Benzo heterocyclic compound and use thereof

Abstract

A benzo heterocyclic compound and a use thereof. The compound has the general formula of formula I. The compound has good GPR40 agonistic activity and has a good proprietary drug prospect.

Description

Benzoheterocyclic compounds and their applications

[0001] This application claims priority to Chinese patent application No. 2023116655229, filed December 6, 2023. This application incorporates the entirety of the aforementioned Chinese patent application. Technical Field

[0002] The present invention relates to a benzoheterocyclic compound and application thereof. Background Art

[0003] GPR40 is a member of the GPCR family, also known as FFA1 receptor, a class A G protein-coupled receptor that can be activated by endogenous medium- and long-chain fatty acids (such as decanoic acid, palmitic acid, oleic acid, docosahexaenoic acid, etc.) in the body. GPR40 is mainly expressed in pancreatic β cells, intestinal endocrine cells and the brain. It is also expressed in tissues such as the gastrointestinal tract, liver, heart, skeletal muscle, and taste buds. When GPR40 is activated by its endogenous ligand, it can induce insulin secretion only when blood sugar levels are high (GPR40 is activated and promotes Ca secretion in pancreatic β cells). 2+ GPR40 is a key target for the treatment of diabetes, obesity, cardiovascular disease, and dyslipidemia. Its distribution in the brain may be related to pain regulation, neuroprotection, and behavioral regulation, making it a potential target for the treatment of neurological diseases.

[0004] Given the importance of GPR40, the development of drugs that can activate GPR40 is of great significance. Summary of the Invention

[0005] The present invention aims to overcome the limited availability of GPR40 agonist drugs in the prior art. To this end, a benzoheterocyclic compound, a preparation method thereof, and its use are provided. The compounds of the present invention exhibit excellent GPR40 agonist activity, and further possess the advantages of good pharmacokinetics and low toxicity.

[0006] The present invention solves the above technical problems through the following technical solutions.

[0007] The present invention provides a compound as shown in Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof:

[0008] Wherein, X is O or NR 3, R 3 is H or C1-C6 alkyl;

[0009] Z and Y are independently CH or N;

[0010] G 1 is H, C1-C6 alkyl, one or more G 1-1 Substituted C1-C6 alkyl, C6-C 14 Aryl, one or more G 1-2 Substituted C6-C 14 Aryl, 5-10 membered heteroaryl, one or more G 1-3 Substituted 5-10 membered heteroaryl, C1-C6 alkoxy, one or more G 1-4 Substituted C1-C6 alkoxy, C2-C6 alkenyl, one or more G 1- 5 Substituted C2-C6 alkenyl, C2-C6 alkynyl, one or more G 1-6 Substituted C2-C6 alkynyl, C3-C8 cycloalkyl, one or more G 1-7 Substituted C3-C8 cycloalkyl, C3-C8 cycloalkenyl, one or more G 1-8 Substituted C3-C8 cycloalkenyl, 3-8 membered heterocycloalkyl, one or more G 1-9 Substituted 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl or one or more G 1-10 substituted 3-8 membered heterocycloalkenyl;

[0011] Each G 1-1 , each G 1-2 , each G 1-3 , each G 1-4 , each G 1-5 , each G 1-6 , each G 1-7 , each G 1-8 , each G 1-9 and each G 1-10 are independently deuterium, halogen, cyano, -NG 1-1-1 G 1-1-2 、-NC(=O)G 1-1-3 G 1-1-4 , hydroxyl, -S(=O)2-C1-C6 alkyl, C1-C6 alkyl, one or more G 1-1-5 Substituted C1-C6 alkyl, C1-C6 alkoxy, one or more G 1-1-6 Substituted C1-C6 alkoxy, -S-C1-C6 alkyl, one or more G 1-1-7 Substituted -S-C1-C6 alkyl, C3-C8 cycloalkyl, one or more G 1-1-8Substituted C3-C8 cycloalkyl, -O-C3-C8 cycloalkyl, substituted by one or more G 1-1- 9 Substituted-O-C3-C8 cycloalkyl or -C(=O)NG 1-1-11 G 1-1-12 ;

[0012] Or, any two adjacent G 1-2 Together with the carbon atoms to which it is connected, it forms a 3-8 membered heterocycloalkyl group, which is surrounded by one or more G 1-1-9 Substituted 3-8 membered heterocycloalkyl, C3-C8 cycloalkyl or one or more G 1-1-10 substituted C3-C8 cycloalkyl;

[0013] G 1-1-1 , G 1-1-2 , G 1-1-3 , G 1-1-4 , G 1-1-11 and G 1-1-12 are independently H, C1-C6 alkyl, C3-C8 cycloalkyl, 5-10 membered heteroaryl or substituted by one or more G 1-1-10-1 substituted 5-10 membered heteroaryl;

[0014] Each G 1-1-10-1 are independently C1-C6 alkyl;

[0015] Each G 1-1-5 , each G 1-1-6 , each G 1-1-7 , each G 1-1-8 , each G 1-1-9 and each G 1-1-10 are independently halogen, oxo, C1-C6 alkyl or C3-C8 cycloalkyl;

[0016] L 1 is a connecting bond or a C1-C6 alkylene group;

[0017] Ring A is a C4-C6 cycloalkyl group, surrounded by one or more A 1 Substituted C4-C6 cycloalkyl, C4-C6 cycloalkenyl, substituted by one or more A 2 Substituted C4-C6 cycloalkenyl, 4-6 membered heterocycloalkyl, substituted by one or more A 1 substituted 4-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl or substituted by one or more A 4 substituted 4-6 membered heterocycloalkenyl; said 4-6 membered heterocycloalkyl, said 1 substituted 4-6 membered heterocycloalkyl, the 4-6 membered heterocycloalkenyl and the substituted 4-6 membered heterocycloalkyl, the substituted ... 4The heteroatoms in the substituted 4-6 membered heterocycloalkenyl are independently one or more of N, S or O, and the number is 1 or 2;

[0018] Each A 1 、A 2 、A 3 and each A 4 are independently deuterium, halogen, cyano, -NA 1-1 A 1-2 、-NC(=O)A 1-3 A 1- 4 , hydroxyl, C1-C6 alkyl, one or more A 1-5 Substituted C1-C6 alkyl, C1-C6 alkoxy or one or more A 1-6 Substituted C1-C6 alkoxy;

[0019] A 1-1 、A 1-2 、A 1-3 、A 1-4 are independently deuterium, halogen, cyano, C1-C6 alkyl or C1-C6 alkoxy;

[0020] Each A 1-5 and each A 1-6 are independently hydrogen, deuterium, halogen, cyano, C1-C6 alkyl or C1-C6 alkoxy;

[0021] R 1 C1-C6 alkyl, C7-C 12 Straight chain alkyl, C2-C 12 Alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 14 Aryl, 5-10 membered heteroaryl, one or more R 1-1 Substituted C1-C6 alkyl, one or more R 1-1 Substituted C7-C 12 Straight chain alkyl, separated by one or more R 1-1 Substituted C2-C 12 Alkenyl, one or more R 1-1 Substituted C2-C6 alkynyl, one or more R 1-2 Substituted C3-C 10 Cycloalkyl, one or more R 1-3 Substituted C6-C 14 Aryl or one or more R -1-4 substituted 5-10 membered heteroaryl;

[0022] Each R 1-1 , each R 1-2 , each R 1-3 and R1-4 are independently halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 14 Aryl, C1-C6 alkoxy, 5-10 membered heteroaryl, one or more R 1-1-1 Substituted C1-C6 alkyl, one or more R 1-1-1 Substituted C3-C8 cycloalkyl, one or more R 1-1-1 Substituted C6-C 14 Aryl, one or more R 1- 1-1 Substituted C1-C6 alkoxy or one or more R 1-1-1 substituted 5-10 membered heteroaryl;

[0023] R 1-1-1 is halogen, C1-C6 alkyl or C6-C 14 aryl;

[0024] R 2 is hydrogen, deuterium, halogen, cyano, C1-C6 alkyl or C1-C6 alkoxy;

[0025] L 2 is C1-C6 alkylene, one or more L 2-1 Substituted C1-C6 alkylene, C3-C8 cycloalkylene or one or more L 2-2 Substituted C3-C8 cycloalkylene;

[0026] Each L 2-1 and each L 2-2 are independently halogen, C1-C6 alkyl, 2-1-1 Substituted C1-C6 alkyl, C1-C6 alkoxy, substituted by one or more L 2-1-2 Substituted C1-C6 alkoxy, C3-C8 cycloalkyl, one or more L 2- 1-3 Substituted C3-C8 cycloalkyl, C2-C6 alkynyl or one or more L 2-1-4 substituted C2-C6 alkynyl;

[0027] Each L 2-1-1 , each L 2-1-2 , each L 2-1-3 and each L 2-1-4 is independently C3-C8 cycloalkyl or is replaced by one or more L 2-1- 1-1 substituted C3-C8 cycloalkyl;

[0028] G 2 -C(=O)G 2-1 、-C(=O)NG 2-2 G2-3 or a 5-10 membered heteroaryl group;

[0029] G 2-1 is hydroxy, C1-C6 alkyl or -O-NH2;

[0030] G 2-2 and G 2-3 independently H, -S(=O)2-C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl or substituted by one or more G 2-2-1 Substituted C1-C6 alkyl;

[0031] Each G 2-2-1 are independently carboxyl or -S(=O)2OH;

[0032] The heteroatoms in each of the 5-10 membered heteroaryl groups, each of the 3-8 membered heterocycloalkenyl groups and each of the 3-8 membered heterocycloalkyl groups are independently one or more of N, S and O, and the number of the heteroatoms is independently 1, 2, 3 or 4.

[0033] In some embodiments, the compound is represented by Formula Ia, preferably represented by Formula Ia1:

[0034] in,

[0035] Ring A is a C4-C6 cycloalkyl group, surrounded by one or more A 1 Substituted C4-C6 cycloalkyl, C4-C6 cycloalkenyl, substituted by one or more A 2 Substituted C4-C6 cycloalkenyl, 4-6 membered heterocycloalkyl, substituted by one or more A 1 substituted 4-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl or substituted by one or more A 4 substituted 4-6 membered heterocycloalkenyl; said 4-6 membered heterocycloalkyl, said 1 substituted 4-6 membered heterocycloalkyl, the 4-6 membered heterocycloalkenyl and the substituted 4-6 membered heterocycloalkyl, the substituted ... 4 The heteroatoms in the substituted 4-6 membered heterocycloalkenyl are independently one or more of N, S or O, and the number is 1 or 2;

[0036] Each A 1 、A 2 、A 3 and each A 4 are independently deuterium, halogen, cyano, -NA 1-1 A 1-2 、-NC(=O)A 1-3 A 1- 4 , hydroxyl, C1-C6 alkyl, one or more A1-5 Substituted C1-C6 alkyl, C1-C6 alkoxy or one or more A 1-6 Substituted C1-C6 alkoxy;

[0037] A 1-1 、A 1-2 、A 1-3 、A 1-4 are independently deuterium, halogen, cyano, C1-C6 alkyl or C1-C6 alkoxy;

[0038] Each A 1-5 and each A 1-6 are independently hydrogen, deuterium, halogen, cyano, C1-C6 alkyl or C1-C6 alkoxy;

[0039] R 3 and R 4 Independently H, deuterium, halogen, cyano, -NR 3-1 R 3-2 、-NC(=O)R 3-3 R 3-4 , hydroxyl, -S(=O)2-C1-C6 alkyl, C1-C6 alkyl, one or more R 3-5 Substituted C1-C6 alkyl, C1-C6 alkoxy, one or more R 3-6 Substituted C1-C6 alkoxy, -S-C1-C6 alkyl, substituted by one or more R 3-7 Substituted -S-C1-C6 alkyl, C3-C8 cycloalkyl, one or more R 3-8 Substituted C3-C8 cycloalkyl, -O-C3-C8 cycloalkyl, substituted by one or more R 3-9 Substituted-O-C3-C8 cycloalkyl or -C(=O)NR 3-10 R 3-11 ;

[0040] Or, any two adjacent R 3 and R 4 Together with the carbon atoms to which it is connected, it forms a 3-8 membered heterocycloalkyl group, which is supported by one or more R 3-8 Substituted 3-8 membered heterocycloalkyl, C3-C8 cycloalkyl or one or more R 3-8 substituted C3-C8 cycloalkyl;

[0041] R 3-1 、R 3-2 、R 3-3 、R 3-4 、R 3-10 and R 3-11 are independently H, C1-C6 alkyl, C3-C8 cycloalkyl, 5-10 membered heteroaryl or substituted by one or more R 3-10-1substituted 5-10 membered heteroaryl;

[0042] Each R 3-10-1 are independently C1-C6 alkyl;

[0043] Each R 3-5 , each R 3-6 , each R 3-7 , each R 3-8 and each R 3-9 are independently halogen, oxo, C1-C6 alkyl or C3-C8 cycloalkyl;

[0044] R 1 C1-C6 alkyl, C7-C 12 Straight chain alkyl, C2-C 12 Alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 14 Aryl, 5-10 membered heteroaryl, one or more R 1-1 Substituted C1-C6 alkyl, one or more R 1-1 Substituted C7-C 12 Straight chain alkyl, separated by one or more R 1-1 Substituted C2-C 12 Alkenyl, one or more R 1-1 Substituted C2-C6 alkynyl, one or more R 1-2 Substituted C3-C 10 Cycloalkyl, one or more R 1-3 Substituted C6-C 14 Aryl or one or more R -1-4 substituted 5-10 membered heteroaryl;

[0045] Each R 1-1 , each R 1-2 , each R 1-3 and R 1-4 are independently halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 14 Aryl, C1-C6 alkoxy, 5-10 membered heteroaryl, one or more R 1-1-1 Substituted C1-C6 alkyl, one or more R 1-1-1 Substituted C3-C8 cycloalkyl, one or more R 1-1-1 Substituted C6-C 14 Aryl, one or more R 1- 1-1 Substituted C1-C6 alkoxy or one or more R 1-1-1 substituted 5-10 membered heteroaryl;

[0046] R 1-1-1is halogen, C1-C6 alkyl or C6-C 14 aryl;

[0047] R 5 is H, halogen, C1-C6 alkyl, one or more R 5-1 Substituted C1-C6 alkyl, C1-C6 alkoxy, one or more R 5-2 Substituted C1-C6 alkoxy, C3-C8 cycloalkyl, one or more R 5-3 Substituted C3-C8 cycloalkyl, C2-C6 alkynyl or one or more R 5-4 substituted C2-C6 alkynyl;

[0048] Each R 5-1 , each R 5-2 , each R 5-3 and each R 5-4 are independently C3-C8 cycloalkyl.

[0049] In some embodiments, Ring A is a 4-6 membered heterocycloalkyl or a C4-C6 cycloalkenyl.

[0050] In some embodiments, R 3 and R 4 are independently H, halogen, C1-C6 alkyl, 3-5 Substituted C1-C6 alkyl, C1-C6 alkoxy, one or more R 3-6 Substituted C1-C6 alkoxy; or, any two adjacent R 3 and R 4 Together with the carbon atom to which it is connected, it forms a 3-8 membered heterocycloalkyl group. For example, the 3-8 membered heterocycloalkyl group may be dioxolane.

[0051] In some embodiments, each R 3-5 , each R 3-6 are independently halogen.

