Pyrazolopyridine derivatives and their medical applications

Abstract

The present invention relates to compounds according to general formula (I) or their stereoisomers, tautomers, deuterated products, solvates, prodrugs, metabolites, pharma- ceutically acceptable salts or cocrystals, as well as intermediates and processes for their preparation, and their application in the manufacture of medicaments for treating diseases associated with the activity or expression level of USP1. [C1] TIFF2025508420000120.tif28156

Description

[Technical field]

[0001] The present invention relates to compounds according to general formula (I) or their stereoisomers, tautomers, deuterated products, solvates, prodrugs, metabolites, pharma- ceutically acceptable salts or cocrystals, as well as intermediates and processes for their preparation, and their application in the manufacture of medicaments for treating diseases associated with the activity or expression level of USP1. [Background technology]

[0002] Cellular protein ubiquitination is an important protein modification that can regulate multiple cellular processes. Protein ubiquitination is synergistically controlled by E3 ubiquitin ligases and deubiquitinating enzymes (DUBs). DUBs can be responsible for cleaving the isopeptide bond between ubiquitin and the modified protein, removing ubiquitin from the target protein and rescuing it from the degradation pathway, and are also involved in the post-degradation editing, maturation, and recycling of ubiquitin molecules. Currently, over 100 deubiquitinating enzymes are known, and these proteins are subdivided into six subfamilies. The ubiquitin-specific protease (USP) subfamily is the largest of these, with 58 members currently known. USPs are cysteine ​​proteases that contain a highly conserved catalytic domain, and USP1 is one of the USP subfamily in DUBs (Cancers, 2020, 12, 1579; Molecular Cell, 2018, 72, 925-941).

[0003] The Fanconi Anemia (FA) and DNA Translesion Synthesis (TLS) pathways are the earliest DNA damage resistance and repair pathways found to be regulated by reversible ubiquitination, and USP1 can be involved in the regulation of DNA damage-repair pathways by regulating the deubiquitination of specific proteins in the FA and TLS pathways (Nature Chemical Biology, 2014, 10, 298-304). USP1 plays an important role in DNA repair in tumor cells, and it has been reported that deletion of USP1 leads to reduced viability and replication fork disassembly in BRCA1-deficient cells (Molecular Cell, 2018, 72, 925-941). As a cofactor for USP1, USP12 and USP46, UAF1 (USP1-associated factor 1) can enhance the activity of their deubiquitinases by forming a stable USP / UAF1 protein complex, which deubiquitinates various substrates and is involved in the regulation of DNA repair processes, tumor development mechanisms and antiviral innate immunity (Nat Commun, 2020, 11, 6042). There are currently no drugs against the USP1 protein on the market, and research into USP1 inhibitors has the potential for widespread application. Summary of the Invention [Means for solving the problem]

[0004] The object of the present invention is to provide a compound capable of inhibiting USP1 or its stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharma- ceutically acceptable salt or cocrystal, as well as intermediates and preparation methods thereof, and applications in the manufacture of medicines for treating diseases related to the activity or expression level of USP1.

