Propionic acid derivative and application thereof in medicine

Abstract

The invention relates to a compound shown in a general formula (I) or a stereoisomer, a racemate, a deuterated compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal of the compound, an intermediate and a preparation method of the compound, and application of the compound in preparation of drugs for treating diseases related to activity or expression quantity of integrin alpha4beta7. # imgabs0 #

Description

A propionic acid derivative and its application in medicine Technical Field

[0001] The present invention relates to a compound described by general formula (I) or its stereoisomers, racemates, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, as well as intermediates and preparation methods, and use of the compounds in preparing drugs for treating diseases related to integrin α4β7 activity or expression. Background Art

[0002] The integrin family consists of dimers of two subunits: α (120-185 kDa) and β (90-110 kDa). There are 18 α subunits and 8 β subunits in mammals. Different combinations of these subunits can form over 20 different integrins. α4β7 is a member of the integrin family. Intestinal inflammatory diseases 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 high endothelial veins of mucosal lymphoid organs and in the intestinal lamina propria. Under inflammatory conditions, various cytokines promote high expression of MAdCAM-1 on endothelial cells, which then mediate the migration of α4β7-expressing leukocytes to the site of inflammation. Targeting either integrin α4β7 or MAdCAM-1 can reduce intestinal inflammation. Currently, there are no small molecule compounds specifically targeting α4β7-mediated inflammation on the market. Natalizumab, a humanized monoclonal antibody targeting the α4 subunit, is used clinically to treat multiple sclerosis and Crohn's disease, but has been associated with PML (progressive multifocal leukoencephalopathy) as a side effect. Therefore, there is a need to develop a small molecule compound that can inhibit the integrin α4β7 protein for the treatment of diseases associated with integrin α4β7 activity or expression.

[0003] Summary of the Invention

[0004] The present invention has developed an integrin α4β7 inhibitor with novel structure, good efficacy, better α4β1 / α4β7 selectivity, better liver microsomal stability, greater safety, and no obvious hERG or CYP inhibitory activity. These compounds have good pharmacokinetic properties and good safety, and are used to treat diseases related to integrin α4β7, such as intestinal inflammatory diseases.

[0005] The purpose of the present invention is to provide a compound capable of inhibiting integrin α4β7 or its stereoisomers, racemates, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, as well as intermediates and preparation methods, and their use in the preparation of drugs for treating diseases related to integrin α4β7 activity or expression.

[0006] The present invention provides a compound of general formula (I) or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein

[0007] In some embodiments, R 1 Selected from -CHR 1a R 1b or -NR 1a R 1b ;

[0008] In some embodiments, R 1 Selected from b is selected from 0, 1, 2, 3;

[0009] In some embodiments, R 1 Selected from In some embodiments, R 1 Selected from

[0010] In some embodiments, R 1 Selected from

[0011] In some embodiments, R 1 Selected from In some embodiments, R 1 Selected from In some embodiments, R 1 Selected from In some embodiments, R 1 Selected from In some embodiments, R 1 Selected from In some embodiments, R 1 Selected from

[0012] In some embodiments, R 1 Selected from In some embodiments, R 1 Selected from

[0013] In some embodiments, R b1 Selected from H, F, CH2F, CHF2, CF3, methyl, -CH2CH2N(CH3)2;

[0014] In some embodiments, R b2 、R b Each independently selected from R ba 、 or one of the following groups which are optionally substituted: ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetanyl, oxolyl, oxetanyl, 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, -CH2-azetidinyl, - CH2-azetidinyl, -CH2-azetidinyl, -CH2-oxetanyl, -CH2-oxetanyl, -CH2-oxetanyl, -CH2-oxetanyl, -CH2-morpholinyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclopentyl, -CH2CH2-cyclohexyl, -CH2CH2-azetidinyl, -CH2CH2-azetidinyl, -CH2CH2-azetidinyl, -CH2CH2-azetidinyl, -CH2CH2-azetidinyl, -CH2CH2-azetidinyl, -CH2CH2-azetidinyl, -CH2CH2-azetidinyl, -CH2CH2-oxetanyl, -CH2CH2-oxetanyl, -CH2CH2-oxetanyl, -CH2CH2-oxetanyl, -CH2CH2-morpholinyl, -CH2-phenyl, -CH2-pyridinyl, -CH2CH2-phenyl, -CH2CH2-pyridinyl, When substituted, it is replaced by 1 to 4 groups 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 substituted by a substituent;

[0015] In some embodiments, R b2 、R b Each independently selected from R ba 、

[0016] In some embodiments, R ba Selected from

[0017] In some embodiments, R b1 Selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, CN, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0018] In some embodiments, R b2 Selected from H, R ba , substituted or unsubstituted one of the following groups: C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -CH2CH2-NHC 1-4 Alkyl, -CH2CH2-N(C 1-4 Alkyl)2, -CH2CH2-C 3-6 Cycloalkyl, -CH2CH2-3 to 7 membered heterocycloalkyl, wherein said CH2, alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, N(C 1-4 Alkyl)(C 3-6 Cycloalkyl), NH(C 3-6 Cycloalkyl), C 1-4 Alkyl, C 2-4 Alkynyl, C1-4 Alkoxy, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy, C 1-4 Alkoxyalkyl or R k Substituents substituted, the heteroaryl or heterocycloalkyl contains 1 to 4 heteroatoms selected from O, S, N;

[0019] In some embodiments, R 1a Selected from C 1-6 Alkyl, wherein the alkyl group is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 substituted by a cycloalkyl substituent;

[0020] In some embodiments, R 1a Selected from methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl, -CH2-cyclopropyl, -CH2-cyclobutyl;

[0021] In some embodiments, R 1a Selected from

[0022] In some embodiments, R 1b Selected from C 4-10 Carbocyclic ring, 5 to 10 membered heterocyclic ring, said carbocyclic ring or heterocyclic ring is optionally substituted by 0 to 4 R b Substitution, the heterocycle contains 1 to 4 heteroatoms selected from O, S, and N;

[0023] In some embodiments, R b Each independently selected from deuterium, halogen, OH, =O, cyano, COOH, NH2, -C 0-4 Alkyl-NHC 1-6 Alkyl, -C 0-4 Alkyl-N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -C 0-4 Alkyl-C 3-10 Carbocyclic ring, -C 0-4 Alkyl-3 to 10 membered heterocyclic ring or R ba The alkyl, alkynyl, alkoxy, carbocyclic or heterocyclic ring is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, CONH2, CONHC 1-6 Alkyl, CON(C 1-6Alkyl)2, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, N(C 1-6 Alkyl)(C 3-6 Cycloalkyl), NH(C 3-6 Cycloalkyl), C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogen-substituted C 1-6 Alkyl, halogen-substituted C 1-6 Alkoxy, C 1-6 Alkoxyalkyl or R k Substituents are substituted, and the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N;

[0024] In some embodiments, R b Each independently selected from deuterium, halogen, OH, =O, cyano, COOH, NH2, -C 0-4 Alkyl-NHC 1-4 Alkyl, -C 0-4 Alkyl-N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, -C 0-4 Alkyl-C 3-6 Carbocyclic ring, -C 0-4 Alkyl-3 to 7 membered heterocyclic ring or R ba The alkyl, alkoxy, carbocyclic or heterocyclic ring is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, CONH2, CONHC 1-4 Alkyl, CON(C 1-4 Alkyl)2, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, N(C 1-4 Alkyl)(C 3-6 Cycloalkyl), NH(C 3-6 Cycloalkyl), C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy, C 1-4 Alkoxyalkyl or R k Substituents are substituted, and the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N;

[0025] In some embodiments, R b Selected from R ba ;

[0026] In some embodiments, Rb Each independently selected from deuterium, halogen, OH, =O, cyano, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, phenyl, 5- to 6-membered heteroaryl, -CH2NHC 1-4 Alkyl, -CH2N(C 1-4 Alkyl)2, -CH2CH2-NHC 1-4 Alkyl, -CH2CH2-N(C 1-4 Alkyl)2, C 3-6 Cycloalkyl, 3 to 7 membered heterocycloalkyl, -CH2-C 3-6 Cycloalkyl, -CH2-3 to 7 membered heterocycloalkyl, -CH2CH2-C 3-6 Cycloalkyl, -CH2CH2-3 to 7 membered heterocycloalkyl or R ba , wherein the CH2, alkyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, CONH2, CONHC 1-4 Alkyl, CON(C 1-4 Alkyl)2, NH2, NHC 1-4 Alkyl, N(C 1-4 alkyl)2, N(C 1-4 Alkyl)(C 3-6 Cycloalkyl), NH(C 3-6 Cycloalkyl), C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy, C 1-4 Alkoxyalkyl or R k Substituents substituted, the heteroaryl or heterocycloalkyl contains 1 to 4 heteroatoms selected from O, S, N;

[0027] In some embodiments, R b Each independently selected from deuterium, F, Cl, Br, I, OH, =O, cyano, R ba , or R bEach independently selected from one of the following substituted or unsubstituted groups: methyl, ethyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetanyl, oxolanyl, oxetanyl, 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, -CH2-azepanyl, -CH2-azepanyl, -CH2-azepanyl, -CH2-azepanyl, -CH2-azepanyl, -CH2-azepanyl, -CH2-azepanyl, -CH2-azepanyl, -CH2-azepanyl, -CH2-azepanyl, -CH2-azepanyl, -CH2-azepanyl, -CH2-azepanyl, -CH2-azepanyl, -CH2-azepanyl, -CH2-azepanyl, -CH2-azepanyl, -CH2-azepanyl, -CH2-azepanyl, -CH2-azepanyl, -CH2-azepanyl, -CH2-azepanyl, -CH2-azepanyl, -CH2-azepanyl, -CH2-azepanyl, -CH2-azepanyl, -CH2-azepanyl, -CH2-azepanyl, -CH2-azepanyl, -CH2-azepanyl, -CH2-azepanyl, -CH2-azepanyl, -CH2-azepanyl, -CH2- 1-4 Alkyl, CON(C 1-4 Alkyl)2, NH2, NHC 1-4 Alkyl, N(C 1-4 alkyl)2, N(C 1-4 Alkyl)(C 3-6 Cycloalkyl), NH(C 3-6 Cycloalkyl), C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy, C 1-4 Alkoxyalkyl or R k substituted by a substituent;

[0028] In some embodiments, R b Each independently selected from deuterium, F, Cl, Br, OH, cyano, R ba , or R bEach independently selected from one of the following substituted or unsubstituted groups: methyl, ethyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetyl, oxetyl, morpholinyl, phenyl, pyridine, -CH2NH(CH2CH3), -CH2N(CH2CH3)2, -CH2CH2NH(CH3), -CH2CH2N(CH3)2, -CH2CH2NH(CH2CH3), -CH2CH2N(CH2CH3)2, -C H2CH2N(CH3)(CH2CH3), -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-azetidinyl, -CH2-azetidinyl, -CH2-azetidinyl, -CH2-azetidinyl, -CH2-azetidinyl, -CH2-oxetanyl, -CH2-oxetanyl, -CH2-morpholinyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclopentyl, -CH2CH2-cyclohexyl, -CH2CH2-azetidinyl, -CH2CH2- Azopentyl, -CH2CH2-azetidinyl, -CH2CH2-oxetanyl, -CH2CH2-oxolanyl, -CH2CH2-oxetanyl, -CH2CH2-morpholinyl, when substituted, by 0 to 4 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 substituted by a substituent;

[0029] In some embodiments, R b Selected from R b2 ;

[0030] In some embodiments, R ba Selected from -C 0-4 Alkyl-7 to 12 membered heterocyclic ring, -C 0-4 Alkyl - a 4- to 6-membered heterocyclic ring attached via a carbon atom, The R ba Optionally substituted by 1 to 4 groups selected from H, halogen, OH, =O, cyano, COOH, CONH2, CONHC 1-6 Alkyl, CON(C 1-6 Alkyl)2, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogen-substituted C 1-6 Alkyl, halogen-substituted C 1-6 Alkoxy, C 1-6 Alkoxyalkyl or R k Substituents are substituted, and the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N;

[0031] In some embodiments, R ba Selected from -C 0-2 Alkyl-7 to 8-membered monocyclic heterocycloalkyl, -C 0-2 Alkyl-7 to 11-membered spirocyclic heterocycloalkyl, -C 0-2 Alkyl-7 to 11-membered bridged heterocycloalkyl, -C 0-2 Alkyl - a 4- to 6-membered monocyclic heterocycloalkyl group attached via a carbon atom, The R ba Optionally substituted by 1 to 4 groups selected from H, halogen, OH, =O, cyano, COOH, CONH2, CONHC 1-4 Alkyl, CON(C 1-4 Alkyl)2, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy, C 1-4 Alkoxyalkyl or R k Substituents are substituted, wherein the heterocycloalkyl group contains 1 to 4 heteroatoms selected from O, S, and N;

[0032] In some embodiments, R ba Selected from 7 to 8 membered monocyclic heterocycloalkyl, 7 to 11 membered spirocyclic heterocycloalkyl, 7 to 11 membered bridged heterocycloalkyl, 4 to 6 membered monocyclic heterocycloalkyl connected through a carbon atom, -CH2-7 to 8 membered monocyclic heterocycloalkyl, -CH2-7 to 11 membered spirocyclic heterocycloalkyl, -CH2-7 to 11 membered bridged heterocycloalkyl, -CH2-4 to 6 membered monocyclic heterocycloalkyl connected through a carbon atom, -CH2CH2-7 to 8 membered monocyclic heterocycloalkyl, -CH2CH2-7 to 11 membered spirocyclic heterocycloalkyl, -CH2CH2-7 to 11 membered bridged heterocycloalkyl, -CH2CH2-4 to 6 membered monocyclic heterocycloalkyl connected through a carbon atom, The R ba Optionally substituted by 1 to 4 groups selected from H, halogen, OH, =O, cyano, COOH, CONH2, CONHC 1-4Alkyl, CON(C 1-4 Alkyl)2, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy, C 1-4 Alkoxyalkyl or R k Substituents are substituted, wherein the heterocycloalkyl group contains 1 to 4 heteroatoms selected from O, S, and N;

[0033] In some embodiments, R ba is selected from one of the following optionally substituted groups: When substituted, it is optionally replaced by 1 to 4 groups selected from deuterium, halogen, OH, =O, cyano, CONH2, CONHC 1-4 Alkyl, CON(C 1-4 Alkyl)2, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, N(C 1-4 Alkyl)(C 3-6 Cycloalkyl), NH(C 3-6 Cycloalkyl), C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy, C 1-4 Alkoxyalkyl or R k substituted by a substituent;

[0034] In some embodiments, R ba is selected from one of the following optionally substituted groups: When substituted, it is optionally replaced by 1 to 4 groups 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 substituted by a substituent;

[0035] In some embodiments, R k Selected from -C1-4 Alkyl-NH2, -C 1-4 Alkyl-NHC 1-6 Alkyl, -C 1-4 Alkyl-N(C 1-6 Alkyl)2, -C 0-4 Alkyl-C 3-10 Carbocycle or -C 0-4 Alkyl-3 to 10 membered heterocycle, wherein the alkyl, carbocycle or heterocycle is optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, halogen-substituted C 1-6 Alkyl, halogen-substituted C 1-6 Alkoxy, C 1-6 substituted by an alkoxyalkyl substituent, wherein the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N; and wherein the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N;

[0036] In some embodiments, R k Selected from -C 1-2 Alkyl-NH2, -C 1-2 Alkyl-NHC 1-4 Alkyl, -C 1-2 Alkyl-N(C 1-4 Alkyl)2, -C 0-2 Alkyl-C 3-6 Carbocycle or -C 0-2 Alkyl-3 to 6 membered heterocycle, wherein the alkyl, carbocycle or heterocycle is optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy, C 1-4 substituted by an alkoxyalkyl substituent, wherein the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N;

[0037] In some embodiments, R k Selected from -C 1-4 Alkyl-NH2, -C 1-4 Alkyl-NHC 1-4 Alkyl, -C 1-4 Alkyl-N(C 1-4 Alkyl)2, -C 0-4 Alkyl-C 3-6 Carbocycle or -C0-4 Alkyl-3 to 6 membered heterocycle, wherein the alkyl, carbocycle or heterocycle is optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy, C 1-4 substituted by an alkoxyalkyl substituent, wherein the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N;

[0038] In some embodiments, R k Selected from -CH2N(CH3)2, -CH2-cyclopropyl, -CH2-cyclobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetyl, wherein the cyclopropyl, or cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetyl is optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, =O, cyano, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, N(C 1-4 Alkyl)(C 3-6 Cycloalkyl), NH(C 3-6 Cycloalkyl), C 1-4 Alkyl, C 1-4 Alkoxy, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy, C 1-4 substituted by an alkoxyalkyl substituent;

[0039] In some embodiments, R k Selected from -CH2N(CH3)2, -CH2-cyclopropyl, -CH2-cyclobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetanyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetanyl are optionally substituted with 1 to 4 substituents 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, methoxy, ethoxy, methoxymethyl, ethoxymethyl, methoxyethyl;

[0040] In some embodiments, R 2 Selected from C 1-6 Alkyl, C6-10 Aromatic ring, 5- to 10-membered heteroaromatic ring, C 3-10 Carbocyclic ring, 5 to 10 membered heterocyclic ring, said R 2 Optional 0 to 4 R 2a Substitution, the heteroaromatic ring or heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N;

[0041] In some embodiments, R 2 Selected from C 1-4 Alkyl, benzene ring, naphthalene ring, 5- to 6-membered heteroaromatic ring, 9- to 10-membered heteroaromatic ring, C 3-10 Non-aromatic carbocyclic rings, 5- to 10-membered non-aromatic heterocyclic rings, benzo C 4-6 Carbocyclic or benzo 4 to 6 membered heterocyclic group, said R 2 Optional 0 to 4 R 2a Substitution, the heteroaromatic ring or heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N;

[0042] In some embodiments, R 2 Selected from benzene ring, naphthalene ring, 5- to 6-membered heteroaromatic ring, 9- to 10-membered heteroaromatic ring, C 3-6 Cycloalkyl, 3 to 7 membered heterocycloalkyl, benzo C 4-6 Carbocyclic or benzo 4 to 6 membered heterocyclic group, said R 2 Optional 0 to 4 R 2a Substitution, the heteroaromatic ring, heterocycloalkyl contains 1 to 4 heteroatoms selected from O, S, N; in some embodiments, R 2 Selected from phenyl ring, pyridyl, pyridonyl, pyrazinyl, pyrimidinyl, thienyl, thiazolyl, furyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetyl, oxetyl, morpholinyl, The R 2 Optional 0 to 4 R 2a Substituted; in some embodiments, R 2 Selected from p1 is selected from 0, 1, 2, 3 or 4;

[0043] In some embodiments, R 2 Selected from Selected from

[0044] In some embodiments, R 2 Selected from phenyl, pyridyl, pyridonyl, azacyclopentyl, morpholinyl, The R 2Optionally substituted with 0 to 4 substituents selected from deuterium, F, Cl, Br, OH, CF3, cyano, methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl;

[0045] In some embodiments, R 2 Selected from The R 2 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;

[0046] In some embodiments, R 2 Selected from In some embodiments, R 2 Selected from In some embodiments, R 2 Selected from In some embodiments, R 2 Selected from

[0047] In some embodiments, R 2a Each independently selected from deuterium, halogen, OH, cyano, =O, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3 to 7 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic group is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S;

[0048] In some embodiments, R 2a Each independently selected from deuterium, halogen, OH, cyano, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6Cycloalkyl, 3 to 7 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic group is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S;

[0049] In some embodiments, R 2a Selected from deuterium, halogen, OH, CN, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or 4 to 6 membered heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl is optionally substituted by 0 to 4 atoms selected from deuterium, halogen, OH, CN, C 1-4 Alkyl, C 1-4 The heterocycloalkyl group is substituted by an alkoxy substituent, wherein the heterocycloalkyl group contains 1 to 4 heteroatoms selected from O, S, and N;

[0050] In some embodiments, R 2a Each independently selected from deuterium, halogen, OH, cyano, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0051] In some embodiments, R 2a Each independently selected from deuterium, F, Cl, Br, I, OH, =O, cyano, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl or cyclobutyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl or cyclobutyl is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0052] In some embodiments, R 2a Selected from deuterium, F, Cl, Br, I, OH, cyano, methyl, ethyl, methoxy, ethoxy;

[0053] In some embodiments, R 2a With R 2a Direct connection to form C 4-7 4- to 7-membered carbocyclic ring or heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, cyano, =O, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-6 substituted by a cycloalkyl or 3- to 7-membered heterocycloalkyl substituent, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 substituents selected from deuterium, halogen, OH, and cyano;

[0054] In some embodiments, R 2a With R 2a Direct connection to form C 4-7 4- to 7-membered carbocyclic ring or heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, cyano, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 substituted by a cycloalkyl or 3- to 7-membered heterocycloalkyl substituent, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 substituents selected from deuterium, halogen, OH, and cyano;

[0055] In some embodiments, R 2a With R 2a Directly connected 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, a 6-membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, cyano, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 substituted by a cycloalkyl or 3- to 7-membered heterocycloalkyl substituent, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 substituents selected from deuterium, halogen, OH, and cyano (e.g., F, Cl, Br, I, OH, and cyano);

[0056] In some embodiments, R 3 Selected from H, C 1-6 Alkyl, wherein the alkyl group is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6Alkyl, C 1-6 Alkoxy, C 3-6 substituted by a carbocyclic substituent;

[0057] In some embodiments, R 3 Selected from H, C 1-4 Alkyl, wherein the alkyl group is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 substituted by a carbocyclic substituent;

[0058] In some embodiments, R 3 Selected from H, C 1-4 Alkyl, wherein the alkyl group is optionally 0 to 4 selected from deuterium, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, substituted by a substituent on a benzene ring;

[0059] In some embodiments, R 3 Selected from H, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl, benzyl;

[0060] In some embodiments, Ring A is selected from C 8-10 Cyclic carbon ring (such as benzo C 4-6 The ring A is optionally substituted with 0 to 4 R a5 Substitution; In some embodiments, Ring A is selected from The ring A is optionally substituted with 0 to 4 R a5 Substitution; In some embodiments, Ring A is selected from

[0061] In some embodiments, Ring A is selected from The ring A is 1 selected from C 2-6 Alkenyl or C 2-6 Alkynyl is substituted with 1 to 3 substituents selected from R a5 Substitution; In some embodiments, Ring A is selected from The ring A is replaced by 1 R ak substituted, optionally with 1 to 3 selected from R a5 Substitution; In some embodiments, Ring A is selected from Ring A is optionally substituted by 1 to 3 selected from R a5 replace;

[0062] In some embodiments, R ak Selected from C 2-4Alkynyl (e.g., ethynyl, propynyl, propargyl)

[0063] In some embodiments, Ring A is selected from The ring A is substituted by one substituent selected from vinyl, ethynyl, propynyl, propargyl, and optionally substituted by 1 to 3 substituents selected from R a5 replace;

[0064] In some embodiments, R a5 Selected from halogen, OH, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3 to 7 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic group is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 substituted by a cycloalkyl substituent, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S;

[0065] In some embodiments, R a5 Selected from halogen, OH, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic group is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 substituted by a cycloalkyl substituent, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S;

[0066] In some embodiments, R a5 Selected from halogen, OH, cyano, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6Cycloalkyl, wherein the alkyl, alkynyl, alkoxy, cycloalkyl, heterocyclic group is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 substituted by a cycloalkyl substituent;

[0067] In some embodiments, R a5 Each independently selected from F, Cl, Br, I, OH, CN, ethynyl, propynyl, propargyl, methyl, ethyl, cyclopropyl, methoxy, ethoxy, wherein the ethynyl, propynyl, propargyl, methyl, ethyl, cyclopropyl, methoxy, ethoxy is optionally substituted by 1 to 4 selected from deuterium, halogen, OH, =O, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Substituted by a cycloalkyl group

[0068] In some embodiments, R a5 Each is independently selected from F, Cl, Br, I, OH, CN, ethynyl, methyl, ethyl;

[0069] In some embodiments, R a5 Each independently selected from H, halogen, OH, =O, cyano, COOH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl;

[0070] In some embodiments, R a5 Each independently selected from H, halogen, OH, =O, cyano, COOH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl;

[0071] In some embodiments, R a5 Each is independently selected from F, Cl, Br, OH, cyano, CF3, methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl;

[0072] In some embodiments, Ring A is selected from Upper left and R2 Direct connection, p2 is selected from 0, 1 or 2;

[0073] In some embodiments, R 1b Selected from

[0074] In some embodiments, R 1b Selected from

[0075] In some embodiments, R b1 Each independently selected from H, halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, CN, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-4 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0076] In some embodiments, R b1 Each independently selected from H, halogen, CN, C 1-4 Alkyl, C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, CN, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0077] In some embodiments, the compound is not the structure shown in Table E-2 and its stereoisomers;

[0078] 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).

