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 is widely distributed in the mucosa of the pancreas, stomach and small intestine, as well as the heart, lungs and central nervous system. GLP-1 specifically binds to the GLP-1 receptor (GLP-1R) in vivo and activates the cyclic adenosine monophosphate (cAMP) and mitogen-activated protein kinase (MAPK) pathway in the cell membrane to play various roles such as promoting glucose-dependent insulin secretion, inhibiting glucagon secretion, inhibiting islet β-cell apoptosis, delaying gastric emptying, inhibiting food intake, etc. Currently, GLP-1 receptor agonists (GLP-1RAs) are being developed as therapeutic agents for type II diabetes. Also, more and more clinical experiments 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 nervous system disease. In addition, GLP-1 can bind to relevant receptors such as those in the kidney and skin and affect 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, since GLP-1, a peptide, has poor oral bioavailability and is inconvenient to take, small molecule GLP-1 receptor agonists with excellent oral bioavailability are highly anticipated. Currently, small molecule GLP-1 receptor agonists in clinical development include TTP-273 from vTv and PF-06882961 from Pfizer, and the development of further GLP-1 receptor agonists is urgently needed.

[0004] 〔overview〕 One object of the present invention is to provide a benzimidazole compound or an azabenzimidazole compound, for example, a benzimidazole compound or an azabenzimidazole compound 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 a pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate thereof.

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

[0006] Another object of the present invention is to provide the use of a compound of the above general formula, or a pharma- ceutically 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 pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate thereof, in the preparation of a medicament for the treatment and / or prevention of 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 a 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 pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate thereof: [ka]

[0011] Where: R1 is 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; R2 is selected from: [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 is the same or different and is independently selected from 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 restriction 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 pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate thereof, is preferably: R1 is selected from hydrogen, halogen, cyano, and C1-C6 alkyl, the C1-C6 alkyl being optionally substituted with one or more halogens; R3 are the same or different and are independently selected from hydrogen, halogen, cyano and C1-C6 alkyl, the C1-C6 alkyl being optionally substituted with one or more halogens; R4 is the same or different and is independently selected from a hydrogen atom, a halogen, a cyano, and a C1-C6 alkyl, the C1-C6 alkyl being 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 pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate thereof, is preferably: R5 are the same or different and are independently selected from hydrogen, halogen, cyano and C1-C6 alkyl, the C1-C6 alkyl being optionally substituted with one or more halogens; R6 are the same or different and are independently selected from hydrogen, halogen, cyano and C1-C6 alkyl, or two adjacent R6 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 are independently selected from hydrogen, halogen, cyano and C1-C6 alkyl, the C1-C6 alkyl being optionally substituted with one or more halogens; R 10 is selected from a hydrogen atom, halogen, cyano, and C1-C6 alkyl, the C1-C6 alkyl being 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 pharma- ceutically 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, the C1-C6 alkyl being 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 pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate thereof, is preferably: Ring A is selected from: [ka] Ring B is selected from: [ka] The restriction is that ring A is: [ka] Z is CR 10 When selected from, ring B is not selected from: [ka]

[0021] In some embodiments of the present invention, the compound represented by the above general formula (I), or a pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate thereof, is preferably: Ring B is selected from: [ka] R7 is the same or different and is independently selected from a hydrogen atom and a halogen; 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 pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate thereof: [ka]

[0023] Where: R2 is selected from: [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, which may be further substituted with one or more halogens; R5 is independently selected from halogen; R6 is independently selected from a hydrogen atom, a halogen atom, a C1-C6 alkyl, a C3-C6 cycloalkyl, a phenyl, a furan, and a 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 pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate thereof, has a structure represented by general formula (II-1). [ka]

[0025] Where: R2 is selected from: [ka] R3 is independently selected from a hydrogen atom and a halogen; R4 is independently selected from a hydrogen atom, a halogen, a cyano, and a C1-C6 alkyl, the C1-C6 alkyl being optionally further substituted with one or more halogens; R5 is independently selected from halogen; R6 is independently selected from a hydrogen atom, a halogen atom, a C1-C6 alkyl, a C3-C6 cycloalkyl, a phenyl, a furan, and a 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 pharma- ceutically 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 pharma- ceutically 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 pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate thereof, has a structure represented by general formula (II-2). [ka]

[0029] Where: R2 is selected from: [ka] R3 is independently selected from a hydrogen atom and a halogen; R4 is independently selected from a hydrogen atom, a halogen, a cyano, and a C1-C6 alkyl, the C1-C6 alkyl being optionally 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 pharma- ceutically 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 pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate thereof, has a structure represented by general formula (II-2-1). [ka] Wherein 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 pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate thereof: [ka]

[0033] Where: R2 is selected from: [ka] R4 is independently selected from a hydrogen atom, a halogen, and a cyano; 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 pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate thereof: [ka]

[0035] Where: R2 is selected from: [ka] R3 is independently selected from a hydrogen atom and a halogen; R4 is independently selected from a hydrogen atom, a halogen, and a cyano; 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 R6 are linked to form a ring;

[0037] Preferably, the compound, or a pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate thereof, has a structure according to general formula (IV-1): [ka] Here, 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 pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate thereof, has a structure according to 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 pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate thereof: [ka] Wherein R2 is selected from: [ka] R4 is independently selected from a hydrogen atom, halogen, cyano, and C1-C6 alkyl, which 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 pharma- ceutically 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] Or, preferably, the compound, or a pharma- ceutically 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; 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 pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate thereof: [ka] Wherein R2 is selected from: [ka] R4 is independently selected from hydrogen, halogen, and cyano; R6 is independently selected from hydrogen, halogen, and 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 pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate thereof: [ka] Wherein R2 is selected from: [ka] R4 is independently selected from hydrogen, halogen, and cyano; R6 is independently selected from hydrogen and halogen; W is 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 pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate thereof: [ka] Wherein 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 C2-C4 alkenyl; or two R6 are linked together 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 pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate thereof: [ka] Wherein 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 pharma- ceutically 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: [ka] R3 is independently selected from a hydrogen atom and a halogen; R4 is independently selected from a hydrogen atom, a halogen, and a cyano; R5 is independently selected from halogen; R6 is independently selected from a hydrogen atom, a halogen, and a 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, or 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 pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate thereof, has a structure represented by general formula (II-3-1): [ka] Here, R 1a and R 1b is 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 pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate thereof, has a structure represented by general formula (II-3-2): [ka] Here, R 3a and R 3b is independently selected from F and a hydrogen atom; R4 is independently selected from F, Cl, and cyano; R 5a , R 5b and R 5c is 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 At the same time, F and R 5a and R 5c are independently selected from a hydrogen atom and F; R 5b is a hydrogen atom.

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

[0051] Where: R2 is selected from: [ka] 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, a halogen, and a 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 pharma- ceutically 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 pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate thereof: [ka]

[0054] Where: R1 is selected from a hydrogen atom and a halogen; R2 is selected from: [ka] R3 is independently selected from a hydrogen atom and a halogen; R4 is independently selected from a hydrogen atom, a halogen, a cyano, and a C1-C6 alkyl, the C1-C6 alkyl being optionally 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 pharma- ceutically 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] Or, preferably, the compound, or a pharma- ceutically 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, and a cyano; R6 is independently selected from a hydrogen atom, a halogen, and a 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 a structure 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 is 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 is independently selected from F and a hydrogen atom; R4 is independently selected from F, Cl, and cyano; R 5a , R 5b and R 5c is 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 At the same time, F and 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, a pharmaceutical composition is provided that comprises at least one compound of the invention as described herein, or a pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate thereof, and a pharma- ceutically 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 as described herein, or a pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate thereof, and the aforementioned pharmaceutical compositions, 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 compound of the present invention as described herein, or a pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate 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 compound of the present invention as described herein, or a pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate 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 without a specific definition 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 in the present invention refers to saturated aliphatic hydrocarbyl groups, including linear and branched hydrocarbyls, such as C1-C6 alkyl. "C1-C6 alkyl" refers to alkyls having 1-6 carbon atoms, such as alkyls having 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 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 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 certain substituents found in the present invention and a pharmaceutically acceptable acid or base.

[0074] The term "stereoisomers" as used herein refers to compounds which have identical chemical constitution, but differ in 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] As used herein, the term "solvate" is used to describe a molecular complex comprising a compound of any of the above formulas, or a pharma-ceutically acceptable salt thereof, and one or more pharma-ceutically acceptable solvent molecules, such as ethanol. When the solvent is water, the term "hydrate" is used.

[0077] The term "pharmaceutical acceptable carrier" as used herein refers to any formulation carrier or vehicle capable of delivering an effective amount of the active agent of the present invention, not inhibiting the biological activity of the active agent, and not having any toxicity or side effects on the host or patient. Representative carriers include water, oil, vegetable and mineral, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, 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 The compound may be radiolabeled with a radioactive isotope, such as C. 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 the 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, for example, the in vitro cell activity 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 is significantly superior to the cell activity of the compounds of the prior art. For example, the in vivo blood glucose lowering effect of compound 17, compound 19, compound 21, compound 38, compound 61, compound 93, compound 94, compound 99, compound 100, compound 106 and compound 107 is significantly superior to the blood glucose lowering effect of the compounds of the prior art.

[0081] 2) The compounds of the present invention have good pharmacokinetic properties, such as effectively extending half-life and increasing plasma exposure, and the in vivo half-lives of compounds 21, 93, 94, 99, 100, etc. are significantly superior to 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 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 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 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 conjunction with the following embodiments described to further illustrate the implementation of the present application, but 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 replacements thereof by those skilled in the art are also within the scope of the present application, which is determined by the scope of 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] Compound 1-Boc-4-piperidine ethyl acetate 2.0g (1.0 equivalent) was weighed and added to a 50mL round bottom flask, 5mL of ethyl acetate was added, followed by 20mL of 10% ethyl acetate hydrochloride solution, and the reaction mixture was stirred at room temperature for 3-4 hours. After TLC showed that the raw material 1-Boc-4-piperidine ethyl acetate had reacted completely, the reaction solution was concentrated under reduced pressure to obtain compound 1-A (4-piperidine ethyl acetate hydrochloride). This product could be used as it is in the next reaction without purification.

[0094] Compound 1-B:

[0095] [ka] Weigh out 589.9 mg of compound 1-A (1.0 equivalent) and add it to a 50 mL round bottom flask, add 10 mL of DMF, followed by 1.85 g of Cs2CO3 (2.0 equivalent). After stirring the reaction solution at room temperature for 30 minutes, add 500 mg of 2-bromo-6-fluoropyridine (1.0 equivalent), stir the reaction solution uniformly, and place it at 70 °C to react for 1 to 2 hours under heating. TLC showed that the raw material 2-bromo-6-fluoropyridine had reacted completely. Then, stop heating, cool the reaction solution to room temperature, add 16 mL of water, and extract the system twice with 10 mL x 2 of ethyl acetate. The organic phases were combined and washed twice with 10 mL x 2 of water, and then washed with saturated saline. The organic phase was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure to obtain brown oily compound 1-B (850 mg, yield 91.50%). The 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 eq.), 20.74 g of 2-bromo-1,1-diethoxyethane (1.5 eq.) and 14.54 g of K2CO3 (1.5 eq.) were weighed and added to a 500 mL round-bottom flask, and 200 mL of DMF was added. Then, under nitrogen protection, the reaction solution was stirred uniformly and heated at 120 °C for 16 hours. TLC showed that the raw material 5-chloro-2-methylphenol had reacted completely, heating was stopped, and the reaction solution was cooled to room temperature. Then, 400 mL of water was added to the reaction solution, and it was extracted three times with 150 mL x 3 ethyl acetate. The organic phases were combined, washed twice with 200 mL x 2 water, and washed twice with 200 mL x 2 saturated saline. Then, the organic phase was 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: 12.39g of compound 01-C1 (1.0 eq) and 24.33g of polyphosphoric acid (1.5 eq) were weighed and added to a 500mL round bottom flask. 250ml of toluene was added. The reaction was then stirred homogeneously under nitrogen protection and heated at 90°C for 15 hours. TLC showed that compound 01-C1 had reacted completely. After stopping the heating and cooling the reaction to room temperature, the reaction was quenched with 250mL of water and allowed to settle for stratification. The organic phase was washed once with 150mL of water, twice with 150mL×2 saturated NaHCO3 solution, and then once with 150mL of saturated saline. 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: 9.25g of crude compound 01-C2 obtained above, 11.85g of NBS (1.2 equivalents) and 1.82g of 2-2-azodiisobutyronitrile (0.2 equivalents) were added to a 250mL round bottom flask. 100mL of DCE (1,2-dichloroethane) was added. The reaction mixture was stirred homogeneously and then heated at 72°C for 12 hours. TLC showed that the raw materials were essentially completely reacted, and heating was stopped. After cooling slightly, 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 (9.0g, yield 66.04%).

