] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR spectra were obtained using a Bruker Avance-500 instrument with deuterated dimethyl sulfoxide, deuterated chloroform, and deuterated methanol as solvents, and tetramethylsilane (TMS) as an internal standard. Mass spectra were obtained using an Agilent Technologies 6110 liquid chromatography-mass spectrometry (LC-MS) system with an ESI ion source.

[0243] The microwave reaction was carried out in the Explorer fully automated microwave synthesizer manufactured by CEM Corporation in the United States, with a magnetron frequency of 2450MHz and a continuous microwave output power of 300W.

[0244] The instrument used for HPLC preparation was a Waters 2767, and the preparative column 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 ammonium bicarbonate aqueous solution. The flow rate was 15 mmL / min. The gradient was 20%–70% (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.

[0245] Example 1

[0246] (S,E)-1-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-3-trifluoromethylbenzyl)piperidine-2-carboxylic acid (Compound 1)

[0247]

[0248] Synthesis of compound 1-c

[0249] 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(diphenylphosphine)ferrocene]palladium dichloride (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, concentrated under reduced pressure, and 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%).

[0250] Synthesis of compound 1-b

[0251] To a solution of compound 1-c (1.50 g, 7.0 mmol) and vinylpinacol 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 hours. 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, yield: 82%).

[0252] 1 H NMR (400MHz, CD3Cl): δ7.67 (dd, J=1.2Hz, 7.6Hz, 1H), 7.59 (t, J=8.0Hz, 1H), 7.53-7.56 (m, 2H), 7.44-7.50 (m, 3H), 7.37 (dd, J=1.2Hz, 7.6Hz, 1H), 7.20 (dd, J=10.8Hz, 17.6Hz, 1H), 5.96 (d, J=17.6Hz, 1H), 5.57 (d, J=10.8Hz, 1H) ppm

[0253] Synthesis of compound 1-a

[0254] Compound 1-b (100 mg, 0.487 mmol) and 4-bromo-3-trifluoromethylbenzaldehyde (123 mg, 0.487 mmol) were dissolved in toluene solution (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 three times at room temperature, 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 successively with water (100 mL × 3) and saturated brine (100 mL). The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and 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%).

[0255] 1H NMR (400MHz, CDCl3): δ10.01(s,1H),8.15(s,1H),8.05-8.00(m,2H),7.77-7.75(d,J=8.0Hz,1H),7.67-7.60(m,3H),7.51-7.39(m,6H)ppm

[0256] Synthesis of Compound 1

[0257] 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 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 then subjected to high performance liquid chromatography to prepare compound 1 (15 mg, yield: 18.8%).

[0258] LC-MS (ESI): m / z = 491.0 [M+H] + .

[0259] 1 H NMR (400MHz, CD3OD): δ8.08-8.06(d,J=8.0Hz,1H),8.03(s,1H),7.93-7.88(m,2H),7.81 -7.77(t,J=8.0Hz,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=12.8Hz,1H),4.21-4.17(m,1H),3.53-3.50(m,1H),3.39-3.36(m,1H),3.02-2.9 7(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.

[0260] Example 2

[0261] (S,E)-1-(3-chloro-4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)benzyl)piperidin-2-carboxylic acid (compound 2)

[0262]

[0263] Synthesis of compound 2-a

[0264] Compound 1-b (205.0 mg, 1.0 mmol) and 4-bromo-3-chlorobenzaldehyde (240.9 mg, 1.1 mmol) were dissolved in toluene solution (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 three times at room temperature, heated to 90 °C, and stirred for 10 hours. 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, concentrated under reduced pressure, and 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%).

[0265] Synthesis of Compound 2

[0266] 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 mixture was heated to 60 °C and stirred for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was then treated by high performance liquid chromatography to obtain a white solid 2 (75 mg, yield: 32%).

[0267] LC-MS (ESI): m / z = 457.3 [M+H] + .

[0268] 1 H NMR (400MHz, CD3OD): δ7.97(d,J=7.2Hz,1H),7.93(t,J=8.0Hz,1H),7.82-7.75(m,3H),7.66-7.47(m,3H),4.62(d, J=12.8Hz,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.

[0269] Example 3

[0270] (S,E)-1-(3-chloro-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)benzyl)piperidin-2-carboxylic acid (compound 3)

[0271]

[0272] Synthesis of compound 3-c

[0273] Phenylated acid (1.626 g, 13.34 mmol) and 2,6-dibromotoluene (5.0 g, 20.0 mmol) were dissolved in a mixed solution of 1,4-dioxane (60 mL) and water (3 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (1.154 g, 1.334 mmol) and sodium carbonate (3.535 g, 33.35 mmol) were added. The reaction mixture was purged with nitrogen three times, 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 successively with water (100 mL × 3) and saturated brine (100 mL). The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to give compound 3-c (1.9 g, yield: 57.2%).

[0274] 1 H NMR (400MHz, CDCl3): δ7.56-7.54(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

[0275] Synthesis of compound 3-b

[0276] Compound 3-c (1.071 g, 4.33 mmol) and pinacol vinylborate (800.9 mg, 5.20 mmol) were dissolved in toluene (50 mL). Di(tri-tert-butylphosphine)palladium (154.8 mg, 0.303 mmol) and triethylamine (3.51 g, 34.64 mmol) were added. The reaction mixture was purged with nitrogen three times and then heated to 80 °C with stirring for 16 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (50 mL), and then washed successively with water (50 mL × 3) and saturated brine (50 mL). The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to give compound 3-b (0.89 g, yield: 64.1%).

[0277] 1 H NMR (400MHz, CDCl3): δ7.75-7.71(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

[0278] Synthesis of compound 3-a

[0279] 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(diphenylphosphine)ferrocene]palladium dichloride (79 mg, 0.091 mmol) were added. The reaction mixture was purged three times with nitrogen at room temperature. The mixture was heated to 80 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 mL), then washed with water (100 mL × 3) and saturated brine (100 mL). The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1 to 5:1) to give compound 3-a (175 mg, yield: 57.8%).

[0280] 1 H NMR (400MHz, CDCl3): δ9.90 (s, 1H), 7.85-7.79 (m, 2H), 7.72-7.70 (d, J = 8.0Hz, 1H), 7.6 0-7.57(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

[0281] Synthesis of Compound 3

[0282] Compound 3-a (175 mg, 0.526 mmol) was suspended in methanol (15 mL) solution, 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, concentrated under reduced pressure, and the residue was treated by high performance liquid chromatography to obtain compound 3 (43 mg, yield: 18.3%).

[0283] LC-MS (ESI): m / z = 446.0 [M+H] + .

[0284] 1H NMR (400MHz, CD3OD): δ7.82-7.80(d,J=8.0Hz,1H),7.58(s,1H),7.52-7.48(m,2H),7.41-7.39(d, J=7.2Hz,1H),7.34-7.25(m,4H),7.20-7.16(m,3H),7.07-7.06(d,J=6.8Hz,1H),4.50-4.47(d,J=1 2.4Hz,1H),3.99-3.94(m,1H),3.37-3.34(d,J=10.4Hz,1H),3.28-3.25(m,1H),2.88-2.82(t,J=1 2.4Hz,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.

[0285] Example 4

[0286] (S,E)-1-(4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-3-trifluoromethylbenzyl)piperidine-2-carboxylic acid (compound 4)

[0287]

[0288] Synthesis of compound 4-a

[0289] 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(diphenylphosphine)ferrocene]palladium dichloride (69 mg, 0.079 mmol) were added. The reaction mixture was purged three times with nitrogen at room temperature. The mixture was heated to 80 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 mL), then washed with water (100 mL × 3) and saturated brine (100 mL). The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1 to 5:1) to give compound 4-a (132 mg, yield: 45.7%).

[0290] 1H NMR (400MHz, CDCl3): δ9.98 (s, 1H), 8.12 (s, 1H), 8.01-7.98 (d, J = 8.4Hz, 1H), 7. 92-7.90(d,J=8.4Hz,1H),7.54-7.48(m,2H),7.38-7.22(m,8H),2.26(s,3H)ppm

[0291] Synthesis of Compound 4

[0292] Compound 4-a (132 mg, 0.36 mmol) was suspended in methanol (15 mL) solution, 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, concentrated under reduced pressure, and the residue was treated by high performance liquid chromatography to obtain compound 4 (39 mg, yield: 22.7%).

[0293] LC-MS (ESI): m / z = 480.0 [M+H] + .

[0294] 1 H NMR (400MHz, CD3OD): δ7.99-7.97(d,J=8.0Hz,1H),7.88(s,1H),7.75-7.73(d,J=8.0Hz,1H),7.56-7.52( d,J=16.0Hz,1H),7.49-7.47(d,J=8.0Hz,1H),7.37-7.34(t,J=7.2Hz,2H),7.30-7.19(m,5H),7.12-7.10( d,J=7.2Hz,1H),4.63-4.59(d,J=12.8Hz,1H),4.10-4.07(m,1H),3.41-3.39(d,J=10.4Hz,1H),2.93-2.87 (t,J=10.8Hz,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.

[0295] Example 5

[0296] (S,E)-1-(-5-chloro-2-methyl-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)benzyl)piperidin-2-carboxylic acid (compound 5)

[0297]

[0298] Synthesis of compound 5-c

[0299] 5-Chloro-2-methylphenol (2.85 g, 20.0 mmol) was dissolved in anhydrous dichloromethane (100 mL), and titanium tetrachloride (11.38 g, 60.0 mmol) was added. The reaction solution was cooled to 0 °C. Under nitrogen protection, dichloromethoxymethane (6.90 g, 60.0 mmol) was added dropwise. After the addition was complete, the reaction solution was brought to room temperature and stirred for 2 hours. Then, the reaction solution was quenched in crushed ice, extracted with ethyl acetate (100 mL × 2), and the organic phases were combined and washed successively with water (100 mL) and saturated brine (100 mL). The obtained organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 to 3:1) to give compound 5-c (1.569 g, yield: 45.9%).

[0300] LC-MS(ESI): m / z = 171.0 [M+H] + .

[0301] Synthesis of compound 5-b

[0302] Compound 5-c (1.05 g, 6.16 mmol) was dissolved in 100 mL of anhydrous dichloromethane solution, and triethylamine (1.25 g, 12.32 mmol) was added. The reaction mixture was cooled to -78 °C under nitrogen protection, and trifluoromethanesulfonic anhydride (2.61 g, 9.23 mmol) was added dropwise. After the addition was complete, the reaction mixture was brought to room temperature and stirred for 2 hours. The reaction mixture was cooled to room temperature, diluted with 100 mL of ethyl acetate, and washed with 100 mL of water and saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 50:1–10:1) to give compound 5-b (1.50 g, yield: 80.2%).

[0303] Synthesis of compound 5-a

[0304] Compounds 3-b (634.7 mg, 1.982 mmol) and 5-b (500 mg, 1.652 mmol) were dissolved in toluene solution (20 mL) at room temperature. Potassium phosphate (701.4 mg, 3.304 mmol), cesium fluoride (501.9 mg, 3.304 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (142.7 mg, 0.165 mmol) were added. The reaction mixture was heated to 80 °C and stirred under nitrogen protection for 16 hours. The reaction mixture 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, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 50:1–20:1) to give compound 5-a (501 mg, yield: 87.6%).

[0305] Synthesis of Compound 5

[0306] To a methanol (10 mL) solution of compound 5-a (70 mg, 0.20 mmol) and L-piperidin-2-carboxylic acid (52 mg, 0.40 mmol), dichloromethane (10 mL) was added. After stirring the mixture at room temperature for 1 hour, sodium cyanoborohydride (32 mg, 0.50 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours, then concentrated under reduced pressure. The residue was washed with water (100 mL), filtered, and subjected to high-performance liquid chromatography (HPLC) to prepare a white solid 5 (34 mg, yield: 37%).

[0307] LC-MS (ESI): m / z = 460 [M+H] + .

[0308] 1 H NMR (400MHz, CD3Cl): δ7.77(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.

[0309] Example 6

[0310] (S,E)-1-(2-methoxy-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-5-trifluoromethylbenzyl)piperidine-2-carboxylic acid (compound 6)

[0311]

[0312]

[0313] Synthesis of compound 6-b

[0314] At 0 °C, titanium tetrachloride (2.84 g, 15.0 mmol) was added to a dry dichloromethane (30 mL) solution of 2-bromo-4-methoxy-1-(trifluoromethyl)benzene (1.28 g, 5.0 mmol). 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 complete, the reaction was continued at 0 °C for 3 hours. The reaction was quenched by slowly adding ice water (30 mL). The mixture was extracted with ethyl acetate (30 mL × 3), and washed successively with water (30 mL × 2) and saturated brine (30 mL × 2). 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%).

[0315] 1 H NMR (400MHz, CD3Cl): δ10.40(s,1H),8.14(s,1H),7.35(s,1H), 4.01(s,3H)ppm

[0316] Synthesis of compound 6-a

[0317] 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(diphenylphosphine)ferrocene]palladium dichloride (48 mg, 0.12 mmol), potassium phosphate (212 mg, 1.0 mmol), and cesium fluoride (150 mg, 1.0 mmol) were added, and the mixture was stirred at 80 °C for 16 hours 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 = 6:1 to 4:1) to give compound 6-a (107 mg, yield: 54%).

[0318] LC-MS (ESI): m / z = 397 [M+H] + .

[0319] Synthesis of Compound 6

[0320] To a methanol (10 mL) solution of compound 6-a (80 mg, 0.20 mmol) and L-piperidin-2-carboxylic acid (52 mg, 0.40 mmol), dichloromethane (10 mL) was added. After stirring the mixture at room temperature for 1 hour, 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 then purified by high-performance liquid chromatography to obtain a white solid product 6 (41 mg, yield: 40%).

[0321] LC-MS (ESI): m / z = 510 [M+H] + .

[0322] 1 H NMR (400MHz, CD3OD): δ7.81(s,1H),7.54(d,J=16.0Hz,1H),7.45(d,J=16.0Hz,1H),7.4 4(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,3H),3.40~3.44(m,1H),2.87 ~2.94(m,1H),2.21(s,3H),2.14~2.17(m,1H),1.67~1.77(m,3H),1.45~1.51(m,1H)ppm.

[0323] Example 7

[0324] (S,E)-1-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-methoxy-5-trifluoromethylbenzyl)piperidine-2-carboxylic acid (compound 7)

[0325]

[0326] Synthesis of compound 7-a

[0327] Compound 1-b (100 mg, 0.487 mmol) and 4-bromo-2-methoxy-5-trifluoromethylbenzaldehyde (138 mg, 0.487 mmol) were dissolved in toluene solution (20 mL). 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 for one minute at room temperature, heated to 110 °C in a microwave oven, 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, concentrated under reduced pressure, and 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%).

[0328] LC-MS(ESI): m / z = 408.0 [M+H] + .

[0329] Synthesis of Compound 7

[0330] 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 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 then subjected to high performance liquid chromatography to prepare compound 7 (3.7 mg, yield: 7.0%).

[0331] LC-MS (ESI): m / z = 521.0 [M+H] + .

[0332] 1 H NMR (400MHz, CD3OD): δ7.86 (s, 1H), 7.80 (d, J = 7.6Hz, 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=13.2Hz,2H),4.32-4.29(d,J=12.8Hz,1H),3.98(s,3H),3.43-3.41(m,1H), 2.93-2.87(m,1H),2.17-2.14(m,1H),1.79-1.61(m,4H),1.48-1.45(m,1H)ppm.

[0333] Example 8

[0334] (S,E)-1-(5-chloro-4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-methylbenzyl)piperidin-2-carboxylic acid (compound 8)

[0335]

[0336] Synthesis of compound 8-c

[0337] Method 1:

[0338] Biphenyl-2-carboxylic acid (5 g, 25.22 mmol) was dissolved in anhydrous tetrahydrofuran (180 mL). The mixture was stirred dry under nitrogen protection and cooled to -78 °C in an ice-cold acetone bath. Under nitrogen protection, a 1.3 M solution of s-butyllithium n-hexane (44 mL, 57.2 mmol) was added dropwise to the mixture over 30 minutes. After the addition was complete, stirring continued at -78 °C under nitrogen for 2.5 hours. 1,2-Dibromotetrachloroethane (24.6 g, 75.6 mmol) was added to the resulting orange-red solution. The ice-cold acetone bath was removed, and the reaction was allowed to return to room temperature and stirred for 16 hours. Water (30 mL) was added to the reaction mixture, and the mixture was separated. The aqueous phase was washed with diethyl ether (40 mL) and then the pH was adjusted to 1 with 4 N hydrochloric acid. Extracted with diethyl ether (20 mL × 4), the organic phases were combined and 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 [MH] + .

[0339] 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. Oxaloyl chloride (5.54 g, 20 mmol) was added dropwise with stirring until the addition was complete, and the mixture was stirred for one hour. The solution was evaporated to dryness to obtain crude acyl chloride. This acyl chloride was dissolved in dichloromethane (50 mL), and the solution was then slowly added dropwise with concentrated ammonia solution (50 mL) under stirring. The mixture was stirred for one hour after the addition was complete, and the solution was extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed with brine (20 mL), and concentrated under reduced pressure to give compound 8-d (2.56 g, yield: 93%), which was used directly in the next reaction. LC-MS (ESI): m / z = 277 [M + H] + .

[0340] 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 the mixture was stirred for two hours. The reaction solution was diluted with ethyl acetate (200 mL), washed with brine (20 mL × 3), and concentrated under reduced pressure to give a white solid 8-c (2.10 g, yield: 92%), which was used directly in the next step of the reaction.

[0341] Method 2

[0342] Phenylated acid (3.06 g, 10 mmol) and 2-bromo-6-iodobenzonitrile (3.0 g, 12 mmol) were dissolved in a mixed solution of 1,4-dioxane (40 mL) and water (4 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (731 mg, 1.0 mmol) and sodium carbonate (4.08 g, 30 mmol) were added. The reaction mixture was purged with nitrogen three times, heated to 40 °C, and stirred for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and 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%).

[0343] Synthesis of compound 8-b

[0344] Compound 8-c (516 mg, 2 mmol) and pinacol vinylboronate (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 three times and then heated to 80 °C with stirring for 12 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound 8-b (364 mg, yield: 55%).

[0345] 1 H NMR (400MHz, DMSO-d6): δ8.01(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

[0346] Synthesis of compound 8-a

[0347] Compound 8-b (110 mg, 0.332 mmol) and compound 8-f (84 mg, 0.277 mmol) were dissolved in toluene solution (20 mL), and potassium phosphate (118 mg, 0.554 mmol), cesium fluoride (84 mg, 0.554 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (24 mg, 0.028 mmol) were added. The reaction solution was purged with nitrogen three times, then heated to 90 °C and stirred for 16 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed successively with water (100 mL) and saturated brine (100 mL). The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and 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%).

[0348] Synthesis of Compound 8

[0349] 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 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 then subjected to high performance liquid chromatography to prepare compound 8 (21.9 mg, yield: 29.7%).

[0350] LC-MS (ESI): m / z = 471.0 [M+H] + .

[0351] 1 H NMR (400MHz, CD3OD): δ7.85-7.84(d,J=7.6Hz,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.

[0352] Example 9

[0353] (S,E)-4-(5-chloro-4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-methylbenzyl)morpholine-3-carboxylic acid (compound 9)

[0354]

[0355] Synthesis of Compound 9

[0356] Compound 8-a (100 mg, 0.279 mmol) and (S)-morpholino-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 mixture was heated to 70 °C and stirred for 16 hours. After the reaction was complete, the solution was evaporated to dryness, and the resulting white residue was dissolved in ethyl acetate and washed once each with water and saturated brine. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed successively with water (100 mL) and saturated brine (100 mL). The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to high-performance liquid chromatography (HPLC) to prepare compound 9 (7.3 mg, yield: 5.5%).

[0357] LC-MS (ESI): m / z = 473.0 [M+H] + .

[0358] 1 H NMR (400MHz, CD3OD): δ7.81-7.79(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),3.92-3.8 9(dd,J=3.6Hz,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.

[0359] Example 10

[0360] (S,E)-1-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2,5-dimethylbenzyl)piperidine-3-carboxylic acid (compound 10)

[0361]

[0362] Synthesis of compound 10-b

[0363] 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 under nitrogen atmosphere and stirring, 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 heated to -20 °C. Ten minutes later, the temperature was lowered back to -78 °C, and anhydrous NN'-dimethylformamide (876 mg, 12.0 mmol) was added dropwise. The mixture was stirred for 30 minutes, the ice-water bath was removed, and the reaction system was allowed to warm naturally to room temperature. Stirring was continued for 10 hours. The reaction solution was quenched in an ice-water mixture, 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, concentrated under reduced pressure, and 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%).

[0364] 1 H NMR: (400MHz DMSO-d6): δ10.17(s,3H),7.75(s,1H),7.62(s,1H),2.56(s,3H),2.38(s,3H)ppm

[0365] Synthesis of compound 10-a

[0366] 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). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (73.1 mg, 0.1 mmol), potassium phosphate (424 mg, 2.0 mmol), and cesium fluoride (304 mg, 2.0 mmol) were added to the mixture. Under nitrogen protection, the reaction mixture was stirred at 100 °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 = 15:1–5:1) to give a yellow solid 10-a (80 mg, yield: 48%).

[0367] Synthesis of Compound 10

[0368] 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), and sodium cyanoborohydride (37.3 mg, 0.59 mmol) was added. 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 then subjected to high performance liquid chromatography to prepare a white solid 10 (36.1 mg, yield: 34%).

[0369] LC-MS (ESI): m / z = 451.3 [M+H] + .

[0370] 1 H NMR(400MHz CD3OD): δ7.96(d,J=8.0Hz,1H),7.74(t,J=8.0Hz,1H),7.67(d,J=16.0Hz,1H),7.59-7.45(m,9H),4.67(d,J=12.8Hz,1H),4.06(d,J=12 .8Hz,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.

[0371] Example 11

[0372] (S,E)-4-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2,5-dimethylbenzyl)morpholine-3-carboxylic acid (compound 11)

[0373]

[0374] Synthesis of Compound 11

[0375] Compound 10-a (80.0 mg, 0.237 mmol) and (S)-morpholino-3-carboxylic acid (62 mg, 0.474 mmol) were dissolved in methanol (25 mL), and sodium cyanoborohydride (37.3 mg, 0.59 mmol) was added. 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 then subjected to high performance liquid chromatography to prepare a white solid 11 (50 mg, yield: 46%).

[0376] LC-MS (ESI): m / z = 453.3 [M+H] + .

[0377] 1H NMR (400MHz) CD3OD): δ7.95(d,J=7.6Hz,1H),7.73(t,J=8.0Hz,1H),7.66(d,J=16.4Hz,1H),7. 59-7.47(m,7H),7.44(d,J=7.2Hz,1H),7.38(s,1H),4.55(d,J=12.8Hz,1H),4.16 (dd, J1=3.6Hz, J2=12.0Hz,1H),3.94(d,J=12.8Hz,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.