[0005] The present invention provides a compound according to general formula (I) or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharma- ceutically acceptable salt or co-crystal thereof, wherein: [ka] In some embodiments, ring A is [ka] The left side is R. 2 is connected to In some embodiments, ring A is [ka] The left side is R. 2 is connected to In some embodiments, ring A is [ka] The left side is R. 2 is connected to In some embodiments, R 1 and R 9 are each independently H, a halogen, a cyano group, or C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group or C 1-6 alkoxy groups, wherein the alkyl, alkenyl, alkynyl or alkoxy groups are optionally selected from H, halogen, OH, =O, cyano, NH, C 1-6 Alkyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy groups, halogen-substituted C 1-6 C substituted with alkyl or hydroxy groups 1-6 C substituted with alkyl or cyano groups 1-6 is further substituted with 0 to 4 substituents selected from an alkyl group; In some embodiments, R 1 and R 9 are each independently H, a halogen, a cyano group, or C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group or C 1-4alkoxy groups, wherein the alkyl, alkenyl, alkynyl or alkoxy groups are optionally selected from H, halogen, OH, =O, cyano, NH, C 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy groups, halogen-substituted C 1-4 C substituted with alkyl or hydroxy groups 1-4 C substituted with alkyl or cyano groups 1-4 is further substituted with 0 to 4 substituents selected from an alkyl group; In some embodiments, R 1 and R 9 are each independently selected from H, F, Cl, Br, I, a cyano group, a methyl group, or an ethyl group; In some embodiments, R 1 is H, In some embodiments, R 9 is H, In some embodiments, R 8 is a halogen, a cyano group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group or C 1-6 alkoxy groups, wherein the alkyl, alkenyl, alkynyl or alkoxy groups are optionally selected from H, halogen, OH, =O, cyano, NH, C 1-6 Alkyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy groups, halogen-substituted C 1-6 C substituted with alkyl or hydroxy groups 1-6 C substituted with alkyl or cyano groups 1-6 is further substituted with 0 to 4 substituents selected from an alkyl group; In some embodiments, R 8 is a halogen, a cyano group, C 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 The alkyl, alkynyl and alkoxy groups are optionally selected from H, halogen, OH, cyano, NH, C1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 is further substituted with 0 to 4 substituents selected from an alkoxy group; In some embodiments, R 8 is selected from F, Cl, Br, I, CN, methyl, ethyl, ethynyl, methoxy or ethoxy; In some embodiments, R 8 is selected from F, Cl, Br, CN, a methyl group, an ethynyl group or a methoxy group, In some embodiments, R 8 is selected from F or Cl, In some embodiments, R 2 is C 6-10 a carbocycle or a 5-10 membered heterocycle, said carbocycle or heterocycle optionally having 0-4 R 2a is further substituted with In some embodiments, R 2 is a phenyl group, a six-membered heteroaryl group, a benzo C 4-6 Carbocyclic, 4-6 membered benzo heterocyclic, pyrido C 4-6 selected from carbocycles, pyrido 4- to 6-membered heterocycles; In some embodiments, R 2 is selected from a phenyl group, a pyridine, a pyrimidine, a pyrrole, a pyrazole, an imidazole, a furan, a thiophene, a thiazole, or an oxazole, and the phenyl group, the pyridine, the pyrimidine, the pyrrole, the pyrazole, an imidazole, a furan, a thiophene, a thiazole, or an oxazole is optionally selected from 0 to 4 R 2a is further substituted with In some embodiments, R 2 teeth, [ka] wherein R is selected from 2 Optionally, 0 to 4 R 2a is further substituted with In some embodiments, R 2pyrrole, pyrazole, imidazole, pyrimidine, [ka] The pyrrole, pyrazole, imidazole, pyrimidine, [ka] is optionally H, F, Cl, Br, I, cyano, -SO2-methyl, -SO2-ethyl, -SO2-propyl, -SO2-isopropyl, -SO2-cyclopropyl, CH2F, CHF2, CF3, -OCH2F, -OCHF2, -OCF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, -OCD3, methylthio, ethylthio, propylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azacyclopentyl group, azacyclohexyl group, piperazine, oxetanyl group, oxacyclopentyl group, oxacyclohexyl group, morpholine, -O-azetidinyl, -O-azacyclopentyl, -O-azacyclohexyl, -O-oxetanyl, -O-oxacyclopentyl, -O-oxacyclohexyl, -OCH2-phenyl, -OCH2-cyclopropyl, -OCH2-cyclobutyl, -OCH2-cyclopentyl, -OCH2-cyclohexyl, [ka] Pyrrole, pyrazole, imidazole, thiazole, thiophene, furan, oxazole, [ka] is further substituted with 0 to 4 substituents selected from In some embodiments, R 2 teeth, [ka] is selected from In some embodiments, R 2 teeth, [ka] is selected from In some embodiments, R 2a are each independently H, halogen, OH, =O, cyano group, NH2, NH(C 1-6 alkyl), N(C 1-6 Alkyl)2, -SO2-C 1-6 Alkyl, -SO2-C 3-6 Cycloalkyl, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, -ZC 3-6 cycloalkyl or -Z-3 to 8 membered heterocycle, wherein the alkyl group, cycloalkyl group, alkoxy group, alkylthio group or heterocycle is optionally selected from H, D, halogen, OH, =O, cyano group, NH2, C 1-6 Alkyl group, C 2-6 Alkynyl group, C 1-6 is further substituted with 0 to 4 substituents selected from an alkoxy group, and the heterocycle contains 1 to 4 heteroatoms selected from O, S and N; In some embodiments, R 2a are each independently H, halogen, OH, =O, cyano group, NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl)2, -SO2-C 1-4 Alkyl, -SO2-C 3-6 Cycloalkyl, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 1-4 Alkylthio group, -ZC 3-6 cycloalkyl or -Z-3 to 6 membered heterocycle, wherein the alkyl group, cycloalkyl group, alkoxy group, alkylthio group or heterocycle is optionally selected from H, D, halogen, OH, =O, cyano group, NH2, C 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 is further substituted with 0 to 4 substituents selected from an alkoxy group, and the heterocycle contains 1 to 4 heteroatoms selected from O, S and N; In some embodiments, R 2a are each independently selected from H, F, Cl, Br, I, or a cyano group, or R 2a are each independently a substituted or unsubstituted group: -SO2-methyl, -SO2-ethyl, -SO2-propyl, -SO2-isopropyl, -SO2-cyclopropyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, piperazine, o and optionally, when substituted, H, D, halogen, OH, =O, cyano, NH, C, C-C-H ... 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 is further substituted with 0 to 4 substituents selected from an alkoxy group; In some embodiments, Z is a bond, O, S, NH, N(C 1-4 alkyl), C(=O)NH, NHC(=O), -OCH2-, -CH2O- or C 1-3 alkylene groups, In some embodiments, R 3 and R 4 are each independently H, halogen, OH, cyano group, NH2, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group or C 1-6 alkoxy groups, wherein the alkyl, alkenyl, alkynyl or alkoxy groups are optionally selected from H, halogen, OH, =O, cyano, NH, C 1-6 Alkyl group, C 2-6Alkynyl group, C 1-6 Alkoxy groups, halogen-substituted C 1-6 C substituted with alkyl or hydroxy groups 1-6 C substituted with alkyl or cyano groups 1-6 Alkyl group, C 3-6 It is further substituted with 0 to 4 substituents selected from a cycloalkyl group or a 3- to 8-membered heterocyclic group, and the heterocyclic group contains 1 to 4 heteroatoms selected from O, S and N, In some embodiments, R 3 and R 4 are each independently H, a halogen, OH, a cyano group, or C 1-4 alkyl groups, In some embodiments, R 3 and R 4 are each independently selected from H, F, Cl, Br, I, a methyl group, and an ethyl group; In some embodiments, R 3 and R 4 is H, In some embodiments, Cy is C 3-12 A carbocycle or a 4- to 12-membered heterocycle, wherein Cy is optionally selected from H, halogen, OH, =O, a cyano group, NH, C 1-6 Alkyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy groups, halogen-substituted C 1-6 C substituted with alkyl or hydroxy groups 1-6 C substituted with alkyl or cyano groups 1-6 Alkyl group, C 3-6 is further substituted with 0 to 4 substituents selected from a cycloalkyl group or a 3- to 8-membered heterocyclic group, the heterocyclic group containing 1 to 4 heteroatoms selected from O, S and N; In some embodiments, Cy is C 3-6 Monocyclic cycloalkyl groups, C 5-11 Fused-ring cycloalkyl groups, C 5-11 Spirocyclic cycloalkyl groups, C 5-11Bridged ring cycloalkyl group, 4-7 membered monocyclic heterocycloalkyl group, 6-11 membered condensed ring heterocycloalkyl group, 6-11 membered spiro ring heterocycloalkyl group, 6-11 membered bridged ring heterocycloalkyl group, benzene ring, Benzo C 4-6 Carbocycle, 4-6 membered benzo heterocycle, 5-6 membered heteroaryl ring, 8-10 membered fused heteroaryl ring, wherein Cy is optionally H, halogen, OH, =O, cyano group, NH, C 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy groups, halogen-substituted C 1-4 C substituted with alkyl or hydroxy groups 1-4 C substituted with alkyl or cyano groups 1-4 Alkyl group, C 3-6 is further substituted with 0 to 4 substituents selected from a cycloalkyl group or a 3- to 8-membered heterocycle, the heterocycle containing 1 to 4 heteroatoms selected from O, S and N; In some embodiments, Cy is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a bicyclo[2.2.2]octyl, a bicyclo[1.1.1]pentanyl, a cyclopentyl-fused cyclopentyl, a cyclobutyl-spiro-cyclohexyl, a cyclobutyl-spiro-cyclopentyl, an azetidinyl group, an azacyclopentyl group, an azacyclohexyl group, an azetidinyl-spiro-cyclobutyl, an azetidinyl-spiro-cyclopentyl, an azetidinyl-spiro-cyclohexyl, an azetidinyl-spiro-azetidinyl, an azetidinyl-spiro-azacyclopentyl, an azetidinyl-spiro-azacyclohexyl, [ka] Benzene ring, thiophene, furan, pyrrole, thiazole, oxazole, pyrazole, pyrazine, pyrimidine, [ka] benzothiazole, benzothiophene, benzofuran, benzoxazole, benzopyrrole, benzopyrazole, benzimidazole, indolizine, pyridopyrrole, pyridoimidazole, pyridopyrazole, pyrimidoimidazole, pyrimidopyrazole, pyridotriazole or 2-pyridone, wherein Cy is optionally selected from H, halogen, OH, =O, a cyano group, NH, C 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy groups, halogen-substituted C 1-4 C substituted with alkyl or hydroxy groups 1-4 C substituted with alkyl or cyano groups 1-4 Alkyl group, C 3-6 is further substituted with 0 to 4 substituents selected from a cycloalkyl group or a 3- to 8-membered heterocycle, the heterocycle containing 1 to 4 heteroatoms selected from O, S and N; In some embodiments, Cy is [ka] wherein Cy is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, a cyano group, CHF, CHF, CF, a methyl group, an ethyl group, a propyl group, an isopropyl group, a methoxy group, an ethoxy group, or a cyclopropyl group; In some embodiments, Cy is [ka] wherein Cy is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, a cyano group, CHF, CHF, CF, a methyl group, an ethyl group, a propyl group, an isopropyl group, a methoxy group, an ethoxy group, or a cyclopropyl group; In some embodiments, R 5 -ZC 3-12 Carbocyclic ring or -Z-4 to 12-membered heterocyclic ring, 5 Optionally, 0 to 4 R 5a is further substituted with In some embodiments, R 5 -ZC 6-12 Carbocyclic ring or -Z-5 to 12 membered heterocyclic ring, 5 Optionally, 0 to 4 R 5a is further substituted with In some embodiments, R 5 -ZC 3-10 Carbocyclic ring or -Z-4 to 10-membered heterocyclic ring, 5 Optionally, 0 to 4 R 5a is further substituted with In some embodiments, R 5 -ZC 6-10 Carbocyclic ring or -Z-5 to 10 membered heterocyclic ring, 5 Optionally, 0 to 4 R 5a is further substituted with In some embodiments, Z is a bond, O, S, NH, N(C 1-4 alkyl), C(=O)NH, NHC(=O), -OCH2-, -CH2O- or C 1-3 alkylene groups, In some embodiments, R 5 is selected from imidazole and imidazo 4-9 membered heterocycles, 5 Optionally, 0 to 4 R 5a is further substituted with In some embodiments, R 5 is selected from a benzene ring, pyrazole, pyrrole, imidazole, triazole, pyridine, pyrimidine, pyrazine, or pyridazine; 5 Optionally, 0 to 4 R 5a is further substituted with In some embodiments, R 5is selected from pyrrole, pyrazole or imidazole, said pyrrole, pyrazole or imidazole optionally being selected from H, F, Cl, Br, I, a cyano group, CH2F, CHF2, CF3, CD3, a methyl group, an ethyl group, a propyl group, an isopropyl group, -CH2CH2F, a methoxy group, an ethoxy group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an oxetanyl group, an oxacyclopentyl group, an oxacyclohexyl group, an azetidinyl group, an N-methylazetidinyl group, an azacyclopentyl group, an azacyclohexyl group, [ka] -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-oxetanyl, -CH2-oxacyclopentyl, -CH2-oxacyclohexyl, -CH2-azetidinyl, -CH2-azacyclopentyl, -CH2-azacyclohexyl, [ka] or a propargyl group, In some embodiments, R 5 teeth, [ka] wherein R is selected from 5 is optionally H, F, Cl, Br, I, a cyano group, CH2F, CHF2, CF3, CD3, a methyl group, an ethyl group, a propyl group, an isopropyl group, -CH2CH2F, a methoxy group, an ethoxy group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an oxetanyl group, an oxacyclopentyl group, an oxacyclohexyl group, an azetidinyl group, an N-methylazetidinyl group, an azacyclopentyl group, an azacyclohexyl group, [ka] -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-oxetanyl, -CH2-oxacyclopentyl, -CH2-oxacyclohexyl, -CH2-azetidinyl, -CH2-azacyclopentyl, -CH2-azacyclohexyl, [ka] or a propargyl group, In some embodiments, R 5 is selected from pyrrole, pyrazole or imidazole, said pyrrole, pyrazole or imidazole being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, cyano, CHF, CHF, CF, CD, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxacyclopentyl, oxacyclohexyl, azetidinyl, N-methylazetidinyl, azacyclopentyl or azacyclohexyl; In some embodiments, R 5 is selected from pyrrole, pyrazole or imidazole, said pyrrole, pyrazole or imidazole being optionally further substituted with 0-4 substituents selected from H, F, Cl, Br, I, cyano, CHF, CHF, CF, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; In some embodiments, R 5 teeth, [ka] is selected from In some embodiments, R 5 teeth, [ka] is selected from In some embodiments, R 5 teeth, [ka] wherein R is selected from 5 Optionally, 0 to 4 R 5a is further substituted with In some embodiments, R 5 teeth, [ka] [ka] is selected from In some embodiments, R 5a are each independently H, halogen, OH, cyano group, NH2, NHC 1-6 Alkyl group, N(C 1-6 Alkyl)2, C 1-6 Alkyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -C 1-4 Alkylene-3 to 6-membered heterocycle, C 3-6 Cycloalkyl groups, 3-8 membered heterocycles, -CONHC 1-6 Alkyl, -CONHC 1-6 Alkoxy, -CONHC 3-6 Cycloalkyl, -CONH3-8 membered heterocycle, -NHCO-C 1-6 Alkyl, -NHCO-C 1-6 Alkoxy, -NHCO-C 3-6 cycloalkyl or -NHCO-3 to 8 membered heterocycle, wherein the alkyl group, alkylene group, alkynyl group, alkoxy group, cycloalkyl group or heterocycle is optionally selected from H, D, halogen, OH, =O, cyano group, NH2, -C(=O)NH2, -C(=O)NHC 1-6 Alkyl group, -C(=O)N(C 1-6 Alkyl)2, C 1-6 Alkyl group, C 2-6 Alkynyl group, C1-6 Alkoxy groups, halogen-substituted C 1-6 C substituted with alkyl or hydroxy groups 1-6 C substituted with alkyl or cyano groups 1-6 Alkyl group, C 3-6 Cycloalkyl groups, halogen-substituted C 3-6 is further substituted with 0 to 4 substituents selected from a cycloalkyl group or a 3- to 8-membered heterocycle, the heterocycle containing 1 to 4 heteroatoms selected from O, S and N; In some embodiments, R 5a are each independently H, halogen, OH, cyano group, NH2, C 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy group, -C 1-2 Alkylene-C 3-6 Cycloalkyl, -C 1-2 Alkylene-3 to 6-membered heterocycle, C 3-6 The alkyl group, alkylene group, alkynyl group, alkoxy group, cycloalkyl group, or heterocycle may optionally be selected from H, D, halogen, OH, =O, cyano group, NH2, -C(=O)NH2, -C(=O)NHC 1-4 Alkyl, -C(=O)N(C 1-4 Alkyl)2, C 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy groups, halogen-substituted C 1-4 C substituted with alkyl or hydroxy groups 1-4 C substituted with alkyl or cyano groups 1-4 Alkyl group, C 3-6 Cycloalkyl groups, halogen-substituted C 3-6 is further substituted with 0 to 4 substituents selected from a cycloalkyl group or a 3- to 8-membered heterocycle, the heterocycle containing 1 to 4 heteroatoms selected from O, S and N; In some embodiments, R 5aeach independently represents H, F, Cl, Br, I, cyano, methyl, ethyl, propyl, isopropyl, propargyl, butynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxacyclopentyl, oxacyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-oxetanyl, -CH2-oxacyclo pentyl, -CH2-oxacyclohexyl, -CH2-azetidinyl, -CH2-azacyclopentyl, -CH2-azacyclohexyl, said methyl, ethyl, propyl, isopropyl, propargyl, butynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxacyclopentyl, oxacyclohexyl, azetidinyl, azacyclopentyl or azacyclohexyl group optionally being selected from H, halogen, OH, =O, cyano, NH, C 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, halogen-substituted C 3-6 is further substituted with 0 to 4 substituents selected from a cycloalkyl group; In some embodiments, the compound represented by general formula (I) is selected from the compounds represented by general formula (Ia), and the definitions of the compound groups represented by general formula (Ia) are the same as those of the compounds represented by general formula (I).