[0100] Compound 1-C:

[0101] [ka] 9.0g of compound 01-C3 (1.0 equiv.) was weighed and added to a 250mL round bottom flask. 90mL of DMF was added and stirred to dissolve, then 36.0g of potassium acetate (10.0 equiv.) was added and the mixture was stirred at room temperature for 2.5 hours. TLC showed that the raw material had reacted completely. 270mL of water and 100mL of ethyl acetate were added to the system, and the system was left to stand for liquid phase separation. The aqueous phase was extracted twice with 100mL×2 of ethyl acetate. The ethyl acetate organic phases were combined and washed twice with 100mL×2 of water, then washed twice with 100mL×2 of saturated saline, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a yellow oil. Then, 40mL of THF was added to the oil and stirred uniformly, after which 14.68mL of 5mol / L sodium methoxide solution was added, and the mixture was stirred at room temperature for 1.5 hours. TLC showed that the raw material had disappeared. The reaction was stopped, and 120 mL of water and 100 mL of ethyl acetate were added to the reaction solution, and the reaction solution was allowed to stand for liquid phase separation. The aqueous phase was extracted twice with 100 mL x 2 ethyl acetate. The organic phases were combined and washed twice with 100 mL x 2 saturated saline. 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 uniformly, purged with nitrogen three times, and heated at 110 °C under nitrogen protection for 4 to 5 hours. TLC showed that the two raw materials had reacted completely. Heating was stopped, the reaction solution was cooled to room temperature, and filtered through diatomaceous earth. Then, 50 mL of water was added to the filtrate, and the system was left to stand for liquid phase separation. The toluene phase was washed twice with 30 mL × 2 of saturated saline, 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 equivalent) was weighed and added to a 100 mL round bottom flask. 30 mL of a mixed solution of MeOH / THF=1 / 1 (volume ratio) was added, followed by 4.5 mL of 2 mol / L NaOH solution. The reaction mixture was heated at 40°C for 2 hours. TLC showed that the raw materials had reacted completely. Heating was stopped, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and then 15 mL of water was added. The pH of the reaction solution was adjusted to about 4 with 2 mol / L hydrochloric acid solution. The reaction solution was then extracted twice with 15 mL x 2 of ethyl acetate, and the combined organic phase was washed twice with 30 mL x 2 of saturated saline, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a yellow oily compound 1-E (560 mg, yield 93.76%).

[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 solution was stirred at room temperature and reacted for 16 hours. TLC showed that the raw material was essentially completely reacted. The mixture was then concentrated under reduced pressure to remove THF, and then 540 mL of water was 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 equiv.) was weighed and added to a 250 mL round bottom flask. After adding 90 mL of methanol and stirring to form a suspension, 600 mg of Pd / C (10%) was added and the system was purged with hydrogen three times. The reaction solution was reacted under hydrogen atmosphere at room temperature for 3 hours. TLC showed that the raw materials had reacted completely. The mixed reaction solution was then filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain brown oily compound 1-F (5.3 g, 100% yield). 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 solution was stirred at 0°C for 10 minutes. Then, 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 solution was kept at 0°C and reacted for 1 hour. Then, the ice bath was removed and the reaction was allowed to warm to room temperature and react for 1-2 hours. TLC showed that the two raw materials had reacted completely. A large amount of solid was precipitated, filtered, and the filter cake was washed with 1 mL of acetonitrile to obtain 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 solution was placed at 85° C. and reacted under heating for 1.5 hours. TLC showed that the raw materials were completely reacted. The reaction solution was then cooled to room temperature and concentrated under reduced pressure, after which 10 mL of water and 15 mL of ethyl acetate were added, and the resulting system was allowed to stand for liquid phase separation. The aqueous phase was extracted with 10 mL of ethyl acetate, and the combined organic phase was washed twice with 30 mL × 2 of saturated saline, then 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 white foam compound 1-H (240 mg, 79.85% yield). MS m / z (ESI): 601.2213 (M+H) + , 1HNMR (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] [Chemical formula] 240 mg of compound 1-H (1.0 equiv.) was weighed and added to a 50 mL round-bottom flask. 5 mL of acetonitrile, 2.5 mL of methanol, and 2.5 mL of water were added, followed by the addition of 25.18 mg of LiOH.H2O (1.5 equiv.). The reaction mixture was stirred uniformly and reacted at 45°C for 4-5 hours. TLC showed that the raw materials were completely reacted. Then, the reaction solution was cooled to room temperature and concentrated under reduced pressure, and then 5 mL of water was added. The pH of the reaction solution was adjusted to 4-5 with citric acid. Then, 10 mL of ethyl acetate was added, and then the resulting system was allowed to stand for liquid phase separation. The aqueous phase was extracted twice with 10 mL x 2 of ethyl acetate, and the combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography to obtain compound 1 (150 mg, yield 63.87%). MS m / z (ESI): 587.2058(M+H) + , 1 HNMR (400 MHz, MeOD) δ =8.29 (s, 1H), 7.99 (d, J = 8.5 Hz, 1H), 7.84 (d, J = 2.1 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.40 (t, J = 7.9 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 6.89 (d, J = 2.1 Hz, 1H), 6.25 (d, J = 8.1 Hz, 1H), 6.07 (d, J = 7.8 Hz, 1H), 5.58 (s, 2H), 5.17 (m, 1H), 4.69-4.56 (m, 2H), 4.50 (dd, J = 15.6, 2.3 Hz, 1H), 4.37-4.32 (m, 1H), 4.23 (d, J = 13.0 Hz, 2H), 2.99-2.92 (m, 2H), 2.81-2.70 (m, 3H), 2.52-2.40 (m, 1H), 2.33-2.18 (m, 1H), 1.71 (d, J = 11.5 Hz, 2H), 1.31-1.25 (m, 2H).

[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 min and 9.13 mL of triethylphosphonoacetate (1.4 equiv.) was added dropwise. After the dropwise addition, the reaction solution was stirred for 1 h. Then, 6.5 g of 1-Boc-4-piperidone (1.0 equiv.) was added in one portion. The reaction solution was then stirred at room temperature for 2-3 h and TLC showed that the raw materials had reacted completely. The reaction solution was quenched by slowly adding 150 mL of water dropwise and extracted three times with 100 mL x 3 ethyl acetate. The organic phases were combined and washed twice with 100 mL x 2 saturated saline. 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 equiv.) 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. Then, 20 mL of 10% hydrogen chloride in ethyl acetate solution was added and the reaction was stirred at room temperature for 4 hours. TLC showed that the raw materials were completely reacted. The reaction was concentrated under reduced pressure to obtain compound 2-B hydrochloride. Compound 2-B hydrochloride was used directly in the next step without 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 was stirred at room temperature for 30 minutes, after which 1.11 g of 2-bromo-6-fluoropyridine (1.0 equiv.) was added. The reaction was then heated at 70° C. for 1 hour. TLC showed that the raw materials had reacted completely. The reaction was then cooled to room temperature, 50 mL of water was added, and the resulting system was extracted twice with 20 mL x 2 ethyl acetate. The organic phases were combined and washed twice with 25 mL x 2 saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain oily compound 2-C (1.57 g, 77.72% yield). This compound 2-C was used directly in the next reaction without 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 homogeneously and purged with nitrogen three times, then heated at 110 °C under nitrogen protection for 16 h. TLC showed that the two raw materials were completely reacted. Heating was stopped, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a yellow oil, which was purified by column chromatography (petroleum ether / ethyl acetate = 95 / 5 as eluent) to obtain 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 mixed solution of MeOH / THF=1 / 1 was added. Then, 1.6 mL of 2 mol / L NaOH solution was added. The reaction solution was then heated at 40°C for 2-3 hours. TLC showed that the raw materials had reacted completely. The reaction solution was then cooled to room temperature and concentrated under reduced pressure. 15 mL of water was added to the concentrated solution, and the pH of the reaction solution was adjusted to about 4 with 2 mol / L hydrochloric acid solution. The aqueous phase was extracted twice with 15 mL x 2 of ethyl acetate, and the combined organic phase was washed twice with 15 mL x 2 of saturated saline, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a total of 402 mg of a pale green oily compound 2-E crude product, which was used directly in the next reaction without purification.

[0128] Compound 2-F:

[0129] [ka] 402 mg of compound 2-E (1.0 equivalent) 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 equivalent) were added. The reaction solution was then stirred at 0 °C for 10 minutes. 336.0 mg of N-methylimidazole (4.0 equivalent) and 396.0 mg of TCFH (1.4 equivalent) were added. After the addition, the reaction solution was kept at 0 °C and reacted for 3 to 4 hours. TLC showed that the two raw materials had reacted completely. 10 mL of water was added to the reaction solution, and the resulting system was extracted with 15 mL of ethyl acetate. The organic phase was washed twice with 15 mL × 2 saturated saline, 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 was heated at 80° C. for 0.5 h. TLC showed that the raw materials were completely reacted. The reaction was then cooled to room temperature. 5 mL of water and saturated NaHCO3 solution were added to the reaction to adjust the pH of the reaction to about 8. Then, 15 mL of ethyl acetate was added and the system thus obtained was allowed to stand for liquid phase separation. The aqueous phase was extracted with 15 mL of ethyl acetate, and the combined organic phase was washed twice with 10 mL × 2 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 obtain yellow foam compound 2-G (270 mg, 76.3% yield).

[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 mixture of THF / MeOH / water = 6 mL / 6 mL / 3 mL, and 28.37 mg of LiOH·H2O (1.5 equiv.) were added. The reaction solution was heated at room temperature overnight. TLC showed that the raw materials had reacted completely. The reaction solution was then cooled to room temperature and concentrated under reduced pressure. 5 mL of water was added to the concentrated solution, and the pH of the reaction solution was adjusted to 4-5 with citric acid. The aqueous phase was extracted twice with 10 mL x 2 of ethyl acetate, and the combined organic phase was washed twice with 10 mL x 2 of saturated saline, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain an oil. 1 mL of methanol was added to this oil to pulp it, and then filtered to obtain 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: 10.0g of 5-bromo-2-methylphenol (1.0 equiv.) was weighed and added to a 500mL round bottom flask. 200mL of DMF, 12.5g of 2-bromo-1,1-diethoxyethane (1.2 equiv.), 15.0g of potassium carbonate (2.0 equiv.) and 1.0g of KI (0.11 equiv.) were added. The reaction solution was stirred uniformly and then placed at 120°C for 16 hours under heating and stirring. TLC showed that the raw materials were essentially completely reacted. After that, the reaction solution was cooled to room temperature and quenched by adding 200mL of water, and the resulting system was extracted twice with 200mL×ethyl acetate. The ethyl acetate organic phase was combined and washed twice with 200mL×water, then washed with 200mL×saturated saline, 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: 7.6g of compound 03-A1 (1.0 equiv.) was weighed and added to a 500mL round bottom flask. 150mL of toluene and 20.96g of polyphosphoric acid (2.5 equiv.) were added. The reaction solution was then placed at 90°C for 10 hours under heating and stirring. TLC showed that the raw materials were essentially completely reacted. After cooling to room temperature, 200mL of water was added to the reaction solution, and the resulting system was stirred and allowed to stand to stratify. The toluene phase was washed with 150mL of saturated NaHCO3, washed with 150mL of saturated saline, then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give oily compound 03-A2 (5.4g), which was used directly in the next step without purification.

[0139] Compound 03-A3: 3.76g of compound 03-A2 (1.0 equiv.), 4.79g of CuCN (3.0 equiv.) and 6.79g of CuI (2.0 equiv.) were weighed and added to a 150mL round bottom flask. 56.4mL of DMF was added. The reaction solution was stirred uniformly and placed at 150°C for 9 hours under heating and stirring. TLC showed that the raw materials were essentially completely reacted. After that, after cooling to room temperature, 150mL of water and 150mL of ethyl acetate were added, and a large amount of solid was generated in the reaction system. The reaction solution was then filtered through diatomaceous earth. The filtrate was allowed to stand and stratified, and the ethyl acetate phase was collected. The organic phase was washed twice with 30mL x 2 of 25% aqueous ammonia solution, then twice with 50mL x 2 of water, twice with 50mL x 2 of saturated saline, 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: 2.1g of compound 03-A3 (1.0 equiv.), 2.85g of NBS (1.2 equiv.) and 438.7mg of 2,2-azobisisobutyronitrile (0.2 equiv.) were weighed and added into a 50mL round bottom flask. 25mL of dichloroethane was added. The reaction was stirred homogeneously and placed at 72°C for reaction under heating and stirring for 12 hours. TLC showed that the raw materials were essentially completely reacted. Then the reaction was cooled to room temperature and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (PE as eluent) to give compound 03-A4 (2.4g, 76.20% yield) as an off-white solid.

[0141] Compound 3-A:

[0142] [ka] 2.4g of compound 03-A4 (1.0 equivalent) was weighed and added to a 150mL round bottom flask. 24mL of DMF and 9.84g of potassium acetate (10.0 equivalent) were added. The reaction solution was stirred at room temperature for 3.0 hours. TLC showed that the raw materials were completely reacted. Then, 72mL of water was added to quench, and the resulting system was extracted twice with 50mL×2 of ethyl acetate. The ethyl acetate organic phases were combined and washed twice with 50mL×2 of water, and then washed with 50mL×2 of saturated saline. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain an oily substance. 12mL of THF was added to this oily substance, and the resulting system was stirred uniformly, after which 4.1mL of 5mol / L sodium methoxide solution was added, and the reaction solution was stirred at room temperature for 1 hour to react. TLC showed that the raw materials had disappeared. The reaction was stopped. 36 mL of water and 50 mL of ethyl acetate were added to the reaction solution, and the resulting system was allowed to stand for liquid phase separation. The aqueous phase was extracted twice with 50 mL x 2 ethyl acetate, and the combined organic phase was washed twice with 75 mL x 2 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 homogeneously, purged with nitrogen three times, and heated to 110 °C for 16 h under nitrogen protection to react. TLC showed that the two raw materials had reacted completely. Then, heating was stopped and the reaction solution 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, yield 66.06%).

