Sulfonamide compound and pharmaceutical use thereof

Abstract

A sulfonamide compound and a pharmaceutical use thereof, specifically relating to a compound of general formula (II) or a racemate, stereoisomer, tautomer, pharmaceutically acceptable salt, and intermediate thereof, a preparation method therefor, and a use thereof in the preparation of drugs for treating solid tumors.

Description

Sulfonamide compounds and their use in medicine TECHNICAL FIELD

[0001] The present application relates to a compound of general formula (I) or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt, and intermediates and preparation methods thereof, and the use in the preparation of drugs for treating solid tumors. BACKGROUND

[0002] PARG, poly(ADP-ribose) glycohydrolase, is composed of 18 exons in full length, and human PARG is encoded by a single locus, with 5 subtypes having different subcellular localization due to alternative splicing. It is the main enzyme for the catabolism of poly-ADP-ribose.

[0003] PARG can hydrolyze the PAR chains of PARP and DNA repair-related proteins, and is involved in the homeostasis of protein PAR modification. During DNA replication, replication fork reversal is an intrinsic mechanism to protect the stability of replication forks when replication is stalled, and the PAR chain hydrolysis of RECQ1 is a necessary factor for the restart of stalled replication forks, so the inhibition of PARG can accumulate stalled replication forks and prevent the restart of replication forks. It has been found that PARG regulates transcription through PAR and induces the occurrence and progression of tumors (PARG expression is up-regulated in various tumors such as lung squamous carcinoma and lung adenocarcinoma).

[0004] PARG is highly expressed in various cancers, and high PARG levels are associated with poor prognosis (especially in breast cancer HER2-positive and triple-negative subtypes), and knocking down PARG can significantly reduce tumor growth. Various information indicates that PARG inhibitors have the potential to become new anticancer drugs, and drugs targeting this site have entered clinical studies. SUMMARY

[0005] The purpose of the present application is to provide a class of compounds that have inhibitory activity against PARG, which have good inhibitory activity, oral bioavailability, and no significant inhibition of hERG potassium ion channels.

[0006] The present application provides a compound represented by general formula (I) or (II), or a stereoisomer, a pharmaceutically acceptable salt or a co-crystal thereof,

[0007] In some embodiments, the compound of general formula (II) is selected from general formula (II-a) or (II-b),

[0008] In some embodiments, m1 is selected from 2, 3 or 4;

[0009] In some embodiments, m2 is selected from 0, 1, 2 or 3;

[0010] In some embodiments, X is selected from O or N(R x ) ;

[0011] In some embodiments, X is selected from O or NH;

[0012] In some embodiments, X1is selected from CR x1 or N;

[0013] In some embodiments, X2is selected from CR x2 or N;

[0014] In some embodiments, X1is selected from N;

[0015] In some embodiments, X2is selected from CH;

[0016] In some embodiments, Y1is selected from N or CR 6 ;

[0017] In some embodiments, Y2is selected from N or CR 7 ; In some embodiments, Y1is selected from CR 6 , Y2is selected from CR 7 ;

[0018] In some embodiments, is selected from

[0019] In some embodiments, R x is each independently selected from H, CN, OH, C 1-6 alkyl, C 3-6 cycloalkyl, said alkyl or cycloalkyl optionally substituted with 1 to 4 R k ;

[0020] In some embodiments, R 1 is selected from C 2-6 alkynyl, -OCH2-4 to 12 membered heterocyclyl, -N(C 1-6 alkyl)-C 3-6 cycloalkyl, -N(C 1-6 alkyl)-4 to 7 membered heterocycloalkyl, -N(C 3-6 cycloalkyl)2, -N(C 3-6 cycloalkyl)-4 to 7 membered heterocycloalkyl, -C 3-12 carbocyclyl-R 1b , -4 to 12 membered heterocyclyl-R 1b , said alkynyl, alkyl, cycloalkyl, heterocycloalkyl, carbocyclyl or heterocyclyl optionally substituted with 1 to 4 R 1a ;

[0021] In some embodiments, R1 selected from C 2-5 alkynyl, -OCH2-4- to 7-membered heterocycloalkyl, -N(C 1-6 alkyl)-C 3-6 cycloalkyl, -N(C 1-6 alkyl)-4- to 7-membered heterocycloalkyl, -N(C 3-6 cycloalkyl)2, -N(C 3-6 alkyl)-4- to 7-membered heterocycloalkyl, -C 3-6 cycloalkyl-R 1b , -C 5-10 bridged cycloalkyl-R 1b , -C 6-12 fused cycloalkyl-R 1b , -C 6-12 spirocycloalkyl-R 1b , -4- to 7-membered heterocycloalkyl-R 1b , -6- to 10-membered bridged heterocycloalkyl-R 1b , -6- to 12-membered fused heterocycloalkyl-R 1b , -6- to 12-membered spiroheterocycloalkyl-R 1b , said alkynyl, alkyl, cycloalkyl, heterocycloalkyl, carbocyclyl or heterocyclyl being optionally substituted with 1 to 4 R 1a ;

[0022] In some embodiments, R 1 is selected from one of the following groups, optionally substituted with 1 to 4 R 1a : ethynyl, propynyl, propargyl, -OCH2-oxetanyl, -OCH2-tetrahydrofuranyl, -OCH2-oxepanyl, -OCH2-azetidinyl, -OCH2-pyrrolidinyl, -OCH2-piperidinyl, -OCH2-piperazinyl, -N(CH3)-azetidinyl, -N(CH3)-pyrrolidinyl, -N(CH3)-piperidinyl, -N(CH3)-piperazinyl, -N(CH3)-morpholinyl, -N(CH3)-oxetanyl, -N(CH3)-tetrahydrofuranyl, -N(CH3)-oxepanyl, -N(CH2CH3)-azetidinyl, -N(CH2CH3)-pyrrolidinyl, -N(CH2CH3)-piperidinyl, -N(CH2CH3)-piperazinyl, -N(CH2CH3)-morpholinyl, -N(CH2CH3)-oxetanyl, -N(CH2CH3)-tetrahydrofuranyl, -N(CH2CH3)-oxepanyl, -N(cyclopropyl)-azetidinyl, -N(cyclopropyl)-pyrrolidinyl, -N(cyclopropyl)-piperidinyl, -N(cyclopropyl)-piperazinyl, -N(cyclopropyl)-morpholinyl, -N(cyclopropyl)-oxetanyl, -N(cyclopropyl)-tetrahydrofuranyl, -N(cyclopropyl)-oxepanyl, -N(cyclopropyl)2,

[0023] In some embodiments, R 1 is selected from n is selected from 0, 1, 2, 3, or 4;

[0024] In some embodiments, R 1 is selected from m is selected from 0, 1, 2, or 3;

[0025] In some embodiments, R 1 is selected from

[0026] In some embodiments, R 1A is selected from R 1 , -Ring A1-R 1B , Ring A2, said Ring A1 or Ring A2 is selected from 4 to 12 membered heterocyclyl, said Ring A1 is substituted with 2 to 4 R 1a , said Ring A2 is substituted with 1 C 3-6 ycloalkyl, said cycloalkyl is optionally substituted with 1 to 4 R k , said Ring A2 is optionally further substituted with 1 to 4 R 1a ; preferably, Ring A1 or Ring A2 is selected from 4 to 7 membered heterocycloalkyl, 6 to 10 membered bridged heterocycloalkyl, 6 to 12 membered fused heterocycloalkyl, 6 to 12 membered spiro heterocycloalkyl; preferably, Ring A1 or Ring A2 is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,

[0027] In some embodiments, Ring A2 is selected from

[0028] In some embodiments, Ring A2 is selected from

[0029] In some embodiments, R 1A is selected from R 1 ,

[0030] In some embodiments, R 1A is selected from R 1 ,

[0031] In some embodiments, s2 is selected from 1, 2, 3, or 4;

[0032] In some embodiments, R 1A is selected from R 1b Selected from R 1B Selected from s1 is selected from 1, 2, 3, or 4;

[0033] In some implementation schemes, R 1a Each of the following groups is independently selected from deuterium, F, Cl, Br, CN, OH, =O, NH2, -CH2NH2, -CH(CH3)NH2, -C(CH3)2NH2, SF5, or optionally substituted: methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -C(=O)-CH3, -C( =O)-CH2CH3, -C(=O)-CH(CH3)2, -C(=O)-C(CH3)3, -C(=O)-cyclopropyl, -C(=O)-cyclobutyl, -C(=O)-cyclopentyl, when substituted, are replaced by 1 to 4 substituents selected from deuterium, halogen, CN, OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl, ethyl, methoxy, ethoxy, and -O-cyclopropyl;

[0034] In some implementation schemes, R 1a Each of the following groups is independently selected from deuterium, F, Cl, Br, CN, OH, NH2, -CH2NH2, -CH(CH3)NH2, -C(CH3)2NH2, SF5, or optionally substituted: methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, and when substituted, is replaced by 1 to 4 substituents selected from deuterium, halogen, CN, OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl, ethyl, methoxy, ethoxy, -O-cyclopropyl;

[0035] In some implementation schemes, R 1aa Selected from H or R 1a ;

[0036] In some implementation schemes, R 1aa Each is independently selected from H or arbitrarily selected by 1 to 4 Rs. k Substitution with one of the following groups: C(=O)NH2, -C(=O)-N(R) 1bb 2. C(=O)NHC 1-4 Alkyl, C(=O)N(C) 1-4 Alkyl)2、C(=O)NHC 3-6Cycloalkyl, C(=O)N(C) 3-6 cycloalkyl)2, C(=O)N(C 1-4 Alkyl)(C 3-6 cycloalkyl), C(=O)N(R 1bb (C) 1-4 Alkyl), C(=O)N(C 1-4 Alkyl)(C 1-2 Alkylene-C 3-6 cycloalkyl), C(=O)NH(C 1-2 Alkylene-C 3-6 Cycloalkyl), C(=O)NH-4 to 7-membered heterocyclic groups, C(=O)N(C 1-4 Alkyl groups (4 to 7-membered heterocyclic groups), C(=S)NHC 1-4 Alkyl, C(=S)N(C 1-4 Alkyl)2、C(=O)OC 1-4 Alkyl, C(=O)C 3-6 Cycloalkyl, C(=S)OC 1-4 Alkyl, C(=O)SC 1- 4-alkyl group, -C(=O)C 1-4 Alkyl group, -C(=O)C 3-6 Cycloalkyl, -C(=O)-4 to 7-membered heterocyclic groups, -C(=S)C 1-4 Alkyl group, -C(=S)C 3-6 Cycloalkyl, -C(=S)-4 to 7-membered heterocycloalkyl, -C(=NR)- 1bb C 1-4 Alkyl group, -C (=NR) 1bb C 3-6 Cycloalkyl, -C (=NR) 1bb NHC 1-4 Alkyl group, -C (=NR) 1bb )NH2、-C(=NR 1bb )N(C 1-4 Alkyl)2、-C(=NR) 1bb NHC 3-6 cycloalkyl;

[0037] In some implementation schemes, R 1aa Each is independently selected from H or arbitrarily selected by 1 to 4 Rs. k Substitution with one of the following groups: C(=O)NH2, -C(=O)-N(R) 1bb 2. C(=O)NHC 1-6 Alkyl, C(=O)N(C) 1-6 Alkyl)2、C(=O)NHC 3-6 Cycloalkyl, C(=O)N(C) 3-6 cycloalkyl)2, C(=O)N(C1-6 Alkyl)(C 3-6 cycloalkyl), C(=S)NHC 1-6 Alkyl, C(=S)N(C 1-6 Alkyl)2、C(=O)OC 1-6 Alkyl, C(=O)C 3-6 Cycloalkyl, OC (=S)OC 1-6 Alkyl, C(=O)SC 1-6 Alkyl group, -C(=O)C 1-4 Alkyl group, -C(=O)C 3-6 Cycloalkyl, -C(=O)-4 to 7-membered heterocycloalkyl, -C(=NR)- 1bb C 1-4 Alkyl group, -C (=NR) 1bb C 3-6 Cycloalkyl, -C (=NR) 1bb NHC 1-4 Alkyl group, -C (=NR) 1bb NHC 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl or heterocycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0038] In some implementation schemes, R 1aa Each is independently selected from H or arbitrarily selected by 1 to 4 Rs. k The substituted group is one of the following: oxetyl, oxetyl, pyrrolidinyl, pyrazolyl, -C(=O)C 1-4 Alkyl group, -C(=O)C 3-6Cycloalkyl, -C(=O)-4 to 7-membered heterocycloalkyl, -C(=O)-CH3, -C(=O)-CH2CH3, -C(=O)-CH(CH3)2, -C(=O)-C(CH3)3, -C(=O)-cyclopropyl, -C(=O)-cyclobutyl, -C(=O)-cyclopentyl, -C(=O)-cyclohexyl, -C(=O)-bicyclo[1.1.1]pentyl, -C(=O)-oxacyclobutyl, -C(=O)-tetrahydrofuranyl, -C(=O)-oxacyclohexyl, -C(=O)-morpholinyl, -C(=O)-azacyclobutyl, -C(=O)-pyrroleyl, -C(=O)-piperidinyl, -C(=O) -piperazinyl, -C(=S)-CH3, -C(=S)-CH2CH3, -C(=S)-CH(CH3)2, -C(=S)-C(CH3)3, -C(=S)-cyclopropyl, -C(=S)-cyclobutyl, -C(=S)-cyclopentyl, -C(=S)-cyclohexyl, -C(=S)-bicyclo[1.1.1]pentyl, -C(=S)-oxacyclobutyl, -C(=S)-tetrahydrofuranyl, -C(=S)-oxacyclohexyl, -C(=S)-azacyclobutyl, -C(=S)-pyrrolidinyl, -C(=S)-piperidinyl, -C(=S)-piperazinyl, -C(=O)NH2, -C(=O)-N(R 1bb 2. -C(=O)-N(OH)(CH3), -C(=O)-NH-cyclobutyl, -C(=O)-NH(CH2cyclobutyl), -C(=O)-NH-azacyclobutyl, -C(=O)-NH-pyrroleyl, -C(=O)-NHCH3, -C(=O)-NHCH2CH3, -C(=O)-N(CH3)2, -C(=O)-N(CH2CH3)2, -C(=O)-N(CH3)(CH2CH3), -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)SC H3, -C(=O)SCH2CH3, -C(=N-CN)-CH3, -C(=N-CN)-CH2CH3, -C(=N-CN)-cyclopropyl, -C(=N-CN)-cyclobutyl, -C(=N-OH)-CH3, -C(=N-OH)-CH2CH3, -C(=N-OH)-cyclopropyl, -C(=N-OH)-cyclobutyl, -C(=N-OCH3)-CH3, -C(=N-OCH3)-CH2CH3, -C(=N-OCH3)-cyclopropyl, -C(=N-OCH3)-cyclobutyl

[0039] In some implementation schemes, R 1aaeach independently selected from H or optionally substituted one of oxetanyl, oxolanyl, pyrrolidinyl, pyrazolyl, -C(=0)-CH3, -C(=0)-CH2CH3, -C(=0)-CH(CH3)2, -C(=0)-C(CH3)3, -C(=0)-cyclopropyl, -C(=0)-cyclobutyl, -C(=0)-cyclopentyl, -C(=0)-cyclohexyl, -C(=0)-bicyclo[l. l. l]pentyl, -C(=0)-oxetanyl, -C(=0)-tetrahydrofuranyl, -C(=0)-oxanyl, -C(=0)-azetidinyl, -C(=0)-pyrrolidinyl, -C(=0)-piperidinyl, -C(=0)-piperazinyl, -C(=S)-CH3, -C(=S)-CH2CH3, -C(=S)-CH(CH3)2, -C(=S)-C(CH3)3, -C(=S)-cyclopropyl, -C(=S)-cyclobutyl, -C(=S)-cyclopentyl, -C(=S)-cyclohexyl, -C(=S)-bicyclo[l. l. l]pentyl, -C(=S)-oxetanyl, -C(=S)-tetrahydrofuranyl, -C(=S)-oxanyl, -C(=S)-azetidinyl, -C(=S)-pyrrolidinyl, -C(=S)-piperidinyl, -C(=S)-piperazinyl, -C(=0)NH2, -C(=0)-N(OH)(CH3), -C(=0)-N(OCH3)(CH3), -C(=0)-NHCH3, -C(=0)-NHCH2CH3, -C(=0)-N(CH3)2, -C(=0)-N(CH2CH3)2, -C(=0)-N(CH3)(CH2CH3), -C(=0)OCH3, -C(=0)OCH2CH3, -C(=0)SCH3, -C(=0)SCH2CH3, when substituted, is substituted with one to four substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, -CH2CF3, CH2CN, CD3, CHD2, CH2D, CH2CH2F, -OCH2CH2F, -OCH2CH2OCH3, methyl, ethyl, isopropyl, methoxy, ethoxy, -CH2CN, -CH2OH, -CH2OCH3, -0-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, N(CH3)2, vinyl,

[0040] In some embodiments, R 1be is selected from one of the following groups optionally substituted with one to four R k substituents: C 3-6 cycloalkyl; ​

[0041] In some embodiments, R 1be is selected from one of the following optionally substituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, when substituted, with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl, ethyl, methoxy, ethoxy, -CH2CN, -CH2OH, -CH2OCH3, -O-cyclopropyl, ethenyl, ;

[0042] In some embodiments, R 1b is selected from -C 0-4 alkylene-CN, -C 3-6 alkylene-OC 1-4 alkylene-CN, -C 1-4 alkylene-OC 1-4 alkylene-CN, -C 2-6 alkylene-CN, -C 1-6 alkylene-CN, -C 3-6 alkylene-CN, -C 3-6 alkylene-CN, -C 1ba alkylene-CN, -C 3-6 alkylene-CN, -C 1d alkylene-CN, -C 1c alkylene-CN, -C 1bb alkylene-CN, -C 1-6 alkylene-CN, -C 1bb alkylene-CN, -C 3-6 alkylene-CN, -C 1bb alkylene-CN, -C 1-6 alkylene-CN, -C 1bb alkylene-CN, -C 3-6 alkylene-CN, -C 1bc alkylene-CN, -C 1bc alkylene-CN, -C 1bc alkylene-CN, -C k alkylene-CN, -C

[0043] In some embodiments, R 1b is selected from one of the following optionally substituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, when substituted, with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl, ethyl, methoxy, ethoxy, -CH2CN, -CH2OH, -CH2OCH3, -O-cyclopropyl, ethenyl, ksubstituted with one of the following: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2CN, -CH2OCH3, -CH2OCH2CH3, ethynyl, -CH2-ethynyl, propynyl, -C(=S)-CH3, -C(=S)-CH2CH3, -C(=S)-CH(CH3)2, -C(=S)-C(CH3)3, -C(=S)-cyclopropyl, -C(=S)-cyclobutyl, -C(=S)-cyclopentyl, -C(=S)-cyclohexyl, -C(=S)-bicyclo[l. l. l]pentyl, -C(=S)-oxetanyl, -C(=S)-tetrahydrofuranyl, -C(=S)-oxepanyl, -C(=S)-azetidinyl, -C(=S)-pyrrolidinyl, -C(=S)-piperidinyl, -C(=S)-piperazinyl, -C(=O)-cyclopropyl-R 1ba , -C(=O)-cyclobutyl-R 1ba , -C(=O)-cyclopentyl-R 1ba , -C(=O)-cyclohexyl-R 1ba , -C(=O)-cyclopropyl=C(R 1d R 1c ), -C(=O)-cyclobutyl=C(R 1d R 1c ), -C(=O)-cyclopentyl=C(R 1d R 1c ), -C(=O)-cyclohexyl=C(R 1d R 1c ), -C(=NR 1bb )-CH3, -C(=NR 1bb )-CH2CH3, -C(=NR 1bb )-cyclopropyl, -C(=NR 1bb )-cyclobutyl, -C(=NR 1bb )NHCH3, C(=NR 1bb )NH-cyclopropyl, -C(=O)-phenyl-R 1bc , -C(=O)-pyrazolyl-R 1bc , -C(=O)-triazolyl-R 1bc , -C(=O)-imidazolyl-R 1bc ,

[0044] In some embodiments, R 1bselected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2CN, -CH2OCH3, -CH2OCH2CH3, ethynyl, -CH2-ethynyl, propynyl, -C(=S)-CH3, -C(=S)-CH2CH3, -C(=S)-CH(CH3)2, -C(=S)-C(CH3)3, -C(=S)-cyclopropyl, -C(=S)-cyclobutyl, -C(=S)-cyclopentyl, -C(=S)-cyclohexyl, -C(=S)-bicyclo[l. l. l]pentyl, -C(=S)-oxetanyl, -C(=S)-tetrahydrofuranyl, -C(=S)-oxepanyl, -C(=S)-azetidinyl, -C(=S)-pyrrolidinyl, -C(=S)-piperidinyl, -C(=S)-piperazinyl,

[0045] In some embodiments, R 1ba each independently is selected from deuterium, halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclyl, 4- to 7-membered heterocyclyl, -C 1-4 alkylene-C 3-6 carbocyclyl, -C 1-4 alkylene-4- to 7-membered heterocyclyl, -O-C 3-6 cycloalkyl, said alkylene, alkyl, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with 1 to 4 R k ;

[0046] In some embodiments, R 1ba each independently is selected from deuterium, halogen, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, -C 1-4 alkylene-C 3-6 cycloalkyl, -C 1-4 alkylene-4- to 7-membered heterocycloalkyl, -O-C 3-6 cycloalkyl, said alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocycloalkyl, heteroaryl is optionally substituted with 1 to 4 R k ;

[0047] In some embodiments, R 1baselected from the group consisting of deuterium, F, CI, Br, CN, methyl, ethyl, vinyl, -CH2-vinyl, ethynyl, cyclopropyl, -O-cyclopropyl, phenyl, said CH2, methyl, ethyl, vinyl, ethynyl, cyclopropyl or phenyl being optionally substituted with one to four substituents selected from the group consisting of deuterium, halogen, CN, OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl, ethyl, methoxy, ethoxy; 1-4 alkyl, C 1-4 alkoxy, said alkyl, alkoxy or cycloalkyl being optionally substituted with one to four R

[0048] In some embodiments, R 1ba selected from the group consisting of deuterium, F, CI, Br, CN, methyl, ethyl, vinyl, -CH2-vinyl, ethynyl, cyclopropyl, -O-cyclopropyl, phenyl, said CH2, methyl, ethyl, vinyl, ethynyl, cyclopropyl or phenyl being optionally substituted with one to four substituents selected from the group consisting of deuterium, halogen, CN, OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl, ethyl, methoxy, ethoxy;

[0049] In some embodiments, R 1bb selected from the group consisting of H, CN, OH, NO2, -SO2C 1-6 alkyl, -SO2C 3-6 cycloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, said alkyl, alkoxy or cycloalkyl being optionally substituted with one to four R k substituents;

[0050] In some embodiments, R 1bb selected from the group consisting of H, CN, OH, NO2, -SO2C 1-4 alkyl, -SO2C 3-6 cycloalkyl, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, said alkyl, alkoxy or cycloalkyl being optionally substituted with one to four R k substituents;

[0051] In some embodiments, R 1bb selected from the group consisting of H, CN, OH, NO2, methyl, ethyl, methoxy or ethoxy;

[0052] In some embodiments, R 1bc selected from the group consisting of C 3-6 carbocyclyl, -C 1-4 alkylene-C 3-6 carbocyclyl, -C(=O)-C 1-6 alkyl, -C(=O)-C 3-6The carbocyclic group, wherein the alkylene group, alkyl group, or carbocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0053] In some implementation schemes, R 1bc Selected from C 3-6 cycloalkyl, phenyl, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -C(=O)-C 1-4 Alkyl, -C(=O)-C 3-6 Cycloalkyl, wherein the alkylene, alkyl, cycloalkyl or phenyl is optionally surrounded by 1 to 4 R... k replace;

[0054] In some implementation schemes, R 1bc Selected from 1 to 4 Rs k The substitution may be made with one of the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -C(=O)-CH3, -C(=O)-CH2CH3, -C(=O)-CH(CH3)2, -C(=O)-C(CH3)3, -C(=O)-cyclopropyl, -C(=O)-cyclobutyl, -C(=O)-cyclopentyl;

[0055] In some implementation schemes, R 1bc The group is selected from one of the following optionally substituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -C(=O)-CH3, -C(=O)-CH2CH3, -C(=O)-CH(CH3)2, -C(=O)-C(CH3)3, -C(=O)-cyclopropyl, -C(=O)-cyclobutyl, -C(=O)-cyclopentyl, and when substituted, is selected from 1 to 4 groups selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl, ethyl, methoxy, ethoxy, -CH2CN, -CH2OH, -CH2OCH3, -O-cyclopropyl, vinyl, The substituents are replaced;

[0056] In some implementation schemes, R 1B Selected from R 1b R 1a or -C(=O)-C 3-6 cycloalkyl-R 1bd The cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0057] In some implementation schemes, R 1B Selected from R 1b R 1a-C(=O)-cyclopropyl-R 1bd -C(=O)-cyclobutyl-R 1bd -C(=O)-cyclopentyl-R 1bd -C(=O)-cyclohexyl-R 1bd , said cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl being optionally substituted with 1 to 4 R k ;

[0058] In some embodiments, R 1B is selected from R 1b , R 1a , -C(=O)-cyclopropyl-R 1bd , -C(=O)-cyclobutyl-R 1bd , -C(=O)-cyclopentyl-R 1bd , -C(=O)-cyclohexyl-R 1bd , said cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl being optionally substituted with 1 to 4 substituents selected from deuterium, halogen, CN, OH, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 halogenated alkyl, C 3-6 cycloalkyl, C 3-6 deuterated cycloalkyl, C 3-6 halogenated cycloalkyl;

[0059] In some embodiments, R 1bd is selected from OH or C 1-6 alkoxy, said alkoxy being optionally substituted with 1 to 4 R k ;

[0060] In some embodiments, R 1bd is selected from OH, methoxy, ethoxy, propoxy, said methoxy, ethoxy, propoxy being optionally substituted with 1 to 4 R k ;

[0061] In some embodiments, R 1bd is selected from OH, methoxy, ethoxy, propoxy, said methoxy, ethoxy, propoxy being optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, CN, OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, -OCF3, -OCHF2, -OCH2F, -OCD3, -OCHD2, -OCH2D, methyl, ethyl, methoxy, ethoxy or cyclopropyl;

[0062] In some embodiments, R 4 is selected from H, C 1-6 alkyl, C 6-10aryl or 5- to 10-membered heteroaryl, which alkyl, aryl or heteroaryl is optionally substituted with 1 to 4 R 4a substituted;

[0063] In some embodiments, R 4 is selected from H or optionally R 4a substituted C 1-6 alkyl, phenyl, benzC 4- 6 carbocyclyl, benzene 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl or 8- to 10-membered annulated heteroaryl;

[0064] In some embodiments, R 4 is selected from H or optionally R 4a substituted C 1-4 alkyl, phenyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, pyrazolyl, thiadiazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl;

[0065] In some embodiments, R 4 is selected from H,

[0066] In some embodiments, R 1a , R 4a are each independently selected from deuterium, halogen, CN, =O, OH, SF5, C(=O)NH2, -C(=O)-N(R 1bb )2, C(=O)NHC 1-6 alkyl, C(=O)N(C 1-6 alkyl)2, C(=O)NHC 3-6 cycloalkyl, C(=O)N(R 1bb )(C 1-6 alkyl), C(=O)NH-4- to 7-membered heterocyclyl, C(=O)N(C 1-6 alkyl)(4- to 7-membered heterocyclyl), C(=O)N(C 1-6 alkyl)(C 1-4 alkylene-C 3-6 cycloalkyl), C(=O)NH(C 1-4 alkylene-C 3-6 cycloalkyl), C(=O)N(C 3-6 cycloalkyl)2, C(=O)N(C 1-6 alkyl)(C 3-6 cycloalkyl), C(=S)NHC 1-6 alkyl, C(=S)N(C 1-6 alkyl)2, C(=O)OC 1-6 alkyl, C(=O)C 3-6 cycloalkyl, OC(=S)OC1-6 alkyl, C(=O)SC 1-6 alkyl, -C 0-4 alkylene-NH2, -C 0-4 alkylene-NHC 1-6 alkyl, -C 0-4 alkylene-N(C 1-6 alkyl)2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -SC 1-6 alkyl, -C 0-4 alkylene-C 3-6 cycloalkyl, -C 0-4 alkylene-4- to 7-membered heterocyclyl, -C 0-4 alkylene-4- to 7-membered heterocyclyl-C(=O)C 1-6 alkyl, -C(=O)C 1-6 alkyl, -C(=O)C 2-6 alkenyl, -C(=O)C 3-7 carbocyclyl, -C(=O)-4- to 7-membered heterocyclyl, -C(=S)C 1-6 alkyl, -C(=S)C 2-6 alkenyl, -C(=S)C 3-7 carbocyclyl, -C(=S)-4- to 7-membered heterocyclyl, -NHC(=O)C 1-6 alkyl, -NHC(=O)C 3-6 cycloalkyl, -S(=O)C 1-6 alkyl, -S(=O)C 3-7 carbocyclyl, -NHS(=O)C 1-6 alkyl, -S(=O)2C 1-6 alkyl, -S(=O)2C 3-7 carbocyclyl, -NHS(=O)2C 1-6 alkyl, -S(=O)2NHC 1-6 alkyl, -P(=O)(C 1-6 alkyl)2, -C(=NR 1bb )C 1-6 alkyl, -C(=NR 1bb )C 3-6 cycloalkyl, -C(=NR 1bb )NH2, -C(=NR 1bb )N(C 1-6 alkyl)2, -C(=NR 1bb )NHC 1-6 alkyl, -C(=NR 1bb )NHC 3-6cycloalkyl, said alkylene, alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl, heterocyclyl, cycloalkyl is optionally substituted with 1 to 4 R k substituted;

[0067] In some embodiments, R 1a , R 4a each independently is selected from the group consisting of deuterium, halogen, CN, OH, =0, SF5, C(=0)NH2, -C(=0)-N(R 1bb )2, C(=0)NHC 1-4 alkyl, C(=0)N(C 1-4 alkyl)2, C(=0)NHC 3-6 cycloalkyl, C(=0)N(C 3-6 cycloalkyl)2, C(=0)N(C 1-4 alkyl)(C 3-6 cycloalkyl), C(=0)N(R 1bb )(C 1-4 alkyl), C(=0)N(C 1-4 alkyl)(C 1-4 alkylene-C 3-6 cycloalkyl), C(=0)NH(C 1-4 alkylene-C 3-6 cycloalkyl), C(=0)NH-4- to 7-membered heterocyclyl-, C(=0)N(C 1-4 alkyl)(4- to 7-membered heterocyclyl), C(=S)NHC 1-4 alkyl, C(=S)N(C 1-4 alkyl)2, C(=0)OC 1-4 alkyl, C(=0)C 3-6 cycloalkyl, C(=S)OC 1-4 alkyl, C(=0)SC 1- 4alkyl, -C 0-4 alkylene-NH2, -C 0-4 alkylene-NHC 1-4 alkyl, -C 0-4 alkylene-N(C 1-4 alkyl)2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -SC 1-4 alkyl, -C 0-4 alkylene-C 3-6 cycloalkyl, -C 0-4 alkylene-4- to 7-membered heterocyclyl, -C 0-4 alkylene-4- to 7-membered heterocyclyl-C(=0)C 1-4 alkyl, -C(=0)C 1-4Alkyl group, -C(=O)C 2-4 alkenyl, -C(=O)C 3-7 Carbocyclic groups, -C(=O)-4 to 7-membered heterocyclic groups, -C(=S)C 1-4 Alkyl group, -C(=S)C 2-4 alkenyl, -C(=S)C 3-7 Carbocyclic groups, -C(=S)-4 to 7-membered heterocyclic groups, -NHC(=O)C 1-4 Alkyl group, -NHC(=O)C 3-6 cycloalkyl, -S(=O)C 1-4 Alkyl group, -S(=O)C 3-7 Carbocyclic group, -NHS(=O)C 1-4 Alkyl group, -S(=O)2C 1-4 Alkyl group, -S(=O)2C 3-7 Carbocyclic group, -NHS(=O)2C 1-4 Alkyl group, -S(=O)2NHC 1-4 Alkyl, -P(=O)(C 1-4 Alkyl)2, -C(=NR 1bb C 1-4 Alkyl group, -C (=NR) 1bb C 3-6 Cycloalkyl, -C (=NR) 1bb NHC 1-4 Alkyl group, -C (=NR) 1bb )NH2、-C(=NR 1bb )N(C 1-4 Alkyl)2、-C(=NR) 1bb NHC 3-6 Cycloalkyl, wherein the alkylene group, alkyl group, alkenyl group, alkynyl group, alkoxy group, carbocyclic group, heterocyclic group, or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0068] In some implementation schemes, R 1a Each element is independently selected from deuterium, halogens, CN, OH, =O, SF5, C(=O)NH2, -C(=O)-N(R) 1bb 2. C(=O)NHC 1-4 Alkyl, C(=O)N(C) 1-4 Alkyl)2、C(=O)NHC 3-6 Cycloalkyl, C(=O)N(C) 3-6 cycloalkyl)2, C(=O)N(C 1-4 Alkyl)(C 3-6 cycloalkyl), C(=O)N(C 1-4 Alkyl groups (4 to 7-membered heterocyclic groups), C(=O)N(C 1-4Alkyl groups (4 to 7-membered heterocyclic groups), C(=S)NHC 1-4 Alkyl, C(=S)N(C 1-4 Alkyl)2、C(=O)OC 1-4 Alkyl, C(=O)C 3-6 Cycloalkyl, C(=S)OC 1-4 Alkyl, C(=O)SC 1- 4-alkyl, -C 0-2 Alkylene-NH2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, -SC 1-4 Alkyl, -C 0-2 Alkylene-C 3-6 cycloalkyl, -C 0-2 Alkylene-4 to 7-membered heterocyclic alkyl, -C 0-2 alkylene-5 to 6-membered heteroaryl, -C(=O)C 1-4 Alkyl group, -C(=O)C 3-6 Cycloalkyl, -C(=O)-4 to 7-membered heterocyclic groups, -C(=S)C 1-4 Alkyl group, -C(=S)C 3-6 Cycloalkyl, -C(=S)-4 to 7-membered heterocycloalkyl, -C(=NR)- 1bb C 1-4 Alkyl group, -C (=NR) 1bb C 3-6 Cycloalkyl, -C (=NR) 1bb )NH2、-C(=NR 1bb NHC 1-4 Alkyl group, -C (=NR) 1bb )N(C 1-4 Alkyl)2、-C(=NR) 1bb NHC 3-6 Cycloalkyl, wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, or heteroaryl group is optionally surrounded by 1 to 4 R groups. k replace;

