Propionic acid derivatives and their medical applications

Abstract

The present invention relates to a compound according to general formula (I) or a stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, as well as intermediates and methods for preparing the same, and their application in the manufacture of a medicament for treating a disease associated with the activity or expression level of integrin α4β7. [C1] TIFF2025530250000257.tif30156

Description

[Technical Field]

[0001] The present invention relates to compounds of general formula (I) or their stereoisomers, racemates, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, intermediates and processes for their preparation, and their use in the manufacture of pharmaceuticals for treating diseases associated with the activity or expression level of integrin α4β7. [Background technology]

[0002] The integrin family is a dimer consisting of two subunits, α (120-185 kD) and β (90-110 kD). Mammals have a total of 18 α subunits and 8 β subunits. Different combinations of these subunits can form more than 20 different integrins. α4β7 is a member of the integrin / integrin family. Intestinal inflammatory diseases currently associated with α4β7 include Crohn's disease and ulcerative colitis. The primary ligand for α4β7 is mucosal addressin cell adhesion molecule-1 (MADCAM-1). MAdCAM-1 is a transmembrane glycoprotein selectively expressed in the high endothelial veins of mucosal lymphoid organs and the intestinal lamina propria veins. During inflammation, various cytokines can promote high expression of MAdCAM-1 on endothelial cells, which then mediates the migration of α4β7-expressing leukocytes to the inflammatory site. Targeting either integrin α4β7 or MAdCAM-1 can reduce the severity of intestinal inflammation. Currently, there are no small molecule compounds on the market that specifically target α4β7-mediated inflammation. Natalizumab, a humanized monoclonal antibody currently in clinical use, targets the α4 subunit and is primarily used to treat multiple sclerosis and Crohn's disease. However, it has been associated with the side effect of progressive multifocal leukoencephalopathy (PML). Therefore, there is a need to develop small molecule compounds that can inhibit integrin α4β7 protein to treat diseases associated with integrin α4β7 activity or expression. Summary of the Invention [Problem to be solved by the invention]

[0003] The present invention develops integrin α4β7 inhibitors that have a novel structure, good pharmacodynamics, better α4β1 / α4β7 selectivity, better liver microsomal stability, and are safer, and have no obvious hERG or CYP inhibitory activity.These compounds have good pharmacokinetic properties and good safety, and are used to treat diseases associated with integrin α4β7, such as intestinal inflammatory diseases.

[0004] The object of the present invention is to provide a compound capable of inhibiting integrin α4β7 or its stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, intermediates and preparation methods thereof, and application in the manufacture of pharmaceuticals for treating diseases associated with the activity or expression level of integrin α4β7. [Means for solving the problem]

[0005] The present invention provides a compound according to general formula (I) or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein: [ka] In some embodiments, R 1 is -CHR 1a R 1b or -NR 1a R 1b is selected from In some embodiments, R 1 teeth, [ka] a is selected from 0, 1, 2, 3; In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is selected from In some embodiments, R 1 teeth, [ka] is selected from In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is selected from In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is selected from In some embodiments, R b1 is selected from H, F, CH2F, CHF2, CF3, a methyl group, -CH2CH2N(CH3)2, In some embodiments, R b2 , R b are each independently R ba , [ka] or optionally substituted groups: ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, oxetanyl, oxacyclopentyl, oxacyclohexyl, morpholinyl, phenyl, pyridyl, -CH2NH(CH2CH3), -CH2N(CH2CH3), -CH2CH2NH(CH3), -CH2CH2N(CH3)2, -CH2CH2NH(CH2CH3), -CH2CH2N(CH2CH3), -CH2CH2N(CH2CH3)2, -CH2CH2N(CH3)(CH2CH3), -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-azetidinyl, -CH2 -azacyclopentyl group, -CH2-azacyclohexyl group, -CH2-oxetanyl group, -CH2-oxacyclopentyl group, -CH2-oxacyclohexyl group, -CH2-morpholinyl group, -CH2CH2-cyclopropyl group, -CH2CH2-cyclobutyl group, -CH2CH2-cyclopentyl group, -CH2CH2-cyclohexyl group, -CH2CH2-azetidinyl group, -CH2CH2-azacyclopentyl group, -CH2CH2-azacyclohexyl group, -CH2CH2-oxetanyl group, -CH2CH2-oxacyclopentyl group, -CH2CH2-oxacyclohexyl group, -CH2CH2-morpholinyl group, -CH2-phenyl group, -CH2-pyridyl group, -CH2CH2-phenyl group, -CH2CH2-pyridyl group, [ka] and when substituted, is selected from deuterium, F, Cl, Br, OH, =O, cyano, CONH2, CONHCH3, CON(CH3)2, NH2, NHCH3, N(CH3)2, N(CH3)(cyclopropyl), NHCH2CH3, N(CH2CH3)2, CH2F, CHF2, CF3, methyl, ethyl, isopropyl, ethynyl, methoxy, ethoxy, methoxymethyl, ethoxymethyl, methoxyethyl, or R k is substituted with 1 to 4 substituents selected from In some embodiments, R b2 , R b are each independently R ba , [ka] is selected from In some embodiments, R ba teeth, [ka] is selected from In some embodiments, R b1 is H, C 1-4 Alkyl group, C 3-6 cycloalkyl groups, wherein the alkyl or cycloalkyl groups are optionally selected from deuterium, halogen, OH, CN, NHC 1-4 Alkyl group, N(C 1-4 Alkyl)2, C 1-4 Alkyl group, C 1-4 substituted with 0 to 4 substituents selected from alkoxy groups; In some embodiments, R b2 H, R ba , substituted or unsubstituted groups: 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy group, -CH2CH2-NHC 1-4 Alkyl group, -CH2CH2-N(C 1-4 alkyl)2, -CH2CH2-C 3-6a cycloalkyl group, -CH2CH2-, and a 3- to 7-membered heterocycloalkyl group, wherein the CH2, alkyl group, cycloalkyl group, or heterocycloalkyl group may optionally be selected from the group consisting of deuterium, halogen, OH, ═O, cyano, COOH, NH2, NHC 1-4 Alkyl group, N(C 1-4 alkyl)2, N(C 1-4 Alkyl)(C 3-6 cycloalkyl), NH(C 3-6 cycloalkyl), C 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy groups, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy group, C 1-4 Alkoxyalkyl group or R k and the heteroaryl or heterocycloalkyl group contains 1 to 4 heteroatoms selected from O, S, and N; In some embodiments, R 1a is C 1-6 alkyl groups, wherein the alkyl groups are optionally selected from deuterium, halogen, OH, ═O, cyano, COOH, NH, NHC 1-6 Alkyl group, N(C 1-6 Alkyl)2, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 substituted with 0 to 4 substituents selected from cycloalkyl groups; In some embodiments, R 1a is selected from the group consisting of methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl, -CH2-cyclopropyl and -CH2-cyclobutyl; In some embodiments, R 1a teeth, [ka] is selected from In some embodiments, R 1b is C4-10 a carbocycle, a 5- to 10-membered heterocycle, wherein the carbocycle or heterocycle optionally contains 0 to 4 R b and the heterocycle contains 1 to 4 heteroatoms selected from O, S, and N; In some embodiments, R b are independently deuterium, halogen, OH, =O, cyano group, COOH, NH2, -C 0-4 Alkyl-NHC 1-6 Alkyl group, -C 0-4 Alkyl-N(C 1-6 Alkyl)2, C 1-6 Alkyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, -C 0-4 Alkyl-C 3-10 Carbocycle, -C 0-4 alkyl-3 to 10-membered heterocycle or R ba wherein the alkyl, alkynyl, alkoxy, carbocyclic or heterocyclic ring is optionally selected from the group consisting of deuterium, halogen, OH, ═O, cyano, COOH, CONH, CONHC 1-6 Alkyl group, CON(C 1-6 alkyl)2, NH2, NHC 1-6 Alkyl group, N(C 1-6 alkyl)2, N(C 1-6 Alkyl)(C 3-6 cycloalkyl), NH(C 3-6 cycloalkyl), C 1-6 Alkyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy groups, halogen-substituted C 1-6 Alkyl, halogen-substituted C 1-6 Alkoxy group, C 1-6 Alkoxyalkyl group or R k and the heterocycle contains 1 to 4 heteroatoms selected from O, S, and N; In some embodiments, R b are independently deuterium, halogen, OH, =O, cyano group, COOH, NH2, -C 0-4 Alkyl-NHC 1-4Alkyl group, -C 0-4 Alkyl-N(C 1-4 Alkyl)2, C 1-4 Alkyl group, C 1-4 Alkoxy group, -C 0-4 Alkyl-C 3-6 Carbocycle, -C 0-4 alkyl-3 to 7-membered heterocycle or R ba wherein the alkyl group, alkoxy group, carbocycle or heterocycle is optionally selected from the group consisting of deuterium, halogen, OH, ═O, cyano, COOH, CONH, CONHC 1-4 Alkyl group, CON(C 1-4 alkyl)2, NH2, NHC 1-4 Alkyl group, N(C 1-4 alkyl)2, N(C 1-4 Alkyl)(C 3-6 cycloalkyl), NH(C 3-6 cycloalkyl), C 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy groups, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy group, C 1-4 Alkoxyalkyl group or R k and the heterocycle contains 1 to 4 heteroatoms selected from O, S, and N; In some embodiments, R b is R ba is selected from In some embodiments, R b are independently deuterium, halogen, OH, =O, cyano group, C 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy group, phenyl group, 5- to 6-membered heteroaryl group, -CH2NHC 1-4 Alkyl group, -CHN(C 1-4 alkyl)2, -CH2CH2-NHC 1-4 Alkyl group, -CH2CH2-N(C 1-4 Alkyl)2, C 3-6Cycloalkyl groups, 3- to 7-membered heterocycloalkyl groups, -CH2-C 3-6 Cycloalkyl groups, -CH2-3 to 7-membered heterocycloalkyl groups, -CH2CH2-C 3-6 Cycloalkyl group, -CH2CH2- 3 to 7-membered heterocycloalkyl group or R ba wherein said CH2, alkyl group, alkynyl group, cycloalkyl group or heterocycloalkyl group is optionally selected from deuterium, halogen, OH, =O, cyano group, COOH, CONH2, CONHC 1-4 Alkyl group, CON(C 1-4 alkyl)2, NH2, NHC 1-4 Alkyl group, N(C 1-4 alkyl)2, N(C 1-4 Alkyl)(C 3-6 cycloalkyl), NH(C 3-6 cycloalkyl), C 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy groups, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy group, C 1-4 Alkoxyalkyl group or R k and the heteroaryl or heterocycloalkyl group contains 1 to 4 heteroatoms selected from O, S, and N; In some embodiments, R b are independently deuterium, F, Cl, Br, I, OH, =O, cyano group, R ba or R bare each independently substituted or unsubstituted one of the following groups: methyl, ethyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, oxetanyl, oxacyclopentyl, oxacyclohexyl, morpholinyl, phenyl, pyridine, -CH2NH(CH2CH3), -CH2N(CH2CH3)2, -CH2CH2NH(CH3), -CH2CH2N(CH3)2, -CH2CH2NH(CH2CH3), -CH2CH2N(CH2CH3)2, -CH2CH2N(CH3)(CH2CH3), -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2 -azetidinyl group, -CH2-azacyclopentyl group, -CH2-azacyclohexyl group, -CH2-oxetanyl group, -CH2-oxacyclopentyl group, -CH2-oxacyclohexyl group, -CH2-morpholinyl group, -CH2CH2-cyclopropyl group, -CH2CH2-cyclobutyl group, -CH2CH2-cyclopentyl group, -CH2CH2-cyclohexyl group, -CH2CH2-azetidinyl group, -CH2CH2-azacyclopentyl group, -CH2CH2-azacyclohexyl group, -CH2CH2-oxetanyl group, -CH2CH2-oxacyclopentyl group, -CH2CH2-oxacyclohexyl group, -CH2CH2-morpholinyl group, and when substituted, deuterium, halogen, OH, =O, cyano group, CONH2, CONHC 1-4 Alkyl group, CON(C 1-4 alkyl)2, NH2, NHC 1-4 Alkyl group, N(C 1-4 alkyl)2, N(C 1-4 Alkyl)(C 3-6 cycloalkyl), NH(C 3-6 cycloalkyl), C 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy groups, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy group, C 1-4Alkoxyalkyl group or R k and is substituted with 0 to 4 substituents selected from In some embodiments, R b are independently deuterium, F, Cl, Br, OH, cyano group, and R ba or R b are each independently substituted or unsubstituted one of the following groups: methyl group, ethyl group, ethynyl group, methoxy group, ethoxy group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, azetidinyl group, azacyclopentyl group, azacyclohexyl group, oxetanyl group, oxacyclopentyl group, oxacyclohexyl group, morpholinyl group, phenyl group, pyridine, -CH2NH(CH2CH3), -CH2N(CH2CH3)2, -CH2CH2NH(CH 3), -CH2CH2N(CH3)2, -CH2CH2NH(CH2CH3), -CH2CH2N(CH2CH3)2, -CH2CH2N(CH3)(CH2CH3), -CH2-cyclopropyl group, -CH2-cyclobutyl group, -CH2-cyclopentyl group, -CH2-cyclohexyl group, -CH2-azetidinyl group, -CH2-azacyclopentyl group, -CH2-azacyclohexyl group, -CH2-oxetanyl group, -CH2-oxacyclopentyl group, -CH2 -oxacyclohexyl group, -CH2-morpholinyl group, -CH2CH2-cyclopropyl group, -CH2CH2-cyclobutyl group, -CH2CH2-cyclopentyl group, -CH2CH2-cyclohexyl group, -CH2CH2-azetidinyl group, -CH2CH2-azacyclopentyl group, -CH2CH2-azacyclohexyl group, -CH2CH2-oxetanyl group, -CH2CH2-oxacyclopentyl group, -CH2CH2-oxacyclohexyl group, -CH2CH 2-morpholinyl group, and when substituted, deuterium, F, Cl, Br, OH, =O, cyano group, CONH2, CONHCH3, CON(CH3)2, NH2, NHCH3, N(CH3)2, N(CH3) (cyclopropyl group), NHCH2CH3, N(CH2CH3)2, CH2F, CHF2, CF3, methyl group, ethyl group, isopropyl group, ethynyl group, methoxy group, ethoxy group, methoxymethyl group, ethoxymethyl group, methoxyethyl group or Rk and is substituted with 0 to 4 substituents selected from In some embodiments, R b is R b2 is selected from In some embodiments, R ba -C 0-4 Alkyl-7 to 12-membered heterocycle, -C 0-4 alkyl-4-6 membered heterocycle linked via a carbon atom; [ka] wherein R is selected from ba is optionally H, halogen, OH, =O, cyano group, COOH, CONH2, CONHC 1-6 Alkyl group, CON(C 1-6 alkyl)2, NH2, NHC 1-6 Alkyl group, N(C 1-6 Alkyl)2, C 1-6 Alkyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy groups, halogen-substituted C 1-6 Alkyl, halogen-substituted C 1-6 Alkoxy group, C 1-6 Alkoxyalkyl group or R k and the heterocycle contains 1 to 4 heteroatoms selected from O, S, and N; In some embodiments, R ba -C 0-2 Alkyl-7-8 membered monocyclic heterocycloalkyl group, -C 0-2 Alkyl-7 to 11-membered spirocyclic heterocycloalkyl group, -C 0-2 Alkyl-7 to 11-membered bridged heterocycloalkyl group, -C 0-2 a 4- to 6-membered monocyclic heterocycloalkyl group linked via an alkyl carbon atom; [ka] wherein R is selected from ba is optionally H, halogen, OH, =O, cyano group, COOH, CONH2, CONHC1-4 Alkyl group, CON(C 1-4 alkyl)2, NH2, NHC 1-4 Alkyl group, N(C 1-4 Alkyl)2, C 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy groups, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy group, C 1-4 Alkoxyalkyl group or R k and the heterocycloalkyl group contains 1 to 4 heteroatoms selected from O, S, and N; In some embodiments, R ba represents a 7- to 8-membered monocyclic heterocycloalkyl group, a 7- to 11-membered spirocyclic heterocycloalkyl group, a 7- to 11-membered bridged cyclic heterocycloalkyl group, a 4- to 6-membered monocyclic heterocycloalkyl group linked via a carbon atom, -CH2-7- to 8-membered monocyclic heterocycloalkyl group, -CH2-7- to 11-membered spirocyclic heterocycloalkyl group, -CH2-7- to 11-membered bridged cyclic heterocycloalkyl group, a 4- to 6-membered monocyclic heterocycloalkyl group linked via a -CH2- carbon atom, -CH2CH2-7- to 8-membered monocyclic heterocycloalkyl group, -CH2CH2-7- to 11-membered spirocyclic heterocycloalkyl group, -CH2CH2-7- to 11-membered bridged cyclic heterocycloalkyl group, a 4- to 6-membered monocyclic heterocycloalkyl group linked via a -CH2CH2- carbon atom, [ka] wherein R is selected from ba is optionally H, halogen, OH, =O, cyano group, COOH, CONH2, CONHC 1-4 Alkyl group, CON(C 1-4 alkyl)2, NH2, NHC 1-4 Alkyl group, N(C 1-4 Alkyl)2, C 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy groups, halogen-substituted C 1-4Alkyl, halogen-substituted C 1-4 Alkoxy group, C 1-4 Alkoxyalkyl group or R k and the heterocycloalkyl group contains 1 to 4 heteroatoms selected from O, S, and N; In some embodiments, R ba is an optionally substituted group: [ka] and when substituted, optionally deuterium, halogen, OH, ═O, cyano group, CONH2, CONHC 1-4 Alkyl group, CON(C 1-4 alkyl)2, NH2, NHC 1-4 Alkyl group, N(C 1-4 alkyl)2, N(C 1-4 Alkyl)(C 3-6 cycloalkyl), NH(C 3-6 cycloalkyl), C 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy groups, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy group, C 1-4 Alkoxyalkyl group or R k is substituted with 1 to 4 substituents selected from In some embodiments, R ba is an optionally substituted group: [ka] and when substituted, optionally is selected from deuterium, F, Cl, Br, OH, ═O, cyano, CONH, CONHCH, CON(CH), NH, NHCH, N(CH), N(CH) (cyclopropyl), NHCH, N(CHCH), CHF, CHF, CF, methyl, ethyl, isopropyl, ethynyl, methoxy, ethoxy, methoxymethyl, ethoxymethyl, methoxyethyl, or R k is substituted with 1 to 4 substituents selected from In some embodiments, R k -C 1-4 Alkyl-NH2, -C 1-4 Alkyl-NHC 1-6 Alkyl group, -C 1-4 Alkyl-N(C 1-6 alkyl)2, -C 0-4 Alkyl-C 3-10 Carbocyclic or -C 0-4 alkyl-3 to 10 membered heterocycle, wherein the alkyl group, carbocycle or heterocycle is optionally selected from the group consisting of deuterium, halogen, OH, ═O, cyano, COOH, NH, NHC 1-6 Alkyl group, N(C 1-6 Alkyl)2, C 1-6 Alkyl group, C 1-6 Alkoxy groups, halogen-substituted C 1-6 Alkyl, halogen-substituted C 1-6 Alkoxy group, C 1-6 substituted with 1 to 4 substituents selected from alkoxyalkyl groups, and the heterocycle contains 1 to 4 heteroatoms selected from O, S, and N; In some embodiments, R k -C 1-2 Alkyl-NH2, -C 1-2 Alkyl-NHC 1-4 Alkyl group, -C 1-2 Alkyl-N(C 1-4 alkyl)2, -C 0-2 Alkyl-C 3-6 Carbocyclic or -C 0-2alkyl-3 to 6 membered heterocycle, wherein the alkyl group, carbocycle or heterocycle is optionally selected from deuterium, halogen, OH, ═O, cyano, COOH, NH, NHC 1-4 Alkyl group, N(C 1-4 Alkyl)2, C 1-4 Alkyl group, C 1-4 Alkoxy groups, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy group, C 1-4 substituted with 1 to 4 substituents selected from alkoxyalkyl groups, and the heterocycle contains 1 to 4 heteroatoms selected from O, S, and N; In some embodiments, R k -C 1-4 Alkyl-NH2, -C 1-4 Alkyl-NHC 1-4 Alkyl group, -C 1-4 Alkyl-N(C 1-4 alkyl)2, -C 0-4 Alkyl-C 3-6 Carbocyclic or -C 0-4 alkyl-3 to 6 membered heterocycle, wherein the alkyl group, carbocycle or heterocycle is optionally selected from deuterium, halogen, OH, ═O, cyano, COOH, NH, NHC 1-4 Alkyl group, N(C 1-4 Alkyl)2, C 1-4 Alkyl group, C 1-4 Alkoxy groups, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy group, C 1-4 substituted with 1 to 4 substituents selected from alkoxyalkyl groups, and the heterocycle contains 1 to 4 heteroatoms selected from O, S, and N; In some embodiments, R kis selected from -CH2N(CH3)2, -CH2-cyclopropyl, -CH2-cyclobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, and oxetanyl, and the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, and oxetanyl groups may optionally be deuterium, halogen, OH, ═O, cyano, NH2, NHC 1-4 Alkyl group, N(C 1-4 alkyl)2, N(C 1-4 Alkyl)(C 3-6 cycloalkyl), NH(C 3-6 cycloalkyl), C 1-4 Alkyl group, C 1-4 Alkoxy groups, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy group, C 1-4 substituted with 1 to 4 substituents selected from alkoxyalkyl groups; In some embodiments, R k is selected from -CHN(CH), -CH-cyclopropyl, -CH-cyclobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, and oxetanyl, and the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, and oxetanyl groups are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, =O, cyano, NH, NHCH, N(CH), N(CH)(cyclopropyl), NHCHCH, N(CHCH), CHF, CHF, CF, methyl, ethyl, methoxy, ethoxy, methoxymethyl, ethoxymethyl, and methoxyethyl; In some embodiments, R 2 is C 1-6 Alkyl group, C 6-10 Aromatic ring, 5-10 membered heteroaromatic ring, C 3-10a carbocyclic ring, a 5- to 10-membered heterocyclic ring, 2 optionally 0 to 4 R 2a and the heteroaromatic ring or heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N; In some embodiments, R 2 is C 1-4 Alkyl group, benzene ring, naphthalene ring, 5-6 membered heteroaromatic ring, 9-10 membered heteroaromatic ring, C 3-10 Non-aromatic carbocycles, 5- to 10-membered non-aromatic heterocycles, benzo-C 4-6 a carbocyclic group or a 4- to 6-membered benzoheterocyclic group, 2 optionally 0 to 4 R 2a and the heteroaromatic ring or heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N; In some embodiments, R 2 is a benzene ring, a naphthalene ring, a 5- to 6-membered heteroaromatic ring, a 9- to 10-membered heteroaromatic ring, C 3-6 Cycloalkyl groups, 3- to 7-membered heterocycloalkyl groups, benzo C 4-6 a carbocyclic group or a 4- to 6-membered benzoheterocyclic group, 2 optionally 0 to 4 R 2a and the heteroaromatic ring, heterocycloalkyl group contains 1 to 4 heteroatoms selected from O, S, and N, and in some embodiments, R 2 is a benzene ring, a pyridyl group, a pyridonyl group, a pyrazinyl group, a pyrimidinyl group, a thienyl group, a thiazolyl group, a furyl group, an oxazolyl group, a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an azetidinyl group, an azacyclopentyl group, an azacyclohexyl group, an oxetanyl group, an oxacyclopentyl group, an oxacyclohexyl group, a morpholinyl group, [ka] wherein R is selected from 2 optionally 0 to 4 R 2a and in some embodiments, R 2 teeth, [ka] and p1 is selected from 0, 1, 2, 3 or 4; In some embodiments, R 2 teeth, [ka] is selected from [ka] is selected from In some embodiments, R 2 represents a phenyl group, a pyridyl group, a pyridonyl group, an azacyclopentyl group, a morpholinyl group, [ka] wherein R is selected from 2 is optionally substituted with 0 to 4 substituents selected from deuterium, F, Cl, Br, OH, CF, cyano, methyl, ethyl, methoxy, ethoxy, cyclopropyl, or cyclobutyl; In some embodiments, R 2 teeth, [ka] wherein R is selected from 2 is optionally substituted with 1 to 4 substituents selected from deuterium, CD3, -OCD3, F, Cl, Br, OH, CF3, cyano, methyl, ethyl, methoxy, ethoxy, cyclopropyl, or cyclobutyl; In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] is selected from In some embodiments, R 2a are independently deuterium, halogen, OH, cyano group, =O, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 3-6 The alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, and heterocyclic group may optionally contain deuterium, halogen, OH, ═O, cyano group, COOH, NH, NHC, or the like. 1-6 Alkyl group, N(C 1-6 Alkyl)2, C 1-6 Alkyl group, C 1-6 alkoxy groups, and the heterocyclic group contains 1 to 3 heteroatoms selected from N, O, or S; In some embodiments, R 2a are independently deuterium, halogen, OH, cyano group, =O, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy group, C 3-6 The alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, and heterocyclic group may optionally contain deuterium, halogen, OH, ═O, cyano group, COOH, NH, NHC, or the like. 1-4 Alkyl group, N(C 1-4 Alkyl)2, C 1-4 Alkyl group, C 1-4alkoxy groups, and the heterocyclic group contains 1 to 3 heteroatoms selected from N, O, or S; In some embodiments, R 2a Deuterium, halogens, OH, CN, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy group, C 3-6 The alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, and heterocycloalkyl group are optionally selected from the group consisting of deuterium, halogen, OH, CN, C 1-4 Alkyl group, C 1-4 alkoxy groups, wherein the heterocycloalkyl group contains 1 to 4 heteroatoms selected from O, S, and N; In some embodiments, R 2a are independently deuterium, halogen, OH, cyano group, =O, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy group, C 3-6 The alkyl, alkenyl, alkynyl, alkoxy, and cycloalkyl groups are optionally selected from the group consisting of deuterium, halogen, OH, ═O, cyano, C 1-4 Alkyl group, C 1-4 substituted with 0 to 4 substituents selected from alkoxy groups; In some embodiments, R 2a are each independently selected from deuterium, F, Cl, Br, I, OH, ═O, cyano, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, or cyclobutyl, and the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, or cyclobutyl groups are optionally selected from deuterium, halogen, OH, ═O, cyano, C 1-4 Alkyl group, C 1-4substituted with 0 to 4 substituents selected from alkoxy groups; In some embodiments, R 2a is selected from deuterium, F, Cl, Br, I, OH, cyano, methyl, ethyl, methoxy, and ethoxy groups; In some embodiments, R 2a and R 2a can be directly linked to C 4-7 Forming a carbocyclic ring or a 4- to 7-membered heterocyclic ring, the carbocyclic ring or heterocyclic ring optionally containing deuterium, halogen, OH, cyano group, ═O, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 3-6 substituted with 1 to 4 substituents selected from a cycloalkyl group and a 3- to 7-membered heterocycloalkyl group, and the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group or heterocycloalkyl group is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, OH and a cyano group; In some embodiments, R 2a and R 2a can be directly linked to C 4-7 Forming a carbocyclic ring or a 4- to 7-membered heterocyclic ring, the carbocyclic ring or heterocyclic ring optionally containing deuterium, halogen, OH, cyano group, ═O, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy group, C 3-6 substituted with 1 to 4 substituents selected from a cycloalkyl group and a 3- to 7-membered heterocycloalkyl group, and the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group or heterocycloalkyl group is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, OH and a cyano group; In some embodiments, R 2a and R 2aare directly linked to form a 4-membered carbocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, or a 6-membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring optionally contains deuterium, halogen, OH, a cyano group, ═O, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy group, C 3-6 substituted with 1 to 4 substituents selected from a cycloalkyl group and a 3- to 7-membered heterocycloalkyl group, and the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, or heterocycloalkyl group is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, OH, and a cyano group (e.g., F, Cl, Br, I, OH, and a cyano group); In some embodiments, R 3 is H, C 1-6 alkyl groups, wherein the alkyl groups are optionally selected from deuterium, halogen, OH, ═O, cyano, COOH, NH, NHC 1-6 Alkyl group, N(C 1-6 Alkyl)2, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 substituted with 0 to 4 substituents selected from carbocycles; In some embodiments, R 3 is H, C 1-4 alkyl groups, wherein the alkyl groups are optionally selected from deuterium, halogen, OH, ═O, cyano, COOH, NH, NHC 1-4 Alkyl group, N(C 1-4 Alkyl)2, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 substituted with 0 to 4 substituents selected from carbocycles; In some embodiments, R 3 is H, C 1-4 alkyl groups, wherein the alkyl groups are optionally selected from deuterium, halogen, C 1-4 Alkyl group, C 1-4 substituted with 0 to 4 substituents selected from an alkoxy group and a benzene ring; In some embodiments, R 3 is selected from H, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl, and benzyl; In some embodiments, ring A is C 8-10 fused ring carbocycles (e.g., benzo C4-6 carbocycles), wherein ring A is optionally selected from 0 to 4 R a5 In some embodiments, ring A is substituted with [ka] wherein ring A is optionally selected from 0 to 4 R a5 In some embodiments, ring A is substituted with [ka] is selected from In some embodiments, ring A is [ka] wherein ring A is selected from C 2-6 Alkenyl group or C 2-6 alkynyl groups, optionally substituted with one substituent selected from R a5 In some embodiments, ring A is substituted with 1 to 3 selected from: [ka] wherein ring A is selected from one R ak and optionally R a5 In some embodiments, ring A is substituted with 1 to 3 selected from: [ka] and ring A is optionally selected from R a5 and is substituted with 1 to 3 selected from In some embodiments, R ak is C 2-4alkynyl groups (e.g., ethynyl, propynyl, propargyl); In some embodiments, ring A is [ka] wherein ring A is substituted with one substituent selected from vinyl, ethynyl, propynyl, and propargyl groups, and optionally R a5 and is substituted with 1 to 3 selected from In some embodiments, R a5 is a halogen, OH, cyano group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 3-6 The alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, and heterocyclic group may optionally contain deuterium, halogen, OH, ═O, cyano group, COOH, NH, NHC, or the like. 1-6 Alkyl group, N(C 1-6 Alkyl)2, C 1-6 Alkyl group, C 1-6 Alkoxy group or C 3-6 cycloalkyl groups, and the heterocyclic group contains 1 to 3 heteroatoms selected from N, O, or S; In some embodiments, R a5 is a halogen, OH, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy group, C 3-6 The alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, and heterocyclic group are optionally selected from the group consisting of deuterium, halogen, OH, ═O, cyano group, COOH, NH, NHC, and the like. 1-4 Alkyl group, N(C 1-4 Alkyl)2, C 1-4 Alkyl, halogen-substituted C 1-4C substituted with alkyl or cyano groups 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 cycloalkyl groups, and the heterocyclic group contains 1 to 3 heteroatoms selected from N, O, or S; In some embodiments, R a5 is a halogen, OH, cyano group, C 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy group, C 3-6 The alkyl group, alkynyl group, alkoxy group, cycloalkyl group, and heterocyclic group are optionally selected from the group consisting of deuterium, halogen, OH, ═O, cyano, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 substituted with 0 to 4 substituents selected from cycloalkyl groups; In some embodiments, R a5 are each independently selected from F, Cl, Br, I, OH, CN, ethynyl, propynyl, propargyl, methyl, ethyl, cyclopropyl, methoxy, and ethoxy, and the ethynyl, propynyl, propargyl, methyl, ethyl, cyclopropyl, methoxy, and ethoxy groups are optionally selected from deuterium, halogen, OH, ═O, cyano, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 substituted with 1 to 4 substituents selected from cycloalkyl groups In some embodiments, R a5 are each independently selected from F, Cl, Br, I, OH, CN, an ethynyl group, a methyl group, and an ethyl group; In some embodiments, R a5 are each independently H, halogen, OH, =O, cyano group, COOH, NH2, NHC 1-6 Alkyl group, N(C 1-6 Alkyl)2, C 1-6 Alkyl, halogen-substituted C 1-6 C substituted with alkyl or cyano groups1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 cycloalkyl groups, In some embodiments, R a5 are each independently H, halogen, OH, =O, cyano group, COOH, NH2, NHC 1-4 Alkyl group, N(C 1-4 Alkyl)2, C 1-4 Alkyl, halogen-substituted C 1-4 C substituted with alkyl or cyano groups 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 cycloalkyl groups, In some embodiments, R a5 are each independently selected from F, Cl, Br, OH, cyano, CF, methyl, ethyl, methoxy, ethoxy, cyclopropyl, and cyclobutyl; In some embodiments, ring A is [ka] The top left is R. 2 and p2 is selected from 0, 1 or 2; In some embodiments, R 1b teeth, [ka] is selected from In some embodiments, R 1b teeth, [ka] is selected from In some embodiments, R b1 are independently H, halogen, CN, or C 1-6 Alkyl group, C 3-6 cycloalkyl groups, wherein the alkyl or cycloalkyl groups are optionally selected from deuterium, halogen, OH, CN, NHC 1-6 Alkyl group, N(C1-6 Alkyl)2, C 1-4 Alkyl group, C 1-6 substituted with 0 to 4 substituents selected from alkoxy groups; In some embodiments, R b1 are independently H, halogen, CN, or C 1-4 Alkyl group, C 3-6 cycloalkyl groups, wherein the alkyl or cycloalkyl groups are optionally selected from deuterium, halogen, OH, CN, NHC 1-4 Alkyl group, N(C 1-4 Alkyl)2, C 1-4 Alkyl group, C 1-4 substituted with 0 to 4 substituents selected from alkoxy groups; In some embodiments, the compound is not one of the structures shown in Table E-2 and its stereoisomers, In some embodiments, the compound represented by general formula (I) is selected from the compounds represented by general formula (Ia), (Ib), (Ia-1), and (Ib-1): [ka] In some embodiments, the compound represented by general formula (I) is selected from the compounds represented by general formula (If), (Ig), (If-1), (Ig-1), (Ih), (Ii), (Ih-1), (Ii-1), [ka] In some embodiments, R in general formula (Ia), (Ib), (Ia-1), (Ib-1), (If), (Ig), (If-1), (Ig-1), (Ih), (Ii), (Ih-1), (Ii-1) 2a , R 1a , R ak , R a5 , R b2 , R b1 , R 3 The definition of is the same as in any one of the above embodiments, In some embodiments, the definition of ring A in general formula (Ia) or (Ib) is the same as any one of the above embodiments of ring A, In some embodiments, in general formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (If), (Ig), (If-1), (Ig-1), (Ih), (Ii), (Ih-1), (Ii-1), p1 is selected from 0, 1, 2, 3, or 4; In some embodiments, R in general formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (If), (Ig), (If-1), (Ig-1), (Ih), (Ii), (Ih-1), (Ii-1) 2a Deuterium, halogens, OH, CN, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 The alkyl group, alkoxy group, cycloalkyl group, and heterocycloalkyl group are optionally selected from the group consisting of deuterium, halogen, OH, CN, C 1-4 Alkyl group, C 1-4 alkoxy groups, wherein the heterocycloalkyl group contains 1 to 4 heteroatoms selected from O, S, and N; In some embodiments, R in general formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (If), (Ig), (If-1), (Ig-1), (Ih), (Ii), (Ih-1), (Ii-1) 1a teeth, [ka] is selected from In some embodiments, R in general formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (If), (Ig), (If-1), (Ig-1), (Ih), (Ii), (Ih-1), (Ii-1) b1 is H, C 1-4 Alkyl group, C 3-6cycloalkyl groups, wherein the alkyl or cycloalkyl groups are optionally selected from deuterium, halogen, OH, CN, NHC 1-4 Alkyl group, N(C 1-4 Alkyl)2, C 1-4 Alkyl group, C 1-4 substituted with 0 to 4 substituents selected from alkoxy groups; In some embodiments, R in general formula (I), (Ia), (Ib), (If), (Ig), (If-1), (Ig-1), (Ih), (Ii), (Ih-1), (Ii-1) b1 is selected from H, F, CH2F, CHF2, CF3, a methyl group, -CH2CH2N(CH3)2, In some embodiments, R in general formula (I), (Ia), (Ib), (If), (Ig), (If-1), (Ig-1), (Ih), (Ii), (Ih-1), (Ii-1) b2 H, R ba , substituted or unsubstituted groups: 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy group, -CH2CH2-NHC 1-4 Alkyl group, -CH2CH2-N(C 1-4 alkyl)2, -CH2CH2-C 3-6 a cycloalkyl group, -CH2CH2-, and a 3- to 7-membered heterocycloalkyl group, wherein the CH2, alkyl group, cycloalkyl group, or heterocycloalkyl group may optionally be selected from the group consisting of deuterium, halogen, OH, ═O, cyano, COOH, NH2, NHC 1-4 Alkyl group, N(C 1-4 alkyl)2, N(C 1-4 Alkyl)(C 3-6 cycloalkyl), NH(C 3-6 cycloalkyl), C 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy groups, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy group, C 1-4Alkoxyalkyl group or R k and the heteroaryl or heterocycloalkyl group contains 1 to 4 heteroatoms selected from O, S, and N; In some embodiments, R in general formula (I), (Ia), (Ib), (If), (Ig), (If-1), (Ig-1), (Ih), (Ii), (Ih-1), (Ii-1) b2 H, R ba , substituted or unsubstituted groups: methyl group, ethyl group, ethynyl group, methoxy group, ethoxy group, -CH2NH(CH2CH3), -CH2N(CH2CH3)2, -CH2CH2NH(CH3), -CH2CH2N(CH3)2, -CH2CH2NH(CH2CH3), -CH2CH2N(CH2CH3)2, -CH2CH2N(CH2CH3)2, -CH2CH2N(CH3)(CH2CH3), -CH2CH2-cyclopropyl group, -CH2CH2-cyclobutyl group, -CH2CH2-cyclopentyl group, -CH2CH2-cyclohexyl group, -CH2CH2-azetidinyl group, -CH2CH2-azacyclopentyl group, - It is one selected from CH2CH2-azacyclohexyl, -CH2CH2-oxetanyl, -CH2CH2-oxacyclopentyl, -CH2CH2-oxacyclohexyl, and -CH2CH2-morpholine, and when substituted, it can be selected from deuterium, F, Cl, Br, OH, =O, cyano, NH2, NHCH3, N(CH3)2, N(CH3)(cyclopropyl), NHCH2CH3, N(CH2CH3)2, CH2F, CHF2, CF3, methyl, ethyl, isopropyl, ethynyl, methoxy, ethoxy, methoxymethyl, ethoxymethyl, methoxyethyl, R k and is substituted with 1, 2 or 3 substituents selected from In some embodiments, R in general formula (Ia), (Ib), (If), (Ig), (If-1), (Ig-1), (Ih), (Ii), (Ih-1), (Ii-1) ba , R k The definition of is the same as in any one of the above embodiments, In some embodiments, R in general formula (I), (Ia), (Ib), (If), (Ig), (If-1), (Ig-1), (Ih), (Ii), (Ih-1), (Ii-1) 2a is selected from deuterium, -CD3, -OCD3, F, Cl, Br, I, OH, cyano, methyl, ethyl, methoxy, and ethoxy groups; In some embodiments, p2 in general formula (I), (If), (Ig), (If-1), (Ig-1), (Ih), (Ii), (Ih-1), (Ii-1) is selected from 0, 1, or 2; In some embodiments, R in general formula (I), (Ig), (Ig-1), (Ii), and (Ii-1) ak is C 2-4 alkynyl groups, In some embodiments, R in general formula (I), (If), (Ig), (If-1), (Ig-1), (Ih), (Ii), (Ih-1), (Ii-1) a5 is selected from F, Cl, Br, I, OH, cyano, methyl, ethyl, methoxy, ethoxy, and ethynyl; In some embodiments, n1 in general formula (I) is selected from 1, 2, or 3.