[0378] Example 12

[0379] (S,E)-2-((4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2,5-dimethylbenzyl)amino)-3-hydroxy-2-methylpropionic acid (compound 12)

[0380]

[0381] Synthesis of Compound 12

[0382] Methylserine (127 mg, 1.06 mmol) was dissolved in methanol (10 mL), and 0.53 M sodium hydroxide aqueous solution (2 mL, 1.06 mmol) was added dropwise with stirring for 10 minutes. The reaction solution was cooled to 0 °C, and a tetrahydrofuran solution of compound 10-a (120.0 mg, 0.35 mmol) (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 solution was concentrated under reduced pressure, and the residue was prepared by high performance liquid chromatography to give a white solid 12 (12 mg, yield: 7%).

[0383] LC-MS (ESI): m / z = 441.4 [M+H] + .

[0384] 1H NMR(400MHz DMSO-d6): δ8.07(d,J=7.6Hz,1H),7.77(t,J=8.0Hz,1H),7.68(d,J=16.0Hz,1H),7.61-7.47(m,6H),7.43(s,2H),7.32( d,J=16.0Hz,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.

[0385] Example 13

[0386] (S,E)-1-(5-chloro-4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-methylbenzyl)piperazine-2-carboxylic acid (compound 13)

[0387]

[0388] Synthesis of compound 13-a

[0389] Compound 8-a (100 mg, 0.279 mmol) and (S)-4-Boc-piperazin-2-carboxylic acid (129 mg, 0.559 mmol) were dissolved in methanol (20 mL), and sodium cyanoborohydride (36 mg, 0.559 mmol) was added. The mixture 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 ethyl acetate (100 mL) and washed successively 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 then subjected to high-performance liquid chromatography (HPLC) to prepare compound 13-a (28 mg, yield: 17.5%).

[0390] LC-MS (ESI): m / z = 572.0 [M+H] + .

[0391] Synthesis of Compound 13

[0392] Compound 13-a (28 mg, 0.049 mmol) was dissolved in dichloromethane solution (10 mL), and trifluoroacetic acid (2 mL) was added. The reaction solution was stirred at room temperature for 2 hours, concentrated under reduced pressure, and the residue was used to prepare compound 13 (10.9 mg, yield: 47.4%) by high performance liquid chromatography.

[0393] LC-MS (ESI): m / z = 472.0 [M+H] + .

[0394] 1H NMR (400MHz, CD3OD): δ7.93-7.91(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.

[0395] Example 14

[0396] (S,E)-1-(5-chloro-4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-methylbenzyl)-4-methylpiperazine-2-carboxylic acid (Compound 14)

[0397]

[0398] Synthesis of compound 14-c

[0399] Methyl (S)-1-Boc-piperazine-2-carboxylate (200 mg, 0.819 mmol) was dissolved in methanol (20 mL), and 37% formaldehyde aqueous solution (0.5 mL, 4.10 mmol), glacial acetic acid (99 mg, 1.64 mmol), and 10% Pd-C (50 mg) were added. The reaction mixture was stirred at room temperature under hydrogen atmosphere for 16 hours. The reaction mixture was filtered through diatomaceous earth, washed with methanol (30 mL × 3), and the filtrates were combined and 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%).

[0400] LC-MS(ESI):m / z=159.0[M-Boc+H] + .

[0401] Synthesis of compound 14-b

[0402] Compound 14-c (204 mg, 0.79 mmol) was dissolved in dichloromethane (30 mL), and trifluoroacetic acid (6 mL) was added. The reaction mixture was stirred at room temperature for 2 hours, concentrated under reduced pressure, and the residue was added to dichloromethane (30 mL), concentrated under reduced pressure, and repeated once. The residue was then added to toluene (30 mL), concentrated under reduced pressure, and repeated once. The residue was dried under vacuum to give compound 14-b (123 mg, yield: 99.0%), which was used directly in the next reaction.

[0403] LC-MS (ESI): m / z = 159.0 [M+H] + .

[0404] Synthesis of compound 14-a

[0405] Compound 8-a (136 mg, 0.38 mmol) and compound 14-b (195 mg, 0.76 mmol) were dissolved in methanol (20 mL), and sodium cyanoborohydride (48 mg, 0.76 mmol) and sodium acetate (155 mg, 1.14 mmol) were added. The reaction 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 dichloromethane (100 mL) and washed successively with water (100 mL) and saturated brine (100 mL). The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to high-performance liquid chromatography (HPLC) to prepare compound 14-a (30 mg, yield: 15.8%).

[0406] LC-MS (ESI): m / z = 500.0 [M+H] + .

[0407] Synthesis of Compound 14

[0408] Compound 14-a (70 mg, 0.185 mmol) was dissolved in a mixed solution of methanol (5 mL), tetrahydrofuran (5 mL), and water (1 mL), and sodium hydroxide (23 mg, 0.371 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, 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, and a white solid precipitated. The solid was filtered, and the filter cake was subjected to high-performance liquid chromatography to prepare compound 14 (11.0 mg, yield: 37.9%).

[0409] LC-MS (ESI): m / z = 486.0 [M+H] + .

[0410] 1 H NMR (400MHz, CD3OD): δ7.92-7.90(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.

[0411] Example 15

[0412] (S,E)-1-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-(4-cyanobutoxy)-5-methylbenzyl)piperidine-2-carboxylic acid (compound 15)

[0413]

[0414] Synthesis of compound 15-c

[0415] A mixture of 3-bromo-4-methylphenol (374 mg, 1.0 mmol), 5-bromopentanilonitrile (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 h. The reaction mixture 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, 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 (petroleum ether: ethyl acetate = 10:1) to give a white solid 15-C (536 mg, yield: 100%).

[0416] 1 H NMR (400MHz, CDCl3): δ7.12(d,J=8.4Hz,1H),7.08(d,J=2.6Hz,1H),6.74(dd,J=8.4,2.6 Hz,1H),3.96(t,J=5.7Hz,2H),2.44(t,J=6.8Hz,2H),2.32(s,3H),1.97–1.82(m,4H)ppm

[0417] Synthesis of compounds 15-b-1 and 15-b-2

[0418] 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 the mixture was stirred for 2 hours. 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 a white solid 15-b-1 (141 mg, yield: 48%) and a pale yellow solid 15-b-2 (100 mg, yield: 34%).

[0419] Compound 15-b-1:

[0420] 1H NMR (400MHz, CDCl3): δ10.39(s,1H),7.67(s,1H),7.18(s,1H),4.11(t,J=5.9Hz,2H), 2.47(t,J=6.9Hz,2H),2.36(s,3H),2.03(dt,J=8.8,5.8Hz,2H),1.96–1.84(m,2H)ppm

[0421] Compound 15-b-2:

[0422] 1 H NMR (400MHz, CDCl3): δ10.41(s,1H),7.34(d,J=8.5Hz,1H),6.85(d,J=8.5Hz,1H),4.07(t,J=5.7Hz,2H),2.48(t,J=6.8Hz,2H),2.08–1.85(m,4H)ppm

[0423] Synthesis of compound 15-a

[0424] A mixture of compound 15-b-2 (135 mg, 0.46 mmol), compound 8-b (181 mg, 0.55 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (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 protection for 16 h. The reaction mixture 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 purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give compound 15-a (130 mg, yield: 68%).

[0425] LC-MS(ESI): m / z = 421.4 [M+H] + .

[0426] 1 H NMR (400MHz, CDCl3): δ10.45(s,1H),7.80(d,J=7.6Hz,1H),7.70–7.63(m,2H),7.60–7.42(m,8H),7.21(s ,1H),4.22(t,J=5.9Hz,2H),2.48(t,J=7.0Hz,2H),2.42(s,3H),2.12–2.02(m,2H),2.00–1.89(m,2H)ppm

[0427] Synthesis of Compound 15

[0428] Sodium cyanoborohydride (15 mg, 0.24 mmol) was added to a mixture of compound 15-a (50 mg, 0.12 mmol), (S)-piperidin-2-carboxylic acid (31 mg, 0.24 mmol), methanol (1 mL), and tetrahydrofuran (1 mL). 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 then subjected to high-performance liquid chromatography (HPLC) to prepare a white solid 15 (32 mg, yield: 50%).

[0429] LC-MS (ESI): m / z = 534.5 [M+H] + .

[0430] 1 H NMR (400MHz, CD3OD): δ7.96(d,J=7.8Hz,1H),7.73(t,J=7.9Hz,1H),7.67(d,J=16.1Hz,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=12.9Hz,1H),4.34(d,J=12.7Hz,1 H),4.22(t,J=6.1Hz,2H),3.53(d,J=7.5Hz,1H),3.32(s,1H),2.99(t,J=12.3Hz,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.

[0431] Example 16

[0432] (E)-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-(4-cyanobutoxy)-5-methylbenzyl)glycine (Compound 16)

[0433]

[0434] Synthesis of Compound 16

[0435] Sodium cyanoborohydride (60 mg, 0.95 mmol) was added 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). The reaction mixture was heated to 70 °C and stirred for 1 hour, after which sodium cyanoborohydride (60 mg, 0.95 mmol) was added, and stirring was continued for another hour. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was treated by high performance liquid chromatography to obtain a white solid 16 (19.6 mg, yield: 21%).

[0436] LC-MS (ESI): m / z = 480.5 [M+H] + .

[0437] 1 H NMR (400MHz, DMSO-d6): δ8.05(d,J=7.9Hz,1H),7.79(t,J=7.9Hz,1H),7.67(d,J=16.0Hz,1H),7.62–7.47(m,6H),7.40(d,J=16.0Hz,1H),7.26( d,J=5.6Hz,2H),4.12(t,J=6.0Hz,2H),3.94(s,2H),3.13(s,2H),2.60( t,J=7.0Hz,2H),2.38(s,3H),1.93–1.84(m,2H),1.83–1.74(m,2H)ppm.

[0438] Example 17

[0439] (S,E)-4-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-(4-cyanobutoxy)-5-methylbenzyl)morpholine-3-carboxylic acid (compound 17)

[0440]

[0441] Synthesis of Compound 17

[0442] Sodium cyanoborohydride (38 mg, 0.60 mmol) was added 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). 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 then subjected to high performance liquid chromatography to prepare a white solid 17 (46.1 mg, yield: 57%).

[0443] LC-MS (ESI): m / z = 536.4 [M+H] + .

[0444] 1 H NMR (400MHz, CD3OD): δ7.95(d,J=7.9Hz,1H),7.72(t,J=7.9Hz,1H),7.66(d,J=16.1Hz,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=12.8Hz,1H),4.33(d,J=12. 7Hz,1H),4.26–4.13(m,3H),3.93(d,J=12.8Hz,1H),3.82–3.64(m,3H),3.25(d,J=12.6Hz,1H),3. 09(t,J=9.8Hz,1H),2.57(t,J=7.0Hz,2H),2.44(s,3H),2.09–1.98(m,2H),1.95–1.83(m,2H)ppm.

[0445] Example 18

[0446] (S,E)-1-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-(4-cyanobutoxy)-5-methylbenzyl)piperazine-2-carboxylic acid (compound 18)

[0447]

[0448] Synthesis of Compound 18

[0449] Sodium cyanoborohydride (38 mg, 0.60 mmol) was added to a mixture of compound 15-a (63 mg, 0.15 mmol), (S)-4-(tert-butoxycarbonyl)piperazin-2-carboxylic acid (69 mg, 0.30 mmol), methanol (1 mL), and tetrahydrofuran (1 mL). The reaction mixture was heated to 60 °C and stirred for 1 hour, then cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (1 mL) and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was treated by high performance liquid chromatography to obtain a white solid 18 (36.5 mg, yield: 45%).

[0450] LC-MS (ESI): m / z = 535.5 [M+H] + .

[0451] 1H NMR (400MHz, CD3OD): δ7.94(d,J=8.0Hz,1H),7.71(t,J=7.9Hz,1H),7.65( d,J=16.0Hz,1H),7.59–7.39(m,7H),7.31(s,1H),7.22(s,1H),4.12(t,J=5 .8Hz,2H),3.92(s,2H),3.42(t,J=4.9Hz,1H),3.29(s,1H),3.19–3.05(m,3 H), 2.69 (m, 1H), 2.56 (t, J = 6.9Hz, 2H), 2.42 (s, 3H), 2.03–1.83 (m, 4H) ppm.

[0452] Example 19

[0453] (E)-(5-chloro-4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-methylbenzyl)glycine (compound 19)

[0454]

[0455] Synthesis of compound 19-c

[0456] Compound 8-a (260 mg, 0.727 mmol) was dissolved in a mixture of methanol (5 mL) and tetrahydrofuran (5 mL), and sodium borohydride (55 mg, 1.454 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 mL). The residue was washed successively with water (50 mL) and saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and 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%).

[0457] Synthesis of compound 19-b

[0458] Compound 19-c (116 mg, 0.322 mmol) was dissolved in dichloromethane (10 mL), and one drop of N,N'-dimethylformamide was added, followed by dropwise addition of thionyl chloride (0.5 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was concentrated under reduced pressure after adding dichloromethane (50 mL × 2). The residue was dried under vacuum to give compound 19-b (122 mg, yield: 99.0%), which was used directly in the next step of the reaction.

[0459] Synthesis of compound 19-a

[0460] Serine methyl ester 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 mixture was heated to 80 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane (50 mL) and washed successively with water (50 mL) and saturated brine (50 mL). The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and 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%).

[0461] LC-MS(ESI): m / z = 431.0 [M+H] + .

[0462] Synthesis of Compound 19

[0463] Compound 19-a (63 mg, 0.146 mmol) was dissolved in a mixed solution 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 the reaction was completed, the solution 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, which was filtered. The filter cake was subjected to high-performance liquid chromatography (HPLC) to prepare compound 19 (10.0 mg, yield: 16.4%).

[0464] LC-MS (ESI): m / z = 417.0 [M+H] + .

[0465] 1 H NMR (400MHz, CD3OD): δ7.97-7.95 (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.

[0466] Example 20

[0467] (S,E)-1-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-hydroxymethyl-5-trifluoromethylbenzyl)piperidine-2-carboxylic acid (compound 20)

[0468]

[0469] Synthesis of compound 20-h

[0470] 5-Bromophthalide (6.3 g, 30 mmol) was dissolved in trifluoromethanesulfonic acid (60 mL) and cooled to 0 °C with stirring. N-iodosuccinimide powder (16.8 g, 75 mmol) was slowly added to the reaction mixture. The ice bath was then removed, and the mixture was brought to room temperature and stirred for 16 hours. The reaction mixture was poured into ice water (200 mL), resulting in the precipitation of a large amount of deep yellow solid. This 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 required no further purification and was used directly in the next reaction.

[0471] Synthesis of compound 20-g

[0472] Compound 20-h (6.7 g, 20 mmol), methyl fluorosulfonyl difluoroacetate (19 g, 100 mmol), and cuprous iodide (760 mg, 2 mmol) were mixed in N,N-dimethylformamide (50 mL), and the reaction was carried out under a nitrogen atmosphere at 90 °C for 16 hours. The reaction solution was cooled to room temperature, filtered, and ethyl acetate (300 mL) was added to the filtrate. The solution was washed successively with water (50 mL × 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give 20-g (900 mg, yield: 16.0%) of white solid.

[0473] LC-MS(ESI): m / z = 282[M+H] + .

[0474] Synthesis of compound 20-f

[0475] 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 the mixture was stirred at room temperature for 16 hours. The pH was adjusted to 1 with 1 N hydrochloric acid, and the solution was concentrated under reduced pressure and purified by reversed-phase chromatography (Biotage Flash) to give a white solid 20-f (650 mg, yield: 75.6%).

[0476] LC-MS (ESI): m / z = 299 [MH] + .

[0477] Synthesis of compound 20-e

[0478] 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 reaction mixture was stirred at room temperature for 16 hours. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water (20 mL × 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and 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%).

[0479] 1 ¹H NMR (400MHz, DMSO-d⁶): δ 8.19 (s, 1H), 8.11 (s, 1H), 5.10 (s, 2H), 5.10 (s, 9H), 0.11 (s, 6H) ppm. Synthesis of compound 20-d.

[0480] Compound 20-e (413 mg, 1 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL). Borane tetrahydrofuran solution (5 mL, 5 mmol) was added dropwise at 0 °C under nitrogen protection, and the mixture was refluxed for 16 hours after the addition was complete. The reaction solution was cooled to room temperature, and methanol (10 mL) was slowly added dropwise, refluxed for one hour after the addition was complete. The reaction solution was then concentrated under reduced pressure after cooling to room temperature. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound 20-d (260 mg, yield: 65.0%).

[0481] LC-MS (ESI): m / z = 399 [MH] + .

[0482] Synthesis of compound 20-c

[0483] 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. The mixture 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%). No further purification was required for the product.

[0484] Synthesis of compound 20-b

[0485] 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), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (31 mg, 0.042 mmol), 1,4-dioxane (5 mL), and water (0.5 mL) was stirred at 80 °C under nitrogen protection for 16 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and 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%).

[0486] LC-MS (ESI): m / z = 522 [M+H] + .

[0487] Synthesis of compound 20-a

[0488] A mixture of compound 20-b (50 mg, 0.096 mmol), L-piperidin-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 protection for 3 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by reversed-phase chromatography (Biotage Flash) to give compound 20-a (35 mg, yield: 57.6%).

[0489] LC-MS (ESI): m / z = 635 [M+H] + .

[0490] Synthesis of Compound 20

[0491] 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. The reaction solution was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was prepared by high performance liquid chromatography to obtain compound 20 (8 mg, yield: 33.3%).

[0492] LC-MS (ESI): m / z = 521 [M+H] + .

[0493] 1H NMR (400MHz, CD3OD): δ8.04(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.

[0494] Example 21

[0495] (S,E)-4-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-hydroxymethyl-5-trifluoromethylbenzyl)morpholine-3-carboxylic acid (compound 21)

[0496]

[0497] Synthesis of compound 21-a

[0498] A mixture of compound 20-b (50 mg, 0.096 mmol), L-morpholino-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 protection for 3 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by reversed-phase chromatography (Biotage Flash) to give compound 21-a (35 mg, yield: 57.6%).

[0499] LC-MS (ESI): m / z = 635 [M+H] + .

[0500] Synthesis of Compound 21

[0501] Compound 21-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. The mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was then processed by high performance liquid chromatography to obtain compound 21 (8 mg, yield: 33.3%).

[0502] LC-MS (ESI): m / z = 523 [M+H] + .

[0503] 1 H NMR (400MHz, CD3OD): δ8.03 (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,J=12.8Hz,1H),4.03-3.99(m,1H),3.88-3.74(m,3H),3.66 -3.61(m,1H),3.43-3.42(m,1H),3.00-2.96(m,1H),2.63-2.59(m,1H)ppm.

[0504] Example 22

[0505] (S,E)-4-(5-chloro-2-methyl-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)benzyl)morpholine-3-carboxylic acid (compound 22)

[0506]

[0507] Synthesis of Compound 22

[0508] Compound 5-a (100 mg, 0.288 mmol) and (S)-morpholino-3-carboxylic acid (75.7 mg, 0.577 mmol) were dissolved in methanol (10 mL), and sodium cyanoborohydride (36.3 mg, 0.577 mmol) was added. The reaction 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 then treated by high performance liquid chromatography to obtain a white solid 22 (37.2 mg, yield: 27.8%).

[0509] LC-MS (ESI): m / z = 462.0 [M+H] + .

[0510] 1H NMR (400MHz, CD3OD): δ7.69(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=4.0 Hz,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.

[0511] Example 23

[0512] (S,E)-1-(5-chloro-2-methyl-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)benzyl)piperazine-2-carboxylic acid (compound 23)

[0513]

[0514] Synthesis of compound 23-a

[0515] Compound 5-a (100 mg, 0.288 mmol) and (S)-4-(tert-butoxycarbonyl)piperazin-2-carboxylic acid (133 mg, 0.577 mmol) were dissolved in methanol (10 mL), and sodium cyanoborohydride (36 mg, 0.577 mmol) was added. The reaction 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 then subjected to high performance liquid chromatography to prepare compound 23-a (76 mg, yield: 46.9%).

[0516] LC-MS (ESI): m / z = 561.0 [M+H] + .

[0517] Synthesis of Compound 23

[0518] Compound 23-a (76 mg, 0.135 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to obtain compound 23 (29.4 mg, yield: 46.8%).

[0519] LC-MS(ESI): m / z = 461.0 [M+H] + .

[0520] 1 H NMR (400MHz, CD3OD): δ7.63(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.

[0521] Example 24

[0522] (S,E)-1-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-(2-methoxyethoxy)-5-methylbenzyl)piperidine-2-carboxylic acid (compound 24)

[0523]

[0524] Synthesis of compound 24-c

[0525] A mixture of 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) was heated under reflux for 4 hours. The reaction mixture was cooled to room temperature, diluted with water (500 mL), and 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), concentrated under reduced pressure, and 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%).

[0526] Synthesis of compound 24-b

[0527] 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 hours. The reaction mixture was cooled to room temperature and diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (50 mL), and 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 a white solid 24-b (624 mg, yield: 76%).

[0528] 1 H NMR (400MHz, CDCl3): δ10.43(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

[0529] Synthesis of compound 24-a

[0530] A mixture of compound 24-b (273 mg, 1.0 mmol), compound 8-b (397 mg, 1.2 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (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 protection for 16 hours. The reaction mixture 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, concentrated under reduced pressure, and the residue was washed with ethyl acetate (50 mL) to give a pale green solid 24-a (330 mg, yield: 83%).

[0531] LC-MS (ESI): m / z = 398.4 [M+H] + .

[0532] Synthesis of Compound 24

[0533] Sodium cyanoborohydride (38 mg, 0.60 mmol) was added to a mixture of compound 24-a (60 mg, 0.15 mmol), (S)-piperidin-2-carboxylic acid (39 mg, 0.30 mmol), methanol (1 mL), and tetrahydrofuran (1 mL). 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 then subjected to high performance liquid chromatography to prepare a white solid 24 (35.2 mg, yield: 46%).

[0534] LC-MS (ESI): m / z = 511.5 [M+H] + .

[0535] 1 H NMR (400MHz, CD3OD): δ7.96(d,J=7.9Hz,1H),7.73(t,J=7.9Hz,1H),7.66(d,J=16.1Hz,1H),7.60–7.5 4(m,2H),7.54–7.44(m,5H),7.34(s,2H),4.82–4.77(m,1H),4.60(d,J=12.8Hz,1H),4.36–4.26(m,2H) ,4.22(d,J=13.1Hz,1H),3.94–3.74(m,2H),3.57–3.48(m,1H),3.45(s,3H),2.95(t,J=12.0Hz,1H),2 .44(s,3H),2.34–2.20(m,J=15.8Hz,1H),1.94–1.76(m,3H),1.74–1.62(m,1H),1.61–1.47(m,1H)ppm.