[0079] 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), and (Ii-1).

[0080] In some embodiments, R in 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 definitions are the same as for any of the above embodiments;

[0081] In some embodiments, the definition of Ring A in Formula (Ia) and (Ib) is the same as any of the aforementioned embodiments of Ring A;

[0082] In some embodiments, in 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;

[0083] In some embodiments, R in Formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (If), (Ig), (If-1), (Ig-1), (Ih), (Ii), (Ih-1), (Ii-1) 2a Selected from deuterium, halogen, OH, CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or 4 to 6 membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl, heterocycloalkyl is optionally substituted by 0 to 4 atoms selected from deuterium, halogen, OH, CN, C 1-4 Alkyl, C 1-4 The heterocycloalkyl group is substituted by an alkoxy substituent, wherein the heterocycloalkyl group contains 1 to 4 heteroatoms selected from O, S, and N;

[0084] In some embodiments, R in Formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (If), (Ig), (If-1), (Ig-1), (Ih), (Ii), (Ih-1), (Ii-1) 1a Selected from

[0085] In some embodiments, R in Formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (If), (Ig), (If-1), (Ig-1), (Ih), (Ii), (Ih-1), (Ii-1) b1 Selected from H, C 1-4 Alkyl, C 3-6Cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, CN, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0086] In some embodiments, R in Formula (I), (Ia), (Ib), (If), (Ig), (If-1), (Ig-1), (Ih), (Ii), (Ih-1), (Ii-1) b1 Selected from H, F, CH2F, CHF2, CF3, methyl, -CH2CH2N(CH3)2;

[0087] In some embodiments, R in Formula (I), (Ia), (Ib), (If), (Ig), (If-1), (Ig-1), (Ih), (Ii), (Ih-1), (Ii-1) b2 Selected from H, R ba , substituted or unsubstituted one of the following groups: C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -CH2CH2-NHC 1-4 Alkyl, -CH2CH2-N(C 1-4 Alkyl)2, -CH2CH2-C 3-6 Cycloalkyl, -CH2CH2-3 to 7 membered heterocycloalkyl, wherein said CH2, alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, N(C 1-4 Alkyl)(C 3-6 Cycloalkyl), NH(C 3-6 Cycloalkyl), C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy, C 1-4 Alkoxyalkyl or R k Substituents substituted, the heteroaryl or heterocycloalkyl contains 1 to 4 heteroatoms selected from O, S, N;

[0088] In some embodiments, R in the general formula (I), (Ia), (Ib), (If), (Ig), (If-1), (Ig-1), (Ih), (Ii), (Ih-1), (Ii-1) b2 Selected from H, R ba , substituted or unsubstituted one of the following groups: methyl, ethyl, ethynyl, methoxy, ethoxy, -CH2NH(CH2CH3), -CH2N(CH2CH3)2, -CH2CH2NH(CH3), -CH2CH2N(CH3)2, -CH2CH2NH(CH2CH3), -CH2CH2N(CH2CH3)2, -CH2CH2N(CH3)(CH2CH3), -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclopentyl, -CH2CH2-cyclohexyl, -CH2CH2-azetidinyl, -CH 2CH2-azetidinyl, -CH2CH2-azetidinyl, -CH2CH2-oxetanyl, -CH2CH2-oxetanyl, -CH2CH2-oxetanyl, -CH2CH2-oxetanyl, -CH2CH2-morpholine, when substituted, by 1, 2 or 3 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 substituted by a substituent;

[0089] In some embodiments, R in 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 any of the above embodiments;

[0090] In some embodiments, R in Formula (I), (Ia), (Ib), (If), (Ig), (If-1), (Ig-1), (Ih), (Ii), (Ih-1), (Ii-1) 2a Selected from deuterium, -CD3, -OCD3, F, Cl, Br, I, OH, cyano, methyl, ethyl, methoxy, ethoxy;

[0091] In some embodiments, in Formula (I), (If), (Ig), (If-1), (Ig-1), (Ih), (Ii), (Ih-1), (Ii-1), p2 is selected from 0, 1 or 2;

[0092] In some embodiments, R ak Selected from C 2-4 Alkynyl;

[0093] In some embodiments, R in the general formula (I), (If), (Ig), (If-1), (Ig-1), (Ih), (Ii), (Ih-1), (Ii-1) a5 Selected from F, Cl, Br, I, OH, cyano, methyl, ethyl, methoxy, ethoxy, ethynyl;

[0094] In some embodiments, n1 in Formula (I) is selected from 1, 2 or 3.

[0095] As a first embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0096] R 1 Selected from -CHR 1a R 1b or -NR 1a R 1b ;

[0097] R 1a Selected from C 1-6 Alkyl, wherein the alkyl group is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 substituted by a cycloalkyl substituent;

[0098] R 1b Selected from C 4-10 Carbocyclic ring, 5 to 10 membered heterocyclic ring, said carbocyclic ring or heterocyclic ring is optionally substituted by 0 to 4 R b Substitution, the heterocycle contains 1 to 4 heteroatoms selected from O, S, and N;

[0099] R b Each independently selected from deuterium, halogen, OH, =O, cyano, COOH, NH2, -C 0-4 Alkyl-NHC 1-6 Alkyl, -C 0-4 Alkyl-N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkynyl, C1-6 Alkoxy, -C 0-4 Alkyl-C 3-10 Carbocyclic ring, -C 0-4 Alkyl-3 to 10 membered heterocyclic ring or R ba The alkyl, alkynyl, alkoxy, carbocyclic or heterocyclic ring is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, CONH2, CONHC 1-6 Alkyl, CON(C 1-6 Alkyl)2, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, N(C 1-6 Alkyl)(C 3-6 Cycloalkyl), NH(C 3-6 Cycloalkyl), C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogen-substituted C 1-6 Alkyl, halogen-substituted C 1-6 Alkoxy, C 1-6 Alkoxyalkyl or R k Substituents are substituted, and the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N;

[0100] R ba Selected from -C 0-4 Alkyl-7 to 12 membered heterocyclic ring, -C 0-4 Alkyl - a 4- to 6-membered heterocyclic ring attached via a carbon atom, The R ba Optionally substituted by 1 to 4 groups selected from H, halogen, OH, =O, cyano, COOH, CONH2, CONHC 1-6 Alkyl, CON(C 1-6 Alkyl)2, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogen-substituted C 1-6 Alkyl, halogen-substituted C 1-6 Alkoxy, C 1-6 Alkoxyalkyl or R k Substituents are substituted, and the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N;

[0101] R k Selected from -C 1-4 Alkyl-NH2, -C 1-4 Alkyl-NHC 1-6 Alkyl, -C 1-4Alkyl-N(C 1-6 Alkyl)2, -C 0-4 Alkyl-C 3-10 Carbocycle or -C 0-4 Alkyl-3 to 10 membered heterocycle, wherein the alkyl, carbocycle or heterocycle is optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, halogen-substituted C 1-6 Alkyl, halogen-substituted C 1-6 Alkoxy, C 1-6 substituted by an alkoxyalkyl substituent, wherein the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N;

[0102] R 2 Selected from C 1-6 Alkyl, C 6-10 Aromatic ring, 5- to 10-membered heteroaromatic ring, C 3-10 Carbocyclic ring, 5 to 10 membered heterocyclic ring, said R 2 Optional 0 to 4 R 2a Substitution, the heteroaromatic ring or heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N;

[0103] R 2a Each independently selected from deuterium, halogen, OH, cyano, =O, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3 to 7 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic group is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S;

[0104] Alternatively, R 2a With R 2a Direct connection to form C 4-7 4- to 7-membered carbocyclic ring or heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, cyano, =O, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-6substituted by a cycloalkyl or 3- to 7-membered heterocycloalkyl substituent, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 substituents selected from deuterium, halogen, OH, and cyano;

[0105] R 3 Selected from H, C 1-6 Alkyl, wherein the alkyl group is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 substituted by a carbocyclic substituent;

[0106] Ring A is selected from C 8-10 and a carbocyclic ring, wherein the ring A is optionally substituted by 0 to 4 R a5 replace;

[0107] Or ring A is selected from The ring A is 1 selected from C 2-6 Alkenyl or C 2-6 Alkynyl is substituted with 1 to 3 R a5 replace;

[0108] R a5 Selected from halogen, OH, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3 to 7 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic group is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 The heterocyclic group is substituted by a substituent of the cycloalkyl group, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S.

[0109] As a second embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0110] R 1 Selected from

[0111] b is selected from 0, 1, 2, 3;

[0112] R b Each independently selected from deuterium, halogen, OH, =O, cyano, COOH, NH2, -C 0-4 Alkyl-NHC 1-4 Alkyl, -C 0-4 Alkyl-N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -C 0-4 Alkyl-C 3-6 Carbocyclic ring, -C 0-4 Alkyl-3 to 7 membered heterocyclic ring or R ba The alkyl, alkynyl, alkoxy, carbocyclic or heterocyclic ring is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, CONH2, CONHC 1-4 Alkyl, CON(C 1-4 Alkyl)2, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, N(C 1-4 Alkyl)(C 3-6 Cycloalkyl), NH(C 3-6 Cycloalkyl), C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy, C 1-4 Alkoxyalkyl or R k Substituents are substituted, and the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N;

[0113] R ba Selected from -C 0-2 Alkyl-7 to 8-membered monocyclic heterocycloalkyl, -C 0-2 Alkyl-7 to 11-membered spirocyclic heterocycloalkyl, -C 0-2 Alkyl-7 to 11-membered bridged heterocycloalkyl, -C 0-2 Alkyl - a 4- to 6-membered monocyclic heterocycloalkyl group attached via a carbon atom, The R ba Optionally substituted by 1 to 4 groups selected from H, halogen, OH, =O, cyano, COOH, CONH2, CONHC 1-4 Alkyl, CON(C 1-4 Alkyl)2, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C2-4 Alkynyl, C 1-4 Alkoxy, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy, C 1-4 Alkoxyalkyl or R k Substituents are substituted, wherein the heterocycloalkyl group contains 1 to 4 heteroatoms selected from O, S, and N;

[0114] R k Selected from -C 1-2 Alkyl-NH2, -C 1-2 Alkyl-NHC 1-4 Alkyl, -C 1-2 Alkyl-N(C 1-4 Alkyl)2, -C 0-2 Alkyl-C 3-6 Carbocycle or -C 0-2 Alkyl-3 to 6 membered heterocycle, wherein the alkyl, carbocycle or heterocycle is optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy, C 1-4 substituted by an alkoxyalkyl substituent, wherein the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N;

[0115] R 2 Selected from C 1-4 Alkyl, benzene ring, naphthalene ring, 5- to 6-membered heteroaromatic ring, 9- to 10-membered heteroaromatic ring, C 3-10 Non-aromatic carbocyclic rings, 5- to 10-membered non-aromatic heterocyclic rings, benzo C 4-6 Carbocyclic or benzo 4 to 6 membered heterocyclic group, said R 2 Optional 0 to 4 R 2a Substitution, the heteroaromatic ring or heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N;

[0116] R 2a Each independently selected from deuterium, halogen, OH, cyano, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3 to 7 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic group is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, NH2, NHC 1-4 Alkyl, N(C1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S;

[0117] Alternatively, R 2a With R 2a Direct connection to form C 4-7 4- to 7-membered carbocyclic ring or heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, cyano, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 substituted by a cycloalkyl or 3- to 7-membered heterocycloalkyl substituent, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 substituents selected from deuterium, halogen, OH, and cyano;

[0118] R 3 Selected from H, C 1-4 Alkyl, wherein the alkyl group is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 substituted by a carbocyclic substituent;

[0119] Ring A is selected from benzo C 4-6 Carbocyclic ring, wherein the ring A is optionally substituted by 0 to 4 R a5 replace;

[0120] Or ring A is selected from The ring A is 1 selected from C 2-4 Alkenyl or C 2-4 Alkynyl is substituted with 1 to 3 substituents selected from R a5 replace;

[0121] R a5 Selected from halogen, OH, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic group is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C1-4 Alkyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 substituted by a cycloalkyl substituent, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S;

[0122] The definitions of the remaining substituents are consistent with those of the present invention.

[0123] As a third embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0124] R b Each independently selected from deuterium, halogen, OH, =O, cyano, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, phenyl, 5- to 6-membered heteroaryl, -CH2NHC 1-4 Alkyl, -CH2N(C 1-4 Alkyl)2, -CH2CH2-NHC 1-4 Alkyl, -CH2CH2-N(C 1-4 alkyl)2, phenyl, 5- to 6-membered heteroaryl, C 3-6 Cycloalkyl, 3 to 7 membered heterocycloalkyl, -CH2-phenyl, -CH2-5 to 6 membered heteroaryl, -CH2-C 3-6 Cycloalkyl, -CH2-3 to 7 membered heterocycloalkyl, -CH2CH2-phenyl, -CH2CH2-5 to 6 membered heteroaryl, -CH2CH2-C 3-6 Cycloalkyl, -CH2CH2-3 to 7 membered heterocycloalkyl, R ba The CH2, alkyl, alkynyl, phenyl, heteroaryl, cycloalkyl, heterocycloalkyl are optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, CONH2, CONHC 1-4 Alkyl, CON(C 1-4 Alkyl)2, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, N(C 1-4 Alkyl)(C 3-6 Cycloalkyl), NH(C 3-6 Cycloalkyl), C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy, C 1-4 Alkoxyalkyl or Rk Substituents substituted, the heteroaryl or heterocycloalkyl contains 1 to 4 heteroatoms selected from O, S, N;

[0125] R ba Selected from 7 to 8 membered monocyclic heterocycloalkyl, 7 to 11 membered spirocyclic heterocycloalkyl, 7 to 11 membered bridged heterocycloalkyl, 4 to 6 membered monocyclic heterocycloalkyl connected through a carbon atom, -CH2-7 to 8 membered monocyclic heterocycloalkyl, -CH2-7 to 11 membered spirocyclic heterocycloalkyl, -CH2-7 to 11 membered bridged heterocycloalkyl, -CH2-4 to 6 membered monocyclic heterocycloalkyl connected through a carbon atom, -CH2CH2-7 to 8 membered monocyclic heterocycloalkyl, -CH2CH2-7 to 11 membered spirocyclic heterocycloalkyl, -CH2CH2-7 to 11 membered bridged heterocycloalkyl, -CH2CH2-4 to 6 membered monocyclic heterocycloalkyl connected through a carbon atom, The R ba Optionally substituted by 1 to 4 groups selected from H, halogen, OH, =O, cyano, COOH, CONH2, CONHC 1-4 Alkyl, CON(C 1-4 Alkyl)2, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy, C 1-4 Alkoxyalkyl or R k Substituents substituted, wherein the heterocycloalkyl group contains 1 to 4 heteroatoms selected from O, S, and N;

[0126] R k Selected from -C 1-4 Alkyl-NH2, -C 1-4 Alkyl-NHC 1-4 Alkyl, -C 1-4 Alkyl-N(C 1-4 Alkyl)2, -C 0-4 Alkyl-C 3-6 Carbocycle or -C 0-4 Alkyl-3 to 6 membered heterocycle, wherein the alkyl, carbocycle or heterocycle is optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy, C 1-4substituted by an alkoxyalkyl substituent, wherein the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N;

[0127] R 2 Selected from benzene ring, naphthalene ring, 5- to 6-membered heteroaromatic ring, 9- to 10-membered heteroaromatic ring, C 3-6 Cycloalkyl, 3 to 7 membered heterocycloalkyl, benzo C 4-6 Carbocyclic or benzo 4 to 6 membered heterocyclic group, said R 2 Optional 0 to 4 R 2a Substitution, the heteroaromatic ring, heterocycloalkyl contains 1 to 4 heteroatoms selected from O, S, and N;

[0128] R 2a Each independently selected from deuterium, halogen, OH, cyano, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0129] Alternatively, R 2a With R 2a Directly connected 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, a 6-membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, cyano, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 substituted by a cycloalkyl or 3- to 7-membered heterocycloalkyl substituent, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 substituents selected from deuterium, halogen, OH, and cyano;

[0130] R 3 Selected from H, C 1-4 Alkyl, wherein the alkyl group is optionally 0 to 4 selected from deuterium, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, substituted by a substituent on a benzene ring;

[0131] Ring A is selected from The ring A is optionally substituted with 0 to 4 R a5 replace;

[0132] Or ring A is selected from The ring A is 1 selected from C2-4 Alkenyl or C 2-4 Alkynyl is substituted with 1 to 3 substituents selected from R a5 replace;

[0133] R a5 Selected from halogen, OH, cyano, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, wherein the alkyl, alkynyl, alkoxy, cycloalkyl, heterocyclic group is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 substituted by a cycloalkyl substituent;

[0134] The definitions of the remaining substituents are the same as those in either Scheme 1 or 2 of the present invention.

[0135] As a fourth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0136] R 1a Selected from methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl, -CH2-cyclopropyl, -CH2-cyclobutyl;

[0137] R b Each independently selected from deuterium, F, Cl, Br, I, OH, =O, cyano, R ba , or R bEach independently selected from one of the following groups, substituted or unsubstituted: methyl, ethyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetanyl, oxetanyl, oxetanyl, 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, -CH2-azacyclopentyl -CH2-azetidinyl, -CH2-oxetanyl, -CH2-oxolanyl, -CH2-oxetanyl, -CH2-morpholinyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclopentyl, -CH2CH2-cyclohexyl, -CH2CH2-azetidinyl, -CH2CH2-azetidinyl, -CH2CH2-azetidinyl, -CH2CH2-azetidinyl, -CH2CH2-azetidinyl, -CH2CH2-azetidinyl, -CH2CH2-azetidinyl, -CH2CH2-azetidinyl, -CH2CH2-azetidinyl, -CH2CH2-oxetanyl, -CH2CH2-oxolanyl, -CH2CH2-oxetanyl, -CH2CH2-morpholinyl, -CH2-phenyl, -CH2-pyridinyl, -CH2CH2-phenyl, -CH2CH2-pyridinyl, when substituted, by 0 to 4 atoms selected from deuterium, halogen, OH, =O, cyano, CONH2, CONHC 1-4 Alkyl, CON(C 1-4 Alkyl)2, NH2, NHC 1-4 Alkyl, N(C 1-4 alkyl)2, N(C 1-4 Alkyl)(C 3-6 Cycloalkyl), NH(C 3-6 Cycloalkyl), C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy, C 1-4 Alkoxyalkyl or R k substituted by a substituent;

[0138] R ba is selected from one of the following optionally substituted groups: When substituted, it is optionally replaced by 1 to 4 groups selected from deuterium, halogen, OH, =O, cyano, CONH2, CONHC 1-4 Alkyl, CON(C1-4 Alkyl)2, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, N(C 1-4 Alkyl)(C 3-6 Cycloalkyl), NH(C 3-6 Cycloalkyl), C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy, C 1-4 Alkoxyalkyl or R k substituted by a substituent;

[0139] R k Selected from -CH2N(CH3)2, -CH2-cyclopropyl, -CH2-cyclobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetanyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetanyl is optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, =O, cyano, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, N(C 1-4 Alkyl)(C 3-6 Cycloalkyl), NH(C 3-6 Cycloalkyl), C 1-4 Alkyl, C 1-4 Alkoxy, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy, C 1-4 substituted by an alkoxyalkyl substituent;

[0140] R 2 Selected from phenyl ring, pyridyl, pyridonyl, pyrazinyl, pyrimidinyl, thienyl, thiazolyl, furyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetyl, oxetyl, morpholinyl, The R 2 Optional 0 to 4 R 2a replace;

[0141] R 2aEach independently selected from deuterium, F, Cl, Br, I, OH, =O, cyano, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl or cyclobutyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl or cyclobutyl is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0142] R 3 Selected from H, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl, benzyl;

[0143] Ring A is selected from The ring A is optionally substituted with 0 to 4 R a5 replace;

[0144] Or ring A is selected from The ring A is substituted by one substituent selected from vinyl, ethynyl, propynyl, propargyl, and optionally substituted by 1 to 3 substituents selected from R a5 replace;

[0145] R a5 Each independently selected from F, Cl, Br, I, OH, CN, ethynyl, propynyl, propargyl, methyl, ethyl, cyclopropyl, methoxy, ethoxy, wherein the ethynyl, propynyl, propargyl, methyl, ethyl, cyclopropyl, methoxy, ethoxy is optionally substituted by 1 to 4 selected from deuterium, halogen, OH, =O, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 substituted by a cycloalkyl substituent;

[0146] The definitions of the remaining substituents are the same as those in Scheme 1, 2 or 3 of the present invention.