[0006] As a first embodiment of the present invention, there is provided a compound represented by the above-mentioned general formula (I) or a stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, R 1 is -CHR 1a R 1b or -NR 1a R 1b is selected from R 1a is C 1-6 alkyl groups, wherein the alkyl groups are optionally selected from deuterium, halogen, OH, ═O, cyano, COOH, NH, NHC 1-6 Alkyl group, N(C 1-6 Alkyl)2, C 1-6 Alkyl group, C1-6 Alkoxy group, C 3-6 substituted with 0 to 4 substituents selected from cycloalkyl groups; R 1b is C 4-10 a carbocycle, a 5- to 10-membered heterocycle, wherein the carbocycle or heterocycle optionally contains 0 to 4 R b and the heterocycle contains 1 to 4 heteroatoms selected from O, S, and N; R b are independently deuterium, halogen, OH, =O, cyano group, COOH, NH2, -C 0-4 Alkyl-NHC 1-6 Alkyl group, -C 0-4 Alkyl-N(C 1-6 Alkyl)2, C 1-6 Alkyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, -C 0-4 Alkyl-C 3-10 Carbocycle, -C 0-4 alkyl-3 to 10-membered heterocycle or R ba wherein the alkyl, alkynyl, alkoxy, carbocyclic or heterocyclic ring is optionally selected from the group consisting of deuterium, halogen, OH, ═O, cyano, COOH, CONH, CONHC 1-6 Alkyl group, CON(C 1-6 alkyl)2, NH2, NHC 1-6 Alkyl group, N(C 1-6 alkyl)2, N(C 1-6 Alkyl)(C 3-6 cycloalkyl), NH(C 3-6 cycloalkyl), C 1-6 Alkyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy groups, halogen-substituted C 1-6 Alkyl, halogen-substituted C 1-6 Alkoxy group, C 1-6 Alkoxyalkyl group or R k and the heterocycle contains 1 to 4 heteroatoms selected from O, S, and N; R ba -C 0-4Alkyl-7 to 12-membered heterocycle, -C 0-4 alkyl-4-6 membered heterocycle linked via a carbon atom; [ka] wherein R is selected from ba is optionally H, halogen, OH, =O, cyano group, COOH, CONH2, CONHC 1-6 Alkyl group, CON(C 1-6 alkyl)2, NH2, NHC 1-6 Alkyl group, N(C 1-6 Alkyl)2, C 1-6 Alkyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy groups, halogen-substituted C 1-6 Alkyl, halogen-substituted C 1-6 Alkoxy group, C 1-6 Alkoxyalkyl group or R k and the heterocycle contains 1 to 4 heteroatoms selected from O, S, and N; R k -C 1-4 Alkyl-NH2, -C 1-4 Alkyl-NHC 1-6 Alkyl group, -C 1-4 Alkyl-N(C 1-6 alkyl)2, -C 0-4 Alkyl-C 3-10 Carbocyclic or -C 0-4 alkyl-3 to 10 membered heterocycle, wherein the alkyl group, carbocycle or heterocycle is optionally selected from the group consisting of deuterium, halogen, OH, ═O, cyano, COOH, NH, NHC 1-6 Alkyl group, N(C 1-6 Alkyl)2, C 1-6 Alkyl group, C 1-6 Alkoxy groups, halogen-substituted C 1-6 Alkyl, halogen-substituted C 1-6 Alkoxy group, C 1-6 substituted with 1 to 4 substituents selected from alkoxyalkyl groups, and the heterocycle contains 1 to 4 heteroatoms selected from O, S, and N; R 2 is C 1-6 Alkyl group, C 6-10 Aromatic ring, 5-10 membered heteroaromatic ring, C 3-10 a carbocyclic ring, a 5- to 10-membered heterocyclic ring, 2 optionally 0 to 4 R 2a Substitution, the heteroaromatic ring, the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N; R 2a are independently deuterium, halogen, OH, cyano group, =O, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 3-6 The alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, and heterocyclic group may optionally contain deuterium, halogen, OH, ═O, cyano group, COOH, NH, NHC, or the like. 1-6 Alkyl group, N(C 1-6 Alkyl)2, C 1-6 Alkyl group, C 1-6 alkoxy groups, and the heterocyclic group contains 1 to 3 heteroatoms selected from N, O, or S; As an option, R 2a and R 2a can be directly linked to C 4-7 Forming a carbocyclic ring or a 4- to 7-membered heterocyclic ring, the carbocyclic ring or heterocyclic ring optionally containing deuterium, halogen, OH, cyano group, ═O, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 3-6 substituted with 1 to 4 substituents selected from a cycloalkyl group and a 3- to 7-membered heterocycloalkyl group, and the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group or heterocycloalkyl group is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, OH and a cyano group; R 3 is H, C 1-6alkyl groups, wherein the alkyl groups are optionally selected from deuterium, halogen, OH, ═O, cyano, COOH, NH, NHC 1-6 Alkyl group, N(C 1-6 Alkyl)2, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 substituted with 0 to 4 substituents selected from carbocycles; Ring A is C 8-10 fused carbocycles, wherein ring A is optionally selected from 0 to 4 R a5 is replaced by Or ring A is [ka] wherein ring A is selected from C 2-6 Alkenyl group or C 2-6 alkynyl group, and optionally 1 to 3 R a5 is replaced by R a5 is a halogen, OH, cyano group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 3-6 The alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, and heterocyclic group may optionally contain deuterium, halogen, OH, ═O, cyano group, COOH, NH, NHC, or the like. 1-6 Alkyl group, N(C 1-6 Alkyl)2, C 1-6 Alkyl group, C 1-6 Alkoxy group or C 3-6 The heterocyclic group is substituted with 0 to 4 substituents selected from a cycloalkyl group, and the heterocyclic group contains 1 to 3 heteroatoms selected from N, O, and S.

[0007] As a second embodiment of the present invention, there is provided a compound represented by the above-mentioned general formula (I) or a stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, R 1 teeth, [ka] is selected from b is selected from 0, 1, 2, and 3; R b are independently deuterium, halogen, OH, =O, cyano group, COOH, NH2, -C 0-4 Alkyl-NHC 1-4 Alkyl group, -C 0-4 Alkyl-N(C 1-4 Alkyl)2, C 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy group, -C 0-4 Alkyl-C 3-6 Carbocycle, -C 0-4 alkyl-3 to 7-membered heterocycle or R ba wherein the alkyl, alkynyl, alkoxy, carbocyclic or heterocyclic ring is optionally selected from the group consisting of deuterium, halogen, OH, ═O, cyano, COOH, CONH, CONHC 1-4 Alkyl group, CON(C 1-4 alkyl)2, NH2, NHC 1-4 Alkyl group, N(C 1-4 alkyl)2, N(C 1-4 Alkyl)(C 3-6 cycloalkyl), NH(C 3-6 cycloalkyl), C 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy groups, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy group, C 1-4 Alkoxyalkyl group or R k and the heterocycle contains 1 to 4 heteroatoms selected from O, S, and N; R ba -C 0-2 Alkyl-7-8 membered monocyclic heterocycloalkyl group, -C 0-2 Alkyl-7 to 11-membered spirocyclic heterocycloalkyl group, -C 0-2Alkyl-7 to 11-membered bridged heterocycloalkyl group, -C 0-2 a 4- to 6-membered monocyclic heterocycloalkyl group linked via an alkyl carbon atom; [ka] wherein R is selected from ba is optionally H, halogen, OH, =O, cyano group, COOH, CONH2, CONHC 1-4 Alkyl group, CON(C 1-4 alkyl)2, NH2, NHC 1-4 Alkyl group, N(C 1-4 Alkyl)2, C 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy groups, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy group, C 1-4 Alkoxyalkyl group or R k and the heterocycloalkyl group contains 1 to 4 heteroatoms selected from O, S, and N; R k -C 1-2 Alkyl-NH2, -C 1-2 Alkyl-NHC 1-4 Alkyl group, -C 1-2 Alkyl-N(C 1-4 alkyl)2, -C 0-2 Alkyl-C 3-6 Carbocyclic or -C 0-2 alkyl-3 to 6 membered heterocycle, wherein the alkyl group, carbocycle or heterocycle is optionally selected from deuterium, halogen, OH, ═O, cyano, COOH, NH, NHC 1-4 Alkyl group, N(C 1-4 Alkyl)2, C 1-4 Alkyl group, C 1-4 Alkoxy groups, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy group, C 1-4substituted with 1 to 4 substituents selected from alkoxyalkyl groups, and the heterocycle contains 1 to 4 heteroatoms selected from O, S, and N; R 2 is C 1-4 Alkyl group, benzene ring, naphthalene ring, 5-6 membered heteroaromatic ring, 9-10 membered heteroaromatic ring, C 3-10 Non-aromatic carbocycles, 5- to 10-membered non-aromatic heterocycles, benzo-C 4-6 a carbocyclic group or a 4- to 6-membered benzoheterocyclic group, 2 optionally 0 to 4 R 2a and the heteroaromatic ring or heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N; R 2a are independently deuterium, halogen, OH, cyano group, =O, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy group, C 3-6 The alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, and heterocyclic group may optionally contain deuterium, halogen, OH, ═O, cyano group, COOH, NH, NHC, or the like. 1-4 Alkyl group, N(C 1-4 Alkyl)2, C 1-4 Alkyl group, C 1-4 alkoxy groups, and the heterocyclic group contains 1 to 3 heteroatoms selected from N, O, or S; As an option, R 2a and R 2a can be directly linked to C 4-7 Forming a carbocyclic ring or a 4- to 7-membered heterocyclic ring, the carbocyclic ring or heterocyclic ring optionally containing deuterium, halogen, OH, cyano group, ═O, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy group, C 3-6substituted with 1 to 4 substituents selected from a cycloalkyl group and a 3- to 7-membered heterocycloalkyl group, and the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group or heterocycloalkyl group is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, OH and a cyano group; R 3 is H, C 1-4 alkyl groups, wherein the alkyl groups are optionally selected from deuterium, halogen, OH, ═O, cyano, COOH, NH, NHC 1-4 Alkyl group, N(C 1-4 Alkyl)2, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 substituted with 0 to 4 substituents selected from carbocycles; Ring A is benzo C 4-6 carbocyclic rings, wherein ring A is optionally selected from 0 to 4 R a5 is replaced by Or ring A is [ka] wherein ring A is selected from C 2-4 Alkenyl group or C 2-4 alkynyl groups, optionally substituted with one substituent selected from R a5 and is substituted with 1 to 3 selected from R a5 is a halogen, OH, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy group, C 3-6 The alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, and heterocyclic group are optionally selected from the group consisting of deuterium, halogen, OH, ═O, cyano group, COOH, NH, NHC, and the like. 1-4 Alkyl group, N(C 1-4 Alkyl)2, C 1-4 Alkyl, halogen-substituted C 1-4 C substituted with alkyl or cyano groups1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 cycloalkyl groups, and the heterocyclic group contains 1 to 3 heteroatoms selected from N, O, or S; The definitions of the other substituents are consistent with form 1 of the invention.

[0008] As a third embodiment of the present invention, there is provided a compound represented by the above-mentioned general formula (I) or a stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, R b are independently deuterium, halogen, OH, =O, cyano group, C 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy group, phenyl group, 5- to 6-membered heteroaryl group, -CH2NHC 1-4 Alkyl group, -CHN(C 1-4 alkyl)2, -CH2CH2-NHC 1-4 Alkyl group, -CH2CH2-N(C 1-4 alkyl)2, phenyl group, 5-6 membered heteroaryl group, C 3-6 Cycloalkyl group, 3- to 7-membered heterocycloalkyl group, -CH2-phenyl group, -CH2-5- to 6-membered heteroaryl group, -CH2-C 3-6 Cycloalkyl group, -CH2-3 to 7-membered heterocycloalkyl group, -CH2CH2-phenyl group, -CH2CH2-5 to 6-membered heteroaryl group, -CH2CH2-C 3-6 Cycloalkyl group, -CH2CH2- 3 to 7-membered heterocycloalkyl group, R ba wherein the CH2, alkyl group, alkynyl group, phenyl group, heteroaryl group, cycloalkyl group, and heterocycloalkyl group are optionally selected from the group consisting of deuterium, halogen, OH, =O, cyano group, COOH, CONH2, CONHC 1-4 Alkyl group, CON(C 1-4 alkyl)2, NH2, NHC 1-4 Alkyl group, N(C 1-4 alkyl)2, N(C 1-4 Alkyl)(C3-6 cycloalkyl), NH(C 3-6 cycloalkyl), C 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy groups, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy group, C 1-4 Alkoxyalkyl group or R k and the heteroaryl or heterocycloalkyl group contains 1 to 4 heteroatoms selected from O, S, and N; R ba represents a 7- to 8-membered monocyclic heterocycloalkyl group, a 7- to 11-membered spirocyclic heterocycloalkyl group, a 7- to 11-membered bridged cyclic heterocycloalkyl group, a 4- to 6-membered monocyclic heterocycloalkyl group linked via a carbon atom, -CH2-7- to 8-membered monocyclic heterocycloalkyl group, -CH2-7- to 11-membered spirocyclic heterocycloalkyl group, -CH2-7- to 11-membered bridged cyclic heterocycloalkyl group, a 4- to 6-membered monocyclic heterocycloalkyl group linked via a -CH2- carbon atom, -CH2CH2-7- to 8-membered monocyclic heterocycloalkyl group, -CH2CH2-7- to 11-membered spirocyclic heterocycloalkyl group, -CH2CH2-7- to 11-membered bridged cyclic heterocycloalkyl group, a 4- to 6-membered monocyclic heterocycloalkyl group linked via a -CH2CH2- carbon atom, [ka] wherein R is selected from ba is optionally H, halogen, OH, =O, cyano group, COOH, CONH2, CONHC 1-4 Alkyl group, CON(C 1-4 alkyl)2, NH2, NHC 1-4 Alkyl group, N(C 1-4 Alkyl)2, C 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy groups, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy group, C1-4 Alkoxyalkyl group or R k and the heterocycloalkyl group contains 1 to 4 heteroatoms selected from O, S, and N; R k -C 1-4 Alkyl-NH2, -C 1-4 Alkyl-NHC 1-4 Alkyl group, -C 1-4 Alkyl-N(C 1-4 alkyl)2, -C 0-4 Alkyl-C 3-6 Carbocyclic or -C 0-4 alkyl-3 to 6 membered heterocycle, wherein the alkyl group, carbocycle or heterocycle is optionally selected from deuterium, halogen, OH, ═O, cyano, COOH, NH, NHC 1-4 Alkyl group, N(C 1-4 Alkyl)2, C 1-4 Alkyl group, C 1-4 Alkoxy groups, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy group, C 1-4 substituted with 1 to 4 substituents selected from alkoxyalkyl groups, and the heterocycle contains 1 to 4 heteroatoms selected from O, S, and N; R 2 is a benzene ring, a naphthalene ring, a 5- to 6-membered heteroaromatic ring, a 9- to 10-membered heteroaromatic ring, C 3-6 Cycloalkyl groups, 3- to 7-membered heterocycloalkyl groups, benzo C 4-6 a carbocyclic group or a 4- to 6-membered benzoheterocyclic group, 2 optionally 0 to 4 R 2a and the heteroaromatic ring or heterocycloalkyl group contains 1 to 4 heteroatoms selected from O, S, and N; R 2a are independently deuterium, halogen, OH, cyano group, =O, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy group, C 3-6The alkyl, alkenyl, alkynyl, alkoxy, and cycloalkyl groups are optionally selected from the group consisting of deuterium, halogen, OH, ═O, cyano, C 1-4 Alkyl group, C 1-4 substituted with 0 to 4 substituents selected from alkoxy groups; As an option, R 2a and R 2a are directly linked to form a 4-membered carbocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, or a 6-membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring optionally contains deuterium, halogen, OH, a cyano group, ═O, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy group, C 3-6 substituted with 1 to 4 substituents selected from a cycloalkyl group and a 3- to 7-membered heterocycloalkyl group, and the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group or heterocycloalkyl group is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, OH and a cyano group; R 3 is H, C 1-4 alkyl groups, wherein the alkyl groups are optionally selected from deuterium, halogen, C 1-4 Alkyl group, C 1-4 substituted with 0 to 4 substituents selected from an alkoxy group and a benzene ring; Ring A is [ka] wherein ring A is optionally selected from 0 to 4 R a5 is replaced by Or ring A is [ka] wherein ring A is selected from C 2-4 Alkenyl group or C 2-4 alkynyl groups, optionally substituted with one substituent selected from R a5 and is substituted with 1 to 3 selected from R a5 is a halogen, OH, cyano group, C 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy group, C 3-6 The alkyl group, alkynyl group, alkoxy group, cycloalkyl group, and heterocyclic group are optionally selected from the group consisting of deuterium, halogen, OH, ═O, cyano, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 substituted with 0 to 4 substituents selected from cycloalkyl groups; The definitions of the other substituents are the same as in one of the first or second forms of the present invention.

[0009] As a fourth embodiment of the present invention, there is provided a compound represented by the above-mentioned general formula (I) or a stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, R 1a is selected from the group consisting of methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl, -CH2-cyclopropyl and -CH2-cyclobutyl; R b are independently deuterium, F, Cl, Br, I, OH, =O, cyano group, R ba or R bare each independently substituted or unsubstituted one of the following groups: methyl group, ethyl group, ethynyl group, methoxy group, ethoxy group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, azetidinyl group, azacyclopentyl group, azacyclohexyl group, oxetanyl group, oxacyclopentyl group, oxacyclohexyl group, morpholinyl group, phenyl group, pyridine, -CH2NH(CH2CH3), -C H2N(CH2CH3)2, -CH2CH2NH(CH3), -CH2CH2N(CH3)2, -CH2CH2NH(CH2CH3), -CH2CH2N(CH2CH3)2, -CH2CH2N(CH3)(CH2CH3), -CH2-cyclopropyl group, -CH2-cyclobutyl group, -CH2-cyclopentyl group, -CH2-cyclohexyl group, -CH2-azetidinyl group, -CH2-azacyclopentyl group, -CH2-Azacyclohexyl group, -CH2-oxetanyl group, -CH2-oxacyclopentyl group, -CH2-oxacyclohexyl group, -CH2-morpholinyl group, -CH2CH2-cyclopropyl group, -CH2CH2-cyclobutyl group, -CH2CH2-cyclopentyl group, -CH2CH2-cyclohexyl group, -CH2CH2-azetidinyl group, -CH2CH2-azacyclopentyl group, -CH2CH It is one selected from the group consisting of 2-azacyclohexyl, -CH2CH2-oxetanyl, -CH2CH2-oxacyclopentyl, -CH2CH2-oxacyclohexyl, -CH2CH2-morpholinyl, -CH2CH2-phenyl, -CH2-pyridyl, -CH2CH2-phenyl, and -CH2CH2-pyridyl, and when substituted, it is selected from the group consisting of deuterium, halogen, OH, ═O, cyano, CONH2, CONHC 1-4 Alkyl group, CON(C 1-4 alkyl)2, NH2, NHC 1-4 Alkyl group, N(C 1-4 alkyl)2, N(C 1-4 Alkyl)(C 3-6 cycloalkyl), NH(C 3-6 cycloalkyl), C 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy groups, halogen-substituted C 1-4Alkyl, halogen-substituted C 1-4 Alkoxy group, C 1-4 Alkoxyalkyl group or R k and is substituted with 0 to 4 substituents selected from R ba is an optionally substituted group: [ka] and when substituted, optionally deuterium, halogen, OH, ═O, cyano group, CONH2, CONHC 1-4 Alkyl group, CON(C 1-4 alkyl)2, NH2, NHC 1-4 Alkyl group, N(C 1-4 alkyl)2, N(C 1-4 Alkyl)(C 3-6 cycloalkyl), NH(C 3-6 cycloalkyl), C 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy groups, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy group, C 1-4 Alkoxyalkyl group or R k is substituted with 1 to 4 substituents selected from R k is selected from -CH2N(CH3)2, -CH2-cyclopropyl, -CH2-cyclobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, and oxetanyl groups, and said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, and azacyclohexyl groups are optionally substituted with deuterium, halogen, OH, ═O, cyano, NH2, NHC 1-4 Alkyl group, N(C 1-4 alkyl)2, N(C 1-4 Alkyl)(C 3-6 cycloalkyl), NH(C 3-6 cycloalkyl), C 1-4 Alkyl group, C1-4 Alkoxy groups, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy group, C 1-4 substituted with 1 to 4 substituents selected from alkoxyalkyl groups; R 2 is a benzene ring, a pyridyl group, a pyridonyl group, a pyrazinyl group, a pyrimidinyl group, a thienyl group, a thiazolyl group, a furyl group, an oxazolyl group, a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an azetidinyl group, an azacyclopentyl group, an azacyclohexyl group, an oxetanyl group, an oxacyclopentyl group, an oxacyclohexyl group, a morpholinyl group, [ka] wherein R is selected from 2 optionally 0 to 4 R 2a is replaced by R 2a are each independently selected from deuterium, F, Cl, Br, I, OH, ═O, cyano, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, or cyclobutyl, and the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, or cyclobutyl groups are optionally selected from deuterium, halogen, OH, ═O, cyano, C 1-4 Alkyl group, C 1-4 substituted with 0 to 4 substituents selected from alkoxy groups; R 3 is selected from H, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl, and benzyl; Ring A is [ka] wherein ring A is optionally selected from 0 to 4 R a5 is replaced by Or ring A is [ka] wherein ring A is substituted with one substituent selected from vinyl, ethynyl, propynyl, and propargyl groups, and optionally R a5 and is substituted with 1 to 3 selected from R a5 are each independently selected from F, Cl, Br, I, OH, CN, ethynyl, propynyl, propargyl, methyl, ethyl, cyclopropyl, methoxy, and ethoxy, and the ethynyl, propynyl, propargyl, methyl, ethyl, cyclopropyl, methoxy, and ethoxy groups are optionally selected from deuterium, halogen, OH, ═O, cyano, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 substituted with 1 to 4 substituents selected from cycloalkyl groups; The definitions of the other substituents are the same as in one of the forms 1, 2 or 3 of the present invention.

[0010] As a fifth embodiment of the present invention, there is provided a compound represented by the above general formula (I) or a stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, R 1 teeth, [ka] is selected from R b are independently deuterium, F, Cl, Br, OH, cyano group, and R ba or R bare each independently substituted or unsubstituted one of the following groups: methyl, ethyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, oxetanyl, oxacyclopentyl, oxacyclohexyl, morpholinyl, phenyl, pyridyl, -CH2NH(CH2CH3), -CH2N(CH2CH3)2, -CH2CH2NH(CH3), -CH2CH2N(CH3)2, -CH2CH2NH(CH2CH3), -CH2CH2N(CH2CH3)2, -CH2CH2N(CH3)(CH2CH3), -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH 2-azetidinyl group, -CH2-azacyclopentyl group, -CH2-azacyclohexyl group, -CH2-oxetanyl group, -CH2-oxacyclopentyl group, -CH2-oxacyclohexyl group, -CH2-morpholinyl group, -CH2CH2-cyclopropyl group, -CH2CH2-cyclobutyl group, -CH2CH2-cyclopentyl group, -CH2CH2-cyclohexyl group, -CH2CH2-azetidinyl group, -CH2CH2-azacyclopentyl group, -CH2CH2-azacyclohexyl group, -CH2CH2-oxetanyl group, -CH2CH2-oxacyclopentyl group, -CH2CH2-oxacyclohexyl group, -CH2CH2-morpholinyl group, -CH2-phenyl group, -CH2-pyridyl group, -CH2CH2-phenyl group, -CH2CH2-pyridyl group, [ka] and when substituted, is selected from deuterium, F, Cl, Br, OH, =O, cyano, CONH2, CONHCH3, CON(CH3)2, NH2, NHCH3, N(CH3)2, N(CH3)(cyclopropyl), NHCH2CH3, N(CH2CH3)2, CH2F, CHF2, CF3, methyl, ethyl, isopropyl, ethynyl, methoxy, ethoxy, methoxymethyl, ethoxymethyl, methoxyethyl, or R k and is substituted with 0 to 4 substituents selected from R ba is an optionally substituted group: [ka] and when substituted, optionally is selected from deuterium, F, Cl, Br, OH, ═O, cyano, CONH, CONHCH, CON(CH), NH, NHCH, N(CH), N(CH) (cyclopropyl), NHCH, N(CHCH), CHF, CHF, CF, methyl, ethyl, isopropyl, ethynyl, methoxy, ethoxy, methoxymethyl, ethoxymethyl, methoxyethyl, or R k is substituted with 1 to 4 substituents selected from R k is selected from -CHN(CH), -CH-cyclopropyl, -CH-cyclobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, and oxetanyl, and the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, and oxetanyl groups are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, =O, cyano, NH, NHCH, N(CH), N(CH)(cyclopropyl), NHCHCH, N(CHCH), CHF, CHF, CF, methyl, ethyl, isopropyl, methoxy, ethoxy, methoxymethyl, ethoxymethyl, and methoxyethyl; R 2 represents a phenyl group, a pyridyl group, a pyridonyl group, an azacyclopentyl group, a morpholinyl group, [ka] wherein R is selected from 2 is optionally substituted with 0 to 4 substituents selected from deuterium, F, Cl, Br, OH, CF, cyano, methyl, ethyl, methoxy, ethoxy, cyclopropyl, or cyclobutyl; or R 2 teeth, [ka] wherein R is selected from 2 is optionally substituted with 1 to 4 substituents selected from deuterium, CD3, -OCD3, F, Cl, Br, OH, CF3, cyano, methyl, ethyl, methoxy, ethoxy, cyclopropyl, or cyclobutyl; Ring A is [ka] is selected from The definitions of the other substituents are the same as in one of the forms 1, 2, 3 or 4 of the present invention.

[0011] As a sixth embodiment of the present invention, there is provided a compound represented by the above general formula (I) or a stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, R 1 teeth, [ka] is selected from or R 1 teeth, [ka] is selected from or R 1 teeth, [ka] is selected from or R 1 teeth, [ka] is selected from or R 1 teeth, [ka] is selected from or R 1 teeth, [ka] is selected from or R 1 teeth, [ka] is selected from R 2 teeth, [ka] is selected from or R 2 teeth, [ka] is selected from or R 2 teeth, [ka] is selected from R 1a teeth, [ka] is selected from The definitions of the other substituents are the same as in one of the forms 1, 2, 3, 4 or 5 of the present invention.

[0012] As a seventh embodiment of the present invention, there is provided a compound represented by the above general formula (I) or a stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein the compound is selected from the compounds represented by general formula (Ia), (Ib), general formula (Ia-1), and (Ib-1), [ka] Ring A, R 3is the same as any one of 2, 3, 4, 5, or 6 in the embodiment of the present invention; p1 is selected from 0, 1, 2, 3 or 4; R 2a Deuterium, halogens, OH, CN, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 The alkyl group, alkoxy group, cycloalkyl group, and heterocycloalkyl group are optionally selected from the group consisting of deuterium, halogen, OH, CN, C 1-4 Alkyl group, C 1-4 alkoxy groups, wherein the heterocycloalkyl group contains 1 to 4 heteroatoms selected from O, S, and N; R 1a teeth, [ka] is selected from R b1 is H, C 1-4 Alkyl group, C 3-6 cycloalkyl groups, wherein the alkyl or cycloalkyl groups are optionally selected from deuterium, halogen, OH, CN, NHC 1-4 Alkyl group, N(C 1-4 Alkyl)2, C 1-4 Alkyl group, C 1-4 substituted with 0 to 4 substituents selected from alkoxy groups; R b2 H, R ba , substituted or unsubstituted groups: 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy group, -CH2CH2-NHC 1-4 Alkyl group, -CH2CH2-N(C 1-4 alkyl)2, -CH2CH2-C 3-6a cycloalkyl group, -CH2CH2-, and a 3- to 7-membered heterocycloalkyl group, wherein the CH2, alkyl group, cycloalkyl group, or heterocycloalkyl group may optionally be selected from the group consisting of deuterium, halogen, OH, ═O, cyano, COOH, NH2, NHC 1-4 Alkyl group, N(C 1-4 alkyl)2, N(C 1-4 Alkyl)(C 3-6 cycloalkyl), NH(C 3-6 cycloalkyl), C 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy groups, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy group, C 1-4 Alkoxyalkyl group or R k and the heteroaryl or heterocycloalkyl group contains 1 to 4 heteroatoms selected from O, S, and N; n1 is selected from 1, 2 or 3; R ba , R k is the same as any one of 2, 3, 4, 5, or 6 in the embodiment of the present invention.

[0013] As an eighth embodiment of the present invention, there is provided a compound represented by the above general formula (I) or a stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein the compound is selected from the compounds represented by general formulas (Ia), (Ib), (Ia-1) and (Ib-1), R 2a is selected from deuterium, CD3, -OCD3, F, Cl, Br, I, OH, cyano, methyl, ethyl, methoxy, and ethoxy groups; R b1 is selected from H, F, CH2F, CHF2, CF3, a methyl group, -CH2CH2N(CH3)2, R b2 H, R ba, substituted or unsubstituted groups: methyl group, ethyl group, ethynyl group, methoxy group, ethoxy group, -CH2NH(CH2CH3), -CH2N(CH2CH3)2, -CH2CH2NH(CH3), -CH2CH2N(CH3)2, -CH2CH2NH(CH2CH3), -CH2CH2N(CH2CH3)2, -CH2CH2N(CH2CH3)2, -CH2CH2N(CH3)(CH2CH3), -CH2CH2-cyclopropyl group, -CH2CH2-cyclobutyl group, -CH2CH2-cyclopentyl group, -CH2CH2-cyclohexyl group, -CH2CH2-azetidinyl group, -CH2CH2-azacyclopentyl group, - is one selected from CH2CH2-azacyclohexyl, -CH2CH2-oxetanyl, -CH2CH2-oxacyclopentyl, -CH2CH2-oxacyclohexyl, -CH2CH2-morpholine, and when substituted, deuterium, F, Cl, Br, OH, =O, cyano, NH2, NHCH3, N(CH3)2, N(CH3)(cyclopropyl), NHCH2CH3, N(CH2CH3)2, CH2F, CHF2, CF3, methyl, ethyl, isopropyl, ethynyl, methoxy, ethoxy, methoxymethyl, ethoxymethyl, methoxyethyl, or R k and is substituted with 1, 2 or 3 substituents selected from The definitions of the other groups are the same as in embodiment 7 of the present invention.

[0014] As a ninth embodiment of the present invention, there is provided a compound represented by the above general formula (I) or a stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from the compounds represented by general formulas (If), (Ig), (If-1), (Ig-1), (Ih), (Ii), (Ih-1) and (Ii-1), [ka] R 1b teeth, [ka] is selected from p2 is selected from 0, 1 or 2; R ak is C 2-4 alkynyl groups, R a5 is the same as in any one of the first, second, third or fourth embodiments of the present invention, The definitions of the other groups are the same as in either one of the seventh or eighth embodiments of the present invention.

[0015] As a tenth embodiment of the present invention, there is provided a compound represented by the above general formula (I) or a stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from the group consisting of compounds represented by general formulas (If), (Ig), (If-1), (Ig-1), (Ih), (Ii), (Ih-1) and (Ii-1), R ak is selected from an ethynyl group, a propynyl group, and a propargyl group; R a5 is selected from F, Cl, Br, I, OH, cyano, methyl, ethyl, methoxy, ethoxy, and ethynyl; The definitions of other groups are the same as in the ninth embodiment of the present invention.

[0016] As a tenth embodiment of the present invention, there is provided a compound represented by the above general formula (I) or a stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from general formula (Ij) or (Ik): [ka] R a6 is selected from H or F, R 2 is a phenyl group or [ka] wherein R is selected from 2 is optionally a halogen, C 1-4 Alkyl group, C 1-4 Alkoxy group, C substituted with 1 to 4 halogens1-4 Alkyl groups, C substituted with 1 to 4 halogens 1-4 Alkoxy group, 1 to 4 deuterium substituted C 1-4 Alkyl group, 1 to 4 deuterium substituted C 1-4 substituted with 1 to 4 substituents selected from alkoxy groups, preferably [ka] and R b1 is selected from CH2F, CHF2, CF3, and a methyl group, preferably CF3; R b2 is -CH2CH2N(CH3)2, -CH2CH2NH(CH2CH3), -CH2-azetidinyl group, -CH2-azacyclopentyl group, -CH2-azacyclohexyl group, -CH2-morpholinyl group, -CH2CH2-azetidinyl group, -CH2CH2-azacyclopentyl group, -CH2CH2-azacyclohexyl group, [ka] wherein R is selected from b2 is optionally deuterium, F, Cl, Br, NHCH2CH3, N(CH2CH3)2, CH2F, CHF2, CF3, a methyl group, an ethyl group, an isopropyl group, a methoxy group, an ethoxy group, a -CH2-cyclopropyl group, [ka] and is substituted with 1 to 4 substituents selected from, preferably [ka] and The present invention relates to some specific compounds of general formula (I), which are selected from Table E-1.