[0536] Example 25

[0537] (S,E)-4-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-(2-methoxyethoxy)-5-methylbenzyl)morpholine-3-carboxylic acid (compound 25)

[0538]

[0539] Synthesis of Compound 25

[0540] Sodium cyanoborohydride (38 mg, 0.60 mmol) was added 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). 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 then subjected to high performance liquid chromatography to prepare a white solid 25 (41.0 mg, yield: 53%).

[0541] LC-MS (ESI): m / z = 513.5 [M+H] + .

[0542] 1H NMR (400MHz, CD3OD): δ7.96(d,J=7.9Hz,1H),7.73(t,J=7.9Hz,1H),7.66(d,J=1 6.1Hz,1H),7.59–7.54(m,J=8.0,1.6Hz,2H),7.54–7.44(m,5H),7.36(s,1H),7. 34(s,1H),4.65(d,J=12.7Hz,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.

[0543] Example 26

[0544] (S,E)-4-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-(2-hydroxyethoxy)-5-methylbenzyl)piperidine-2-carboxylic acid (compound 26)

[0545]

[0546]

[0547] Synthesis of compound 26-b

[0548] 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 hours. The reaction mixture 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, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to give a white solid 26-b (767 mg, yield: 68%).

[0549] Synthesis of compound 26-a

[0550] A mixture of compound 26-b (373 mg, 1.0 mmol), compound 8-b (397 mg, 1.2 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (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 protection for 16 hours. The reaction mixture 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, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give a yellow solid 26-a (355 mg, yield: 71%).

[0551] LC-MS (ESI): m / z = 498.5 [M+H] + .

[0552] Synthesis of Compound 26

[0553] Sodium cyanoborohydride (38 mg, 0.60 mmol) was added to a mixture of compound 26-a (75 mg, 0.15 mmol), (S)-piperidin-2-carboxylic acid (39 mg, 0.30 mmol), methanol (1 mL), and tetrahydrofuran (1 mL). The reaction mixture was heated to 60 °C and stirred for 1 hour, then concentrated under reduced pressure. The residue was added to tetrahydrofuran (1 mL), water (one drop), and trifluoroacetic acid (0.5 mL), and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was treated by high performance liquid chromatography to obtain a white solid 26 (48.3 mg, yield: 53%).

[0554] LC-MS (ESI): m / z = 497.5 [M+H] + .

[0555] 1 H NMR (400MHz, DMSO-d6): δ8.05(d,J=8.0Hz,1H),7.79(t,J=7.9Hz,1H),7.67(d,J=16 .0Hz,1H),7.63–7.47(m,6H),7.40(d,J=16.0Hz,1H),7.27(s,2H),7.07(s,1H),4.13 –3.90(m,5H),3.75(t,J=4.6Hz,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.

[0556] Example 27

[0557] (S,E)-1-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-(2-methoxyethoxy)-5-methylbenzyl)piperazine-2-carboxylic acid (compound 27)

[0558]

[0559] Synthesis of Compound 27

[0560] Sodium cyanoborohydride (38 mg, 0.60 mmol) was added to a mixture of compound 24-a (60 mg, 0.15 mmol), (S)-4-(tert-butoxycarbonyl)piperazin-2-carboxylic acid (69 mg, 0.30 mmol), methanol (1 mL), and tetrahydrofuran (1 mL). The reaction mixture was heated to 60 °C and stirred for 1 hour, then cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane (1.5 mL) and trifluoroacetic acid (0.5 mL) and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was treated by high performance liquid chromatography to obtain a white solid 27 (66.7 mg, yield: 87%).

[0561] LC-MS (ESI): m / z = 512.4 [M+H] + .

[0562] 1 H NMR (400MHz, CD3OD): δ7.95(d,J=7.9Hz,1H),7.72(t,J=7.8Hz,1H),7.65(d,J=16.1Hz,1H),7.59–7.54( m,J=8.0,1.5Hz,2H),7.53–7.41(m,5H),7.30(s,1H),7.27(s,1H),4.22(t,J=4.4Hz,2H),4.06(d,J=13. 1Hz,1H),3.97(d,J=13.4Hz,1H),3.85–3.75(m,2H),3.49(dd,J=7.0,3.5Hz,1H),3.44(s,3H),3.35(dd, J=12.9,3.5Hz,1H),3.25(dd,J=13.1,6.9Hz,1H),3.18–3.08(m,3H),2.79–2.71(m,1H),2.42(s,3H)ppm.

[0563] Example 28

[0564] (S,E)-1-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-hydroxymethyl-5-trifluoromethylbenzyl)piperazine-2-carboxylic acid (compound 28)

[0565]

[0566] Synthesis of compound 28-a

[0567] A mixture of compound 20-b (50 mg, 0.096 mmol), (S)-4-tert-butoxycarbonyl-2-piperazinic acid (44 mg, 0.19 mmol), sodium cyanoborohydride (12 mg, 0.19 mmol), and methanol (3 mL) was stirred at 80 °C under nitrogen protection for 3 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by reversed-phase chromatography (Biotage Flash) to give compound 28-a (42 mg, yield: 60%).

[0568] LC-MS (ESI): m / z = 736 [M+H] + .

[0569] Synthesis of Compound 28

[0570] Compound 28-a (34 mg, 0.047 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to give compound 28 (11 mg, yield: 45%).

[0571] LC-MS (ESI): m / z = 522 [M+H] + .

[0572] 1 H NMR (400MHz, DMSO-d6): δ8.01(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 = 38.4Hz, 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.

[0573] Example 29

[0574] (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)

[0575]

[0576] Synthesis of compound 29-c

[0577] Methyl (S)-1-Boc-piperazine-2-carboxylate (733 mg, 3.0 mmol) and triethylamine (3.036 g, 30.0 mmol) were dissolved in tetrahydrofuran solution (50 mL), cooled to 0 °C in an ice bath, and trimethylsilyl isocyanate (3.456 g, 30.0 mmol) was added dropwise. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was diluted with 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, concentrated under reduced pressure, and 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%).

[0578] LC-MS(ESI): m / z = 288.0 [M+H] + .

[0579] Synthesis of compound 29-b

[0580] Compound 29-c (663 mg, 2.308 mmol) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (3 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The solution was concentrated under reduced pressure, and the residue was added to toluene (20 mL), concentrated under reduced pressure, and the residue was again added to toluene (20 mL), concentrated under reduced pressure, and the residue was dried under vacuum to give compound 29-b (1.132 g, yield: 99%), which was used directly in the next reaction.

[0581] Synthesis of compound 29-a

[0582] 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 mixture was heated to 80 °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 (50 mL) and washed successively with water (50 mL) and saturated brine (50 mL). The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to prepare compound 29-a (56 mg, yield: 50.9%).

[0583] LC-MS (ESI): m / z = 529.0 [M+H] + .

[0584] Synthesis of Compound 29

[0585] 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 1 N hydrochloric acid, and the reaction solution was concentrated under reduced pressure. The residue was then subjected to high performance liquid chromatography to prepare compound 29 (14.9 mg, yield: 27.3%).

[0586] LC-MS (ESI): m / z = 515.0 [M+H] + .

[0587] 1 H NMR (400MHz, CD3OD): δ7.95-7.93(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.

[0588] Example 30

[0589] (S,E)-4-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-(2-hydroxyethoxy)-5-methylbenzyl)morpholine-3-carboxylic acid (compound 30)

[0590]

[0591] Synthesis of Compound 30

[0592] Sodium cyanoborohydride (38 mg, 0.60 mmol) was added to a mixture of compound 26-a (75 mg, 0.15 mmol), (S)-morpholino-3-carboxylic acid (39 mg, 0.30 mmol), methanol (1 mL), and tetrahydrofuran (1 mL). The reaction mixture was heated to 65 °C and stirred for 1 hour, then cooled to room temperature and concentrated under reduced pressure. The residue was then added to tetrahydrofuran (1.0 mL), water (0.5 mL), and trifluoroacetic acid (0.5 mL), and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was treated by high performance liquid chromatography to obtain a white solid 30 (66 mg, yield: 88%).

[0593] LC-MS (ESI): m / z = 499.5 [M+H] + .

[0594] 1 H NMR (400MHz, DMSO-d6): δ8.05(d,J=7.8Hz,1H),7.78(t,J=7.9Hz,1H),7.66(d,J =16.0Hz,1H),7.63–7.47(m,6H),7.37(d,J=16.0Hz,1H),7.23(s,1H),7.20(s,1 H),4.06(t,J=5.1Hz,2H),3.85(d,J=13.9Hz,1H),3.81–3.67(m,5H),3.59(bs,2 H),3.24(t,J=4.6Hz,1H),3.02–2.94(m,1H),2.38(s,3H),2.36–2.31(m,1H)ppm.

[0595] Example 31

[0596] (S,E)-1-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-hydroxy-5-methylbenzyl)piperidine-2-carboxylic acid (compound 31)

[0597]

[0598] Synthesis of compound 31-a

[0599] A mixture of compound 24-c (215 mg, 1.0 mmol), compound 8-b (397 mg, 1.2 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (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 under nitrogen protection for 16 hours. The reaction mixture 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 residue was washed with ethyl acetate (50 mL) to give a brown solid 31-a (210 mg, yield: 62%).

[0600] LC-MS (ESI): m / z = 340.3 [M+H] + .

[0601] Synthesis of Compound 31

[0602] Sodium cyanoborohydride (38 mg, 0.60 mmol) was added to a mixture of compound 31-a (51 mg, 0.15 mmol), (S)-piperidin-2-carboxylic acid (39 mg, 0.30 mmol), methanol (1 mL), and tetrahydrofuran (1 mL). The reaction mixture was heated to 65 °C and stirred for 1 hour, then cooled to room temperature and concentrated under reduced pressure. The residue was then subjected to high performance liquid chromatography to prepare a white solid 31 (21.6 mg, yield: 32%).

[0603] LC-MS (ESI): m / z = 453.4 [M+H] + .

[0604] 1 H NMR (400MHz, DMSO-d6): δ8.08(d,J=8.0Hz,1H),7.78(t,J=7.9Hz,1H),7.64(d,J=16.0Hz ,1H),7.61–7.47(m,6H),7.30(d,J=16.0Hz,1H),7.06(s,1H),7.02(s,1H),4.01(d,J=13 .6Hz,1H),3.48(d,J=13.5Hz,1H),3.09(d,J=6.1Hz,1H),2.93(d,J=11.8Hz,1H),2.33(s ,3H),2.28(t,J=9.6Hz,1H),1.96–1.85(m,1H),1.73–1.51(m,3H),1.51–1.30(m,2H)ppm.

[0605] Example 32

[0606] (S,E)-4-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-hydroxy-5-methylbenzyl)morpholine-3-carboxylic acid (compound 32)

[0607]

[0608] Synthesis of Compound 32

[0609] Sodium cyanoborohydride (38 mg, 0.60 mmol) was added 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). The reaction mixture was heated to 65 °C and stirred for 1 hour, then cooled to room temperature and concentrated under reduced pressure. The residue was then subjected to high performance liquid chromatography to prepare a white solid 32 (19.8 mg, yield: 29%).

[0610] LC-MS (ESI): m / z = 455.4 [M+H] +.

[0611] 1 H NMR (400MHz, DMSO-d6): δ8.09(d,J=8.0Hz,1H),7.77(t,J=7.8Hz,1H),7.65(d,J= 16.0Hz,1H),7.62–7.46(m,6H),7.29(d,J=16.0Hz,1H),7.09(s,1H),7.04(s,1H), 3.93(d,J=13.9Hz,1H),3.83(dd,J=11.2,3.5Hz,1H),3.70(dd,J=11.2,6.6Hz,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.

[0612] Example 33

[0613] (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)

[0614]

[0615] Synthesis of compound 33-c

[0616] Potassium carbonate (1.66 g, 12.0 mmol) was added to a solution of 2,4-dihydroxy-5-chlorobenzaldehyde (1.73 g, 10.0 mmol) in N,N-dimethylformamide (16 mL). The mixture was stirred at 0 °C for 15 minutes. The mixture was then cooled to -10 °C, and a solution of N-phenyl(bis(trifluoromethanesulfonyl)imide) (3.56 g, 10.0 mmol) in N,N-dimethylformamide (20 mL) was added dropwise. After the addition was complete, the mixture was reacted at -10 °C for 2 hours. 100 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined and washed successively with water (30 mL × 1) and saturated brine (30 mL × 1). The mixture was concentrated under reduced pressure, and 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%).

[0617] 1 H NMR (400MHz, CD3Cl): δ10.07(s,1H),7.99(s,1H),7.07(s,1H)ppm

[0618] Synthesis of compound 33-b

[0619] 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(diphenylphosphine)ferrocene]palladium dichloride (88 mg, 0.12 mmol), potassium phosphate (733 mg, 3.46 mmol), and cesium fluoride (519 mg, 3.46 mmol) were added, and the mixture was stirred at 80 °C for 16 hours under a nitrogen atmosphere. The mixture was concentrated under reduced pressure, the residue was diluted with water, the pH was adjusted to less than 3 with 1 M hydrochloric acid, and extracted with dichloromethane (30 mL × 3). The organic phases were combined and washed with saturated brine (30 mL × 1). The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to give compound 33-b (447 mg, yield: 72%).

[0620] LC-MS (ESI): m / z = 358 [MH] - .

[0621] Synthesis of compound 33-a

[0622] 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. 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, washed with water (30 mL × 2), and then washed with saturated brine (30 mL). The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to give compound 33-a (347 mg, yield: 83%).

[0623] LC-MS(ESI): m / z = 418[M+H] + .

[0624] Synthesis of Compound 33

[0625] To a solution of compound 33-a (84 mg, 0.20 mmol) in dichloromethane (10 mL), (S)-piperidin-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. The mixture was concentrated under reduced pressure, and the residue was prepared by high performance liquid chromatography to give compound 33 (35 mg, yield: 28%).

[0626] LC-MS (ESI): m / z = 531 [M+H] + .

[0627] 1 H NMR (400MHz, CD3Cl): δ8.30(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,2H),3.40(s,3H),2.94~3.00 (m,1H),2.29~2.33(m,1H),1.80~1.87(m,3H),1.68~1.71(m,1H),1.54~1.61(m,1H)ppm.

[0628] Example 34

[0629] (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)

[0630]

[0631] Synthesis of Compound 34

[0632] To a solution of compound 33-a (84 mg, 0.20 mmol) in dichloromethane (10 mL), (S)-morpholine-3-carboxylic acid (39 mg, 0.30 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. 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 prepared by high performance liquid chromatography to give compound 34 (36 mg, yield: 28%).

[0633] LC-MS (ESI): m / z = 533 [M+H] + .

[0634] 1H NMR (400MHz, DMSO-d6): δ8.09(d,J=7.6Hz,1H),8.05(d,J=18.0Hz,1H),7.78(t,J=8.0 Hz,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),3.50~3.5 7(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.

[0635] Example 35

[0636] (S,E)-2-((5-chloro-2-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-4-(2-methoxyethoxy)benzyl)amino)-3-hydroxy-2-methylpropionic acid (compound 35)

[0637]

[0638] Synthesis of Compound 35

[0639] To a suspension of (S)-methylserine (60 mg, 0.50 mmol) in methanol (10 mL), 1 M sodium hydroxide aqueous solution (1 mL, 1.0 mmol) was added, and the mixture was stirred until the solid dissolved. A tetrahydrofuran solution (5 mL) of compound 33-a (63 mg, 0.15 mmol) was added to this mixture, and the mixture was stirred for 16 hours. Sodium borohydride (19 mg, 0.50 mmol) was added, and the mixture was stirred for another hour. The mixture was concentrated under reduced pressure, and the residue was washed with water, extracted with ethyl acetate, concentrated under reduced pressure, and purified by preparative liquid chromatography to give compound 35 (21 mg, yield: 27%).

[0640] LC-MS (ESI): m / z = 521 [M+H] + .

[0641] 1H NMR (400MHz, DMSO-d6): δ8.21(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,1 H),7.47(s,1H),4.30~4.32(m,2H),4.00(dd,J=24.0Hz,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.

[0642] Example 36

[0643] (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)

[0644]

[0645] Synthesis of compound 36-b

[0646] 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) were added to a 100 mL reaction flask. p-Toluenesulfonyl chloride (2.29 g, 12 mmol) was added in portions to this mixture 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, concentrated under reduced pressure, and 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%).

[0647] Synthesis of compound 36-a

[0648] 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 for 16 hours under nitrogen protection and at 50 °C, then cooled to room temperature, and water (100 mL) was added to form a suspension. The suspension was then adjusted to pH 7 by adding 4N dilute hydrochloric acid. The mixture was extracted with ethyl acetate (150 mL), and the organic phase was washed with water (60 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10⁻³: 1) to give a yellow solid 36-a (80 mg, yield: 77%).

[0649] LC-MS (ESI): m / z = 480.1 [M+H] + .

[0650] Synthesis of Compound 36

[0651] 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), and sodium cyanoborohydride (27.7 mg, 0.44 mmol) was added. 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 then subjected to high performance liquid chromatography to prepare a white solid 36 (28.1 mg, yield: 28%).

[0652] LC-MS (ESI): m / z = 593.2 [M+H] + .

[0653] 1 H NMR (400MHz, DMSO-d6): δ8.17-7.81(m,2H),7.79(t,J=8.0Hz,1H),7.62-7 .50(m,6H),7.45(s,1H),7.44-7.41(m,2H),4.30(t,J=6.4Hz,2H),4.02(d ,J=12.8Hz,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.

[0654] Example 37

[0655] (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)

[0656]

[0657] Synthesis of Compound 37

[0658] Compound 36-a (150 mg, 0.31 mmol) and (S)-morpholino-3-carboxylic acid (131 mg, 1.0 mmol) were dissolved in methanol (20 ml), sodium cyanoborohydride (63.0 mg, 1.0 mmol) was added, the mixture was heated to 60 °C, stirred for 2 hours, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was prepared by high performance liquid chromatography to obtain a white solid 37 (15.0 mg, yield: 5.0%).

[0659] LC-MS (ESI): m / z = 595.2 [M+H] + .

[0660] 1 H NMR (400MHz, DMSO-d6): δ8.10(d,J=8.0Hz,1H),8.06(d,J=16.0Hz,1H),7.80( t,J=8.0Hz,1H),7.62-7.51(m,6H),7.46-7.42(m,3H),4.29(t,J=6.0Hz,2H), 4.03(d,J=12.8Hz,1H),3.75-3.72(m,2H),3.59-3.52(m,3H),3.31-3.28(m,3 H),3.22-3.20(m,1H),3.05(s,3H),2.82-2.78(m,1H),2.29-2.20(m,3H)ppm.

[0661] Example 38

[0662] (S,E)-2-((5-chloro-2-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-4-(3-methylsulfonyl)propoxy)benzyl)amino)-3-hydroxy-2-methylpropionic acid (compound 38)

[0663]

[0664] Synthesis of Compound 38

[0665] (S)-Methylserine (74.5 mg, 0.626 mmol) was dissolved in methanol (8 mL), and 0.313 M sodium hydroxide aqueous solution (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 tetrahydrofuran solution (6 mL) of compound 36-a (120.0 mg, 0.35 mmol) was slowly added dropwise. After the addition was complete, the mixture was heated to room temperature and stirred for 16 hours. Sodium borohydride (27.0 mg, 0.71 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was prepared by high performance liquid chromatography to give a white solid 38 (27.0 mg, yield: 22%).

[0666] LC-MS (ESI): m / z = 441.4 [M+H] + .

[0667] 1 H NMR (400MHz, DMSO-d6): δ8.21(d,J=8.0Hz,1H),8.05(d,J=6.0Hz,1H),7.77(t,J=8.0Hz,1H),7.60-7.44(m,9H),4.30(t, J=6.4Hz,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.

[0668] Example 39

[0669] (S,E)-1-(5-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-(4-cyanobutoxy)-4-methylbenzyl)piperidine-2-carboxylic acid (compound 39)

[0670]

[0671] Synthesis of compound 39-c

[0672] 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 under reflux for 3 hours. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and the pH was adjusted to approximately 3 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate (100 mL × 2). The organic phases were combined, washed with water (100 mL) and saturated brine (50 mL), respectively, concentrated under reduced pressure, and 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%).

[0673] Synthesis of compound 39-b

[0674] A mixture of compound 39-c (500 mg, 2.33 mmol), 5-bromopentonitrile (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 hours. The reaction mixture 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, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give a white solid 39-b (550 mg, yield: 80%).

[0675] 1 H NMR (400MHz, CDCl3): δ10.33(s,1H),7.95(s,1H),6.86(s,1H),4.12(t,J=5.9Hz, 2H),2.47(t,J=6.9Hz,2H),2.44(s,3H),2.09–2.00(m,2H),1.96–1.86(m,2H)ppm

[0676] Synthesis of compound 39-a

[0677] A mixture of compound 39-b (296 mg, 1.0 mmol), compound 8-b (397 mg, 1.2 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (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 protection for 16 hours. The reaction mixture was diluted with saturated brine (20 mL). The resulting mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give compound 39-a (260 mg, yield: 62%).

[0678] LC-MS (ESI): m / z = 421.3 [M+H] + .

[0679] Synthesis of Compound 39

[0680] Sodium cyanoborohydride (30 mg, 0.24 mmol) was added to a mixture of compound 39-a (50 mg, 0.12 mmol), (S)-piperidin-2-carboxylic acid (31 mg, 0.24 mmol), methanol (1 mL), and tetrahydrofuran (1 mL). The reaction mixture was stirred at 65 °C for 1 hour. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was prepared by high performance liquid chromatography to give a white solid 39 (37.7 mg, yield: 56%).

[0681] LC-MS (ESI): m / z = 534.6 [M+H] + .

[0682] 1H NMR (400MHz, CD3OD): δ7.88(d,J=7.9Hz,1H),7.82(s,1H),7.70(t,J=8.0Hz,1H),7.61(d,J=16.1Hz,1H),7.5 8–7.45(m,5H),7.43(d,J=7.6Hz,1H),7.39(d,J=16.1Hz,1H),7.00(s,1H),4.57(d,J=12.8Hz,1H),4.37(d,J =12.7Hz,1H),4.17(t,J=6.1Hz,2H),3.56(d,J=6.5Hz,1H),3.32(s,1H),3.03(t,J=10.3Hz,1H),2.58(t,J=7 .0Hz,2H),2.50(s,3H),2.23(d,J=13.3Hz,1H),2.09–1.98(m,2H),1.98–1.81(m,4H),1.80–1.51(m,3H)ppm.