[0006] As a first embodiment of the present invention, there is provided a compound represented by the above-mentioned general formula (I) or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharma- ceutically acceptable salt or cocrystal thereof, Ring A is [ka] The left side is R. 2 is connected to R1 and R 9 are each independently H, a halogen, a cyano group, or C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group or C 1-6 alkoxy groups, wherein the alkyl, alkenyl, alkynyl or alkoxy groups are optionally selected from H, halogen, OH, =O, cyano, NH, C 1-6 Alkyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy groups, halogen-substituted C 1-6 C substituted with alkyl or hydroxy groups 1-6 C substituted with alkyl or cyano groups 1-6 is further substituted with 0 to 4 substituents selected from an alkyl group; R 8 is a halogen, a cyano group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group or C 1-6 alkoxy groups, wherein the alkyl, alkenyl, alkynyl or alkoxy groups are optionally selected from H, halogen, OH, =O, cyano, NH, C 1-6 Alkyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy groups, halogen-substituted C 1-6 C substituted with alkyl or hydroxy groups 1-6 C substituted with alkyl or cyano groups 1-6 is further substituted with 0 to 4 substituents selected from an alkyl group; R 2 is C 6-10 a carbocycle or a 5-10 membered heterocycle, said carbocycle or heterocycle optionally having 0-4 R 2a is further substituted with R 2a are each independently H, halogen, OH, =O, cyano group, NH2, NH(C 1-6 alkyl), N(C 1-6 Alkyl)2, -SO2-C 1-6 Alkyl, -SO2-C3-6 Cycloalkyl, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, -ZC 3-6 cycloalkyl or -Z-3 to 8 membered heterocycle, wherein the alkyl group, cycloalkyl group, alkoxy group, alkylthio group or heterocycle is optionally selected from H, D, halogen, OH, =O, cyano group, NH2, C 1-6 Alkyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 3-6 is further substituted with 0 to 4 substituents selected from a cycloalkyl group, and the heterocycle contains 1 to 4 heteroatoms selected from O, S and N; R 3 and R 4 are each independently H, halogen, OH, cyano group, NH2, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group or C 1-6 alkoxy groups, wherein the alkyl, alkenyl, alkynyl or alkoxy groups are optionally selected from H, halogen, OH, =O, cyano, NH, C 1-6 Alkyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy groups, halogen-substituted C 1-6 C substituted with alkyl or hydroxy groups 1-6 C substituted with alkyl or cyano groups 1-6 Alkyl group, C 3-6 It is further substituted with 0 to 4 substituents selected from a cycloalkyl group or a 3- to 8-membered heterocyclic group, and the heterocyclic group contains 1 to 4 heteroatoms selected from O, S and N, Cy is C 3-12 A carbocycle or a 4- to 12-membered heterocycle, wherein Cy is optionally selected from H, halogen, OH, =O, a cyano group, NH, C 1-6 Alkyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy groups, halogen-substituted C 1-6C substituted with alkyl or hydroxy groups 1-6 C substituted with alkyl or cyano groups 1-6 Alkyl group, C 3-6 is further substituted with 0 to 4 substituents selected from a cycloalkyl group or a 3- to 8-membered heterocyclic group, the heterocyclic group containing 1 to 4 heteroatoms selected from O, S and N; R 5 -ZC 3-12 Carbocyclic ring or -Z-4 to 12-membered heterocyclic ring, 5 Optionally, 0 to 4 R 5a is further substituted with R 5a are each independently H, halogen, OH, cyano group, NH2, NHC 1-6 Alkyl group, N(C 1-6 Alkyl)2, C 1-6 Alkyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -C 1-4 Alkylene-3 to 6-membered heterocycle, C 3-6 Cycloalkyl groups, 3-8 membered heterocycles, -CONHC 1-6 Alkyl, -CONHC 1-6 Alkoxy, -CONHC 3-6 Cycloalkyl, -CONH3-8 membered heterocycle, -NHCO-C 1-6 Alkyl, -NHCO-C 1-6 Alkoxy, -NHCO-C 3-6 cycloalkyl or -NHCO-3 to 8 membered heterocycle, wherein the alkyl group, alkylene group, alkynyl group, alkoxy group, cycloalkyl group or heterocycle is optionally selected from H, D, halogen, OH, =O, cyano group, NH2, -C(=O)NH2, -C(=O)NHC 1-6 Alkyl, -C(=O)N(C 1-6 Alkyl)2, C 1-6 Alkyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy groups, halogen-substituted C 1-6 C substituted with alkyl or hydroxy groups1-6 C substituted with alkyl or cyano groups 1-6 Alkyl group, C 3-6 Cycloalkyl groups, halogen-substituted C 3-6 is further substituted with 0 to 4 substituents selected from a cycloalkyl group or a 3- to 8-membered heterocycle, the heterocycle containing 1 to 4 heteroatoms selected from O, S and N; Z is a bond, O, S, NH, N(C 1-4 alkyl), C(=O)NH, NHC(=O), -OCH2-, -CH2O- or C 1-3 The alkylene group is selected from the group consisting of aryl, ... and aryl groups.