[0147] As a fifth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0148] R 1 Selected from

[0149] R b Each independently selected from deuterium, F, Cl, Br, OH, cyano, R ba , or R bEach independently selected from one of the following groups, substituted or unsubstituted: methyl, ethyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetanyl, oxetanyl, oxetanyl, 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, - CH2-azetidinyl, -CH2-azepanyl, -CH2-azepanyl, -CH2-azepanyl, -CH2-oxetanyl, -CH2-oxolanyl, -CH2-oxetanyl, -CH2-morpholinyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclopentyl, -CH2CH2-cyclohexyl, -CH2CH2-azetidinyl, -CH2CH2-azepanyl, -CH2CH2-azepanyl, -CH2CH2-azepanyl, -CH2CH2-azepanyl, -CH2CH2-azepanyl, -CH2CH2-azepanyl, -CH2CH2-azepanyl, -CH2CH2-azepanyl, -CH2CH2-azepanyl, -CH2CH2-azepanyl, -CH2CH2-azepanyl, -CH2CH2-azepanyl, -CH2CH2-oxetanyl, -CH2CH2-oxolanyl, -CH2CH2-oxetanyl, -CH2CH2-morpholinyl, -CH2-phenyl, -CH2-pyridinyl, -CH2CH2-phenyl, -CH2CH2-pyridinyl, When substituted, 0 to 4 radicals 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 substituted by a substituent;

[0150] R ba is selected from one of the following optionally substituted groups: When substituted, it is optionally replaced by 1 to 4 groups 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 substituted by a substituent;

[0151] R k Selected from -CH2N(CH3)2, -CH2-cyclopropyl, -CH2-cyclobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetanyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetanyl are optionally substituted with 1 to 4 substituents 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, methoxy, ethoxy, methoxymethyl, ethoxymethyl, methoxyethyl;

[0152] R 2 Selected from phenyl, pyridyl, pyridonyl, azacyclopentyl, morpholinyl, The R 2 Optionally substituted with 0 to 4 substituents selected from deuterium, F, Cl, Br, OH, CF3, cyano, methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl;

[0153] or R 2 Selected from The R 2 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;

[0154] Ring A is selected from

[0155] The definitions of the remaining substituents are the same as those in Scheme 1, 2, 3 or 4 of the present invention.

[0156] As a sixth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0157] R 1 Selected from

[0158] or R 1 Selected from

[0159] or R 1 Selected from

[0160] or R 1 Selected from

[0161] or R 1 Selected from

[0162] or R 1 Selected from

[0163] or R 1 Selected from

[0164] R 2 Selected from

[0165] or R 2 Selected from

[0166] or R 2 Selected from

[0167] R 1a Selected from

[0168] The definitions of the remaining substituents are the same as those in Scheme 1, 2, 3, 4 or 5 of the present invention.

[0169] As a seventh embodiment of the present invention, the compound represented by the above-mentioned general formula (I) or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is selected from the compounds represented by the general formula (Ia), (Ib), (Ia-1) and (Ib-1),

[0170] Ring A, R 3 The definition is the same as any one of the second, third, fourth, fifth or sixth embodiments of the present invention;

[0171] p1 is selected from 0, 1, 2, 3 or 4;

[0172] R 2a Selected from deuterium, halogen, OH, CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6Cycloalkyl or 4 to 6 membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl, heterocycloalkyl is optionally substituted by 0 to 4 atoms selected from deuterium, halogen, OH, CN, C 1-4 Alkyl, C 1-4 The heterocycloalkyl group is substituted by an alkoxy substituent, wherein the heterocycloalkyl group contains 1 to 4 heteroatoms selected from O, S, and N;

[0173] R 1a Selected from

[0174] R b1 Selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, CN, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0175] R b2 Selected from H, R ba , substituted or unsubstituted one of the following groups: C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -CH2CH2-NHC 1-4 Alkyl, -CH2CH2-N(C 1-4 Alkyl)2, -CH2CH2-C 3-6 Cycloalkyl, -CH2CH2-3 to 7 membered heterocycloalkyl, wherein said CH2, alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, N(C 1-4 Alkyl)(C 3-6 Cycloalkyl), NH(C 3-6 Cycloalkyl), C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy, C 1-4 Alkoxyalkyl or R k Substituents substituted, the heteroaryl or heterocycloalkyl contains 1 to 4 heteroatoms selected from O, S, N;

[0176] n1 is selected from 1, 2 or 3;

[0177] R ba 、R kThe definition of is the same as any one of the second, third, fourth, fifth or sixth embodiments of the present invention.

[0178] As an eighth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is selected from the compounds represented by the general formula (Ia), (Ib), (Ia-1) and (Ib-1),

[0179] R 2a Selected from deuterium, CD3, -OCD3, F, Cl, Br, I, OH, cyano, methyl, ethyl, methoxy, ethoxy;

[0180] R b1 Selected from H, F, CH2F, CHF2, CF3, methyl, -CH2CH2N(CH3)2;

[0181] R b2 Selected from H, R ba , substituted or unsubstituted one of the following groups: methyl, ethyl, ethynyl, methoxy, ethoxy, -CH2NH(CH2CH3), -CH2N(CH2CH3)2, -CH2CH2NH(CH3), -CH2CH2N(CH3)2, -CH2CH2NH(CH2CH3), -CH2CH2N(CH2CH3)2, -CH2CH2N(CH3)(CH2CH3), -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclopentyl, -CH2CH2-cyclohexyl, -CH2CH2-azetidinyl, -CH 2CH2-azetidinyl, -CH2CH2-azetidinyl, -CH2CH2-oxetanyl, -CH2CH2-oxetanyl, -CH2CH2-oxetanyl, -CH2CH2-oxetanyl, -CH2CH2-morpholine, when substituted, by 1, 2 or 3 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 or R k substituted by a substituent;

[0182] The definitions of the remaining groups are the same as those in the seventh embodiment of the present invention.

[0183] As a ninth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is selected from the compounds represented by the general formula (If), (Ig), (If-1), (Ig-1), (Ih), (Ii), (Ih-1), and (Ii-1):

[0184] R 1b Selected from

[0185] p2 is selected from 0, 1 or 2;

[0186] R ak Selected from C 2-4 Alkynyl;

[0187] R a5 The definitions are the same as in any of the first, second, third or fourth embodiments of the present invention;

[0188] The remaining groups are defined the same as in any of the seventh or eighth embodiments of the present invention.

[0189] As a tenth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is selected from the compounds represented by the general formula (If), (Ig), (If-1), (Ig-1), (Ih), (Ii), (Ih-1), (Ii-1)

[0190] R ak Selected from ethynyl, propynyl, propargyl;

[0191] R a5 Selected from F, Cl, Br, I, OH, cyano, methyl, ethyl, methoxy, ethoxy, ethynyl;

[0192] The definitions of the remaining groups are the same as those of the ninth embodiment of the present invention.

[0193] As a tenth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, the compound is selected from the general formula (Ij) or (Ik)

[0194] R a6 Selected from H or F;

[0195] R 2 Selected from phenyl or The R2 Optionally substituted by 1 to 4 selected from halogen, C 1-4 Alkyl, C 1-4 Alkoxy, 1 to 4 halogen-substituted C 1-4 Alkyl, 1 to 4 halogen-substituted C 1-4 Alkoxy, 1 to 4 deuterium-substituted C 1-4 Alkyl, 1 to 4 deuterium substituted C 1-4 Alkoxy is substituted by a substituent, preferably

[0196] R b1 Selected from CH2F, CHF2, CF3, methyl; preferably CF3;

[0197] R b2 Selected from -CH2CH2N(CH3)2, -CH2CH2NH(CH2CH3), -CH2-azetidinyl, -CH2-azacyclopentyl, -CH2-azacyclohexyl, -CH2-morpholinyl, -CH2CH2-azetidinyl, -CH2CH2-azacyclopentyl, -CH2CH2-azacyclohexyl, The R b2 Optionally substituted by 1 to 4 groups selected from deuterium, F, Cl, Br, NHCH2CH3, N(CH2CH3)2, CH2F, CHF2, CF3, methyl, ethyl, isopropyl, methoxy, ethoxy, -CH2-cyclopropyl, Substituted by a substituent; preferably

[0198] The present invention relates to some specific compounds of general formula (I), which are selected from Table E-1.

[0199] 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.

[0200] Table E-1

[0201] Table E-2

[0202] Table E-3

[0203] Table E-4

[0204] Table E-5

[0205] The present invention relates to a pharmaceutical composition comprising the compound of the present invention or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier.

[0206] The present invention relates to the use of a compound of the present invention or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the preparation of a medicament for treating diseases related to α4β7 activity or expression, preferably in the preparation of a medicament for intestinal inflammatory diseases.

[0207] The present invention relates to a pharmaceutical composition or pharmaceutical formulation comprising 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, and a pharmaceutically acceptable 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 "drug strength").

[0208] The present invention also provides a method for treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of the present invention, or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, cocrystal, or pharmaceutical composition thereof. In some embodiments, the mammal of the present invention comprises a human.

[0209] As used herein, an "effective amount" or "therapeutically effective amount" refers to administering a sufficient amount of a compound disclosed herein to alleviate, to some extent, one or more symptoms of the disease or condition being treated (e.g., an inflammatory bowel disease). In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease symptoms.Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 mg, 6-600 mg, 10-600 mg, 20-600 mg, 25-600 mg, 30-600 mg, 40-600 mg, 50-600 mg, 60-600 mg, 70-600 mg, 75-600 mg, 80-600 mg, 90-600 mg, 100-600 mg, 200-600 mg, 1-500 mg, 2-500mg, 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 , 80-500mg, 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg, 400-500mg, 5-400mg, 10-400mg, 20-400mg, 25-40 0mg, 30-400mg, 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, 90-300mg, 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, 80-800mg.

[0210] In some embodiments, the pharmaceutical composition includes but is not limited to 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, 1 25 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, 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 substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

[0211] A method for treating a disease in a mammal, 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 1-1500 mg, and the disease is preferably an intestinal inflammatory disease.

[0212] A method for treating a disease in a mammal, comprising administering to a subject a compound of the present invention or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof at a daily dose of 1-1000 mg / day, wherein the daily dose can be a single dose or divided doses. In some embodiments, the daily dose includes but is not limited to 10-1500 mg / day, 10-1000 mg / day, 10-800 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, / day, 25-400 mg / day, 50-400 mg / day, 100-400 mg / day, 200-400 mg / day, in some embodiments, daily doses include but are 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, 1000 mg / day.

[0213] The present invention relates to a kit, which may include a composition in single-dose or multi-dose form, wherein the kit contains a compound of the present invention or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and the amount of the compound of the present invention or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is the same as the amount in the above-mentioned pharmaceutical composition.

[0214] The amount of the compound of the invention or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the present invention is in each case calculated as the free base.

[0215] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0216] The synthetic method of the compound of the present invention:

[0217] The compound of the general formula (Z-1) and the compound of the general formula (Z-2) are reacted by coupling or substitution to obtain the compound of the general formula (Z-3);

[0218] Removing the protecting group from the compound of the general formula (Z-3) gives the compound of the general formula (Z-4);

[0219] The compound of the general formula (Z-4) and the compound of the general formula (Z-5) are reacted by coupling or substitution to obtain the compound of the general formula (I):

[0220] R m1 Selected from Boc; Cbz; tert-butylsulfinyl, etc.;

[0221] R m2 , R m3 Each is independently selected from H, Cl, Br, I, OTf, B(OH)2, borate group, alkyl-substituted tin group, etc.;

[0222] R m4 Selected from Cl, Br, I, OH, etc.;

[0223] The definitions of the remaining groups are the same as those in any of the embodiments of the general formula (I) above.

[0224] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0225] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl, bromine include 79 Br and 81 Br.

[0226] "Alkyl" refers to a straight 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 further 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; the alkyl group is optionally substituted by 0 to 6 groups selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, amide, alkenyl, alkynyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 The alkylene group is substituted by an alkoxy group, a 3- to 8-membered carbocyclyl group, a 3- to 8-membered heterocyclyl group, a 3- to 8-membered carbocyclyloxy group, a 3- to 8-membered heterocyclyloxy group, a carboxyl group, or a carboxylate group.

[0227] "Alkylene" refers to straight-chain and branched divalent saturated hydrocarbon groups, including -(CH2) v -(v is an integer from 1 to 10), examples of alkylene include but are not limited to methylene, ethylene, propylene and butylene; the alkylene is optionally substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, thiol, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl or carboxylate.

[0228] "Cycloalkyl" refers to a monovalent saturated carbocyclic hydrocarbon group, typically having 3 to 12 carbon atoms, including monocyclic cycloalkyl, paracyclic cycloalkyl, spirocyclic cycloalkyl, or bridged cycloalkyl groups, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. 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, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl, or carboxylate.

[0229] "Alkenyl" refers to a linear or branched monovalent unsaturated hydrocarbon group having at least one, typically one, two or three, carbon-carbon double bonds, with a main chain comprising 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and more preferably 2 to 4 carbon atoms in the main chain. Examples of alkenyl groups include, but are not limited to, 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, 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, etc.; the alkenyl group is optionally substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, thiol, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl or carboxylate.

[0230] "Alkynyl" refers to straight and branched unsaturated hydrocarbon groups having at least one, typically one, two or three carbon-carbon triple bonds, with a backbone comprising 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and more preferably 2 to 4 carbon atoms in the backbone. Examples of alkynyl groups include, but are not limited to, 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-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, 4-decynyl, etc.; the alkynyl group is optionally substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, sulfhydryl, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl, or carboxylate. The alkynyl group appearing herein has the same definition as this one.

[0231] "Alkoxy" refers to an -O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyloxy, and cyclobutyloxy. The alkoxy group is optionally substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, sulfhydryl, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl, or carboxylate.

[0232] "Carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, which can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring, or a 10-15 membered tricyclic ring system, and the carbocyclyl can be attached to the aromatic or non-aromatic ring, which can be optionally a monocyclic ring, a bridged ring, or a 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, a benzene ring, a naphthalene ring, The carbocycle is optionally substituted with 0 to 5 substituents selected from F, Cl, Br, I, =O, hydroxy, thiol, nitro, cyano, amino, alkylamino, amide, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl or carboxylate.

[0233] "Heterocyclyl" 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 system, and contains 1 to 3 heteroatoms selected from N, O, or S, preferably a 3- to 8-membered heterocyclyl. The N and S optionally substituted in the heterocyclyl ring may be oxidized to various oxidation states. The heterocyclic group can be connected to a heteroatom or a carbon atom, the heterocyclic group can be connected to an aromatic ring or a non-aromatic ring, and the heterocyclic group can be connected to a bridged ring or a spiro ring. Non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, py ... furanyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophenyl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptanyl, The heterocyclyl group is optionally substituted with 0 to 5 substituents selected from F, Cl, Br, I, =O, hydroxy, thiol, nitro, cyano, amino, alkylamino, amide, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl or carboxylate.

[0234] "Heterocycloalkyl" refers to a substituted or unsubstituted saturated heterocyclic group, which can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, or a 10- to 15-membered tricyclic ring system, and contains 1 to 3 heteroatoms selected from N, O, or S. A 3- to 8-membered heterocyclic group is preferred. The N and S optionally substituted in the heterocycloalkyl ring can be oxidized to various oxidation states. Heterocycloalkyl groups can be attached to a heteroatom or a carbon atom. Non-limiting examples include oxiranyl, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, piperidinyl, and morpholinyl. The heterocycloalkyl group is optionally substituted with 0 to 5 substituents selected from F, Cl, Br, I, =O, hydroxy, thiol, nitro, cyano, amino, alkylamino, amide, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl or carboxylate.

[0235] "Spirocycle" refers to a 5- to 20-membered polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called 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). Preferably, it is 6 to 14 members, more preferably 6 to 12 members, and more preferably 6 to 10 members. Non-limiting examples include:

[0236] "Parallel ring" refers to a polycyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, wherein one or more rings may contain zero or more double bonds and may be substituted or unsubstituted, and each ring in the phenylenediamine 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 is 5 to 20-membered, more preferably 5 to 14-membered, more preferably 5 to 12-membered, and even more preferably 5 to 10-membered. Non-limiting examples include:

[0237] "Bridged ring" refers to a polycyclic group of any two atoms that are not directly connected, may contain zero or more double bonds, and may be substituted or unsubstituted. Any ring in the bridged ring system may contain zero to five heteroatoms or groups selected from N, S(=O)n or O (wherein n is 0, 1, or 2). The ring atoms 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 The definition of bridged rings appearing in this article is consistent with this definition.

[0238] "Carbospirocycle," "spirocarbocyclyl," "spirocarbocyclyl," or "carbospirocyclyl" refers to a "spirocycle" wherein the ring system consists of only carbon atoms.

[0239] "Carbocyclyl," "carbocyclyl," "carbocyclyl," or "carbocyclyl" refers to a "carbocyclyl" ring system consisting of only carbon atoms.

[0240] "Carbobridged ring," "bridged carbocyclic group," "bridged carbocyclic group," or "carbon-bridged cyclic group" refers to a "bridged ring" in which the ring system consists of only carbon atoms.

[0241] "Heteromonocycle", "monocyclic heterocyclyl" or "heteromonocyclyl" refers to a monocyclic ring system of "heterocyclyl" or "heterocycle"

[0242] "Heterocyclic ring", "heterocyclic group", "heterocyclic ring heterocyclyl" or "heterocyclic group" refers to a "cyclic ring" containing a heteroatom.

[0243] "Heterospirocycle," "heterospirocyclyl," "spiroheterocyclyl," or "spiroheterocyclyl" refers to a spirocycle containing a heteroatom.

[0244] The term "heterobridged ring", "heterobridged ring group" or "bridged heterocyclic group" refers to a "bridged ring" containing a heteroatom.

[0245] "Aryl" or "aromatic ring" refers to a monovalent aromatic hydrocarbon group having a single ring or condensed rings, usually having 6 to 12 carbon atoms, and may be substituted or unsubstituted. The aryl or aromatic ring appearing herein has the same definition as this definition.

[0246] "Heteroaryl" 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, and more preferably a 5- to 6-membered heteroaromatic ring. Non-limiting examples of heteroaryl include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include

[0247] “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.

[0248] "Substituted" or "substituted" refers to substitution by one or more (including but not limited to 2, 3, 4 or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged ring, spiro ring, cycloalkyl, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(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), arylthio, thiocarbonyl, silyl or -NR b R c etc., where R b With R c R is independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, b With R c Can form five or six-membered cycloalkyl or heterocyclic group, R a With R d Each is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring or paracyclic group.

[0249] "Replaced by 0 to X substituents" means substituted by 0, 1, 2, 3, ..., X substituents, where X is selected from any integer between 1 and 10. For example, "replaced by 0 to 4 substituents" means substituted by 0, 1, 2, 3, or 4 substituents. For example, "replaced by 0 to 5 substituents" means substituted by 0, 1, 2, 3, 4, or 5 substituents. For example, "a heterobridged ring is optionally substituted by 0 to 4 substituents selected from H or F" means that the heterobridged ring is optionally substituted by 0, 1, 2, 3, or 4 substituents selected from H or F.

[0250] XY-membered rings (where X is selected from an integer less than Y and greater than or equal to 3, and Y is selected from any integer between 4 and 12) include rings with X, X+1, X+2, X+3, X+4, and so on. Rings include heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heteroparallel rings, heterospirocyclic rings, and heterobridged rings. For example, "4-7-membered heteromonocyclic ring" refers to a 4-, 5-, 6-, or 7-membered heteromonocyclic ring, and "5-10-membered heteroparallel ring" refers to a 5-, 6-, 7-, 8-, 9-, or 10-membered heteroparallel ring.

[0251] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not. For example, "alkyl optionally substituted with F" means that the alkyl group may but need not be substituted with F, and the description includes instances where the alkyl group is substituted with F and instances where the alkyl group is not substituted with F.

[0252] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, or the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0253] "Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, their pharmaceutically acceptable salts or prodrugs and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0254] "Carrier" refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

[0255] "Animal" is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

[0256] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers. DETAILED DESCRIPTION

[0257] In order to accomplish the purpose of the present invention, the compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources, including Shanghai Aladdin Biochemical Technology Co., Ltd., Shanghai McLean Biochemical Technology Co., Ltd., Sigma-Aldrich, Alfa Aesar (China) Chemical Co., Ltd., Tokyo Chemical Industry Development Co., Ltd., Anage Chemical, Shanghai Titan Technology Co., Ltd., Kelon Chemical, Bailingwei Technology Co., Ltd., etc.

[0258] The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.

[0259] The structures of the compounds were confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) are given in units of 10-6 (ppm). NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0260] MS was determined using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0261] HPLC determination was performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM);

[0262] Thin layer chromatography silica gel plates used were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of the silica gel plates used for thin layer chromatography (TLC) were 0.15 mm to 0.20 mm, and the specifications used for thin layer chromatography separation and purification products were 0.4 mm to 0.5 mm.

[0263] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0264] Boc: tert-butyloxycarbonyl; Ts: p-toluenesulfonyl; Cbz: benzyloxycarbonyl; TMS: trimethylsilyl;

[0265] TIPS: triisopropylsilyl; Bpin: monazol borate; MOM: methylene methyl ether; THF: tetrahydrofuran

[0266] HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate;

[0267] PdCl2(dppf): CAS 72287-26-4. XPhos Pd G2: CAS 1310584-14-5

[0268] The * next to the chemical bond indicates that the chirality of the chiral atom is R or S;

[0269] Retention time (Rt, retention time): Unless otherwise specified in the examples, it is the retention time of the analytical method, and the method is as follows:

[0270] Detection wavelength: 254nm / 210nm Flow rate: 1.0ml / min Column temperature: 35℃

[0271] Injection volume: 2 μl Acquisition time: 10 min

[0272] Gradient elution program:

[0273] Acidic conditions: Mobile phase A is 0.05% TFA solution, mobile phase B is acetonitrile

[0274] Chromatographic column brand: Yuexu, chromatographic column model: Xtimate C18 4.6*50mm, 3μm

[0275] Instrument model 1: Shimadzu LC-20AT, instrument code: CH-Y-J0460

[0276] Instrument model 2: Agilent 1260 Infinity, instrument code: CH-Y-J0692

[0277] The specific methods for preparative HPLC (prep-HPLC) are as follows: Method 1: Instrument: Waters 2767 Preparative chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); (Mobile phase composition: Mobile phase A: acetonitrile, Mobile phase B: Water (containing 0.1% ammonium acetate). Method 2: Instrument: Waters 2767 Preparative chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); (Mobile phase composition: Mobile phase A: acetonitrile, Mobile phase B: Water (containing 0.1% trifluoroacetic acid).