[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 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 was stirred at room temperature for 24 hours. TLC showed that the raw materials were essentially completely reacted. The reaction was stopped and the pH of the reaction was adjusted to about 5.0 with citric acid. The reaction was extracted twice with 15 mL x 2 ethyl acetate. The combined organic phase was washed twice with 30 mL x 2 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 eq) 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 eq) were added. The reaction solution was placed at 0°C and reacted under stirring. Then, 335.6 mg of N-methylimidazole (4.0 eq) and 401.5 mg of TCFH (1.4 eq) were added. The reaction solution was then kept at 0°C and reacted for 1 hour. The ice bath was removed and the reaction was allowed to warm to room temperature and continued to react for 2 hours. TLC showed that the raw material compound 1-F had reacted completely. The reaction solution was concentrated under reduced pressure, evaporated to dryness, pulped with 4 mL of acetonitrile, and the resulting system was filtered. The filter cake was washed with 0.5 mL of acetonitrile to obtain 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 solution was stirred homogeneously and placed at 80° C. for 1 hour under heating. TLC showed that the raw materials were completely reacted. Then, the reaction solution was cooled to room temperature and concentrated under reduced pressure to evaporate methanol. 10 mL of water and 15 mL of ethyl acetate were added to the concentrated solution, and the resulting system was allowed to stand for liquid phase separation. Then, the aqueous phase was extracted with 10 mL of ethyl acetate. The combined organic phase was washed twice with 15 mL × 2 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 white foam compound 3-E (220 mg, 73.2% yield).

[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 TBD solution (103.6 mg (2.0 equiv.) dissolved in 1.0 mL of water). The reaction was stirred at room temperature for 24 hours. TLC showed that the raw materials were essentially completely reacted. The reaction was stopped and the pH of the reaction was adjusted to about 5.0 with citric acid. The reaction was extracted twice with 10 mL x 2 ethyl acetate. The combined organic phase was washed twice with 20 mL x 2 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 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 eq.), 1.45 g of 2-bromo-6-fluoropyridine (1.5 eq.) and 3.75 g of cesium carbonate (2.0 eq.) were weighed and added to a 100 mL round bottom flask. Then, 30 mL of DMF was added. Then, the reaction solution was heated to 90° C. and reacted for 4 hours. Then, the heating was stopped and the reaction solution was cooled to room temperature. 120 mL of water was added, and the resulting system was stirred at room temperature for 0.5 hours and then filtered. The filter cake was dried at 50° C. for 12 hours to obtain 1.8 g of compound 7-A in a yield of 97%.

[0160] Compound 7-B:

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

[0162] Compound 7-C:

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

[0164] Compound 7-D:

[0165] [ka] 0.465g of compound 7-C (1.0 equivalent) and 0.304g of compound 1-F (1.1 equivalent) were weighed and added to a 50mL round bottom flask. 10.0mL of acetonitrile was added. After the reaction solution was stirred in an ice bath for 15 minutes, 0.304g of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (1.1 equivalent) and 0.202g of N-methylimidazole (2.1 equivalent) were weighed and added. The reaction solution was continuously stirred and reacted in an ice bath for 0.5 hours. The reaction solution was then transferred to room temperature and continued to react for 3 hours. After the reaction, 30mL of H2O was added to the reaction system, stirred for 0.5 hours, and then filtered. The filter cake was washed with 20mL x 3 of H2O and dried at 50°C to obtain 0.607g of compound 7-D in 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. Then, 2.95 g of acetic acid (50.0 equiv.) was added dropwise. After the dropwise addition, the reaction solution was heated at 80°C for 15 hours. The reaction solution was cooled to room temperature. 10 mL of water and 25 mL of ethyl acetate were added, and the pH of the system was adjusted to 7-8 with 5% NaHCO3 solution. Then, the reaction solution was allowed to stand. The organic phase was separated, and the aqueous phase was washed twice with 25 mL x 2 of ethyl acetate in succession. The combined organic phase was washed with saturated saline, dried over anhydrous Na2SO4 for 5 minutes, filtered, concentrated to dryness, and purified by column chromatography to obtain 0.345 g of compound 7-E in 58.7% yield. MS m / z (ESI): 598.2109 (M+H) + .

[0168] Compound 7:

[0169] [ka] 0.34g of compound 7-E (1.0 equivalent) was weighed and added to a 25mL round bottom flask. 1.7mL of methanol and 5.0mL of tetrahydrofuran were added. Then, 0.56mL of 2N sodium hydroxide solution was added. Then, the reaction solution was reacted at room temperature. After 20 hours, the reaction solution was concentrated. After concentration, 6mL of water was added, and the pH of the reaction solution was adjusted to 4-5 with 1mol / L HCl solution. Then, the reaction solution was filtered. The filter cake was pulped with 5mL of ethyl acetate and 1mL of methanol, and then filtered. The filter cake was washed with 3mL of ethyl acetate x 3, and then dried to obtain 0.177g of compound 7 in a yield of 53.3%. 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 eq), 0.492 g of 1-pinacolborate-4-ethylacetate-1-cyclohexene (1.1 eq), 0.111 g of Pd(dppf)Cl2 (0.1 eq) and 0.255 g of sodium bicarbonate (2 eq) 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 solution was then degassed twice with nitrogen and heated to 110 °C under a nitrogen atmosphere to react. After 2 hours of reaction, the heating was stopped, the reaction solution was cooled to room temperature, filtered through a funnel with diatomaceous earth, and the filter cake was washed with 15 mL x 2 of ethyl acetate. The filtrate was then concentrated to dryness and purified by column chromatography to obtain 0.506 g of compound 8-B in 80% yield.

[0176] Compound 8-C:

[0177] [ka] 0.5g of compound 8-B (1.0 equivalent) was weighed and added to a 50mL round bottom flask. 15mL of acetonitrile was added, followed by TBD solution (1,5,7-triazabicyclo[4.4.0]dec-5-ene, TBD (2.0 equivalent) dissolved in 4.0mL of water). The reaction solution was stirred at room temperature for 24 hours. After the reaction was completed, the reaction solution was concentrated, 15mL of water and 35mL of ethyl acetate were added, and the pH of the reaction system was adjusted to 4-5 with citric acid. Then, the reaction solution was left to stand, the organic phase was separated, and the aqueous phase was washed twice with 35mL x 2 of ethyl acetate in succession. The organic phases were combined, washed with saturated saline, dried over anhydrous Na2SO4 for 5 minutes, and then filtered. The filtrate was concentrated to dryness to obtain 0.364g of compound 8-C in a yield of 78%.

[0178] Compound 8-D:

[0179] [ka] 0.3 g of compound 8-C (1.0 eq), 0.201 g of compound 1-F (1.1 eq) and 0.298 g of TBTU (1.2 eq) were weighed and added to a 50 mL round bottom flask. 15.0 mL of DMF was added. The reaction solution was stirred in an ice bath for 10 minutes, and then 0.199 g of N,N-diisopropylethylamine (2.0 eq) was added dropwise. After the dropwise addition, the reaction solution was stirred in an ice bath for 3 hours. After the reaction, 30 mL of H2O and 30 mL of ethyl acetate were added to the reaction system, and the resulting system was stirred for 5 minutes and allowed to stand. The organic phase was separated, and the aqueous phase was washed twice with 30 mL x 2 of ethyl acetate in succession. The combined organic phase was washed with saturated saline, 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] 0.25g of compound 8-D was weighed and added to a 50mL round bottom flask. 10mL of methanol and 78.0mg of pTSA (1.1 equivalents) were added. The reaction solution was stirred uniformly and reacted under heating at 80°C for 2 hours. After that, the reaction solution was cooled to room temperature, concentrated, and purified by column chromatography to obtain 0.143g of compound 8-E with a yield of 59%.

[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, and TBD solution (TBD (2.0 equivalent) dissolved in 1.0 mL of water) was added. The reaction solution was stirred at room temperature for 24 hours. Then, the reaction solution was concentrated, and 30 mL of ethyl acetate was added. Then, the pH of the reaction system was adjusted to 4-5 with citric acid. Then, the reaction solution was left to stand, the organic phase was separated, and the aqueous phase was washed twice with 20 mL x 2 of ethyl acetate in succession. The organic phases were combined, washed with saturated saline, dried with anhydrous Na2SO4 for 5 minutes, and then filtered. The filtrate was concentrated to dryness and purified by column chromatography to obtain 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. Then, 64 mL of acetonitrile, 3.81 g of 2-chloro-1,1,1-trimethoxyethane (1.1 equiv.) and 213.0 mg of pTSA·H2O (0.05 equiv.) were added. The reaction was then heated at 50°C for 1.5 h. TLC showed that the raw material had reacted completely. The reaction was cooled slightly and then concentrated under reduced pressure. To the concentrated solution, 50 mL of water and 35 mL of ethyl acetate were added and allowed to stand for liquid phase separation. The aqueous phase was washed twice with 20 mL x 2 ethyl acetate, and the organic phases were combined, then washed with saturated saline, 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 to pulp, 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 equivalents) of 1M ZnEt2 toluene solution were added to a 250 mL three-neck flask. The resulting system was cooled to -40°C and stirred. 10 mL of dichloromethane dilution containing 37.46 g of diiodomethane (16.0 equivalents) was slowly added dropwise. After the addition, the reaction solution was kept at -40°C and stirred for about 1 hour, after which 7.97 g of trifluoroacetic acid (8.0 equivalents) was added dropwise, the resulting system was warmed to -15°C and stirred for 1 hour, after which 10 mL of dichloromethane dilution containing 3 g of N-Cbz-3,6-dihydro-2H-pyridine-4-boronic acid pinacol ester (1.0 equivalents) was added dropwise. After the addition, the reaction solution was stirred at room temperature for about 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, then stirred to separate the liquid phase. The organic phase was washed with 50 mL of water and 50 mL of saturated sodium chloride solution, successively, 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 thus obtained system was stirred to dissolve. 3.11 g of N-bromosuccinimide (2 equivalents) was added. The thus obtained system was continuously stirred for about 2 hours, after which 100 mL of ethyl acetate and 50 mL of saturated sodium bicarbonate solution were added, and the thus obtained system was stirred to separate the liquid phase. 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 separation to obtain 830 mg of compound 10-A with 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 eq.) and 1.22 g of KHF2 (7.0 eq.) were weighed and added to a 25 mL round-bottom flask. 8 mL of methanol was added. The reaction mixture was reacted and refluxed for about 15 hours until TLC showed the reaction was complete. After cooling to room temperature, the reaction solution was concentrated, then 5 mL of petroleum ether and 1 mL of methyl tert-butyl ether were added, and the resulting system was filtered after pulping at room temperature for about 0.5 hours. 8 mL of acetonitrile was added to the filter cake, and the mixture was stirred under reflux for about 15 hours, and then filtered. The filtrate was concentrated to give 630 mg of compound 10-B in a yield of 83.4%.

[0192] Compound 10-C:

[0193] [ka] 400 mg of compound 7-A (1.0 eq.), 438 mg of compound 10-B (1.1 eq.), 47 mg of tBuXPhos-Pd-G3 (0.05 eq.) and 1.15 g of cesium carbonate (3.0 eq.) were weighed and added to a 25 mL round-bottom flask. Then, 5 mL of toluene and 1 mL of water were added. The reaction solution was stirred uniformly and then degassed with nitrogen twice. Then, under a nitrogen atmosphere, the reaction solution was heated to 80° C. and stirred for about 6 hours until TLC showed the reaction was complete. The reaction solution 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 successively with 20 mL of water and 20 mL of saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by column chromatography separation to obtain 350 mg of compound 10-C in a yield of 60.6%.

[0194] Compound 10-D:

[0195] [ka] 340 mg of compound 10-C (1.0 eq.), 202 mg of triethylsilane (2.5 eq.), 35 mg of triethylamine (0.5 eq.) and 16 mg of palladium acetate (0.1 eq.) were weighed and added to a 25 mL round-bottom flask. 5 mL of ethanol was added. After the reaction solution was stirred uniformly, it was reacted at room temperature under a nitrogen atmosphere for about 16 hours until TLC showed the reaction was complete. The reaction solution was filtered through a funnel with diatomaceous earth. 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 separation to obtain 198 mg of compound 10-D with a yield of 80.2%.

[0196] Compound 10-E:

[0197] [ka] 190 mg of compound 10-D (1.0 eq.), 158 mg of compound 001-M07 (1.0 eq.) and 148 mg of potassium carbonate (2.0 eq.) were weighed and added to a 50 mL round bottom flask. 10 mL of acetonitrile was added. The reaction mixture was heated to 50° C. and reacted for about 4 hours until TLC showed the reaction was complete. The reaction was then cooled to room temperature, 20 mL of water and 30 mL of ethyl acetate were added, and the resulting system was allowed to stand for liquid phase separation. The aqueous phase was extracted three times with 20 mL of ethyl acetate x 3, and the organic phases were combined, 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 separation to obtain 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 eq.) and 21 mg of lithium hydroxide monohydrate (1.5 eq.) were weighed and added to a 50 mL round bottom flask. Then, 3 mL of acetonitrile, 1 mL of methanol, and 1 mL of water were added. The reaction was heated to 40°C and reacted for about 5.5 hours until TLC showed the reaction was complete. Then, the reaction was 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 was adjusted to 4-5 with citric acid. Then, the aqueous phase was extracted with 15 mL of ethyl acetate x 3, and the organic phases were combined and 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 obtain 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 equivalent) was weighed and added to a 50 mL round-bottom flask. 10 mL of tetrahydrofuran was added. The system thus obtained was stirred to dissolve, then stirred in an ice bath for 5 minutes, and then 215 mg of lithium aluminum hydride (2.0 equivalent) was added. After the addition, the reaction solution was allowed to continue reacting at 0-10°C for about 1 hour. TLC showed the reaction was complete. Then, 10 mL of saturated aqueous ammonium chloride solution was added dropwise to the reaction solution until no bubbles were observed. Then, the reaction solution was filtered through a funnel using diatomaceous earth, 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 yield of 79.8%.