[0007] As a second embodiment of the present invention, there is provided a compound represented by the following general formula (Ia) or a stereoisomer, tautomer, deuterated product, solvate, prodrug, metabolite, pharma- ceutically acceptable salt, or cocrystal thereof, wherein: [ka] R 1 and R 9 are each independently H, a halogen, a cyano group, or C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group or C 1-4 alkoxy groups, wherein the alkyl, alkenyl, alkynyl or alkoxy groups are optionally selected from H, halogen, OH, =O, cyano, NH, C 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy groups, halogen-substituted C 1-4 C substituted with alkyl or hydroxy groups 1-4 C substituted with alkyl or cyano groups 1-4 is further substituted with 0 to 4 substituents selected from an alkyl group; R 8 is a halogen, a cyano group, C 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4The alkyl, alkynyl and alkoxy groups are optionally selected from H, halogen, OH, cyano, NH, C 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 is further substituted with 0 to 4 substituents selected from an alkoxy group; R 2a are each independently H, halogen, OH, =O, cyano group, NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl)2, -SO2-C 1-4 Alkyl, -SO2-C 3-6 Cycloalkyl, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 1-4 Alkylthio group, -ZC 3-6 cycloalkyl or -Z-3 to 6 membered heterocycle, wherein the alkyl group, cycloalkyl group, alkoxy group, alkylthio group or heterocycle is optionally selected from H, D, halogen, OH, =O, cyano group, NH2, C 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy group, C 3-6 is further substituted with 0 to 4 substituents selected from a cycloalkyl group, and the heterocycle contains 1 to 4 heteroatoms selected from O, S and N; R 3 and R 4 are each independently H, a halogen, OH, a cyano group, or C 1-4 alkyl groups, Cy is C 3-6 Monocyclic cycloalkyl groups, C 5-11 Fused-ring cycloalkyl groups, C 5-11 Spirocyclic cycloalkyl groups, C 5-11 Bridged ring cycloalkyl group, 4-7 membered monocyclic heterocycloalkyl group, 6-11 membered condensed ring heterocycloalkyl group, 6-11 membered spiro ring heterocycloalkyl group, 6-11 membered bridged ring heterocycloalkyl group, benzene ring, Benzo C 4-6Carbocycle, 4-6 membered benzo heterocycle, 5-6 membered heteroaryl ring, 8-10 membered fused heteroaryl ring, wherein Cy is optionally H, halogen, OH, =O, cyano group, NH, C 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy groups, halogen-substituted C 1-4 C substituted with alkyl or hydroxy groups 1-4 C substituted with alkyl or cyano groups 1-4 Alkyl group, C 3-6 is further substituted with 0 to 4 substituents selected from a cycloalkyl group or a 3- to 8-membered heterocycle, the heterocycle containing 1 to 4 heteroatoms selected from O, S and N; R 5 -ZC 6-12 Carbocyclic ring or -Z-5 to 12 membered heterocyclic ring, 5 Optionally, 0 to 4 R 5a is further substituted with R 5a are each independently H, halogen, OH, cyano group, NH2, C 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy group, -C 1-2 Alkylene-C 3-6 Cycloalkyl, -C 1-2 Alkylene-3 to 6-membered heterocycle, C 3-6 The alkyl group, alkylene group, alkynyl group, alkoxy group, cycloalkyl group, or heterocycle may optionally be selected from H, D, halogen, OH, =O, cyano group, NH2, -C(=O)NH2, -C(=O)NHC 1-4 Alkyl, -C(=O)N(C 1-4 Alkyl)2, C 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy groups, halogen-substituted C 1-4 C substituted with alkyl or hydroxy groups 1-4 C substituted with alkyl or cyano groups 1-4 Alkyl group, C 3-6Cycloalkyl groups, halogen-substituted C 3-6 is further substituted with 0 to 4 substituents selected from a cycloalkyl group or a 3- to 8-membered heterocycle, the heterocycle containing 1 to 4 heteroatoms selected from O, S and N; The definitions of other substituents are the same as those in the first embodiment of the present invention.

[0008] As a third embodiment of the present invention, there is provided a compound represented by the above-mentioned general formula (Ia) or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharma- ceutically acceptable salt or cocrystal thereof, R 1 and R 9 are each independently selected from H, F, Cl, Br, I, a cyano group, a methyl group, or an ethyl group; R 8 is selected from F, Cl, Br, I, CN, methyl, ethyl, ethynyl, methoxy or ethoxy; R 2 is selected from a phenyl group, a pyridine, a pyrimidine, a pyrrole, a pyrazole, an imidazole, a furan, a thiophene, a thiazole, or an oxazole, and the phenyl group, the pyridine, the pyrimidine, the pyrrole, the pyrazole, an imidazole, a furan, a thiophene, a thiazole, or an oxazole is optionally selected from 0 to 4 R 2a or or R 2 teeth, [ka] wherein R is selected from 2 Optionally, 0 to 4 R 2a is further substituted with R 2a are each independently selected from H, F, Cl, Br, I, or a cyano group, or R 2aare each independently a substituted or unsubstituted group: -SO2-methyl, -SO2-ethyl, -SO2-propyl, -SO2-isopropyl, -SO2-cyclopropyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, piperazine, oxetanyl, oxacyclopentyl, oxacyclohexyl, and optionally, when substituted, H, D, halogen, OH, =O, a cyano group, NH, C, C-alkyl, aryl, aryl- ... 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy group, C 3-6 is further substituted with 0 to 4 substituents selected from a cycloalkyl group; R 3 and R 4 are each independently selected from H, F, Cl, Br, I, a methyl group, and an ethyl group; Cy is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a bicyclo[2.2.2]octyl group, a bicyclo[1.1.1]pentanyl group, a cyclopentyl-fused cyclopentyl group, a cyclobutyl-spiro-cyclohexyl group, a cyclobutyl-spiro-cyclopentyl group, an azetidinyl group, an azacyclopentyl group, an azacyclohexyl group, an azetidinyl-spiro-cyclobutyl group, an azetidinyl-spiro-cyclopentyl group, an azetidinyl-spiro-cyclohexyl group, an azetidinyl-spiro-azetidinyl group, an azetidinyl-spiro-azacyclopentyl group, an azetidinyl-spiro-azacyclohexyl group, [ka] Benzene ring, thiophene, furan, pyrrole, thiazole, oxazole, pyrazole, pyrazine, pyrimidine, [ka] benzothiazole, benzothiophene, benzofuran, benzoxazole, benzopyrrole, benzopyrazole, benzimidazole, indolizine, pyridopyrrole, pyridoimidazole, pyridopyrazole, pyrimidoimidazole, pyrimidopyrazole, pyridotriazole or 2-pyridone, wherein Cy is optionally selected from H, halogen, OH, =O, a cyano group, NH, C 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy groups, halogen-substituted C 1-4 C substituted with alkyl or hydroxy groups 1-4 C substituted with alkyl or cyano groups 1-4 Alkyl group, C 3-6 is further substituted with 0 to 4 substituents selected from a cycloalkyl group or a 3- to 8-membered heterocycle, the heterocycle containing 1 to 4 heteroatoms selected from O, S and N; R 5 is selected from a benzene ring, pyrazole, pyrrole, imidazole, triazole, pyridine, pyrimidine, pyrazine, or pyridazine; 5 Optionally, 0 to 4 R 5a or or R 5 teeth, [ka] wherein R is selected from 5 Optionally, 0 to 4 R 5a is further substituted with R 5aeach independently represents F, Cl, Br, I, cyano, methyl, ethyl, propyl, isopropyl, propargyl, butynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxacyclopentyl, oxacyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-oxetanyl, -CH2-oxa ...pentyl, -CH2-cyclohexyl, -CH2- methyl, ethyl, propyl, isopropyl, propargyl, butynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxacyclopentyl, oxacyclohexyl, azetidinyl, azacyclopentyl or azacyclohexyl group may optionally be selected from the group consisting of H, halogen, OH, =O, cyano, NH, C 1-4 Alkyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, halogen-substituted C 3-6 is further substituted with 0 to 4 substituents selected from a cycloalkyl group; The definitions of other substituents are the same as in the first or second embodiment of the present invention.

[0009] As a fourth embodiment of the present invention, there is provided a compound represented by the above general formula (Ia) or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharma- ceutically acceptable salt or cocrystal thereof, R 1 and R 9 is H, R 8 is selected from F, Cl, Br, CN, a methyl group, an ethynyl group or a methoxy group, R 2 pyrrole, pyrazole, imidazole, pyrimidine, [ka] The pyrrole, pyrazole, imidazole, pyrimidine, [ka] is optionally H, F, Cl, Br, I, cyano, -SO2-methyl, -SO2-ethyl, -SO2-propyl, -SO2-isopropyl, -SO2-cyclopropyl, CH2F, CHF2, CF3, -OCH2F, -OCHF2, -OCF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, -OCD3, methylthio, ethylthio, propylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azacyclopentyl group, azacyclohexyl group, piperazine, oxetanyl group, oxacyclopentyl group, oxacyclohexyl group, morpholine, -O-azetidinyl, -O-azacyclopentyl, -O-azacyclohexyl, -O-oxetanyl, -O-oxacyclopentyl, -O-oxacyclohexyl, -OCH2-phenyl, -OCH2-cyclopropyl, -OCH2-cyclobutyl, -OCH2-cyclopentyl, -OCH2-cyclohexyl, [ka] Pyrrole, pyrazole, imidazole, thiazole, thiophene, furan, oxazole, [ka] is further substituted with 0 to 4 substituents selected from Cy: [ka] wherein Cy is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, cyano, CHF, CHF, CF, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, or cyclopropyl; or Cy is [ka] wherein Cy is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, a cyano group, CHF, CHF, CF, a methyl group, an ethyl group, a propyl group, an isopropyl group, a methoxy group, an ethoxy group, or a cyclopropyl group; R 5 is selected from pyrrole, pyrazole or imidazole, said pyrrole, pyrazole or imidazole optionally being selected from H, F, Cl, Br, I, a cyano group, CH2F, CHF2, CF3, CD3, a methyl group, an ethyl group, a propyl group, an isopropyl group, -CH2CH2F, a methoxy group, an ethoxy group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an oxetanyl group, an oxacyclopentyl group, an oxacyclohexyl group, an azetidinyl group, an N-methylazetidinyl group, an azacyclopentyl group, an azacyclohexyl group, [ka] -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-oxetanyl, -CH2-oxacyclopentyl, -CH2-oxacyclohexyl, -CH2-azetidinyl, -CH2-azacyclopentyl, -CH2-azacyclohexyl, [ka] or a propargyl group; or R 5 teeth, [ka] wherein R is selected from 5is optionally H, F, Cl, Br, I, a cyano group, CH2F, CHF2, CF3, CD3, a methyl group, an ethyl group, a propyl group, an isopropyl group, -CH2CH2F, a methoxy group, an ethoxy group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an oxetanyl group, an oxacyclopentyl group, an oxacyclohexyl group, an azetidinyl group, an N-methylazetidinyl group, an azacyclopentyl group, an azacyclohexyl group, [ka] -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-oxetanyl, -CH2-oxacyclopentyl, -CH2-oxacyclohexyl, -CH2-azetidinyl, -CH2-azacyclopentyl, -CH2-azacyclohexyl, [ka] or a propargyl group, The definitions of other substituents are the same as in the first, second or third embodiment of the present invention.

