Benzimidazole or azabenzimidazole compounds, their preparation process and their use

Abstract

The present invention discloses benzimidazole or azabenzimidazole compounds, their preparation methods and their use. The benzimidazole or azabenzimidazole compounds have the structure shown in formula (I). The use of said compounds and their pharma- ceutically acceptable salts, stereoisomers, solvates or hydrates in the preparation of GLP-1 receptor agonists, and in the preparation of medicaments for the treatment and / or prevention of metabolic diseases. [Formula 1] TIFF2025507804000374.tif30170

Description

Detailed Description of the Invention

[0001] [Technical Field] The present invention belongs to the technical field of chemical medicine, in particular to benzimidazole or azabenzimidazole compounds, their preparation process and their use.

[0002] 〔background〕 Glucagon-like peptide-1 (GLP-1) is a peptide hormone secreted by intestinal epithelial L cells and widely distributed in the mucosa of the pancreas, stomach, and small intestine, as well as the heart, lungs, and central nervous system. In vivo, GLP-1 specifically binds to the GLP-1 receptor (GLP-1R) and activates the cyclic adenosine monophosphate (cAMP) and mitogen-activated protein kinase (MAPK) pathways in the cell membrane, thereby promoting glucose-dependent insulin secretion, inhibiting glucagon secretion, inhibiting pancreatic islet β-cell apoptosis, delaying gastric emptying, and inhibiting food intake. Currently, GLP-1 receptor agonists (GLP-1RAs) are being developed as treatments for type 2 diabetes. Furthermore, increasing clinical trials have demonstrated that GLP-1RAs not only play a dominant role in the treatment of diabetes, but also play various roles in obesity, nonalcoholic steatohepatitis (NASH), cardiovascular disease, and neurological disorders. Furthermore, GLP-1 can bind to related receptors in the kidney and skin, affecting tissue metabolism (Sichuan Medical Journal, 2020, 41(10):1089-1093).

[0003] Currently, commercially available GLP-1 receptor agonists are polypeptide drugs such as semaglutide, liraglutide, exenatide, and dulaglutide. However, GLP-1, a peptide, has poor oral bioavailability and is inconvenient to take. Therefore, there is great demand for small molecule GLP-1 receptor agonists with excellent oral bioavailability. Small molecule GLP-1 receptor agonists currently in clinical development include vTv's TTP-273 and Pfizer's PF-06882961, and the development of additional GLP-1 receptor agonists is urgently needed.

[0004] 〔overview〕 An object of the present invention is to provide benzimidazole compounds or azabenzimidazole compounds, for example, benzimidazole compounds or azabenzimidazole compounds represented by general formula (I), general formula (II), general formula (II'), general formula (III), general formula (IV), general formula (V), general formula (VI), general formula (VII), general formula (VIII), general formula (IX), general formula (II-3), general formula (V-3), etc., and pharmaceutically acceptable salts, stereoisomers, solvates, or hydrates thereof.

[0005] Another object of the present invention is to provide a pharmaceutical composition comprising the above compound, or any of its pharmaceutically acceptable salts, stereoisomers, solvates or hydrates, as an active ingredient in combination with a pharmaceutically acceptable carrier.

[0006] Another object of the present invention is to provide the use of a compound of the above general formula, or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, as a GLP-1R agonist.

[0007] Another object of the present invention is the use of a compound of the above general formula, or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, in the preparation of a medicament for treating and / or preventing type I diabetes, type II diabetes, malnutrition-related diabetes, diabetic complications, obesity, metabolic syndrome, hyperglycemia, glucose intolerance, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cardiovascular disease, dyslipidemia, cerebral infarction, stroke, Parkinson's disease, dementia, insulin resistance, and hepatic insulin resistance, Preferably, the present invention provides use in the preparation of a medicament for treating and / or preventing type I diabetes, type II diabetes, malnutrition-related diabetes (diabetes mellitus), diabetic complications, obesity, metabolic syndrome, hyperglycemia, glucose intolerance, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cardiovascular disease and dyslipidemia.

[0008] Another object of the present invention is to provide a process for the preparation of compounds of the above general formula.

[0009] To achieve the above objectives, the present invention adopts the following technical solutions:

[0010] In some embodiments, the present invention provides a compound represented by general formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof: [ka]

[0011] where: R1 is selected from a hydrogen atom, halogen, cyano, C1-C6 alkyl, alkenyl, alkynyl, C1-C6 alkoxy, amino, hydroxyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the C1-C6 alkyl, the alkenyl, the alkynyl, the C1-C6 alkoxy, the amino, the cycloalkyl, the heterocyclyl, the aryl, and the heteroaryl are optionally substituted by one or more substituents selected from halogen, cyano, C1-C6 alkyl, alkenyl, alkynyl, C1-C6 alkoxy, amino, hydroxyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R2 is selected from the following: [ka] R3 are the same or different and are independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, alkenyl, alkynyl, C1-C6 alkoxy, amino, hydroxyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the C1-C6 alkyl, the alkenyl, the alkynyl, the C1-C6 alkoxy, the amino, the cycloalkyl, the heterocyclyl, the aryl, and the heteroaryl are optionally substituted by one or more substituents selected from halogen, cyano, C1-C6 alkyl, alkenyl, alkynyl, C1-C6 alkoxy, amino, hydroxyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R4 are the same or different and are independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, alkenyl, alkynyl, C1-C6 alkoxy, amino, hydroxyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the C1-C6 alkyl, the alkenyl, the alkynyl, the C1-C6 alkoxy, the amino, the cycloalkyl, the heterocyclyl, the aryl, and the heteroaryl are optionally substituted by one or more substituents selected from halogen, cyano, C1-C6 alkyl, alkenyl, alkynyl, C1-C6 alkoxy, amino, hydroxyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0012] Ring A is selected from: [ka] Ring B is selected from: [ka]

[0013] R5 are the same or different and are independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, alkenyl, alkynyl, C1-C6 alkoxy, amino, hydroxyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the C1-C6 alkyl, the alkenyl, the alkynyl, the C1-C6 alkoxy, the amino, the cycloalkyl, the heterocyclyl, the aryl, and the heteroaryl are optionally substituted by one or more substituents selected from halogen, cyano, C1-C6 alkyl, alkenyl, alkynyl, C1-C6 alkoxy, amino, hydroxyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R6 are the same or different and are independently selected from a hydrogen atom, halogen, cyano, C1-C6 alkyl, alkenyl, alkynyl, C1-C6 alkoxy, amino, hydroxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two adjacent R6 are linked to form a 3-6 membered carbocyclic or heterocyclic ring and a benzene ring, and the C1-C6 alkyl, the alkenyl, the alkynyl, the C1-C6 alkoxy, the amino, the cycloalkyl, the heterocyclyl, the aryl and the heteroaryl are optionally substituted by one or more substituents selected from halogen, cyano, C1-C6 alkyl, alkenyl, alkynyl, C1-C6 alkoxy, amino, hydroxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R7 are the same or different and are independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, alkenyl, alkynyl, C1-C6 alkoxy, amino, hydroxyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the C1-C6 alkyl, the alkenyl, the alkynyl, the C1-C6 alkoxy, the amino, the cycloalkyl, the heterocyclyl, the aryl, and the heteroaryl are optionally substituted by one or more substituents selected from halogen, cyano, C1-C6 alkyl, alkenyl, alkynyl, C1-C6 alkoxy, amino, hydroxyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0014] The constraint is that ring A is: [ka] Z is CR 10 When selected from, ring B is not selected from: [ka]

[0015] [ka] is a single or double bond; W is N and CR 10 Selected from; X1 is N and CR 10 Selected from; X2 is N and CR 10 Selected from; Y is selected from O and NH; Z is N and CR 10 Selected from; m is selected from 0, 1 or 2; n is selected from 0, 1 or 2; p is selected from 0, 1, 2 or 3; q is selected from 0, 1, 2, 3 or 4;

[0016] R8 is selected from a hydrogen atom, halogen, C1-C6 alkyl, C1-C6 cycloalkyl, heterocyclyl, and aryl; R9 is selected from a hydrogen atom, a C1-C6 alkyl, and an alkenyl; R 10 is selected from a hydrogen atom, halogen, cyano, C1-C6 alkyl, alkenyl, alkynyl, C1-C6 alkoxy, amino, hydroxyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and the C1-C6 alkyl, alkenyl, alkynyl, C1-C6 alkoxy, amino, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted by one or more substituents selected from halogen, cyano, C1-C6 alkyl, alkenyl, alkynyl, C1-C6 alkoxy, amino, hydroxyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0017] In some embodiments of the present invention, the compound represented by the above general formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, is preferably: R1 is selected from hydrogen, halogen, cyano, and C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halogens; R3 are the same or different and independently selected from hydrogen, halogen, cyano, and C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halogens; R4 are the same or different and are independently selected from hydrogen atoms, halogens, cyano and C1-C6 alkyls, wherein the C1-C6 alkyls are optionally substituted with one or more halogens.

[0018] In some embodiments of the present invention, the compound represented by the above general formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, is preferably: R5 are the same or different and independently selected from hydrogen, halogen, cyano, and C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halogens; R6 are the same or different and are independently selected from hydrogen atoms, halogens, cyano, and C1-C6 alkyls, or two adjacent R6s are linked together to form a 3-6 membered carbon atom ring or heterocyclic ring and a benzene ring, and the C1-C6 alkyl is optionally substituted with one or more halogens; R7 are the same or different and independently selected from hydrogen, halogen, cyano, and C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halogens; R 10 is selected from a hydrogen atom, halogen, cyano, and C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halogens.

[0019] In some embodiments of the present invention, the compound represented by the above general formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, is preferably: W is N and CR 10 Selected from; X1 is N and CR 10 Selected from; X2 is N and CR 10 Selected from; Y is selected from O; Z is N and CR 10 Selected from; R 10 is selected from a hydrogen atom, halogen, cyano, and C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halogens.

[0020] In some embodiments of the present invention, the compound represented by the above general formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, is preferably: Ring A is selected from: [ka] Ring B is selected from: [ka] The constraint is that ring A is: [ka] Z is CR 10 When ring B is selected from the following, ring B is not selected from the following: [ka]

[0021] In some embodiments of the present invention, the compound represented by the above general formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, is preferably: Ring B is selected from: [ka] R7 are the same or different and are independently selected from hydrogen atoms and halogens; R8 is selected from a hydrogen atom, F, Cl, methyl, ethyl, cyclopropyl, phenyl and furyl.

[0022] In some embodiments, the present invention provides a compound represented by general formula (II), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof: [ka]

[0023] where: R2 is selected from the following: [ka] Selected from; R3 is independently selected from a hydrogen atom and a halogen; R4 is independently selected from a hydrogen atom, halogen, cyano, and C1-C6 alkyl, wherein C1-C6 alkyl may be further substituted with one or more halogens; R5 is independently selected from halogen; R6 is independently selected from a hydrogen atom, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, furan, and C2-C4 alkenyl; or two adjacent R6 are linked to form a ring; W is N and CR 10 Selected from; X2 is N and CR 10 Selected from; Q is selected from N and CH; p is selected from 0, 1, 2 or 3; m is selected from 0, 1 or 2; n is selected from 0, 1, 2 or 3; q is selected from 0, 1 or 2; R 10 is selected from a hydrogen atom and a halogen.

[0024] In some embodiments of the present invention, the compound represented by the above general formula (II), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, has a structure represented by general formula (II-1). [ka]

[0025] where: R2 is selected from the following: [ka] R3 is independently selected from a hydrogen atom and a halogen; R4 is independently selected from a hydrogen atom, halogen, cyano, and C1-C6 alkyl, wherein the C1-C6 alkyl may be further substituted with one or more halogens; R5 is independently selected from halogen; R6 is independently selected from a hydrogen atom, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, furan, and C2-C4 alkenyl; or two adjacent R6 are linked to form a ring; W is N and CR 10 Selected from; X2 is N and CR 10 Selected from; Q is selected from N and CH; p is selected from 0, 1, 2 or 3; m is selected from 0, 1 or 2; n is selected from 0, 1, 2 or 3; R 10 is selected from a hydrogen atom and a halogen.

[0026] In some embodiments of the present invention, in the compound represented by the above general formula (II-1), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, preferably: R3 is selected from a hydrogen atom and F; R4 is selected from a hydrogen atom, F, Cl, cyano, CF3, and CHF2; X2 and Q are selected from CH; R 10 is selected from a hydrogen atom and F.

[0027] In some embodiments of the present invention, the compound represented by the above general formula (II-1), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, has a structure represented by general formula (II-1-1). [ka] wherein preferably: R4 is selected from Cl and cyano; R6 is selected from a hydrogen atom and F; R 10 is selected from a hydrogen atom.

[0028] In some embodiments of the present invention, the compound represented by the above general formula (II), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, has a structure represented by general formula (II-2). [ka]

[0029] where: R2 is selected from the following: [ka] R3 is independently selected from a hydrogen atom and a halogen; R4 is independently selected from a hydrogen atom, halogen, cyano, and C1-C6 alkyl, wherein the C1-C6 alkyl may be further substituted with one or more halogens; R5 is independently selected from halogen; W is N and CR10 Selected from; X2 is N and CR 10 Selected from; p is selected from 0, 1, 2 or 3; n is selected from 0, 1, 2 or 3; R 10 is selected from a hydrogen atom and a halogen.

[0030] In some embodiments of the present invention, in the compound represented by the above general formula (II-2), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, preferably: R5 is selected from F; R3 is selected from a hydrogen atom and F; X2 is selected from CH; R 10 is selected from a hydrogen atom and F.

[0031] In some embodiments of the present invention, the compound represented by the above general formula (II-2), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, has a structure represented by general formula (II-2-1). [ka] where preferably: R4 is selected from a hydrogen atom, Cl and cyano; R 10 is selected from a hydrogen atom.

[0032] In some embodiments, the present invention provides a compound of general formula (III), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof: [ka]

[0033] where: R2 is selected from the following: [ka] R4 is independently selected from a hydrogen atom, a halogen atom, and a cyano atom; R6 is independently selected from a hydrogen atom, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, and furan; W is N and CR 10 Selected from; Q is selected from N and CH; A is selected from O and S; n is selected from 0, 1, 2 or 3; R 10 is selected from a hydrogen atom and a halogen; [ka] is a single or double bond; Preferably, R6 is independently selected from a hydrogen atom and a halogen; R 10 is selected from a hydrogen atom.

[0034] In some embodiments, the present invention provides a compound of general formula (IV), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof: [ka]

[0035] where: R2 is selected from the following: [ka] R3 is independently selected from a hydrogen atom and a halogen; R4 is independently selected from a hydrogen atom, a halogen atom, and a cyano atom; R6 is independently selected from a hydrogen atom, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, furan, and C2-C4 alkenyl; or two adjacent R6 are linked to form a ring.

[0036] W is N and CR 10 Selected from; Q is selected from N and CH; A is selected from O and S; E is selected from N and CH; m is selected from 0, 1 or 2; n is selected from 0, 1 or 2; q is selected from 0, 1 or 2; R 10 is selected from a hydrogen atom and a halogen; When E is CH and Q is CH, two adjacent R6s are linked to form a ring;

[0037] Preferably, the compound, or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, has a structure represented by general formula (IV-1): [ka] where R 10 is selected from a hydrogen atom and F; at least one of Q and E is N; A is selected from O; R6 is selected from a hydrogen atom and F; n is 1;

[0038] Alternatively, preferably, the compound, or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, has a structure represented by general formula (IV-2): [ka] More preferably, R3 is selected from a hydrogen atom and F; R 10 is selected from a hydrogen atom and F; A is selected from O; E is selected from CH; n is 1; more preferably, R2 is selected from [ka] R 10is selected from a hydrogen atom.

[0039] In some embodiments, the present invention provides a compound of general formula (V), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof: [ka] where R2 is selected from: [ka] R4 is independently selected from a hydrogen atom, halogen, cyano, and C1-C6 alkyl, and the C1-C6 alkyl may be further substituted with one or more halogens; R6 is independently selected from a hydrogen atom, halogen, C1-C6 alkyl, phenyl, furan, and C2-C4 alkenyl; or two adjacent R6 are linked to form a ring; W is selected from N and CR 10 n is selected from 0, 1, 2, or 3; q is selected from 0, 1, or 2; R 10 is selected from a hydrogen atom and a halogen;

[0040] Preferably, the compound, or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, has a structure represented by general formula (V-1). [ka] More preferably, R4 is selected from a hydrogen atom, F, Cl, cyano, CF3 and CHF2; R6 is selected from a hydrogen atom and F; R 10 is selected from a hydrogen atom; n is 1; more preferably, R4 is selected from a hydrogen atom, Cl and cyano;

[0041] Alternatively, preferably, the compound, or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, has a structure represented by general formula (V-2). [ka] More preferably, R4 is selected from a hydrogen atom and Cl; R 10 is selected from a hydrogen atom; and n is 1.

[0042] In some embodiments, the present invention provides a compound of general formula (VI), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof: [ka] where R2 is selected from: [ka] R4 is independently selected from a hydrogen atom, a halogen atom, and a cyano; R6 is independently selected from a hydrogen atom, a halogen atom, and a C1-C6 alkyl; W is selected from N and CR 10 Q is selected from N and CH; A is selected from O and S; n is selected from 0, 1 or 2; R 10 is selected from a hydrogen atom and a halogen.

[0043] In some embodiments, the present invention provides a compound of general formula (VII), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof: [ka] where R2 is selected from: [ka] R4 is independently selected from a hydrogen atom, a halogen atom, and a cyano; R6 is independently selected from a hydrogen atom and a halogen atom; W is selected from N and CR 10n is selected from 0, 1, or 2; R 10 is selected from a hydrogen atom and a halogen.

[0044] In some embodiments, the present invention provides a compound of general formula (VIII), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof: [ka] where R2 is selected from: [ka] R4 is independently selected from a hydrogen atom, halogen, and cyano; R6 is independently selected from a hydrogen atom and C2-C4 alkenyl; or two R6 are linked to form a ring; W is selected from N and CR 10 Q is selected from N and CH; A is selected from O and S; n is selected from 0, 1 or 2; q is selected from 0 or 1; R 10 is selected from a hydrogen atom and a halogen.

[0045] In some embodiments, the present invention provides a compound of general formula (IX), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof: [ka] where R2 is selected from: [ka] R4 is independently selected from a hydrogen atom, a halogen, and a cyano; R5 is independently selected from a hydrogen atom and F; R6 is independently selected from a hydrogen atom and a halogen; n is independently selected from 0, 1, or 2; and q is independently selected from 0 or 1.

[0046] In some embodiments, the present invention provides a compound of general formula (II-3), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof: [ka]

[0047] where: R1 is selected from a hydrogen atom and a halogen; R2 is independently selected from the following: [ka] R3 is independently selected from a hydrogen atom and a halogen; R4 is independently selected from a hydrogen atom, a halogen atom, and a cyano atom; R5 is independently selected from halogen; R6 is independently selected from a hydrogen atom, halogen, and C1-C6 alkyl; W is selected from N and CH; p is selected from 0, 1, 2 or 3; m is selected from 0, 1, 2, 3; n is selected from 0, 1, 2 or 3; q is selected from 0, 1 or 2; s is selected from 0, 1 or 2;

[0048] Preferably, the compound, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, has a structure represented by general formula (II-3-1). [ka] where R 1a and R 1b are independently selected from a hydrogen atom and F; R2 is: [ka] R6 is independently selected from a hydrogen atom and a halogen; m is selected from 1 or 2; p is selected from 1, 2 or 3;

[0049] More preferably, the compound, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, has a structure represented by general formula (II-3-2). [ka] where R 3a and R 3b are independently selected from F and a hydrogen atom; R4 is independently selected from F, Cl, and cyano; R 5a , R 5b and R 5c are independently selected from a hydrogen atom and F; R6 is independently selected from a hydrogen atom, F, and Cl; More preferably, R 3a and R 3b is not F at the same time, but R 5a and R 5c are independently selected from a hydrogen atom and F; R 5b is a hydrogen atom.

[0050] In some embodiments, the present invention provides a compound of general formula (V-3), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof: [ka]

[0051] where: R2 is selected from the following: [ka] R3 is selected from a hydrogen atom and a halogen; R4 is selected from a hydrogen atom, a halogen atom, and a cyano atom; R6 is selected from a hydrogen atom, halogen, and C1-C6 alkyl; W is selected from N and CH; m is selected from 0, 1 or 2; n is selected from 0, 1, 2 or 3; q is selected from 0, 1 or 2;

[0052] Preferably, the compound, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, has a structure represented by general formula (V-3-1). [ka] wherein R3 is selected from a hydrogen atom and a halogen; R4 is selected from a hydrogen atom, a halogen, and a cyano; R6 is selected from a hydrogen atom and a halogen; More preferably, R3 is selected from a hydrogen atom and F; R4 is selected from a hydrogen atom, Cl and cyano; R6 is selected from a hydrogen atom and Cl; More preferably, R4 is Cl.

[0053] In some embodiments, the present invention provides a compound of general formula (II'), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof: [ka]

[0054] where: R1 is selected from a hydrogen atom and a halogen; R2 is selected from the following: [ka] R3 is independently selected from a hydrogen atom and a halogen; R4 is independently selected from a hydrogen atom, halogen, cyano, and C1-C6 alkyl, wherein the C1-C6 alkyl may be further substituted with one or more halogens; R5 is independently selected from a hydrogen atom and a halogen; R6 is independently selected from a hydrogen atom, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, furan, and C2-C4 alkenyl; W is N and CR 10 Selected from; X2 is N and CR 10 Selected from; Q is selected from N and CH; p is selected from 0, 1, 2 or 3; m is selected from 0, 1, 2 or 3; n is selected from 0, 1, 2 or 3; q is selected from 0, 1 or 2; s is selected from 0, 1 or 2; R 10 is selected from a hydrogen atom and a halogen;

[0055] Preferably, the compound, or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, has a structure represented by general formula (II'-1). [ka] where: R3 is selected from a hydrogen atom and F; R4 is selected from a hydrogen atom, F, Cl, cyano, CF3 and CHF2; X2 and Q are selected from CH; R 10 is selected from a hydrogen atom and F;

[0056] Alternatively, preferably, the compound, or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, has a structure represented by general formula (II'-3). [ka] where: R4 is independently selected from a hydrogen atom, a halogen atom, and a cyano atom; R6 is independently selected from a hydrogen atom, halogen, and C1-C6 alkyl; W is selected from N and CH.

[0057] In some embodiments of the present invention, the structure represented by general formula (II'-1) is further represented by general formula (II'-1-1). [ka] where: R4 is selected from Cl and cyano; R6 is selected from a hydrogen atom and F; R 10 is selected from a hydrogen atom.

[0058] In some embodiments of the present invention, the structure represented by general formula (II'-3) is further represented by general formula (II'-3-1). [ka] where: R 1a and R 1b are independently selected from a hydrogen atom and F; R2 is: [ka] R6 is independently selected from a hydrogen atom and a halogen; m is selected from 1 or 2; p is selected from 1, 2 or 3;

[0059] Preferably, the structure represented by general formula (II'-3) is further a structure represented by general formula (II'-3-2). [ka] where: R 3a and R 3b are independently selected from F and a hydrogen atom; R4 is independently selected from F, Cl, and cyano; R 5a , R 5b and R 5c are independently selected from a hydrogen atom and F; R6 is independently selected from a hydrogen atom, F, and Cl; More preferably, R 3a and R 3b is not F at the same time, but R 5a and R 5c are independently selected from a hydrogen atom and F; R 5b is a hydrogen atom.

[0060] In some embodiments of the present invention, the following compounds are provided, although the present invention is not limited to these specific compounds: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0061] In some embodiments of the present invention, pharmaceutical compositions are provided that include at least one compound of the invention as described herein, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, and a pharmaceutically acceptable carrier, excipient, or vehicle.

[0062] In some embodiments of the present invention, there is provided the use of a compound of the present invention described herein, or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, and the aforementioned pharmaceutical composition, in the preparation of a medicament for a GLP-1 receptor agonist.

[0063] In some embodiments of the present invention, there is provided a use of the compounds of the present invention described herein, or pharmaceutically acceptable salts, stereoisomers, solvates or hydrates thereof, and the aforementioned pharmaceutical compositions in the preparation of a medicament for treating and / or preventing type I diabetes, type II diabetes, malnutrition-related diabetes, diabetic complications, obesity, metabolic syndrome, hyperglycemia, glucose intolerance, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cardiovascular disease, dyslipidemia, cerebral infarction, stroke, Parkinson's disease, dementia, insulin resistance, and hepatic insulin resistance; preferably, there is provided a use of the compounds of the present invention described herein, or pharmaceutically acceptable salts, stereoisomers, solvates or hydrates thereof, and the aforementioned pharmaceutical compositions in the preparation of a medicament for treating and / or preventing type I diabetes, type II diabetes, malnutrition-related diabetes, diabetic complications, obesity, metabolic syndrome, hyperglycemia, glucose intolerance, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cardiovascular disease, and dyslipidemia.

[0064] [Definitions and General Terms] The following terms and conditions are used to describe the present invention. As will be understood by those skilled in the art, terms not specifically defined should be understood to be given a meaning consistent with the meaning of the term as used in the context of the present invention.

[0065] The term "alkyl" as used herein refers to saturated aliphatic hydrocarbyl groups, including straight-chain and branched-chain hydrocarbyls, such as C1-C6 alkyl. "C1-C6 alkyl" refers to alkyls having 1 to 6 carbon atoms, such as alkyls having 1, 2, 3, 4, 5, and 6 carbon atoms, including, but not limited to, methyl, ethyl, propyl (such as n-propyl and isopropyl), butyl (such as n-butyl, isobutyl, and tert-butyl), pentyl (such as n-pentyl, isopentyl, and neopentyl), hexyl (such as n-hexyl), and the like.

[0066] The term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine, preferably fluorine and chlorine.

[0067] The term "alkenyl" as used herein refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond, preferably a straight or branched chain having 2 to 10 carbon atoms, such as vinyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl.

[0068] The term "alkynyl" as used herein refers to straight or branched chain hydrocarbyl having at least one carbon-carbon triple bond, preferably straight or branched chain hydrocarbyl having 2 to 10 carbon atoms, such as ethynyl, propynyl, and butynyl.

[0069] The term "cycloalkyl" as used herein refers to a non-aromatic monocyclic or polycyclic ring system such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, preferably cyclopropyl.

[0070] The term "heterocyclyl" as used herein means a "heterocyclyl" or "heterocycle", which is a saturated or unsaturated monocyclic or polycyclic system containing one or more heteroatoms selected from O, N, or S, preferably a 3- to 10-membered monocyclic or polycyclic system.

[0071] The term "aryl" as used herein refers to aromatic groups such as phenyl, naphthyl, tetrahydronaphthyl, indanyl and biphenyl, preferably phenyl.

[0072] The term "heteroaryl" as used herein refers to an aromatic ring containing one or more heteroatoms selected from O, N, or S, and heteroaryl may be a monocyclic, bicyclic, or tricyclic ring system, such as quinolyl, pyrazolyl, pyrrolyl, thienyl, furyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, imidazolyl, oxazolyl, isoxazolyl, pyridazinyl, benzofuryl, benzothiophenyl, benzoxazolyl, indolyl, and the like.