[0207] Compound 13-B:

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

[0209] Compound 13-C:

[0210] [ka] 600 mg of compound 13-B (1.0 eq.), 576 mg of N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (1.1 eq.), 124 mg of Pd(dppf)Cl2 (0.1 eq.) and 285 mg of sodium bicarbonate (2.0 eq.) 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 solution was stirred uniformly and degassed twice with nitrogen, then heated to 110°C and reacted under nitrogen atmosphere for about 2 hours until TLC showed the reaction was complete. The reaction solution was then cooled to room temperature and 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 separation to obtain 710 mg of compound 13-C in a yield of 91.8%.

[0211] Compound 13-D:

[0212] [ka] 700 mg of compound 13-C (1.0 equivalent) and 875 mg of p-toluenesulfonic acid monohydrate (3.0 equivalent) were weighed and added to a 25 mL round-bottom flask. 15 mL of ethyl acetate was added. The reaction mixture was heated to 60 °C and reacted for about 2 hours until TLC showed the reaction was complete. The reaction solution was then cooled to room temperature and diluted with 30 mL of ethyl acetate. The pH of the reaction solution was adjusted to 8-9 with saturated sodium bicarbonate solution, and the reaction solution was allowed to stand for liquid 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 yield of 93.2%.

[0213] Compound 13-E:

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

[0215] Compound 13:

[0216] [ka] 385 mg of compound 13-E (1.0 eq.) and 39 mg of lithium hydroxide monohydrate (1.5 eq.) were weighed and added to a 25 mL round bottom flask. Then, 6 mL of acetonitrile, 2 mL of methanol, and 2 mL of water were added. The reaction mixture was heated to 40°C and reacted for about 6 hours until TLC showed the reaction was complete. After cooling to room temperature, the reaction was concentrated to remove most of the organic solvent. 20 mL of water was added to dilute the mixture, and the pH of the reaction was adjusted to 4-5 with citric acid solution. The aqueous phase was extracted with 20 mL x 3 of ethyl acetate. The combined ethyl acetate phase was washed with 20 mL of water and 20 mL of saturated sodium chloride solution, respectively, dried over anhydrous Na2SO4, and then filtered. The filtrate was concentrated to dryness and recrystallized with 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]

change

[0219]

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[0220]

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

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

[0223] Compound 002-M05: 3.35 g of compound 002-M04 (1.0 eq), 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 solution was then degassed twice with nitrogen and twice with hydrogen, and reacted under hydrogen atmosphere at room temperature for 15 hours. After the reaction, the reaction solution was filtered through a diatomaceous earth funnel, and the filter cake was washed with ethyl acetate 50 mL x 2. The filtrate was then concentrated to dryness to obtain 2.97 g of compound 002-M05, which was used directly in the next reaction without purification.

[0224] Compound 002-M06:

[0225] [ka] 1.275g of compound 002-M05 (1.0 equiv.), 0.965g of chloroacetic anhydride (1.05 equiv.) and 25mL of THF were weighed and added to a 50mL round bottom flask. The reaction mixture was heated to 60°C to react. After 1.5 hours of reaction, the heating was stopped, the reaction solution was cooled to room temperature and concentrated. After concentration, 25mL of saturated sodium bicarbonate solution and 25mL of ethyl acetate were added to the residue, and then the organic phase was separated. The aqueous phase was washed twice with 25mL×2 of ethyl acetate in succession, and the combined organic phase was washed with saturated saline, dried over anhydrous Na2SO4 for 5 minutes, and then filtered. The filtrate was concentrated to dryness and purified by column chromatography to obtain 1.07g 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] 0.15g of compound 002-M06 (1.0 equivalent), 0.199g of compound 13-D (1.1 equivalent) and 91mg of potassium carbonate (2.0 equivalent) were weighed and added to a 25mL round bottom flask. 5mL of acetonitrile was added. The reaction solution was heated to 60°C to react. After reacting for 3 hours, heating was stopped, the reaction solution was cooled to room temperature and concentrated. After concentration, 10mL of water was added to the residue, followed by stirring for about 0.5 hours to precipitate a large amount of solid, and then subjected to suction filtration. The filter cake was washed with 10mL of water x 3, dried, and then purified by column chromatography to obtain 0.165g of compound 14-A in a yield of 53%.

[0228] Compound 14:

[0229] [ka] 0.164g of compound 14-A (1.0 equivalent) was weighed and added to a 25mL round bottom flask. 1.0mL of methanol and 3.0mL of tetrahydrofuran were added, followed by 0.27mL of 2N sodium hydroxide solution. The reaction solution was then reacted at room temperature. After 15 hours, the reaction solution was concentrated. After concentration, 4mL of water was added to the residue, and the pH of the reaction solution was adjusted to 4-5 with 1mol / L HCl. The reaction solution was then filtered. The filter cake was pulped with 2mL of ethyl acetate and 0.5mL of pulping methanol, and then filtered. The filter cake was washed with 2mL of ethyl acetate x 3 and dried to obtain 0.118g of compound 14 in a yield of 73.6%. 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]

change

[0232]

change

[0233]

change

[0234] Compound 15-B:

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

[0236] Compound 15-C:

[0237] [ka] 0.3 g of compound 15-B (1.0 eq.), 0.188 g of compound 1-F (1.1 eq.) and 0.279 g of TBTU (1.2 eq.) were weighed and added to a 50 mL round bottom flask. 15.0 mL of DMF was added. The reaction solution was stirred in an ice bath for 10 minutes, and then 0.188 g of diisopropylethylamine (2.0 eq.) was added dropwise. After the dropwise addition, the reaction solution was continuously stirred in an ice bath for 3 hours. After the reaction, 30 mL of H2O and 30 mL of ethyl acetate were added to the reaction system, and the resulting system was stirred for 5 minutes and allowed to stand. The organic phase was separated, and the aqueous phase was washed twice with 30 mL x 2 of ethyl acetate in succession. 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] 0.2g of compound 15-C was weighed and added to a 50mL round bottom flask. 4.0mL of 1,4-dioxane was added. Then, 1mL of acetic acid was added dropwise. After the dropwise addition, the reaction solution was heated to 80°C to react. After 5 hours, the reaction solution was cooled to room temperature. The reaction solution was then concentrated and purified by column chromatography to obtain 0.12g of compound 15-D in a yield of 62%.

[0240] Compound 15:

[0241] [ka] 0.1g of compound 15-D (1.0 equivalent) and 20.5mg of lithium hydroxide monohydrate were weighed and added to a 25mL round bottom flask. 1.0mL of methanol, 1.0mL of tetrahydrofuran and 0.1mL of H2O were added. The reaction solution was then heated to 40°C to react. After 5 hours, the reaction solution was cooled to room temperature and concentrated. After concentration, 30mL of ethyl acetate was added to the residue, the pH of the reaction system was adjusted to 4-5 with 1mol / L HCl solution, and the reaction solution was allowed to stand. The organic phase was separated, the aqueous phase was washed twice with 20mL of ethyl acetate, and the combined organic phase was washed with saturated saline, dried with anhydrous Na2SO4 for 5 minutes, and then filtered. The filtrate was concentrated to dryness and purified by column chromatography to obtain 53.7mg of compound 15 in a yield of 55%. 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] Referring to the synthesis method of compound 15, compound 13-B therein 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 eq), 6.09 g of bis(pinacolato)diboron (1.2 eq), 0.44 g of Pd(dppf)Cl2 (0.03 eq) and 4.91 g of potassium acetate (2.5 eq) were weighed and added to a round bottom flask. 30 mL of 1,4-dioxane was added. The reaction solution was then degassed twice with nitrogen and heated to 100 °C under a nitrogen atmosphere to react. After reacting for 2 hours, the heating was stopped and the reaction solution was cooled to room temperature. The reaction solution was then filtered through a funnel using diatomaceous earth, and the filter cake was washed with 20 mL x 2 of ethyl acetate. The filtrate was then concentrated to dryness to obtain 6.87 g of compound 17-B, which was used directly in the next reaction without purification.

[0249] Compound 17-D:

[0250] [ka] 0.353 g of compound 17-B (1.2 eq), 0.338 g of compound 7-A (1.0 eq), 0.022 g of Pd(dppf)Cl2 (0.03 eq) and 0.815 g of Cs2CO3 (2.5 eq) were weighed and added to a 50 mL round bottom flask. 13.0 mL of 1,4-dioxane and 2.0 mL of H2O were added. The reaction solution was then degassed twice with nitrogen and heated to 90 °C under a nitrogen atmosphere to react. After reacting for 2 hours, heating was stopped and the reaction solution was cooled to room temperature. The reaction solution was then filtered through a funnel using diatomaceous earth, and the filter cake was washed with ethyl acetate 10 mL x 2. The filtrate was then concentrated to dryness and purified by column chromatography to obtain 0.328 g of compound 17-D in 77.0% yield.

[0251] Compound 17-F:

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

[0253] Compound 17-G:

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

[0255] Compound 17-I:

[0256] [ka] 0.160g of compound 17-G was weighed and added to a 50mL round bottom flask. 4.0mL of 1,4-dioxane was added, and then 0.58mL of acetic acid was added dropwise. After the addition, the reaction solution was heated at 80°C to react. After reacting for 5 hours, the reaction solution was cooled to room temperature. The reaction solution was then concentrated and purified by column chromatography to obtain 86mg of compound 17-I in a yield of 55.5%. 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 H2O were added. The reaction solution was then heated at 40°C to react. After 5 hours of reaction, the reaction solution was cooled to room temperature. The reaction solution was then concentrated. After concentration, 30 mL of ethyl acetate was added to the residue, and the pH of the reaction solution was adjusted to 4-5 with 1 mol / L HCl solution. The reaction solution was then left to stand, the organic phase was separated, the aqueous phase was washed twice with 20 mL of ethyl acetate, and the combined organic phase was washed with saturated saline, dried with anhydrous Na2SO4 for 5 minutes, and then filtered. The filtrate was concentrated to dryness and purified by column chromatography to obtain 60 mg of compound 17 in a yield of 71.8%. 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] With reference to the synthesis of Compound 17, Compound 1-F was replaced with Compound 18-A1, and finally 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]

Chemical formula

[0264]

Chemical formula

[0265]

Chemical formula

[0266] Compound 19-C:

[0267] [ka] 0.70 g of compound 19-B (1.0 eq.), 0.78 g of compound 1-F (1.1 eq.) and 1.16 g of TBTU (1.2 eq.) were weighed and added to a 100 mL round-bottom flask. 15.0 mL of DMF was added. The reaction solution was stirred in an ice bath for 10 minutes, and then 1.0 mL of diisopropylethylamine (2.0 eq.) was added dropwise. After the dropwise addition, the reaction solution was continuously stirred in an ice bath for 3 hours. After the reaction was completed, 30 mL of H2O and 30 mL of ethyl acetate were added to the reaction system, and the resulting system was stirred for 5 minutes. The reaction solution was allowed to stand, the organic phase was separated, the aqueous phase was washed twice with 25 mL x 2 of ethyl acetate, and the combined organic phase was washed with saturated saline, 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 dropwise addition of 0.81 mL (20.0 equivalents) of acetic acid. After dropwise addition, the reaction solution was heated at 60° C. to react. After 5 hours of reaction, the reaction solution was cooled to room temperature, and then the reaction solution was concentrated. After concentration, 25.0 mL of ethyl acetate was added to the residue, and then 30.0 mL of 3% K2CO3 aqueous solution was added under stirring. Then, the reaction solution was left to stand, the organic phase was separated, the aqueous phase was washed twice with 15 mL x 2 of ethyl acetate, and the combined organic phase was washed with saturated saline, dried over anhydrous Na2SO4 for 5 minutes, and then filtered. The filtrate was concentrated to dryness to obtain 0.31 g of compound 19-D in 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 solution was then degassed twice with nitrogen and heated to 100 °C under a nitrogen atmosphere to react. After 2 hours of reaction, heating was stopped, the reaction solution was cooled to room temperature, filtered through a diatomaceous earth funnel, and the filter cake was washed with 20 mL x 2 of ethyl acetate. The filtrate was then concentrated to dryness and purified by column chromatography to obtain 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 eq.), 0.104 g of compound 8-A (1.0 eq.), 8.0 mg of Pd(dppf)Cl2 (0.03 eq.) and 260 mg of Cs2CO3 (2.5 eq.) were weighed and added to a 50 mL round bottom flask. 5.0 mL of 1,4-dioxane and 2.0 mL of H2O were added. The reaction solution was then degassed twice with nitrogen and heated to 90 °C under a nitrogen atmosphere to react. After 2 hours of reaction, the heating was stopped, the reaction solution was cooled to room temperature, filtered through a diatomaceous earth funnel, and the filter cake was washed with ethyl acetate 10 mL x 2. The filtrate was then concentrated to dryness and purified by column chromatography to obtain 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 reacted at room temperature for about 36 hours until TLC showed the reaction was complete. The reaction was concentrated and 5 mL of water was added, after which the pH of the reaction was adjusted to 4-5 with citric acid solution. After a large amount of off-white solid precipitated, the reaction was continued to stir for about 0.5 hours, filtered and washed. The filter cake was recrystallized with 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 the reaction solution was stirred 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 equivalent) were weighed and added. The reaction solution was continuously stirred in an ice bath for 0.5 hours. The reaction solution was then transferred to room temperature and reacted for 3 hours. After the reaction was completed, 12 mL of H2O was added to the reaction system, stirred for 0.5 hours, and then filtered. The filter cake was washed with 4 mL of water x 3 and purified by column chromatography to obtain 0.122 g of compound 38-A in a yield of 39.8%.