[0069] In some implementation schemes, R 1a Each element is independently selected from deuterium, F, Cl, Br, CN, OH, =O, NH2, -CH2NH2, -CH(CH3)NH2, -C(CH3)2NH2, SF5, or optionally substituted with 1 to 4 Rs. ksubstituted with one of the following groups: methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, oxetanyl, pyrrolidinyl, pyrazolyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -C(=O)-CH3, -C(=O)-CH2CH3, -C(=O)-CH(CH3)2, -C(=O)-C(CH3)3, -C(=O)-cyclopropyl, -C(=O)-cyclobutyl, -C(=O)-cyclopentyl, -C(=O)-cyclohexyl, -C(=O)-bicyclo[l. l. l]pentyl, -C(=O)-oxetanyl, -C(=O)-tetrahydrofuranyl, -C(=O)-oxepanyl, -C(=O)-azetidinyl, -C(=O)-pyrrolidinyl, -C(=O)-piperidinyl, -C(=O)-piperazinyl, -C(=O)-morpholinyl, -C(=O)NH-azetidinyl, -C(=O)N(methyl)(azetidinyl), -C(=S)-CH3, -C(=S)-CH2CH3, -C(=S)-CH(CH3)2, -C(=S)-C(CH3)3, -C(=S)-cyclopropyl, -C(=S)-cyclobutyl, -C(=S)-cyclopentyl, -C(=S)-cyclohexyl, -C(=S)-bicyclo[l. l. l]pentyl, -C(=S)-oxetanyl, -C(=S)-tetrahydrofuranyl, -C(=S)-oxepanyl, -C(=S)-azetidinyl, -C(=S)-pyrrolidinyl, -C(=S)-piperidinyl, -C(=S)-piperazinyl, -C(=O)NH2, -C(=O)-N(OH)(methyl), -C(=O)-N(methoxy)(methyl), -C(=O)-NHCH3, -C(=O)-NHCH2CH3, -C(=O)-N(CH3)2, -C(=O)-N(CH2CH3)2, -C(=O)-N(CH3)(CH2CH3), -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)SCH3, -C(=O)SCH2CH3, -C(=NH)NH2, -C(=NOH)NH2,

[0070] In some embodiments, R 4a each independently selected from deuterium, halogen, CN, OH, SF5, C(=O)NH2, C(=O)NHC 1-4 alkyl, C(=O)N(C 1-4 alkyl)2, -C 0-4 alkylene-NH2, -C 0-4 alkylene-NHC 1-4 alkyl, -C 0-4alkylene-N(C 1-4 alkyl)2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -SC 1-4 alkyl, -C 0-4 alkylene-C 3-6 cycloalkyl, -C 0-4 alkylene-4- to 7-membered heterocycloalkyl, -C 0-4 alkylene-4- to 7-membered heterocyclyl-C(=O)C 1-4 alkyl, -C(=O)C 1-4 alkyl, -C(=O)C 2-4 alkenyl, -C(=O)C 3-6 cycloalkyl, -C(=O)-4- to 7-membered heterocycloalkyl, -NHC(=O)C 1-4 alkyl, -NHC(=O)C 3-6 cycloalkyl, -S(=O)C 1-4 alkyl, -S(=O)C 3-6 cycloalkyl, -NHS(=O)C 1-4 alkyl, -S(=O)2C 1-4 alkyl, -S(=O)2C 3-6 cycloalkyl, -NHS(=O)2C 1-4 alkyl, -S(=O)2NHC 1-4 alkyl, -P(=O)(C 1-4 alkyl)2, said alkylene, alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl, heterocyclyl, cycloalkyl, heterocycloalkyl being optionally substituted with 1 to 4 R k groups;

[0071] In some embodiments, R 4a each independently is selected from deuterium, F, Cl, Br, CN, OH, SF5, C(=O)NH2or is optionally substituted with 1 to 4 R ksubstituted with one of the following: C(=O)NHCH3, C(=O)NHCH2CH3, C(=O)N(CH3)2, C(=O)N(CH2CH3)2, NH2, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH2CH2CH2CH2NH2, -NHCH3, -CH2NHCH3, -CH2CH2NHCH3, -CH2CH2CH2NHCH3, -CH2CH2CH2CH2NHCH3, -N(CH3)2, -CH2N(CH3)2, -CH2CH2N(CH3)2, -CH2CH2CH2N(CH3)2, -CH2CH2CH2CH2N(CH3)2, methyl, ethyl, propyl, isopropyl, ethenyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, oxetanyl, tetrahydrofuranyl, oxepanyl, azetidinyl, pyrrolidinyl, piperidinyl, -CH2-oxetanyl, -CH2-tetrahydrofuranyl, -CH2-oxepanyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-morpholinyl, -CH2-azetidinyl-C(=O)-CH3, -CH2-azetidinyl-C(=O)-CH2CH3, -CH2-azetidinyl-C(=O)-CH(CH3)2, -CH2-pyrrolidinyl-C(=O)-CH3, -CH2-pyrrolidinyl-C(=O)-CH2CH3, -CH2-pyrrolidinyl-C(=O)-CH(CH3)2, -C(=O)-CH3, -C(=O)-CH2CH3, -C(=O)-CH(CH3)2, -C(=O)-cyclopropyl, -C(=O)-cyclobutyl, -C(=O)-cyclopentyl;

[0072] In some embodiments, R 4aselected from deuterium, F, Cl, Br, CN, OH, SF5, C(=O)NH2, or optionally substituted one of C(=O)NHCH3, C(=O)NHCH2CH3, C(=O)N(CH3)2, C(=O)N(CH2CH3)2, NH2, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH2CH2CH2CH2NH2, -NHCH3, -CH2NHCH3, -CH2CH2NHCH3, -CH2CH2CH2NHCH3, -CH2CH2CH2CH2NHCH3, -N(CH3)2, -CH2N(CH3)2, -CH2CH2N(CH3)2, -CH2CH2CH2N(CH3)2, -CH2CH2CH2CH2N(CH3)2, methyl, ethyl, propyl, isopropyl, ethenyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, oxetanyl, tetrahydrofuranyl, oxepanyl, azetidinyl, pyrrolidinyl, piperidinyl, -CH2-oxetanyl, -CH2-tetrahydrofuranyl, -CH2-oxepanyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-morpholinyl, -CH2-azetidinyl-C(=O)-CH3, -CH2-azetidinyl-C(=O)-CH2CH3, -CH2-azetidinyl-C(=O)-CH(CH3)2, -CH2-pyrrolidinyl-C(=O)-CH3, -CH2-pyrrolidinyl-C(=O)-CH2CH3, -CH2-pyrrolidinyl-C(=O)-CH(CH3)2, -C(=O)-CH3, -C(=O)-CH2CH3, -C(=O)-CH(CH3)2, -C(=O)-cyclopropyl, -C(=O)-cyclobutyl, -C(=O)-cyclopentyl, when substituted, substituted with one to four substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl, ethyl, methoxy, ethoxy, -CH2CN, -CH2OH, -CH2OCH3, -O-cyclopropyl;

[0073] In some embodiments, R 1d , R 1c are each independently selected from H, deuterium, halogen, CN, C 1-6 alkyl, said alkyl is optionally substituted with one to four R k ;

[0074] Alternatively, R 1d , R 1c are directly linked to form C3-6 cycloalkyl or 4- to 7-membered heterocyclyl, said cycloalkyl or heterocyclyl being optionally substituted with 1 to 4 R k substituents;

[0075] In some embodiments, R 1d , R 1c are each independently selected from H, deuterium, halogen, CN, OH, NH2, NHC 1-4 alkyl, said alkyl being optionally substituted with 1 to 4 R k substituents;

[0076] In some embodiments, R 1d , R 1c are directly linked to form a C 3-6 cycloalkyl or 4- to 7-membered heterocyclyl, said cycloalkyl or heterocyclyl being optionally substituted with 1 to 4 R k substituents;

[0077] In some embodiments, R 5 is selected from

[0078] In some embodiments, R 5 is selected from

[0079] In some embodiments, R x1 , R x2 , R 5a , R 6 , R 7 are each independently selected from H, deuterium, halogen, CN, OH, NH2, NHC 1-6 alkyl, N(C 1-6 alkyl)2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -OC 3-7 carbocyclyl, -C 0-4 alkylene-C 3-7 carbocyclyl, -C 0-4 alkylene-4- to 7-membered heterocyclyl, said alkylene, alkyl, alkenyl, alkynyl, carbocyclyl or heterocyclyl being optionally substituted with 1 to 4 R k substituents;

[0080] In some embodiments, R x1 , R x2 , R 5a , R 6 , R 7 are each independently selected from H, deuterium, halogen, CN, OH, NH2, NHC 1-4 alkyl, N(C 1-4alkyl, -OC 1-4 alkyl, -OC 2-4 alkenyl, -OC 2-4 alkynyl, -OC 1-4 alkyl, -SC 1-4 alkyl, -OC 3-6 cycloalkyl, -C 0-4 alkylene-C 3-6 cycloalkyl, -C 0-4 alkylene-4- to 7-membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl being optionally substituted with 1 to 4 R k substituents;

[0081] In some embodiments, R 5a each independently is selected from H, deuterium, halogen, CN, OH, NH2, NHC 1-4 alkyl, N(C 1-4 alkyl, -OC 1-4 alkyl, -OC 2-4 alkenyl, -OC 2-4 alkynyl, -OC 1-4 alkyl, -SC 1-4 alkyl, -OC 3-6 cycloalkyl, 5-membered heteroaryl, 4- to 7-membered heterocyclyl, or C 3-6 cycloalkyl, said alkyl, alkynyl, cycloalkyl, heteroaryl, or heterocyclyl being optionally substituted with 1 to 4 R k substituents; in some embodiments, R 5a each independently is selected from H, deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl, propyl, isopropyl, ethenyl, ethynyl, -CH2-ethynyl, methoxy, ethoxy, -O-cyclopropyl, pyrazolyl, or cyclopropyl, said CH2, methyl, ethyl, propyl, isopropyl, ethenyl, ethynyl, methoxy, ethoxy, pyrazolyl, or cyclopropyl being optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, C 1-4 alkyl, -OC 1-4 alkoxy;

[0082] In some embodiments, R 5aeach independently selected from H, deuterium, F, CI, Br, CN, OH, NH2, methyl, ethyl, propyl, isopropyl, ethynyl, -CH2-ethynyl, methoxy, ethoxy, -O-cyclopropyl, or cyclopropyl, said CH2, methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, ethoxy, or cyclopropyl being optionally substituted with one to four substituents selected from deuterium, F, CI, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl, ethyl, methoxy;

[0083] In some embodiments, R x1 , R x2 , R 6 , R 7 each independently selected from H, deuterium, halogen, CN, OH, C 1-4 alkyl, C 2-4 alkenyl, -OC 1-4 alkyl, -SC 1-4 alkyl, -OC 3-6 cycloalkyl, C 3-6 cycloalkyl, -CH2-C 3-6 cycloalkyl, said alkyl, alkenyl, cycloalkyl being optionally substituted with one to four R k ;

[0084] In some embodiments, R 6 , R 7 each independently selected from H, deuterium, F, CI, Br, CN, OH, methyl, ethyl, ethynyl, methoxy, ethoxy, cyclopropyl, said methyl, ethyl, methoxy, ethoxy, cyclopropyl being optionally substituted with one to four substituents selected from deuterium, halogen, CN, OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, C 1-4 alkyl, C 1-4 alkoxy;

[0085] In some embodiments, R 6 , R 7 each independently selected from H, deuterium, F, CI, Br, CN, OH, methyl, ethyl, ethynyl, methoxy, ethoxy, cyclopropyl, CF3, CHF2, CH2F, CD3, CHD2, CH2D

[0086] In some embodiments, R 5b is selected from H or F, R 5c is selected from H, methyl or CN;

[0087] R 5b is selected from one of the following groups optionally substituted with one to four R k ;1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-7 Carbocyclic group, -C 0-4 Alkylene-C 3-7 Carbocyclic group, -C 0-4 When alkylene-4 to 7-membered heterocyclic groups are involved, R 5c Selected from deuterium, CN, OH, NH2, or optionally coated with 1 to 4 Rs k One of the following groups is substituted: NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-7 Carbocyclic group, -C 0-4 Alkylene-C 3-7 Carbocyclic group, -C 0-4 alkylene-4 to 7-membered heterocyclic groups;

[0088] In some implementation schemes, R 5b When selected from H or F, R 5c Selected from H, methyl, or CN;

[0089] R 5b Selected from 1 to 4 Rs k One of the following groups is substituted: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 cycloalkyl, -C 0-4 Alkylene-C 3-6 cycloalkyl, -C 0-4 When alkylene-4 to 7-membered heterocyclic alkyl, R 5c Selected from deuterium, CN, OH, NH2, or optionally coated with 1 to 4 Rs k One of the following groups is substituted: NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 cycloalkyl, -C 0-4 Alkylene-C3-6 cycloalkyl, -C 0-4 alkylene-4- to 7-membered heterocycloalkyl;

[0090] In some embodiments, R k each independently selected from deuterium, =0, halogen, CN, OH, COOH, NH2, NHC 1-6 alkyl, N(C 1- 6alkyl)2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -O-C 3-6 carbocyclyl, -O-4- to 7-membered heterocyclyl, -NH-C 3-6 carbocyclyl, -N(C 1-6 alkyl)(C 3-6 carbocyclyl), -NH-4- to 7-membered heterocyclyl, -C 1-4 alkylene-C 3-6 carbocyclyl, -C 1-4 alkylene-4- to 7-membered heterocyclyl, C 3-6 carbocyclyl, 4- to 7-membered heterocyclyl, said alkyl, alkylene, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =0, CN, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy;

[0091] In some embodiments, R k each independently selected from deuterium, =0, halogen, CN, OH, COOH, NH2, NHC 1-4 alkyl, N(C 1- 4alkyl)2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -SC 1-4 alkyl, -O-C 3-6 carbocyclyl, -O-4- to 7-membered heterocyclyl, -NH-C 3-6 carbocyclyl, -N(C 1-4 alkyl)(C 3-6 carbocyclyl), -NH-4- to 7-membered heterocyclyl, -C 1-2 alkylene-C 3-6 carbocyclyl, -C 1-2 alkylene-4- to 7-membered heterocyclyl, C 3-6 carbocyclyl, 4- to 7-membered heterocyclyl, said alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with one to four substituents selected from the group consisting of deuterium, halogen, =0, CN, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy, and

[0092] In some embodiments, R k each independently selected from the group consisting of deuterium, =0, F, Cl, Br, I, CN, OH, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, isopropyl, ethenyl, ethynyl, methoxy, ethoxy, methylthio, -0-cyclopropyl, -NH-cyclopropyl, -N(methyl)(cyclopropyl), -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, said methyl, ethyl, isopropyl, ethenyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is optionally substituted with one to four substituents selected from the group consisting of deuterium, halogen, CN, OH, NH2, C 1-4 alkyl, C 1-4 alkoxy, and

[0093] In some embodiments, R k each independently selected from the group consisting of deuterium, F, Cl, Br, I, CN, OH, -CH2OH, CF3, CHF2, CH2F, -CH2CF3, CD3, CHD2, CH2D, CH2CN, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, or optionally substituted one of the following groups: methyl, ethyl, isopropyl, ethenyl, ethynyl, methoxy, ethoxy, -CH2OCH3, methylthio, -0-cyclopropyl, -NH-cyclopropyl, -N(methyl)(cyclopropyl), -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, when substituted, is substituted with one to four substituents selected from the group consisting of deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl, methoxy, ethoxy.

[0094] As a first embodiment of the present application, the above-mentioned compound represented by the general formula (I) or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt, preferably, the compound represented by the general formula (II) is selected from the group consisting of the compounds represented by the general formula (I);

[0095] R 1A selected from the group consisting of R 1 , -cycloA1-R 1B, ring A2, said ring A1or ring A2is selected from 4- to 12-membered heterocyclyl, said ring A1is substituted with 2 to 4 R 1a substituents, said ring A2is substituted with 1 C 3-6 cycloalkyl, said cycloalkyl is optionally substituted with 1 to 4 R k substituents, said ring A2is optionally further substituted with 1 to 4 R 1a substituents;

[0096] R 1B is selected from R 1b , R 1a or -C(=O)-C 3-6 cycloalkyl-R 1bd , said cycloalkyl is optionally substituted with 1 to 4 R k substituents;

[0097] X is selected from O or N(R x );

[0098] X1is selected from CR x1 or N;

[0099] X2is selected from CR x2 or N;

[0100] Y1is selected from N or CR 6 ;

[0101] Y2is selected from N or CR 7 ;

[0102] R x is each independently selected from H, CN, OH, C 1-6 alkyl, C 3-6 cycloalkyl, said alkyl or cycloalkyl is optionally substituted with 1 to 4 R k substituents;

[0103] R 1 is selected from C 2-6 alkynyl, -OCH2-4- to 12-membered heterocyclyl, -N(C 1-6 alkyl)-C 3-6 cycloalkyl, -N(C 1-6 alkyl)-4- to 7-membered heterocycloalkyl, -N(C 3-6 cycloalkyl)2, -N(C 3-6 cycloalkyl)-4- to 7-membered heterocycloalkyl, -C 3-12 carbocyclyl-R 1b , -4- to 12-membered heterocyclyl-R 1b , said alkynyl, alkyl, cycloalkyl, heterocycloalkyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R 1a substituents;

[0104] R 1b is selected from -C0-4 Alkylene-C 3-6 cycloalkyl, -C 1-4 Alkylene-CN, -C 1-4 Alkylene-OC 1-4 Alkyl, C 2-6 alkynyl group, -C(=S)-C 1-6 Alkyl, -C(=S)-C 3-6 Cycloalkyl, -C(=S)-4 to 7-membered heterocyclic groups, -C(=O)-C 3-6 cycloalkyl-R 1ba -C(=O)-C 3-6 Cycloalkyl = C(R) 1d R 1c -C (=NR) 1bb C 1-6 Alkyl group, -C (=NR) 1bb C 3-6 Cycloalkyl, -C (=NR) 1bb NHC 1-6 Alkyl group, -C (=NR) 1bb NHC 3-6 Cycloalkyl, -C(=O)-phenyl-R 1bc -C(=O)-5 to 6-membered heteroaryl-R 1bc -C(=O)-4 to 7-membered heterocyclic alkyl-R 1bc The cycloalkyl, alkyl, heterocycloalkyl, heterocyclic, phenyl, or heteroaryl groups are optionally surrounded by 1 to 4 R groups. k replace;

[0105] R 1ba Each element is independently selected from deuterium, halogens, CN, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Carbocyclic groups, 4- to 7-membered heterocyclic groups, -C 1-4 Alkylene-C 3-6 Carbocyclic group, -C 1-4 Alkyl-4 to 7-membered heterocyclic groups, -OC 3-6 cycloalkyl, The alkylene, alkyl, alkenyl, ynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0106] R 1bb Selected from H, CN, OH, NO2, -SO2C 1-6 Alkyl, -SO2C 3-6 cycloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6cycloalkyl, said alkyl, alkoxy or cycloalkyl being optionally substituted with 1 to 4 R k substituents;

[0107] R 1bc is selected from OH or C 3-6 alkyl, -C(=O)-C 1-4 alkylene-C 3-6 alkyl, -C(=O)-C 1-6 alkyl, -C(=O)-C 3-6 cycloalkyl, said alkyl, alkoxy or cycloalkyl being optionally substituted with 1 to 4 R k substituents;

[0108] R 1bd is selected from OH or C 1-6 alkyl, -C(=O)-C k substituents;

[0109] R 4 is selected from H, C 1-6 alkyl, C 6-10 aryl or 5- to 10-membered heteroaryl, said alkyl, aryl or heteroaryl being optionally substituted with 1 to 4 R 4a substituents;

[0110] R 1a , R 4a each independently is selected from deuterium, halogen, CN, =O, OH, SF5, C(=O)NH2, -C(=O)-N(R 1bb )2, C(=O)NHC 1-6 alkyl, C(=O)N(C 1-6 alkyl)2, C(=O)NHC 3-6 cycloalkyl, C(=O)N(R 1bb )(C 1-6 alkyl), C(=O)NH-4- to 7-membered heterocyclyl, C(=O)N(C 1-6 alkyl)(4- to 7-membered heterocyclyl), C(=O)N(C 1-6 alkyl)(C 1-4 alkylene-C 3-6 cycloalkyl), C(=O)NHC 1-4 alkylene-C 3- 6cycloalkyl), C(=O)N(C 3-6 cycloalkyl)2, C(=O)N(C 1-6 alkyl)(C 3-6 cycloalkyl), C(=S)NHC 1-6 alkyl, C(=S)N(C 1-6 alkyl)2, C(=O)OC 1-6 alkyl, C(=O)C 3-6cycloalkyl, OC(=S)OC 1-6 alkyl, C(=O)SC 1-6 alkyl, -C 0-4 alkylene-NH2, -C 0-4 alkylene-NHC 1-6 alkyl, -C 0-4 alkylene-N(C 1-6 alkyl)2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -SC 1-6 alkyl, -C 0-4 alkylene-C 3-6 cycloalkyl, -C 0-4 alkylene-4- to 7-membered heterocyclyl, -C 0-4 alkylene-4- to 7-membered heterocyclyl-C(=O)C 1-6 alkyl, -C(=O)C 1-6 alkyl, -C(=O)C 2-6 alkenyl, -C(=O)C 3-7 carbocyclyl, -C(=O)-4- to 7-membered heterocyclyl, -C(=S)C 1-6 alkyl, -C(=S)C 2- alkenyl, -C(=S)C 3-7 carbocyclyl, -C(=S)-4- to 7-membered heterocyclyl, -NHC(=O)C 1-6 alkyl, -NHC(=O)C 3-6 cycloalkyl, -S(=O)C 1- alkyl, -S(=O)C 3-7 carbocyclyl, -NHS(=O)C 1-6 alkyl, -S(=O)2C 1-6 alkyl, -S(=O)2C 3-7 carbocyclyl, -NHS(=O)2C 1-6 alkyl, -S(=O)2NHC 1-6 alkyl, -P(=O)(C 1-6 alkyl)2, -C(=NR 1bb )C 1-6 alkyl, -C(=NR 1bb )C 3-6 cycloalkyl, -C(=NR 1bb )NH2, -C(=NR 1bb )N(C 1-6 alkyl)2, -C(=NR 1bb )NHC 1-6 alkyl, -C(=NR 1bb )NHC3-6 cycloalkyl, said alkylene, alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl, heterocyclyl, cycloalkyl is optionally substituted with 1 to 4 R k substituents;

[0111] R 1d , R 1c are each independently selected from the group consisting of H, deuterium, halogen, CN, OH, NH2, NHC 1-6 alkyl, said alkyl is optionally substituted with 1 to 4 R k substituents;

[0112] R 1d , R 1c are directly linked to form a C 3-6 cycloalkyl or 4- to 7-membered heterocyclyl, said cycloalkyl or heterocyclyl is optionally substituted with 1 to 4 R k substituents;

[0113] R 5 is selected from the group consisting of

[0114] R x1 , R x2 , R 5a , R 6 , R 7 are each independently selected from the group consisting of H, deuterium, halogen, CN, OH, NH2, NHC 1-6 alkyl, N(C 1-6 alkyl)2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -OC 3-7 carbocyclyl, -C 0-4 alkylene-C 3-7 carbocyclyl, -C 0-4 alkylene-4- to 7-membered heterocyclyl, said alkylene, alkyl, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k substituents;

[0115] R 5b when R 5c is selected from H, methyl or CN;

[0116] R 5b is selected from one of the following groups optionally substituted with 1 to 4 R k substituents: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -OC 3-7carbocyclyl, -C 0-4 alkylene-C 3-7 carbocyclyl, -C 0-4 alkylene-4- to 7-membered heterocyclyl, R 5c is selected from deuterium, CN, OH, NH2or optionally substituted by 1 to 4 R k is selected from one of the following groups, which is optionally substituted by 1 to 4 R 1-6 alkyl, N(C 1-6 alkyl)2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -OC 3-7 carbocyclyl, -C 0-4 alkylene-C 3-7 carbocyclyl, -C 0-4 alkylene-4- to 7-membered heterocyclyl;

[0117] R k each independently selected from deuterium, =0, halogen, CN, OH, COOH, NH2, NHC 1-6 alkyl, N(C 1-6 alkyl)2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -O-C 3-6 carbocyclyl, -O-4- to 7-membered heterocyclyl, -NH-C 3-6 carbocyclyl, -N(C 1-6 alkyl)(C 3-6 carbocyclyl), -NH-4- to 7-membered heterocyclyl, -C 1-4 alkylene-C 3-6 carbocyclyl, -C 1-4 alkylene-4- to 7-membered heterocyclyl, C 3-6 carbocyclyl, 4- to 7-membered heterocyclyl, said alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 substituents selected from deuterium, halogen, =0, CN, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy.

[0118] as a second embodiment of the present application, the above-mentioned compounds of general formula (I) or general formula (II) or racemates, stereoisomers, tautomers, pharmaceutically acceptable salts,

[0119] R 1 is selected from C 2-5alkynyl, -OCH2-4- to 7-membered heterocycloalkyl, -N(C 1-6 alkyl)-C 3-6 cycloalkyl, -N(C 1-6 alkyl)-4- to 7-membered heterocycloalkyl, -N(C 3-6 cycloalkyl)2, -N(C 3-6 cycloalkyl)-4- to 7-membered heterocycloalkyl, -C 3-6 cycloalkyl-R 1b , -C 5-10 bridged cycloalkyl-R 1b , -C 6-12 fused cycloalkyl-R 1b , -C 6-12 spirocycloalkyl-R 1b , -4- to 7-membered heterocycloalkyl-R 1b , -6- to 10-membered bridged heterocycloalkyl-R 1b , -6- to 12-membered fused heterocycloalkyl-R 1b , -6- to 12-membered spiroheterocycloalkyl-R 1b , which alkynyl, alkyl, cycloalkyl, heterocycloalkyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R 1a ;

[0120] ring A2is selected from 4- to 8-membered heterocyclyl, which ring A2is substituted with 1 C 3-6 cycloalkyl, which cycloalkyl is optionally substituted with 1 to 4 R k , which ring A2is optionally further substituted with 1 to 4 R 1a ;

[0121] R 1ba is each independently selected from deuterium, halogen, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, -C 1-4 alkylene-C 3-6 cycloalkyl, -C 1-4 alkylene-4- to 7-membered heterocycloalkyl, -O-C 3-6 cycloalkyl, which alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocycloalkyl, heteroaryl is optionally substituted with 1 to 4 R k ;

[0122] R 1bb is selected from H, CN, OH, NO2, -SO2C 1-4 alkyl, -SO2C 3-6 cycloalkyl, C 1-4 alkyl, C 1-4 alkoxy, C3-6 cycloalkyl, said alkyl, alkoxy or cycloalkyl being optionally substituted with 1 to 4 R k substituents;

[0123] R 1bc is selected from the group consisting of C 3-6 cycloalkyl, phenyl, -C 1-4 alkylene-C 3-6 cycloalkyl, -C(=O)-C 1-4 alkyl, -C(=O)-C 3-6 cycloalkyl, said alkylene, alkyl, cycloalkyl or phenyl being optionally substituted with 1 to 4 R k substituents;

[0124] R 4 is selected from H or is optionally substituted with 1 to 4 R 4a substituents; C 1-6 alkyl, phenyl, benzo 4-6 carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl or 8- to 10-membered annulated heteroaryl;

[0125] R 1a , R 4a are each independently selected from the group consisting of deuterium, halogen, CN, OH, =O, SF5, C(=O)NH2, -C(=O)-N(R 1bb )2, C(=O)NHC 1-4 alkyl, C(=O)N(C 1-4 alkyl)2, C(=O)NHC 3-6 cycloalkyl, C(=O)N(C 3-6 cycloalkyl)2, C(=O)N(C 1-4 alkyl)(C 3-6 cycloalkyl), C(=O)N(R 1bb )(C 1-4 alkyl), C(=O)N(C 1-4 alkyl)(C 1-4 alkylene-C 3-6 cycloalkyl), C(=O)NH(C 1-4 alkylene-C 3-6 cycloalkyl), C(=O)NH-4- to 7-membered heterocyclyl-, C(=O)N(C 1-4 alkyl)(4- to 7-membered heterocyclyl), C(=S)NHC 1-4 alkyl, C(=S)N(C 1-4 alkyl)2, C(=O)OC 1-4 alkyl, C(=O)C 3-6 cycloalkyl, C(=S)OC 1-4 alkyl, C(=O)SC 1-4 alkyl, -C 0-4alkylene-NH2, -C 0-4 alkylene-NHC 1-4 alkyl, -C 0-4 alkylene-N(C 1-4 alkyl)2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -SC 1-4 alkyl, -C 0-4 alkylene-C 3-6 cycloalkyl, -C 0-4 alkylene-4- to 7-membered heterocyclyl, -C 0-4 alkylene-4- to 7-membered heterocyclyl-C(=O)C 1-4 alkyl, -C(=O)C 1- 4alkyl, -C(=O)C 2-4 alkenyl, -C(=O)C 3-7 carbocyclyl, -C(=O)-4- to 7-membered heterocyclyl, -C(=S)C 1-4 alkyl, -C(=S)C 2-4 alkenyl, -C(=S)C 3-7 carbocyclyl, -C(=S)-4- to 7-membered heterocyclyl, -NHC(=O)C 1-4 alkyl, -NHC(=O)C 3-6 cycloalkyl, -S(=O)C 1-4 alkyl, -S(=O)C 3-7 carbocyclyl, -NHS(=O)C 1-4 alkyl, -S(=O)2C 1-4 alkyl, -S(=O)2C 3-7 carbocyclyl, -NHS(=O)2C 1-4 alkyl, -S(=O)2NHC 1-4 alkyl, -P(=O)(C 1-4 alkyl)2, -C(=NR 1bb )C 1-4 alkyl, -C(=NR 1bb )C 3-6 cycloalkyl, -C(=NR 1bb )NHC 1-4 alkyl, -C(=NR 1bb )NH2, -C(=NR 1bb )N(C 1-4 alkyl)2, -C(=NR 1bb )NHC 3-6 cycloalkyl, said alkylene, alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl, heterocyclyl, cycloalkyl being optionally substituted with 1 to 4 R k groups;

[0126] R 1d R 1c Each element is independently selected from H, deuterium, halogens, CN, and C. 1-4 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0127] As an option, R 1d R 1c Direct connection forms C 3-6 Cycloalkyl or 4- to 7-membered heterocyclic groups, wherein the cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0128] R x1 R x2 R 5a R 6 R 7 Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 cycloalkyl, -C 0-4 Alkylene-C 3-6 cycloalkyl, -C 0-4 Alkylene-4 to 7-membered heterocyclic alkylene, wherein the alkylene, alkyl, alkenyl, ynyl, cycloalkyl or heterocyclic alkylene is optionally surrounded by 1 to 4 R groups. k replace;

[0129] R 5b When selected from H or F, R 5c Selected from H, methyl, or CN;

[0130] R 5b Selected from 1 to 4 Rs k One of the following groups is substituted: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 cycloalkyl, -C 0-4 Alkylene-C 3-6 cycloalkyl, -C 0-4 When alkylene-4 to 7-membered heterocyclic alkyl, R 5c Selected from deuterium, CN, OH, NH2, or optionally coated with 1 to 4 Rs ksubstituted by one of the following groups: NHC 1-4 alkyl, N(C 1-4 alkyl)2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -SC 1-4 alkyl, -OC 3-6 cycloalkyl, -C 0-4 alkylene-C 3-6 cycloalkyl, -C 0-4 alkylene-4- to 7-membered heterocycloalkyl;

[0131] R k each independently selected from the group consisting of deuterium, =0, halogen, CN, OH, COOH, NH2, NHC 1-4 alkyl, N(C 1-4 alkyl)2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -SC 1-4 alkyl, -O-C 3-6 carbocyclyl, -O-4- to 7-membered heterocyclyl, -NH-C 3-6 carbocyclyl, -N(C 1-4 alkyl)(C 3-6 carbocyclyl), -NH-4- to 7-membered heterocyclyl, -C 1-2 alkylene-C 3-6 carbocyclyl, -C 1-2 alkylene-4- to 7-membered heterocyclyl, C 3-6 carbocyclyl, 4- to 7-membered heterocyclyl, said alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 substituents selected from the group consisting of deuterium, halogen, =0, CN, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy;

[0132] the remaining groups are defined as in the first embodiment of the present application.