[0073] The term "pharmaceutically acceptable salt" as used herein refers to a salt of a compound of the present invention prepared from a compound having a particular substituent found in the present invention and a pharmaceutically acceptable acid or base.

[0074] The term "stereoisomers" as used herein refers to compounds that have identical chemical constitution, but differ with regard to the arrangement of the atoms and groups in space, and includes enantiomers, diastereomers, geometric isomers, trans-hindered isomers, or conformational isomers.

[0075] The term "racemate" as used herein refers to a mixture of two equimolar enantiomers devoid of optical activity, and mixtures thereof, such as racemic mixtures.

[0076] The term "solvate" is used herein to describe a molecular complex comprising a compound of any of the above formulas, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable solvent molecules (such as ethanol). When the solvent is water, the term "hydrate" is used.

[0077] The term "pharmaceutically acceptable carrier" as used herein refers to any pharmaceutical carrier or vehicle capable of delivering an effective amount of the active substance of the present invention, not inhibiting the biological activity of the active substance, and not toxic or having adverse effects on the host or patient. Representative carriers include water, oil, vegetable and mineral bases, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, adhesives, transdermal absorption enhancers, etc.

[0078] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds of the present invention may contain deuterium (D), tritium ( 3 H), iodine-125( 125 I) or carbon-14 ( 14 All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0079] Additionally, prodrugs and esters of compounds of any of the above formulas are within the scope of the present invention.

[0080] The beneficial technical effects obtained are as follows: 1) The compounds of the present invention have excellent biological activity, and the in vitro cellular activities of 25 compounds, such as Compound 14, Compound 17, Compound 18, Compound 19, Compound 21, Compound 38, Compound 67, Compound 87, Compound 91, Compound 92, Compound 93, Compound 94, Compound 95, Compound 96, Compound 97, Compound 99, Compound 100, Compound 101, Compound 102, Compound 103, Compound 104, Compound 105, Compound 106, Compound 107, and Compound 108, are significantly superior to those of prior art compounds. For example, the in vivo blood glucose-lowering effects of Compound 17, Compound 19, Compound 21, Compound 38, Compound 61, Compound 93, Compound 94, Compound 99, Compound 100, Compound 106, and Compound 107 are significantly superior to those of prior art compounds.

[0081] 2) The compounds of the present invention have favorable pharmacokinetic properties, such as effectively extending half-life and increasing plasma exposure, and the in vivo half-lives of compounds such as Compound 21, Compound 93, Compound 94, Compound 99, and Compound 100 are significantly longer than those of the compounds of the prior art.

[0082] 3) The compounds of the present invention also have safe hERG cardiotoxicity.

[0083] BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows the blood glucose concentration curves of compounds 17, 19, 38 and 61 of the present invention and comparative examples.

[0084] FIG. 2 shows the blood glucose AUC (0 to 120 minutes) of compounds 17, 19, 38 and 61 of the present invention and a comparative example.

[0085] FIG. 3 shows the blood glucose concentration curves of compounds 17, 93 and 100 of the present invention and a comparative example.

[0086] FIG. 4 shows the blood glucose AUC (0 to 120 minutes) of compounds 17, 93 and 100 of the present invention and a comparative example.

[0087] FIG. 5 shows the blood glucose concentration curves of compounds 21, 94, 99, 106 and 107 of the present invention and comparative examples.

[0088] FIG. 6 shows the blood glucose AUC (0 to 120 minutes) of compounds 21, 94, 99, 106 and 107 of the present invention and comparative examples.

[0089] Detailed Description The present application will be described below in connection with the following embodiments, which are described to further illustrate the implementation of the present application. However, it should be noted that the embodiments described below are only used to illustrate the present application and are not to be construed as limiting the present application. Modifications and substitutions thereof by those skilled in the art are also within the scope of the present application, as determined by the appended claims. The reagents used in the embodiments of the present application are all commercially available.

[0090] Example 1: Synthesis of Compound 1

[0091] [ka] Synthesis Route:

[0092] [ka] Compound 1-A:

[0093] [ka] 2.0 g (1.0 equivalent) of compound 1-Boc-4-piperidine acetic acid ester was weighed and added to a 50 mL round-bottom flask. 5 mL of ethyl acetate was added, followed by 20 mL of 10% ethyl acetate hydrochloride solution. The reaction mixture was stirred at room temperature for 3-4 hours. After TLC showed that the starting material, 1-Boc-4-piperidine acetic acid ester, had reacted completely, the reaction mixture was concentrated under reduced pressure to obtain compound 1-A (4-piperidine acetic acid ethyl hydrochloride). This product could be used directly in the next reaction without purification.

[0094] Compound 1-B:

[0095] [ka] 589.9 mg of compound 1-A (1.0 equiv.) was weighed and added to a 50 mL round-bottom flask. 10 mL of DMF was added, followed by 1.85 g of Cs2CO3 (2.0 equiv.). The reaction mixture was stirred at room temperature for 30 minutes, after which 500 mg of 2-bromo-6-fluoropyridine (1.0 equiv.) was added. The mixture was stirred uniformly and heated to 70 °C for 1-2 hours. TLC showed that the starting material, 2-bromo-6-fluoropyridine, had completely reacted. The heating was then stopped, the reaction mixture was cooled to room temperature, and 16 mL of water was added. The mixture was then extracted twice with 10 mL of ethyl acetate. The combined organic phase was washed twice with 10 mL of water, followed by a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure to give compound 1-B (850 mg, 91.50% yield) as a brown oil. This product was used directly in the next step without purification.

[0096] Compound 1-C:

[0097] [ka] Compound 01-C1: 10.0 g of 5-chloro-2-methylphenol (1.0 equivalent), 20.74 g of 2-bromo-1,1-diethoxyethane (1.5 equivalents), and 14.54 g of K2CO3 (1.5 equivalents) were weighed and added to a 500 mL round-bottom flask, followed by 200 mL of DMF. The reaction mixture was then heated at 120 °C for 16 hours under nitrogen protection with uniform stirring. TLC showed that the starting material, 5-chloro-2-methylphenol, had completely reacted. Heating was stopped and the reaction mixture was cooled to room temperature. 400 mL of water was then added to the reaction mixture, which was then extracted three times with 150 mL of ethyl acetate. The combined organic phase was washed twice with 200 mL of water and twice with 200 mL of saturated brine. The organic phase was then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give an oily crude product, which was purified by column chromatography (PE as eluent) to give compound 01-C1 (12.39 g, yield 68.41%).

[0098] Compound 01-C2: 12.39 g of compound 01-C1 (1.0 equivalent) and 24.33 g of polyphosphoric acid (1.5 equivalents) were weighed and added to a 500 mL round-bottom flask. 250 mL of toluene was added. The reaction mixture was then stirred uniformly under nitrogen protection and heated at 90 °C for 15 hours. TLC showed that compound 01-C1 had reacted completely. After heating was stopped and the reaction mixture was cooled to room temperature, it was quenched with 250 mL of water and allowed to stand for stratification. The organic phase was washed once with 150 mL of water, twice with 150 mL of saturated NaHCO3 solution, and once with 150 mL of saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give oily compound 01-C2, which was used directly in the next step without purification.

[0099] Compound 01-C3: 9.25 g of the crude compound 01-C2 obtained above, 11.85 g of NBS (1.2 equivalents), and 1.82 g of 2-azodiisobutyronitrile (0.2 equivalents) were added to a 250 mL round-bottom flask. 100 mL of DCE (1,2-dichloroethane) was added. The reaction mixture was stirred uniformly and then heated at 72 °C for 12 hours. TLC showed that the starting materials had essentially reacted completely, so heating was stopped. After slight cooling, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (PE as eluent) to obtain oily compound 01-C3 (9.0 g, 66.04% yield).

[0100] Compound 1-C:

[0101] [ka] 9.0 g of compound 01-C3 (1.0 equiv.) was weighed and added to a 250 mL round-bottom flask. 90 mL of DMF was added and stirred to dissolve. 36.0 g (10.0 equiv.) of potassium acetate was added, and the mixture was stirred at room temperature for 2.5 hours. TLC indicated that the starting material had completely reacted. 270 mL of water and 100 mL of ethyl acetate were added to the mixture, and the mixture was allowed to stand for phase separation. The aqueous phase was extracted twice with 100 mL of ethyl acetate. The combined organic phases were washed twice with 100 mL of water, then twice with 100 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a yellow oil. 40 mL of THF was then added to the oil, and after uniform stirring, 14.68 mL of 5 mol / L sodium methoxide solution was added, and the mixture was stirred at room temperature for 1.5 hours. TLC indicated that the starting material had disappeared. The reaction was stopped, and 120 mL of water and 100 mL of ethyl acetate were added to the reaction solution. The reaction solution was allowed to stand for phase separation. The aqueous phase was extracted twice with 100 mL of ethyl acetate. The organic phases were combined and washed twice with 100 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a crude yellow oil, which was purified by column chromatography to give compound 1-C (4.5 g, 67.5% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ = 8.12 (s, 1H), 7.34-7.32 (m, 2H), 7.01 (s, 1H), 5.39 (t, J = 5.6Hz, 1H), 4.79 (d, J = 5.6 Hz, 2H).

[0102] Compound 1-D:

[0103] [ka] 850 mg of compound 1-B (1.0 equiv.) was weighed and added to a 100 mL round-bottom flask. 473.63 mg of compound 1-C (1.0 equiv.), 1.69 g of Cs2CO3 (2.0 equiv.), 300.42 mg of Xantphos (0.2 equiv.), and 237.54 mg of Pd2(dba)3 (0.1 equiv.) were added, followed by 32 mL of toluene. The reaction mixture was stirred evenly, purged with nitrogen three times, and heated at 110 °C under nitrogen protection for 4–5 h. TLC indicated complete reaction of the two starting materials. Heating was stopped, the reaction mixture was cooled to room temperature, and filtered through diatomaceous earth. 50 mL of water was then added to the filtrate, and the mixture was allowed to stand for liquid phase separation. The toluene phase was washed twice with 30 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give a yellow oil, which was purified by column chromatography (petroleum ether / ethyl acetate=95 / 5 as eluent) to give oily compound 1-D (640 mg, yield 57.45%).

[0104] Compound 1-E:

[0105] [ka] 640 mg of compound 1-D (1.0 equiv.) was weighed and added to a 100 mL round-bottom flask. 30 mL of a 1:1 (volume ratio) MeOH / THF mixture and 4.5 mL of 2 mol / L NaOH solution were added. The reaction mixture was heated at 40 °C for 2 hours. TLC showed that the starting materials had completely reacted. Heating was stopped, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, and 15 mL of water was added. The pH of the reaction mixture was adjusted to approximately 4 with 2 mol / L hydrochloric acid solution. The reaction mixture was then extracted twice with 15 mL of ethyl acetate. The combined organic phases were washed twice with 30 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 1-E (560 mg, 93.76% yield) as a yellow oil.

[0106] Compound 1-F:

[0107] [ka] Compound 01-F1: 9.0 g of methyl 3-fluoro-4-nitrobenzoate (1.0 equiv.) was weighed and added to a 500 mL round-bottom flask. 180 mL of DMF and 180 mL of THF were added, followed by 13.00 mL of TEA (2.0 equiv.). The reaction mixture was stirred uniformly, and 4.8 g of (S)-2-(aminomethyl)oxetane (1.2 equiv.) was added. The reaction mixture was stirred at room temperature for 16 hours. TLC indicated that the starting material had essentially reacted completely. The mixture was then concentrated under reduced pressure to remove THF. 540 mL of water was then added to the remaining DMF solution, and the mixture was stirred for 3-4 hours to allow crystallization. The mixture was filtered to obtain a yellow solid, compound 01-F1 (9.88 g, 82.47% yield).

[0108] Compound 1-F:

[0109] [ka] 6.0 g of compound 01-F1 (1.0 equivalent) was weighed and added to a 250 mL round-bottom flask. 90 mL of methanol was added and stirred to form a suspension. 600 mg of Pd / C (10%) was then added, and the system was purged with hydrogen three times. The reaction mixture was reacted under a hydrogen atmosphere at room temperature for 3 hours. TLC showed that the starting materials had completely reacted. The reaction mixture was then filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give compound 1-F (5.3 g, 100% yield) as a brown oil. 1 HNMR (400 MHz, CDCl3) δ=7.41 (dd, J = 8.1, 1.5 Hz, 1H), 7.30 (s, 1H), 6.62 (d, J = 8.1 Hz, 1H), 5.05-5.02 (m, 1H), 4.67 (dd, J = 14.1, 7.7 Hz, 1H), 4.57-4.52 (m, 1H), 4.16(brs, 3H), 3.81 (s, 3H), 3.38 (dd, J = 12.9, 6.9 Hz, 1H), 3.28 (dd, J = 12.9, 3.5 Hz, 1H), 2.72 - 2.61 (m, 1H), 2.55 - 2.42 (m, 1H).

[0110] Compound 1-G:

[0111] [ka] 560 mg of compound 1-E (1.0 equiv.) was weighed and added to a 50 mL round-bottom flask. 10 mL of acetonitrile was added, followed by 314 mg of compound 1-F (0.95 equiv.). The reaction mixture was stirred at 0 °C for 10 minutes. Next, 460 mg of N-methylimidazole (4.0 equiv.) and 550 mg of TCFH (N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate, 1.4 equiv.) were added. After the addition, the reaction mixture was kept at 0 °C and reacted for 1 hour. The ice bath was then removed, and the reaction mixture was allowed to warm to room temperature and react for 1-2 hours. TLC indicated that the two starting materials had completely reacted. A large amount of solid precipitated, which was then filtered, and the filter cake was washed with 1 mL of acetonitrile to obtain an off-white solid, compound 1-G (310 mg, 35.75% yield).

[0112] Compound 1-H:

[0113] [ka] 310 mg of compound 1-G (1.0 equiv.) was weighed and added to a 50 mL round-bottom flask. 9 mL of methanol was added, followed by 94.71 mg of pTSA (p-toluenesulfonic acid, 1.1 equiv.). The reaction mixture was heated at 85°C for 1.5 hours. TLC showed that the starting materials had completely reacted. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. 10 mL of water and 15 mL of ethyl acetate were added, and the resulting mixture was allowed to stand for phase separation. The aqueous phase was extracted with 10 mL of ethyl acetate. The combined organic phase was washed twice with 30 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (dichloromethane / methanol = 98 / 2 as eluent) to obtain compound 1-H (240 mg, 79.85% yield) as a white foam. MS m / z (ESI): 601.2213 (M+H). + , 11H NMR (400 MHz, CDCl3) δ = 8.12 (s, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.68 (d, J = 2.1 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 6.88 (d, J = 2.1 Hz, 1H), 6.20 (d, J = 8.0 Hz, 1H), 6.13 (d, J = 7.8 Hz, 1H), 5.62 (s, 2H), 5.24 - 5.15 (m, 1H), 4.63 (dd, J = 13.9, 7.8 Hz, 1H), 4.47 - 4.34 (m, 3H), 4.27 (d, J = 12.9 Hz, 2H), 3.97 (s, 3H), 2.97 (d, J = 7.1 Hz, 2H), 2.91 - 2.81 (m, 3H), 2.80 - 2.71 (m, 1H), 2.47 - 2.41 (m, 1H), 1.85 (d, J = 12.8 Hz, 2H), 1.40 - 1.34 (m, 2H).

[0114] Compound 1:

[0115]

Chem.

[0116] Example 2: Synthesis of compound 2:

[0117] [ka] Synthesis Route:

[0118] [ka] Compound 2-A:

[0119] [ka] 75 mL of anhydrous THF was added to a 250 mL round-bottom flask, and 2.9 g of NaH (60%, 2.3 equiv.) was added in one portion at room temperature. The reaction mixture was then stirred for 30 minutes, followed by the dropwise addition of 9.13 mL of triethylphosphonoacetate (1.4 equiv.). After the dropwise addition, the reaction mixture was stirred for 1 hour. 6.5 g of 1-Boc-4-piperidone (1.0 equiv.) was then added in one portion. The reaction mixture was then stirred at room temperature for 2-3 hours, and TLC showed that the starting material had completely reacted. The reaction mixture was quenched by the slow dropwise addition of 150 mL of water and extracted three times with 100 mL of ethyl acetate. The organic phases were combined and washed twice with 100 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give an oil, which was purified by column chromatography (PE / EA=95 / 5) to give compound 2-A (1.67 g, yield 18.9%). 1 HNMR(400MHz, CDCl3)δ =5.54 (tt, J = 3.2, 1.5 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 3.91 (tq, J = 2.8, 1.4 Hz, 2H), 3.52 (t, J = 5.7 Hz, 2H), 3.03 (d, J = 1.7 Hz, 2H), 2.16 (tt, J = 5.7, 2.4 Hz, 2H), 1.48 (s, 9H), 1.28 (t, J = 7.2 Hz, 3H).

[0120] Compound 2-B:

[0121] [ka] 1.67 g of compound 2-A (1.0 equivalent) was weighed and added to a 50 mL round-bottom flask. 4 mL of ethyl acetate was added, and the resulting system was stirred to dissolve. 20 mL of a 10% hydrogen chloride ethyl acetate solution was then added, and the reaction mixture was stirred at room temperature for 4 hours. TLC showed that the starting material had completely reacted. The reaction mixture was concentrated under reduced pressure to give compound 2-B hydrochloride, which was used directly in the next step without further purification.

[0122] Compound 2-C:

[0123] [ka] Compound 2-B hydrochloride (1.0 equiv.) obtained in the previous step was weighed and added to a 250 mL round-bottom flask. 25 mL of DMF and 6.17 g of cesium carbonate (3.0 equiv.) were added. The reaction mixture was stirred at room temperature for 30 minutes, and then 1.11 g of 2-bromo-6-fluoropyridine (1.0 equiv.) was added. The reaction mixture was then heated at 70 °C for 1 hour. TLC showed that the starting materials had reacted completely. The reaction mixture was then cooled to room temperature, 50 mL of water was added, and the resulting mixture was extracted twice with 20 mL of ethyl acetate. The combined organic phases were washed twice with 25 mL of saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 2-C (1.57 g, 77.72% yield) as an oil. This compound 2-C was used directly in the next reaction without further purification.

[0124] Compound 2-D:

[0125] [ka] 960.0 mg of compound 2-C (1.0 equiv.) was weighed and added to a 100 mL round-bottom flask. 512.0 mg of compound 1-C (0.95 equiv.), 1.92 g of Cs2CO3 (2.0 equiv.), 340.8 mg of Xantphos (0.2 equiv.), 269 mg of Pd2(dba)3 (0.1 equiv.), and 32 mL of toluene were added. The reaction mixture was stirred evenly and purged with nitrogen three times. Then, under nitrogen protection, it was heated at 110 °C for 16 h. TLC showed that the two starting materials had completely reacted. Heating was stopped, the reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give a yellow oil, which was purified by column chromatography (petroleum ether / ethyl acetate = 95 / 5 as eluent) to give oily compound 2-D (402 mg, 33.5% yield).

[0126] Compound 2-E:

[0127] [ka] 402 mg of compound 2-D (1.0 equiv.) was weighed and added to a 100 mL round-bottom flask. 10 mL of a 1:1 mixture of MeOH / THF was added. 1.6 mL of 2 mol / L NaOH solution was then added. The reaction mixture was then heated at 40 °C for 2-3 hours. TLC showed that the starting material had completely reacted. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. 15 mL of water was added to the concentrated mixture, and the pH of the reaction mixture was adjusted to approximately 4 with 2 mol / L hydrochloric acid. The aqueous phase was extracted twice with 15 mL of ethyl acetate. The combined organic phase was washed twice with 15 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain 402 mg of crude compound 2-E as a pale green oil, which was used directly in the next reaction without further purification.

[0128] Compound 2-F:

[0129] [ka] 402 mg of compound 2-E (1.0 equiv.) was weighed and added to a 50 mL round-bottom flask. 8 mL of acetonitrile and 226.23 mg of compound 1-F (0.95 equiv.) were added. The reaction mixture was then stirred at 0 °C for 10 min. 336.0 mg of N-methylimidazole (4.0 equiv.) and 396.0 mg of TCFH (1.4 equiv.) were added. After the addition, the reaction mixture was kept at 0 °C and reacted for 3–4 h. TLC showed that the two starting materials had completely reacted. 10 mL of water was added to the reaction mixture, and the resulting mixture was extracted with 15 mL of ethyl acetate. The organic phase was washed twice with 15 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a pale green oily compound, which was purified by silica gel column chromatography (DCM:MeOH=98:2) to give compound 2-F (365 mg, yield 61.66%).

[0130] Compound 2-G:

[0131] [ka] 365 mg of compound 2-F (1.0 equiv.) was weighed and added to a 50 mL round-bottom flask. 11 mL of methanol and 112.10 mg of pTSA (1.1 equiv.) were added. The reaction mixture was heated at 80 °C for 0.5 h. TLC showed that the starting materials had completely reacted. The reaction mixture was then cooled to room temperature. 5 mL of water and saturated NaHCO3 solution were added to the reaction mixture to adjust the pH to approximately 8. 15 mL of ethyl acetate was then added, and the resulting mixture was allowed to stand for phase separation. The aqueous phase was extracted with 15 mL of ethyl acetate, and the combined organic phases were washed twice with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 98:2 as eluent) to give compound 2-G (270 mg, 76.3% yield) as a yellow foam.

[0132] Compound 2:

[0133] [ka] 270 mg of compound 2-G (1.0 equiv.) was weighed and added to a 50 mL round-bottom flask. A 6 mL / 6 mL / 3 mL mixture of THF / MeOH / water and 28.37 mg of LiOH·HO (1.5 equiv.) were added. The reaction mixture was heated at room temperature overnight. TLC showed complete reaction of the starting material. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. 5 mL of water was added to the concentrate, and the pH of the reaction mixture was adjusted to 4-5 with citric acid. The aqueous phase was extracted twice with 10 mL of ethyl acetate. The combined organic phase was washed twice with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give an oil. 1 mL of methanol was added to the oil to pulp it, and the mixture was filtered to give compound 2 (180 mg, 68.2% yield). MS m / z (ESI): 585.1902 (M+H). + , 1 HNMR (400 MHz, CDCl3) δ= 8.22 (d, J = 1.5 Hz, 1H), 8.11 (dd, J = 8.5, 1.5 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 2.2 Hz, 1H), 7.40 (t, J = 7.9 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 2.2 Hz, 1H), 6.19-6.08 (m, 2H), 5.66-5.59 (m, 2H), 5.56 (s, 1H), 5.18 (qd, J = 7.0, 3.0 Hz, 1H), 4.63 (td, J = 8.0, 6.0 Hz, 1H), 4.52-4.33 (m, 3H), 4.03-3.83 (m, 4H), 3.71 (m, 2H), 2.78-2.67 (m, 1H), 2.42 (m, 1H), 2.24 (s, 2H).

[0134] Example 3: Synthesis of compound 3:

[0135] [ka] Synthesis Route:

[0136] [ka] Compound 3-A:

[0137] [ka] Compound 03-A1: 10.0 g of 5-bromo-2-methylphenol (1.0 equiv.) was weighed and added to a 500 mL round-bottom flask. 200 mL of DMF, 12.5 g of 2-bromo-1,1-diethoxyethane (1.2 equiv.), 15.0 g of potassium carbonate (2.0 equiv.), and 1.0 g of KI (0.11 equiv.) were added. The reaction mixture was stirred until homogeneous and then heated to 120 °C for 16 hours under stirring. TLC indicated that the starting materials had essentially reacted completely. The reaction mixture was then cooled to room temperature and quenched with 200 mL of water. The resulting mixture was extracted twice with 200 mL of ethyl acetate. The combined ethyl acetate organic phase was washed twice with 200 mL of water, then washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by column chromatography (PE as eluent) to give oily compound 03-A1 (7.6 g, yield 46.9%).

[0138] Compound 03-A2: 7.6 g of compound 03-A1 (1.0 equivalent) was weighed and added to a 500 mL round-bottom flask. 150 mL of toluene and 20.96 g of polyphosphoric acid (2.5 equivalents) were then added. The reaction mixture was then heated to 90 °C and stirred for 10 hours. TLC showed that the starting materials had essentially reacted completely. After cooling to room temperature, 200 mL of water was added to the reaction mixture, and the resulting mixture was stirred and allowed to stand to form a layer. The toluene phase was washed with 150 mL of saturated NaHCO3 and 150 mL of saturated brine, then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 03-A2 (5.4 g) as an oil, which was used directly in the next step without further purification.

[0139] Compound 03-A3: 3.76 g of compound 03-A2 (1.0 equiv.), 4.79 g of CuCN (3.0 equiv.), and 6.79 g of CuI (2.0 equiv.) were weighed and added to a 150 mL round-bottom flask. 56.4 mL of DMF was added. The reaction mixture was stirred uniformly and heated to 150 °C for 9 hours under stirring. TLC showed that the starting materials had essentially reacted completely. After cooling to room temperature, 150 mL of water and 150 mL of ethyl acetate were added, and a large amount of solid was produced in the reaction system. The reaction mixture was then filtered through diatomaceous earth. The filtrate was allowed to settle and stratified, and the ethyl acetate phase was collected. The organic phase was washed twice with 30 mL of 25% aqueous ammonia, twice with 50 mL of water, and twice with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a yellow solid crude product, which was purified by column chromatography (PE as eluent) to give compound 03-A3 (2.1 g, 75% yield) as a white solid. 1 HNMR (400 MHz, CDCl3) δ =7.80 (d, J = 2.3 Hz, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.18 (d, J = 7.7 Hz, 1H), 7.00 (d, J = 2.2 Hz, 1H), 2.61 (s, 3H).

[0140] Compound 03-A4: 2.1 g of compound 03-A3 (1.0 eq.), 2.85 g of NBS (1.2 eq.), and 438.7 mg of 2,2-azobisisobutyronitrile (0.2 eq.) were weighed and added to a 50 mL round-bottom flask. 25 mL of dichloroethane was added. The reaction mixture was stirred uniformly and heated to 72 °C for 12 hours under stirring. TLC showed that the starting materials had essentially reacted completely. The reaction mixture was then cooled to room temperature, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (PE as eluent) to obtain compound 03-A4 (2.4 g, 76.20% yield) as an off-white solid.