[0683] Example 40

[0684] (S,E)-4-(5-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-(4-cyanobutoxy)-4-methylbenzyl)morpholine-3-carboxylic acid (compound 40)

[0685]

[0686] Synthesis of Compound 40

[0687] Sodium cyanoborohydride (30 mg, 0.24 mmol) was added 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). The reaction mixture was stirred at 65 °C for 1 hour. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was prepared by high performance liquid chromatography to give a white solid 40 (39 mg, yield: 61%).

[0688] LC-MS (ESI): m / z = 536.5 [M+H] + .

[0689] 1H NMR (400MHz, DMSO-d6): δ8.08(d,J=8.0Hz,1H),7.76(t,J=7.9Hz,1H),7.71 (s,1H),7.68(d,J=16.0Hz,1H),7.63–7.48(m,5H),7.46(d,J=7.7Hz,1H),7 .28(d,J=16.0Hz,1H),6.88(s,1H),4.05(t,J=5.9Hz,2H),3.91–3.81(m,2H ),3.77–3.62(m,3H),3.61–3.54(m,1H),3.29(t,J=3.8Hz,1H),3.10–3.02(m 1H), 2.60 (t, J = 7.0Hz, 2H), 2.44 (s, 3H), 2.38–2.30 (m, 1H), 1.88–1.80 (m, 2H), 1.79–1.70 (m, 2H)ppm.

[0690] Example 41

[0691] (S,E)-1-(5-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-(2-hydroxyethoxy)-4-methylbenzyl)piperidine-2-carboxylic acid (compound 41)

[0692]

[0693]

[0694] Synthesis of compound 41-b

[0695] 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 hours. The reaction mixture was cooled to room temperature and diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with water (50 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30:1) to give a white solid 41-b (526 mg, yield: 76%).

[0696] Synthesis of compound 41-a

[0697] A mixture of compound 41-b (373 mg, 1.0 mmol), compound 8-b (397 mg, 1.2 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (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 protection for 16 hours. The reaction mixture 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, concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to give a yellow solid 41-a (420 mg, yield: 84%).

[0698] LC-MS (ESI): m / z = 498.5 [M+H] + .

[0699] Synthesis of Compound 41

[0700] Sodium cyanoborohydride (38 mg, 0.60 mmol) was added to a mixture of compound 41-a (75 mg, 0.15 mmol), (S)-piperidin-2-carboxylic acid (39 mg, 0.30 mmol), methanol (1 mL), and tetrahydrofuran (1 mL). The reaction mixture was stirred at 65 °C for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was then added to tetrahydrofuran (1 mL), water (0.5 mL), and trifluoroacetic acid (0.5 mL), and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was treated by high performance liquid chromatography to obtain a white solid 41 (40.2 mg, yield: 54%).

[0701] LC-MS (ESI): m / z = 495.5 [MH] + .

[0702] 1H NMR (400MHz, DMSO-d6): δ8.06(d,J=7.9Hz,1H),7.76(t,J=7.9Hz,1H),7.74(s,1H),7.66(d,J=1 6.0Hz,1H),7.62–7.58(m,2H),7.57–7.48(m,3H),7.47(d,J=7.6Hz,1H),7.27(d,J=16.0Hz,1H) ,6.91(s,1H),4.10–3.97(m,4H),3.81(d,J=13.7Hz,1H),3.73(t,J=4.6Hz,2H),3.12(dd,J=8.2 ,3.9Hz,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.

[0703] Example 42

[0704] (S,E)-4-(5-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-(2-hydroxyethoxy)-4-methylbenzyl)morpholine-3-carboxylic acid (compound 42)

[0705]

[0706] Synthesis of Compound 42

[0707] Sodium cyanoborohydride (38 mg, 0.60 mmol) was added to a mixture of compound 41-a (75 mg, 0.15 mmol), (S)-morpholino-3-carboxylic acid (39 mg, 0.30 mmol), methanol (1 mL), and tetrahydrofuran (1 mL). The reaction mixture was stirred at 65 °C for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was added to tetrahydrofuran (1 mL), water (0.5 mL), and trifluoroacetic acid (0.5 mL), and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was treated by high performance liquid chromatography to obtain a white solid 42 (53.3 mg, yield: 58%).

[0708] LC-MS (ESI): m / z = 499.5 [M+H] + .

[0709] 1H NMR (400MHz, DMSO-d6): δ8.08(d,J=7.9Hz,1H),7.76(t,J=7.9Hz,1H),7.72(s,1H),7.68(d,J =16.0Hz,1H),7.63–7.50(m,5H),7.46(d,J=7.7Hz,1H),7.28(d,J=16.0Hz,1H),6.88(s,1H),4 .03(t,J=4.1Hz,2H),3.92(d,J=14.4Hz,1H),3.80–3.71(m,4H),3.67(d,J=14.5Hz,1H),3.61( t,J=4.7Hz,2H),3.22(t,J=4.5Hz,1H),3.02–2.95(m,1H),2.44(s,3H),2.37–2.28(m,1H)ppm.

[0710] Example 43

[0711] (S,E)-1-(5-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-(2-methoxyethoxy)-4-methylbenzyl)piperidine-2-carboxylic acid (compound 43)

[0712]

[0713] Synthesis of compound 43-b

[0714] 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 mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with water (50 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the 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%).

[0715] Synthesis of compound 43-a

[0716] A mixture of compound 43-b (273 mg, 1.0 mmol), compound 8-b (397 mg, 1.2 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (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 protection for 16 hours. The reaction mixture 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, concentrated under reduced pressure, and the residue was washed with ethyl acetate (20 mL) to give a grayish-white solid 43-a (284 mg, yield: 71%).

[0717] LC-MS (ESI): m / z = 398.4 [M+H] + .

[0718] Synthesis of Compound 43

[0719] Sodium cyanoborohydride (25 mg, 0.4 mmol) was added to a mixture of compound 43-a (40 mg, 0.1 mmol), (S)-piperidin-2-carboxylic acid (26 mg, 0.2 mmol), methanol (1 mL), and tetrahydrofuran (1 mL). The reaction mixture was stirred at 65 °C for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was then subjected to high performance liquid chromatography to prepare a white solid 43 (33.2 mg, 65% yield).

[0720] LC-MS (ESI): m / z = 511.4 [M+H] + .

[0721] 1 H NMR (400MHz, CD3OD): δ7.89(d,J=8.0Hz,1H),7.76(s,1H),7.70(t,J=7.8Hz,1H),7.61(d,J=16. 1Hz,1H),7.58–7.45(m,5H),7.43(d,J=7.6Hz,1H),7.38(d,J=16.1Hz,1H),6.99(s,1H),4.68(d ,J=12.7Hz,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=11.6Hz,1H),2.50(s,3H),2.25(s,1H),1.99–1.49(m,5H)ppm.

[0722] Example 44

[0723] (S,E)-4-(5-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-(2-methoxyethoxy)-4-methylbenzyl)morpholine-3-carboxylic acid (compound 44)

[0724]

[0725] Synthesis of Compound 44

[0726] Sodium cyanoborohydride (25 mg, 0.4 mmol) was added 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). The reaction mixture was stirred at 65 °C for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was then subjected to high performance liquid chromatography to prepare a white solid 44 (26 mg, yield: 51%).

[0727] LC-MS (ESI): m / z = 513.4 [M+H] + .

[0728] 1 H NMR (400MHz, DMSO-d6): δ8.08(d,J=8.0Hz,1H),7.76(t,J=7.8Hz,1H),7.74(s,1 H),7.68(d,J=16.0Hz,1H),7.64–7.48(m,5H),7.46(d,J=7.6Hz,1H),7.29(d,J= 16.1Hz,1H),6.89(s,1H),4.18–4.10(m,2H),3.90–3.81(m,2H),3.78–3.55(m,7 H), 3.33 (s, 3H), 3.06 (t, J = 10.8Hz, 1H), 2.44 (s, 3H), 2.36 (d, J = 12.0Hz, 1H) ppm.

[0729] Example 45

[0730] (S,E)-1-(2-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-6-(4-cyanobutoxy)-3-methylbenzyl)piperidine-2-carboxylic acid (compound 45)

[0731]

[0732] Synthesis of compound 45-a

[0733] A mixture of compound 15-b-1 (250 mg, 0.84 mmol), compound 8-b (334 mg, 1.01 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (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 under nitrogen protection for 16 hours. The reaction mixture 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 washed with acetonitrile (20 mL) and a 5:1 mixture of dioxane and water (20 mL) to give a grayish-white solid 45-a (280 mg, yield: 79%).

[0734] LC-MS(ESI): m / z = 421.4 [M+H] + .

[0735] Synthesis of Compound 45

[0736] Sodium cyanoborohydride (25 mg, 0.4 mmol) was added to a mixture of compound 45-a (42 mg, 0.1 mmol), (S)-piperidin-2-carboxylic acid (26 mg, 0.2 mmol), methanol (1 mL), and tetrahydrofuran (1 mL). The reaction mixture was stirred at 65 °C for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was then subjected to high performance liquid chromatography to prepare a white solid 45 (30.8 mg, yield: 58%).

[0737] LC-MS (ESI): m / z = 534.5 [M+H] + .

[0738] 1H NMR (400MHz, CD3OD): δ8.11(d,J=7.9Hz,1H),7.79(t,J=7.9Hz,1H),7.62(d,J=16.8Hz,1H),7.59–7.45( m,6H),7.39(d,J=8.5Hz,1H),7.06(d,J=6.8Hz,1H),7.03(d,J=14.9Hz,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=7.0Hz,2H),2. 39(s,3H),2.17–1.99(m,J=9.0,5.9Hz,4H),1.94–1.85(m,2H),1.85–1.75(m,1H),1.75–1.54(m,3H)ppm.

[0739] Example 46

[0740] (S,E)-4-(2-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-6-(4-cyanobutoxy)-3-methylbenzyl)morpholine-3-carboxylic acid (compound 46)

[0741]

[0742] Synthesis of Compound 46

[0743] Sodium cyanoborohydride (25 mg, 0.4 mmol) was added to a mixture of compound 45-a (42 mg, 0.1 mmol), (S)-morpholino-3-carboxylic acid (26 mg, 0.2 mmol), methanol (1 mL), and tetrahydrofuran (1 mL). The reaction mixture was stirred at 65 °C for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was then subjected to high performance liquid chromatography to prepare a white solid 46 (25.3 mg, yield: 47%).

[0744] LC-MS (ESI): m / z = 536.5 [M+H] + .

[0745] 1H NMR (400MHz, CD3OD): δ8.18(d,J=7.9Hz,1H),7.78(t,J=7.9Hz,1H),7.71(d,J=16.5Hz,1H),7.60–7.54(m,2H),7 .54–7.44(m,4H),7.37(d,J=8.6Hz,1H),7.06(d,J=16.9Hz,1H),7.02(d,J=9.2Hz,1H),4.71(d,J=13.0Hz,1H),4 .55(d,J=13.2Hz,1H),4.22–4.13(m,2H),4.10(dd,J=12.6,3.8Hz,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=7.0Hz,2H),2.40(s,3H),2.10–1.98(m,2H),1.94–1.82(m,2H)ppm

[0746] Example 47

[0747] (S,E)-1-(5-chloro-2-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-4-(cyanomethoxy)benzyl)piperidine-2-carboxylic acid (compound 47)

[0748]

[0749] Synthesis of compound 47-a

[0750] 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 protection for about 5 hours, and then cooled to room temperature. Water (100 mL) was added to form a suspension, and the pH was adjusted to 7 with 4N 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, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10⁻³:1) to give compound 47-a (70 mg, yield: 41%).

[0751] LC-MS (ESI): m / z = 399.1 [M+H] + .

[0752] Synthesis of Compound 47

[0753] 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, the mixture was heated to 60 °C, stirred for 2 hours, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was treated by high performance liquid chromatography to obtain a white solid 47 (25.0 mg, yield: 28%).

[0754] LC-MS (ESI): m / z = 512.3 [M+H] + .

[0755] 1 H NMR:(400MHz DMSO-d6): δ8.14(s,1H),8.11(d,J=9.6Hz,1H),7.79(t,J=8.0Hz,1H),7.61-7.44(m,9H),5.40(s,2H),7.44-7.41(m,2H),3.98(d,J=1 3.2Hz,1H),3.43(d,J=13.2Hz,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.

[0756] Example 48

[0757] (S,E)-1-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-(cyanomethoxy)-5-methylbenzyl)piperidine-2-carboxylic acid (compound 48)

[0758]

[0759] Synthesis of compound 48-b

[0760] 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 mixture was diluted with water (20 mL). The precipitated solid was filtered and dried to give a white solid 48-b (213 mg, yield: 84%).

[0761] Synthesis of compound 48-a

[0762] A mixture of compound 48-b (210 mg, 0.826 mmol), compound 8-b (328 mg, 0.992 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (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 under nitrogen protection for 16 hours. The reaction mixture 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 washed with ethyl acetate (20 mL × 2) to give a pale green solid 48-a (300 mg, yield: 96%).

[0763] LC-MS (ESI): m / z = 379.3 [M+H] + .

[0764] Synthesis of Compound 48

[0765] Sodium cyanoborohydride (38 mg, 0.60 mmol) was added to a mixture of compound 48-a (57 mg, 0.15 mmol), (S)-piperidin-2-carboxylic acid (39 mg, 0.30 mmol), methanol (1 mL), and tetrahydrofuran (1 mL). The reaction mixture was stirred at 65 °C for 1 hour. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to give a white solid 48 (14.7 mg, yield: 20%).

[0766] LC-MS (ESI): m / z = 492.4 [M+H] + .

[0767] 1 H NMR (400MHz, CD3OD): δ7.97(d,J=8.0Hz,1H),7.75(t,J=7.9Hz,1H),7.69(d,J= 16.1Hz,1H),7.62–7.44(m,9H),5.20(s,2H),4.49(d,J=12.9Hz,1H),4.34(d,J =12.8Hz,1H),3.50(d,J=8.4Hz,1H),3.42–3.33(m,1H),2.97(t,J=10.5Hz,1H) ,2.49(s,3H),2.26(d,J=12.2Hz,1H),1.95–1.66(m,4H),1.63–1.46(m,1H)ppm.

[0768] Example 49

[0769] (S,E)-1-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-(methoxymethyl)-5-trifluoromethylbenzyl)piperidine-2-carboxylic acid (compound 49)

[0770]

[0771] Synthesis of compound 49-d

[0772] Compound 20-f (600 mg, 2 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL). Sodium hydride (80 mg, 4 mmol) was added under nitrogen protection at 0 °C. After the addition was complete, the mixture was brought to room temperature and stirred for 30 minutes. Iodomethane (570 mg, 4 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction was quenched with water (1 mL), and the mixture was extracted with ethyl acetate (100 mL). The extract was washed successively with water (20 mL × 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and 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%).

[0773] 1 H NMR (400MHz, DMSO-d6): δ8.22(s,1H),8.09(s,1H),4.87(s,2H),3.92(s,3H),3.46(s,3H)ppm.

[0774] Synthesis of compound 49-c

[0775] 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 protection at 0 °C. After the reaction was completed, the solution was refluxed 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 = 10:1) to give compound 49-c (170 mg, yield: 65.0%).

[0776] LC-MS (ESI): m / z = 299 [MH] + .

[0777] Synthesis of compound 49-b

[0778] 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 mixture was stirred at room temperature for 16 hours. The mixture was filtered, and the filter 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%).

[0779] Synthesis of compound 49-a

[0780] 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(diphenylphosphine)ferrocene]palladium dichloride (31 mg, 0.042 mmol) were added to a mixed solution of 1,4-dioxane (5 mL) and water (0.5 mL). The mixture was stirred at 80 °C under nitrogen protection for 16 h. 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 49-a (65 mg, yield: 43.0%).

[0781] LC-MS(ESI): m / z = 422[M+H] + .

[0782] Synthesis of Compound 49

[0783] 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 protection for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was prepared by high performance liquid chromatography to give compound 49 (10 mg, yield: 26.3%).

[0784] LC-MS (ESI): m / z = 535 [M+H] + .

[0785] 1H NMR (400MHz, DMSO-d6): δ7.97(d,J=8.0Hz,1H),7.93(s,1H),7.83(d,J=8.0Hz,1H),7.80(s,1H),7.66-7.46(m,8H),4.67(s,2H),3.87(d,J=14.4H z,1H),3.57(d,J=14.4Hz,1H),3.38(s,3H),3.17(t,J=5.6Hz,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.

[0786] Example 50

[0787] (S,E)-4-(4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-(methoxymethyl)-5-trifluoromethylbenzyl)morpholine-3-carboxylic acid (compound 50)

[0788]

[0789] Synthesis of Compound 50

[0790] A mixture of compound 49-a (30 mg, 0.07 mmol), (S)-morpholino-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 protection for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was prepared by high performance liquid chromatography to give compound 50 (10 mg, yield: 33.3%).

[0791] LC-MS (ESI): m / z = 537 [M+H] + .

[0792] 1 H NMR (400MHz, DMSO-d6): δ7.90(d,J=8.0Hz,1H),7.87(s,1H),7.83(t,J=8.0Hz,1H),7.69(s,1H),7.59-7.39(m,8H),4.61(s,2H),3.91(d,J=14 .4Hz,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.

[0793] Example 51

[0794] (S,E)-1-(2-methoxy-4-(2-(2-methyl-d3)-[1,1'-biphenyl]-3-yl)vinyl)-5-trifluoromethylbenzyl)piperidine-2-carboxylic acid (compound 51)

[0795]

[0796] Synthesis of compound 51-c

[0797] 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 mixture 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, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to give compound 51-c (550 mg, yield: 88%).

[0798] 1 H NMR (400MHz, DMSO-d6): δ7.67–7.59(m,1H),7.49–7.37(m,3H),7.35–7.28(m,2H),7.23–7.17(m,2H)ppm

[0799] Synthesis of compound 51-b

[0800] A mixture of compound 51-c (500 mg, 2.0 mmol), vinylpinacol borate (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 protection for 16 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50:1) to give compound 51-b (450 mg, yield: 70%).

[0801] Synthesis of compound 51-a

[0802] A mixture of compound 6-b (113 mg, 0.4 mmol), compound 51-b (155 mg, 0.48 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (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 protection for 5 hours. The reaction mixture 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, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50:1). The product was washed with methanol (1.5 mL × 2) to give a white solid 51-a (75 mg, yield: 47%).

[0803] LC-MS(ESI): m / z = 400.4 [M+H] + .

[0804] 1 H NMR (400MHz, CDCl3): δ10.44(s,1H),8.16(s,1H),7.59(dd,J=7.6,1.0Hz,1H),7.51–7.28(m,10H),7.25–7.23(m,1H),4.07(s,3H)ppm

[0805] Synthesis of Compound 51

[0806] Sodium cyanoborohydride (25 mg, 0.4 mmol) was added to a mixture of compound 51-a (40 mg, 0.1 mmol), (S)-piperidin-2-carboxylic acid (26 mg, 0.2 mmol), methanol (1 mL), and tetrahydrofuran (1 mL). The reaction mixture was stirred at 65 °C for 1 hour. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was treated by high performance liquid chromatography to obtain a white solid 51 (16.2 mg, yield: 32%).

[0807] LC-MS (ESI): m / z = 513.5 [M+H] + .

[0808] 1H NMR (400MHz, CD3OD): δ7.89 (s, 1H), 7.62 (d, J = 15.8Hz, 1H), 7.56–7.51 (m, 2H), 7 .42(t,J=7.3Hz,2H),7.37–7.24(m,5H),7.20–7.15(m,1H),4.53(d,J=12.9Hz,1 H),4.40(d,J=12.9Hz,1H),4.06(s,3H),3.57–3.46(m,1H),3.31(s,1H),3.00(t ,J=10.7Hz,1H),2.24(d,J=14.8Hz,1H),1.97–1.64(m,4H),1.63–1.48(m,1H)ppm

[0809] Example 52

[0810] (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)

[0811]

[0812] Synthesis of compound 52-a

[0813] 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), followed by the addition of potassium carbonate (269.1 mg, 1.95 mmol). The reaction mixture was stirred for 12 hours under nitrogen protection and at 30 °C, then allowed to return to room temperature. Water (100 mL) was added to form a suspension, which was then adjusted to neutral by dropwise addition of 4N hydrochloric acid solution. Extraction was performed with ethyl acetate (150 mL × 3), and the organic phase was washed with water (60 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20-10:1) to give a white solid 52-a (110 mg, yield: 75%).

[0814] LC-MS (ESI): m / z = 377.4 [M+H] + .

[0815] Synthesis of Compound 52

[0816] 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), and sodium cyanoborohydride (36.8 mg, 0.58 mmol) was added. 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 then subjected to high performance liquid chromatography to prepare a white solid 52 (19.0 mg, yield: 13%).

[0817] LC-MS (ESI): m / z = 490.4 [M+H] + .

[0818] 1 H NMR (400MHz, DMSO-d6): δ8.17-8.13(m,2H),7.78(t,J=8.0Hz,1H),7.62-7.41(m,9H),4.00(d,J=12.4Hz,1 H), 3.41 (d, J = 12.8Hz, 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.

[0819] Example 53

[0820] (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)

[0821]

[0822] Synthesis of compound 53-d

[0823] Compound 20-f (600 mg, 2 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL). Sodium hydride (80 mg, 4 mmol) was added under nitrogen protection in an ice bath. After the addition was complete, the mixture was brought 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. The reaction was quenched with water (1 mL), followed by the addition of ethyl acetate (100 mL). The mixture was washed with water (20 mL × 3), then with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound 53-d (292 mg, yield: 45.0%).

[0824] Synthesis of compound 53-c

[0825] 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 protection at 0 °C. The reaction mixture was refluxed for 16 hours. 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%).

[0826] LC-MS (ESI): m / z = 301 [MH] + .

[0827] Synthesis of compound 53-b

[0828] Compound 53-c (170 mg, 0.56 mmol) was dissolved in dichloromethane (10 mL), and manganese dioxide (493 mg, 5.6 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The mixture was filtered, and the manganese dioxide was washed with dichloromethane. 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-b (114 mg, yield: 68%).

[0829] 1 H NMR (400MHz, DMSO-d6): δ10.17(s,1H),8.31(s,1H),8.08(s,1H),4.88(s,2H)ppm

[0830] Synthesis of compound 53-a

[0831] 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(diphenylphosphine)ferrocene]palladium dichloride (31 mg, 0.042 mmol), 1,4-dioxane (5 mL), and water (0.5 mL) was stirred at 80 °C under nitrogen protection for 16 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and 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%).

[0832] LC-MS (ESI): m / z = 425 [M+H] + .

[0833] Synthesis of Compound 53

[0834] A mixture of compound 53-a (30 mg, 0.07 mmol), (S)-piperidin-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 protection for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to prepare compound 53 (10 mg, yield: 26.3%).

[0835] LC-MS (ESI): m / z = 538 [M+H] + .