[0052] In some embodiments, R 1 is a C1-C6 alkyl group, 1-1 Substituted C1-C6 alkyl, C7-C 12 Straight chain alkyl, C2-C 12 Alkenyl, C2-C6 alkynyl, one or more R 1-1 Substituted C1-C6 alkoxy, C3-C 10 Cycloalkyl, one or more R 1-2 Substituted C3-C 10 Cycloalkyl, C6-C 14 Aryl or one or more R 1-3 Substituted C6-C 14 Aryl.

[0053] In some embodiments, each R 1-1 , each R 1-2 , each R 1-3 are independently halogen, C1-C6 alkyl, 1-1-1 Substituted C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 14 Aryl, C1-C6 alkoxy, one or more R 1-1-1 substituted C1-C6 alkoxy or 5-10 membered heteroaryl.

[0054] In some embodiments, R 1-1-1 is halogen, C1-C6 alkyl or C6-C 14 Aryl.

[0055] In some embodiments, R 5 is H or halogen.

[0056] In some embodiments, the compound shown in Formula Ia satisfies the following conditions:

[0057] (1) Ring A is a 4-6 membered heterocycloalkyl or C4-C6 cycloalkenyl group;

[0058] (2)R 3 and R 4 are independently H, halogen, C1-C6 alkyl, 3-5 Substituted C1-C6 alkyl, C1-C6 alkoxy, one or more R 3-6 Substituted C1-C6 alkoxy; or, any two adjacent R 3 and R 4 Together with the carbon atom to which it is connected, it forms a 3-8 membered heterocycloalkyl group. For example, the 3-8 membered heterocycloalkyl group can be dioxolane;

[0059] (3) Each R 3-5 , each R 3-6 are independently halogen;

[0060] (4)R 1 is a C1-C6 alkyl group, 1-1 Substituted C1-C6 alkyl, C7-C 12 Straight chain alkyl, C2-C 12 Alkenyl, C2-C6 alkynyl, one or more R 1-1 Substituted C1-C6 alkoxy, C3-C 10 Cycloalkyl, one or more R 1-2 Substituted C3-C 10 Cycloalkyl, C6-C 14 Aryl or one or more R 1-3Substituted C6-C 14 aryl;

[0061] (5) Each R 1-1 , each R 1-2 , each R 1-3 are independently halogen, C1-C6 alkyl, 1-1-1 Substituted C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 14 Aryl, C1-C6 alkoxy, one or more R 1-1-1 Substituted C1-C6 alkoxy or 5-10 membered heteroaryl;

[0062] (6)R 1-1-1 is halogen, C1-C6 alkyl or C6-C 14 aryl; and

[0063] (7)R 5 is H or halogen.

[0064] In some embodiments, Ring A is a 4-6 membered heterocycloalkyl.

[0065] In some embodiments, R 3 and R 4 are H or C1-C6 alkoxy respectively, and further, the C1-C6 alkoxy is located at the meta position.

[0066] In some embodiments, R 5 For H.

[0067] In some embodiments, the compound shown in Formula Ia satisfies the following conditions:

[0068] (1) Ring A is a 4-6 membered heterocycloalkyl group;

[0069] (2)R 3 and R 4 are H or C1-C6 alkoxy, respectively, and further, the C1-C6 alkoxy is located at the meta position; and

[0070] (3)R 5 For H.

[0071] In some embodiments, in ring A, the C4-C6 cycloalkenyl group is a cyclohexenyl group, and the 4-6 membered heterocycloalkyl group is a saturated cycloalkyl group containing 1-2 N atoms, for example, a piperidinyl group.

[0072] In some embodiments, R 3 and R 4 wherein the C1-C6 alkyl group, the one or more R 3-5The C1-C6 alkyl group in the substituted C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0073] In some embodiments, R 3 and R 4 wherein the C1-C6 alkoxy group, the one or more R 3-6 The C1-C6 alkoxy groups in the substituted C1-C6 alkoxy groups are independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

[0074] In some embodiments, R 3 and R 4 In the above example, any two adjacent R 3 and R 5 The heterocycloalkyl group in the 3-8 membered heterocycloalkyl group formed together with the carbon atom to which it is connected is a 5-6 membered heterocycloalkyl group containing 1-2 oxygen atoms, for example, dioxolane.

[0075] In some embodiments, R 3 and R 4 wherein the halogen is fluorine or chlorine.

[0076] In some embodiments, each R 3-5 , each R 3-6 wherein the halogen is fluorine.

[0077] In some embodiments, R 1 wherein the C1-C6 alkyl group, the one or more R 1-1 The C1-C6 alkyl groups in the substituted C1-C6 alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -n-C5H 11 、-n-C6H 13 、

[0078] In some embodiments, R 1 In the C7-C 12 Straight chain alkyl, separated by one or more R 1-1 Substituted C7-C 12 C7-C in straight chain alkyl 12 The straight chain alkyl group is C8-C 12 Straight chain alkyl.

[0079] In some embodiments, R 1 In the C2-C 12 Alkenyl, one or more R 1-1 Substituted C2-C 12 C2-C in alkenyl 12Alkenyl is a C4-C 10 Alkenyl.

[0080] In some embodiments, R 1 wherein the C2-C6 alkynyl group is replaced by one or more R 1-1 The C2-C6 substituted C2-C6 alkynyl 12 Alkynyl is a C3-C4 alkynyl group containing one triple bond.

[0081] In some embodiments, R 1 wherein the C1-C6 alkoxy group is replaced by one or more R 1-1 The C1-C6 alkoxy group in the substituted C1-C6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

[0082] In some embodiments, R 1 In the C3-C 10 Cycloalkyl, said 1-2 Substituted C3-C 10 C3-C in cycloalkyl 10 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentane or cyclohexane.

[0083] In some embodiments, R 1 In the C6-C 14 Aryl, said one or more R 1-3 Substituted C6-C 14 C6-C in aromatic groups 14 Aryl is phenyl.

[0084] In some embodiments, each R 1-1 , each R 1-2 , each R 1-3 , each R 1-4 wherein the halogen is fluorine.

[0085] In some embodiments, each R 1-1 , each R 1-2 , each R 1-3 , each R 1-4 wherein the C1-C6 alkyl group is replaced by one or more R 1-1-1 The C1-C6 alkyl groups in the substituted C1-C6 alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0086] In some embodiments, each R 1-1 , each R 1-2 , each R 1-3 , each R 1-4wherein the C3-C8 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentane or cyclohexane.

[0087] In some embodiments, each R 1-1 , each R 1-2 , each R 1-3 , each R 1-4 In the C6-C 14 Aryl, said one or more R 1-1-1 Substituted C6-C 14 C6-C in aromatic groups 14 Aryl is phenyl.

[0088] In some embodiments, each R 1-1 , each R 1-2 , each R 1-3 , each R 1-4 wherein the C1-C6 alkoxy groups are independently methoxy and ethoxy.

[0089] In some embodiments, each R 1-1 , each R 1-2 , each R 1-3 , each R 1-4 In the above, the 5-10 membered heteroaryl group is independently a 5-6 membered heteroaryl group containing one S atom or a 5-6 membered heteroaryl group containing one N atom, and further selected from thiophene, pyridine and benzothiophene.

[0090] In some embodiments, each R 1-1-1 wherein the halogen is fluorine, chlorine or bromine.

[0091] In some embodiments, each R 1-1-1 wherein the C1-C6 alkyl group is a methyl group or an ethyl group.

[0092] In some embodiments, each R 1-1-1 In the C6-C 14 Aryl is phenyl.

[0093] In some embodiments, R 5 wherein the halogen is fluorine.

[0094] In some embodiments, A is

[0095] In some embodiments, R 3 and R 4 are independently H, -OCH3, F, Cl, -CH3, -CF3, -OCF3 or

[0096] In some embodiments, R 1 Methyl, ethyl, propyl, n-butyl,

[0097] In some embodiments, R 5 For H.

[0098] In some scenarios, the following conditions are met:

[0099] (1) A is

[0100] (2)R 3 and R 4 are independently H, -OCH3, F, Cl, -CH3, -CF3, -OCF3 or

[0101] (3)R 1 Methyl, ethyl, propyl, n-butyl, as well as

[0102] (4)R 5 For H.

[0103] In some embodiments, R 1 is a C3-C6 alkyl group, 1-1 Substituted C1-C6 alkyl, C3-C 10 Cycloalkyl, one or more R 1-2 Substituted C3-C 10 Cycloalkyl, phenyl or one or more R 1-3 Substituted phenyl.

[0104] In some embodiments, each R 1-1 are independently fluoro, phenyl.

[0105] In some embodiments, each R 1-2 are independently C1-C3 alkyl, 1-1-1 Substituted C1-C3 alkyl.

[0106] In some embodiments, each R 1-3 are independently fluorine, C1-C3 alkyl, 1-1-1 Substituted C1-C3 alkyl.

[0107] In some embodiments, each R 1-1-1 are independently phenyl.

[0108] In some embodiments, R 3 is H, methoxy or is replaced by one or more R 3-5 Substituted C1-C6 alkyl.

[0109] In some embodiments, R 4 is methoxy or is replaced by one or more R 3-5 Substituted C1-C6 alkyl.

[0110] In some embodiments, each R 3-5 For fluorine.

[0111] In some scenarios, the following conditions are met:

[0112] (1)R 1 is a C3-C6 alkyl group, 1-1 Substituted C1-C6 alkyl, C3-C 10 Cycloalkyl, one or more R 1-2 Substituted C3-C 10 Cycloalkyl, phenyl or one or more R 1-3 substituted phenyl;

[0113] (2) Each R 1-1 are independently fluoro, phenyl;

[0114] (3) Each R 1-2 are independently C1-C3 alkyl, 1-1-1 Substituted C1-C3 alkyl;

[0115] (4) Each R 1-3 are independently fluorine, C1-C3 alkyl, 1-1-1 Substituted C1-C3 alkyl;

[0116] (5) Each R 1-1-1 are independently phenyl;

[0117] (6)R 3 is H, methoxy or is replaced by one or more R 3-5 Substituted C1-C6 alkyl;

[0118] (7)R 4 is methoxy or is replaced by one or more R 3-5 Substituted C1-C6 alkyl; and

[0119] (8) Each R 3-5 For fluorine.

[0120] In some embodiments, the compound represented by Formula I is any of the following compounds:

[0121] On the other hand, the present invention also provides a pharmaceutical composition comprising the compound of Formula I, a pharmaceutically acceptable salt, a solvate, or a solvate of a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0122] On the other hand, the present invention also provides a use of the compound represented by Formula I or a pharmaceutically acceptable salt thereof in the preparation of a GPR40 agonist.

[0123] On the other hand, the present invention also provides a use of the compound of Formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing a disease associated with GPR40;

[0124] In the application, the GPR40-related disease is, for example, diabetes.

[0125] The present invention also provides a use of the compound represented by general formula I or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating or preventing diabetes.

[0126] The present invention also provides a method for treating a disease related to GPR40 (preferably diabetes), comprising administering to a patient an effective amount of the compound represented by general formula I or a pharmaceutically acceptable salt thereof.

[0127] The present invention also provides a method for treating diabetes, comprising administering an effective amount of the compound represented by the general formula I or a pharmaceutically acceptable salt thereof to a patient.

[0128] The phrase "a group B substituted by one or more groups A" means two, three, four or five groups. The phrase "a group B substituted by one or more groups A" means that one, two, three, four or five hydrogen atoms in the group B are independently replaced by groups A. When multiple A groups appear at the same time, unless otherwise specified, their definitions are independent of each other and do not affect each other. For example, "a C6-C substituted by three halogens" means that 10 "Aryl" refers to C6-C 10 The aromatic group may be substituted by three halogens, and the definitions of the three halogens are independent of each other and do not affect each other.

[0129] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When the compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When the compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. For details, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

[0130] In the structure fragment It means that the structural fragment is connected to the rest of the molecule through this site. For example, It refers to cyclohexyl.

[0131] The "-" at the end of a group means that the group is attached to the rest of the molecule through that site. For example, -C5H 11 It refers to n-pentane.

[0132] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0133] The term "alkyl" refers to a linear or branched, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C1-C6). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like.

[0134] The term "heterocycloalkyl" refers to a cyclic group having a specified number of ring atoms (e.g., 5-10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S). Heterocycloalkyl groups include, but are not limited to, dioxolane, piperidine, and the like.

[0135] The term "alkoxy" refers to a group R X -O-, R X The same definition as the term "alkyl". Alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and the like.

[0136] The term "alkylene" is a divalent group that is attached to the rest of the molecule by two single bonds, and the rest of the definition is the same as the term "alkyl".

[0137] The term "cycloalkyl" refers to a cyclic, saturated, monovalent hydrocarbon radical having a specified number of carbon atoms (e.g., C3-C8) that is a single ring. Cycloalkyl groups include, but are not limited to: wait.

[0138] The term "aryl" refers to a group having the specified number of carbon atoms (e.g., C6-C 10 ) is a cyclic, unsaturated, monovalent hydrocarbon group, which may be monocyclic or polycyclic (e.g., 2 or 3). In the case of polycyclic rings, the monocyclic rings share two atoms and one bond, and each ring is aromatic. Aryl groups include, but are not limited to, phenyl, naphthyl, and the like.

[0139] The term "heteroaryl" refers to a cyclic, unsaturated, monovalent group having a specified number of ring atoms (e.g., 5-10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of P, N, O, and S). It is a single ring or multiple rings (e.g., 2 or 3), with the single rings sharing two atoms and one bond, and each ring is aromatic. A heteroaryl group is attached to the rest of the molecule through a carbon atom or a heteroatom; a heteroaryl group is attached to the rest of the molecule through a ring containing heteroatoms or a ring without heteroatoms.

[0140] The term "pharmaceutically acceptable excipients" refers to all substances contained in pharmaceutical preparations other than the active pharmaceutical ingredient, and is generally divided into two categories: excipients and additives. For details, see the Pharmacopoeia of the People's Republic of China (2020 Edition) and the Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0141] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0142] The reagents and raw materials used in the present invention are commercially available.

[0143] The positive progress of the present invention is that the compound of the present invention has good agonist activity on GPR40 and has good drug development prospects. DETAILED DESCRIPTION

[0144] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0145] Synthesis of starting material 1-1:

[0146] Following the above route, a mixture of commercially available starting compound M-1 (S)-methyl 3-cyclopropyl-3-(3-hydroxyphenyl)propionate (10 g, 45.5 mmol, CAS No. 1142223-08-2), N-iodosuccinimide (9.21 g, 41.0 mmol), and dichloromethane (200 mL) was stirred at room temperature for 1 hour. The reaction mixture was directly concentrated, and the resulting crude product was purified by normal phase column chromatography (dichloromethane:petroleum ether = 50%) to obtain compound M-2 (9.10 g, 58% yield) as a yellow oil. LCMS: [M+H] + =346.8.

[0147] A mixture of compound M-2 (1.35 g, 3.9 mmol), compound M-3 (815 mg, 3.9 mmol), triethylamine (788 mg, 7.8 mmol), cuprous iodide (74 mg, 0.39 mmol), bistriphenylphosphine palladium dichloride (137 mg, 0.195 mmol), and acetonitrile (27 mL) was reacted at 80°C under nitrogen for 4 hours. The reaction solution was directly concentrated, and the resulting crude product was purified by normal phase column chromatography (ethyl acetate:petroleum ether = 10%) to obtain compound M-4 (1.4 g, 84% yield) as a yellow oil. LCMS: [M-55] + =372.1.