[0301] Compound 38-B:

[0302] [ka] 0.12 g of compound 38-A (1.0 equivalent) was weighed and added to a 50 mL round-bottom flask. 1.8 mL of 1,4-dioxane was added. Then, 0.47 g of acetic acid (40.0 equivalent) was added dropwise. After the dropwise addition, the reaction solution was heated at 80 ° C to react. After 3 hours, the reaction solution was cooled to room temperature, 5 mL of water and 10 mL of ethyl acetate were added, and the pH of the reaction solution was adjusted to 7-8 with 5% NaHCO3 solution. Then, the reaction solution was left to stand, the organic phase was separated, the aqueous phase was washed twice with 10 mL x 2 of ethyl acetate, the organic phase was combined, washed with saturated saline, dried with anhydrous Na2SO4 for 5 minutes, and then filtered. The filtrate was concentrated to dryness and purified by column chromatography to obtain 90 mg of compound 38-B in a yield of 77.2%.

[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. Then, 0.14 mL of 2 mol / L sodium hydroxide solution was added. Then, the reaction solution was reacted at room temperature. After 15 hours, the reaction solution was concentrated. After concentration, 2.5 mL of water was added to the residue, and the pH of the reaction system was adjusted to 4-5 with 1 mol / L HCl solution. Then, the reaction solution was filtered, and the filter cake was purified by column chromatography to obtain 32 mg of compound 38 in a yield of 38.5%. 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 eq.), 155 mg of compound 13-B (1.05 eq.), 9 mg of Pd(dppf)Cl2 (0.03 eq.) and 339 mg of cesium carbonate (2.5 eq.) 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 was stirred homogeneously, degassed twice with nitrogen, and heated to 90° C. under nitrogen atmosphere for about 2 hours until TLC showed the reaction was complete. The reaction was then cooled to room temperature, filtered through a diatomaceous earth funnel, the filter cake was washed with a small amount of dichloromethane, and the filtrate was concentrated to dryness, separated 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, the resulting system was stirred uniformly, and 0.2 mL of 2 mol / L NaOH solution (2.0 equiv.) was slowly added dropwise, and then the resulting system was allowed to continue reacting at room temperature overnight until TLC showed the reaction was complete. The reaction solution was concentrated and about 10 mL of water was added. The pH of the reaction solution was adjusted to 4-5 with citric acid solution, and a large amount of off-white solid was precipitated. The reaction solution was continued to be stirred for about 0.5 hours, filtered, and washed with water. The filter cake was recrystallized with dichloromethane / methanol to obtain 79 mg of compound 61 in 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] Synthesis route:

[0325]

Chem.

[0326] Example 30: Synthesis of Compound 72:

[0327]

Chem.

[0328]

Chem.

[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: 1.02g of methyl 2,3-difluoro-4-nitrobenzoate (1.0 equivalent) was weighed and added to a 50mL round bottom flask. 5mL of DMF and 5mL of THF were added, followed by 0.95g of TEA (2.0 equivalent). After the reaction mixture was stirred uniformly, 0.5g of (S)-2-(aminomethyl)oxetane (1.2 equivalent) was added, and the resulting system was heated to 60°C to react. After 6 hours of reaction, the heating was stopped, the reaction solution was cooled to room temperature, and then 20mL of water and 20mL of ethyl acetate were added, and then allowed to stand. The organic phase was separated, the aqueous phase was extracted with 20mL of ethyl acetate, and the combined organic phase was washed with saturated saline, 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. Then, 0.14 g of Pd / C (10%) was added. The reaction mixture was purged with hydrogen three times and reacted at room temperature under a hydrogen atmosphere for 15 hours. The reaction solution was then filtered through a diatomaceous earth funnel, and the filter cake was washed with 20 mL x 2 of ethyl acetate. 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] 0.2g of compound 19-B (1.0 eq.), 0.24g of compound 91-A (1.1 eq.) and 0.148g of N-methylimidazole (2.1 eq.) were weighed and added to a 25mL round bottom flask. 4mL of acetonitrile was added. The reaction solution was stirred in an ice bath for 20 minutes, after which 0.265g of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH) (1.1 eq.) was added. The reaction solution was continued to be stirred in an ice bath for 0.5 hours, and then transferred to room temperature for continued reaction. After 3 hours of reaction, 12mL of water was added to the reaction solution, and the thus obtained system was stirred for 0.5 hours and filtered. The filter cake was washed with 5mL x 2 water and purified by column chromatography to obtain 0.155g of compound 91-B in 38.5% yield.

[0357] Compound 91-C:

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

[0359] Compound 91-D:

[0360] [ka] 0.134 g of compound 91-C (1.0 eq.), 91 mg of bis(pinacolato)diboron (1.2 eq.), 7 mg of Pd(dppf)Cl2 (0.03 eq.) and 74 mg of potassium acetate (2.5 eq.) were weighed and added to a 25 mL round bottom flask. 2 mL of 1,4-dioxane was added. The reaction was then degassed twice with nitrogen and heated to 100° C. under nitrogen atmosphere. After 2 hours of reaction, the heating was stopped and the reaction was cooled to room temperature. The reaction was then filtered through a funnel with diatomaceous earth and silica gel. The filter cake was washed with a mixture of petroleum ether and ethyl acetate (1:1). 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 equivalent), compound 91-D obtained in the previous step, 5.5 mg of Pd(dppf)Cl2 (0.03 equivalent) and 202 mg of Cs2CO3 (2.5 equivalent) were weighed and added to a 50 mL round-bottom flask. 2.5 mL of 1,4-dioxane and 0.4 mL of H2O were added. The reaction solution was then degassed twice with nitrogen and heated to 90 °C under a nitrogen atmosphere to react. After 3 hours of reaction, the heating was stopped and the reaction solution was cooled to room temperature. The reaction solution was then filtered through a funnel using diatomaceous earth, and the filter cake was washed with ethyl acetate 10 mL x 2. The filtrate was then concentrated to dryness and purified by column chromatography to obtain 0.141 g of compound 91-E in a yield of 90.4%. MS m / z (ESI): 630.1602 (M+H) + .

[0363] Compound 91:

[0364] [ka] 0.14 g of compound 91-E (1.0 equiv.) 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 solution was then reacted at room temperature. After 20 hours, the reaction solution was concentrated. After concentration, 4 mL of water and 0.5 mL of acetone were added to the residue. The pH of the reaction system was adjusted to 4-5 with 1 mol / L HCl, the system was 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 yield of 76.7%. 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]

change

[0367]

change

[0368]

change

[0369] Compound 93-B:

[0370] [ka] 0.3 g of compound 93-A (1.0 eq), 0.17 g of compound 1-C (1.5 eq), 57 mg of Pd2(dba)3 (0.1 eq), 59 mg of 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (0.2 eq) and 0.404 g of cesium carbonate (2 eq) were weighed and added to a 25 mL round bottom flask. 4.5 mL of toluene was added. The reaction solution was then degassed twice with nitrogen and heated to 110 °C under a nitrogen atmosphere to react. After 12 hours of reaction, heating was stopped and the reaction solution was cooled to room temperature. The reaction solution was then filtered through a funnel using diatomaceous earth, and the filter cake was washed with 10 mL x 2 of ethyl acetate. The filtrate was then concentrated to dryness and purified by column chromatography to obtain 0.112 g of compound 93-B in a yield of 28.7%. 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 solution was then reacted at room temperature. After 20 hours, the reaction solution was concentrated. After concentration, 4 mL of water and 0.5 mL of acetone were added to the residue. The pH of the reaction system was adjusted to 4-5 with 1 mol / L HCl, the system was 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, and then filtered. The filter cake was washed with 1 mL of ethyl acetate x 2 and dried to obtain 65 mg of compound 93 in a yield of 60.4%. 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 eq.) and 0.565 g of imidazole (1.5 eq.) were weighed and added to a 50 mL round-bottom flask. 22 mL of DMF was added. Then, the reaction mixture was stirred uniformly in an ice bath, cooled to 0 °C, and TBDPSCl was added dropwise. After the dropwise addition, the reaction solution was kept at a low temperature and reacted for 1 h, then the ice bath was removed, the reaction solution was returned to room temperature, and stirred and reacted for 2 h. TLC showed that the raw materials were completely reacted. Then, 44 mL of water and 30 mL of ethyl acetate were added to the reaction solution for extraction. The organic phase was washed three times with 15 mL of water each time and three times with 15 mL of saturated saline each time, then 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 as eluent) to obtain compound 94-A1 (2.30 g, 100% yield).

[0378] Compound 94-A2: 1.5g of compound 94-A1 (1.0 equivalent) was weighed and added to a 50mL three-neck flask. 20mL of anhydrous THF was added under nitrogen protection. The reaction mixture was stirred to dissolve, then cooled to -75°C. When the temperature of the reaction solution was cooled to -75°C, 5.16mL of LDA (2mol / L, 3.0 equivalent) was added dropwise to the reaction solution. After the dropwise addition, the reaction solution was kept at a low temperature and reacted for 1 hour. Next, a THF solution of NFSI (N-fluorobenzenesulfonimide) (1.63g dissolved in 5mL of THF, 1.5 equivalent) was added dropwise. After the dropwise addition, the reaction solution was kept at a low temperature and reacted for 1 hour. Cooling was stopped, and the reaction solution was slowly returned to room temperature. A saturated ammonium chloride solution was added to the reaction solution to quench it. The reaction solution 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 saline, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain an oily crude product, which was purified by silica gel column chromatography (PE as eluent) to obtain 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 solution was reacted overnight. TLC showed that the raw materials were completely reacted. Then, 15 mL of ethyl acetate was added to the reaction solution for extraction. The organic phase was washed twice with 10 mL of water and twice with 10 mL of saturated saline, then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a clear oil, which was purified by column chromatography (PE / EA=94 / 6) to obtain compound 94-A (125 mg, yield 88.03%). 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 equivalent), 140.0 mg of compound 94-A (1.2 equivalent), 64.0 mg of Pd2(dba)3 (0.12 equivalent), 65.30 mg of RuPhos (2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl) (0.24 equivalent) and 455.11 mg of cesium carbonate (2.4 equivalent) were weighed and added to a 25 mL round-bottom flask. 8 mL of toluene was added. The reaction solution was then degassed twice with nitrogen and heated to 90 °C under a nitrogen atmosphere to react. After 3 hours of reaction, heating was stopped and the reaction solution was cooled to room temperature. The reaction solution was then filtered through a funnel using diatomaceous earth. The filtrate was concentrated to dryness and purified by column chromatography (PE / EA=60 / 40) to give compound 94-B (190 mg, 50.4% yield). 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, and then 1.5 mL of water was added. After the reaction solution was stirred uniformly, 28.20 mg of LiOH-H2O (3.0 equiv.) was added. The reaction solution was stirred at room temperature and reacted overnight. TLC showed that the raw material was completely reacted. The reaction solution was concentrated under reduced pressure to remove the solvent, and then 5 mL of water was added. The pH of the reaction solution 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 formed by 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 eq.), 319 mg of 2-bromo-3,6-difluoropyridine (1.0 eq.) and 1.07 g of cesium carbonate (2.0 eq.) 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. for reaction. After about 4 hours of reaction, the reaction was cooled to room temperature, 18 mL of water was added, and extracted with 20 mL x 3 of ethyl acetate until TLC showed the reaction was complete. The organic phases were combined, washed with 20 x 2 saturated sodium chloride solution, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to give 547 mg of compound 95-A in 93.3% yield.

[0386] Compound 95-B:

[0387] [ka] 117 mg of compound 95-A (1.05 eq.), 150 mg of compound 19-E (1.0 eq.), 7 mg of Pd(dppf)Cl2 (0.03 eq.) and 254 mg of Cs2CO3 (2.5 eq.) were weighed and added to a 50 mL round bottom flask. Then, 5.0 mL of 1,4-dioxane and 1.0 mL of H2O were added. Then, the reaction solution was degassed twice with nitrogen and heated to 90 °C under nitrogen atmosphere to react. After 4 hours of reaction, heating was stopped and the reaction solution was cooled to room temperature. Then, the reaction solution was filtered through a funnel with diatomaceous earth and the filter cake was washed with about 20 mL of dichloromethane. Then, the filtrate was concentrated to dryness and purified by column chromatography to obtain 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 NaOH aqueous solution was added dropwise. After the addition, the reaction was allowed to react at room temperature for about 36 hours until TLC showed the reaction was complete. The reaction was concentrated, and 5 mL of water and 1 mL of acetone were added. The pH of the reaction was adjusted to 4-5 with citric acid solution. A large amount of off-white solid was precipitated, and the reaction was continued to be stirred for about 0.5 hours, subjected to suction filtration, 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 system thus obtained was stirred to dissolve, and then 0.16 mL of 2 mol / L aqueous NaOH solution (3.0 equiv.) was added dropwise. After the addition, the reaction was reacted at room temperature for about 36 hours until TLC showed the reaction was complete. The reaction was concentrated, and 4 mL of water and 0.5 mL of acetone were added. The pH of the reaction was adjusted to 4-5 with citric acid solution. A large amount of off-white solid was precipitated, and the reaction was continued to be stirred for about 0.5 hours, filtered, and washed with water. The filter cake was dried to obtain 50 mg of compound 97 in 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] Following 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 eq.), 900.57 mg of Cs2CO3 (2.0 eq.) and 267.50 mg of 2-bromo-6-fluoropyridine (1.1 eq.) were weighed and added to a 50 mL round-bottom flask. 10 mL of DMF was added. The reaction mixture was stirred to dissolve, then stirred uniformly, and then placed at 90 °C to react under heating for 4 hours. TLC showed that the two raw materials were essentially completely reacted. Heating was stopped and the reaction solution was cooled to room temperature. 30 mL of water and 20 mL of ethyl acetate were added to the reaction solution to extract, and the aqueous phase was extracted with 10 mL of ethyl acetate. The organic phases were combined, washed three times with 15 mL × 3 of water, washed three times with 15 mL × 3 of saturated saline, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain an oily crude product, which was dried to obtain 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 eq.), 803.13 mg of compound 19-E (1.2 eq.), 61.16 mg of Pd(dppf)Cl2 (0.06 eq.) and 1.13 g of cesium carbonate (2.5 eq.) 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, heated to 90 °C under nitrogen atmosphere and reacted for 2.5 h. TLC showed that the two raw materials were essentially completely reacted. Heating was stopped and the reaction solution was cooled to room temperature. The reaction solution 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 (PE / EA=60 / 40) to obtain compound 99-C (600 mg, yield 66.7%). 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 eq) 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 system thus obtained was stirred to dissolve, and then 1.0 mL of 2 mol / L NaOH solution (4.0 eq) was added. The reaction solution was stirred uniformly and then reacted at room temperature overnight. TLC showed that the raw materials were essentially completely reacted. The reaction solution was then cooled to room temperature and concentrated under reduced pressure. 10 mL of water was added to the concentrated solution, and the pH of the reaction solution was adjusted to about 4 with citric acid solution. A large amount of white solid was precipitated, 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 solution was then reacted at room temperature. After 22 hours, the reaction solution 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 system was adjusted to 4-5 with 1 mol / L HCl aqueous solution. The reaction solution 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 yield of 90.4%. 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] 0.703g of compound 101-A (1.0 equivalent) was weighed and added to a 25mL round bottom flask. 11mL of 1,2-dichloroethane was added, and then 3.5mL of acetic acid (40.0 equivalent) was added dropwise. After the dropwise addition, the reaction solution was placed at 80°C and reacted while being heated. After reacting for 3 hours, the reaction solution was cooled to room temperature, and then the reaction solution was concentrated. After concentration, 10mL of water was added to the reaction solution, and 3% K2CO3 aqueous solution was added under stirring. The pH of the reaction system was adjusted to 7-8. Then, the system was filtered, and the filter cake was washed with a small amount of water, and the filter cake was dried to obtain 0.642g of compound 101-B with a yield of 94.9%.