[0278] Intermediate 1: Preparation of Intermediate 1

[0279] Step 1: Synthesis of 1B

[0280] Under nitrogen, 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 minutes, a solution of elemental bromine (8.80 g, 55.08 mmol) in dichloromethane (50 mL) was added and the mixture was allowed to react at room temperature for 2 hours. The reaction mixture was poured into ice water (200 mL), and dichloromethane (100 mL) was added. The mixture was washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain 1B (8.0 g, 85.05%).

[0281] LC-Ms m / z(ESI):241.1[M+H] +

[0282] Step 2: Synthesis of 1C

[0283] 1B (8.1 g, 33.88 mmol) was dissolved in DME (100 mL), and 1M sodium hypochlorite solution (188 mL) and 10N sodium hydroxide solution (18.5 mL) were added. The mixture was reacted at 50°C for 1 h. Water (150 mL) was added, and the mixture was extracted with diethyl ether (200 mL). The aqueous phase was adjusted to pH 1-2 with hydrochloric acid and extracted with diethyl ether (150 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to afford 1C (7.6 g, 93.05%).

[0284] LC-Ms m / z(ESI):240.9[M+H] +

[0285] Step 3: 1D synthesis

[0286] 1C (7.6 g, 31.52 mmol) was dissolved in methanol (50 mL), and thionyl chloride (11.25 g, 94.56 mmol) was added, and the mixture was reacted at 70°C for 2 h. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1D (8.0 g, 99.49%).

[0287] LC-Ms m / z(ESI):255.0[M+H] +

[0288] Step 4: Synthesis of 1E

[0289] Under nitrogen, 1D (2 g, 7.84 mmol), 4-fluoro-2,6-dimethylphenylboronic 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 sealed and reacted at 100°C for 5 h. After cooling to room temperature, the mixture was filtered through celite and ethyl acetate (50 mL) was added. The mixture was washed sequentially with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and flash-chromatographed on a silica gel column to afford 1E (2.2 g, yield: 94.05%).

[0290] Step 5: Synthesis of 1F

[0291] Under nitrogen, 1E (2.13 g, 7.14 mmol) was dissolved in dry THF (30 mL). Lithium aluminum tetrahydride (406 mg, 10.71 mmol) was slowly added at 0°C. The mixture was allowed to react for 1 h at room temperature. 10% aqueous sodium sulfate solution (20 mL) was added, the mixture was filtered, and the solvent was removed under reduced pressure to obtain crude product 1F.

[0292] Step 6: Synthesis of 1g

[0293] Under nitrogen, the crude product 1F (1.87 g, 6.92 mmol) was dissolved in dry dichloromethane (35 mL). Sodium bicarbonate (1.16 g, 13.84 mmol) and Dess-Martin periodinane (3.81 g, 9.00 mmol) were added at room temperature and allowed to react for 1 h. Saturated sodium thiosulfate solution (10 mL) and saturated sodium bicarbonate solution (10 mL) were added, and the product was extracted with dichloromethane (50 mL x 3). The product was dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure. 1G (1.63 g, 87.68%) was obtained by silica gel column chromatography.

[0294] Step 7: Synthesis of 1H

[0295] Under nitrogen protection, 1G (1.61 g, 6.00 mmol) and R-tert-butylsulfenamide (1.01 g, 9.00 mmol) were dissolved in THF (35 mL), and tetraethyl titanate (2.05 g, 9.00 mmol) was slowly added. The reaction was carried out at 45 ° C for 15 h, and the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel flash column chromatography to obtain 1H (1.73 g, yield 77.61%).

[0296] LC-Ms m / z(ESI):329.3[M+H] +

[0297] Step 8: Synthesis of 1I

[0298] Zinc powder (915 mg, 14 mmol) was added to dry THF (5 mL), the nitrogen atmosphere was replaced three times, and CuCl (297 mg, 3 mmol) was added. The reaction was allowed to proceed at 60°C for 2 h. After cooling to room temperature, ethyl bromoacetate (835 mg, 5 mmol) was slowly added. The reaction was continued at 60°C for 1 h. After cooling to 0°C, 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 Celite, saturated ammonium chloride solution (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The mixture was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash column chromatography to afford 1I (386 mg, 83.98% yield).

[0299] LC-Ms m / z(ESI):460.2[M+H] +

[0300] Step 9: Synthesis of Intermediate 1

[0301] 1I (272 mg, 0.27 mmol) was dissolved in THF (2 mL), 4N hydrochloric acid in dioxane (2 mL) was added, and the mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure to obtain crude intermediate 1.

[0302] LC-Ms m / z(ESI):356.3[M+H] +

[0303] Intermediate 2: Preparation of Intermediate 2

[0304] Step 1: Synthesis of 2B

[0305] Under nitrogen, 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). The mixture was reacted at 60°C for 72 h, and then concentrated under reduced pressure. The mixture was purified by silica gel column chromatography to give 2B (8.5 g, 40.02%).

[0306] Step 2: Synthesis of 2C

[0307] Under nitrogen, 2B (8.5 g, 36.79 mmol) was dissolved in THF (75 mL). Lithium diisopropylamide (5.91 g, 55.19 mmol) was added at -78°C and stirred for 1 h. DMF (5.38 g, 73.58 mmol) was then 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 x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to afford 2C (7.2 g, 75.55%).

[0308] Step 3: 2D synthesis

[0309] Under nitrogen protection, 2C (7.2 g, 27.79 mmol) and R-tert-butylsulfenamide (4.04 g, 33.35 mmol) were dissolved in THF (75 mL), and tetraethyl titanate (9.51 g, 41.69 mmol) was slowly added. The reaction was carried out at 45°C for 3 h, and the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography on a silica gel column to obtain 2D (6.80 g, yield 67.55%).

[0310] Step 4: Synthesis of 2E

[0311] Zinc powder (17.19 g, 262.78 mmol) was added to dry THF (45 mL). The nitrogen atmosphere was replaced three times, and CuCl (5.57 g, 56.31 mmol) was added. 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. The reaction was continued at 60°C for 1 h. The mixture was cooled to 0°C, and a solution of 2D (6.8 g, 18.77 mmol) in THF (10 mL) was added. The mixture was stirred at 0°C for 3 h. The mixture was filtered through Celite, and saturated ammonium chloride solution (200 mL) was added. 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 afford 2E (7.0 g, 82.81% yield).

[0312] Step 5: Synthesis of 2F

[0313] 2E (3.0 g, 6.66 mmol) was dissolved in dichloromethane (10 mL), 4N hydrochloric acid in dioxane (5 mL) was added, and the mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure to obtain crude product 2F.

[0314] Step 6: Synthesis of 2G

[0315] Under nitrogen, crude 2F (2.0 g, 5.78 mmol) was dissolved in dry dichloromethane (35 mL). 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 for 3 h. The solvent was removed under reduced pressure, and the product was purified by silica gel column chromatography to afford 2G (1.3 g, 50.40%).

[0316] Step 7: Synthesis of 2H

[0317] Under nitrogen protection, 2G (0.45 g, 1.11 mmol) and 2,6-dimethylphenylboronic acid (0.50 g, 3.33 mmol), potassium phosphate (0.47 g, 2.21 mmol), RuPhos Pd G3 (0.19 g, 0.22 mmol) were dissolved in DMF (8 mL) and water (0.8 mL), stirred at 75 ° C for 3 h, 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 flash column chromatography to give 2H (0.3 g, yield 57.38%).

[0318] Step 8: Synthesis of Intermediate 2

[0319] 2H (300 mg, 0.64 mmol) was dissolved in dichloromethane (2 mL), 4N hydrochloric acid in dioxane (2 mL) was added, and the mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure to obtain the crude intermediate 2.

[0320] LC-Ms m / z(ESI):372.2[M+H] +

[0321] Intermediate 4:

[0322] Step 1: Synthesis of 4A

[0323] Under nitrogen protection, 1a (1.5 g, 4.32 mmol, synthesis steps refer to WO2021076890A1) 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 stirred for 16 h. After concentration under reduced pressure, 4A (1.0 g, yield 54.05%) was obtained by flash column chromatography on a silica gel column.

[0324] LC-Ms m / z(ESI):429.2[M+H] +

[0325] Step 2: Synthesis of Intermediate 4

[0326] 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 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. Column chromatography afforded intermediate 4 (650 mg, 69.55%).

[0327] LC-Ms m / z(ESI):401.2[M+H] +

[0328] Intermediate 5: Preparation of Intermediate 5

[0329] Step 1: Synthesis of 5A

[0330] Under nitrogen protection, 1,4-oxazepane hydrochloride (360 mg, 2.59 mmol) was dissolved in 1,2-dichloroethane (8 mL), DIPEA was added, and the reaction was carried out at room temperature for 15 min. 1a (0.9 g, 2.59 mmol, synthesis steps refer to WO2021076890A1) 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, which was purified by flash column chromatography on a silica gel column to obtain 5A (0.49 g, yield 43.75%).

[0331] LC-Ms m / z(ESI):433.7[M+H] +

[0332] Step 2: Synthesis of Intermediate 5

[0333] Dissolve 5A (0.72 g, 1.66 mmol) in 6 mL of ethanol and 0.6 mL of water, add lithium hydroxide monohydrate (210 mg, 4.98 mmol), and react at room temperature for 3 h. Adjust the pH to 4 with 1N hydrochloric acid, concentrate under reduced pressure, and perform column chromatography to obtain Intermediate 5 (530 mg, yield: 78.95%).

[0334] LC-Ms m / z(ESI):405.6[M+H] +

[0335] Intermediate 6: Preparation of Intermediate 6

[0336] Step 1: Synthesis of 6B

[0337] Dissolve 6A (1720 mg, 6.96 mmol) in trifluoroacetic acid (25 mL) and add triethylsilane (25 mL). Allow to react at room temperature for 48 hours, then continue adding triethylsilane (15 mL) and stirring overnight. Concentrate under reduced pressure at 30°C, and the residue is purified by silica gel column chromatography to obtain crude compound 6B (1700 mg).

[0338] Step 2: Synthesis of 6C

[0339] Under nitrogen, crude product 6B (1700 mg, 7.29 mmol) was dissolved in dry THF (70 mL). Lithium diisopropylamide (1.56 g, 14.58 mmol) was slowly added at -78°C. After stirring for 0.5 h at the same temperature, dry DMF (2.6 g, 36.45 mmol) was added. The reaction was continued at -78°C for 1 h. The reaction was quenched by the addition of ammonium chloride solution (50 mL). The product was extracted with ethyl acetate (80 mL × 3), dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure. Purification by silica gel column chromatography afforded 6C (1.58 g, two-step yield: 83.02%).

[0340] Step 3: 6D synthesis

[0341] Under nitrogen, 6C (1580 mg, 6.05 mmol) and R-tert-butylsulfenamide (1100 mg, 9.7 mmol) were dissolved in THF (35 mL), and tetraethyl titanate (2070 mg, 9.07 mmol) was slowly added. The reaction was carried out at 45°C for 15 h, and the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography on a silica gel column to obtain 6D (2100 mg, yield 95.29%).

[0342] LC-Ms m / z(ESI):364.2[M+H] +

[0343] Step 4: Synthesis of 6E

[0344] Zinc powder (1.2 g, 18.34 mmol) was added to dry THF (8 mL), and the nitrogen atmosphere was replaced 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. After cooling to 0°C, a solution of 6D (478 mg, 1.31 mmol) in THF (3 mL) was added and stirred at 0°C for 3 h. Filtered through Celite, saturated ammonium chloride solution (30 mL) was added, and the mixture was extracted with ethyl acetate (40 mL x 3). The mixture was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash column chromatography to afford 6E (498 mg, 84.04% yield).

[0345] LC-Ms m / z(ESI):452.4[M+H] +

[0346] Step 5: Synthesis of 6F

[0347] 6E (448 mg, 0.99 mmol) was dissolved in dichloromethane (3 mL), 4N hydrochloric acid in dioxane (2.5 mL) was added, and the mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure to obtain the crude hydrochloride of 6F.

[0348] LC-Ms m / z(ESI):348.3[M+H] +

[0349] Step 6: Synthesis of 6G

[0350] 6F was dissolved in THF (4 mL) and water (4 mL), and sodium carbonate (210 mg, 1.98 mmol) and Boc2O (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 x 3). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. After flash column chromatography, 6G (420 mg, 86.31% yield over two steps) was obtained.

[0351] LC-Ms m / z(ESI):350.0[M+H-Boc] +

[0352] Step 7: Synthesis of 6H

[0353] Under nitrogen, 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), followed by Xphos-G2-Pd (40 mg, 0.051 mmol). The mixture 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 flash chromatography on a silica gel column afforded 6H (210 mg, 83.77% yield).

[0354] LC-Ms m / z(ESI):392.6[M+H-Boc] +

[0355] Step 8: Synthesis of Intermediate 6

[0356] 6H (210 mg, 0.43 mmol) was dissolved in THF (3 mL), 4N hydrochloric acid in dioxane (2.5 mL) was added, and the mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure to obtain the hydrochloride salt of the crude intermediate 6.

[0357] LC-Ms m / z(ESI):392.6[M+H] +

[0358] Intermediate 7: Preparation of Intermediate 7

[0359] Step 1: Synthesis of 7C

[0360] Under nitrogen, 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 under nitrogen for 4 h. The mixture was diluted with 100 mL of ethyl acetate, and the organic phase was washed with 50 mL of water (3 times), then washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to afford 7C (2.18 g, 99%).

[0361] LC-Ms m / z(ESI):287.1[M+H] +

[0362] Step 2: 7D synthesis

[0363] 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 mixed solution of toluene (30 mL) and water (6 mL). Sodium carbonate (2.2 g, 20.76 mmol) and PdCl2(dppf) (506 mg, 0.692 mmol) were added. The mixture was reacted at 100°C under a nitrogen atmosphere overnight. 50 mL of water was added to dilute the system, and 80 mL of ethyl acetate was added 3 times 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 obtain 7D (2.27 g, 99%).

[0364] LC-Ms m / z(ESI):309.1[M+H] +

[0365] Step 3: Synthesis of 7E

[0366] 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 h and concentrated under reduced pressure to obtain a crude product of intermediate 7E.

[0367] LC-Ms m / z(ESI):295.1[M+H] +

[0368] Step 4: Synthesis of 7F

[0369] Under nitrogen, the crude product 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. The mixture was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (4.38 g, 20.76 mmol) was added and the reaction was allowed to proceed overnight. The system was diluted with 100 mL of water and the pH was adjusted to 9-10 by adding saturated sodium bicarbonate solution. The mixture was extracted 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 afford 7F (1.25 g, 48% over two steps).

[0370] LC-Ms m / z(ESI):354.2[M+H]+

[0371] Step 5: Synthesis of Intermediate 7

[0372] 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 reacted 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.

[0373] LC-Ms m / z(ESI):362.2[M+H] +

[0374] Example 1: Preparation of Compound 1

[0375] Step 1: Preparation of 1b

[0376] Under nitrogen protection, 1a (3.0 g, 8.64 mmol, synthesis steps refer to WO2021076890A1) and methylamine hydrochloride (1.16 g, 17.28 mmol) were dissolved in 1,2-dichloroethane (30 mL), 5 drops of acetic acid were added dropwise, and the mixture was stirred at room temperature for 2 h. Sodium triacetoxyborohydride (3.65 g, 17.28 mmol) was added and stirring was continued for 16 h. The mixture was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by flash column chromatography on a silica gel column to obtain 1b (1.0 g, yield 31.95%).

[0377] LC-Ms m / z(ESI):363.2[M+H] +

[0378] Step 2: Preparation of 1d

[0379] Under nitrogen, 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). The mixture was stirred at 60°C for 24 h and concentrated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography on a silica gel column to give 1d (1.0 g, yield 80.08%).

[0380] LC-Ms m / z(ESI):453.2[M+H] +

[0381] Step 3: Preparation of 1e

[0382] 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 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. Column chromatography afforded 1e (700 mg, 74.62%).

[0383] LC-Ms m / z(ESI):425.2[M+H] +

[0384] Step 4: Preparation of 1f

[0385] Under nitrogen, 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. The reaction was allowed to proceed overnight at room temperature, and ethyl acetate (80 mL) was added. The mixture was washed with water (20 mL × 2) and saturated brine (20 mL × 1) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to give 1f (300 mg).

[0386] LC-Ms m / z(ESI):762.4[M+H] +

[0387] Step 5: Preparation of compounds 1-1 and 1-2

[0388] 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 afford crude compound 1. This crude product was then separated and purified by prep-HPLC (Method 1) to afford 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%).

[0389] Compound 1-1:

[0390] LC-Ms m / z(ESI):734.3[M+H] +

[0391] 1 H NMR(400MHz,Methanol-d4)δ7.93(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).

[0392] Compound 1-2:

[0393] LC-Ms m / z(ESI):734.3[M+H] +

[0394] 1H NMR(400MHz,Methanol-d4)δ7.93(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),3.08–2.9 5(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).

[0395] Example 2: Preparation of Compound 2

[0396] Step 1: Synthesis of 2b

[0397] Under nitrogen, 2a (6.0 g, 15.62 mmol, synthesis procedure see WO2021076890A1) 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. The mixture was reacted at 70°C for 30 h. After the reaction was complete, ethyl acetate (180 mL) was added for extraction. The mixture was 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 obtain 2b (5.0 g, yield: 65.79%).

[0398] LC-Ms m / z(ESI):487.3[M+H] +

[0399] Step 2: Synthesis of 2c

[0400] Under hydrogen, 2b (5.0 g, 10.28 mmol) was dissolved in methanol (50 mL), and an equal amount of Pd / C was added. The reaction was allowed to react at room temperature for 2 h. The solid was removed by filtration, and the filtrate was concentrated and purified by column chromatography to afford 2c (2.5 g, 49.78% yield).

[0401] LC-Ms m / z(ESI):489.3[M+H] +

[0402] Step 3: 2D synthesis

[0403] Dissolve 2c (480.0 mg, 0.98 mmol) in dichloromethane (5 mL), add 1,4-dioxane hydrochloride (3 mL), and react for 1 h. After the reaction is complete, remove the solvent under reduced pressure to obtain crude compound 2d.

[0404] LC-Ms m / z(ESI):389.2[M+H] +

[0405] Step 4: Synthesis of 2e

[0406] 2d (350.0 mg, 0.90 mmol) was dissolved in methanol (4 mL), and triethylamine (273.21 mg, 2.7 mmol) and methyl (2,2-difluorocyclopropyl)methanesulfonate (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 complete, the product was purified by column chromatography to afford 2e (280.0 mg, 65.02% yield).

[0407] LC-Ms m / z(ESI):465.90[M+H] +

[0408] Step 5: Synthesis of 2f

[0409] Dissolve 2e (280.0 mg, 0.60 mmol) in methanol (2 mL) and water (1 mL), add lithium hydroxide (28.47 mg, 1.20 mmol), and react at room temperature for 1-2 h. After the reaction is complete, 2f (100.0 mg, 37.0% yield) is obtained by purification via reverse phase chromatography.

[0410] LC-Ms m / z(ESI):451.70[M+H] +

[0411] Step 6: Synthesis of 2g

[0412] Under nitrogen, 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. The mixture was allowed to react at room temperature overnight, and ethyl acetate (80 mL) was added. 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 and purified by silica gel column chromatography to afford 2g (50.0 mg, yield: 28.59%).

[0413] LC-Ms m / z(ESI):788.4[M+H] +

[0414] Step 7: Synthesis of Compound 2-1 and Compound 2-2

[0415] 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 obtain a crude product of compound 2. The crude product was separated and purified by prep-HPLC (Method 2) to obtain the trifluoroacetic acid salt of compound 2-1 (4.0 mg, Rt = 5.955 min, yield 8.36%) and the trifluoroacetic acid salt of compound 2-2 (3.0 mg, Rt = 5.989 min, yield 6.27%).

[0416] Trifluoroacetate of compound 2-1:

[0417] LC-Ms m / z(ESI):760.3[M+H] +

[0418] 1 H NMR(400MHz,Methanol-d4)δ9.16(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),2.04–1.9 3(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).

[0419] Trifluoroacetate of compound 2-2:

[0420] LC-Ms m / z(ESI):760.3[M+H] +

[0421] 1H NMR(400MHz, Methanol-d4)δ7.87(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),2.2 2–1.99(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).

[0422] Example 3: Preparation of Compound 3

[0423] Step 1: Preparation of 3b

[0424] Dissolve 1a (1.4 g crude product), 3a (1.2 g, 7.2 mmol), and glacial acetic acid (220 mg, 3.6 mmol) in 1,2-dichloroethane (20 mL). Stir at room temperature under nitrogen for 30 min. Then, add sodium triacetoxyborohydride (1.5 g, 7.2 mmol). Stir overnight at room temperature. Add 50 mL of ethyl acetate, wash sequentially with water (30 mL x 1) and saturated brine (30 mL x 1). Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Column chromatography affords 3b (1.05 g, 71% yield).

[0425] LCMS m / z=413.2[M+H] +

[0426] Step 2: Preparation of 3c

[0427] 3b (1.05 g, 2.55 mmol) was dissolved in ethanol (15 mL) and water (1.5 mL), and lithium hydroxide monohydrate (321 mg, 7.65 mmol) was added. The reaction was allowed to react at room temperature for 5 h. The solvent was removed by concentration under reduced pressure, 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), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was then subjected to reverse phase chromatography (0.1% trifluoroacetic acid) to afford 3c (410 mg, 42% yield).

[0428] LCMS m / z=385.2[M+H] + ;

[0429] Step 3: 3D preparation

[0430] 3c (0.200 g, 0.52 mmol) and intermediate 1 (0.18 g, 0.52 mmol) were dissolved in 5 mL of DMF. HOBT (0.14 g, 1.04 mmol), DIPEA (0.27 g, 2.05 mmol), and EDCI (0.20 g, 1.04 mmol) were added and stirred at room temperature for 2 h. 30 mL of ethyl acetate was added, and the mixture was washed with water twice (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The title compound 3d was obtained by column chromatography as a yellow oil (0.21 g, 55.95% yield).