[0836] 1 H NMR (400MHz, DMSO-d6): δ7.97(d,J=8.0Hz,1H),7.94(s,1H),7.82(t,J=8.0Hz,1H),7.80(s,1H),7.66-7.46(m,8H),4.66(s,2H),3.91(d, J=14.0Hz,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

[0837] Example 54

[0838] (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)

[0839]

[0840] Synthesis of Compound 54

[0841] A mixture of compound 53-a (30 mg, 0.07 mmol), (S)-morpholino-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 protection for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to prepare compound 54 (10 mg, yield: 33.3%).

[0842] LC-MS (ESI): m / z = 540 [M+H] + .

[0843] 1H NMR (400MHz, DMSO-d6): δ7.97(d,J=8.0Hz,1H),7.93(s,1H),7.82(t,J=8.0Hz,1H),7.79(s,1H),7.61-7.49(m,8H),4.71(s,2H) ,4.06(d,J=14.0Hz,1H),3.74-3.73(m,2H),3.58-3.52(m,3H),3.06(d,J=14.4Hz,1H),2.82-2.79(m,1H),2.20-2.15(m,1H)ppm

[0844] Example 55

[0845] (S,E)-3-hydroxy-2-methyl-((3-(2-(2-methyl-d3)-[1,1'-biphenyl]-3-yl)vinyl)-4-trifluoromethylbenzyl)amino)propionic acid (compound 55)

[0846]

[0847] Synthesis of compound 55-a

[0848] 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 protection for 16 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 0-0.04:1) to give compound 55-a (92 mg, yield: 50%).

[0849] Synthesis of Compound 55

[0850] Sodium cyanoborohydride (25 mg, 0.4 mmol) was added to a mixture of compound 55-a (37 mg, 0.1 mmol), (S)-2-amino-3-hydroxy-2-methylpropionic acid (24 mg, 0.2 mmol), methanol (1 mL), and tetrahydrofuran (1 mL). The reaction mixture was heated to 65 °C and stirred for 1 hour, then cooled to room temperature and concentrated under reduced pressure. The residue was then subjected to high performance liquid chromatography to prepare a white solid 55 (18.4 mg, yield: 39%).

[0851] LC-MS (ESI): m / z = 473.5 [M+H] + .

[0852] 1H NMR (400MHz, CD3OD): δ8.15(s,1H),7.80(d,J=8.1Hz,1H),7.67–7.59(m,2H),7.55(dd,J=7.7Hz,1H),7.46–7.39(m,2H),7.39–7 .25(m,5H),7.18(dd,J=7.6,1.2Hz,1H),4.35(q,J=12.5Hz,2H),4.06(d,J=12.2Hz,1H),3.86(d,J=12.1Hz,1H),1.60(s,3H)ppm

[0853] Example 56

[0854] (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)

[0855]

[0856] Synthesis of compound 56-d

[0857] At room temperature, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (57.8 mg, 0.079 mmol) and sodium carbonate (216.2 g, 2.4 mmol) were added to 20 mL of 1,4-dioxane (20 mL) of 3-bromo-4-trifluoromethylbenzaldehyde (253 mg, 0.79 mmol) and 3-b (300 mg, 0.79 mmol) and water (2 mL). The reaction mixture was heated to 80 °C and stirred under nitrogen for 16 hours. 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 = 15:1) to give compound 56-d (136 mg, yield: 47%).

[0858] Synthesis of compound 56-c

[0859] At room temperature, sodium hydroxide (360.0 mg, 9.0 mmol) was added to silver oxide (510.4 mg, 2.2 mmol) in 20 mL of water and 50 mL of dioxane. Compound 56-d (732.0 mg, 2.0 mmol) was added in portions. The reaction mixture was heated to 70 °C and stirred for 12 hours, then cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in water (40 mL) and the pH was adjusted to 4-5 with 4 M hydrochloric acid solution. A large amount of white solid precipitated. The mixture was filtered, and the filter cake was dried to give white solid 56-c (740 mg, yield: 96%). This product did not require further purification.

[0860] 1¹H NMR (400MHz, 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. Synthesis of compound 56-b.

[0861] 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 for 16 hours under nitrogen protection at room temperature. 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 continued for 16 hours at room temperature. The mixture was concentrated under reduced pressure, and the residue was added to water (50 mL) and adjusted to neutral with 4 M hydrochloric acid. 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, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10⁻²:1) to give a white solid 56-b (630 mg, yield: 88%).

[0862] 1 H NMR (400MHz, DMSO-d6): δ7.95(s,1H),7.73(d,J=8.4Hz,1H),7.58(d,J=2.8Hz,1H),7.56(d,J=11. 6Hz,1H),7.49-7.45(m,3H),7.40-7.24(m,5H),7.19(d,J=7.2Hz,1H),5.40(s,1H),2.28(s,3H)ppm

[0863] Synthesis of compound 56-a

[0864] Compound 56-b (630 mg, 1.70 mmol) was dissolved in anhydrous dichloromethane (50 mL), and thionyl chloride (2.02 g, 17.0 mmol) and anhydrous N,N-dimethylformamide (0.5 mL) were added. The mixture was heated to 70 °C and stirred for 6 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30:10⁻¹) to give compound 56-a (600 mg, yield: 90%).

[0865] 1H NMR (400MHz, DMSO-d6): δ8.15(s,1H),7.80(d,J=8.0Hz,1H),7.65-7.59(m,3H),7.50-7.23(m,7H),7.21(d,J=7.2Hz,1H),2.31(s,3H)ppm

[0866] Synthesis of Compound 56

[0867] Compound 56-a (116.4 mg, 0.30 mmol) and the starting material (S)-2-methylserine methyl ester hydrochloride (183.0 mg, 0.60 mmol) were dissolved in acetonitrile (20 mL), and potassium carbonate (207 mg, 1.5 mmol) and sodium iodide (45.0 mg, 0.30 mmol) were added. The mixture was heated to 80 °C and stirred for 5 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to prepare compound 56 (13.5 mg, yield: 9.5%).

[0868] LC-MS (ESI): m / z = 572.5 [M+H] + .

[0869] 1 H NMR (400MHz, DMSO-d6): δ 8.05 (s, 1H), 7.77 (d J=8.4Hz,1H),7.65-7.58(m2H),7.52-7.46(m,3H),7.42-7.32(m,4H),7.29-7.24(m,1H),7 .21(d,J=6.8Hz,1H),5.06(t,J=6.0Hz,1H),3.61-3.57(dd,J1=5.6Hz,J2=10.0Hz,1H),3.41 3.37(dd,J1=5.2Hz,J2=10.0Hz,1H),2.29(s,3H),1.94(bs,1H),1.20(s,3H)ppm

[0870] Example 57

[0871] (S,E)-1-(5-chloro-4-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-2-methoxybenzyl)piperidine-2-carboxylic acid (compound 57)

[0872]

[0873] Synthesis of compound 57-c

[0874] Hexamethylenetetramine (1.54 g, 11.0 mmol) was slowly added in portions to a mixture of 3-bromo-4-chlorophenol (2.07 g, 10.0 mmol) and methanesulfonic acid (15 mL). The mixture was stirred at 105 °C for 1 hour. The reaction mixture was cooled to room temperature and a mixture of ice and water (100 mL) was added. The mixture was extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed successively with water (30 mL) and saturated brine (30 mL). 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 57-c (750 mg, yield: 32%).

[0875] 1 H NMR (400MHz, CDCl3): δ10.90(brs,1H), 9.83(s,1H), 7.62(s,1H), 7.34(s,1H)ppm

[0876] Synthesis of compound 57-b

[0877] Iodomethane (362 mg, 2.55 mmol) was added 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), and the mixture was stirred at room temperature for 4 hours. The mixture was diluted with water (100 mL), extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed successively with water (30 mL) and saturated brine (30 mL). 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 57-b (170 mg, yield: 80%).

[0878] Synthesis of compound 57-a

[0879] To a mixture of compound 57-b (150 mg, 0.60 mmol) and compound 8-b (260 mg, 0.78 mmol) in toluene (25 mL), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (44 mg, 0.06 mmol), potassium phosphate (318 mg, 1.5 mmol), and cesium fluoride (225 mg, 1.5 mmol) were added. The mixture was stirred at 90 °C for 16 hours under a nitrogen atmosphere. 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%).

[0880] 1H NMR (400MHz, CDCl3): δ10.41 (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

[0881] Synthesis of Compound 57

[0882] To a solution of 57-a (112 mg, 0.30 mmol) in 10 mL of dichloromethane, (S)-piperidin-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, followed by stirring at room temperature for 16 hours. The mixture was concentrated under reduced pressure, and the residue was prepared by high performance liquid chromatography to give compound 57 (56 mg, yield: 38%).

[0883] LC-MS (ESI): m / z = 487 [M+H] + .

[0884] 1 H NMR (400MHz, 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

[0885] Example 58

[0886] (S,E)-1-(5-chloro-2-methoxy-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)benzyl)piperidin-2-carboxylic acid (compound 58)

[0887]

[0888] Synthesis of compound 58-a

[0889] To a mixture of compound 57-b (250 mg, 1.00 mmol) and compound 3-b (400 mg, 1.25 mmol) in toluene (20 mL), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (73 mg, 0.10 mmol), potassium phosphate (424 mg, 2.0 mmol), and cesium fluoride (300 mg, 2.0 mmol) were added, and the mixture was stirred at 90 °C for 16 hours 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 = 5:1) to give compound 58-a (272 mg, yield: 75%).

[0890] 1 H NMR (400MHz, CDCl3): δ10.39(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

[0891] Synthesis of Compound 58

[0892] To a solution of compound 58-a (109 mg, 0.30 mmol) in dichloromethane (10 mL), (S)-piperidin-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, followed by stirring at room temperature for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to give compound 58 (66 mg, yield: 46%).

[0893] LC-MS (ESI): m / z = 476 [M+H] + .

[0894] 1 H NMR (400MHz, CD3OD): δ7.59-7.65(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

[0895] Example 59

[0896] (S,E)-1-(5-chloro-2-(methoxy-d3)-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)benzyl)piperidin-2-carboxylic acid (compound 59)

[0897]

[0898]

[0899] Synthesis of compound 59-b

[0900] 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 the mixture was stirred at room temperature for 16 hours. The mixture was diluted with water (50 mL), extracted with ethyl acetate (30 mL × 3), and the organic phases were combined and washed successively with water (30 mL) and saturated brine (30 mL). 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 59-b (136 mg, yield: 85%).

[0901] 1 H NMR (400MHz, CDCl3): δ10.35(s,1H),7.87(s,1H),7.28(s,1H)ppm

[0902] Synthesis of compound 59-a

[0903] 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(diphenylphosphine)ferrocene]palladium dichloride (65 mg, 0.089 mmol), potassium phosphate (212 mg, 1.0 mmol), and cesium fluoride (150 mg, 1.0 mmol) were added, and the mixture was stirred at 90 °C for 16 hours 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 = 7:1) to give compound 59-a (123 mg, yield: 67%).

[0904] 1H NMR (400MHz, CDCl3): δ10.39(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

[0905] Synthesis of Compound 59

[0906] To a solution of compound 59-a (120 mg, 0.33 mmol) in dichloromethane (10 mL), (S)-piperidin-2-carboxylic acid (109 mg, 0.78 mmol) and methanol (10 mL) were added. The mixture was stirred at room temperature for 1 hour, and then sodium cyanoborohydride (100 mg, 1.58 mmol) was added, followed by stirring at room temperature for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to give compound 59 (62 mg, yield: 43%).

[0907] LC-MS (ESI): m / z = 479 [M+H] + .

[0908] 1 H NMR (400MHz, CD3OD): δ7.59-7.65(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),2.3 0(s,1H),2.22-2.26(m,1H),1.76-1.86(m,5H),1.54-1.60(m,1H)ppm.

[0909] Example 60

[0910] (S,E)-1-(2-(methoxy-d3)-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-5-trifluoromethylbenzyl)piperidine-2-carboxylic acid (compound 60)

[0911]

[0912]

[0913] Synthesis of compound 60-c

[0914] To a solution of 4-bromo-2-methoxy-5-trifluoromethylbenzaldehyde (283 mg, 1.0 mmol) in dichloromethane (10 mL), a solution of 1.0 M boron tribromide in dichloromethane (2.5 mL, 2.5 mmol) was slowly added dropwise at 0 °C. After the addition was complete, the ice bath was removed, and the mixture was stirred at room temperature for 16 hours. The mixture was then slowly added to 50 mL of saturated sodium bicarbonate aqueous solution, and extracted with ethyl acetate (30 mL × 3). The organic phases were combined and washed successively with water (30 mL) and saturated brine (30 mL). 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 60-c (142 mg, yield: 53%).

[0915] LC-MS (ESI): m / z = 267 [MH] - .

[0916] Synthesis of compound 60-b

[0917] 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), deuterated iodomethane (290 mg, 2.00 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed successively with water (30 mL) and saturated brine (30 mL). 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 60-b (106 mg, yield: 78%).

[0918] Synthesis of compound 60-a

[0919] 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(diphenylphosphine)ferrocene]palladium dichloride (25 mg, 0.035 mmol), potassium phosphate (148 mg, 0.7 mmol), and cesium fluoride (105 mg, 0.7 mmol) were added, and the mixture was stirred at 90 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 6:1) to give compound 60-a (95 mg, yield: 68%).

[0920] MS(ESI): m / z = 400[M+H] + .

[0921] Synthesis of Compound 60

[0922] 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, and then sodium cyanoborohydride (16 mg, 0.25 mmol) was added. 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, yield: 39%).

[0923] LC-MS (ESI): m / z = 513 [M+H] + .

[0924] 1 H NMR (400MHz, 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.

[0925] Example 61

[0926] (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)

[0927]

[0928] Synthesis of compound 61-d

[0929] To a solution of 1-bromo-3-chloro-2-methylbenzene (2.05 g, 10.0 mmol) and pinacol vinylborate (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. The mixture was stirred at 80 °C for 16 hours 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 = 10:1) to give compound 61-d (2.36 g, yield: 85%).

[0930] Synthesis of compound 61-c

[0931] 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(diphenylphosphine)ferrocene]palladium dichloride (73 mg, 0.10 mmol), potassium phosphate (424 mg, 2.0 mmol), and cesium fluoride (300 mg, 2.0 mmol) were added, and the mixture was stirred at 90 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to give compound 61-c (205 mg, yield: 58%).

[0932] Synthesis of compound 61-b

[0933] To a mixture of compound 61-c (200 mg, 0.56 mmol) and pinacol diboronate (200 mg, 0.78 mmol) in toluene (15 mL), tris(dibenzylacetone)dipalladium (37 mg, 0.04 mmol), 2-cyclohexylphosphine-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 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 7:1) to give compound 61-b (103 mg, yield: 41%).

[0934] 1 H NMR (400MHz, CD3Cl): δ10.44(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

[0935] Synthesis of compound 61-a

[0936] To a toluene (10 mL) solution of compound 61-b (100 mg, 0.22 mmol) and pentadeuterated bromobenzene (54 mg, 0.33 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (32 mg, 0.044 mmol), potassium phosphate (93 mg, 0.44 mmol), and cesium fluoride (66 mg, 0.44 mmol) were added. The mixture was stirred at 90 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give compound 61-a (60 mg, yield: 68%).

[0937] 1 H NMR (400MHz, CD3Cl): δ10.44(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

[0938] Synthesis of Compound 61

[0939] 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, and then sodium cyanoborohydride (28 mg, 0.45 mmol) was added. 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, yield: 27%).

[0940] LC-MS (ESI): m / z = 515 [M+H] + .

[0941] 1H NMR (400MHz, CD3OD): δ7.90 (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,1 H),2.30(s,3H),2.23~2.27(m,1H),1.67~1.85(m,5H),1.54~1.59(m,1H)ppm.

[0942] Example 62

[0943] (R,E)-1-(2-methoxy-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-5-trifluoromethylbenzyl)piperidine-2-carboxylic acid (compound 62)

[0944]

[0945] Synthesis of Compound 62

[0946] Sodium cyanoborohydride (63 mg, 1.0 mmol) was added to a methanol (30 mL) solution of compound 6-a (198 mg, 0.5 mmol) and D-piperidin-2-carboxylic acid (161.2 mg, 1.25 mmol). The mixture was heated to 60 °C and stirred for 2 hours, then cooled to room temperature and concentrated under reduced pressure. The residue was washed with water (30 mL × 3), filtered, concentrated under reduced pressure, and then purified by high performance liquid chromatography to obtain a white solid product 62 (110 mg, yield: 43%).

[0947] LC-MS (ESI): m / z = 510.5 [M+H] + .

[0948] 1 H NMR:(400MHz DMSO-d6): δ7.78(s,1H),7.65(d,J=16.0Hz,1H),7.58(d,J=7.6Hz,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.

[0949] Example 63

[0950] (S,E)-1-(2,5-dimethoxy-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)benzyl)piperidine-2-carboxylic acid (compound 63)

[0951]

[0952] Synthesis of compound 63-a

[0953] 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(diphenylphosphine)ferrocene]palladium dichloride (36.6 mg, 0.05 mmol), potassium phosphate (318 mg, 1.5 mmol), and cesium fluoride (231 mg, 1.5 mmol) were added, and the mixture was stirred at 110 °C for 12 hours 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 = 20–3:1) to give compound 63-a (140 mg, yield: 78%).

[0954] LC-MS (ESI): m / z = 359.2 [M+H] + .

[0955] Synthesis of Compound 63

[0956] To a methanol (20 mL) solution of compound 63-a (140.0 mg, 0.39 mmol), (S)-piperidine-2-carboxylic acid (126.1 mg, 0.97 mmol) and sodium cyanoborohydride (49.1 mg, 0.78 mmol) were added, and the mixture was heated to 60 °C and stirred for 2 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to prepare compound 63 (110 mg, yield: 59%).

[0957] LC-MS(ESI): m / z = 472.3[M+H]+.

[0958] 1H NMR (400MHz, CD3OD): δ7.60 (d, J=12.0Hz, 1H), 7.56 (d, J=2.0Hz, 1H), 7.43-7.4 0(m,2H),7.39-7.21(m,6H),7.11(d,J=7.2Hz,1H),4.47(d,J=12.4Hz,1H),4.3 6(d,J=12.4Hz,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

[0959] Example 64

[0960] (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)

[0961]

[0962]

[0963] Synthesis of compound 64-d

[0964] 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 hours, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10⁻⁵: 1) to give colorless crystals 64-d (1.9 g, yield: 96.9%).

[0965] LC-MS(ESI): m / z = 197.2 [M+H] + .

[0966] Synthesis of compound 64-c

[0967] Compound 64-d (3.92 g, 20 mmol) was dissolved in N,N-dimethylformamide (39 mL), and triphenylphosphine (6.1 g, 23.28 mmol) was added. The mixture was heated to 100 °C, and then a solution of 2.0 M sodium dichlorofluoroacetate (4.4 g, 29.1 mmol) in N,N-dimethylformamide was added dropwise. The mixture was stirred at 100 °C for 1 hour. The mixture was poured into water (200 mL), extracted with ethyl acetate (100 mL × 2), and the organic phase was washed successively with water (100 mL) and saturated brine (100 mL). The mixture was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether) to give compound 64-c (2.67 g, yield: 58.1%).

[0968] Synthesis of compound 64-b

[0969] Compound 64-c (2.3 g, 10 mmol) was dissolved in tetrahydrofuran (30 mL), and pinacol diborate (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 mixture was stirred at 40 °C for 16 hours. 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 = 9:1) to give compound 64-b (3.0 g, yield: 90%).

[0970] Synthesis of compound 64-a

[0971] 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), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (43 mg, 0.059 mmol), 1,4-dioxane (5 mL), and water (0.5 mL) were stirred at 80 °C under nitrogen protection for 16 hours 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 = 10:1) to give compound 64-a (154 mg, yield: 63.0%).

[0972] LC-MS (ESI): m / z = 415 [M+H] + .

[0973] Synthesis of Compound 64

[0974] A mixture of compound 64-a (29 mg, 0.07 mmol), (S)-piperidin-2-carboxylic acid (24 mg, 0.19 mmol), sodium cyanoborohydride (12 mg, 0.19 mmol), and methanol (3 mL) was stirred for 3 hours at 80 °C under nitrogen protection and then cooled to room temperature. The mixture was concentrated under reduced pressure, and the residue was prepared by high performance liquid chromatography to give compound 64 (15 mg, yield: 40.6%).

[0975] LC-MS (ESI): m / z = 528 [M+H] + .

[0976] 1 H NMR (400MHz, DMSO-d6): δ7.87(s,1H),7.62(d,J=7.6Hz,1H),7.46(d,J=7.6Hz, 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 =36.8Hz,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

[0977] Example 65

[0978] (Z)-2-((4-(1-fluoro-2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-2-methoxy-5-trifluoromethylbenzyl)amino)-1-ethanol (Compound 65)

[0979]

[0980] Synthesis of Compound 65

[0981] 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 for 3 hours at 80 °C under nitrogen protection and then cooled to room temperature. The mixture was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to give compound 64 (18 mg, yield: 50.1%).

[0982] LC-MS (ESI): m / z = 460 [M+H] + .

[0983] 1H NMR (400MHz, DMSO-d6): δ7.83(s,1H),7.62(d,J=7.6Hz,1H),7.46(d,J=7.6Hz,2H),7.39(t,J=7.2Hz,1H),7.35-7.31(m,4H),7.17(d,J=7.6H z,1H),6.50(d,J=36.8Hz,1H),4.51(t,J=5.2Hz,1H),3.96(s,3H),3.77(s,3H),3.49(q,J=5.6Hz,2H),2.60(t,J=5.6Hz,2H),2.20(s,3H)ppm

[0984] Example 66

[0985] (Z)-2-((4-(1-bromo-2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-2-methoxy-5-trifluoromethylbenzyl)amino)-1-ethanol (Compound 66)

[0986]

[0987]

[0988] Synthesis of compound 66-c

[0989] Compound 6-b (1.42 g, 5.0 mmol) and compound bis-pinacolyl diborone (1.90 g, 7.5 mmol) were dissolved in toluene (60 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (366 mg, 0.5 mmol) and potassium acetate (1.47 g, 15.0 mmol) were added to the solution. The reaction mixture was heated to 100 °C and stirred for 6 hours, 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 = 15-3:1) to give a pale yellow solid 66-c (1.5 g, yield: 90%).

[0990] Synthesis of compound 66-b

[0991] 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 brought to room temperature and stirred for 1 hour. 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, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100-20:1) to give a colorless oily compound 66-b (1.05 g, yield: 99%).

[0992] 1 H NMR (400MHz, CDCl3): δ7.52(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

[0993] Synthesis of compound 66-a

[0994] Compound 66-b (220 mg, 0.625 mmol) and compound 66-c (247.5 mg, 0.75 mmol) were dissolved in a mixed solution of dioxane (30 mL) and water (10 mL). Bis(dibenzylacetone)palladium (28.6 mg, 0.03 mmol), tris(2-furanyl)phosphine (43.5 mg, 0.187 mmol), and cesium fluoride (406.2 mg, 1.25 mmol) were added to the solution. The reaction mixture was stirred at 65 °C for 16 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was then subjected to high-performance liquid chromatography (HPLC) to prepare a white solid 66-a (80 mg, yield: 27%).