[0010] As a fifth embodiment of the present invention, there is provided a compound represented by the above general formula (Ia) or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharma- ceutically acceptable salt or cocrystal thereof, R 2 teeth, [ka] is selected from R 5 teeth, [ka] is selected from R 5 teeth, [ka] [ka] is selected from R 8 is selected from F or Cl, The definitions of the other substituents are the same as in the first, second, third or fourth embodiment of the present invention.

[0011] The present invention relates to the following compound or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharma- ceutically acceptable salt, or co-crystal thereof, wherein the compound is selected from one of the structures shown in Table E.

[0012] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7]

[0013] The present invention relates to pharmaceutical compositions, comprising a compound according to the present invention or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharma- ceutically acceptable salt, or co-crystal thereof, and a pharma- ceutically acceptable carrier.

[0014] The present invention relates to the application of the compounds according to the present invention or their stereoisomers, tautomers, deuterated products, solvates, prodrugs, metabolites, pharma- ceutically acceptable salts or cocrystals in the manufacture of medicaments for treating diseases associated with the activity or expression level of USP1, preferably in the manufacture of medicaments for tumor diseases.

[0015] The present invention relates to the application of any of the above compounds or their stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharma- ceutically acceptable salts or cocrystals, or the above pharmaceutical compositions, in the manufacture of a medicament for treating a disease associated with the activity or expression level of USP1, preferably, the disease is selected from tumors.

[0016] The present invention relates to a pharmaceutical composition or formulation, comprising a therapeutically effective amount of a compound according to the present invention or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharma- ceutically acceptable salt or co-crystal thereof, and a pharmaceutical excipient. The pharmaceutical composition may be in the form of a unit dosage form (the amount of active ingredient in a unit dosage form is also referred to as the "formulation specification").

[0017] The present invention further provides a method for treating a disease in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound according to the present invention or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharma- ceutically acceptable salt or co-crystal thereof, or a pharmaceutical composition. In some embodiments, the mammal according to the present invention comprises a human.

[0018] An "effective amount" or "therapeutically effective amount" as used herein includes administering a sufficient amount of a compound disclosed herein that alleviates to some extent one or more symptoms of the disease or condition being treated (e.g., a disease associated with the activity or expression of USP1, such as a tumor). In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein that is required to provide a clinically significant reduction in a disease symptom.Examples of therapeutically effective amounts include 1-1500mg, 1-1400mg, 1-1200mg, 1-600mg, 2-600mg, 3-600mg, 4-600mg, 5-600mg, 6-600mg, 10-600mg, 20-600mg, 25-600mg, 30-600mg, 40-600mg, 50-600mg, 60-600mg, 70-600mg, 75-600mg, 80-600mg, 90-600mg, 100-600mg, 200-600mg, 1-500mg, 2-500mg, 3-500mg, 4-500mg, 5-500mg, 6-50 0mg, 10~500mg, 20~500mg, 25~500mg, 30~500mg, 40~500mg, 50~500mg, 60~500mg, 70~500mg, 75~500mg, 80~500mg, 90~500mg, 100~500mg, 125~500mg, 150~500mg, 200~500mg, 250~500mg, 300~500mg, 400~500mg, 5~400mg, 10~400mg, 20~400mg, 25~400mg, 30~400mg, 40~400mg, 50~400mg, 60~400mg, 70~ 400mg, 75~400mg, 80~400mg, 90~400mg, 100~400mg, 125~400mg, 150~400mg, 200~400mg, 250~400mg, 300~400mg, 1~300mg, 2~300mg, 5~300mg, 10~300 mg, 20~300mg, 25~300mg, 30~300mg, 40~300mg, 50~300mg, 60~300mg, 70~300mg, 75~300mg, 80~300mg, 90~300mg, 100~300mg, 125~300mg, 150~300mg, 2 Including, but not limited to, 00-300mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-200mg, 40-200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg, 100-1000mg, 200-1000mg, 400-1000mg, 100-800mg, 200-800mg, 400-800mg. In some embodiments, the pharmaceutical composition contains 1-1500 mg, 1-1400 mg, 1-1200 mg, 1-600 mg, 20-400 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, 12 mg, 14 mg, 16 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 35 mg, 36 mg, 37 mg, 38 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, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 10

[0113] The present invention also includes, but is not limited to, 0 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, 400 mg, 480 mg, 500 mg of a compound of the present invention or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharma- ceutically acceptable salt, or co-crystal thereof.

[0019] A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharma- ceutically acceptable salt, or cocrystal thereof, wherein the therapeutically effective amount is preferably 1-1500 mg, and the disease is preferably a tumor.

[0020] A method for treating a disease in a mammal, the method comprising administering to a subject a pharmaceutical compound of the present invention or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharma- ceutically acceptable salt, or co-crystal thereof in a daily dose of 1-1500 mg / day, which may be a single dose or divided doses, and in some embodiments, the daily dose is 10-1500 mg / day, 10-800 mg / day, 25-800 mg / day, 50-800 mg / day, ... In some embodiments, the daily dose includes, but is not limited to, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 400 mg / day, 600 mg / day, 800 mg / day, 1000 mg / day, 1200 mg / day.

[0021] The present invention relates to a kit, which may comprise a composition in the form of a single dose or multiple doses, comprising a compound of the present invention or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharma- ceutically acceptable salt or co-crystal thereof, wherein the amount of the compound of the present invention or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharma- ceutically acceptable salt or co-crystal thereof is the same as that amount in said pharmaceutical composition.

[0022] In the present invention, the amounts of the compounds of the invention or their stereoisomers, deuterated forms, solvates, prodrugs, metabolites, pharma- ceutically acceptable salts or cocrystals are in each case calculated in the form of the free base. Synthesis method 1: [ka] R a1 is selected from halogen or OH, R a2 is selected from halogens, preferably selected from Br or Cl, R a3is selected from an amino protecting group or H; The definitions of the other groups are consistent with the specification. The compound of general formula (Ia-1) and the compound of general formula (Ia-2) are subjected to a substitution reaction to give a compound of general formula (Ia-3), or the amino protecting group of the compound of general formula (Ia-2) is removed, and then the compound of general formula (Ia-1) is subjected to a substitution reaction to give a compound of general formula (Ia-3), The compound of general formula (Ia-3) undergoes a coupling reaction to give the compound of general formula (Ia).

[0023] Unless otherwise stated, terms used in the specification and claims have the following meanings.

[0024] Carbon, hydrogen, oxygen, sulfur, nitrogen, or F, Cl, Br, I in the groups and compounds described in the present invention include their isotopic status, and carbon, hydrogen, oxygen, sulfur, or nitrogen in the groups and compounds described in the present invention are optionally further replaced by one or more corresponding isotopes, where the isotope of carbon is: 12 C and 13 C and 14 C; isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called tritium); isotopes of oxygen include 16 O and 17 O and 18 The isotopes of sulfur include 32 S and 33 S and 34 S and 36 S and the nitrogen isotopes are 14 N and 15 N and the fluorine isotope is 17 F and 19 F and the chlorine isotope is 35 Cl and 37 The isotopes of bromine include Cl and 79 Br and 81 Includes Br.

[0025] “Halogen” refers to F, Cl, Br or I.

[0026] "Halogen substitution" refers to F, Cl, Br or I substitution, including, but not limited to, substitution with 1 to 10 substituents selected from F, Cl, Br or I, substitution with 1 to 6 substituents selected from F, Cl, Br or I, substitution with 1 to 4 substituents selected from F, Cl, Br or I. "Halogen substitution" is abbreviated as "halogenation".

[0027] "Alkyl group" refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group, including, but not limited to, alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, and alkyl groups of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched chain isomers thereof. Definitions of alkyl groups described herein are consistent with this definition. Alkyl groups may be monovalent, divalent, trivalent, or tetravalent.

[0028] An "alkylene group" is a substituted or unsubstituted straight-chain or branched-chain divalent saturated hydrocarbon group, -(CH2) v - (where v is an integer from 1 to 10), and examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene groups.

[0029] "Cycloalkyl group" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, typically having 3 to 10 carbon atoms, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. The definition of cycloalkyl group as described herein is as described above. Cycloalkyl group may be monovalent, divalent, trivalent, or tetravalent.

[0030] "Heterocycloalkyl group" refers to a substituted or unsubstituted saturated heteroatom-containing cyclic hydrocarbon group, containing 3-10 atoms, 3-8 atoms, but not limited to, 1-3 heteroatoms selected from N, O, or S, and optionally substituted N, S in the ring of the heterocycloalkyl group can be oxidized to various oxidation states. Heterocycloalkyl groups can be linked on heteroatoms or carbon atoms, heterocycloalkyl groups can be linked on aromatic or non-aromatic rings, and heterocycloalkyl groups can be linked to bridged or spiro rings, non-limiting examples include oxiranyl, azacyclopropyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl, dioxanyl, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinanyl, morpholinyl, hexahydropyrimidinyl, and piperazinyl groups. The heterocycloalkyl group may be monovalent, divalent, trivalent or tetravalent.

[0031] An "alkenyl group" is a substituted or unsubstituted straight and branched chain unsaturated hydrocarbon group that has at least one, and typically one, two or three, carbon-carbon double bonds and a backbone that contains 2 to 10, 2 to 6 or 2 to 4 carbon atoms, including, but not limited to, examples of alkenyl groups include vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, and 2-methyl-1-butenyl. Examples of alkenyl groups include, but are not limited to, 1-pentenyl, 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. The definition of the alkenyl group described herein is consistent with this definition. The alkenyl group may be monovalent, divalent, trivalent, or tetravalent.