[0017] The present invention relates to some specific compounds of general formula (I), which are selected from Table E-3, Table E-4, and Table E-5.

[0018]

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

[0019]

Table 2-1

Table 2-2

Table 2-3

Table 2-4

Table 2-5

[0020]

Table 3-1

Table 3-2

Table 3-3

Table 3-4

[0021]

Table 4-1

Table 4-2

Table 4-3

Table 4-4

Table 4-5

Table 4-6

Table 4-7

Table 4-8

Table 4-9

Table 4-10

Table 4-11

[0022]

Table 5-1

Table 5-2

Table 5-3

Table 5-4

Table 5-5

Table 5-6

Table 5-7

Table 5-8

Table 5-9

Table 5-10

Table 5-11

Table 5-12

Table 5-13

[0023] The present invention relates to pharmaceutical compositions, comprising a compound according to the present invention or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable carrier.

[0024] The present invention relates to the application of the compounds described in the present invention or their stereoisomers, racemates, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals in the manufacture of pharmaceuticals for treating diseases associated with the activity or expression level of α4β7, preferably in the manufacture of pharmaceuticals for intestinal inflammatory diseases.

[0025] The present invention relates to a pharmaceutical composition or formulation comprising a therapeutically effective amount of a compound according to the present invention or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutical excipient. The pharmaceutical composition may be in the form of a unit dosage form (the amount of the active ingredient in a unit dosage form is also referred to as the "formulation specification").

[0026] The present invention further provides a method for treating a disease in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound according to the present invention or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal or pharmaceutical composition thereof. In some embodiments, the mammal according to the present invention comprises a human.

[0027] As used herein, an "effective amount" or "therapeutically effective amount" includes administering a sufficient amount of a compound disclosed herein that relieves to some extent one or more symptoms of the disease or condition being treated (e.g., intestinal inflammatory disease). In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is that amount of a compound disclosed herein necessary to provide a clinically significant reduction in disease symptoms.Examples of therapeutically effective amounts include 1 to 1500 mg, 1 to 1200 mg, 1 to 1000 mg, 1 to 900 mg, 1 to 800 mg, 1 to 700 mg, 1 to 600 mg, 2 to 600 mg, 3 to 600 mg, 4 to 600 mg, 5 to 600 mg, 6 to 600 mg, 10 to 600 mg, 20 to 600 mg, 25 to 600 mg, 30 to 600 mg, 40 to 600 mg, 50 to 600 mg, 60 to 600 mg, 70 to 600 mg, 75 to 600 mg, 80 to 600 mg, 90 to 600 mg, 100 to 600 mg, 200 to 600 mg, 1 to 500 mg, and 2 to 500 mg , 3~500mg, 4~500mg, 5~500mg, 6~500mg, 10~500mg, 20~500mg, 25~500mg, 30~500mg, 40~500mg, 50~500mg, 60~500mg, 70~500mg, 75~500mg, 80~500m g, 90~500mg, 100~500mg, 125~500mg, 150~500mg, 200~500mg, 250~500mg, 300~500mg, 400~500mg, 5~400mg, 10~400mg, 20~400mg, 25~400mg, 30~40 0mg, 40~400mg, 50~400mg, 60~400mg, 70~400mg, 75~400mg, 80~400mg, 90~400mg, 100~400mg, 125~400mg, 150~400mg, 200~400mg, 250~400mg, 300~ 400mg, 1~300mg, 2~300mg, 5~300mg, 10~300mg, 20~300mg, 25~300mg, 30~300mg, 40~300mg, 50~300mg, 60~300mg, 70~300mg, 75~300mg, 80~300mg, 9 Including, but not limited to, 0-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-200mg, 40-200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg, 80-1000mg, and 80-800mg.

[0028] In some embodiments, the pharmaceutical composition contains 1-1000 mg, 20-800 mg, 40-800 mg, 40-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 2 Including, but not limited to, 40 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, 840 mg of a compound of the present invention or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof.

[0029] A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, wherein the therapeutically effective amount is preferably 1 to 1500 mg, and the disease is preferably an intestinal inflammatory disease.

[0030] A method for treating a disease in a mammal, the method comprising administering to a subject a pharmaceutical compound of the present invention or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof in a daily dose of 1 to 1000 mg / day, which may be a single dose or divided doses, and in some embodiments, the daily dose is 10 to 1500 mg / day, 10 to 1000 mg / day, 10 to 800 mg / day, 25 to 800 mg / day, 50 to 800 mg / day, 100 to 800 mg / day, 20 In some embodiments, the daily dose includes, but is not limited to, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 80 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 160 mg / day, 200 mg / day, 300 mg / day, 320 mg / day, 400 mg / day, 480 mg / day, 600 mg / day, 640 mg / day, 800 mg / day, and 1000 mg / day.

[0031] The present invention relates to a kit, which may comprise a composition in single-dose or multiple-dose form, comprising a compound of the present invention or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein the amount of the compound of the present invention or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof is the same as the amount in the pharmaceutical composition.

[0032] In the present invention, the amounts of the compounds of the invention or their stereoisomers, racemates, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals are in each case calculated in terms of the form of the free base.

[0033] "Preparation specifications" refers to the weight of the active ingredient contained in one unit dosage form, one tablet, or each other unit dosage form.

[0034] Methods for synthesizing the compounds of the present invention: [ka] The compound of general formula (Z-1) and the compound of general formula (Z-2) are subjected to a coupling or substitution reaction to obtain the compound of general formula (Z-3), The protecting group is removed from the compound of the general formula (Z-3) to obtain a compound of the general formula (Z-4), Compound (Z-4) of the general formula and compound (Z-5) of the general formula are subjected to a coupling or substitution reaction to obtain compound (I) of the general formula, R m1 is selected from Boc, Cbz, tert-butylsulfinyl groups, etc. R m2 , R m3 are each independently selected from H, Cl, Br, I, OTf, B(OH)2, a borate ester group, a tin group substituted with an alkyl group, etc. R m4 is selected from Cl, Br, I, OH, etc. The definitions of the other groups are the same as those in any one of the embodiments in the above general formula (I).

[0035] Unless otherwise stated, terms used in the specification and claims have the following meanings:

[0036] Carbon, hydrogen, oxygen, sulfur, nitrogen, or F, Cl, Br, I in the groups and compounds described in the present invention include their isotope status, and carbon, hydrogen, oxygen, sulfur, or nitrogen in the groups and compounds described in the present invention are optionally substituted with one or more corresponding isotopes, where the isotope of carbon is 12 C and 13 C and 14 C, isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called tritium), and isotopes of oxygen include 16 O and 17 O and 18 Isotopes of sulfur include O and 32 S and 33 S and 34 S and 36S and nitrogen isotopes include 14 N and 15 N and fluorine isotopes include 17 F and 19 The isotopes of chlorine include F and 35 Cl and 37 The isotopes of bromine include Cl and 79 Br and 81 Contains Br.

[0037] "Alkyl group" refers to a linear or branched saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and even more preferably an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched isomers thereof, wherein the alkyl group optionally contains F, Cl, Br, I, hydroxy, mercapto, nitro, cyano, amino, alkylamino, amido, alkenyl, alkynyl, C 1-6 Alkyl group, C 1-6 Hydroxyalkyl group, C 1-6 It is substituted with 0 to 6 substituents selected from an alkoxy group, a 3- to 8-membered carbocyclic group, a 3- to 8-membered heterocyclic group, a 3- to 8-membered carbocyclyloxy group, a 3- to 8-membered heterocyclyloxy group, a carboxyl group, or a carboxylic acid ester group.

[0038] An "alkylene group" is a straight-chain or branched-chain divalent saturated hydrocarbon group, -(CH2) v- (v is an integer of 1 to 10), and examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene, and the alkylene group is optionally substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxy, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclic, heterocyclic, carbocyclyloxy, heterocyclyloxy, carboxyl, or carboxylic acid ester.

[0039] A "cycloalkyl group" is a monovalent saturated carbocyclic hydrocarbon group, typically having 3 to 12 carbon atoms, including a monocyclic cycloalkyl group, a fused-ring cycloalkyl group, a spirocyclic cycloalkyl group, or a bridged-ring cycloalkyl group, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl groups. The cycloalkyl group is optionally substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxy, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclic, heterocyclic, carbocyclyloxy, heterocyclyloxy, carboxyl, or carboxylic acid ester groups.

[0040] "Alkenyl group" refers to straight- and branched-chain monovalent unsaturated hydrocarbon groups having at least one, and typically one, two, or three, carbon-carbon double bond; the main chain contains 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms in the main chain; examples of alkenyl groups include vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, Examples of alkenyl groups include, but are not limited to, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, and 1,4-hexadiene. The alkenyl group is optionally substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxy, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclic, heterocyclic, carbocyclyloxy, heterocyclyloxy, carboxyl, or carboxylic acid ester.

[0041] "Alkynyl group" refers to straight- and branched-chain unsaturated hydrocarbon groups which have at least one, and typically one, two, or three, carbon-carbon triple bonds, and a backbone containing 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms in the backbone. Examples of alkynyl groups include ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5- Examples of alkynyl groups include, but are not limited to, hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, and 4-decynyl. The alkynyl groups are optionally substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxy, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclic, heterocyclic, carbocyclyloxy, heterocyclyloxy, carboxyl, and carboxylic acid ester. The definition of alkynyl groups described herein is consistent with this definition.

[0042] "Alkoxy" refers to an -O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropoxy, and cyclobutoxy. The alkoxy group is optionally substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxy, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclic, heterocyclic, carbocyclyloxy, heterocyclyloxy, carboxyl, or carboxylic acid ester.

[0043] "Carbocyclic group" or "carbocycle" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic ring, where the aromatic or non-aromatic ring may be a 3- to 8-membered monocyclic, a 4- to 12-membered bicyclic, or a 10- to 15-membered tricyclic system, and the carbocyclic group may be linked to an aromatic or non-aromatic ring, which may optionally be a monocyclic, bridged, or spirocyclic ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, benzene ring, naphthalene ring, [ka] The carbocycle is optionally substituted with 0 to 5 substituents selected from F, Cl, Br, I, ═O, hydroxy, mercapto, nitro, cyano, amino, alkylamino, amido, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclic, heterocyclic, carbocyclyloxy, heterocyclyloxy, carboxyl, or carboxylic acid ester.

[0044] The term "heterocyclic group" or "heterocycle" refers to a substituted or unsubstituted, saturated or unsaturated aromatic or non-aromatic ring, which may be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, or a 10- to 15-membered tricyclic ring, and which contains 1 to 3 heteroatoms selected from N, O, and S, and is preferably a 3- to 8-membered heterocyclic group, and the N and S optionally substituted in the ring of the heterocyclic group may be oxidized to various oxidation states. Heterocyclic groups may be attached at a heteroatom or carbon atom, may be attached at an aromatic or non-aromatic ring, or may have bridged or spiro rings attached to them, non-limiting examples of which include oxiranyl, azacyclopropyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azacycloheptyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuryl, dihydropyranyl, dithiolanyl, and tetrahydrofuranyl. , tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuryl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl, benzofuryl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonane, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptyl, [ka] The heterocyclic group is optionally substituted with 0 to 5 substituents selected from F, Cl, Br, I, ═O, hydroxy, mercapto, nitro, cyano, amino, alkylamino, amido, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclic, heterocyclic, carbocyclyloxy, heterocyclyloxy, carboxyl, or carboxylic acid ester.

[0045] A "heterocycloalkyl group" is a substituted or unsubstituted saturated heterocyclic group, which may be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, or a 10- to 15-membered tricyclic ring, and contains 1 to 3 heteroatoms selected from N, O, and S, preferably a 3- to 8-membered heterocyclic group, and the N and S optionally substituted in the heterocycloalkyl ring may be oxidized to various oxidation states. The heterocycloalkyl group may be attached via a heteroatom or a carbon atom, and non-limiting examples include oxiranyl, azacyclopropyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azacycloheptyl, piperidinyl, and morpholinyl. The heterocycloalkyl group is optionally substituted with 0 to 5 substituents selected from F, Cl, Br, I, ═O, a hydroxy group, a mercapto group, a nitro group, a cyano group, an amino group, an alkylamino group, an amido group, an alkenyl group, an alkynyl group, an alkyl group, a hydroxyalkyl group, an alkoxy group, a carbocyclic group, a heterocyclic group, a carbocyclyloxy group, a heterocyclyloxy group, a carboxyl group, or a carboxylic acid ester group.

[0046] The term "spiro ring" refers to a substituted or unsubstituted 5- to 20-membered polycyclic group in which the monocyclic rings share one atom (referred to as a spiro atom), which may contain 0 to 5 double bonds and 0 to 5 heteroatoms selected from N, O, or S(=O)n (n is selected from 0, 1, or 2). The spiro ring is preferably 6 to 14-membered, more preferably 6 to 12-membered, and even more preferably 6 to 10-membered. Non-limiting examples of spiro rings include: [ka] Includes:

[0047] "Fused ring" refers to a polycyclic group in which each ring in the system shares an adjacent atom pair with another ring in the system, where one or more rings may contain zero or more double bonds, may be substituted or unsubstituted, and each ring in the fused ring system may contain zero to five heteroatoms selected from N, S(=O)n, or O (n is selected from 0, 1, or 2). Preferably, the ring has 5 to 20 members, also preferably 5 to 14 members, more preferably 5 to 12 members, and even more preferably 5 to 10 members. Non-limiting examples include the following: [ka] [ka]

[0048] A "bridged ring" refers to a polycyclic group of any two atoms that are not directly linked, which may contain zero or more double bonds and may be substituted or unsubstituted, and any ring in the bridged ring system may contain zero to five heteroatoms or groups selected from N, S(=O)n, or O (where n is 0, 1, or 2). The ring atoms may contain 5 to 20 atoms, preferably 5 to 14 atoms, more preferably 5 to 12 atoms, and even more preferably 5 to 10 atoms. Non-limiting examples include: [ka] and adamantane. Definitions of bridged rings provided herein are consistent with this definition.

[0049] The terms "carbospirocycle", "spirocyclic carbocyclic group", "spirocarbocyclic group" or "carbospirocyclic group" refer to a "spirocycle" whose ring system consists only of carbon atoms.

[0050] The terms "fused carbocyclic ring", "fused ring carbocyclic group", "fused carbocyclic group" or "fused carbocyclic group" refer to a "fused ring" whose ring system consists only of carbon atoms.

[0051] The terms "carbobridged ring", "bridged cyclic carbocyclic group", "bridged carbocyclic group" or "carbobridged ring group" refer to a "bridged ring" whose ring system consists only of carbon atoms.

[0052] The terms "heteromonocycle", "monocyclic heterocyclic group" or "heteromonocyclic group" refer to a monocyclic "heterocyclic group" or "heterocycle".

[0053] The terms "fused heterocyclic ring", "fused heterocyclic group", "fused ring heterocyclic group" or "fused heterocyclic group" refer to a "fused ring" that contains a heteroatom.

[0054] The terms "heterospirocycle", "heterospirocyclic group", "spirocyclic heterocyclic group" or "spiroheterocyclic group" refer to a "spirocycle" containing a heteroatom.

[0055] The terms "heterobridged ring", "heterobridged ring group", and "bridged heterocyclic group" refer to a "bridged ring" containing a heteroatom.

[0056] An "aryl group" or "aromatic ring" refers to a monovalent aromatic hydrocarbon group having a single ring or fused rings, generally having 6 to 12 carbon atoms, and may be substituted or unsubstituted. The definition of an aryl group or aromatic ring described herein is consistent with this definition.

[0057] The term "heteroaryl group" refers to a substituted or unsubstituted 5- to 15-membered aromatic ring containing 1 to 5 heteroatoms or groups selected from N, O, or S(=O)n, preferably a 5- to 10-membered heteroaromatic ring, more preferably a 5- to 6-membered heteroaromatic ring. Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, etc. The heteroaryl ring can be fused with an aryl group, a heterocyclic group, or a cycloalkyl group ring, where the ring connected to the basic skeleton is the heteroaryl ring. Non-limiting examples include: [ka] Includes:

[0058] "Containing 1 to 4 heteroatoms selected from O, S, and N" means containing 1, 2, 3, or 4 heteroatoms selected from O, S, and N.

[0059] "Substituted" or "substituted" refers to substitution with one or more (including, but not limited to, 2, 3, 4, or 5) substituents, which substituents include H, F, Cl, Br, I, alkyl groups, cycloalkyl groups, alkoxy groups, halogenated alkyl groups, thiol, hydroxy groups, nitro groups, mercapto groups, amino groups, cyano groups, isocyano groups, aryl groups, heteroaryl groups, heterocyclic groups, bridged ring groups, spirocyclic groups, fused ring groups, hydroxyalkyl groups, =0, carbonyl groups, aldehydes, carboxylic acids, formates, -(CH2) m -C(=O)-R a , -O-(CH2) m -C(=O)-R a , -(CH2) m -C(=O)-NR b R c , -(CH2) m S(=O) n R a , -(CH2) m -Alkenyl-R a , OR d or -(CH2) m -alkynyl-R a (wherein m and n are 0, 1, or 2), an arylthio group, a thiocarbonyl group, a silyl group, or —NR b R c and the like, where R b and R c are independently selected from H, a hydroxy group, an amino group, a carbonyl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a sulfonyl group, and a trifluoromethanesulfonyl group; and optionally, R b and R c can form a 5- or 6-membered cycloalkyl group or a heterocyclic group, R aand R d are each independently selected from an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro ring group, or a fused ring group.

[0060] "Substituted with 0 to X substituents" refers to substitution with 0, 1, 2, 3, ..., X substituents, where X is selected from any integer from 1 to 10. For example, "substituted with 0 to 4 substituents" refers to substitution with 0, 1, 2, 3, or 4 substituents. For example, "substituted with 0 to 5 substituents" refers to substitution with 0, 1, 2, 3, 4, or 5 substituents. "The heterobridged ring is optionally substituted with 0 to 4 substituents selected from H or F" refers to substitution with 0, 1, 2, 3, or 4 substituents selected from H or F.

[0061] An X- to Y-membered ring (X is an integer of 3 or more and less than Y, and Y is an integer of 4 to 12) includes X, X+1, X+2, X+3, X+4, ..., Y-membered rings. The ring includes a heterocycle, a carbocycle, an aromatic ring, an aryl group, a heteroaryl group, a cycloalkyl group, a heteromonocycle, a heterofused ring, a heterospirocycle, or a heterobridged ring. For example, a "4- to 7-membered heteromonocycle" refers to a 4-, 5-, 6-, or 7-membered heteromonocycle, and a "5- to 10-membered heterofused ring" refers to a 5-, 6-, 7-, 8-, 9-, or 10-membered heterofused ring.

[0062] "Optionally" or "optionally" means that the subsequently described event or circumstance may, but does not necessarily, occur, and the description includes both cases where the event or circumstance occurs and cases where it does not occur. For example, "an alkyl group optionally substituted with F" means that the alkyl group may, but is not necessarily, substituted with F, and includes cases where the alkyl group is substituted with F and cases where the alkyl group is not substituted with F.

[0063] "Pharmaceutically acceptable salt" or "a pharmaceutically acceptable salt thereof" refers to a salt in which the compounds of the present invention retain the biological effectiveness and properties of the free acid or free base and which is obtained by reaction of said free acid with a non-toxic inorganic or organic base, or by reaction of said free base with a non-toxic inorganic or organic acid.

[0064] A "pharmaceutical composition" refers to a mixture of one or more compounds according to the present invention, pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, where "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and / or one or more other therapeutic agents.

[0065] A "carrier" refers to a material that does not cause significant irritation to an organism and does not abolish the biological activity and properties of the administered compound.

[0066] "Animal" includes mammals such as humans, companion animals, zoo animals, and farm animals, and is preferably a human, horse, or dog.

[0067] "Stereoisomer" refers to isomers that result from differences in the way atoms in molecules are arranged in space, and includes cis-trans isomers, enantiomers, and conformational isomers. DETAILED DESCRIPTION OF THE INVENTION

[0068] To achieve the objectives of the present invention, the compounds used in the reactions described herein are prepared based on organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or compounds described in the chemical literature, where "commercially available chemicals" are obtained from standard commercial sources, including Shanghai Aldring Biochemical Technology Co., Ltd., Shanghai McKinney Biochemical Technology Co., Ltd., Sigma-Aldrich, Alfa Acer (China) Chemical Co., Ltd., Teijin Chemical (Shanghai) Chemical Industry Development Co., Ltd., Ananji Chemical, Shanghai Taitan Technology Co., Ltd., Kelong Chemical, Bailingwei Technology Co., Ltd., and the like.

[0069] The following examples will illustrate the technical solutions of the present invention in detail, and the protection scope of the present invention includes but is not limited to them.

[0070] The structures of the compounds were confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR displacements (δ) are given in units of 10-6 (ppm). NMR measurements were performed using nuclear magnetometers (Bruker Avance III 400 and Bruker Avance 300). The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS). MS measurements were performed using Agilent 6120B (ESI) and Agilent 6120B (APCI). HPLC measurements were performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM). The silica gel plate used for thin layer chromatography is Yantai Yellow Sea HSGF254 or Qingdao GF254. The silica gel plate specifications used for thin layer chromatography (TLC) are 0.15mm to 0.20mm, and the specifications used for separating and purifying the finished product by thin layer chromatography are 0.4mm to 0.5mm. For column chromatography, Yantai Yellow Sea silica gel 200-300 mesh silica gel was generally used as the carrier.

[0071] Boc: tert-butoxycarbonyl group, Ts: p-toluenesulfonyl group, Cbz: benzyloxycarbonyl group, TMS: trimethylsilyl group, TIPS: triisopropylsilyl group, Bpin: pinacol boronate, MOM: methylene methyl ether, THF: tetrahydrofuran HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; PdCl2(dppf):CAS 72287-26-4. XPhos Pd G2 :CAS 1310584-14-5 An * next to a chemical bond indicates that the chirality of the chiral atom is R or S.

[0072] Retention time (Rt): Unless otherwise specified in the examples, this is the retention time of the analytical method, which is as follows:

[0073] Detection wavelength: 254 nm / 210 nm Flow rate: 1.0 ml / min Column temperature: 35°C Sample input volume: 2 μl Collection time: 10 min Gradient elution procedure:

[0074] [Table 6] Acidic conditions: Mobile phase A is 0.05% TFA solution, and mobile phase B is acetonitrile Chromatography column brand: Tsukiasahi, Chromatography column model number: Xtimate C18 4.6*50mm, 3μm Instrument model number 1: Shimadzu LC-20AT, instrument code: CH-Y-J0460 Instrument model number 2: Agilent 1260Infinity, instrument code: CH-Y-J0692

[0075] The specific methods for preparative HPLC (prep-HPLC) are as follows. Method 1: Instrument: Waters 2767. Preparative chromatography column: SunFire@Prep C18 (19 mm x 150 mm), (mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% ammonium acetate). Method 2: Instrument: Waters 2767. Preparative chromatography column: SunFire@Prep C18 (19 mm x 150 mm), (mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% trifluoroacetic acid).

[0076] Intermediate 1: Preparation of Intermediate 1 [ka]

[0077] Step 1: Synthesis of 1B Under nitrogen gas protection, intermediate 1a (6.3 g, 39.34 mmol) was dissolved in dichloromethane (150 mL) and anhydrous aluminum chloride (13.11 g, 98.35 mmol) was added. After reacting at room temperature for 5 min, a solution of elemental bromine (8.80 g, 55.08 mmol) in dichloromethane (50 mL) was added and reacted at room temperature for 2 h. The reaction mixture was poured into ice water (200 mL), dichloromethane (100 mL) was added, washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give 1B (8.0 g, 85.05%). LC-Ms m / z (ESI): 241.1[M+H] +

[0078] Step 2: Synthesis of 1C 1B (8.1 g, 33.88 mmol) was dissolved in DME (100 mL), 1 M sodium hypochlorite solution (188 mL) and 10 N sodium hydroxide solution (18.5 mL) were added, and the mixture was allowed to react at 50 °C for 1 h. Water (150 mL) was added, and the mixture was extracted with ethyl ether (200 mL). The pH of the aqueous phase was adjusted to 1-2 with hydrochloric acid, and the mixture was extracted with ethyl ether (150 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give 1C (7.6 g, 93.05%). LC-Ms m / z (ESI): 240.9[M+H] +

[0079] Step 3: 1D Compositing 1C (7.6 g, 31.52 mmol) was dissolved in methanol (50 mL), thionyl chloride (11.25 g, 94.56 mmol) was added, and the mixture was reacted for 2 hours at 70° C. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to give 1D (8.0 g, 99.49%). LC-Ms m / z (ESI): 255.0[M+H] +

[0080] Step 4: Synthesis of 1E Under nitrogen gas protection, 1D (2 g, 7.84 mmol), 4-fluoro-2,6-dimethylbenzeneboronic acid (2.63 g, 15.68 mmol), and cesium carbonate (7.66 g, 23.52 mmol) were added to 1,4-dioxane (30.0 mL) and water (3.0 mL). Pd(PPh3)4 (1.81 g, 1.57 mmol) was added, and the mixture was reacted in a sealed tube at 100 °C for 5 h. After cooling to room temperature, the mixture was filtered through diatomaceous earth, added with ethyl acetate (50 mL), washed sequentially with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column flash chromatography to give 1E (2.2 g, yield: 94.05%).

[0081] Step 5: Synthesis of 1F Under nitrogen gas protection, 1E (2.13 g, 7.14 mmol) was dissolved in dry THF (30 mL), and lithium aluminum tetrahydrogen (406 mg, 10.71 mmol) was slowly added at 0 °C. The reaction was allowed to proceed at room temperature for 1 h. 10% aqueous sodium sulfate solution (20 mL) was added, filtered, and the solvent was removed under reduced pressure to obtain crude product 1F.

[0082] Step 6: Synthesis of 1g Under nitrogen gas protection, crude 1F (1.87 g, 6.92 mmol) was dissolved in dry dichloromethane (35 mL), and sodium bicarbonate (1.16 g, 13.84 mmol) and Dess-Martin oxidant (3.81 g, 9.00 mmol) were added at room temperature. The mixture was then reacted at room temperature for 1 h. Saturated sodium thiosulfate solution (10 mL) and saturated sodium bicarbonate solution (10 mL) were added, and the mixture was extracted with dichloromethane (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. 1G (1.63 g, 87.68%) was obtained by silica gel column chromatography.

[0083] Step 7: Synthesis of 1H Under nitrogen gas protection, 1G (1.61 g, 6.00 mmol) and R-tert-butylsulfenamide (1.01 g, 9.00 mmol) were dissolved in THF (35 mL), tetraethyl titanate (2.05 g, 9.00 mmol) was slowly added, and the mixture was reacted at 45 °C for 15 h. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column flash column chromatography to obtain 1H (1.73 g, 77.61% yield). LC-Ms m / z (ESI): 329.3[M+H] +

[0084] Step 8: Synthesis of 1I Zinc powder (915 mg, 14 mmol) was added to dry THF (5 mL), and the mixture was purged with nitrogen gas three times. CuCl (297 mg, 3 mmol) was added and the mixture was reacted at 60 °C for 2 h. After cooling to room temperature, ethyl bromoacetate (835 mg, 5 mmol) was slowly added and the mixture was reacted at 60 °C for 1 h. The mixture was then cooled to 0 °C, and a solution of 1H (371 mg, 1 mmol) in THF (1 mL) was added and stirred at 0 °C for 3 h. The mixture was filtered through diatomaceous earth, saturated ammonium chloride solution (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash column chromatography to give 1I (386 mg, 83.98% yield). LC-Ms m / z (ESI): 460.2[M+H] +

[0085] Step 9: Synthesis of Intermediate 1 1I (272 mg, 0.27 mmol) was dissolved in THF (2 mL), and 4N hydrochloric acid in dioxane (2 mL) was added, followed by stirring at room temperature for 3 hours. The mixture was concentrated under reduced pressure to give a crude product, Intermediate 1. LC-Ms m / z (ESI): 356.3[M+H] +

[0086] Intermediate 2: Preparation of Intermediate 2 [ka]

[0087] Step 1: Synthesis of 2B Under nitrogen gas protection, 2A (25 g, 91.94 mmol), CuI (3.5 g, 18.39 mmol), PdCl2(PPh3)2 (6.45 g, 9.19 mmol), 1-(trimethylsilyl)propyne (9.29 g, 82.75 mmol), and cesium fluoride (41.90 g, 275.82 mmol) were dissolved in THF (250 mL) and reacted at 60 °C for 72 h. The mixture was then concentrated under reduced pressure and purified by silica gel column chromatography to give 2B (8.5 g, 40.02%).

[0088] Step 2: Synthesis of 2C Under nitrogen gas protection, 2B (8.5 g, 36.79 mmol) was dissolved in THF (75 mL), and lithium diisopropylamide (5.91 g, 55.19 mmol) was added at -78 °C. The mixture was stirred for 1 h, and DMF (5.38 g, 73.58 mmol) was added dropwise and stirred for 30 min. Saturated aqueous ammonium chloride (150 mL) was added, and the mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give 2C (7.2 g, 75.55%).

[0089] Step 3: 2D Compositing Under nitrogen gas protection, 2C (7.2 g, 27.79 mmol) and R-tert-butylsulfenamide (4.04 g, 33.35 mmol) were dissolved in THF (75 mL), tetraethyl titanate (9.51 g, 41.69 mmol) was slowly added, and the mixture was reacted at 45 °C for 3 h. The mixture was concentrated under reduced pressure to give a crude product, which was purified by silica gel column flash column chromatography to give 2D (6.80 g, 67.55% yield).

[0090] Step 4: Synthesis of 2E Zinc powder (17.19 g, 262.78 mmol) was added to dry THF (45 mL), and the mixture was purged with nitrogen gas three times. CuCl (5.57 g, 56.31 mmol) was added and the mixture was reacted at 60 °C for 2 h. After cooling to room temperature, ethyl bromoacetate (15.67 g, 93.85 mmol) was slowly added and the mixture was reacted at 60 °C for 1 h. The mixture was then cooled to 0 °C, and a solution of 2D (6.8 g, 18.77 mmol) in THF (10 mL) was added and stirred at 0 °C for 3 h. The mixture was filtered through diatomaceous earth, saturated ammonium chloride solution (200 mL) was added, and the mixture was extracted with ethyl acetate (300 mL x 3), washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash column chromatography to give 2E (7.0 g, 82.81% yield).

[0091] Step 5: Synthesis of 2F 2E (3.0 g, 6.66 mmol) was dissolved in dichloromethane (10 mL), and a 4N solution of hydrochloric acid in dioxane (5 mL) was added, followed by stirring at room temperature for 3 hours. The mixture was concentrated under reduced pressure to give crude product 2F.

[0092] Step 6: Synthesis of 2G Under nitrogen gas protection, crude 2F (2.0 g, 5.78 mmol) was dissolved in dry dichloromethane (35 mL), and triethylamine (1.75 g, 17.34 mmol) and di-tert-butyl dicarbonate (1.51 g, 6.94 mmol) were added at room temperature. The mixture was allowed to react at room temperature for 3 h. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give 2G (1.3 g, 50.40%).

[0093] Step 7: Synthesis of 2H Under nitrogen gas protection, 2G (0.45 g, 1.11 mmol), 2,6-dimethylphenylboronic acid (0.50 g, 3.33 mmol), potassium phosphate (0.47 g, 2.21 mmol), and RuPhos Pd G3 (0.19 g, 0.22 mmol) were dissolved in DMF (8 mL) and water (0.8 mL). The mixture was stirred at 75 °C for 3 h, and then water (20 mL) was added. The mixture was extracted with ethyl acetate (30 mL × 3), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash column chromatography to give 2H (0.3 g, 57.38% yield).

[0094] Step 8: Synthesis of Intermediate 2 2H (300 mg, 0.64 mmol) was dissolved in dichloromethane (2 mL), and a 4N solution of hydrochloric acid in dioxane (2 mL) was added, followed by stirring at room temperature for 3 hours. The mixture was concentrated under reduced pressure to give crude intermediate 2. LC-Ms m / z (ESI): 372.2[M+H] +

[0095] Intermediate 4: [ka]

[0096] Step 1: Synthesis of 4A Under nitrogen gas protection, 1a (1.5 g, 4.32 mmol, see WO2021076890A1 for synthetic steps) and 5-azaspiro[2.4]heptane (0.42 g, 4.32 mmol) were dissolved in 1,2-dichloroethane (10 mL), 0.5 mL of acetic acid was added dropwise, and the mixture was stirred at room temperature for 2 h. Sodium triacetoxyborohydride (1.82 g, 8.64 mmol) was added, and the mixture was stirred for 16 h. After concentration under reduced pressure, 4A (1.0 g, yield 54.05%) was obtained by silica gel column flash column chromatography. LC-Ms m / z (ESI): 429.2[M+H] +

[0097] Step 2: Synthesis of intermediate 4 4A (1.0 g, 2.34 mmol) was dissolved in 3 mL of THF and 1 mL of water, and lithium hydroxide monohydrate (112 mg, 4.68 mmol) was added. The mixture was allowed to react at room temperature for 5 h. The pH was adjusted to 5-6 with 1N hydrochloric acid, and the mixture was concentrated under reduced pressure. Intermediate 4 (650 mg, 69.55%) was obtained by column chromatography. LC-Ms m / z (ESI): 401.2[M+H] +

[0098] Intermediate 5: Preparation of Intermediate 5 [ka]

[0099] Step 1: Synthesis of 5A Under nitrogen gas protection, 1,4-oxazepane hydrochloride (360 mg, 2.59 mmol) was dissolved in 1,2-dichloroethane (8 mL), DIPEA was added, and the mixture was allowed to react at room temperature for 15 min. 1a (0.9 g, 2.59 mmol, see WO2021076890A1 for the synthesis steps) and 0.15 mL of acetic acid were added, and the mixture was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (820 mg, 3.86 mmol) was added, and the mixture was stirred for 16 h. The mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column flash column chromatography to obtain 5A (0.49 g, 43.75% yield). LC-Ms m / z (ESI): 433.7[M+H] +

[0100] Step 2: Synthesis of intermediate 5 5A (0.72 g, 1.66 mmol) was dissolved in 6 mL of ethanol and 0.6 mL of water, and lithium hydroxide monohydrate (210 mg, 4.98 mmol) was added. The mixture was allowed to react at room temperature for 3 h. The pH was adjusted to 4 with 1N hydrochloric acid, and the mixture was concentrated under reduced pressure. Intermediate 5 (530 mg, 78.95% yield) was obtained by column chromatography. LC-Ms m / z (ESI): 405.6[M+H] +

[0101] Intermediate 6: Preparation of Intermediate 6 [ka]

[0102] Step 1: Synthesis of 6B 6A (1720 mg, 6.96 mmol) was dissolved in trifluoroacetic acid (25 mL), triethylsilane (25 mL) was added, and the mixture was allowed to react at room temperature for 48 h. After that, triethylsilane (15 mL) was added and the mixture was stirred overnight. The mixture was concentrated under reduced pressure at 30 °C, and the residue was purified by silica gel column chromatography to obtain crude compound 6B (1700 mg).

[0103] Step 2: Synthesis of 6C Under nitrogen gas protection, crude 6B (1700 mg, 7.29 mmol) was dissolved in dry THF (70 mL), and lithium diisopropylamide (1.56 g, 14.58 mmol) was slowly added at −78° C. After stirring at the same temperature for 0.5 h, dry DMF (2.6 g, 36.45 mmol) was added and the reaction was continued at −78° C. for 1 h. The reaction was quenched by adding ammonium chloride solution (50 mL). The mixture was extracted with ethyl acetate (80 mL × 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The product was purified by silica gel column chromatography to give 6C (1.58 g, 83.02% yield for two steps).