[0995] Synthesis of Compound 66

[0996] 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 mixture was stirred at room temperature for 2 hours, then sodium cyanoborohydride (21.4 mg, 0.34 mmol) was added, and stirring continued for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was treated by high-performance liquid chromatography to obtain a white solid 66 (30.9 mg, yield: 35%).

[0997] LC-MS (ESI): m / z = 520.1 [M+H] + .

[0998] 1H NMR (400MHz, CD3OD): δ7.71(s,1H),7.51(d,J=8.0Hz,1H),7.48-7.43(m,2H),7.39-7.37(m,1H),7.34-7.30(m,3H),7.22(d,J =6.8Hz,1H),7.17(s,1H),7.08(s,1H),4.04(s,3H),3.90(s,2H),3.71(t,J=6.0Hz,2H),2.76(t,J=6.0Hz,2H),2.20(s,3H)ppm

[0999] Example 67

[1000] (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)

[1001]

[1002] Synthesis of Compound 67

[1003] A mixture of compound 66-a (110 mg, 0.23 mmol), (S)-piperidin-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 hours and then cooled to room temperature. The mixture was concentrated under reduced pressure, and the residue was prepared by high performance liquid chromatography to give compound 67 (46 mg, yield: 34%).

[1004] LC-MS (ESI): m / z = 588.2 [M+H] + .

[1005] 1 H NMR (400MHz, CD3OD): δ8.00 (s, 1H), 7.53 (d, J = 7.6Hz, 1H), 7.48-7.43 (m, 2H), 7.3 8(d,J=7.2Hz,1H),7.34-7.30(m,4H),7.23(d,J=7.2Hz,1H),7.12(s,1H),4.59(d, J=13.2Hz,1H),4.45(d,J=12.4Hz,1H),4.05(s,3H),3.57-3.53(m,1H),3.43-3.3 9(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

[1006] Example 68

[1007] (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)

[1008]

[1009] Synthesis of compound 68-f

[1010] The mixture of 3-bromo-2-methyl-1,1'-biphenyl (989 mg, 4.0 mmol), bis-pinacolborate (1.52 g, 6.0 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (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 protection for 16 hours. 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 = 20:1) to give a colorless liquid 68-f (1.0 g, yield: 85%).

[1011] 1 H NMR (400MHz, CD3OD): δ7.76(dd,J=7.2,1.3Hz,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

[1012] Synthesis of compound 68-e

[1013] A mixture of 4-bromo-2-hydroxy-5-methylbenzaldehyde (6.45 g, 30.0 mmol), methyl iodoform (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 mixture 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 a white solid 68-e (5.59 g, yield: 81%).

[1014] Synthesis of compound 68-d

[1015] 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 hour. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and dried under vacuum. The resulting product, 68-d (6.75 g), was used directly in the next step.

[1016] Synthesis of compound 68-c

[1017] Compound 68-d (1.52 g, 5.0 mmol) was dissolved in dry tetrahydrofuran (15 mL). Butyllithium (2.2 mL, 2.5 M n-hexane solution) was slowly added dropwise at -78 °C. After the addition was complete, the mixture was stirred at -78 °C for 0.5 hours, followed by the addition of N,N'-dimethylformamide (431 mg, 10 mmol). After the addition was complete, the mixture was stirred at -78 °C for 2 hours. The reaction mixture was then quenched with saturated sodium bicarbonate solution (10 mL) after reaching room temperature. 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 a pale yellow liquid 68-c (1.07 g, yield: 85%).

[1018] 1 H NMR (400MHz, DMSO-d6): δ10.24(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=7.0Hz,6H)ppm

[1019] Synthesis of compound 68-b

[1020] A solution of 1.72 g of carbon tetrabromide in 5 mL of dichloromethane 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, the mixture was stirred at 0 °C for 10 minutes. Then, a solution of 1.01 g of compound 68-c (4.0 mmol) and triethylamine (1.21 g) in 5 mL of dichloromethane was added dropwise. After the addition was complete, the reaction mixture was brought to room temperature and stirred for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to give a white solid 68-b (700 mg, yield: 52%).

[1021] 1H NMR (400MHz, 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

[1022] Synthesis of compound 68-a

[1023] A mixture of compound 68-b (586 mg, 1.75 mmol), compound 68-f (397 mg, 1.35 mmol), bis(dibenzylacetone)palladium (62 mg, 0.068 mmol), tris(2-furanyl)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. After cooling to room temperature, the reaction mixture 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 treated by high-performance liquid chromatography to prepare compound 68-a (88 mg, yield: 10%).

[1024] LC-MS(ESI): m / z = 421.2 [M+H] + .

[1025] Synthesis of Compound 68

[1026] Sodium cyanoborohydride (25 mg, 0.40 mmol) was added to a mixture of compound 68-a (42 mg, 0.10 mmol), (S)-piperidin-2-carboxylic acid (26 mg, 0.20 mmol), methanol (1 mL), and tetrahydrofuran (1 mL). The reaction mixture was stirred at 60 °C for 1 hour, cooled to room temperature, concentrated under reduced pressure, and the residue was treated by high performance liquid chromatography to obtain a white solid 68 (21 mg, yield: 39%).

[1027] LC-MS (ESI): m / z = 534.2 [M+H] + .

[1028] 1H NMR (400MHz, CD3OD): δ7.47–7.25(m,9H),7.22(dd,J=7.5,1.4Hz,1H),7.03(s,1H),4.47(d,J=12.7Hz,1H),4.34(d,J=12.8Hz,1H),3.94(s,3H),3.5 0(d,J=11.3Hz,1H),3.32(s,1H),2.97(t,J=11.9Hz,1H),2.32(s,3H),2.3 1(s,3H),2.23(d,J=10.5Hz,1H),1.98–1.63(m,4H),1.61–1.46(m,1H)ppm

[1029] Example 69

[1030] (Z)-2-((4-(2-bromo-2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-2-methoxy-5-methylbenzyl)amino)-1-ethanol (Compound 69)

[1031]

[1032] Synthesis of Compound 69

[1033] Sodium cyanoborohydride (18 mg, 0.28 mmol) was added 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). The reaction mixture was stirred at 60 °C for 1 hour, cooled to room temperature, concentrated under reduced pressure, and the residue was treated by high performance liquid chromatography to obtain a white solid 69 (17 mg, yield: 52%).

[1034] LC-MS(ESI):m / z=466.2,468.2[M+H] + .

[1035] 1 H NMR (400MHz, CD3OD): δ8.53(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

[1036] Example 70

[1037] (S,E)-1-(2-methoxy-5-methyl-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)benzyl)piperidine-2-carboxylic acid (Compound 70)

[1038]

[1039] Synthesis of compound 70-a

[1040] 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(diphenylphosphine)ferrocene]palladium dichloride (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 under nitrogen protection for 16 hours. The reaction mixture 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, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give a yellow solid 70-a (135 mg, yield: 79%).

[1041] Synthesis of Compound 70

[1042] Sodium cyanoborohydride (37 mg, 0.60 mmol) was added to a mixture of compound 70-a (51 mg, 0.15 mmol), (S)-piperidin-2-carboxylic acid (38 mg, 0.30 mmol), methanol (1 mL), and tetrahydrofuran (1 mL). The reaction mixture was stirred at 60 °C for 1 hour, cooled to room temperature, concentrated under reduced pressure, and the residue was treated by high performance liquid chromatography to obtain a white solid 70 (26 mg, yield: 38%).

[1043] LC-MS (ESI): m / z = 456.3 [M+H] + .

[1044] 1 ¹H NMR (400MHz, CD₃OD): δ 7.60 (d, J = 7.5Hz, 1H), 7.48–7.19 (m, 10H), 7.14 (d, J = 7.4Hz, 1H), 4.46 (d, J = 12.7Hz, 1H), 4.33 (d, J = 12.7Hz, 1H), 3.96 (s, 3H), 3.48 (d, J = 7.1Hz, 1H), 3.38–3.32 (m, 1H), 2.96 (t, J = 11.7Hz, 1H), 2.40 (s, 3H), 2.29 (s, 3H), 2.23 (d, J = 13.4Hz, 1H), 1.97–1.43 (m, 5H) ppm Example 71

[1045] (S,E)-1-(4-(2-(2-chloro-[1,1'-biphenyl]-3-yl)vinyl)-2-methoxy-5-trifluoromethylbenzyl)piperidine-2-carboxylic acid (compound 71)

[1046]

[1047] Synthesis of compound 71-c

[1048] A mixture of 3-bromo-2-chlorobenzaldehyde (878 mg, 4.0 mmol), phenylboronic acid (536 mg, 4.4 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (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 hours under nitrogen protection. The reaction mixture 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, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30:1) to give a colorless liquid 71-c (764 mg, yield: 88%).

[1049] Synthesis of compound 71-b

[1050] Potassium tert-butoxide (787 mg, 4.02 mmol) was added to a mixture of methyltriphenylphosphonium bromide (2.51 g, 7.02 mmol) and tetrahydrofuran (20 mL) at room temperature, and the mixture was stirred for 2 hours at room temperature. The reaction mixture was cooled to -78 °C, and compound 71-c (760 mg, 3.51 mmol) was added. The reaction mixture was then heated to room temperature and stirred for 16 hours. The reaction mixture 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, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether) to give a colorless liquid compound 71-b (360 mg, yield: 48%).

[1051] Synthesis of compound 71-a

[1052] 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 at 80 °C for 16 hours under nitrogen protection. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give a yellow solid 71-a (60 mg, yield: 29%).

[1053] LC-MS (ESI): m / z = 417.2 [M+H] + .

[1054] Synthesis of Compound 71

[1055] Sodium cyanoborohydride (36 mg, 0.576 mmol) was added to a mixture of compound 71-a (60 mg, 0.144 mmol), (S)-piperidin-2-carboxylic acid (37 mg, 0.288 mmol), methanol (1 mL), and tetrahydrofuran (1 mL). The reaction mixture was stirred at 60 °C for 1 hour, cooled to room temperature, concentrated under reduced pressure, and the residue was treated by high performance liquid chromatography to obtain a white solid 71 (19 mg, yield: 25%).

[1056] LC-MS (ESI): m / z = 530.2 [M+H] + .

[1057] 1 H NMR (400MHz, CD3OD): δ7.93(s,1H),7.75–7.66(m,2H),7.52–7.35(m,8H),7.33(dd,J=7.5,1.3Hz,1H),4.45(d,J=13.0Hz,1H),4.30(d,J=13. 1Hz,1H),4.05(s,3H),3.43(dd,J=10.5,3.3Hz,1H),3.30–3.24(m,1H),2.88(t,J=10.6Hz,1H),2.21(d,J=11.9Hz,1H),1.94–1.44(m,5H)ppm

[1058] Example 72

[1059] (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)

[1060]

[1061] Synthesis of compound 72-d

[1062] Compound 3-c (1.0 g, 4.05 mmol) and trimethylethynylsilane (596.2 mg, 6.07 mmol) were dissolved in N,N-dimethylformamide (15 mL), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (142.5 mg, 0.203 mmol) and triethylamine (3.279 g, 32.4 mmol) were added. The reaction mixture was heated to 70 °C and stirred for 16 hours under nitrogen protection, cooled to room temperature, diluted with ethyl acetate (15 mL), and washed once each with water (50 mL) and saturated brine (50 mL). The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether) to give compound 72-d (551 mg, yield: 51.5%).

[1063] 1 H NMR (400MHz, CDCl3): δ7.56-7.54 (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

[1064] Synthesis of compound 72-c

[1065] 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 mixture was stirred at room temperature for 0.5 hours. The reaction mixture was concentrated under reduced pressure, and 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, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether) to give the target compound 72-c (361 mg, yield: 90.3%).

[1066] 1 H NMR (400MHz, CDCl3): δ7.50-7.48(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

[1067] Synthesis of compound 72-b

[1068] Compound 72-c (100 mg, 0.52 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL). The reaction solution was cooled to -50 °C in an ice-salt bath, and a 1.56 M n-butyllithium hexane solution (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 hours.

[1069] Solid dry ice was added to the above reaction solution, and the mixture was stirred for 0.5 hours. Then, the reaction solution was brought to room temperature and stirred for another hour. The reaction was quenched with water (10 mL), and the solution was adjusted to pH 1–2 with dilute hydrochloric acid (1 N). The mixture was extracted with ethyl acetate (50 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was slurried with petroleum ether to give compound 72-b (83 mg, yield: 67.5%).

[1070] 1 H NMR (400MHz, DMSO-d6): δ7.62-7.58(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

[1071] Synthesis of compound 72-a

[1072] Compound 72-b (83 mg, 0.351 mmol) and bis-pinacol boronic acid ester (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(diphenylphosphine)-9,9-dimethyloxanthracene (20.3 mg, 0.035 mmol), and heavy water (42 mg, 2.106 mmol) were added. The mixture was stirred overnight at room temperature under nitrogen protection.

[1073] Compound 6-b (99 mg, 0.351 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (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 protection. The reaction solution was cooled to room temperature, diluted with ethyl acetate (20 mL), and washed successively with water (20 mL × 2) and saturated brine (20 mL × 2). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether) to give compound 72-a (41 mg, yield: 29.5%).

[1074] 1H NMR (400MHz, CDCl3): δ10.442(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

[1075] Synthesis of Compound 72

[1076] Compound 72-a (56 mg, 0.106 mmol) was dissolved in a mixed solution of methanol (5.5 mL) and dichloromethane (5.5 mL), and glacial acetic acid (9 mg, 0.212 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, followed by the addition of sodium cyanoborohydride (56 mg, 0.106 mmol) and stirring for another 16 hours. The reaction mixture was concentrated under reduced pressure, and 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, concentrated under reduced pressure, and the residue was subjected to high-performance liquid chromatography (HPLC) to prepare compound 72 (11.6 mg, yield: 25.4%).

[1077] LC-MS (ESI): m / z = 444 [M+H] + .

[1078] 1 ¹H NMR (400MHz, 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 Example 73

[1079] (S,E)-1-(4-(2-(2-fluoromethyl-[1,1'-biphenyl]-3-yl)vinyl)-2-methoxy-5-trifluoromethylbenzyl)piperidine-2-carboxylic acid (compound 73)

[1080]

[1081] Synthesis of compound 73-c

[1082] Diethylaminosulfur trifluoride (1.90 g, 11.8 mmol) was slowly added dropwise to a solution of 2,6-dibromo-benzyl alcohol (2.40 g, 9.06 mmol) in dry dichloromethane (60 mL) at -78 °C. After the addition was complete, the mixture was stirred at -78 °C for 30 minutes. The cold bath was removed, and the mixture was allowed to warm to room temperature naturally and stirred at room temperature for 1 hour. The reaction mixture was quenched by slowly adding saturated sodium bicarbonate aqueous solution (50 mL). The organic layer was separated, and the aqueous layer was extracted with dichloromethane (30 mL × 2). The organic phases were combined and washed successively with water (30 mL) and saturated brine (30 mL). The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether) to give compound 73-c (1.86 g, yield: 78%).

[1083] Synthesis of compound 73-b

[1084] To a mixture of compound 6-b (1.40 g, 5.0 mmol), pinacol vinylborate (1.15 g, 7.5 mmol), triethylamine (1.51 g, 15.0 mmol), and toluene (20 mL), bis(tri-tert-butylphosphine)palladium (255 mg, 0.50 mmol) was added. The reaction mixture was stirred at 80 °C for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture 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%).

[1085] LC-MS (ESI): m / z = 357 [M+H] + .

[1086] Synthesis of compound 73-a

[1087] 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), phenylboronic acid (134 mg, 1.1 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (146 mg, 0.2 mmol), potassium phosphate (848 mg, 4.0 mmol), and cesium fluoride (600 mg, 4.0 mmol) were added. The reaction mixture was stirred at 100 °C for 16 hours 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 = 8:1) to give compound 73-a (150 mg, yield: 36%).

[1088] LC-MS (ESI): m / z = 415 [M+H] + .

[1089] Synthesis of Compound 73

[1090] To a solution of compound 73-a (41 mg, 0.10 mmol) in dichloromethane (10 mL), (S)-piperidin-2-carboxylic acid (39 mg, 0.3 mmol) and methanol (10 mL) were added. The mixture was stirred at room temperature for 1 hour, and then sodium cyanoborohydride (16 mg, 0.25 mmol) was added. 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, yield: 42%).

[1091] LC-MS (ESI): m / z = 528 [M+H] + .

[1092] 1 H NMR (400MHz, 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=1 2.8Hz,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

[1093] Example 74

[1094] (E)-2-((4-(2-(2-fluoromethyl-[1,1'-biphenyl]-3-yl)vinyl)-2-methoxy-5-trifluoromethylbenzyl)amino)-1-ethanol (Compound 74)

[1095]

[1096] Synthesis of Compound 74

[1097] To a solution of 73-a (41 mg, 0.10 mmol) in 10 mL of dichloromethane, ethanolamine (31 mg, 0.5 mmol) and methanol (10 mL) were added. The mixture was stirred at room temperature for 1 hour, and then sodium cyanoborohydride (20 mg, 0.31 mmol) was added. 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, yield: 50%).

[1098] LC-MS (ESI): m / z = 460 [M+H] + .

[1099] 1 H NMR (400MHz, CD3OD): δ7.69(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.

[1100] Example 75

[1101] (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)

[1102]

[1103] Synthesis of compound 75-b

[1104] Compounds 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(diphenylphosphine)ferrocene]palladium dichloride (48 mg, 0.065 mmol) and potassium carbonate (359 mg, 2.6 mmol) were added. The reaction mixture was purged three times with nitrogen to remove oxygen, and then heated and stirred at 90 °C for 16 hours. The reaction mixture was cooled to room temperature, and water (20 mL) was added. The mixture was extracted with dichloromethane (40 mL × 2), and 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, washed, and filtered to give a brown solid 75-b (189 mg, yield: 44%). LC-MS (ESI): m / z = 329.27 (M+H) + .

[1105] Synthesis of compound 75-a

[1106] 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 mixture was heated and stirred at 50 °C for 16 hours. After cooling to room temperature, the reaction mixture was directly separated by reversed-phase chromatography (mobile phase: 0.1% formic acid aqueous solution: acetonitrile = 0%-100%) to give a pale yellow solid 75-a (33 mg, yield: 61%). LC-MS (ESI): m / z = 545.09 (M+H) + .

[1107] Synthesis of Compound 75

[1108] Compound 75-a (33 mg, 0.061 mmol) and (S)-piperidin-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 mixture was heated and stirred at 60 °C for 1 hour. The reaction mixture was cooled to room temperature and prepared by high performance liquid chromatography (HPLC) (mobile phase: 1% formic acid aqueous solution: acetonitrile = 20%-70%) to give a white solid 75 (12 mg, yield: 30%). LC-MS (ESI): m / z = 658.36 (M+H) + .

[1109] 1 H-NMR (400MHz, 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

[1110] Example 76

[1111] (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)

[1112]

[1113] Synthesis of compound 76-a

[1114] 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 mixture was heated and stirred at 50 °C for 1 hour. The reaction mixture was cooled to room temperature and then directly separated by reversed-phase chromatography (mobile phase: 0.1% formic acid aqueous solution: acetonitrile = 0%-100%) to give a pale yellow solid 76-a (40 mg, yield: 67%).

[1115] Synthesis of Compound 76

[1116] Compound 76-a (40 mg, 0.067 mmol) and (S)-piperidin-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 mixture was heated and stirred at 60 °C for 1 hour. The reaction mixture was cooled to room temperature and directly prepared by high performance liquid chromatography (HPLC) (mobile phase: 0.1% formic acid aqueous solution: acetonitrile = 20%-70%) to give a white solid 76 (13 mg, yield: 27%). LC-MS (ESI): m / z = 712.4 (M+H) + .

[1117] 1 H-NMR (400MHz, 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

[1118] Example 77

[1119] (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)

[1120]

[1121] Synthesis of compound 77-a

[1122] 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 mixture was heated and stirred at 50 °C for 1 hour. The reaction mixture was cooled to room temperature and then directly separated by reversed-phase chromatography (mobile phase: 0.1% formic acid aqueous solution: acetonitrile = 0-100%) to give a pale yellow solid 77-a (50 mg, yield: 84%).

[1123] Synthesis of Compound 77

[1124] Compound 77-a (40 mg, 0.067 mmol) and (S)-piperidin-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 mixture was heated and stirred at 60 °C for 1 hour. After cooling to room temperature, the reaction mixture was directly subjected to preparative high-performance liquid chromatography (HPLC) (mobile phase: 0.1% formic acid aqueous solution: acetonitrile = 20%-70%) to give a white solid 377 (18 mg, yield: 38%). LC-MS (ESI): m / z = 712.4 (M+H) + .

[1125] 1 H-NMR (400MHz, 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

[1126] Example 78

[1127] (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)

[1128]

[1129] Synthesis of compound 78-a

[1130] 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 mixture was heated and stirred at 50 °C for 1 hour. The reaction mixture was cooled to room temperature and then directly separated by reversed-phase chromatography (mobile phase: 0.1% formic acid aqueous solution: acetonitrile = 0-100%) to give a pale yellow solid 78-a (50 mg, yield: 84%).

[1131] Synthesis of Compound 78

[1132] A mixture of compound 78-a (40 mg, 0.067 mmol), (S)-piperidin-2-carboxylic acid (17 mg, 0.13 mmol), methanol (1 mL), and tetrahydrofuran (1 mL) was reacted with sodium cyanoborohydride (17 mg, 0.27 mmol). The reaction mixture was stirred at 60 °C for 1 hour. After cooling to room temperature, the resulting mixture was subjected to preparative high-performance liquid chromatography (HPLC) (mobile phase: 0.1% formic acid aqueous solution: acetonitrile = 20%-70%) to give a white solid 78 (20 mg, yield: 42%). LC-MS (ESI): m / z = 712.4 (M+H) + .

[1133] 1 H-NMR (400MHz, 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),3.45-3.3 4(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

[1134] Example 79

[1135] (S,E)-1-(2-((4-iodopyridin-2-yl)methoxy)-5-methyl-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)benzyl)piperidine-2-carboxylic acid (Compound 79)

[1136]

[1137] Synthesis of compound 79-c

[1138] 4-Iodopyridinic acid (500 mg, 2 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and borane tetrahydrofuran solution (4 mL, 4 mmol) was added. 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 cooled to room temperature, concentrated under reduced pressure, and 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) + .

[1139] Synthesis of compound 79-b

[1140] Compound 79-c (300 mg, 1.2 mmol) was dissolved in dichloromethane (10 mL), and thionyl chloride (400 mg, 3.6 mmol) was slowly added. The reaction mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, 79-b (355 mg, yield: 96.2%) was obtained and used directly in the next reaction without purification. LC-MS (ESI): m / z = 254 (M+H) + .