[0133] as a third embodiment of the present application, the above-mentioned compounds of general formula (I) or general formula (II) or racemates, stereoisomers, tautomers, pharmaceutically acceptable salts,

[0134] X is selected from O or NH;

[0135] R 1 selected from the group consisting of optionally substituted by 1 to 4 R 1asubstituted one of ethynyl, propynyl, propargyl, -OCH2-oxetanyl, -OCH2-tetrahydrofuranyl, -OCH2-oxepanyl, -OCH2-azetidinyl, -OCH2-pyrrolidinyl, -OCH2-piperidinyl, -OCH2-piperazinyl, -N(CH3)-azetidinyl, -N(CH3)-pyrrolidinyl, -N(CH3)-piperidinyl, -N(CH3)-piperazinyl, -N(CH3)-morpholinyl, -N(CH3)-oxetanyl, -N(CH3)-tetrahydrofuranyl, -N(CH3)-oxepanyl, -N(CH2CH3)-azetidinyl, -N(CH2CH3)-pyrrolidinyl, -N(CH2CH3)-piperidinyl, -N(CH2CH3)-piperazinyl, -N(CH2CH3)-morpholinyl, -N(CH2CH3)-oxetanyl, -N(CH2CH3)-tetrahydrofuranyl, -N(CH2CH3)-oxepanyl, -N(cyclopropyl)-azetidinyl, -N(cyclopropyl)-pyrrolidinyl, -N(cyclopropyl)-piperidinyl, -N(cyclopropyl)-piperazinyl, -N(cyclopropyl)-morpholinyl, -N(cyclopropyl)-oxetanyl, -N(cyclopropyl)-tetrahydrofuranyl, -N(cyclopropyl)-oxepanyl, -N(cyclopropyl)2,

[0136] ring A2is selected from optionally substituted one of C 4a substituted one of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, said ring A2is further substituted with 1 C 3-6 cycloalkyl;

[0137] R 4 selected from H or optionally substituted one of C 4a substituted one of C 1-4 alkyl, phenyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, pyrazolyl, thiadiazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl;

[0138] R 1a each independently selected from deuterium, halogen, CN, OH, =O, SF5, C(=O)NH2, C(=O)NHC 1-4 alkyl, C(=O)N(C 1-4 alkyl)2, C(=O)NHC 3-6 cycloalkyl, -C(=O)-N(R 1bb )2, C(=O)N(C 3-6 cycloalkyl)2, C(=O)N(C 1-4 alkyl)(C 3-6alkyl, C(=O)NHC(=O)alkyl, C(=O)N(C(=O)alkyl)2, C(=O)NHC(=O)OC 1-4 alkyl, C(=O)NHC(=O)alkyl, C(=O)N(C(=O)alkyl)2, C(=O)NHC(=O)OC 1-4 alkyl, C(=O)NHC(=O)alkyl, C(=O)N(C(=O)alkyl)2, C(=O)NHC(=O)OC 1-4 alkyl, C(=O)NHC(=O)alkyl, C(=O)N(C(=O)alkyl)2, C(=O)NHC(=O)OC 1-4 alkyl, C(=O)NHC(=O)alkyl, C(=O)N(C(=O)alkyl)2, C(=O)NHC(=O)OC 1-4 alkyl, C(=O)NHC(=O)alkyl, C(=O)N(C(=O)alkyl)2, C(=O)NHC(=O)OC 3-6 alkyl, C(=O)NHC(=O)alkyl, C(=O)N(C(=O)alkyl)2, C(=O)NHC(=O)OC 1-4 alkyl, C(=O)NHC(=O)alkyl, C(=O)N(C(=O)alkyl)2, C(=O)NHC(=O)OC 1-4 alkyl, C(=O)NHC(=O)alkyl, C(=O)N(C(=O)alkyl)2, C(=O)NHC(=O)OC 0-2 alkyl, C(=O)NHC(=O)alkyl, C(=O)N(C(=O)alkyl)2, C(=O)NHC(=O)OC 1-4 alkyl, C(=O)NHC(=O)alkyl, C(=O)N(C(=O)alkyl)2, C(=O)NHC(=O)OC 2-4 alkyl, C(=O)NHC(=O)alkyl, C(=O)N(C(=O)alkyl)2, C(=O)NHC(=O)OC 2-4 alkyl, C(=O)NHC(=O)alkyl, C(=O)N(C(=O)alkyl)2, C(=O)NHC(=O)OC 1-4 alkyl, C(=O)NHC(=O)alkyl, C(=O)N(C(=O)alkyl)2, C(=O)NHC(=O)OC 1-4 alkyl, C(=O)NHC(=O)alkyl, C(=O)N(C(=O)alkyl)2, C(=O)NHC(=O)OC 0-2 alkyl, C(=O)NHC(=O)alkyl, C(=O)N(C(=O)alkyl)2, C(=O)NHC(=O)OC 3-6 alkyl, C(=O)NHC(=O)alkyl, C(=O)N(C(=O)alkyl)2, C(=O)NHC(=O)OC 0-2 alkyl, C(=O)NHC(=O)alkyl, C(=O)N(C(=O)alkyl)2, C(=O)NHC(=O)OC 0-2 alkyl, C(=O)NHC(=O)alkyl, C(=O)N(C(=O)alkyl)2, C(=O)NHC(=O)OC 1-4 alkyl, C(=O)NHC(=O)alkyl, C(=O)N(C(=O)alkyl)2, C(=O)NHC(=O)OC 3-6 alkyl, C(=O)NHC(=O)alkyl, C(=O)N(C(=O)alkyl)2, C(=O)NHC(=O)OC 1-4 alkyl, C(=O)NHC(=O)alkyl, C(=O)N(C(=O)alkyl)2, C(=O)NHC(=O)OC 3-6 alkyl, C(=O)NHC(=O)alkyl, C(=O)N(C(=O)alkyl)2, C(=O)NHC(=O)OC 1bb alkyl, C(=O)NHC(=O)alkyl, C(=O)N(C(=O)alkyl)2, C(=O)NHC(=O)OC 1-4 alkyl, C(=O)NHC(=O)alkyl, C(=O)N(C(=O)alkyl)2, C(=O)NHC(=O)OC 1bb alkyl, C(=O)NHC(=O)alkyl, C(=O)N(C(=O)alkyl)2, C(=O)NHC(=O)OC 3-6 alkyl, C(=O)NHC(=O)alkyl, C(=O)N(C(=O)alkyl)2, C(=O)NHC(=O)OC 1bb alkyl, C(=O)NHC(=O)alkyl, C(=O)N(C(=O)alkyl)2, C(=O)NHC(=O)OC 1bb alkyl, C(=O)NHC(=O)alkyl, C(=O)N(C(=O)alkyl)2, C(=O)NHC(=O)OC 1-4 alkyl, C(=O)NHC(=O)alkyl, C(=O)N(C(=O)alkyl)2, C(=O)NHC(=O)OC 1bb alkyl, C(=O)NHC(=O)alkyl, C(=O)N(C(=O)alkyl)2, C(=O)NHC(=O)OC 1-4 alkyl, C(=O)NHC(=O)alkyl, C(=O)N(C(=O)alkyl)2, C(=O)NHC(=O)OC 1bb alkyl, C(=O)NHC(=O)alkyl, C(=O)N(C(=O)alkyl)2, C(=O)NHC(=O)OC 3-6 alkyl, C(=O)NHC(=O)alkyl, C(=O)N(C(=O)alkyl)2, C(=O)NHC(=O)OC k alkyl, C(=O)NHC(=O)alkyl, C(=O)N(C(=O)alkyl)2, C(=O)NHC(=O)OC

[0139] R 1b alkyl, C(=O)NHC(=O)alkyl, C(=O)N(C(=O)alkyl)2, C(=O)NHC(=O)OC ksubstituted one of the following: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2CN, -CH2OCH3, -CH2OCH2CH3, ethynyl, -CH2-ethynyl, propynyl, -C(=S)-CH3, -C(=S)-CH2CH3, -C(=S)-CH(CH3)2, -C(=S)-C(CH3)3, -C(=S)-cyclopropyl, -C(=S)-cyclobutyl, -C(=S)-cyclopentyl, -C(=S)-cyclohexyl, -C(=S)-bicyclo[l. l. l]pentyl, -C(=S)-oxetanyl, -C(=S)-tetrahydrofuranyl, -C(=S)-oxepanyl, -C(=S)-azetidinyl, -C(=S)-pyrrolidinyl, -C(=S)-piperidinyl, -C(=S)-piperazinyl, -C(=O)-cyclopropyl-R 1ba , -C(=O)-cyclobutyl-R 1ba , -C(=O)-cyclopentyl-R 1ba , -C(=O)-cyclohexyl-R 1ba , -C(=O)-cyclopropyl=C(R 1d R 1c ), -C(=O)-cyclobutyl=C(R 1d R 1c ), -C(=O)-cyclopentyl=C(R 1d R 1c ), -C(=O)-cyclohexyl=C(R 1d R 1c ), -C(=NR 1bb )-CH3, -C(=NR 1bb )-CH2CH3, -C(=NR 1bb )-cyclopropyl, -C(=NR 1bb )-cyclobutyl, -C(=NR 1bb )NHCH3, C(=NR 1bb )NH-cyclopropyl, -C(=O)-phenyl-R 1bc , -C(=O)-pyrazolyl-R 1bc , -C(=O)-triazolyl-R 1bc , -C(=O)-imidazolyl-R 1bc ,

[0140] R 4a each independently is selected from the group consisting of deuterium, halogen, CN, OH, SF5, C(=O)NH2, C(=O)NHC 1-4 alkyl, C(=O)N(C 1-4 alkyl)2, -C0-4 Alkylene -NH2, -C 0-4 Alkylene-NHC 1-4 Alkyl, -C 0-4 Alkylene-N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1- 4-alkoxy, -SC 1-4 Alkyl, -C 0-4 Alkylene-C 3-6 cycloalkyl, -C 0-4 Alkylene-4 to 7-membered heterocyclic alkyl, -C 0-4 Alkylene-4 to 7-membered heterocyclic-C(=O)C 1-4 Alkyl group, -C(=O)C 1-4 Alkyl group, -C(=O)C 2-4 alkenyl, -C(=O)C 3-6 Cycloalkyl, -C(=O)-4 to 7-membered heterocycloalkyl, -NHC(=O)C 1-4 Alkyl group, -NHC(=O)C 3-6 cycloalkyl, -S(=O)C 1-4 Alkyl group, -S(=O)C 3-6 cycloalkyl, -NHS(=O)C 1-4 Alkyl group, -S(=O)2C 1-4 Alkyl group, -S(=O)2C 3-6 cycloalkyl, -NHS(=O)2C 1-4 Alkyl group, -S(=O)2NHC 1-4 Alkyl, -P(=O)(C 1-4 Alkyl)2, wherein the alkylene, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic, heterocyclic, cycloalkyl, or heterocyclic alkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0141] R 5a Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 cycloalkyl or C 3-6 Cycloalkyl, 5-membered heteroaryl, 4-7-membered heterocyclic, wherein the alkyl, alkynyl, cycloalkyl, heteroaryl or heterocyclic group is optionally surrounded by 1 to 4 R groups. k Replace; R x1 Rx2 R 6 R 7 each independently is selected from the group consisting of H, deuterium, halogen, CN, OH, C 1-4 alkyl, C 2-4 alkynyl, -OC 1-4 alkyl, -SC 1-4 alkyl, -OC 3-6 cycloalkyl, C 3-6 cycloalkyl, -CH2-C 3-6 cycloalkyl, said alkyl, alkynyl, cycloalkyl being optionally substituted with 1 to 4 R k substituents;

[0142] the remaining group definitions are identical with the first or second embodiment of the present application.

[0143] As a fourth embodiment of the present application, the above-mentioned compounds of general formula (I) or general formula (II) or racemates, stereoisomers, tautomers, pharmaceutically acceptable salts,

[0144] X1is selected from N;

[0145] X2is selected from CH;

[0146] R 6 R 7 each independently is selected from the group consisting of H, deuterium, F, Cl, Br, CN, OH, methyl, ethyl, ethynyl, methoxy, ethoxy, cyclopropyl, said methyl, ethyl, methoxy, ethoxy, cyclopropyl being optionally substituted with 1 to 4 substituents selected from the group consisting of deuterium, halogen, CN, OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, C 1-4 alkyl, C 1-4 alkoxy;

[0147] R 1a each independently is selected from the group consisting of deuterium, F, Cl, Br, CN, OH, =0, NH2, -CH2NH2, -CH(CH3)NH2, -C(CH3)2NH2, SF5 or optionally substituted with 1 to 4 R ksubstituted with one of the following groups: methyl, ethyl, propyl, isopropyl, ethenyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, oxetanyl, pyrrolidinyl, pyrazolyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -C(=0)-CH3, -C(=0)-CH2CH3, -C(=0)-CH(CH3)2, -C(=0)-C(CH3)3, -C(=0)-cyclopropyl, -C(=0)-cyclobutyl, -C(=0)-cyclopentyl, -C(=0)-cyclohexyl, -C(=0)-bicyclo[l. l. l]pentyl, -C(=0)-oxetanyl, -C(=0)-tetrahydrofuranyl, -C(=0)-oxepanyl, -C(=0)-azetidinyl, -C(=0)-pyrrolidinyl, -C(=0)-piperidinyl, -C(=0)-piperazinyl, -C(=0)-morpholinyl, -C(=0)-NH-azetidinyl, -C(=0)-N(methyl)-azetidinyl, -C(=S)-CH3, -C(=S)-CH2CH3, -C(=S)-CH(CH3)2, -C(=S)-C(CH3)3, -C(=S)-cyclopropyl, -C(=S)-cyclobutyl, -C(=S)-cyclopentyl, -C(=S)-cyclohexyl, -C(=S)-bicyclo[l. l. l]pentyl, -C(=S)-oxetanyl, -C(=S)-tetrahydrofuranyl, -C(=S)-oxepanyl, -C(=S)-azetidinyl, -C(=S)-pyrrolidinyl, -C(=S)-piperidinyl, -C(=S)-piperazinyl, -C(=0)NH2, -C(=0)-N(OH)(methyl), -C(=0)-NHCH3, -C(=0)-NHCH2CH3, -C(=0)-N(CH3)2, -C(=0)-N(CH2CH3)2, -C(=0)-N(CH3)(CH2CH3), -C(=0)OCH3, -C(=0)OCH2CH3, -C(=0)SCH3, -C(=0)SCH2CH3, -C(=NH)NH2, -C(=NOH)NH2, -C(=NH)N(methyl)2,

[0148] R 1bSelected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2CN, -CH2OCH3, -CH2OCH2CH3, ethynyl, -CH2-ethynyl, propynyl, -C(=S)-CH3, -C(=S)-CH2CH3, -C(=S)-CH(CH3)2, -C(=S)-C(CH3) 3. -C(=S)-cyclopropyl, -C(=S)-cyclobutyl, -C(=S)-cyclopentyl, -C(=S)-cyclohexyl, -C(=S)-bicyclo[1.1.1]pentyl, -C(=S)-oxacyclobutyl, -C(=S)-tetrahydrofuranyl, -C(=S)-oxacyclohexyl, -C(=S)-azacyclobutyl, -C(=S)-pyrrolidinyl, -C(=S)-piperidinyl, -C(=S)-piperazinyl,

[0149] R 1ba The group selected from deuterium, F, Cl, Br, CN, methyl, ethyl, vinyl, -CH2-vinyl, ethynyl, cyclopropyl, -O-cyclopropyl, phenyl, wherein the CH2, methyl, ethyl, vinyl, ethynyl, cyclopropyl, or phenyl group is optionally selected from 1 to 4 of deuterium, halogen, CN, OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0150] R 1bc Selected from 1 to 4 Rs k The substitution may be made with one of the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -C(=O)-CH3, -C(=O)-CH2CH3, -C(=O)-CH(CH3)2, -C(=O)-C(CH3)3, -C(=O)-cyclopropyl, -C(=O)-cyclobutyl, -C(=O)-cyclopentyl;

[0151] R 1bd Selected from OH, methoxy, ethoxy, and propoxy, wherein the methoxy, ethoxy, and propoxy groups are optionally surrounded by 1 to 4 R groups. k replace;

[0152] R 4a Each element is independently selected from deuterium, F, Cl, Br, CN, OH, SF5, C(=O)NH2, or arbitrarily coated with 1 to 4 Rs. ksubstituted with one of the following groups: C(=O)NHCH3, C(=O)NHCH2CH3, C(=O)N(CH3)2, C(=O)N(CH2CH3)2, NH2, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH2CH2CH2CH2NH2, -NHCH3, -CH2NHCH3, -CH2CH2NHCH3, -CH2CH2CH2NHCH3, -CH2CH2CH2CH2NHCH3, -N(CH3)2, -CH2N(CH3)2, -CH2CH2N(CH3)2, -CH2CH2CH2N(CH3)2, -CH2CH2CH2CH2N(CH3)2, methyl, ethyl, propyl, isopropyl, ethenyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, oxetanyl, tetrahydrofuranyl, oxepanyl, azetidinyl, pyrrolidinyl, piperidinyl, -CH2-oxetanyl, -CH2-tetrahydrofuranyl, -CH2-oxepanyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-morpholinyl, -CH2-azetidinyl-C(=O)-CH3, -CH2-azetidinyl-C(=O)-CH2CH3, -CH2-azetidinyl-C(=O)-CH(CH3)2, -CH2-pyrrolidinyl-C(=O)-CH3, -CH2-pyrrolidinyl-C(=O)-CH2CH3, -CH2-pyrrolidinyl-C(=O)-CH(CH3)2, -C(=O)-CH3, -C(=O)-CH2CH3, -C(=O)-CH(CH3)2, -C(=O)-cyclopropyl, -C(=O)-cyclobutyl, -C(=O)-cyclopentyl;

[0153] R 5a each independently selected from H, deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl, propyl, isopropyl, ethenyl, ethynyl, -CH2-ethynyl, methoxy, ethoxy, -O-cyclopropyl, pyrazolyl, or cyclopropyl, said CH2, methyl, ethyl, propyl, isopropyl, ethenyl, ethynyl, methoxy, ethoxy, pyrazolyl, or cyclopropyl being optionally substituted with one to four substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, C 1-4 alkyl, C 1-4 alkoxy, said CH2, methyl, ethyl, propyl, isopropyl, ethenyl, ethynyl, methoxy, ethoxy, pyrazolyl, or cyclopropyl being optionally substituted with one to four substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, C

[0154] R keach independently selected from the group consisting of deuterium, =0, F, CI, Br, I, CN, OH, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, ethynyl, methoxy, ethoxy, methylthio, -0-cyclopropyl, -NH-cyclopropyl, -N(methyl)(cyclopropyl), -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, said methyl, ethyl, isopropyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl being optionally substituted with one to four substituents selected from the group consisting of deuterium, halogen, CN, OH, NH2, C 1-4 alkyl, C 1-4 alkoxy;

[0155] Preferably, R k each independently selected from the group consisting of deuterium, F, CI, Br, I, CN, OH, -CH2OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, -CH2CF3, CH2CN, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, or optionally substituted one of the following groups: methyl, ethyl, isopropyl, ethynyl, methoxy, ethoxy, -CH2OCH3, methylthio, -0-cyclopropyl, -NH-cyclopropyl, -N(methyl)(cyclopropyl), -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, when substituted, with one to four substituents selected from the group consisting of deuterium, F, CI, Br, CN, OH, NH2, methyl, ethyl, methoxy, ethoxy;

[0156] the remaining groups being defined as in the first, second or third embodiment of the application.

[0157] As a fifth embodiment of the application, the above-mentioned compounds of general formula (I) or general formula (II) or racemates, stereoisomers, tautomers, pharmaceutically acceptable salts,

[0158] R 1 selected from the group consisting of

[0159] ring A2is selected from the group consisting of

[0160] R 1aeach independently selected from deuterium, F, Cl, Br, CN, OH, NH2, -CH2NH2, -CH(CH3)NH2, -C(CH3)2NH2, SF5, or optionally substituted one of the following groups: methyl, ethyl, propyl, isopropyl, ethenyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, when substituted, with 1 to 4 substituents selected from deuterium, halogen, CN, OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl, ethyl, methoxy, ethoxy, -O-cyclopropyl;

[0161] R 1aa each independently selected from H or optionally substituted one of the following groups: oxetanyl, oxetanyl, pyrrolidinyl, pyrazolyl, -C(=O)-CH3, -C(=O)-CH2CH3, -C(=O)-CH(CH3)2, -C(=O)-C(CH3)3, -C(=O)-cyclopropyl, -C(=O)-cyclobutyl, -C(=O)-cyclopentyl, -C(=O)-cyclohexyl, -C(=O)-bicyclo[l. l. l]pentyl, -C(=O)-oxetanyl, -C(=O)-tetrahydrofuranyl, -C(=O)-oxepanyl, -C(=O)-azetidinyl, -C(=O)-pyrrolidinyl, -C(=O)-piperidinyl, -C(=O)-piperazinyl, -C(=S)-CH3, -C(=S)-CH2CH3, -C(=S)-CH(CH3)2, -C(=S)-C(CH3)3, -C(=S)-cyclopropyl, -C(=S)-cyclobutyl, -C(=S)-cyclopentyl, -C(=S)-cyclohexyl, -C(=S)-bicyclo[l. l. l]pentyl, -C(=S)-oxetanyl, -C(=S)-tetrahydrofuranyl, -C(=S)-oxepanyl, -C(=S)-azetidinyl, -C(=S)-pyrrolidinyl, -C(=S)-piperidinyl, -C(=S)-piperazinyl, -C(=O)NH2, -C(=O)-N(OH)(CH3), -C(=O)-N(OCH3)(CH3), -C(=O)-NHCH3, -C(=O)-NHCH2CH3, -C(=O)-N(CH3)2, -C(=O)-N(CH2CH3)2, -C(=O)-N(CH3)(CH2CH3), -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)SCH3, -C(=O)SCH2CH3, when substituted, is substituted with one to four substituents selected from the group consisting of deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, -CH2CF3, CH2CN, CD3, CHD2, CH2D, CH2CH2F, -OCH2CH2F, -OCH2CH2OCH3, methyl, ethyl, isopropyl, methoxy, ethoxy, -CH2CN, -CH2OH, -CH2OCH3, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, N(CH3)2, vinyl, when substituted, is substituted with one to four substituents selected from the group consisting of deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, -CH2CF3, CH2CN, CD3, CHD2, CH2D, CH2CH2F, -OCH2CH2F, -OCH2CH2OCH3, methyl, ethyl, isopropyl, methoxy, ethoxy, -CH2CN, -CH2OH, -CH2OCH3, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, N(CH3)2, vinyl,

[0162] R 1ba is selected from the group consisting of deuterium, F, Cl, Br, CN, methyl, ethyl, vinyl, -CH2-vinyl, ethynyl, cyclopropyl, -O-cyclopropyl, phenyl, said CH2, methyl, ethyl, vinyl, ethynyl, cyclopropyl or phenyl optionally substituted with one to four substituents selected from the group consisting of deuterium, halogen, CN, OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl, ethyl, methoxy, ethoxy;

[0163] R 1bc is selected from the group consisting of optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -C(=O)-CH3, -C(=O)-CH2CH3, -C(=O)-CH(CH3)2, -C(=O)-C(CH3)3, -C(=O)-cyclopropyl, -C(=O)-cyclobutyl, -C(=O)-cyclopentyl, when substituted, is substituted with one to four substituents selected from the group consisting of deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl, ethyl, methoxy, ethoxy, -CH2CN, -CH2OH, -CH2OCH3, -O-cyclopropyl, vinyl, when substituted, is substituted with one to four substituents selected from the group consisting of deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, -CH2CF3, CH2CN, CD3, CHD2, CH2D, CH2CH2F, -OCH2CH2F, -OCH2CH2OCH3, methyl, ethyl, isopropyl, methoxy, ethoxy, -CH2CN, -CH2OH, -CH2OCH3, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, N(CH3)2, vinyl,

[0164] R 1bd is selected from the group consisting of OH, methoxy, ethoxy, propoxy, said methoxy, ethoxy, propoxy optionally substituted with one to four substituents selected from the group consisting of deuterium, F, Cl, Br, CN, OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, -OCF3, -OCHF2, -OCH2F, -OCD3, -OCHD2, -OCH2D, methyl, ethyl, methoxy, ethoxy or cyclopropyl;

[0165] R 1beis selected from optionally substituted one of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, when substituted, with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl, ethyl, methoxy, ethoxy, -CH2CN, -CH2OH, -CH2OCH3, -O-cyclopropyl, ethenyl, ethynyl, is selected from optionally substituted one of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, when substituted, with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl, ethyl, methoxy, ethoxy, -CH2CN, -CH2OH, -CH2OCH3, -O-cyclopropyl, ethenyl, ethynyl,

[0166] R 4 is selected from H,

[0167] R 4a is selected from deuterium, F, Cl, Br, CN, OH, SF5, C(=O)NH2, or optionally substituted one of C(=O)NHCH3, C(=O)NHCH2CH3, C(=O)N(CH3)2, C(=O)N(CH2CH3)2, NH2, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH2CH2CH2CH2NH2, -NHCH3, -CH2NHCH3, -CH2CH2NHCH3, -CH2CH2CH2NHCH3, -CH2CH2CH2CH2NHCH3, -N(CH3)2, -CH2N(CH3)2, -CH2CH2N(CH3)2, -CH2CH2CH2N(CH3)2, -CH2CH2CH2CH2N(CH3)2, methyl, ethyl, propyl, isopropyl, ethenyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, oxetanyl, tetrahydrofuranyl, oxepanyl, azetidinyl, pyrrolidinyl, piperidinyl, -CH2-oxetanyl, -CH2-tetrahydrofuranyl, -CH2-oxepanyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-morpholinyl, -CH2-azetidinyl, -CH2-azetidinyl-C(=O)-CH3, -CH2-azetidinyl-C(=O)-CH2CH3, -CH2-azetidinyl-C(=O)-CH(CH3)2, -CH2-pyrrolidinyl-C(=O)-CH3, -CH2-pyrrolidinyl-C(=O)-CH2CH3, -CH2-pyrrolidinyl-C(=O)-CH(CH3)2, -C(=O)-CH3, -C(=O)-CH2CH3, -C(=O)-CH(CH3)2, -C(=O)-cyclopropyl, -C(=O)-cyclobutyl, -C(=O)-cyclopentyl, when substituted, are substituted with one to four substituents selected from the group consisting of deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl, ethyl, methoxy, ethoxy, -CH2CN, -CH2OH, -CH2OCH3, -O-cyclopropyl;

[0168] R 5 is selected from the group consisting of

[0169] R 5a each independently is selected from the group consisting of H, deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl, propyl, isopropyl, ethenyl, ethynyl, -CH2-ethynyl, methoxy, ethoxy, -O-cyclopropyl or cyclopropyl, pyrazolyl, said CH2, methyl, ethyl, propyl, isopropyl, ethenyl, ethynyl, methoxy, ethoxy or cyclopropyl, pyrazolyl being optionally substituted with one to four substituents selected from the group consisting of deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl, ethyl, methoxy;

[0170] R 6 , R 7 each independently is selected from the group consisting of H, deuterium, F, Cl, Br, CN, OH, methyl, ethyl, ethynyl, methoxy, ethoxy, cyclopropyl, CF3, CHF2, CH2F, CD3, CHD2, CH2D;

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

[0172] the remaining group definitions are the same as in the first, second, third or fourth embodiment of the present application.

[0173] As a sixth embodiment of the present application, the above-mentioned compound represented by the general formula (II-a) or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt,

[0174] Y1is selected from CH, Y2is selected from CH;

[0175] X1is selected from N;

[0176] X2is selected from CH;

[0177] X is selected from O or NH;

[0178] m2is selected from 0, 1, 2 or 3;

[0179] is selected from

[0180] R 1be is selected from one of the following groups optionally substituted with 1 to 4 R k ; preferably, R 3-6 is selected from one of the following groups optionally substituted with 1 to 4 R 1be ; preferably, R 1be is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, when substituted, with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl, ethyl, methoxy, ethoxy, -CH2CN, -CH2OH, -CH2OCH3, -O-cyclopropyl, ethenyl, ; more preferably, R 1be is selected from cyclopropyl, cyclobutyl;

[0181] R 1aa are each independently selected from H or one of the following groups optionally substituted with 1 to 4 R k ; preferably, R 1bb is selected from one of the following groups: C(=O)NH2, -C(=O)-N(R 1-4 )2, C(=O)NHC 1-4 alkyl, C(=O)N(C 3-6 alkyl)2, C(=O)NHC 3-6 cycloalkyl, C(=O)N(C 1-4 alkyl)(C 3-6 cycloalkyl), C(=O)N(R 1bb )(C 1-4 alkyl), C(=O)N(C 1-4 alkyl)(C 1-2 alkylene-C 3-6 cycloalkyl), C(=O)NH(C 1-2 alkylene-C 3-6C(=O)NH-4 to 7 membered heterocyclyl, C(=O)N(C 1-4 alkyl)2, C(=O)OC 1-4 alkyl, C(=S)NHC 1-4 alkyl)2, C(=O)OC 1-4 alkyl, C(=O)C 3-6 alkyl, C(=S)OC 1-4 alkyl, C(=O)SC 1-4 alkyl, -C(=O)C 1-4 alkyl, -C(=O)C 3-6 alkyl, -C(=S)C 1-4 alkyl, -C(=S)C 3-6 alkyl, -C(=S)-4 to 7 membered heterocycloalkyl, -C(=NR 1bb )C 1-4 alkyl, -C(=NR 1bb )C 3-6 alkyl, -C(=NR 1bb )NHC 1-4 alkyl, -C(=NR 1bb )NH2, -C(=NR 1bb )N(C 1-4 alkyl)2, -C(=NR 1bb )NHC 3-6 alkyl;

[0182] R 4 is selected from H,

[0183] R 5 is selected from

[0184] R 5a are each independently selected from H, deuterium, halogen, CN, OH, NH2, NHC 1-4 alkyl, N(C 1-4 alkyl)2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -SC 1-4 alkyl, -OC 3-6 cycloalkyl or C 3-6 cycloalkyl, heteroaryl or 4-7 membered heterocyclyl, said alkyl, alkynyl, cycloalkyl, heteroaryl or heterocyclyl being optionally substituted with 1 to 4 R k substituents;

[0185] R 5aEach of the following is independently selected from H, deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, -CH2-ethynyl, methoxy, ethoxy, -O-cyclopropyl, pyrazolyl, or cyclopropyl, wherein CH2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, pyrazolyl, or cyclopropyl is optionally selected from 1 to 4 of deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups; more preferably, R 5a Each is independently selected from H, deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl, methoxy, ethoxy, CF3, CHF2, CH2F, CD3, CHD2, CH2D;

[0186] The definitions of the remaining functional groups are the same as those in the first, second, third, fourth, or fifth embodiments of the present invention.

[0187] This invention relates to compounds as shown below, or their racemates, stereoisomers, tautomers, or pharmaceutically acceptable salts, wherein the compound is selected from one of the structures shown in Table E.

[0188] Table E

[0189] The present application relates to a pharmaceutical composition comprising any of the above-mentioned compounds, racemates, stereoisomers, tautomers, pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.

[0190] The present application relates to a pharmaceutical composition comprising a therapeutically effective amount of any of the above-mentioned compounds of the present application, racemates, stereoisomers, tautomers, pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.

[0191] In some embodiments, the pharmaceutical composition of the present application can be in the form of a unit dosage formulation (the amount of the main drug in the unit dosage formulation is also referred to as "formulation specification").

[0192] An "effective amount" or "therapeutically effective amount" as described herein refers to an amount of a compound disclosed herein that, when administered to a subject for treating a disease or condition (e.g., a solid tumor (e.g., breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, uterine cancer, gastric cancer, colorectal cancer)) will alleviate, to some extent, one or more of the signs or symptoms of the disease or condition. In some embodiments, the result is a reduction and / or alleviation of signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of a compound disclosed herein that elicits a clinically significant decrease 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, 2-500 mg, 3-500 mg, 4-500 mg, 5-500 mg, 6-500 mg, 10-500 mg, 20-500 mg, 25-500 mg, 30-500 mg, 40-500 mg, 50-500 mg, 60-500 mg, 70-500 mg, 75-500 mg, 80-500 mg, 90-500 mg, 100-500 mg, 125-500 mg, 150-500 mg, 200-500 mg, 250-500 mg, 300-500 mg, 400-500 mg, 5-400 mg, 10-400 mg, 20-400 mg, 25-400 mg, 30-400 mg, 40-400 mg, 50-400 mg, 60-400 mg, 70-400 mg, 75-400 mg, 80-400 mg, 90-400 mg, 100-400 mg, 125-400 mg, 150-400 mg, 200-400 mg, 250-400 mg, 300-400 mg, 1-300 mg, 2-300 mg, 5-300 mg, 10-300 mg, 20-300 mg, 25-300 mg, 30-300 mg, 40-300 mg, 50-300 mg, 60-300 mg, 70-300 mg, 75-300 mg, 80-300 mg, 90-300 mg, 100-300 mg, 125-300 mg, 150-300 mg, 200-300 mg, 250-300 mg, 1-200 mg, 2-200 mg, 5-200 mg, 10-200 mg, 20-200 mg, 25-200 mg, 30-200 mg, 40-200 mg, 50-200 mg, 60-200 mg, 70-200 mg, 75-200 mg, 80-200 mg, 90-200 mg, 100-200 mg, 125-200 mg, 150-200 mg, 80-1000 mg, 80-800 mg.

[0193] In some embodiments, the pharmaceutical composition comprises, 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, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, 840 mg of the compound of the present application or a stereoisomer, a pharmaceutically acceptable salt, or a co-crystal thereof.

[0194] A method for treating a disease in a mammal, the method comprising administering to the subject a therapeutically effective amount, preferably 1-1500 mg, of the compound of the present application or a stereoisomer, a pharmaceutically acceptable salt, or a co-crystal thereof, the disease preferably being a solid tumor (e.g., breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, uterine cancer, gastric cancer, colorectal cancer).

[0195] A method for treating or alleviating a disease in a mammal, the method comprising administering to the subject a pharmaceutical compound of the present application or a stereoisomer, a pharmaceutically acceptable salt, or a co-crystal thereof in a daily dose of 1-1000 mg / day, the daily dose can be in a single dose or in divided doses, in some embodiments, the daily dose comprises, 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, 25-400 mg / day, 50-400 mg / day, 100-400 mg / day, 200-400 mg / day, in some embodiments, the daily dose comprises, but is not limited to, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 80 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 160 mg / day, 200 mg / day, 300 mg / day, 320 mg / day, 400 mg / day, 480 mg / day, 600 mg / day, 640 mg / day, 800 mg / day, 1000 mg / day.

[0196] The present application relates to a kit which can include a composition in single or multiple dose form, comprising a compound of the present application or a stereoisomer, a pharmaceutically acceptable salt or a co-crystal thereof, a racemate, a stereoisomer, a tautomer, a pharmaceutically acceptable salt of the compound of the present application in the same amount as in the above pharmaceutical composition.