[0148] A mixture of compound M-4 (1.1 g, 2.58 mmol), N-bromosuccinimide (918 mg, 5.16 mmol), and tetrahydrofuran (20 mL) was stirred at room temperature for 3 hours. The reaction solution was directly concentrated, and the resulting crude product was purified by normal phase column chromatography (ethyl acetate:petroleum ether = 10%) to obtain compound M-5 (982 mg, 75% yield) as a yellow oil. LCMS: [M-55] + =449.9

[0149] A mixture of compound M-5 (760 mg, 1.50 mmol), trifluoroacetic acid (513 mg, 4.50 mmol), and dichloromethane (10 mL) was stirred at room temperature for 2 hours. After the reaction was completed, saturated sodium bicarbonate solution (10 mL) was added, followed by extraction with dichloromethane (20 mL x 3). The organic phase was concentrated, and the resulting crude product was purified by normal phase column chromatography (ethyl acetate:petroleum ether = 50%) to obtain compound 1-1 (565 mg, 93% yield) as a yellow oil. LCMS: [M+H] + =406.2.

[0150] Example 1

[0151] The synthesis route of compound 1 is as follows:

[0152] Compound 1-1 (5.65 g, 13.9 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (1.21 g, 1.9 mmol), palladium acetate (400 mg, 1.9 mmol), compound 1-2 (4.28 g, 20.8 mmol), and cesium carbonate (18.12 g, 55.6 mol) were added to toluene (100 mL) and stirred at 100°C overnight. LCMS showed that the compound had reacted completely. After stopping the reaction, dichloromethane (200 mL) and water (200 mL) were added to the reaction solution. The reaction solution was separated by extraction and the organic phase was concentrated. The crude product was purified by normal phase column chromatography (ethyl acetate:petroleum ether = 50%) to obtain compound 1-3 (949 mg, 13% yield) as a white solid. LCMS: [M+H] + =526.1.

[0153] Compound 1-3 (525 mg, 1.0 mmol), compound 1-4 (385 mg, 2.5 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (40 mg, 0.5 mmol), and cesium carbonate (975 mg, 3 mmol) were added to a 5:1 mixture of 1,4-dioxane and water (25 mL). The mixture was stirred at 80°C for 16 hours. LCMS showed that the reaction was complete. The reaction solution was extracted with ethyl acetate (50 mL) and concentrated. The crude product was purified by normal phase column chromatography (ethyl acetate:petroleum ether = 20%) to obtain compound 1-5 (390 mg, 97% yield) as a yellow oil. LCMS: [M+H] + =460.2.

[0154] Compound 1-5 (390 mg, 0.85 mmol) and 2,6-lutidine (182 mg, 1.7 mmol) were added to a 3:1 mixture of 1,4-dioxane and water (40 mL). Potassium osmate dihydrate (15.5 mg, 0.0425 mmol) and sodium periodate (910 mg, 4.25 mmol) were added at 0°C. The mixture was stirred at 0°C for 4 hours. LCMS showed that the reaction was complete. Saturated aqueous sodium thiosulfate solution (25 mL) was added at 0°C. The reaction solution was extracted with ethyl acetate (50 mL) and concentrated. The crude product was purified by normal phase column chromatography (ethyl acetate:petroleum ether = 20%) to obtain compound 1-6 (195 mg, 49% yield) as a yellow oil. LCMS: [M+H] + =462.2.

[0155] Compound 1-6 (195 mg, 0.425 mmol) and 2-methyl-2-butene (600 mg, 8.5 mmol) were added to a 1:1 mixture of tetrahydrofuran and tert-butanol (20 mL). A solution of sodium dihydrogen phosphate (700 mg, 5.1 mmol) and sodium chlorite (192 mg, 2.15 mmol) in water (10 mL) was added dropwise at 25°C. The mixture was stirred at 25°C for 4 hours. LCMS showed that the reaction was complete. The reaction solution was extracted with ethyl acetate (30 mL) and concentrated. The crude product was purified by normal phase column chromatography (ethyl acetate:petroleum ether = 50%) to obtain compound 1-7 (128 mg, 63% yield) as a yellow oil. LCMS: [M+H] + =478.2.

[0156] Compound 1-7 (56 mg, 0.117 mmol), lithium hydroxide (15 mg, 0.587 mmol), tetrahydrofuran (5 mL), methanol (5 mL), and water (5 ml) were reacted at 50°C for 2 hours. LCMS showed that the reaction was complete. The reaction solution was extracted with ethyl acetate (30 mL) and concentrated. The crude product was purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 60%] to obtain compound 1 (40 mg, yield 71%) as a white solid. LCMS: [M+H] + =464.0.

[0157] 1 H NMR(400MHz, CDCl3)δ7.90(d,J=8.0Hz,1H),7.39(s,1H),7.23–7.15(m,2H),6.74–6.40(m,3H),3.84–3.79(m,6H),2.96–2.83(m,4H),2.51–2.4 5(m,1H),2.26–2.07(m,2H),2.02–1.94(m,2H),1.13–1.06(m,1H),0.70 –0.61(m,1H),0.52–0.43(m,1H),0.35–0.31(m,1H),0.26–0.20(m,1H).

[0158] Example 2

[0159] The synthesis route of compound 2 is as follows:

[0160] Compound 1-7 (200 mg, 0.420 mmol) was dissolved in toluene (5 mL), sodium hydride (50 mg, 1.66 mmol) was added at 0°C, and the mixture was allowed to react at room temperature for 1 hour. Compound 2-1 (346 mg, 2.94 mmol) was added and the mixture was allowed to react at 50°C for 1 hour. 1N aqueous hydrochloric acid solution (30 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by normal phase column chromatography (ethyl acetate:petroleum ether = 50%) to obtain 2-2 as a white solid (200 mg, yield 84%). LCMS: [M+H] + =564.1.

[0161] Compound 2-2 (50 mg, 0.105 mmol) was dissolved in N,N-dimethylformamide (3 mL), and compound 2-3 (50.4 mg, 0.355 mmol) and potassium carbonate (25 mg, 0.176 mmol) were added. The mixture was reacted at 70°C overnight, diluted with water (10 mL), and extracted with ethyl acetate (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by normal phase column chromatography (ethyl acetate:petroleum ether = 15%) to obtain 2-4 (33.3 mg, 55% yield) as a white solid. LCMS: [M+H] + =578.3.

[0162] Compound 2-4 (28.9 mg, 0.05 mmol) in tetrahydrofuran (3 mL) and N,N-dimethylformamide (1 mL) was added to a reaction tube. Tetrabutylammonium fluoride (0.07 mL, 1 M) was added and the mixture was reacted at room temperature for 1 hour. The solvent was then dried and the resulting crude product was purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 70%] to afford compound 2 as a white solid (11.2 mg, 47% yield). LCMS: [M+H] + =478.1.

[0163] 1 H NMR(400MHz, CDCl3)δ7.90(d,J=8.0Hz,1H),7.38(s,1H),7.26–7.20(m,2H),6.72–6 .65(m,1H),6.65–6.55(m,1H),6.53–6.47(m,1H),3.98(s,3H),3.90–3.81(m,6H),3. 01–2.83(m,4H),2.55–2.49(m,1H),2.29–2.17(m,2H),2.07–1.98(m,2H),1.18–1.07 (m,1H),0.71–0.60(m,1H),0.50–0.42(m,1H),0.42–0.31(m,1H),0.24–0.15(m,1H).

[0164] Example 3

[0165] The synthesis route of compound 3 is as follows:

[0166] Referring to the synthesis of compound 2, white solid compound 3 (4.0 mg, yield 9%) was obtained. LCMS: [M+H] + =492.1.

[0167] 1 H NMR(400MHz, CDCl3)δ7.91(d,J=8.0Hz,1H),7.40(s,1H),7.28–7.22(m,2H),6 .93–6.42(m,3H),4.45(q,J=7.2Hz,2H),3.94–3.82(m,6H),3.06–2.80(m,4H), 2.55–2.49(m,1H),2.25–2.01(m,4H),1.48(t,J=7.2Hz,3H),1.15–1.08(m,1H ),0.68–0.62(m,1H),0.51–0.45(m,1H),0.39–0.34(m,1H),0.26–0.18(m,1H).

[0168] Example 4

[0169] The synthesis route of compound 4 is as follows:

[0170] Referring to the synthesis of compound 2, white solid compound 4 (11.1 mg, yield 12%) was obtained. LCMS: [M+H] + =506.2.

[0171] 1H NMR(400MHz, CDCl3)δ7.92(d,J=8.0Hz,1H),7.37(s,1H),7.26–7.17(m,2H),6.64(dd,J=8.0 ,2.4Hz,1H),6.56(t,J=2.4Hz,1H),6.46(dd,J=8.0,2.4Hz,1H),4.35(t,J=6.4Hz,2H),3.94– 3.78(m,6H),2.97–2.78(m,4H),2.55–2.48(m,1H),2.25–2.00(m,4H),1.92–1.82(m,2H),1. 13–1.06(m,4H),0.67–0.60(m,1H),0.49–0.42(m,1H),0.38–0.32(m,1H),0.23–0.16(m,1H).

[0172] Example 5

[0173] The synthesis route of compound 5 is as follows:

[0174] Referring to the synthesis of compound 2, white solid compound 5 (11.9 mg, yield 16%) was obtained. LCMS: [M+H] + =506.2.

[0175] 1 H NMR(400MHz, CDCl3)δ7.90(d,J=8.0Hz,1H),7.40(s,1H),7.26–7.19(d,J=8.0H z,2H),6.95–6.51(m,3H),5.36–5.24(m,1H),3.89–3.76(m,6H),3.11–2.82(m,4 H),2.55–2.48(m,1H),2.19–2.00(m,4H),1.45(d,J=6.4Hz,6H),1.12–1.04(m,1 H),0.70–0.60(m,1H),0.51–0.44(m,1H),0.39–0.33(m,1H),0.24–0.17(m,1H).

[0176] Example 6

[0177] The synthesis route of compound 6 is as follows:

[0178] Referring to the synthesis of compound 2, white solid compound 6 (23.7 mg, yield 22%) was obtained. LCMS: [M+H] + =520.2.

[0179] 1 H NMR (400MHz, CDCl3) δ7.94(d,J=8.0Hz,1H),7.38(s,1H),7.25–7.20(m,2H),6.65(dd,J=8.0,2.4H z,1H),6.57(t,J=2.4Hz,1H),6.47(dd,J=8.0,2.4Hz,1H),4.19(d,J=6.4Hz,2H),3.96–3.80(m,6H ),3.00–2.76(m,4H),2.55–2.48(m,1H),2.26–2.11(m,3H),2.04–2.01(m,2H),1.10(d,J=6.8Hz,6 H),1.09–1.01(m,1H),0.67–0.61(m,1H),0.49–0.43(m,1H),0.38–0.31(m,1H),0.23–0.18(m,1H).

[0180] Example 7

[0181] The synthesis route of compound 7 is as follows:

[0182] Referring to the synthesis of compound 2, white solid compound 7 (4.2 mg, yield 5%) was obtained. LCMS: [M+H] + =518.1.

[0183] 1 H NMR(400MHz, CDCl3) δ7.94(d,J=8.0Hz,1H),7.45(s,1H),7.26–7.20(m,2H),7.13(d,J=8.4Hz,1H),6.72 (d,J=2.4Hz,1H),6.64(dd,J=8.4,2.4Hz,1H),4.84(s,1H),4.73(s,1H),3.84–3.78(m,4H),3.42(s,2H), 3.22(d,J=11.6Hz,2H),2.97–2.79(m,4H),2.59–2.51(m,1H),2.21–2.15(m,2H),1.99–1.98(m,2H),1.7 6(s,3H),1.16–1.11(m,1H),0.71–0.64(m,1H),0.52–0.44(m,1H),0.39–0.35(m,1H),0.28–0.22(m,1H).

[0184] Example 8

[0185] The synthesis route of compound 8 is as follows:

[0186] Compound 1-7 (50 mg, 0.105 mmol) was dissolved in toluene (3 mL), and compound 8-1 (212 mg, 1.05 mmol) was added. The mixture was reacted at 80°C for 2 hours. The solvent was concentrated to dryness to obtain crude compound 8-2, which was directly used in the next step. LCMS: [M+H] + =534.0.

[0187] A reaction tube was added with crude compound 8-2 (50 mg, 0.0936 mmol), lithium hydroxide (12 mg, 0.468 mmol), tetrahydrofuran (3 mL), methanol (3 mL), and water (3 mL). The mixture was reacted at 50°C for 2 hours. After the reaction was complete, the mixture was directly concentrated and then purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 50% to 70%] to obtain compound 8 (35 mg, 70% yield) as a white solid. LCMS: [M+H] + =520.1.

[0188] 1 H NMR(400MHz,cdcl3)δ7.88(d,J=8.0Hz,1H),7.34(s,1H),7.22–7.15(m,2H ),6.72–6.36(m,3H),3.84–3.81(m,6H),3.02–2.75(m,4H),2.52–2.44(m,1 H),2.27–2.06(m,2H),2.05–1.98(m,2H),1.66(s,9H),1.11–1.06(m,1H),0 .64–0.58(m,1H),0.46–0.40(m,1H),0.35–0.29(m,1H),0.20–0.16(m,1H).

[0189] Example 9

[0190] The synthesis route of compound 9 is as follows:

[0191] Referring to the synthesis of compound 2, white solid compound 9 (12.1 mg, yield 13%) was obtained. LCMS: [M+H] + =534.2.

[0192] 1H NMR (400MHz, CDCl3) δ7.94 (d, J=8.0Hz, 1H), 7.39–3.37 (m, 1H), 7.28–7.18 (m, 2H), 6.64 (dd, J=8.0,2.4Hz,1H),6.57(t,J=2.4Hz,1H),6.46(dd,J=8.0,2.4Hz,1H),4.11(s,2H),3.95–3. 84(m,6H),3.01–2.78(m,4H),2.54–2.48(m,1H),2.28–2.12(m,2H),2.05–2.02(m,2H),1.20 –0.95(m,10H),0.68–0.61(m,1H),0.50–0.43(m,1H),0.39–0.33(m,1H),0.23–0.17(m,1H).

[0193] Example 10

[0194] The synthesis route of compound 10 is as follows:

[0195] Referring to the synthesis of compound 2, white solid compound 10 (52 mg, yield 61%) was obtained. LCMS: [M+H] + =532.1.

[0196] 1 H NMR (400MHz, DMSO-d6) δ7.77(d,J=8.0Hz,1H),7.55(s,1H),7.26(d,J=8.0Hz,1H),7.13(t,J=8.0Hz,1H),6.58 (dd,J=8.0,2.0Hz,1H),6.50(t,J=2.0Hz,1H),6.37(dd,J=8.0,2.0Hz,1H),5.51(t,J=7.2Hz,1H),4.82(d,J=7 .2Hz,2H),3.91–3.77(m,3H),3.73(s,3H),2.87–2.77(m,2H),2.75–2.65(m,2H),2.43–2.34(m,1H),2.0–1.88 (m,4H),1.77(s,3H),1.76(s,3H),1.12–1.02(m,1H),0.56–0.48(m,1H),0.34–0.22(m,2H),0.18–0.10(m,1H).