[0032] An "alkynyl group" refers to a substituted or unsubstituted straight or branched chain monovalent unsaturated hydrocarbon group that has at least one, and typically one, two or three, carbon-carbon triple bonds and a main chain containing from 2 to 10 carbon atoms, from 2 to 6 carbon atoms in the main chain, and from 2 to 4 carbon atoms in the main chain, including, but not limited to, ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3 ... Alkynyl groups include, but are not limited to, alkynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, etc. Alkynyl groups may be monovalent, divalent, trivalent or tetravalent.

[0033] "Alkoxy" refers to a substituted or unsubstituted -O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropoxy, and cyclobutoxy.

[0034] "Carbocyclic group" or "carbocycle" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic ring, which may be a 3- to 8-membered monocyclic, 4- to 12-membered bicyclic, or 10- to 15-membered tricyclic system, and the carbocyclic group may be linked onto an aromatic or non-aromatic ring, which may optionally be a monocyclic, bridged, or spirocyclic ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, benzene ring, naphthalene ring, [ka] A "carbocyclic group" or "carbocycle" may be monovalent, divalent, trivalent or tetravalent.

[0035] A "heterocyclic group" or "heterocycle" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic ring, which may be a 3- to 8-membered monocyclic, 4- to 12-membered bicyclic, or 10- to 15-membered tricyclic system, containing one or more (including but not limited to 2, 3, 4, or 5) heteroatoms selected from N, O, or S, and wherein the optionally substituted N, S in the ring of the heterocyclic group can be oxidized to various oxidation states. Heterocyclic groups may be attached at a heteroatom or carbon atom, heterocyclic groups may be attached at an aromatic or non-aromatic ring, and heterocyclic groups may be attached to bridged or spiro rings, non-limiting examples of which are oxiranyl, azacyclopropyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azacycloheptyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuryl, dihydropyranyl, dithiolanyl, and tetrahydrofuranyl. , tetrahydropyrrolyl group, tetrahydroimidazolyl group, tetrahydrothiazolyl group, tetrahydropyranyl group, benzimidazolyl group, benzopyridyl group, pyrrolopyridyl group, benzodihydrofuryl group, pyrrolyl group, pyrazolyl group, thiazolyl group, oxazolyl group, pyrazinyl group, indazolyl group, benzothienyl group, benzofuryl group, benzopyrrolyl group, benzimidazolyl group, benzothiazolyl group, benzoxazolyl group, benzopyridyl group, benzopyrimidinyl group, benzopyrazinyl group, piperazinyl group, azabicyclo[3.2.1]octyl group, azabicyclo[5.2.0]nonyl group, oxatricyclo[5.3.1.1]dodecyl group, azaadamantyl group, oxaspiro[3.3]heptyl group, [ka] A "heterocyclic group" or "heterocycle" may be monovalent, divalent, trivalent or tetravalent.

[0036] "Spiro ring" or "spirocyclic group" refers to a polycyclic group that shares one atom (called a spiro atom) between substituted or unsubstituted monocyclic rings, where the number of ring atoms in the spiro ring system can be, but is not limited to, 5-20, 6-14, 6-12, or 6-10, and where one or more of the rings can contain zero or more (including but not limited to, 1, 2, 3, or 4) double bonds and optionally contain N, O, or S(=O). n It may contain 0 to 5 heteroatoms selected from: [ka] A "spiro ring" or "spirocyclic group" may be monovalent, divalent, trivalent or tetravalent.

[0037] "Fused ring" or "fused ring group" refers to a polycyclic group in which each ring in the system shares an adjacent pair of atoms with another ring in the system, where one or more of the rings may contain zero or more (including but not limited to 1, 2, 3 or 4) double bonds, may be substituted or unsubstituted, and each ring in the fused ring system may contain 0-5 heteroatoms or groups containing heteroatoms (N, S(=O) n or O, where n is 0, 1 or 2. The number of ring atoms in the fused ring system may include, but is not limited to, 5 to 20, 5 to 14, 5 to 12, 5 to 10. Non-limiting examples include: [ka] The "fused ring" or "fused ring group" may be monovalent, divalent, trivalent or tetravalent.

[0038] A "bridged ring" or "bridged cyclic group" refers to a substituted or unsubstituted polycyclic group containing two atoms that are not directly linked, and may contain zero or more double bonds, and any ring in the fused ring system may contain zero to five groups selected from or containing heteroatoms, 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, 5-20, 5-14, 5-12, or 5-10. Non-limiting examples include: [ka] cubane, adamantane. A "bridged ring" or "bridged cyclic group" may be monovalent, divalent, trivalent, or tetravalent.

[0039] "Carbospirocycle", "spirocyclic carbocyclic group", "spirocarbocyclic group" or "carbospirocyclic group" refers to a "spirocycle" whose ring system consists only of carbon atoms. The definition of "carbospirocycle", "spirocyclic carbocyclic group", "spirocarbocyclic group" or "carbospirocyclic group" as described herein is consistent with spirocycle.

[0040] "Carbofused ring", "fused ring carbocyclic group", "fused carbocyclic group" or "carbofused cyclic group" refers to a "fused ring" whose ring system consists only of carbon atoms. The definition of "carbofused ring", "fused ring carbocyclic group", "fused carbocyclic group" or "carbofused cyclic group" as used herein is consistent with fused ring.

[0041] A "carbon bridged ring", "bridged-ring carbocyclic group", "bridged carbocyclic group" or "carbon bridged cyclic group" refers to a "bridged ring" whose ring system consists only of carbon atoms. The definition of a "carbon bridged ring", "bridged-ring carbocyclic group", "bridged carbocyclic group" or "carbon bridged cyclic group" as used herein is consistent with a bridged ring.

[0042] A "heteromonocycle", "monocyclic heterocyclic group" or "heteromonocyclic group" refers to a monocyclic "heterocyclic group" or "heterocycle", and the definitions of heterocyclic group, "monocyclic heterocyclic group" or "heteromonocyclic group" described herein are consistent with heterocycle.

[0043] A "heterofused ring", "heterofused cyclic group", "fused-ring heterocyclic group" or "heterofused cyclic group" refers to a "fused ring" that contains a heteroatom. The definitions of heterofused ring, "heterofused cyclic group", "fused-ring heterocyclic group" or "heterofused cyclic group" described herein are consistent with the fused ring.

[0044] A "heterospirocycle", "heterospirocyclic group", "spirocyclic heterocyclic group" or "heterospirocyclic group" refers to a "spirocycle" containing a heteroatom. The definitions of heterospirocycle, "heterospirocyclic group", "spirocyclic heterocyclic group" or "heterospirocyclic group" described herein are consistent with spirocycle.

[0045] A "heterobridged ring", "heterobridged cyclic group", "bridged-ring heterocyclic group" or "heterobridged cyclic group" refers to a "bridged ring" containing a heteroatom. The definitions of heterobridged ring, "heterobridged cyclic group", "bridged-ring heterocyclic group" or "heterobridged cyclic group" described herein are consistent with the bridged ring.

[0046] "Aryl group" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a single ring or fused rings, the number of ring atoms in the aromatic ring including, but not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring can be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, where the ring connected to the base skeleton is an aryl ring, non-limiting examples of which include a benzene ring, a naphthalene ring, [ka] The "aryl group" or "aromatic ring" may be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the linking site is on the aryl ring.

[0047] A "heteroaryl group" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having 1 to 5 groups selected from or containing heteroatoms (N, O, or S(=O) nand n is 0, 1, 2), and the number of ring atoms in the heteroaromatic ring includes, but is not limited to, 5-15, 5-10, or 5-6. Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, and the like. The heteroaryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, where the ring connected to the base skeleton is a heteroaryl ring, and non-limiting examples include [ka] The definition of the heteroaryl group described herein is consistent with this definition. The heteroaryl group may be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the linking site is on the heteroaryl ring.

[0048] "Substituted" or "unsubstituted" refers to substitution with one or more (including but not limited to 2, 3, 4, or 5) substituents, which can be any of the following: H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, halogenated alkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged ring, spirocyclic, fused ring, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH2) m -C(=O)-R a , -O-(CH2) m -C(=O)-R a , -(CH2) m -C(=O)-NR b R c , -(CH2) m S(=O) n R a , -(CH2) m -Alkenyl group -R a , OR d or -(CH2) m-Alkynyl group -R a (wherein m and n are 0, 1 or 2), an arylthio group, a thiocarbonyl group, a silyl group or -NR b R c Wherein R b and R c are independently selected from H, a hydroxy group, an amino group, a carbonyl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a sulfonyl group, and a trifluoromethanesulfonyl group; b and R c can form a 5- or 6-membered cycloalkyl or heterocyclic group, R a and R d are each independently selected from an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro ring group, or a fused ring group.

[0049] "Containing 1 to 4 heteroatoms selected from O, S, and N" refers to containing 1, 2, 3, or 4 heteroatoms selected from O, S, and N.

[0050] "Substituted with 0 to X substituents" refers to substitution with 0, 1, 2, 3....X substituents, where X is selected from any integer from 1 to 10. For example, "substituted with 0 to 4 substituents" refers to substitution with 0, 1, 2, 3, or 4 substituents. For example, "substituted with 0 to 5 substituents" refers to substitution with 0, 1, 2, 3, 4, or 5 substituents. For example, "the heterobridged ring is optionally further substituted with 0 to 4 substituents selected from H or F" refers to the heterobridged ring being optionally further substituted with 0, 1, 2, 3, or 4 substituents selected from H or F.