[0104] Step 3: 6D Compositing Under nitrogen gas protection, 6C (1580 mg, 6.05 mmol) and R-tert-butylsulfenamide (1100 mg, 9.7 mmol) were dissolved in THF (35 mL), tetraethyl titanate (2070 mg, 9.07 mmol) was slowly added, and the mixture was reacted at 45 °C for 15 h. The mixture was concentrated under reduced pressure to give a crude product, which was purified by silica gel column flash column chromatography to give 6D (2100 mg, 95.29% yield). LC-Ms m / z (ESI): 364.2[M+H] +

[0105] Step 4: Synthesis of 6E Zinc powder (1.2 g, 18.34 mmol) was added to dry THF (8 mL), and the mixture was purged with nitrogen gas three times. CuCl (389 mg, 3.93 mmol) was added and the mixture was reacted at 60 °C for 2 h. After cooling to room temperature, ethyl bromoacetate (1.09 g, 6.55 mmol) was slowly added and the mixture was reacted at 60 °C for 1 h. The mixture was then cooled to 0 °C, and a solution of 6D (478 mg, 1.31 mmol) in THF (3 mL) was added and stirred at 0 °C for 3 h. The mixture was filtered through diatomaceous earth, saturated ammonium chloride solution (30 mL) was added, and the mixture was extracted with ethyl acetate (40 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash column chromatography to give 6E (498 mg, 84.04% yield). LC-Ms m / z (ESI): 452.4[M+H] +

[0106] Step 5: Synthesis of 6F 6E (448 mg, 0.99 mmol) was dissolved in dichloromethane (3 mL), and a 4N solution of hydrochloric acid in dioxane (2.5 mL) was added, followed by stirring at room temperature for 3 hours. Concentration under reduced pressure gave crude 6F hydrochloride. LC-Ms m / z (ESI): 348.3[M+H] +

[0107] Step 6: Synthesis of 6G 6F was dissolved in THF (4 mL) and water (4 mL), and sodium carbonate (210 mg, 1.98 mmol) and BocO (240 mg, 1.09 mmol) were added. The mixture was stirred at room temperature for 3 h. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The extract was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash column chromatography to give 6G (420 mg, 86.31% yield for two steps). LC-Ms m / z (ESI): 350.0[M+H-Boc] +

[0108] Step 7: Synthesis of 6H Under nitrogen gas protection, 6G (230 mg, 0.51 mmol), 2,6-dimethyl-4-fluorophenylboronic acid (128 mg, 0.77 mmol), and potassium phosphate (325 mg, 1.53 mmol) were added to 1,4-dioxane (2.5 mL) and water (0.25 mL). Xphos-G2-Pd (40 mg, 0.051 mmol) was added and the tube was sealed and reacted at 100 °C for 24 h. After cooling to room temperature, ethyl acetate (40 mL) was added, and the mixture was washed sequentially with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column flash chromatography to give 6H (210 mg, 83.77% yield). LC-Ms m / z (ESI): 392.6[M+H-Boc] +

[0109] Step 8: Synthesis of Intermediate 6 6H (210 mg, 0.43 mmol) was dissolved in THF (3 mL), and a 4N solution of hydrochloric acid in dioxane (2.5 mL) was added, followed by stirring at room temperature for 3 hours. The mixture was concentrated under reduced pressure to give the crude product, Intermediate 6, hydrochloride salt. LC-Ms m / z (ESI): 392.6[M+H] +

[0110] Intermediate 7: Preparation of Intermediate 7 [ka]

[0111] Step 1: Synthesis of 7C Under nitrogen gas protection, 7A (1.0 g, 6.92 mmol) and 7B (2.14 g, 9.0 mmol) were dissolved in ultra-dry DMF (42 mL), potassium carbonate (1.91 g, 13.84 mmol) was added, and the mixture was reacted at 80 °C for 4 h under nitrogen gas atmosphere. 100 mL of ethyl acetate was added to dilute the mixture, and 3 x 50 mL of water was added to wash the organic phase. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give 7C (2.18 g, 99%). LC-Ms m / z (ESI): 287.1[M+H] +

[0112] Step 2: 7D Compositing 7C (2 g, 6.92 mmol) and (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.06 g, 10.38 mmol) were dissolved in a mixture of toluene (30 mL) and water (6 mL). Sodium carbonate (2.2 g, 20.76 mmol) and PdCl(dppf) (506 mg, 0.692 mmol) were added, and the mixture was reacted overnight at 100 °C under a nitrogen atmosphere. 50 mL of water was added to dilute the mixture, and 3 portions of ethyl acetate (80 mL each) were added for extraction. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give 7D (2.27 g, 99%). LC-Ms m / z (ESI): 309.1[M+H] +

[0113] Step 3: Synthesis of 7E 7D (2.27 g, 6.92 mmol) was dissolved in dichloromethane (50 mL), trifluoroacetic acid (15 mL) was added, and the mixture was reacted at room temperature for 2 hours. After concentration under reduced pressure, a crude product of intermediate 7E was obtained. LC-Ms m / z (ESI): 295.1[M+H] +

[0114] Step 4: Synthesis of 7F Under nitrogen gas protection, crude 7E was dissolved in 1,2-dichloroethane (20 mL) and methanol (20 mL). 3-Fluoroazetidine hydrochloride (780 mg, 10.38 mmol) and acetic acid (0.5 mL) were added and stirred at room temperature for 1 h. Sodium triacetoxyborohydride (4.38 g, 20.76 mmol) was added and the mixture was allowed to react overnight. 100 mL of water was added to dilute the mixture, and saturated sodium bicarbonate solution was added to adjust the pH to 9-10. Extraction was performed with 100 mL of dichloromethane (3 times). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give 7F (1.25 g, 48% yield over two steps). LC-Ms m / z (ESI): 354.2[M+H]+

[0115] Step 5: Synthesis of Intermediate 7 7F (1.25 g, 3.54 mmol) was dissolved in 15 mL of ethanol and 1.5 mL of water, and lithium hydroxide monohydrate (446 mg, 10.62 mmol) was added. The mixture was allowed to react at room temperature for 3 h. The pH was adjusted to 4 with 1N hydrochloric acid, and the mixture was concentrated under reduced pressure. Intermediate 7 (700 mg, 61%) was obtained by column chromatography. LC-Ms m / z (ESI): 362.2[M+H] +

[0116] Example 1: Preparation of Compound 1 [ka]

[0117] Step 1: Fabrication of 1b Under nitrogen gas protection, 1a (3.0 g, 8.64 mmol, see WO2021076890A1 for synthesis steps) and methylamine hydrochloride (1.16 g, 17.28 mmol) were dissolved in 1,2-dichloroethane (30 mL), 5 drops of acetic acid were added, and the mixture was stirred at room temperature for 2 h. Sodium triacetoxyborohydride (3.65 g, 17.28 mmol) was added, and the mixture was stirred for 16 h. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column flash column chromatography to obtain 1b (1.0 g, 31.95% yield). LC-Ms m / z (ESI): 363.2[M+H] +

[0118] Step 2: Fabrication of 1d Under nitrogen gas protection, 1b (1.0 g, 2.76 mmol) and 1c (1.02 g, 5.52 mmol) were dissolved in DMF (30 mL) and potassium carbonate (1.14 g, 8.28 mmol), stirred at 60 °C for 24 h, concentrated under reduced pressure to give a crude product, which was purified by silica gel column flash column chromatography to give 1d (1.0 g, 80.08% yield). LC-Ms m / z (ESI): 453.2[M+H] +

[0119] Step 3: Fabrication of 1e 1d (1.0 g, 2.21 mmol) was dissolved in 3 mL of THF and 1 mL of water, and lithium hydroxide monohydrate (112 mg, 4.68 mmol) was added. The mixture was allowed to react at room temperature for 5 h. The pH was adjusted to 5-6 with 1N hydrochloric acid, and the mixture was concentrated under reduced pressure. 1e (700 mg, 74.62%) was obtained by column chromatography. LC-Ms m / z (ESI): 425.2[M+H] +

[0120] Step 4: Fabrication of 1f Under nitrogen gas protection, 1e (280 mg, 0.66 mmol) was dissolved in dry DMF (1.5 mL), and HATU (376 mg, 0.99 mmol) and DIPEA (225 mg, 1.74 mmol) were added. After stirring at room temperature for 40 min, intermediate 1 (234 mg, 0.66 mmol) was added and the mixture was allowed to react at room temperature overnight. Ethyl acetate (80 mL) was added, and the mixture was washed sequentially with water (20 mL × 2) and saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 1f (300 mg) was obtained by silica gel column chromatography. LC-Ms m / z (ESI): 762.4[M+H] +

[0121] Step 5: Preparation of Compounds 1-1 and 1-2 1f (300 mg) was dissolved in 3 mL of THF and 1 mL of water, and lithium hydroxide monohydrate (45 mg, 1.08 mmol) was added. The mixture was allowed to react at room temperature for 5 h. The pH was adjusted to 5-6 with 1N hydrochloric acid, and the mixture was concentrated under reduced pressure to give crude compound 1. The crude product was separated and purified by prep-HPLC (Method 1) to give compound 1-1 (15 mg, Rt = 4.325 min, yield 5.19%) and compound 1-2 (15 mg, Rt = 4.429 min, yield 5.19%).

[0122] Compound 1-1: LC-Ms m / z (ESI): 734.3[M+H] + 1H NMR (400MHz, Methanol-d4) δ 7.93 (s,1H),7.17 (s,1H),6.84 - 6.72 (m,4H),5.75 (t,1H),5.34 - 5.28 (m,1H),3.54 - 3.43 (m,1H),3.40 - 3.33 (m,2H),3.09 - 2.95 (m,5H),2.95 - 2.89 (m,2H),2.86 - 2.80 (m,2H),2.44 - 2.36 (m,2H),2.19 - 2.08 (m,1H),2.02 - 1.93 (m,4H),1.88 (s,3H),1.80 (s,4H),1.55 - 1.41 (m,2H),1.01 - 0.91 (m,6H). Compound 1-2: LC-Ms m / z (ESI): 734.3[M+H] + 1 H NMR (400MHz, Methanol-d4) δ 7.93 (s,1H),7.22 (s,1H),6.89 (s,1H),6.85 (s,1H),6.84 - 6.79 (m,2H),5.73 (t,1H),5.31 (t,1H),3.53 - 3.45 (m,1H),3.41 - 3.33 (m,3H),3.08 - 2.95 (m,7H),2.89 - 2.76 (m,2H),2.49 - 2.42 (m,2H),2.21 - 2.09 (m,1H),2.06 - 2.00 (m,2H),1.94 (s,6H),1.85 - 1.78 (m,3H),1.54 - 1.45 (m,1H),1.38 - 1.27 (m,1H),0.92 - 0.83 (m,6H).

[0123] Example 2: Production of Compound 2

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[0124] Synthesis of ステップ1:2b Under nitrogen gas protection, 2a (6.0 g, 15.62 mmol; see WO2021076890A1 for synthetic steps) was dissolved in 1,4-dioxane (60 mL) and water (6 mL). N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (5.8 g, 18.74 mmol), Pd(PPh3)4 (1.8 g, 1.56 mmol), and potassium carbonate (6.48 g, 46.86 mmol) were added sequentially and reacted at 70 °C for 30 h. After the reaction was complete, the mixture was extracted with ethyl acetate (180 mL), washed with water (50 mL × 2) and saturated brine (50 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to give 2b (5.0 g, yield: 65.79%). LC-Ms m / z (ESI): 487.3[M+H] +

[0125] Step 2: Synthesis of 2c Under hydrogen gas conditions, 2b (5.0 g, 10.28 mmol) was dissolved in methanol (50 mL), and an equal amount of Pd / C was added. The mixture was allowed to react at room temperature for 2 h. The solid was removed by filtration, and the filtrate was concentrated and purified by chromatography to give 2c (2.5 g, yield: 49.78%). LC-Ms m / z (ESI): 489.3[M+H] +

[0126] Step 3: 2D Compositing 2c (480.0 mg, 0.98 mmol) was dissolved in dichloromethane (5 mL), and hydrochloric acid-1,4-dioxane (3 mL) was added and reacted for 1 h. After the reaction was completed, the solvent was removed under reduced pressure to obtain crude compound 2d. LC-Ms m / z (ESI): 389.2[M+H] +

[0127] Step 4: Synthesis of 2e 2d (350.0 mg, 0.90 mmol) was dissolved in methanol (4 mL), and triethylamine (273.21 mg, 2.7 mmol) and (2,2-difluorocyclopropyl)methanesulfonic acid methyl ester (201.07 mg, 1.08 mmol) were added sequentially. The reaction was allowed to proceed at 60°C for 16 h. After the reaction was completed, the product was purified by chromatography to give 2e (280.0 mg, yield: 65.02%). LC-Ms m / z (ESI): 465.90[M+H] +

[0128] Step 5: Synthesis of 2f 2e (280.0 mg, 0.60 mmol) was dissolved in methanol (2 mL) and water (1 mL), and lithium hydroxide (28.47 mg, 1.20 mmol) was added. The mixture was allowed to react at room temperature for 1-2 h. After the reaction was complete, the product was purified by reverse-phase chromatography to give 2f (100.0 mg, 37.0% yield). LC-Ms m / z (ESI): 451.70[M+H] +

[0129] Step 6: Synthesis of 2g Under nitrogen gas protection, intermediate 1 (80.0 mg, 0.23 mmol) was dissolved in dry DMF (1.5 mL) and HOBt (62.16 mg, 0.46 mmol), EDCI (88.18 mg, 0.46 mmol), and DIPEA (118.90 mg, 0.92 mmol) were added sequentially. After stirring at room temperature for 40 min, 2e (100.0 mg, 0.23 mmol) was added and the mixture was allowed to react overnight at room temperature. Ethyl acetate (80 mL) was added, and the mixture was washed sequentially with water (20 mL × 2) and saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 2g (50.0 mg, yield: 28.59%) was obtained by silica gel column chromatography. LC-Ms m / z (ESI): 788.4[M+H] +

[0130] Step 7: Synthesis of Compound 2-1 and Compound 2-2 Compound 2g (50.0 mg, 0.063 mmol) was dissolved in 1 mL of methanol and 0.5 mL of water, and lithium hydroxide monohydrate (3.02 mg, 0.13 mmol) was added. The mixture was allowed to react at room temperature for 30 min. The pH was adjusted to 5-6 with 1N hydrochloric acid, and the mixture was concentrated under reduced pressure to give crude compound 2. The crude product was separated and purified by prep-HPLC (Method 2) to give the trifluoroacetate salt of compound 2-1 (4.0 mg, Rt = 5.955 min, yield 8.36%) and the trifluoroacetate salt of compound 2-2 (3.0 mg, Rt = 5.989 min, yield 6.27%).

[0131] Trifluoroacetate salt of compound 2-1: LC-Ms m / z (ESI): 760.3[M+H] + 1 H NMR (400MHz,Methanol-d4) δ 9.16 (d,1H),7.81 (s,1H),7.16 (d,1H),6.83 - 6.74 (m,3H),6.72 (d,1H),5.76 (t,1H),5.38 - 5.29 (m,1H),4.55 - 4.45 (m,1H),3.77 - 3.61 (m,2H),3.50 - 3.39 (m,1H),3.26 - 3.10 (m,3H),3.04 - 2.79 (m,6H),2.45 - 2.35 (m,2H),2.22 - 2.07 (m,2H),2.04 - 1.93 (m,4H),1.88 - 1.81 (m,4H),1.78 (s,3H),1.65 (d,1H),1.53 - 1.41 (m,2H),1.04 - 0.91 (m,6H). Trifluoroacetate salt of compound 2-2: LC-Ms m / z (ESI): 760.3[M+H] + 1H NMR (400MHz,Methanol-d4) δ 7.87 (s,1H),7.23 (d,1H),6.91 - 6.74 (m,4H),5.77 - 5.70 (m,1H),5.36 - 5.24 (m 1H),4.56 - 4.45 (m,1H),3.79 - 3.64 (m,2H),3.48 - 3.39 (m,1H),3.26 - 3.12 (m,2H),3.00 - 2.93 (m,2H),2.90 - 2.76 (m,2H),2.49 - 2.38 (m,2H),2.22 - 1.99 (m,5H),1.94 (s,6H),1.88 - 1.78 (m,2H),1.77 - 1.68 (m,1H),1.68 - 1.61 (m,2H),1.55 - 1.43 (m,1H),1.37 - 1.26 (m,2H),0.96 - 0.78 (m,6H).

[0132] Example 3: Preparation of Compound 3 [ka]

[0133] Step 1: Fabrication of 3b 1a (1.4 g crude), 3a (1.2 g, 7.2 mmol), and glacial acetic acid (220 mg, 3.6 mmol) were dissolved in 1,2-dichloroethane (20 mL) and stirred at room temperature for 30 min under nitrogen gas protection. Sodium triacetoxyborohydride (1.5 g, 7.2 mmol) was added and the mixture was stirred at room temperature overnight. 50 mL of ethyl acetate was added, and the mixture was washed sequentially with water (30 mL × 1) and saturated brine (30 mL × 1). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 3b (1.05 g, 71% yield) was obtained by column chromatography. LCMS m / z=413.2[M+H] +

[0134] Step 2: Fabrication of 3c 3b (1.05 g, 2.55 mmol) was dissolved in ethanol (15 mL) and water (1.5 mL), lithium hydroxide monohydrate (321 mg, 7.65 mmol) was added, and the mixture was allowed to react at room temperature for 5 h. The mixture was concentrated under reduced pressure to remove the solvent, and 20 mL of water was added to the residue. The pH was adjusted to approximately 2-3 with 1N hydrochloric acid. The aqueous phase was extracted with ethyl acetate (50 mL x 2), and the organic phases were combined. The organic phase was washed with saturated brine (30 mL x 1), and the organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (0.1% trifluoroacetic acid) to give 3c (410 mg, 42% yield). LCMS m / z=385.2[M+H] + ;

[0135] Step 3: 3D Fabrication 3c (0.200 g, 0.52 mmol) and intermediate 1 (0.18 g, 0.52 mmol) were dissolved in 5 mL of DMF, and HOBT (0.14 g, 1.04 mmol), DIPEA (0.27 g, 2.05 mmol), and EDCI (0.20 g, 1.04 mmol) were added. The mixture was stirred at room temperature for 2 h. 30 mL of ethyl acetate was added, and the mixture was washed twice with water (20 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain the target compound 3d as a yellow oil (0.21 g, yield: 55.95%). LCMS m / z=722.90[M+H] + ;

[0136] Step 4: Preparation of Compounds 3-1 and 3-2 3d (0.18 g, 0.25 mmol) was dissolved in 3 mL of THF and 1 mL of water, and lithium hydroxide monohydrate (31.5 mg, 0.75 mmol) was added. The mixture was allowed to react at room temperature for 5 h. The pH was adjusted to 5-6 with 1N hydrochloric acid, and the mixture was concentrated under reduced pressure to give crude compound 3. The crude product was separated and purified by prep-HPLC (Method 1) to give compound 3-1 (25 mg, Rt = 4.300 min, yield: 14%) and compound 3-2 (30 mg, Rt = 4.398 min, yield: 17%).

[0137] Compound 3-1: LC-Ms m / z (ESI): 694.3[M+H] + 1 H NMR (400MHz, Methanol-d4) δ 9.16 (d,1H), δ 7.89 (s,1H), 7.19 (d,1H), 6.87 - 6.73 (m,4H), 5.80 - 5.69 (m,1H), 5.40 - 5.29 (m,1H), 4.54 - 4.33 (m,2H),4.29 - 4.12 (m,2H),3.79 - 3.70 (m,1H),3.49 - 3.35 (m,2H),2.98 - 2.90 (m,3H),2.88 - 2.76 (m,4H),2.44 - 2.37 (m,2H),2.04 - 1.93 (m,4H),1.89 (s,3H),1.82 (s,3H),1.52 - 1.39 (m,1H),1.01 - 0.92 (m,6H). Compound 3-2: LC-Ms m / z (ESI): 694.3[M+H] + 1 H NMR (400MHz, Methanol-d4) δ 7.89 (s,1H),7.24 (d,1H),6.93 - 6.79 (m,4H),5.78 - 5.69 (m,1H),5.38 - 5.29 (m,1H),4.57 - 4.35 (m,2H),4.31 - 4.16 m,2H),3.85 - 3.69 (m,1H),3.54 - 3.35 (m,2H),3.07 - 2.94 (m,3H),2.94 - 2.77 (m,4H),2.49 - 2.41 (m,2H),2.08 - 1.98 (m,2H),1.94 (s,6H),1.85 - 1.76 (m,2H),1.39 - 1.27 (m,1H),0.93 - 0.81 (m,6H).

[0138] Example 4: Production of Compound 4

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[0139] Step 1: Synthesis of 4b Under nitrogen gas protection, 1D (1.8 g, 7.06 mmol), 2,6-dimethylbenzeneboronic acid (1.27 g, 8.47 mmol), and cesium carbonate (6.90 g, 21.18 mmol) were added to 1,4-dioxane (40.0 mL) and water (4.0 mL). Pd(PPh3)4 (1.63 g, 1.41 mmol) was added and the mixture was reacted in a sealed tube at 100 °C for 5 h. After cooling to room temperature, the mixture was filtered through diatomaceous earth, added with ethyl acetate (50 mL), washed sequentially with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column flash chromatography to give 4b (1.4 g, yield: 70.73%).

[0140] Step 2: Synthesis of 4c Under nitrogen gas protection, 4b (1.4 g, 4.99 mmol) was dissolved in dry THF (30 mL), and lithium aluminum tetrahydrogen (380 mg, 10.03 mmol) was slowly added at 0 °C. The mixture was then reacted at room temperature for 1 h. 10% aqueous sodium sulfate solution (20 mL) was added, filtered, and the solvent was removed under reduced pressure to give 4c (800 mg, 67.27%).

[0141] Step 3: 4D Compositing Under nitrogen gas protection, 4c (800 mg, 3.17 mmol) was dissolved in dry dichloromethane (20 mL), sodium bicarbonate (0.53 g, 6.31 mmol) and Dess-Martin oxidant (1.75 g, 4.13 mmol) were added, and the mixture was allowed to react at room temperature for 1 h. Saturated sodium thiosulfate solution (10 mL) and saturated sodium bicarbonate solution (10 mL) were added, and the mixture was extracted with dichloromethane (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. 4d (650 mg, 81.91%) was obtained by silica gel column chromatography.

[0142] Step 4: Synthesis of 4e Under nitrogen gas protection, 4d (600 mg, 2.40 mmol) and R-tert-butylsulfenamide (0.35 g, 2.88 mmol) were dissolved in THF (20 mL), tetraethyl titanate (1.64 g, 7.22 mmol) was slowly added, and the mixture was reacted at 45 °C for 15 h. The mixture was concentrated under reduced pressure to give a crude product, which was purified by silica gel column flash column chromatography to give 4e (800 mg, 94.29% yield). LC-Ms m / z (ESI): 354.5[M+H] +

[0143] Step 5: Synthesis of 4f Zinc powder (1.81 g, 27.72 mmol) was added to dry THF (5 mL), and the mixture was purged with nitrogen gas three times. CuCl (590 mg, 5.94 mmol) was added and the mixture was reacted at 60 °C for 2 h. After cooling to room temperature, ethyl bromoacetate (1.65 g, 9.9 mmol) was slowly added and the mixture was reacted at 60 °C for 1 h. The mixture was then cooled to 0 °C, and a solution of 4e (700 mg, 1.98 mmol) in THF (1 mL) was added and stirred at 0 °C for 3 h. The mixture was filtered through diatomaceous earth, saturated ammonium chloride solution (20 mL) was added, extracted with ethyl acetate (30 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash column chromatography to give 4f (750 mg, 85.77% yield). LC-Ms m / z (ESI): 442.6[M+H] +

[0144] Step 6: Synthesis of 4g 4f (600 mg, 1.36 mmol) was dissolved in THF (2 mL), and 4N hydrochloric acid in dioxane (2 mL) was added, followed by stirring at room temperature for 3 hours. Concentration under reduced pressure gave a crude product (4 g). LC-Ms m / z (ESI): 338.4[M+H] +

[0145] Step 7: Synthesis of compound 4h Under nitrogen gas protection, intermediate 3 (260 mg, 0.74 mmol, see WO2021076890A1 for synthetic steps) was dissolved in dry DMF (10 mL) and EDCI (280 mg, 1.46 mmol), HOBT (200 mg, 1.48 mmol), and DIPEA (290 mg, 2.24 mmol) were added. After stirring at room temperature for 40 min, crude 4g (250 mg, 0.74 mmol) was added and reacted at room temperature overnight. Ethyl acetate (80 mL) was added, and the mixture was washed sequentially with water (20 mL × 2) and saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 4h (350 mg, yield: 70.83%) was obtained by silica gel column chromatography. LC-Ms m / z (ESI): 668.8[M+H] +

[0146] Step 8: Synthesis of Compounds 4-1 and 4-2 4h (350 mg, 0.52 mmol) was dissolved in 6 mL of THF and 2 mL of water, and lithium hydroxide monohydrate (31 mg, 1.29 mmol) was added. The mixture was allowed to react at room temperature for 5 h. The pH was adjusted to 5-6 with 1N hydrochloric acid, and the mixture was concentrated under reduced pressure to give crude compound 4. The crude product was separated and purified by prep-HPLC (Method 2) to give the trifluoroacetate salt of compound 4-1 (16 mg, Rt = 4.135 min, yield 4.81%) and compound 4-2 (18 mg, Rt = 4.039 min, yield 5.41%).

[0147] Trifluoroacetate salt of compound 4-1: LC-Ms m / z (ESI): 640.7[M+H] + 1H NMR (400MHz,Methanol-d4) δ 9.15 (d,1H),7.92 (s,1H),7.22 (s,1H),7.15 - 7.05 (m,3H),6.88 (s,1H),6.84 - 6.79 (m,1H),5.74 (t,1H),5.35 - 5.28 (m,1H),3.66 - 3.27 (m,2H),3.05 - 2.91 (m,10H),2.90 - 2.77 (m,2H),2.49 - 2.40 (m,2H),2.07 - 1.98 (m,2H),1.93 (s,6H),1.86 - 1.78 (m,2H),1.39 - 1.28 (m,1H),0.93 - 0.81 (m,6H). Trifluoroacetate salt of compound 4-2: LC-Ms m / z (ESI): 640.7[M+H] + 1 H NMR (400MHz,Methanol-d4) δ 9.17 (d,1H),7.92 (s,1H),7.16 (d,1H),7.13 - 6.99 (m,3H),6.79 (s,1H),6.76 (d,1H),5.75 (t,1H),5.38 - 5.27 (m,1H),3.31 - 3.19 (m,2H),3.06 - 2.87 (m,10H),2.87 - 2.75 (m,2H),2.44 - 2.34 (m,2H),2.04 - 1.92 (m,4H),1.87 (s,3H),1.80 (s,3H),1.50 - 1.41 (m,1H),1.01 - 0.90 (m,6H).

[0148] Example 5: Preparation of Compound 5 [ka] The crude product of compound 5 was obtained by following the method for preparing compound 3. The crude product was separated and purified by prep-HPLC (Method 1) to obtain compound 5-1 (2 mg, Rt=4.184 min) and compound 5-2 (2 mg, Rt=4.283 min).

[0149] Compound 5-1: LC-Ms m / z (ESI): 710.3[M+H] + 1 H NMR (400MHz, Methanol-d4) δ 7.85 (s,1H),7.17 (t,1H),7.12 - 7.02 (m,3H),6.83 (s,1H),5.83 - 5.76 (m,1H),5.73 - 5.67 (m,1H),5.36 - 5.32 (m,1H),4.46 - 4.37 (m,1H),4.26 - 4.15 (m,2H),3.79 - 3.72 (m,1H),3.49 - 3.38 (m,2H),3.15 - 3.08 (m,1H),2.95 - 2.93 (m,1H),2.89 - 2.81 (m,2H),2.19 (t,1H),2.09 - 2.00 (m,4H),1.99 - 1.91 (m,4H),1.89 (s,3H),1.65 - 1.55 (m,1H),1.00 - 0.91 (m,6H). Compound 5-2: LC-Ms m / z (ESI): 710.3[M+H] + 1 H NMR (400MHz, Methanol-d4) δ 7.88 (s,1H),7.23 - 7.03 (m,4H),6.89 (s,1H),5.84 - 5.77 (m,1H),5.71 (t,1H),5.34 (t,1H),4.51 - 4.37 (m,1H),4.27 - 4.16 (m,1H),3.82 - 3.71 (m,1H),3.52 - 3.39 (m,3H),3.15 - 3.03 (m,2H),2.97 - 2.83 (m,3H),2.24 - 2.14 (m,2H),2.10 - 1.95 (m,7H),1.92 - 1.78 (m,2H),1.66 - 1.53 (m,1H),0.95 - 0.79 (m,6H).

[0150] Example 6: Production of Compound 6

change

[0151] Compound 6-1: LC-Ms m / z (ESI): 726.3[M+H] + 1 H NMR (400MHz,Methanol-d4) δ 7.75 (s,1H),7.14 (t,1H),7.10 - 7.01 (m,2H),6.96 (t,1H),6.78 (s,1H),5.77 - 5.70 (m,1H),5.68 - 5.62 (m,1H),2.89 - 2.80 (m,1H),2.81 - 2.73 (m,3H),2.74 - 2.62 (m,3H),2.61 - 2.51 (m,4H),2.02 (s,3H),1.99 (s,3H),1.97 - 1.89 (m,2H),1.86 - 1.79 (m,4H),1.44 - 1.36 (m,1H),0.98 - 0.91 (m,6H),0.62 - 0.52 (m,4H). Compound 6-2: LC-Ms m / z (ESI): 726.3[M+H] + 1H NMR (400MHz,Methanol-d4) δ 8.51 (s,1H),7.83 (s,1H),7.20 - 7.15 (m,1H),7.13 - 7.05 (m,3H),6.90 (s,1H),5.84 - 5.75 (m,1H),5.64 (t,1H),3.56 - 3.47 (m,2H),3.44 - 3.37 (m,1H),3.25 (s,2H),3.03 - 2.94 (m,2H),2.88 - 2.78 (m,1H),2.60 - 2.51 (m,1H),2.09 - 1.97 (m,11H),1.94 -1.84 (m,1H),1.77 - 1.63 (m,1H),1.40 - 1.32 (m,1H),0.94 - 0.85 (m,6H),0.85 - 0.70 (m,4H).

[0152] Example 7: Preparation of Compound 7 [ka] The crude product of compound 7 was obtained by following the method for preparing compound 1. The crude product was separated and purified by prep-HPLC (Method 1) to obtain compound 7-1 (20 mg, Rt = 4.323 min) and compound 7-2 (20 mg, Rt = 4.240 min).

[0153] Compound 7-1: LC-Ms m / z (ESI): 750.3[M+H] + 1H NMR (400MHz,Methanol-d4) δ 7.85 (d,1H),7.20 - 7.13 (m,1H),7.12 - 7.01 (m,3H),6.80 (s,1H),5.77 (t,1H),5.65 (t,1H),3.34 (s,3H),2.88 - 2.55 (m,6H),2.49 - 2.38 (m,1H),2.36 - 2.30 (m,2H),2.10 - 1.94 (m,9H),1.82 - 1.75 (m,2H),1.55 - 1.44 (m,1H),1.32 - 1.23 (m,1H),1.10 - 1.01 (m,1H),0.93 - 0.80 (m,6H). Compound 7-2: LC-Ms m / z (ESI): 750.3[M+H] + 1 H NMR (400MHz,Methanol-d4) δ 7.75 (d,1H),7.14 (t,1H),7.09 - 7.01 (m,2H),6.96 (t,1H),6.78 (s,1H),5.74 (t,1H),5.69 - 5.60 (m,1H),3.34 (s,3H),2.91 - 2.82 (m,1H),2.74 - 2.51 (m,5H),2.48 - 2.34 (m,1H),2.35 - 2.28 (m,2H),2.02 (s,3H),1.98 (s,3H),1.93 (t,1H),1.84 (s,3H),1.77 - 1.68 (m,1H),1.53 - 1.35 (m,2H),1.09 - 0.99 (m,1H),0.98 - 0.85 (m,6H).

[0154] Example 8: Preparation of Compound 8 [ka] The crude product of compound 8 was obtained by referring to the preparation method of compound 4. The crude product was separated and purified by prep-HPLC (Method 2) to obtain the trifluoroacetate salt of compound 8-1 (25 mg, Rt=4.269 min, yield 6.53%) and the trifluoroacetate salt of compound 8-2 (28 mg, Rt=4.171 min, yield 7.32%).

[0155] Trifluoroacetate of Compound 8-1: LC-Ms m / z (ESI): 696.7 [M+H] + 1 H NMR (400 MHz, Methanol-d4) δ 7.90 (s, 1H), 7.21 (s, 1H), 7.15 - 7.02 (m, 3H), 6.87 (s, 1H), 6.83 (d, 1H), 5.74 - 5.66 (m, 1H), 5.34 (t, 1H), 3.93 - 3.87 (m, 2H), 3.83 (t, 2H), 3.49 - 3.42 (m, 2H), 3.42 - 3.37 (m, 2H), 3.35 - 3.30 (m, 2H), 3.05 - 2.90 (m, 4H), 2.80 - 2.74 (m, 2H), 2.45 (t, 2H), 2.19 - 2.09 (m, 2H), 2.08 - 1.96 (m, 2H), 1.93 (s, 6H), 1.89 - 1.74 (m, 2H), 1.39 - 1.28 (m, 1H), 0.92 - 0.84 (m, 6H). Trifluoroacetate of Compound 8-2: LC-Ms m / z (ESI): 696.7 [M+H] + 1 H NMR (400 MHz, Methanol-d4) δ 7.92 (s, 1H), 7.16 (s, 1H), 7.13 - 6.99 (m, 3H), 6.81 - 6.72 (m, 2H), 5.78 - 5.70 (m, 1H), 5.37 - 5.28 (m, 1H), 3.95 - 3.87 (m, 2H), 3.86 - 3.77 (m, 2H), 3.48 - 3.42 (m, 2H), 3.42 - 3.37 (m, 2H), 3.30 - 3.20 (m, 2H), 3.06 - 2.88 (m, 4H), 2.87 - 2.77 (m, 2H), 2.43 - 2.36 (m, 2H), 2.17 - 2.09 (m, 2H), 2.03 - 1.91 (m, 4H), 1.87 (s, 3H), 1.80 (s, 3H), 1.51 - 1.39 (m, 1H), 0.99 - 0.91 (m, 6H).

[0156] Example 9: Preparation of Compound 9 [ka]

[0157] Step 1: Synthesis of 9a 1a (3.0 g, 8.64 mmol) was dissolved in 30 mL of ultra-dry DCE, and diethylamine (0.95 g, 12.96 mmol) and AcOH (0.10 mg, 1.73 mmol) were added sequentially. The mixture was allowed to react at room temperature for 1 h. Sodium triacetoxyborohydride (3.66 g, 17.28 mmol) was added, and the reaction was continued for 16 h. 200 mL of ethyl acetate and 100 mL of saturated aqueous NaHCO3 were added, followed by extraction and separation. The aqueous phase was extracted with ethyl acetate (100 mL × 1). The combined ethyl acetate layer was washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography to give 9a (2.8 g, 80.12% yield). LC-Ms m / z (ESI): 405.3[M+H] +

[0158] Step 2: Synthesis of 9b 9a (2.8 g, 6.92 mmol) was dissolved in THF (30 mL) and water (10 mL), lithium hydroxide (331.55 mg, 13.85 mmol) was added, and the reaction was continued for 30 min. Purification by reverse phase chromatography column gave 9b (1.2 g, yield: 46.05%). LC-Ms m / z (ESI): 377.2[M+H] +

[0159] Step 3: Synthesis of 9c Under nitrogen gas protection, intermediate 1 (300.0 mg, 0.84 mmol) was dissolved in dry DMF (5 mL) and HOBt (227.00 mg, 1.68 mmol), EDCI (322.06 mg, 1.68 mmol), and DIPEA (434.25 mg, 3.36 mmol) were added sequentially. After stirring at room temperature for 40 min, compound 9b (316.18 mg, 0.84 mmol) was added and the mixture was allowed to react overnight at room temperature. Ethyl acetate (100 mL) was added, and the mixture was washed sequentially with water (40 mL × 2) and saturated brine (40 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 9c (400.0 mg, 66.71% yield) was obtained by silica gel column chromatography. LC-Ms m / z (ESI): 714.4[M+H] +

[0160] Step 4: Synthesis of Compound 9-1 and Compound 9-2 9d (400.0 mg, 0.56 mmol) was dissolved in 3 mL of methanol and 1 mL of water, and lithium hydroxide monohydrate (27.0 mg, 1.12 mmol) was added. The mixture was allowed to react at room temperature for 30 min. The pH was adjusted to 5-6 with 1N hydrochloric acid, and the mixture was concentrated under reduced pressure to give crude compound 9. The crude product was separated and purified by prep-HPLC (Method 2) to give the trifluoroacetate salt of compound 9-1 (76.0 mg, 8.36% yield) and the trifluoroacetate salt of compound 9-2 (81.0 mg, 6.27% yield).