[0421] Compound 101-C:

[0422] [ka] 0.3 g of compound 101-B (1.0 eq.), 203 mg of bis(pinacolato)diboron (1.2 eq.), 15 mg of Pd(dppf)Cl2 (0.03 eq.) and 163 mg of potassium acetate (2.5 eq.) were weighed and added to a 25 mL round bottom flask. 4.5 mL of 1,4-dioxane was added. The reaction solution was then degassed twice with nitrogen and heated to 100°C under nitrogen atmosphere for reaction. After reacting for 2 hours, the heating was stopped and the reaction solution was cooled to room temperature. The reaction solution was then filtered through a funnel using diatomaceous earth and silica gel, and the filter cake was washed with a mixture of petroleum ether and ethyl acetate (1:1). After collecting the filtrate, the filtrate was concentrated to dryness to obtain 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 eq.), compound 101-C obtained in the previous step, 12.2 mg of Pd(dppf)Cl2 (0.03 eq.), and 0.451 g of Cs2CO3 (2.5 eq.) were weighed and added to a 50 mL round-bottom flask. 5.6 mL of 1,4-dioxane and 1 mL of H2O were added. The reaction solution was then degassed twice with nitrogen and heated to 90 °C under a nitrogen atmosphere to react. After 3 hours of reaction, the heating was stopped and the reaction solution was cooled to room temperature. The reaction solution was then filtered through a funnel using diatomaceous earth, and the filter cake was washed with ethyl acetate 10 mL x 2. The filtrate was then concentrated to dryness and purified by column chromatography to obtain 0.248 g of compound 101-D in 71% yield. MS m / z (ESI): 630.1534 (M+H) + .

[0425] Compound 101:

[0426] [ka] 0.247g of compound 101-D (1.0 equivalent) was weighed and added to a 25mL round bottom flask. 1.3mL of methanol and 3.7mL of tetrahydrofuran were added, followed by 0.6mL of 2mol / L sodium hydroxide solution. The reaction solution was then reacted at room temperature. After 20 hours, the reaction solution was concentrated. After concentration, 6mL of water and 0.5mL of acetone were added to the reaction solution, and the pH of the reaction system was adjusted to 4-5 with 1mol / L HCl solution. The reaction solution was filtered, and the filter cake was washed with a small amount of water and then dried to obtain 0.228g of compound 101 in a yield of 94.4%. 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] 1.87g of 4-chloro-2-hydroxy-benzoic acid methyl ester (1.0 eq), 1.42g of 3-bromopropyne (1.2 eq) and 2.1g of potassium carbonate (1.5 eq) were weighed and added to a 50mL three-neck flask. 20mL of N,N-dimethylformamide was added. The reaction mixture was stirred uniformly and placed at 50℃ for 5 hours under heating. TLC showed that the raw materials were essentially completely reacted, the reaction was stopped and the reaction solution was cooled to room temperature. 40mL of water and 20mL of ethyl acetate were added to the reaction solution to extract, the aqueous phase was extracted with 15mL of ethyl acetate, the organic phase was combined, washed twice with 15mL of water, washed three times with 15mL of saturated saline, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain an oily product 102-A crude product. This product was used as it is in the next feed without purification.

[0431] Compound 102-B:

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

[0433] Compound 102-C:

[0434] [ka] 1.16 g of compound 102-B (1.0 equiv.) 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 equiv.) was weighed and added, and the solution was stirred overnight to react. TLC showed that the raw materials were essentially completely reacted. The reaction was stopped. 30 mL of water was slowly added dropwise to the reaction solution, after which a large amount of solid was precipitated, which was stirred at room temperature for about 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] 400mg of compound 102-C (1.0 equiv.), 1.32g of Cs2CO3 (2.0 equiv.) and 428.7mg of 2-bromo-6-fluoropyridine (1.2 equiv.) were weighed and added to a 25mL round bottom flask. 12mL of DMF was added. The reaction mixture was stirred uniformly and then placed at 90°C for 5 hours under heating. TLC showed that the two raw materials were essentially completely reacted. Heating was stopped and cooled to room temperature. After adding 24mL of water to the reaction solution, a large amount of solid matter was precipitated, which was stirred at room temperature for about 30 minutes and then filtered. The filter cake was washed with water and dried to obtain solid compound 102-D (640mg, 89.38% yield).

[0437] Compound 102-E:

[0438] [ka] 340 mg of compound 102-D (1.0 eq.), 509 mg of compound 19-E (1.0 eq.), 42.32 mg of Pd(dppf)Cl2 (0.06 eq.), and 785.2 mg of cesium carbonate (2.5 eq.) 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 homogeneously, purged with nitrogen three times, heated to 90 °C under nitrogen atmosphere, and reacted for 2.5 h. TLC showed that the two raw materials were essentially completely reacted. Heating was stopped, and the reaction solution was cooled to room temperature. The reaction solution 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, yield 87.8%).

[0439] Compound 102:

[0440] [ka] 530mg of compound 102-E (1.0 equiv.) was weighed and added to a 25mL round bottom flask. 9mL of tetrahydrofuran and 1.5mL of methanol were added. The system thus obtained was stirred to dissolve, and then 0.85mL of 2mol / L NaOH solution (2.0 equiv.) was added. The reaction solution was stirred uniformly and reacted at room temperature overnight. TLC showed that the raw materials were essentially completely reacted. The reaction solution was then cooled to room temperature and concentrated under reduced pressure. 10mL of water was added to the concentrated solution, and the pH of the reaction solution was adjusted to about 4 with citric acid solution. A large amount of white solid was precipitated, 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 (400mg, 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 99-A was replaced 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) by referring to the synthesis method of compound 100, to finally obtain compound 104. 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 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 eq.), 600 mg of compound 105-B (1.1 eq.), 370 mg of NMI (2.1 eq.) and 662 mg of TCFH (1.1 eq.) 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 about 0.5 h and allowed to react at room temperature overnight until TLC showed the reaction was complete. 20 mL of water was added to the reaction to precipitate a large amount of off-white solid, and the reaction was continued to stir for about 0.5 h, then suction filtered and washed with water. The filter cake was dried to give 507 mg of compound 105-C in 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 equivalent) 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 about 6 hours until TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, concentrated, and 5 mL of water was added. The pH of the reaction solution was adjusted to neutral with 5% sodium bicarbonate solution. A large amount of solid matter was precipitated, and the reaction system 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 with a yield of 67.6%.

[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 solution was then degassed twice with nitrogen and heated to 100 °C under a nitrogen atmosphere to react. After reacting for 2 hours, heating was stopped and the reaction solution was cooled to room temperature. The reaction solution was then filtered through a funnel with diatomaceous earth and the filter cake was washed with ethyl acetate 20 mL x 2. The filtrate was then concentrated to dryness and purified by column chromatography to obtain 261 mg of compound 105-E in 71.7% yield.

[0459] Compound 105-F:

[0460] [ka] 260 mg of compound 105-E (1.1 eq), 161 mg of compound 7-A (1.0 eq), 10.4 mg of Pd(dppf)Cl2 (0.03 eq) and 387 mg of Cs2CO3 (2.5 eq) were weighed and added to a 50 mL round bottom flask. 5.0 mL of 1,4-dioxane and 1.0 mL of H2O were added. The reaction solution was then degassed twice with nitrogen and heated to 90 °C under a nitrogen atmosphere to react. After reacting for 2 hours, heating was stopped and the reaction solution was cooled to room temperature. The reaction solution was then filtered through a funnel using diatomaceous earth, and the filter cake was washed with ethyl acetate 10 mL x 2. The filtrate was then concentrated to dryness and purified by column chromatography to obtain 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 system was stirred to dissolve, and then 0.57 mL of 2 mol / L aqueous NaOH solution (4.0 equiv.) was slowly added dropwise. After addition, the reaction was allowed to react at room temperature for about 36 hours until TLC showed the reaction was complete. The reaction was concentrated, and 5 mL of water and 1 mL of acetone were added. The pH of the reaction was adjusted to 4-5 with citric acid solution. A large amount of off-white solid was precipitated, which was stirred continuously for about 0.5 hours, filtered, and washed with water. The filter cake was dried to give 157 mg of compound 105 in 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 eq), 1.01 g of compound 1-pinacolborate-4-ethylacetate-1-cyclohexene (1.2 eq), 0.208 g of Pd(dppf)Cl2 (0.1 eq) and 2.32 g of cesium carbonate (2.5 eq) 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 solution was then degassed twice with nitrogen and heated to 80 °C under a nitrogen atmosphere to react. After reacting for 2 hours, the heating was stopped and the reaction solution was cooled to room temperature. The reaction solution was then filtered through a funnel using diatomaceous earth, and the filter cake was washed with ethyl acetate 15 mL x 2. The filtrate was then concentrated to dryness and purified by column chromatography to obtain 0.769 g of compound 106-A in a yield of 90.6%.

[0467] Compound 106-B:

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

[0469] Compound 106-C:

[0470] [ka] 0.61g of compound 106-B (1.0 eq), 0.615g of compound 1-F (1.1 eq) and 0.390g of N-methylimidazole (2.1 eq) were weighed and added to a 50mL round bottom flask. 13.0mL of acetonitrile was added. After the reaction solution was stirred in an ice bath for 20 minutes, 0.697g of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (1.1 eq) was weighed and added. The reaction solution was stirred and reacted in an ice bath for 0.5 hours. The reaction solution was then transferred to room temperature and reacted for 3 hours. After the reaction, 36mL of H2O was added to the reaction system, stirred for 0.5 hours, and filtered. The filter cake was washed with 20mL x 3 of H2O and dried at 50°C to obtain 1.0g of compound 106-C in a yield of 90.6%. 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, and then 4.923 g of acetic acid (40.0 equivalent) was added dropwise. After the dropwise addition, the reaction solution was placed at 90°C and reacted under heating. After 5 hours, the reaction solution was cooled to room temperature and concentrated to remove the solvent, and then 15 mL of water was added and the pH of the reaction solution was adjusted to 7-8 with 5% NaHCO3 aqueous solution. The reaction solution 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 84% yield. MS m / z (ESI): 470.1629 (M+H) + .

[0473] Compound 106-E:

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

[0475] Compound 106:

[0476] [ka] 0.2g of compound 106-E (1.0 equivalent) was weighed and added to a 25mL round bottom flask. 1mL of methanol and 3mL of tetrahydrofuran were added, followed by 0.6mL of 2mol / L sodium hydroxide solution. The reaction solution was then reacted at room temperature. After 20 hours, the reaction solution was concentrated. After concentration, 5mL of water and 0.5mL of acetone were added to the reaction solution. The pH of the reaction system was adjusted to 4-5 with 1mol / L HCl solution. The reaction system was filtered, and the filter cake was washed with a small amount of water and then dried to obtain 0.182g of compound 106 in a yield of 93.1%. 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]

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[0479]

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[0480]

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[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 solution was then reacted at room temperature. After 20 hours, the reaction solution was concentrated. After concentration, 2 mL of water and 0.25 mL of acetone were added to the reaction solution. The pH of the reaction system was adjusted to 4-5 with 1 mol / L HCl solution. The reaction system 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 a yield of 83.6%. 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]

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[0485]

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[0486]

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[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 system thus obtained was stirred to dissolve, and then 1.0 mL of 2 mol / L NaOH solution was added dropwise. After the dropwise addition, the reaction solution was allowed to react for 3.0 hours at room temperature. After the reaction was completed, the reaction solution was concentrated. After the concentration, 10 mL of water and 30 mL of ethyl acetate were added to the reaction solution, and the pH of the reaction solution was adjusted to 4-5 with 1 mol / L HCl solution. The reaction solution was left to stand for liquid phase separation, and the organic phase was collected. The organic phase was washed twice with 15 mL of saturated saline, 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 eq.) and 183.6 mg of compound 1-F (1.05 eq.) were weighed and added to a 50 mL round-bottom flask. 10.0 mL of acetonitrile was added. After the reaction solution was stirred in an ice bath for 15 minutes, 290.64 mg of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (1.4 eq.) and 243.0 mg of N-methylimidazole (4.0 eq.) were weighed and added. The reaction solution was continuously stirred and reacted in an ice bath for 1 hour. The reaction solution was then transferred to room temperature and continuously reacted for 3 hours. After the reaction, 30 mL of H2O was added to the reaction system, and the system was stirred for 0.5 hours and filtered. After washing the filter cake with 20 mL of water, the filter cake was collected and dried to obtain 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 at 90 °C to react. After 1.5 h, TLC showed that the raw materials were essentially completely reacted. The reaction solution 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 solution was adjusted to 7-8 with saturated NaHCO3 aqueous solution. Then, the reaction solution was left to stand for liquid 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 obtain compound 108-D (220 mg, yield 55.21%).