[0197] Example 11

[0198] The synthesis route of compound 11 is as follows:

[0199] In a reaction tube, compound 1-7 (40 mg, 0.083 mmol), compound 11-1 (76 mg, 0.42 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (48 mg, 0.25 mmol), 4-dimethylaminopyridine (15 mg, 0.13 mmol), and dichloromethane (4 mL) were added under nitrogen. The reaction was allowed to proceed overnight at room temperature. After cooling to room temperature, the mixture was diluted with ethyl acetate (30 mL) and washed with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by normal phase column chromatography (ethyl acetate:petroleum ether = 30%) to afford compound 11-2 (53.7 mg, 99% yield) as an oil. LCMS: [M+H] + =642.2

[0200] Compound 11-2 (53.7 mg, 0.083 mmol) and trimethyltin hydroxide (30 mg, 0.17 mmol) were added to a reaction tube in 1,2-dichloroethane (5 mL) and heated to 90°C with stirring overnight. After the reaction was complete, dilute hydrochloric acid was added to adjust the pH to 3. The mixture was extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by reverse-phase column chromatography [acetonitrile / water (0.05% formic acid) = 50% to 70%] to afford Compound 20 (23 mg, 44% yield) as a white solid. LCMS: [M+H] + =628.2.

[0201] 1 H NMR(400MHz, CDCl3)δ7.87(d,J=8.0Hz,1H),7.40(s,1H),7.28–7.21(m,2H),6.64(dd,J =8.0Hz,2.0Hz,1H),6.56(t,J=2.0Hz,1H),6.47(dd,J=8.0Hz,2.0Hz,1H),3.89–3.72(m, 6H),2.98–2.81(m,4H),2.54–2.48(m,1H),2.25–2.14(m,5H),2.05–1.97(m,2H),1.15–1 .06(m,1H),0.69–0.62(m,1H),0.50–0.44(m,1H),0.39–0.33(m,1H),0.23–0.17(m,1H).

[0202] Example 12

[0203] The synthesis route of compound 12 is as follows:

[0204] Referring to the synthesis of compound 11, white solid compound 12 (16.5 mg, yield 14%) was obtained. LCMS: [M+H] + =682.2.

[0205] 1 H NMR(400MHz, CDCl3)δ7.83(d,J=8.0Hz,1H),7.42(s,1H),7.31–7.27(m,1H),7.23(t,J=8.0Hz ,1H),6.63(dd,J=8.0Hz,2.0Hz,1H),6.56(t,J=2.0Hz,1H),6.47(dd,J=8.0Hz,2.0Hz,1H),3.9 0–3.72(m,6H),2.98–2.81(m,4H),2.54–2.47(m,1H),2.24–2.15(m,2H),2.05–2.00(m,2H),1 .15–1.05(m,1H),0.69–0.62(m,1H),0.50–0.44(m,1H),0.39–0.33(m,1H),0.23–0.17(m,1H).

[0206] Example 13

[0207] The synthesis route of compound 13 is as follows:

[0208] In a reaction tube, compound 1-7 (105 mg, 0.22 mmol), compound 13-1 (35 mg, 0.26 mmol), anhydrous potassium carbonate (36 mg, 0.26 mmol), and DMF (2 mL) were added under nitrogen. The reaction was allowed to proceed overnight at room temperature. After cooling to room temperature, the mixture was diluted with ethyl acetate (30 mL) and washed with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by normal phase column chromatography (ethyl acetate:petroleum ether = 1:2) to afford compound 13-2 (98 mg, 84%) as an oil. LCMS: [M+H] + =530.1

[0209] Compound 13-2 (98 mg, 0.185 mmol) and THF (2 mL) were added to a reaction tube. 0.4 mL of LiOH (9 mg, 0.37 mmol) in water was then added dropwise to the reaction mixture. The reaction was allowed to proceed overnight at room temperature. Dilute hydrochloric acid was added to adjust the pH to 3. The mixture was extracted with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by reverse-phase column chromatography [acetonitrile / water (0.05% formic acid) = 50% to 70%] to afford Compound 13 (17.5 mg, 19%) as a white solid. LCMS: [M+H] + =516.1.

[0210] 1 H NMR (400MHz, CDCl3) δ7.92 (d, J=8.0Hz, 1H), 7.34 (s, 1H), 7.24–7.15 (m, 2H), 6.60 (dd, J= 8.0,2.4Hz,1H),6.53(t,J=2.4Hz,1H),6.43(dd,J=8.0,2.4Hz,1H),4.93(s,2H),3.92–3 .77(m,6H),2.97–2.74(m,4H),2.53–2.46(m,1H),2.21–2.08(m,2H),2.05–1.96(m,2H), 1.89(s,3H),1.12–1.05(m,1H),0.49–0.42(m,2H),0.36–0.27(m,1H),0.20–0.14(m,1H).

[0211] Example 14

[0212] The synthesis route of compound 14 is as follows:

[0213] Referring to the synthesis of compound 2, white solid compound 14 (49 mg, yield 50%) was obtained. LCMS: [M+H] + =520.1.

[0214] 1 H NMR (400MHz, DMSO-d6) δ7.85–7.72(m,1H),7.55(s,1H),7.27(d,J=8.0Hz,1H),7.13(t,J=8.0Hz,1H),6.58(dd,J =8.4,2.0Hz,1H),6.51(t,J=2.0Hz,1H),6.37(dd,J=8.4,2.0Hz,1H),4.32(t,J=6.4Hz,2H),3.91–3.75(m,3H),3 .73(s,3H),2.88–2.76(m,2H),2.73–2.66(m,2H),2.42–2.35(m,1H),2.03–1.87(m,4H),1.79–1.70(m,2H),1.52 –1.42(m,2H),1.10–1.02(m,1H),0.96(t,J=6.4Hz,3H),0.56–0.47(m,1H),0.33–0.23(m,2H),0.19–0.08(m,1H).

[0215] Example 15

[0216] The synthesis route of compound 15 is as follows:

[0217] Referring to the synthesis of compound 2, white solid compound 15 (41 mg, yield 63%) was obtained. LCMS: [M+H] + =534.1.

[0218] 1 H NMR (400MHz, DMSO-d6) δ7.79(d,J=7.6Hz,1H),7.55(s,1H),7.26(d,J=7.6Hz,1H),7.12(t,J=8.0Hz,1H),6.58( dd,J=8.0,2.0Hz,1H),6.50(t,J=2.0Hz,1H),6.40–6.34(m,1H),4.31(t,J=6.4Hz,2H),3.92–3.74(m,3H),3.73 (s,3H),2.87–2.77(m,2H),2.74–2.68(m,2H),2.42–2.34(m,1H),2.03–1.88(m,4H),1.80–1.71(m,2H),1.46–1 .34(m,4H),1.10–1.02(m,1H),0.90(t,J=6.4Hz,3H),0.55–0.47(m,1H),0.33–0.23(m,2H),0.18–0.10(m,1H).

[0219] Example 16

[0220] The synthesis route of compound 16 is as follows:

[0221] Referring to the synthesis of compound 2, white solid compound 16 (14 mg, yield 13%) was obtained. LCMS: [M+H] + =548.1.

[0222] 1H NMR (400MHz, CDCl3) δ7.88(d,J=8.0Hz,1H),7.34(s,1H),7.24–7.18(m,2H),6.62(d,J=7.6Hz,1H),6.55(s ,1H),6.44(d,J=7.6Hz,1H),4.35(t,J=6.4Hz,2H),3.91–3.78(m,6H),2.97–2.76(m,4H),2.54–2.47(m,1H) ,2.22–2.15(m,2H),2.04–1.97(m,2H),1.85–1.79(m,2H),1.55–1.47(m,2H),1.42–1.30(m,4H),1.10–1.03 (m,1H),0.91(t,J=6.4Hz,3H),0.65–0.57(m,1H),0.47–0.40(m,1H),0.35–0.28(m,1H),0.21–0.14(m,1H).

[0223] Example 17

[0224] The synthesis route of compound 17 is as follows:

[0225] Referring to the synthesis of compound 2, white solid compound 17 (17 mg, yield 16%) was obtained. LCMS: [M+H] + =576.1.

[0226] 1 H NMR (400MHz, CDCl3) δ7.88(d,J=8.0Hz,1H),7.34(s,1H),7.24–7.17(m,2H),6.62(d,J=7.6Hz,1H),6.54(s ,1H),6.44(d,J=7.6Hz,1H),4.35(t,J=6.4Hz,2H),3.91–3.77(m,6H),2.98–2.75(m,4H),2.54–2.43(m,1H) ,2.23–2.11(m,2H),2.04–1.95(m,2H),1.86–1.75(m,2H),1.55–1.44(m,2H),1.39–1.26(m,8H),1.13–1.01 (m,1H),0.88(t,J=6.4Hz,3H),0.65–0.57(m,1H),0.47–0.39(m,1H),0.35–0.28(m,1H),0.21–0.13(m,1H).

[0227] Example 18

[0228] The synthesis route of compound 18 is as follows:

[0229] Referring to the synthesis of compound 2, white solid compound 18 (16 mg, yield 13%) was obtained. LCMS: [M+H] + =632.1.

[0230] 1 H NMR (400MHz, CDCl3) δ7.88(d,J=8.0Hz,1H),7.34(s,1H),7.23–7.16(m,2H),6.62(d,J=8.8Hz,1H),6.54(s, 1H),6.44(d,J=8.8Hz,1H),4.35(t,J=6.4Hz,2H),3.93–3.77(m,6H),2.98–2.76(m,4H),2.53–2.45(m,1H), 2.25–2.10(m,2H),2.03–1.95(m,2H),1.87–1.76(m,2H),1.54–1.44(m,2H),1.35–1.21(m,16H),1.14–1.01 (m,1H),0.88(t,J=6.4Hz,3H),0.65–0.57(m,1H),0.48–0.39(m,1H),0.35–0.28(m,1H),0.22–0.14(m,1H).

[0231] Example 19

[0232] The synthesis route of compound 19 is as follows:

[0233] Referring to the synthesis of compound 11, white solid compound 19 (7.9 mg, yield 13%) was obtained. LCMS: [M+H] + =518.2.

[0234] 1H NMR (400MHz, CDCl3) δ7.87 (d, J=8.0Hz, 1H), 7.36 (s, 1H), 7.25–7.20 (m, 2H), 6.64 (dd, J=8.4Hz, 2.0Hz,1H),6.56(t,J=2.0Hz,1H),6.46(dd,J=8.0Hz,2.0Hz,1H),3.91–3.81(m,6H),2.99–2.79( m,4H),2.55–2.47(m,1H),2.22–2.11(m,2H),2.04–1.99(m,2H),1.72(s,3H),1.14–1.04(m,3H) ,0.84–0.78(m,2H),0.68–0.61(m,1H),0.49–0.42(m,1H),0.38–0.32(m,1H),0.22–0.16(m,1H).

[0235] Example 20

[0236] The synthesis route of compound 20 is as follows:

[0237] Compounds 1-7 and 20-1 were synthesized according to the procedure of compound 11 to obtain white solid compound 20 (17.5 mg, 50%). LCMS: [M+H] + =580.1.

[0238] 1 H NMR(400MHz, CDCl3)δ7.99(d,J=8.0Hz,1H),7.40–7.33(m,5H),7.29–7.18(m,3H),6.67–6.59(m ,1H),6.59–6.51(m,1H),6.50–6.40(m,1H),3.89–3.80(m,6H),2.97–2.80(m,4H),2.57–2.48(m ,1H),2.24–2.09(m,2H),1.99(d,J=12.9Hz,2H),1.53–1.49(m,2H),1.45–1.41(m,2H),1.18–1. 07(m,1H),0.72–0.59(m,1H),0.53–0.43(m,J=4.8Hz,1H),0.41–0.32(m,1H),0.25–0.18(m,1H).

[0239] Example 21

[0240] The synthesis route of compound 21 is as follows:

[0241] Referring to the synthesis of compound 11, white solid compound 21 (15.4 mg, yield 18%) was obtained. LCMS: [M+H] + =594.2.

[0242] 1 H NMR (400MHz, CDCl3) δ7.75(d,J=8.0Hz,1H),7.34(s,1H),7.30–7.21(m,6H),7.17(d,J=8.0Hz,1H),6.62(d d,J=8.0Hz,1.6Hz,1H),6.55(t,J=1.6Hz,1H),6.47(dd,J=8.0Hz,1.6Hz,1H),3.87–3.75(m,5H),3.64–3.5 5(m,1H),3.31(s,2H),2.91–2.71(m,4H),2.52–2.46(m,1H),2.14–2.02(m,2H),1.91–1.83(m,2H),1.13–1 .03(m,3H),0.99–0.94(m,2H),0.67–0.60(m,1H),0.48–0.42(m,1H),0.37–0.31(m,1H),0.22–0.15(m,1H).

[0243] Example 22

[0244] The synthesis route of compound 22 is as follows:

[0245] Referring to the synthesis of compound 13, white solid compound 22 (8.8 mg, yield 13%) was obtained. LCMS: [M+H] + =554.1.

[0246] 1 H NMR(400MHz, CDCl3)δ7.90(d,J=8.0Hz,1H),7.51(d,J=6.8Hz,2H),7.48–7.34(m, 4H),7.27–7.16(m,2H),6.78–6.35(m,3H),5.43(s,2H),3.94–3.81(m,6H),2.92–2 .80(m,4H),2.53–2.46(m,1H),2.26–2.14(m,2H),2.06–1.98(m,2H),1.13–1.04(m ,1H),0.67–0.61(m,1H),0.49–0.43(m,1H),0.37–0.32(m,1H),0.22–0.16(m,1H).

[0247] Example 23

[0248] The synthesis route of compound 23 is as follows:

[0249] Compound 1-7 (72 mg, 0.151 mmol) was dissolved in dichloromethane (3 mL), and oxalyl chloride (28 mg, 0.226 mmol) was added at 0°C. The mixture was allowed to react at room temperature for 2 hours. The solvent was concentrated to dryness, dissolved in dichloromethane (2 mL), and added dropwise to compound 23-1 (27.6 mg, 0.226 mmol). The mixture was allowed to react at room temperature overnight. After concentration, the mixture was purified by normal phase column chromatography (ethyl acetate:petroleum ether = 10%) to give 23-2 (52.6 mg, yield = 60%) as a white solid. LCMS: [M+H] + =582.2.

[0250] Compound 23-2 (35 mg, 0.06 mmol) and trimethyltin hydroxide (22 mg, 0.12 mmol) were added to 1,2-dichloroethane (5 mL) and heated to 90°C and stirred overnight. After the reaction was completed, the mixture was filtered and concentrated, and then subjected to reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 50% to 70%] to obtain a white solid compound 23 (6.0 mg, yield 17.5%). LCMS: [M+H] + =568.2.

[0251] 1 H NMR (400MHz, CDCl3) δ7.95 (d, J = 8.0Hz, 1H), 7.47–7.44 (m, 2H), 7.40–7.31 (m, 4H), 7.23–7.16 (m, 2H), 6. 59(dd,J=8.0Hz,1.6Hz,1H),6.53–6.50(m,1H),6.42(dd,J=8.4Hz,2.0Hz,1H),6.16(q,J=6.4Hz,1H),3.8 7–3.75(m,6H),2.90–2.81(m,4H),2.51–2.45(m,1H),2.17–2.09(m,2H),1.98–1.95(m,2H),1.72(d,J=6. 4Hz,6H),1.11–1.05(m,1H),0.66–0.59(m,1H),0.47–0.40(m,1H),0.36–0.30(m,1H),0.21–0.15(m,1H).