[0141] Compound 3-A:

[0142] [ka] 2.4 g of compound 03-A4 (1.0 equivalent) was weighed and added to a 150 mL round-bottom flask. 24 mL of DMF and 9.84 g (10.0 equivalents) of potassium acetate were added. The reaction mixture was stirred at room temperature for 3.0 hours. TLC indicated that the starting material had completely reacted. 72 mL of water was then added to quench the reaction, and the resulting mixture was extracted twice with 50 mL of ethyl acetate. The combined ethyl acetate organic phases were washed twice with 50 mL of water, followed by two 50 mL washes with saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain an oil. 12 mL of THF was added to the oil, and the resulting mixture was stirred until homogenous. 4.1 mL of 5 mol / L sodium methoxide solution was added, and the reaction mixture was stirred at room temperature for 1 hour. TLC indicated that the starting material had disappeared. The reaction was then stopped. 36 mL of water and 50 mL of ethyl acetate were added to the reaction mixture, and the resulting mixture was allowed to stand for phase separation. The aqueous phase was extracted twice with 50 mL of ethyl acetate. The combined organic phase was washed twice with 75 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a crude yellow oil, which was purified by column chromatography (petroleum ether / ethyl acetate = 85 / 15 as eluent) to give compound 3-A (1.2 g, 68.18%) as a pale yellow solid. 1HNMR (400 MHz, CDCl3) δ 7.81 (d, J = 2.2 Hz, 1H), 7.62 (d, J = 7.7 Hz, 1H), 7.47 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 2.2 Hz, 1H), 5.10 (s, 2H).

[0143] Compound 3-B:

[0144] [ka] 850 mg of compound 1-B (1.0 equiv.) was weighed and added to a 100 mL round-bottom flask. 450 mg of compound 3-A (1.0 equiv.), 1.69 g of Cs2CO3 (2.0 equiv.), 300.0 mg of Xantphos (0.2 equiv.), 237.7 mg of Pd2(dba)3 (0.1 equiv.), and 32 mL of toluene were added. The reaction mixture was then stirred evenly, purged with nitrogen three times, and heated at 110 °C under nitrogen protection for 16 h. TLC showed that the two starting materials had completely reacted. After that, heating was stopped, the reaction mixture was cooled to room temperature, and then filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (petroleum ether / ethyl acetate = 95 / 5 as eluent) to obtain compound 3-B (720 mg, 66.06% yield).

[0145] Compound 3-C:

[0146] [ka] 720 mg of compound 3-B (1.0 equiv.) was weighed and added to a 50 mL round-bottom flask. 15 mL of acetonitrile was added, followed by a TBD solution (1,5,7-triazabicyclo[4.4.0]dec-5-ene, 475.9 mg of TBD (2.0 equiv.) dissolved in 3.0 mL of water). The reaction mixture was stirred at room temperature for 24 hours. TLC showed that the starting materials were essentially completely reacted. The reaction was stopped, and the pH of the reaction mixture was adjusted to approximately 5.0 with citric acid. The reaction mixture was extracted twice with 15 mL of ethyl acetate. The combined organic phase was washed twice with 30 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 3-C (640 mg, 95.06% yield).

[0147] Compound 3-D:

[0148] [ka] 400 mg of compound 3-C (1.0 equiv.) was weighed and added to a 50 mL round-bottom flask. 8 mL of acetonitrile and 241.50 mg of compound 1-F (1.0 equiv.) were added. The reaction mixture was placed at 0 °C and stirred. 335.6 mg of N-methylimidazole (4.0 equiv.) and 401.5 mg of TCFH (1.4 equiv.) were then added. The reaction mixture was then kept at 0 °C and reacted for 1 hour. The ice bath was removed, and the reaction mixture was allowed to warm to room temperature and react for 2 hours. TLC indicated that the starting compound 1-F had completely reacted. The reaction mixture was concentrated under reduced pressure, evaporated to dryness, and pulped with 4 mL of acetonitrile. The resulting mixture was filtered. The filter cake was washed with 0.5 mL of acetonitrile to give solid compound 3-D (340 mg, 54.6% yield).

[0149] Compound 3-E:

[0150] [ka] 310 mg of compound 3-D (1.0 equiv.) was weighed and added to a 50 mL round-bottom flask. 9 mL of methanol and 96.23 mg of pTSA (1.1 equiv.) were added. The reaction mixture was stirred evenly and heated at 80 °C for 1 hour. TLC showed that the starting materials had completely reacted. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure to evaporate the methanol. 10 mL of water and 15 mL of ethyl acetate were added to the concentrate, and the resulting mixture was allowed to stand for phase separation. The aqueous phase was then extracted with 10 mL of ethyl acetate. The combined organic phases were washed twice with 15 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (DCM:MeOH = 98:2 as eluent) to obtain compound 3-E (220 mg, 73.2% yield) as a white foam.

[0151] Compound 3:

[0152] [ka] 220 mg of compound 3-E (1.0 equiv.) was weighed and added to a 50 mL round-bottom flask. 5 mL of acetonitrile was added, followed by a TBD solution (103.6 mg (2.0 equiv.) dissolved in 1.0 mL of water). The reaction mixture was stirred at room temperature for 24 hours. TLC showed that the starting materials were essentially completely reacted. The reaction was stopped, and the pH of the reaction mixture was adjusted to approximately 5.0 with citric acid. The reaction mixture was extracted twice with 10 mL of ethyl acetate. The combined organic phase was washed twice with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography to give compound 3 (110 mg, 51.14% yield). MS m / z (ESI): 578.2408 (M+H). + , 1HNMR (400 MHz, CDCl3) δ= 8.22 (s, 1H), 8.10 (dd, J = 8.5, 1.2 Hz, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.81 (d, J = 2.2 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.00 (d, J = 2.2 Hz, 1H), 6.19 (d, J = 8.1 Hz, 1H), 6.15 (d, J = 7.8 Hz, 1H), 5.70 (s, 2H), 5.26 - 5.17 (m, 1H), 4.64 (d, J = 6.0 Hz, 1H), 4.55 - 4.33 (m, 3H), 4.25 - 4.17 (m, 2H), 3.00 (d, J = 7.1 Hz, 2H), 2.86 - 2.71 (m, 3H), 2.51 - 2.31 (m, 2H), 1.83 (d, J = 12.8 Hz, 2H), 1.37 - 1.30 (m, 2H).

[0153] Example 4: Synthesis of compound 4:

[0154] [ka] Synthesis Route:

[0155] [ka] Compound 4 was obtained by replacing compound 1-C with compound 3-A in Example 2 using the preparation method of compound 2. MS m / z (ESI): 576.2243 (M+H) + .

[0156] Example 5: Synthesis of compound 7:

[0157] [ka] Synthesis Route:

[0158] [ka] Compound 7-A:

[0159] [ka] 1 g of compound 1-C (1.0 equivalent), 1.45 g of 2-bromo-6-fluoropyridine (1.5 equivalents), and 3.75 g of cesium carbonate (2.0 equivalents) were weighed and added to a 100 mL round-bottom flask. 30 mL of DMF was then added. The reaction mixture was then heated to 90 °C and reacted for 4 hours. The heating was then stopped, and the reaction mixture was cooled to room temperature. 120 mL of water was added, and the resulting mixture was stirred at room temperature for 0.5 hours and then filtered. The filter cake was dried at 50 °C for 12 hours to give 1.8 g of compound 7-A in a 97% yield.

[0160] Compound 7-B:

[0161] [ka] 0.5 g of compound 7-A (1.0 equiv.), 0.478 g of compound 1-pinacolborate-4-ethylacetate-1-cyclohexene (1.1 equiv.), 0.108 g of Pd(dppf)Cl2 (0.1 equiv.), and 0.249 g of sodium bicarbonate (2 equiv.) were weighed and added to a 50 mL round-bottom flask. 7.5 mL of toluene, 2.5 mL of ethanol, and 2.5 mL of water were then added. The reaction mixture was degassed twice with nitrogen and heated to 110 °C under a nitrogen atmosphere. After 2 h of reaction, the heating was stopped, the reaction mixture was cooled to room temperature, filtered through a diatomaceous earth funnel, and the filter cake was washed with 15 mL of ethyl acetate twice. The filtrate was then concentrated to dryness and purified by column chromatography to give 0.6 g of compound 7-B in 95.4% yield.

[0162] Compound 7-C:

[0163] [ka] 0.6 g of compound 7-B (1.0 equivalent) was weighed and added to a 50 mL round-bottom flask. 6 mL of methanol and 9 mL of tetrahydrofuran were added. Then, 1.4 mL of 2 mol / L NaOH solution (2.0 equivalents) was added dropwise to the reaction mixture at room temperature. After the dropwise addition, the reaction mixture was allowed to react at room temperature for 1.5 hours. After the reaction, the reaction mixture was concentrated. After concentration, 15 mL of water and 30 mL of ethyl acetate were added, and the pH of the system was adjusted to 4-5 with 1 mol / L HCl solution. The organic phase was then separated and washed twice with 35 mL of ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4 for 5 minutes, and then filtered. The filtrate was concentrated to dryness to obtain 0.468 g of compound 7-C in an 83.5% yield.

[0164] Compound 7-D:

[0165] [ka] 0.465 g of compound 7-C (1.0 equivalent) and 0.304 g of compound 1-F (1.1 equivalents) were weighed and added to a 50 mL round-bottom flask. 10.0 mL of acetonitrile was added. After stirring the reaction mixture in an ice bath for 15 minutes, 0.304 g of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (1.1 equivalents) and 0.202 g of N-methylimidazole (2.1 equivalents) were weighed and added. The reaction mixture was stirred and reacted in an ice bath for 0.5 hours. The reaction mixture was then transferred to room temperature and allowed to react for 3 hours. After the reaction, 30 mL of HO was added to the reaction mixture, which was stirred for 0.5 hours and then filtered. The filter cake was washed with 20 mL of HO three times and dried at 50 °C to obtain 0.607 g of compound 7-D in an 84% yield.

[0166] Compound 7-E:

[0167] [ka] 0.605 g of compound 7-D (1.0 equiv.) was weighed and added to a 50 mL round-bottom flask. 10.0 mL of 1,4-dioxane was added. 2.95 g of acetic acid (50.0 equiv.) was then added dropwise. After the addition, the reaction mixture was heated at 80 °C for 15 hours. The reaction mixture was cooled to room temperature. 10 mL of water and 25 mL of ethyl acetate were added, and the pH of the mixture was adjusted to 7-8 with 5% NaHCO3 solution. The reaction mixture was then allowed to stand. The organic phase was separated, and the aqueous phase was washed twice with 25 mL of ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4 for 5 minutes, filtered, concentrated to dryness, and purified by column chromatography to give 0.345 g of compound 7-E in 58.7% yield. MS m / z (ESI): 598.2109 (M+H). + .

[0168] Compound 7:

[0169] [ka] 0.34 g of compound 7-E (1.0 equivalent) was weighed and added to a 25 mL round-bottom flask. 1.7 mL of methanol and 5.0 mL of tetrahydrofuran were added. 0.56 mL of 2N sodium hydroxide solution was then added. The reaction mixture was then allowed to react at room temperature. After 20 hours, the reaction mixture was concentrated. After concentration, 6 mL of water was added, and the pH of the reaction mixture was adjusted to 4-5 with 1 mol / L HCl solution. The reaction mixture was then filtered. The filter cake was pulped with 5 mL of ethyl acetate and 1 mL of methanol, and then filtered. The filter cake was washed with 3 mL of ethyl acetate three times and dried to obtain 0.177 g of compound 7 in a 53.3% yield. MS m / z (ESI): 584.1953 (M+H) + , 1H NMR (400 MHz, DMSO-d6) δ= 8.21 (s, 1H), 8.17 (d, J = 2.0Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.68-7.60 (m, 2H), 7.42 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.07-7.04 (m, 2H), 6.74-6.70 (m, 2H), 5.65 (s, 2H), 5.03 (d, J = 6.4 Hz, 1H), 4.63 (dd, J = 15.2, 6.8 Hz, 1H), 4.52-4.43 (m, 2H), 4.32-4.28 (m, 1H), 3.04-2.92 (m, 2H), 2.72-2.64 (m, 2H), 2.41-2.33 (m, 4H), 2.07-1.96 (m, 2H), 1.50-1.47 (m, 1H).

[0170] Example 6: Synthesis of compound 8:

[0171]

change

[0172]

change

[0173]

change

[0174] Compound 8-B:

[0175] [ka] 0.5 g of compound 8-A (1.0 equiv.), 0.492 g of 1-pinacolborate-4-ethylacetate-1-cyclohexene (1.1 equiv.), 0.111 g of Pd(dppf)Cl2 (0.1 equiv.), and 0.255 g of sodium bicarbonate (2 equiv.) were weighed and added to a 50 mL round-bottom flask. 7.5 mL of toluene, 2.5 mL of ethanol, and 2.5 mL of water were added. The reaction mixture was then degassed twice with nitrogen and heated to 110 °C under a nitrogen atmosphere. After 2 h of reaction, the heating was stopped, the reaction mixture was cooled to room temperature, filtered through a diatomaceous earth funnel, and the filter cake was washed with 15 mL of ethyl acetate twice. The filtrate was then concentrated to dryness and purified by column chromatography to give 0.506 g of compound 8-B in 80% yield.

[0176] Compound 8-C:

[0177] [ka] 0.5 g of compound 8-B (1.0 equiv.) was weighed and added to a 50 mL round-bottom flask. 15 mL of acetonitrile was added, followed by a TBD solution (1,5,7-triazabicyclo[4.4.0]dec-5-ene, TBD (2.0 equiv.) dissolved in 4.0 mL of water). The reaction mixture was stirred at room temperature for 24 hours. After completion of the reaction, the reaction mixture was concentrated, and 15 mL of water and 35 mL of ethyl acetate were added. The pH of the reaction mixture was adjusted to 4-5 with citric acid. The reaction mixture was then allowed to stand, and the organic phase was separated. The aqueous phase was washed twice with 35 mL of ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4 for 5 minutes, and then filtered. The filtrate was concentrated to dryness to obtain 0.364 g of compound 8-C in a 78% yield.

[0178] Compound 8-D:

[0179] [ka] 0.3 g of compound 8-C (1.0 equivalent), 0.201 g of compound 1-F (1.1 equivalents), and 0.298 g of TBTU (1.2 equivalents) were weighed and added to a 50 mL round-bottom flask. 15.0 mL of DMF was added. The reaction mixture was stirred in an ice bath for 10 minutes, and then 0.199 g of N,N-diisopropylethylamine (2.0 equivalents) was added dropwise. After the addition, the reaction mixture was stirred in the ice bath for 3 hours. After the reaction, 30 mL of H2O and 30 mL of ethyl acetate were added to the reaction mixture, and the resulting mixture was stirred for 5 minutes and allowed to stand. The organic phase was separated, and the aqueous phase was washed twice with 30 mL of ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4 for 5 minutes, and filtered. The filtrate was concentrated to dryness and purified by column chromatography to give 0.265 g of compound 8-D in 56% yield. MS m / z (ESI): 607.2553 (M+H). + .

[0180] Compound 8-E:

[0181] [ka] 0.25 g of compound 8-D was weighed and added to a 50 mL round-bottom flask. 10 mL of methanol and 78.0 mg of pTSA (1.1 equivalents) were added. The reaction mixture was stirred uniformly and heated at 80 °C for 2 hours. The reaction mixture was then cooled to room temperature, concentrated, and purified by column chromatography to give 0.143 g of compound 8-E in a 59% yield.

[0182] Compound 8:

[0183] [ka] 0.1 g of compound 8-E (1.0 equivalent) was weighed and added to a 25 mL round-bottom flask. 5 mL of acetonitrile was added, followed by a TBD solution (TBD (2.0 equivalents) dissolved in 1.0 mL of water). The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was then concentrated, and 30 mL of ethyl acetate was added. The pH of the reaction mixture was then adjusted to 4-5 with citric acid. The reaction mixture was then allowed to stand, the organic phase was separated, and the aqueous phase was washed twice with 20 mL of ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4 for 5 minutes, and then filtered. The filtrate was concentrated to dryness and purified by column chromatography to give 19.5 mg of compound 8 in a 20% yield. MS m / z (ESI): 575.2291 (M+H). + .

[0184] Example 7: Synthesis of compound 10:

[0185] [ka] Synthesis Route:

[0186] [ka] Compound 001-M7:

[0187] [ka] 5.30 g of compound 1-F (1.0 equiv.) was weighed and added to a 250 mL round-bottom flask. 64 mL of acetonitrile, 3.81 g of 2-chloro-1,1,1-trimethoxyethane (1.1 equiv.), and 213.0 mg of pTSA·HO (0.05 equiv.) were then added. The reaction mixture was then heated at 50 °C for 1.5 hours. TLC indicated complete reaction of the starting material. The reaction mixture was cooled slightly and then concentrated under reduced pressure. 50 mL of water and 35 mL of ethyl acetate were added to the concentrate, and the mixture was allowed to stand for phase separation. The aqueous phase was washed twice with 20 mL of ethyl acetate. The combined organic phase was then washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give an oil. Then, 8 mL of ethyl acetate and 40 mL of petroleum ether were added to the oil and pulped, and the resulting system was filtered to obtain solid compound 001-M07 (5.2 g, 78.67%). 1 HNMR (400 MHz, CDCl3) δ =8.16 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 5.24 (d, J = 6.4 Hz, 1H), 5.08 (s, 2H), 4.65 (dd, J = 14.8, 6.9 Hz, 2H), 4.56 (d, J = 13.9 Hz, 1H), 4.36 (dd, J = 5.9, 3.2 Hz, 1H), 3.98 (s, 3H), 2.79 (dt, J = 14.0, 7.8 Hz, 1H), 2.51-2.38 (m, 1H).

[0188] Compound 10-A:

[0189] [ka] Under nitrogen protection, 45 mL of dichloromethane and 70 mL (8.0 equiv.) of a 1 M ZnEt2 toluene solution were added to a 250 mL three-neck flask. The resulting mixture was cooled to -40 °C and stirred. 10 mL of a dichloromethane solution containing 37.46 g of diiodomethane (16.0 equiv.) was slowly added dropwise. After the addition, the reaction mixture was maintained at -40 °C and stirred for approximately 1 hour. 7.97 g of trifluoroacetic acid (8.0 equiv.) was then added dropwise. The resulting mixture was warmed to -15 °C and stirred for another hour. 10 mL of a dichloromethane solution containing 3 g of N-Cbz-3,6-dihydro-2H-pyridine-4-boronic acid pinacol ester (1.0 equiv.) was then added dropwise. After the addition, the reaction mixture was stirred at room temperature for approximately 15 hours and then filtered through diatomaceous earth. The filtrate was added with 100 mL of dichloromethane and 50 mL of saturated sodium bicarbonate solution, and then stirred to separate the liquid phases. The organic phase was washed with 50 mL of water and 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. After concentration, 60 mL of tetrahydrofuran and 30 mL of water were added to the residue, and the resulting system was stirred to dissolve. 3.11 g of N-bromosuccinimide (2 equivalents) was added. The resulting system was stirred for approximately 2 hours, after which 100 mL of ethyl acetate and 50 mL of saturated sodium bicarbonate solution were added, and the resulting system was stirred to separate the liquid phases. The organic phase was washed again with 50 mL of water and 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by column chromatography to obtain 830 mg of compound 10-A in a yield of 26.6%. MS m / z (ESI): 358.2192 (M+H). + , 1 H NMR (400 MHz, CDCl3) δ =7.43-7.29 (m, 5H), 5.13 (s, 2H), 3.92 (t, J = 11.5 Hz, 1H), 3.57 (dd, J = 10.3, 6.6 Hz, 2H), 2.97 (s, 1H), 2.13 (dd, J = 9.4, 4.8 Hz, 1H), 1.31-1.12 (m, 14H), 0.96-0.87 (m, 1H), 0.45 (m, 1H).

[0190] Compound 10-B:

[0191] [ka] 800 mg of compound 10-A (1.0 equivalent) and 1.22 g of KHF2 (7.0 equivalents) were weighed and added to a 25 mL round-bottom flask. 8 mL of methanol was added. The reaction mixture was refluxed for approximately 15 hours until TLC showed the reaction was complete. After cooling to room temperature, the reaction mixture was concentrated, and then 5 mL of petroleum ether and 1 mL of methyl tert-butyl ether were added. The mixture was stirred at room temperature for approximately 0.5 hours, and then the resulting mixture was filtered. 8 mL of acetonitrile was added to the filter cake, and the mixture was stirred under reflux for approximately 15 hours, and then filtered. The filtrate was concentrated to give 630 mg of compound 10-B in an 83.4% yield.

[0192] Compound 10-C:

[0193] [ka] 400 mg of compound 7-A (1.0 equiv.), 438 mg of compound 10-B (1.1 equiv.), 47 mg of tBuXPhos-Pd-G3 (0.05 equiv.), and 1.15 g of cesium carbonate (3.0 equiv.) were weighed and added to a 25 mL round-bottom flask. 5 mL of toluene and 1 mL of water were then added. The reaction mixture was stirred uniformly and degassed twice with nitrogen. The reaction mixture was then heated to 80 °C under a nitrogen atmosphere and stirred for approximately 6 hours until TLC showed the reaction was complete. The reaction mixture was cooled to room temperature and filtered through diatomaceous earth. The filter cake was washed with 50 mL of ethyl acetate, and the filtrate was collected. The filtrate was washed sequentially with 20 mL of water and 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by column chromatography to give 350 mg of compound 10-C in 60.6% yield.

[0194] Compound 10-D:

[0195] [ka] 340 mg of compound 10-C (1.0 equiv.), 202 mg of triethylsilane (2.5 equiv.), 35 mg of triethylamine (0.5 equiv.), and 16 mg of palladium acetate (0.1 equiv.) were weighed and added to a 25 mL round-bottom flask. 5 mL of ethanol was added. The reaction mixture was stirred until homogeneous and then reacted at room temperature under a nitrogen atmosphere for approximately 16 hours until TLC showed the reaction was complete. The reaction mixture was filtered through a diatomaceous earth funnel. The filter cake was washed with an appropriate amount of ethanol, and the filtrate was collected. The filtrate was then concentrated and purified by column chromatography to give 198 mg of compound 10-D in an 80.2% yield.

[0196] Compound 10-E:

[0197] [ka] 190 mg of compound 10-D (1.0 equivalent), 158 mg of compound 001-M07 (1.0 equivalent), and 148 mg of potassium carbonate (2.0 equivalents) were weighed and placed in a 50 mL round-bottom flask. 10 mL of acetonitrile was added. The reaction mixture was heated to 50 °C and reacted for approximately 4 hours until TLC showed the reaction was complete. The reaction mixture was then cooled to room temperature, and 20 mL of water and 30 mL of ethyl acetate were added. The resulting mixture was allowed to stand for phase separation. The aqueous phase was extracted three times with 20 mL of ethyl acetate. The combined organic phases were washed with 20 mL of water and 20 mL of saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, and filtered. After concentration, the filtrate was purified by column chromatography to give 220 mg of compound 10-E in 67.1% yield. MS m / z (ESI): 613.2215 (M+H). + .

[0198] Compound 10:

[0199] [ka] 200 mg of compound 10-E (1.0 equiv.) and 21 mg of lithium hydroxide monohydrate (1.5 equiv.) were weighed and added to a 50 mL round-bottom flask. 3 mL of acetonitrile, 1 mL of methanol, and 1 mL of water were then added. The reaction mixture was heated to 40 °C and reacted for approximately 5.5 hours until TLC showed the reaction was complete. The reaction mixture was then cooled to room temperature and concentrated to remove most of the organic solvent. 15 mL of water was added to the residue to dilute it, and the pH of the reaction mixture was adjusted to 4-5 with citric acid. The aqueous phase was then extracted with 15 mL of ethyl acetate three times. The combined organic phases were washed with 15 mL of water and 15 mL of saturated sodium chloride solution, respectively, dried over anhydrous Na2SO4, and filtered. After concentration, the filtrate was purified by column chromatography to give 124 mg of compound 10 in 63.6% yield. MS m / z (ESI): 599.2063 (M+H). + .

[0200] Example 8: Synthesis of compound 11:

[0201] [ka] Synthesis Route:

[0202] [ka] Compound 11 was obtained by replacing compound 7-A with compound 8-A according to the preparation method of compound 10. MS m / z (ESI): 590.2409 (M+H) + .

[0203] Example 9: Synthesis of compound 13:

[0204] [ka] Synthesis Route:

[0205] [ka] Compound 13-A:

[0206] [ka] 600 mg of dibenzofuran-4-carboxylic acid (1.0 equiv.) was weighed and added to a 50 mL round-bottom flask. 10 mL of tetrahydrofuran was added. The resulting mixture was stirred to dissolve, then stirred in an ice bath for 5 minutes. 215 mg of lithium aluminum hydride (2.0 equiv.) was then added. After the addition, the reaction mixture was allowed to react at 0-10°C for approximately 1 hour. TLC showed the reaction was complete. 10 mL of saturated aqueous ammonium chloride solution was then added dropwise to the reaction mixture until no more bubbles were observed. The reaction mixture was then filtered through a diatomaceous earth funnel, and the filter cake was washed with 50 mL of ethyl acetate. After concentration, the filtrate was purified by column chromatography to obtain 447 mg of compound 13-A in a 79.8% yield.

[0207] Compound 13-B:

[0208] [ka] 420 mg of compound 13-A (1.0 equivalent), 410 mg of 2-bromo-6-fluoropyridine (1.1 equivalents), and 1.38 g of cesium carbonate (2.0 equivalents) were weighed and added to a 50 mL round-bottom flask. 5 mL of N,N-dimethylformamide was added. The reaction mixture was heated to 90 °C and reacted for approximately 2 hours until TLC showed the reaction was complete. The reaction mixture was then cooled to room temperature, and 15 mL of water was added to precipitate a large amount of solid. The resulting mixture was stirred for approximately 0.5 hours and then filtered. The filter cake was washed with a small amount of water and dried to obtain 600 mg of compound 13-B in an 80.0% yield.

[0209] Compound 13-C:

[0210] [ka] 600 mg of compound 13-B (1.0 equiv.), 576 mg of N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (1.1 equiv.), 124 mg of Pd(dppf)Cl2 (0.1 equiv.), and 285 mg of sodium bicarbonate (2.0 equiv.) were weighed and added to a 100 mL round-bottom flask. 7.5 mL of toluene, 2.5 mL of ethanol, and 2.5 mL of water were added. The reaction mixture was stirred evenly and degassed twice with nitrogen. The mixture was then heated to 110 °C and reacted under a nitrogen atmosphere for approximately 2 hours until TLC showed the reaction was complete. The reaction mixture was then cooled to room temperature, filtered through a diatomaceous earth funnel, and the filter cake was washed with a small amount of dichloromethane. The filtrate was concentrated to dryness and purified by column chromatography to give 710 mg of compound 13-C in 91.8% yield.

[0211] Compound 13-D:

[0212] [ka] 700 mg of compound 13-C (1.0 equiv.) and 875 mg of p-toluenesulfonic acid monohydrate (3.0 equiv.) were weighed and placed in a 25 mL round-bottom flask. 15 mL of ethyl acetate was added. The reaction mixture was heated to 60 °C and reacted for approximately 2 hours until TLC indicated completion of the reaction. The reaction mixture was then cooled to room temperature and diluted with 30 mL of ethyl acetate. The pH of the reaction mixture was adjusted to 8-9 with saturated sodium bicarbonate solution, and the reaction mixture was allowed to stand for phase separation. The ethyl acetate phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness to obtain 510 mg of compound 13-D in a 93.2% yield.