[0431] LCMS m / z=722.90[M+H] + ;

[0432] Step 4: Preparation of compounds 3-1 and 3-2

[0433] 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 afford crude compound 3. This crude product was then separated and purified by prep-HPLC (Method 1) to afford compound 3-1 (25 mg, Rt = 4.300 min, yield: 14%) and compound 3-2 (30 mg, Rt = 4.398 min, yield: 17%).

[0434] Compound 3-1:

[0435] LC-Ms m / z(ESI):694.3[M+H] +

[0436] 1H NMR(400MHz,Methanol-d4)δ9.16(d,1H),δ7.89(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).

[0437] Compound 3-2:

[0438] LC-Ms m / z(ESI):694.3[M+H] +

[0439] 1 H NMR(400MHz,Methanol-d4)δ7.89(s,1H),7.24(d,1H),6.93–6.79(m,4H),5.78–5.6 9(m,1H),5.38–5.29(m,1H),4.57–4.35(m,2H),4.31–4.16m,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).

[0440] Example 4: Preparation of Compound 4

[0441] Step 1: Synthesis of 4b

[0442] Under nitrogen, 1D (1.8 g, 7.06 mmol), 2,6-dimethylphenylboronic 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 sealed and reacted at 100°C for 5 h. After cooling to room temperature, the mixture was filtered through celite and ethyl acetate (50 mL) was added. The mixture was washed sequentially with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was then purified by flash chromatography on a silica gel column to afford 4b (1.4 g, yield: 70.73%).

[0443] Step 2: Synthesis of 4c

[0444] Under nitrogen, 4b (1.4 g, 4.99 mmol) was dissolved in dry THF (30 mL), and lithium aluminum tetrahydride (380 mg, 10.03 mmol) was slowly added at 0°C. The mixture was allowed to react at room temperature for 1 h. A 10% aqueous sodium sulfate solution (20 mL) was added, the mixture was filtered, and the solvent was removed under reduced pressure to afford 4c (800 mg, 67.27%).

[0445] Step 3: 4D synthesis

[0446] Under nitrogen, 4c (800 mg, 3.17 mmol) was dissolved in dry dichloromethane (20 mL), and sodium bicarbonate (0.53 g, 6.31 mmol) and Dess-Martin periodinane (1.75 g, 4.13 mmol) were added. The mixture was 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 × 3). The mixture was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography to afford 4d (650 mg, 81.91%).

[0447] Step 4: Synthesis of 4e

[0448] Under nitrogen, 4d (600 mg, 2.40 mmol) and R-tert-butylsulfenamide (0.35 g, 2.88 mmol) were dissolved in THF (20 mL), and tetraethyl titanate (1.64 g, 7.22 mmol) was slowly added. The reaction was carried out at 45°C for 15 h, and the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography on a silica gel column to obtain 4e (800 mg, yield 94.29%).

[0449] LC-Ms m / z(ESI):354.5[M+H] +

[0450] Step 5: Synthesis of 4f

[0451] Zinc powder (1.81 g, 27.72 mmol) was added to dry THF (5 mL), and the nitrogen atmosphere was replaced 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. After cooling to 0°C, 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 celite, and saturated ammonium chloride solution (20 mL) was added. 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 afford 4f (750 mg, 85.77% yield).

[0452] LC-Ms m / z(ESI):442.6[M+H] +

[0453] Step 6: Synthesis of 4g

[0454] 4f (600 mg, 1.36 mmol) was dissolved in THF (2 mL), 4N hydrochloric acid in dioxane (2 mL) was added, and the mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure to obtain 4 g of a crude product.

[0455] LC-Ms m / z(ESI):338.4[M+H] +

[0456] Step 7: Synthesis of compound 4h

[0457] Under nitrogen protection, intermediate 3 (260 mg, 0.74 mmol, synthesis steps refer to WO2021076890A1) 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 minutes, 4g of crude product (250 mg, 0.74 mmol) was added. The reaction was allowed to proceed 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) in sequence. It was 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.

[0458] LC-Ms m / z(ESI):668.8[M+H] +

[0459] Step 8: Synthesis of compounds 4-1 and 4-2

[0460] 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 obtain crude compound 4. The crude product was separated and purified by prep-HPLC (Method 2) to obtain 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%).

[0461] Trifluoroacetate of compound 4-1:

[0462] LC-Ms m / z(ESI):640.7[M+H] +

[0463] 1 H NMR(400MHz,Methanol-d4)δ9.15(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),2.07–1.9 8(m,2H),1.93(s,6H),1.86–1.78(m,2H),1.39–1.28(m,1H),0.93–0.81(m,6H).

[0464] Trifluoroacetate of compound 4-2:

[0465] LC-Ms m / z(ESI):640.7[M+H] +

[0466] 1 H NMR(400MHz, Methanol-d4)δ9.17(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).

[0467] Example 5: Preparation of Compound 5

[0468] Referring to the preparation method of compound 3, a crude product of compound 5 was obtained, and 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).

[0469] Compound 5-1:

[0470] LC-Ms m / z(ESI):710.3[M+H] +

[0471] 1 H NMR(400MHz,Methanol-d4)δ7.85(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).

[0472] Compound 5-2:

[0473] LC-Ms m / z(ESI):710.3[M+H] +

[0474] 1H NMR(400MHz, Methanol-d4)δ7.88(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).

[0475] Example 6: Preparation of Compound 6

[0476] Referring to the preparation method of compound 3, a crude product of compound 6 was obtained, and the crude product was separated and purified by prep-HPLC (method 1) to obtain compound 6-1 (20 mg, Rt = 4.255 min) and compound 6-2 (20 mg, Rt = 4.342 min).

[0477] Compound 6-1:

[0478] LC-Ms m / z(ESI):726.3[M+H] +

[0479] 1 H NMR(400MHz,Methanol-d4)δ7.75(s,1H),7.14(t,1H),7.10–7.01(m,2H),6.96(t,1 H),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).

[0480] Compound 6-2:

[0481] LC-Ms m / z(ESI):726.3[M+H] +

[0482] 1 H NMR(400MHz,Methanol-d4)δ8.51(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).

[0483] Example 7: Preparation of Compound 7

[0484] Referring to the preparation method of compound 1, the crude product of compound 7 was obtained, and 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).

[0485] Compound 7-1:

[0486] LC-Ms m / z(ESI):750.3[M+H] +

[0487] 1 H NMR(400MHz,Methanol-d4)δ7.85(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).

[0488] Compound 7-2:

[0489] LC-Ms m / z(ESI):750.3[M+H] +

[0490] 1 H NMR(400MHz,Methanol-d4)δ7.75(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).

[0491] Example 8: Preparation of Compound 8

[0492] Referring to the preparation method of compound 4, a crude product of compound 8 was obtained, and 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%).

[0493] Trifluoroacetate salt of compound 8-1:

[0494] LC-Ms m / z(ESI):696.7[M+H] +

[0495] 1 H NMR(400MHz, Methanol-d4)δ7.90(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).

[0496] Trifluoroacetate salt of compound 8-2:

[0497] LC-Ms m / z(ESI):696.7[M+H] +

[0498] 1 H NMR(400MHz,Methanol-d4)δ7.92(s,1H),7.16(s,1H),7.13–6.99(m,3H),6.81–6.72(m,2H),5.7 8–5.70(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).

[0499] Example 9: Preparation of Compound 9

[0500] Step 1: Synthesis of 9a

[0501] 1a (3.0 g, 8.64 mmol) was dissolved in 30 mL of ultra-dry DCE. Diethylamine (0.95 g, 12.96 mmol) and AcOH (0.10 mg, 1.73 mmol) were added sequentially. The reaction was allowed to proceed at room temperature for 1 h. Sodium triacetoxyborohydride (3.66 g, 17.28 mmol) was added and the reaction continued for 16 h. The mixture was extracted with 200 mL of ethyl acetate and 100 mL of saturated aqueous NaHCO₃. The aqueous phase was then extracted with ethyl acetate (100 mL x 1). The ethyl acetate layers were combined, washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to afford 9a (2.8 g, 80.12% yield).

[0502] LC-Ms m / z(ESI):405.3[M+H] +

[0503] Step 2: Synthesis of 9b

[0504] 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. 9b (1.2 g, yield: 46.05%) was obtained by purification via reverse phase chromatography.

[0505] LC-Ms m / z(ESI):377.2[M+H] +

[0506] Step 3: Synthesis of 9c

[0507] Under nitrogen, 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. The mixture was allowed to react at room temperature overnight, and ethyl acetate (100 mL) was added. 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 and purified by silica gel column chromatography to afford 9c (400.0 mg, yield: 66.71%).

[0508] LC-Ms m / z(ESI):714.4[M+H] +

[0509] Step 4: Synthesis of Compound 9-1 and Compound 9-2

[0510] 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 afford crude compound 9. The crude product was then separated and purified by prep-HPLC (Method 2) to afford the trifluoroacetic acid salt of compound 9-1 (76.0 mg, 8.36% yield) and the trifluoroacetic acid salt of compound 9-2 (81.0 mg, 6.27% yield).

[0511] Trifluoroacetate of compound 9-1:

[0512] LC-Ms m / z(ESI):686.2[M+H] +

[0513] 1H NMR (400MHz, CD3OD) δ7.91(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).

[0514] Trifluoroacetate of compound 9-2:

[0515] LC-Ms m / z(ESI):686.2[M+H] +

[0516] 1 H NMR(400MHz,CD3OD)δ7.86(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).

[0517] Example 10: Preparation of Compound 10

[0518] Step 1: Synthesis of 10a

[0519] Under nitrogen, 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 sealed and reacted at 100°C for 12 h. After cooling to room temperature, the mixture was filtered through celite and ethyl acetate (50 mL) was added. The mixture was washed sequentially with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and flash chromatographed on a silica gel column to afford 10a (1.6 g, yield: 65.75%).

[0520] Step 2: Synthesis of 10b

[0521] Under nitrogen, 10a (1.6 g, 5.15 mmol) was dissolved in dry THF (10 mL). Lithium aluminum tetrahydride (8 mL) was slowly added at 0°C and allowed to react at room temperature for 1 h. A 10% aqueous sodium sulfate solution (20 mL) was added, the mixture was filtered, and the solvent was removed under reduced pressure. The mixture was flash-chromatographed on a silica gel column to afford 10b (1.0 g, 68.76% yield).

[0522] Step 3: Synthesis of 10c

[0523] Under nitrogen, 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 periodinane (2.25 g, 5.31 mmol) were added at room temperature and reacted 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). The mixture was dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure. The mixture was then purified by silica gel column chromatography to afford 10c (0.8 g, 80.58% yield).

[0524] Step 4: 10d synthesis

[0525] Under nitrogen, 10c (1.4 g, 4.99 mmol) and R-tert-butylsulfenamide (0.82 g, 5.99 mmol) were dissolved in THF (15 mL), and tetraethyl titanate (1.71 g, 7.50 mmol) was slowly added. The reaction was carried out at 45°C for 15 h, and the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography on a silica gel column to obtain 10d (1.9 g, yield: 99.27%).

[0526] Step 5: Synthesis of 10e

[0527] Zinc powder (4.77 g, 72.94 mmol) was added to dry THF (5 mL). The nitrogen atmosphere was replaced three times, and CuCl (1.55 g, 15.63 mmol) was added. 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. The reaction was continued at 60°C for 1 h. The mixture was cooled to 0°C, and a solution of 10d (2.0 g, 5.21 mmol) in THF (1 mL) was added. The mixture was stirred at 0°C for 3 h. Filtered through Celite, saturated ammonium chloride solution (80 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The mixture was washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash column chromatography to afford 10e (2.0 g, yield: 81.39%).

[0528] Step 6: Synthesis of 10f

[0529] 10e (500.0 mg, 1.06 mmol) was dissolved in THF (5 mL), 4N hydrochloric acid in dioxane (5 mL) was added, and the mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure to obtain crude product 10f.

[0530] LC-Ms m / z(ESI):368.0[M+H] +

[0531] Step 7: Synthesis of 10g

[0532] Under nitrogen, 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 product 10f (200.0 mg, 0.54 mmol) was added. The reaction was allowed to proceed overnight at room temperature, and ethyl acetate (80 mL) was added. The product 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 and purified by silica gel column chromatography to afford 10 g (180.0 mg, yield: 47.39%).

[0533] LC-Ms m / z(ESI):698.3[M+H] +

[0534] Step 8: Synthesis of Compound 10-1 and Compound 10-2

[0535] 10 g (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. 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 obtain a crude product of compound 10. The crude product was separated and purified by prep-HPLC (Method 2) to obtain 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%).

[0536] Trifluoroacetate salt of compound 10-1:

[0537] LC-Ms m / z(ESI):670.3[M+H] +

[0538] 1H NMR(400MHz,CD3OD)δ7.92(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).

[0539] Trifluoroacetate salt of compound 10-2:

[0540] LC-Ms m / z(ESI):670.3[M+H] +

[0541] 1 H NMR(400MHz,CD3OD)δ7.92(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,2H),1.39–1.25(m,1H),0.95–0.81(m,6H).

[0542] Example 11: Preparation of Compound 11

[0543] Step 1: Synthesis of 11a

[0544] Under nitrogen, 2 g (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 sealed and reacted at 100°C for 12 h. The mixture was cooled to room temperature, filtered through celite, and ethyl acetate (50 mL) was added. The mixture was washed sequentially with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and flash chromatographed on silica gel to afford 11a (300.0 mg, yield: 92.22%).

[0545] Step 2: Synthesis of 11b

[0546] 11a (300.0 mg, 0.60 mmol) was dissolved in acetonitrile (3 mL), and a hydrochloric acid-1,4-dioxane solution (2 mL) was added, and the mixture was stirred at room temperature for 30 min. The solvent was removed by drying under reduced pressure to obtain crude product 11b.

[0547] LC-Ms m / z(ESI):402.7[M+H] +

[0548] Step 3: Synthesis of 11c

[0549] Under nitrogen, 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 product 11b (200.0 mg, 0.50 mmol) was added. The reaction was allowed to proceed overnight at room temperature, and ethyl acetate (80 mL) was added. 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 and purified by silica gel column chromatography to afford 11c (300.0 mg, yield: 81.99%).

[0550] LC-Ms m / z(ESI):732.3[M+H] +

[0551] Step 4: Synthesis of Compound 11-1 and Compound 11-2

[0552] 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 afford crude compound 11. This crude product was then separated and purified by prep-HPLC (Method 2) to afford the trifluoroacetic acid salt of compound 11-1 (23 mg, Rt = 4.024 min, yield: 7.97%) and the trifluoroacetic acid salt of compound 11-2 (27 mg, Rt = 4.165 min, yield: 9.36%).

[0553] Trifluoroacetate salt of compound 11-1:

[0554] LC-Ms m / z(ESI):704.3[M+H] +

[0555] 1 H NMR(400MHz,CD3OD)δ7.87(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).

[0556] Trifluoroacetate salt of compound 11-1:

[0557] LC-Ms m / z(ESI):704.3[M+H] +

[0558] 1 H NMR(400MHz,CD3OD)δ7.83(s,1H),7.08(t,1H),6.90(s,1H),6.69(s,2H),5.8 1–5.74(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).

[0559] Example 12: Synthesis of Compound 12

[0560] Referring to the preparation method of compound 9, the crude product of compound 12 was obtained, and 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).

[0561] Trifluoroacetate salt of compound 12-1:

[0562] LC-Ms m / z(ESI):702.3[M+H] +

[0563] 1 H NMR(400MHz,CD3OD)δ7.88(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).

[0564] Trifluoroacetate salt of compound 12-2:

[0565] LC-Ms m / z(ESI):702.3[M+H] +

[0566] 1 H NMR (400MHz, CD3OD) δ7.89–7.83(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).

[0567] Example 13: Preparation of Compound 13

[0568] Step 1: Preparation of 13b

[0569] 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. Stirring was carried out at 80°C under nitrogen for 3 h. The mixture was cooled to room temperature and diluted with 100 mL of ethyl acetate. The mixture was 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.

[0570] LCMS m / z=485.2[M+H] +

[0571] Step 2: Preparation of 13c

[0572] 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. The mixture was concentrated under reduced pressure to obtain crude product 13c (1.8 g).

[0573] LCMS m / z=385.2[M+H] +

[0574] Step 3: Preparation of 13d

[0575] Crude product 13c (1.8 g), aqueous formaldehyde solution (5 mL), and glacial acetic acid (230 mg, 3.84 mmol) were dissolved in methanol (20 mL). Stirred at room temperature under nitrogen for 30 min, and sodium triacetoxyborohydride (1.62 g, 7.68 mmol) was added. Stirring was continued at room temperature overnight. The solvent was removed by concentration under reduced pressure, and 30 mL of water was added. 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), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Column chromatography afforded 13d (0.91 g, 60% yield over two steps).

[0576] LCMS m / z=399.2[M+H] +

[0577] Step 4: Preparation of 13e

[0578] 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 reaction was allowed to react at room temperature for 5 h. The solvent was removed by concentration under reduced pressure, 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), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was then subjected to reverse phase chromatography (0.1% trifluoroacetic acid) to afford 13e (200 mg, 24% yield).

[0579] LCMS m / z=371.2[M+H] + ;

[0580] Step 5: Preparation of 13f

[0581] 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 and stirred at room temperature for 2 h. After the reaction, 30 ml of ethyl acetate was added, and the mixture was washed with water twice (20 mL×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 13f (0.13 g, yield: 42.71%).

[0582] LCMS m / z=708.9[M+H] + ;

[0583] Step 6: Preparation of compounds 13-1 and 13-2

[0584] 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 afford crude compound 13. The crude product was separated and purified by prep-HPLC (Method 1) to afford compound 13-1 (0.55 mg, Rt = 4.271 min) and compound 13-2 (0.6 mg, Rt = 4.358 min).

[0585] Compound 13-1:

[0586] LC-Ms m / z(ESI):680.2[M+H] +

[0587] 1H NMR(400MHz,Methanol-d4)δ8.03(s,1H),7.15(s,1H),6.84–6.70(m,4H),5.7 2–5.65(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)

[0588] Compound 13-2:

[0589] LC-Ms m / z(ESI):680.2[M+H] +

[0590] 1 H NMR(400MHz,Methanol-d4)δ8.08(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).

[0591] Example 14: Preparation of Compound 14

[0592] Step 1: Synthesis of 14b

[0593] Under nitrogen, 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), tri(o-methylphenyl)phosphine (6.32 g, 20.8 mmol), and triethylamine (15.8 g, 156.12 mmol) were added sequentially. The reaction was carried out at 100°C for 24 h. Ethyl acetate (180 mL) was added for extraction, and the mixture was 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 afford 14b (4.0 g, yield: 16.27%).

[0594] LC-Ms m / z(ESI):473.5[M+H] +

[0595] Step 2: Synthesis of 14c

[0596] 14b (4.0 g, 8.46 mmol) was dissolved in methanol (10 mL), and Pd / C (2.0 g) was added. The mixture was reacted under a hydrogen atmosphere at room temperature for 0.5 h. The solid was removed by filtration, and the filtrate was concentrated and purified by column chromatography to afford 14c (3.6 g, yield: 89.68%).

[0597] LC-Ms m / z(ESI):475.5[M+H] +

[0598] Step 3: Synthesis of 14d

[0599] 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 obtain the hydrochloride salt of crude product 14d.

[0600] Step 4: Synthesis of 14e

[0601] The hydrochloride salt of 14d (1.3 g, 3.47 mmol) was dissolved in ultra-dry 1,2-dichloroethane (30 mL). Acetone (400 mg, 6.87 mmol) and glacial acetic acid (21.0 mg, 0.35 mmol) were added sequentially and reacted at 60°C for 2 h. After cooling to room temperature, sodium triacetoxyborohydride (1.84 g, 8.68 mmol) was added and allowed to react overnight at room temperature. Ethyl acetate (20 mL) was added for extraction, and the mixture was washed 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 and purified by silica gel column chromatography to afford 14e (1.0 g, yield: 69.20%).

[0602] LC-Ms m / z(ESI):417.4[M+H]+

[0603] Step 5: Synthesis of 14f

[0604] 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 reacted at room temperature for 2 h. 14f (800 mg, yield: 85.82%) was obtained by purification via reverse phase chromatography.

[0605] LC-Ms m / z(ESI):389.4[M+H] +

[0606] Step 6: Synthesis of 14g

[0607] Under nitrogen, 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. The reaction was allowed to proceed overnight at room temperature, and ethyl acetate (80 mL) was added. 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 and purified by silica gel column chromatography to afford 14 g (368 mg, yield: 72.43%).

[0608] LC-Ms m / z(ESI):726.8[M+H] +

[0609] Step 7: Synthesis of Compound 14-1 and Compound 14-2

[0610] 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 obtain crude compound 14. The crude product was separated and purified by prep-HPLC (Method 2) to obtain the trifluoroacetic acid salt of compound 14-1 (20 mg, Rt = 4.295 min, yield 5.62%) and the trifluoroacetic acid salt of compound 14-2 (25 mg, Rt = 4.378 min, yield 7.02%).

[0611] Trifluoroacetate salt of compound 14-1:

[0612] LC-Ms m / z(ESI):698.8[M+H] +

[0613] 1 H NMR (400MHz, CD3OD) δ7.90–7.68(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).

[0614] Trifluoroacetate salt of compound 14-2:

[0615] LC-Ms m / z(ESI):698.8[M+H] +

[0616] 1 H NMR(400MHz,CD3OD)δ7.91–7.76(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,2 H),1.96(s,6H),1.91–1.78(m,2H),1.40–1.20(m,7H),0.96–0.85(m,6H).

[0617] Example 15: Preparation of Compound 15

[0618] Referring to the preparation method of compound 14, the crude product of compound 15 was obtained, and the crude product was separated and purified by prep-HPLC (method 2) to obtain trifluoroacetate salt of compound 15-1 (15 mg, Rt = 4.354 min) and trifluoroacetate salt of compound 15-2 (17 mg, Rt = 4.455 min).

[0619] Trifluoroacetate salt of compound 15-1:

[0620] LC-Ms m / z(ESI):710.8[M+H] +

[0621] 1H NMR (400MHz, CD3OD) δ7.89–7.72(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).

[0622] Trifluoroacetate salt of compound 15-2:

[0623] LC-Ms m / z(ESI):710.8[M+H] +

[0624] 1 H NMR(400MHz,CD3OD)δ7.92–7.74(s,1H),7.25(s,1H),6.93–6.77(m,4H),5 .83–5.73(m,1H),5.38–5.28(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).