[0252] Example 24

[0253] The synthesis route of compound 24 is as follows:

[0254] Referring to the synthesis of compound 23, white solid compound 24 (8.8 mg, yield 13%) was obtained. LCMS: [M+H] + =568.2.

[0255] 1 H NMR(400MHz, CDCl3)δ7.98(d,J=8.0Hz,1H),7.52–7.47(m,2H),7.43–7.32(m,4H),7.26–7.20(m,2H),6.6 3(dd,J=8.0Hz,2.0Hz,1H),6.55(t,J=2.0Hz,1H),6.46(dd,J=8.4Hz,2.0Hz,1H),6.20(q,J=6.4Hz,1H),3. 92–3.78(m,6H),2.94–2.82(m,4H),2.55–2.49(m,1H),2.19–2.10(m,2H),2.02–1.97(m,2H),1.76(d,J=6 .4Hz,3H),1.15–1.07(m,1H),0.70–0.61(m,1H),0.51–0.43(m,1H),0.39–0.33(m,1H),0.24–0.18(m,1H).

[0256] Example 25:

[0257] The synthesis route of compound 25 is as follows:

[0258] Referring to the synthesis of compound 23, white solid compound 25 (20.8 mg, yield 32%) was obtained. LCMS: [M+H] + =582.2.

[0259] 1 H NMR(400MHz, CDCl3)δ8.00(d,J=8.0Hz,1H),7.49–7.44(m,2H),7.41–7.35(m,3H),7.31–7.2 8(m,1H),7.26–7.18(m,2H),6.62(d,J=8.0Hz,1H),6.56(s,1H),6.46(d,J=8.0Hz,1H),3.87– 3.76(m,6H),2.94–2.80(m,4H),2.55–2.49(m,1H),2.24–2.09(m,2H),2.04–1.94(m,8H),1. 16–1.07(m,1H),0.69–0.62(m,1H),0.51–0.44(m,1H),0.39–0.33(m,1H),0.24–0.18(m,1H).

[0260] Example 26

[0261] The synthesis route of compound 26 is as follows:

[0262] Under nitrogen, compound 8-2 (118 mg, 0.22 mmol) was added to a tetrahydrofuran (5 mL) solution. Lithium bis(trimethylsilyl)amide (0.44 mL, 0.44 mmol, 1 mol / L) was slowly added to the reaction solution at -78°C and stirred at -78°C for 1 hour. A solution of N-fluorobisbenzenesulfonamide (139 mg, 0.44 mmol) in tetrahydrofuran (2 mL) was then added to the reaction solution and stirred for two hours. After the reaction was completed, ethyl acetate (50 mL) was added, and the organic phase was washed with saturated brine (30 mL) and concentrated to obtain a crude product. The crude product was then separated by normal phase column chromatography (ethyl acetate:petroleum ether = 10%) to obtain a yellow oil 26-1 (85 mg, yield 70%). MS (ESI, m / z): 552.2 [M+H] + .

[0263] Compound 26-1 (85 mg, 0.15 mmol) was added to a mixed solution of tetrahydrofuran (4 mL) and methanol (4 mL). A solution of lithium hydroxide (43 mg, 1.54 mmol) in water (1 mL) was added to the reaction solution, and the temperature was raised to 60°C and stirred for 2 hours. After the reaction was completed, the mixture was directly concentrated and separated by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 50% to 70%] to obtain compound 26 (10.1 mg, yield 12%) as a white solid. MS (ESI, m / z): 538.2 [M+H] + .

[0264] 1H NMR (400MHz, CDCl3) δ7.94(d,J=8.0Hz,1H),7.53(s,1H),7.32(d,J=8.8Hz,1H),7.27(t,J=8.0Hz,1H),6 .70(dd,J=8.4Hz,2.0Hz,1H),6.65(t,J=2.0Hz,1H),6.52(dd,J=8.4Hz,2.0Hz,1H),5.21(d,J=48.4Hz,1 H),3.93–3.83(m,6H),3.01–2.95(m,2H),2.74–2.58(m,1H),2.32–2.18(m,2H),2.10–2.02(m,2H),1.69 (s,9H),1.52–1.47(m,1H),0.79–0.70(m,1H),0.64–0.54(m,1H),0.53–0.44(m,2H),0.16–0.09(m,1H).

[0265] Example 27

[0266] The synthesis route of compound 27 is as follows:

[0267] Under nitrogen, compound 8-2 (133 mg, 0.25 mmol) was added to a tetrahydrofuran (5 mL) solution. Lithium bis(trimethylsilyl)amide (0.75 mL, 0.75 mmol, 1 mol / L) was slowly added to the reaction solution at -78°C and stirred at -78°C for 1 hour. Methyl iodide (177 mg, 1.24 mmol) was then added to the reaction solution and stirred for 2 hours. After the reaction was completed, ethyl acetate (50 mL) was added, and the organic phase was washed with saturated brine (30 mL) and concentrated to obtain a crude product. The crude product was then separated by normal phase column chromatography (ethyl acetate: petroleum ether = 10%) to obtain a yellow oil 27-1 (110 mg, yield 81%). MS (ESI, m / z): 548.2 [M+H] + .

[0268] Compound 27-1 (110 mg, 0.2 mmol) was added to a mixed solution of tetrahydrofuran (4 mL) and methanol (4 mL). A solution of lithium hydroxide (56 mg, 2.0 mmol) in water (1 mL) was added to the reaction solution, and the temperature was raised to 60°C and stirred for 2 hours. After the reaction was completed, the mixture was directly concentrated and separated by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 50% to 70%] to obtain compound 27 (5.2 mg, yield 5%) as a white solid. MS (ESI, m / z): 534.2 [M+H] + .

[0269] 1H NMR (400MHz, CDCl3) δ7.89 (d, J=8.0Hz, 1H), 7.35 (s, 1H), 7.25–7.19 (m, 2H), 6.64 (dd, J=8.0 Hz,2.0Hz,1H),6.56(t,J=2.0Hz,1H),6.46(dd,J=8.0Hz,2.0Hz,1H),3.90–3.82(m,6H),3.0 2–2.89(m,3H),2.38–2.33(m,1H),2.20–2.12(m,2H),2.05–2.00(m,2H),1.67(s,9H),1.33( d,J=6.8Hz,3H),1.16–1.10(m,1H),0.72–0.68(m,1H),0.47–0.38(m,2H),0.04–0.02(m,1H).

[0270] Example 28

[0271] The synthesis route of compound 28 is as follows:

[0272] Referring to the synthesis of compound 1, compound 28-5 was obtained, and then referring to the synthesis of compound 8, white solid compound 28 (42 mg, yield 57%) was obtained. LCMS: [M+H] + =538.2.

[0273] 1 H NMR(400MHz, CDCl3)δ7.90(d,J=8.0Hz,1H),7.36(s,1H),7.21(d,J=8.0Hz,1H),7.00–6.95 (m,1H),6.63–6.55(m,1H),6.50–6.42(m,1H),3.90–3.78(m,4H),3.62(d,J=11.2Hz,2H),2. 95–2.80(m,4H),2.54–2.48(m,1H),2.34–2.19(m,2H),2.08–1.99(m,2H),1.68(s,9H),1.1 6–1.04(m,1H),0.68–0.58(m,1H),0.50–0.41(m,1H),0.39–0.30(m,1H),0.24–0.15(m,1H).

[0274] Example 29

[0275] The synthesis route of compound 29 is as follows:

[0276] Referring to the synthesis of compound 1, compound 29-5 was obtained, and then referring to the synthesis of compound 8, white solid compound 29 (25 mg, yield 50%) was obtained. LCMS: [M+H] + =508.2.

[0277] 1 H NMR (400MHz, CDCl3) δ7.91(d,J=8.0Hz,1H),7.37(s,1H),7.22(d,J=8.0Hz,1H),7.14 –7.02(m,3H),7.01–6.94(m,1H),3.92–3.79(m,1H),3.66–3.59(m,2H),2.96–2.82(m, 4H),2.56–2.48(m,1H),2.33–2.20(m,2H),2.09–2.01(m,2H),1.68(s,9H),1.17–1.0 8(m,1H),0.69–0.62(m,1H),0.51–0.43(m,1H),0.41–0.33(m,1H),0.27–0.17(m,1H).

[0278] Example 30

[0279] The synthesis route of compound 30 is as follows:

[0280] Referring to the synthesis of compound 1, compound 30-5 was obtained, and then referring to the synthesis of compound 8, white solid compound 30 (20 mg, yield 38%) was obtained. LCMS: [M+H] + =524.2.

[0281] 1 H NMR(400MHz, CDCl3)δ7.91(d,J=8.0Hz,1H),7.43–7.38(m,2H),7.27–7.19(m,2H),7.12 (d,J=8.0Hz,1H),7.01(t,J=7.6Hz,1H),3.90–3.82(m,1H),3.58–3.52(m,2H),2.92–2.8 1(m,4H),2.56–2.48(m,1H),2.35–2.23(m,2H),2.09–2.02(m,2H),1.68(s,9H),1.17–1 .07(m,1H),0.68–0.58(m,1H),0.52–0.42(m,1H),0.40–0.31(m,1H),0.25–0.18(m,1H).

[0282] Example 31

[0283] The synthesis route of compound 31 is as follows:

[0284] Referring to the synthesis of compound 1, compound 31-5 was obtained, and then referring to the synthesis of compound 8, white solid compound 31 (17.2 mg, yield 19%) was obtained. LCMS: [M+H] + =504.2.

[0285] 1 H NMR(400MHz, CDCl3)δ8.01(d,J=8.0Hz,1H),7.47–7.38(m,2H),7.31–7.22(m,2 H),7.18–7.06(m,2H),3.95–3.83(m,3H),3.15–2.87(m,4H),2.65–2.45(m,1H), 2.32(s,3H),2.23–2.03(m,2H),2.09–2.04(m,2H),1.71(s,9H),1.17–1.08(m,1 H),0.72–0.63(m,1H),0.55–0.43(m,1H),0.43–0.32(m,1H),0.30–0.16(m,1H).

[0286] Example 32:

[0287] The synthesis route of compound 32 is as follows:

[0288] Referring to the synthesis of compound 1, compound 32-5 was obtained, and then referring to the synthesis of compound 8, white solid compound 32 (20 mg, yield 29%) was obtained. LCMS: [M+H] + =558.2.

[0289] 1 H NMR (400MHz, CDCl3) δ7.91 (d, J=8.0Hz, 1H), 7.42–7.36 (m, 2H), 7.25–7.19 (m ,2H),7.18–7.09(m,2H),3.95–3.86(m,3H),3.05–2.81(m,4H),2.57–2.47(m ,1H),2.23–2.13(m,2H),2.09–2.04(m,2H),1.69(s,9H),1.13–1.08(m,1H), 0.69–0.61(m,1H),0.50–0.43(m,1H),0.40–0.32(m,1H),0.29–0.16(m,1H).

[0290] Example 33

[0291] The synthesis route of compound 33 is as follows:

[0292] Referring to the synthesis of compound 1, compound 33-5 was obtained, and then referring to the synthesis of compound 8, white solid compound 33 (18 mg, yield 32%) was obtained. LCMS: [M+H] + =574.3.

[0293] 1 H NMR (400MHz, CDCl3) δ7.91(d,J=8.0Hz,1H),7.37(s,1H),7.30–7.27(m,1H),7.22(d,J=8.0Hz ,1H),6.91(dd,J=8.4,2.0Hz,1H),6.83–6.79(m,1H),6.73(d,J=8.0Hz,1H),3.92–3.83(m,3H ),3.04–2.83(m,4H),2.57–2.48(m,1H),2.21–2.12(m,2H),2.08–2.02(m,2H),1.69(s,9H),1 .14–1.08(m,1H),0.68–0.62(m,1H),0.50–0.43(m,1H),0.41–0.33(m,1H),0.23–0.15(m,1H).

[0294] Example 34

[0295] The synthesis route of compound 34 is as follows:

[0296] Referring to the synthesis of compound 1, compound 34-5 was obtained, and then referring to the synthesis of compound 8, white solid compound 34 (11 mg, yield 11%) was obtained. LCMS: [M+H] + =538.3.

[0297] 1H NMR (400MHz, CDCl3) δ7.91(d,J=8.0Hz,1H),7.37(s,1H),7.22(d,J=8.0Hz,1H),7.02(t,J= 8.0Hz,1H),6.71–6.66(m,2H),3.92(s,3H),3.90–3.80(m,1H),3.62(d,J=12.0Hz,2H),3.0 2–2.78(m,4H),2.56–2.48(m,1H),2.32–2.22(m,2H),2.08–2.00(m,2H),1.68(s,9H),1.13 –1.08(m,1H),0.71–0.56(m,1H),0.48–0.42(m,1H),0.41–0.31(m,1H),0.28–0.14(m,1H).

[0298] Example 35

[0299] The synthesis route of compound 35 is as follows:

[0300] Referring to the synthesis of compound 23, compound 35-2 was obtained, and then referring to the synthesis of compound 2, a white solid compound 35 (12 mg, yield 20%) was obtained. LCMS: [M+H] + =558.2.

[0301] 1 H NMR(400MHz, CDCl3)δ8.02(d,J=8.0Hz,1H),7.45(s,1H),7.38–7.30(m,2H),7.29 –7.20(m,4H),6.80–6.39(m,3H),4.00–3.90(m,1H),3.88–3.80(m,5H),3.03–2.8 4(m,4H),2.58–2.50(m,1H),2.40–2.18(m,2H),2.16–2.06(m,2H),1.17–1.07(m, 1H),0.70–0.63(m,1H),0.51–0.45(m,1H),0.40–0.33(m,1H),0.25–0.18(m,1H).

[0302] Example 36

[0303] The synthesis route of compound 36 is as follows:

[0304] Referring to the synthesis of compound 35, white solid compound 36 (30 mg, yield 58%) was obtained. LCMS: [M+H] + =557.2.

[0305] 1 H NMR(400MHz, CDCl3) δ7.99(d,J=8.0Hz,1H),7.48–7.41(m,2H),7.28(d,J=8.0Hz,1H),7.22(t ,J=8.0Hz,1H),7.13–7.03(m,3H),6.67–6.61(m,1H),6.60–6.55(m,1H),6.50–6.45(m,1H),3. 93–3.82(m,6H),2.98–2.85(m,4H),2.59–2.51(m,1H),2.29–2.17(m,2H),2.12–2.05(m,2H),1 .18–1.11(m,1H),0.71–0.64(m,1H),0.54–0.47(m,1H),0.40–0.33(m,1H),0.27–0.19(m,1H).

[0306] Example 37

[0307] The synthesis route of compound 37 is as follows:

[0308] Referring to the synthesis of compound 35, white solid compound 37 (12 mg, yield 53%) was obtained. LCMS: [M+H] + =558.2.

[0309] 1 H NMR (400MHz, CDCl3) δ7.97 (d, J=8.0Hz, 1H), 7.45 (s, 1H), 7.29–7.11 (m, 6H), 6.62 (dd, J=8.0,2.0Hz,1H),6.57–6.52(m,1H),6.46(dd,J=8.0,2.0Hz,1H),3.94–3.83(m,6H), 2.93–2.85(m,5H),2.61–2.53(m,1H),2.27–2.14(m,2H),2.08–2.01(m,2H),1.15–1.0 5(m,1H),0.68–0.58(m,1H),0.49–0.43(m,1H),0.40–0.34(m,1H),0.23–0.16(m,1H).