[0197] The present application relates to the use of any of the above-mentioned compounds or a racemate, a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of solid tumors (e.g. breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, uterine cancer, gastric cancer, colorectal cancer).

[0198] The present application relates to the use of the above-mentioned pharmaceutical composition for the manufacture of a medicament for the treatment of solid tumors (e.g. breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, uterine cancer, gastric cancer, colorectal cancer).

[0199] The amount of the compound of the present application, a racemate, a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof is converted into the form of free base in each case.

[0200] "Formulation strength" means the weight of the main drug contained in each dose, tablet or other unit formulation.

[0201] Unless otherwise specified, the terms used in the specification and claims have the following meanings.

[0202] The compounds of the present application include a racemate, a stereoisomer, a tautomer, a deuterated compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof.

[0203] The carbon, hydrogen, oxygen, sulfur, nitrogen, phosphorus, F, Cl, Br, I and the like involved in the groups and compounds described in the present application include their isotopes, i.e. the carbon, hydrogen, oxygen, sulfur, nitrogen, phosphorus, F, Cl, Br, I and the like involved in the groups and compounds described in the present application are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 11 C、 12 C、 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super-heavy hydrogen), the isotopes of oxygen include 15 O、 16 O、 17 O and 18 O, the isotopes of sulfur include 32 S、 33 S、 34 S、 35 S and 36 S, the isotopes of nitrogen include 13 N,14 N and 15 N, isotopes of fluorine include 17 F, 18 F and 19 F, isotopes of chlorine include 35 Cl, 36 Cl and 37 Cl, isotopes of bromine include 79 Br and 81 Br, isotopes of iodine include 123 I, 125 I, isotopes of phosphorus include 31 P, 32 P.

[0204] "CN" means cyano.

[0205] "Halogen" means F, Cl, Br, or I.

[0206] "Halogen substituted" means F, Cl, Br, or I substitution, including but not limited to substitution with 1 to 10 substituents selected from F, Cl, Br, or I, 1 to 6 substituents selected from F, Cl, Br, or I, 1 to 4 substituents selected from F, Cl, Br, or I. "Halogen substituted" is abbreviated as "halo".

[0207] "Alkyl" means a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group, including but not limited to alkyl of 1 to 20 carbon atoms, alkyl of 1 to 8 carbon atoms, alkyl of 1 to 6 carbon atoms, alkyl of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, n-hexyl, and various branched isomers thereof; alkyl can be monovalent, divalent, trivalent, or tetravalent.

[0208] "Alkylene" means a substituted or unsubstituted straight chain and branched chain divalent saturated hydrocarbon radical, 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, etc.

[0209] "Cycloalkyl" means a substituted or unsubstituted saturated carbocyclic hydrocarbon radical, typically having from 3 to 12 carbon atoms, cycloalkyl can be monocyclic, fused, bridged, and spirocyclic. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl fused cyclobutyl, cyclobutyl spiro cyclobutyl, adamantyl, etc. Cycloalkyl can be monovalent, divalent, trivalent, or tetravalent.

[0210] "Heterocycloalkyl" refers to substituted or unsubstituted saturated heteroatom-containing cyclic hydrocarbon groups, including but not limited to 3 to 12 atoms, 3 to 8 atoms, containing 1 to 3 heteroatoms selected from N, O, S, or Se, the C, N, S of the ring of the heterocycloalkyl group can be oxidized to various oxidation states. Heterocycloalkyl groups can be monocyclic, annulated, bridged, and spirocyclic. Heterocycloalkyl groups can be attached at a heteroatom or carbon atom, non-limiting examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl, dioxanyl, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinanyl, morpholinyl, hexahydropyrimidinyl, piperazinyl, Heterocycloalkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0211] "Alkenyl" refers to substituted or unsubstituted straight chain and branched chain unsaturated hydrocarbon groups having at least one, and usually one, two, or three carbon-carbon double bonds, the main chain including but not limited to 2 to 10, 2 to 6, or 2 to 4 carbon atoms, examples of alkenyl groups include but are not limited to ethenyl, 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, and the like; alkenyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0212] "Alkynyl" refers to substituted or unsubstituted straight chain and branched chain unsaturated hydrocarbon groups having at least one, and usually one, two, or three carbon-carbon triple bonds, the main chain including 2 to 10 carbon atoms, including but not limited to 2 to 6 carbon atoms in the main chain, 2 to 4 carbon atoms in the main chain, 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-nonyl, 3-nonyl, 1-decynyl, 4-decynyl, and the like; alkynyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0213] "Alkoxy" means a substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, sec-butyloxy, t-butyloxy, n-pentyloxy, n-hexyloxy, cyclopropyloxy, and cyclobutyloxy.

[0214] "Carbocyclyl" or "carbocyclic" means a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3- to 8-membered monocyclic, 4- to 12-membered bicyclic, 10- to 15-membered tricyclic, 12- to 18-membered tetracyclic ring system, which can be attached to the rest of the molecule at a carbon atom of the ring, and which optionally is mono-, bi-, or spiro-cyclic. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-l-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, benzene, naphthalene, indane, tetralin, biphenyl, and the like. "Carbocyclyl" or "carbocyclic" can be monovalent, divalent, trivalent, or tetravalent.

[0215] "Heterocyclyl" or "heterocyclic" means a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3- to 8-membered monocyclic, 4- to 12-membered bicyclic, or 10- to 15-membered tricyclic, 12- to 18-membered tetracyclic ring system, which contains 1 or more (including, but not limited to, 2, 3, 4, or 5) heteroatoms selected from N, O, S, or Se, and which optionally is mono-, bi-, or spiro-cyclic. The ring of the heterocyclyl group optionally has one or more (including, but not limited to, 2, 3, 4, or 5) ring carbon atoms that are oxidized, such as to form a carbonyl group. The heterocyclyl group can be attached to the rest of the molecule at a heteroatom or carbon atom of the ring. Non-limiting examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxananyl, azepanyl, pyridyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dihydrothiopyranyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecanyl, azadamantanyl, oxaspiro[3.3]heptanyl, "Heterocyclyl" or "heterocycle" can be monovalent, divalent, trivalent, or tetravalent.

[0216] "Spirocycle" or "spirocyclyl" refers to a polycyclic group in which the rings share one atom (referred to as the spiro atom) between the rings, which can be substituted or unsubstituted, the number of ring atoms in the spiro system includes, but is not limited to, 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more rings can contain 0 or more (including but not limited to 1, 2, 3, or 4) double bonds, and optionally can contain 0 to 5 heteroatoms or heteroatom containing groups (including but not limited to N, S(=O)n or O, where n is 0, 1, or 2). n Non-limiting examples include: "Spirocycle" or "spirocyclyl" can be monovalent, divalent, trivalent, or tetravalent.

[0217] "Fused cycle" or "fused cyclyl" refers to a polycyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, wherein one or more rings can contain 0 or more (including but not limited to 1, 2, 3, or 4) double bonds, and can be substituted or unsubstituted, each ring in the fused system can contain 0 to 5 heteroatoms or heteroatom containing groups (including but not limited to N, S(=O)n or O, where n is 0, 1, or 2). The number of ring atoms in the fused system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, 5 to 10. Non-limiting examples include: n "Fused cycle" or "fused cyclyl" can be monovalent, divalent, trivalent, or tetravalent. "Fused cycle" or "fused cyclyl" can be monovalent, divalent, trivalent, or tetravalent.

[0218] "Bridged cycle" or "bridged cyclyl" refers to a polycyclic group containing any two non-adjacent atoms, which can be substituted or unsubstituted, can contain 0 or more double bonds, any ring in the bridged system can contain 0 to 5 heteroatoms or heteroatom containing groups (including but not limited to N, S(=O)n or O, where n is 0, 1, 2). The number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include: "Fused cycle" or "fused cyclyl" can be monovalent, divalent, trivalent, or tetravalent.

[0219] "Carbospirocycle", "spirocarbocyclyl", "spirocarbocyclyl", or "carbospirocyclyl" refers to a "spirocycle" in which the ring system consists only of carbon atoms.

[0220] "Carbospirocycle", "spirocarbocyclyl", "spirocarbocyclyl", or "carbospirocyclyl" refers to a "spirocycle" in which the ring system consists only of carbon atoms.

[0221] "Carbospirocycle", "spirocarbocyclyl", "spirocarbocyclyl", or "carbospirocyclyl" refers to a "spirocycle" in which the ring system consists only of carbon atoms.

[0222] "Heteromonocyclic," "monocyclic heterocyclyl," or "monocyclic heterocyclyl group" means a "heterocyclyl" or "heterocycle" that is a monocyclic ring system.

[0223] "Heteroannelated," "heteroannelated ring," "annelated heterocyclyl," or "annelated heterocyclyl group" means an "annelated" ring that contains a heteroatom.

[0224] "Heterospiro," "heterospirocyclyl," "spirocyclyl heterocyclyl," or "spiroheterocyclyl group" means a "spirocyclic" ring that contains a heteroatom.

[0225] "Heterobridged," "heterobridged ring," "bridged heterocyclyl," or "bridged heterocyclyl group" means a "bridged" ring that contains a heteroatom.

[0226] "Aryl" or "aromatic ring" means a substituted or unsubstituted aromatic hydrocarbon group having a single ring or multiple condensed rings constituting a ring system having aromatic character. The number of rings in the ring system or the size of the aryl group is not critical to the scope of the present application, and aryl groups can contain, for example, 6-18, 6-12, or 6-10 carbon atoms. The aryl group can be fused to a saturated or unsaturated carbocyclic ring, wherein the ring that is attached to the parent structure is an aryl ring. Non-limiting examples include phenyl, naphthyl, indanyl, indenyl, fluorenyl, and the like. "Aryl" or "aromatic ring" can be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent, or tetravalent, the point of attachment is on the aryl ring.

[0227] "Heteroaryl" or "heteroaromatic ring" means a substituted or unsubstituted aromatic hydrocarbon group that contains from 1 to 5 atoms selected from a heteroatom or a group containing a heteroatom (including, but not limited to, N, O, S(=O)n, or Se(=O)n, n is 0, 1, 2), and the ring system contains from 5 to 15, 5 to 10, or 5 to 6 ring atoms. The atoms C, N, S in the ring are optionally oxidized (i.e., C(=O), NO, S(=O)n, Se(=O)n, n is 1, 2). Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furanyl, thiophenyl, selenophenyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, benzopyrazolyl, benzimidazolyl, benzopyridazinyl, pyrrolopyridyl, pyridinone, and the like. The heteroaryl ring can be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring that is attached to the parent structure is an aryl ring. Non-limiting examples include: Heteroaryl groups appearing herein are defined in accordance with the present definition. Heteroaryl groups can be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent, or tetravalent, the point of attachment is on the ring having aromatic character.

[0228] "Substituted" or "substitution" means substituted with 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, thio, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged cyclyl, spirocyclyl, annelated cyclyl, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, carboxylate, -(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, n are 0, 1, or 2), arylthio, thiocarbonyl, silyl, or -NR b R c , etc., wherein R b and R c are independently selected from the group consisting of H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethylsulfonyl, and, optionally, R b and R c may form a five or six membered cycloalkyl or heterocyclyl ring, and R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged cyclyl, spirocyclyl, or annelated cyclyl.

[0229] "1 to X substituents selected from" means 1, 2, 3,... X substituents selected from the group consisting of the substituents listed. For example, "1 to 4 R k substituents" means 1, 2, 3, or 4 R k substituents. For example, "1 to 5 substituents selected from" means 1, 2, 3, 4, or 5 substituents selected from the group consisting of the substituents listed. For example, "hetero bridged cyclyl optionally substituted with 1 to 4 substituents selected from H or F" means hetero bridged cyclyl optionally substituted with 1, 2, 3, or 4 substituents selected from H or F.

[0230] A ring of X-Y members (X, Y are integers, and 3 < X < Y, X < Y < 20 is selected from any integer between 4 and 20) includes a ring of X, X+1, X+2, X+3, X+4,... Y members. A ring includes a heterocyclic ring, a carbocyclic ring, an aromatic ring, an aryl group, a heteroaryl group, a cycloalkyl group, a heteromonocyclic ring, a heteroannular ring, a heterospiro ring, or a heterobridged ring. For example, "4-7 membered heteromonocyclic ring" means a 4-, 5-, 6-, or 7-membered heteromonocyclic ring, and "5-10 membered heteroannular ring" means a 5-, 6-, 7-, 8-, 9-, or 10-membered heteroannular ring.

[0231] C x-y A carbocyclic ring (including an aryl group, a cycloalkyl group, a monocyclic carbocyclic ring, a spiro carbocyclic ring, an annular carbocyclic ring, or a bridged carbocyclic ring) includes a ring of C x , C x+1 , C x+2 , C x+3 , C x+4 ... C y members (x is an integer, and 3 < x < y, y is selected from any integer between 4 and 20), for example. For example, a "C3-C6 cycloalkyl group" means a C3, C4, C5, or C6 cycloalkyl group. 3-6 A cycloalkyl group" means a C3, C4, C5, or C6 cycloalkyl group.

[0232] When a group has one or more connectable sites, any one or more sites of the group can be connected to other groups by a chemical bond. When the connection mode of the chemical bond is not fixed, and there is a hydrogen atom at the connectable site, the number of H atoms at the site will be reduced to the corresponding valence number of groups corresponding to the number of connected chemical bonds. For example indicates that any connectable site on the piperidyl group can be connected to other groups by 1 chemical bond, at least including These 4 connection modes, even if the H atoms are drawn on the -N-, also include For example indicates that the R group on the piperidyl group can be located on C or N, at least including For example, the general fragment is When X is selected from CH2or NH, it indicates that the R group on the general fragment can be located on C or X, and when X is selected from CH2, the general fragment can be When X is selected from NH, the general fragment can be

[0233] Unless otherwise specified, a wedge-shaped solid line bond and a wedge-shaped dashed line bond indicate the absolute configuration of a stereocenter, and a straight solid line bond and a straight dashed line bond indicate the relative configuration of a stereocenter.

[0234] When the linking groups recited do not specify the direction of attachment, the direction of attachment includes both left-to-right and right-to-left reading order, e.g., A-L-B, L selected from -M-W-, includes A-M-W-B and A-W-M-B.

[0235] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and thus such phrases include instances where the event or circumstance occurs and instances where it does not. For example, "an alkyl group optionally substituted with F" means that the alkyl group can or can 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.

[0236] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" means a salt of a compound of the present application that retains the biological effectiveness and properties of the free acids or free bases and is obtained by reaction of the free acid with a non-toxic inorganic or organic base, or the free base with a non-toxic inorganic or organic acid.

[0237] "Pharmaceutical composition" means a mixture of one or more compounds of the present application, or stereoisomers, tautomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, and other chemical components, where the "other chemical components" means pharmaceutically acceptable carriers, excipients, and / or one or more other therapeutic or active agents.

[0238] "Carrier" means a material that does not itself induce the production of antibodies to it, and it does not have a significant stimulating effect on the biological activity and properties of the given compound.

[0239] "Prodrug" means a compound of the present application that can be converted in vivo into a biologically active compound. The prodrugs of the present application are prepared by modifying the amino or carboxyl groups of the compounds of the present application in such a way that the modifications can be easily removed in vivo to give the parent compound. When the prodrugs of the present application are administered to a mammalian subject, the prodrugs are cleaved to form the free amino or carboxyl groups.

[0240] "Co-crystal" means a crystal formed by the combination of an active pharmaceutical ingredient (API) and a co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, wherein the pure state of the API and the CCF are both solid at room temperature, and there is a fixed stoichiometric ratio between the components. Co-crystals are a kind of multi-component crystals, including binary co-crystals formed between two neutral solids, and multi-component co-crystals formed between a neutral solid and a salt or a solvate.

[0241] "Stereoisomer" means isomers that have the same molecular formula but differ in the arrangement of atoms in space. Stereoisomers include enantiomers, diastereomers, and conformers.

[0242] "tautomer" refers to isomers of a functional group that result from the rapid movement of an atom in a molecule between two positions, such as keto-enol isomerism and amide-imidol isomerism.

[0243] "animal" refers to mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

[0244] "IC 50 " is the concentration of a drug or inhibitor required to inhibit a specified biological process (or a component of that process such as an enzyme, receptor, cell, etc.) by half. DETAILED DESCRIPTION

[0245] The following examples illustrate the technical solutions of the present application, but the protection scope of the present application includes but is not limited to this.

[0246] The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in units of 10 -6 (ppm). The NMR is measured by a nuclear magnetic instrument (Bruker Avance III 400 and Bruker Avance 300), and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS);

[0247] The MS is measured by (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0248] The HPLC is measured by using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100x4.6mm, 3.5μM);

[0249] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, and the specification of the silica gel plate used in the thin layer chromatography (TLC) is 0.15mm-0.20mm, and the specification of the thin layer chromatography separation and purification product is 0.4mm-0.5mm;

[0250] The column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0251] Synthetic method one:

[0252] The general formula (Z1) and the general formula (Z2) undergo substitution reaction under alkaline conditions to obtain the corresponding general formula (Z3), the general formula (Z3) and benzyl mercaptan undergo coupling reaction under the catalysis of a metal catalyst to obtain the corresponding general formula (Z4), the general formula (Z4) and 1,3-dichloro-5,5-dimethylhydantoin (cas: 118-52-5) undergo reaction under the catalysis of an acid to obtain the corresponding general formula and the general formula (Z5), the general formula (Z5) and the general formula (Z6) undergo sulfonylation reaction to obtain the corresponding general formula (Z7), the general formula (Z7) and the general formula (Z8) undergo substitution reaction under alkaline conditions and heating to obtain the corresponding general formula (I').

[0253] To accomplish the objectives of the present application, the compounds used in the reactions described herein are prepared from commercially available chemicals and / or compounds described in chemical literature according to organic synthesis techniques known to those skilled in the art. The "commercially available chemicals" are obtained from standard commercial sources, including Shanghai Aldrin Biochemical Technology Co., Ltd., Shanghai McLean Biotechnology Co., Ltd., Sigma-Aldrich, Alfa Aesar (China) Chemical Co., Ltd., TCI (Shanghai) Chemical Industry Development Co., Ltd., Angene Chemicals, Shanghai Titan Scientific Co., Ltd., Kelong Chemical, Bailingwei Technology Co., Ltd., etc.

[0254] Example 1: Preparation of compound 1

[0255] Step 1: Preparation of compound 1c

[0256] 1a (50 mg, 0.12 mmol, synthesis method refers to the patent: WO2024148280) was dissolved in dimethyl sulfoxide (1.5 mL) and added to a 10 mL sealed tube, 1b (54 mg, 0.24 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.91 mmol) were added. The reaction system was replaced with nitrogen three times, and stirred at 110°C for 8 hours. Diluted with water (20 mL), extracted with ethyl acetate (10 mL x 3), the separated organic layer was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated and purified by silica gel column chromatography to obtain 1c (50 mg, yield 66%)

[0257] LCMS m / z = 608.1 [M-H] - ;

[0258] Step 2: Preparation of compound 1

[0259] Dissolve 1c (50 mg, 0.08 mmol) in dichloromethane (1 mL), drop trifluoroacetic acid (56 mg, 0.49 mmol) in ice bath. Stir at room temperature for 12 hours. Dilute with water (5 mL), extract with ethyl acetate (5 mL x 3); adjust the pH of the aqueous phase to 8-9 with saturated sodium bicarbonate solution, then extract with ethyl acetate (5 mL x 3) again, dry the combined organic phase over anhydrous sodium sulfate and filter, concentrate the filtrate and prepare by pre-HPLC (Instrument: waters 2767 preparative liquid phase; color column: SUNFIRE® Prep C18 (19 mm x 250 mm); preparative chromatography conditions: mobile phase A: acetonitrile, mobile phase B: water (containing 50 mM ammonium bicarbonate)) to obtain compound 1 (9 mg, yield 23%).

[0260] LCMS m / z = 510.2 [M+H] + ;

[0261] Example 2: Preparation of compound 2

[0262] First step: Preparation of compound 2c

[0263] Dissolve 1a in dimethyl sulfoxide (1.5 mL) into a 10 mL sealed tube, add 2b (54 mg, 0.24 mmol) and N, N-diisopropyl ethylamine (0.15 mL, 0.91 mmol). Replace the reaction system with nitrogen three times, stir at 110°C for 8 hours. Dilute with water (20 mL), extract with ethyl acetate (10 mL x 3), dry the separated organic layer over anhydrous sodium sulfate, filter, concentrate the filtrate and purify by silica gel column chromatography to obtain 2c (50 mg, yield 66.2%).

[0264] Second step: Preparation of compound 2

[0265] Dissolve 2c (50 mg, 0.08 mmol) in dichloromethane (1 mL), drop trifluoroacetic acid (56 mg, 0.49 mmol) in ice bath. Stir at room temperature for 12 hours. Dilute with water (5 mL), extract with ethyl acetate (5 mL x 3); adjust the pH of the aqueous phase to 8-9 with saturated sodium bicarbonate solution, then extract with ethyl acetate (5 mL x 3) again, dry the combined organic phase over anhydrous sodium sulfate and filter, concentrate the filtrate and prepare by pre-HPLC (Instrument: waters 2767 preparative liquid phase; color column: SUNFIRE® Prep C18 (19 mm x 250 mm); preparative chromatography conditions: mobile phase A: acetonitrile, mobile phase B: water (containing 50 mM ammonium bicarbonate)) to obtain compound 2 (11 mg, yield 28%).

[0266] LCMS m / z = 510.1 [M+H]+

[0267] Example 3: Preparation of compound 3

[0268] First step: synthesis of 3A

[0269] DMF (50 mL) was added to Boc-L-cyclopropylglycine (5 g, 23.23 mmol), HATU (17.67 g, 46.46 mmol) and DIPEA (9.01 g, 69.69 mmol) were added, after stirring at room temperature for 10 min, dibenzylamine (6.87 g, 34.84 mmol) was added, and the reaction was carried out at room temperature for 18 hours. After adding water to the reaction solution, it was extracted with ethyl acetate three times, the combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-10 / 1) to obtain 3A (3.7 g, yield: 40%).

[0270] LCMS m / z = 395.1 [M+1] +

[0271] Second step: synthesis of 3B

[0272] 3A (3.2 g, 8.11 mmol) was dissolved in 15 mL of dichloromethane, 10 mL of trifluoroacetic acid was added, and stirring was carried out at room temperature for 2 hours. After the reaction solution was concentrated under reduced pressure, dichloromethane was added, washed with saturated aqueous sodium bicarbonate solution twice, dried over anhydrous sodium sulfate, and concentrated to obtain 3B (2.35 g).

[0273] LCMS m / z = 295.1 [M+1] +

[0274] Third step: synthesis of 3C

[0275] 3B (2.5 g, 8.49 mmol) was dissolved in 20 mL of tetrahydrofuran, and 10M borane-dimethyl sulfide solution (8.49 mL, 84.9 mmol) was slowly added under ice bath stirring, and the reaction was carried out at 25°C for 48 hours. The reaction was cooled in an ice bath, quenched with 10% hydrochloric acid, and the pH was adjusted to basic with 50% aqueous sodium hydroxide solution. After stirring the reaction at 70°C for 3 hours, it was cooled to room temperature, water and ethyl acetate were added, stirred, and separated into layers, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol (V / V) = 1 / 0-20 / 1) to obtain 3C (1.4 g, yield: 59%).

[0276] Fourth step: synthesis of 3D

[0277] Into a reaction flask was added methyl D-lactate (0.65 g, 6.24 mmol) and dichloromethane (10 mL), triflic anhydride (1.81 g, 6.43 mmol) was added dropwise at about 0 °C, 2,6-lutidine (0.77 g, 7.18 mmol) in dichloromethane (3 mL) was added after 10 min at 0 °C, the reaction solution was stirred at 0 °C for 10 min, and then used in the next step.

[0278] Fifth step: synthesis of 3E

[0279] A solution of 3C (1.4 g, 4.99 mmol) and triethylamine (0.81 g, 7.98 mmol) in dichloromethane (5 mL) was added to the reaction solution of 3D from the previous step, and stirred in an ice bath for 2 h and at room temperature overnight. Dichloromethane and saturated aqueous sodium bicarbonate solution were added, and after stirring, the layers were separated. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-20 / 1) to give 3E (0.86 g, yield: 47%).

[0280] Sixth step: synthesis of 3F

[0281] 3E (0.26 g, 0.71 mmol) was dissolved in 6 mL of ethanol, 10 wt% palladium-carbon (0.1 g) and concentrated hydrochloric acid (12 N, 0.095 mL) were added, and the hydrogen was replaced three times. After stirring at room temperature for 3 h, diatomite was filtered, and concentrated to give 3F (0.19 g).

[0282] LCMS m / z = 277.1 [M+1] +

[0283] Seventh step: synthesis of 3G

[0284] 3F (0.19 g, 0.69 mmol) was dissolved in 5 mL of ethanol, p-toluenesulfonic acid (0.048 g, 0.28 mmol) was added, and stirred at 85 °C overnight. The reaction solution was cooled to room temperature, concentrated, and then water was added. The organic phase was extracted twice with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (V / V) = 1 / 0-15 / 1) to give 3G (0.12 g, yield: 71%).

[0285] LCMS m / z = 245.2 [M+1] +

[0286] Eighth step: synthesis of 3H

[0287] Lithium tetrahydroaluminate (56.93 mg, 1.5 mmol) was added into 5 mL of tetrahydrofuran, a solution of 3G (0.12 g, 0.5 mmol) in 3 mL of tetrahydrofuran was added into the flask, stirred at room temperature for 1 hour, and stirred at 80 °C for 2 hours. The reaction solution was cooled to room temperature, 50 microliters of water was added to quench the reaction, 50 microliters of 1 N aqueous sodium hydroxide solution was added, and then 150 microliters of water was added, stirred for 10 minutes, filtered, the filter cake was washed twice with tetrahydrofuran, and the filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 3H (0.11 g).

[0288] LCMS m / z = 231.1 [M+1] +

[0289] Ninth step: synthesis of 3I

[0290] 3H (0.11 g, 0.48 mmol) was dissolved in dichloromethane (3 mL), 1 N sodium hydroxide (0.038 g, 0.96 mmol) and di-tert-butyl dicarbonate (0.12 g, 0.53 mmol) were added, and the reaction was carried out at room temperature for 16 h. The reaction was quenched by adding water, extracted twice with dichloromethane, the combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-20 / 1) to obtain 3I (92 mg, yield: 58%).

[0291] Tenth step: synthesis of 3J

[0292] 3I (92 mg, 0.28 mmol) was dissolved in 3 mL of methanol, 10 wt% palladium-carbon (40 mg) was added, and the reaction was carried out under hydrogen atmosphere for 2 hours at room temperature. The reaction was filtered through diatomite, and the filtrate was concentrated to obtain 3J (60 mg).

[0293] LCMS m / z = 241.1 [M+1] +

[0294] Eleventh step: synthesis of 3K

[0295] 3J (54 mg, 0.22 mmol) was dissolved in 3 mL of DMSO, 1a (60 mg, 0.15 mmol) and DIPEA (232.63 mg, 1.8 mmol) were added, and the reaction was carried out by stirring at 140 °C for 8 hours. The reaction solution was cooled to room temperature, water and ethyl acetate were added, the layers were separated, the aqueous phase was extracted once with ethyl acetate, the combined organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol (V / V) = 1 / 0-20 / 1) to obtain 3K (46 mg, yield: 49%).

[0296] Twelfth step: synthesis of compound 3

[0297] Compound 3 trifluoroacetate salt (25 mg) was obtained by dissolving 3K (46 mg, 0.074 mmol) in 3 mL of dichloromethane, adding 0.6 mL of trifluoroacetic acid, stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (instrument: waters 2767 preparative liquid; column: XBridge®Prep C18(30 mm x 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)) and freeze-dried from the preparative liquid.

[0298] LCMS m / z = 524.2 [M+1] +

[0299] 1 H NMR (400 MHz, DMSO-d6) δ 9.28 - 9.02 (m, 2H), 8.81 (s, 1H), 8.54 (s, 1H), 8.37 (s, 1H), 7.61 (t, 1H), 7.23 (s, 1H), 4.02 - 3.89 (m, 1H), 3.74 - 3.65 (m, 1H), 3.64 - 3.51 (m, 2H), 3.34-3.28 (m, 1H), 3.09 - 2.96 (m, 1H), 1.51 - 1.32 (m, 4H), 1.09 (s, 3H), 0.79 - 0.52 (m, 6H), 0.49 - 0.34 (m, 2H).

[0300] Example 4: Preparation of compound 4

[0301] First step: synthesis of 4A

[0302] DMF (50 mL) was added to Boc-D-cyclopropylglycine (5 g, 23.23 mmol), HATU (17.67 g, 46.46 mmol) and DIPEA (9.01 g, 69.69 mmol) were added, the reaction was stirred at room temperature for 10 min, dibenzylamine (6.87 g, 34.84 mmol) was added, and the reaction was carried out at room temperature for 18 hours. The reaction solution was extracted with ethyl acetate three times after adding water, the combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-10 / 1) to obtain 4A (4.6 g, yield: 50%).

[0303] LCMS m / z = 395.1 [M+1] +

[0304] Second step: synthesis of 4B

[0305] To a solution of 4A (4.6 g, 11.66 mmol) in 20 mL of dichloromethane was added 15 mL of trifluoroacetic acid and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, then dichloromethane was added and washed twice with saturated aqueous sodium bicarbonate solution. After drying over anhydrous sodium sulfate, the mixture was concentrated to give 4B (3.4 g).

[0306] LCMS m / z = 295.1 [M+1] +

[0307] Third Step: Synthesis of 4C

[0308] To a solution of 4B (3.4 g, 11.55 mmol) in 30 mL of tetrahydrofuran was added 10 M borane-dimethyl sulfide solution (11.5 mL, 115.5 mmol) slowly under ice-bath stirring. The reaction mixture was stirred at 25 °C for 48 hours. The reaction mixture was cooled in an ice-bath, quenched with 10% hydrochloric acid, and then the pH was adjusted to basic with 50% aqueous sodium hydroxide solution. After stirring at 70 °C for 3 hours, the reaction mixture was cooled to room temperature, and then water and ethyl acetate were added. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (V / V) = 1 / 0-20 / 1) to give 4C (2.4 g, yield: 74%).

[0309] Fourth Step: Synthesis of 4D

[0310] To a solution of 4C (2.4 g, 8.56 mmol) and triethylamine (1.39 g, 13.70 mmol) in dichloromethane (5 mL) was added to a solution of 3D (2.43 g, 10.27 mmol) in dichloromethane (20 mL) under ice-bath stirring. The reaction mixture was stirred for 2 hours in an ice-bath and then at room temperature overnight. Dichloromethane and saturated aqueous sodium bicarbonate solution were added, and then the mixture was stirred and separated. The organic phase was washed with saturated brine once, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-20 / 1) to give 4D (1.9 g, yield: 61%).

[0311] Fifth Step: Synthesis of 4E

[0312] To a solution of 4D (1.9 g, 5.18 mmol) in 20 mL of ethanol was added 10 wt% palladium-carbon (0.73 g) and concentrated hydrochloric acid (12 N, 0.66 mL). After three times of hydrogen replacement, the reaction mixture was stirred at room temperature for 12 hours. The mixture was filtered through celite, and then concentrated to give 4E (0.9 g).

[0313] LCMS m / z = 187.1 [M+1] +

[0314] Sixth Step: Synthesis of 4F

[0315] Compound 4F (0.26 g, 1.69 mmol) was dissolved in ethyl acetate (10 mL), di-tert-butyl dicarbonate (1.84 g, 8.45 mmol) was added, and the reaction was stirred at 80 °C for 0.5 h. The reaction was quenched by adding water, and extracted with ethyl acetate twice. The organic phase was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol (V / V) = 1 / 0-20 / 1) to give 4G (0.4 g, yield: 93%).

[0316] LCMS m / z = 155.1 [M+1] +

[0317] Seventh step: synthesis of 4G

[0318] Compound 4F (0.26 g, 1.69 mmol) was dissolved in ethyl acetate (10 mL), di-tert-butyl dicarbonate (1.84 g, 8.45 mmol) was added, and the reaction was stirred at 80 °C for 0.5 h. The reaction was quenched by adding water, and extracted with ethyl acetate twice. The organic phase was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol (V / V) = 1 / 0-20 / 1) to give 4G (0.4 g, yield: 93%).

[0319] Eighth step: synthesis of 4H

[0320] Compound 4G (0.1 g, 0.39 mmol) was dissolved in 3 mL of tetrahydrofuran, and 10 M borane-dimethyl sulfide solution (0.23 mL, 2.34 mmol) was slowly added while stirring in an ice bath. After the addition was complete, the reaction was raised to 25 °C and stirred for 24 h. The reaction was cooled in an ice bath, and then quenched with methanol. After stirring at 70 °C for 3 h, the reaction was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane / methanol (V / V) = 1 / 0-20 / 1) to give 4H (0.054 g, yield: 57%).

[0321] Ninth step: synthesis of 4I

[0322] Compound 4H (54 mg, 0.22 mmol) was dissolved in 3 mL of DMSO, and 1a (60 mg, 0.15 mmol) and DIPEA (232.63 mg, 1.8 mmol) were added. After the addition was complete, the reaction was stirred at 140 °C for 8 h. The reaction was cooled to room temperature, and water and ethyl acetate were added. The layers were separated, and the aqueous phase was extracted with ethyl acetate once. The organic phase was combined, washed with saturated brine once, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol (V / V) = 1 / 0-20 / 1) to give 4I (15 mg, yield: 16%).

[0323] Tenth step: synthesis of compound 4

[0324] Compound 4 (15 mg, 0.024 mmol) was dissolved in 2 mL of dichloromethane, 0.4 mL of trifluoroacetic acid was added, and the reaction was stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure, and the residue was purified by preparative HPLC (instrument: waters 2767 preparative liquid; column: XBridge®Prep C18(30 mm x 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)) and lyophilized from the preparative liquid to give the trifluoroacetate salt of compound 4 (7 mg).