[0161] Trifluoroacetate salt of compound 9-1: LC-Ms m / z (ESI): 686.2[M+H] + 11H NMR (400 MHz, CD3OD) δ 7.91 (s, 1H), 7.19 (s, 1H), 6.82 - 6.73 (m, 4H), 5.74 - 5.66 (m, 1H), 5.35 - 5.27 (m, 1H), 3.21 - 3.06 (m, 6H), 3.00 - 2.85 (m, 4H), 2.73 - 2.63 (m, 2H), 2.43 - 2.35 (m, 2H), 2.02 - 1.92 (m, 4H), 1.89 (s, 3H), 1.82 (s, 3H), 1.48 - 1.36 (m, 1H), 1.26 (t, 6H), 0.99 - 0.90 (m, 6H). Trifluoroacetate of Compound 9-2 LC-Ms m / z (ESI): 686.2 [M+H] + 1 1H NMR (400 MHz, CD3OD) δ 7.86 (s, 1H), 7.22 (s, 1H), 6.90 - 6.77 (m, 4H), 5.66 - 5.57 (m, 1H), 5.41 - 5.33 (m, 1H), 3.30 - 3.17 (m, 6H), 3.03 - 2.90 (m, 4H), 2.68 - 2.53 (m, 2H), 2.48 - 2.38 (m, 2H), 2.07 - 1.89 (m, 9H), 1.78 - 1.67 (m, 1H), 1.43 - 1.34 (m, 1H), 1.29 (t, 6H), 0.92 - 0.82 (m, 6H).

[0162] Example 10: Preparation of Compound 10

Chemical Structure

[0163] Step 1: Synthesis of 10a Under nitrogen gas protection, 1D (2.0 g, 7.84 mmol), 2,6-dimethyl-4-methoxyphenylboronic acid (2.82 g, 15.68 mmol), and cesium carbonate (7.66 g, 23.52 mmol) were added to 1,4-dioxane (30.0 mL) and water (3.0 mL). Pd(PPh3)4 (0.29 g, 0.78 mmol) was added and the mixture was reacted in a sealed tube at 100 °C for 12 h. After cooling to room temperature, the mixture was filtered through diatomaceous earth, added with ethyl acetate (50 mL), washed sequentially with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column flash chromatography to give 10a (1.6 g, yield: 65.75%).

[0164] Step 2: Synthesis of 10b Under nitrogen gas protection, 10a (1.6 g, 5.15 mmol) was dissolved in dry THF (10 mL), and lithium aluminum tetrahydrogen (8 mL) was slowly added at 0 °C. The mixture was then reacted at room temperature for 1 h. 10% aqueous sodium sulfate solution (20 mL) was added, filtered, and the solvent was removed under reduced pressure. 10b (1.0 g, yield: 68.76%) was obtained by silica gel column flash chromatography.

[0165] Step 3: Synthesis of 10c Under nitrogen gas protection, compound 10b (1.0 g, 3.54 mmol) was dissolved in dry dichloromethane (10 mL). Sodium bicarbonate (0.6 g, 7.08 mmol) and Dess-Martin oxidant (2.25 g, 5.31 mmol) were added at room temperature, and the mixture was allowed to react for 1 h. Saturated sodium thiosulfate solution (10 mL) and saturated sodium bicarbonate solution (10 mL) were added, and the mixture was extracted with dichloromethane (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. 10c (0.8 g, 80.58% yield) was obtained by silica gel column chromatography.

[0166] Step 4: Synthesis of 10d Under nitrogen gas protection, 10c (1.4 g, 4.99 mmol) and R-tert-butylsulfenamide (0.82 g, 5.99 mmol) were dissolved in THF (15 mL), tetraethyl titanate (1.71 g, 7.50 mmol) was slowly added, and the mixture was reacted at 45 °C for 15 h. The mixture was concentrated under reduced pressure to give a crude product, which was purified by silica gel column flash column chromatography to give 10d (1.9 g, yield: 99.27%).

[0167] Step 5: Synthesis of 10e Zinc powder (4.77 g, 72.94 mmol) was added to dry THF (5 mL), and the mixture was purged with nitrogen gas three times. CuCl (1.55 g, 15.63 mmol) was added and the mixture was reacted at 60 °C for 2 h. After cooling to room temperature, ethyl bromoacetate (4.35 g, 26.05 mmol) was slowly added and the mixture was reacted at 60 °C for 1 h. The mixture was then cooled to 0 °C, and a solution of 10d (2.0 g, 5.21 mmol) in THF (1 mL) was added and stirred at 0 °C for 3 h. The mixture was filtered through diatomaceous earth, saturated ammonium chloride solution (80 mL) was added, extracted with ethyl acetate (100 mL x 3), washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash column chromatography to give 10e (2.0 g, 81.39% yield).

[0168] Step 6: Synthesis of 10f 10e (500.0 mg, 1.06 mmol) was dissolved in THF( To the mixture was added 4N hydrochloric acid in dioxane (5 mL), and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to give crude product 10f. LC-Ms m / z (ESI): 368.0[M+H] +

[0169] Step 7: Synthesis of 10g Under nitrogen gas protection, intermediate 3 (189.6 mg, 0.54 mmol) was dissolved in dry DMF (1.5 mL) and HOBt (147.08 mg, 1.090 mmol), EDCI (168.98 mg, 1.09 mmol), and DIPEA (220.3 mg, 2.18 mmol) were added sequentially. After stirring at room temperature for 40 min, crude 10f (200.0 mg, 0.54 mmol) was added and the mixture was allowed to react overnight at room temperature. Ethyl acetate (80 mL) was added, and the mixture was washed sequentially with water (20 mL × 2) and saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purified by silica gel column chromatography to give 10g (180.0 mg, yield: 47.39%). LC-Ms m / z (ESI): 698.3[M+H] +

[0170] Step 8: Synthesis of Compound 10-1 and Compound 10-2 10g (180.0 mg, 0.26 mmol) was dissolved in 3 mL of THF and 1 mL of water, and lithium hydroxide monohydrate (12.45 mg, 0.52 mmol) was added and reacted at room temperature for 5 h. The pH was adjusted to 5-6 with 1N hydrochloric acid and the mixture was concentrated under reduced pressure to give crude compound 10. The crude product was separated and purified by prep-HPLC (Method 2) to give the trifluoroacetate salt of compound 10-1 (17 mg, yield: 9.76%) and the trifluoroacetate salt of compound 10-2 (15 mg, yield: 8.61%).

[0171] Trifluoroacetate salt of compound 10-1: LC-Ms m / z (ESI): 670.3[M+H] + 11H NMR (400 MHz, CD3OD) δ 7.92 (s, 1H), 7.14 (s, 1H), 6.80 (s, 1H), 6.74 (s, 1H), 6.67 - 6.56 (m, 2H), 5.79 - 5.70 (m, 1H), 5.37 - 5.27 (m, 1H), 3.77 (s, 3H), 3.29 - 3.20 (m, 2H), 3.05 - 2.88 (m, 10H), 2.87 - 2.76 (m, 2H), 2.46 - 2.35 (m, 2H), 2.04 - 1.89 (m, 4H), 1.85 (s, 3H), 1.78 (s, 3H), 1.51 - 1.39 (m, 1H), 1.02 - 0.91 (m, 6H). Trifluoroacetate of Compound 10-2 LC-Ms m / z (ESI): 670.3 [M+H] + 1 1H NMR (400 MHz, CD3OD) δ 7.92 (s, 1H), 7.20 (s, 1H), 6.88 (s, 1H), 6.82 (s, 1H), 6.66 (s, 2H), 5.78 - 5.69 (m, 1H), 5.37 - 5.24 (m, 1H), 3.78 (s, 3H), 3.35 - 3.24 (m, 2H), 3.05 - 2.92 (m, 10H), 2.89 - 2.76 (m, 2H), 2.50 - 2.42 (m, 2H), 2.09 - 1.96 (m, 2H), 1.91 (s, 6H), 1.86 - 1.77 (m,​​​​​​​​​​​​​​​Under nitrogen gas protection, 2g (300.0 mg, 0.67 mmol), 2,6-dimethyl-4-methoxyphenylboronic acid (242.0 mg, 1.34 mmol), and cesium carbonate (0.65 g, 2.01 mmol) were added to 1,4-dioxane (5.0 mL) and water (0.5 mL). Pd(PPh3)4 (77.0 mg, 0.067 mmol) was added and the mixture was reacted in a sealed tube at 100 °C for 12 h. The mixture was cooled to room temperature, filtered through diatomaceous earth, added with ethyl acetate (50 mL), washed sequentially with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column flash chromatography to give 11a (300.0 mg, yield: 92.22%).

[0174] Step 2: Synthesis of 11b 11a (300.0 mg, 0.60 mmol) was dissolved in acetonitrile (3 mL), and a solution of hydrochloric acid in 1,4-dioxane (2 mL) was added, followed by stirring at room temperature for 30 minutes. The solvent was removed by drying under reduced pressure to obtain crude product 11b. LC-Ms m / z (ESI): 402.7 [M+H] +

[0175] Step 3: Synthesis of 11c Under nitrogen gas protection, intermediate 3 (174.18 mg, 0.50 mmol) was dissolved in dry DMF (5 mL) and HOBt (135.12 mg, 1.00 mmol), EDCI (191.70 mg, 1.00 mmol), and DIPEA (258.48 mg, 2.00 mmol) were added sequentially. After stirring at room temperature for 40 min, crude 11b (200.0 mg, 0.50 mmol) was added and the mixture was allowed to react overnight at room temperature. Ethyl acetate (80 mL) was added, and the mixture was washed with water (20 mL × 2) and saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 11c (300.0 mg, 81.99% yield) was obtained by silica gel column chromatography. LC-Ms m / z (ESI): 732.3[M+H] +

[0176] Step 4: Synthesis of Compound 11-1 and Compound 11-2 11c (300.0 mg, 0.41 mmol) was dissolved in 3 mL of THF and 1 mL of water, and lithium hydroxide monohydrate (19.46 mg, 0.82 mmol) was added. The mixture was allowed to react at room temperature for 5 h. The pH was adjusted to 5-6 with 1N hydrochloric acid, and the mixture was concentrated under reduced pressure to give crude compound 11. The crude product was separated and purified by prep-HPLC (Method 2) to give the trifluoroacetate salt of compound 11-1 (23 mg, Rt = 4.024 min, yield: 7.97%) and the trifluoroacetate salt of compound 11-2 (27 mg, Rt = 4.165 min, yield: 9.36%).

[0177] Trifluoroacetate salt of compound 11-1: LC-Ms m / z (ESI): 704.3 [M+H] + 1 H NMR (400MHz,CD3OD) δ 7.87 (s,1H),7.03 (t,1H),6.84 (s,1H),6.69 - 6.63 (m,2H),5.76 - 5.62 (m,2H),3.78 (s,3H),3.24 - 3.14 (m,2H),3.03 - 2.89 (m,3H),2.85 (s,6H),2.81 - 2.70 (m,1H),2.03 (s,3H),2.01 - 1.92 (m,5H),1.87 (s,3H),1.46 - 1.32 (m,1H),0.99 - 0.88 (m,6H). Trifluoroacetate salt of compound 11-1: LC-Ms m / z (ESI): 704.3 [M+H] + 1H NMR (400MHz,CD3OD) δ 7.83 (s,1H),7.08 (t,1H),6.90 (s,1H),6.69 (s,2H),5.81 - 5.74 (m,1H),5.70 - 5.61 (m,1H),3.79 (s,3H),3.30 - 3.17 (m,2H),3.05 - 2.95 (m,2H),2.91 - 2.78 (m,7H),2.69 - 2.58 (m,1H),2.06 (s,3H),2.02 - 1.96 (m,6H),1.94 - 1.82 (m,1H),1.81 - 1.70 (m,1H),1.41 - 1.25 (m,1H),0.94 - 0.82 (m,6H).

[0178] Example 12: Synthesis of Compound 12 [ka] The crude product of compound 12 was obtained by following the method for preparing compound 9. The crude product was separated and purified by prep-HPLC (Method 2) to obtain the trifluoroacetate salt of compound 12-1 (11 mg, Rt=4.191 min) and the trifluoroacetate salt of compound 12-2 (17 mg, Rt=4.332 min).

[0179] Trifluoroacetate salt of compound 12-1: LC-Ms m / z (ESI): 702.3 [M+H] + 1 H NMR (400MHz,CD3OD) δ 7.88 (s,1H),7.19 - 7.11 (m,1H),7.10 - 6.98 (m,3H),6.84 (s,1H),5.77 - 5.64 (m,2H),3.22 - 3.10 (m,6H),3.03 - 2.87 (m,3H),2.72 - 2.63 (m,1H),2.03 (s,3H),2.00 - 1.93 (m,5H),1.89 (s,3H),1.46 - 1.34 (m,1H),1.27 (t,6H),0.98 - 0.87 (m,6H). Trifluoroacetate salt of compound 12-2: LC-Ms m / z (ESI): 702.3 [M+H] + 1 H NMR (400MHz,CD3OD) δ 7.89 - 7.83 (m,1H),7.20 - 7.14 (m,1H),7.13 - 7.02 (m,3H),6.89 (s,1H),5.80 - 5.72 (m,1H),5.69 - 5.62 (m,1H),3.29 - 3.18 (m,6H),3.01- 2.92 (m,2H),2.90 - 2.80 (m,1H),2.68 - 2.57 (m,1H),2.06 (s,3H),2.03 - 1.98 (m,6H),1.94 - 1.83 (m,1H),1.78 - 1.67 (m,1H),1.39 - 1.24 (m,7H),0.93 - 0.82 (m,6H).

[0180] Example 13: Preparation of Compound 13 [ka]

[0181] Step 1: Fabrication of 13b 2a (2.0 g, 5.2 mmol), 13a (1.9 g, 10.4 mmol), triethylamine (1.4 mL, 10.4 mmol), cuprous iodide (4.0 g, 20.8 mmol), anhydrous lithium chloride (1.76 g, 41.6 mmol), and (PPh3)2PdCl2 (730 mg, 1.04 mmol) were placed in a sealed tube, and DMF (30 mL) and water (3 mL) were added. The mixture was stirred at 80 °C for 3 h under nitrogen gas protection. After cooling to room temperature, the mixture was diluted with 100 mL of ethyl acetate and washed sequentially with water (50 mL × 3) and saturated brine (50 mL × 1). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 13b (1.86 g, 74% yield) was obtained by column chromatography. LCMS m / z=485.2[M+H] +

[0182] Step 2: Fabrication of 13c 13b (1.86 g, 3.84 mmol) was dissolved in 20 mL of dichloromethane, 5 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 3 h. Concentration under reduced pressure gave crude 13c (1.8 g). LCMS m / z=385.2[M+H] +

[0183] Step 3: Fabrication of 13d Crude 13c (1.8 g), aqueous formaldehyde (5 mL), and glacial acetic acid (230 mg, 3.84 mmol) were dissolved in methanol (20 mL) and stirred at room temperature for 30 min under nitrogen gas protection. Sodium triacetoxyborohydride (1.62 g, 7.68 mmol) was added. Stirring was continued at room temperature overnight. The mixture was concentrated under reduced pressure to remove the solvent, and 30 mL of water was added. The aqueous phase was extracted with ethyl acetate (50 mL × 2). The organic phases were combined. The organic phase was washed with saturated brine (30 mL × 1). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 13d (0.91 g, 60% yield for two steps) was obtained by column chromatography. LCMS m / z=399.2[M+H] +

[0184] Step 4: Fabrication of 13e 13d (0.91 g, 2.29 mmol) was dissolved in ethanol (15 mL) and water (1.5 mL), and lithium hydroxide monohydrate (288 mg, 6.86 mmol) was added. The mixture was allowed to react at room temperature for 5 h. The solvent was removed by concentration under reduced pressure. 20 mL of water was added to the residue, and the pH was adjusted to approximately 2-3 with 1N hydrochloric acid. The aqueous phase was extracted with ethyl acetate (50 mL x 2), and the organic phases were combined. The organic phase was washed with saturated brine (30 mL x 1), and the organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (0.1% trifluoroacetic acid) to give 13e (200 mg, 24% yield). LCMS m / z=371.2[M+H] + ;

[0185] Step 5: Fabrication of 13f 13e (0.160 g, 0.43 mmol) and intermediate 1 (0.15 g, 0.43 mmol) were dissolved in 5 mL of DMF, and HOBT (0.12 g, 0.86 mmol), DIPEA (0.22 g, 1.72 mmol), and EDCI (0.16 g, 0.86 mmol) were added. The mixture was stirred at room temperature for 2 h. After the reaction was completed, 30 mL of ethyl acetate was added, and the mixture was washed twice with water (20 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give 13f (0.13 g, yield: 42.71%). LCMS m / z=708.9[M+H] + ;

[0186] Step 6: Preparation of Compounds 13-1 and 13-2 13f (0.13 g, 0.18 mmol) was dissolved in 3 mL of THF and 1 mL of water, and lithium hydroxide monohydrate (23 mg, 0.55 mmol) was added. The mixture was allowed to react at room temperature for 5 h. The pH was adjusted to 5-6 with 1N hydrochloric acid, and the mixture was concentrated under reduced pressure to give crude compound 13. The crude product was separated and purified by prep-HPLC (Method 1) to give compound 13-1 (0.55 mg, Rt = 4.271 min) and compound 13-2 (0.6 mg, Rt = 4.358 min).

[0187] Compound 13-1: LC-Ms m / z (ESI): 680.2[M+H] + 1 H NMR (400MHz,Methanol-d4) δ 8.03 (s,1H),7.15 (s,1H),6.84 - 6.70 (m,4H),5.72 - 5.65 (m,1H),5.31 (t,1H),3.93 - 3.81 (m,1H),3.58 - 3.48 (m,2H),3.15 - 3.12 (m,1H),2.95 - 2.85 (m,2H),2.70 (d,2H),2.52 (s,3H),2.42 -2.35 (m,2H),2.03 - 1.91 (m,4H),1.89 (s,3H),1.79 (s,3H),1.48 - 1.29 (m,2H),1.00 - 0.90 (m,6H) Compound 13-2: LC-Ms m / z (ESI): 680.2[M+H] + 1 H NMR (400MHz,Methanol-d4) δ 8.08 (s,1H),7.23 (s,1H),6.86 - 6.78 (m,4H),5.69 - 5.58 (m,1H),5.40 - 5.29 (m,1H),3.96 - 3.87 (m,1H),3.70 -3.47 (m,2H),3.14 - 3.10 (m,1H),2.99 - 2.91 (m,2H),2.72 - 2.64 (m,2H),2.55 (s,3H),2.48 - 2.39 (m,2H),2.22 - 2.14 (m,1H),2.06 - 1.98 (m,3H),1.96 - 1.90 (m,6H),1.77 - 1.69 (m,1H),1.66 - 1.55 (m,1H),0.91 - 0.83 (m,6H).

[0188] Example 14: Preparation of Compound 14 [ka]

[0189] Step 1: Synthesis of 14b Under nitrogen gas protection, 2a (20.0 g, 52.04 mmol) was dissolved in DMF (60 mL), and 14a (10.56 g, 62.44 mmol), palladium acetate (3.32 g, 10.4 mmol), tris(o-methylphenyl)phosphine (6.32 g, 20.8 mmol), and triethylamine (15.8 g, 156.12 mmol) were added sequentially and reacted at 100 °C for 24 h. The mixture was extracted with ethyl acetate (180 mL), washed with water (50 mL × 2) and saturated brine (50 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 14b (4.0 g, 16.27% yield) was obtained by silica gel column chromatography. LC-Ms m / z (ESI): 473.5[M+H] +

[0190] Step 2: Synthesis of 14c 14b (4.0 g, 8.46 mmol) was dissolved in methanol (10 mL), Pd / C (2.0 g) was added, and the mixture was reacted at room temperature under a hydrogen atmosphere for 0.5 h. The solid was removed by filtration, and the filtrate was concentrated and purified by chromatography to give 14c (3.6 g, yield: 89.68%). LC-Ms m / z (ESI): 475.5[M+H] +

[0191] Step 3: Synthesis of 14d 14c (3.6 g, 7.59 mmol) was dissolved in dichloromethane (5 mL), and hydrochloric acid-1,4-dioxane (3 mL) was added and reacted for 1 h. The solvent was removed under reduced pressure to give crude hydrochloride 14d.

[0192] Step 4: Synthesis of 14e The hydrochloride salt of 14d (1.3 g, 3.47 mmol) was dissolved in ultra-dry 1,2-dichloroethane (30 mL), and acetone (400 mg, 6.87 mmol) and glacial acetic acid (21.0 mg, 0.35 mmol) were added sequentially. The mixture was incubated at 60 °C for 2 h. After cooling to room temperature, sodium triacetoxyborohydride (1.84 g, 8.68 mmol) was added and the mixture was incubated overnight at room temperature. The mixture was extracted with ethyl acetate (20 mL), washed with water (30 mL x 2) and saturated brine (30 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 14e (1.0 g, yield: 69.20%) was obtained by silica gel column chromatography. LC-Ms m / z (ESI): 417.4[M+H] +

[0193] Step 5: Synthesis of 14f 14e (1.0 g, 2.40 mmol) was dissolved in THF (9 mL) and water (3 mL), and lithium hydroxide (170 mg, 7.10 mmol) was added. The mixture was allowed to react at room temperature for 2 h. Purification by reverse-phase chromatography gave 14f (800 mg, 85.82% yield). LC-Ms m / z (ESI): 389.4[M+H]+

[0194] Step 6: Synthesis of 14g Under nitrogen gas protection, intermediate 1 (250.0 mg, 0.70 mmol) was dissolved in dry DMF (1.5 mL) and HOBt (190 mg, 1.41 mmol), EDCI (270 mg, 1.41 mmol), and DIPEA (270 mg, 2.09 mmol) were added sequentially. After stirring at room temperature for 40 min, 14f (270 mg, 0.70 mmol) was added and the mixture was allowed to react overnight at room temperature. Ethyl acetate (80 mL) was added, and the mixture was washed sequentially with water (20 mL × 2) and saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 14f (368 mg, yield: 72.43%) was obtained by silica gel column chromatography. LC-Ms m / z (ESI): 726.8[M+H] +

[0195] Step 7: Synthesis of Compound 14-1 and Compound 14-2 Compound 14g (368 mg, 0.51 mmol) was dissolved in 1.5 mL of methanol and 0.5 mL of water, and lithium hydroxide monohydrate (31 mg, 1.27 mmol) was added. The mixture was allowed to react at room temperature for 30 min. The pH was adjusted to 5-6 with 1N hydrochloric acid, and the mixture was concentrated under reduced pressure to give crude compound 14. The crude product was separated and purified by prep-HPLC (Method 2) to give the trifluoroacetate salt of compound 14-1 (20 mg, Rt = 4.295 min, yield 5.62%) and the trifluoroacetate salt of compound 14-2 (25 mg, Rt = 4.378 min, yield 7.02%).

[0196] Trifluoroacetate salt of compound 14-1: LC-Ms m / z (ESI): 698.8[M+H] + 1H NMR (400MHz,CD3OD) δ 7.90 - 7.68 (m,1H),7.20 (s,1H),6.88 - 6.73 (m,4H),5.84 - 5.75 (m,1H),5.39 - 5.27 (m,1H),4.32 - 3.83 (m,4H),3.52 - 3.34 (m,1H),3.20 - 2.81 (m,7H),2.49 - 2.34 (m,2H),2.10 - 1.92 (m,4H),1.90 (m,3H),1.83 (s,3H),1.52 - 1.35 (m,1H),1.30 - 1.11 (m,6H),1.05 - 0.93 (m,6H). Trifluoroacetate salt of compound 14-2: LC-Ms m / z (ESI): 698.8[M+H] + 1 H NMR (400MHz,CD3OD) δ 7.91 - 7.76 (m,1H),7.25 (s,1H),6.92 - 6.78 (m,4H),5.84 - 5.73 (m,1H),5.39 - 5.26 (m,1H),4.34 - 3.85 (m,4H),3.53 - 3.35 (m,1H),3.24 - 2.95 (m,4H),2.94 - 2.77 (m,3H),2.53 - 2.43 (m,2H),2.12 - 2.00 (m,2H),1.96 (s,6H),1.91 - 1.78 (m,2H),1.40 - 1.20 (m,7H),0.96 - 0.85 (m,6H).

[0197] Example 15: Preparation of Compound 15 [ka] The crude product of compound 15 was obtained by following the method for preparing compound 14. The crude product was separated and purified by prep-HPLC (Method 2) to obtain the trifluoroacetate salt of compound 15-1 (15 mg, Rt = 4.354 min) and the trifluoroacetate salt of compound 15-2 (17 mg, Rt = 4.455 min).

[0198] Trifluoroacetate salt of compound 15-1: LC-MS m / z (ESI): 710.8 [M+H] + 1 1H NMR (400 MHz, CD3OD) δ 7.89 - 7.72 (s, 1H), 7.20 (s, 1H), 6.89 - 6.72 (m, 4H), 5.84 - 5.75 (m, 1H), 5.38 - 5.28 (m, 1H), 4.36 - 3.84 (m, 4H), 3.27 - 2.79 (m, 9H), 2.48 - 2.37 (m, 2H), 2.09 - 1.93 (m, 4H), 1.92 - 1.81 (m, 6H), 1.51 - 1.38 (m, 1H), 1.07 - 0.94 (m, 7H), 0.74 - 0.63 (m, 2H), 0.44 - 0.34 (m, 2H). Trifluoroacetate of Compound 15-2: LC-MS m / z (ESI): 710.8 [M+H] + 1 1H NMR (400 MHz, CD3OD) δ 7.92 - 7.74 (s, 1H), 7.25 (s, 1H), 6.93 - 6.77 (m, 4H), 5.83 - 5.73 (m, 1H), 5.38 - �.28 (m, 1H), 4.36 - 3.86 (m, 4H), 3.30 - 2.76 (m, 9H), 2.52 - 2.43 (m, 2H), 2.12 - 2.01 (m, 2H), 1.96 (s, 6H), 1.93 - 1.74 (m, 2H), 1.41 - 1.27 (m, 1H), 1.11 - 0.84 (m, 7H), 0.76 - 0.61 (m, 2H), 0.47 - 0.38 (m, 2H).

[0199] Example 16: Preparation of Compound 16

Chemical Structure

[0200] Trifluoroacetate salt of compound 16-1: LC-Ms m / z (ESI): 728.7[M+H] + 1 H NMR (400MHz,CD3OD) δ 7.92 (s,1H),7.23 - 7.15 (m,1H),7.14 - 7.03 (m,3H),6.86 (s,1H),5.87 - 5.76 (m,1H),5.75 - 5.64 (m,1H),4.77 - 4.68 (m,1H),4.61 - 4.47 (m,1H),4.23 - 4.02 (m,1H),3.97 - 3.84 (m,1H),3.77 - 3.35 (m,4H),3.19 - 2.86 (m,4H),2.38 - 2.18 (m,2H),2.12 - 1.84 (m,11H),1.50 - 1.35 (m,1H), 1.05 - 0.90 (m,6H). Trifluoroacetate salt of compound 16-2: LC-Ms m / z (ESI): 728.7[M+H] + 1H NMR (400MHz,CD3OD) δ 7.95 (s,1H),7.25 - 7.07 (m,4H),6.92 (s,1H),5.87 - 5.78 (m,1H),5.75 - 5.66 (m,1H),4.77 - 4.70 (m,1H),4.62 - 4.51 (m,1H),4.26 - 4.04 (m,1H),3.94 - 3.85 (m,1H),3.75 - 3.36 (m,4H),3.14 - 2.89 (m,4H),2.39 - 2.18 (m,2H),2.12 - 1.98 (m,9H),1.97 - 1.73 (m,2H),1.41 - 1.25 (m,1H),0.94 - 0.85 (m,6H).

[0201] Example 17: Preparation of Compound 17 [ka] The crude product of compound 17 was obtained by following the method for preparing compound 3. The crude product was separated and purified by prep-HPLC (Method 2) to obtain the trifluoroacetate salt of compound 17-1 (17 mg, Rt=4.035 min) and the trifluoroacetate salt of compound 17-2 (18 mg, Rt=4.118 min).

[0202] Trifluoroacetate salt of compound 17-1: LC-Ms m / z (ESI): 728.7[M+H] + 11H NMR (400 MHz, CD3OD) δ 8.01 - 7.80 (s, 1H), 7.23 - 7.15 (m, 1H), 7.14 - 7.03 (m, 3H), 6.86 (s, 1H), 5.88 - 5.78 (m, 1H), 5.76 - 5.64 (m, 1H), 4.79 - 4.65 (m, 1H), 4.62 - 4.46 (m, 1H), 4.41 - 3.97 (m, 1H), 3.96 - 3.64 (m, 2H), 3.60 - 3.40 (m, 2H), 3.32 - 3.22 (m, 1H), 3.19 - 2.85 (m, 4H), 2.45 - 2.13 (m, 2H), 2.11 - 1.85 (m, 11H), 1.50 - 1.37 (m, 1H), 1.04 - 0.90 (m, 6H). Trifluoroacetate of Compound 17-2 LC-Ms m / z (ESI): 728.7 [M+H] + 1 1H NMR (400 MHz, CD3OD) δ 7.93 (s, 1H), 7.25 - 7.06 (m, 4H), 6.92 (s, 1H), 5.88 - 5.77 (m, 1H), 5.75 - 5.64 (m, 1H), 4.79 - 4.68 (m, 1H), 4.62 - 4.48 (m, 1H), 4.24 - 3.98 (m, 1H), 3.97 - 3.84 (m, 1H), 3.82 - 3.62 (m, 1H), 3.62 - 3.37 (m, 3H), 3.15 - 2.89 (m, 4H), 2.44 - 2.16 (m, 2H), 2.09 (s, 3H), 2.04 (s, 6H), 1.95 - 1.71 (m, 2H), 1.38 - 1.26 (m, 1H), 0.98 - 0.84 (m, 6H).

[0203] Example 18: Preparation of Compound 18

Chemical Structure

[0204] Trifluoroacetate salt of compound 18-1: LC-Ms m / z (ESI): 714.7[M+H] + 1 H NMR (400MHz,CD3OD) δ 7.97 - 7.77 (m,1H),7.25 - 7.18 (m,1H),7.18 - 7.09 (m,3H),6.89 (s,1H),5.89 - 5.79 (m,1H),5.77 - 5.65 (m,1H),4.34 - 4.05 (m,2H),4.03 - 3.85 (m,2H),3.55 - 3.36 (m,1H),3.24 - 3.03 (m,2H),3.00 - 2.79 (m,3H),2.08 (s,3H),2.04 (s,6H),1.93 - 1.71 (m,2H),1.39 - 1.20 (m,7H),0.97 - 0.85 (m,6H). Trifluoroacetate salt of compound 18-2: LC-Ms m / z (ESI): 714.7[M+H] + 1H NMR (400MHz,CD3OD) δ 7.91 - 7.72 (m,1H),7.22 - 7.15 (m,1H),7.14 - 7.04 (m,3H),6.84 (s,1H),5.88 - 5.79 (m,1H),5.75 - 5.65 (m,1H),4.33 - 4.14 (m,1H),4.10 - 3.81 (m,3H),3.51 - 3.35 (m,1H),3.22 - 3.07 (m,2H),3.06 - 2.81 (m,3H),2.14 - 2.04 (m,4H),2.02 - 1.83 (m,7H),1.48 - 1.35 (m,1H),1.32 - 1.17 (m,6H),1.04 - 0.93 (m,6H).

[0205] Example 19: Preparation of Compound 19 [ka] The crude product of compound 19 was obtained by following the method for preparing compound 14. The crude product was separated and purified by prep-HPLC (Method 2) to obtain the trifluoroacetate salt of compound 19-1 (18 mg, Rt=4.218 min) and the trifluoroacetate salt of compound 19-2 (19 mg, Rt=4.297 min).

[0206] Trifluoroacetate salt of compound 19-1: LC-Ms m / z (ESI): 726.8[M+H] + 1H NMR (400MHz,Methanol-d4) δ 9.36 - 9.20 (m,1H),7.88 -7.69 (m,1H),7.23 - 7.04 (m,4H),6.88 -6.77 (m,1H),5.87 - 5.76 (m,1H),5.75 -5.65 (m,1H),4.34 - 3.85 (m,4H),3.26 - 2.87 (m,7H),2.12 -2.01 (m,4H),2.01 - 1.93 (m,4H),1.92 -1.84 (m,3H),1.46 - 1.35 (m,1H),1.06 -1.93 (m,7H),0.74 -0.64 (m,2H),0.47 - 0.35 (m,2H). Trifluoroacetate salt of compound 19-2: LC-Ms m / z (ESI): 726.8[M+H] + 1 H NMR (400MHz,Methanol-d4) δ 9.51 - 9.33 (m,1H),7.94 - 7.77 (m,1H),7.27 -7.04 (m,4H),6.89 (d,1H),5.88 -5.78 (m,1H),5.76 -5.65 (m,1H),4.37 - 3.90 (m,4H),3.29 - 2.82 (m,7H),2.08 (s,3H),2.04 (s,6H),1.92 - 1.69 (m,2H),1.39 -1.25 (m,1H),1.11 -0.96 (m,1H),0.96 - 0.86 (m,6H),0.75 -0.64 (m,2H),0.45 -0.36 (m,2H).

[0207] Example 20: Preparation of Compound 20 [ka] The crude product of compound 20 was obtained by following the preparation method of Example 21, and the crude product was separated and purified by prep-HPLC (Method 2) to obtain the trifluoroacetate salt of compound 20-1 (16 mg, Rt=4.007 min, yield 5.51%) and the trifluoroacetate salt of compound 20-2 (17 mg, Rt=4.095 min, yield 5.85%).

[0208] Trifluoroacetate salt of compound 20-1: LC-Ms m / z (ESI): 676.7[M+H] + 1 H NMR (400MHz,Methanol-d4) δ 9.20 (d,1H),7.89 (s,1H),7.20 - 7.04 (m,3H),6.82 (s,1H),5.82 -5.73 (m,1H),5.74 -5.64 (m,1H),3.29 - 3.23 (m,2H),3.16 - 2.82 (m,12H),2.50 -2.35 (m,2H),2.08 - 1.88 (m,7H),1.86 (s,3H),1.47 -1.34 (m,1H),1.00- 0.89 (m,6H). Trifluoroacetate salt of compound 20-2: LC-Ms m / z (ESI): 676.7[M+H] + 1 H NMR (400MHz,Methanol-d4) δ 9.33 (d,1H),7.91 (s,1H),7.20 - 7.07 (m,3H),6.88 (s,1H),5.82 - 5.66 (m,2H),3.37 - 3.30 (m,2H),3.08 - 2.86 (m,12H),2.48 (t,2H),2.14 - 2.01 (m,2H),1.98 (s,6H),1.86 - 1.73 (m,2H),1.36 -1.23 (m,1H),0.93 -0.81 (m,6H).

[0209] Example 21: Preparation of Compound 21 [ka]

[0210] Step 1: Synthesis of 21a Under nitrogen gas protection, 6G (400 mg, 0.89 mmol) was dissolved in 1,4-dioxane (6 mL) and water (0.6 mL). 2,6-dimethyl-4-methoxyphenylboronic acid (240 mg, 1.33 mmol), XPhos Pd G2 (110 mg, 0.13 mmol), and potassium phosphate (570 mg, 2.67 mmol) were added sequentially and reacted at 100 °C for 24 h. The mixture was extracted with ethyl acetate (80 mL), washed with water (50 mL × 2) and saturated brine (50 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 21a (230 mg, yield: 51.32%) was obtained by silica gel column chromatography. LC-Ms m / z (ESI): 404.5[M+H-Boc] +

[0211] Step 2: Synthesis of 21b 21a (230 mg, 0.46 mmol) was dissolved in dichloromethane (6 mL), and hydrochloric acid-1,4-dioxane (6 mL) was added and reacted for 1 h. The solvent was removed under reduced pressure to obtain the hydrochloride salt of crude product 21b.