[0213] Compound 13-E:

[0214] [ka] 250 mg of compound 001-M07 (1.0 equivalent), 317 mg of compound 13-D (1.05 equivalent), and 234 mg of cesium carbonate (2.0 equivalents) were weighed and added to a 100 mL round-bottom flask. 15 mL of acetonitrile was added. The reaction mixture was heated to 50°C for approximately 3 hours until TLC showed the reaction was complete. The reaction mixture was then cooled to room temperature, and 30 mL of water was added to precipitate a large amount of solid. The resulting mixture was stirred for approximately 0.5 hours and then subjected to suction filtration. The filter cake was washed with a small amount of water and dried to obtain 385 mg of compound 13-E in a 73.9% yield. MS m / z (ESI): 615.2605 (M+H). + .

[0215] Compound 13:

[0216] [ka] 385 mg of compound 13-E (1.0 equiv.) and 39 mg of lithium hydroxide monohydrate (1.5 equiv.) were weighed and added to a 25 mL round-bottom flask. 6 mL of acetonitrile, 2 mL of methanol, and 2 mL of water were then added. The reaction mixture was heated to 40 °C and reacted for approximately 6 hours until TLC showed the reaction was complete. After cooling to room temperature, the reaction mixture was concentrated to remove most of the organic solvent. 20 mL of water was added for dilution, and the pH of the reaction mixture was adjusted to 4-5 with citric acid solution. The aqueous phase was extracted with 20 mL of ethyl acetate three times. The combined ethyl acetate phases were washed with 20 mL of water and 20 mL of saturated sodium chloride solution, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to dryness and recrystallized from dichloromethane / methanol to give 241 mg of compound 13 in 64.1% yield. MS m / z (ESI): 601.2457 (M+H). + , 1H NMR (400 MHz, DMSO) δ =12.90 (s, 1H), 8.28 (s, 1H), 8.09 (t, J = 8.1 Hz, 2H), 7.85 (d, J = 8.4 Hz, 1H), 7.67 (dd, J = 14.6, 8.0 Hz, 3H), 7.59 (d, J = 7.3 Hz, 1H), 7.37 (t, J = 7.6 Hz, 2H), 7.27 (t, J = 7.4 Hz, 1H), 7.05 (d, J = 7.4 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H), 6.67 (s, 1H), 5.73 (s, 2H), 5.03 (d, J = 5.3 Hz, 1H), 4.76 (dd, J = 15.2, 7.1 Hz, 1H), 4.61 (d, J = 14.2 Hz, 1H), 4.46 (dd, J = 13.6, 7.0 Hz, 1H), 4.34 (dd, J = 14.3, 5.9 Hz, 1H), 4.02 (d, J = 13.5 Hz, 1H), 3.86 (d, J = 13.4 Hz, 1H), 3.10 (q, J = 16.9 Hz, 2H), 2.62 (s, 3H), 2.39 (d, J = 18.4 Hz, 3H).

[0217] Example 10: Synthesis of compound 14:

[0218]

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[0219]

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[0220]

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[0221] Compound 002-M03: 8.5 g of compound 002-M02 (1.0 equivalent) was weighed and added to a 250 mL round-bottom flask. 85 mL of dichloromethane was added. The reaction mixture was stirred in an ice bath for 0.5 hours. 10.65 g of oxalyl chloride (2.0 equivalents) and 0.52 mL of DMF (0.16 equivalents) were weighed and added. The reaction mixture was slowly heated to room temperature and allowed to react for 1.0 hour. 4.03 g of methanol (3.0 equivalents) was weighed and added. The reaction mixture was allowed to react for 15 hours at room temperature. After the reaction, the reaction mixture was concentrated and purified by column chromatography to obtain 8.0 g of compound 002-M03 in an 88% yield.

[0222] Compound 002-M04: 4.0 g of compound 002-M03 (1.0 equivalent), 1.93 g of compound (S)-oxetan-2-ylmethanamine, 3.74 g of triethylamine (2.0 equivalents), 80 mL of DMF, and 80 mL of THF were weighed and added to a 250 mL round-bottom flask. The reaction mixture was then reacted at room temperature for 15 hours. After the reaction, the reaction mixture was concentrated to remove the THF, and 160 mL of water was added. The resulting mixture was stirred for 2 hours and filtered. The filter cake was washed with water and dried at 50 °C for 12 hours to obtain 3.35 g of compound 002-M04 in a 68% yield. MS m / z (ESI): 268.0925 (M+H). + .

[0223] Compound 002-M05: 3.35 g of compound 002-M04 (1.0 equivalent), 0.335 g of palladium on carbon (10%), and 50 mL of methanol were weighed and added to a 100 mL round-bottom flask. The reaction mixture was then degassed twice with nitrogen and twice with hydrogen, and reacted at room temperature under a hydrogen atmosphere for 15 hours. After the reaction, the reaction mixture was filtered through a diatomaceous earth funnel, and the filter cake was washed with 50 mL of ethyl acetate twice. The filtrate was then concentrated to dryness to give 2.97 g of compound 002-M05, which was used directly in the next reaction without further purification.

[0224] Compound 002-M06:

[0225] [ka] 1.275 g of compound 002-M05 (1.0 equivalent), 0.965 g of chloroacetic anhydride (1.05 equivalents), and 25 mL of THF were weighed and added to a 50 mL round-bottom flask. The reaction mixture was heated to 60 °C. After 1.5 hours of reaction, the heating was stopped, the reaction mixture was cooled to room temperature, and concentrated. After concentration, 25 mL of saturated sodium bicarbonate solution and 25 mL of ethyl acetate were added to the residue, and the organic phase was separated. The aqueous phase was washed twice with 25 mL of ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4 for 5 minutes, and then filtered. The filtrate was concentrated to dryness and purified by column chromatography to obtain 1.07 g of compound 002-M06 in 67.3% yield. MS m / z (ESI): 296.0798 (M+H). + , 1 HNMR(400MHz, CDCl3)δ =8.14-8.10 (m, 2H), 5.23-5.17 (m, 1H), 5.07 (q, J = 12.4 Hz, 2H), 4.82-4.70 (m, 2H), 4.58 (q, J = 7.6 Hz, 1H), 4.32-4.26 (m, 1H), 3.99 (s, 3H), 2.80-2.71 (m, 1H), 2.46-2.37 (m, 1H).

[0226] Compound 14-A:

[0227] [ka] 0.15 g of compound 002-M06 (1.0 equivalent), 0.199 g of compound 13-D (1.1 equivalent), and 91 mg of potassium carbonate (2.0 equivalents) were weighed and added to a 25 mL round-bottom flask. 5 mL of acetonitrile was added. The reaction mixture was heated to 60 °C. After 3 hours of reaction, heating was stopped, the reaction mixture was cooled to room temperature, and concentrated. After concentration, 10 mL of water was added to the residue, followed by stirring for approximately 0.5 hours. A large amount of solid precipitated, which was then subjected to suction filtration. The filter cake was washed with 10 mL of water three times, dried, and then purified by column chromatography to obtain 0.165 g of compound 14-A in a 53% yield.

[0228] Compound 14:

[0229] [ka] 0.164 g of compound 14-A (1.0 equivalent) was weighed and added to a 25 mL round-bottom flask. 1.0 mL of methanol and 3.0 mL of tetrahydrofuran were added, followed by 0.27 mL of 2N sodium hydroxide solution. The reaction mixture was then allowed to react at room temperature. After 15 hours, the reaction mixture was concentrated. After concentration, 4 mL of water was added to the residue, and the pH of the reaction mixture was adjusted to 4-5 with 1 mol / L HCl. The reaction mixture was then filtered. The filter cake was pulped with 2 mL of ethyl acetate and 0.5 mL of pulping methanol, followed by filtration. The filter cake was washed with 2 mL of ethyl acetate three times and dried to obtain 0.118 g of compound 14 in a 73.6% yield. MS m / z (ESI): 602.2403 (M+H). + , 1H NMR (400 MHz, DMSO-d6) δ =8.17 (d, J = 8.2 Hz, 1H), 8.10-8.02 (m, 3H), 7.69-7.64 (m, 2H), 7.58 (d, J = 7.2 Hz, 1H), 7.39-7.34 (m, 2H), 7.25 (t, J = 7.6 Hz, 1H), 7.04 (d, J = 7.2 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.67 (s, 1H), 5.72 (s, 2H), 5.14-5.08 (m, 1H), 4.82-4.64 (m, 2H), 4.47-4.30 (m, 2H), 4.02 (dd, J = 38.4, 13.2 Hz, 2H), 3.19-3.08 (m, 2H), 2.67-2.62 (m, 3H), 2.47-2.42 (m, 3H).

[0230] Example 11: Synthesis of compound 15:

[0231]

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[0232]

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[0233]

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[0234] Compound 15-B:

[0235] [ka] 0.45 g of compound 15-A (1.0 equivalent) was weighed and added to a 50 mL round-bottom flask. 6.5 mL of methanol and 10 mL of tetrahydrofuran were added. Then, 1.02 mL of 2 mol / L NaOH solution (2.0 equivalents) was added dropwise to the reaction mixture at room temperature. After the dropwise addition, the reaction mixture was allowed to react at room temperature for 1.5 hours. After the reaction was completed, the reaction mixture was concentrated. After concentration, 15 mL of water and 35 mL of ethyl acetate were added to the residue, and the pH of the reaction mixture was adjusted to 4-5 with 1 mol / L HCl solution. The resulting mixture was then allowed to stand. The organic phase was separated, and the aqueous phase was washed twice with 35 mL of ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4 for 5 minutes, and then filtered. The filtrate was concentrated to dryness to obtain 0.316 g of compound 15-B in a 75% yield.

[0236] Compound 15-C:

[0237] [ka] 0.3 g of compound 15-B (1.0 equivalent), 0.188 g of compound 1-F (1.1 equivalents), and 0.279 g of TBTU (1.2 equivalents) were weighed and added to a 50 mL round-bottom flask. 15.0 mL of DMF was added. The reaction mixture was stirred in an ice bath for 10 minutes, and then 0.188 g of diisopropylethylamine (2.0 equivalents) was added dropwise. After the dropwise addition, the reaction mixture was continued stirring in the ice bath for 3 hours. After the reaction, 30 mL of H2O and 30 mL of ethyl acetate were added to the reaction mixture, and the resulting mixture was stirred for 5 minutes and allowed to stand. The organic phase was separated, and the aqueous phase was washed twice with 30 mL of ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4 for 5 minutes, and filtered. The filtrate was concentrated to dryness and purified by column chromatography to give 0.247 g of compound 15-C in a yield of 53.9%.

[0238] Compound 15-D:

[0239] [ka] 0.2 g of compound 15-C was weighed and added to a 50 mL round-bottom flask. 4.0 mL of 1,4-dioxane was added. 1 mL of acetic acid was then added dropwise. After the addition, the reaction mixture was heated to 80°C and allowed to react. After 5 hours, the reaction mixture was cooled to room temperature. The reaction mixture was then concentrated and purified by column chromatography to obtain 0.12 g of compound 15-D in a 62% yield.

[0240] Compound 15:

[0241] [ka] 0.1 g of compound 15-D (1.0 equivalent) and 20.5 mg of lithium hydroxide monohydrate were weighed and added to a 25 mL round-bottom flask. 1.0 mL of methanol, 1.0 mL of tetrahydrofuran, and 0.1 mL of HO were then added. The reaction mixture was then heated to 40 °C for reaction. After 5 h, the reaction mixture was cooled to room temperature and concentrated. After concentration, 30 mL of ethyl acetate was added to the residue, and the pH of the reaction mixture was adjusted to 4-5 with 1 mol / L HCl solution. The reaction mixture was then allowed to stand. The organic phase was separated, and the aqueous phase was washed twice with 20 mL of ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous NaSO for 5 minutes, and filtered. The filtrate was concentrated to dryness and purified by column chromatography to give 53.7 mg of compound 15 in a 55% yield. MS m / z (ESI): 600.2493 (M+H). + , 1 H NMR (400 MHz, DMSO-d6) δ=8.23 (s, 1H), 8.13-8.10 (m, 2H), 7.83-7.59 (m, 5H), 7.44-7.33 (m, 3H), 7.04 (d, J = 7.2 Hz, 1H), 6.73 (d, J = 7.2 Hz, 2H), 5.74 (s, 2H), 5.01 (d, J = 5.2 Hz, 1H), 4.64-4.59 (m, 1H), 4.51-4.44 (m, 2H), 4.29 (d, J = 6.0 Hz, 1H), 4.05-4.01 (m, 1H), 2.94-2.93 (m, 3H), 2.72-2.64 (m, 1H), 2.33-2.29 (m, 4H), 1.99 (s, 2H).

[0242] Example 12: Synthesis of compound 16:

[0243] [ka] Synthesis Route:

[0244] [ka] Following the synthesis method of compound 15, compound 13-B was replaced with compound 16-A to finally obtain compound 16. MS m / z (ESI): 634.2103 (M+H) + .

[0245] Example 13: Synthesis of compound 17:

[0246] [ka] Synthesis Route:

[0247] [ka] Compound 17-B:

[0248] [ka] 4.94 g of compound 17-A (1.0 equiv.), 6.09 g of bis(pinacolato)diboron (1.2 equiv.), 0.44 g of Pd(dppf)Cl2 (0.03 equiv.), and 4.91 g of potassium acetate (2.5 equiv.) were weighed and added to a round-bottom flask. 30 mL of 1,4-dioxane was added. The reaction mixture was then degassed twice with nitrogen and heated to 100 °C under a nitrogen atmosphere. After 2 h of reaction, the heating was stopped and the reaction mixture was cooled to room temperature. The reaction mixture was then filtered through a diatomaceous earth funnel, and the filter cake was washed with 20 mL of ethyl acetate twice. The filtrate was then concentrated to dryness to give 6.87 g of compound 17-B, which was used directly in the next reaction without further purification.

[0249] Compound 17-D:

[0250] [ka] 0.353 g of compound 17-B (1.2 equiv.), 0.338 g of compound 7-A (1.0 equiv.), 0.022 g of Pd(dppf)Cl2 (0.03 equiv.), and 0.815 g of Cs2CO3 (2.5 equiv.) were weighed and added to a 50 mL round-bottom flask. 13.0 mL of 1,4-dioxane and 2.0 mL of HO were added. The reaction mixture was then degassed twice with nitrogen and heated to 90 °C under a nitrogen atmosphere. After 2 h of reaction, the heating was stopped and the reaction mixture was cooled to room temperature. The reaction mixture was then filtered through a diatomaceous earth funnel, and the filter cake was washed with 10 mL of ethyl acetate twice. The filtrate was then concentrated to dryness and purified by column chromatography to give 0.328 g of compound 17-D in 77.0% yield.

[0251] Compound 17-F:

[0252] [ka] 0.328 g of compound 17-D (1.0 equivalent) was weighed and added to a 50 mL round-bottom flask. 4.0 mL of methanol and 6.0 mL of tetrahydrofuran were added. Then, 0.77 mL (2.0 equivalents) of 2 mol / L NaOH solution was added dropwise to the reaction mixture at room temperature. After the dropwise addition, the reaction mixture was allowed to react at room temperature for 1.5 hours. After the reaction was completed, the reaction mixture was concentrated. 10 mL of water and 25 mL of ethyl acetate were added to the reaction mixture, and the pH of the reaction mixture was adjusted to 4-5 with 1 mol / L HCl solution. The reaction mixture was then allowed to stand, and the organic phase was separated. The aqueous phase was washed twice with 25 mL of ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4 for 5 minutes, and then filtered. The filtrate was concentrated to dryness and dried to obtain 0.261 g of compound 17-F as a white solid in an 82.3% yield. MS m / z (ESI): 412.0751 (M+H) + .

[0253] Compound 17-G:

[0254] [ka] 0.261 g of compound 17-F (1.0 equiv.), 0.165 g of compound 1-F (1.1 equiv.), and 0.250 g of TBTU (1.2 equiv.) were weighed and added to a 50 mL round-bottom flask. 10.0 mL of DMF was added. The reaction mixture was stirred in an ice bath for 10 minutes, followed by the dropwise addition of 0.22 mL of diisopropylethylamine (2.0 equiv.). After the dropwise addition, the reaction mixture was stirred in the ice bath for 3 hours. After the reaction was complete, 30 mL of H2O and 30 mL of ethyl acetate were added to the reaction mixture, stirred for 5 minutes, and allowed to stand. The organic phase was separated, and the aqueous phase was washed twice with 25 mL of ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4 for 5 minutes, and then filtered. The filtrate was concentrated to dryness and purified by column chromatography to give 0.160 g of compound 17-G in a 40.0% yield. MS m / z (ESI): 630.1805 (M+H) + .

[0255] Compound 17-I:

[0256] [ka] 0.160 g of compound 17-G was weighed and added to a 50 mL round-bottom flask. 4.0 mL of 1,4-dioxane was added, followed by dropwise addition of 0.58 mL of acetic acid. After the dropwise addition, the reaction mixture was heated to 80°C. After 5 hours of reaction, the reaction mixture was cooled to room temperature. The reaction mixture was then concentrated and purified by column chromatography to obtain 86 mg of compound 17-I in a 55.5% yield. MS m / z (ESI): 612.1707 (M+H). + .

[0257] Compound 17:

[0258] [ka] 86 mg of compound 17-I and 17.6 mg of lithium hydroxide monohydrate were weighed and added to a 25 mL round-bottom flask. 1.0 mL of methanol, 1.0 mL of tetrahydrofuran, and 0.1 mL of HO were then added. The reaction mixture was then heated at 40 °C. After 5 hours of reaction, the reaction mixture was cooled to room temperature. The reaction mixture was then concentrated. 30 mL of ethyl acetate was added to the residue, and the pH of the reaction mixture was adjusted to 4-5 with 1 mol / L HCl solution. The reaction mixture was then allowed to stand, the organic phase was separated, and the aqueous phase was washed twice with 20 mL of ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous NaSO for 5 minutes, and filtered. The filtrate was concentrated to dryness and purified by column chromatography to obtain 60 mg of compound 17 in a 71.8% yield. MS m / z (ESI): 598.1536 (M+H). + , 1 H NMR (400 MHz, DMSO) δ =12.70 (s, 1H), 8.25 (s, 1H), 8.19 (d, J = 2.0 Hz, 1H), 7.93 - 7.77 (m, 4H), 7.61 (dd, J = 21.2, 8.0 Hz, 2H), 7.52 - 7.33 (m, 3H), 7.06 (d, J = 2.4 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 5.77 (s, 2H), 5.05 (d, J = 4.8 Hz, 1H), 4.72 (dd, J = 15.5, 7.0 Hz, 1H), 4.63 - 4.32 (m, 5H), 2.70 (m, 1H), 2.44 - 2.32 (m, 1H).

[0259] Example 14: Synthesis of compound 18:

[0260] [ka] Synthesis Route:

[0261] [ka] Compound 17 was synthesized as a reference, compound 1-F was substituted for compound 18-A1, and the final compound 18 was obtained. MS m / z (ESI):636.1810 (M+H) + , 1 HNMR (400 MHz, DMSO-d6) δ=12.81 (brs, 1H), 8.18 (dd, J = 7.0, 1.9 Hz, 2H), 7.82 (m, 4H), 7.64 (dd, J = 15.6, 8.9 Hz, 3H), 7.48 (d, J = 8.0 Hz, 1H), 7.39 (dd, J = 15.2,8.0 Hz, 2H), 7.06 (d, J = 2.3 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.48 (s, 1H), 5.77 (s, 2H), 5.73 (s, 2H), 4.39 (s, 2H), 3.97 (q, J = 7.2 Hz, 2H), 1.17 (t, J = 7.2 Hz, 3H).

[0262] Example 15: Synthesis of compound 19:

[0263]

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[0264]

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[0265]

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[0266] Compound 19-C:

[0267] [ka] 0.70 g of compound 19-B (1.0 equivalent), 0.78 g of compound 1-F (1.1 equivalent), and 1.16 g of TBTU (1.2 equivalents) were weighed and added to a 100 mL round-bottom flask. 15.0 mL of DMF was added. The reaction mixture was stirred in an ice bath for 10 minutes, followed by the dropwise addition of 1.0 mL (2.0 equivalents) of diisopropylethylamine. After the dropwise addition, the reaction mixture was stirred in the ice bath for 3 hours. After the reaction was complete, 30 mL of H2O and 30 mL of ethyl acetate were added to the reaction mixture, and the resulting mixture was stirred for 5 minutes. The reaction mixture was allowed to stand, the organic phase was separated, and the aqueous phase was washed twice with 25 mL of ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4 for 5 minutes, and then filtered. The filtrate was concentrated to dryness and purified by column chromatography to give 0.70 g of compound 19-C as a white solid in 51.9% yield. MS m / z (ESI): 451.0664 (M+H). + .

[0268] Compound 19-D:

[0269] [ka] 0.32 g of compound 19-C was weighed and added to a 50 mL round-bottom flask. 5.0 mL of 1,2-dichloroethane was added, followed by the dropwise addition of 0.81 mL (20.0 equivalents) of acetic acid. After the dropwise addition, the reaction mixture was heated at 60 °C. After 5 hours of reaction, the reaction mixture was cooled to room temperature and then concentrated. After concentration, 25.0 mL of ethyl acetate was added to the residue, followed by the addition of 30.0 mL of 3% aqueous K2CO3 solution under stirring. The reaction mixture was then allowed to stand, the organic phase was separated, and the aqueous phase was washed twice with 15 mL of ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4 for 5 minutes, and then filtered. The filtrate was concentrated to dryness to give 0.31 g of compound 19-D in a 100% yield (crude product). MS m / z (ESI): 433.0565 (M+H). + This was used directly in the next reaction without purification.

[0270] Compound 19-E:

[0271] [ka] 0.31 g of compound 19-D (1.0 equiv.), 0.22 g of bis(pinacolato)diboron (1.2 equiv.), 16.0 mg of Pd(dppf)Cl2 (0.03 equiv.), and 176 mg of potassium acetate (2.5 equiv.) were weighed and added to a 50 mL round-bottom flask. 12.0 mL of 1,4-dioxane was added. The reaction mixture was then degassed twice with nitrogen and heated to 100 °C under a nitrogen atmosphere. After 2 h of reaction, the heating was stopped, the reaction mixture was cooled to room temperature, and the mixture was filtered through a diatomaceous earth funnel. The filter cake was washed with 20 mL of ethyl acetate twice. The filtrate was then concentrated to dryness and purified by column chromatography to give 0.16 g of compound 19-E in 47.6% yield.

[0272] Compound 19-F:

[0273] [ka] 0.16 g of compound 19-E (1.05 equiv.), 0.104 g of compound 8-A (1.0 equiv.), 8.0 mg of Pd(dppf)Cl2 (0.03 equiv.), and 260 mg of Cs2CO3 (2.5 equiv.) were weighed and added to a 50 mL round-bottom flask. 5.0 mL of 1,4-dioxane and 2.0 mL of HO were added. The reaction mixture was then degassed twice with nitrogen and heated to 90 °C under a nitrogen atmosphere. After 2 h of reaction, the heating was stopped, the reaction mixture was cooled to room temperature, filtered through a diatomaceous earth funnel, and the filter cake was washed with 10 mL of ethyl acetate twice. The filtrate was then concentrated to dryness and purified by column chromatography to give 0.12 g of compound 19-F in 62.8% yield.

[0274] Compound 19:

[0275] [ka] 0.12 g of compound 19-F (1.0 equiv.) and 55 mg of TBD (2.0 equiv.) were weighed and added to a 25 mL round-bottom flask. 2.5 mL of acetonitrile and 0.5 mL of water were added. The reaction mixture was allowed to react at room temperature for approximately 36 hours until TLC showed the reaction was complete. The reaction mixture was concentrated, 5 mL of water was added, and the pH of the reaction mixture was adjusted to 4-5 with citric acid solution. After a large amount of off-white solid precipitated, the reaction mixture was continued to stir for approximately 0.5 hours, filtered, and washed. The filter cake was recrystallized from dichloromethane / methanol to give 74 mg of compound 19 in 58.3% yield. MS m / z (ESI): 589.1881 (M+H). + ; 1H NMR (400 MHz, DMSO) δ =12.85 (s, 1H), 8.36 (d, J = 1.9 Hz, 1H), 8.25 (s, 1H), 7.93 - 7.74 (m, 5H), 7.69 - 7.55 (m, 3H), 7.40 (t, J = 8.0 Hz, 1H), 7.24 (d, J = 2.0 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 5.88 (d, J = 11.9 Hz, 2H), 5.07 (dd, J = 15.9, 9.4 Hz, 1H), 4.80 - 4.26 (m, 6H), 2.69 (dd, J = 16.6, 8.7 Hz, 1H), 2.37 (dd, J = 18.2, 8.3 Hz, 1H).

[0276] Example 16: Synthesis of compound 21:

[0277] [ka] Synthesis Route:

[0278] [ka] Referring to the synthesis method of compound 19, compound 8-A was replaced with compound 21-A to finally obtain compound 21. MS m / z (ESI): 616.1447 (M+H) + , 1H NMR (400 MHz, DMSO-d6) δ=12.74 (brs, 1H), 8.25 (s, 1H), 7.86-7.79 (m, 4H), 7.61 (dd, J = 15.6, 7.2 Hz, 2H), 7.46 (d, J = 8.4 Hz, 1H), 7.41 (t, J = 8.4 Hz, 2H), 6.90 (d, J = 8.4 Hz, 1H), 6.51 (d, J = 6.4 Hz, 1H), 5.71 (s, 2H), 5.07-5.02 (m, 1H), 4.72 (dd, J = 15.6, 7.2 Hz, 1H), 4.61-4.33 (m, 5H), 2.74-2.66 (m, 1H), 2.42-2.38 (m, 1H).

[0279] Example 17: Synthesis of compound 23:

[0280] [ka] Synthesis Route:

[0281] [ka] Referring to the synthesis method of compound 17, compound 17-B was replaced with compound 23-B, and compound 7-A was replaced with compound 21-A to finally obtain compound 23. MS m / z (ESI): 634.1352 (M+H) + .

[0282] Example 18: Synthesis of compound 24:

[0283] [ka] Synthesis Route:

[0284] [ka] Referring to the synthesis method of compound 17, compound 17-A was replaced with compound 24-A to finally obtain compound 24. MS m / z (ESI): 598.1541 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ=12.34 (brs, 1H), 8.25 (s, 1H), 8.19 (d, J = 1.8 Hz, 1H), 7.89 - 7.73 (m, 4H), 7.67-7.64 (m, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.45 - 7.32 (m, 3H), 7.06 (d, J = 1.8 Hz, 1H), 5.85 (s, 2H), 5.05 (d, J = 5.3 Hz, 1H), 4.74-4.69 (m, 1H), 4.64 - 4.23 (m, 5H), 2.72-2.65(m, 1H), 2.45 - 2.25 (m, 1H).