[1141] Synthesis of compound 79-a

[1142] Compounds 79-b (57 mg, 0.2 mmol) and 75-b (50 mg, 0.13 mmol) were dissolved in N,N-dimethylformamide (5 mL), and potassium carbonate (54 mg, 0.39 mmol) and potassium iodide (214 mg, 1.3 mmol) were added. The reaction mixture was heated and stirred at 50 °C for 30 minutes. After cooling to room temperature, 79-a (30 mg, yield 38.4%) was prepared directly by high-performance liquid chromatography (HPLC). LC-MS (ESI): m / z = 546 (M+H) + .

[1143] Synthesis of Compound 79

[1144] Compound 79-a (20 mg, 0.037 mmol) and s-piperidin-2-carboxylic acid (7 mg, 0.054 mmol) were dissolved in methanol (3 mL). Sodium cyanoborohydride (5 mg, 0.075 mmol) was added. The reaction mixture was purged three times with nitrogen to remove oxygen, and then heated at 60 °C for 30 minutes. The reaction mixture was cooled to room temperature. The solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (HPLC) to obtain 79 (6 mg, yield 29.7%). LC-MS (ESI): m / z = 659 (M+H) + .

[1145] 1 H-NMR(400MHz,MeOD)δ:8.33(d,J=5.2Hz,1H),7.99(s,1H),7.59-7.27(m,2H),7.43-7.3 1(m,5H),7.28-7.21(m,5H),7.12(d,J=7.6Hz,1H),5.28(s,3H),4.45-4.42(m,1H),4.27 -4.24(m,1H),3.42-3.41(m,1H),2.90-2.78(m,1H),2.28-2.25(m,1H),2.39(s,3H),2.2 4(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

[1146] Example 80

[1147] (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)

[1148]

[1149] Synthesis of compound 80-a

[1150] 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 mg, 0.39 mmol) and potassium iodide (214 mg, 1.3 mmol) were added. The reaction mixture was heated and stirred at 50 °C for 30 minutes. After cooling to room temperature, 80-a (30 mg, yield: 38.4%) was prepared directly by high-performance liquid chromatography (HPLC). LC-MS (ESI): m / z = 600 (M+H) + .

[1151] Synthesis of Compound 80

[1152] Compound 80-a (20 mg, 0.037 mmol) and s-piperidin-2-carboxylic acid (7 mg, 0.054 mmol) were dissolved in methanol (3 mL), and sodium cyanoborohydride (5 mg, 0.075 mmol) was added. The reaction mixture was purged three times with nitrogen to remove oxygen, and then heated at 60 °C for 30 minutes. The reaction mixture was cooled to room temperature. The mixture was concentrated under reduced pressure, and the residue was analyzed by high performance liquid chromatography (HPLC) to prepare 80 (8 mg, yield: 30.7%). LC-MS (ESI): m / z = 713 (M+H) + .

[1153] 1 H-NMR(400MHz, MeOD)δ:8.27(d J=5.6Hz, 1H), 8.09 (s, 1H), 7.91 (s, 1H), 7.81 (dJ=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), 4.7 2-4.64(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

[1154] Example 81

[1155] (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)

[1156]

[1157] Synthesis of compound 81-c

[1158] 2-Iodoisonicotinic acid (500 mg, 2 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and boranetetrahydrofuran solution (4 mL, 4 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 cooled to room temperature, concentrated under reduced pressure, and 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) + .

[1159] Synthesis of compound 81-b

[1160] 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. The reaction mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, 81-b (342 mg, yield: 97.0%) was obtained and used directly in the next reaction without purification. LC-MS (ESI): m / z = 254 (M+H) + .

[1161] Synthesis of compound 81-a

[1162] 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), and potassium carbonate (54 mg, 0.39 mmol) and potassium iodide (214 mg, 1.3 mmol) were added. The reaction mixture was heated and stirred at 50 °C for 30 minutes. After cooling to room temperature, 81-a (30 mg, yield: 38.4%) was prepared directly by high-performance liquid chromatography (HPLC). LC-MS (ESI): m / z = 600 (M+H) + .

[1163] Synthesis of Compound 81

[1164] Compound 81-a (20 mg, 0.037 mmol) and s-piperidin-2-carboxylic acid (7 mg, 0.054 mmol) were dissolved in methanol (3 mL), and sodium cyanoborohydride (5 mg, 0.075 mmol) was added. The reaction mixture was purged three times with nitrogen to remove oxygen, and then heated at 60 °C for 30 min. The reaction was cooled to room temperature. The mixture was concentrated under reduced pressure, and the residue was analyzed by high performance liquid chromatography (HPLC) to prepare 81 (9 mg, yield: 34.6%). LC-MS (ESI): m / z = 713 (M+H) + .

[1165] 1H-NMR(400MHz,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=7.2H z,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

[1166] Example 82

[1167] (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)

[1168]

[1169] Synthesis of compound 82-c

[1170] 5-Iodonicotinic acid (250 mg, 1 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and borane tetrahydrofuran solution (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 cooled to room temperature, concentrated under reduced pressure, and diluted with ethyl acetate (10 mL). The organic phase was washed successively with water (10 mL × 3) and saturated brine (10 mL × 1). The obtained organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 82-c (141 mg, yield: 59.7%), which could be used directly in the next reaction without purification. LC-MS (ESI): m / z = 236.0 [M + H] + .

[1171] Synthesis of compound 82-b

[1172] 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. The reaction mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, 82-b (146 mg, 96.2%) was obtained and used directly in the next reaction without purification.

[1173] Synthesis of compound 82-a

[1174] Compound 82-b (43 mg, 0.170 mmol) and compound 4-a (50 mg, 0.131 mmol) were dissolved in N,N-dimethylformamide solution (2 mL), and sodium carbonate (41.7 mg, 0.393 mmol) and potassium iodide (65.2 mg, 0.393 mmol) were added. The reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (10 mL). The organic phase was washed successively with water (10 mL × 3) and saturated brine (10 mL × 1). The obtained organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and 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] + .

[1175] Synthesis of Compound 82

[1176] Compound 82-a (48.8 mg, 0.082 mmol) and s-piperidin-2-carboxylic acid (21.2 mg, 0.164 mmol) were dissolved in a mixed solution of methanol and tetrahydrofuran (10 mL, 1:1 in v:v). Glacial acetic acid (9.8 mg, 0.164 mmol) and sodium cyanoborohydride (25.8 mg, 0.41 mmol) were added. The reaction mixture was purged three times with nitrogen to remove oxygen, and then heated at 60 °C for 30 min. The reaction was cooled to room temperature. The mixture was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (HPLC) to obtain 82 (16.4 mg, yield: 28.2%). LC-MS (ESI): m / z = 713.0 [M+H] + ;

[1177] 1 H-NMR (400MHz, 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(dJ=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

[1178] Example 83

[1179] (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)

[1180]

[1181] Synthesis of compound 83-a

[1182] 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 mixture was stirred at 60 °C for 16 hours. The reaction mixture 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, concentrated under reduced pressure, and 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] + .

[1183] Synthesis of Compound 83

[1184] Compound 83-a (180 mg, 0.447 mmol) and s-piperidin-2-carboxylic acid (115.5 mg, 0.894 mmol) were dissolved in a mixed solution 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. Then, sodium cyanoborohydride (140.5 mg, 2.235 mmol) was added, and the mixture was stirred for 0.5 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was analyzed by high performance liquid chromatography (HPLC) to prepare 83 (61.9 mg, yield: 26.9%). LC-MS (ESI): m / z = 516.0 [M+H] + ;

[1185] 1H-NMR(400MHz,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,1 H),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.

[1186] Example 84

[1187] (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)

[1188]

[1189] Synthesis of compound 84-a

[1190] 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 mixture was heated and stirred at 60 °C for 16 hours. The reaction mixture 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, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give 84-a (200 mg, yield: 84.7%). LC-MS (ESI): m / z = 389.0 [M+H] + ;

[1191] Synthesis of Compound 84

[1192] Compound 84-a (200 mg, 0.515 mmol) and s-piperidin-2-carboxylic acid (133 mg, 1.03 mmol) were dissolved in a mixed solution 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. Then, sodium cyanoborohydride (161.8 mg, 2.575 mmol) was added, and the mixture was stirred for 0.5 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was then subjected to high-performance liquid chromatography (HPLC) to prepare 84 (60.5 mg, yield: 23.4%). LC-MS (ESI): m / z = 502.0 [M+H] + ;

[1193] 1 H-NMR(400MHz,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.

[1194] Example 85

[1195] (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)

[1196]

[1197] Synthesis of compound 85-a

[1198] 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-4-fluorobutane (21 mg, 0.136 mmol) were dissolved in N,N-dimethylformamide (3 mL), and potassium carbonate (37.3 mg, 0.273 mmol) was added. The reaction mixture was stirred at 60 °C for 16 hours. The reaction mixture 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, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give 85-a (37 mg, yield: 65.1%). LC-MS(ESI): m / z = 626.0 [M+H] + .

[1199] Synthesis of Compound 85

[1200] Compound 85-a (37 mg, 0.059 mmol) was dissolved in a hydrochloric acid / dioxane solution (4.0 M, 10 mL). The reaction mixture 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] + ;

[1201] 1 H-NMR (400MHz, 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.

[1202] Example 86

[1203] (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)

[1204]

[1205] Synthesis of compound 86-a

[1206] 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), and potassium carbonate (37.3 mg, 0.273 mmol) was added. The reaction mixture was stirred at 60 °C for 16 hours. The reaction mixture 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, concentrated under reduced pressure, and 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] + .

[1207] Synthesis of Compound 86

[1208] Compound 86-a (47 mg, 0.077 mmol) was dissolved in a hydrochloric acid / dioxane solution (4.0 M, 10 mL). The reaction mixture 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] + ;

[1209] 1H-NMR (400MHz, 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),4.6 6-4.64(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.

[1210] Example 87

[1211] (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)

[1212]

[1213] Synthesis of compound 87-a

[1214] 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), and potassium carbonate (37.3 mg, 0.273 mmol) was added. The reaction mixture was stirred at 60 °C for 16 hours. The reaction mixture 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, concentrated under reduced pressure, and 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] + .

[1215] Synthesis of Compound 87

[1216] Compound 87-a (47 mg, 0.077 mmol) was dissolved in a hydrochloric acid / dioxane solution (4.0 M, 10 mL). The reaction mixture 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] + ;

[1217] 1 H-NMR(400MHz,DMSO-d6)δ:7.79(s,1H),7.66-7.62(d,J=16.0Hz,1H),7.57-7.52(m,2H),7.4 8-7.45(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=14.8Hz,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.

[1218] Example 88

[1219] (S,E)-1-(2-((5-fluoropyridin-3-yl)methoxy)-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-5-(trifluoromethyl)benzyl)piperidine-2-carboxylic acid (Compound 88)

[1220]

[1221] Synthesis of compound 88-a

[1222] 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), and potassium carbonate (75.16 mg, 0.544 mmol) was added. The reaction mixture was stirred at 60 °C for 12 hours. The reaction mixture 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, concentrated under reduced pressure, and 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] + .

[1223] Synthesis of Compound 88

[1224] Compound 88-a (119 mg, 0.180 mmol) was dissolved in a hydrochloric acid / dioxane solution (4.0 M, 10 mL). The reaction mixture 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] + .

[1225] Example 89

[1226] (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)

[1227]

[1228] Synthesis of compound 89-a

[1229] 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-(bromomethyl)-4-fluorobenzene (34.21 mg, 0.181 mmol) were dissolved in N,N-dimethylformamide (3 mL), and potassium carbonate (75.16 mg, 0.544 mmol) was added. The reaction mixture was stirred at 60 °C for 12 hours. The reaction mixture 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, concentrated under reduced pressure, and 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] + .

[1230] Synthesis of Compound 89

[1231] Compound 89-a (118 mg, 0.179 mmol) was dissolved in a hydrochloric acid / dioxane solution (4.0 M, 10 mL). The reaction mixture 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] + .

[1232] Example 90

[1233] (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)

[1234]

[1235] Synthesis of compound 90-a

[1236] 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 3-(chloromethyl)pyridine (25.51 mg, 0.2 mmol) were dissolved in N,N-dimethylformamide (3 mL), and potassium carbonate (69.0 mg, 0.5 mmol) was added. The reaction mixture was stirred at 50 °C for 5 hours. The reaction mixture 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, concentrated under reduced pressure, and 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] + .

[1237] Synthesis of Compound 90

[1238] 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-carboxylic acid ester (50 mg, 0.078 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (5.0 mL) was added. The reaction mixture 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] + .

[1239] 1 H-NMR(CD3OD-d4)δ: 8.77(s,1H),8.59(s,1H),8.11(d,J=8.0Hz,1H),8.00(s,1H),7.66(s,1 H),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 .2Hz,1H),5.52(s,2H),4.58(d,J=12.8Hz,1H),4.42(d,J=12.8Hz,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.

[1240] Example 91

[1241] (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)

[1242]

[1243] Synthesis of compound 91-a

[1244] 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), and potassium carbonate (69 mg, 0.5 mmol) was added. The reaction mixture was stirred at 50 °C for 12 hours. The reaction mixture 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, concentrated under reduced pressure, and 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] + .

[1245] Synthesis of Compound 91

[1246] 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-carboxylic acid ester (110 mg, 0.165 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (5.0 mL) was added. The reaction mixture 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] + .

[1247] 1H-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=8.0Hz,1H),5.5 5(s,2H),4.60(d,J=12.8Hz,1H),4.44(d,J=12.8Hz,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.

[1248] Example 1: Homogeneous Time-Resolved Fluorescence Method

[1249] The binding ability of the compounds of the present invention to PD-1 / PD-L1 was detected by homogeneous time-resolved fluorescence (HTRF) binding assay.

[1250] The purchased kit (CisBio, #64CUS000C-1) contains the reagents required for the experiment, including PD-1, PD-L1, anti-tag1-Eu, Anti-tag2-XL665, Dilute Buffer, and Detection Buffer.

[1251] Experimental steps

[1252] 1. Prepare 10 concentrations of the compound with 100% DMSO, each with a concentration gradient of 3.

[1253] 2. Add the DMSO solution of the compound to the dilution buffer, mix well, and then transfer to a 96-well plate.

[1254] 3. Dilute PD-L1 with dilution buffer and then add it to the 96-well plate.

[1255] 4. Dilute PD-1 with dilution buffer, then add it to the 96-well plate and incubate at room temperature for 30 minutes.

[1256] 5. Add one part anti-tag1-Eu and one part Anti-tag2-XL665 to the detection buffer solution, mix well, and then transfer to the 96-well plate mentioned above.

[1257] 6. Incubate the mixture in this 96-well plate at room temperature for 1 to 24 hours.

[1258] 7. Use Envision to read the HTRF value.

[1259] Experimental results

[1260] The biological activity of the compounds of this invention was determined by the above experiments, and the results are shown in Table 1 below:

[1261] Table 1 shows the IC50 of some compounds of the present invention for binding to PD-1 / PD-L1. 50 value

[1262]

[1263]

[1264]

[1265] Example 2: Pharmacokinetic Study in Mice

[1266] Reagents: Acetonitrile, formic acid, and methanol (HPLC grade) were purchased from Sigma-Aldrich (USA), and purified water was purchased from Hangzhou Wahaha Group Co., Ltd. (Hangzhou, China). All other chemical reagents were of analytical grade.

[1267] Experimental instrument: Liquid chromatography-mass spectrometry (UPLC-MS / MS, consisting of an AB SCIEX TRIPLE QUAD 6500 triple quadrupole mass spectrometer and a Shimadzu high-performance liquid chromatography system. Analyst 1.6.2 data acquisition and processing system was used).

[1268] Other instruments: Mettler-Toledo XP26 and XS60025 electronic balances (USA); Thermo Fisher – 70°C ultra-low temperature freezer (USA); Thermo Heraeus Multifuge X3R cryogenic centrifuge (Germany); IKA VIBRAX VXR basic shaker (Germany); IKA disperser (Germany); SCIENTZ-48L cryogenic high-throughput tissue homogenizer (Ningbo, China), etc.

[1269] Experimental animals: Six male CD1 mice, weighing 29-30g before drug administration, were purchased from Shanghai Jihui Experimental Animal Breeding Co., Ltd., animal qualification certificate number SCXK(SH)2017-0012 20170012001403. Animals were kept in captivity for at least 3 days before the experiment to acclimatize. Throughout the experiment, animals had free access to food and water.

[1270] Experimental steps:

[1271] 1) Preparation of stock solution: Weigh a certain amount of the test drug and place it in a clean sample bottle, add dimethyl sulfoxide, vortex thoroughly for 1 minute, and sonicate for 5 minutes to obtain a 4 mg / mL solution.

[1272] Preparation of intravenous drug: Take a certain amount of the above solution and place it in a clean sample bottle. Add polyethylene glycol-15 hydroxystearate, vortex thoroughly for 1 minute, add physiological saline, and continue vortexing for 1 minute to obtain solution A with a concentration of 4 mg / mL.

[1273] Preparation of oral administration drug: Weigh a certain amount of the test drug into a clean sample bottle, add the pre-prepared solvent "10% (w / v) polyoxyethylene 40 hydrogenated castor oil + 20% (w / v) sulfobutyl ether β-cyclodextrin + 70% water", vortex thoroughly for 1 minute, stir magnetically for 20-25 minutes, and sonicate for 10 minutes to obtain a 1 mg / mL solution B.

[1274] 2) Intravenous administration: 3 mice were injected with 2 mg / kg (5 mL / kg) of solution A via tail vein injection.

[1275] Oral administration: Three mice were given solution B at a dose of 10 mg / kg (10 mL / kg) by gavage.

[1276] 3) Plasma Sample Collection and Storage: Blood samples were collected from the orbital venous plexus of mice at predetermined time points (5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours). 25 μL of blood was placed in an EDTA-K2 anticoagulant tube (placed on wet ice), and 20 μL of blood was immediately diluted with 60 μL of water and vortexed thoroughly until homogeneous. The plasma was stored at -70°C until sample analysis.

[1277] 4) Analysis of plasma samples: Add 200 μL of acetonitrile (containing 100 ng / mL internal standard) to 25 μL of plasma sample, vortex for 10 minutes, and centrifuge at 5800 rpm for 10 minutes. Transfer 70 μL of supernatant to a 96-well plate. Perform LC-MS / MS analysis on 1 μL of plasma sample.

[1278] 5) Calculate the pharmacokinetic parameters based on the test results.

[1279] Experimental results

[1280] Some pharmacokinetic parameters of certain compounds and their control compounds of this invention can be obtained through the above experiments, and the results are shown in Table 2 below:

[1281] Table 2: Kinetic parameters of some compounds of the present invention and their control compounds

[1282]

[1283] As shown in Table 2, compared with the control compound, the compound of the present invention exhibits significantly higher peak drug concentration, larger area under the curve, and better oral bioavailability in pharmacokinetic studies in mice.

Claims

1. An aromatic vinyl compound as shown in Formula I-0, its stereoisomer or racemate, or a pharmaceutically acceptable salt thereof; in: R 1 It can be cyano, C1-C4 alkyl, C1-C4 alkyl substituted with one or more deuterium, halogen, or C1-C4 alkyl substituted with one or more halogens; R 3 R 6 R 12 R 13 and R 14 Independently, it can be either H or deuterium; R 2 It is a halogen, C1-C4 alkyl, or formed by one or more R A-1 Substituted C1-C4 alkyl groups; R A-1 It can be either deuterium or a halogen independently; R 4 for R 5 It is a C1-C4 alkyl group, with one or more R B-1 Substituted C1-C4 alkyl, C1-C6 alkoxy, or substituted with one or more R B-2 Substituted C1-C6 alkoxy groups; R B-1 Independently, it can be either deuterium or hydroxyl; R B-2 Independently deuterium, hydroxyl, halogen, cyano, and surrounded by one or more R groups B-1-4 The heteroaryl group is a substituted 3-12-membered heteroaryl group, a C1-C4 alkoxy group, or a C1-C4 alkoxy group substituted with one or more deuterium atoms; wherein the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-4. R B-1-4 Halogens are independent of each other; R B-1-1 For H or deuterium; R B-1-2 For one or more R B-1-1-1 Substituted C1-C4 alkyl groups, wherein R B-1-1-1 For deuterium, hydroxyl, or COOR B-1-1-5 ; Or, R B-1-1 R B-1-2 Together with the nitrogen atoms bonded to them, they form 5-7 nucleotides bounded by one or more R atoms. B-1-1-2 A substituted carbon heterocycle, wherein the number of heteroatoms in the carbon heterocycle is 1, wherein R B-1-1-2 For deuterium or COOR B-1-1-6 ; R B-1-1-5 and R B-1-1-6 Independently, it can be either H or deuterium; R 7 R 8 R 9 R 10 and R 11 Independently, it can be either H or deuterium; R 15 For H or deuterium; R 16 It can be H or deuterium.

2. The aromatic vinyl compounds of formula I-0 as described in claim 1, their stereoisomers or racemates, or pharmaceutically acceptable salts thereof, characterized in that, R B-1 Independently, it can be either deuterium or hydroxyl; R B-2 It is independently a deuterium, hydroxyl, halogen, cyano, C1-C4 alkoxy or a C1-C4 alkoxy substituted with one or more deuterium groups.

3. The aromatic vinyl compounds of formula I-0 as described in claim 1, their stereoisomers or racemates, or their pharmaceutically acceptable salts, characterized in that, The aromatic vinyl compounds represented by Formula I-0 are as follows: in: R 1 It is cyano, C1-C4 alkyl, or C1-C4 alkyl substituted with one or more deuterium groups; R 3 R 6 R 12 R 13 and R 14 Independently, it can be either H or deuterium; R 2 It is a halogen, C1-C4 alkyl, or formed by one or more R A-1 Substituted C1-C4 alkyl groups; R A-1 It can be either deuterium or a halogen independently; R 4 for R 5 It is a C1-C4 alkyl group, with one or more R B-1 Substituted C1-C4 alkyl, C1-C6 alkoxy, or substituted with one or more R B-2 Substituted C1-C6 alkoxy groups; R B-1 Independently, it can be either deuterium or hydroxyl; R B-2 Independently, it is deuterium, hydroxyl, halogen, cyano, C1-C4 alkoxy or a C1-C4 alkoxy substituted with one or more deuterium groups; R B-1-1 For H or deuterium; R B-1-2 For one or more R B-1-1-1 Substituted C1-C4 alkyl groups, wherein R B-1-1-1 For deuterium, hydroxyl, or COOR B-1-1-5 ; Or, R B-1-1 R B-1-2 Together with the nitrogen atoms bonded to them, they form 5-7 nucleotides bounded by one or more R atoms. B-1-1-2 A substituted carbon heterocycle, wherein the number of heteroatoms in the carbon heterocycle is 1, wherein R B-1-1-2 For deuterium or COOR B-1-1-6 ; R B-1-1-5 and R B-1-1-6 Independently, it can be either H or deuterium; R 7 R 8 R 9 R 10 and R 11 Independently, it is either H or deuterium.