[0212] Step 3: Synthesis of 21c Under nitrogen gas protection, intermediate 3 (160 mg, 0.46 mmol) was dissolved in dry DMF (8 mL), and HATU (350 mg, 0.92 mmol) and DIPEA (230 mg, 1.81 mmol) were added sequentially. After stirring at room temperature for 40 min, the hydrochloride salt of 21b (185 mg, 0.46 mmol) was added and the mixture was allowed to react overnight at room temperature. Ethyl acetate (80 mL) was added, and the mixture was washed sequentially with water (20 mL × 2) and saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 21c (240 mg, yield: 71.10%) was obtained by silica gel column chromatography. LC-Ms m / z (ESI): 734.8[M+H] +

[0213] Step 4: Synthesis of Compound 21-1 and Compound 21-2 Compound 21c (240 mg, 0.33 mmol) was dissolved in 6 mL of THF and 2 mL of water, and lithium hydroxide monohydrate (20 mg, 0.83 mmol) was added. The mixture was allowed to react at room temperature for 30 min. The pH was adjusted to 5-6 with 1N hydrochloric acid, and the mixture was concentrated under reduced pressure to give crude compound 21. The crude product was separated and purified by prep-HPLC (Method 2) to give the trifluoroacetate salts of compound 21-1 (19 mg, Rt = 3.973 min, 8.16% yield) and compound 21-2 (20 mg, Rt = 4.051 min, 8.59% yield).

[0214] Trifluoroacetate salt of compound 21-1: LC-Ms m / z (ESI): 706.7[M+H] + 1 H NMR (400MHz,Methanol-d4) δ 7.89 (s,1H),6.82 (s,1H),6.67 (s,2H),5.82 -5.74 (m,1H),5.72 -5.63 (m,1H),3.78 (s,3H),3.32 - 3.24 (m,2H),3.14 - 2.83 (m,12H),2.49 -2.38 (m,2H),2.08 - 1.92 (m,4H),1.90 (s,3H),1.83 (s,3H),1.47 - 1.35 (m,1H),1.01 -0.86 (m,6H). Trifluoroacetate salt of compound 21-2: LC-Ms m / z (ESI): 706.7[M+H] + 1H NMR (400MHz,Methanol-d4) δ 9.33 (d,1H),7.91 (s,1H),6.88 (s,1H),6.70 (s,2H),5.82 -5.75 (m,1H),5.74 -5.63 (m,1H),3.79 (s,3H),3.36 -3.29 (m,2H),3.10 - 2.83 (m,12H),2.53 -2.43 (m,2H),2.13 - 2.01 (m,2H),1.95 (s,6H),1.87 - 1.74 (m,2H),1.35 -1.23 (m,1H),0.93 -0.82 (m,6H)

[0215] The structure of compound 21-A is: [ka] and is a racemic mixture of four chiral isomers in equal proportions.

[0216] Example 22: Preparation of Compound 22 [ka] The crude product of compound 22 was obtained by following the method for preparing compound 14. The crude product was separated and purified by prep-HPLC (Method 2) to obtain the trifluoroacetate salt of compound 22-1 (10 mg, Rt = 4.334 min) and the trifluoroacetate salt of compound 22-2 (10 mg, Rt = 4.411 min).

[0217] Trifluoroacetate salt of compound 22-1: LC-Ms m / z (ESI): 726.4[M+H] + 1H NMR (400MHz,Methanol-d4) δ 7.74 (s,1H),7.18 (s,1H),6.86 - 6.70 (m,4H),5.76 (t,1H),5.33 (t,1H),3.50 - 3.35 (m,3H),3.06 - 2.97 (m,1H),2.96 - 2.81 (m,5H),2.61 - 2.49 (m,2H),2.40 (t,2H),2.07 - 1.90 (m,6H),1.86 (s,3H),1.81 (s,3H),1.55 - 1.37 (m,4H),1.34 (s,3H),1.32 (s,3H),1.00 - 0.92 (m,6H). Trifluoroacetate salt of compound 22-2: LC-Ms m / z (ESI): 726.4[M+H] + 1 H NMR (400MHz,Methanol-d4) δ 9.12 (d,1H),7.79 (s,1H),7.23 (d,1H),6.88 - 6.79 (m,4H),5.76 (t,1H),5.31 (q,1H),3.52 - 3.41 (m,3H),3.10 - 2.94 (m,4H),2.86 - 2.78 (m,2H),2.65 - 2.42 (m,4H),2.11 - 1.98 (m,4H),1.96 - 1.90 (m,6H),1.83 - 1.77 (m,2H),1.57 - 1.26 (m,10H),0.92 - 0.83 (m,6H).

[0218] Example 23: Preparation of Compound 23 [ka] The crude product of compound 23 was obtained by following the method for preparing compound 14. The crude product was separated and purified by prep-HPLC (Method 2) to obtain the trifluoroacetate salt of compound 23-1 (10 mg, Rt=4.233 min) and the trifluoroacetate salt of compound 23-2 (10 mg, Rt=4.411 min).

[0219] Trifluoroacetate salt of compound 23-1: LC-Ms m / z (ESI): 742.4[M+H] + 1 H NMR (400MHz,Methanol-d4) δ 9.29 (d,1H),7.74 (s,1H),7.20 - 7.03 (m,4H),6.81 (s,1H),5.84 - 5.75 (m,1H),5.73 - 5.63 (m,1H),3.51 - 3.38 (m,2H),3.13 - 2.87 (m,5H),2.60 - 2.48 (m,2H),2.04 (s,3H),2.02 - 1.89 (m,6H),1.88 - 1.71 (m,5H),1.55 - 1.25 (m,10H),1.00 - 0.89 (m,6H). Trifluoroacetate salt of compound 23-2: LC-Ms m / z (ESI): 742.4[M+H] + 1 H NMR (400MHz,Methanol-d4) δ 7.79 (s,1H),7.24 - 7.07 (m,4H),6.86 (s,1H),5.83 - 5.74 (m,1H),5.76 - 5.64 (m,1H),3.55 - 3.40 (m,3H),3.12 - 2.87 (m,4H),2.65 - 2.47 (m,2H),2.15 - 1.96 (m,11H),1.90 - 1.72 (m,3H),1.58 - 1.44 (m,2H),1.41 - 1.21 (m,7H),0.95 - 0.81 (m,6H).

[0220] Example 24: Preparation of Compound 24 [ka] The crude product of compound 24 was obtained by referring to the preparation method of compound 14. The crude product was separated and purified by prep-HPLC (Method 1) to obtain compound 24-1 (34 mg, Rt = 4.300 min) and compound 24-2 (35 mg, Rt = 4.374 min).

[0221] Compound 24-1: LC-Ms m / z (ESI): 760.3[M+H] + 1 H NMR (400MHz, Methanol-d4) δ 7.71 (s,1H),6.89 - 6.82 (m 2H),6.81 (s,1H),5.81 - 5.74 (m,1H),5.73 - 5.67 (m,1H),3.31 - 3.24 (m,2H),3.04 - 2.93 (m,3H),2.80 - 2.73 (m,1H),2.70 - 2.53 (m,2H),2.54 - 2.43 (m,4H),2.23 - 2.16 (m,1H),2.12 - 2.02 (m,2H),2.01 - 1.91 (m,5H),1.86 (s,3H),1.82 - 1.77 (m,2H),1.70 - 1.61 (m,1H),1.41 - 1.25 (m,3H),0.98 - 0.93 (m,6H),0.77 - 0.65 (m,4H). Compound 24-2: LC-Ms m / z (ESI): 760.3[M+H] + 1 H NMR (400MHz, Methanol-d4) δ 7.78 (s,1H),6.91 (s,1H),6.89 - 6.85 (m,2H),5.81 - 5.75 (m,1H),5.75 - 5.68 (m,1H),3.47 - 3.38 (m,2H),3.01 (t,2H),2.94 - 2.84 (m,1H),2.82 - 2.58 (m,4H),2.57 - 2.47 (m,3H),2.33 - 2.26 (m,1H),2.15 - 2.05 (m,2H),2.02 - 1.96 (m,6H),1.89 - 1.71 (m,4H),1.59 - 1.50 (m,1H),1.40 - 1.24 (m,3H),0.91 - 0.85 (m,6H),0.84 - 0.79 (m,2H),0.77 - 0.71 (m,2H).

[0222] Example 25: Production of Compound 25

change

[0223] Step 1: Synthesis of 25a Under nitrogen gas protection, 9b (140 mg, 0.33 mmol) and intermediate 6 (124 mg, 0.33 mmol) were dissolved in dry DMF (3.0 mL), and EDCI (126 mg, 0.66 mmol), HOBT (90 mg, 0.66 mmol), and DIPEA (128 mg, 0.99 mmol) were added. The mixture was allowed to react at room temperature overnight, and then ethyl acetate (80 mL) was added. The mixture was washed with water (20 mL × 2) and saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Crude 25a (250 mg) was obtained by silica gel column chromatography. LC-Ms m / z (ESI): 750.2[M+H] +

[0224] Step 2: Preparation of Compounds 25-1 and 25-2 The crude product 25a (250 mg) was dissolved in 4 mL of THF and 1 mL of water, and lithium hydroxide monohydrate (45 mg, 1.08 mmol) was added. The mixture was allowed to react at room temperature for 5 h. The pH was adjusted to 5-6 with 1N hydrochloric acid, and the mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (Method 1) to give compound 25-1 (29 mg, Rt = 4.237 min, 2-step yield: 10.86%) and compound 25-2 (36 mg, Rt = 4.294 min, 2-step yield: 13.48%).

[0225] Compound 25-1: LC-Ms m / z (ESI): 722.3[M+H] + 1H NMR (400MHz, Methanol-d4) δ 7.91 (s,1H),6.90 - 6.76 (m,3H),5.78 - 5.68 (m,2H),3.26 - 3.11 (m,6H),3.02 - 2.89 (m,5H),2.71 - 2.62 (m,1H),2.50 - 2.43 (m,2H),2.11 - 1.98 (m,4H),1.97 (s,3H),1.90 (s,3H),1.45 - 1.34 (m,1H),1.34 - 1.28 (m,6H),0.99 - 0.90 (m,6H). Compound 25-2: LC-Ms m / z (ESI): 722.3[M+H] + 1 H NMR (400MHz, Methanol-d4) δ 7.88 (s,1H),6.93 - 6.86 (m,3H),5.83 - 5.75 (m,1H),5.70 - 5.61 (m,1H),3.29 - 3.15 (m,6H),3.05 - 2.94 (m,4H),2.89 - 2.79 (m,1H),2.64 - 2.55 (m,1H),2.56 -2.46 (m,2H),2.14 - 2.04 (m,2H),2.02 - 1.97 (m,6H),1.95 - 1.87 (m,1H),1.78 - 1.69 (m,1H),1.39 - 1.28 (m,7H),0.93 - 0.86 (m,6H).

[0226] Example 26: Production of Compound 26

change

[0227] Synthesis of ステップ1:26a Under nitrogen gas protection, 2a (1.68 g, 4.72 mmol) was dissolved in DMF (29 mL) and water (2.9 mL). 1-BOC-3-ethynylpyrrolidine (1.84 g, 9.44 mmol), cuprous iodide (3.6 g, 18.88 mmol), lithium chloride (1.6 g, 37.76 mmol), and PdCl(dppf) (578 mg, 0.71 mmol) were added sequentially and reacted at 80 °C for 5 h. The mixture was filtered through diatomaceous earth, added with ethyl acetate (100 mL), washed sequentially with water (30 mL × 2) and saturated brine (30 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 26a (1.7 g, 72.24% yield) was obtained by silica gel column chromatography. LC-Ms m / z (ESI): 443.2[M+Ht-Bu] +

[0228] Step 2: Synthesis of 26b Under nitrogen gas protection, 26a (1.3 g, 2.61 mmol) was dissolved in methanol (22 mL), 10% w / w Pd / C (2.2 g, 2.09 mmol) was added, and the mixture was purged with hydrogen gas three times. The mixture was reacted under hydrogen balloon protection at room temperature for 0.5 h. The solid was removed by filtration, and the filtrate was concentrated to give crude 26b (1.3 g). LC-Ms m / z (ESI): 447.2[M+Ht-Bu] +

[0229] Step 3: Synthesis of 26c The crude product 26b (1.3 g) from the previous step was dissolved in dichloromethane (14 mL), and hydrochloric acid-1,4-dioxane (10 mL) was added and the reaction was allowed to proceed for 3 h. The solvent was removed under reduced pressure to give crude product 26c (1.4 g). LC-Ms m / z (ESI): 403.6[M+H] +

[0230] Step 4: Synthesis of 26d Crude 26c (1.4 g, 3.48 mmol) was dissolved in DCE (23 mL), and paraformaldehyde (209 mg, 6.96 mmol), acetic acid (105 mg, 1.74 mmol), and sodium triacetoxyborohydride (1475 mg, 6.96 mmol) were added sequentially. The mixture was then reacted at 60 °C for 16 h. Dichloromethane (80 mL) and water (30 mL) were added, and the mixture was washed with saturated brine (30 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 26d (750 mg, 51.75% yield for three steps) was obtained by silica gel column chromatography. LC-Ms m / z (ESI): 417.6[M+H] +

[0231] Step 5: Synthesis of 26e 26d (780 mg, 1.87 mmol) was dissolved in 8 mL of THF and 2 mL of water, and lithium hydroxide monohydrate (235 mg, 5.61 mmol) was added. The mixture was allowed to react at room temperature for 3 h. The pH was adjusted to 5-6 with 1 N hydrochloric acid, and the mixture was concentrated under reduced pressure to give the crude compound. The crude product was separated on a C18 column (mobile phase A: acetonitrile, mobile phase B: 0.5% aqueous NH4HCO3, gradient elution of 10% to 40% A in B) to give 26e (620 mg, 85.36%). LC-Ms m / z (ESI): 389.4[M+H] +

[0232] Step 6: Synthesis of 26f Under nitrogen gas protection, 26e (155 mg, 0.40 mmol) and intermediate 6 (157 mg, 0.40 mmol) were dissolved in dry DMF (3.0 mL), and EDCI (153 mg, 0.80 mmol), HOBT (108 mg, 0.80 mmol), and DIPEA (155 mg, 1.20 mmol) were added. The mixture was allowed to react at room temperature overnight, and then ethyl acetate (80 mL) was added. The mixture was washed with water (20 mL × 2) and saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 26f (189 mg, 62.02%) was obtained by silica gel column chromatography. LC-Ms m / z (ESI): 762.7[M+H] +

[0233] Step 7: Preparation of Compounds 26-1 and 26-2 26f (189 mg, 0.25 mmol) was dissolved in 4 mL of THF and 1 mL of water, and lithium hydroxide monohydrate (32 mg, 0.75 mmol) was added. The mixture was allowed to react at room temperature for 5 h. The pH was adjusted to 5-6 with 1 N hydrochloric acid, and the mixture was concentrated under reduced pressure to give crude compound 26. The crude product was separated and purified by prep-HPLC (Method 2) to give the trifluoroacetate salts of compound 26-1 (30 mg, Rt = 4.218 min, 2-step yield: 16.35%) and compound 26-2 (30 mg, Rt = 4.305 min, 2-step yield: 16.35%).

[0234] Trifluoroacetate salt of compound 26-1: LC-Ms m / z (ESI): 734.3[M+H] + 1 H NMR (400MHz,Methanol-d4) δ 9.16 (t,1H),7.76 (d,1H),6.91 - 6.83 (m,2H),6.81 (s,1H),5.84 - 5.76 (m,1H),5.75 - 5.67 (m,1H),3.87 - 3.63 (m,2H),3.29 - 3.01 (m,3H),3.01 - 2.86 (m,5H),2.81 - 2.53 (m,3H),2.53 - 2.42 (m,2H),2.38 - 2.18 (m,2H),2.12 - 2.03 (m,3H),2.02 - 1.99 (m,1H),1.94 (d,3H),1.89 (d,3H),1.82 - 1.69 (m,2H),1.45 - 1.33 (m,2H),1.01 - 0.93 (m,6H). Trifluoroacetate salt of compound 26-2: LC-Ms m / z (ESI): 734.3[M+H] + 1H NMR (400MHz,Methanol-d4) δ 9.32 (d,1H),7.85 (s,1H),6.96 - 6.84 (m,3H),5.80 (t,1H),5.75 - 5.66 (m,1H),3.88 - 3.64 (m,2H),3.25 - 2.83 (m,8H),2.82 - 2.56 (m,3H),2.54 - 2.45 (m,2H),2.41 - 2.18 (m,1H),2.17 - 2.06 (m,2H),2.00 (s,6H),1.90 - 1.70 (m,5H),1.40 - 1.23 (m,2H),0.95 - 0.83 (m,6H).

[0235] Example 27: Preparation of Compound 27 [ka] The crude product of compound 27 was obtained by following the method for preparing compound 26. The crude product was separated and purified by prep-HPLC (Method 2) to obtain the trifluoroacetate salt of compound 27-1 (58 mg, Rt=4.134 min) and the trifluoroacetate salt of compound 27-2 (86 mg, Rt=4.243 min).

[0236] Trifluoroacetate salt of compound 27-1: LC-Ms m / z (ESI): 714.3[M+H] + 1H NMR (400MHz,Methanol-d4) δ 9.27 (t,1H),7.75 (s,1H),7.19 (t,1H),7.13 - 7.04 (m,3H),6.82 (s,1H),5.83 - 5.74 (m,1H),5.74 - 5.63 (m,1H),3.87 - 3.55 (m,2H),3.26 - 3.02 (m,2H),3.00 - 2.88 (m,4H),2.81 - 2.46 (m,3H),2.46 - 2.15 (m,2H),2.06 (s,3H),2.00 - 1.91 (m,4H),1.90 - 1.84 (m,4H),1.79 - 1.66 (m,2H),1.47 - 1.33 (m,2H),1.01 - 0.92 (m,6H). Trifluoroacetate salt of compound 27-2: LC-Ms m / z (ESI): 714.3[M+H] + 1 H NMR (400MHz,Methanol-d4) δ 9.47 - 9.37 (m,1H),7.84 (d,1H),7.26 - 7.09 (m,4H),6.87 (s,1H),5.86 - 5.76 (m,1H),5.76 - 5.65 (m,1H),3.90 - 3.54 (m,2H),3.25 - 3.03 (m,2H),3.02 - 2.88 (m,4H),2.84 - 2.51 (m,3H),2.52 - 2.18 (m,2H),2.14 - 2.00 (m,9H),1.92 - 1.60 (m,5H),1.42 - 1.22 (m,2H),0.96 - 0.82 (m,6H).

[0237] Example 28: Preparation of Compound 28 [ka] The crude product of compound 28 was obtained by following the method for preparing compound 26. The crude product was separated and purified by prep-HPLC (Method 2) to obtain the trifluoroacetate salt of compound 28-1 (37 mg, Rt = 4.218 min) and the trifluoroacetate salt of compound 28-2 (50 mg, Rt = 4.343 min).

[0238] Trifluoroacetate of Compound 28-1: LC-Ms m / z (ESI): 734.2 [M+H] + 1 H NMR (400 MHz, Methanol-d4) δ 9.20 (t, 1H), 7.84 (d, 1H), 6.91 - 6.78 (m, 3H), 5.86 - 5.78 (m, 1H), 5.76 - 5.65 (m, 1H), 3.75 - 3.63 (m, 1H), 3.41 - 3.37 (m, 1H), 3.21 - 3.06 (m, 2H), 3.01 - 2.94 (m, 3H), 2.93 - 2.86 (m, 2H), 2.78 - 2.61 (m, 2H), 2.56 - 2.44 (m, 2H), 2.41 - 2.15 (m, 3H), 2.13 - 2.00 (m, 4H), 1.99 - 1.92 (m, 4H), 1.89 (d, 3H), 1.85 - 1.74 (m, 2H), 1.47 - 1.33 (m, 2H), 1.01 - 0.94 (m, 6H). Trifluoroacetate of Compound 28-2: LC-Ms m / z (ESI): 734.2 [M+H] + 1 H NMR (400 MHz, Methanol-d4) δ 9.35 (d, 1H), 7.87 (s, 1H), 6.94 - 6.81 (m, 3H), 5.81 (t, 1H), 5.74 - 5.65 (m, 1H), 3.75 - 5.65 (m, 1H), 3.23 - 3.14 (m, 1H), 3.11 - 2.98 (m, 4H), 2.94 - 2.86 (m, 3H), 2.85 - 2.74 (m, 1H), 2.70 - 2.61 (m, 1H), 2.52 (t, J=7.4 Hz, 3H), 2.25 - 2.04 (m, 5H), 2.00 (s, 6H), 1.87 - 1.76 (m, 4H), 1.41 - 1.26 (m, 2H), 0.95 - 0.84 (m, 6H).

[0239] Example 29: Preparation of Compound 29 [ka] The crude product of compound 29 was obtained by following the method for preparing compound 26. The crude product was separated and purified by prep-HPLC (Method 2) to obtain the trifluoroacetate salt of compound 29-1 (60 mg, Rt = 4.181 min) and the trifluoroacetate salt of compound 29-2 (88 mg, Rt = 4.279 min).

[0240] Trifluoroacetate salt of compound 29-1: LC-Ms m / z (ESI): 714.2[M+H] + 1 H NMR (400MHz,Methanol-d4) δ 9.31 (t,1H),7.83 (d,1H),7.19 (t,1H),7.14 - 7.03 (m,3H),6.83 (s,1H),5.86 - 5.78 (m,1H),5.73 - 5.64 (m,1H),3.75 - 3.64 (m,1H),3.22 - 3.10 (m,2H),2.98 (s,1H),2.96 - 2.88 (m,1H),2.86 (s,1H),2.81 - 2.51 (m,3H),2.36 - 2.33 (m,1H),2.24 - 2.09 (m,2H),2.08 - 2.01 (m,5H),2.01 - 1.91 (m,4H),1.88 (d,3H),1.85 - 1.74 (m,2H),1.49 - 1.31 (m,2H),1.01 - 0.93 (m,6H). Trifluoroacetate salt of compound 29-2: LC-Ms m / z (ESI): 714.2[M+H] + 1H NMR (400MHz,Methanol-d4) δ 9.45 (d,1H),7.88 (d,1H),7.25 - 7.09 (m,4H),6.88 (d,1H),5.86 - 5.78 (m,1H),5.73 - 5.64 (m,1H),3.75 - 3.64 (m,1H),3.43 - 3.37 (m,1H),3.24 - 3.03 (m,2H),3.01 - 2.90 (m,4H),2.86 - 2.50 (m,3H),2.41 - 2.29 (m,1H),2.25 - 2.11 (m,2H),2.11 - 1.97 (m,9H),1.89 - 1.73 (m,4H),1.39 - 1.26 (m,2H),0.95 - 0.86 (m,6H).

[0241] Example 30: Preparation of Compound 30 and Isomers [ka]

[0242] Step 1: Synthesis of 30b Under nitrogen gas protection, 30a (1.76 g, 8.26 mmol) was dissolved in 1,4-dioxane (60 mL), and bis(pinacolato)diboron (3.15 g, 12.39 mmol), PdCl(dppf) (0.60 g, 0.83 mmol), and potassium acetate (2.43 g, 24.78 mmol) were added sequentially. The mixture was incubated at 100 °C for 2 h. The mixture was extracted with ethyl acetate (180 mL), washed with water (50 mL × 2) and saturated brine (50 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 22b (1.35 g, 62.86%) was obtained by silica gel column chromatography.

[0243] Referring to the preparation method of compound 20, 30b and intermediate 6 were used as starting materials to obtain crude compound 30. The crude product was separated and purified by prep-HPLC (Method 2) to obtain the trifluoroacetate salt of compound 30-1 (10 mg, Rt = 4.121 min, yield 10.4%) and the trifluoroacetate salt of compound 30-2 (10 mg, Rt = 4.175 min, yield 10.4%).

[0244] Trifluoroacetate of Compound 30-1: LC-Ms m / z (ESI): 704.3 [M+H] + 1 H NMR (400 MHz, CD3OD) δ 7.90 (d, 1H), 7.04 (s, 1H), 6.84 (s, 1H), 6.76 (d, 1H), 5.85 - 5.76 (m, 1H), 5.75 - 5.65 (m, 1H), 4.52 - 4.42 (m, 2H), 3.30 - 3.25 (m, 1H), 3.24 - 3.15 (m, 2H), 3.05 - 3.05 (m, 1H), 3.05 - 2.87 (m, 10H), 2.87 - 2.74 (m, 2H), 2.69 - 2.55 (m, 1H), 2.30 - 2.22 (m, 3H), 2.11 - 1.86 (m, 4H), 1.47 - 1.33 (m, 1H), 1.00 - 0.89 (m, 6H). Trifluoroacetate of Compound 30-2: LC-Ms m / z (ESI): 704.3 [M+H] + 1 H NMR (400 MHz, CD3OD) δ 7.90 (s, 1H), 7.06 (s, 1H), 6.88 (s, 1H), 6.77 (d, 1H), 5.84 - 5.74 (m, 1H), 5.73 - 5.61 (m, 1H), 4.54 - 4.44 (m, 2H), 3.37 - 3.31 (m, 1H), 3.26 - 3.18 (m, 2H), 3.14 - 2.91 (m, 11H), 2.90 - 2.75 (m, 2H), 2.73 - 2.54 (m, 1H), 2.32 - 2.24 (m, 3H), 2.14 - 2.00 (m, 2H), 1.87 - 1.77 (m, 2H), 1.38 - 1.24 (m, 1H), 0.98 - 0.83 (m, 6H).

[0245] [[ID=2"]] Example 32: Preparation of Compound 32 and Isomers

Chemical Structure

[0246] Trifluoroacetate salt of compound 32-1: LC-Ms m / z (ESI): 734.8[M+H] + 1 H NMR (400MHz,CD3OD) δ 9.23 - 9.07 (m,1H),7.82 (s,1H),6.89 - 6.78 (m,3H),5.85 - 5.76 (m,1H),5.74 - 5.64 (m,1H),4.33 - 3.83 (m,4H),3.51 - 3.35 (m,1H),3.18 - 2.81 (m,7H),2.50 - 2.39 (m,2H),2.13 - 1.99 (m,3H),1.94 - 1.83 (m,6H),1.40 - 1.29 (m,2H),1.27 - 1.16 (m,6H),1.02 - 0.88 (m,6H). Trifluoroacetate salt of compound 32-2: LC-Ms m / z (ESI): 734.8[M+H] + 1 H NMR (400MHz,CD3OD) δ 7.94 - 7.73 (m,1H),6.93 - 6.83 (m,3H),5.84 - 5.65 (m,2H),4.26 - 4.07 (m,2H),4.00 - 3.83 (m,2H),3.46 - 3.35 (m,1H),3.19 - 2.77 (m,7H),2.53 - 2.43 (m,2H),2.16 - 2.03 (m,2H),1.98 (s,6H),1.87 - 1.70 (m,2H),1.38 - 1.18 (m,7H),0.97 - 0.81 (m,6H).

[0247] Example 33: Preparation of Compound 33 and Isomers [ka] The crude product of compound 33 was obtained by following the preparation method of Example 21. The crude product was separated and purified by prep-HPLC (Method 1) to obtain compound 33-1 (20 mg, Rt = 3.714 min, yield 7.50%) and compound 33-2 (25 mg, Rt = 3.765 min, yield 9.38%).

[0248] Compound 33-1: LC-Ms m / z (ESI): 702.7[M+H] + 1 H NMR (400MHz,CD3OD) δ 7.84 (d,1H),7.52 - 7.42 (m,2H),7.36 - 7.30 (m,1H),6.87 - 6.80 (m,1H),5.76 - 5.61 (m,2H),3.05 - 2.83 (m,7H),2.76 - 2.58 (m,7H),2.54 - 2.41 (m,2H),2.19 - 1.91 (m,7H),1.43 - 1.31 (m,1H),0.97 - 0.85 (m,6H). Compound 33-2: LC-Ms m / z (ESI): 702.7[M+H] + 1 H NMR (400MHz,CD3OD) δ 7.83 - 7.78 (m,1H),7.53 - 7.45 (m,2H),7.40 - 7.33 (m,1H),6.92 - 6.87 (m,1H),5.87 - 5.79 (m,1H),5.68 - 5.58 (m,1H),3.28 - 3.14 (m,2H),3.06 - 2.94 (m,4H),2.85 - 2.75 (m,7H),2.62 - 2.42 (m,3H),2.21 - 2.16 (m,3H),2.13 - 2.02 (m,2H),1.97 - 1.85 (m,1H),1.81 - 1.70 (m,1H),1.40 - 1.27 (m,1H),0.94 - 0.81 (m,6H).

[0249] Example 35: Preparation of Compound 35 [ka]

[0250] Step 1: Synthesis of 35b Under nitrogen gas protection, intermediate 9 (synthesis see WO2021076902) (390 mg, 1.08 mmol) was dissolved in dry DMF (5 mL), and HATU (750 mg, 1.97 mmol) and DIPEA (510 mg, 3.98 mmol) were added sequentially. After stirring at room temperature for 40 min, intermediate 21a (400 mg, 0.99 mmol) was added and the mixture was allowed to react at room temperature overnight. Ethyl acetate (80 mL) was added, and the mixture was washed sequentially with water (20 mL × 2) and saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 35b (500 mg, yield: 67.72%) was obtained by silica gel column chromatography. LC-Ms m / z (ESI): 746.8[M+H] +

[0251] Step 2: Synthesis of Compound 35-1 and Compound 35-2 35b (500 mg, 0.67 mmol) was dissolved in 9 mL of THF and 3 mL of water, and lithium hydroxide monohydrate (40 mg, 1.68 mmol) was added. The mixture was allowed to react at room temperature for 30 min. The pH was adjusted to 5-6 with 1N hydrochloric acid, and the mixture was concentrated under reduced pressure to give crude compound 35. The crude product was separated and purified by prep-HPLC (Method 1) to give compound 35-1 (21 mg, Rt = 4.109 min, yield 4.37%) and compound 35-2 (22 mg, Rt = 4.204 min, yield 4.57%).

[0252] Compound 35-1 LC-Ms m / z (ESI): 718.7[M+H] + 1H NMR (400MHz,CD3OD) δ 7.77 (s,1H),6.88 (s,1H),6.68 (s,2H),5.75 - 5.68 (m,1H),5.68 - 5.60 (m,1H),4.06 - 3.95 (m,4H),3.78 (s,3H),3.00 - 2.82 (m,5H),2.69 - 2.59 (m,1H),2.51 - 2.37 (m,4H),2.11 - 2.01 (m,2H),2.00 - 1.86 (s,9H),1.46 - 1.34 (m,1H),0.97 - 0.86 (m,6H). Compound 35-2 LC-Ms m / z (ESI): 718.7[M+H] + 1 H NMR (400MHz,CD3OD) δ 7.66 (s,1H),6.92 (s,1H),6.70 (s,2H),5.92 - 5.85 (m,1H),5.63 - 5.56 (m,1H),4.17 - 4.06 (m,4H),3.79 (s,3H),3.46 - 3.32 (m,2H),3.02 - 2.88 (m,3H),2.87 - 2.72 (m,2H),2.53 - 2.39 (m,5H),2.14 - 2.03 (m,2H),2.00 - 1.90 (m,7H),1.77 - 1.68 (m,1H),1.43 - 1.31 (m,1H),0.93 - 0.84 (m,6H).

[0253] Example 36: Preparation of Compound 36 [ka] The crude product of compound 36 was obtained by following the preparation method of Example 35. The crude product was separated and purified by prep-HPLC (Method 1) to obtain compound 36-1 (19 mg, Rt=5.540 min, yield 6.57%) and compound 36-2 (21 mg, Rt=5.599 min, yield 7.26%).

[0254] Compound 36-1 LC-Ms m / z (ESI): 706.7[M+H]+ 1 H NMR (400MHz,CD3OD) δ 7.86 (s,1H),6.91 - 6.78 (m,3H),5.83 - 5.66 (m,2H),4.43 - 4.01 (m,4H),3.45 - 3.33 (m,2H),3.15 - 3.04 (m,1H),2.99 - 2.76 (m,5H),2.68 - 2.54 (m,1H),2.53 - 2.37 (m,3H),2.11 - 1.99 (m,3H),1.97 - 1.83 (m,7H),1.47 - 1.33 (m,1H),1.00 - 0.89 (m,6H). Compound 36-2 LC-Ms m / z (ESI): 706.7[M+H] + 1 H NMR (400MHz,CD3OD) δ 7.67 (s,1H),6.95 - 6.84 (m,3H),5.94 - 5.85 (m,1H),5.64 - 5.55 (m,1H),4.17 - 4.04 (m,4H),3.46 - 3.33 (m,2H),3.04 - 2.71 (m,5H),2.53 - 2.39 (m,5H),2.16 - 2.03 (m,2H),2.01 - 1.87 (m,7H),1.77 - 1.67 (m,1H),1.42 - 1.30 (m,1H),0.93 - 0.82 (m,6H).

[0255] Example 37: Preparation of Compound 37 [ka] The crude product of compound 37 was obtained by following the preparation method of Example 20. The crude product was separated and purified by prep-HPLC (Method 1) to obtain compound 37-1 (18 mg, Rt=5.359 min, yield 6.21%) and compound 37-2 (19 mg, Rt=5.401 min, yield 6.56%). Compound 37-1: LC-Ms m / z (ESI): 690.7[M+H] + 1 H NMR (400MHz, CD3OD) δ 7.86 (s,1H),7.12 (s,1H),6.98 (d,1H),6.83 (s,1H),6.73 (d,1H),5.74 - 5.64 (m,2H),4.56 (t,2H),3.26 - 3.17 (m,2H),3.12 - 3.02 (m,2H),2.98 - 2.84 (m,5H),2.79 - 2.65 (m,9H),2.08 - 1.94 (m,4H),1.46 - 1.35 (m,1H),0.97 - 0.91 (m,6H). Compound 37-2: LC-Ms m / z (ESI): 690.7[M+H] + 1 H NMR (400MHz, CD3OD) δ 7.80 (s,1H),7.16 (s,1H),7.02 (d,1H),6.91 (s,1H),6.77 (d,1H),5.85 - 5.77 (m,1H),5.69 - 5.60 (m,1H),4.58 (t,2H),3.29 - 3.12 (m,4H),3.05 - 2.89 (m,4H),2.83 - 2.72 (m,9H),2.57 - 2.48 (m,1H),2.11 - 2.00 (m,2H),1.96 - 1.88 (m,1H),1.81 - 1.70 (m,1H),1.41 - 1.28 (m,1H),0.93 - 0.82 (m,6H).

[0256] Example 38: Production of Compound 38

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[0257] Synthesis of ステップ1:38b Under nitrogen gas protection, 38a (3 g, 14.91 mmol), bis(pinacolato)diboron (4.54 g, 17.88 mmol), potassium carbonate (2.06 g, 14.91 mmol), and PdCl(dppf)-DCM (CAS: 95464-05-4) (1.22 g, 1.49 mmol) were dissolved in 1,4-dioxane (30 mL) and water (3 mL). The mixture was refluxed at 100 °C overnight, and then water (20 mL) was added. The mixture was extracted with ethyl acetate (30 mL × 3), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash column chromatography to give 38b (2.8 g, 75.68% yield).

[0258] Step 2: Synthesis of 38c 38b (2.8 g, 11.28 mmol) was dissolved in dichloromethane (20 mL), and NaH (0.54 g, 22.5 mmol) was added slowly in several portions under ice bath. After stirring for 20 min, deuterated methyl iodide (3.27 g, 22.56 mmol) was added and the mixture was allowed to react overnight. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash column chromatography to give 38c (1.9 g, 63.52% yield).

[0259] Steps 3 to 6 were carried out in accordance with the preparation method of Example 21 to obtain crude compound 38. The crude product was separated and purified by prep-HPLC (Method 1) to obtain compound 38-1 (20 mg, Rt = 4.048 min, yield 9.41%) and compound 38-2 (25 mg, Rt = 4.301 min, yield 11.76%).