[0325] LCMS m / z = 524.1 [M+1] +

[0326] 1 H NMR (400 MHz, DMSO-d6) δ 9.26 - 9.06 (m, 1H), 9.02 (s, 1H), 8.95 - 8.76 (m, 1H), 8.56 (s, 1H), 8.37 (s, 1H), 7.61 (t, 1H), 7.25 (s, 1H), 4.03 - 3.78 (m, 2H), 3.69 - 3.53 (m, 1H), 3.15 (t, 1H), 3.01 - 2.78 (m, 2H), 1.36 (d, 3H), 1.08 (s, 3H), 1.05 - 0.92 (m, 1H), 0.79 - 0.52 (m, 6H), 0.50 - 0.30 (m, 2H).

[0327] Example 5: Preparation of compound 5

[0328] First step: synthesis of 5A

[0329] DMF (15 mL) was added to Boc-L-cyclopropylglycine (1.1 g, 5.11 mmol), and then HATU (3.89 g, 10.22 mmol) and DIPEA (1.98 g, 15.33 mmol) were added to the reaction. After the addition was complete, the reaction was stirred at room temperature for 10 min, and then methyl 2-(benzylamino)acetate (1.37 g, 7.67 mmol) was added to the reaction. After the addition was complete, the reaction was stirred at room temperature for 18 hours. The reaction was extracted with ethyl acetate three times after water was added, and the combined organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-4 / 1) to give 5A (1.6 g, yield: 83%).

[0330] Second step: synthesis of 5B

[0331] To a solution of 5A (1.4 g, 3.72 mmol) in 15 mL of tetrahydrofuran, 1 M borane-tetrahydrofuran solution (7.44 mL, 7.44 mmol) was added slowly under ice-bath stirring, and the reaction was allowed to warm to 25 °C for 24 h. The reaction was cooled in an ice-bath, and quenched with methanol. The reaction was stirred at 70 °C for 3 h, and then allowed to cool to room temperature. The reaction was concentrated under reduced pressure, and the residue was dissolved in dichloromethane. The solution was washed with saturated aqueous sodium bicarbonate solution twice, and then dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate (V / V) = 1 / 0-10 / 1) to give 5B (0.39 g, yield: 29%).

[0332] Step 3: Synthesis of 5C

[0333] To a solution of 5B (0.39 g, 1.08 mmol) in 6 mL of dichloromethane, 1.5 mL of trifluoroacetic acid was added, and the reaction was stirred at room temperature for 2 h. The reaction was concentrated under reduced pressure, and the residue was dissolved in dichloromethane. The solution was washed with saturated aqueous sodium bicarbonate solution twice, and then dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give 5C (0.28 g).

[0334] Step 4: Synthesis of 5D

[0335] To a solution of 5C (0.28 g, 1.07 mmol) in 8 mL of ethanol, p-toluenesulfonic acid (0.074 g, 0.43 mmol) was added, and the reaction was stirred at 85 °C overnight. The reaction was allowed to cool to room temperature, and concentrated. Water was added, and the mixture was extracted with dichloromethane twice. The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol (V / V) = 1 / 0-15 / 1) to give 5D (0.21 g, yield: 85%).

[0336] LCMS m / z = 231.1 [M+1] +

[0337] Step 5: Synthesis of 5E

[0338] To a solution of 5D (100 mg, 0.43 mmol) in 6 mL of methanol, 10 wt% palladium on carbon (39 mg) was added, and the reaction was stirred at room temperature for 2 h under hydrogen atmosphere. The reaction was filtered through celite, and the filtrate was concentrated to give 5E (60 mg).

[0339] Step 6: Synthesis of compound 5

[0340] Compound 5 (30 mg) was obtained by the following procedure. Compound 5E (57 mg, 0.41 mmol) was dissolved in 3 mL of DMSO, 1a (150 mg, 0.137 mmol) and DIPEA (286.91 mg, 2.22 mmol) were added, and the tube was sealed and stirred at 140 °C for 8 h. The reaction solution was cooled to room temperature, water and ethyl acetate were added, the layers were separated, the aqueous phase was extracted once with ethyl acetate, the combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (instrument: waters 2767 preparative liquid; column: XBridge® Prep C18 (30 mm x 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)), and the preparative liquid was lyophilized to obtain compound 5 (30 mg).

[0341] LCMS m / z = 524.2 [M+1] +

[0342] 1 H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.44 (s, 1H), 8.42-8.35 (m, 1H), 8.30 (s, 1H), 7.60 (t, 1H), 7.13 (s, 1H), 4.03 (s, 2H), 3.82-3.68 (m, 2H), 2.97-2.84 (m, 1H), 1.15-1.01 (m, 4H), 0.72-0.60 (m, 2H), 0.59-0.47 (m, 2H), 0.47-0.32 (m, 4H).

[0343] Example 6: Preparation of compound 6

[0344] First step: Preparation of 6b

[0345] Compound 6a (530 mg, 1.44 mmol) was dissolved in dichloromethane (5 mL) and added to a 50 mL sealed tube, followed by the addition of an ammonia 1,4-dioxane solution (11.52 mL, 5.76 mmol, 0.5 M), sealed, and then stirred at 40 °C for 16 h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and then purified by flash column chromatography (mobile phase: petroleum ether / ethyl acetate (v / v) = 3 / 1) to obtain 6b (290 mg, yield 58%).

[0346] LCMS m / z = 350.0 [M+H] +

[0347] Second step: Preparation of 6c

[0348] Dissolve 6b (290 mg, 0.83 mmol) in dimethyl sulfoxide (10 mL), add 3j (199 mg, 0.83 mmol) and N,N-diisopropyl ethylamine (322 mg, 2.49 mmol), then raise the reaction system to 140 °C and stir for 8 hours. Cool the reaction to room temperature, dilute the reaction with 200 mL of ethyl acetate, wash with water 3 times, wash with saturated sodium chloride 1 time, collect the organic phase by liquid-liquid separation, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by flash column chromatography (mobile phase: petroleum ether / ethyl acetate (v / v) = 2 / 1) to obtain 6c (240 mg, yield 51%).

[0349] Third step: preparation of 6d

[0350] Dissolve 6c (240 mg, 0.42 mmol) in anhydrous tetrahydrofuran (15 mL), add sodium hydride (34 mg, 0.84 mmol) in batches under ice bath, react for 0.5 hours under ice bath, then add tert-butyldimethylsilyl chloride (95 mg, 0.63 mmol), and then raise the reaction system to room temperature and stir for 1 hour. Quench the reaction with water, extract with 200 mL of ethyl acetate, wash the organic phase with water 3 times, wash with saturated sodium chloride 1 time, collect the organic phase by liquid-liquid separation, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by flash column chromatography (mobile phase: petroleum ether / ethyl acetate (v / v) = 3 / 1) to obtain 6d (258 mg, yield 90%).

[0351] LCMS m / z = 682.4 [M-H] -

[0352] Fourth step: preparation of compound 6e

[0353] Dissolve triphenylphosphine dichloride (95 mg, 0.29 mmol) in anhydrous dichloromethane (5 mL), replace with nitrogen 3 times, add N,N-diisopropyl ethylamine (49 mg, 0.38 mmol) dropwise under ice bath, stir the reaction under ice bath for 0.5 hours, then add 6d (130 mg, 0.19 mmol), raise the temperature to room temperature, stir the reaction for 0.5 hours, and let the reaction stand.

[0354] Fifth step: preparation of compound 6f

[0355] Into a 25 mL single necked flask, 1-methylcyclopropylamine hydrochloride (102 mg, 0.95 mmol) was added, followed by the addition of anhydrous dichloromethane (5 mL), and then dropwise addition of N,N-diisopropylethylamine (123 mg, 0.95 mmol). The resulting solution was stirred at room temperature for 0.5 h. The resulting solution was then added dropwise to the reaction solution from the previous step under ice-bath conditions, and then allowed to warm to room temperature for 16 h. The reaction solution was quenched with water, and extracted with 100 mL of dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography (mobile phase: petroleum ether / ethyl acetate (v / v) = 3 / 1) to give 6f (45 mg, yield 32%).

[0356] LCMS m / z = 735.4 [M-H] -

[0357] Sixth step: Preparation of compound 6

[0358] Compound 6 trifluoroacetate salt (40 mg) was obtained by dissolving 6f (45 mg, 0.061 mmol) in dichloromethane (3 mL), followed by dropwise addition of trifluoroacetic acid (3 mL), and stirring at room temperature for 1 h. The reaction solution was directly concentrated under reduced pressure, and purified by flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 9 / 1).

[0359] LCMS m / z = 523.3 [M+H] +

[0360] Example 7: Preparation of compound 7

[0361] First step: Synthesis of 7A

[0362] DMF (50 mL) was added to Boc-L-cyclobutylglycine (3 g, 13.09 mmol), followed by the addition of HATU (9.95 g, 26.18 mmol) and DIPEA (5.08 g, 39.27 mmol) to the reaction solution. After the addition was complete, the reaction was stirred at room temperature for 10 min, and then dibenzylamine (3.36 g, 17.02 mmol) was added to the reaction. After the addition was complete, the reaction was allowed to proceed at room temperature for 18 h. The reaction solution was extracted with ethyl acetate three times after the addition of water, and the combined organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 0-10 / 1) to give 7A (5 g, yield: 93%).

[0363] LCMS m / z = 409.3 [M+1] +

[0364] Second step: Synthesis of 7B

[0365] Dissolve 7A (5 g, 12.24 mmol) in 40 mL of dichloromethane, add 10 mL of trifluoroacetic acid, stir at room temperature for 2 hours. Concentrate the reaction solution under reduced pressure, then add dichloromethane, wash twice with saturated aqueous sodium bicarbonate solution, dry over anhydrous sodium sulfate, and concentrate to give 7B (3.7 g).

[0366] LCMS m / z = 309.2 [M+1] +

[0367] Third Step: Synthesis of 7C

[0368] Dissolve 7B (3.7 g, 12 mmol) in 40 mL of tetrahydrofuran, slowly add 10 M borane-dimethyl sulfide solution (12 mL, 120 mmol) under ice bath stirring, then raise the temperature to 70°C and react for 18 hours. Cool the reaction under ice bath, then quench the reaction with 10% hydrochloric acid, then adjust the pH to basic with 50% aqueous sodium hydroxide solution. Stir the reaction at 70°C for 3 hours, then lower the temperature to room temperature, add water and ethyl acetate, stir to separate the layers, wash the organic phase with saturated brine, dry the organic phase over anhydrous sodium sulfate, then concentrate under reduced pressure, and purify the residue by silica gel column chromatography (dichloromethane / methanol (V / V) = 1 / 0-20 / 1) to give 7C (3 g, yield: 85%).

[0369] Fourth Step: Synthesis of 7D

[0370] Dissolve 7C (3 g, 10.19 mmol) and triethylamine (1.65 g, 16.30 mmol) in dichloromethane (5 mL) under ice bath stirring, add to a dichloromethane solution (30 mL) of 3D (2.89 g, 12.23 mmol), then stir for 2 hours under ice bath and overnight after raising the temperature to room temperature. Add dichloromethane and saturated aqueous sodium bicarbonate solution, stir, then separate the layers. Wash the organic phase with saturated brine once, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-20 / 1) to give 7D (2.5 g, yield: 64%).

[0371] Fifth Step: Synthesis of 7E

[0372] Dissolve 7D (2.5 g, 6.57 mmol) in 30 mL of ethanol, add 10 wt% palladium-carbon (0.92 g) and concentrated hydrochloric acid (12 N, 0.83 mL), replace with hydrogen gas three times, stir at room temperature for 4 hours. Filter through diatomite, concentrate to give 7E (1.9 g).

[0373] LCMS m / z = 291.3 [M+1] +

[0374] Sixth Step: Synthesis of 7F

[0375] Compound 7E (1.9 g, 6.54 mmol) was dissolved in 30 mL of ethanol, and p-toluenesulfonic acid (0.45 g, 2.62 mmol) was added. After the addition was completed, the reaction was stirred at 85°C overnight. The reaction was cooled to room temperature, concentrated, and then water was added. The mixture was extracted with dichloromethane twice, and the combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol (V / V) = 1 / 0-15 / 1) to obtain 7F (0.73 g, yield: 43%).

[0376] Seventh step: Synthesis of 7G

[0377] Compound 7F (0.65 g, 2.52 mmol) was dissolved in 10 mL of tetrahydrofuran, and 10 M borane-dimethyl sulfide solution (2.52 mL, 25.2 mmol) was slowly added while stirring in an ice bath. After the addition was completed, the reaction was allowed to react at 25°C for 24 hours. The reaction was cooled in an ice bath, and then methanol was added to quench the reaction. After stirring at 70°C for 3 hours, the reaction was cooled to room temperature, and concentrated under reduced pressure to obtain 7G (0.6 g).

[0378] Eighth step: Synthesis of 7H

[0379] Compound 7G (0.6 g, 2.46 mmol) was dissolved in dichloromethane (10 mL), and 1 N sodium hydroxide (0.20 g, 4.92 mmol) and di-tert-butyl dicarbonate (0.59 g, 2.71 mmol) were added. The reaction was allowed to react at room temperature for 16 hours. Water was added to quench the reaction, and the mixture was extracted with dichloromethane twice. The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate (V / V) = 1 / 0-20 / 1) to obtain 7H (660 mg, yield: 78%).

[0380] Ninth step: Synthesis of 7I

[0381] Compound 7H (300 mg, 0.87 mmol) was dissolved in 8 mL of methanol, and 10 wt% palladium-carbon (122 mg) was added. After the addition was completed, the reaction was replaced with hydrogen three times, and stirred at room temperature for 2 hours. The reaction was filtered through diatomite, and the filtrate was concentrated to obtain 7I (220 mg).

[0382] Tenth step: Synthesis of 7J

[0383] Compound 7 was prepared according to the following procedure: First step: synthesis of compound 7I

[0384] Tenth step: synthesis of compound 7

[0385] Compound 7J (150 mg, 0.24 mmol) was dissolved in 5 mL of dichloromethane, 1 mL of trifluoroacetic acid was added, and the reaction was stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure, and the residue was purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge@Prep C18(30 mm x 150 mm); mobile phase composition: acetonitrile, water containing 0.1% trifluoroacetic acid). The prepared liquid was lyophilized to obtain the trifluoroacetate salt of compound 7 (80 mg).

[0386] LCMS m / z = 538.3 [M+1] +

[0387] Example 8: preparation of compound 8

[0388] DCM (3 mL) was added to 1-methoxycyclopropanecarboxylic acid (8.22 mg, 0.071 mmol), and then HATU (44.87 mg, 0.12 mmol) and DIPEA (22.88 mg, 0.18 mmol) were added to the reaction. After the addition was complete, compound 1 (30 mg, 0.059 mmol) was added to the reaction, and the reaction was stirred at room temperature for 18 hours. The reaction was extracted with dichloromethane three times after water was added, and the combined organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-60 / 40) to obtain compound 8 (20 mg, yield: 56%).

[0389] LCMS m / z = 608.3 [M+1] +

[0390] 1H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.48 (s, 1H), 8.30 (s, 1H), 7.60 (t, 1H), 7.21 (s, 1H), 4.55 - 4.33 (m, 1H), 4.16 - 3.64 (m, 4H), 3.28 (s, 3H), 3.22 - 2.97 (m, 2H), 1.78 - 1.54 (m, 1H), 1.09 (s, 3H), 1.06 - 0.80 (m, 4H), 0.75 - 0.59 (m, 3H), 0.58 - 0.31 (m, 5H).

[0391] Example 9: Preparation of compound 9

[0392] Compound 3 (0.05 g, 0.095 mmol) was dissolved in dichloromethane (5 mL), triethylamine (0.019 g, 0.19 mmol) was added, acetyl chloride (0.0075 g, 0.095 mmol) was added dropwise under ice bath, after addition, the reaction was stirred at room temperature for 5 minutes. The reaction solution was diluted with 50 mL dichloromethane, washed with sodium bicarbonate aqueous solution once, separated, collected the organic phase, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and compound 10 (26 mg, yield 46%) was obtained by silica gel column flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 15 / 1).

[0393] LCMS m / z = 566.2 [M+H] +

[0394] Example 10: Preparation of compound 10

[0395] Compound 3 (0.05 g, 0.095 mmol) was dissolved in dichloromethane (5 mL), triethylamine (0.019 g, 0.19 mmol) was added, acetyl chloride (0.0075 g, 0.095 mmol) was added dropwise under ice bath, after addition, the reaction was stirred at room temperature for 5 minutes. The reaction solution was diluted with 50 mL dichloromethane, washed with sodium bicarbonate aqueous solution once, separated, collected the organic phase, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and compound 10 (26 mg, yield 46%) was obtained by silica gel column flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 15 / 1).

[0396] LCMS m / z = 566.2 [M+H] +

[0397] Example 11: Preparation of compound 11

[0398] Compound 11 (15 mg, yield: 31%) was obtained by the following procedure. 1-Methoxycyclopropanecarboxylic acid (18 mg, 0.16 mmol) was added to DMF (3 mL), and HATU (60 mg, 0.16 mmol) and DIPEA (39 mg, 0.30 mmol) were added to the reaction solution. After stirring at room temperature for 10 min, compound 3 (40 mg, 0.076 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 3 h. After the reaction solution was added to water, the mixture was extracted with dichloromethane three times. The combined organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate (V / V) = 1 / 0-60 / 40), and the obtained crude product was purified by preparative HPLC (instrument: waters 2767 preparative liquid chromatograph; column: XBridge® Prep C18 (30 mm x 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)). The product was lyophilized to obtain compound 11 (15 mg, yield: 31%).

[0399] LCMS m / z = 622.3 [M+1] +

[0400] Example 12: Preparation of compound 12

[0401] Compound 12 (30 mg, yield: 64%) was obtained by the following procedure. 3-Oxetanecarboxylic acid (16 mg, 0.16 mmol) was added to DMF (3 mL), and HATU (60 mg, 0.16 mmol) and DIPEA (40 mg, 0.31 mmol) were added to the reaction solution. After stirring at room temperature for 10 min, compound 3 (40 mg, 0.076 mmol) was added to the reaction solution, and the mixture was stirred at room temperature overnight. After the reaction solution was added to water, the mixture was extracted with dichloromethane three times. The combined organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (dichloromethane / methanol (V / V) = 1 / 0-10 / 1) to obtain compound 12 (30 mg, yield: 64%).

[0402] LCMS m / z = 608.2 [M+1] +

[0403] Example 13: Preparation of compound 13

[0404] DMF (5 mL) was added to 1-methoxycyclobutane-1-carboxylic acid (21 mg, 0.16 mmol), HATU (76 mg, 0.20 mmol) and DIPEA (42 mg, 0.32 mmol) were added to the reaction flask, after addition, the reaction was stirred at room temperature for 10 min, then 13A (40 mg, 0.080 mmol; CAS: 2988890-20-4, synthesis reference WO2024 / 148280) was added to the reaction, and the reaction was carried out at room temperature overnight. After the reaction was added to water, it was extracted with dichloromethane three times, the combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-60 / 40) to obtain compound 13 (15 mg, yield: 30%).

[0405] LCMS m / z = 610.3 [M+1] +

[0406] Example 14: Preparation of compound 14

[0407] DMF (5 mL) was added to 1-methoxycyclobutane-1-carboxylic acid (21 mg, 0.16 mmol), HATU (76 mg, 0.20 mmol) and DIPEA (42 mg, 0.32 mmol) were added to the reaction flask, after addition, the reaction was stirred at room temperature for 10 min, then 13A (40 mg, 0.080 mmol; CAS: 2988890-20-4, synthesis reference WO2024 / 148280) was added to the reaction, and the reaction was carried out at room temperature overnight. After the reaction was added to water, it was extracted with dichloromethane three times, the combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-60 / 40) to obtain compound 13 (15 mg, yield: 30%).

[0408] LCMS m / z = 596.3 [M+1] +

[0409] Example 15: Preparation of compound 15

[0410] To compound 3 (0.04 g, 0.076 mmol), DIPEA (0.020 g, 0.15 mmol), dichloromethane (3 mL), a solution of cyclopropylcarbonyl chloride (0.012 g, 0.11 mmol) in dichloromethane (2 mL) was added under ice water cooling. After the addition was completed, the reaction was stirred for 1 h under ice water cooling. Water was added, and the mixture was stirred. The organic layer was separated and concentrated under reduced pressure. Purification was performed by column chromatography (eluent: PE-EA = 100-0 to 60-40). Compound 15 (0.031 g, yield: 69%) was obtained.

[0411] LCMS m / z = 592.2 [M+1] +

[0412] Example 16: Preparation of compound 16

[0413] DCM (3 mL) was added to compound 1 (40 mg, 0.078 mmol), and isobutyryl chloride (9.97 mg, 0.094 mmol) and triethylamine (15.79 mg, 0.16 mmol) were sequentially added with stirring at room temperature. After the addition was completed, the reaction was stirred for 18 h at room temperature. The reaction solution was extracted with dichloromethane three times after the addition of saturated sodium bicarbonate. The combined organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate (V / V) = 1 / 0-60 / 40). Compound 16 (25 mg, yield: 55%) was obtained.

[0414] LCMS m / z = 580.3 [M+1] +

[0415] Example 17: Preparation of compound 17

[0416] First step: synthesis of 17A

[0417] DCM (30 mL) was added to Boc-L-cyclopentylglycine (2 g, 8.22 mmol), and N,N'-dicyclohexylcarbodiimide (2.04 g, 9.86 mmol) was added to the reaction solution. After the addition was completed, the reaction was stirred for 30 min at room temperature, and dibenzylamine (1.78 g, 9.04 mmol) was added to the reaction. After the addition was completed, the reaction was stirred for 18 h at room temperature. The reaction solution was filtered to remove white solids, and the filter cake was washed with dichloromethane. The filtrate was collected and directly concentrated under reduced pressure. Purification was performed by flash column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-10 / 1). 17A (2 g, yield: 57%) was obtained.

[0418] LCMS m / z = 423.3 [M+1] +

[0419] Second step: synthesis of 17B

[0420] Dissolve 17A (2 g, 4.73 mmol) in 20 mL of dichloromethane, add 5 mL of trifluoroacetic acid, stir at room temperature for 2 hours. Concentrate the reaction solution under reduced pressure, then add dichloromethane, wash twice with saturated aqueous sodium bicarbonate solution, dry over anhydrous sodium sulfate, and concentrate to give 17B (1.5 g).

[0421] LCMS m / z = 323.2 [M+1] +

[0422] Third Step: Synthesis of 17C

[0423] Dissolve 17B (1.5 g, 4.65 mmol) in 20 mL of tetrahydrofuran, slowly add 10 M borane-dimethyl sulfide solution (4.65 mL, 46.5 mmol) under ice bath stirring, then raise the temperature to 70°C and react for 18 hours. Cool the reaction under ice bath, then quench the reaction with 10% hydrochloric acid, then adjust the pH to basic with 50% aqueous sodium hydroxide solution. Stir the reaction at 70°C for 3 hours, then lower the temperature to room temperature, add water and ethyl acetate, stir to separate the layers, wash the organic phase with saturated brine, dry the organic phase over anhydrous sodium sulfate, then concentrate under reduced pressure, and purify the residue by silica gel column chromatography (dichloromethane / methanol (V / V) = 1 / 0-20 / 1) to give 17C (1.2 g, yield: 84%).

[0424] Fourth Step: Synthesis of 17D

[0425] Dissolve 17C (1.2 g, 3.89 mmol) and triethylamine (0.63 g, 6.22 mmol) in dichloromethane (5 mL) under ice bath stirring, add to a dichloromethane solution (20 mL) of 3D (1.10 g, 4.67 mmol), then stir for 2 hours under ice bath and overnight after raising the temperature to room temperature. Add dichloromethane and saturated aqueous sodium bicarbonate solution, stir, then separate the layers. Wash the organic phase with saturated brine once, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-20 / 1) to give 17D (1 g, yield: 65%).

[0426] Fifth Step: Synthesis of 17E

[0427] Dissolve 17D (1 g, 2.53 mmol) in 20 mL of ethanol, add 10 wt% palladium-carbon (0.36 g) and concentrated hydrochloric acid (12 N, 0.32 mL), replace with hydrogen gas three times, stir at room temperature for 4 hours. Filter through diatomite, concentrate to give 17E (0.75 g).

[0428] LCMS m / z = 305.2 [M+1] +

[0429] Step 6: Synthesis of 17F

[0430] Dissolve 17E (0.7 g, 2.30 mmol) in 20 mL of ethanol, add p-toluenesulfonic acid (0.16 g, 0.92 mmol), and stir overnight at 85 °C. Cool the reaction to room temperature, concentrate, add water, then extract twice with dichloromethane. Dry the combined organic phases over anhydrous sodium sulfate and concentrate under reduced pressure. Purify the residue by column chromatography on silica gel (dichloromethane / methanol (V / V) = 1 / 0-15 / 1) to give 17F (0.5 g, yield: 80%).

[0431] Step 7: Synthesis of 17G

[0432] Dissolve 17F (0.5 g, 1.84 mmol) in 10 mL of tetrahydrofuran, and slowly add 10 M borane-dimethyl sulfide complex (1.84 mL, 18.4 mmol) while stirring in an ice bath. After the addition, raise the temperature to 25 °C and stir for 24 h. Cool the reaction in an ice bath, then quench with methanol. Stir at 70 °C for 3 h, then cool to room temperature. Concentrate under reduced pressure to give 17G (0.42 g).

[0433] Step 8: Synthesis of 17H

[0434] Dissolve compound 17G (0.42 g, 1.63 mmol) in dichloromethane (8 mL), and add 1 N sodium hydroxide (0.13 g, 3.26 mmol) and di-tert-butyl dicarbonate (0.39 g, 1.79 mmol). Stir at room temperature for 16 h. Quench with water, extract twice with dichloromethane, dry the combined organic phases over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify the residue by column chromatography on silica gel (petroleum ether / ethyl acetate (V / V) = 1 / 0-20 / 1) to give 17H (510 mg, yield: 87%).

[0435] Step 9: Synthesis of 17I

[0436] Dissolve 17H (510 mg, 1.42 mmol) in 10 mL of methanol, and add 10 wt% palladium on carbon (199 mg). Replace the atmosphere with hydrogen three times, and stir at room temperature for 2 h. Filter through celite, and concentrate the filtrate to give 17I (370 mg).

[0437] Step 10: Synthesis of 17J

[0438] Compound 17 was prepared according to the procedures described in Scheme 1. Step 1: Synthesis of compound 17a

[0439] Tenth step: Synthesis of compound 17

[0440] Compound 17J (110 mg, 0.17 mmol) was dissolved in 3 mL of dichloromethane, 0.6 mL of trifluoroacetic acid was added, and stirring was performed at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge@Prep C18(30 mm x 150 mm); mobile phase composition: acetonitrile, water containing 0.1% trifluoroacetic acid) and then lyophilized to obtain a trifluoroacetate salt of compound 17 (45 mg).

[0441] LCMS m / z = 552.3 [M+1] +

[0442] Example 18: Preparation of compound 18

[0443] DCM (3 mL) was added to compound 1 (40 mg, 0.078 mmol), and stirring was performed at room temperature after the addition of cyclopropyl chloride (9.78 mg, 0.094 mmol) and triethylamine (15.79 mg, 0.16 mmol) in sequence. After completion of the addition, the reaction was performed at room temperature for 18 hours. After the addition of saturated sodium bicarbonate to the reaction solution, extraction was performed with dichloromethane three times, the combined organic phase was dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-60 / 40) to obtain compound 18 (20 mg, yield: 44%).

[0444] LCMS m / z = 578.2 [M+1] +

[0445] Example 19: Preparation of compound 19

[0446] DCM (3 mL) was added to 1-methoxycyclobutanecarboxylic acid (9.21 mg, 0.071 mmol), and then HATU (44.87 mg, 0.12 mmol) and DIPEA (22.88 mg, 0.18 mmol) were added to the reaction solution. After stirring at room temperature for 10 min, compound 1 (30 mg, 0.059 mmol) was added to the reaction solution, and the reaction was carried out at room temperature for 18 h. After the reaction solution was added to water, extraction was performed with dichloromethane three times, and the combined organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-60 / 40) to obtain compound 19 (20 mg, yield: 55%).

[0447] LCMS m / z = 622.1 [M+1] +

[0448] Example 20: Preparation of compound 20

[0449] First step: Preparation of compound 20a

[0450] Compound 20a (180 mg, 0.43 mmol) was dissolved in 10 mL of DCM, and then 3- methyl-3-oxetanamine (60 mg, 0.71 mmol) and triethylamine (190 mg, 1.86 mmol) were added to the reaction solution. After stirring at room temperature for 16 h, water and dichloromethane / methanol ((V / V) = 10 / 1) were added, and the aqueous phase was extracted with dichloromethane / methanol ((V / V) = 10 / 1) once. The combined organic phase was washed with saturated brine once, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (V / V) = 1 / 0-20 / 1) to obtain compound 20 (120 mg, yield: 69%).

[0451] LCMS m / z = 420.0 [M+1] +

[0452] Second step: Preparation of compound 20b

[0453] To a solution of 20a (100 mg, 0.24 mmol) in 4 mL of DMSO was added 3J (69 mg, 0.29 mmol) and DIPEA (155.09 mg, 1.2 mmol), and the mixture was stirred at 140 °C for 8 h. The reaction mixture was cooled to room temperature, diluted with water and ethyl acetate, and the layers were separated. The aqueous layer was extracted with ethyl acetate once, and the combined organic layers were washed with saturated brine once, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol (V / V) = 1 / 0-20 / 1) to give 20b (120 mg, yield: 78%).

[0454] Step 3: Preparation of compound 20

[0455] To a solution of 20b (120 mg, 0.19 mmol) in 4 mL of dichloromethane was added 1 mL of trifluoroacetic acid, and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge® Prep C18 (30 mm x 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)) and lyophilized to give the trifluoroacetate salt of compound 20 (30 mg).

[0456] LCMS m / z = 540.1 [M+1] +

[0457] 1 H NMR (400 MHz, DMSO-d6) δ 9.22 - 9.00 (m, 2H), 8.81 (s, 1H), 8.67 (s, 1H), 8.53 (s, 1H), 7.60 (t, 1H), 7.30 - 7.18 (m, 1H), 4.59 (t, 2H), 4.18 - 4.10 (m, 2H), 4.01 - 3.88 (m, 1H), 3.75 - 3.67 (m, 1H), 3.65 - 3.53 (m, 2H), 3.41 - 3.34 (m, 1H), 3.08 - 2.94 (m, 1H), 1.52 - 1.32 (m, 7H), 0.77 - 0.56 (m, 4H).

[0458] Example 21: Preparation of compound 21

[0459] Step 1: Preparation of 21B

[0460] Compound 21A (1.0 g, 2.55 mmol) was dissolved in acetonitrile (15 mL), and water (2.02 g, 112 mmol) and glacial acetic acid (1.53 g, 25.5 mmol) were added after ice bath cooling for ten minutes. After the addition was completed, the reaction was incubated for 5 minutes, and 1,3-dichloro-5,5-dimethylhydantoin (0.75 g, 3.82 mmol) was added. After the addition was completed, the ice bath was removed, and the reaction was incubated at room temperature for 1 hour. The reaction solution was diluted with water, and dichloromethane (60 mL x 2) was added for extraction. The organic phase was dried and concentrated to obtain a residue, which was separated and purified by a medium-pressure silica gel column (PE / EA = 0% to 6%) to obtain 21B (700 mg, yield 74.5%).

[0461] Second Step: Preparation of 21C

[0462] Compound 21B (0.46 g, 1.25 mmol) was added after ice bath cooling for ten minutes, and DMAP (0.15 g, 1.25 mmol) was added after ice bath cooling for five minutes. After the addition was completed, the natural temperature was increased overnight. Water (60 mL) was added to the reaction solution, and dichloromethane (60 mL x 2) was added for extraction. The combined organic phase was dried with anhydrous sodium sulfate, and the solution was concentrated under reduced pressure by adding an appropriate amount of silica gel. The residue was separated and purified by a medium-pressure silica gel column (PE / EA: 0% to 25%) to obtain 21C (257 mg, yield 49%).

[0463] LCMS m / z = 422.0 [M+1] +

[0464] Third Step: Preparation of 21D

[0465] Compound 21C (130 mg, 0.31 mmol) was dissolved in 5 mL of DMSO, and (2S,6S)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (86 mg, 0.40 mmol) and DIPEA (120 mg, 0.93 mmol) were added. After the addition was completed, the reaction was stirred at 140°C for 8 hours. The reaction solution was cooled to room temperature, and water and ethyl acetate were added. After the separation of the layers, the aqueous phase was extracted once with ethyl acetate, and the combined organic phase was washed once with saturated brine. After drying with anhydrous sodium sulfate, the solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0 to 4 / 1) to obtain 21D (100 mg, yield: 52%).

[0466] LCMS m / z = 560.2 [M-55] +

[0467] Fourth Step: Preparation of 21E

[0468] Compound 21 was prepared according to the following scheme:

[0469] LCMS m / z = 516.2 [M+1] +

[0470] Fifth step: Preparation of compound 21

[0471] DMF (3 mL) was added to 1-methoxycyclopropanecarboxylic acid (37.16 mg, 0.32 mmol), then HATU (150 mg, 0.40 mmol) and DIPEA (100 mg, 0.80 mmol) were added to the reaction solution. After addition, the reaction solution was stirred at room temperature for 10 min, then compound 21E (83 mg, 0.16 mmol) was added to the reaction solution. After addition, the reaction solution was stirred at room temperature for 18 h. The reaction solution was added to ethyl acetate (50 mL), then washed with water (50 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-60 / 40) to obtain compound 21 (66 mg, yield: 67%).