[0051] The X-Y membered ring (X is selected from an integer of 3 or more and less than Y, and Y is selected from any integer of 4 to 12) includes X, X+1, X+2, X+3, X+4....Y membered rings. The ring includes a heterocycle, a carbocycle, an aromatic ring, an aryl group, a heteroaryl group, a cycloalkyl group, a heteromonocycle, a heterocondensed ring, a heterospirocycle, or a heterobridged ring. For example, a "4- to 7-membered heteromonocycle" refers to a 4-, 5-, 6-, or 7-membered heteromonocycle, and a "5- to 10-membered heterocondensed ring" refers to a 5-, 6-, 7-, 8-, 9-, or 10-membered heterocondensed ring.

[0052] "Optionally" or "optionally" means that the subsequently described event or circumstance may, but does not necessarily, occur, and the description includes both cases where the event or circumstance occurs and cases where it does not occur. For example, "an alkyl group optionally substituted with F" means that the alkyl group may, but does not necessarily, be substituted with F, and indicates that the alkyl group is substituted with F and the alkyl group is not substituted with F.

[0053] "Stereoisomer" refers to isomers that result from different ways in which atoms are arranged in molecules, and includes cis-trans isomers, enantiomers and conformational isomers.

[0054] "Tautomer" refers to a functional isomer produced when an atom in a molecule rapidly shifts between two positions, for example, keto-enol isomers and amide-imido alcohol isomers.

[0055] "Formulation specifications" refers to the weight of the active ingredient contained in one unit dosage form, one tablet unit dosage form, or each other unit dosage form.

[0056] "Subject" refers to a human or other mammal. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0057] The following examples are provided to illustrate the technical solutions of the present invention in detail, and the protection scope of the present invention includes but is not limited to these.

[0058] The structures of the compounds were confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR displacements (δ) are given in units of 10-6 (ppm). NMR measurements were performed using nuclear magnetometers (Bruker Avance III 400 and Bruker Avance 300), the solvents used were deuterated dimethylsulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS). The MS measurements were performed using Agilent 6120B (ESI) and Agilent 6120B (APCI). HPLC measurements were performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM). Thin-layer chromatography silica gel plates are Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plates. The silica gel plate specifications used in thin-layer chromatography (TLC) are 0.15mm~0.20mm, and the specifications used for separation and purification of finished products by thin-layer chromatography are 0.4mm~0.5mm. In column chromatography, Yantai Yellow Sea silica gel 200-300 mesh silica gel was generally used as the carrier.

[0059] The known starting materials of the present invention may be synthesized using or according to methods known in the art, or may be purchased from companies such as Taitan Technology, Ananji Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

[0060] Tf: trifluoromethanesulfonyl group, Ts: p-toluenesulfonyl group, TMS: trimethylsilyl group, SEM: [ka] , THP: [ka] , Boc: tert-butoxycarbonyl group, Ms: [ka] , TBS: [ka] , MTBE: methyl tert-butyl ether, Bn: benzyl group, DIPEA: N,N-diisopropylethylamine, DMAc: N,N-dimethylacetamide, DMF: N,N-dimethylcarboxamide, DMSO: dimethylsulfoxide, DCM: dichloromethane, Cbz: [ka] , LDA: lithium diisopropylamide, Pd(dppf)Cl2·CH2Cl2:CAS 95464-05-4, XPhos Pd G2:CAS 1310584-14-5 Example 1: [ka]

[0061] Step 1: Manufacturing 1A Sodium acetate (4.15 g, 50.55 mmol) was added to a solution of 1,1-dibromo-3,3,3-trifluoroacetone (12.4 g, 45.95 mmol) in water (24 mL), heated at 100 ° C for 1 h, cooled to room temperature, 4-formylbenzoic acid methyl ester (8.3 g, 50.55 mmol) in methanol (180 mL) and ammonia water (44 mL) was added, stirred at room temperature for 40 minutes, reacted at 100 ° C for 2 h, cooled to room temperature, quenched by adding water (50 mL), extracted with ethyl acetate (60 mL × 3), combined organic phase, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10 ~ 1 / 1) to obtain 1A (8 g, yield: 64.43%). LCMS m / z=271.1[M+H] +

[0062] Step 2: Manufacturing 1B 1A (17 g, 62.91 mmol) was dissolved in 200 mL of DMF, and isopropyl iodide (32.08 g, 188.73 mmol) and cesium carbonate (61.49 g, 188.75 mmol) were added in sequence, and the mixture was allowed to react overnight at 90° C. The mixture was cooled to room temperature, and water and ethyl acetate were added for extraction. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 20 to 1 / 1) to obtain 1B (11.8 g, yield: 60%). LCMS m / z=313.1[M+H] +

[0063] Step 3: Manufacturing 1C 1B (11.8 g, 37.79 mmol) was dissolved in 150 mL of THF, lithium borohydride (4.12 g, 188.95 mmol) was added, and the mixture was heated to 50° C. and stirred for 2 h. The mixture was cooled to room temperature, and the reaction was quenched by adding a saturated aqueous ammonium chloride solution in an ice-water bath, followed by extraction with water and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 1C (10 g). LCMS m / z=285.1[M+H]+

[0064] Step 4: 1D Fabrication 2-Chloro-3-fluoropyridine (5g, 38.03mmol) was dissolved in THF (25mL) and cooled to -70°C under nitrogen gas protection, and a THF solution of lithium bistrimethylsilylamide (57mL, 1N, 57mmol) was slowly added dropwise. After completion, the mixture was warmed to -30°C and stirred for 1h. Hexachloroethane (10.80g, 45.64mmol) was added at -30°C. After completion, the mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched by sequential addition of 20mL of saturated aqueous ammonium chloride solution, 100mL of water and 100mL of ethyl acetate were added and layered. The organic layer was washed with 100mL of saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / petroleum ether (V / V) = 0 / 1 to 1 / 4) to obtain 1D (2g, yield 32%). 1 H NMR(400 MHz,CDCl3)δ 8.13(d,1H),7.34(t,1H).

[0065] Step 5: Fabrication of 1E 1D (2 g, 12.02 mmol) was dissolved in THF (10 mL) and cooled to -70°C under nitrogen gas protection. A THF solution of LDA (14.4 mL, 1N, 14.42 mmol) was slowly added dropwise at -70°C. The mixture was stirred at -70°C for 1 h, and DMF (1.76 g, 24.04 mmol) was slowly added dropwise and stirred for 30 min. The reaction was quenched by adding 10 mL of saturated aqueous ammonium chloride solution, and the mixture was allowed to warm to room temperature. Then, 20 mL of water and 20 mL of ethyl acetate were added and layered. The organic layer was washed with 20 mL of saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 1 to 1 / 4.) to obtain 1E (0.56 g, yield: 24%). 1 H NMR(400 MHz,CDCl3)δ 10.40(s,1H),8.69(s,1H).

[0066] Step 6: Fabrication of 1F 1E (0.55 g, 2.84 mmol) was dissolved in n-butanol (10 mL), hydrazine hydrate (0.89 g, 14.2 mmol, wt%=80%) was added, and the mixture was stirred at 100° C. for 8 h. The mixture was cooled to room temperature, 20 mL of water and 20 mL of ethyl acetate were added, layered, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V)=1 / 10-1 / 2) to obtain 1F (0.28 g, yield: 57%). LCMS m / z=172.1[M+H] +

[0067] Step 7: Manufacturing 1G 1F (0.09 g, 0.52 mmol), 1C (0.15 g, 0.52 mmol) and tri-n-butylphosphine (0.21 g, 1.04 mmol) were added to THF (5 mL) in sequence, and diethyl azodicarboxylate (0.18 g, 1.03 mmol) was added dropwise at room temperature under nitrogen gas protection, and the mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10 to 1 / 2) to obtain 1G (0.15 g, yield: 66%). LCMS m / z=438.1[M+H] +

[0068] Step 8: Preparation of Compound 1 1G (0.13 g, 0.30 mmol) was dissolved in a mixed solvent of 1,4-dioxane (4 mL) and water (1 mL), and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (0.12 g, 0.62 mmol), potassium phosphate (0.13 g, 0.60 mmol) and XPhos G3 (CAS: 1445085-55-1, 0.025 g, 0.030 mmol) were added in sequence, and the mixture was heated to 90 ° C under nitrogen gas protection and stirred overnight. The mixture was cooled to room temperature, and 10 mL of ethyl acetate and 10 mL of water were added, layered, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5 to 1 / 1) to obtain compound 1 (80 mg, yield: 48%). LCMS m / z=552.2[M+H] + 1 H NMR(400 MHz,DMSO-d6)δ 9.08(d,1H),8.71(s,1H),8.54(d,1H),8.18-8.13(m,1H),7.60-7.50(m,2H),7.41-7.33(m,2H),5.84(s,2H),4.50- 4.32(m,1H),3.83(s,3H),1.74-1.64(m,1H),1.38(d,6H),1.15-1.06(m,1H),1.04-0.96(m,1H),0.94-0.79(m,2H). Example 2: [ka]

[0069] Step 1: Manufacturing 2A 4-(Methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (5 g, 23.58 mmol) was dissolved in THF (60 mL), and borane tetrahydrofuran solution (47 mL, 1 M) was slowly added dropwise at 0° C. and stirred at room temperature overnight. The mixture was quenched by adding methanol at 0° C. and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 20 to 1 / 2) to give 2A (3.8 g, yield: 81%). LCMS m / z=199.2[M+H] +