[0285] Example 19: Synthesis of compound 25:

[0286] [ka] Synthesis Route:

[0287] [ka] Referring to the synthesis method of compound 17, compound 17-A was replaced with compound 23-A to finally obtain compound 25. MS m / z (ESI): 616.1447 (M+H) + . 1H NMR (400 MHz, DMSO-d6) δ =12.65 (s, 1H), 8.21 (s, 1H), 8.20 (d, J = 2.0 Hz, 1H), 7.91-7.76 (m, 4H), 7.61 (dd, J = 21.2, 8.0 Hz, 2H), 7.52 - 7.35 (m, 2H), 7.06 (d, J = 2.4 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 5.75 (s, 2H), 5.03 (d, J = 4.8 Hz, 1H), 4.71 (dd, J = 15.5, 7.0 Hz, 1H), 4.65 - 4.35 (m, 5H), 2.70 (m, 1H), 2.44 - 2.35 (m, 1H).

[0288] Example 20: Synthesis of compound 26:

[0289] [ka] Synthesis Route:

[0290] [ka] Referring to the synthesis method of compound 17, compound 17-A was replaced with compound 26-A to finally obtain compound 26. MS m / z (ESI): 634.1353 (M+H) + .

[0291] Example 21: Synthesis of compound 27:

[0292] [ka] Synthesis Route:

[0293] [ka] Referring to the synthesis of compound 17, compound 7-A was replaced with compound 27-A to finally obtain compound 27 (200 mg, yield 66.0%). MS m / z (ESI): 599.1493 (M+H) + , 1 H NMR (400 MHz, DMSO) δ=12.71 (s, 1H), 8.91 (s, 1H), 8.37 (s, 1H), 8.26 (s, 1H), 8.20 (s, 1H), 8.02 - 7.89 (m, 2H), 7.79 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.51 (t, J = 7.7 Hz, 2H), 7.38 (dd, J = 8.0, 1.8 Hz, 1H), 7.07 (t, J = 2.1 Hz, 1H), 5.82 (s, 2H), 5.06 (td, J = 9.0, 6.3 Hz, 1H), 4.74 (dd, J = 15.6, 7.0 Hz, 1H), 4.65 - 4.55 (m, 1H), 4.55 - 4.30 (m, 4H), 2.71 (tt, J = 15.1, 7.4 Hz, 1H), 2.39 (m, 1H).

[0294] Example 22: Synthesis of compound 31:

[0295] [ka] Synthesis Route:

[0296] [ka] Referring to the synthesis method of compound 13, compound 13-A was replaced with compound 31-A to finally obtain compound 31. MS m / z (ESI): 586.1853 (M+H) + .

[0297] Example 23: Synthesis of compound 38:

[0298] [ka] Synthesis Route:

[0299] [ka] Compound 38-A:

[0300] [ka] 0.2 g of compound 17-F (1.0 equivalent) and 0.127 g of compound 002-M05 (1.1 equivalent) were weighed and added to a 25 mL round-bottom flask. 4.0 mL of acetonitrile was added. After stirring the reaction mixture in an ice bath for 15 minutes, 0.15 g of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (1.1 equivalent) and 84 mg of N-methylimidazole (2.1 equivalents) were weighed and added. The reaction mixture was continued to stir in the ice bath for 0.5 hours. The reaction mixture was then transferred to room temperature and allowed to react for 3 hours. After completion of the reaction, 12 mL of HO was added to the reaction mixture, which was stirred for 0.5 hours and then filtered. The filter cake was washed with 4 mL of water three times and purified by column chromatography to give 0.122 g of compound 38-A in a 39.8% yield.

[0301] Compound 38-B:

[0302] [ka] 0.12 g of compound 38-A (1.0 equiv.) was weighed and added to a 50 mL round-bottom flask. 1.8 mL of 1,4-dioxane was added. 0.47 g of acetic acid (40.0 equiv.) was then added dropwise. After the addition, the reaction mixture was heated at 80 °C. After 3 h, the reaction mixture was cooled to room temperature, 5 mL of water and 10 mL of ethyl acetate were added, and the pH of the reaction mixture was adjusted to 7-8 with 5% NaHCO3 solution. The reaction mixture was then allowed to stand, and the organic phase was separated. The aqueous phase was washed twice with 10 mL of ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4 for 5 min, and then filtered. The filtrate was concentrated to dryness and purified by column chromatography to obtain 90 mg of compound 38-B in a 77.2% yield.

[0303] Compound 38:

[0304] [ka] 85 mg of compound 38-B (1.0 equivalent) was weighed and added to a 25 mL round-bottom flask. 0.5 mL of methanol and 1.3 mL of tetrahydrofuran were added. 0.14 mL of 2 mol / L sodium hydroxide solution was then added. The reaction mixture was then allowed to react at room temperature. After 15 hours, the reaction mixture was concentrated. After concentration, 2.5 mL of water was added to the residue, and the pH of the reaction mixture was adjusted to 4-5 with 1 mol / L HCl solution. The reaction mixture was then filtered, and the filter cake was purified by column chromatography to obtain 32 mg of compound 38 in a 38.5% yield. MS m / z (ESI): 599.1494 (M+H). + , 1H NMR (400 MHz, DMSO-d6) δ= 9.08 (s, 1H), 8.17 (s, 1H), 8.05 (d, J = 7.6 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.89-7.82 (m, 2H), 7.49-7.36 (m, 2H), 7.14-7.07 (m, 2H), 6.99 (d, J = 7.6 Hz, 1H), 6.89 (d, J = 7.6 Hz, 1H), 6.70 (m, 1H), 5.78 (s, 2H), 5.15 (s, 1H), 4.76-4.37 (m, 4H), 3.99-3.96 (m, 1H), 2.76-2.67 (m, 1H), 2.04-1.96 (m, 1H).

[0305] Example 24: Synthesis of compound 39:

[0306] [ka] Synthesis Route:

[0307] [ka] Referring to the synthesis method of compound 13, compound 13-B was replaced with compound 39-C to finally obtain compound 39. MS m / z (ESI): 552.2243 (M+H) + .

[0308] Example 25: Synthesis of compound 45:

[0309] [ka] Synthesis Route:

[0310] [ka] Referring to the synthesis method of compound 13, compound 13-B was replaced with compound 45-C to finally obtain compound 45. MS m / z (ESI): 603.2007 (M+H) + .

[0311] Example 26: Synthesis of compound 61:

[0312] [ka] Synthesis Route:

[0313] [ka] Compound 61-A:

[0314] [ka] 200 mg of compound 19-E (1.0 equiv.), 155 mg of compound 13-B (1.05 equiv.), 9 mg of Pd(dppf)Cl2 (0.03 equiv.), and 339 mg of cesium carbonate (2.5 equiv.) were weighed and added to a 25 mL round-bottom flask. 5 mL of 1,4-dioxane and 1 mL of water were added. The reaction mixture was stirred uniformly, degassed twice with nitrogen, and heated to 90 °C under a nitrogen atmosphere for approximately 2 hours until TLC showed the reaction was complete. The reaction mixture was then cooled to room temperature, filtered through a diatomaceous earth funnel, and the filter cake was washed with a small amount of dichloromethane. The filtrate was concentrated to dryness and purified by column chromatography to give 131 mg of compound 61-A in 50.2% yield. MS m / z (ESI): 628.2249 (M+H). + .

[0315] Compound 61:

[0316] [ka] 126 mg of compound 61-A (1.0 equiv.) was weighed and added to a 25 mL round-bottom flask. 3 mL of tetrahydrofuran and 1 mL of methanol were added, and the resulting system was stirred uniformly. 0.2 mL of 2 mol / L NaOH solution (2.0 equiv.) was slowly added dropwise. The resulting system was then allowed to react at room temperature overnight until TLC showed the reaction was complete. The reaction solution was concentrated, and approximately 10 mL of water was added. The pH of the reaction solution was adjusted to 4-5 with citric acid solution, resulting in the precipitation of a large amount of off-white solid. The reaction solution was stirred for approximately 0.5 hours, filtered, and washed with water. The filter cake was recrystallized from dichloromethane / methanol to obtain 79 mg of compound 61 in a 64.2% yield. MS m / z (ESI): 614.2094 (M+H). + ; 1 H NMR (400 MHz, DMSO) δ =12.82 (s, 1H), 8.26 (s, 1H), 8.13 (dd, J = 12.6, 7.6 Hz, 2H), 7.91 (d, J = 11.5 Hz, 1H), 7.82 (dd, J = 13.6, 5.7 Hz, 3H), 7.74 (d, J = 8.2 Hz, 1H), 7.70 - 7.56 (m, 3H), 7.42 (ddd, J = 23.4, 15.3, 7.4 Hz, 3H), 7.29 (t, J = 8.0 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 5.86 (s, 2H), 5.04 (d, J = 5.4 Hz, 1H), 4.70 (dd, J = 15.6, 7.0 Hz, 1H), 4.62 - 4.29 (m, 5H), 2.75 - 2.58 (m, 1H), 2.45 - 2.27 (m, 1H).

[0317] Example 27: Synthesis of compound 66:

[0318] [ka] Synthesis Route:

[0319] [ka] Referring to the synthesis method of compound 21, compound 19-E was replaced with compound 66-E to finally obtain compound 66. MS m / z (ESI): 617.1401 (M+H) + .

[0320] Example 28: Synthesis of compound 67:

[0321] [ka] Synthesis Route:

[0322] [ka] Referring to the synthesis method of compound 19, compound 19-E was replaced with compound 66-E to finally obtain compound 67. MS m / z (ESI): 590.1831 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ= 12.64 (brs, 1H), 8.25 (s, 1H), 8.11 (d, J = 7.6 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.84-7.81 (m, 2H), 7.49-7.36 (m, 2H), 7.14-7.07 (m, 2H), 6.93 (d, J = 7.6 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.70 (m, 1H), 5.78 (s, 2H), 5.15-5.13 (m, 1H), 4.76-4.60 (m, 1H), 4.57-4.33 (m, 5H), 2.76-2.67 (m, 1H), 2.01-1.93 (m, 1H).

[0323] Example 29: Synthesis of compound 71:

[0324] [ka] Synthetic ルート:

[0325]

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[0326] Example 30: Synthesis of compound 72:

[0327]

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[0328]

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[0329] Example 31: Synthesis of compound 76:

[0330] [ka] Synthesis Route:

[0331] [ka] Referring to the synthesis method of compound 13, compound 13-B was replaced with compound 71-A to finally obtain compound 76. MS m / z (ESI): 566.2401(M+H) + .

[0332] Example 32: Synthesis of compound 82:

[0333] [ka] Synthesis Route:

[0334] [ka] Referring to the synthesis method of compound 13, compound 13-A was replaced with compound 82-A to finally obtain compound 82. MS m / z (ESI): 592.2553 (M+H) + .

[0335] Example 33: Synthesis of compound 83:

[0336] [ka] Synthesis Route:

[0337] [ka] Referring to the synthesis method of compound 61, compound 19-E was replaced with compound 83-E to finally obtain compound 83. MS m / z (ESI): 615.2039 (M+H) + .

[0338] Example 34: Synthesis of compound 84:

[0339] [ka] Synthesis Route:

[0340] [ka] Referring to the synthesis method of compound 61, compound 13-B was replaced with compound 7-A, and compound 19-E was replaced with compound 83-E to finally obtain compound 84. MS m / z (ESI): 599.1492 (M+H) + .

[0341] Example 35: Synthesis of compound 87:

[0342] [ka] Synthesis Route:

[0343] [ka] Referring to the synthesis method of compound 17, compound 7-A was replaced with compound 87-A to finally obtain compound 87. MS m / z (ESI): 582.1837 (M+H) + ,1 H NMR (400 MHz, DMSO) δ =8.23 (s, 1H), 8.12 (d, J = 2.0 Hz, 1H), 7.89-7.80 (m, 4H), 7.63 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.49 (dd, J = 8.4, 5.6 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.13-7.09 (m, 2H), 6.87 (d, J = 8.0 Hz, 1H), 5.75 (s, 2H), 5.08-5.03 (m, 1H), 4.70 (dd, J = 15.6, 6.8 Hz, 1H), 4.59-4.33 (m, 5H), 2.74-2.66 (m, 1H), 2.43-2.34 (m, 1H).

[0344] Example 36: Synthesis of compound 88:

[0345] [ka] Synthesis Route:

[0346] [ka] Referring to the synthesis method of compound 17, compound 7-A was replaced with compound 88-A to finally obtain compound 88. MS m / z (ESI): 632.1802 (M+H) + .

[0347] Example 37: Synthesis of compound 89:

[0348] [ka] Synthesis Route:

[0349] [ka] Compound 89 was obtained by replacing compound 7-A with compound 89-A according to the synthesis method of compound 17. MS m / z (ESI): 614.1898 (M+H) + .

[0350] Example 38: Synthesis of compound 91:

[0351] [ka] Synthesis Route:

[0352] [ka] Compound 91-A:

[0353] [ka] Compound 91-A-1: 1.02 g of methyl 2,3-difluoro-4-nitrobenzoate (1.0 equivalent) was weighed and added to a 50 mL round-bottom flask. 5 mL of DMF and 5 mL of THF were added, followed by 0.95 g of TEA (2.0 equivalents). The reaction mixture was stirred uniformly, and then 0.5 g of (S)-2-(aminomethyl)oxetane (1.2 equivalents) was added. The resulting system was heated to 60 °C for reaction. After 6 hours of reaction, heating was stopped, and the reaction solution was cooled to room temperature. 20 mL of water and 20 mL of ethyl acetate were added, and then the mixture was allowed to stand. The organic phase was separated, and the aqueous phase was extracted with 20 mL of ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4 for 5 minutes, and then filtered. The filtrate was concentrated to dryness to obtain compound 91-A-1, which was used directly in the next step.

[0354] Compound 91-A: Compound 91-A-1 (1.0 equivalent) obtained in the previous step was weighed and added to a 50 mL round-bottom flask. 20 mL of methanol was added. 0.14 g of Pd / C (10%) was then added. The reaction mixture was purged with hydrogen three times and reacted at room temperature under a hydrogen atmosphere for 15 hours. The reaction mixture was then filtered through a diatomaceous earth funnel, and the filter cake was washed with 20 mL of ethyl acetate twice. The filtrate was concentrated to dryness to obtain 1.2 g of compound 91-A-1, which was used directly in the next step.

[0355] Compound 91-B:

[0356] [ka] 0.2 g of compound 19-B (1.0 equivalent), 0.24 g of compound 91-A (1.1 equivalent), and 0.148 g of N-methylimidazole (2.1 equivalents) were weighed and added to a 25 mL round-bottom flask. 4 mL of acetonitrile was added. The reaction mixture was stirred in an ice bath for 20 minutes, followed by the addition of 0.265 g of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH) (1.1 equivalents). The reaction mixture was stirred in the ice bath for 0.5 hours, then transferred to room temperature and allowed to continue the reaction. After 3 hours of reaction, 12 mL of water was added to the reaction mixture. The resulting mixture was stirred for 0.5 hours and filtered. The filter cake was washed with 5 mL of water twice and purified by column chromatography to give 0.155 g of compound 91-B in a 38.5% yield.

[0357] Compound 91-C:

[0358] [ka] 0.155 g of compound 91-B (1.0 equiv.) was weighed and added to a 25 mL round-bottom flask. 2.5 mL of 1,2-dichloroethane was added. 0.8 mL of acetic acid (40.0 equiv.) was then added dropwise. After the addition, the reaction mixture was heated at 80 °C. After 3 hours of reaction, the reaction mixture was cooled to room temperature and concentrated. After concentration, 3 mL of water was added to the residue, and 3% K2CO3 solution was added under stirring. The pH of the reaction mixture was adjusted to 7-8, and the reaction mixture was filtered. The filter cake was washed with a small amount of water. The filter cake was dried to obtain 0.134 g of compound 91-C in an 89.9% yield.

[0359] Compound 91-D:

[0360] [ka] 0.134 g of compound 91-C (1.0 equiv.), 91 mg of bis(pinacolato)diboron (1.2 equiv.), 7 mg of Pd(dppf)Cl2 (0.03 equiv.), and 74 mg of potassium acetate (2.5 equiv.) were weighed and added to a 25 mL round-bottom flask. 2 mL of 1,4-dioxane was added. The reaction mixture was then degassed twice with nitrogen and heated to 100 °C under a nitrogen atmosphere. After 2 h of reaction, the heating was stopped and the reaction mixture was cooled to room temperature. The reaction mixture was then filtered through a funnel containing diatomaceous earth and silica gel. The filter cake was washed with a 1:1 mixture of petroleum ether and ethyl acetate. The filtrate was then concentrated to dryness to give compound 91-D, which was used directly in the next step.

[0361] Compound 91-E:

[0362] [ka] 84 mg of compound 7-A (1.0 equiv.), compound 91-D obtained in the previous step, 5.5 mg of Pd(dppf)Cl2 (0.03 equiv.), and 202 mg of Cs2CO3 (2.5 equiv.) were weighed and added to a 50 mL round-bottom flask. 2.5 mL of 1,4-dioxane and 0.4 mL of HO were added. The reaction mixture was then degassed twice with nitrogen and heated to 90 °C under a nitrogen atmosphere. After 3 hours of reaction, the heating was stopped and the reaction mixture was cooled to room temperature. The reaction mixture was then filtered through a diatomaceous earth funnel, and the filter cake was washed with 10 mL of ethyl acetate twice. The filtrate was concentrated to dryness and purified by column chromatography to give 0.141 g of compound 91-E in 90.4% yield. MS m / z (ESI): 630.1602 (M+H). + .

[0363] Compound 91:

[0364] [ka] 0.14 g of compound 91-E (1.0 equivalent) was weighed and added to a 25 mL round-bottom flask. 0.7 mL of methanol and 2.1 mL of tetrahydrofuran were added, followed by 0.35 mL of 2 mol / L sodium hydroxide solution. The reaction mixture was then allowed to react at room temperature. After 20 hours, the reaction mixture was concentrated. After concentration, 4 mL of water and 0.5 mL of acetone were added to the residue. The pH of the reaction mixture was adjusted to 4-5 with 1 mol / L HCl, filtered, and the filter cake was washed with a small amount of water. The filter cake was dried to obtain 104 mg of compound 91 in a 76.7% yield. MS m / z (ESI): 616.1450 (M+H). + , 1H NMR (400 MHz, DMSO-d6) δ =8.18 (s, 1H), 7.89-7.81 (m, 3H), 7.66-7.63 (m, 2H), 7.48-7.35 (m, 4H), 7.06 (s, 1H), 6.89 (d, J = 8.0 Hz, 1H), 5.77 (s, 2H), 5.10 (d, J = 6.4 Hz, 1H), 4.78 (dd, J = 15.6, 7.2 Hz, 1H), 4.61 (d, J = 13.6 Hz, 1H), 4.54-4.50 (m, 2H), 4.45-4.38 (m, 2H), 2.80-2.72 (m, 1H), 2.47-2.39 (m, 1H).

[0365] Example 39: Synthesis of compound 93:

[0366]

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[0367]

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[0368]

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[0369] Compound 93-B:

[0370] [ka] 0.3 g of compound 93-A (1.0 equiv.), 0.17 g of compound 1-C (1.5 equiv.), 57 mg of Pd2(dba)3 (0.1 equiv.), 59 mg of 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (0.2 equiv.), and 0.404 g of cesium carbonate (2 equiv.) were weighed and added to a 25 mL round-bottom flask. 4.5 mL of toluene was added. The reaction mixture was degassed twice with nitrogen and heated to 110 °C under a nitrogen atmosphere. After 12 h of reaction, the heating was stopped and the reaction mixture was cooled to room temperature. The reaction mixture was then filtered through a diatomaceous earth funnel, and the filter cake was washed with 10 mL of ethyl acetate twice. The filtrate was concentrated to dryness and purified by column chromatography to give 0.112 g of compound 93-B in 28.7% yield. MS m / z (ESI): 630.1609 (M+H) + .

[0371] Compound 93:

[0372] [ka] 0.11 g of compound 93-B (1.0 equivalent) was weighed and added to a 25 mL round-bottom flask. 0.6 mL of methanol and 1.65 mL of tetrahydrofuran were added, followed by 0.22 mL of 2 mol / L sodium hydroxide solution. The reaction mixture was then allowed to react at room temperature. After 20 hours, the reaction mixture was concentrated. After concentration, 4 mL of water and 0.5 mL of acetone were added to the residue. The pH of the reaction mixture was adjusted to 4-5 with 1 mol / L HCl, filtered, and the filter cake was washed with a small amount of water. The filter cake was pulped with 1 mL of ethyl acetate and 0.2 mL of methanol, then filtered. The filter cake was washed with 1 mL of ethyl acetate twice and dried to obtain 65 mg of compound 93 in a 60.4% yield. MS m / z (ESI): 616.1442 (M+H). + , 1 H NMR (400 MHz, DMSO-d6) δ= 8.22 (d, J = 24 Hz, 2H), 7.85-7.78 (m, 4H), 7.66 (d, J = 6.8 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 8 Hz, 1H), 7.42-7.37 (m, 2H), 7.04 (d, J = 20 Hz, 1H), 5.86 (s, 2H), 5.05 (d, J = 5.6 Hz, 1H), 4.72 (dd, J = 15.6, 7.2 Hz, 1H), 4.61-4.33 (m, 5H), 2.74-2.66 (m, 1H), 2.42-2.34 (m, 1H).

[0373] Example 40: Synthesis of compound 94:

[0374] [ka] Synthesis Route:

[0375] [ka] Compound 94 was finally obtained by replacing compound 1-C with compound 94-A according to the synthesis method of compound 93.

[0376] Compound 94-A:

[0377] [ka] Compound 94-A1: 1.0 g of compound 1-C (1.0 equivalent) and 0.565 g of imidazole (1.5 equivalents) were weighed and added to a 50 mL round-bottom flask. 22 mL of DMF was added. The reaction mixture was then stirred uniformly in an ice bath, cooled to 0 °C, and TBDPSCl was added dropwise. After the addition, the reaction mixture was kept at a low temperature for 1 h. The ice bath was then removed, and the reaction mixture was allowed to warm to room temperature and stirred for 2 h. TLC showed that the starting materials had completely reacted. The reaction mixture was then extracted with 44 mL of water and 30 mL of ethyl acetate. The organic phase was washed three times with 15 mL of water and three times with 15 mL of saturated brine, then dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give an oily crude product, which was purified by column chromatography (PE as eluent) to give compound 94-A1 (2.30 g, 100% yield).

[0378] Compound 94-A2: 1.5 g of compound 94-A1 (1.0 equivalent) was weighed and added to a 50 mL three-neck flask. 20 mL of anhydrous THF was added under nitrogen protection. The reaction mixture was stirred to dissolve the compound and then cooled to -75 °C. Once the reaction mixture had cooled to -75 °C, 5.16 mL of LDA (2 mol / L, 3.0 equivalents) was added dropwise to the reaction mixture. After the addition, the reaction mixture was kept at a low temperature and reacted for 1 hour. Next, a THF solution of NFSI (N-fluorobenzenesulfonimide) (1.63 g dissolved in 5 mL of THF, 1.5 equivalents) was added dropwise. After the addition, the reaction mixture was kept at a low temperature and reacted for 1 hour. After cooling, the reaction mixture was slowly returned to room temperature. The reaction mixture was quenched by adding saturated ammonium chloride solution to the reaction mixture. The reaction mixture was extracted twice with 25 mL of ethyl acetate each time, and the combined organic phase was washed twice with 20 mL of water and twice with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give an oily crude product, which was purified by silica gel column chromatography (PE as eluent) to give compound 94-A2 (310 mg, yield 20.52%).

[0379] Compound 94-A: 310 mg of compound 94-A2 (1.0 equiv.) was weighed and added to a 25 mL round-bottom flask. 5.0 mL of tetrahydrofuran was added and stirred to dissolve. 1.0 g of triethylamine trihydrofluoride (8.8 equiv.) was added dropwise at room temperature. After the addition, the reaction mixture was allowed to react overnight. TLC showed that the starting materials had completely reacted. The reaction mixture was then extracted with 15 mL of ethyl acetate. The organic phase was washed twice with 10 mL of water and twice with 10 mL of saturated brine, then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a clear oil, which was purified by column chromatography (PE / EA = 94 / 6) to give compound 94-A (125 mg, 88.03% yield). 1 H NMR (400 MHz, DMSO-d6) δ= 7.35 (q, J = 8.4 Hz, 2H), 6.46 (d, J = 9.6 Hz, 1H), 5.43 (t, J = 5.6 Hz, 1H), 4.71 (d, J = 5.6 Hz, 2H).

[0380] Compound 94-B 281.60 mg of compound 93-A (1.0 equiv.), 140.0 mg of compound 94-A (1.2 equiv.), 64.0 mg of Pd2(dba)3 (0.12 equiv.), 65.30 mg of RuPhos (2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl) (0.24 equiv.), and 455.11 mg of cesium carbonate (2.4 equiv.) were weighed and added to a 25 mL round-bottom flask. 8 mL of toluene was added. The reaction mixture was then degassed twice with nitrogen and heated to 90 °C under a nitrogen atmosphere. After 3 hours of reaction, heating was stopped and the mixture was cooled to room temperature. The mixture was then filtered through a diatomaceous earth funnel. The filtrate was concentrated to dryness and purified by column chromatography (PE / EA=60 / 40) to give compound 94-B (190 mg, yield 50.4%). MS m / z (ESI): 648.1514 (M+H) + .

[0381] compound 94 145 mg of compound 94-B (1.0 equiv.) was weighed and added to a 25 mL round-bottom flask. 3 mL of tetrahydrofuran was added to dissolve the compound, followed by the addition of 1.5 mL of water. After stirring the reaction mixture until uniform, 28.20 mg of LiOH-HO (3.0 equiv.) was added. The reaction mixture was stirred at room temperature overnight. TLC showed that the starting material had completely reacted. The reaction mixture was concentrated under reduced pressure to remove the solvent, and 5 mL of water was added. The pH of the reaction mixture was adjusted to 4-5 with citric acid solution. The solid was precipitated and filtered. The filter cake was washed with a small amount of water. After drying, the filter cake was pulped with a mixed solvent of 2 mL of acetone and 2 mL of ethyl acetate to obtain compound 94 (67 mg, 47.18% yield). MS m / z (ESI): 634.1353 (M+H). + , 1HNMR (400 MHz, DMSO-d6) δ=12.61(bs, 1H), 8.25 (s, 1H), 7.92-7.75 (m, 4H), 7.67 (dd, J = 8.2, 2.8 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.2 Hz, 1H), 7.41 (dd, J = 11.3, 7.9 Hz, 2H), 6.53 (d, J = 6.3 Hz, 1H), 5.80 (s, 2H), 5.05 (m, 1H), 4.72 (dd, J = 15.6, 7.1 Hz, 1H), 4.64-4.30 (m, 5H), 2.70 (m, 1H), 2.38 (m, 1H).