[0472] LCMS m / z = 614.2 [M+1] +

[0473] Example 22: Preparation of compound 22

[0474] 1-methyl-3-azetidinecarboxylic acid (0.017 g, 0.15 mmol) was added to DMF (2 mL), then HATU (0.058 g, 0.15 mmol) and DIPEA (0.029 g, 0.23 mmol) were added to the reaction solution. After addition, the reaction solution was stirred at room temperature for 10 min, then compound 3 (0.040 g, 0.076 mmol) was added to the reaction solution. After addition, the reaction solution was stirred at room temperature for 2 h. The reaction solution was added to water, then extracted with dichloromethane three times. The combined organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / ammonia methanol (2N) (V / V) = 1 / 0-10 / 1), and the obtained residue was purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; chromatographic column: XBridge® Prep C18 (30 mm x 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)) to obtain trifluoroacetate of compound 22 (5 mg).

[0475] LCMS m / z = 621.3 [M+1] +

[0476] Example 23: Preparation of compound 23

[0477] DCM (3 mL) was added to compound 1 (40 mg, 0.078 mmol), acetyl chloride (7.35 mg, 0.094 mmol) and triethylamine (15.79 mg, 0.16 mmol) were added successively at room temperature, after addition, the reaction was stirred at room temperature for 18 hours. The reaction solution was added to saturated sodium bicarbonate, extracted with dichloromethane three times, the combined organic phase was dried over anhydrous sodium sulfate and concentrated, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-25 / 75) to obtain compound 23 (20 mg, yield: 46%).

[0478] LCMS m / z = 552.2 [M+1] +

[0479] Example 24: Preparation of compound 24

[0480] First step: preparation of 24A

[0481] 21C (130 mg, 0.31 mmol) was dissolved in 5 mL of DMSO, 3J (74.5 mg, 0.31 mmol) and DIPEA (120 mg, 0.93 mmol) were added, after addition, the reaction was stirred at 140°C for 8 hours. The reaction solution was cooled to room temperature, water and ethyl acetate were added, the layers were separated, the aqueous phase was extracted with ethyl acetate once, the combined organic phase was washed with saturated brine once, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-4 / 1) to obtain 24A (47 mg, yield: 24%).

[0482] LCMS m / z = 640.3 [M-H] -

[0483] Second step: synthesis of compound 24

[0484] 24A (47 mg, 0.073 mmol) was dissolved in 5 mL of dichloromethane, 1 mL of trifluoroacetic acid was added, and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was purified by preparative HPLC (instrument: waters 2767 preparative liquid; column: XBridge@Prep C18(30mmx150mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)), and the prepared liquid was freeze-dried to obtain the trifluoroacetate salt of compound 24 (27 mg).

[0485] LCMS m / z = 542.3 [M+1] +

[0486] 1 H NMR (400 MHz, DMSO-d6) δ 9.21 - 8.98 (m, 2H), 8.81 (s, 1H), 8.75 (s, 1H), 8.52 (s, 1H), 7.61 (t, 1H), 7.23 (s, 1H), 4.32 - 4.20 (m, 1H), 4.18 - 4.07 (m, 1H), 4.03 - 3.85 (m, 1H), 3.77 - 3.64 (m, 1H), 3.64 - 3.52 (m, 2H), 3.33 (dd, 1H), 3.10 - 2.95 (m, 1H), 1.44 (d, 3H), 1.41 - 1.30 (m, 1H), 0.86 - 0.66 (m, 6H), 0.66 - 0.53 (m, 2H).

[0487] Example 25: Preparation of compound 25

[0488] First step: synthesis of 25A

[0489] Into a flask was added 2-bromocyclopropaneethanone (6.9 g, 42.33 mmol), methanol (60 mL), and dibenzylamine (8.35 g, 42.33 mmol) was added dropwise slowly under ice water cooling, and the reaction was allowed to proceed overnight at room temperature. Water (180 mL) was added, and sodium carbonate was added to adjust the pH to about 10. The organic layer was washed once with saturated sodium chloride solution, and silica gel was added to the residue, which was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE-EA = 100-0 to 90-10) to obtain the product. The product was dissolved in ethyl acetate (50 mL), and 6N hydrochloric acid was added dropwise under ice water cooling to adjust the pH to about 2. The mixture was stirred for 1 hour, and the precipitate was filtered and dried under reduced pressure to obtain 25A (7.6 g, yield: 57%).

[0490] LCMS m / z = 280.2 [M+1] +

[0491] Second step: synthesis of 25B

[0492] Into a flask was added 25A (2 g, 6.33 mmol), palladium on carbon (0.80 g), hydrochloric acid (2 mL), and methanol (20 mL). After the reaction was carried out under a hydrogen atmosphere for 3 hours, the mixture was filtered through celite, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure, and ethyl acetate and saturated potassium carbonate solution were added to adjust the pH to about 10. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 25B (1.1 g).

[0493] LCMS m / z = 190.1 [M+1] +

[0494] Third Step: Synthesis of 25C

[0495] A reaction flask was charged with Boc-L-cyclopropylglycine (1.50 g, 6.97 mmol), N,N'-dicyclohexylcarbodiimide (1.56 g, 7.55 mmol), dichloromethane (20 mL), stirred at room temperature for about 30 minutes, then added 25B (1.1 g, 5.81 mmol), stirred at room temperature for 2 hours, filtered, the filter cake was washed with dichloromethane, the filtrate was concentrated under reduced pressure after adding appropriate amount of silica gel, the residue was separated and purified by silica gel column chromatography (eluent: PE-EA = 100-0 to 75-25) to obtain 25C (2 g, yield: 89.03%).

[0496] LCMS m / z = 387.2 [M+1] +

[0497] Fourth Step: Synthesis of 25D

[0498] A reaction flask was charged with 25C (2 g, 5.17 mmol), methanol (20 mL), stirred to dissolve, then added 4N HCl-methanol solution (20 mL), heated at 30°C in an oil bath for 2 hours, concentrated under reduced pressure after the reaction was completed by TLC detection, and dried to obtain 25D (1.58 g) which was directly used in the next step.

[0499] Fifth Step: Synthesis of 25E

[0500] A reaction flask was charged with 25D (1.58 g, 5.18 mmol), dichloromethane (20 mL), stirred and added sodium triacetoxyborohydride (2.20 g, 10.36 mmol), stirred at room temperature after the addition was completed overnight. After stirring and separating the layers after adding dichloromethane and saturated aqueous sodium bicarbonate solution, the organic layer was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: DCM-MeOH = 100-0 to 90-10) to obtain 25E (0.9 g, yield: 64%)

[0501] Sixth Step: Synthesis of 25F

[0502] A reaction flask was charged with 25E (0.9 g, 3.33 mmol), tetrahydrofuran (10 mL), lithium aluminum hydride solution in tetrahydrofuran (2.5M, 10 mL), heated at 60°C in an oil bath for 3 hours. After cooling with ice water, water (2 mL) was added dropwise, filtered with diatomite, the filtrate was stirred and separated into layers after adding ethyl acetate and saturated aqueous ammonium chloride solution, the organic layer was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: DCM-MeOH = 100-0 to 80-20) to obtain 25F (0.6 g, yield: 70%)

[0503] Step 7: Synthesis of 25G

[0504] Into a reaction flask was added 25F (0.2 g, 0.78 mmol), palladium on carbon (0.1 g), methanol (5 mL), and the reaction was hydrogenated overnight after purging with hydrogen gas three times. The reaction was filtered through celite, the filter cake was washed with methanol, and the filtrate was concentrated under reduced pressure to give 25G (0.12 g).

[0505] LCMS m / z = 167.2 [M+1] +

[0506] Step 8: Synthesis of compound 25

[0507] Into a reaction flask was added 25G (120 mg, 0.74 mmol), 1a (300 mg, 0.74 mmol), DIPEA (190 mg, 1.48 mmol), DMSO (5 mL), and the reaction was heated at 140 °C in an oil bath for about 7 h. After cooling to room temperature, ethyl acetate was added and the reaction was washed twice with saturated aqueous sodium chloride. The residue was purified by column chromatography on silica gel (eluent: DCM-MeOH = 100-0 to 80-20), and the product was purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge® Prep C18 (30 mm x 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)) to give trifluoroacetate salt of compound 25 (99 mg).

[0508] LCMS m / z = 550.3 [M+1] +

[0509] Example 26: Preparation of compound 26

[0510] Into a reaction flask was added 1-methyl-3-azetidinecarboxylic acid (0.008 g, 0.07 mmol), HATU (0.049 g, 0.12 mmol), and DIPEA (0.023 g, 0.18 mmol), and the reaction was stirred at room temperature for 10 min. Compound 1 (0.030 g, 0.059 mmol) was added to the reaction, and the reaction was stirred at room temperature for 18 h. The reaction was extracted with dichloromethane three times after adding water, and the combined organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge® Prep C18 (30 mm x 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)) to give trifluoroacetate salt of compound 26 (5 mg).

[0511] LCMS m / z = 607.3 [M+1]+

[0512] Example 27: Preparation of compound 27

[0513] DCM (3 mL) was added to compound 1 (40 mg, 0.078 mmol) and glycolic acid (7.12 mg, 0.094 mmol), then HOBT (11.59 mg, 0.086 mmol), EDCI (22.43 mg, 0.12 mmol) and N-methylmorpholine (17.36 mg, 0.17 mmol) were added to the reaction solution. After addition, the reaction was stirred at room temperature for 18 hours. The reaction solution was extracted with dichloromethane three times after adding water, and the combined organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-40 / 60) to obtain compound 27 (15 mg, yield: 34%).

[0514] LCMS m / z = 568.3 [M+1] +

[0515] Example 28: Preparation of compound 28

[0516] DCM (3 mL) was added to methoxyacetic acid (6.38 mg, 0.071 mmol), then HATU (44.87 mg, 0.12 mmol) and DIPEA (22.88 mg, 0.18 mmol) were added to the reaction solution. After addition, the reaction was stirred at room temperature for 10 minutes, then compound 1 (30 mg, 0.059 mmol) was added to the reaction. After addition, the reaction was stirred at room temperature for 18 hours. The reaction solution was extracted with dichloromethane three times after adding water, and the combined organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-60 / 40) to obtain trifluoroacetate of compound 28 (15 mg).

[0517] LCMS m / z = 582.2 [M+1] +

[0518] Example 29: Preparation of compound 29

[0519] First step: Preparation of compound 29a

[0520] Compound 29 (5 mg, yield 2%) was obtained by the following procedures. Acetaldoxime (220 mg, 3.72 mmol) was dissolved in dichloromethane (5 mL), N-chlorosuccinimide (520 mg, 3.91 mmol) was added, and then the temperature was raised to 40 °C and stirred for 22 h. After the reaction was completed, water (20 mL) was added to dilute the system, dichloromethane (10 mL x 3) was added for extraction, and the separated organic phase was dried over anhydrous sodium sulfate and filtered to obtain 29a (350 mg).

[0521] Second Step: Preparation of compound 29

[0522] Compound 1 (200 mg, 0.39 mmol) was dissolved in dichloromethane (3 mL), triethylamine (0.16 mL, 1.17 mmol) and 29a (73 mg, 0.78 mmol) were added, and stirred at room temperature for 16 h. After the reaction was completed, water (5 mL) was added to dilute the system, dichloromethane (5 mL x 3) was added for extraction, and the combined organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-60 / 40), and the obtained crude product was prepared by pre-HPLC (instrument: waters 2767 preparative liquid phase; color column: SUNFIRE@Prep C18 (19 mm x 250 mm); preparative chromatography conditions: mobile phase A: acetonitrile, mobile phase B: water (containing 50 mM ammonium bicarbonate)) to obtain compound 29 (5 mg, yield 2%).

[0523] LCMS m / z = 567.2 [M+H] +

[0524] Example 30: Preparation of compound 30

[0525] Compound 3 (100 mg, 0.19 mmol) was dissolved in dichloromethane (3 mL), triethylamine (58 mg, 0.57 mmol) and 29a (34 mg, 0.36 mmol) were added, and stirred at room temperature for 16 h. After the reaction was completed, water (5 mL) was added to dilute the system, dichloromethane (5 mL x 3) was added for extraction, and the combined organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-60 / 40), and the obtained crude product was prepared by pre-HPLC (instrument: waters 2767 preparative liquid phase; color column: SUNFIRE@Prep C18 (19 mm x 250 mm); preparative chromatography conditions: mobile phase A: acetonitrile, mobile phase B: water (containing 50 mM ammonium bicarbonate)) to obtain compound 30 (3 mg, yield 3%).

[0526] LCMS m / z = 581.2 [M+H] +

[0527] Example 31: Preparation of compound 31

[0528] To a flask, 1-methoxycyclopropanecarboxylic acid (37.9 mg, 0.33 mmol) was added into dichloromethane (5 mL), then HATU (127 mg, 0.33 mmol) and DIPEA (82 mg, 0.64 mmol) were added into the reaction solution. After addition, the reaction solution was stirred at room temperature for 10 min, then compound 2 (80 mg, 0.16 mmol) was added into the reaction solution. After addition, the reaction solution was stirred at room temperature for 18 h. The reaction solution was added into water, then extracted with dichloromethane for three times. The combined organic phase was dried over anhydrous sodium sulfate, then concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-60 / 40). The obtained crude product was purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge@Prep C18 (30 mm x 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)). The product was lyophilized to obtain compound 31 trifluoroacetate (10 mg).

[0529] LCMS m / z = 608.3 [M+1] +

[0530] Example 32: Preparation of compound 32

[0531] First step: synthesis of 32A

[0532] Into a flask, 1-amino-1-cyclopropylcyanide hydrochloride (0.14 g, 1.22 mmol), pyridine (3 mL), cesium carbonate (0.53 g, 1.62 mmol), DMAP (0.099 g, 0.81 mmol) were added, stirred for 5 min, then 6a (0.3 g, 0.81 mmol) in pyridine (3 mL) was added dropwise under ice-water cooling. After addition, the reaction solution was stirred at room temperature for 2 h. The reaction solution was added into ethyl acetate, then washed with saturated sodium chloride aqueous solution for two times, 1N hydrochloric acid for two times, water for one time. The residue was concentrated under reduced pressure, then purified by silica gel column chromatography (eluent: PE-EA = 100-0 to 60-40) to obtain 32A (0.28 g, yield: 83%)

[0533] LCMS m / z = 414.7 [M+1] +

[0534] Second step: synthesis of 32B

[0535] A reaction flask was charged with 32A (120 mg, 0.29 mmol), 3J (70 mg, 0.29 mmol), DIPEA (75 mg, 0.58 mmol) and DMSO (5 mL), the reaction was heated in an oil bath at 140 °C for about 7 hours, after the reaction was cooled to room temperature, ethyl acetate was added, washed with saturated sodium chloride solution twice, concentrated under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent: PE-EA = 100-0 to 60-40), 32B (130 mg, yield: 71%) was obtained.

[0536] Step 3: Synthesis of compound 32

[0537] 32B (130 mg, 0.20 mmol) was dissolved in 2 mL of dichloromethane, 0.5 mL of trifluoroacetic acid was added, and stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure, and the residue was purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge@Prep C18 (30 mm x 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)), and the trifluoroacetate salt of compound 32 (13 mg) was obtained by freeze-drying of the preparative liquid.

[0538] LCMS m / z = 535.0 [M+1] +

[0539] 1 H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 9.18-9.00 (m, 2H), 8.85 (s, 1H), 8.58 (s, 1H), 7.61 (t, 1H), 7.28-7.23 (m, 1H), 4.02-3.87 (m, 1H), 3.78-3.68 (m, 1H), 3.68-3.54 (m, 2H), 3.40-3.35 (m, 1H), 3.08-2.95 (m, 1H), 1.50-1.40 (m, 5H), 1.40-1.30 (m, 3H), 0.76-0.65 (m, 2H), 0.65-0.54 (m, 2H).

[0540] Example 33: Preparation of compound 33

[0541] A reaction vial was charged with compound 1 (44 mg, 0.086 mmol), triethylamine (26 mg, 0.26 mmol) and dichloromethane (3 mL), a solution of dimethylaminocarbonyl chloride (0.018 g, 0.17 mmol) in dichloromethane (2 mL) was added dropwise under ice-water cooling, after the addition was completed, the reaction was stirred at room temperature for 3 hours. Water and dichloromethane were added and stirred to separate the layers, the organic layer was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: petroleum ether-ethyl acetate = 100-0 to 50-50), the obtained product was purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge@Prep C18(30mmx150mm); mobile phase composition: acetonitrile, water containing 0.1% trifluoroacetic acid), and the preparative liquid was freeze-dried to obtain compound 33 (14 mg, yield: 28%).

[0542] LCMS m / z = 581.2 [M+1] +

[0543] 1 H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.46 (s, 1H), 8.31 (s, 1H), 7.60 (t, 1H), 7.24-7.14 (m, 1H), 3.87-3.70 (m, 2H), 3.66-3.52 (m, 1H), 3.50-3.38 (m, 1H), 3.31-3.22 (m, 1H), 3.16-2.98 (m, 2H), 2.77 (s, 6H), 1.64-1.51 (m, 1H), 1.09 (s, 3H), 0.73-0.62 (m, 2H), 0.60-0.52 (m, 1H), 0.52-0.44 (m, 1H), 0.44-0.35 (m, 3H), 0.35-0.26 (m, 1H).

[0544] Example 34: Preparation of compound 34

[0545] Compound 34A (100 mg, 0.21 mmol) was dissolved in dichloromethane (3 mL), triethylamine (64 mg, 0.63 mmol) and 29a (39 mg, 0.42 mmol) were added, and stirred at room temperature for 16 hours. After the reaction was completed, it was diluted with water (5 mL), extracted with dichloromethane (5 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol (V / V) = 1 / 0-20 / 1), and the obtained crude product was purified by pre-HPLC (instrument: waters 2767 preparative liquid phase; column: SUNFIRE@Prep C18(19mm x 250mm); preparative chromatography conditions: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% trifluoroacetic acid) to obtain compound 34 (10 mg, yield 9%).

[0546] LCMS m / z = 541.2 [M+H] +

[0547] Example 35: Preparation of compound 35

[0548] A reaction bottle was added with compound 1 (50 mg, 0.098 mmol), triethylamine (20 mg, 0.20 mmol) and dichloromethane (3 mL), and under ice water cooling, triphosgene (32 mg, 0.11 mmol) was added, and after the addition was completed, the reaction was stirred in an ice bath for 0.5 h, then 0.5 mL of anhydrous methanol was added, and the stirring was continued at room temperature for 0.5 h. Water and dichloromethane were added and stirred to separate the layers, and the organic layer was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 1 / 0-20 / 1), and the obtained product was purified by HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge@Prep C18(30mm x 150mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)), and the preparation liquid was freeze-dried to obtain compound 35 (5 mg, yield: 9%).

[0549] LCMS m / z = 568.2 [M+1] +

[0550] Example 36: Preparation of compound 36

[0551] A reaction vial was charged with compound 1 (0.048 g, 0.094 mmol), DIPEA (0.036 g, 0.28 mmol) and dichloromethane (3 mL), a solution of methanecarbamic acid chloride (0.013 g, 0.14 mmol) in dichloromethane (2 mL) was added dropwise under ice water cooling, the reaction was stirred at room temperature for 1 hour after the addition was completed, water and dichloromethane were added and stirred to separate the layers, the organic phase was concentrated under reduced pressure, the residue was separated and purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge@Prep C18(30mmx150mm); mobile phase composition: acetonitrile, water containing 0.1% trifluoroacetic acid), and the preparative liquid was freeze-dried to give compound 36 (21 mg, yield: 39%)

[0552] LCMS m / z = 567.2 [M+1] +

[0553] Example 37: Preparation of compound 37

[0554] A reaction vial was charged with 34A (0.1 g, 0.21 mmol), cyanomethyl formate (0.062 g, 0.63 mmol), methanol (10 mL) and DBU (0.048 g, 0.32 mmol), the reaction was heated at 65°C in an oil bath for about 18 hours, concentrated under reduced pressure, ethyl acetate and water were added and stirred to separate the layers, the organic layer was concentrated under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent: PE-EA = 100-0 to 60-40), the obtained product was separated and purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge@Prep C18(30mmx150mm); mobile phase composition: acetonitrile, water containing 0.1% trifluoroacetic acid), and the preparative liquid was freeze-dried to give compound 37 (6 mg, yield: 5%).

[0555] LCMS m / z = 550.2 [M+1] +

[0556] Example 38: Preparation of compound 38

[0557] First step: synthesis of 38A

[0558] A reaction flask was charged with hydroxylamine hydrochloride (6.25 g, 89.88 mmol), water (20 mL) and sodium carbonate (6.35 g, 59.92 mmol), and a solution of cyclopropylcarboxaldehyde (4.2 g, 59.92 mmol) in ethanol (20 mL) was added with stirring. The reaction was stirred at room temperature for 3 hours. Ethyl acetate and water were added, and the mixture was stirred and partitioned. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was stirred in petroleum ether for 1 hour, filtered, and the filter cake was dried to give 38A (1.8 g, yield: 35%).

[0559] Second Step: Synthesis of 38B

[0560] A reaction flask was charged with 38A (0.3 g, 3.53 mmol), N-chlorosuccinimide (0.49 g, 3.71 mmol) and dichloromethane (10 mL), and the reaction was heated at 40 °C in an oil bath for 3 hours, and then allowed to cool to room temperature. Water was added, and the mixture was stirred and partitioned. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 38B (0.3 g).

[0561] Third Step: Synthesis of Compound 38

[0562] A reaction flask was charged with 34A (0.11 g, 0.23 mmol), triethylamine (0.070 g, 0.69 mmol) and dichloromethane (5 mL), and a solution of 38B (0.027 g, 0.23 mmol) in dichloromethane (5 mL) was added with stirring. The reaction was stirred at room temperature overnight. Water was added, and the mixture was stirred and partitioned. The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: PE-EA = 100-0 to 40-60). The product was further purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge® Prep C18 (30 mm x 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)), and the preparation was lyophilized to give trifluoroacetate of compound 38 (50 mg).

[0563] LCMS m / z = 567.2 [M+1] +

[0564] Example 39: Preparation of Compound 39

[0565] First Step: Preparation of 39A

[0566] Into a 100 mL reaction flask, 3-(fluoromethyl)oxetan-3-amine hydrochloride (0.38 g, 2.71 mmol), triethylamine (0.82 g, 8.13 mmol) and DCM (30 mL) were added, after cooling in ice bath for ten minutes, compound 21B (1.0 g, 2.71 mmol) was added, after stirring for 5 minutes, DMAP (0.66 g, 5.42 mmol) was added, after the addition was completed, the natural temperature was increased overnight. After water (60 mL) was added to the reaction solution, it was extracted with dichloromethane (60 mL x 2), the combined organic phase was dried with anhydrous sodium sulfate, after suction filtration, the solution was added with appropriate amount of silica gel and concentrated under reduced pressure, the residue was separated and purified by medium pressure preparative silica gel column (PE / EA: 0%-20%) to obtain 39A (400 mg, yield 34%).

[0567] LCMS m / z = 438.0 [M+1] +

[0568] Second step: preparation of 39B

[0569] 39A (150 mg, 0.34 mmol) was dissolved in 5 mL of DMSO, 3J (90 mg, 0.37 mmol) and DIPEA (220 mg, 1.7 mmol) were added, after the addition was completed, the reaction was stirred at 140°C for 8 hours. The reaction solution was cooled to room temperature, water and ethyl acetate were added and stirred, then separated into layers, the aqueous phase was extracted with ethyl acetate three times, the combined organic phase was washed with saturated brine twice, dried with anhydrous sodium sulfate and concentrated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-4 / 1) to obtain 39B (200 mg, yield: 88%).

[0570] LCMS m / z = 658.3 [M+1] +

[0571] Third step: preparation of compound 39

[0572] 39B (200 mg, 0.30 mmol) was dissolved in 5 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, dichloromethane (50 mL) was added to the residue, and then saturated sodium bicarbonate solution (50 mL x 2), saturated brine (50 mL) was washed, the organic phase was dried and concentrated, the obtained crude product was purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge@Prep C18(30mm x 150mm); mobile phase composition: acetonitrile, water containing 0.1% trifluoroacetic acid), and then freeze-dried to obtain the trifluoroacetate salt of compound 39 (80 mg).

[0573] LCMS m / z = 558.2 [M+1] +

[0574] 1 H NMR (400 MHz, DMSO-d6) δ 9.23 - 9.04 (m, 2H), 9.02 (s, 1H), 8.82 (s, 1H), 8.55 (s, 1H), 7.61 (t, 1H), 7.33 - 7.19 (m, 1H), 4.73 - 4.53 (m, 4H), 4.40 - 4.31 (m, 2H), 4.03 - 3.87 (m, 1H), 3.77 - 3.54 (m, 3H), 3.34 (dd, 1H), 3.07 - 2.97 (m, 1H), 1.55 - 1.25 (m, 4H), 0.85 - 0.45 (m, 4H).

[0575] Example 40: Preparation of compound 40

[0576] First Step: Synthesis of 40A

[0577] Into a reaction vial was added cyclopropylamine (0.23 g, 4.08 mmol) and dichloromethane (5 mL), a solution of 6a (0.25 g, 0.68 mmol) in dichloromethane (5 mL) was added dropwise under ice water cooling, after the addition was completed, the reaction was stirred at room temperature for 1 hour. Water was added and stirred, the organic layer was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: PE-EA = 100-0 to 60-40) to give 40A (0.17 g, yield: 66%).

[0578] LCMS m / z = 390.0 [M+1] +

[0579] Second Step: Synthesis of 40B

[0580] Into a reaction vial was added 40A (0.090 g, 0.23 mmol), 3J (0.055 g, 0.23 mmol), DIPEA (0.089 g, 0.69 mmol) and DMSO (5 mL), and the reaction was heated at 140 °C in an oil bath for about 7 hours. After cooling to room temperature, ethyl acetate was added, and washed with saturated aqueous sodium chloride solution twice, the organic layer was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: PE-EA = 100-0 to 60-40) to give 40B (0.050 g, yield: 35%).

[0581] LCMS m / z = 610.3 [M+1] +

[0582] Third Step: Synthesis of compound 40

[0583] Into a reaction vial was placed 40B (0.050 g, 0.082 mmol) and dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added with stirring, the reaction was stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure, the residue was separated and purified by HPLC (Instrument: waters 2767 preparative liquid; column: XBridge®Prep C18(30 mm x 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)), and the trifluoroacetate salt of compound 40 (27 mg) was obtained by lyophilization of the preparative liquid.

[0584] LCMS m / z = 510.1 [M+1] +

[0585] Example 41: Preparation of compound 41

[0586] First step: synthesis of 41A

[0587] Into a reaction vial was placed 1-difluoromethylcyclopropane-1-amine hydrochloride (0.20 g, 1.36 mmol), DMAP (0.083 g, 0.68 mmol), cesium carbonate (0.44 g, 1.36 mmol) and pyridine (3 mL), a solution of 6a (0.25 g, 0.68 mmol) in pyridine (3 mL) was added with ice water cooling, the reaction was stirred at room temperature for 1 hour after addition. Ethyl acetate was added, the organic layer was washed with water once, 1N hydrochloric acid twice, water once, the organic layer was concentrated under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent: PE-EA = 100-0 to 60-40) to give 41A (0.15 g, yield: 50%).

[0588] LCMS m / z = 440.0 [M+1] +

[0589] Second step: synthesis of 41B

[0590] Into a reaction vial was placed 41A (0.010 g, 0.23 mmol), 3J (0.055 g, 0.23 mmol), DIPEA (0.089 g, 0.69 mmol) and DMSO (5 mL), the reaction was heated at 140°C in an oil bath for about 7 hours, then cooled to room temperature, ethyl acetate was added, the organic layer was washed with saturated aqueous sodium chloride solution twice, then concentrated under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent: PE-EA = 100-0 to 60-40) to give 41B (0.060 g, yield: 40%).

[0591] LCMS m / z = 660.3 [M+1] +

[0592] Third step: synthesis of compound 41

[0593] Into a reaction vial was placed 41B (0.060 g, 0.082 mmol) and dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added with stirring, the reaction was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was separated and purified by preparative HPLC (instrument: waters 2767 preparative liquid; column: XBridge®Prep C18(30 mm x 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)), the preparative liquid was lyophilized to give trifluoroacetate salt of compound 41 (33 mg).

[0594] LCMS m / z = 560.2 [M+1] +

[0595] Example 42: Preparation of compound 42

[0596] First Step: Synthesis of 42A

[0597] Into a reaction vial was placed 1-(methoxymethyl)cyclopropane-1-amine hydrochloride (0.15 g, 1.08 mmol), DMAP (0.066 g, 0.54 mmol), cesium carbonate (0.35 g, 1.08 mmol) and pyridine (3 mL), a solution of 6a (0.20 g, 0.54 mmol) in pyridine (3 mL) was added with ice water cooling, the reaction was stirred at room temperature for 1 hour after addition. Ethyl acetate was added, the organic layer was washed with water once, 1N hydrochloric acid twice, water once, the organic layer was concentrated under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent: PE-EA = 100-0 to 60-40) to give 42A (0.14 g, yield: 58%).

[0598] LCMS m / z = 434.0 [M+1] +

[0599] Second Step: Synthesis of 42B

[0600] Into a reaction vial was placed 42A (0.010 g, 0.23 mmol), 3J (0.055 g, 0.23 mmol), DIPEA (0.089 g, 0.69 mmol) and DMSO (5 mL), the reaction was heated at 140°C in an oil bath for about 7 hours. After cooling to room temperature, ethyl acetate was added, the organic layer was washed with saturated aqueous sodium chloride solution twice, then concentrated under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent: PE-EA = 100-0 to 60-40) to give 42B (0.035 g, yield: 23%).

[0601] LCMS m / z = 598.2 [M-55] +

[0602] Step 3: Synthesis of compound 42

[0603] Into a reaction vial was placed 42B (0.035 g, 0.054 mmol) and dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added with stirring, the reaction was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was separated and purified by preparative HPLC (instrument: waters 2767 preparative liquid; column: XBridge@Prep C18(30 mm x 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)), and the trifluoroacetate salt of compound 42 (23 mg) was obtained by freeze-drying of the preparative liquid.

[0604] LCMS m / z = 554.2 [M+1] +

[0605] Example 43: Preparation of compound 43

[0606] Step 1: Synthesis of 43A

[0607] Into a reaction vial was placed 1-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1- amine dihydrochloride (0.17 g, 0.81 mmol), pyridine (3 mL), cesium carbonate (0.70 g, 2.16 mmol), DMAP (0.066 g, 0.54 mmol), stirred for 10 minutes, a solution of 6a (0.2 g, 0.54 mmol) in pyridine (3 mL) was added dropwise under ice-water cooling, after the addition was completed, the reaction was stirred at room temperature for 16 hours. Ethyl acetate was added to the reaction solution, which was washed twice with saturated aqueous sodium chloride solution and once with water, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: PE-EA = 100-0 to 50-50) to give 43A (0.05 g, yield: 20%)

[0608] LCMS m / z = 470.1 [M+1] +

[0609] Step 2: Synthesis of 43B

[0610] Into a reaction vial was placed 43A (50 mg, 0.11 mmol), 3J (40 mg, 0.17 mmol), DIPEA (71 mg, 0.55 mmol) and DMSO (3 mL), heated to react at 140°C for about 7 hours, the reaction solution was cooled to room temperature, ethyl acetate was added, washed twice with saturated sodium chloride solution, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: PE-EA = 100-0 to 50-50) to give 43B (40 mg, yield: 54%).

[0611] Step 3: Synthesis of compound 43

[0612] Compound 43 (40 mg, 0.058 mmol) was dissolved in 3 mL of dichloromethane, 0.6 mL of trifluoroacetic acid was added, and the reaction was stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure, and the residue was purified by preparative HPLC (instrument: waters 2767 preparative liquid; column: XBridge®Prep C18(30 mm x 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)) and lyophilized from the preparative liquid to obtain the trifluoroacetate salt of compound 43 (10 mg).

[0613] LCMS m / z = 590.2 [M+1] +

[0614] Example 44: Preparation of compound 44

[0615] Compound 2 (0.060 g, 0.12 mmol) was added to DCM (3 mL), HATU (0.091 g, 0.24 mmol) and DIPEA (0.046 g, 0.36 mmol) were added to the reaction, and the reaction was stirred at room temperature for 10 min. 1-Methyl-3-azabutane carboxylic acid (0.016 g, 0.14 mmol) was added to the reaction, and the reaction was stirred at room temperature for 18 h. The reaction was extracted with dichloromethane three times after being added to saturated aqueous sodium bicarbonate solution, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: DCM-MeOH = 100-0 to 90-10) to obtain compound 44 (20 mg, yield: 28%).

[0616] LCMS m / z = 607.3 [M+1] +

[0617] Example 45: Preparation of compound 45

[0618] Compound 2 (40 mg, 0.078 mmol) was added to DCM (3 mL), dimethylcarbamoyl chloride (10.07 mg, 0.094 mmol) and triethylamine (15.79 mg, 0.16 mmol) were added to the reaction with stirring at room temperature, and the reaction was stirred at room temperature for 18 h. The reaction was extracted with dichloromethane three times after being added to saturated aqueous sodium bicarbonate solution, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-50 / 50) to obtain compound 45 (10 mg, yield: 22%).

[0619] LCMS m / z = 581.2 [M+1] +

[0620] 1 H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.46 (s, 1H), 8.31 (s, 1H), 7.60 (t, 1H), 7.23-7.16 (m, 1H), 3.90-3.69 (m, 2H), 3.65-3.51 (m, 1H), 3.49-3.38 (m, 1H), 3.29-3.21 (m, 1H), 3.15-3.02 (m, 2H), 2.77 (s, 6H), 1.66-1.50 (m, 1H), 1.09 (s, 3H), 0.73-0.61 (m, 2H), 0.61-0.52 (m, 1H), 0.52-0.43 (m, 1H), 0.43-0.35 (m, 3H), 0.35-0.26 (m, 1H).

[0621] Example 46: Preparation of compound 46

[0622] Compound 2 (40 mg, 0.078 mmol), N,N-diisopropyl ethylamine (40 mg, 0.31 mmol) and dichloromethane (3 mL), under ice water cooling, triphosgene (11.57 mg, 0.039 mmol) was added, after adding, the reaction was stirred at room temperature for 0.5 h, then N-methyl hydroxylamine hydrochloride (33 mg, 0.39 mmol) in dichloromethane (1 mL) was added to the reaction solution, and stirring was continued at room temperature overnight. Saturated sodium bicarbonate and dichloromethane were added and stirred to separate the layers, the organic layer was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 0-30 / 70) to obtain compound 46 (20 mg, yield: 44%).