[0625] Example 16: Preparation of Compound 16

[0626] Referring to the preparation method of compound 3, the crude product of compound 16 was obtained, and the crude product was separated and purified by prep-HPLC (method 2) to obtain the trifluoroacetate salt of compound 16-1 (15 mg, Rt = 4.077 min) and the trifluoroacetate salt of compound 16-2 (16 mg, Rt = 4.178 min).

[0627] Trifluoroacetate salt of compound 16-1:

[0628] LC-Ms m / z(ESI):728.7[M+H] +

[0629] 1H NMR(400MHz,CD3OD)δ7.92(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).

[0630] Trifluoroacetate salt of compound 16-2:

[0631] LC-Ms m / z(ESI):728.7[M+H] +

[0632] 1 H NMR(400MHz,CD3OD)δ7.95(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).

[0633] Example 17: Preparation of Compound 17

[0634] Referring to the preparation method of compound 3, the crude product of compound 17 was obtained, and 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).

[0635] Trifluoroacetate salt of compound 17-1:

[0636] LC-Ms m / z(ESI):728.7[M+H] +

[0637] 1 H NMR (400MHz, CD3OD) δ8.01–7.80(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).

[0638] Trifluoroacetate salt of compound 17-2:

[0639] LC-Ms m / z(ESI):728.7[M+H] +

[0640] 1 H NMR(400MHz,CD3OD)δ7.93(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).

[0641] Example 18: Preparation of Compound 18

[0642] Referring to the preparation method of compound 14, the crude product of compound 18 was obtained, and the crude product was separated and purified by prep-HPLC (method 2) to obtain the trifluoroacetate salt of compound 18-1 (12 mg, Rt = 4.164 min) and the trifluoroacetate salt of compound 18-2 (13 mg, Rt = 4.268 min).

[0643] Trifluoroacetate salt of compound 18-1:

[0644] LC-Ms m / z(ESI):714.7[M+H] +

[0645] 1 H NMR (400MHz, CD3OD) δ7.97–7.77(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).

[0646] Trifluoroacetate salt of compound 18-2:

[0647] LC-Ms m / z(ESI):714.7[M+H] +

[0648] 1 H NMR(400MHz,CD3OD)δ7.91–7.72(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).

[0649] Example 19: Preparation of Compound 19

[0650] Referring to the preparation method of compound 14, the crude product of compound 19 was obtained, and 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).

[0651] Trifluoroacetate salt of compound 19-1:

[0652] LC-Ms m / z(ESI):726.8[M+H] +

[0653] 1 H NMR(400MHz, Methanol-d4)δ9.36–9.20(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).

[0654] Trifluoroacetate salt of compound 19-2:

[0655] LC-Ms m / z(ESI):726.8[M+H] +

[0656] 1 H NMR(400MHz,Methanol-d4)δ9.51–9.33(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,1 H),1.11-0.96(m,1H),0.96–0.86(m,6H),0.75-0.64(m,2H),0.45-0.36(m,2H).

[0657] Example 20: Preparation of Compound 20

[0658] The crude product of compound 20 was obtained by the preparation method of reference example 21, and the crude product was separated and purified by prep-HPLC (method 2) to give 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%).

[0659] Trifluoroacetate salt of compound 20-1:

[0660] LC-Ms m / z(ESI):676.7[M+H] +

[0661] 1 H NMR(400MHz,Methanol-d4)δ9.20(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).

[0662] Trifluoroacetate salt of compound 20-2:

[0663] LC-Ms m / z(ESI):676.7[M+H] +

[0664] 1 H NMR(400MHz, Methanol-d4)δ9.33(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).

[0665] Example 21: Preparation of Compound 21

[0666] Step 1: Synthesis of 21a

[0667] Under nitrogen, 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 the mixture was reacted at 100°C for 24 h. Ethyl acetate (80 mL) was added for extraction, and the mixture was 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 afford 21a (230 mg, yield: 51.32%).

[0668] LC-Ms m / z(ESI):404.5[M+H-Boc] +

[0669] Step 2: Synthesis of 21b

[0670] 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.

[0671] Step 3: Synthesis of 21c

[0672] Under nitrogen, 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. The reaction was allowed to proceed overnight at room temperature, and ethyl acetate (80 mL) was added. 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 and purified by silica gel column chromatography to afford 21c (240 mg, yield: 71.10%).

[0673] LC-Ms m / z(ESI):734.8[M+H] +

[0674] Step 4: Synthesis of Compound 21-1 and Compound 21-2

[0675] 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 afford crude compound 21. The crude product was then separated and purified by prep-HPLC (Method 2) to afford the trifluoroacetic acid salt of compound 21-1 (19 mg, Rt = 3.973 min, 8.16% yield) and the trifluoroacetic acid salt of compound 21-2 (20 mg, Rt = 4.051 min, 8.59% yield).

[0676] Trifluoroacetate salt of compound 21-1:

[0677] LC-Ms m / z(ESI):706.7[M+H] +

[0678] 1 H NMR(400MHz, Methanol-d4)δ7.89(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).

[0679] Trifluoroacetate salt of compound 21-2:

[0680] LC-Ms m / z(ESI):706.7[M+H] +

[0681] 1 H NMR(400MHz,Methanol-d4)δ9.33(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)

[0682] The structure of compound 21-A is It is a racemate consisting of four chiral isomers in equal proportions.

[0683] Example 22: Preparation of Compound 22

[0684] Referring to the preparation method of compound 14, the crude product of compound 22 was obtained, and 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).

[0685] Trifluoroacetate salt of compound 22-1:

[0686] LC-Ms m / z(ESI):726.4[M+H] +

[0687] 1 H NMR(400MHz,Methanol-d4)δ7.74(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).

[0688] Trifluoroacetate salt of compound 22-2:

[0689] LC-Ms m / z(ESI):726.4[M+H] +

[0690] 1 H NMR(400MHz, Methanol-d4)δ9.12(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).

[0691] Example 23: Preparation of Compound 23

[0692] Referring to the preparation method of compound 14, the crude product of compound 23 was obtained, and the crude product was separated and purified by prep-HPLC (method 2) to obtain trifluoroacetate salt of compound 23-1 (10 mg, Rt = 4.233 min) and trifluoroacetate salt of compound 23-2 (10 mg, Rt = 4.411 min).

[0693] Trifluoroacetate salt of compound 23-1:

[0694] LC-Ms m / z(ESI):742.4[M+H] +

[0695] 1 H NMR(400MHz, Methanol-d4)δ9.29(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).

[0696] Trifluoroacetate salt of compound 23-2:

[0697] LC-Ms m / z(ESI):742.4[M+H] +

[0698] 1 H NMR(400MHz, Methanol-d4)δ7.79(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).

[0699] Example 24: Preparation of Compound 24

[0700] Referring to the preparation method of compound 14, a crude product of compound 24 was obtained, and 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).

[0701] Compound 24-1:

[0702] LC-Ms m / z(ESI):760.3[M+H] +

[0703] 1 H NMR(400MHz,Methanol-d4)δ7.71(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),3.0 4–2.93(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,2 H),1.70–1.61(m,1H),1.41–1.25(m,3H),0.98–0.93(m,6H),0.77–0.65(m,4H).

[0704] Compound 24-2:

[0705] LC-Ms m / z(ESI):760.3[M+H] +

[0706] 1H NMR(400MHz,Methanol-d4)δ7.78(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),2.5 7–2.47(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).

[0707] Example 25: Preparation of Compound 25

[0708] Step 1: Synthesis of 25a

[0709] Under nitrogen 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 reacted at room temperature overnight, and ethyl acetate (80 mL) was added. The mixture was washed with water (20 mL × 2) and saturated brine (20 mL × 1) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. After that, the crude product 25a (250 mg) was obtained by silica gel column chromatography.

[0710] LC-Ms m / z(ESI):750.2[M+H] +

[0711] Step 2: Preparation of compounds 25-1 and 25-2

[0712] 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 separated and purified by prep-HPLC (Method 1) to give compound 25-1 (29 mg, Rt = 4.237 min, two-step yield: 10.86%) and compound 25-2 (36 mg, Rt = 4.294 min, two-step yield: 13.48%).

[0713] Compound 25-1:

[0714] LC-Ms m / z(ESI):722.3[M+H] +

[0715] 1 H NMR(400MHz, Methanol-d4)δ7.91(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).

[0716] Compound 25-2:

[0717] LC-Ms m / z(ESI):722.3[M+H] +

[0718] 1 H NMR(400MHz,Methanol-d4)δ7.88(s,1H),6.93–6.86(m,3H),5.83–5.75(m,1 H),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).

[0719] Example 26: Preparation of Compound 26

[0720] Step 1: Synthesis of 26a

[0721] Under nitrogen, 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 PdCl2(dppf) (578 mg, 0.71 mmol) were added sequentially. The reaction was continued at 80°C for 5 h. The mixture was filtered through celite, and ethyl acetate (100 mL) was added. The mixture was 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. The mixture was then purified by silica gel column chromatography to afford 26a (1.7 g, yield: 72.24%).

[0722] LC-Ms m / z(ESI):443.2[M+Ht-Bu] +

[0723] Step 2: Synthesis of 26b

[0724] Under nitrogen, 26a (1.3 g, 2.61 mmol) was dissolved in methanol (22 mL), and 10% w / w Pd / C (2.2 g, 2.09 mmol) was added. The atmosphere was replaced with hydrogen three times, and the mixture was reacted at room temperature under a hydrogen balloon for 0.5 h. The solid was removed by filtration, and the filtrate was concentrated to afford crude product 26b (1.3 g).

[0725] LC-Ms m / z(ESI):447.2[M+Ht-Bu] +

[0726] Step 3: Synthesis of 26c

[0727] The crude product 26b (1.3 g) from the previous step was dissolved in dichloromethane (14 mL), and 1,4-dioxane hydrochloride (10 mL) was added and reacted for 3 h. The solvent was removed under reduced pressure to obtain the crude product 26c (1.4 g).

[0728] LC-Ms m / z(ESI):403.6[M+H] +

[0729] Step 4: Synthesis of 26d

[0730] Crude product 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 reacted at 60°C for 16 h. Dichloromethane (80 mL) and water (30 mL) were added, and the product was washed with saturated brine (30 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to afford 26d (750 mg, three-step yield: 51.75%).

[0731] LC-Ms m / z(ESI):417.6[M+H] +

[0732] Step 5: Synthesis of 26e

[0733] 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 1N hydrochloric acid, and the mixture was concentrated under reduced pressure to afford the crude compound. The crude product was then purified on a C18 column (mobile phase A: acetonitrile, mobile phase B: 0.5% aqueous NH4HCO3, gradient elution from 10% of mobile phase A to 40% of mobile phase B) to afford 26e (620 mg, 85.36%).

[0734] LC-Ms m / z(ESI):389.4[M+H] +

[0735] Step 6: Synthesis of 26f

[0736] Under nitrogen 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 reaction was allowed to react at room temperature overnight. Ethyl acetate (80 mL) was added, and the mixture was washed with water (20 mL × 2) and saturated brine (20 mL × 1) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to give 26f (189 mg, 62.02%).

[0737] LC-Ms m / z(ESI):762.7[M+H] +

[0738] Step 7: Preparation of compounds 26-1 and 26-2

[0739] 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 reaction 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 afford crude compound 26. This crude product was then separated and purified by prep-HPLC (Method 2) to afford the trifluoroacetic acid salt of compound 26-1 (30 mg, Rt = 4.218 min, two-step yield: 16.35%) and the trifluoroacetic acid salt of compound 26-2 (30 mg, Rt = 4.305 min, two-step yield: 16.35%).

[0740] Trifluoroacetate salt of compound 26-1:

[0741] LC-Ms m / z(ESI):734.3[M+H] +

[0742] 1 H NMR(400MHz, Methanol-d4)δ9.16(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).

[0743] Trifluoroacetate salt of compound 26-2:

[0744] LC-Ms m / z(ESI):734.3[M+H] +

[0745] 1H NMR(400MHz, Methanol-d4)δ9.32(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).

[0746] Example 27: Preparation of Compound 27

[0747] Referring to the preparation method of compound 26, the crude product of compound 27 was obtained, and the crude product was separated and purified by prep-HPLC (method 2) to obtain trifluoroacetate of compound 27-1 (58 mg, Rt = 4.134 min) and trifluoroacetate of compound 27-2 (86 mg, Rt = 4.243 min).

[0748] Trifluoroacetate salt of compound 27-1:

[0749] LC-Ms m / z(ESI):714.3[M+H] +

[0750] 1 H NMR(400MHz,Methanol-d4)δ9.27(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),2.00–1.9 1(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).

[0751] Trifluoroacetate salt of compound 27-2:

[0752] LC-Ms m / z(ESI):714.3[M+H] +

[0753] 1 H NMR(400MHz,Methanol-d4)δ9.47–9.37(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).

[0754] Example 28: Preparation of Compound 28

[0755] Referring to the preparation method of compound 26, the crude product of compound 28 was obtained, and 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).

[0756] Trifluoroacetate salt of compound 28-1:

[0757] LC-Ms m / z(ESI):734.2[M+H] +

[0758] 1 H NMR(400MHz,Methanol-d4)δ9.20(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).

[0759] Trifluoroacetate salt of compound 28-2:

[0760] LC-Ms m / z(ESI):734.2[M+H] +

[0761] 1 H NMR(400MHz,Methanol-d4)δ9.35(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=7.4Hz,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).

[0762] Example 29: Preparation of Compound 29

[0763] Referring to the preparation method of compound 26, the crude product of compound 29 was obtained. The crude product was separated and purified by prep-HPLC (method 2) to obtain the trifluoroacetic acid salt of compound 29-1 (60 mg, Rt = 4.181 min) and the trifluoroacetic acid salt of compound 29-2 (88 mg, Rt = 4.279 min).

[0764] Trifluoroacetate salt of compound 29-1:

[0765] LC-Ms m / z(ESI):714.2[M+H] +

[0766] 1H NMR(400MHz,Methanol-d4)δ9.31(t,1H),7.83(d,1H),7.19(t,1H),7.14–7.03(m,3H),6.83(s,1 H),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),2.9 6–2.88(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).

[0767] Trifluoroacetate salt of compound 29-2:

[0768] LC-Ms m / z(ESI):714.2[M+H] +

[0769] 1 H NMR(400MHz,Methanol-d4)δ9.45(d,1H),7.88(d,1H),7.25–7.09(m,4H),6.88(d,1 H),5.86–5.78(m,1H),5.73–5.64(m,1H),3.75–3.64(m,1H),3.43–3.37(m,1H),3.2 4–3.03(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).

[0770] Example 30: Preparation of Compound 30 and its isomers

[0771] Step 1: Synthesis of 30b

[0772] Under nitrogen, 30a (1.76 g, 8.26 mmol) was dissolved in 1,4-dioxane (60 mL). Diboronic acid pinacol ester (3.15 g, 12.39 mmol), PdCl2(dppf) (0.60 g, 0.83 mmol), and potassium acetate (2.43 g, 24.78 mmol) were added sequentially, and the mixture was reacted at 100°C for 2 h. Ethyl acetate (180 mL) was added for extraction, and the mixture was 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 afford 22b (1.35 g, yield: 62.86%).

[0773] Referring to the preparation method of compound 20, 30b and intermediate 6 were used as starting materials to obtain a crude compound 30, which 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%).

[0774] Trifluoroacetate salt of compound 30-1:

[0775] LC-Ms m / z(ESI):704.3[M+H] +

[0776] 1 H NMR(400MHz,CD3OD)δ7.90(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).

[0777] Trifluoroacetate salt of compound 30-2:

[0778] LC-Ms m / z(ESI):704.3[M+H] +

[0779] 1H NMR(400MHz,CD3OD)δ7.90(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).

[0780] Example 32: Preparation of Compound 32 and Isomers

[0781] The crude product of compound 32 was obtained by the preparation method of reference example 21. The crude product was separated and purified by prep-HPLC (method 2) to give the trifluoroacetate salt of compound 32-1 (19 mg, Rt = 4.790 min, yield 8.93%) and the trifluoroacetate salt of compound 32-2 (20 mg, Rt = 4.862 min, yield 8.46%).

[0782] Trifluoroacetate salt of compound 32-1:

[0783] LC-Ms m / z(ESI):734.8[M+H] +

[0784] 1 H NMR (400MHz, CD3OD) δ9.23–9.07(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).

[0785] Trifluoroacetate salt of compound 32-2:

[0786] LC-Ms m / z(ESI):734.8[M+H] +

[0787] 1 H NMR (400MHz, CD3OD) δ7.94–7.73(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).

[0788] Example 33: Preparation of Compound 33 and Isomers

[0789] The crude product of compound 33 was obtained by the preparation method of reference example 21, and the crude product was separated and purified by prep-HPLC (method 1) to give 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%).

[0790] Compound 33-1:

[0791] LC-Ms m / z(ESI):702.7[M+H] +

[0792] 1 H NMR(400MHz,CD3OD)δ7.84(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).

[0793] Compound 33-2:

[0794] LC-Ms m / z(ESI):702.7[M+H] +

[0795] 1H NMR (400MHz, CD3OD) δ7.83–7.78(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).

[0796] Example 35: Preparation of Compound 35

[0797] Step 1: Synthesis of 35b

[0798] Under nitrogen, intermediate 9 (synthesis reference 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. The reaction was allowed to proceed overnight at room temperature, and ethyl acetate (80 mL) was added. 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 and purified by silica gel column chromatography to afford 35b (500 mg, yield: 67.72%).

[0799] LC-Ms m / z(ESI):746.8[M+H] +

[0800] Step 2: Synthesis of Compound 35-1 and Compound 35-2

[0801] 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 afford crude compound 35. The crude product was separated and purified by prep-HPLC (Method 1) to afford compound 35-1 (21 mg, Rt = 4.109 min, 4.37% yield) and compound 35-2 (22 mg, Rt = 4.204 min, 4.57% yield).

[0802] Compound 35-1

[0803] LC-Ms m / z(ESI):718.7[M+H] +

[0804] 1 H NMR (400MHz, CD3OD) δ7.77(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).

[0805] Compound 35-2

[0806] LC-Ms m / z(ESI):718.7[M+H] +

[0807] 1 H NMR(400MHz,CD3OD)δ7.66(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).

[0808] Example 36: Preparation of Compound 36

[0809] The crude product of compound 36 was obtained by referring to the preparation method of Example 35. The crude product was separated and purified by prep-HPLC (method 1) to give 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%).

[0810] Compound 36-1

[0811] LC-Ms m / z(ESI):706.7[M+H]+

[0812] 1 H NMR(400MHz,CD3OD)δ7.86(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).

[0813] Compound 36-2

[0814] LC-Ms m / z(ESI):706.7[M+H] +

[0815] 1 H NMR (400MHz, CD3OD) δ7.67(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).

[0816] Example 37: Preparation of Compound 37

[0817] Referring to the preparation method of Example 20, a crude compound 37 was obtained, and the crude product was separated and purified by prep-HPLC (Method 1) to give 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%).

[0818] Compound 37-1:

[0819] LC-Ms m / z(ESI):690.7[M+H] +

[0820] 1H NMR(400MHz,CD3OD)δ7.86(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).

[0821] Compound 37-2:

[0822] LC-Ms m / z(ESI):690.7[M+H] +

[0823] 1 H NMR(400MHz,CD3OD)δ7.80(s,1H),7.16(s,1H),7.02(d,1H),6.91(s,1H),6.7 7(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).

[0824] Example 38: Preparation of Compound 38

[0825] Step 1: Synthesis of 38b

[0826] Under nitrogen, 38a (3 g, 14.91 mmol), diboronic acid pinacol ester (4.54 g, 17.88 mmol), potassium carbonate (2.06 g, 14.91 mmol), and PdCl2(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 reaction was refluxed at 100°C overnight. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 ml × 3). The mixture was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. After flash column chromatography, 38b (2.8 g, yield 75.68%) was obtained.

[0827] Step 2: Synthesis of 38c

[0828] 38b (2.8 g, 11.28 mmol) was dissolved in dichloromethane (20 mL). NaH (0.54 g, 22.5 mmol) was slowly added portionwise under ice-cooling. After stirring for 20 minutes, deuterated iodomethane (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). The mixture was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. After flash column chromatography, 38c (1.9 g, 63.52% yield) was obtained.

[0829] The third to sixth steps were carried out according to the preparation method of Example 21 to obtain a crude compound 38, which 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%).

[0830] Compound 38-1:

[0831] LC-Ms m / z(ESI):709.7[M+H] +

[0832] 1 H NMR (400MHz, CD3OD) δ7.83(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).

[0833] Compound 38-2:

[0834] LC-Ms m / z(ESI):709.7[M+H] +

[0835] 1H NMR(400MHz,CD3OD)δ7.85(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),2.7 3–2.62(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).

[0836] Example 39: Preparation of Compound 39

[0837] Referring to the preparation methods of intermediate 6 and compound 21, crude compound 39 was obtained, and 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).

[0838] Compound 39-1:

[0839] LC-Ms m / z(ESI):706.7[M+H] +

[0840] 1 H NMR(400MHz,CD3OD)δ7.85(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).

[0841] Compound 39-2:

[0842] LC-Ms m / z(ESI):706.7[M+H] +

[0843] 1H NMR(400MHz,CD3OD)δ7.80(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).

[0844] Example 40: Preparation of Compound 40

[0845] Referring to the preparation method of compound 38, a crude compound 40 was obtained, and the crude product was separated and purified by prep-HPLC (method 1) to give compound 40-1 (11 mg, Rt = 4.152 min) and compound 40-2 (10 mg, Rt = 4.238 min).

[0846] Compound 40-1:

[0847] LC-Ms m / z(ESI):721.7[M+H] +

[0848] 1 H NMR(400MHz,CD3OD)δ7.76(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).

[0849] Compound 40-2:

[0850] LC-Ms m / z(ESI):721.7[M+H] +

[0851] 1H NMR(400MHz,CD3OD)δ7.66(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),3.0 3–2.70(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).

[0852] Example 41: Preparation of Compound 41

[0853] Referring to the preparation method of compound 9, the crude product of compound 41 was obtained, and the crude product was separated and purified by prep-HPLC (method 1) to obtain compound 41-1 (20 mg, Rt = 4.286 min) and compound 41-2 (25 mg, Rt = 4.371 min).

[0854] Compound 41-1:

[0855] LC-Ms m / z(ESI):750.3[M+H] +

[0856] 1 H NMR (400MHz, CD3OD) δ7.80(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).

[0857] Compound 41-2:

[0858] LC-Ms m / z(ESI):750.3[M+H] +

[0859] 1H NMR(400MHz,CD3OD)δ7.74(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).