[0260] Compound 38-1: LC-Ms m / z (ESI): 709.7[M+H] + 1H NMR (400MHz,CD3OD) δ 7.83 (s,1H),6.82 (s,1H),6.68 - 6.62 (m,2H),5.74 - 5.63 (m,2H),3.00 - 2.83 (m,7H),2.71 - 2.58 (m,7H),2.48 - 2.39 (m,2H),2.08 - 1.93 (m,4H),1.91 (s,3H),1.83 (s,3H),1.46 - 1.34 (m,1H),0.97 - 0.88 (m,6H). Compound 38-2: LC-Ms m / z (ESI): 709.7[M+H] + 1 H NMR (400MHz,CD3OD) δ 7.85 (s,1H),6.90 (s,1H),6.69 (s,2H),5.81 - 5.74 (m,1H),5.71 - 5.64 (m,1H),3.29 - 3.18 (m,2H),3.06 - 2.82 (m,11H),2.73 - 2.62 (m,1H),2.53 - 2.43 (m,2H),2.13 - 2.01 (m,2H),1.94 (s,6H),1.91 - 1.82 (m,1H),1.82 - 1.72 (m,1H),1.41 - 1.26 (m,1H),0.94 - 0.82 (m,6H).

[0261] Example 39: Preparation of Compound 39 [ka] The crude product of compound 39 was obtained by following the preparation methods of intermediate 6 and compound 21. The crude product was separated and purified by prep-HPLC (Method 1) to obtain compound 39-1 (28 mg, Rt = 4.070 min) and compound 39-2 (30 mg, Rt = 4.143 min).

[0262] Compound 39-1: LC-Ms m / z (ESI): 706.7[M+H] + 1H NMR (400MHz, CD3OD) δ 7.85 (s,1H),6.83 (s,1H),6.67 (s,2H),5.72 - 5.63 (m,2H),3.78 (s,3H),3.11 - 2.99 (m,2H),2.98 - 2.86 (m,5H),2.75 - 2.62 (m,7H),2.48 - 2.40 (m,2H),2.09 - 2.00 (m,2H),1.99 - 1.94 (m,2H),1.92 (s,3H),1.85 (s,3H),1.47 - 1.33 (m,1H),0.99 - 0.87 (m,6H). Compound 39-2: LC-Ms m / z (ESI): 706.7[M+H] + 1 H NMR (400MHz, CD3OD) δ 7.80 (s,1H),6.90 (s,1H),6.69 (s,2H),5.86 - 5.79 (m,1H),5.65 - 5.59 (m,1H),3.79 (s,3H),3.28 - 3.10 (m,2H),3.02 - 2.93 (m,4H),2.83 - 2.72 (m,7H),2.58 - 2.44 (m,3H),2.13 - 2.01 (m,2H),1.97 - 1.87 (m,7H),1.79 - 1.70 (m,1H),1.41 - 1.29 (m,1H),0.93 - 0.83 (m,6H).

[0263] Example 40: Production of Compound 40

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[0264] Compound 40-1: LC-Ms m / z (ESI): 721.7[M+H] + 1 H NMR (400MHz, CD3OD) δ 7.76 (s,1H),6.88 (s,1H),6.67 (s,2H),5.75 - 5.68 (m,1H),5.67 - 5.59 (m,1H),4.03 - 3.90 (m,4H),3.35 - 3.22 (m,2H),3.00 - 2.92 (m,2H),2.92 - 2.80 (m,3H),2.67 - 2.59 (m,1H),2.51 - 2.36 (m,4H),2.11 - 2.00 (m,2H),1.99 - 1.92 (m,5H),1.89 (s,3H),1.47 - 1.35 (m,1H),0.98 - 0.87 (m,6H). Compound 40-2: LC-Ms m / z (ESI): 721.7[M+H] + 1 H NMR (400MHz, CD3OD) δ 7.66 (s,1H),6.92 (s,1H),6.69 (s,2H),5.89 (dd,1H),5.59 (t,1H),4.16 - 4.03 (s,4H),3.45 - 3.33 (m,2H),3.03 - 2.70 (m,5H),2.53 - 2.38 (m,5H),2.13 - 2.03 (m,2H),2.00 - 1.88 (m,7H),1.79 - 1.68 (m,1H),1.43 - 1.33 (m,1H),0.95 - 0.83 (m,6H).

[0265] Example 41: Production of Compound 41

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[0266] Compound 41-1: LC-Ms m / z (ESI): 750.3[M+H] + 1 H NMR (400MHz,CD3OD) δ 7.80 (s,1H),6.80 (s,1H),6.69 - 6.63 (m,2H),5.74 - 5.66 (m,2H),3.78 (s,3H),3.73 - 3.47 (m,4H),3.05 - 2.87 (m,5H),2.82 - 2.74 (m,1H),2.73 - 2.60 (m,2H),2.48 - 2.40 (m,2H),2.09 - 1.98 (m,2H),1.98 - 1.88 (m,5H),1.83 (s,3H),1.63 - 1.52 (m,3H),1.47 - 1.36 (m,1H),0.99 - 0.90 (m,6H). Compound 41-2: LC-Ms m / z (ESI): 750.3[M+H] + 1 H NMR (400MHz,CD3OD) δ 7.74 (s,1H),6.88 (s,1H),6.69 (s,2H),5.84 - 5.76 (m,1H),5.70 - 5.62 (m,1H),4.03 - 3.75 (m,7H),3.20 - 3.13 (m,2H),3.02 - 2.94 (m,2H),2.91 - 2.70 (m,3H),2.68 - 2.59 (m,1H),2.53 - 2.45 (m,2H),2.13 - 2.02 (m,2H),1.97 - 1.83 (m,7H),1.81 - 1.71 (m,1H),1.66 - 1.55 (m,3H),1.40 - 1.29 (m,1H),0.95 - 0.83 (m,6H).

[0267] Example 42: Preparation of Compound 42 [ka] The crude product of compound 42 was obtained by following the method for preparing compound 35. The crude product was separated and purified by prep-HPLC (Method 1) to obtain compound 42-1 (15 mg, Rt=4.071 min) and compound 42-2 (18 mg, Rt=4.228 min).

[0268] Compound 42-1: LC-Ms m / z (ESI): 683.3[M+H] + 1 H NMR (400MHz, CD3OD) δ 7.29 (s,1H),6.69 (s,2H),5.56 (dd,1H),5.49 (t,1H),5.34 - 5.12 (m,1H),4.32 - 4.08 (m,2H),3.93 - 3.82 (m,1H),3.80 - 3.69 (m,4H),3.49 - 3.33 (m,2H),3.00 - 2.85 (m,3H),2.85 - 2.75 (m,1H),2.66 - 2.43 (m,4H),2.24 - 2.14 (m,4H),2.12 - 2.02 (m,2H),1.96 - 1.90 (m,6H),1.79 - 1.70 (m,1H),1.41 - 1.28 (m,1H),0.91 - 0.83 (m,6H). Compound 42-2: LC-Ms m / z (ESI): 683.3[M+H] + 1 H NMR (400MHz, CD3OD) δ 7.28 - 7.24 (m,1H),6.69 (s,2H),5.73 (dd,1H),5.66 - 5.59 (m,1H),5.40 - 5.17 (m,1H),4.43 - 4.26 (m,2H),4.10 - 3.88 (m,2H),3.79 (s,3H),3.49 - 3.40 (m,2H),3.02 - 2.83 (m,4H),2.70 - 2.60 (m,1H),2.55 - 2.44 (m,3H),2.21 - 2.15 (m,3H),2.14 - 2.02 (m,3H),1.96 - 1.91 (m,6H),1.88 - 1.78 (m,1H),1.41 - 1.27 (m,1H),0.91 - 0.82 (m,6H).

[0269] Example 43: Production of Compound 43

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[0270] Compound 43-1: LC-Ms m / z (ESI): 671.3[M+H] + 1 H NMR (400MHz,CD3OD) δ 7.32 - 7.27 (m,1H),6.92 - 6.82 (m,2H),5.60 - 5.47 (m,2H),5.33 - 5.08 (m,1H),4.19 - 3.96 (m,2H),3.81 - 3.61 (m,2H),3.37 - 3.23 (m,2H),3.02 - 2.92 (m,2H),2.90 - 2.70 (m,2H),2.67 - 2.54 (m,2H),2.52 - 2.41 (m,2H),2.24 - 2.13 (m,4H),2.13 - 2.02 (m,2H),1.99 - 1.94 (m,6H),1.80 - 1.70 (m,1H),1.42 - 1.26 (m,1H),0.92 - 0.81 (m,6H). Compound 43-2: LC-Ms m / z (ESI): 671.3[M+H] + 1H NMR (400MHz,CD3OD) δ 7.29 - 7.25 (m,1H),6.90 - 6.84 (m,2H),5.76 - 5.69 (m,1H),5.65 - 5.58 (m,1H),5.41 - 5.19 (m,1H),4.44 - 4.31 (m,2H),4.12 - 3.92 (m,2H),3.50 - 3.44 (m,2H),3.02 - 2.84 (m,4H),2.70 - 2.61 (m,1H),2.54 - 2.45 (m,3H),2.20 - 2.16 (m,3H),2.14 - 2.03 (m,3H),1.99 - 1.93 (m,6H),1.88 - 1.79 (m,1H),1.40 - 1.27 (m,1H),0.90 - 0.83 (m,6H).

[0271] Example 44: Preparation of Compound 44 [ka] The crude product of compound 44 was obtained by following the method for preparing compound 35. The crude product was separated and purified by prep-HPLC (Method 1) to obtain compound 44-1 (84 mg, Rt = 4.315 min) and compound 44-2 (96 mg, Rt = 4.398 min).

[0272] Compound 44-1: LC-Ms m / z (ESI): 738.3[M+H] + 1H NMR (400MHz, CD3OD) δ 7.79 (s,1H),6.88 - 6.80 (m,2H),6.79 (s,1H),5.74 - 5.64 (m,2H),3.63 - 3.38 (m,4H),3.02 - 2.90 (m,3H),2.88 - 2.80 (m,2H),2.80 - 2.71 (m,1H),2.71 - 2.57 (m,2H),2.49 - 2.39 (m,2H),2.10 - 2.01 (m,2H),2.00 - 1.91 (m,5H),1.85 - 1.82 (m,3H),1.56 (d,3H),1.47 - 1.36 (m,1H),0.99 - 0.89 (m,6H). Compound 44-2: LC-Ms m / z (ESI): 738.3[M+H] + 1 H NMR (400MHz, CD3OD) δ 7.74 (s,1H),6.91 - 6.84 (m,3H),5.83 - 5.76 (m,1H),5.70 - 5.61 (m,1H),4.02 - 3.75 (m,4H),3.20 - 3.13 (m,2H),3.04 - 2.94 (m,2H),2.91 - 2.70 (m,3H),2.69 - 2.60 (m,1H),2.53 - 2.44 (m,2H),2.14 - 2.03 (m,2H),1.98 (s,6H),1.94 - 1.84 (m,1H),1.83 - 1.71 (m,1H),1.63 - 1.58 (m,3H),1.42 - 1.28 (m,1H),0.94 - 0.84 (m,6H).

[0273] Example 45: Production of Compound 45

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[0274] Compound 45-1:LC-Ms m / z (ESI): 718.3[M+H] + Compound 45-2:LC-Ms m / z (ESI): 718.3[M+H] +

[0275] Example 46: Synthesis of Compound 46 [ka]

[0276] Step 1: Synthesis of 46b 2-Thiouracil (10 g, 78.03 mmol) and potassium carbonate (32 g, 234.02 mmol) were dissolved in tetrahydrofuran (500 mL) at room temperature, and methyl iodide (15 mL, 234.04 mmol) was added. The mixture was then reacted for 3 hours. Water was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 46b (6.8 g, 55.79% yield). LC-Ms m / z (ESI): 157.2[M+H] +

[0277] Step 2: Synthesis of 46c 46b (6.8 g, 43.54 mmol) was dissolved in a 5:1 mixture of 1,4-dioxane and water (200 mL) at room temperature, and potassium peroxymonosulfonate (40.15 g, 65.31 mmol) was added. The mixture was then reacted at 100° C. for 4 hours. Water was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 46c (4.9 g, 89.24% yield). LC-Ms m / z (ESI): 127.2[M+H] +

[0278] Step 3: Synthesis of 46d 46c (4.9 g, 38.87 mmol) was dissolved in 50 mL of acetonitrile at room temperature, and N-bromosuccinimide (6.92 g, 38.87 mmol) and glacial acetic acid (0.22 mL, 3.85 mmol) were added. The mixture was reacted for 4 h. The reaction was quenched by adding aqueous sodium bicarbonate solution, extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 46d (5.5 g, 69.02% yield). LC-Ms m / z (ESI): 206.1[M+H] +

[0279] Step 4: Synthesis of 46e 46d (5.5 g, 26.83 mmol) and the intermediate ethyl 2-(methanesulfonyloxy)-4-methylpentanoate (7.67 g, 32.20 mmol) were dissolved in acetonitrile (80 mL) at room temperature, and potassium carbonate (11.12 g, 80.53 mmol) was added. The mixture was then heated to 80 °C and reacted overnight. The reaction mixture was filtered through diatomaceous earth and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 46e (4.7 g, yield: 50.45%). LC-Ms m / z (ESI): 348.2[M+H] +

[0280] Step 5: Synthesis of 46f 46e (4.7 g, 13.54 mmol) and (E)-1-ethoxyethene-2-boronic acid pinacol ester (3.22 g, 16.25 mmol) were dissolved in 1,4-dioxane and water (v / v = 10:1, 110 mL). Potassium carbonate (5.61 g, 40.62 mmol) and tetrakis(triphenylphosphine)palladium (1.56 g, 1.35 mmol) were added, and the mixture was purged with nitrogen gas three times and reacted at 70 °C for 24 h. The mixture was quenched with water and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 46f (1.8 g, 39.28% yield). LC-Ms m / z (ESI): 339.4[M+H] +

[0281] Step 6: Synthesis of compound 46g 46f (1.8 g, 5.32 mmol) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (10 mL, 134.19 mmol) was slowly added, and the mixture was allowed to react overnight at room temperature. The mixture was concentrated under reduced pressure, and the pH was adjusted to neutral with aqueous sodium bicarbonate solution. Extraction was performed with ethyl acetate (20 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 46 g of crude product, which was directly used in the next step without further purification.

[0282] Steps 7-10: Synthesis of compound 46 Using 46g as the starting material, the crude product of compound 46 was obtained by referring to the synthetic route and preparation method of compound 3. The crude product was separated and purified by prep-HPLC ((Preparation Method 1)) to obtain compound 46-1 (20 mg, retention time = 4.122 min) and compound 46-2 (18 mg, retention time = 4.250 min).

[0283] Compound 46-1: LC-Ms m / z (ESI): 713.3[M+H]+ 1 H NMR (400MHz, CD3OD) δ 7.70 (s,1H),6.68 (s,2H),5.73 - 5.65 (m,1H),5.45 - 5.37 (m,1H),4.47 - 4.26 (m,4H),3.79 (s,3H),3.56 - 3.38 (m,2H),3.25 (s,3H),3.12 - 3.02 (m,1H),2.99 - 2.91 (m,2H),2.89 - 2.81 (m,1H),2.80 - 2.71 (m,1H),2.66 - 2.56 (m,1H),2.52 - 2.39 (m,2H),2.10 - 2.01 (m,2H),2.00 - 1.90 (m,4H),1.89 - 1.75 (m,4H),1.71 - 1.61 (m,3H),1.54 - 1.43 (m,1H),1.00 - 0.91 (m,6H). Compound 46-2: LC-Ms m / z (ESI): 713.3[M+H] + 1 H NMR (400MHz, CD3OD) δ 7.71 (s,1H),6.70 (s,2H),5.74 - 5.64 (m,1H),5.48 - 5.40 (m,1H),4.52 - 4.26 (m,4H),3.79 (s,3H),3.58 - 3.38 (m,2H),3.32 (s,3H),3.09 - 3.01 (m,1H),3.00 - 2.93 (m,2H),2.91 - 2.72 (m,2H),2.66 - 2.56 (m,1H),2.53 - 2.44 (m,2H),2.12 - 2.01 (m,2H),1.94 (s,6H),1.83 - 1.73 (m,1H),1.71 - 1.60 (m,4H),1.45 - 1.32 (m,1H),0.95 - 0.85 (t,6H).

[0284] Example 47: Production of Compound 47

change

[0285] Trifluoroacetate salt of compound 47-1: LC-Ms m / z (ESI): 706.3[M+H] + 1 H NMR (400MHz,CD3OD) δ 9.26 (d,1H),7.86 (s,1H),7.15 - 7.05 (m,1H),7.02 - 6.93 (m,1H),6.82 (s,1H),5.85 - 5.65 (m,2H),4.42 - 4.03 (m,4H),3.44 - 3.33 (m,2H),3.15 - 3.05 (m,1H),3.00 - 2.78 (m,5H),2.67 - 2.53 (m,1H),2.51 - 2.36 (m,3H),2.13 - 1.99 (m,3H),1.97 - 1.76 (m,7H),1.47 - 1.35 (m,1H),1.00 - 0.90 (m,6H). Trifluoroacetate salt of compound 47-2: LC-Ms m / z (ESI): 706.3[M+H]+ 1 H NMR (400MHz,CD3OD) δ 9.38 (d,1H),7.88 (s,1H),7.17 - 7.10 (m,1H),7.04 - 6.96 (m,1H),6.88 (s,1H),5.83 - 5.66 (m,2H),4.42 - 4.05 (m,4H),3.50 - 3.33 (m,2H),3.11 - 2.95 (m,3H),2.95 - 2.80 (m,3H),2.71 - 2.56 (m,1H),2.53 - 2.39 (m,3H),2.15 - 2.04 (m,2H),1.95 (s,3H),1.90 (d,3H),1.87 - 1.71 (m,2H),1.37 - 1.23 (m,1H),0.98 - 0.83 (m,6H).

[0286] Example 48: Preparation of Compound 48 [ka] The crude product of compound 48 was obtained by referring to the synthetic route and preparation method of compound 35. The crude product was separated and purified by prep-HPLC (Preparation Method 2) to obtain compound 48-1 (54 mg, retention time = 4.179 min) and compound 48-2 (62 mg, retention time = 4.271 min).

[0287] Trifluoroacetate salt of compound 48-1: LC-Ms m / z (ESI): 694.3[M+H] + 1 H NMR (400MHz,CD3OD) δ 9.23 (d,1H),7.90 (s,1H),7.13 - 7.04 (m,1H),7.01 - 6.91 (m,1H),6.82 (s,1H),5.82 - 5.74 (m,1H),5.73 - 5.64 (m,1H),3.36 - 3.22 (m,2H),3.15 - 2.83 (m,12H),2.52 - 2.36 (m,2H),2.13 - 1.98 (m,3H),1.97 - 1.74 (m,7H),1.48 - 1.35 (m,1H),1.01 - 0.94 (m,6H). Trifluoroacetate salt of compound 48-2: LC-Ms m / z (ESI): 694.3[M+H] + 1H NMR (400MHz,CD3OD) δ 9.35 (d,1H),7.92 (s,1H),7.16 - 7.08 (m,1H),7.04 - 6.94 (m,1H),6.88 (s,1H),5.82 - 5.64 (m,2H),3.39 - 3.24 (m,2H),3.10 - 2.84 (m,12H),2.55 - 2.45 (m,2H),2.16 - 2.03 (m,2H),1.95 (s,3H),1.90 (d,3H),1.87 - 1.71 (m,2H),1.38 - 1.23 (m,1H),0.98 - 0.81 (m,6H).

[0288] Example 49: Preparation of Compound 49 [ka]

[0289] Step 1: Synthesis of compound 49B Substrate 49A (5.00 g, 24.99 mmol) was dissolved in 10% aqueous sulfuric acid (50 mL) in an ice bath, and sodium nitrite (1.72 g, 24.99 mmol) dissolved in water (10 mL) was added dropwise. After the addition was complete, the reaction was continued for 1 h in an ice bath. 50% aqueous sulfuric acid (50 mL) was then added dropwise. After the addition was complete, the reaction was heated to 100 °C and continued for 1 h. The reaction was cooled to room temperature and slowly poured into stirring ice water (300 mL). Stirring was continued for 30 min. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to give 49B (2.89 g, 57.52% yield).

[0290] Step 2: Synthesis of compound 49C Substrate 49B (2.89 g, 14.37 mmol) was dissolved in acetonitrile (30 mL), and potassium carbonate (3.97 g, 28.72 mmol) and methyl iodide (3.06 g, 21.55 mmol) were added. After the addition was complete, the mixture was heated to 60 °C under a nitrogen atmosphere and reacted for 18 h. The reaction was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (5 mL × 2). The filtrate was collected and concentrated to give the crude product, which was purified by silica gel column chromatography to give 49C (2.65 g, 85.74% yield).

[0291] Step 3: Synthesis of compound 49D Substrate 49C (2.65 g, 12.32 mmol) was dissolved in ultra-dry tetrahydrofuran (40 mL) and pre-cooled to -78 °C for 10 min under a nitrogen atmosphere. n-Butyllithium (0.89 g, 13.91 mmol) was slowly added dropwise. After completion of the addition, the mixture was stirred at -78 °C for 1 h. Trimethyl borate (1.71 g, 16.47 mmol) was added dropwise to the mixture. After completion of the addition, the mixture was allowed to warm to room temperature under a nitrogen atmosphere for 18 h. The reaction mixture was poured into 10% aqueous hydrochloric acid (50 mL) and stirred in an ice bath for 30 min. The mixture was extracted with ethyl acetate (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to give 49D (0.84 g, 37.88% yield).

[0292] The crude product of compound 49 was obtained by referring to the synthetic route and preparation method of compound 35. The crude product was separated and purified by prep-HPLC (Preparation Method 1) to obtain compound 49-1 (32 mg, retention time = 4.218 min) and compound 49-2 (35 mg, retention time = 4.303 min).

[0293] Compound 49-1: LC-Ms m / z (ESI): 718.3[M+H] + 1H NMR (400MHz, CD3OD) δ 7.76 (s,1H),7.06 (d,1H),6.88 (s,1H),6.85 (d,1H),5.75 - 5.68 (m,1H),5.67 - 5.59 (m,1H),4.05 - 4.39 (m,4H),3.82 (s,3H),3.37 - 3.31 (m,2H),2.96 (t,2H),2.92 - 2.82 (m,3H),2.69 - 2.60 (m,1H),2.49 - 2.36 (m,4H),2.12 - 2.01 (m,2H),2.00 - 1.92 (m,2H),1.89 - 1.76 (m,6H),1.47 - 1.34 (m,1H),0.97 - 0.87 (m,6H). Compound 49-2: LC-Ms m / z (ESI): 718.3[M+H]+ 1 H NMR (400MHz, CD3OD) δ 7.66 (s,1H),7.08 (d,1H),6.92 (s,1H),6.86 (d,1H),5.92 - 5.86 (m,1H),5.60 (t,1H),4.11 (t,4H),3.83 (s,3H),3.46 - 3.32 (m,2H),3.03 - 2.87 (m,3H),2.86 - 2.71 (m,2H),2.53 - 2.39 (m,5H),2.13 - 2.02 (m,2H),1.99 - 1.92 (m,1H),1.91 - 1.81 (m,6H),1.78 - 1.67 (m,1H),1.43 - 1.32 (m,1H),0.93 - 0.84 (m,6H).

[0294] Example 50: Production of Compound 50

change

[0295] Compound 50-1: LC-Ms m / z (ESI): 706.4[M+H] + 1H NMR (400MHz, CD3OD) δ 7.85 (s,1H),7.08 - 7.02 (m,1H),6.87 - 6.81 (m,2H),5.72 - 5.63 (m,2H),3.82 (s,3H),3.14 - 3.00 (m,2H),2.99 - 2.87 (m,5H),2.71 (m,6H),2.70 - 2.63 (m,1H),2.46 - 2.39 (m,2H),2.09 - 2.00 (m,2H),1.99 - 1.91 (m,2H),1.89 - 1.72 (m,6H),1.47 - 1.35 (m,1H),0.97 - 0.88 (m,6H). Compound 50-2: LC-Ms m / z (ESI): 706.4[M+H] + 1H NMR (400MHz, CD3OD) δ 7.79 (s,1H),7.08 (d,1H),6.90 (s,1H),6.86 (d,1H),5.87 - 5.78 (m,1H),5.61 (t,1H),3.83 (s,3H),3.25 - 3.11 (m,2H),3.03 - 2.92 (m,4H),2.83 - 2.72 (m,7H),2.58 - 2.50 (m,1H),2.46 (t,2H),2.14 - 2.02 (m,2H),1.98 - 1.91 (m,1H),1.90 - 1.81 (m,6H),1.79 - 1.69 (m,1H),1.42 - 1.31 (m,1H),0.94 - 0.81 (m,6H).

[0296] Biological test: 1. Experimental results of インテグリンα4β7 ELISA: MAdCAM was prepared at a final concentration of 2.5 μg / ml in TBS buffer, and 50 μl of the solution was transferred to a 96-well plate and coated overnight at 4°C. The plate was washed three times with TBS buffer, and then 150 μl of blocking solution (TBS buffer containing 1% BSA) was added and blocked at 37°C for 1 hour. The plate was washed three times with TBS buffer, and 1 μg / ml α4β7 integrin protein was prepared in TBS buffer containing 0.1% BSA. 50 μl of the integrin protein was transferred to a 96-well plate, and 1 μl of different concentrations of compounds or DMSO was added and incubated at room temperature for 2 hours. Biotinylated anti-β7 antibody was prepared at 1 μg / ml in TBS buffer containing 0.1% BSA. The plate was washed three times with TBS buffer, and 50 μl of the antibody was added and incubated at room temperature for 1 hour. The plate was washed three times with TBS buffer, and 50 μl of streptavidin-HRP was added and incubated at room temperature for 20 minutes. The plate was washed three times with TBS buffer, and 50 μl of TMB substrate was added. The mixture was incubated at room temperature for 5-30 min. Finally, 25 μl of stop buffer (high-concentration phosphate solution) was added, and the OD value of the plate was read at 450 nm using a microplate reader. IC was calculated using GraphPad Prism 6 software. 50 values ​​were calculated.

[0297] Conclusion: The compounds of the present invention, for example, the compounds of the Examples, had good inhibitory activity against integrin α4β7.

[0298] 2. Integrin α4β7 cell adhesion assay MAdCAM-1 was prepared in TBS buffer to a final concentration of 2 μg / ml, and 50 μl of the solution was transferred to a 96-well plate and coated overnight at 4°C. The plate was washed three times with TBS buffer, and 150 μl of blocking solution (TBS buffer containing 1% BSA) was added and blocked for 1 hour at 37°C. RPMI8866 cells were harvested, washed twice with DPBS buffer, and 4 × 10 cells were plated in TBS buffer. 5 The cells were resuspended at 2 × 10 cells / ml, and 50 μl of the cell suspension was transferred to a 96-well plate.5 To cells / well, 1 μl of compounds at different concentrations or DMSO was added and incubated at 37°C for 1 or 2 hours. The plate was washed with TBS buffer to remove non-adherent cells, and 50 μl of substrate (4-nitrophenyl-N-acetyl-β-D-glucosaminide) was added. The plate was incubated at 37°C for 2 hours. Finally, 90 μl of stop solution (50 mM glycine and 5 mM EDTA, pH 10.4) was added, and the OD value of the plate was read at 405 nm using a microplate reader. IC was measured using GraphPad Prism 6 software. 50 The values ​​were calculated and the results are shown in Table 1.

[0299] 3. Integrin α4β1 cell adhesion experiments VCAM was prepared in coating buffer to a final concentration of 0.5 μg / ml, and 50 μl of the solution was transferred to a 96-well plate and coated overnight at 4°C. The plate was washed three times with coating buffer, and 150 μl of blocking solution (coating buffer containing 1% BSA) was added and blocked at 37°C for 1 hour. Jurkat cells were harvested, washed twice with DPBS buffer, and then 4 × 10 cells were added to the plate in working buffer. 6 The cells were resuspended at 2 × 10 cells / ml, and 50 μl of the cell suspension was transferred to a 96-well plate. 5 To each well, 1 μl of test compound or DMSO at different concentrations was added and incubated at 37°C for 1 hour. The plate was washed with coating buffer to remove non-adherent cells, and 50 μl of substrate (4-nitrophenyl-N-acetyl-β-D-glucosaminide) was added. The plate was incubated at 37°C for 2 hours. Finally, 90 μl of stop solution (50 mM glycine and 5 mM EDTA, pH 10.4) was added, and the OD of the plate was read at 405 nm.

[0300] Coating solution Buffer: DMEM + 20 mM HEPES + 0.4 mM MnCl2 Action Buffer:DMEM+20mM HEPES+0.1% BSA+0.4mM MnCl2 DMEM:dulbecco's modified eagle medium HEPES:2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid

[0301] [Table 7]

[0302] A<10 nM, control compound A [ka] is Conclusion: The compounds of the present invention, for example, the compounds of the Examples, have good inhibitory effects on cell adhesion mediated by integrin α4β7, and have better selectivity compared with the control compound A.

[0303] 4. CYP450 enzyme inhibition test The objective of this study was to evaluate the effects of test compounds on the activity of five cytochrome P450 (CYP) isoenzymes (CYP1A2, CYP2C9, CYP2D6, and CYP3A4) in human liver microsomes using an in vitro test system. Specific probe substrates for each CYP450 isoenzyme were incubated with human liver microsomes and various concentrations of test compounds. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction. After the reaction was completed, metabolites generated by the specific substrates were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS). Changes in CYP enzyme activity were measured, and IC50 values ​​were calculated to evaluate the potential inhibitory activity of test compounds against each of the CYP subtypes CYP1A2, CYP2C9, CYP2D6, and CYP3A4-M (using midazolam as a substrate).

[0304] Conclusion: The compounds of the present invention, for example, the compounds of the Examples, did not have any clear inhibitory effect on each subtype of CYP enzymes.

[0305] 5. Pharmacokinetic studies in mice Test animals: male BALB / c mice, 20-25 g, 6 mice / compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0306] Experimental design: On the day of the experiment, six BALB / c mice were randomly divided into groups according to their weight. One day before administration, they were fasted for 12-14 hours without water restriction, and fed 4 hours after administration.

[0307] [Table 8]

[0308] Before and after administration, 0.06 mL of blood was collected from the orbit under isoflurane anesthesia. The blood was placed in an EDTAK2 centrifuge tube and centrifuged at 5000 rpm at 4°C for 10 minutes to collect plasma. Blood was collected at 0, 5, 15, 30 minutes, 1, 2, 4, 6, 8, and 24 hours for both the intravenous and intragastric administration groups. All samples were stored at -80°C before analytical detection and quantitative analysis of the samples was performed by LC-MS / MS.

[0309] [Table 9]

[0310] Conclusion: The compounds of the present invention, for example, the compounds of the Examples, have good oral absorption performance in mice and low clearance.

[0311] 6. Pharmacokinetic study in rats Test animals: Male SD rats, approximately 220 g, 6-8 weeks old, 6 rats / compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0312] Experimental design: On the day of the experiment, six SD rats per compound were randomly divided into groups according to weight. One day before administration, they were fasted for 12-14 hours without water restriction, and fed 4 hours after administration.

[0313] [Table 10]

[0314] Before and after administration, 0.10 mL of blood was collected from the orbit under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm at 4°C for 10 minutes to collect plasma. Blood was collected at 0, 5, 15, and 30 minutes, and 1, 2, 4, 6, 8, and 24 hours for both the intravenous and intragastric administration groups. All samples were stored at -80°C before analytical detection, and quantitative analysis of the samples was performed by LC-MS / MS.

[0315] [Table 11]

[0316] Conclusion: The compounds of the present invention, for example, the compounds of the Examples, have good oral absorption performance and / or low clearance in rats.

[0317] 7. Pharmacokinetic study in beagle dogs Test animals: male beagle dogs, weighing approximately 8-11 kg, 5-6 dogs per compound, purchased from Beijing Masu Biotechnology Co., Ltd.

[0318] Test method: On the day of the test, 5-6 beagle dogs per compound were randomly assigned to groups based on weight. One day before administration, they were fasted for 12-14 hours without water prohibition, and fed 4 hours after administration.

[0319] [Table 12]

[0320] Before and after administration, 1 ml of blood was collected from the jugular or limb vein and placed in an EDTAK2 centrifuge tube. Plasma was collected by centrifugation at 5000 rpm and 4°C for 10 minutes. Blood was collected at 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24 h, 48, and 72 h for the intravenous and intragastric administration groups in groups G1 and G2. Blood was collected at 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, and 24 h for the intravenous and intragastric administration groups in groups G3 and G4. All samples were stored at -80°C before analysis and quantitative analysis was performed on the samples by LC-MS / MS.

[0321] Conclusion: The compounds of the present invention, for example, the compounds of the Examples, had good oral absorption performance in beagle dogs.

[0322] 8. Pharmacokinetic studies in monkeys Test animals: male cynomolgus monkeys, 3-5 kg, 3-6 years old, 4-6 animals per compound. Purchased from Suzhou Xishan Biotechnology Co., Ltd.

[0323] Test method: On the day of the test, 4-6 monkeys per compound were randomly assigned to groups based on weight. One day before administration, they were fasted for 14-18 hours without water prohibition, and fed 4 hours after administration.

[0324] [Table 13]

[0325] Before and after administration, 1.0 mL of blood was collected from a limb vein and placed in an EDTAK2 centrifuge tube. Plasma was collected by centrifugation at 5000 rpm and 4°C for 10 minutes. Blood was collected at 0, 5, 15, 30 minutes, 1, 2, 4, 6, 8, 10, 12, and 24 hours for both the intravenous and intragastric administration groups. All samples were stored at -80°C before analytical detection, and quantitative analysis of the samples was performed by LC-MS / MS.

[0326] Conclusion: The compounds of the present invention, for example, the compounds of the Examples, had good oral absorption performance in monkeys.

[0327] 9. hERG potassium ion channel activity test Experimental platform: electrophysiological manual patch clamp system Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium ion channel Experimental Method: hERG potassium channel currents were recorded at room temperature using the whole-cell patch clamp technique in CHO (Chinese Hamster Ovary) cells stably expressing the hERG potassium channel. Glass microelectrodes were fabricated by pulling glass electrode blanks with a BF150-86-10 Sutter puller. After filling the electrode with internal solution, the tip resistance was approximately 2-5 MΩ. The glass microelectrode was then inserted into the amplifier probe for connection to the patch clamp amplifier. Voltage clamping and data recording were computer-controlled using pClamp 10 software, with a sampling frequency of 10 kHz and a filter frequency of 2 kHz. After whole-cell recording, the cells were clamped to -80 mV, and a step voltage was applied to elicit the hERG potassium current (I hERG) by depolarizing from -80 mV for 2 s to +20 mV, repolarizing to -50 mV for 1 s, and then returning to -80 mV. The stimulation was repeated every 10 s, and the hERG potassium current was stabilized (for at least 1 min) before the administration process began. Compounds were administered for at least 1 min per test concentration, and at least two cells were tested for each concentration (n ≥ 2).

[0328] Data processing: Data analysis and processing were performed using pClamp 10, GraphPad Prism 5, and Excel software. The inhibition of hERG potassium current (peak hERG tail current evoked at -50 mV) by different compound concentrations was calculated using the following formula:

[0329] Inhibition%=[1-(I / Io)]×100% Here, Inhibition% represents the percentage of inhibition of the hERG potassium current by the compound, and I and Io represent the amplitude of the hERG potassium current after administration and before administration, respectively.

[0330] Compound IC50 was calculated by fitting the following equation using GraphPad Prism 5 software:

[0331] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)×HillSlope)) where X is the Log value of the sample detection concentration, Y is the percentage inhibition at the corresponding concentration, and Bottom and Top are the minimum and maximum percentage inhibition, respectively.

[0332] Conclusion: The compounds of the present invention, for example, the compounds of the Examples, did not have any obvious hERG inhibitory activity.

[0333] 10. Liver microsome stability test In this study, liver microsomes from three genera, monkey, rat and mouse, were used as an in vitro model to evaluate the metabolic stability of the test substance.

[0334] At 37°C, 1 μM of the test substance was incubated with microsomal protein and coenzyme NADPH for a certain period of time (5, 10, 20, 30, 60 min). The reaction was stopped by adding cold acetonitrile containing an internal standard. The concentration of the test substance in the sample was detected by LC-MS / MS. The T was calculated from the ln value of the drug residual rate in the incubation system and the incubation time. 1 / 2 was determined, and the liver microsome specific clearance CLint(mic) and liver specific clearance CLint(Liver) were further calculated.

[0335] [Table 14]

[0336] Conclusion: The compounds of the present invention, for example, the compounds of the Examples, had good stability in liver microsomes of monkeys, mice and rats.