[0382] Example 41: Synthesis of compound 95:

[0383] [ka] Synthesis Route:

[0384] [ka] Compound 95-A

[0385] [ka] 300 mg of compound 1-C (1.0 equiv.), 319 mg of 2-bromo-3,6-difluoropyridine (1.0 equiv.), and 1.07 g of cesium carbonate (2.0 equiv.) were weighed and added to a 150 mL round-bottom flask. 6 mL of DMF was added. The reaction mixture was heated to 90 °C. After approximately 4 hours of reaction, TLC showed the reaction was complete. The reaction mixture was cooled to room temperature, 18 mL of water was added, and the mixture was extracted with 20 mL of ethyl acetate three times. The combined organic phases were washed with 20 mL of saturated sodium chloride solution, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to give 547 mg of compound 95-A in a 93.3% yield.

[0386] Compound 95-B:

[0387] [ka] 117 mg of compound 95-A (1.05 equiv.), 150 mg of compound 19-E (1.0 equiv.), 7 mg of Pd(dppf)Cl2 (0.03 equiv.), and 254 mg of Cs2CO3 (2.5 equiv.) were weighed and added to a 50 mL round-bottom flask. 5.0 mL of 1,4-dioxane and 1.0 mL of HO were then added. The reaction mixture was degassed twice with nitrogen and heated to 90 °C under a nitrogen atmosphere. After 4 hours of reaction, the heating was stopped and the reaction mixture was cooled to room temperature. The reaction mixture was then filtered through a diatomaceous earth funnel, and the filter cake was washed with approximately 20 mL of dichloromethane. The filtrate was concentrated to dryness and purified by column chromatography to give 138 mg of compound 95-B in 69.7% yield. MS m / z (ESI): 630.1616 (M+H). + .

[0388] compound 95

[0389] [ka] 138 mg of compound 95-B (1.0 equiv.) was weighed and added to a 25 mL round-bottom flask. 3 mL of tetrahydrofuran and 1 mL of methanol were added. The resulting system was stirred to dissolve, and then 0.33 mL of 2 mol / L aqueous NaOH solution was added dropwise. After the addition, the reaction mixture was allowed to react at room temperature for approximately 36 hours until TLC showed the reaction was complete. The reaction mixture was concentrated, and 5 mL of water and 1 mL of acetone were added. The pH of the reaction mixture was adjusted to 4-5 with citric acid solution. A large amount of off-white solid precipitated, and the reaction mixture was stirred for approximately 0.5 hours, filtered with suction, and washed with water. The filter cake was dried to obtain 135 mg of compound 95 in 100% yield. MS m / z (ESI): 616.1457 (M+H). + , 1H NMR (400 MHz, DMSO) δ =8.25 (s, 1H), 8.17 (s, 1H), 7.90-7.67 (m, 4H), 7.59 (d, J = 8.4 Hz, 1H), 7.52 - 7.43 (m, 2H), 7.36 (d, J = 8.0 Hz, 1H), 7.06 (s, 1H), 7.02-6.93 (m, 1H), 5.72 (s, 2H), 5.06 (d, J = 6.4 Hz, 1H), 4.76-4.70 (m, 1H), 4.62-4.41 (m, 4H), 4.39-4.34 (m, 1H), 2.73-2.66 (m, 1H), 2.45-2.29 (m, 1H).

[0390] Example 42: Synthesis of compound 97:

[0391]

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[0392]

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[0393]

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[0394] compound 97

[0395] [ka] 70 mg of compound 97-A (1.0 equiv.) was weighed and added to a 25 mL round-bottom flask. 3 mL of tetrahydrofuran and 1 mL of methanol were added. The resulting mixture was stirred to dissolve, and then 0.16 mL of 2 mol / L aqueous NaOH (3.0 equiv.) was added dropwise. After the addition, the reaction mixture was allowed to react at room temperature for approximately 36 hours until TLC showed the reaction was complete. The reaction mixture was concentrated, and 4 mL of water and 0.5 mL of acetone were added. The pH of the reaction mixture was adjusted to 4-5 with citric acid solution. A large amount of off-white solid precipitated. The reaction mixture was stirred for approximately 0.5 hours, filtered, and washed with water. The filter cake was dried to obtain 50 mg of compound 97 in a 73.5% yield. MS m / z (ESI): 632.1995 (M+H). + , 1H NMR (400 MHz, DMSO-d6) δ=12.84 (s, 1H), 8.26 (s, 1H), 8.14 (t, J = 6.6 Hz, 2H), 7.92-7.78 (m, 4H), 7.73 (d, J = 8.2 Hz, 1H), 7.68-7.65 (m, 2H), 7.60 (d, J = 8.4 Hz, 1H), 7.48-7.35(m, 3H), 7.29-7.25(m, 1H), 5.94 (s, 2H), 5.04 (d, J = 5.6 Hz, 1H), 4.72-4.67 (m, 1H), 4.58-4.31 (m, 5H), 2.76-2.60 (m, 1H), 2.42-2.26 (m, 1H).

[0396] Example 43: Synthesis of compound 98:

[0397] [ka] Synthesis Route:

[0398] [ka] Referring to the preparation of compound 95, compound 1-C was replaced with compound 13-A to finally obtain compound 98. MS m / z (ESI): 632.2004 (M+H) + , 1H NMR (400 MHz, DMSO-d6) δ=12.69 (s, 1H), 8.27 (s, 1H), 8.14 (t, J = 8.4 Hz, 2H), 7.88-7.69 (m, 5H), 7.63 (dd, J = 15.7, 7.9 Hz, 2H), 7.50-7.29 (m, 4H), 7.00 (dd, J = 8.9, 2.6 Hz, 1H), 5.80 (s, 2H), 5.07-5.03 (m, 1H), 4.74-4.68 (m, 1H), 4.61-4.32 (m, 5H), 2.74-2.65 (m, 1H), 2.41-2.33 (m, 1H).

[0399] Example 44: Synthesis of compound 99:

[0400]

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[0401]

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[0402]

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[0403] Compound 99-B:

[0404] [ka] 299 mg of compound 99-A (1.0 equiv.), 900.57 mg of Cs2CO3 (2.0 equiv.), and 267.50 mg of 2-bromo-6-fluoropyridine (1.1 equiv.) were weighed and placed in a 50 mL round-bottom flask. 10 mL of DMF was added. The reaction mixture was stirred to dissolve the components, then heated to 90 °C for 4 hours. TLC indicated that the two starting materials had essentially reacted completely. Heating was stopped, and the reaction mixture was cooled to room temperature. 30 mL of water and 20 mL of ethyl acetate were added to the reaction mixture for extraction, and the aqueous phase was extracted with 10 mL of ethyl acetate. The combined organic phase was washed three times with 15 mL of water and three times with 15 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude oil, which was dried to give compound 99-B (520 mg, 100% yield). Compound 99-B was used as is in the next feed.

[0405] Compound 99-C:

[0406] [ka] 520 mg of compound 99-B (1.0 equiv.), 803.13 mg of compound 19-E (1.2 equiv.), 61.16 mg of Pd(dppf)Cl2 (0.06 equiv.), and 1.13 g of cesium carbonate (2.5 equiv.) were weighed and added to a 50 mL round-bottom flask. 10 mL of 1,4-dioxane was added. The reaction mixture was stirred evenly, purged with nitrogen three times, and heated to 90 °C under a nitrogen atmosphere for 2.5 h. TLC indicated that the two starting materials had essentially reacted completely. Heating was stopped, and the reaction mixture was cooled to room temperature. The reaction mixture was then filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (PE / EA = 60 / 40) to give compound 99-C (600 mg, 66.7% yield). MS m / z (ESI): 646.1310 (M+H) + , 1HNMR (400 MHz, DMSO-d6) δ=8.28 (s, 1H), 7.91-7.77 (m, 4H), 7.63 (t, J = 7.2 Hz, 2H), 7.49 (d, J = 8.2 Hz, 1H), 7.41 (t, J = 8.0 Hz, 2H), 7.19 (s, 1H), 6.90 (d, J = 8.2 Hz, 1H), 5.73 (s, 2H), 5.12-5.00 (m, 1H), 4.74 (dd, J = 15.6, 7.2 Hz, 1H), 4.65-4.30 (m, 5H), 3.88 (s, 3H), 2.76-2.64 (m, 1H), 2.43-2.32 (m,1H).

[0407] Compound 99:

[0408] [ka] 320 mg of compound 99-C (1.0 equivalent) was weighed and added to a 25 mL round-bottom flask. 6.5 mL of tetrahydrofuran and 1.0 mL of methanol were added. The resulting mixture was stirred to dissolve, and then 1.0 mL of 2 mol / L NaOH solution (4.0 equivalents) was added. The reaction mixture was stirred uniformly and then reacted at room temperature overnight. TLC showed that the raw materials had essentially reacted completely. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. 10 mL of water was added to the concentrate, and the pH of the reaction mixture was adjusted to approximately 4 with citric acid solution. A large amount of white solid precipitated, which was stirred at room temperature for 30 minutes and filtered. The filter cake was collected and dried to obtain compound 99 (250 mg, 79.85% yield) as a white solid. MS m / z (ESI): 632.1150 (M+H) + , 1HNMR (400 MHz, DMSO-d6) δ=12.60 (brs, 1H), 8.25 (s, 1H), 7.89-7.76 (m, 4H), 7.62 (dd, J = 17.1, 7.9 Hz, 2H), 7.49 (d, J = 8.1 Hz, 1H), 7.40 (q, J = 6.8 Hz, 2H), 7.18 (s, 1H), 6.90 (d, J = 8.2 Hz, 1H), 5.73 (s, 2H), 5.05 (d,J = 6.5 Hz, 1H), 4.72 (dd, J =15.6, 7.2 Hz, 1H), 4.64-4.32 (m,5H), 2.75-2.65 (m, 1H), 2.42-2.32 (m, 1H).

[0409] Example 45: Synthesis of compound 100:

[0410]

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[0411]

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[0412]

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[0413] Compound 100:

[0414] [ka] 45 mg of compound 100-A (1.0 equivalent) was weighed and added to a 25 mL round-bottom flask. 0.25 mL of methanol and 0.75 mL of tetrahydrofuran were added, followed by 0.15 mL of 2 mol / L sodium hydroxide solution. The reaction mixture was then allowed to react at room temperature. After 22 hours, the reaction mixture was concentrated. After concentration, 2 mL of water and 0.25 mL of acetone were added to the residue, and the pH of the reaction mixture was adjusted to 4-5 with 1 mol / L aqueous HCl. The reaction mixture was filtered, and the filter cake was washed with a small amount of water. The filter cake was dried to obtain 40 mg of compound 100 in a 90.4% yield. MS m / z (ESI): 650.1068 (M+H) + , 1H NMR (400 MHz, DMSO-d6) δ= 8.25 (s, 1H), 7.85-7.78 (m, 4H), 7.67 (dd, J = 8.4, 2.8 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.52-7.49 (m, 1H), 7.43-7.37 (m, 2H), 7.19 (s, 1H), 5.84 (s, 2H), 5.08-5.02 (m, 1H), 4.72 (dd, J = 15.6, 6.8 Hz, 1H), 4.59 (d, J = 15.6 Hz, 1H), 4.53-4.33 (m, 4H), 2.74-2.66 (m, 1H), 2.42-2.34 (m, 1H).

[0415] Example 46: Synthesis of compound 101:

[0416]

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[0417]

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[0418]

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[0419] Compound 101-B:

[0420] [ka] 0.703 g of compound 101-A (1.0 equivalent) was weighed and added to a 25 mL round-bottom flask. 11 mL of 1,2-dichloroethane was added, followed by the dropwise addition of 3.5 mL of acetic acid (40.0 equivalents). After the dropwise addition, the reaction mixture was heated at 80 °C and allowed to react. After 3 hours of reaction, the reaction mixture was cooled to room temperature and then concentrated. After concentration, 10 mL of water was added to the reaction mixture, followed by the addition of a 3% aqueous solution of K2CO3 under stirring. The pH of the reaction mixture was adjusted to 7-8. The mixture was then filtered, and the filter cake was washed with a small amount of water and dried to obtain 0.642 g of compound 101-B in a 94.9% yield.

[0421] Compound 101-C:

[0422] [ka] 0.3 g of compound 101-B (1.0 equiv.), 203 mg of bis(pinacolato)diboron (1.2 equiv.), 15 mg of Pd(dppf)Cl2 (0.03 equiv.), and 163 mg of potassium acetate (2.5 equiv.) were weighed and added to a 25 mL round-bottom flask. 4.5 mL of 1,4-dioxane was added. The reaction mixture was then degassed twice with nitrogen and heated to 100 °C under a nitrogen atmosphere. After 2 h of reaction, the heating was stopped and the reaction mixture was cooled to room temperature. The reaction mixture was then filtered through a diatomaceous earth and silica gel funnel, and the filter cake was washed with a 1:1 mixture of petroleum ether and ethyl acetate. The filtrate was collected and concentrated to dryness to give compound 101-C, which was used directly in the next step.

[0423] Compound 101-D:

[0424] [ka] 0.188 g of compound 7-A (1.0 equiv.), compound 101-C obtained in the previous step, 12.2 mg of Pd(dppf)Cl2 (0.03 equiv.), and 0.451 g of Cs2CO3 (2.5 equiv.) were weighed and added to a 50 mL round-bottom flask. 5.6 mL of 1,4-dioxane and 1 mL of HO were added. The reaction mixture was then degassed twice with nitrogen and heated to 90 °C under a nitrogen atmosphere. After 3 h of reaction, the heating was stopped and the reaction mixture was cooled to room temperature. The reaction mixture was then filtered through a diatomaceous earth funnel, and the filter cake was washed with 10 mL of ethyl acetate twice. The filtrate was then concentrated to dryness and purified by column chromatography to give 0.248 g of compound 101-D in 71% yield. MS m / z (ESI): 630.1534 (M+H). + .

[0425] Compound 101:

[0426] [ka] 0.247 g of compound 101-D (1.0 equivalent) was weighed and added to a 25 mL round-bottom flask. 1.3 mL of methanol and 3.7 mL of tetrahydrofuran were added, followed by 0.6 mL of 2 mol / L sodium hydroxide solution. The reaction mixture was then allowed to react at room temperature. After 20 hours, the reaction mixture was concentrated. After concentration, 6 mL of water and 0.5 mL of acetone were added to the reaction mixture, and the pH of the reaction mixture was adjusted to 4-5 with 1 mol / L HCl solution. The reaction mixture was filtered, and the filter cake was washed with a small amount of water and dried to obtain 0.228 g of compound 101 in a 94.4% yield. MS m / z (ESI): 616.1446 (M+H). + , 1 H NMR (400 MHz, DMSO-d6) δ=8.25 (s, 1H), 8.17 (s, 1H), 7.88-7.77(m, 4H), 7.72 (d, J = 7.2 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.06 (s, 1H), 6.94 (d, J = 8.0 Hz, 1H), 5.79 (s, 2H), 5.14-5.10 (m, 1H), 4.80 (dd, J = 15.6, 6.8 Hz, 1H), 4.67 (d, J = 14.8 Hz, 1H), 4.58-4.42 (m, 3H), 4.36 (dd, J = 14.8, 6.0 Hz, 1H), 2.78-2.70 (m, 1H), 2.44-2.35 (m, 1H).

[0427] Example 47: Synthesis of compound 102:

[0428] [ka] Synthesis Route:

[0429] [ka] Compound 102-A:

[0430] [ka] 1.87 g of 4-chloro-2-hydroxybenzoic acid methyl ester (1.0 equivalent), 1.42 g of 3-bromopropyne (1.2 equivalents), and 2.1 g of potassium carbonate (1.5 equivalents) were weighed and added to a 50 mL three-neck flask. 20 mL of N,N-dimethylformamide was added. The reaction mixture was stirred evenly and heated at 50 °C for 5 hours. When TLC showed that the starting materials had essentially reacted completely, the reaction was stopped and the reaction solution was cooled to room temperature. 40 mL of water and 20 mL of ethyl acetate were added to the reaction solution for extraction. The aqueous phase was extracted with 15 mL of ethyl acetate. The combined organic phases were washed twice with 15 mL of water and three times with 15 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give crude oil 102-A. This product was used directly in the next feed without further purification.

[0431] Compound 102-B:

[0432] [ka] The crude product 102-A from the previous step was added to 15 mL of N,N-diethylaniline and dissolved with stirring. 2.67 g of cesium fluoride (1.3 equiv.) was weighed and quickly added. The reaction mixture was stirred uniformly and heated to 220 °C for 3 hours. TLC showed that the starting materials were essentially completely reacted. The reaction was stopped and the mixture was cooled to room temperature. 30 mL of water was added to the reaction mixture, and the pH of the reaction mixture was adjusted to 4 with 2 mol / L HCl solution. 20 mL of ethyl acetate was added for extraction. The aqueous phase was extracted once with 20 mL of ethyl acetate. The combined organic phases were washed twice with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a black oil, which was purified by silica gel column chromatography (PE / EA = 95 / 5) to give compound 102-B (1.16 g, two-step yield 51.6%).

[0433] Compound 102-C:

[0434] [ka] 1.16 g of compound 102-B (1.0 equivalent) was weighed and added to a 50 mL round-bottom flask. 15 mL of methanol was added. The resulting system was stirred at room temperature to dissolve. 3.90 g of sodium borohydride (20.0 equivalents) was weighed and added, and the solution was stirred overnight to react. TLC showed that the raw materials had essentially reacted completely. The reaction was then stopped. 30 mL of water was slowly added dropwise to the reaction solution, and a large amount of solid precipitated. The mixture was stirred at room temperature for approximately 30 minutes and then filtered. The filter cake was collected and dried to obtain compound 102-C (950 mg, 94.06% yield) as a yellow solid.

[0435] Compound 102-D:

[0436] [ka] 400 mg of compound 102-C (1.0 equiv.), 1.32 g of Cs2CO3 (2.0 equiv.), and 428.7 mg of 2-bromo-6-fluoropyridine (1.2 equiv.) were weighed and added to a 25 mL round-bottom flask. 12 mL of DMF was added. The reaction mixture was stirred uniformly and then heated to 90 °C for 5 hours. TLC showed that the two starting materials had essentially reacted completely. Heating was stopped and the mixture was cooled to room temperature. 24 mL of water was added to the reaction mixture, and a large amount of solid precipitated. The mixture was stirred at room temperature for approximately 30 minutes and then filtered. The filter cake was washed with water and dried to obtain solid compound 102-D (640 mg, 89.38% yield).

[0437] Compound 102-E:

[0438] [ka] 340 mg of compound 102-D (1.0 equiv.), 509 mg of compound 19-E (1.0 equiv.), 42.32 mg of Pd(dppf)Cl2 (0.06 equiv.), and 785.2 mg of cesium carbonate (2.5 equiv.) were weighed and added to a 50 mL round-bottom flask. 9 mL of 1,4-dioxane was added. The reaction mixture was then stirred evenly, purged with nitrogen three times, and heated to 90 °C under a nitrogen atmosphere for 2.5 h. TLC indicated that the two starting materials had essentially reacted completely. Heating was stopped, and the reaction mixture was cooled to room temperature. The reaction mixture was then filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (DCM / MeOH = 98 / 2) to obtain compound 102-E (530 mg, 87.8% yield).

[0439] Compound 102:

[0440] [ka] 530 mg of compound 102-E (1.0 equiv.) was weighed and added to a 25 mL round-bottom flask. 9 mL of tetrahydrofuran and 1.5 mL of methanol were added. The resulting system was stirred to dissolve, and then 0.85 mL (2.0 equiv.) of 2 mol / L NaOH solution was added. The reaction mixture was stirred uniformly and allowed to react at room temperature overnight. TLC showed that the raw materials had essentially reacted completely. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. 10 mL of water was added to the concentrate, and the pH of the reaction mixture was adjusted to approximately 4 with citric acid solution. A large amount of white solid precipitated, which was stirred at room temperature for 30 minutes and filtered. The filter cake was collected, pulped with a mixed solvent (DCM / MeOH=1:1), and purified to obtain compound 102 (400 mg, 77.16% yield) as a white solid. MS m / z (ESI): 612.1696 (M+H) + , 1HNMR (400 MHz, DMSO-d6) δ=12.71 (s, 1H), 8.26 (s, 1H), 7.95-7.74 (m, 4H), 7.61 (dd, J = 13.3, 7.9 Hz, 2H), 7.41(t,J=8.0Hz,1H),7.32 (dd, J = 35.5,8.0Hz, 2H), 6.89 (d, J = 8.2 Hz, 1H), 6.68 (s, 1H), 5.73 (s, 2H), 5.05 (dd, J = 7.3, 2.7 Hz, 1H), 4.72 (dd, J = 15.6, 7.1 Hz, 1H), 4.66-4.29 (m, 5H), 2.76-2.63 (m, 1H), 2.46 (d, J = 11.5 Hz, 3H), 2.38 (m, 1H).

[0441] Example 48: Synthesis of compound 103:

[0442] [ka] Synthesis Route:

[0443] [ka] Referring to the synthesis method of compound 93, compound 1-C was replaced with compound 87-A1 to finally obtain compound 103. MS m / z (ESI): 600.1743 (M+H) + , 1H NMR (400 MHz, DMSO-d6) δ= 8.25 (d, J = 24 Hz, 2H), 7.88-7.76 (m, 4H), 7.65 (d, J = 6.8 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.43-7.38 (m, 2H), 7.03 (d, J = 20 Hz, 1H), 5.85 (s, 2H), 5.07 (d, J = 5.6 Hz, 1H), 4.75 (dd, J = 15.6, 7.2 Hz, 1H), 4.58-4.31 (m, 5H), 2.75-2.67 (m, 1H), 2.41-2.35 (m, 1H).

[0444] Example 49: Synthesis of compound 104:

[0445] [ka] Synthesis Route:

[0446] [ka] Compound 104 was finally obtained by replacing compound 99-A with compound 104-A (wherein the preparation method of 104A was the same as that of compound 99-A, and compound 1-C was replaced with compound 87-A1), following the synthesis method of compound 100. MS m / z (ESI): 634.1350 (M+H). + , 1H NMR (400 MHz, DMSO-d6) δ= 8.28 (s, 1H), 7.87-7.77 (m, 4H), 7.68 (dd, J = 8.4, 2.6 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.50-7.46 (m, 1H), 7.45-7.36 (m, 2H), 7.20 (s, 1H), 5.85 (s, 2H), 5.10-5.03 (m, 1H), 4.75 (dd, J = 15.6, 6.8 Hz, 1H), 4.57 (d, J = 15.6 Hz, 1H), 4.55-4.31 (m, 4H), 2.75-2.68 (m, 1H), 2.45-2.36 (m, 1H).

[0447] Example 50: Synthesis of compound 105:

[0448]

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[0449]

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[0450]

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[0451] Compound 105-B:

[0452] [ka] 1.91 g of compound 105-A (1.0 equiv.) was weighed and added to a 100 mL round-bottom flask. 30 mL of methanol was added. The reaction mixture was then stirred to form a suspension. 287 mg of Pd / C (10%) was then added, and the system was purged with hydrogen three times. The reaction mixture was reacted under a hydrogen atmosphere at room temperature for 4 hours until TLC showed the reaction was complete. The reaction mixture was then filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give 1.71 g of compound 105-B in 100% yield.

[0453] Compound 105-C:

[0454] [ka] 500 mg of compound 19-B (1.0 equiv.), 600 mg of compound 105-B (1.1 equiv.), 370 mg of NMI (2.1 equiv.), and 662 mg of TCFH (1.1 equiv.) were weighed and added to a 100 mL round-bottom flask. 10 mL of acetonitrile was added. The reaction mixture was then stirred in an ice bath for approximately 0.5 hours and then allowed to react at room temperature overnight until TLC showed the reaction was complete. 20 mL of water was added to the reaction mixture to precipitate a large amount of off-white solid. The reaction mixture was stirred for approximately 0.5 hours, then suction filtered and washed with water. The filter cake was dried to give 507 mg of compound 105-C in a 50.3% yield.

[0455] Compound 105-D:

[0456] [ka] 507 mg of compound 105-C (1.0 equivalent) and 2.60 g of acetic acid (40.0 equivalents) were weighed and added to a 100 mL round-bottom flask. 10 mL of 1,2-dichloroethane was added. The reaction mixture was then stirred uniformly and heated to 80 °C for approximately 6 hours until TLC showed the reaction was complete. The reaction mixture was cooled to room temperature, concentrated, and 5 mL of water was added. The pH of the reaction mixture was adjusted to neutral with 5% sodium bicarbonate solution. A large amount of solid matter precipitated. The reaction mixture was stirred for a while, then suction filtered and washed with a small amount of water to obtain a filter cake. The filter cake was purified by silica gel column chromatography to obtain 330 mg of compound 105-D in a 67.6% yield.

[0457] Compound 105-E:

[0458] [ka] 330 mg of compound 105-D (1.0 equiv.), 223 mg of bis(pinacolato)diboron (1.2 equiv.), 16.0 mg of Pd(dppf)Cl2 (0.03 equiv.), and 179 mg of potassium acetate (2.5 equiv.) were weighed and added to a 50 mL round-bottom flask. 5.0 mL of 1,4-dioxane was added. The reaction mixture was then degassed twice with nitrogen and heated to 100 °C under a nitrogen atmosphere. After 2 h of reaction, the heating was stopped and the reaction mixture was cooled to room temperature. The reaction mixture was then filtered through a diatomaceous earth funnel, and the filter cake was washed with 20 mL of ethyl acetate twice. The filtrate was then concentrated to dryness and purified by column chromatography to give 261 mg of compound 105-E in 71.7% yield.

[0459] Compound 105-F:

[0460] [ka] 260 mg of compound 105-E (1.1 equiv.), 161 mg of compound 7-A (1.0 equiv.), 10.4 mg of Pd(dppf)Cl2 (0.03 equiv.), and 387 mg of Cs2CO3 (2.5 equiv.) were weighed and added to a 50 mL round-bottom flask. 5.0 mL of 1,4-dioxane and 1.0 mL of HO were added. The reaction mixture was then degassed twice with nitrogen and heated to 90 °C under a nitrogen atmosphere. After 2 h of reaction, the heating was stopped and the reaction mixture was cooled to room temperature. The reaction mixture was then filtered through a diatomaceous earth funnel, and the filter cake was washed with 10 mL of ethyl acetate twice. The filtrate was then concentrated to dryness and purified by column chromatography to give 185 mg of compound 105-F in 61.7% yield.

[0461] Compound 105:

[0462] [ka] 180 mg of compound 105-F (1.0 equiv.) was weighed and added to a 25 mL round-bottom flask. 3 mL of tetrahydrofuran and 1 mL of methanol were added. The resulting mixture was stirred to dissolve, and then 0.57 mL of 2 mol / L aqueous NaOH (4.0 equiv.) was slowly added dropwise. After the addition, the reaction mixture was allowed to react at room temperature for approximately 36 hours until TLC indicated the reaction was complete. The reaction mixture was concentrated, and 5 mL of water and 1 mL of acetone were added. The pH of the reaction mixture was adjusted to 4-5 with citric acid solution. A large amount of off-white solid precipitated, which was stirred for approximately 0.5 hours, filtered, and washed with water. The filter cake was dried to obtain 157 mg of compound 105 in an 89.2% yield. MS m / z (ESI): 616.1452 (M+H). + , 1 H NMR (400 MHz, DMSO-d6) δ= 8.18 (s, 1H), 8.13 (s, 1H), 7.96-7.77 (m, 3H), 7.64 (d, J = 7.4 Hz, 1H), 7.56-7.40 (m, 3H), 7.36 (d, J = 8.0 Hz, 1H), 7.06 (s, 1H), 6.89 (d, J = 8.2 Hz, 1H), 5.77 (s, 2H), 5.05 (d, J = 5.6 Hz, 1H), 4.78-4.72 (m, 1H), 4.67-4.31 (m, 5H), 2.77-2.62 (m, 1H), 2.45-2.30 (m, 1H).