[0860] Example 42: Preparation of Compound 42

[0861] Referring to the preparation method of compound 35, a crude compound 42 was obtained, and the crude product was separated and purified by prep-HPLC (method 1) to give compound 42-1 (15 mg, Rt = 4.071 min) and compound 42-2 (18 mg, Rt = 4.228 min).

[0862] Compound 42-1:

[0863] LC-Ms m / z(ESI):683.3[M+H] +

[0864] 1 H NMR(400MHz,CD3OD)δ7.29(s,1H),6.69(s,2H),5.56(dd,1H),5.49(t,1H),5.34–5.1 2(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),2.12–2.0 2(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).

[0865] Compound 42-2:

[0866] LC-Ms m / z(ESI):683.3[M+H] +

[0867] 1 H NMR(400MHz,CD3OD)δ7.28–7.24(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).

[0868] Example 43: Preparation of Compound 43

[0869] Referring to the preparation method of compound 35, a crude compound 42 was obtained, and the crude product was separated and purified by prep-HPLC (method 1) to give compound 43-1 (98 mg, Rt = 4.126 min) and compound 43-2 (103 mg, Rt = 4.303 min).

[0870] Compound 43-1:

[0871] LC-Ms m / z(ESI):671.3[M+H] +

[0872] 1 H NMR (400MHz, CD3OD) δ7.32–7.27(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).

[0873] Compound 43-2:

[0874] LC-Ms m / z(ESI):671.3[M+H] +

[0875] 1 H NMR (400MHz, CD3OD) δ7.29–7.25(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).

[0876] Example 44: Preparation of Compound 44

[0877] Referring to the preparation method of compound 35, a crude compound 44 was obtained, and the crude product was separated and purified by prep-HPLC (method 1) to give compound 44-1 (84 mg, Rt = 4.315 min) and compound 44-2 (96 mg, Rt = 4.398 min).

[0878] Compound 44-1:

[0879] LC-Ms m / z(ESI):738.3[M+H] +

[0880] 1 H NMR(400MHz,CD3OD)δ7.79(s,1H),6.88–6.80(m,2H),6.79(s,1H),5.74–5.6 4(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).

[0881] Compound 44-2:

[0882] LC-Ms m / z(ESI):738.3[M+H] +

[0883] 1 H NMR(400MHz,CD3OD)δ7.74(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).

[0884] Example 45: Preparation of Compound 45

[0885] Using (S)-tert-butylsulfenamide and 6c as starting materials, referring to the preparation methods of intermediate 6 and compound 35, the crude compound 45 was obtained. The crude product was separated and purified by prep-HPLC (method 1) to give compound 45-1 (5 mg, retention time = 3.918 min) and compound 45-2 (6 mg, retention time = 4.001 min).

[0886] Compound 45-1: LC-Ms m / z (ESI): 718.3 [M+H] +

[0887] Compound 45-2: LC-Ms m / z (ESI): 718.3 [M+H] +

[0888] Example 46: Synthesis of Compound 46

[0889] Step 1: Synthesis of 46b

[0890] 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 iodomethane (15 mL, 234.04 mmol) was added and allowed to react for 3 hours. Water was added, and the mixture was 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 afford 46b (6.8 g, yield: 55.79%).

[0891] LC-Ms m / z(ESI):157.2[M+H] +

[0892] Step 2: Synthesis of 46c

[0893] At room temperature, 46b (6.8 g, 43.54 mmol) was dissolved in a mixture of 1,4-dioxane and water (5:1, 200 mL). Potassium peroxymonosulfate (40.15 g, 65.31 mmol) was added and reacted at 100°C for 4 hours. Water was added and the mixture was 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 afford compound 46c (4.9 g, yield: 89.24%).

[0894] LC-Ms m / z(ESI):127.2[M+H] +

[0895] Step 3: Synthesis of 46d

[0896] At room temperature, 46c (4.9 g, 38.87 mmol) was dissolved in 50 mL of acetonitrile. N-bromosuccinimide (6.92 g, 38.87 mmol) and glacial acetic acid (0.22 mL, 3.85 mmol) were added, respectively, and the mixture was allowed to react for 4 hours. The reaction was quenched by the addition of aqueous sodium bicarbonate solution, and 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 afford compound 46d (5.5 g, yield: 69.02%).

[0897] LC-Ms m / z(ESI):206.1[M+H] +

[0898] Step 4: Synthesis of 46e

[0899] At room temperature, 46d (5.5 g, 26.83 mmol) and the intermediate ethyl 2-(methylsulfonyloxy)-4-methylpentanoate (7.67 g, 32.20 mmol) were dissolved in acetonitrile (80 mL). Potassium carbonate (11.12 g, 80.53 mmol) was added, and the temperature was then raised to 80°C for overnight reaction. The reaction solution was filtered through Celite and extracted with ethyl acetate (30 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 afford compound 46e (4.7 g, yield: 50.45%).

[0900] LC-Ms m / z(ESI):348.2[M+H] +

[0901] Step 5: Synthesis of 46f

[0902] 46e (4.7 g, 13.54 mmol) and (E)-1-ethoxyvinyl-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 tetrakistriphenylphosphine palladium (1.56 g, 1.35 mmol) were added. The atmosphere was purged with nitrogen three times and the mixture was reacted at 70°C for 24 hours. The mixture was quenched with water and extracted with ethyl acetate (30 mL × 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 afford 46f (1.8 g, yield: 39.28%).

[0903] LC-Ms m / z(ESI):339.4[M+H] +

[0904] Step 6: Synthesis of compound 46g

[0905] 46f (1.8 g, 5.32 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (10 mL, 134.19 mmol) was slowly added. The reaction was allowed to react at room temperature overnight. The mixture was concentrated under reduced pressure, and the pH was adjusted to neutral by adding aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 46 g of crude product, which was directly used in the next step without purification.

[0906] Steps 7 to 10: Synthesis of compound 46

[0907] Using 46 g as the starting material, referring to the synthetic route and preparation method of compound 3, the crude product of compound 46 was obtained. The crude product was separated and purified by prep-HPLC (Preparation Method 1) to give compound 46-1 (20 mg, retention time = 4.122 min) and compound 46-2 (18 mg, retention time = 4.250 min).

[0908] Compound 46-1:

[0909] LC-Ms m / z(ESI):713.3[M+H] +

[0910] 1H NMR (400MHz, CD3OD) δ7.70(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).

[0911] Compound 46-2:

[0912] LC-Ms m / z(ESI):713.3[M+H] +

[0913] 1 H NMR(400MHz,CD3OD)δ7.71(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).

[0914] Example 47: Preparation of Compound 47

[0915] Referring to the synthetic route and preparation method of compound 35, crude compound 47 was obtained, and the crude product was separated and purified by prep-HPLC ((Preparation Method 2)) to give compound 47-1 (40 mg, retention time = 4.179 min) and compound 47-2 (45 mg, retention time = 4.271 min).

[0916] Trifluoroacetate salt of compound 47-1:

[0917] LC-Ms m / z(ESI):706.3[M+H] +

[0918] 1 H NMR(400MHz,CD3OD)δ9.26(d,1H),7.86(s,1H),7.15–7.05(m,1H),7.02–6.9 3(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).

[0919] Trifluoroacetate salt of compound 47-2:

[0920] LC-Ms m / z(ESI):706.3[M+H]+

[0921] 1 H NMR(400MHz,CD3OD)δ9.38(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).

[0922] Example 48: Preparation of Compound 48

[0923] Referring to the synthetic route and preparation method of compound 35, crude compound 48 was obtained, and the crude product was separated and purified by prep-HPLC (Preparation Method 2) to give compound 48-1 (54 mg, retention time = 4.179 min) and compound 48-2 (62 mg, retention time = 4.271 min).

[0924] Trifluoroacetate salt of compound 48-1:

[0925] LC-Ms m / z(ESI):694.3[M+H] +

[0926] 1 H NMR(400MHz,CD3OD)δ9.23(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).

[0927] Trifluoroacetate salt of compound 48-2:

[0928] LC-Ms m / z(ESI):694.3[M+H] +

[0929] 1 H NMR (400MHz, CD3OD) δ9.35(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).

[0930] Example 49: Preparation of Compound 49

[0931] Step 1: Synthesis of compound 49B

[0932] Substrate 49A (5.00 g, 24.99 mmol) was dissolved in 10% aqueous sulfuric acid (50 mL) under ice-cooling. Sodium nitrite (1.72 g, 24.99 mmol) dissolved in water (10 mL) was then added dropwise to the mixture. The reaction was continued under ice-cooling for 1 hour. 50% aqueous sulfuric acid (50 mL) was then added dropwise to the mixture. After addition, the temperature was raised to 100°C and the reaction was continued for 1 hour. The reaction system was cooled to room temperature and slowly poured into stirred ice water (300 mL). Stirring was continued for 30 minutes. 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 obtain the crude product, which was purified by silica gel column chromatography to afford 49B (2.89 g, 57.52% yield).

[0933] Step 2: Synthesis of compound 49C

[0934] Substrate 49B (2.89 g, 14.37 mmol) was dissolved in acetonitrile (30 mL), followed by the addition of potassium carbonate (3.97 g, 28.72 mmol) and iodomethane (3.06 g, 21.55 mmol). After addition, the mixture was heated to 60°C under a nitrogen atmosphere for 18 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (5 mL x 2). The filtrate was collected and concentrated to obtain the crude product, which was purified by silica gel column chromatography to afford 49C (2.65 g, 85.74% yield).

[0935] Step 3: Synthesis of compound 49D

[0936] Substrate 49C (2.65 g, 12.32 mmol) was dissolved in ultra-dry tetrahydrofuran (40 mL) and pre-cooled at -78°C under a nitrogen atmosphere for 10 minutes. Then, n-butyllithium (0.89 g, 13.91 mmol) was slowly added dropwise. After addition, the mixture was stirred at -78°C for 1 hour. Trimethyl borate (1.71 g, 16.47 mmol) was then added dropwise. After addition, the mixture was allowed to warm to room temperature under a nitrogen atmosphere and allowed to react for 18 hours. The reaction mixture was poured into 10% aqueous hydrochloric acid (50 mL) under an ice bath and stirred for 30 minutes. The mixture was extracted with ethyl acetate (30 mL 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified by silica gel column chromatography to afford 49D (0.84 g, 37.88% yield).

[0937] Referring to the synthetic route and preparation method of compound 35, crude compound 49 was obtained, and the crude product was separated and purified by prep-HPLC (Preparation Method 1) to give compound 49-1 (32 mg, retention time = 4.218 min) and compound 49-2 (35 mg, retention time = 4.303 min).

[0938] Compound 49-1:

[0939] LC-Ms m / z(ESI):718.3[M+H] +

[0940] 1 H NMR(400MHz,CD3OD)δ7.76(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).

[0941] Compound 49-2:

[0942] LC-Ms m / z(ESI):718.3[M+H]+

[0943] 1 H NMR(400MHz,CD3OD)δ7.66(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),3.03–2.8 7(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).

[0944] Example 50: Preparation of Compound 50

[0945] Referring to the synthetic route and preparation method of compound 35, a crude compound 50 was obtained, and the crude product was separated and purified by prep-HPLC ((Preparation Method 1)) to give compound 50-1 (35 mg, retention time = 4.184 min) and compound 50-2 (37 mg, retention time = 4.260 min).

[0946] Compound 50-1:

[0947] LC-Ms m / z(ESI):706.4[M+H] +

[0948] 1H NMR(400MHz,CD3OD)δ7.85(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),1.9 9–1.91(m,2H),1.89–1.72(m,6H),1.47–1.35(m,1H),0.97–0.88(m,6H).

[0949] Compound 50-2:

[0950] LC-Ms m / z(ESI):706.4[M+H] +

[0951] 1H NMR(400MHz,CD3OD)δ7.79(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),2.8 3–2.72(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).

[0952] Biological testing:

[0953] 1. Integrin α4β7 ELISA test:

[0954] MAdCAM was diluted to a final concentration of 2.5 μg / ml in TBS buffer, and 50 μl of the solution was transferred to a 96-well plate for overnight coating at 4°C. The plate was washed three times with TBS buffer, followed by the addition of 150 μl of blocking buffer (TBS buffer containing 1% BSA) and blocking at 37°C for 1 hour. The plate was washed three times with TBS buffer, and α4β7 integrin protein was diluted to 1 μg / ml in TBS buffer containing 0.1% BSA. 50 μl of the integrin protein was transferred to a 96-well plate, followed by the addition of 1 μl of various concentrations of compound or DMSO, and incubation at room temperature for 2 hours. Biotinylated anti-β7 antibody was diluted to 1 μg / ml in TBS buffer containing 0.1% BSA, and the plate was washed three times with TBS buffer. 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. Wash the plate three times with TBS buffer, add 50ul of TMB substrate, and incubate at room temperature for 5-30min. Finally, add 25ul of stop buffer (high concentration phosphate solution) and read the OD value of the plate at 450nm on a microplate reader. Calculate IC using GraphPad Prism 6 software. 50 value.

[0955] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good inhibitory activity against integrin α4β7.

[0956] 2. Integrin α4β7 Cell Adhesion Assay

[0957] MAdCAM-1 was prepared to a final concentration of 2 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. RPMI8866 cells were collected, washed twice with DPBS buffer, and then resuspended in TBS buffer to 4 × 10 5 cells / ml, transfer 50 μl of cell solution to a 96-well plate to make the cell density 2×10 5cells / well, then add 1 μl of different concentrations of compound or DMSO, and incubate at 37°C for 1 hour or 2 hours. Wash the plate with TBS buffer to remove non-adherent cells, add 50 μl of substrate (4-nitrophenyl-N-acetyl-β-D-glucosaminide), incubate at 37°C for 2 hours, and finally add 90 μl of stop solution (50 mM glycine and 5 mM EDTA, pH 10.4). Read the OD value of the plate at 405 nm using a microplate reader. Calculate the IC using GraphPad Prism 6 software. 50 The results are shown in Table 1.

[0958] 3. Integrin α4β1 Cell Adhesion Assay

[0959] VCAM was prepared with 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 at 4°C overnight. The plate was washed three times with coating buffer, and then 150 μl of blocking buffer (containing 1% BSA) was added and blocked at 37°C for 1 hour. Jurkat cells were collected, washed twice with DPBS buffer, and then resuspended in the reaction buffer to 4 × 10 6 cells / ml, transfer 50 μl of cell solution to a 96-well plate to make the cell density 2×10 5 Cells / well were plated, followed by the addition of 1 μl of test compound or DMSO at various concentrations, and incubation at 37°C for 1 hour. The plate was washed with coating buffer to remove unadhered 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.

[0960] Coating buffer: DMEM + 20mM HEPES + 0.4mM MnCl2

[0961] Buffer: DMEM + 20mM HEPES + 0.1% BSA + 0.4mM MnCl2

[0962] DMEM:dulbecco's modified eagle medium;

[0963] HEPES:2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid

[0964] Table 1 Adhesion results of compounds to α4β7 and α4β1 cells

[0965] A<10nM; control compound A is

[0966] Conclusion: The compounds of the present invention, such as the compounds in the examples, have a good inhibitory effect on cell adhesion mediated by integrin α4β7 and have better selectivity than the control compound A.

[0967] 4.CYP450 enzyme inhibition test

[0968] The purpose of this study was to evaluate the effects of test substances on the activities of five cytochrome P450 (CYP) isoforms (CYP1A2, CYP2C9, CYP2D6, and CYP3A4) in human liver microsomes using an in vitro assay system. Specific probe substrates for each CYP450 isoform were incubated with human liver microsomes and varying concentrations of the test substances. The reactions were initiated by the addition of reduced nicotinamide adenine dinucleotide phosphate (NADPH). Following the reaction, samples were processed and metabolites generated from 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 inhibitory potential of the test substances against each CYP isoform, CYP1A2, CYP2C9, CYP2D6, and CYP3A4-M (using midazolam as a substrate).

[0969] Conclusion: The compounds of the present invention, such as the compounds in the examples, have no significant inhibitory effect on any subtype of CYP enzymes.

[0970] 5. Pharmacokinetic Testing in Mice

[0971] Experimental animals: Male BALB / c mice, 20-25 g, 6 mice per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0972] Experimental Design: On the day of the experiment, six BALB / c mice were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0973] Table 2. Dosing Information Note: Intravenous administration vehicle: 5% DMA + 5% Solutol + 90% Saline; Oral administration vehicle: 5% DMSO + 95% (20% SBE-β-CD in saline) (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; DMSO: dimethyl sulfoxide; SBE-β-CD: sulfobutyl-β-cyclodextrin)

[0974] Before and after drug administration, 0.06 mL of blood was collected via the orbital cavity 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 from both the intravenous and oral gavage groups at 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0975] Table 3

[0976] Conclusion: The compounds of the present invention, such as the compounds in the examples, have better oral absorption properties and lower clearance rates in mice.

[0977] 6. Pharmacokinetic Test in Rat

[0978] Experimental animals: Male SD rats, about 220 g, 6 to 8 weeks old, 6 rats per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0979] Experimental design: On the day of the experiment, 6 SD rats / compound were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0980] Table 4. Dosing Information Note: Intravenous administration vehicle: 5% DMA + 5% Solutol + 90% Saline; Oral administration vehicle: 5% DMSO + 95% (20% SBE-β-CD in saline) (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; DMSO: dimethyl sulfoxide; SBE-β-CD: sulfobutyl-β-cyclodextrin)

[0981] Before and after drug administration, 0.10 mL of blood was collected via the orbital cavity 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 from both the intravenous and oral gavage groups at 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0982] Table 5 *Compound A iv 2.5 mg / kg; PO: 10 mg / kg

[0983] Conclusion: The compounds of the present invention, such as the compounds in the examples, have better oral absorption properties and / or lower clearance rates in rats.

[0984] 7. Beagle Dog Pharmacokinetic Test

[0985] Experimental animals: Male beagle dogs, weighing about 8-11 kg, 5-6 per compound, purchased from Beijing Masi Biotechnology Co., Ltd.

[0986] Test method: On the test day, 5-6 beagle dogs were randomly divided into groups according to body weight. The dogs were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0987] Table 6 Dosage information Note: Intravenous administration vehicle: 5% DMA + 5% Solutol + 90% Saline; Oral administration vehicle: 5% DMSO + 95% (20% SBE-β-CD in saline) (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; DMSO: dimethyl sulfoxide; SBE-β-CD: sulfobutyl-β-cyclodextrin)

[0988] Before and after administration, 1 ml of blood was collected from the jugular vein or limb vein and placed in an EDTAK2 centrifuge tube. The blood was centrifuged at 5000 rpm at 4°C for 10 min, and plasma was collected. For both the intravenous and oral gavage groups in groups G1 and G2, blood was collected at the following time points: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, 48, and 72 h. For both the intravenous and oral gavage groups in groups G3 and G4, blood was collected at the following time points: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, and 24 h. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0989] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption properties in beagle dogs.

[0990] 8. Monkey Pharmacokinetic Test

[0991] Experimental animals: Male cynomolgus monkeys, 3-5 kg, 3-6 years old, 4-6 per compound, purchased from Suzhou Xishan Biotechnology Co., Ltd.

[0992] Test method: On the day of the test, 4-6 monkeys / compound were randomly divided into groups according to body weight. The monkeys were fasted but not watered for 14-18 hours before administration and fed 4 hours after administration.

[0993] Table 7. Dosing Information Note: Intravenous administration vehicle: 5% DMA + 5% Solutol + 90% Saline; Oral administration vehicle: 5% DMSO + 95% (20% SBE-β-CD in saline) (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; DMSO: dimethyl sulfoxide; SBE-β-CD: sulfobutyl-β-cyclodextrin). *Dosage is based on the free base.

[0994] Before and after dosing, 1.0 mL of blood was collected from a limb vein and placed in an EDTAK2 centrifuge tube. The samples were centrifuged at 5000 rpm at 4°C for 10 minutes, and plasma was collected. Blood was collected from both the intravenous and oral administration groups at the following time points: 0, 5 minutes, 15 minutes, 30 minutes, and 1, 2, 4, 6, 8, 10, 12, and 24 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0995] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption properties in monkeys.

[0996] 9. hERG potassium channel effect test

[0997] Experimental platform: electrophysiology manual patch clamp system

[0998] Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channel

[0999] Experimental Methods: hERG potassium channel currents were recorded using the whole-cell patch-clamp technique at room temperature in CHO (Chinese Hamster Ovary) cells stably expressing the hERG potassium channel. Glass microelectrodes were pulled from glass electrode blanks (BF150-86-10, Sutter) using a puller. After perfusion with electrode solution, the tip resistance was approximately 2-5 MΩ. The microelectrodes were connected to the patch-clamp amplifier by inserting them into the amplifier headstage. Clamping voltage and data recording were controlled and recorded by a computer using pClamp 10 software with a sampling frequency of 10 kHz and a filter frequency of 2 kHz. After whole-cell recordings were obtained, cells were clamped at -80 mV. To elicit hERG potassium currents (I hERG ), a 2-second depolarization step from -80 mV to +20 mV was applied, followed by repolarization to -50 mV, which was maintained for 1 second before returning to -80 mV. This voltage stimulus was applied every 10 seconds, and drug administration was initiated after confirming the stability of the hERG potassium current (at least 1 minute). Compounds were administered for at least 1 minute at each tested concentration, and at least two cells were tested at each concentration (n≥2).

[1000] Data processing: Data analysis was performed using pClamp 10, GraphPad Prism 5, and Excel software. The degree of inhibition of hERG potassium current (peak hERG tail current induced at -50 mV) by different compound concentrations was calculated using the following formula: Inhibition% = [1–(I / Io)] × 100%

[1001] Wherein, Inhibition% represents the inhibition percentage of the compound on hERG potassium current, and I and Io represent the amplitude of hERG potassium current before and after drug addition, respectively.

[1002] The IC50 of the compound was calculated using GraphPad Prism 5 software by fitting the following equation: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X)×HillSlope))

[1003] Where X is the Log value of the test sample concentration, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[1004] Conclusion: The compounds of the present invention, such as the compounds in the examples, have no significant hERG inhibitory activity.

[1005] 10. Liver microsome stability test

[1006] In this study, liver microsomes from three species, monkey, rat and mouse, were used as in vitro models to evaluate the metabolic stability of the test substances.

[1007] At 37°C, 1 μM of the test substance was incubated with microsomal proteins and coenzyme NADPH. The reaction was terminated by adding ice-cold acetonitrile containing an internal standard after a certain time (5, 10, 20, 30, 60 min). The concentration of the test substance in the sample was detected by LC-MS / MS. The T value was calculated based on the ln value of the drug residual rate in the incubation system and the incubation time. 1 / 2 , and further calculated the liver microsomal intrinsic clearance CLint(mic) and liver intrinsic clearance CLint(Liver).