[0623] LCMS m / z = 583.1 [M+1] +

[0624] 1 H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.46 (s, 1H), 8.31 (s, 1H), 7.60 (t, 1H), 7.23-7.16 (m, 1H), 3.90-3.69 (m, 2H), 3.65-3.51 (m, 1H), 3.49-3.38 (m, 1H), 3.29-3.21 (m, 1H), 3.15-3.02 (m, 2H), 2.77 (s, 6H), 1.66-1.50 (m, 1H), 1.09 (s, 3H), 0.73-0.61 (m, 2H), 0.61-0.52 (m, 1H), 0.52-0.43 (m, 1H), 0.43-0.35 (m, 3H), 0.35-0.26 (m, 1H).

[0625] Example 47: Preparation of compound 47

[0626] Compound 2 (40 mg, 0.078 mmol), N,N-diisopropylethylamine (40 mg, 0.31 mmol) and dichloromethane (3 mL), under ice-water cooling, were added with triphosgene (11.57 mg, 0.039 mmol), and after the addition was completed, the reaction was stirred at room temperature for 0.5 h. A solution of N-methylcyclopropylamine hydrochloride (41.95 mg, 0.39 mmol) in dichloromethane (1 mL) was added to the reaction solution, and stirring was continued at room temperature overnight. Saturated sodium bicarbonate and dichloromethane were added, and the organic layer was separated by stirring. The residue obtained after concentration under reduced pressure was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 0-30 / 70), to obtain compound 47 (20 mg, yield: 42%).

[0627] LCMS m / z = 607.2 [M+1] +

[0628] Example 48: Preparation of compound 48

[0629] Compound 1 (40 mg, 0.078 mmol) and dichloromethane (5 mL) were added with triphosgene (12 mg, 0.039 mmol) under ice-water cooling, and then DIPEA (60 mg, 0.47 mmol) was added dropwise. After the addition was completed, the reaction was stirred at room temperature for 1 h. N-methylcyclopropylamine hydrochloride (34 mg, 0.31 mmol) was added under ice-water cooling, and after the addition was completed, the reaction was stirred at room temperature for about 3 h. Water was added to quench the reaction, and the layers were separated after standing. The residue obtained after concentration under reduced pressure was separated and purified by silica gel column chromatography (eluent: PE-EA = 100-0 to 40-60), to obtain compound 48 (18 mg, yield: 38%).

[0630] LCMS m / z = 607.3 [M+1] +

[0631] Example 49: Preparation of compound 49

[0632] First step: Preparation of 49A

[0633] To a solution of 21C (100 mg, 0.24 mmol), (2S)-2-cyclopropylpiperazine-1- carboxylic acid tert-butyl ester (65 mg, 0.29 mmol), DIPEA (93 mg, 0.72 mmol) and dimethylsulfoxide (2 mL) in an oil bath at 140 °C for about 7 hours. After cooling to room temperature, ethyl acetate was added. The organic phase was washed with saturated aqueous sodium chloride solution twice, and then concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: PE-EA = 100-0 to 60-40) to obtain 49A (100 mg, yield: 67%).

[0634] LCMS m / z = 628.3 [M+1] +

[0635] Second Step: Preparation of 49B

[0636] To a solution of 49A (100 mg, 0.16 mmol) and dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added with stirring. The reaction was stirred at room temperature for 2 hours. After concentration under reduced pressure, dichloromethane was added. The pH was adjusted to about 9 with saturated aqueous potassium carbonate solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 49B (72 mg).

[0637] LCMS m / z = 528.2 [M+1] +

[0638] Third Step: Preparation of Compound 49

[0639] To a solution of 49B (72 mg, 0.14 mmol) and dichloromethane (5 mL) under ice water cooling, triphosgene (21 mg, 0.070 mmol) was added, followed by dropwise addition of DIPEA (110 mg, 0.84 mmol). After addition, the reaction was stirred at room temperature for 1 hour. Dimethylamine hydrochloride (46 mg, 0.56 mmol) was added under ice water cooling. After addition, the reaction was stirred at room temperature for about 16 hours. Water was added to quench the reaction. After standing, the layers were separated. The organic layer was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: PE-EA = 100-0 to 40-60) to obtain compound 49 (44 mg, yield: 54%).

[0640] LCMS m / z = 599.2 [M+1] +

[0641] Example 50: Preparation of Compound 50

[0642] To a solution of compound 2 (50 mg, 0.098 mmol) in dichloromethane (5 mL) was added triphosgene (15 mg, 0.049 mmol) dropwise under ice-water cooling. After the addition was completed, DIPEA (76 mg, 0.59 mmol) was added dropwise, and the reaction was stirred at room temperature for 1 hour. (S)-3-hydroxypyrrolidine hydrochloride (48 mg, 0.39 mmol) was added under ice-water cooling, and the reaction was stirred at room temperature for about 16 hours. The reaction was quenched by the addition of water, and the mixture was allowed to stand to separate into layers. The organic layer was concentrated under reduced pressure, and the residue was separated and purified by column chromatography on silica gel (dichloromethane / methanol (V / V) = 1 / 0 to 10 / 1) to obtain compound 50 (45 mg, yield: 73%).

[0643] LCMS m / z = 623.3 [M+H] +

[0644] 1 H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.46 (s, 1H), 8.31 (s, 1H), 7.60 (t, 1H), 7.20 (s, 1H), 4.95 (d, 1H), 4.29 - 4.11 (m, 1H), 3.92 - 3.71 (m, 2H), 3.67 - 3.49 (m, 2H), 3.47 - 3.33 (m, 3H), 3.25 - 3.01 (m, 4H), 1.97 - 1.82 (m, 1H), 1.78 - 1.65 (m, 1H), 1.65 - 1.53 (m, 1H), 1.09 (s, 3H), 0.74 - 0.62 (m, 2H), 0.62 - 0.35 (m, 6H).

[0645] Example 51: Preparation of compound 51

[0646] To a solution of compound 2 (50 mg, 0.098 mmol) in dichloromethane (5 mL) was added triphosgene (15 mg, 0.049 mmol) dropwise under ice-water cooling. After the addition was completed, DIPEA (76 mg, 0.59 mmol) was added dropwise, and the reaction was stirred at room temperature for 1 hour. (S)-3-hydroxypyrrolidine hydrochloride (48 mg, 0.39 mmol) was added under ice-water cooling, and the reaction was stirred at room temperature for about 16 hours. The reaction was quenched by the addition of water, and the mixture was allowed to stand to separate into layers. The organic layer was concentrated under reduced pressure, and the residue was separated and purified by column chromatography on silica gel (dichloromethane / methanol (V / V) = 1 / 0 to 10 / 1) to obtain compound 50 (45 mg, yield: 73%).

[0647] LCMS m / z = 623.2 [M+H] +

[0648] 1H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.46 (s, 1H), 8.32 (s, 1H), 7.60 (t, 1H), 7.19 (s, 1H), 4.84 (d, 1H), 4.30 - 4.18 (m, 1H), 3.90 - 3.74 (m, 2H), 3.66 - 3.46 (m, 4H), 3.28 - 3.16 (m, 3H), 3.12 - 2.99 (m, 2H), 1.86 - 1.70 (m, 2H), 1.66 - 1.55 (m, 1H), 1.09 (s, 3H), 0.75 - 0.62 (m, 2H), 0.60 - 0.52 (m, 1H), 0.51 - 0.32 (m, 5H).

[0649] Example 52: Preparation of compound 52

[0650] To a solution of compound 1 (50 mg, 0.098 mmol) in dichloromethane (5 mL) was added triphosgene (15 mg, 0.049 mmol) under ice-water cooling, then DIPEA (76 mg, 0.59 mmol) was added dropwise. After the addition was completed, the reaction was stirred at room temperature for 1 hour. (R)-3-hydroxypyrrolidine hydrochloride (48 mg, 0.39 mmol) was added under ice-water cooling, and the reaction was stirred at room temperature for about 16 hours. The reaction was quenched by adding water, and the layers were separated after standing. The organic layer was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: PE-EA = 100-0 to 40-60) to obtain compound 52 (20 mg, yield: 33%).

[0651] LCMS m / z = 623.2 [M+1] +

[0652] 1 H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.46 (s, 1H), 8.32 (s, 1H), 7.60 (t, 1H), 7.19 (s, 1H), 4.84 (d, 1H), 4.30 - 4.18 (m, 1H), 3.90 - 3.74 (m, 2H), 3.66 - 3.46 (m, 4H), 3.28 - 3.16 (m, 3H), 3.12 - 2.99 (m, 2H), 1.86 - 1.70 (m, 2H), 1.66 - 1.55 (m, 1H), 1.09 (s, 3H), 0.75 - 0.62 (m, 2H), 0.60 - 0.52 (m, 1H), 0.51 - 0.32 (m, 5H).

[0653] Example 53: Preparation of compound 53

[0654] Triphosgene (15 mg, 0.049 mmol) and dichloromethane (5 mL) were added under ice-water cooling, followed by the addition of compound 1 (50 mg, 0.098 mmol), and then DIPEA (76 mg, 0.59 mmol) was added dropwise. The mixture was stirred at room temperature for 1 hour after the addition was complete. (S)-3-hydroxypyrrolidine hydrochloride (48 mg, 0.39 mmol) was added under ice-water cooling, and the mixture was stirred at room temperature for approximately 16 hours after the addition was complete. The reaction was quenched with water, and the mixture was allowed to stand to separate into layers. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: PE-EA = 100-0 to 40-60) to give compound 53 (33 mg, yield: 54%).

[0655] LCMS m / z = 623.3[M+1] +

[0656] 1 H NMR(400MHz,DMSO-d6)δ8.77(s,1H),8.46(s,1H),8.31(s,1H),7.60(t,1H), 7.20(s,1H),4.83(d,1H),4.32–4.19(m,1H),3.91–3.74(m,2H),3.65–3.47( m,4H),3.27–3.14(m,3H),3.10–2.98(m,2H),1.88–1.69(m,2H),1.67–1.53( m,1H),1.09(s,3H),0.74–0.62(m,2H),0.61–0.51(m,1H),0.51–0.30(m,5H).

[0657] Reference compound 1:

[0658] Biological test cases

[0659] 1. PARG enzyme activity assay

[0660] This study evaluated the ability of the compound to inhibit the activity of poly(ADP-ribose) hydrolase PARG in vitro. The experiment used homogeneous time-resolved fluorescence (HTRF) to measure the hydrolytic effect of PARG on the substrate ADP-ribose. In this experiment, the substrate PARylation was first prepared in 50 mM Tris-HCl (pH 7.5), 4 mM MgCl2, 100 mM NaCl, 0.01% BSA, and 2 mM DTT buffer. His-PARP1 (ICE, S2202T-H27H) was added to a final concentration of 0.4 mg / ml, DNA (Genecipt, C779NHF090) to a final concentration of 100 nM, and NAD+ to a final concentration of 100 μM. +Bio-NAD (Sigma, N6522) at a final concentration of 20 μΜ + (TOCRIS, 6573), after 60 min incubation at 25°C the solution was moved into a dialysis bag and dialyzed overnight at 4°C in the same buffer; inhibitors containing 1% DMSO were added to the 384-well plates using the Echo, 2.5 μL of PARG (ICE, 2022.03.23) solution at a final concentration of 150 pM in 50 mM Tris-HCl pH 7.5, 3 mM EDTA, 0.4 mM EGTA, 50 mM KCl, 0.01% Tween-20, 1 M DTT and 0.01% BSA buffer were added, the reaction was carried out at 25°C for 15 min, followed by the addition of 2.5 μL of substrate PARylation at a final concentration of 80 nM, the reaction was carried out at 25°C for 60 min. A mixture solution of MAb Anti-6HIS-Tb cryptate Gold (Perkin Elmer, 61HI2TLB) at a final concentration of 0.665 nM and Streptavidin-XL665 (Perkin Elmer, 610SAXLB) at a final concentration of 3333.34 nM was prepared, 5 ul was added to each well and the reaction was carried out at 25°C for 60 min. Data were read using a BMG instrument, the ratio of the emission values at 665 nm (acceptor) and 615 nm (donor) was calculated, IC50values were determined by fitting the data to a sigmoidal dose-response curve using a non-linear regression equation.

[0661] Table 1-1 Results of PARG enzyme inhibitory activity of test compounds

[0662] Note: A < 100 nM in Table 1-1

[0663] Conclusion: The compounds of the present application, such as the example compounds, have good inhibitory activity on PARG enzyme.

[0664] 2. MDA-MB-436 cell viability assay

[0665] Cell viability studies were performed on the MDA-MB-436 cell line. Cells were cultured in DMEM medium (ATCC, Cat# 30-2002) supplemented with 10% v / v FBS (Gibico, Cat# 10091148), 1% v / v penicillin streptomycin (Invitrogen, Cat# 15140122). Cells were plated in 384-well plates (Corning, Cat# 3765) at a density of 300 cells / well. Test compounds were dissolved in 100% DMSO to 10 mM. On the day of the experiment, compounds were diluted in 10 concentration points starting from 10 mM using an Agilent Bravo automated liquid handling platform (#16050-102). Diluted compounds were dispensed into cell plates using an Echo liquid handling workstation (LABCYTE #Echo550). Cell plates were incubated at 37°C in a 5% CO2 incubator for 7 days. Cell viability was measured using the reagent Cell Titer-Glo (Promega, Cat# G7573) according to the manufacturer's instructions. Luminescent signal was measured using a multimode plate reader (Perkin Elmer, Envision 2104). The average signal value of DMSO treated wells on the plate was calculated and used as the high control (HC). The average signal value of 10 uM positive compound was calculated and used as the low control (LC). % inhibition = (Signal Ave HC -Signal Cmpd ) / (Signal Ave HC -Signal Ave LC ) x 100.

[0666] IC50 values were determined using XLfit software fitting the data to the Hill Slope standard 4 parameter.

[0667] Table 2-1 Results of MDA-MB-436 cell viability inhibition activity of test compounds

[0668] Note: A < 1 uM in Table 2-1

[0669] Conclusion: The compounds of the present application, such as the example compounds, have good inhibition activity on MDA-MB-436 cells.

[0670] 3. hERG Potassium Ion Channel Effect Test

[0671] Experimental platform: electrophysiological manual patch clamp system

[0672] Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium ion channel

[0673] Experimental method: CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channel were used to record hERG potassium channel current by whole-cell patch clamp technique at room temperature. Glass microelectrode was drawn from glass electrode embryo (BF150-86-10, Sutter) by a puller, and the tip resistance of the electrode after being filled with internal solution was about 2-5 MΩ. The glass microelectrode was inserted into the amplifier probe and then connected to the patch clamp amplifier. The clamping voltage and data recording were controlled and recorded by computer through pClamp 10 software, and the sampling frequency was 10 kHz and the filter frequency was 2 kHz. After obtaining the whole-cell recording, the cell was clamped at -80 mV, and the step voltage of hERG potassium current (I hERG ) was given from -80 mV to a 2s depolarization voltage to +20 mV, and then repolarized to -50 mV, and then returned to -80 mV for 1s. The voltage stimulation was given every 10s, and after the hERG potassium current was determined to be stable (at least 1 minute), the drug administration process was started. Each test concentration of the compound was given for at least 1 minute, and at least 2 cells were tested for each concentration (n≥2).

[0674] Data processing: pClamp 10, GraphPad Prism 5 and Excel software were used for data analysis and processing. The inhibition degree of different compound concentrations on hERG potassium current (peak value of hERG tail current induced at -50 mV) was calculated by the following formula: Inhibition% = [1-(I / Io)]x100%

[0675] Wherein, Inhibition% represents the inhibition percentage of the compound on hERG potassium current, and I and Io represent the amplitude of hERG potassium current after and before drug administration, respectively.

[0676] Compound IC 50 The following equation was used to calculate the fitting calculation by using GraphPad Prism 5 software: Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0677] Wherein, X is the Log value of the test concentration of the test product, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0678] Table 3-1 Results of the effect of test compounds on hERG potassium ion channel

[0679] Conclusion: The compound of the present application, for example, the compound of the examples, has no obvious inhibitory effect on the hERG potassium ion channel.

[0680] 4. Caco2 permeability test

[0681] The test uses single layer Caco-2 cells, incubated in triplicate in 96-well Transwell plates. Transport buffer solution (HBSS, 10 mM HEPES, pH 7.4 ± 0.05) containing the compound of the application (5 μM) is added to the donor wells on either the apical or basolateral side. DMSO-containing transport buffer solution is added to the corresponding receiver wells. After incubation at 37 ± 1 °C for 2 hours, the cell plates are removed and an aliquot of sample is taken from both the apical and basolateral sides into fresh 96-well plates. Acetonitrile containing internal standard is then added to precipitate the protein. The samples are analyzed using LC MS / MS and the concentration of the compound of the application and control compound is determined. The concentration data is used to calculate the apparent permeability coefficient for transport from the apical side to the basolateral side of the monolayer, and vice versa, and thus the efflux ratio. The integrity of the monolayer after 2 hours of incubation is assessed by leakage of fluorescein.

[0682] Conclusion: The compounds of the application, for example the example compounds, have good Caco2 permeability.

[0683] 5. Mouse pharmacokinetic test

[0684] Objective: The test determines the concentration of the test substance in the plasma of mice and evaluates the pharmacokinetic characteristics and bioavailability of the test substance in mice by single-dose intravenous and gavage administration of the test substance to ICR mice.

[0685] Test animals: Male ICR mice, 20-35 g. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd. or Sichuan Vantoll Life Experimental Animal Technology Co., Ltd.

[0686] Test method: On the test day, ICR mice were randomly divided by weight. Fasting overnight, but not water restriction, 4 hours after administration, resume feeding.

[0687] * Dose is calculated as free form;

[0688] Sampling: At the designated time point, blood was taken through the orbit and placed in an EDTAK2 centrifuge tube. Centrifuged at 5000 rpm for 10 min, and the plasma was collected.

[0689] G1 group blood plasma collection time points: 0, 5 min, 15 min, 30 min, 1, 2, 4, 7, 24 h;

[0690] G2 group blood plasma collection time points: 0, 5 min, 15 min, 30 min, 1, 2, 4, 7, 24 h;

[0691] Before analysis, all samples were stored below -60°C. The samples were quantitatively analyzed by LC-MS / MS.

[0692] Table 5-1 Test compound pharmacokinetic data in mice

[0693] *Note: i.g. (intragastric) administration of compound.

[0694] Conclusion: The compounds of the present application, such as the example compounds, have good oral absorption performance in mice.

[0695] 6. Rat pharmacokinetic test

[0696] Test animals: male SD rats, 180-200 g. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0697] Test design: On the test day, the SD rats were randomly divided by weight. Fasting overnight before administration, without water, and food was restored 4 h after administration.

[0698] Note: Intravenous administration vehicle: 5% DMA + 5% Solutol + 90% saline;

[0699] Intragastric administration vehicle: 8% DMSO + 72% PEG 400 + 20% (10% TPGS in purified water).

[0700] At the designated time points, blood was taken through the orbit and placed in EDTAK2 centrifuge tubes. Centrifugation at 5000 rpm for 10 min, and the plasma was collected.

[0701] Blood sampling time points for intravenous group: 0, 5, 15, 30 min, 1, 2, 4, 7, 24 h; blood sampling time points for intragastric administration group: 0, 5, 15, 30 min, 1, 2, 4, 7, 24 h. Before analysis and detection, all samples were stored below -60°C. The samples were quantitatively analyzed by LC-MS / MS.

[0702] Conclusion: The compounds of the present application, such as the example compounds, have good oral absorption performance in rats.

[0703] 7. Beagle pharmacokinetic test

[0704] Test animals: male beagles, about 8-11 kg, 5-6 per compound.

[0705] Test method: On the test day, the beagles were randomly divided by weight, 5-6 per compound. Fasting for 14-18 h without water 1 day before administration, and food was restored 4 h after administration.

[0706] Note: Intravenous vehicle: 5% DMA + 5% Solutol + 90% Saline; Oral vehicle: 99.5% (0.5% MC) (400 cPs) + 0.5% Tween 80 in distilled water.

[0707] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; 0.5% MC: 0.5% methylcellulose in water.)

[0708] Blood samples (1 ml) were taken from the jugular vein or the limb vein before and after administration and placed in EDTA K2 tubes. Centrifugation was performed at 5000 rpm for 10 min at 4°C, and the plasma was collected. The blood sampling time points for the intravenous group and the oral group in Groups G1 and G2 were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, 48 h, and 72 h. Before analysis, all samples were stored below -60°C, and LC-MS / MS was used for quantitative analysis of the samples.

[0709] Table 7-1 PK data of test compounds in beagle dogs

[0710] Conclusion: The compounds of the present application, such as the compounds of the examples, have good oral absorption performance in beagle dogs.

[0711] 8. Monkey pharmacokinetic test

[0712] Test animals: male cynomolgus monkeys, 3-5 kg, 4-6 monkeys per compound.

[0713] Test method: On the test day, the monkeys were randomly divided into groups according to body weight, 4-6 monkeys per compound. Fasting without water for 14-18 h before administration, and feeding 4 h after administration.

[0714] Note: Intravenous vehicle: 5% DMA + 5% Solutol + 90% Saline; Oral vehicle: 99.5% (0.5% MC) (400 cPs) + 0.5% Tween 80 in distilled water. (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; 0.5% MC: 0.5% methylcellulose in water.)

[0715] Blood samples (1.0 mL) were collected from the vena cubitalis before and after administration and placed in EDTA K2 tubes. Centrifugation was performed at 5000 rpm for 10 min at 4°C, and the plasma was collected. The blood sampling time points for the intravenous group and the gavage group were: 0, 5 min, 15 min, 30 min, 1, 2, 4, 6, 8, 10, 12, 24 h, 48 h, and 72 h. Before analysis, all samples were stored at -80°C, and LC-MS / MS was used for quantitative analysis of the samples.

[0716] Conclusion: The compound of the present application, such as the compound of the examples, has good oral absorption performance in monkeys.

[0717] 9. HCC1428 human breast cancer xenograft model study

[0718] 9.1 Cell culture

[0719] HCC1428 tumor cells were cultured in vitro in a 37°C, 5% CO2 incubator using RPMI 1640 complete medium containing 10% fetal bovine serum. The medium was changed every 1 or 2 days, and the cells were passaged when the confluence rate reached 90%, with no more than 4-5 passages. When the cells were in the logarithmic growth phase, the cells were collected for in vivo inoculation.

[0720] 9.2 Inoculation and grouping of tumor cells

[0721] HCC1428 tumor cells resuspended in RPMI 1640 medium were inoculated subcutaneously on the right side of the experimental animals at 1×107+gel / 0.1 mL, with a total of 80 animals (mice) inoculated. Two days before cell inoculation, estrogen was injected subcutaneously twice a week, 40 μg / 20 μl per animal. When the average tumor length reached about 200 mm 3 , 37 animals with uniform tumor volume were selected for grouping and administration, with a total of 6 groups, 6 / 7 animals in each group.

[0722] 9.3 Detection index

[0723] For routine monitoring, not only the growth of the tumor was monitored, but also the behavioral changes of the animals, such as animal movement, food and water consumption (only observed from the cage side), body weight changes, whether the eyes / hair were shiny, and any other abnormal effects. Any clinical symptoms of death and / or abnormalities were recorded.

[0724] 9.3.1 Body weight

[0725] During the experiment, all animals were weighed twice a week. The percentage of body weight change (BW change, %) was calculated according to the following formula: BW change = (BW Day X / BW Day 0) x 100, wherein BW Day X is the body weight of the animal on the measurement day, and BW Day 0 is the body weight of the animal on the grouping day.

[0726] The long diameter and the short diameter of the tumor were measured using a vernier caliper, and the tumor volume was calculated according to the formula: volume = 0.5 x long diameter x short diameter2. During the experiment, the tumor volume was measured twice a week. The tumor volume was used to calculate the tumor growth inhibition rate TGI (an evaluation index of anti-tumor activity): TGI = (1-T / C) x 100%, wherein T and C are the average relative tumor volumes (average tumor growth percentage) of the treatment group and the control group, respectively.

[0727] 9.4 Sample collection

[0728] 9.4.1 PK detection

[0729] On the fifth day of administration, the plasma of the animals in groups 2-6 was collected at the specified time points.

[0730] 9.4.2 PD detection

[0731] On the seventh day of administration, the tumor of all animals was collected 4 h after the last administration.

[0732] 9.5 Termination of animals

[0733] When an animal shows continuous deterioration of health, reaches a coma state, or shows obvious signs of severe distress and / or pain, it should be given a humane euthanasia treatment, such as carbon dioxide and cervical dislocation.

[0734] 9.6 Statistical analysis

[0735] Data collection: measurement and observation, manual recording or direct recording in the computer database according to the requirements of the experimental scheme.

[0736] Statistical analysis: statistical software SPSS 16.0 was used for statistical analysis between groups, and the mean value and standard error were calculated according to all the measurement parameters of the experimental design. The significance level was set to 0.05 or P < 0.05.

[0737] Conclusion: The compound of the present application, for example, the compound of the examples, has a good inhibitory effect on the growth of the tumor of the HCC1428 human breast cancer xenograft model.

Claims

1. A compound or its racemic, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is selected from compounds represented by general formula (II). R 1A Selected from R 1 - Ring A1-R 1B Ring A2, wherein ring A1 or ring A2 is selected from 4- to 12-membered heterocyclic groups, and ring A1 is divided by 2 to 4 R groups. 1a Instead, the ring A2 is replaced by a C 3-6 Cycloalkyl substitution, wherein the cycloalkyl group is optionally replaced by 1 to 4 R... k Instead, the ring A2 may optionally be further replaced by 1 to 4 R 1a replace; R 1B Selected from R 1b R 1a or -C(=O)-C 3-6 cycloalkyl-R 1bd The cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace; X is selected from O or N(R) x ); X1 is selected from CR x1 Or N; X2 is selected from CR x2 Or N; Y1 is selected from N or CR 6 ; Y2 is selected from N or CR 7 ; R x Each is independently selected from H, CN, OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace; R 1 Selected from C 2-6 Alkyne group, -OCH2-4 to 12-membered heterocyclic group, -N(C 1-6 alkyl)-C 3-6 cycloalkyl, -N(C) 1-6 alkyl)-4 to 7-membered heterocyclic alkyl, -N(C 3-6 cycloalkyl)2, -N(C 3-6 Cycloalkyl)-4 to 7-membered heterocyclic alkyl, -C 3-12 Carbocyclic-R 1b -4 to 12-membered heterocyclic groups -R 1b The alkynyl, alkyl, cycloalkyl, heterocycloalkyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. 1a replace; R 1b Selected from -C 0-4 Alkylene-C 3-6 cycloalkyl, -C 1-4 Alkylene-CN, -C 1-4 Alkylene-OC 1-4 Alkyl, C 2-6 alkynyl group, -C(=S)-C 1-6 Alkyl, -C(=S)-C 3-6 Cycloalkyl, -C(=S)-4 to 7-membered heterocyclic groups, -C(=O)-C 3-6 cycloalkyl-R 1ba -C(=O)-C 3-6 Cycloalkyl = C(R) 1d R 1c -C (=NR) 1bb C 1-6 Alkyl group, -C (=NR) 1bb C 3-6 Cycloalkyl, -C (=NR) 1bb NHC 1-6 Alkyl group, -C (=NR) 1bb NHC 3-6 Cycloalkyl, -C(=O)-phenyl-R 1bc -C(=O)-5 to 6-membered heteroaryl-R 1bc -C(=O)-4 to 7-membered heterocyclic alkyl-R 1bc The cycloalkyl, alkyl, heterocycloalkyl, heterocyclic, phenyl, or heteroaryl groups are optionally surrounded by 1 to 4 R groups. k replace; R 1ba Each element is independently selected from deuterium, halogens, CN, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Carbocyclic groups, 4- to 7-membered heterocyclic groups, -C 1-4 Alkylene-C 3-6 carbonyl group, -C 1-4 Alkyl-4 to 7-membered heterocyclic groups, -OC 3-6 cycloalkyl, The alkylene, alkyl, alkenyl, ynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; R 1bb Selected from H, CN, OH, NO2, -SO2C 1-6 Alkyl, -SO2C 3-6 cycloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace; R 1bc Selected from C 3-6 carbonyl group, -C 1-4 Alkylene-C 3-6 Carbocyclic group, -C(=O)-C 1-6 Alkyl, -C(=O)-C 3-6 The carbocyclic group, wherein the alkylene group, alkyl group, or carbocyclic group is optionally surrounded by 1 to 4 R groups. k replace; R 1bd Selected from OH or C 1-6 Alkyl groups, wherein the alkoxy group is optionally surrounded by 1 to 4 R groups. k replace; R 4 Selected from H, C 1-6 Alkyl, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the alkyl, aryl or heteroaryl group is optionally surrounded by 1 to 4 R groups. 4a replace; R 1a R 4a Each element is independently selected from deuterium, halogens, CN, =O, OH, SF5, C(=O)NH2, -C(=O)-N(R) 1bb 2. C(=O)NHC 1- 6-alkyl, C(=O)N(C 1-6 Alkyl)2、C(=O)NHC 3-6 Cycloalkyl, C(=O)N(R) 1bb (C) 1-6 Alkyl groups, C(=O)NH-4 to 7-membered heterocyclic groups, C(=O)N(C 1-6 Alkyl groups (4 to 7-membered heterocyclic groups), C(=O)N(C 1-6 Alkyl)(C 1-4 Alkylene-C 3-6 cycloalkyl), C(=O)NH(C 1-4 Alkylene-C 3-6 cycloalkyl), C(=O)N(C 3-6 cycloalkyl)2, C(=O)N(C 1-6 Alkyl)(C 3-6 cycloalkyl), C(=S)NHC 1-6 Alkyl, C(=S)N(C 1-6 Alkyl)2、C(=O)OC 1-6 Alkyl, C(=O)C 3-6 Cycloalkyl, OC (=S)OC 1-6 Alkyl, C(=O)SC 1-6 Alkyl, -C 0-4 Alkylene -NH2, -C 0-4 Alkylene-NHC 1-6 Alkyl, -C 0-4 Alkylene-N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, -SC 1-6 Alkyl, -C 0-4 Alkylene-C 3-6 cycloalkyl, -C 0-4 alkylene-4 to 7-membered heterocyclic groups, -C 0-4 Alkylene-4 to 7-membered heterocyclic-C(=O)C 1-6 Alkyl group, -C(=O)C 1-6 Alkyl group, -C(=O)C 2-6 alkenyl, -C(=O)C 3-7 Carbocyclic groups, -C(=O)-4 to 7-membered heterocyclic groups, -C(=S)C 1-6 Alkyl group, -C(=S)C 2-6 alkenyl, -C(=S)C 3-7 Carbocyclic groups, -C(=S)-4 to 7-membered heterocyclic groups, -NHC(=O)C 1-6 Alkyl group, -NHC(=O)C 3-6 cycloalkyl, -S(=O)C 1-6 Alkyl group, -S(=O)C 3-7 Carbocyclic group, -NHS(=O)C 1-6 Alkyl group, -S(=O)2C 1-6 Alkyl group, -S(=O)2C 3-7 Carbocyclic group, -NHS(=O)2C 1-6 Alkyl group, -S(=O)2NHC 1-6 Alkyl, -P(=O)(C 1-6 Alkyl)2, -C(=NR 1bb C 1-6 Alkyl group, -C (=NR) 1bb C 3- 6-cycloalkyl, -C(=NR) 1bb )NH2、-C(=NR 1bb )N(C 1-6 Alkyl)2、-C(=NR) 1bb NHC 1-6 Alkyl group, -C (=NR) 1bb NHC 3-6 Cycloalkyl, wherein the alkylene group, alkyl group, alkenyl group, alkynyl group, alkoxy group, carbocyclic group, heterocyclic group, or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace; R 1d R 1c Each element is independently selected from H, deuterium, halogens, CN, and C. 1-6 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. k replace; As an option, R 1d R 1c Direct connection forms C 3-6 Cycloalkyl or 4- to 7-membered heterocyclic groups, wherein the cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; R 5 Selected from R x1 R x2 R 5a R 6 R 7 Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-7 carbonyl group, -C 0-4 Alkylene-C 3-7 carbonyl group, -C 0-4 Alkylene-4 to 7-membered heterocyclic groups, wherein the alkylene, alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; R 5b When selected from H or F, R 5c Selected from H, methyl, or CN; R 5b Selected from 1 to 4 Rs k One of the following groups is substituted: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1- 6-alkyl, -OC 3-7 carbonyl group, -C 0-4 Alkylene-C 3-7 carbonyl group, -C 0-4 When alkylene-4 to 7-membered heterocyclic groups are involved, R 5c Selected from deuterium, CN, OH, NH2, or optionally coated with 1 to 4 Rs k One of the following groups is substituted: NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-7 carbonyl group, -C 0-4 Alkylene-C 3-7 carbonyl group, -C 0-4 alkylene-4 to 7-membered heterocyclic groups; R k Each element is independently selected from deuterium, ⁵O, halogens, CN, OH, COOH, NH₂, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocyclic groups, -O-4 to 7-membered heterocyclic groups, -NH-C 3-6 Carbocyclic group, -N(C) 1-6 Alkyl)(C 3-6 (carbocyclic group), -NH-4 to 7-membered heterocyclic groups, -C 1-4 Alkylene-C 3-6 carbonyl group, -C 1-4 alkylene-4 to 7-membered heterocyclic groups, C 3-6 Carbocyclic groups, 4- to 7-membered heterocyclic groups, The alkyl, alkylene, alkenyl, alkynyl, carbocyclic, or heterocyclic groups are optionally selected from 1 to 4 deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 The alkoxy group is replaced by a substituent.