[0310] Example 38:

[0311] The synthesis route of compound 38 is as follows:

[0312] Referring to the synthesis of compound 35, white solid compound 38 (12 mg, yield 40%) was obtained. LCMS: [M+H] + =574.2.

[0313] 1 H NMR(400MHz, CDCl3)δ8.06(d,J=8.0Hz,1H),7.56(d,J=7.2Hz,1H),7.44(s,1H),7.42–7.30(m,3H ),7.29–7.26(m,1H),7.22(t,J=8.0Hz,1H),6.69–6.60(m,1H),6.59–6.54(m,1H),6.50–6.43(m,1 H),4.00–3.82(m,6H),2.97–2.85(m,4H),2.58–2.51(m,1H),2.29–2.17(m,2H),2.14–2.07(m,2H ),1.17–1.09(m,1H),0.69–0.61(m,1H),0.51–0.45(m,1H),0.42–0.33(m,1H),0.28–0.19(m,1H).

[0314] Example 39

[0315] The synthesis route of compound 39 is as follows:

[0316] Referring to the synthesis of compound 35, white solid compound 39 (20 mg, yield 60%) was obtained. LCMS: [M+H] + =574.2.

[0317] 1 H NMR(400MHz, CDCl3)δ8.07(d,J=8.0Hz,1H),7.48(s,1H),7.40–7.34(m,2H),7.32–7.1 9(m,4H),6.70–6.64(m,1H),6.61–6.57(m,1H),6.53–6.48(m,1H),4.01–3.84(m,6H), 3.02–2.86(m,4H),2.63–2.52(m,1H),2.35–2.23(m,5H),2.16–2.09(m,2H),1.20–1.1 2(m,1H),0.73–0.67(m,1H),0.57–0.47(m,1H),0.43–0.38(m,1H),0.31–0.23(m,1H).

[0318] Example 40

[0319] The synthesis route of compound 40 is as follows:

[0320] Referring to the synthesis of compound 35, white solid compound 40 (10 mg, yield 69%) was obtained. LCMS: [M+H] + =570.3.

[0321] 1 H NMR(400MHz, CDCl3)δ8.05(d,J=8.0Hz,1H),7.43(s,1H),7.30–7.19(m,4H),7.10–7.01(m, 2H),6.63(dd,J=8.0,2.0Hz,1H),6.57–6.54(m,1H),6.46(dd,J=8.0,2.0Hz,1H),3.97–3.8 3(m,9H),2.98–2.87(m,4H),2.57–2.49(m,1H),2.29–2.17(m,2H),2.12–2.05(m,2H),1.17 –1.07(m,1H),0.70–0.62(m,1H),0.53–0.42(m,1H),0.40–0.35(m,1H),0.26–0.20(m,1H).

[0322] Example 41:

[0323] The synthesis route of compound 41 is as follows:

[0324] Referring to the synthesis of compound 35, white solid compound 41 (11 mg, yield 49%) was obtained. LCMS: [M+H] + =608.3.

[0325] 1H NMR (400MHz, CDCl3) δ8.02(d,J=8.0Hz,1H),7.79(d,J=8.0Hz,1H),7.69(t,J=8.0Hz,1H),7.48–7.42(m,2 H),7.40(d,J=8.0Hz,1H),7.29–7.26(m,1H),7.22(t,J=8.0Hz,1H),6.65–6.61(m,1H),6.57–6.53(m,1H) ,6.49–6.43(m,1H),3.94–3.82(m,6H),2.98–2.87(m,4H),2.59–2.50(m,1H),2.27–2.16(m,2H),2.09–2. 03(m,2H),1.16–1.09(m,1H),0.72–0.63(m,1H),0.54–0.46(m,1H),0.43–0.34(m,1H),0.28–0.20(m,1H).

[0326] Example 42

[0327] The synthesis route of compound 42 is as follows:

[0328] Referring to the synthesis of compound 35, white solid compound 42 (12 mg, yield 56%) was obtained. LCMS: [M+H] + =624.3.

[0329] 1 H NMR(400MHz, CDCl3)δ8.00(d,J=8.0Hz,1H),7.48–7.34(m,5H),7.28(d,J=8.4Hz,1H),7.21(t ,J=8.0Hz,1H),6.63(dd,J=8.0,2.0Hz,1H),6.58–6.55(m,1H),6.46(dd,J=8.0,2.0Hz,1H),3. 93–3.82(m,6H),2.95–2.84(m,4H),2.57–2.50(m,1H),2.26–2.19(m,2H),2.10–2.04(m,2H),1 .18–1.10(m,1H),0.70–0.63(m,1H),0.54–0.45(m,1H),0.41–0.35(m,1H),0.27–0.18(m,1H).

[0330] Example 43

[0331] The synthesis route of compound 43 is as follows:

[0332] Referring to the synthesis of compound 35, white solid compound 43 (22 mg, yield 41%) was obtained. LCMS: [M+H] + =640.3.

[0333] 1 H NMR(400MHz, CDCl3)δ8.02(d,J=8.0Hz,1H),7.44(s,1H),7.29–7.08(m,5H),6.63(dd,J=8.0,2.0Hz,1H), 6.57–6.55(m,1H),6.46(dd,J=8.0,2.0Hz,1H),3.96–3.81(m,6H),2.99–2.84(m,4H),2.60–2.50(m,2H), 2.29–2.17(m,2H),2.13–2.06(m,2H),1.97–1.87(m,4H),1.81–1.75(m,1H),1.47–1.40(m,4H),1.39–1.3 5(m,1H),1.17–1.10(m,1H),0.70–0.63(m,1H),0.55–0.44(m,1H),0.41–0.32(m,1H),0.29–0.18(m,1H).

[0334] Example 44

[0335] The synthesis route of compound 44 is as follows:

[0336] Referring to the synthesis of compound 35, white solid compound 44 (15 mg, yield 34%) was obtained. LCMS: [M+H] + =648.3.

[0337] 1 H NMR(400MHz, CDCl3)δ7.99(d,J=8.0Hz,1H),7.43(s,1H),7.39–7.32(m,2H),7.27–7.09( m,8H),6.67–6.60(m,1H),6.58–6.53(m,1H),6.50–6.44(m,1H),4.03(s,2H),3.92–3.83( m,6H),2.97–2.85(m,4H),2.59–2.50(m,1H),2.26–2.16(m,2H),2.11–2.05(m,2H),1.18– 1.09(m,1H),0.69–0.63(m,1H),0.51–0.44(m,1H),0.40–0.34(m,1H),0.24–0.19(m,1H).

[0338] Example 45

[0339] The synthesis route of compound 45 is as follows:

[0340] Referring to the synthesis of compound 35, white solid compound 45 (18 mg, yield 24%) was obtained. LCMS: [M+H] + =662.3.

[0341] 1 H NMR(400MHz, CDCl3)δ8.02(d,J=8.0Hz,1H),7.44(s,1H),7.36–7.31(m,2H),7.28–7.12(m,7H), 7.10–7.04(m,1H),6.66–6.62(m,1H),6.57–6.55(m,1H),6.49–6.44(m,1H),3.93–3.82(m,6H), 2.98–2.97(m,4H),2.96–2.85(m,4H),2.60–2.51(m,1H),2.30–2.18(m,2H),2.12–2.06(m,2H), 1.17–1.10(m,1H),0.71–0.63(m,1H),0.53–0.46(m,1H),0.44–0.35(m,1H),0.27–0.20(m,1H).

[0342] Example 46

[0343] The synthesis route of compound 46 is as follows:

[0344] A mixture of compound 46-1 (9.48 g, 27.4 mmol), compound 46-2 (4.55 g, 27.4 mmol), cuprous iodide (521 mg, 2.74 mmol), bistriphenylphosphine palladium dichloride (962 mg, 1.37 mmol), triethylamine (8.3 g, 82.2 mmol), and acetonitrile (150 mL) was reacted at 100°C under nitrogen for 16 hours. The reaction solution was concentrated and purified by normal phase column chromatography (ethyl acetate:petroleum ether = 20%) to afford 46-3 (8.75 g, yield = 83%) as a yellow oil. LCMS: [M+H] + =385.2.

[0345] Compound 46-3 (8.75 g, 22.8 mmol) and N-bromosuccinimide (8.1 g, 45.6 mmol) were added to tetrahydrofuran (150 mL) and stirred at room temperature for 1 hour. After the reaction was completed, the mixture was washed with saturated sodium bicarbonate (150 mL). The organic phase was dried, filtered, and concentrated. Normal phase column chromatography (ethyl acetate:petroleum ether = 20%) afforded 46-4 as a yellow oil (9.12 g, yield = 96%). LCMS: [M+H] + =418.9.

[0346] A mixture of compound 46-4 (1.8 g, 4.31 mmol), potassium vinyl trifluoroborate (1.18 g, 8.62 mmol), bistriphenylphosphine palladium dichloride (7.02 mg), potassium carbonate (1.8 g, 12.93 mmol), N,N-dimethylformamide (15 mL), and water (5 mL) was reacted at 100°C under nitrogen for 16 hours. The reaction solution was diluted with ethyl acetate (100 mL) and filtered, and the filtrate was washed with water (100 mL x 2). The organic phase was dried, filtered, and concentrated, and purified by normal phase column chromatography (ethyl acetate:petroleum ether = 20%) to obtain 46-5 (910 mg, yield = 58%) as a yellow oil. LCMS: [M+H] + =367.0.

[0347] To a solution of compound 46-5 (910 mg, 2.49 mmol) in tetrahydrofuran (9 mL) was slowly added dropwise lithium bis(trimethylsilyl)amide (1 M, 3 mL) at -78°C under nitrogen. After the mixture was stirred at -78°C for 1 hour, a solution of N-phenylbis(trifluoromethanesulfonyl)imide (978 mg, 2.74 mmol) in tetrahydrofuran (6 mL) was added dropwise. The mixture was reacted at -78°C for 1 hour and then at room temperature for 1 hour. The reaction solution was quenched with saturated sodium bicarbonate solution (60 mL) and extracted with ethyl acetate (60 mL x 2). The organic phase was dried, filtered, and concentrated. Purification by normal phase column chromatography (ethyl acetate:petroleum ether = 30%) afforded 46-6 (1.2 g, yield = 97%) as a yellow oil. LCMS: [M+H] + =498.9.

[0348] A mixture of compound 46-6 (1.2 g, 2.4 mmol), N-methylmorpholine oxide (421 mg, 3.6 mmol), potassium osmate dihydrate (9 mg, 0.024 mmol), acetone (15 mL), and water (5 mL) was stirred at room temperature for 16 hours. A solution of sodium periodate (842 mg, 7.2 mmol) in water (5 mL) was added to the reaction solution, and stirring was continued for one hour. The reaction solution was diluted with ethyl acetate (100 mL) and washed with saturated brine (100 mL). The organic phase was dried, filtered, and concentrated, and purified by normal phase column chromatography (ethyl acetate:petroleum ether = 30%) to obtain 46-7 (1.2 g, yield = 100%) as a yellow oil. LCMS: [M+H] + =500.9.

[0349] To a mixture of compound 46-7 (1.2 g, 2.4 mmol), 2-methyl-2-butene (3.36 g, 48 mmol), tert-butanol (10 mL), and tetrahydrofuran (10 mL) was added a solution of sodium monohydrogen phosphate (4.62 g, 33.6 mmol) and sodium chlorite (1.13 g, 12 mmol) in water (10 mL). The mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The organic phase was dried, filtered, and concentrated. 46-8 (1.2 g, yield = 97%) was obtained by normal phase column chromatography (ethyl acetate:petroleum ether = 50%). LCMS: [M+H] + =516.8.

[0350] Compound 46-8 (1.2 g, 2.32 mmol), compound 46-9 (527 mg, 3.49 mmol), potassium phosphate (1.48 g, 6.96 mmol), tetrakistriphenylphosphine palladium (268 mg, 0.232 mmol), dioxane (10 ml), and water (2 ml) were stirred at 100°C for 2 hours. The reaction solution was filtered and concentrated, and purified by normal phase column chromatography (ethyl acetate:petroleum ether = 50%) to give compound 46-10 (810 mg, yield = 74%) as a yellow solid. LCMS: [M+H] + =474.8.

[0351] Then, referring to the synthesis of compound 8, a white solid compound 46 (11 mg, yield 34%) was obtained. LCMS: [M+H] + =539.3.

[0352] 1H NMR(400MHz, CDCl3)δ7.92(d,J=8.0Hz,1H),7.37(s,1H),7.29–7.26(m,1H),7.22(d,J=8.0Hz,1H), 7.05(d,J=7.6Hz,1H),7.01–6.97(m,1H),6.87–6.80(m,1H),6.22(d,J=4.4Hz,1H),4.09–3.93(m,1H ),3.87(s,3H),2.94–2.80(m,2H),2.73–2.57(m,4H),2.55–2.47(m,1H),2.25–2.12(m,2H),1.67(s, 9H),1.17–1.04(m,1H),0.69–0.59(m,1H),0.51–0.42(m,1H),0.39–0.31(m,1H),0.25–0.17(m,1H).

[0353] Example 47

[0354] The synthesis route of compound 47 is as follows:

[0355] Referring to the synthesis of compound 13, white solid compound 47 (86 mg, yield 74%) was obtained. LCMS: [M+H] + =517.1.

[0356] 1 H NMR (400MHz, CDCl3) δ7.95(d,J=8.0Hz,1H),7.39(s,1H),7.30–7.28(m,1H),7.24(d,J=8.0Hz,1H),7.05(d ,J=7.6Hz,1H),7.01–6.98(m,1H),6.87–6.82(m,1H),6.22(d,J=4.4Hz,1H),4.19(d,J=6.4Hz,2H),4.11–4. 00(m,1H),3.87(s,3H),2.95–2.81(m,2H),2.74–2.57(m,4H),2.56–2.49(m,1H),2.26–2.18(m,2H),2.17–2 .12(m,1H),1.17–1.07(m,7H),0.70–0.61(m,1H),0.52–0.43(m,1H),0.40–0.32(m,1H),0.26–0.18(m,1H).

[0357] Example 48

[0358] The synthesis route of compound 48 is as follows:

[0359] Referring to the synthesis of compound 22, white solid compound 48 (4.9 mg, yield 11%) was obtained. LCMS: [M+H] + =551.1.

[0360] 1 H NMR (400MHz, CDCl3) δ7.86 (d, J = 8.0Hz, 1H), 7.48–7.42 (m, 2H), 7.40–7.32 (m, 4H), 7.24–7.21 (m, 1H), 7. 16(d,J=8.0Hz,1H),6.99(d,J=7.6Hz,1H),6.93(s,1H),6.79(d,J=7.6Hz,1H),6.19–6.12(m,1H),5.38(s ,2H),4.06–3.94(m,1H),3.82(s,3H),2.91–2.74(m,2H),2.68–2.51(m,4H),2.49–2.42(m,1H),2.19–2.0 6(m,2H),1.12–0.98(m,1H),0.66–0.54(m,1H),0.48–0.37(m,1H),0.35–0.26(m,1H),0.20–0.09(m,1H).

[0361] Example 49

[0362] The synthesis route of compound 49 is as follows:

[0363] Referring to the synthesis of compound 23, white solid compound 49 (14 mg, yield 16%) was obtained. LCMS: [M+H] + =554.2.