[1008] Table 8 Liver microsome stability results

[1009] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good stability in the liver microsomes of monkeys, mice and rats.

Claims

1. A compound or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, the compound being selected from the compound represented by general formula (I), wherein R 1 Selected from -CHR 1a R 1b or -NR 1a R 1b ; R 1a Selected from C 1-6 Alkyl, wherein the alkyl group is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 substituted by a cycloalkyl substituent; R 1b Selected from C 4-10 Carbocyclic ring, 5 to 10 membered heterocyclic ring, said carbocyclic ring or heterocyclic ring is optionally substituted by 0 to 4 R b Substitution, the heterocycle contains 1 to 4 heteroatoms selected from O, S, and N; R b Each independently selected from deuterium, halogen, OH, =O, cyano, COOH, NH2, -C 0-4 Alkyl-NHC 1-6 Alkyl, -C 0-4 Alkyl-N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -C 0-4 Alkyl-C 3-10 Carbocyclic ring, -C 0-4 Alkyl-3 to 10 membered heterocyclic ring or R ba The alkyl, alkynyl, alkoxy, carbocyclic or heterocyclic ring is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, CONH2, CONHC 1-6 Alkyl, CON(C 1-6 Alkyl)2, NH2, NHC 1-6 Alkyl, N(C 1-6 alkyl)2, N(C 1-6 Alkyl)(C 3-6 Cycloalkyl), NH(C 3-6 Cycloalkyl), C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogen-substituted C 1-6 Alkyl, halogen-substituted C 1-6 Alkoxy, C 1-6 Alkoxyalkyl or R k Substituents are substituted, and the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N; R ba Selected from -C 0-4 Alkyl-7 to 12 membered heterocyclic ring, -C 0-4 Alkyl - a 4- to 6-membered heterocyclic ring attached via a carbon atom, The R ba Optionally substituted by 1 to 4 groups selected from H, halogen, OH, =O, cyano, COOH, CONH2, CONHC 1-6 Alkyl, CON(C 1-6 Alkyl)2, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogen-substituted C 1-6 Alkyl, halogen-substituted C 1-6 Alkoxy, C 1-6 Alkoxyalkyl or R k Substituents are substituted, and the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N; R k Selected from -C 1-4 Alkyl-NH2, -C 1-4 Alkyl-NHC 1-6 Alkyl, -C 1-4 Alkyl-N(C 1-6 Alkyl)2, -C 0-4 Alkyl-C 3-10 Carbocycle or -C 0-4 Alkyl-3 to 10 membered heterocycle, wherein the alkyl, carbocycle or heterocycle is optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, halogen-substituted C 1-6 Alkyl, halogen-substituted C 1-6 Alkoxy, C 1-6 substituted by an alkoxyalkyl substituent, wherein the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N; R 2 Selected from C 1-6 Alkyl, C 6-10 Aromatic ring, 5- to 10-membered heteroaromatic ring, C 3-10 Carbocyclic ring, 5 to 10 membered heterocyclic ring, said R 2 Optional 0 to 4 R 2a Substitution, the heteroaromatic ring or heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N; R 2a Each independently selected from deuterium, halogen, OH, cyano, =O, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3 to 7 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic group is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S; Alternatively, R 2a With R 2a Direct connection to form C 4-7 4- to 7-membered carbocyclic ring or heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, cyano, =O, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-6 substituted by a cycloalkyl or 3- to 7-membered heterocycloalkyl substituent, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 substituents selected from deuterium, halogen, OH, and cyano; R 3 Selected from H, C 1-6 Alkyl, wherein the alkyl group is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 substituted by a carbocyclic substituent; Ring A is selected from C 8-10 and a carbocyclic ring, wherein the ring A is optionally substituted by 0 to 4 R a5 replace; Or ring A is selected from The ring A is 1 selected from C 2-6 Alkenyl or C 2-6 Alkynyl is substituted with 1 to 3 R a5 replace; R a5 Selected from halogen, OH, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3 to 7 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic group is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 The heterocyclic group is substituted by a substituent of the cycloalkyl group, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S.

2. The compound according to claim 1 or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: R 1 Selected from b is selected from 0, 1, 2, 3; R b Each independently selected from deuterium, halogen, OH, =O, cyano, COOH, NH2, -C 0-4 Alkyl-NHC 1-4 Alkyl, -C 0-4 Alkyl-N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -C 0-4 Alkyl-C 3-6 Carbocyclic ring, -C 0-4 Alkyl-3 to 7 membered heterocyclic ring or R ba The alkyl, alkynyl, alkoxy, carbocyclic or heterocyclic ring is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, CONH2, CONHC 1-4 Alkyl, CON(C 1-4 Alkyl)2, NH2, NHC 1-4 Alkyl, N(C 1-4 alkyl)2, N(C 1-4 Alkyl)(C 3-6 Cycloalkyl), NH(C 3-6 Cycloalkyl), C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy, C 1-4 Alkoxyalkyl or R k Substituents substituted, said heterocyclic ring contains 1 to 4 selected from O, Heteroatoms of S and N; R ba Selected from -C 0-2 Alkyl-7 to 8-membered monocyclic heterocycloalkyl, -C 0-2 Alkyl-7 to 11-membered spirocyclic heterocycloalkyl, -C 0-2 Alkyl-7 to 11-membered bridged heterocycloalkyl, -C 0-2 Alkyl - a 4- to 6-membered monocyclic heterocycloalkyl group attached via a carbon atom, The R ba Optionally substituted by 1 to 4 groups selected from H, halogen, OH, =O, cyano, COOH, CONH2, CONHC 1-4 Alkyl, CON(C 1-4 Alkyl)2, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy, C 1-4 Alkoxyalkyl or R k Substituents substituted, wherein the heterocycloalkyl group contains 1 to 4 heteroatoms selected from O, S, and N; R k Selected from -C 1-2 Alkyl-NH2, -C 1-2 Alkyl-NHC 1-4 Alkyl, -C 1-2 Alkyl-N(C 1-4 Alkyl)2, -C 0-2 Alkyl-C 3-6 Carbocycle or -C 0-2 Alkyl-3 to 6 membered heterocycle, wherein the alkyl, carbocycle or heterocycle is optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy, C 1-4 substituted by an alkoxyalkyl substituent, wherein the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N; R 2 Selected from C 1-4 Alkyl, benzene ring, naphthalene ring, 5- to 6-membered heteroaromatic ring, 9- to 10-membered heteroaromatic ring, C 3-10 Non-aromatic carbocyclic rings, 5- to 10-membered non-aromatic heterocyclic rings, benzo C 4-6 Carbocyclic or benzo 4 to 6 membered heterocyclic group, said R 2 Optional 0 to 4 R 2a Substitution, the heteroaromatic ring or heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N; R 2a Each independently selected from deuterium, halogen, OH, cyano, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3 to 7 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic group is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S; Alternatively, R 2a With R 2a Direct connection to form C 4-7 4- to 7-membered carbocyclic ring or heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, cyano, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 substituted by a cycloalkyl or 3- to 7-membered heterocycloalkyl substituent, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 substituents selected from deuterium, halogen, OH, and cyano; R 3 Selected from H, C 1-4 Alkyl, wherein the alkyl group is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 substituted by a carbocyclic substituent; Ring A is selected from benzo C 4-6 Carbocyclic ring, wherein the ring A is optionally substituted by 0 to 4 R a5 replace; Or ring A is selected from The ring A is 1 selected from C 2-4 Alkenyl or C 2-4 Alkynyl is substituted with 1 to 3 substituents selected from R a5 replace; R a5 Selected from halogen, OH, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic group is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The heterocyclic group is substituted by a substituent of the cycloalkyl group, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S.

3. The compound according to claim 2, or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, R b Each independently selected from deuterium, halogen, OH, =O, cyano, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, phenyl, 5- to 6-membered heteroaryl, -CH2NHC 1-4 Alkyl, -CH2N(C 1-4 Alkyl)2, -CH2CH2-NHC 1-4 Alkyl, -CH2CH2-N(C 1-4 alkyl)2, phenyl, 5- to 6-membered heteroaryl, C 3-6 Cycloalkyl, 3 to 7 membered heterocycloalkyl, -CH2-phenyl, -CH2-5 to 6 membered heteroaryl, -CH2-C 3-6 Cycloalkyl, -CH2-3 to 7 membered heterocycloalkyl, -CH2CH2-phenyl, -CH2CH2-5 to 6 membered heteroaryl, -CH2CH2-C 3-6 Cycloalkyl, -CH2CH2-3 to 7 membered heterocycloalkyl, R ba The CH2, alkyl, alkynyl, phenyl, heteroaryl, cycloalkyl, heterocycloalkyl are optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, CONH2, CONHC 1-4 Alkyl, CON(C 1-4 Alkyl)2, NH2, NHC 1-4 Alkyl, N(C 1-4 alkyl)2, N(C 1-4 Alkyl)(C 3-6 Cycloalkyl), NH(C 3-6 Cycloalkyl), C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy, C 1-4 Alkoxyalkyl or R k Substituents substituted, the heteroaryl or heterocycloalkyl contains 1 to 4 heteroatoms selected from O, S, N; R ba Selected from 7 to 8 membered monocyclic heterocycloalkyl, 7 to 11 membered spirocyclic heterocycloalkyl, 7 to 11 membered bridged heterocycloalkyl, 4 to 6 membered monocyclic heterocycloalkyl connected through a carbon atom, -CH2-7 to 8 membered monocyclic heterocycloalkyl, -CH2-7 to 11 membered spirocyclic heterocycloalkyl, -CH2-7 to 11 membered bridged heterocycloalkyl, -CH2-4 to 6 membered monocyclic heterocycloalkyl connected through a carbon atom, -CH2CH2-7 to 8 membered monocyclic heterocycloalkyl, -CH2CH2-7 to 11 membered spirocyclic heterocycloalkyl, -CH2CH2-7 to 11 membered bridged heterocycloalkyl, -CH2CH2-4 to 6 membered monocyclic heterocycloalkyl connected through a carbon atom, The R ba Optionally substituted by 1 to 4 groups selected from H, halogen, OH, =O, cyano, COOH, CONH2, CONHC 1-4 Alkyl, CON(C 1-4 Alkyl)2, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy, C 1-4 Alkoxyalkyl or R k Substituents substituted, wherein the heterocycloalkyl group contains 1 to 4 heteroatoms selected from O, S, and N; R k Selected from -C 1-4 Alkyl-NH2, -C 1-4 Alkyl-NHC 1-4 Alkyl, -C 1-4 Alkyl-N(C 1-4 Alkyl)2, -C 0-4 Alkyl-C 3-6 Carbocycle or -C 0-4 Alkyl-3 to 6 membered heterocycle, wherein the alkyl, carbocycle or heterocycle is optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy, C 1-4 substituted by an alkoxyalkyl substituent, wherein the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N; R 2 Selected from benzene ring, naphthalene ring, 5- to 6-membered heteroaromatic ring, 9- to 10-membered heteroaromatic ring, C 3-6 Cycloalkyl, 3 to 7 membered heterocycloalkyl, benzo C 4-6 Carbocyclic or benzo 4 to 6 membered heterocyclic group, said R 2 Optional 0 to 4 R 2a Substitution, the heteroaromatic ring, heterocycloalkyl contains 1 to 4 heteroatoms selected from O, S, and N; R 2a Each independently selected from deuterium, halogen, OH, cyano, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; Alternatively, R 2a With R 2a Directly connected 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, a 6-membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, cyano, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 substituted by a cycloalkyl or 3- to 7-membered heterocycloalkyl substituent, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 substituents selected from deuterium, halogen, OH, and cyano; R 3 Selected from H, C 1-4 Alkyl, wherein the alkyl group is optionally 0 to 4 selected from deuterium, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, substituted by a substituent on a benzene ring; Ring A is selected from The ring A is optionally substituted with 0 to 4 R a5 replace; Or ring A is selected from The ring A is 1 selected from C 2-4 Alkenyl or C 2-4 Alkynyl is substituted with 1 to 3 substituents selected from R a5 replace; R a5 Selected from halogen, OH, cyano, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, wherein the alkyl, alkynyl, alkoxy, cycloalkyl, heterocyclic group is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The cycloalkyl group is substituted with a substituent.

4. The compound according to claim 3 or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, R 1a Selected from methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl, -CH2-cyclopropyl, -CH2-cyclobutyl; R b Each independently selected from deuterium, F, Cl, Br, I, OH, =O, cyano, R ba , or R b Each independently selected from one of the following groups, substituted or unsubstituted: methyl, ethyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetanyl, oxetanyl, oxetanyl, 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, -CH2-azacyclopentyl -CH2-azetidinyl, -CH2-oxetanyl, -CH2-oxolanyl, -CH2-oxetanyl, -CH2-morpholinyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclopentyl, -CH2CH2-cyclohexyl, -CH2CH2-azetidinyl, -CH2CH2-azetidinyl, -CH2CH2-azetidinyl, -CH2CH2-azetidinyl, -CH2CH2-azetidinyl, -CH2CH2-azetidinyl, -CH2CH2-azetidinyl, -CH2CH2-azetidinyl, -CH2CH2-azetidinyl, -CH2CH2-oxetanyl, -CH2CH2-oxolanyl, -CH2CH2-oxetanyl, -CH2CH2-morpholinyl, -CH2-phenyl, -CH2-pyridinyl, -CH2CH2-phenyl, -CH2CH2-pyridinyl, when substituted, by 0 to 4 atoms selected from deuterium, halogen, OH, =O, cyano, CONH2, CONHC 1-4 Alkyl, CON(C 1-4 Alkyl)2, NH2, NHC 1-4 Alkyl, N(C 1-4 alkyl)2, N(C 1-4 Alkyl)(C 3-6 Cycloalkyl), NH(C 3-6 Cycloalkyl), C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy, C 1-4 Alkoxyalkyl or R k substituted by a substituent; R ba is selected from one of the following optionally substituted groups: When substituted, it is optionally replaced by 1 to 4 groups selected from deuterium, halogen, OH, =O, cyano, CONH2, CONHC 1-4 Alkyl, CON(C 1-4 Alkyl)2, NH2, NHC 1-4 Alkyl, N(C 1-4 alkyl)2, N(C 1-4 Alkyl)(C 3-6 Cycloalkyl), NH(C 3-6 Cycloalkyl), C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy, C 1-4 Alkoxyalkyl or R k substituted by a substituent; R k Selected from -CH2N(CH3)2, -CH2-cyclopropyl, -CH2-cyclobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, nitrogen Heterobutyl, azetyl, azetyl, oxetyl, the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetyl, azetyl, azetyl, oxetyl are optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, =O, cyano, NH2, NHC 1-4 Alkyl, N(C 1-4 alkyl)2, N(C 1-4 Alkyl)(C 3-6 Cycloalkyl), NH(C 3-6 Cycloalkyl), C 1-4 Alkyl, C 1-4 Alkoxy, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy, C 1-4 substituted by an alkoxyalkyl substituent; R 2 Selected from phenyl ring, pyridyl, pyridonyl, pyrazinyl, pyrimidinyl, thienyl, thiazolyl, furyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetyl, oxetyl, morpholinyl, The R 2 Optional 0 to 4 R 2a replace; R 2a Each independently selected from deuterium, F, Cl, Br, I, OH, =O, cyano, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl or cyclobutyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl or cyclobutyl is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; R 3 Selected from H, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl, benzyl; Ring A is selected from The ring A is optionally substituted with 0 to 4 R a5 replace; Or ring A is selected from The ring A is substituted by one substituent selected from vinyl, ethynyl, propynyl, propargyl, and optionally substituted by 1 to 3 substituents selected from R a5 replace; R a5 Each independently selected from F, Cl, Br, I, OH, CN, ethynyl, propynyl, propargyl, methyl, ethyl, cyclopropyl, methoxy, ethoxy, wherein the ethynyl, propynyl, propargyl, methyl, ethyl, cyclopropyl, methoxy, ethoxy is optionally substituted by 1 to 4 selected from deuterium, halogen, OH, =O, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The cycloalkyl group is substituted with a substituent.

5. The compound according to claim 4 or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, R 1 Selected from R b Each independently selected from deuterium, F, Cl, Br, OH, cyano, R ba , or R b Each independently selected from one of the following groups, substituted or unsubstituted: methyl, ethyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetanyl, oxetanyl, oxetanyl, 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, - CH2-azetidinyl, -CH2-azepanyl, -CH2-azepanyl, -CH2-azepanyl, -CH2-oxetanyl, -CH2-oxolanyl, -CH2-oxetanyl, -CH2-morpholinyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclopentyl, -CH2CH2-cyclohexyl, -CH2CH2-azetidinyl, -CH2CH2-azepanyl, -CH2CH2-azepanyl, -CH2CH2-azepanyl, -CH2CH2-azepanyl, -CH2CH2-azepanyl, -CH2CH2-azepanyl, -CH2CH2-azepanyl, -CH2CH2-azepanyl, -CH2CH2-azepanyl, -CH2CH2-azepanyl, -CH2CH2-azepanyl, -CH2CH2-azepanyl, -CH2CH2-oxetanyl, -CH2CH2-oxolanyl, -CH2CH2-oxetanyl, -CH2CH2-morpholinyl, -CH2-phenyl, -CH2-pyridinyl, -CH2CH2-phenyl, -CH2CH2-pyridinyl, When substituted, 0 to 4 radicals 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 substituted by a substituent; R ba is selected from one of the following optionally substituted groups: When substituted, it is optionally replaced by 1 to 4 groups 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 substituted by a substituent; R k Selected from -CH2N(CH3)2, -CH2-cyclopropyl, -CH2-cyclobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetanyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetanyl are optionally substituted with 1 to 4 substituents 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, methoxy, ethoxy, methoxymethyl, ethoxymethyl, methoxyethyl; R 2 Selected from phenyl, pyridyl, pyridonyl, azocyclopentyl, morpholinyl, The R 2 Optionally substituted with 0 to 4 substituents selected from deuterium, F, Cl, Br, OH, CF3, cyano, methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl; or R 2 Selected from The R 2 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 selected from 6. The compound according to claim 5, or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, R 1 Selected from or R 1 Selected from or R 1 Selected from or R 1 Selected from or R 1 Selected from or R 1 Selected from or R 1 Selected from R 2 Selected from or R 2 Selected from or R 2 Selected from R 1a Selected from 7. The compound according to claim 1 or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from the group consisting of compounds represented by general formula (Ia), (Ib), (Ia-1) and (Ib-1). Ring A, R 3 The same definition as in any one of claims 2 to 6; p1 is selected from 0, 1, 2, 3 or 4; R 2a Selected from deuterium, halogen, OH, CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or 4 to 6 membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl, heterocycloalkyl is optionally substituted by 0 to 4 atoms selected from deuterium, halogen, OH, CN, C 1-4 Alkyl, C 1-4 The heterocycloalkyl group is substituted by an alkoxy substituent, wherein the heterocycloalkyl group contains 1 to 4 heteroatoms selected from O, S, and N; R 1a Selected from R b1 Selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, CN, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; R b2 Selected from H, R ba , substituted or unsubstituted one of the following groups: C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, phenyl, 5- to 6-membered heteroaryl, -CH2CH2-phenyl, -CH2CH2-5- to 6-membered heteroaryl, -CH2CH2-NHC 1-4 Alkyl, -CH2CH2-N(C 1-4 Alkyl)2, -CH2CH2-C 3-6 Cycloalkyl, -CH2CH2-3 to 7 membered heterocycloalkyl, wherein said CH2, alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by 0 to 4 groups selected from deuterium, halogen, OH, =O, cyano, COOH, NH2, NHC 1-4 Alkyl, N(C 1-4 alkyl)2, N(C 1-4 Alkyl)(C 3-6 Cycloalkyl), NH(C 3-6 Cycloalkyl), C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, halogen-substituted C 1-4 Alkyl, halogen-substituted C 1-4 Alkoxy, C 1-4 Alkoxyalkyl or R k Substituents substituted, the heteroaryl or heterocycloalkyl contains 1 to 4 heteroatoms selected from O, S, N; R ba 、R k The definition is the same as any one of claims 2 to 6.

8. The compound according to claim 7 or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, R 2a Selected from deuterium, -CD3, -OCD3, F, Cl, Br, I, OH, cyano, methyl, ethyl, methoxy, ethoxy; R b1 Selected from H, F, CH2F, CHF2, CF3, methyl, -CH2CH2N(CH3)2; R b2 Selected from H, R ba , substituted or unsubstituted one of the following groups: methyl, ethyl, ethynyl, methoxy, ethoxy, -CH2NH(CH2CH3), -CH2N(CH2CH3)2, -CH2CH2NH(CH3), -CH2CH2N(CH3)2, -CH2CH2NH(CH2CH3), -CH2CH2N(CH2CH3)2, -CH2CH2N(CH3)(CH2CH3), -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclopentyl, -CH2CH2-cyclohexyl, -CH2CH2-azetidinyl, -CH2CH2-azetidinyl, - CH2CH2-azetidinyl, -CH2CH2-oxetanyl, -CH2CH2-oxolanyl, -CH2CH2-oxetanyl, -CH2CH2-morpholinyl, -CH2CH2-phenyl, -CH2CH2-pyridinyl, when substituted, by 1, 2 or 3 groups selected from H, 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 substituted by a substituent.

9. The compound according to claim 1 or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from the group consisting of compounds represented by the general formula (If), (Ig), (If-1), (Ig-1), (Ih), (Ii), (Ih-1), and (Ii-1). R 1b Selected from p2 is selected from 0, 1 or 2; R ak Selected from C 2-4 Alkynyl; R a5 The same as defined in any one of claims 1 to 4; The remaining groups are defined as in claim 7 or 8.

10. The compound according to claim 9 or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, R ak Selected from ethynyl, propynyl, propargyl; R a5 Selected from F, Cl, Br, I, OH, cyano, methyl, ethyl, methoxy, ethoxy, ethynyl.

11. The compound according to claim 1 or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound has one of the structures shown in Table E-1, Table E-3, Table E-4 or Table E-5.

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

13. Use of the compound according to any one of claims 1 to 12, or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, or the pharmaceutical composition according to claim 12, in the preparation of a medicament for treating diseases associated with α4β7 activity or expression.

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

15. A method for treating a disease in a mammal, 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 cocrystal thereof, or a pharmaceutical composition according to claim 12, wherein the therapeutically effective amount is preferably 1-1500 mg, and the disease is preferably an intestinal inflammatory disease.

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