Claims

1. A compound or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, said compound being selected from compounds represented by general formula (I), wherein: 【Chemical 1】 R １ is -CHR １ａ R １ｂ or -NR １ａ R １ｂ is selected from R １ａ is C １－６ alkyl groups, said alkyl groups optionally being selected from deuterium, halogen, OH, ═O, cyano, COOH, NH ２ , N.H.C. １－６ Alkyl group, N(C １－６ alkyl) ２ , C １－６ Alkyl group, C １－６ Alkoxy group, C ３－６ substituted with 0 to 4 substituents selected from cycloalkyl groups; R １ｂ is C ４－１０ a carbocycle, a 5- to 10-membered heterocycle, said carbocycle or heterocycle optionally having 0 to 4 R ｂ wherein the heterocycle contains 1 to 4 heteroatoms selected from O, S, and N; R ｂ are each independently deuterium, halogen, OH, ═O, cyano group, COOH, NH ２ , -C ０－４ Alkyl-NHC １－６ alkyl group, -C ０－４ Alkyl-N(C １－６ alkyl) ２ , C １－６ Alkyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, —C ０－４ Alkyl-C ３－１０ Carbocycle, -C ０－４ alkyl-3 to 10-membered heterocycle or R ｂａ wherein the alkyl group, alkynyl group, alkoxy group, carbocycle or heterocycle is optionally selected from the group consisting of deuterium, halogen, OH, ═O, cyano, COOH, CONH ２ , CONHC １－６ Alkyl group, CON(C １－６ alkyl) ２ , N.H. ２ , N.H.C. １－６ Alkyl group, N(C １－６ alkyl) ２ , N(C １－６ alkyl) (C ３－６ cycloalkyl), NH(C ３－６ cycloalkyl), C １－６ Alkyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, halogen-substituted C １－６ alkyl group, halogen-substituted C １－６ Alkoxy group, C １－６ Alkoxyalkyl group or R ｋ and the heterocycle contains 1 to 4 heteroatoms selected from O, S, and N; R ｂａ is -C ０－４ alkyl-7 to 12 membered heterocycle, —C ０－４ alkyl - a 4- to 6-membered heterocycle linked via a carbon atom; 【Chemistry 2】 wherein R ｂａ is optionally H, halogen, OH, ═O, cyano group, COOH, CONH ２ , CONHC １－６ Alkyl group, CON(C １－６ alkyl) ２ , N.H. ２ , N.H.C. １－６ Alkyl group, N(C １－６ alkyl) ２ , C １－６ Alkyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, halogen-substituted C １－６ alkyl group, halogen-substituted C １－６ Alkoxy group, C １－６ Alkoxyalkyl group or R ｋ and the heterocycle contains 1 to 4 heteroatoms selected from O, S, and N; R ｋ is -C １－４ Alkyl-NH ２ , -C １－４ Alkyl-NHC １－６ alkyl group, -C １－４ Alkyl-N(C １－６ alkyl) ２ , -C ０－４ Alkyl-C ３－１０ Carbocyclic ring or -C ０－４ alkyl-3 to 10 membered heterocycle, wherein said alkyl group, carbocycle or heterocycle optionally contains deuterium, halogen, OH, ═O, cyano group, COOH, NH ２ , N.H.C. １－６ Alkyl group, N(C １－６ alkyl) ２ , C １－６ Alkyl group, C １－６ Alkoxy group, halogen-substituted C １－６ alkyl group, halogen-substituted C １－６ Alkoxy group, C １－６ substituted with 1 to 4 substituents selected from alkoxyalkyl groups, and the heterocycle contains 1 to 4 heteroatoms selected from O, S, and N; R ２ is C １－６ Alkyl group, C ６－１０ Aromatic ring, 5- to 10-membered heteroaromatic ring, C ３－１０ a carbocycle, a 5- to 10-membered heterocycle, ２ optionally 0 to 4 R ２ａ and the heteroaromatic ring or heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N; R ２ａ are each independently deuterium, halogen, OH, cyano group, ═O, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C ３－６ The alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, and heterocyclic group may optionally contain deuterium, halogen, OH, ═O, cyano group, COOH, NH ２ , N.H.C. １－６ Alkyl group, N(C １－６ alkyl) ２ , C １－６ Alkyl group, C １－６ alkoxy groups, and the heterocyclic group contains 1 to 3 heteroatoms selected from N, O, or S; As an option, ２ａ and R ２ａ is directly connected to C ４－７ forming a carbocyclic ring or a 4- to 7-membered heterocyclic ring, said carbocyclic ring or heterocyclic ring optionally containing deuterium, halogen, OH, cyano group, ═O, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C ３－６ substituted with 1 to 4 substituents selected from a cycloalkyl group, a 3- to 7-membered heterocycloalkyl group, and said alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group or heterocycloalkyl group is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, OH and cyano group; R ３ is H, C １－６ alkyl groups, said alkyl groups optionally being selected from deuterium, halogen, OH, ═O, cyano, COOH, NH ２ , N.H.C. １－６ Alkyl group, N(C １－６ alkyl) ２ , C １－６ Alkyl group, C １－６ Alkoxy group, C ３－６ substituted with 0 to 4 substituents selected from carbocycles; Ring A is C ８－１０ fused ring carbocycles, wherein ring A is optionally selected from 0 to 4 R ａ５ is replaced by Or ring A is 【Chemistry 3】 wherein ring A is selected from C ２－６ Alkenyl group or C ２－６ alkynyl groups, and optionally 1 to 3 R ａ５ is replaced by R ａ５ is a halogen, OH, cyano group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C ３－６ The alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, and heterocyclic group may optionally contain deuterium, halogen, OH, ═O, cyano group, COOH, NH ２ , N.H.C. １－６ Alkyl group, N(C １－６ alkyl) ２ , C １－６ Alkyl group, C １－６ Alkoxy group or C ３－６ cycloalkyl groups, wherein said heterocyclic group contains 1 to 3 heteroatoms selected from N, O, or S, or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof.

2. R １ teeth, 【Chemistry 4】 is selected from b is selected from 0, 1, 2, and 3; R ｂ are each independently deuterium, halogen, OH, ═O, cyano group, COOH, NH ２ , -C ０－４ Alkyl-NHC １－４ alkyl group, -C ０－４ Alkyl-N(C １－４ alkyl) ２ , C １－４ Alkyl group, C ２－４ Alkynyl group, C １－４ Alkoxy group, —C ０－４ Alkyl-C ３－６ Carbocycle, -C ０－４ alkyl-3 to 7-membered heterocycle or R ｂａ wherein the alkyl group, alkynyl group, alkoxy group, carbocycle or heterocycle is optionally selected from the group consisting of deuterium, halogen, OH, ═O, cyano, COOH, CONH ２ , CONHC １－４ Alkyl group, CON(C １－４ alkyl) ２ , N.H. ２ , N.H.C. １－４ Alkyl group, N(C １－４ alkyl) ２ , N(C １－４ alkyl) (C ３－６ cycloalkyl), NH(C ３－６ cycloalkyl), C １－４ Alkyl group, C ２－４ Alkynyl group, C １－４ Alkoxy group, halogen-substituted C １－４ alkyl group, halogen-substituted C １－４ Alkoxy group, C １－４ Alkoxyalkyl group or R ｋ and the heterocycle contains 1 to 4 heteroatoms selected from O, S, and N; R ｂａ is -C ０－２ alkyl-7-8 membered monocyclic heterocycloalkyl group, —C ０－２ alkyl-7 to 11-membered spirocyclic heterocycloalkyl group, —C ０－２ alkyl-7 to 11-membered bridged heterocycloalkyl group, —C ０－２ alkyl - a 4- to 6-membered monocyclic heterocycloalkyl group linked via a carbon atom; 【Chemistry 5】 wherein R ｂａ is optionally H, halogen, OH, ═O, cyano group, COOH, CONH ２ , CONHC １－４ Alkyl group, CON(C １－４ alkyl) ２ , N.H. ２ , N.H.C. １－４ Alkyl group, N(C １－４ alkyl) ２ , C １－４ Alkyl group, C ２－４ Alkynyl group, C １－４ Alkoxy group, halogen-substituted C １－４ alkyl group, halogen-substituted C １－４ Alkoxy group, C １－４ Alkoxyalkyl group or R ｋ and the heterocycloalkyl group contains 1 to 4 heteroatoms selected from O, S, and N; R ｋ is -C １－２ Alkyl-NH ２ , -C １－２ Alkyl-NHC １－４ alkyl group, -C １－２ Alkyl-N(C １－４ alkyl) ２ , -C ０－２ Alkyl-C ３－６ Carbocyclic ring or -C ０－２ alkyl-3-6 membered heterocycle, wherein the alkyl group, carbocycle or heterocycle is optionally selected from the group consisting of deuterium, halogen, OH, ═O, cyano, COOH, NH ２ , N.H.C. １－４ Alkyl group, N(C １－４ alkyl) ２ , C １－４ Alkyl group, C １－４ Alkoxy group, halogen-substituted C １－４ alkyl group, halogen-substituted C １－４ Alkoxy group, C １－４ substituted with 1 to 4 substituents selected from alkoxyalkyl groups, and the heterocycle contains 1 to 4 heteroatoms selected from O, S, and N; R ２ is C １－４ Alkyl group, benzene ring, naphthalene ring, 5- to 6-membered heteroaromatic ring, 9- to 10-membered heteroaromatic ring, C ３－１０ Non-aromatic carbocycles, 5- to 10-membered non-aromatic heterocycles, benzo C ４－６ a carbocyclic group or a 4- to 6-membered benzoheterocyclic group, ２ optionally 0 to 4 R ２ａ and the heteroaromatic ring or heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N; R ２ａ are each independently deuterium, halogen, OH, cyano group, ═O, C １－４ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－４ Alkoxy group, C ３－６ The alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, and heterocyclic group may optionally contain deuterium, halogen, OH, ═O, cyano group, COOH, NH ２ , N.H.C. １－４ Alkyl group, N(C １－４ alkyl) ２ , C １－４ Alkyl group, C １－４ alkoxy groups, and the heterocyclic group contains 1 to 3 heteroatoms selected from N, O, or S; As an option, ２ａ and R ２ａ is directly connected to C ４－７ forming a carbocyclic ring or a 4- to 7-membered heterocyclic ring, said carbocyclic ring or heterocyclic ring optionally containing deuterium, halogen, OH, cyano group, ═O, C １－４ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－４ Alkoxy group, C ３－６ substituted with 1 to 4 substituents selected from a cycloalkyl group, a 3- to 7-membered heterocycloalkyl group, and said alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group or heterocycloalkyl group is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, OH and cyano group; R ３ is H, C １－４ alkyl groups, said alkyl groups optionally being selected from deuterium, halogen, OH, ═O, cyano, COOH, NH ２ , N.H.C. １－４ Alkyl group, N(C １－４ alkyl) ２ , C １－４ Alkyl group, C １－４ Alkoxy group, C ３－６ substituted with 0 to 4 substituents selected from carbocycles; Ring A is benzo C ４－６ carbocycle, wherein said ring A is optionally selected from 0 to 4 R ａ５ is replaced by Or ring A is 【Chemistry 6】 wherein ring A is selected from C ２－４ Alkenyl group or C ２－４ alkynyl groups, optionally substituted with one substituent selected from R ａ５ and is substituted with 1 to 3 selected from R ａ５ is a halogen, OH, cyano group, C １－４ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－４ Alkoxy group, C ３－６ The alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, and heterocyclic group may optionally contain deuterium, halogen, OH, ═O, cyano group, COOH, NH ２ , N.H.C. １－４ Alkyl group, N(C １－４ alkyl) ２ , C １－４ alkyl group, halogen-substituted C １－４ C substituted with alkyl group or cyano group １－４ Alkyl group, C １－４ Alkoxy group, C ３－６ 2. The compound of claim 1, or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein the heterocyclic group is substituted with 0 to 4 substituents selected from cycloalkyl groups, and the heterocyclic group contains 1 to 3 heteroatoms selected from N, O, or S.

3. R ｂ are each independently deuterium, halogen, OH, ═O, a cyano group, or C １－４ Alkyl group, C ２－４ Alkynyl group, C １－４ Alkoxy group, phenyl group, 5- to 6-membered heteroaryl group, —CH ２ NHC １－４ Alkyl group, —CH ２ N (C １－４ alkyl) ２ , -CH ２ CH ２ -NHC １－４ Alkyl group, —CH ２ CH ２ -N(C １－４ alkyl) ２ , a phenyl group, a 5- to 6-membered heteroaryl group, C ３－６ cycloalkyl groups, 3- to 7-membered heterocycloalkyl groups, —CH ２ -phenyl group, -CH ２ -5- to 6-membered heteroaryl group, -CH ２ -C ３－６ cycloalkyl group, —CH ２ -3 to 7-membered heterocycloalkyl group, -CH ２ CH ２ -phenyl group, -CH ２ CH ２ -5- to 6-membered heteroaryl group, -CH ２ CH ２ -C ３－６ cycloalkyl group, —CH ２ CH ２ -3 to 7-membered heterocycloalkyl group, R ｂａ wherein said CH ２ , alkyl group, alkynyl group, phenyl group, heteroaryl group, cycloalkyl group, heterocycloalkyl group may optionally be substituted with deuterium, halogen, OH, ═O, cyano group, COOH, CONH ２ , CONHC １－４ Alkyl group, CON(C １－４ alkyl) ２ , N.H. ２ , N.H.C. １－４ Alkyl group, N(C １－４ alkyl) ２ , N(C １－４ alkyl) (C ３－６ cycloalkyl), NH(C ３－６ cycloalkyl), C １－４ Alkyl group, C ２－４ Alkynyl group, C １－４ Alkoxy group, halogen-substituted C １－４ alkyl group, halogen-substituted C １－４ Alkoxy group, C １－４ Alkoxyalkyl group or R ｋ and the heteroaryl or heterocycloalkyl group contains 1 to 4 heteroatoms selected from O, S, and N; R ｂａ represents a 7- to 8-membered monocyclic heterocycloalkyl group, a 7- to 11-membered spirocyclic heterocycloalkyl group, a 7- to 11-membered bridged cyclic heterocycloalkyl group, a 4- to 6-membered monocyclic heterocycloalkyl group linked via a carbon atom, -CH ２ -7- to 8-membered monocyclic heterocycloalkyl group, -CH ２ -7 to 11-membered spirocyclic heterocycloalkyl group, -CH ２ -7 to 11-membered bridged heterocycloalkyl group, -CH ２ - a 4- to 6-membered monocyclic heterocycloalkyl group linked via a carbon atom, -CH ２ CH ２ -7- to 8-membered monocyclic heterocycloalkyl group, -CH ２ CH ２ -7 to 11-membered spirocyclic heterocycloalkyl group, -CH ２ CH ２ -7 to 11-membered bridged heterocycloalkyl group, -CH ２ CH ２ a 4- to 6-membered monocyclic heterocycloalkyl group linked via a carbon atom, 【Chemistry 7】 wherein R ｂａ is optionally H, halogen, OH, ═O, cyano group, COOH, CONH ２ , CONHC １－４ Alkyl group, CON(C １－４ alkyl) ２ , N.H. ２ , N.H.C. １－４ Alkyl group, N(C １－４ alkyl) ２ , C １－４ Alkyl group, C ２－４ Alkynyl group, C １－４ Alkoxy group, halogen-substituted C １－４ alkyl group, halogen-substituted C １－４ Alkoxy group, C １－４ Alkoxyalkyl group or R ｋ and the heterocycloalkyl group contains 1 to 4 heteroatoms selected from O, S, and N; R ｋ is -C １－４ Alkyl-NH ２ , -C １－４ Alkyl-NHC １－４ alkyl group, -C １－４ Alkyl-N(C １－４ alkyl) ２ , -C ０－４ Alkyl-C ３－６ Carbocyclic ring or -C ０－４ alkyl-3-6 membered heterocycle, wherein the alkyl group, carbocycle or heterocycle is optionally selected from the group consisting of deuterium, halogen, OH, ═O, cyano, COOH, NH ２ , N.H.C. １－４ Alkyl group, N(C １－４ alkyl) ２ , C １－４ Alkyl group, C １－４ Alkoxy group, halogen-substituted C １－４ alkyl group, halogen-substituted C １－４ Alkoxy group, C １－４ substituted with 1 to 4 substituents selected from alkoxyalkyl groups, and the heterocycle contains 1 to 4 heteroatoms selected from O, S, and N; R ２ represents a benzene ring, a naphthalene ring, a 5- to 6-membered heteroaromatic ring, a 9- to 10-membered heteroaromatic ring, C ３－６ Cycloalkyl groups, 3- to 7-membered heterocycloalkyl groups, benzo C ４－６ a carbocyclic group or a 4- to 6-membered benzoheterocyclic group, ２ optionally 0 to 4 R ２ａ and the heteroaromatic ring, heterocycloalkyl group contains 1 to 4 heteroatoms selected from O, S, and N; R ２ａ are each independently deuterium, halogen, OH, cyano group, ═O, C １－４ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－４ Alkoxy group, C ３－６ cycloalkyl groups, wherein the alkyl, alkenyl, alkynyl, alkoxy, and cycloalkyl groups are optionally selected from the group consisting of 0 to 4 deuterium atoms, halogen atoms, OH, ═O, cyano groups, C １－４ Alkyl group, C １－４ substituted with a substituent selected from an alkoxy group; As an option, ２ａ and R ２ａ are directly linked to form a 4-membered carbocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, or a 6-membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring optionally contains deuterium, halogen, OH, a cyano group, ═O, C １－４ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－４ Alkoxy group, C ３－６ substituted with 1 to 4 substituents selected from a cycloalkyl group, a 3- to 7-membered heterocycloalkyl group, and said alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group or heterocycloalkyl group is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, OH and cyano group; R ３ is H, C １－４ alkyl groups, wherein the alkyl groups are optionally selected from deuterium, halogen, C １－４ Alkyl group, C １－４ substituted with 0 to 4 substituents selected from an alkoxy group and a benzene ring; Ring A is 【Chemistry 8】 wherein said ring A is optionally selected from 0 to 4 R ａ５ is replaced by Or ring A is 【Chemistry 9】 wherein ring A is selected from C ２－４ Alkenyl group or C ２－４ alkynyl groups, optionally substituted with one substituent selected from R ａ５ and is substituted with 1 to 3 selected from R ａ５ is a halogen, OH, cyano group, C １－４ Alkyl group, C ２－４ Alkynyl group, C １－４ Alkoxy group, C ３－６ The alkyl group, alkynyl group, alkoxy group, cycloalkyl group, and heterocyclic group are optionally selected from the group consisting of deuterium, halogen, OH, ═O, cyano group, C １－４ Alkyl group, C １－４ Alkoxy group, C ３－６ 3. The compound of claim 2, or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, substituted with 0 to 4 substituents selected from cycloalkyl groups.

4. R １ａ is a methyl group, an ethyl group, a propyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, -CH ２ -cyclopropyl group, -CH ２ -cyclobutyl group, R ｂ are each independently deuterium, F, Cl, Br, I, OH, ═O, a cyano group, R ｂａ or R ｂ each independently represents one of the following substituted or unsubstituted groups: a methyl group, an ethyl group, an ethynyl group, a methoxy group, an ethoxy group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an azetidinyl group, an azacyclopentyl group, an azacyclohexyl group, an oxetanyl group, an oxacyclopentyl group, an oxacyclohexyl group, a morpholinyl group, a phenyl group, pyridine, -CH ２ NH (CH ２ CH ３ ), -CH ２ N (CH ２ CH ３ ) ２ , -CH ２ CH ２ NH (CH ３ ), -CH ２ CH ２ N (CH ３ ) ２ , -CH ２ CH ２ NH (CH ２ CH ３ ), -CH ２ CH ２ N (CH ２ CH ３ ) ２ , -CH ２ CH ２ N (CH ３ ) (CH ２ CH ３ ), -CH ２ -cyclopropyl group, -CH ２ -cyclobutyl group, -CH ２ -cyclopentyl group, -CH ２ -cyclohexyl group, -CH ２ -azetidinyl group, -CH ２ -azacyclopentyl group, -CH ２ -azacyclohexyl group, -CH ２ -oxetanyl group, -CH ２ -oxacyclopentyl group, -CH ２ -oxacyclohexyl group, -CH ２ -morpholinyl group, -CH ２ CH ２ -cyclopropyl group, -CH ２ CH ２ -cyclobutyl group, -CH ２ CH ２ -cyclopentyl group, -CH ２ CH ２ -cyclohexyl group, -CH ２ CH ２ -azetidinyl group, -CH ２ CH ２ -azacyclopentyl group, -CH ２ CH ２ -azacyclohexyl group, -CH ２ CH ２ -oxetanyl group, -CH ２ CH ２ -oxacyclopentyl group, -CH ２ CH ２ -oxacyclohexyl group, -CH ２ CH ２ -morpholinyl group, -CH ２ -phenyl group, -CH ２ -pyridyl group, -CH ２ CH ２ -phenyl group, -CH ２ CH ２ -pyridyl group, and when substituted, deuterium, halogen, OH, ═O, cyano group, CONH ２ , CONHC １－４ Alkyl group, CON(C １－４ alkyl) ２ , N.H. ２ , N.H.C. １－４ Alkyl group, N(C １－４ alkyl) ２ , N(C １－４ alkyl) (C ３－６ cycloalkyl), NH(C ３－６ cycloalkyl), C １－４ Alkyl group, C ２－４ Alkynyl group, C １－４ Alkoxy group, halogen-substituted C １－４ alkyl group, halogen-substituted C １－４ Alkoxy group, C １－４ Alkoxyalkyl group or R ｋ is substituted with 0 to 4 substituents selected from R ｂａ is an optionally substituted group: 【Chemistry 10】 and when substituted, optionally deuterium, halogen, OH, ═O, cyano group, CONH ２ , CONHC １－４ Alkyl group, CON(C １－４ alkyl) ２ , N.H. ２ , N.H.C. １－４ Alkyl group, N(C １－４ alkyl) ２ , N(C １－４ alkyl) (C ３－６ cycloalkyl), NH(C ３－６ cycloalkyl), C １－４ Alkyl group, C ２－４ Alkynyl group, C １－４ Alkoxy group, halogen-substituted C １－４ alkyl group, halogen-substituted C １－４ Alkoxy group, C １－４ Alkoxyalkyl group or R ｋ is substituted with 1 to 4 substituents selected from R ｋ is -CH ２ N (CH ３ ) ２ , -CH ２ -cyclopropyl group, -CH ２ - selected from cyclobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, oxetanyl groups, wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl groups are optionally substituted with deuterium, halogen, OH, ═O, cyano, NH ２ , N.H.C. １－４ Alkyl group, N(C １－４ alkyl) ２ , N(C １－４ alkyl) (C ３－６ cycloalkyl), NH(C ３－６ cycloalkyl), C １－４ Alkyl group, C １－４ Alkoxy group, halogen-substituted C １－４ alkyl group, halogen-substituted C １－４ Alkoxy group, C １－４ substituted with 1 to 4 substituents selected from alkoxyalkyl groups; R ２ is a benzene ring, a pyridyl group, a pyridonyl group, a pyrazinyl group, a pyrimidinyl group, a thienyl group, a thiazolyl group, a furyl group, an oxazolyl group, a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an azetidinyl group, an azacyclopentyl group, an azacyclohexyl group, an oxetanyl group, an oxacyclopentyl group, an oxacyclohexyl group, a morpholinyl group, 【Chemistry 11】 wherein R ２ optionally 0 to 4 R ２ａ is replaced by R ２ａ are each independently selected from deuterium, F, Cl, Br, I, OH, ═O, cyano, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, or cyclobutyl, and the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, or cyclobutyl groups are optionally selected from deuterium, halogen, OH, ═O, cyano, C １－４ Alkyl group, C １－４ substituted with 0 to 4 substituents selected from alkoxy groups; R ３ is selected from H, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl, and benzyl; Ring A is 【Chemistry 12】 wherein said ring A is optionally selected from 0 to 4 R ａ５ is replaced by Or ring A is 【Chemistry 13】 wherein ring A is substituted with one substituent selected from vinyl, ethynyl, propynyl, and propargyl groups, and optionally R ａ５ and is substituted with 1 to 3 selected from R ａ５ are each independently selected from F, Cl, Br, I, OH, CN, ethynyl, propynyl, propargyl, methyl, ethyl, cyclopropyl, methoxy, and ethoxy, and the ethynyl, propynyl, propargyl, methyl, ethyl, cyclopropyl, methoxy, and ethoxy groups are optionally selected from deuterium, halogen, OH, ═O, cyano, C １－４ Alkyl group, C １－４ Alkoxy group, C ３－６ 4. The compound of claim 3, or a stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, substituted with 1 to 4 substituents selected from cycloalkyl groups.

5. R １ teeth, 【Chemistry 14】 is selected from R ｂ are each independently deuterium, F, Cl, Br, OH, a cyano group, R ｂａ or R ｂ each independently represents one of the following substituted or unsubstituted groups: a methyl group, an ethyl group, an ethynyl group, a methoxy group, an ethoxy group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an azetidinyl group, an azacyclopentyl group, an azacyclohexyl group, an oxetanyl group, an oxacyclopentyl group, an oxacyclohexyl group, a morpholinyl group, a phenyl group, a pyridyl group, -CH ２ NH (CH ２ CH ３ ), -CH ２ N (CH ２ CH ３ ) ２ , -CH ２ CH ２ NH (CH ３ ), -CH ２ CH ２ N (CH ３ ) ２ , -CH ２ CH ２ NH (CH ２ CH ３ ), -CH ２ CH ２ N (CH ２ CH ３ ) ２ , -CH ２ CH ２ N (CH ３ ) (CH ２ CH ３ ), -CH ２ -cyclopropyl group, -CH ２ -cyclobutyl group, -CH ２ -cyclopentyl group, -CH ２ -cyclohexyl group, -CH ２ -azetidinyl group, -CH ２ -azacyclopentyl group, -CH ２ -azacyclohexyl group, -CH ２ -oxetanyl group, -CH ２ -oxacyclopentyl group, -CH ２ -oxacyclohexyl group, -CH ２ -morpholinyl group, -CH ２ CH ２ -cyclopropyl group, -CH ２ CH ２ -cyclobutyl group, -CH ２ CH ２ -cyclopentyl group, -CH ２ CH ２ -cyclohexyl group, -CH ２ CH ２ -azetidinyl group, -CH ２ CH ２ -azacyclopentyl group, -CH ２ CH ２ -azacyclohexyl group, -CH ２ CH ２ -oxetanyl group, -CH ２ CH ２ -oxacyclopentyl group, -CH ２ CH ２ -oxacyclohexyl group, -CH ２ CH ２ -morpholinyl group, -CH ２ -phenyl group, -CH ２ -pyridyl group, -CH ２ CH ２ -phenyl group, -CH ２ CH ２ -pyridyl group, 【Chemistry 15】 When substituted, it is selected from deuterium, F, Cl, Br, OH, ═O, a cyano group, CONH ２ , CONHCH ３ , CON(CH ３ ) ２ , N.H. ２ , NHCH ３ , N(CH ３ ) ２ , N(CH ３ ) (cyclopropyl group), NHCH ２ CH ３ , N(CH ２ CH ３ ) ２ , C.H. ２ F, CHF ２ , C.F. ３ , a methyl group, an ethyl group, an isopropyl group, an ethynyl group, a methoxy group, an ethoxy group, a methoxymethyl group, an ethoxymethyl group, a methoxyethyl group, or R ｋ is substituted with 0 to 4 substituents selected from R ｂａ is an optionally substituted group: 【Chemistry 16】 and when substituted, optionally deuterium, F, Cl, Br, OH, ═O, cyano group, CONH ２ , CONHCH ３ , CON(CH ３ ) ２ , N.H. ２ , NHCH ３ , N(CH ３ ) ２ , N(CH ３ ) (cyclopropyl group), NHCH ２ CH ３ , N(CH ２ CH ３ ) ２ , C.H. ２ F, CHF ２ , C.F. ３ , a methyl group, an ethyl group, an isopropyl group, an ethynyl group, a methoxy group, an ethoxy group, a methoxymethyl group, an ethoxymethyl group, a methoxyethyl group, or R ｋ is substituted with 1 to 4 substituents selected from R ｋ is -CH ２ N (CH ３ ) ２ , -CH ２ -cyclopropyl group, -CH ２ - selected from cyclobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, oxetanyl, wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, oxetanyl groups are optionally substituted with deuterium, F, Cl, Br, OH, ═O, cyano, NH ２ , NHCH ３ , N(CH ３ ) ２ , N(CH ３ ) (cyclopropyl group), NHCH ２ CH ３ , N(CH ２ CH ３ ) ２ , C.H. ２ F, CHF ２ , C.F. ３ , methyl group, ethyl group, isopropyl group, methoxy group, ethoxy group, methoxymethyl group, ethoxymethyl group, methoxyethyl group; R ２ represents a phenyl group, a pyridyl group, a pyridonyl group, an azacyclopentyl group, a morpholinyl group, 【Chemistry 17】 wherein R ２ is optionally deuterium, F, Cl, Br, OH, CF ３ substituted with 0 to 4 substituents selected from cyano, methyl, ethyl, methoxy, ethoxy, cyclopropyl, and cyclobutyl groups; or R ２ teeth, 【Chemistry 18】 wherein R ２ is optionally deuterium, CD ３ , -OCD ３ , F, Cl, Br, OH, CF ３ , substituted by 1 to 4 substituents selected from cyano, methyl, ethyl, methoxy, ethoxy, cyclopropyl, or cyclobutyl groups; Ring A is 【Chemistry 19】 5. The compound of claim 4, or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, selected from:

6. R １ teeth, 【Chemistry 20】 is selected from or R １ teeth, 【Chemical 21】 is selected from or R １ teeth, 【Chemical formula 22】 is selected from or R １ teeth, 【Chemical 23】 is selected from or R １ teeth, 【Chemistry 24】 is selected from or R １ teeth, 【Chemistry 25】 is selected from or R １ teeth, 【Chemical 26】 is selected from R ２ teeth, 【Chemical 27】 is selected from or R ２ teeth, 【Chemical formula 28】 is selected from or R ２ teeth, 【Chemical Formula 29】 is selected from R １ａ teeth, 【Chemistry 30】 6. The compound of claim 5, or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, selected from:

7. The compound is selected from compounds represented by general formula (I-a), (I-b), general formula (I-a-1), and (I-b-1), 【Chemical Formula 31】 Ring A, R ３ is the same as in any one of claims 2 to 6, p1 is selected from 0, 1, 2, 3 or 4; R ２ａ is deuterium, halogen, OH, CN, C １－４ Alkyl group, C １－４ Alkoxy group, C ３－６ The alkyl, alkoxy, cycloalkyl, and heterocycloalkyl groups are optionally selected from the group consisting of deuterium, halogen, OH, CN, C １－４ Alkyl group, C １－４ alkoxy groups, wherein the heterocycloalkyl group contains 1 to 4 heteroatoms selected from O, S, and N; R １ａ teeth, 【Chemical 32】 is selected from R ｂ１ is H, C １－４ Alkyl group, C ３－６ cycloalkyl groups, wherein the alkyl or cycloalkyl groups are optionally selected from the group consisting of deuterium, halogen, OH, CN, NHC, １－４ Alkyl group, N(C １－４ alkyl) ２ , C １－４ Alkyl group, C １－４ substituted with 0 to 4 substituents selected from alkoxy groups; R ｂ２ is H, R ｂａ , a substituted or unsubstituted group: １－４ Alkyl group, C ２－４ Alkynyl group, C １－４ Alkoxy group, phenyl group, 5- to 6-membered heteroaryl group, —CH ２ CH ２ -phenyl group, -CH ２ CH ２ -5- to 6-membered heteroaryl group, -CH ２ CH ２ -NHC １－４ Alkyl group, —CH ２ CH ２ -N(C １－４ alkyl) ２ , -CH ２ CH ２ -C ３－６ cycloalkyl group, —CH ２ CH ２ - one selected from 3 to 7 membered heterocycloalkyl groups, ２ , alkyl, cycloalkyl or heterocycloalkyl groups may optionally be substituted with deuterium, halogen, OH, ═O, cyano, COOH, NH ２ , N.H.C. １－４ Alkyl group, N(C １－４ alkyl) ２ , N(C １－４ alkyl) (C ３－６ cycloalkyl), NH(C ３－６ cycloalkyl), C １－４ Alkyl group, C ２－４ Alkynyl group, C １－４ Alkoxy group, halogen-substituted C １－４ alkyl group, halogen-substituted C １－４ Alkoxy group, C １－４ Alkoxyalkyl group or R ｋ and the heteroaryl or heterocycloalkyl group contains 1 to 4 heteroatoms selected from O, S, and N; R ｂａ , R ｋ or a stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof according to claim 1, wherein the definition of

8. R ２ａ is deuterium, -CD ３ , -OCD ３ , F, Cl, Br, I, OH, cyano, methyl, ethyl, methoxy, and ethoxy groups; R ｂ１ are H, F, and CH ２ F, CHF ２ , C.F. ３ , methyl group, —CH ２ CH ２ N (CH ３ ) ２ is selected from R ｂ２ is H, R ｂａ , substituted or unsubstituted groups such as methyl, ethyl, ethynyl, methoxy, ethoxy, -CH ２ NH (CH ２ CH ３ ), -CH ２ N (CH ２ CH ３ ) ２ , -CH ２ CH ２ NH (CH ３ ), -CH ２ CH ２ N (CH ３ ) ２ , -CH ２ CH ２ NH (CH ２ CH ３ ), -CH ２ CH ２ N (CH ２ CH ３ ) ２ , -CH ２ CH ２ N (CH ３ ) (CH ２ CH ３ ), -CH ２ CH ２ -cyclopropyl group, -CH ２ CH ２ -cyclobutyl group, -CH ２ CH ２ -cyclopentyl group, -CH ２ CH ２ -cyclohexyl group, -CH ２ CH ２ -azetidinyl group, -CH ２ CH ２ -azacyclopentyl group, -CH ２ CH ２ -azacyclohexyl group, -CH ２ CH ２ -oxetanyl group, -CH ２ CH ２ -oxacyclopentyl group, -CH ２ CH ２ -oxacyclohexyl group, -CH ２ CH ２ -morpholinyl group, -CH ２ CH ２ -phenyl group, -CH ２ CH ２ -pyridyl group, when substituted, H, F, Cl, Br, OH, ═O, cyano group, NH ２ , NHCH ３ , N(CH ３ ) ２ , N(CH ３ ) (cyclopropyl group), NHCH ２ CH ３ , N(CH ２ CH ３ ) ２ , C.H. ２ F, CHF ２ , C.F. ３ , a methyl group, an ethyl group, an isopropyl group, an ethynyl group, a methoxy group, an ethoxy group, a methoxymethyl group, an ethoxymethyl group, a methoxyethyl group, or R ｋ 8. The compound of claim 7, or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, substituted with one, two, or three substituents selected from:

9. The compound is selected from compounds represented by general formulas (If), (I-g), (If-1), (I-g-1), (I-h), (I-i), (I-h-1), and (I-i-1), 【Chemical 33】 R １ｂ teeth, 【Chemical Formula 34】 is selected from p2 is selected from 0, 1 or 2; R ａｋ is C ２－４ alkynyl groups, R ａ５ is the same as in any one of claims 1 to 4, The compound of claim 1 or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the definitions of other groups are the same as those of claim 7 or 8.

10. R ａｋ is selected from an ethynyl group, a propynyl group, and a propargyl group; R ａ５ is selected from F, Cl, Br, I, OH, a cyano group, a methyl group, an ethyl group, a methoxy group, an ethoxy group, and an ethynyl group, or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof.

11. The compound of claim 1, or a stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein the compound is one selected from the structures shown in Table E-1, Table E-3, Table E-4, and Table E-5.

12. 12. A pharmaceutical composition comprising the compound of any one of claims 1 to 11 or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, and a pharmaceutically acceptable carrier, preferably the pharmaceutical composition comprising 1 to 1500 mg of the compound of any one of claims 1 to 11 or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof.

13. Use of a compound described in any one of claims 1 to 12 or a stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, or a pharmaceutical composition described in claim 12, in the manufacture of a pharmaceutical for treating a disease associated with the activity or expression level of α4β7.

14. The application according to claim 13, wherein the disease is selected from intestinal inflammatory diseases.

15. 13. A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 11 or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, or a pharmaceutical composition according to claim 12, wherein the therapeutically effective amount is preferably 1 to 1500 mg, and the disease is preferably an intestinal inflammatory disease.

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