2. The compound according to claim 1, or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. R 1 Selected from C 2-5 Alkyne group, -OCH2-4 to 7-membered heterocyclic alkyl group, -N(C 1-6 alkyl)-C 3-6 cycloalkyl, -N(C) 1-6 alkyl)-4 to 7-membered heterocyclic alkyl, -N(C 3-6 cycloalkyl)2, -N(C 3-6 Cycloalkyl)-4 to 7-membered heterocyclic alkyl, -C 3-6 cycloalkyl-R 1b -C 5-10 Bridged cycloalkane-R 1b -C 6-12 cycloalkyl-R 1b -C 6-12 Spirocycloalkyl-R 1b -4 to 7-membered heterocyclic alkyl-R 1b -6 to 10-membered bridged heterocyclic alkyl-R 1b -6 to 12 fused-cycloheteroalkyl-R 1b -6 to 12-membered spirocyclic heterocyclic alkyl-R 1b The alkynyl, alkyl, cycloalkyl, heterocycloalkyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. 1a replace; Ring A2 is selected from 4- to 8-membered heterocyclic groups, and ring A2 is separated by 1 C 3-6 Cycloalkyl substitution, wherein the cycloalkyl group is optionally replaced by 1 to 4 R... k Instead, the ring A2 may optionally be further replaced by 1 to 4 R 1a replace; R 1ba Each element is independently selected from deuterium, halogens, CN, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, -C 1-4 Alkylene-C 3-6 cycloalkyl, -C 1-4 Alkylene-4 to 7-membered heterocyclic alkyl, -OC 3-6 cycloalkyl, The alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocycloalkyl, and heteroaryl groups are optionally prefixed with 1 to 4 R groups. k replace; R 1bb Selected from H, CN, OH, NO2, -SO2C 1-4 Alkyl, -SO2C 3-6 cycloalkyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace; R 1bc Selected from C 3-6 cycloalkyl, phenyl, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -C(=O)-C 1-4 Alkyl, -C(=O)-C 3-6 Cycloalkyl, wherein the alkylene, alkyl, cycloalkyl or phenyl is optionally surrounded by 1 to 4 R... k replace; R 4 Selected from H or arbitrarily selected by 1 to 4 Rs 4a One of the following groups is substituted: C 1-6 Alkyl, phenyl, benzo[C] 4-6 Carbocyclic, benzo4- to 6-membered heterocyclic, 5- to 6-membered heteroaryl or 8- to 10-membered fused-ring heteroaryl; R 1a R 4a Each element is independently selected from deuterium, halogens, CN, OH, =O, SF5, C(=O)NH2, -C(=O)-N(R) 1bb 2. C(=O)NHC 1- 4 alkyl groups, C(=O)N(C) 1-4 Alkyl)2、C(=O)NHC 3-6 Cycloalkyl, C(=O)N(C) 3-6 cycloalkyl)2, C(=O)N(C 1-4 Alkyl)(C 3-6 cycloalkyl), C(=O)N(R 1bb (C) 1-4 Alkyl), C(=O)N(C 1-4 Alkyl)(C 1-4 Alkylene-C 3-6 cycloalkyl), C(=O)NH(C 1-4 Alkylene-C 3-6 cycloalkyl), C(=O)NH-4 to 7-membered heterocyclic groups, C(=O)N(C 1-4 Alkyl groups (4 to 7-membered heterocyclic groups), C(=S)NHC 1-4 Alkyl, C(=S)N(C 1-4 Alkyl)2、C(=O)OC 1-4 Alkyl, C(=O)C 3-6 Cycloalkyl, C(=S)OC 1-4 Alkyl, C(=O)SC 1-4 Alkyl, -C 0-4 Alkylene -NH2, -C 0- 4-alkylene-NHC 1-4 Alkyl, -C 0-4 Alkylene-N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, -SC 1-4 Alkyl, -C 0-4 Alkylene-C 3-6 cycloalkyl, -C 0-4 alkylene-4 to 7-membered heterocyclic groups, -C 0-4 Alkylene-4 to 7-membered heterocyclic-C(=O)C 1-4 Alkyl group, -C(=O)C 1-4 Alkyl group, -C(=O)C 2-4 alkenyl, -C(=O)C 3-7 Carbocyclic groups, -C(=O)-4 to 7-membered heterocyclic groups, -C(=S)C 1-4 Alkyl group, -C(=S)C 2-4 alkenyl, -C(=S)C 3-7 Carbocyclic groups, -C(=S)-4 to 7-membered heterocyclic groups, -NHC(=O)C 1-4 Alkyl group, -NHC(=O)C 3-6 cycloalkyl, -S(=O)C 1-4 Alkyl group, -S(=O)C 3-7 Carbocyclic group, -NHS(=O)C 1-4 Alkyl group, -S(=O)2C 1-4 Alkyl group, -S(=O)2C 3-7 Carbocyclic group, -NHS(=O)2C 1-4 Alkyl group, -S(=O)2NHC 1-4 Alkyl, -P(=O)(C 1-4 Alkyl)2, -C(=NR 1bb C 1-4 Alkyl group, -C (=NR) 1bb C 3-6 Cycloalkyl, -C (=NR) 1bb NHC 1-4 Alkyl group, -C (=NR) 1bb )NH2、-C(=NR 1bb )N(C 1-4 Alkyl)2、-C(=NR) 1bb NHC 3-6 Cycloalkyl, wherein the alkylene group, alkyl group, alkenyl group, alkynyl group, alkoxy group, carbocyclic group, heterocyclic group, or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace; R 1d R 1c Each element is independently selected from H, deuterium, halogens, CN, and C. 1-4 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. k replace; As an option, R 1d R 1c Direct connection forms C 3-6 Cycloalkyl or 4- to 7-membered heterocyclic groups, wherein the cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; R x1 R x2 R 5a R 6 R 7 Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 cycloalkyl, -C 0-4 Alkylene-C 3-6 cycloalkyl, -C 0-4 Alkylene-4 to 7-membered heterocyclic alkylene, wherein the alkylene, alkyl, alkenyl, ynyl, cycloalkyl or heterocyclic alkylene is optionally surrounded by 1 to 4 R groups. k replace; R 5b When selected from H or F, R 5c Selected from H, methyl, or CN; R 5b Selected from 1 to 4 Rs k One of the following groups is substituted: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1- 4-alkyl, -OC 3-6 cycloalkyl, -C 0-4 Alkylene-C 3-6 cycloalkyl, -C 0-4 When alkylene-4 to 7-membered heterocyclic alkyl, R 5c Selected from deuterium, CN, OH, NH2, or optionally coated with 1 to 4 Rs k One of the following groups is substituted: NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 cycloalkyl, -C 0-4 Alkylene-C 3-6 cycloalkyl, -C 0-4 Alkylene-4 to 7-membered heterocyclic alkyl groups; R k Each element is independently selected from deuterium, ⁵O, halogens, CN, OH, COOH, NH₂, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 Carbocyclic groups, -O-4 to 7-membered heterocyclic groups, -NH-C 3-6 Carbocyclic group, -N(C) 1-4 Alkyl)(C 3-6 (carbocyclic group), -NH-4 to 7-membered heterocyclic groups, -C 1-2 Alkylene-C 3-6 carbonyl group, -C 1-2 alkylene-4 to 7-membered heterocyclic groups, C 3-6 Carbocyclic groups, 4- to 7-membered heterocyclic groups, The alkyl, alkylene, alkenyl, alkynyl, carbocyclic, or heterocyclic groups are optionally selected from 1 to 4 deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 The alkoxy group is replaced by a substituent.

3. The compound according to claim 2, or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. X is selected from O or NH; R 1 Selected from 1 to 4 Rs 1a The substitution may be made with one of the following groups: ethynyl, propynyl, propargyl, -OCH2-oxetanebutyl, -OCH2-tetrahydrofuranyl, -OCH2-oxetanehexyl, -OCH2-azacyclobutyl, -OCH2-pyrrolylyl, -OCH2-piperidinyl, -OCH2-piperazinyl, -N(CH3)-azacyclobutyl, -N(CH3)-pyrrolylyl, -N(CH3)-piperidinyl, -N(CH3)-piperazinyl, -N(CH3)-morpholinyl, -N(CH3)-oxetanebutyl, -N(CH3)-tetrahydrofuranyl, -N(CH3)-oxetanehexyl, -N(CH2CH3)-azacyclobutyl, - N(CH2CH3)-pyrrolyl, -N(CH2CH3)-piperidinyl, -N(CH2CH3)-piperazinyl, -N(CH2CH3)-morpholinyl, -N(CH2CH3)-oxetanebutyl, -N(CH2CH3)-tetrahydrofuranyl, -N(CH2CH3)-oxetanehexyl, -N(cyclopropyl)-azacyclobutyl, -N(cyclopropyl)-pyrrolyl, -N(cyclopropyl)-piperidinyl, -N(cyclopropyl)-piperazinyl, -N(cyclopropyl)-morpholinyl, -N(cyclopropyl)-oxetanebutyl, -N(cyclopropyl)-tetrahydrofuranyl, -N(cyclopropyl)-oxetanehexyl, -N(cyclopropyl)2 Ring A2 is selected from 1 to 4 R's. 4a The substituted group is one of the following: aziridine, pyrrolidinyl, piperidinyl, piperazineyl, The ring A2 is further divided by 1 C 3-6 Cycloalkyl substitution; R 4 Selected from H or arbitrarily selected by 1 to 4 Rs 4a One of the following groups is substituted: C 1-4 Alkyl, phenyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, pyrazolyl, thiadiazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl; R 1a Each element is independently selected from deuterium, halogens, CN, OH, =O, SF5, C(=O)NH2, C(=O)NHC 1-4 Alkyl, C(=O)N(C) 1-4 Alkyl)2、C(=O)NHC 3-6 Cycloalkyl, -C(=O)-N(R) 1bb )2、C(=O)N(C 3-6 cycloalkyl)2, C(=O)N(C 1-4 Alkyl)(C 3-6 cycloalkyl), C(=O)N(C 1-4 Alkyl groups (4 to 7-membered heterocyclic groups), C(=O)N(C 1-4 Alkyl groups (4 to 7-membered heterocyclic groups), C(=S)NHC 1-4 Alkyl, C(=S)N(C 1- 4alkyl)2、C(=O)OC 1-4 Alkyl, C(=O)C 3-6 Cycloalkyl, C(=S)OC 1-4 Alkyl, C(=O)SC 1-4 Alkyl, -C 0-2 Alkylene-NH2, C 1- 4-alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, -SC 1-4 Alkyl, -C 0-2 Alkylene-C 3-6 cycloalkyl, -C 0-2 Alkylene-4 to 7-membered heterocyclic alkyl, -C 0-2 alkylene-5 to 6-membered heteroaryl, -C(=O)C 1-4 Alkyl group, -C(=O)C 3-6 Cycloalkyl, -C(=O)-4 to 7-membered heterocyclic groups, -C(=S)C 1-4 Alkyl group, -C(=S)C 3-6 Cycloalkyl, -C(=S)-4 to 7-membered heterocycloalkyl, -C(=NR)- 1bb C 1-4 Alkyl group, -C (=NR) 1bb C 3-6 Cycloalkyl, -C (=NR) 1bb )NH2、-C(=NR 1bb NHC 1-4 Alkyl group, -C (=NR) 1bb )N(C 1-4 Alkyl)2、-C(=NR) 1bb NHC 3-6 Cycloalkyl, wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, or heteroaryl group is optionally surrounded by 1 to 4 R groups. k replace; R 1b Selected from 1 to 4 Rs k The substitution is performed with one of the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2CN, -CH2OCH3, -CH2OCH2CH3, ethynyl, -CH2-ethynyl, propynyl, -C(=S)-CH3, -C(=S)-CH2CH3, -C(=S)-CH(CH3)2, -C(=S)-C(CH3)3 -C(=S)-cyclopropyl, -C(=S)-cyclobutyl, -C(=S)-cyclopentyl, -C(=S)-cyclohexyl, -C(=S)-bicyclo[1.1.1]pentyl, -C(=S)-oxacyclobutyl, -C(=S)-tetrahydrofuranyl, -C(=S)-oxacyclohexyl, -C(=S)-azacyclobutyl, -C(=S)-pyrrolidinyl, -C(=S)-piperidinyl, -C(=S)-piperazinyl, -C(=O)-cyclopropyl-R 1ba -C(=O)-cyclobutyl-R 1ba -C(=O)-cyclopentyl-R 1ba -C(=O)-cyclohexyl-R 1ba -C(=O)-cyclopropyl=C(R) 1d R 1c -C(=O)-cyclobutyl=C(R) 1d R 1c -C(=O)-cyclopentyl=C(R) 1d R 1c -C(=O)-cyclohexyl=C(R) 1d R 1c -C (=NR) 1bb -CH3, -C(=NR) 1bb -CH2CH3, -C(=NR) 1bb )-Cyclopropyl, -C(=NR 1bb )-Cyclobutyl, -C(=NR 1bb )NHCH3、C(=NR 1bb )NH-cyclopropyl, -C(=O)-phenyl-R 1bc -C(=O)-pyrazolyl-R 1bc -C(=O)-triazolyl-R 1bc -C(=O)-imidazolyl-R 1bc , R 4a Each element is independently selected from deuterium, halogens, CN, OH, SF5, C(=O)NH2, and C(=O)NHC. 1-4 Alkyl, C(=O)N(C) 1-4 Alkyl)2, -C 0-4 Alkylene -NH2, -C 0-4 Alkylene-NHC 1-4 Alkyl, -C 0-4 Alkylene-N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, -SC 1-4 Alkyl, -C 0-4 Alkylene-C 3-6 cycloalkyl, -C 0-4 Alkylene-4 to 7-membered heterocyclic alkyl, -C 0-4 Alkylene-4 to 7-membered heterocyclic-C(=O)C 1-4 Alkyl group, -C(=O)C 1-4 Alkyl group, -C(=O)C 2-4 alkenyl, -C(=O)C 3-6 Cycloalkyl, -C(=O)-4 to 7-membered heterocycloalkyl, -NHC(=O)C 1-4 Alkyl group, -NHC(=O)C 3-6 cycloalkyl, -S(=O)C 1-4 Alkyl group, -S(=O)C 3-6 cycloalkyl, -NHS(=O)C 1-4 Alkyl group, -S(=O)2C 1-4 Alkyl group, -S(=O)2C 3-6 cycloalkyl, -NHS(=O)2C 1-4 Alkyl group, -S(=O)2NHC 1-4 Alkyl, -P(=O)(C 1-4 Alkyl)2, wherein the alkylene, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic, heterocyclic, cycloalkyl, or heterocyclic alkyl group is optionally surrounded by 1 to 4 R groups. k replace; R 5a Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 cycloalkyl or C 3-6 Cycloalkyl, heteroaryl, or 4-7 membered heterocyclic groups, wherein the alkyl, alkynyl, cycloalkyl, heteroaryl, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; R x1 R x2 R 6 R 7 Each element is independently selected from H, deuterium, halogens, CN, OH, and C. 1-4 Alkyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 cycloalkyl, C 3-6 cycloalkyl, -CH2-C 3-6 Cycloalkyl, wherein the alkyl, alkynyl, or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace.

4. The compound according to claim 3, or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. X1 is selected from N; X2 is selected from CH; R 6 R 7 Each of the following is independently selected from H, deuterium, F, Cl, Br, CN, OH, methyl, ethyl, ethynyl, methoxy, ethoxy, and cyclopropyl, wherein the methyl, ethyl, methoxy, ethoxy, and cyclopropyl groups are optionally selected by 1 to 4 of the following: deuterium, halogen, CN, OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, and C. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups; R 1a Each element is independently selected from deuterium, F, Cl, Br, CN, OH, =O, NH2, -CH2NH2, -CH(CH3)NH2, -C(CH3)2NH2, SF5, or optionally substituted with 1 to 4 Rs. k The substitution may be made with one of the following groups: methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, oxacyclopentyl, pyrrolyl, pyrazolyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -C(=O)-CH3, -C(=O)-CH2CH3, -C(=O)-CH(CH3)2, -C(=O)-C(CH3)3, -C(=O)-cyclopropyl, -C(=O)-cyclobutyl, -C(=O)-cyclopentyl, -C( =O)-cyclohexyl, -C(=O)-bicyclo[1.1.1]pentyl, -C(=O)-oxetanebutyl, -C(=O)-tetrahydrofuranyl, -C(=O)-oxetanehexyl, -C(=O)-azacyclobutyl, -C(=O)-pyrrolidinyl, -C(=O)-piperidinyl, -C(=O)-piperazinyl, -C(=O)-morpholinyl, C(=O)NH-azacyclobutyl, C(=O)N(methyl)(azacyclobutyl), -C(=S)-CH3, -C(=S)-CH2CH3, -C(=S)-CH(C H3)2, -C(=S)-C(CH3)3, -C(=S)-cyclopropyl, -C(=S)-cyclobutyl, -C(=S)-cyclopentyl, -C(=S)-cyclohexyl, -C(=S)-bicyclo[1.1.1]pentyl, -C(=S)-oxacyclobutyl, -C(=S)-tetrahydrofuranyl, -C(=S)-oxacyclohexyl, -C(=S)-azacyclobutyl, -C(=S)-pyrrolidinyl, -C(=S)-piperidinyl, -C(=S)-piperazinyl, C(=O)NH2, -C(=O)-N(OH)(methyl -C(=O)-NHCH3, -C(=O)-NHCH2CH3, -C(=O)-N(CH3)2, -C(=O)-N(CH2CH3)2, -C(=O)-N(CH3)(CH2CH3), -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)SCH3, -C(=O)SCH2CH3, -C(=NH)NH2, -C(=NOH)NH2, -C(=O)-N(methoxy)(CH3), -C(=NH)N(methyl)2. R 1b Selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2CN, -CH2OCH3, -CH2OCH2CH3, ethynyl, -CH2-ethynyl, propynyl, -C(=S)-CH3, -C(=S)-CH2CH3, -C(=S)-CH(CH3)2, -C(=S)-C(CH3) 3. -C(=S)-cyclopropyl, -C(=S)-cyclobutyl, -C(=S)-cyclopentyl, -C(=S)-cyclohexyl, -C(=S)-bicyclo[1.1.1]pentyl, -C(=S)-oxacyclobutyl, -C(=S)-tetrahydrofuranyl, -C(=S)-oxacyclohexyl, -C(=S)-azacyclobutyl, -C(=S)-pyrrolidinyl, -C(=S)-piperidinyl, -C(=S)-piperazinyl, R 1ba The group selected from deuterium, F, Cl, Br, CN, methyl, ethyl, vinyl, -CH2-vinyl, ethynyl, cyclopropyl, -O-cyclopropyl, phenyl, wherein the CH2, methyl, ethyl, vinyl, ethynyl, cyclopropyl, or phenyl group is optionally selected from 1 to 4 of deuterium, halogen, CN, OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups; R 1bc Selected from 1 to 4 Rs k The substitution may be made with one of the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -C(=O)-CH3, -C(=O)-CH2CH3, -C(=O)-CH(CH3)2, -C(=O)-C(CH3)3, -C(=O)-cyclopropyl, -C(=O)-cyclobutyl, -C(=O)-cyclopentyl; R 1bd Selected from OH, methoxy, ethoxy, and propoxy, wherein the methoxy, ethoxy, and propoxy groups are optionally surrounded by 1 to 4 R groups. k replace; R 4a Each element is independently selected from deuterium, F, Cl, Br, CN, OH, SF5, C(=O)NH2, or arbitrarily selected by 1 to 4 Rs. k The substitution is performed using one of the following groups: C(=O)NHCH3, C(=O)NHCH2CH3, C(=O)N(CH3)2, C(=O)N(CH2CH3)2, NH2, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -NHCH3, -CH2NHCH3, -CH2CH2NHCH3, -CH2CH2CH2NHCH3, -CH2CH2CH2CH2 NHCH3, -N(CH3)2, -CH2N(CH3)2, -CH2CH2N(CH3)2, -CH2CH2CH2N(CH3)2, -CH2CH2CH2CH2N(CH3)2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, oxacyclobutyl, tetrahydrofuranyl, oxacyclohexyl, aziridine, pyrrolidinyl, piperidinyl, -CH2-oxetanebutyl, -CH2-tetrahydrofuranyl, -CH2-oxetanehexyl, -CH2-azacyclobutyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-morpholinyl, -CH2-azacyclobutyl-C(=O)-CH3, -CH2-azacyclobutyl-C(=O)-CH2CH3, -CH2-azacyclobutyl-C(=O)-CH(C H3)2, -CH2-pyrrolidinyl-C(=O)-CH3, -CH2-pyrrolidinyl-C(=O)-CH2CH3, -CH2-pyrrolidinyl-C(=O)-CH(CH3)2, -C(=O)-CH3, -C(=O)-CH2CH3, -C(=O)-CH(CH3)2, -C(=O)-cyclopropyl, -C(=O)-cyclobutyl, -C(=O)-cyclopentyl; R 5a Each of the following is independently selected from H, deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, -CH2-ethynyl, methoxy, ethoxy, -O-cyclopropyl, pyrazolyl, or cyclopropyl, wherein CH2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, pyrazolyl, or cyclopropyl is optionally selected from 1 to 4 of deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups; R k Each is independently selected from deuterium, =O, F, Cl, Br, I, CN, OH, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -N(methyl)(cyclopropyl), -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl The methyl, ethyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups are optionally selected from one to four of deuterium, halogens, CN, OH, NH2, and C. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups; Preferably, R k Each of the following groups, independently selected from deuterium, F, Cl, Br, I, CN, OH, -CH2OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, -CH2CF3, CH2CN, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, or optionally substituted, consists of: methyl, ethyl, isopropyl, vinyl, Ethynyl, methoxy, ethoxy, -CH2OCH3, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -N(methyl)(cyclopropyl), -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, when substituted, are replaced by 1 to 4 substituents selected from deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl, methoxy, ethoxy.

5. The compound according to claim 4, or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein, R 1 Selected from Ring A2 is selected from R 1a Each of the following groups is independently selected from deuterium, F, Cl, Br, CN, OH, NH2, -CH2NH2, -CH(CH3)NH2, -C(CH3)2NH2, SF5, or optionally substituted: methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, and when substituted, is replaced by 1 to 4 substituents selected from deuterium, halogen, CN, OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl, ethyl, methoxy, ethoxy, -O-cyclopropyl; R 1aa Each of the following groups, independently selected from H or optionally substituted, consists of: oxetyl, oxetyl, pyrrolidinyl, pyrazolyl, -C(=O)-CH3, -C(=O)-CH2CH3, -C(=O)-CH(CH3)2, -C(=O)-C(CH3)3, -C(=O)-cyclopropyl, -C(=O)-cyclobutyl, -C(=O)-cyclopentyl, -C(=O)-cyclohexyl, -C(=O)-bicyclo[1.1.1] pentyl, -C(=O)-oxetanebutyl, -C(=O)-tetrahydrofuranyl, -C(=O)-oxetanehexyl, -C(=O)-azacyclobutyl, -C(=O)-pyrrolidinyl, -C(=O)-piperidinyl, -C(=O)-piperazinyl, -C(=S)-CH3, -C(=S)-CH2CH3, -C(=S)-CH(CH3)2, -C(=S)-C(CH3)3, -C(=S)-cyclopropyl, -C( =S)-cyclobutyl, -C(=S)-cyclopentyl, -C(=S)-cyclohexyl, -C(=S)-bicyclo[1.1.1]pentyl, -C(=S)-oxacyclobutyl, -C(=S)-tetrahydrofuranyl, -C(=S)-oxacyclohexyl, -C(=S)-azacyclobutyl, -C(=S)-pyrrolidinyl, -C(=S)-piperidinyl, -C(=S)-piperazinyl, -C(=O)NH2, -C(=O)-N(OH)( CH3), -C(=O)-N(OCH3)(CH3), -C(=O)-NHCH3, -C(=O)-NHCH2CH3, -C(=O)-N(CH3)2, -C(=O)-N(C H2CH3)2, -C(=O)-N(CH3)(CH2CH3), -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)SCH3, -C(=O)SCH2CH3, When substituted, it is replaced by 1 to 4 elements selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, -CH2CF3, CH2CN, CD3, CHD2, CH2D, CH2CH2F, -OCH2CH2F, -OCH2CH2OCH3, methyl, ethyl, isopropyl, methoxy, ethoxy, -CH2CN, -CH2OH, -CH2OCH3, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, N(CH3)2, vinyl, The substituents are replaced; R 1ba The group is selected from deuterium, F, Cl, Br, CN, methyl, ethyl, vinyl, -CH2-vinyl, ethynyl, cyclopropyl, -O-cyclopropyl, phenyl, wherein the CH2, methyl, ethyl, vinyl, ethynyl, cyclopropyl or phenyl is optionally substituted by 1 to 4 substituents selected from deuterium, halogen, CN, OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl, ethyl, methoxy, ethoxy; R 1bc The group is selected from one of the following optionally substituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -C(=O)-CH3, -C(=O)-CH2CH3, -C(=O)-CH(CH3)2, -C(=O)-C(CH3)3, -C(=O)-cyclopropyl, -C(=O)-cyclobutyl, -C(=O)-cyclopentyl, and when substituted, is selected from 1 to 4 groups selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl, ethyl, methoxy, ethoxy, -CH2CN, -CH2OH, -CH2OCH3, -O-cyclopropyl, vinyl, The substituents are replaced; R 1bd The group is selected from OH, methoxy, ethoxy, and propoxy, wherein the methoxy, ethoxy, and propoxy groups are optionally replaced by 1 to 4 substituents selected from deuterium, F, Cl, Br, CN, OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, -OCF3, -OCHF2, -OCH2F, -OCD3, -OCHD2, -OCH2D, methyl, ethyl, methoxy, ethoxy, or cyclopropyl. R 1be The group is selected from one of the following optionally substituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and when substituted, is selected from 1 to 4 groups selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl, ethyl, methoxy, ethoxy, -CH2CN, -CH2OH, -CH2OCH3, -O-cyclopropyl, vinyl, The substituents are replaced; R 4 Selected from H, R 4a Selected from deuterium, F, Cl, Br, CN, OH, SF5, C(=O)NH2, or one of the following groups with optional substitution: C(=O)NHCH3, C(=O)NHCH2CH3, C(=O)N(CH3)2, C(=O)N(CH2CH3)2, NH2, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH2CH2CH2CH2NH2, -NHCH3, -CH2NHCH3, -CH2CH2NHCH3, -CH2CH2CH2NH CH3, -CH2CH2CH2CH2NHCH3, -N(CH3)2, -CH2N(CH3)2, -CH2CH2N(CH3)2, -CH2CH2CH2N(CH3)2, -CH2CH2CH2CH2N(CH3)2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, oxacyclobutyl, tetrahydrofuranyl, oxacyclohexyl, aziridine, pyrrolylyl, piperidinyl, -CH2-oxetanebutyl, -CH2-tetrahydrofuranyl, -CH2-oxetanehexyl, -CH2-azacyclobutyl, -CH2-pyrrolyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-morpholinyl, -CH2-azacyclobutyl-C(=O)-CH3, -CH2-azacyclobutyl-C(=O)-CH2CH3, -CH2-azacyclobutyl-C(=O)-CH(CH3)2, -CH2-pyrrolyl-C(=O)-CH3, -CH2-pyrrolyl-C(=O)-CH2CH3, -CH2-pyrrolidine The group -C(=O)-CH(CH3)2, -C(=O)-CH3, -C(=O)-CH2CH3, -C(=O)-CH(CH3)2, -C(=O)-cyclopropyl, -C(=O)-cyclobutyl, -C(=O)-cyclopentyl, when substituted, is replaced by 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl, ethyl, methoxy, ethoxy, -CH2CN, -CH2OH, -CH2OCH3, -O-cyclopropyl; R 5 Selected from R 5a Each of the following groups is independently selected from H, deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, -CH2-ethynyl, methoxy, ethoxy, -O-cyclopropyl or cyclopropyl, pyrazolyl, wherein the CH2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy or cyclopropyl, pyrazolyl groups are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl, ethyl, methoxy; R 6 R 7 Each is independently selected from H, deuterium, F, Cl, Br, CN, OH, methyl, ethyl, ethynyl, methoxy, ethoxy, cyclopropyl, CF3, CHF2, CH2F, CD3, CHD2, CH2D; m is selected from 0, 1, 2 or 3.

6. The compound according to claim 2, or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein, Compounds of general formula (II) are selected from general formula (II-a). Y1 is selected from CH, and Y2 is selected from CH; X1 is selected from N; X2 is selected from CH; X is selected from O or NH; m2 is selected from 0, 1, 2, or 3; R 1be Selected from 1 to 4 Rs k One of the following groups is substituted: C 3-6 cycloalkyl; preferably, R 1be The group is selected from one of the following optionally substituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and when substituted, is selected from 1 to 4 groups selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl, ethyl, methoxy, ethoxy, -CH2CN, -CH2OH, -CH2OCH3, -O-cyclopropyl, vinyl, The substituents are replaced; R 1aa Each is independently selected from H or arbitrarily selected by 1 to 4 Rs. k Substitution with one of the following groups: C(=O)NH2, -C(=O)-N(R) 1bb 2. C(=O)NHC 1-4 Alkyl, C(=O)N(C) 1-4 Alkyl)2、C(=O)NHC 3-6 Cycloalkyl, C(=O)N(C) 3-6 cycloalkyl)2, C(=O)N(C 1-4 Alkyl)(C 3-6 cycloalkyl), C(=O)N(R 1bb (C) 1-4 Alkyl), C(=O)N(C 1-4 Alkyl)(C 1-2 Alkylene-C 3-6 cycloalkyl), C(=O)NH(C 1-2 Alkylene-C 3-6 Cycloalkyl), C(=O)NH-4 to 7-membered heterocyclic groups, C(=O)N(C 1-4 Alkyl groups (4 to 7-membered heterocyclic groups), C(=S)NHC 1-4 Alkyl, C(=S)N(C 1-4 Alkyl)2、C(=O)OC 1-4 Alkyl, C(=O)C 3-6 Cycloalkyl, C(=S)OC 1-4 Alkyl, C(=O)SC 1-4 Alkyl group, -C(=O)C 1-4 Alkyl group, -C(=O)C 3-6 Cycloalkyl, -C(=O)-4 to 7-membered heterocyclic groups, -C(=S)C 1-4 Alkyl group, -C(=S)C 3-6 Cycloalkyl, -C(=S)-4 to 7-membered heterocycloalkyl, -C(=NR)- 1bb C 1-4 Alkyl group, -C (=NR) 1bb C 3-6 Cycloalkyl, -C (=NR) 1bb NHC 1-4 Alkyl group, -C (=NR) 1bb )NH2、-C(=NR 1bb )N(C 1-4 Alkyl)2、-C(=NR) 1bb NHC 3-6 cycloalkyl; preferably, R 1aa Each of the following groups, independently selected from H or optionally substituted, consists of: oxetyl, oxetyl, pyrrolidinyl, pyrazolyl, -C(=O)-CH3, -C(=O)-CH2CH3, -C(=O)-CH(CH3)2, -C(=O)-C(CH3)3, -C(=O)-cyclopropyl, -C(=O)-cyclobutyl, -C(=O)-cyclopentyl, -C(=O)-cyclohexyl, -C(=O)-bicyclo[1.1.1] pentyl, -C(=O)-oxetanebutyl, -C(=O)-tetrahydrofuranyl, -C(=O)-oxetanehexyl, -C(=O)-azacyclobutyl, -C(=O)-pyrrolidinyl, -C(=O)-piperidinyl, -C(=O)-piperazinyl, -C(=S)-CH3, -C(=S)-CH2CH3, -C(=S)-CH(CH3)2, -C(=S)-C(CH3)3, -C(=S)-cyclopropyl, -C( =S)-cyclobutyl, -C(=S)-cyclopentyl, -C(=S)-cyclohexyl, -C(=S)-bicyclo[1.1.1]pentyl, -C(=S)-oxacyclobutyl, -C(=S)-tetrahydrofuranyl, -C(=S)-oxacyclohexyl, -C(=S)-azacyclobutyl, -C(=S)-pyrrolidinyl, -C(=S)-piperidinyl, -C(=S)-piperazinyl, -C(=O)NH2, -C(=O)-N(OH)( CH3), -C(=O)-N(OCH3)(CH3), -C(=O)-NHCH3, -C(=O)-NHCH2CH3, -C(=O)-N(CH3)2, -C(=O)-N(C H2CH3)2, -C(=O)-N(CH3)(CH2CH3), -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)SCH3, -C(=O)SCH2CH3, When substituted, it is replaced by 1 to 4 elements selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, -CH2CF3, CH2CN, CD3, CHD2, CH2D, CH2CH2F, -OCH2CH2F, -OCH2CH2OCH3, methyl, ethyl, isopropyl, methoxy, ethoxy, -CH2CN, -CH2OH, -CH2OCH3, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, N(CH3)2, vinyl, The substituents are replaced; R 4 Selected from H, R 5 Selected from R 5a Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 cycloalkyl or C 3-6 Cycloalkyl, heteroaryl, or 4-7 membered heterocyclic groups, wherein the alkyl, alkynyl, cycloalkyl, heteroaryl, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; Preferably, R 5a Each of the following is independently selected from H, deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, -CH2-ethynyl, methoxy, ethoxy, -O-cyclopropyl, pyrazolyl, or cyclopropyl, wherein CH2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, pyrazolyl, or cyclopropyl is optionally selected from 1 to 4 of deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups; The definitions of the remaining groups are consistent with those of any one of claims 3-5.

7. A compound or a racemic, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is selected from one of the structures shown in Table E.

8. A pharmaceutical composition comprising the compound of any one of claims 1-7 or a racemic, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, preferably comprising 1-1500 mg of the compound of any one of claims 1-7 or a racemic, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

9. The use of the compound according to any one of claims 1-7, or a racemic, stereoisomer, tautomer, pharmaceutically acceptable salt thereof, or the composition according to claim 8, in the preparation of a medicament for treating solid tumors (e.g., breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, uterine cancer, gastric cancer, colorectal cancer).

10. A method for treating or alleviating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of the compound of any one of claims 1-7 or a racemic, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, preferably 1-1500 mg, wherein the disease is preferably a solid tumor (e.g., breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, uterine cancer, gastric cancer, colorectal cancer).

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