[0364] 1H NMR(400MHz, CDCl3)δ8.03(d,J=8.0Hz,1H),7.45(s,1H),7.34(t,J=8.0Hz,1H),7.29–7.20(m,5 H),7.03(d,J=8.0Hz,1H),6.99–6.95(m,1H),6.85–6.80(m,1H),6.24–6.18(m,1H),4.13–4.00( m,1H),3.85(s,3H),2.98–2.82(m,2H),2.77–2.59(m,4H),2.58–2.49(m,1H),2.32–2.14(m,2H) ,1.18–1.07(m,1H),0.71–0.61(m,1H),0.53–0.44(m,1H),0.42–0.33(m,1H),0.27–0.18(m,1H).

[0365] Example 50

[0366] The synthesis route of compound 50 is as follows:

[0367] Referring to the synthesis of compound 1, compound 50-5 was obtained, and then referring to the synthesis of compound 8, white solid compound 50 (55 mg, yield 25%) was obtained. LCMS: [M+H] + =534.3.

[0368] 1 H NMR (400MHz, CDCl3) δ7.90(d,J=8.0Hz,1H),7.36(s,1H),7.21(dd,J=8.0,1.6Hz,1H),6.77(d,J=8 .4Hz,1H),6.67(d,J=2.4Hz,1H),6.48(d,J=8.4Hz,1H),5.94(s,2H),3.86–3.74(m,1H),3.63(d,J= 12.0Hz,2H),2.93–2.78(m,4H),2.56–2.48(m,1H),2.26–2.16(m,2H),2.06–1.98(m,2H),1.67(s,9 H),1.14–1.06(m,1H),0.67–0.60(m,1H),0.48–0.42(m,1H),0.38–0.32(m,1H),0.22–0.16(m,1H).

[0369] Example 51

[0370] The synthesis route of compound 51 is as follows:

[0371] Referring to the synthesis of compound 20, white solid compound 51 (51.6 mg, yield 46%) was obtained. LCMS: [M+H] + =569.3.

[0372] 1 H NMR (400MHz, CDCl3) δ8.71–8.66(m,1H),8.03(d,J=8.0Hz,1H),7.74(t,J=8.0Hz,1H),7.47(d,J=7.6Hz,1H) ,7.39(s,1H),7.29–7.17(m,3H),6.67–6.60(m,1H),6.58–6.53(m,1H),6.49–6.43(m,1H),6.26–6.18(m,1H ),3.94–3.79(m,6H),2.95–2.81(m,4H),2.57–2.48(m,1H),2.22–2.12(m,2H),2.06–1.97(m,2H),1.81(d,J =6.0Hz,3H),1.17–1.03(m,1H),0.72–0.60(m,1H),0.51–0.42(m,1H),0.41–0.31(m,1H),0.25–0.14(m,1H).

[0373] Example 52

[0374] The synthesis route of compound 52 is as follows:

[0375] Referring to the synthesis of compound 11, white solid compound 52 (12.7 mg, yield 14%) was obtained. LCMS: [M+H] + =622.2.

[0376] 1H NMR (400MHz, CDCl3) δ7.56–7.48(m,3H),7.32–7.26(m,3H),7.23–7.16(m,2H),7.07(dd,J=8.0,1.2H z,1H),6.62–6.56(m,1H),6.53–6.48(m,1H),6.45–6.39(m,1H),3.81(s,3H),3.77–3.71(m,2H),3.5 9–3.51(m,1H),2.87–2.75(m,4H),2.48–2.42(m,1H),2.08–1.98(m,2H),1.85–1.78(m,2H),1.45(s, 6H),1.12–1.00(m,5H),0.63–0.57(m,1H),0.45–0.38(m,1H),0.33–0.27(m,1H),0.18–0.12(m,1H).

[0377] Experimental example

[0378] This experimental example uses a method based on NFAT-RE reporter gene activity detection to detect the GPR40 agonist activity of the compound in vitro.

[0379] 1. Method

[0380] 1.1 Construction and preparation of plasmid pcDNA3.0-flag-FFAR1(GPR40)

[0381] The pcDNA3.0-flag-FFAR1(GPR40) plasmid was constructed using conventional molecular cloning methods. The main steps were: The full-length human FFAR1(GPR40) cDNA sequence (NM_005303.3) was inserted into the HindIII and XbaI restriction sites of the pcDNA3.0 vector using PCR to generate the pcDNA3.0-flag-FFAR1(GPR40) plasmid. Both pGL4.30[luc2PNFAT-RE](#E8481) and pRL-TK(#E2241) plasmids were purchased from Promega. The plasmids were transformed into DH5α Escherichia coli using the CaCl2 method, cultured and amplified, and then purified using a plasmid extraction kit (TIANGEN, #DP117) to obtain the corresponding plasmid DNA.

[0382] 1.2 Plasmid co-transfection into HEK293T cells and compound treatment

[0383] One day before plasmid transfection, HEK293T cells were plated at 1×10 4 The density of cells / well was seeded in 96-well plates. HD (Promega, #E2311) instructions for cell transfection. The main steps are as follows: Taking one well as an example, add 50 ng, 50 ng, and 5 ng of plasmids pcDNA3.0-flag-FFAR1 (GPR40), pGL4.30 [luc2P NFAT-RE], and pRL-TK to 10 μL of Opti-MEM TM I culture medium (Gibco, #11058021) and mix well; then add 0.2 μL of HD, mix well and let stand at room temperature for 5 minutes; then add this 10 μL mixture to the cell well containing 100 μL culture medium. 24 hours after cell co-transfection, the compound was diluted with half-log dilution multiples at 1 μM as the highest concentration, and a total of 10 concentrations were added to the cell culture medium for 4 hours, divided into 2 replicates, and the compound TAK875 ( It has entered Phase III clinical trials) as a positive control.

[0384] 1.3Dual-Glo Luciferase Assay

[0385] After the cells were treated with the compounds for 4 hours, The Luciferase Assay System (Promega, #E2940) was used for detection. The main steps were: aspirate 50 μL of culture medium from each well, then add 50 μL Luciferase reagent, shake at room temperature for 10 minutes; take 80 μL of the cleavage reaction solution to a white opaque optiPlate-96 well plate, and use an MD i3x multifunctional microplate reader to detect the luminescent signal value (Firefly-Luc) of firefly luciferase; then add 40 μL Stop& The reagent was added and shaken at room temperature for 10 minutes. The luminescence signal of Renilla luciferase (Renilla-Luc) was then measured using an MD i3x multi-function microplate reader. The ratio of Firefly-Luc / Renilla-Luc was used as the GPR40 activation activity of the compound and normalized to the ratio of the solvent group (DMSO). GraphPad Prism 8.0 software was used to fit the dose-response curve using a four-parameter method to calculate the EC50 value.

[0386] 2. Results

[0387] Table 1. In vitro activity test results

[0388] *: EC50>0.1μM; **: 0.1μM≥EC50>0.01μM; ***: 0.01μM≥EC50>0.001μM; ****: 0.001μM≥EC50; NA indicates inactive.

[0389] 100≥Efficacy(%)>50; 150≥Efficacy(%)>100; 200≥Efficacy(%)>150; Efficacy(%)>200.

[0390] It can be seen from the above experimental results that the compound of the present invention has good GPR40 activity.

[0391] Although the above describes specific embodiments of the present invention, it should be understood by those skilled in the art that these are merely illustrative and that various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A compound as shown in formula I, a pharmaceutically acceptable salt, a solvate, or a solvate of a pharmaceutically acceptable salt thereof: in, X is O or NR 3 , R 3 is H or C1-C6 alkyl; Z and Y are independently CH or N; G 1 is H, C1-C6 alkyl, 1-1 Substituted C1-C6 alkyl, C6-C 14 Aryl, one or more G 1-2 Substituted C6-C 14 Aryl, 5-10 membered heteroaryl, substituted by one or more G 1-3 Substituted 5-10 membered heteroaryl, C1-C6 alkoxy, one or more G 1-4 Substituted C1-C6 alkoxy, C2-C6 alkenyl, one or more G 1- 5 Substituted C2-C6 alkenyl, C2-C6 alkynyl, one or more G 1-6 Substituted C2-C6 alkynyl, C3-C8 cycloalkyl, one or more G 1-7 Substituted C3-C8 cycloalkyl, C3-C8 cycloalkenyl, one or more G 1-8 Substituted C3-C8 cycloalkenyl, 3-8 membered heterocycloalkyl, one or more G 1-9 Substituted 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl or one or more G 1-10 Substituted 3-8 membered heterocycloalkenyl; Each G 1-1 , each G 1-2 , each G 1-3 , each G 1-4 , each G 1-5 , each G 1-6 , each G 1-7 , each G 1-8 , each G 1-9 and each G 1-10 are independently deuterium, halogen, cyano, -NG 1-1-1 G 1-1-2 、-NC(=O)G 1-1-3 G 1-1-4 , hydroxyl, -S(=O)2-C1-C6 alkyl, C1-C6 alkyl, one or more G 1-1-5 Substituted C1-C6 alkyl, C1-C6 alkoxy, substituted by one or more G 1-1-6 Substituted C1-C6 alkoxy, -S-C1-C6 alkyl, substituted by one or more G 1-1-7 -S-C1-C6 alkyl, C3-C8 cycloalkyl, substituted by one or more G 1-1-8 Substituted C3-C8 cycloalkyl, -O-C3-C8 cycloalkyl, substituted by one or more G 1-1- 9 Substituted -O-C3-C8 cycloalkyl or -C(=O)NG 1-1-11 G 1-1-12 ; Or, any two adjacent G 1-2 Together with the carbon atoms to which it is connected, it forms a 3-8 membered heterocycloalkyl group, which is surrounded by one or more G 1-1-9 Substituted 3-8 membered heterocycloalkyl, C3-C8 cycloalkyl or one or more G 1-1-10 Substituted C3-C8 cycloalkyl; G 1-1-1 , G 1-1-2 , G 1-1-3 , G 1-1-4 , G 1-1-11 and G 1-1-12 are independently H, C1-C6 alkyl, C3-C8 cycloalkyl, 5-10 membered heteroaryl or substituted by one or more G 1-1-10-1 substituted 5-10 membered heteroaryl; Each G 1-1-10-1 are independently C1-C6 alkyl; Each G 1-1-5 , each G 1-1-6 , each G 1-1-7 , each G 1-1-8 , each G 1-1-9 and each G 1-1-10 are independently halogen, oxo, C1-C6 alkyl or C3-C8 cycloalkyl; L 1 is a connecting bond or a C1-C6 alkylene group; Ring A is a C4-C6 cycloalkyl group, surrounded by one or more A 1 Substituted C4-C6 cycloalkyl, C4-C6 cycloalkenyl, substituted by one or more A 2 Substituted C4-C6 cycloalkenyl, 4-6 membered heterocycloalkyl, substituted by one or more A 1 substituted 4-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl or one or more A 4 substituted 4-6 membered heterocycloalkenyl; the 4-6 membered heterocycloalkyl, the 1 substituted 4-6 membered heterocycloalkyl, the 4-6 membered heterocycloalkenyl and the 4 The heteroatoms in the substituted 4-6 membered heterocycloalkenyl are independently one or more of N, S or O, and the number is 1 or 2; Each A 1 , each A 2 , each A 3 and each A 4 are independently deuterium, halogen, cyano, -NA 1-1 A 1-2 、-NC(=O)A 1-3 A 1- 4 , hydroxyl, C1-C6 alkyl, one or more A 1-5 Substituted C1-C6 alkyl, C1-C6 alkoxy or one or more A 1-6 Substituted C1-C6 alkoxy; A 1-1 , A 1-2 , A 1-3 , A 1-4 are independently deuterium, halogen, cyano, C1-C6 alkyl or C1-C6 alkoxy; Each A 1-5 and each A 1-6 are independently hydrogen, deuterium, halogen, cyano, C1-C6 alkyl or C1-C6 alkoxy; R 1 C1-C6 alkyl, C7-C 12 Straight chain alkyl, C2-C 12 Alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 14 Aryl, 5-10 membered heteroaryl, or one or more R 1-1 Substituted C1-C6 alkyl, one or more R 1-1 Substituted C7-C 12 Straight chain alkyl, separated by one or more R 1-1 Substituted C2-C 12 Alkenyl, one or more R 1-1 Substituted C2-C6 alkynyl, substituted by one or more R 1-2 Substituted C3-C 10 Cycloalkyl, with one or more R 1-3 Substituted C6-C 14 Aryl or one or more R -1-4 substituted 5-10 membered heteroaryl; Each R 1-1 , each R 1-2 , each R 1-3 and R 1-4 are independently halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 14 Aryl, C1-C6 alkoxy, 5-10 membered heteroaryl, substituted by one or more R 1-1-1 Substituted C1-C6 alkyl, one or more R 1-1-1 Substituted C3-C8 cycloalkyl, one or more R 1-1-1 Substituted C6-C 14 Aryl, one or more R 1- 1-1 C1-C6 alkoxy substituted or substituted by one or more R 1-1-1 substituted 5-10 membered heteroaryl; R 1-1-1 is halogen, C1-C6 alkyl or C6-C 14 Aryl; R 2 is hydrogen, deuterium, halogen, cyano, C1-C6 alkyl or C1-C6 alkoxy; L 2 is C1-C6 alkylene, and is replaced by one or more L 2-1 Substituted C1-C6 alkylene, C3-C8 cycloalkylene or one or more L 2-2 Substituted C3-C8 cycloalkylene; Each L 2-1 and each L 2-2 are independently halogen, C1-C6 alkyl, 2-1-1 Substituted C1-C6 alkyl, C1-C6 alkoxy, substituted by one or more L 2-1-2 Substituted C1-C6 alkoxy, C3-C8 cycloalkyl, substituted by one or more L 2- 1-3 Substituted C3-C8 cycloalkyl, C2-C6 alkynyl or one or more L 2-1-4 Substituted C2-C6 alkynyl; Each L 2-1-1 , each L 2-1-2 , each L 2-1-3 and each L 2-1-4 is independently C3-C8 cycloalkyl or is replaced by one or more L 2-1- 1-1 Substituted C3-C8 cycloalkyl; G 2 -C(=O)G 2-1 、-C(=O)NG 2-2 G 2-3 or a 5-10 membered heteroaryl; G 2-1 is hydroxyl, C1-C6 alkyl or -O-NH2; G 2-2 and G 2-3 independently H, -S(=O)2-C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl or substituted by one or more G 2-2-1 Substituted C1-C6 alkyl; Each G 2-2-1 are independently carboxyl or -S(=O)2OH; The heteroatoms in each of the 5-10 membered heteroaryl groups, each of the 3-8 membered heterocycloalkenyl groups and each of the 3-8 membered heterocycloalkyl groups are independently one or more of N, S or O, and the number of the heteroatoms is 1, 2, 3 or 4.