[0463] Example 51: Synthesis of compound 106:

[0464] [ka] Synthesis Route:

[0465] [ka] Compound 106-A:

[0466] [ka] 0.6 g of 2-chloro-3-fluoro-6-bromopyridine (1.0 equivalent), 1.01 g of 1-pinacolborate-4-ethylacetate-1-cyclohexene (1.2 equivalents), 0.208 g of Pd(dppf)Cl2 (0.1 equivalents), and 2.32 g of cesium carbonate (2.5 equivalents) were weighed and added to a 50 mL round-bottom flask. 18 mL of 1,4-dioxane and 3 mL of water were added. The reaction mixture was then degassed twice with nitrogen and heated to 80 °C under a nitrogen atmosphere. After 2 hours of reaction, the heating was stopped and the reaction mixture was cooled to room temperature. The reaction mixture was then filtered through a diatomaceous earth funnel, and the filter cake was washed with 15 mL of ethyl acetate twice. The filtrate was then concentrated to dryness and purified by column chromatography to give 0.769 g of compound 106-A in 90.6% yield.

[0467] Compound 106-B:

[0468] [ka] 0.765 g of compound 106-A (1.0 equivalent) was weighed and added to a 50 mL round-bottom flask. 7.5 mL of methanol and 11.5 mL of tetrahydrofuran were added. 2.6 mL of 2 mol / L NaOH solution (2.0 equivalents) was then added dropwise to the reaction mixture at room temperature. After the dropwise addition, the reaction mixture was allowed to react at room temperature for 1 hour. After the reaction, the reaction mixture was concentrated. After concentration, 20 mL of water was added, and the pH of the reaction system was adjusted to 4-5 with 1 mol / L HCl solution. The reaction mixture was then filtered, and the filter cake was washed with 10 mL of water twice and dried to obtain 0.612 g of compound 106-B in an 88.3% yield.

[0469] Compound 106-C:

[0470] [ka] 0.61 g of compound 106-B (1.0 equivalent), 0.615 g of compound 1-F (1.1 equivalents), and 0.390 g of N-methylimidazole (2.1 equivalents) were weighed and added to a 50 mL round-bottom flask. 13.0 mL of acetonitrile was added. After stirring the reaction mixture in an ice bath for 20 minutes, 0.697 g of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (1.1 equivalents) was weighed and added. The reaction mixture was stirred and reacted in the ice bath for 0.5 hours. The reaction mixture was then transferred to room temperature and reacted for 3 hours. After the reaction, 36 mL of HO was added to the reaction mixture, which was stirred for 0.5 hours and filtered. The filter cake was washed with 20 mL of HO three times and dried at 50 °C to obtain 1.0 g of compound 106-C in a 90.6% yield. MS m / z (ESI): 488.1745 (M+H) + .

[0471] Compound 106-D:

[0472] [ka] 1.0 g of compound 106-C (1.0 equivalent) was weighed and added to a 50 mL round-bottom flask. 15.0 mL of 1,2-dichloroethane was added, followed by the dropwise addition of 4.923 g of acetic acid (40.0 equivalents). After the dropwise addition, the reaction mixture was heated to 90 °C and allowed to react. After 5 hours, the reaction mixture was cooled to room temperature and concentrated to remove the solvent. 15 mL of water was added, and the pH of the reaction mixture was adjusted to 7-8 with 5% aqueous NaHCO3. The reaction mixture was filtered. The filter cake was washed with a small amount of water and dried to obtain 0.81 g of compound 106-D in an 84% yield. MS m / z (ESI): 470.1629 (M+H). + .

[0473] Compound 106-E:

[0474] [ka] 0.35 g of compound 106-D (1.0 equiv.), 0.204 g of compound 1-C (1.5 equiv.), 69 mg of Pd2(dba)3 (0.1 equiv.), 69.5 mg of 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (0.2 equiv.), and 0.485 g of cesium carbonate (2 equiv.) were weighed and added to a 25 mL round-bottom flask. 5.5 mL of toluene was added. The reaction mixture was then degassed twice with nitrogen and heated to 110 °C under a nitrogen atmosphere. After 12 h of reaction, heating was stopped and the reaction mixture was cooled to room temperature. The reaction mixture was then filtered through a diatomaceous earth funnel, and the filter cake was washed with 10 mL of ethyl acetate twice. The filtrate was then concentrated to dryness and purified by column chromatography to give 0.201 g of compound 106-E in 43.9% yield. MS m / z (ESI): 616.2022(M+H) + .

[0475] Compound 106:

[0476] [ka] 0.2 g of compound 106-E (1.0 equivalent) was weighed and added to a 25 mL round-bottom flask. 1 mL of methanol and 3 mL of tetrahydrofuran were added, followed by 0.6 mL of 2 mol / L sodium hydroxide solution. The reaction mixture was then allowed to react at room temperature. After 20 hours, the reaction mixture was concentrated. After concentration, 5 mL of water and 0.5 mL of acetone were added to the reaction mixture. The pH of the reaction mixture was adjusted to 4-5 with 1 mol / L HCl solution. The reaction mixture was filtered, and the filter cake was washed with a small amount of water and then dried to obtain 0.182 g of compound 106 in a 93.1% yield. MS m / z (ESI): 602.1858 (M+H). + , 1H NMR (400 MHz, DMSO-d6) δ= 8.21 (s, 1H), 8.17 (d, J = 2.4 Hz, 1H), 7.81 (dd, J = 8.4, 1.6 Hz, 1H), 7.61 (dd, J = 19.2, 10.4 Hz, 2H), 7.44 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.06 (dd, J = 8.4, 6.4 Hz, 2H), 6.66 (s, 1H), 5.74 (s, 2H), 5.05-5.00 (m, 1H), 4.64 (dd, J = 15.6, 7.2 Hz, 1H), 4.52-4.43 (m, 2H), 4.30 (m, 1H), 3.04-2.92 (m, 2H), 2.73-2.65 (m, 1H), 2.45- 2.33 (m, 4H), 2.06-1.96 (m, 2H), 1.50-1.17 (m, 2H).

[0477] Example 52: Synthesis of compound 107:

[0478]

change

[0479]

change

[0480]

change

[0481] Compound 107:

[0482] [ka] 55 mg of compound 107-A (1.0 equivalent) was weighed and added to a 25 mL round-bottom flask. 0.3 mL of methanol and 0.9 mL of tetrahydrofuran were added, followed by 0.15 mL of 2 mol / L sodium hydroxide solution. The reaction mixture was then allowed to react at room temperature. After 20 hours, the reaction mixture was concentrated. After concentration, 2 mL of water and 0.25 mL of acetone were added to the reaction mixture. The pH of the reaction mixture was adjusted to 4-5 with 1 mol / L HCl solution. The reaction mixture was filtered, and the filter cake was washed with a small amount of water and then dried to obtain 45 mg of compound 107 in an 83.6% yield. MS m / z (ESI): 636.1473 (M+H) + , 1H NMR (400 MHz, DMSO-d6) δ= 12.71 (s, 1H), 8.22 (s, 1H), 7.80 (dd, J = 8.4, 1.2 Hz, 1H), 7.64-7.58 (m, 2H), 7.46-7.35 (m, 2H), 7.17 (s, 1H), 7.06 (dd, J = 7.2, 2.4 Hz, 1H), 6.64 (d, J = 11.6 Hz, 1H), 5.70 (s, 2H), 5.03 (dd, J = 14, 7.2 Hz, 1H), 4.64 (dd, J = 15.6, 7.2 Hz, 1H), 4.53-4.43 (m, 2H), 4.30 (dd, J = 14.8, 6.4 Hz, 1H), 3.04-2.91 (m, 2H), 2.73-2.65 (m, 1H), 2.41-2.33 (m, 4H), 2.06-1.95 (m, 2H), 1.49-1.24 (m, 2H).

[0483] Example 53: Synthesis of compound 108:

[0484]

change

[0485]

change

[0486]

change

[0487] Compound 108-B:

[0488] [ka] 327 mg of compound 108-A (1.0 equivalent) was weighed and added to a 25 mL round-bottom flask. 2 mL of methanol and 2 mL of tetrahydrofuran were added. The resulting mixture was stirred to dissolve, and then 1.0 mL of 2 mol / L NaOH solution was added dropwise. After the addition, the reaction mixture was allowed to react at room temperature for 3.0 hours. After the reaction was completed, the reaction mixture was concentrated. After concentration, 10 mL of water and 30 mL of ethyl acetate were added to the reaction mixture, and the pH of the reaction mixture was adjusted to 4-5 with 1 mol / L HCl solution. The reaction mixture was allowed to stand for phase separation, and the organic phase was recovered. The organic phase was washed twice with 15 mL of saturated brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to dryness to obtain compound 108-B (320 mg) as a white solid.

[0489] Compound 108-C:

[0490] [ka] 320 mg of compound 108-B (1.0 equivalent) and 183.6 mg of compound 1-F (1.05 equivalents) were weighed and added to a 50 mL round-bottom flask. 10.0 mL of acetonitrile was added. After stirring the reaction mixture in an ice bath for 15 minutes, 290.64 mg of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (1.4 equivalents) and 243.0 mg of N-methylimidazole (4.0 equivalents) were weighed and added. The reaction mixture was stirred and reacted in the ice bath for 1 hour. The reaction mixture was then transferred to room temperature and allowed to react for 3 hours. After the reaction, 30 mL of HO was added to the reaction mixture, and the mixture was stirred for 0.5 hours and filtered. The filter cake was washed with 20 mL of water, collected, and dried to give compound 108-C (410 mg, 85.17% yield).

[0491] Compound 108-D:

[0492] [ka] 410 mg of compound 108-C (1.0 equiv.) was weighed and added to a 25 mL round-bottom flask. 4.0 mL of acetic acid was added. The reaction mixture was then stirred uniformly and then heated to 90 °C for reaction. After 1.5 h, TLC showed that the starting materials had essentially reacted completely. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. 10 mL of water and 25 mL of ethyl acetate were added to the residue, and the pH of the reaction mixture was adjusted to 7-8 with saturated aqueous NaHCO3. The reaction mixture was then allowed to stand for phase separation, and the organic phase was separated. The organic phase was washed twice with 10 mL of saturated brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to dryness and purified by column chromatography to give compound 108-D (220 mg, 55.21% yield).

[0493] Preparation of Compound 108:

[0494] [ka] 220 mg of compound 108-D (1.0 equiv.) was weighed and added to a 25 mL round-bottom flask. 1.5 mL of methanol and 2.5 mL of tetrahydrofuran were added. The resulting mixture was stirred to dissolve, and then 0.8 mL of 2 mol / L NaOH aqueous solution was added. The reaction mixture was then allowed to react at room temperature. TLC showed that the starting materials were essentially completely reacted. After concentrating the reaction mixture, 5 mL of water and 3 mL of ethyl acetate were added to the residue, and the resulting mixture was allowed to stand for phase separation. The aqueous phase was recovered, and its pH was adjusted to 4-5 with citric acid solution. 10 mL of ethyl acetate was added for extraction. The organic phase was washed twice with 5 mL of saturated brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to dryness to give compound 108 (200 mg, 93% yield). MS m / z (ESI): 618.1560 (M+H)+ 1 HNMR (400 MHz, CDCl3) δ=8.22 (s, 1H), 8.09 (d, J = 8.6 Hz, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 8.1 Hz, 1H), 6.94 (d, J = 7.5 Hz, 1H), 6.76 (s, 1H), 6.71 (s, 1H), 6.66 (d, J = 8.2 Hz, 1H), 5.65 (s, 2H), 5.21 (d, J = 7.2 Hz, 1H), 4.64 (d, J = 7.2 Hz, 1H), 4.58-4.33 (m, 3H), 3.15 (d, J = 6.5 Hz, 2H), 2.82-2.71 (m, 1H), 2.65 (d, J = 17.4 Hz, 1H), 2.48 (s, 4H), 2.16 (d, J = 13.7 Hz, 2H), 1.63 (m, 1H).

[0495] Example 54: Synthesis of compound DB06:

[0496] [ka] Synthesis Route:

[0497] [ka] Compound DB06-A:

[0498] [ka] 2.0 g of methyl 3-fluoro-4-nitrobenzoate (1.0 equivalent) and 1.45 g of (S)-(tetrahydrofuran-2-yl)formamide hydrochloride (1.05 equivalents) were weighed and added to a 100 mL round-bottom flask. 10 mL of N,N-dimethylformamide, 10 mL of tetrahydrofuran, and 4.07 g of triethylamine (4.0 equivalents) were added. The reaction mixture was stirred uniformly and then heated to 50 °C for approximately 6 hours. After completion of the reaction, the reaction solution was concentrated to remove tetrahydrofuran. 30 mL of water was added to the residue, precipitating a large amount of yellow solid. The reaction solution was stirred for approximately 0.5 hours, then suction filtered and washed with a small amount of water. The filter cake was dried to obtain 2.64 g of compound DB06-A in a 94.0% yield, which was used directly in the next reaction.

[0499] Compound DB06-B:

[0500] [ka] 2.64 g of compound DB06-A (1.0 equivalent) was weighed and added to a 100 mL round-bottom flask. 26 mL of methanol was added. The reaction mixture was stirred uniformly. 260 mg of Pd / C (10%) was then added, and the system was purged with hydrogen three times. The reaction mixture was reacted under a hydrogen atmosphere at room temperature for 3 hours. After the reaction, the reaction mixture was filled with diatomaceous earth and filtered. The filtrate was concentrated under reduced pressure to obtain 2.43 g of brown oily compound DB06-B in a yield of over 100%, which was used directly in the next reaction.

[0501] Compound DB06-C:

[0502] [ka] 2.06 g of compound 19-B (1.0 equivalent) and 2.43 g of compound DB06-B (1.1 equivalent) were weighed and added to a 150 mL round-bottom flask. 41 mL of acetonitrile was added. The reaction mixture was stirred and cooled in an ice bath, followed by the addition of 1.52 g of NMI (2.1 equivalents) and 2.73 g of TCFH (1.1 equivalents). The reaction mixture was stirred for approximately 0.5 hours, then the ice bath was removed and the mixture was allowed to react at room temperature overnight. After the reaction was complete, approximately 80 mL of water was added, precipitating a large amount of off-white solid. The reaction mixture was stirred for approximately 0.5 hours, then suction filtered and washed with water. The filter cake was dried to obtain 2.71 g of compound DB06-C in a 65.9% yield, which was used directly in the next reaction.

[0503] Compound DB06-D:

[0504] [ka] 2.71 g of compound DB06-C was weighed and added to a 150 mL round-bottom flask. 27.0 mL of 1,2-dichloroethane was added, followed by the dropwise addition of 6.7 mL (20.0 equiv.) of acetic acid. After the dropwise addition, the reaction mixture was heated to 60 °C and allowed to react. After 5 hours of reaction, the reaction mixture was cooled to room temperature and then concentrated. After concentration, 20.0 mL of acetonitrile and 20 mL of water were added, and the pH of the reaction mixture was adjusted to 7-8 with saturated sodium bicarbonate solution. After a large amount of off-white solid precipitated, the reaction mixture was stirred at room temperature for 0.5 hours, filtered, and washed with water. The filter cake was dried to obtain 2.28 g of compound DB06-D in an 87.5% yield, which was used directly in the subsequent reaction.

[0505] Compound DB06-E:

[0506] [ka] 2.28 g of compound DB06-D (1.0 equiv.), 1.56 g of bis(pinacolato)diboron (1.2 equiv.), 112 mg of Pd(dppf)Cl2 (0.03 equiv.), and 1.25 g of potassium acetate (2.5 equiv.) were weighed and added to a 150 mL round-bottom flask. 34.0 mL of 1,4-dioxane was added. The reaction mixture was then degassed twice with nitrogen and heated to 100 °C under a nitrogen atmosphere. After 2 h of reaction, the heating was stopped and the reaction mixture was cooled to room temperature. The reaction mixture was then filtered through a diatomaceous earth funnel, and the filter cake was washed with 20 mL of ethyl acetate three times. The filtrate was then concentrated to dryness and purified by column chromatography to give 3.08 g of compound DB06-E in >100% yield, which was used directly in the next reaction.

[0507] Compound DB06-F:

[0508] [ka] 0.47 g of compound DB06-E (1.50 equiv.), 0.20 g of compound 7-A (1.0 equiv.), 14 mg of Pd(dppf)Cl2 (0.03 equiv.), and 515 mg of Cs2CO3 (2.5 equiv.) were weighed and added to a 50 mL round-bottom flask. 4.0 mL of 1,4-dioxane was added. The reaction mixture was then degassed twice with nitrogen and heated to 100 °C under a nitrogen atmosphere. After 2 h of reaction, the heating was stopped and the reaction mixture was cooled to room temperature. The reaction mixture was then filtered through a diatomaceous earth funnel, and the filter cake was washed with 10 mL of ethyl acetate twice. The filtrate was then concentrated to dryness and purified by column chromatography to give 0.29 g of compound DB06-F in 78.3% yield.

[0509] Compound DB06:

[0510] [ka] 0.15 g of compound DB06-F (1.0 equivalent) was weighed and added to a 50 mL round-bottom flask. 6.0 mL of tetrahydrofuran and 2.0 mL of methanol were added. The reaction mixture was stirred uniformly, and 0.51 mL of 2 mol / L sodium hydroxide solution (4.0 equivalents) was slowly added dropwise. The system was heated to 40°C and reacted for approximately 4 hours. After completion of the reaction, the reaction solution was concentrated, and 4 mL of water and 0.5 mL of acetone were added. The pH of the reaction solution was adjusted to 4-5 with citric acid solution, resulting in the precipitation of a large amount of off-white solid. The reaction solution was stirred for approximately 0.5 hours, then suction filtered and washed with water. The filter cake was dried to obtain 127 mg of compound DB06 in an 87.0% yield. MS m / z (ESI): 612.1634 (M+H)+; 1 H NMR (400 MHz, DMSO) δ =12.87 (s, 1H), 8.22 (d, J = 0.9 Hz, 1H), 7.94 - 7.87 (m, 2H), 7.86 - 7.76 (m, 2H), 7.67 - 7.55 (m, 3H), 7.53 - 7.40 (m, 2H), 7.32 (dd, J = 8.2, 1.8 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 5.52 (s, 2H), 4.58 - 4.30 (m, 4H), 4.16 (dt, J = 12.2, 4.8 Hz, 1H), 3.79 (dd, J = 14.7, 6.9 Hz, 1H), 3.63 (dd, J = 14.1, 7.6 Hz, 1H), 2.06 (dt, J = 12.2, 5.9 Hz, 1H), 1.93 - 1.74 (m, 2H), 1.69 - 1.55 (m, 1H).

[0511] Comparative Example 1: Compound PF-06882961:

[0512] [ka] Synthesis Route:

[0513] [ka] Compound DB01-A:

[0514] [ka] 8.0 g of 2,6-dichloropyridine (1.0 equivalent) and 8.6 g of 3-fluoro-4-(hydroxymethyl)benzonitrile (1.0 equivalent) were weighed and added to a 250 mL round-bottom flask. 80 mL of 1,4-dioxane was added, and the resulting mixture was stirred to dissolve. A mixture of 7.28 g of potassium tert-butoxide (1.2 equivalents) in THF (40 mL) was added dropwise to the mixture. After the addition, the reaction mixture was stirred at 40 °C for 60 minutes. TLC showed that the raw materials had disappeared. The reaction mixture was then stopped and cooled to room temperature. 240 mL of water was added to the reaction mixture, and a large amount of solid precipitated. This was then filtered. The filter cake was washed with water and dried to obtain a pale yellow solid, DB01-A (12.42 g, 87.59% yield). 1 HNMR (400 MHz, CDCl3) δ =7.68 (t, J = 7.5 Hz, 1H), 7.59 (dd, J = 8.1, 7.6 Hz, 1H), 7.50 (dd, J = 7.9, 1.5 Hz, 1H), 7.41 (dd, J = 9.2, 1.5 Hz, 1H), 6.98 (dd, J = 7.6, 0.6 Hz, 1H), 6.76 (dd, J = 8.2, 0.6 Hz, 1H), 5.50 (s, 2H).

[0515] Compound DB01-B:

[0516] [ka] 6.0 g of compound DB01-A (1.0 equiv.), 7.73 g of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.1 equiv.), 1.68 g of Pd(dppf)Cl2 (0.1 equiv.), and 2.9 g of NaHCO3 (1.5 equiv.) were weighed and added to a 250 mL round-bottom flask. 90 mL of 1,4-dioxane and 18.0 mL of HO were added. The reaction mixture was then stirred evenly, purged with nitrogen four times, and heated to 90 °C under a nitrogen atmosphere for 3 hours. TLC indicated the disappearance of the starting material. The reaction mixture was then turned off and cooled to room temperature. The reaction mixture was then concentrated and purified by column chromatography (PE / EtOAc=95 / 5) to give a solid product DB01-B (8.6 g, yield 92.0%).

[0517] Compound DB01-C:

[0518] [ka] 8.6 g of compound DB01-B (1.0 equivalent) was weighed and added to a 500 mL round-bottom flask. 2.58 g of Pd / C (10% content) and 215 mL of toluene were added. The reaction mixture was then stirred uniformly, purged with hydrogen three times, and stirred under a hydrogen atmosphere to react. HPLC showed that the starting material had reacted completely. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure to give compound DB01-C (8.17 g, 94.6% yield) as an oil. 1HNMR (400 MHz, CDCl3) δ =7.64 (t, J = 7.5 Hz, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.46 (d, J = 7.9Hz, 1H), 7.40 (d, J = 9.3Hz, 1H), 6.77 (d, J = 7.3 Hz, 1H), 6.67 (d, J = 8.1 Hz, 1H), 5.51 (s, 2H), 4.23 (brs, 2H), 2.83 (t, J = 11.3 Hz, 2H), 2.72 (tt, J = 11.8, 3.7 Hz, 1H), 1.84 (d, J = 12.1 Hz, 2H), 1.69 (d, J = 15.9Hz, 2H), 1.51 (s, 9H).

[0519] Compound DB01-D:

[0520] [ka] 8.2 g of compound DB01-C (1.0 equivalent) and 9.47 g of pTSA monohydrate (2.5 equivalents) were weighed and added to a 250 mL round-bottom flask. 190 mL of ethyl acetate was added. The reaction mixture was then stirred uniformly and reacted at 60 °C for approximately 30 minutes. TLC showed that the raw materials had disappeared. The reaction was then stopped and cooled to room temperature. A large amount of off-white solid compound precipitated, which was filtered and dried to obtain the bimolecular p-toluenesulfonate compound DB01-D (11.14 g, 85.69% yield).

[0521] Compound DB01-E:

[0522] [ka] 2.7 g of compound DB01-D (1.0 equivalent), 1.21 g of compound 001-M07 (1.0 equivalent), and 2.84 g of potassium carbonate (5.0 equivalents) were weighed and added to a 150 mL round-bottom flask. 54 mL of acetonitrile was added. The reaction mixture was stirred evenly and heated at 50 °C for 3 hours. TLC showed that the two raw materials had completely reacted. After heating, the reaction mixture was cooled to room temperature, and 108 mL of water and 50 mL of ethyl acetate were added. The resulting mixture was allowed to stand for liquid phase separation. The aqueous phase was extracted with 50 mL of ethyl acetate. The combined organic phases were washed twice with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain an oil. Pulping and purification using a mixed solvent (PE / EA = 3 / 1) afforded the solid product DB01-E (2.07 g, 88.08% yield).

[0523] Compound PF-06882961:

[0524] [ka] 500 mg of compound DB01-E (1.0 equiv.) was weighed and added to a 50 mL round-bottom flask. 9 mL of acetonitrile was added. 1.8 mL of an aqueous solution containing 245 mg of TBD (2.0 equiv.) was added dropwise under stirring, and the mixture was stirred and reacted at room temperature for 24 hours. TLC showed that the starting material had completely reacted. The pH of the reaction mixture was adjusted to 5.0 with citric acid solution. 20 mL of ethyl acetate was added, and the mixture was allowed to stand for phase separation. The ethyl acetate organic phase was washed with 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oil, which was subjected to column chromatography to obtain the white solid product PF-06882961 (0.44 g, 89.97%). MS m / z (ESI): 556.2366 (M+H)+ 1HNMR (400 MHz, DMSO-d6) δ =12.84 (brs, 1H), 8.28 (s, 1H), 7.89 (d, J = 9.9 Hz, 1H), 7.81 (d, J = 8.9 Hz, 1H), 7.74-7.59 (m, 4H), 6.89 (d, J = 7.3 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 5.47 (s, 2H), 5.11 (d, J = 4.3 Hz, 1H), 4.84-4.79 (m, 1H), 4.69-4.66 (m, 1H), 4.51-4.46 (m, 1H), 4.41-4.36 (m, 1H), 3.95 (d, J = 13.5 Hz, 1H), 3.78 (d, J = 13.5 Hz, 1H), 2.98 (d, J = 10.9 Hz, 1H), 2.84 (d, J = 10.8 Hz, 1H), 2.73-2.67 (m, 1H), 2.61-2.56 (m, 1H), 2.51-2.41 (m, 1H), 2.25-2.13 (m, 2H), 1.79-1.60 (m, 4H).

[0525] Comparative example 2: Compound DB02:

[0526]

change

[0527]

change

[0528]

change

[0529] Compound DB02-C:

[0530] [ka] 404 mg of compound DB02-B (1.0 equivalent) and 522.72 mg of pTSA·HO (3.0 equivalents) were weighed and added to a 50 mL round-bottom flask. 10 mL of ethyl acetate was added. The reaction mixture was stirred uniformly and heated at 65 °C for 2 hours. TLC showed that the starting materials had completely reacted. Heating was stopped and the reaction mixture was cooled to room temperature. 5 mL of water was added to the reaction mixture, and the pH of the reaction mixture was adjusted to approximately 8 with saturated sodium bicarbonate. The reaction mixture was stirred for 10 minutes and then allowed to stand for phase separation. The organic phase was collected, washed twice with 5 mL of water, twice with 5 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound DB02-C as an oil. This compound was used directly in the next feed without calculating the yield or purity.