[0493] Preparation of Compound 108:

[0494] [ka] 220 mg of compound 108-D (1.0 equivalent) 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 system thus obtained was stirred to dissolve, and then 0.8 mL of 2 mol / L NaOH aqueous solution was added. The reaction solution was then reacted at room temperature. TLC showed that the raw materials were essentially completely reacted. After concentrating the reaction solution, 5 mL of water and 3 mL of ethyl acetate were added to the residue, and the resulting system was allowed to stand for liquid phase separation. The aqueous phase was collected, and the pH of the aqueous phase was adjusted to 4-5 with citric acid solution. 10 mL of ethyl acetate was added for extraction, and the organic phase was washed twice with 5 mL of saturated saline, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to dryness to obtain 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 equivalent) 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 equivalent) were added. The reaction mixture was stirred uniformly and then heated to 50°C to react for about 6 hours. After the reaction was completed, the reaction solution was concentrated to remove tetrahydrofuran. 30 mL of water was added to the residue to precipitate a large amount of yellow solid. The reaction solution was continued to be stirred for about 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 yield of 94.0%, which was used as it is in the next reaction.

[0499] Compound DB06-B:

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

[0501] Compound DB06-C:

[0502] [ka] 2.06 g of compound 19-B (1.0 eq.) and 2.43 g of compound DB06-B (1.1 eq.) 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, after which 1.52 g of NMI (2.1 eq.) and 2.73 g of TCFH (1.1 eq.) were added. The reaction mixture was stirred continuously for about 0.5 hours, after which the ice bath was removed and the reaction mixture was reacted at room temperature overnight. After completion of the reaction, about 80 mL of water was added, causing a large amount of off-white solid to precipitate. The reaction mixture was stirred continuously for about 0.5 hours, after which it was suction filtered and washed with water. The filter cake was dried to obtain 2.71 g of compound DB06-C in a yield of 65.9%, 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, and then 6.7 mL (20.0 equivalents) of acetic acid was added dropwise. After the dropwise addition, the reaction solution was placed at 60°C and reacted under heating. After reacting for 5 hours, the reaction solution was cooled to room temperature, and then the reaction solution was concentrated. After concentration, 20.0 mL of acetonitrile and 20 mL of water were added, and the pH of the reaction solution was adjusted to 7-8 with saturated sodium bicarbonate solution. After a large amount of off-white solid was precipitated, the reaction solution was stirred continuously 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 87.5% yield, which was used as it is in the next 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 was then degassed twice with nitrogen and heated to 100° C. under nitrogen atmosphere to react. After 2 hours of reaction, the heating was stopped and the reaction was cooled to room temperature. The reaction was then filtered through a diatomaceous earth funnel and the filter cake was washed with ethyl acetate 20 mL×3. 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 eq.), 0.20 g of compound 7-A (1.0 eq.), 14 mg of Pd(dppf)Cl2 (0.03 eq.) and 515 mg of Cs2CO3 (2.5 eq.) were weighed and added to a 50 mL round-bottom flask. 4.0 mL of 1,4-dioxane was added. The reaction solution was then degassed twice with nitrogen and heated to 100 °C under a nitrogen atmosphere to react. After reacting for 2 hours, heating was stopped and the reaction solution was cooled to room temperature. The reaction solution was then filtered through a funnel using diatomaceous earth, and the filter cake was washed with ethyl acetate 10 mL × 2. The filtrate was then concentrated to dryness and purified by column chromatography to obtain 0.29 g of compound DB06-F in 78.3% yield.

[0509] Compound DB06:

[0510] [ka] 0.15g of compound DB06-F (1.0 equivalent) was weighed and added to a 50mL round bottom flask. 6.0mL of tetrahydrofuran and 2.0mL of methanol were added. The reaction mixture was stirred uniformly, 0.51mL of 2mol / L sodium hydroxide solution (4.0 equivalent) was slowly added dropwise, and the system was heated to 40°C and reacted for about 4 hours. After the reaction was completed, the reaction solution was concentrated, and 4mL of water and 0.5mL of acetone were added. The pH of the reaction solution was adjusted to 4-5 with citric acid solution, and a large amount of off-white solid was precipitated. The reaction solution was stirred continuously for about 0.5 hours, then suction filtered and washed with water. The filter cake was dried to obtain 127mg of compound DB06 in a yield of 87.0%. 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] 8.0g of 2,6-dichloropyridine (1.0 eq.) and 8.6g of 3-fluoro-4-(hydroxymethyl)benzonitrile (1.0 eq.) were weighed and added to a 250mL round-bottom flask. 80mL of 1,4-dioxane was added and the system thus obtained was stirred to dissolve. A mixed solution of 7.28g of potassium tert-butoxide (1.2 eq.) in THF (40mL) was added dropwise to the above mixed solution. After the dropwise addition, the reaction solution was stirred at 40°C for 60 minutes. TLC showed that the raw material had disappeared. The reaction was stopped from heating and the reaction solution was cooled to room temperature. 240mL of water was added to the reaction solution, and then a large amount of solid was precipitated, which was filtered, and the filter cake was washed with water and dried to obtain a pale yellow solid DB01-A (12.42g, yield 87.59%). 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 eq.), 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 eq.), 1.68 g of Pd(dppf)Cl2 (0.1 eq.) and 2.9 g of NaHCO3 (1.5 eq.) were weighed and added into a 250 mL round bottom flask. 90 mL of 1,4-dioxane and 18.0 mL of H2O were added. The reaction mixture was then stirred evenly, purged with nitrogen four times, and placed at 90 °C to react under nitrogen atmosphere and heating for 3 hours. TLC showed that the raw material had disappeared. The reaction was stopped from heating and the reaction solution was cooled to room temperature. The reaction mixture was then concentrated and purified by column chromatography (PE / EtOAc=95 / 5) to give the solid product DB01-B (8.6 g, yield 92.0%).

[0517] Compound DB01-C:

[0518] [ka] 8.6g of compound DB01-B (1.0 equivalent) was weighed and added to a 500mL round bottom flask. 2.58g of Pd / C (10% content) and 215mL of toluene were added. The reaction mixture was then stirred homogeneously, purged with hydrogen three times, and stirred under hydrogen atmosphere to react. HPLC showed that the raw materials were completely reacted. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure to obtain oily compound DB01-C (8.17g, yield 94.6%). 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] 8.2g of compound DB01-C (1.0 eq.) and 9.47g of pTSA monohydrate (2.5 eq.) were weighed and added into a 250mL round bottom flask. 190mL of ethyl acetate was added. Then the reaction mixture was stirred evenly and reacted at 60°C for about 30 minutes. TLC showed that the raw material had disappeared. The reaction was stopped from heating and the reaction solution was cooled to room temperature. A large amount of off-white solid compound was precipitated, which was filtered and dried to obtain 2-molecular p-toluenesulfonate compound DB01-D (11.14g, 85.69% yield).

[0521] Compound DB01-E:

[0522] [ka] 2.7g of compound DB01-D (1.0 equiv.), 1.21g of compound 001-M07 (1.0 equiv.) and 2.84g of potassium carbonate (5.0 equiv.) were weighed and added to a 150mL round bottom flask. 54mL of acetonitrile was added. The reaction solution was stirred uniformly and heated at 50°C for 3 hours. TLC showed that the two raw materials were completely reacted. Heating was stopped, and then the reaction solution was cooled to room temperature, 108mL of water and 50mL of ethyl acetate were added, and the resulting system was allowed to stand for liquid phase separation. The aqueous phase was extracted with 50mL of ethyl acetate, and the combined organic phase was washed twice with 50mL 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 were carried out using a mixed solvent (PE / EA=3 / 1) to obtain the solid product DB01-E (2.07g, 88.08% yield).

[0523] Compound PF-06882961:

[0524] [ka] 500mg of compound DB01-E (1.0 equiv.) was weighed and added to a 50mL round bottom flask. 9mL of acetonitrile was added. An aqueous solution (1.8mL) containing 245mg of TBD (2.0 equiv.) was added dropwise under stirring, and the system was stirred and reacted at room temperature for 24 hours. TLC showed that the raw material was completely reacted. The pH of the reaction solution was adjusted to 5.0 with citric acid solution. 20mL of ethyl acetate was added, and the system was allowed to stand to separate the liquid phases. The ethyl acetate organic phase was washed with 10mL 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 (0.44g, 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 equiv.) and 522.72 mg of pTSA·H2O (3.0 equiv.) were weighed and added to a 50 mL round-bottom flask. 10 mL of ethyl acetate was added. The reaction solution was stirred homogeneously and placed at 65 °C for 2 h under heating. TLC showed that the raw materials were completely reacted. Heating was stopped and the reaction solution was cooled to room temperature. 5 mL of water was added to the reaction solution, and the pH of the reaction solution was adjusted to about 8 with saturated sodium bicarbonate. The reaction solution was stirred for 10 min and allowed to stand for liquid phase separation. The organic phase was collected, washed twice with 5 mL × 2 of water, washed twice with 5 mL × 2 of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain oily compound DB02-C. The compound was used as is in the next feed without calculating the yield and degree of purification.

[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 equivalent) were added. The reaction solution was stirred uniformly and heated at 50 °C for 2 hours. TLC showed that the two raw materials had reacted completely. Then, heating was stopped and the reaction solution was cooled to room temperature. 18 mL of water and 10 mL of ethyl acetate were added to the reaction solution, and the resulting system was allowed to stand for liquid phase separation. The aqueous phase was extracted with 10 mL of ethyl acetate. The organic phases were combined, washed twice with 10 mL × 2 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 / 90-50 / 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·H2O (1.5 equiv.). The reaction solution was stirred homogeneously and placed at 45 °C for 4-5 hours under heating. TLC showed that the raw materials were completely reacted. After the reaction solution was cooled to room temperature, the solvent was evaporated under reduced pressure, and 10 mL of water was added to the residue. The impurities were extracted with 15 mL of ethyl acetate, and the aqueous phase was adjusted with citric acid until the pH of the reaction solution was 4-5. 10 mL of ethyl acetate was added to the aqueous phase, and the system thus obtained was allowed to stand for liquid phase separation. The aqueous phase was extracted twice successively with 10 mL × 2 of ethyl acetate, and the ethyl acetate organic phase was combined. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography to give 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 eq), 0.822 g of 2-bromo-6-fluoropyridine (1.5 eq) and 2.04 g of cesium carbonate (2.0 eq) were weighed and added to a 50 mL round bottom flask. 15 mL of DMF was added. The reaction solution was then heated to 90°C to react. After 4 hours of reaction, the heating was stopped and the reaction solution was cooled to room temperature. 60 mL of water and 30 mL of ethyl acetate were added, and the resulting system was stirred for 5 minutes and then allowed to stand. The organic phase was separated, and the aqueous phase was washed twice in succession with 30 mL x 2 of ethyl acetate, and the organic phase was combined. The organic phase was then washed with saturated saline, dried over anhydrous Na2SO4 for 5 minutes, and then filtered. The filtrate was concentrated to dryness and purified by column chromatography to obtain 0.84 g of compound DB03-A in 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 H2O were added. The reaction solution was then degassed twice with nitrogen and heated to 90 °C under a nitrogen atmosphere to react. After 3 hours of reaction, the heating was stopped and the reaction solution was cooled to room temperature. The reaction solution was then filtered through a funnel with diatomaceous earth, and the filter cake was washed with ethyl acetate 10 mL x 2. The filtrate was then concentrated to dryness and purified by column chromatography to obtain 0.275 g of compound DB03-B in 74% yield. MS m / z (ESI): 590.1583 (M+H)+.

[0541] Compound DB03:

[0542] [ka] 0.272g of compound DB03-B (1.0 equivalent) was weighed and added to a 25mL round bottom flask. 1.5mL of methanol and 4.5mL of tetrahydrofuran were added, followed by 0.47mL of 2N sodium hydroxide solution. The reaction solution was then reacted at room temperature. After 15 hours, the reaction solution was concentrated. After concentration, 5mL of water was added to the residue, and the pH of the reaction system was adjusted to 4-5 with 1mol / L HCl solution. The reaction solution was then filtered. The filter cake was pulped with 5mL of ethyl acetate and 1mL of methanol, and then filtered. The filter cake was washed with 3mL of ethyl acetate x 3 and dried to obtain 0.173g of compound DB03 in 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] 3g of methyl 3-fluoro-4-nitrobenzoate (1.0 equivalent), 1.36g of 2-methoxyethanamine (1.2 equivalent) and 3.05g of triethylamine (2.0 equivalent) were weighed and added to a 250mL round-bottom flask. 15mL of N,N-dimethylformamide and 15mL of tetrahydrofuran were added. The reaction mixture was stirred uniformly and then reacted at 60°C for about 8 hours until TLC showed the completion of the reaction. The reaction solution was cooled to room temperature and concentrated to remove most of the tetrahydrofuran, and then 50mL of water was added to precipitate a large amount of yellow solid. The system was stirred continuously for about 0.5 hours, then suction filtered and washed. The filter cake was dried to obtain 3.39g of compound DB04-A in a yield of 88.5%.