4. The aromatic vinyl compounds, stereoisomers thereof, or racemates thereof, or pharmaceutically acceptable salts thereof, as described in any one of claims 1-3, characterized in that, When R 1 When the alkyl group is C1-C4, the C1-C4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

5. An aromatic vinyl compound of formula I-0 as described in any one of claims 1-3, its stereoisomer or racemate, or a pharmaceutically acceptable salt thereof, characterized in that, When R 1 When the C1-C4 alkyl group is substituted with one or more deuterium alkyl groups, the C1-C4 alkyl group substituted with one or more deuterium alkyl groups is a C1-C2 alkyl group substituted with one or more deuterium alkyl groups.

6. The aromatic vinyl compounds of formula I-0 as described in claim 1 or 2, their stereoisomers or racemates, or pharmaceutically acceptable salts thereof, characterized in that, When R 1 When the halogen is halogen, the halogen is fluorine, chlorine, bromine or iodine.

7. The aromatic vinyl compounds of formula I-0 as described in claim 1 or 2, their stereoisomers or racemates, or pharmaceutically acceptable salts thereof, characterized in that, When R 1 When the alkyl group is a C1-C4 alkyl group substituted with one or more halogens, the halogen is fluorine, chlorine, bromine, or iodine.

8. An aromatic vinyl compound of formula I-0 as claimed in claim 1 or 2, its stereoisomer or racemate, or a pharmaceutically acceptable salt thereof, characterized in that, When R 1 When the C1-C4 alkyl group is substituted with one or more halogens, the C1-C4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

9. An aromatic vinyl compound of formula I-0 as described in any one of claims 1-3, its stereoisomer or racemate, or a pharmaceutically acceptable salt thereof, characterized in that, When R 2 When the halogen is halogen, the halogen is fluorine, chlorine, bromine or iodine.

10. An aromatic vinyl compound of formula I-0 as described in any one of claims 1-3, its stereoisomer or racemate, or a pharmaceutically acceptable salt thereof, characterized in that, When R 2 When the alkyl group is C1-C4, the C1-C4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

11. An aromatic vinyl compound of formula I-0 as described in any one of claims 1-3, its stereoisomers or racemates, or pharmaceutically acceptable salts thereof, characterized in that, When R 2 For one or more R A-1 When the substituted C1-C4 alkyl group is used, the C1-C4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

12. An aromatic vinyl compound of formula I-0 as described in any one of claims 1-3, its stereoisomers or racemates, or pharmaceutically acceptable salts thereof, characterized in that, When R 2 For one or more R A-1 When C1-C4 alkyl groups are substituted, each R A-1 Whether they are the same or different, the "multiple" mentioned refers to 2, 3, 4 or 5.

13. An aromatic vinyl compound of formula I-0 as described in any one of claims 1-3, its stereoisomer or racemate, or a pharmaceutically acceptable salt thereof, characterized in that, When R A-1 When it is a halogen on its own, the halogen is fluorine, chlorine, bromine or iodine.

14. An aromatic vinyl compound of formula I-0 as described in any one of claims 1-3, its stereoisomer or racemate, or a pharmaceutically acceptable salt thereof, characterized in that, When R 5 When the alkyl group is C1-C4, the C1-C4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

15. An aromatic vinyl compound of formula I-0 as described in any one of claims 1-3, its stereoisomer or racemate, or a pharmaceutically acceptable salt thereof, characterized in that, When R 5 For one or more R B-1 When the substituted C1-C4 alkyl group is used, the C1-C4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

16. An aromatic vinyl compound of formula I-0 as described in any one of claims 1-3, its stereoisomer or racemate, or a pharmaceutically acceptable salt thereof, characterized in that, When R 5 For one or more R B-1 When C1-C4 alkyl groups are substituted, each R B-1 The "multiple" can refer to two, three, four, or five items, and can be either the same or different.

17. An aromatic vinyl compound of formula I-0 as described in any one of claims 1-3, its stereoisomer or racemate, or a pharmaceutically acceptable salt thereof, characterized in that, When R 5 When the alkoxy group is C1-C6, the C1-C6 alkoxy group is C1-C4 alkoxy.

18. An aromatic vinyl compound of formula I-0 as described in any one of claims 1-3, its stereoisomer or racemate, or a pharmaceutically acceptable salt thereof, characterized in that, When R 5 For one or more R B-2 When the C1-C6 alkoxy group is substituted, the C1-C6 alkoxy group is a C1-C4 alkoxy group.

19. An aromatic vinyl compound of formula I-0 as described in any one of claims 1-3, its stereoisomer or racemate, or a pharmaceutically acceptable salt thereof, characterized in that, When R 5 For one or more R B-2 When C1-C6 alkoxy groups are substituted, each R B-2 The same or different, the multiple refers to 2, 3, 4 or 5.

20. An aromatic vinyl compound of formula I-0 as described in any one of claims 1-3, its stereoisomer or racemate, or a pharmaceutically acceptable salt thereof, characterized in that, When R B-2 When it is a halogen on its own, the halogen is fluorine, chlorine, bromine or iodine.

21. The aromatic vinyl compounds of formula I-0 as claimed in claim 1, their stereoisomers or racemates, or pharmaceutically acceptable salts thereof, characterized in that, When R B-2 Independently for one or more R B-1-4 When the 3-12-membered heteroaryl group is replaced, the 3-12-membered heteroaryl group is a 5-7-membered heteroaryl group.

22. The aromatic vinyl compounds of formula I-0 as claimed in claim 1, their stereoisomers or racemates, or pharmaceutically acceptable salts thereof, characterized in that, When R B-2 Independently for one or more R B-1-4 When a 3-12-membered heteroaryl group is substituted, the heteroatom of the 3-12-membered heteroaryl group is selected from N, and the number of heteroatoms is 1.

23. The aromatic vinyl compounds of formula I-0 as claimed in claim 1, their stereoisomers or racemates, or pharmaceutically acceptable salts thereof, characterized in that, When R B-2 Independently for one or more R B-1-4 When substituted with 3-12 heteroaryl groups, each R B-1-4 The same or different, the multiple refers to 2, 3, 4 or 5.

24. The aromatic vinyl compounds of formula I-0 as claimed in claim 1, their stereoisomers or racemates, or pharmaceutically acceptable salts thereof, characterized in that, When R B-1-4 The halogen is independent of the halogen, which is fluorine, chlorine, bromine or iodine.

25. An aromatic vinyl compound of formula I-0 as described in any one of claims 1-3, its stereoisomer or racemate, or a pharmaceutically acceptable salt thereof, characterized in that, When R B-2 Independently, it is a C1-C4 alkoxy group, wherein the C1-C4 alkoxy group is a methoxy, ethoxy, n-propoxy, or n-butoxy group.

26. An aromatic vinyl compound of formula I-0 as described in any one of claims 1-3, its stereoisomer or racemate, or a pharmaceutically acceptable salt thereof, characterized in that, When R B-2 When independently a C1-C4 alkoxy group substituted with one or more deuterium ions, the C1-C4 alkoxy group substituted with one or more deuterium ions is a C1-C2 alkoxy group substituted with one or more deuterium ions.

27. An aromatic vinyl compound of formula I-0 as described in any one of claims 1-3, its stereoisomer or racemate, or a pharmaceutically acceptable salt thereof, characterized in that, When R B-1-2 For one or more R B-1-1-1 When the substituted C1-C4 alkyl group is used, the C1-C4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

28. An aromatic vinyl compound of formula I-0 as described in any one of claims 1-3, its stereoisomer or racemate, or a pharmaceutically acceptable salt thereof, characterized in that, When R B-1-2 For one or more R B-1-1-1 When C1-C4 alkyl groups are substituted, each R B-1-1-1 The same or different, the multiple refers to 2, 3, 4 or 5.

29. An aromatic vinyl compound of formula I-0 as described in any one of claims 1-3, its stereoisomer or racemate, or a pharmaceutically acceptable salt thereof, characterized in that, When R B-1-1 R B-1-2 Together with the nitrogen atoms bonded to them, they form 5-7 nucleotides bounded by one or more R atoms. B-1-1-2 When a carbon heterocycle is substituted, each R B-1-1-2 The same or different, the multiple refers to 2, 3, 4 or 5.

30. The aromatic vinyl compounds of formula I-0 as claimed in claim 4, their stereoisomers or racemates, or their pharmaceutically acceptable salts, characterized in that, When R 1 When the alkyl group is C1-C4, the C1-C4 alkyl group is methyl.

31. The aromatic vinyl compounds of formula I-0 as claimed in claim 5, their stereoisomers or racemates, or their pharmaceutically acceptable salts, characterized in that, When R 1 When the C1-C4 alkyl group is substituted with one or more deuterium ions, the C1-C4 alkyl group substituted with one or more deuterium ions is a deuterated methyl group, a dideuterated methyl group, a trideuterated methyl group, a deuterated ethyl group, a dideuterated ethyl group, a trideuterated ethyl group, a tetradeuterated ethyl group, or a pentadeuterated ethyl group.

32. The aromatic vinyl compounds of formula I-0 as claimed in claim 6, their stereoisomers or racemates, or their pharmaceutically acceptable salts, characterized in that, When R 1 When the halogen is halogen, the halogen is chlorine.

33. The aromatic vinyl compounds of formula I-0 as claimed in claim 7, their stereoisomers or racemates, or pharmaceutically acceptable salts thereof, characterized in that, When R 1 When the alkyl group is a C1-C4 alkyl group substituted with one or more halogens, the halogen is fluorine.

34. The aromatic vinyl compounds of formula I-0 as claimed in claim 8, their stereoisomers or racemates, or pharmaceutically acceptable salts thereof, characterized in that, When R 1 When the C1-C4 alkyl group is substituted with one or more halogens, the C1-C4 alkyl group is methyl.

35. The aromatic vinyl compounds of formula I-0 as claimed in claim 9, their stereoisomers or racemates, or pharmaceutically acceptable salts thereof, characterized in that, When R 2 When the halogen is halogen, the halogen is chlorine.

36. The aromatic vinyl compounds of formula I-0 as claimed in claim 10, their stereoisomers or racemates, or pharmaceutically acceptable salts thereof, characterized in that, When R 2 When the alkyl group is C1-C4, the C1-C4 alkyl group is methyl.

37. The aromatic vinyl compounds of formula I-0 as claimed in claim 11, their stereoisomers or racemates, or pharmaceutically acceptable salts thereof, characterized in that, When R 2 For one or more R A-1 When the C1-C4 alkyl group is substituted, the C1-C4 alkyl group is methyl.

38. The aromatic vinyl compounds of formula I-0 as claimed in claim 13, their stereoisomers or racemates, or pharmaceutically acceptable salts thereof, characterized in that, When R A-1 When it is a halogen on its own, the halogen is fluorine.

39. The aromatic vinyl compounds of formula I-0 as claimed in claim 14, their stereoisomers or racemates, or pharmaceutically acceptable salts thereof, characterized in that, When R 5 When the alkyl group is C1-C4, the C1-C4 alkyl group is methyl.

40. The aromatic vinyl compounds of formula I-0 as claimed in claim 15, their stereoisomers or racemates, or pharmaceutically acceptable salts thereof, characterized in that, When R 5 For one or more R B-1 When the C1-C4 alkyl group is substituted, the C1-C4 alkyl group is methyl.

41. The aromatic vinyl compounds of formula I-0 as claimed in claim 17, their stereoisomers or racemates, or pharmaceutically acceptable salts thereof, characterized in that, When R 5 When the alkoxy group is C1-C6, the C1-C6 alkoxy group is methoxy, ethoxy, n-propoxy, or n-butoxy.

42. The aromatic vinyl compounds of formula I-0 as described in claim 18, their stereoisomers or racemates, or pharmaceutically acceptable salts thereof, characterized in that, When R 5 For one or more R B-2 When the C1-C6 alkoxy group is substituted, the C1-C6 alkoxy group is methoxy, ethoxy, n-propoxy, or n-butoxy.

43. The aromatic vinyl compounds of formula I-0 as described in claim 20, their stereoisomers or racemates, or pharmaceutically acceptable salts thereof, characterized in that, When R B-2 When it is a halogen on its own, the halogen is fluorine.

44. The aromatic vinyl compounds of formula I-0 as described in claim 24, their stereoisomers or racemates, or pharmaceutically acceptable salts thereof, characterized in that, When R B-1-4 The halogen is independent of the halogen, which is either fluorine or iodine.

45. The aromatic vinyl compounds of formula I-0 as claimed in claim 25, their stereoisomers or racemates, or pharmaceutically acceptable salts thereof, characterized in that, When R B-2 Independently, it is a C1-C4 alkoxy group, wherein the C1-C4 alkoxy group is a methoxy group.

46. ​​The aromatic vinyl compounds of formula I-0 as claimed in claim 26, their stereoisomers or racemates, or pharmaceutically acceptable salts thereof, characterized in that, When R B-2 When independently a C1-C4 alkoxy group is substituted with one or more deuterium groups, the C1-C4 alkoxy group substituted with one or more deuterium groups is a deuterium methoxy group, a dideuterium methoxy group, a trideuterium methoxy group, a deuterium ethoxy group, a dideuterium ethoxy group, a trideuterium ethoxy group, a tetradeuterium ethoxy group, or a pentadeuterium ethoxy group.

47. The aromatic vinyl compounds of formula I-0 as claimed in claim 27, their stereoisomers or racemates, or pharmaceutically acceptable salts thereof, characterized in that, When R B-1-2 For one or more R B-1-1-1 When the C1-C4 alkyl group is substituted, the C1-C4 alkyl group is methyl, ethyl, or isopropyl.

48. The aromatic vinyl compounds of formula I-0 as claimed in claim 31, their stereoisomers or racemates, or pharmaceutically acceptable salts thereof, characterized in that, When R 1 When the C1-C4 alkyl group is substituted with one or more deuterium ions, the C1-C4 alkyl group substituted with one or more deuterium ions is trideuterylmethyl.

49. The aromatic vinyl compounds of formula I-0 as claimed in claim 41, their stereoisomers or racemates, or pharmaceutically acceptable salts thereof, characterized in that, When R 5 When the alkoxy group is C1-C6, the C1-C6 alkoxy group is a methoxy group.

50. The aromatic vinyl compounds of formula I-0 as described in claim 46, their stereoisomers or racemates, or pharmaceutically acceptable salts thereof, characterized in that, When R B-2 When independently a C1-C4 alkoxy group substituted with one or more deuterium ions, the C1-C4 alkoxy group substituted with one or more deuterium ions is a trideuteroxy group.

51. An aromatic vinyl compound of formula I-0 as described in any one of claims 1-3, its stereoisomer or racemate, or a pharmaceutically acceptable salt thereof, characterized in that, R 3 R 6 R 12 R 13 and R 14 H stands for H independently.

52. The aromatic vinyl compounds of formula I-0 as described in any one of claims 1-3, their stereoisomers or racemates, or pharmaceutically acceptable salts thereof, characterized in that, R A-1 It is a halogen on its own.

53. The aromatic vinyl compounds of formula I-0 as claimed in claim 1, their stereoisomers or racemates, or pharmaceutically acceptable salts thereof, characterized in that, R B-1 Independently deuterium or hydroxyl; R B-2 Independently deuterium, hydroxyl, cyano, or with one or more R groups B-1-4 Substituted 3-12 heteroaryl groups, C1-C4 alkoxy groups, or C1-C4 alkoxy groups substituted with one or more deuterium groups.

54. An aromatic vinyl compound of formula I-0 as described in any one of claims 1-3, its stereoisomer or racemate, or a pharmaceutically acceptable salt thereof, characterized in that, R B-1-1 For H, R B-1-2 For one or more R B -1-1-1 Substituted C1-C4 alkyl; or, R B-1-1 R B-1-2 Together with the nitrogen atoms bonded to them, they form 5-7 nucleotides bounded by one or more R atoms. B-1-1-2 Substituted carbon heterocycles.

55. An aromatic vinyl compound of formula I-0 as described in any one of claims 1-3, its stereoisomer or racemate, or a pharmaceutically acceptable salt thereof, characterized in that, The one or more R B-1-1-1 The substituted C1-C4 alkyl groups are 56. An aromatic vinyl compound of formula I-0 as described in any one of claims 1-3, its stereoisomer or racemate, or a pharmaceutically acceptable salt thereof, characterized in that, R B-1-1-2 For COOR B-1-1-6 .

57. An aromatic vinyl compound of formula I-0 as described in any one of claims 1-3, its stereoisomer or racemate, or a pharmaceutically acceptable salt thereof, characterized in that, The carbon heterocycle is 58. An aromatic vinyl compound of formula I-0 as described in any one of claims 1-3, its stereoisomer or racemate, or a pharmaceutically acceptable salt thereof, characterized in that, R 2 It is a halogen or a C1-C4 alkyl group.

59. The aromatic vinyl compounds of formula I-0 as described in claim 56, their stereoisomers or racemates, or pharmaceutically acceptable salts thereof, characterized in that, R B-1-1-6 For H.

60. The aromatic vinyl compounds of formula I-0 as described in claim 53, their stereoisomers or racemates, or pharmaceutically acceptable salts thereof, characterized in that, R B-1 It is a hydroxyl group.

61. The aromatic vinyl compounds of formula I-0 as described in claim 53, their stereoisomers or racemates, or pharmaceutically acceptable salts thereof, characterized in that, R B-2 For deuterium, cyano, hydroxyl, or with one or more R B-1-4 Substituted 3-12 heteroaryl or C1-C4 alkoxy groups.

62. The aromatic vinyl compounds of formula I-0 as described in claim 53, their stereoisomers or racemates, or pharmaceutically acceptable salts thereof, characterized in that, The one or more R B-1-4 The substituted 3-12 heteroaryl group is 63. The aromatic vinyl compounds of formula I-0 as described in claim 54, their stereoisomers or racemates, or pharmaceutically acceptable salts thereof, characterized in that, R B-1-1-2 It is a carboxyl group.

64. The aromatic vinyl compounds of formula I-0 as described in claim 54, their stereoisomers or racemates, or pharmaceutically acceptable salts thereof, characterized in that, The one or more R B-1-1-2 The substituted carbon heterocycle is 65. The aromatic vinyl compounds of formula I-0 as described in claim 53, their stereoisomers or racemates, or pharmaceutically acceptable salts thereof, characterized in that, R B-1 Independently deuterium or hydroxyl; R B-2 It is independently a deuterium, hydroxyl, cyano, C1-C4 alkoxy or a C1-C2 alkoxy substituted with one or more deuterium groups.

66. An aromatic vinyl compound of formula I-0 as described in any one of claims 1-3, its stereoisomer or racemate, or a pharmaceutically acceptable salt thereof, characterized in that, for 67. An aromatic vinyl compound of formula I-0 as claimed in claim 1 or 2, its stereoisomer or racemate, or a pharmaceutically acceptable salt thereof, characterized in that, R 1 It is a halogen or a C1-C4 alkyl group substituted with one or more halogens.

68. An aromatic vinyl compound of formula I-0 as claimed in claim 1 or 2, its stereoisomer or racemate, or a pharmaceutically acceptable salt thereof, characterized in that, R 15 It is deuterium.

69. An aromatic vinyl compound of formula I-0 as claimed in claim 1 or 2, its stereoisomer or racemate, or a pharmaceutically acceptable salt thereof, characterized in that, R 16 It is deuterium.

70. An aromatic vinyl compound of formula I-0 as described in any one of claims 1-3, its stereoisomer or racemate, or a pharmaceutically acceptable salt thereof, characterized in that, R 2 It is a halogen, C1-C4 alkyl, or formed by one or more R A-1 Replacement C1- C4 alkyl; R A-1 It is a halogen; R 4 for R 5 It is a C1-C4 alkyl group, with one or more R B-1 Substituted C1-C4 alkyl, C1-C6 alkoxy, or substituted with one or more R B-2 Substituted C1-C6 alkoxy groups; R B-1 Independently deuterium or hydroxyl; R B-2 R is independently deuterium, hydroxyl, cyano, C1-C4 alkoxy, or a C1-C2 alkoxy substituted with one or more deuterium groups. 3 R 6 R 12 R 13 and R 14 For H.

71. The aromatic vinyl compounds of formula I-0 as described in claim 1 or 2, their stereoisomers or racemates, or pharmaceutically acceptable salts thereof, characterized in that, R 1 It can be cyano, CH3, CD3, Cl or CH2F.

72. The aromatic vinyl compounds of formula I-0 as described in claim 1 or 2, their stereoisomers or racemates, or pharmaceutically acceptable salts thereof, characterized in that, for 73. The aromatic vinyl compounds of formula I-0 as claimed in claim 1, their stereoisomers or racemates, or pharmaceutically acceptable salts thereof, characterized in that, The aromatic ethylene compound represented by formula I-0 is any of the following aromatic ethylene compounds.

74. Any of the following aromatic vinyl compounds, their stereoisomers or racemates, or their pharmaceutically acceptable salts; 75. The method for preparing aromatic ethylene compounds according to any one of claims 1 to 73, characterized in that, It includes the following method 1 or method 2: Method 1 includes the following steps: In a solvent, under the action of a reducing agent, the compound shown in Formula II-a-0 and the compound shown in Formula III-a undergo a reductive amination reaction as shown below to obtain an aromatic vinyl compound shown in Formula I-0. In Method 1, R 4 for 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 is as described in any one of claims 1 to 73; Method 2 includes the following steps: In a solvent, under the action of a base, the compound shown in Formula II-b-0 and the compound shown in Formula III-a undergo the following substitution reaction to obtain the aromatic ethylene compound shown in Formula I-0. In Method 2, R 4 for 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 is as described in any one of claims 1 to 73, X 1 It is a halogen.

76. Compounds such as II-a-0 or II-b-0, In the above general formula compounds, 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 The definition is as described in any one of claims 1 to 73, X 1 It is a halogen.

77. Any of the following compounds, characterized in that, 78. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises an aromatic vinyl compound as described in any one of claims 1 to 74, its stereoisomer or racemate, or a pharmaceutically acceptable salt thereof, and pharmaceutical excipients; And / or, the pharmaceutical composition comprises an aromatic vinyl compound as described in any one of claims 1 to 74, its stereoisomer or racemate, or a pharmaceutically acceptable salt thereof, and at least one other drug; wherein the other drug is a chemotherapeutic drug or a targeted drug.

79. The pharmaceutical composition of claim 78, characterized in that, The targeted drug is one or more of the following: COX-2 inhibitor, DPP4 inhibitor, CSF-1α inhibitor, and A2a antagonist.

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