[0531] Compound DB02-D:

[0532] [ka] Compound DB02-C (1.0 equivalent) obtained in the previous step was weighed and added to a 50 mL round-bottom flask. 9 mL of acetonitrile, 270 mg of compound 001-M07 (1.0 equivalent), and 253.20 mg of potassium carbonate (2.0 equivalents) were added. The reaction mixture was stirred uniformly and heated at 50 °C for 2 hours. TLC showed that the two starting materials had completely reacted. The heating was then stopped and the reaction mixture was cooled to room temperature. 18 mL of water and 10 mL of ethyl acetate were added to the reaction mixture, and the resulting mixture was allowed to stand for phase separation. The aqueous phase was extracted with 10 mL of ethyl acetate. The combined organic phases were washed twice with 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain an oily crude product, which was purified by column chromatography (PE / EA=10 / 90 to 50 / 50 as a developing agent) to obtain compound DB02-D (460 mg, yield 83.94%).

[0533] Compound DB02:

[0534] [ka] 460 mg of compound DB02-D (1.0 equiv.) was weighed and added to a 50 mL round-bottom flask. A mixed solvent (acetonitrile / methanol / water = 9 mL / 3 mL / 3 mL) was added, followed by 48.40 mg of LiOH·HO (1.5 equiv.). The reaction mixture was stirred uniformly and heated at 45 °C for 4-5 hours. TLC showed that the starting material had completely reacted. After cooling to room temperature, the solvent was evaporated under reduced pressure, and 10 mL of water was added to the residue. Impurities were extracted with 15 mL of ethyl acetate, and the aqueous phase was adjusted with citric acid until the pH of the reaction mixture reached 4-5. 10 mL of ethyl acetate was added to the aqueous phase, and the resulting mixture was allowed to stand for phase separation. The aqueous phase was extracted twice with 10 mL of ethyl acetate, and the ethyl acetate organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography to give the comparative compound DB02 (400 mg, 89.02% yield) as an off-white solid. MS m / z (ESI): 585.1904 (M+H)+; 1 HNMR (400 MHz, MeOD) δ =8.35 (d, J = 0.9 Hz, 1H), 8.05-7.99 (m, 1H), 7.87 (d, J = 2.2 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 7.4 Hz, 1H), 6.93 (d, J = 2.2 Hz, 1H), 6.73 (d, J = 8.2 Hz, 1H), 6.67-6.69 (brs, 1H), 5.68 (s, 2H), 5.27-5.18 (m, 1H), 4.87-4.81 (dd, J = 15.5, 7.1 Hz, 1H), 4.69 (dd, J = 15.5,2.5 Hz, 1H), 4.62(m, 1H),4.49-4.38 (m, 3H), 3.65 (s, 2H), 3.21 (m, 2H), 2.79-2.76 (m,1H), 2.74-2.72 (m, 2H), 2.54-2.45 (m, 1H)

[0535] Comparative Example 3: Compound DB03:

[0536] [ka] Synthesis Route:

[0537] [ka] Compound DB03-A:

[0538] [ka] 0.5 g of compound 2-chloro-4-fluorobenzyl alcohol (1.0 equivalent), 0.822 g of 2-bromo-6-fluoropyridine (1.5 equivalents), and 2.04 g of cesium carbonate (2.0 equivalents) were weighed and added to a 50 mL round-bottom flask. 15 mL of DMF was then added. The reaction mixture was heated to 90 °C. After 4 hours of reaction, the heating was stopped and the reaction mixture was cooled to room temperature. 60 mL of water and 30 mL of ethyl acetate were added, and the resulting mixture was stirred for 5 minutes and then allowed to stand. The organic phase was separated, washed twice with 30 mL of ethyl acetate, and the combined organic phases were then washed with saturated brine, dried over anhydrous Na2SO4 for 5 minutes, and filtered. The filtrate was concentrated to dryness and purified by column chromatography to obtain 0.84 g of compound DB03-A in an 85% yield.

[0539] Compound DB03-B:

[0540] [ka] 0.2 g of compound DB03-A (1.0 equiv.), 0.364 g of compound 19-E (1.2 equiv.), 14 mg of Pd(dppf)Cl2 (0.03 equiv.), and 0.515 g of Cs2CO3 (2.5 equiv.) were weighed and added to a 25 mL round-bottom flask. 6.0 mL of 1,4-dioxane and 1.0 mL of HO were added. The reaction mixture was then degassed twice with nitrogen and heated to 90 °C under a nitrogen atmosphere. After 3 h of reaction, the heating was stopped and the reaction mixture was cooled to room temperature. The reaction mixture was then filtered through a diatomaceous earth funnel, and the filter cake was washed with 10 mL of ethyl acetate twice. The filtrate was then concentrated to dryness and purified by column chromatography to give 0.275 g of compound DB03-B in 74% yield. MS m / z (ESI): 590.1583 (M+H)+.

[0541] Compound DB03:

[0542] [ka] 0.272 g of compound DB03-B (1.0 equivalent) was weighed and added to a 25 mL round-bottom flask. 1.5 mL of methanol and 4.5 mL of tetrahydrofuran were added, followed by 0.47 mL of 2N sodium hydroxide solution. The reaction mixture was then allowed to react at room temperature. After 15 hours, the reaction mixture was concentrated. After concentration, 5 mL of water was added to the residue, and the pH of the reaction mixture was adjusted to 4-5 with 1 mol / L HCl solution. The reaction mixture was then filtered. The filter cake was pulped with 5 mL of ethyl acetate and 1 mL of methanol, followed by filtration. The filter cake was washed with 3 mL of ethyl acetate three times and dried to obtain 0.173 g of compound DB03 in a 65% yield. MS m / z (ESI): 576.1499 (M+H)+ 1H NMR (400 MHz, DMSO-d6) δ = 8.26 (s, 1H), 7.93-7.79 (m, 4H), 7.65-7.58 (m, 3H), 7.48-7.42 (m, 2H), 7.32 (d, J = 8.0 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 5.52 (s, 2H), 5.07-5.02 (m, 1H), 4.73 (dd, J = 15.6, 7.2 Hz, 1H), 4.52-4.33 (m, 5H), 2.74-2.66 (m, 1H), 2.42-2.34 (m, 1H).

[0543] Comparative Example 4: Compound DB04:

[0544] [ka] Synthesis Route:

[0545] [ka] Compound DB04-A:

[0546] [ka] 3 g of methyl 3-fluoro-4-nitrobenzoate (1.0 equiv.), 1.36 g of 2-methoxyethanamine (1.2 equiv.), and 3.05 g of triethylamine (2.0 equiv.) were weighed and added to a 250 mL round-bottom flask. 15 mL of N,N-dimethylformamide and 15 mL of tetrahydrofuran were added. The reaction mixture was stirred until homogeneous and then reacted at 60 °C for approximately 8 hours until TLC indicated the reaction was complete. The reaction mixture was cooled to room temperature and concentrated to remove most of the tetrahydrofuran. 50 mL of water was added to precipitate a large amount of yellow solid. The mixture was stirred for approximately 0.5 hours, then suction filtered and washed. The filter cake was dried to obtain 3.39 g of compound DB04-A in an 88.5% yield.

[0547] Compound DB04-B:

[0548] [ka] 3.39 g of compound DB04-A (1.0 equivalent) was weighed and added to a 250 mL round-bottom flask. 50 mL of methanol was added, and the resulting system was stirred uniformly. 0.51 g of Pd / C (10%) was then added. The reaction mixture was purged with hydrogen three times and reacted under a hydrogen atmosphere at room temperature for approximately 2 hours until TLC showed the reaction was complete. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated to dryness to obtain 2.99 g of compound DB04-B in 100% yield.

[0549] Compound DB04-C:

[0550] [ka] 2.0 g of compound 19-B (1.0 equivalent) and 2.12 g of compound DB04-B (1.1 equivalent) were weighed and added to a 250 mL round-bottom flask. 40 mL of acetonitrile was added, stirred, and cooled in an ice bath. 1.48 g of NMI (2.1 equivalents) and 2.65 g of TCFH (1.1 equivalents) were then added. The reaction mixture was stirred for approximately 0.5 hours. The ice bath was then removed, and the reaction mixture was allowed to react at room temperature overnight until TLC showed the reaction was complete. Approximately 100 mL of water was added to the reaction mixture, precipitating a large amount of off-white solid. The reaction mixture was stirred for approximately 0.5 hours, then filtered and washed with water. The filter cake was dried to obtain 2.98 g of compound DB04-C in a 79.0% yield.

[0551] Compound DB04-D:

[0552] [ka] 2.98 g of compound DB04-C (1.0 equiv.) was weighed and added to a 250 mL round-bottom flask. 45 mL of 1,2-dichloroethane was added. The resulting mixture was stirred uniformly, and 8.15 g of glacial acetic acid (20.0 equiv.) was slowly added dropwise. After the addition, the reaction mixture was heated to 80 °C and reacted for approximately 3 hours until TLC indicated the completion of the reaction. After cooling to room temperature, 100 mL of ethyl acetate and 50 mL of 3% potassium carbonate solution were added. The resulting mixture was stirred for a while, and then the liquid phases were separated. The aqueous phase was extracted with 50 mL of ethyl acetate. The ethyl acetate phases were combined, washed twice with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2.86 g of compound DB04-D in 100% yield.

[0553] Compound DB04-E:

[0554] [ka] 2.86 g of compound DB04-D (1.0 equiv.), 2.07 g of bis(pinacolato)diboron (1.2 equiv.), 149 mg of Pd(dppf)Cl2 (0.03 equiv.), and 1.67 g of potassium acetate (2.5 equiv.) were weighed and added to a 250 mL round-bottom flask. 45 mL of 1,4-dioxane was added. The reaction mixture was then stirred evenly, degassed twice with nitrogen, heated to 100 °C, and reacted under a nitrogen atmosphere for approximately 2 h until TLC showed the reaction was complete. The reaction mixture was then cooled to room temperature, filtered through diatomaceous earth, and washed with dichloromethane. After concentration, the filtrate was purified by column chromatography to give 3.12 g of compound DB04-E in 98.1% yield.

[0555] Compound DB04-F:

[0556] [ka] 200 mg of compound 8-A (1.0 equiv.), 299 mg of compound DB04-E (1.05 equiv.), 13.3 mg of Pd(dppf)Cl2 (0.03 equiv.), and 495 mg of cesium carbonate (2.5 equiv.) were weighed and added to a 25 mL round-bottom flask. 5 mL of 1,4-dioxane and 1 mL of water were added. The reaction mixture was stirred evenly, degassed twice with nitrogen, and heated to 90 °C under a nitrogen atmosphere for approximately 2 hours until TLC indicated completion. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and washed with dichloromethane. After concentration, the filtrate was purified by column chromatography to give 173 mg of compound DB04-F in 48.2% yield. MS m / z (ESI): 591.2046 (M+H). + .

[0557] Compound DB04:

[0558] [ka] 170 mg of compound DB04-F (1.0 equivalent) was weighed and added to a 25 mL round-bottom flask. 5 mL of acetonitrile and 1 mL of water were added. The resulting system was stirred uniformly, and then 100 mg of TBD (2.5 equivalents) was added. The reaction mixture was then stirred and reacted at room temperature for approximately 48 hours until TLC showed the reaction was complete. The reaction solution was concentrated, and 8 mL of water was added to the residue. The pH of the reaction solution was adjusted to approximately 5.0 with citric acid. A large amount of off-white solid precipitated. The reaction solution was continued to stir for approximately 0.5 hours, then suction filtered and washed with a small amount of water. The resulting filter cake was recrystallized from dichloromethane / methanol to obtain 76 mg of compound DB04 in a 45.8% yield. 1H NMR (400 MHz, DMSO) δ =12.56 (s, 1H), 8.36 (d, J = 1.7 Hz, 1H), 8.19 (s, 1H), 7.90 - 7.74 (m, 5H), 7.69 - 7.53 (m, 3H), 7.39 (t, J = 8.0 Hz, 1H), 7.23 (d, J = 1.8 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 5.86 (s, 2H), 4.55 (s, 2H), 4.41 (s, 2H), 3.65 (t, J = 4.6 Hz, 2H), 3.20 (s, 3H).

[0559] Comparative Example 5: Compound DB05:

[0560] [ka] Synthesis Route:

[0561] [ka] Compound DB05-A:

[0562] [ka] 200 mg of compound 7-A (1.0 equiv.), 290 mg of compound DB04-E (1.05 equiv.), 13 mg of Pd(dppf)Cl2 (0.03 equiv.), and 481 mg of cesium carbonate (2.5 equiv.) were weighed and added to a 25 mL round-bottom flask. 5 mL of 1,4-dioxane and 1 mL of water were added. The reaction mixture was stirred evenly, degassed twice with nitrogen, and heated to 90 °C under a nitrogen atmosphere for approximately 2 hours until TLC indicated completion of the reaction. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and washed with dichloromethane. After concentration, the filtrate was purified by column chromatography to give 270 mg of compound DB05-A in 76.3% yield. MS m / z (ESI): 600.1701 (M+H). +.

[0563] Compound DB05:

[0564] [ka] 263 mg of compound DB05-A (1.0 equivalent) was weighed and added to a 25 mL round-bottom flask. 6 mL of tetrahydrofuran and 2 mL of methanol were added. The resulting mixture was stirred at room temperature to dissolve, and then 0.55 mL of 2 mol / L NaOH solution (2.5 equivalents) was slowly added dropwise. The reaction mixture was then stirred overnight at room temperature until TLC showed the reaction was complete. The reaction mixture was concentrated. After concentration, 5 mL of water was added to the residue, and the pH of the reaction mixture was adjusted to 4-5 with 0.5 mol / L HCl solution. The reaction mixture was then filtered. The filter cake was pulped with 5 mL of ethyl acetate and 1 mL of methanol, followed by filtration. The filter cake was washed with a small amount of ethyl acetate and dried to obtain 196 mg of compound DB05 in a 76.3% yield. MS m / z (ESI): 586.1545 (M+H). + ; 1 H NMR (400 MHz, DMSO) δ =12.50 (s, 1H), 8.18 (d, J = 2.4 Hz, 2H), 7.94 - 7.76 (m, 4H), 7.63 (d, J = 7.4 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.44 - 7.33 (m, 2H), 7.06 (d, J = 2.2 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 5.77 (s, 2H), 4.55 (t, J = 4.8 Hz, 2H), 4.42 (s, 2H), 3.66 (t, J = 5.0 Hz, 2H), 3.21 (s, 3H).

[0565] [Experimental Example 1: In vitro activity evaluation] [Experimental Method] Logarithmically grown GLP1R / CRE-LUC HEK293 cells (purchased from Nanjing Cobioer) were digested, and the digested cells were resuspended in DMEM + 10% FBS culture medium until the cell density reached 3.5 × 10 5 This cell solution was added to a 96-well cell culture plate at 100 μL / well, and the plate was cultured overnight in an incubator (37° C., 5% CO 2 ).

[0566] The compounds were dissolved in DMSO to prepare a stock solution with an initial concentration of 10 mM. The initial concentration of the small molecule compound was 0.2 mM, and the compound was diluted 3-fold, 10 times, with the 11th dilution being DMSO. Another 96-well plate was taken, and 95 μL of cell culture medium (DMEM + 10% FBS) was added to each well. Then, 5 μL of test samples with different concentrations were added to each well, and after uniform mixing, 11 μL of test samples with different concentrations were added to each well of the cell culture plate. Each sample was placed in two wells. The culture plate was incubated in an incubator (37°C, 5% CO2) for 6 hours. The 96-well cell culture plate was taken out, and ONE-Glo was added to each well. TM 100 μL of the reagent was added, incubated at room temperature for 10 minutes, and the chemiluminescence signal was measured using an enzyme labeling device. The data were processed and analyzed using Microsoft Excel and Graphpad Prism 6 to calculate the EC values ​​of the compounds. 50 The value was calculated.

[0567] [Experimental results]

[0568] [Table 1]

[0569] Conclusion: As shown in Table 1, the compounds of the present invention could activate GLP1R in hGLP-1R HEK293 cells.

[0570] The activities of Compounds 13, 14, 17, 18, 19, 21, 25, 38, 67, 87, 91, 92, 93, 94, 95, 96, 97, 99, 100, 101, 102, 103, 104, 105, 106, 107, and 108 were higher than those of Comparative Compounds PF-06882961, DB02, DB03, and DB06, and much higher than those of Comparative Compounds DB04 and DB05. In particular, the activities of Compounds 21, 91, 94, 99, 101, 103, and 105 were all more than 10 times higher than those of Comparative Compound DB02, demonstrating better activity.

[0571] [Experimental Example 2: In vivo pharmacological experiment] [Experimental Method] Genetically modified hGLP1R mice (male, purchased from Biocytogen Jiangsu Gene Biotechnology Co., Ltd.) were fasted overnight without water deprivation before a glucose tolerance test (IPTGG). Vehicle or the corresponding compound was administered orally once, and 60 minutes later, a glucose solution (2 g / kg) was injected intraperitoneally. Blood glucose levels were measured before glucose administration (corresponding to the blood glucose level at 0 min) and 15, 30, 60, and 120 minutes after glucose administration. The vehicle was 5% DMSO + 40% PEG400 + 55% saline, and the compound was administered at a dose of 1 mg / kg (n=3).

[0572] [Experimental results] As shown in Figures 1 and 2, when Compounds 17, 19, 38, and 61 of the present invention, as well as PF-06882961 and Comparative Compound DB05 were orally administered once at the same dose (1 mg / kg), the blood glucose curves (Figure 1) and blood glucose AUC (0-120 minutes) (Figure 2) showed that the hypoglycemic effect of the compounds of the present invention was significantly superior to that of PF-06882961 and was also significantly superior to that of Comparative Compound DB05, indicating that the compounds of the present invention exhibited a more rapid hypoglycemic effect than Comparative Compound DB05.

[0573] As shown in Figures 3 and 4, when Compound 17, Compound 93, and Compound 100 of the present invention, as well as PF-06882961 and Comparative Compound DB03, were orally administered once at the same dose (1 mg / kg), the blood glucose curves (Figure 3) and blood glucose AUC (0-120 minutes) (Figure 4) showed that the hypoglycemic effect of the compounds of the present invention was significantly superior to that of PF-06882961 and was also absolutely superior to that of Comparative Compound DB03, indicating that the compounds of the present invention exhibited a more rapid hypoglycemic effect than Comparative Compound DB03.

[0574] As shown in Figures 5 and 6, when Compound 21, Compound 94, Compound 99, Compound 106, and Compound 107 of the present invention, and PF-06882961 were orally administered once at the same dose (1 mg / kg), the blood glucose curves (Figure 5) and blood glucose AUC (0 to 120 minutes) (Figure 6) showed that the hypoglycemic effect of the compounds of the present invention was significantly superior to that of PF-06882961.

[0575] [Experimental Example 3: hERG Test] Test subjects: The effects of compounds on hERG potassium channel current were tested using the automated patch clamp technique.

[0576] [Experimental Method] (1) We employed the HEK-293 cell line stably expressing the hERG potassium channel, and purchased hERG potassium channel cells from Creacell Company. (2) HEK-293 cell lines stably expressing the hERG potassium channel were cultured in DMEM culture medium containing 10% fetal bovine serum and 0.8 mg / mL G418 at 37°C under 5% carbon dioxide. (3) Cell passage: Remove the old culture medium, wash the cells once with PBS, and then add TrypLE TM One mL of Express solution was added and incubated at 37°C for approximately 0.5 minutes. Once the cells had detached from the bottom of the dish, approximately 5 mL of complete culture medium preheated to 37°C was added. The cell suspension was gently blown with a straw to separate clumped cells. The cell suspension was transferred to a sterile centrifuge tube and centrifuged at 1000 rpm for 5 minutes to recover the cells. For culture expansion or maintenance, cells were seeded into 6 cm cell culture dishes, with each cell culture dish containing 2.5 x 10 cells. 5 The cells (final volume: 5 mL) were cultured at a density of 80% to maintain the electrophysiological activity of the cells. (4) For patch clamp detection, trypLE TM Express and separate 4 x 10 cells 3 The cells were spread on cover slips and cultured in 24-well plates (final volume: 500 μL). After 18 hours, the detection test was performed.

[0577] [Data Analysis] First, the current after the action of each drug concentration and the blank control current

number

number

number

[0578] The dose-dependent effect was nonlinearly fitted with the above equation: where C represents the concentration of the test sample and IC 50 represents the half maximal inhibitory concentration, and h represents the Hill coefficient. Curve fitting and IC 50 The calculation was performed using IGOR software. The measurement results are shown in Table 2.

[0579] [Table 2]

[0580] Conclusion: Compared with the comparative compounds, the compounds of the present invention have a weaker inhibitory effect on hERG potassium channel current, a lower risk of cardiotoxicity, and are safer.

[0581] Pharmacokinetic studies showed that the half-lives of Compounds 21, 93, 94, 99, and 100 of the present invention in SD rats were 6 to 10 hours, significantly and effectively prolonging their half-lives compared to those of Comparative Example PF-06882961 and Comparative Example 3, Compound DB03 (the half-life of Comparative Example PF-06882961 in SD rats was 3.13 hours, and the half-life of Comparative Example 3, Compound DB03, was 2.94 hours, respectively). Meanwhile, the plasma exposure was high, reducing the administration frequency and single dose, achieving the goal of reducing the dosage and number of administrations, and providing therapeutic benefits. [Brief explanation of the drawings]

[0582] [Figure 1] FIG. 1 shows the blood glucose concentration curves of compounds 17, 19, 38 and 61 of the present invention and comparative examples. [Figure 2] FIG. 2 shows the blood glucose AUC (0 to 120 minutes) of compounds 17, 19, 38 and 61 of the present invention and a comparative example. [Figure 3]FIG. 3 shows the blood glucose concentration curves of compounds 17, 93 and 100 of the present invention and a comparative example. [Figure 4] FIG. 4 shows the blood glucose AUC (0 to 120 minutes) of compounds 17, 93 and 100 of the present invention and a comparative example. [Figure 5] FIG. 5 shows the blood glucose concentration curves of compounds 21, 94, 99, 106 and 107 of the present invention and comparative examples. [Figure 6] FIG. 6 shows the blood glucose AUC (0 to 120 minutes) of compounds 21, 94, 99, 106 and 107 of the present invention and comparative examples.

Claims

1. A compound of general formula (II) or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof: 【Chemistry 1】 where: R ２ is selected from: 【Chemistry 2】 R ３ are independently selected from a hydrogen atom and a halogen; R ４ is independently selected from a hydrogen atom, halogen, cyano, and C1-C6 alkyl, wherein said C1-C6 alkyl is further substituted with one or more halogens; R ５ is independently selected from halogen; R ６ are independently selected from a hydrogen atom, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, furan, and C2-C4 alkenyl; W is CR １０ and X ２ is N and CR １０ Selected from: Q is selected from N and CH; p is selected from 0, 1, 2 or 3; m is selected from 0, 1 or 2; n is selected from 0, 1, 2 or 3; q is selected from 0, 1 or 2; R １０ is selected from a hydrogen atom and a halogen atom, A compound of general formula (II) or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof:

2. The compound of general formula (II), or the pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, has a structure represented by general formula (II-1): 【Transformation 3】 2. A compound of general formula (II) according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof.

3. R 3 is selected from a hydrogen atom and F; R 4 is selected from a hydrogen atom, F, Cl, cyano, CF 3 and CHF 2 ; X 2 and Q are selected from CH; R 10 is selected from a hydrogen atom and F; 3. A compound of general formula (II) according to claim 2, or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof.

4. The compound of general formula (II), or the pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, has a structure represented by general formula (II-1-1): 【Chemistry 4】 wherein R 4 is selected from Cl and cyano; R 6 is selected from a hydrogen atom and F; and R 10 is selected from a hydrogen atom.

4. A compound of general formula (II) according to claim 3, or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof.

5. A compound selected from any of the following compounds, or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof: 【Chemistry 5-1】 【Chemistry 5-2】 【Chemistry 5-3】 【Chemistry 5-4】 【Transformation 5-5】

6. A compound selected from any of the following compounds, or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof: 【Transformation 6】

7. A compound of general formula (II') or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof: 【Transformation 7】 where: R １ is selected from a hydrogen atom and a halogen; R ２ is selected from: 【Transformation 8】 R ３ are independently selected from a hydrogen atom and a halogen; R ４ is independently selected from a hydrogen atom, halogen, cyano, and C1-C6 alkyl, wherein said C1-C6 alkyl is further substituted with one or more halogens; R ５ are independently selected from a hydrogen atom and a halogen; R ６ are independently selected from a hydrogen atom, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, furan, and C2-C4 alkenyl; W is N and CR １０ Selected from: X ２ is N and CR １０ Selected from: Q is selected from N and CH; p is selected from 0, 1, 2 or 3; m is selected from 0, 1, 2 or 3; n is selected from 0, 1, 2 or 3; q is selected from 0, 1 or 2; s is selected from 0, 1 or 2; R １０ is selected from a hydrogen atom and a halogen atom, A compound of general formula (II') or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof:

8. The compound of general formula (II'), or the pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, has a structure represented by general formula (II'-3): 【Chemistry 9】 where: R 4 is independently selected from a hydrogen atom, halogen, and cyano; R 6 is independently selected from a hydrogen atom, halogen, and C1-C6 alkyl; W is selected from N and CH; 8. A compound of general formula (II') according to claim 7, or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof.

9. The structure represented by general formula (II'-3) is further represented by general formula (II'-3-1): 【Chemistry 10】 where: R １ａ and R １ｂ are independently selected from a hydrogen atom and F; R ２ is: 【Chemistry 11】 R ６ are independently selected from a hydrogen atom and a halogen; m is selected from 1 or 2; p is selected from 1, 2 or 3; 9. A compound of general formula (II') according to claim 8, or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof.

10. The structure represented by general formula (II'-3) is further represented by general formula (II'-3-2): 【Chemistry 12】 where: R 3a and R 3b are independently selected from F and a hydrogen atom; R 4 is independently selected from F, Cl, and cyano; R 5a , R 5b and R 5c are independently selected from a hydrogen atom and F; R 6 is independently selected from a hydrogen atom, F and Cl; 10. A compound of general formula (II') according to claim 9, or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof.

11. R 3a and R 3b are not simultaneously F, R 5a and R 5c are independently selected from a hydrogen atom and F, and R 5b is a hydrogen atom; 11. A compound of general formula (II') according to claim 10, or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, and a pharmaceutically acceptable carrier.

13. 12. Use of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, in the preparation of a medicament for a GLP-1 receptor agonist.

14. Use of the pharmaceutical composition of claim 12 in the preparation of a medicament for a GLP-1 receptor agonist.

15. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, In the preparation of a medicament for treating and / or preventing type I diabetes, type II diabetes, malnutrition-related diabetes, diabetic complications, obesity, metabolic syndrome, hyperglycemia, glucose intolerance, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cardiovascular disease, dyslipidemia, cerebral infarction, stroke, Parkinson's disease, dementia, insulin resistance, and hepatic insulin resistance, use.

16. The pharmaceutical composition of claim 12, In the preparation of a medicament for treating and / or preventing type I diabetes, type II diabetes, malnutrition-related diabetes, diabetic complications, obesity, metabolic syndrome, hyperglycemia, glucose intolerance, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cardiovascular disease, dyslipidemia, cerebral infarction, stroke, Parkinson's disease, dementia, insulin resistance, and hepatic insulin resistance, use.

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