[0547] Compound DB04-B:

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

[0549] Compound DB04-C:

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

[0551] Compound DB04-D:

[0552] [ka] 2.98g of compound DB04-C (1.0 equiv.) was weighed and added to a 250mL round bottom flask. 45mL of 1,2-dichloroethane was added. The system thus obtained was stirred uniformly, and 8.15g of glacial acetic acid (20.0 equiv.) was slowly added dropwise. After the addition, the reaction solution was warmed to 80°C and reacted for about 3 hours until TLC showed the completion of the reaction. After the reaction solution was cooled to room temperature, 100mL of ethyl acetate and 50mL of 3% potassium carbonate solution were added, and the resulting system was stirred for a while, after which liquid phase separation was performed. The aqueous phase was extracted with 50mL of ethyl acetate. The ethyl acetate phases were combined, washed twice with 50mL×2 of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2.86g 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 homogeneously, degassed twice with nitrogen, heated to 100 °C and reacted for about 2 h under nitrogen atmosphere until TLC showed the reaction was complete. The reaction was then cooled to room temperature, filtered through diatomaceous earth and washed with dichloromethane. After concentration, the filtrate was purified by column chromatography to obtain 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 eq.), 299 mg of compound DB04-E (1.05 eq.), 13.3 mg of Pd(dppf)Cl2 (0.03 eq.) and 495 mg of cesium carbonate (2.5 eq.) 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 was stirred homogeneously, degassed twice with nitrogen, heated to 90° C. under nitrogen atmosphere and reacted for about 2 hours until TLC showed the reaction was complete. The reaction 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 equiv.) was weighed and added to a 25 mL round-bottom flask. 5 mL of acetonitrile and 1 mL of water were added. The system thus obtained was stirred uniformly, and then 100 mg of TBD (2.5 equiv.) was added. The reaction mixture was then stirred and reacted at room temperature for about 48 hours until TLC showed the reaction was complete. The reaction solution was concentrated, 8 mL of water was added to the residue, and the pH of the reaction solution was adjusted to about 5.0 with citric acid. A large amount of off-white solid precipitated. The reaction solution was continuously stirred for about 0.5 hours, then suction filtered and washed with a small amount of water. The obtained filter cake was recrystallized with dichloromethane / methanol to obtain 76 mg of compound DB04 in a yield of 45.8%. 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 eq.), 290 mg of compound DB04-E (1.05 eq.), 13 mg of Pd(dppf)Cl2 (0.03 eq.) and 481 mg of cesium carbonate (2.5 eq.) 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 was stirred homogeneously, degassed twice with nitrogen, and heated to 90° C. under nitrogen atmosphere for approximately 2 hours until TLC showed the reaction was complete. The reaction 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 equiv.) was weighed and added to a 25 mL round-bottom flask. 6 mL of tetrahydrofuran and 2 mL of methanol were added. The system thus obtained was stirred at room temperature to dissolve, and then 0.55 mL of 2 mol / L NaOH solution (2.5 equiv.) was slowly added dropwise. The reaction mixture was then stirred at room temperature overnight until TLC showed the completion of the reaction. The reaction solution was concentrated. After concentration, 5 mL of water was added to the residue, and the pH of the reaction solution was adjusted to 4-5 with 0.5 mol / L HCl solution. The reaction solution 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 a small amount of ethyl acetate and dried to obtain 196 mg of compound DB05 in a yield of 76.3%. 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 to a cell density of 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 compounds was 0.2 mM, and the compounds were 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, and 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 in 2 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 min, and the chemiluminescence signal value was measured using an enzyme labeling device. The data was processed and analyzed using Microsoft Excel and Graphpad Prism6 to obtain 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 were able to activate GLP1R in hGLP-1R HEK293 cells.

[0570] The activities of compound 13, compound 14, compound 17, compound 18, compound 19, compound 21, compound 25, 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 were higher than those of comparative compound PF-06882961, comparative compound DB02, comparative compound DB03 and comparative compound DB06, and were much higher than those of comparative compound DB04 and comparative compound DB05. In particular, the activities of compound 21, compound 91, compound 94, compound 99, compound 101, compound 103 and compound 105 were all more than 10 times higher than that of comparative compound DB02, showing 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 glucose tolerance test (IPTGG). Vehicle or corresponding compound was orally administered once, and glucose solution (2g / kg) was intraperitoneally injected 60 minutes after administration. Blood glucose levels before glucose administration (corresponding to blood glucose level at 0 minutes) and 15 minutes, 30 minutes, 60 minutes, and 120 minutes after glucose administration were measured. The vehicle was 5% DMSO + 40% PEG400 + 55% saline, and the compound was administered at a dose of 1mg / kg (n=3).

[0572] [Experimental Results] As shown in FIG. 1 and FIG. 2, when Compound 17, Compound 19, Compound 38, and Compound 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 curve (FIG. 1) and the blood glucose AUC (0-120 min) (FIG. 2) showed that the hypoglycemic effect of the compounds of the present invention was significantly superior to that of PF-06882961, and at the same time, was significantly superior to that of Comparative Compound DB05, and the compounds of the present invention exhibited a hypoglycemic effect more rapidly than that of 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 curve (Figure 3) and the blood glucose AUC (0-120 minutes) (Figure 4) showed that the blood glucose lowering effect of the compounds of the present invention was significantly superior to that of PF-06882961 and was absolutely superior to that of Comparative Compound DB03, and the compounds of the present invention exhibited a blood glucose lowering effect more quickly than the 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 currents 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 the hERG potassium channel cells from Creacell Company. (2) The HEK-293 cell line stably expressing the hERG potassium channel was cultured in DMEM culture medium containing 10% fetal bovine serum and 0.8 mg / mL G418 at 37°C and 5% carbon dioxide. (3) Cell passage: Remove the old culture medium, wash the cells once with PBS, and then incubate them with TrypLE. TM One mL of Express solution was added and incubated at 37°C for approximately 0.5 min. Once the cells had detached from the bottom of the dish, approximately 5 mL of complete culture medium pre-warmed to 37°C was added. The cell suspension was gently blown through a straw to separate any clumped cells. The cell suspension was transferred to a sterile centrifuge tube and centrifuged at 1000 rpm for 5 min to recover the cells. For culture expansion or maintenance, cells were seeded into 6 cm cell culture dishes, with 2.5 × 10 cells seeded into each cell culture dish. 5 The cells (final volume: 5 mL) were cultured at a density of not more than 80% in order to maintain the electrophysiological activity of the cells. (4) For patch clamp detection, trypLE TM Express and separate cells at 4 x 10 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 carried out.

[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 weaker inhibitory effects on hERG potassium channel current, lower risk of cardiotoxicity, and are safer.

[0581] Pharmacokinetic studies showed that the half-life of compound 21, compound 93, compound 94, compound 99 and compound 100 of the present invention in SD rats was 6 hours to 10 hours, and compared with comparative example PF-06882961 and comparative example 3-compound DB03, the half-life could be significantly and effectively extended (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, and the administration frequency and single dose were reduced, so the purpose of reducing the dosage and administration frequency was achieved, and therapeutic benefits were obtained. [Brief description of the drawings]

[0582] [Figure 1] FIG. 1 shows blood glucose concentration curves of compounds 17, 19, 38 and 61 of the present invention and comparative examples. [Diagram 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. [Diagram 3]FIG. 3 shows 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. [Diagram 5] FIG. 5 shows 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 pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate thereof: 【Chemistry 1】 Where: R ２ is selected from: 【Chemistry 2】 R ３ is independently selected from a hydrogen atom and a halogen; R ４ is independently selected from a hydrogen atom, halogen, cyano, and C1-C6 alkyl, said C1-C6 alkyl being 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; or two adjacent R ６ are linked to form a ring; W is N and CR １０ Selected from: X ２ 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; Preferably, the compound, or the pharma- ceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, has a structure represented by general formula (II-1): 【Chemistry 3】 More preferably, R ３ is selected from a hydrogen atom and F; R ４ is a hydrogen atom, F, Cl, cyano, CF ３ and CHF ２ is selected from; ２ and Q is selected from CH; R １０ is selected from a hydrogen atom and F; more preferably, the compound, or the pharma- ceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, has a structure represented by general formula (II-1-1): 【Chemistry 4】 Here, R ４ is selected from Cl and cyano; R ６ is selected from a hydrogen atom and F; R １０ is selected from a hydrogen atom; Alternatively, preferably, the compound, or the pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate thereof, has a structure represented by general formula (II-2): 【Chemistry 5】 More preferably, R ５ is selected from F; R ３ is selected from a hydrogen atom and F; X ２ is selected from CH; R １０ is selected from a hydrogen atom and F; more preferably, the compound, or the pharma- ceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, has a structure represented by general formula (II-2-1): 【Chemistry 6】 Here, R ４ is selected from a hydrogen atom, Cl and cyano; R １０ is selected from a hydrogen atom; A compound of general formula (II) or a pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate thereof:

2. A compound selected from any of the following compounds, or a pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate thereof: 【Chemistry 7-1】 【Chemistry 7-2】 【Chemistry 7-3】 【Chemistry 7-4】 【Chemistry 7-5】 【Chemistry 7-6】 【Chemistry 7-7】

3. A compound of general formula (II-3) or a pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate thereof: 【Chemistry 8】 Where: R １ is selected from a hydrogen atom and a halogen; R ２ are independently selected from: 【Chemistry 9】 R ３ is independently selected from a hydrogen atom and a halogen; R ４ is independently selected from a hydrogen atom, a halogen, and a cyano; R ５ is independently selected from halogen; R ６ are 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 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; Preferably, the compound, or the pharma- ceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, has a structure represented by general formula (II-3-1): 【Chemistry 10】 Here, R １ａ and R １ｂ is independently selected from a hydrogen atom and F; R ２ is: 【Chemistry 11】 R ６ 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; More preferably, the compound, or the pharma- ceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, has a structure represented by general formula (II-3-2): 【Chemistry 12】 Here, R ３ａ and R ３ｂ is 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 is independently selected from a hydrogen atom and F; R ６ is independently selected from a hydrogen atom, F and Cl; More preferably, R ３ａ and R ３ｂ At the same time, it is not F, but R ５ａ and R ５ｃ are independently selected from a hydrogen atom and F; R ５ｂ is a hydrogen atom, A compound of the general formula (II-3), or a pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate thereof:

4. A compound selected from any of the following compounds, or a pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate thereof: 【Chemistry 13】

5. A compound of general formula (II') or a pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate thereof: 【Chemistry 14】 Where: R １ is selected from a hydrogen atom and a halogen; R ２ is selected from: 【Chemistry 15】 R ３ is independently selected from a hydrogen atom and a halogen; R ４ is independently selected from a hydrogen atom, halogen, cyano, and C1-C6 alkyl, said C1-C6 alkyl being further substituted with one or more halogens; R ５ is 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 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; Preferably, the compound, or the pharma- ceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, has a structure represented by general formula (II'-1): 【Chemistry 16】 Where: R ３ is selected from a hydrogen atom and F; R ４ is a hydrogen atom, F, Cl, cyano, CF ３ and CHF ２ Selected from: X ２ and Q is selected from CH; R １０ is selected from a hydrogen atom and F; or Preferably, the compound, or the pharma- ceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, has a structure represented by general formula (II'-3): 【Chemistry 17】 Where: R ４ is independently selected from a hydrogen atom, a halogen, and a cyano; R ６ are independently selected from a hydrogen atom, halogen, and C1-C6 alkyl; W is selected from N and CH; A compound of general formula (II') or a pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate thereof:

6. The structure represented by general formula (II'-1) is further represented by general formula (II'-1-1): 【Chemistry 18】 Where: R ４ is selected from Cl and cyano; R ６ is selected from a hydrogen atom and F; R １０ is selected from a hydrogen atom; The structure represented by general formula (II'-3) is further represented by general formula (II'-3-1): 【Chemistry 19】 Where: R １ａ and R １ｂ is independently selected from a hydrogen atom and F; R ２ is: 【Chemistry 20】 R ６ 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; Preferably, the structure represented by general formula (II'-3) is further represented by general formula (II'-3-2): 【Chemistry 21】 Where: R ３ａ and R ３ｂ is 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 is independently selected from a hydrogen atom and F; R ６ is independently selected from a hydrogen atom, F and Cl; More preferably, R ３ａ and R ３ｂ At the same time, it is not F, but R ５ａ and R ５ｃ are independently selected from a hydrogen atom and F; R ５ｂ is a hydrogen atom, 6. A compound of general formula (II') according to claim 5, or a pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate thereof.

7. 10. A pharmaceutical composition comprising a compound according to claim 1 or 2, or claim 3 or 4, or claim 5 or 6, or a pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate thereof, and a pharma- ceutically acceptable carrier.

8. Use of a compound according to claim 1 or 2, or claim 3 or 4, or claim 5 or 6, or a pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate thereof, or a pharmaceutical composition according to claim 7, in the preparation of a medicament for a GLP-1 receptor agonist.

9. A compound according to claim 1 or 2, or claim 3 or 4, or claim 5 or 6, or a pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate thereof, or a pharmaceutical composition according to claim 7, In the preparation of a medicament for the treatment and / or prevention of 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, in the preparation of a medicament for the treatment and / or prevention of 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, use.

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