2. The compound of formula I according to claim 1, its pharmaceutically acceptable salt, solvate, or solvate of a pharmaceutically acceptable salt, characterized in that: The compound is represented by Formula Ia, preferably by Formula Ia1: in, Ring A is a C4-C6 cycloalkyl group, surrounded by one or more A 1 Substituted C4-C6 cycloalkyl, C4-C6 cycloalkenyl, substituted by one or more A 2 Substituted C4-C6 cycloalkenyl, 4-6 membered heterocycloalkyl, substituted by one or more A 1 substituted 4-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl or one or more A 4 substituted 4-6 membered heterocycloalkenyl; the 4-6 membered heterocycloalkyl, the 1 substituted 4-6 membered heterocycloalkyl, the 4-6 membered heterocycloalkenyl and the 4 The heteroatoms in the substituted 4-6 membered heterocycloalkenyl are independently one or more of N, S or O, and the number is 1 or 2; Each A 1 , each A 2 , each A 3 and each A 4 are independently deuterium, halogen, cyano, -NA 1-1 A 1-2 、-NC(=O)A 1-3 A 1- 4 , hydroxyl, C1-C6 alkyl, one or more A 1-5 Substituted C1-C6 alkyl, C1-C6 alkoxy or one or more A 1-6 Substituted C1-C6 alkoxy; A 1-1 , A 1-2 , A 1-3 , A 1-4 are independently deuterium, halogen, cyano, C1-C6 alkyl or C1-C6 alkoxy; Each A 1-5 and each A 1-6 are independently hydrogen, deuterium, halogen, cyano, C1-C6 alkyl or C1-C6 alkoxy; R 3 and R 4 Independently H, deuterium, halogen, cyano, -NR 3-1 R 3-2 、-NC(=O)R 3-3 R 3-4 , hydroxyl, -S(=O)2-C1-C6 alkyl, C1-C6 alkyl, one or more R 3-5 Substituted C1-C6 alkyl, C1-C6 alkoxy, substituted by one or more R 3-6 Substituted C1-C6 alkoxy, -S-C1-C6 alkyl, substituted by one or more R 3-7 -S-C1-C6 alkyl, C3-C8 cycloalkyl, substituted by one or more R 3-8 Substituted C3-C8 cycloalkyl, -O-C3-C8 cycloalkyl, substituted by one or more R 3-9 Substituted -O-C3-C8 cycloalkyl or -C(=O)NR 3-10 R 3-11 ; Or, any two adjacent R 3 and R 4 Together with the carbon atoms to which it is attached, it forms a 3-8 membered heterocycloalkyl group, which is supported by one or more R 3-8 Substituted 3-8 membered heterocycloalkyl, C3-C8 cycloalkyl or one or more R 3-8 Substituted C3-C8 cycloalkyl; R 3-1 , R 3-2 , R 3-3 , R 3-4 , R 3-10 and R 3-11 are independently H, C1-C6 alkyl, C3-C8 cycloalkyl, 5-10 membered heteroaryl or substituted by one or more R 3-10-1 substituted 5-10 membered heteroaryl; Each R 3-10-1 are independently C1-C6 alkyl; Each R 3-5 , each R 3-6 , each R 3-7 , each R 3-8 and each R 3-9 are independently halogen, oxo, C1-C6 alkyl or C3-C8 cycloalkyl; R 1 C1-C6 alkyl, C7-C 12 Straight chain alkyl, C2-C 12 Alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 14 Aryl, 5-10 membered heteroaryl, or one or more R 1-1 Substituted C1-C6 alkyl, one or more R 1-1 Substituted C7-C 12 Straight chain alkyl, separated by one or more R 1-1 Substituted C2-C 12 Alkenyl, one or more R 1-1 Substituted C2-C6 alkynyl, substituted by one or more R 1-2 Substituted C3-C 10 Cycloalkyl, with one or more R 1-3 Substituted C6-C 14 Aryl or one or more R -1-4 substituted 5-10 membered heteroaryl; Each R 1-1 , each R 1-2 , each R 1-3 and R 1-4 are independently halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 14 Aryl, C1-C6 alkoxy, 5-10 membered heteroaryl, substituted by one or more R 1-1-1 Substituted C1-C6 alkyl, one or more R 1-1-1 Substituted C3-C8 cycloalkyl, one or more R 1-1-1 Substituted C6-C 14 Aryl, one or more R 1- 1-1 C1-C6 alkoxy substituted or substituted by one or more R 1-1-1 substituted 5-10 membered heteroaryl; R 1-1-1 is halogen, C1-C6 alkyl or C6-C 14 Aryl; R 5 is H, halogen, C1-C6 alkyl, or is replaced by one or more R 5-1 Substituted C1-C6 alkyl, C1-C6 alkoxy, substituted by one or more R 5-2 Substituted C1-C6 alkoxy, C3-C8 cycloalkyl, one or more R 5-3 Substituted C3-C8 cycloalkyl, C2-C6 alkynyl or one or more R 5-4 Substituted C2-C6 alkynyl; Each R 5-1 , each R 5-2 , each R 5-3 and each R 5-4 are independently C3-C8 cycloalkyl.

3. The compound of formula I as claimed in claim 2, its pharmaceutically acceptable salt, solvate, or solvate of a pharmaceutically acceptable salt, characterized in that: It meets one or more of the following conditions: (1) Ring A is a 4-6 membered heterocycloalkyl or a C4-C6 cycloalkenyl; (2)R 3 and R 4 are independently H, halogen, C1-C6 alkyl, 3-5 Substituted C1-C6 alkyl, C1-C6 alkoxy, substituted by one or more R 3-6 Substituted C1-C6 alkoxy; or, any two adjacent R 3 and R 4 Together with the carbon atom to which it is connected, it forms a 3-8 membered heterocycloalkyl group. For example, the 3-8 membered heterocycloalkyl group can be dioxopentacyclic ring; (3) Each R 3-5 , each R 3-6 are independently halogen; (4)R 1 is a C1-C6 alkyl group, 1-1 Substituted C1-C6 alkyl, C7-C 12 Straight chain alkyl, C2-C 12 Alkenyl, C2-C6 alkynyl, 1-1 Substituted C1-C6 alkoxy, C3-C 10 Cycloalkyl, with one or more R 1-2 Substituted C3-C 10 Cycloalkyl, C6-C 14 Aryl or one or more R 1-3 Substituted C6-C 14 Aryl; (5) Each R 1-1 , each R 1-2 , each R 1-3 are independently halogen, C1-C6 alkyl, 1-1-1 Substituted C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 14 Aryl, C1-C6 alkoxy, one or more R 1-1-1 Substituted C1-C6 alkoxy or 5-10 membered heteroaryl; (6)R 1-1-1 is halogen, C1-C6 alkyl or C6-C 14 Aryl; (7)R 5 is H or halogen; Preferably, the following conditions are met: (1) Ring A is a 4-6 membered heterocycloalkyl or a C4-C6 cycloalkenyl; (2)R 3 and R 4 are independently H, halogen, C1-C6 alkyl, 3-5 Substituted C1-C6 alkyl, C1-C6 alkoxy, substituted by one or more R 3-6 Substituted C1-C6 alkoxy; or, any two adjacent R 3 and R 4 Together with the carbon atom to which it is connected, it forms a 3-8 membered heterocycloalkyl group. For example, the 3-8 membered heterocycloalkyl group can be dioxopentacyclic ring; (3) Each R 3-5 , each R 3-6 are independently halogen; (4)R 1 is a C1-C6 alkyl group, 1-1 Substituted C1-C6 alkyl, C7-C 12 Straight chain alkyl, C2-C 12 Alkenyl, C2-C6 alkynyl, 1-1 Substituted C1-C6 alkoxy, C3-C 10 Cycloalkyl, with one or more R 1-2 Substituted C3-C 10 Cycloalkyl, C6-C 14 Aryl or one or more R 1-3 Substituted C6-C 14 Aryl; (5) Each R 1-1 , each R 1-2 , each R 1-3 are independently halogen, C1-C6 alkyl, 1-1-1 Substituted C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 14 Aryl, C1-C6 alkoxy, one or more R 1-1-1 Substituted C1-C6 alkoxy or 5-10 membered heteroaryl; (6)R 1-1-1 is halogen, C1-C6 alkyl or C6-C 14 Aryl; and (7)R 5 is H or halogen.

4. The compound of formula I as claimed in claim 2 or 3, its pharmaceutically acceptable salt, solvate, or solvate of a pharmaceutically acceptable salt, characterized in that: It meets one or more of the following conditions: (1) Ring A is a 4-6 membered heterocycloalkyl group; (2)R 3 and R 4 are H or C1-C6 alkoxy respectively, further, the C1-C6 alkoxy is located at the meta position; (3)R 5 is H; Preferably, the following conditions are met: (1) Ring A is a 4-6 membered heterocycloalkyl group; (2)R 3 and R 4 are H or C1-C6 alkoxy respectively, and further, the C1-C6 alkoxy is located at the meta position; and (3)R 5 For H.

5. The compound of formula I as claimed in claim 2 or 3, its pharmaceutically acceptable salt, solvate, or solvate of a pharmaceutically acceptable salt, characterized in that: It meets one or more of the following conditions: (1) In ring A, the C4-C6 cycloalkenyl group is a cyclohexenyl group, and the 4-6-membered heterocycloalkyl group is a saturated cycloalkyl group containing 1-2 N atoms, for example, a piperidinyl group; (2)R 3 and R 4 wherein the C1-C6 alkyl group, the 3-5 The C1-C6 alkyl in the substituted C1-C6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (3)R 3 and R 4 wherein the C1-C6 alkoxy group, the 3-6 The C1-C6 alkoxy in the substituted C1-C6 alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; (4)R 3 and R 4 In the above example, any two adjacent R 3 and R 5 The heterocycloalkyl group in the 3-8-membered heterocycloalkyl group formed together with the carbon atom to which it is connected is a 5-6-membered heterocycloalkyl group containing 1-2 oxygen atoms, for example, dioxopentacyclic ring; (5)R 3 and R 4 wherein the halogen is fluorine or chlorine; (6) Each R 3-5 , each R 3-6 wherein the halogen is fluorine; (7)R 1 wherein the C1-C6 alkyl group, the 1-1 The C1-C6 alkyl in the substituted C1-C6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -C5H 11 、-C6H 13 , (8)R 1 In the C7-C 12 Straight chain alkyl, separated by one or more R 1-1 Substituted C7-C 12 C7-C 12 The straight chain alkyl is C8-C 12 Straight chain alkyl; (9)R 1 In the C2-C 12 Alkenyl, one or more R 1-1 Substituted C2-C 12 C2-C in alkenyl 12 Alkenyl is a C4-C 10 alkenyl; (10)R 1 wherein the C2-C6 alkynyl group is replaced by one or more R 1-1 The C2-C6 substituted alkynyl 12 Alkynyl is a C3-C4 alkynyl group containing one triple bond; (11)R 1 wherein the C1-C6 alkoxy group is replaced by one or more R 1-1 The C1-C6 alkoxy group in the substituted C1-C6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; (12)R 1 In the C3-C 10 Cycloalkyl, the 1-2 Substituted C3-C 10 C3-C in cycloalkyl 10 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentane or cyclohexane; (13)R 1 In the C6-C 14 Aryl, said one or more R 1-3 Substituted C6-C 14 C6-C in aromatic groups 14 Aryl is phenyl; (14) Each R 1-1 , each R 1-2 , each R 1-3 , each R 1-4 wherein the halogen is fluorine; (15) Each R 1-1 , each R 1-2 , each R 1-3 , each R 1-4 wherein the C1-C6 alkyl group is replaced by one or more R 1-1-1 The C1-C6 alkyl in the substituted C1-C6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl; (16) Each R 1-1 , each R 1-2 , each R 1-3 , each R 1-4 wherein the C3-C8 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentane or cyclohexane; (17) Each R 1-1 , each R 1-2 , each R 1-3 , each R 1-4 In the C6-C 14 Aryl, said one or more R 1- 1-1 Substituted C6-C 14 C6-C in aromatic groups 14 Aryl is phenyl; (18) Each R 1-1 , each R 1-2 , each R 1-3 , each R 1-4 In the above, the C1-C6 alkoxy groups are independently methoxy and ethoxy groups; (19) Each R 1-1 , each R 1-2 , each R 1-3 , each R 1-4 In the above, the 5-10 membered heteroaryl group is independently a 5-6 membered heteroaryl group containing 1 S atom or a 5-6 membered heteroaryl group containing 1 N atom, and further thiophene, pyridine and benzothiophene can be selected; (20) Each R 1-1-1 wherein the halogen is fluorine, chlorine or bromine; (21) Each R 1-1-1 In which the C1-C6 alkyl group is methyl or ethyl; (22) Each R 1-1-1 In the C6-C 14 Aryl is phenyl; (23)R 5 wherein the halogen is fluorine.

6. The compound of formula I according to claim 2, its pharmaceutically acceptable salt, solvate, or solvate of a pharmaceutically acceptable salt, characterized in that: It meets one or more of the following conditions: (1) A is (2)R 3 and R 4 independently H, -OCH3, F, Cl, -CH3, -CF3, -OCF3 or (3)R 1 Methyl, ethyl, propyl, n-butyl, (4)R 5 is H; Preferably, the following conditions are met: (1) A is (2)R 3 and R 4 independently H, -OCH3, F, Cl, -CH3, -CF3, -OCF3 or (3)R 1 Methyl, ethyl, propyl, n-butyl, as well as (4)R 5 For H.

7. The compound of formula I as claimed in claim 2, its pharmaceutically acceptable salt, solvate, or solvate of a pharmaceutically acceptable salt, characterized in that: It meets one or more of the following conditions: (1)R 1 is a C3-C6 alkyl group, 1-1 Substituted C1-C6 alkyl, C3-C 10 Cycloalkyl, with one or more R 1-2 Substituted C3-C 10 Cycloalkyl, phenyl or one or more R 1-3 Substituted phenyl; (2) Each R 1-1 are independently fluorine, phenyl; (3) Each R 1-2 are independently C1-C3 alkyl, 1-1-1 Substituted C1-C3 alkyl; (4) Each R 1-3 are independently fluorine, C1-C3 alkyl, 1-1-1 Substituted C1-C3 alkyl; (5) Each R 1-1-1 are independently phenyl; (6)R 3 is H, methoxy or is replaced by one or more R 3-5 Substituted C1-C6 alkyl; (7)R 4 is methoxy or is replaced by one or more R 3-5 Substituted C1-C6 alkyl; (8) Each R 3-5 For fluorine; Preferably, the following conditions are met: (1)R 1 is a C3-C6 alkyl group, 1-1 Substituted C1-C6 alkyl, C3-C 10 Cycloalkyl, with one or more R 1-2 Substituted C3-C 10 Cycloalkyl, phenyl or one or more R 1-3 Substituted phenyl; (2) Each R 1-1 are independently fluorine, phenyl; (3) Each R 1-2 are independently C1-C3 alkyl, 1-1-1 Substituted C1-C3 alkyl; (4) Each R 1-3 are independently fluorine, C1-C3 alkyl, 1-1-1 Substituted C1-C3 alkyl; (5) Each R 1-1-1 are independently phenyl; (6)R 3 is H, methoxy or is replaced by one or more R 3-5 Substituted C1-C6 alkyl; (7)R 4 is methoxy or is replaced by one or more R 3-5 Substituted C1-C6 alkyl; and (8) Each R 3-5 For fluorine.

8. The compound of formula I according to claim 1, its pharmaceutically acceptable salt, solvate, or solvate of a pharmaceutically acceptable salt, characterized in that: The compound represented by formula I is any of the following compounds:

9. A pharmaceutical composition comprising a compound as shown in Formula I as described in any one of claims 1 to 8, a pharmaceutically acceptable salt, a solvate, or a solvate of a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

10. Use of a compound of formula I as described in any one of claims 1 to 8, a pharmaceutically acceptable salt, a solvate, or a solvate of a pharmaceutically acceptable salt thereof in the preparation of a GPR40 agonist.

11. Use of a compound of formula I as described in any one of claims 1 to 8, a pharmaceutically acceptable salt, a solvate, or a solvate of a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing a disease associated with GPR40; In the application, the disease associated with GPR40 is, for example, diabetes.

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