[0070] Step 2: Fabrication of 2B 2A (3.8 g, 19.16 mmol) was dissolved in DCM (100 mL), and Dess-Martin oxidant (16.25 g, 38.32 mmol) was added in small portions at 0°C, and the reaction was allowed to proceed at room temperature for 3 h. The reaction was monitored for completion by TLC, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 20 to 1 / 2) to give 2B (3.02 g, yield: 80%). LCMS m / z=197.1[M+H] +

[0071] Step 3: Manufacturing 2C 1,1-Dibromo-3,3,3-trifluoroacetone (4.98g, 18.49mmol, CAS: 431-67-4) was placed in a 250mL one-neck flask, 30mL of water and sodium acetate (1.89g, 23.09mmol) were added, and the mixture was reacted at 90°C for 1h. The mixture was cooled to room temperature, and 60mL of methanol, 2B (3.02g, 15.39mmol), and concentrated aqueous ammonia (15mL) were added in sequence, and the mixture was reacted at 90°C for 2h. The mixture was cooled to room temperature, and the reaction solution was poured into 200mL of water, filtered, and the filter cake was washed with water (2x10mL), and the filter cake was dried under reduced pressure to obtain 2C (2.9g, yield: 62%). LCMS m / z=303.1[M+H] + 1 H NMR(400 MHz,DMSO-d6)δ 12.36-12.16(m,1H),7.68-7.55(m,1H),3.59(s,3H),1.90-1.72(m,12H).

[0072] Step 4: 2D Fabrication At room temperature, 2C (2.0 g, 6.62 mmol) was dissolved in 30 mL of DMF, and isopropyl iodide (4.50 g, 26.48 mmol) and cesium carbonate (6.47 g, 19.86 mmol) were added in sequence, and the mixture was allowed to react overnight at 90° C. The mixture was cooled to room temperature, and water and ethyl acetate were added for extraction. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 20 to 1 / 1) to obtain 2D (1.2 g, yield: 52%). LCMS m / z=345.2[M+H] +

[0073] Step 5: Fabrication of 2E 2D (1.2 g, 3.48 mmol) was dissolved in 20 mL of THF, lithium borohydride (0.38 g, 17.40 mmol) was added, and the mixture was stirred at 60° C. for 2 h. The mixture was cooled to room temperature, and the reaction was quenched by adding a saturated aqueous solution of ammonium chloride. Extraction was performed by adding water and ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2E (0.9 g, yield: 81%). LCMS m / z=317.2[M+H] +

[0074] Step 6: Fabrication of 2F At 0°C, methanesulfonyl chloride (64 mg, 0.56 mmol) was added to a solution of 2E (0.12 g, 0.37 mmol) and triethylamine (0.11 g, 1.09 mmol) in dichloromethane (15 mL), and the mixture was stirred at room temperature for 1 h. The mixture was quenched by adding 20 mL of saturated aqueous sodium bicarbonate solution, and extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 100 to 1 / 20) to give 2F (0.11 g, 74% yield). LCMS m / z=395.1[M+H] +

[0075] Step 7: Fabricating 2G 1F (0.1g, 0.58mmol) and 2F (0.23g, 0.58mmol) were dissolved in DMF (5mL), cesium carbonate (0.38g, 1.17mmol) and sodium iodide (0.087g, 0.58mmol) were added, and the mixture was reacted at 140°C for 2h. The mixture was cooled to room temperature, and extracted with 20mL of water and 20mL of ethyl acetate. The organic layer was washed with saturated saline (10mLx3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10 to 1 / 2) to obtain 2G (0.060g, yield: 22%). LCMS m / z=470.2[M+H] +

[0076] Step 8: Preparation of Compound 2 2G (0.06 g, 0.13 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (0.050 g, 0.26 mmol), XPhosG3 (0.011 g, 0.013 mmol, CAS: 1445085-55-1) and potassium phosphate (0.056 g, 0.27 mmol) were placed in a 50 mL one-neck flask, 1,4-dioxane (4 mL) and water (1 mL) were added, the atmosphere was replaced with nitrogen gas three times, the temperature was raised to 90 ° C, and the mixture was stirred overnight. The mixture was cooled to room temperature, and 20 mL of water and 20 mL of ethyl acetate were added for extraction. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10 to 1 / 1). After concentration, the residue was purified by secondary silica gel column chromatography (dichloromethane / methanol (V / V) = 100 / 0 to 100 / 3) to obtain compound 2 (30 mg, yield: 39%). LCMS m / z=584.2[M+H] + 1H NMR(400 MHz,CD3OD)δ 8.97(d,1H),8.64(s,1H),8.38(d,1H),7.65-7.58(m,1H),4.93-4.84(m,1H),4.39(s,2H),3.93(s,3H),2. 06-1.94(m,6H),1.74-1.59(m,7H),1.41(d,6H),1.27-1.20(m,1H),1.16-1.09(m,1H),0.99-0.86(m,2H). Example 3: [ka]

[0077] Step 1: Manufacturing 3A Methyl 4-hydrazinobenzoate hydrochloride (2.02 g, 10.0 mmol) was dissolved in hexafluoroisopropanol (10 mL), 1,1,1-trifluoro-2,4-pentanedione (1.54 g, 10.0 mmol) was added, and triethylamine (2.23 g, 22.00 mmol) was slowly added dropwise under nitrogen gas protection and ice bath, and the reaction was allowed to proceed overnight at room temperature. The reaction was quenched by adding water (50 mL), and ethyl acetate (60 mL x 3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10 to 1 / 5) to obtain 3A (2.4 g, yield: 84%). LCMS m / z=285.1[M+H] +

[0078] Step 2: Manufacturing 3B 3A (2.4 g, 8.44 mmol) was dissolved in 50 mL of THF, and lithium borohydride (1.84 g, 84.4 mmol) was slowly added dropwise in an ice-water bath, and the mixture was stirred at 50 ° C for 4 h. After the reaction was completed, the mixture was cooled to room temperature, the reaction flask was placed in an ice-water bath, and the reaction was quenched by slowly adding a saturated aqueous solution of ammonium chloride, 20 mL of water was added, and ethyl acetate (60 mL × 3) was added for extraction, and the organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 3B (2.0 g, yield: 92%). LCMS m / z=257.2[M+H] +

[0079] Step 3: 3C Manufacturing Thionyl chloride (8 mL, 110.28 mmol) was added to a solution of 3B (1.0 g, 3.9 mmol) in dichloromethane (10 mL), and the mixture was stirred at room temperature for 5 h and then concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution and ethyl acetate were added to the resulting crude product, and the organic phase was collected after layering, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 3C (1.0 g, yield: 93%). LCMS m / z=275.0[M+H] +

[0080] Step 4: 3D Fabrication 3C (106 mg, 0.39 mmol) and 1F (60 mg, 0.35 mmol) were dissolved in N,N-dimethylformamide (2 mL) solution, cesium carbonate (342 mg, 1.05 mmol) was added, and the mixture was stirred at room temperature overnight. After the reaction was completed, the residue was removed by filtration through diatomaceous earth, 10 mL of ethyl acetate was added to dilute the filtrate, and water (10 mL x 3) was added to wash the filtrate. The organic phase was collected and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 1 to 1 / 1) to obtain 3D (65 mg, yield 45%). LCMS m / z=410.1[M+H] +

[0081] Step 5: Preparation of the trifluoroacetate salt of compound 3 3D (65 mg, 0.16 mmol) was dissolved in a mixed solvent of 1,4-dioxane (10 mL) and water (1 mL), and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (46.6 mg, 0.24 mmol), potassium phosphate (101.9 mg, 0.48 mmol) and XPhos G3 (CAS: 1445085-55-1, 13.5 mg, 0.016 mmol) were added in sequence, and the temperature was raised to 90 ° C under nitrogen gas protection and stirred overnight. After the reaction was completed, the mixture was concentrated to remove a large amount of solvent, 10 mL of water was added thereto, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (instrument: waters2767 preparative liquid, chromatography column: XBridge@Prep C18 (30 mm×150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% trifluoroacetic acid)), and the fractions were collected and lyophilized to obtain the trifluoroacetate salt of compound 3 (10 mg, yield: 12%). LCMS m / z=524.2[M+H] + 1 H NMR(400 MHz,DMSO-d6)δ 9.08(d,1H),8.71(s,1H),8.55(d,1H),7.60-7.53(m,2H),7.44-7.37(m,2H),6.74(s,1H),5.85(s,2H) ,3.83(s,3H),2.31(s,3H),1.73-1.63(m,1H),1.15-1.06(m,1H),1.04-0.96(m,1H),0.95-0.80(m,2H). Example 4: [ka]

[0082] Step 1: Manufacturing 4A Methyl 3-cyclopropyl-3-oxopropionate (20 g, 140.66 mmol) and formamidine acetate (29.29 g, 281.32 mmol) were dissolved in methanol (400 mL), sodium methoxide (53.19 g, 984.62 mmol) was added, and the mixture was reacted at room temperature for 2 days. The pH was adjusted to 7 with acetic acid, and the mixture was filtered through diatomaceous earth under reduced pressure. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 1-1 / 3) (methanol / dichloromethane (V / V) = 0 / 1-1 / 10) to obtain 4A (9 g, yield: 47%). LCMS m / z=137.1[M+H] +

[0083] Step 2: Fabrication of 4B 4A (8.5 g, 62.43 mmol) was dissolved in acetonitrile (100 mL), NBS (11.67 g, 65.60 mmol) was added, and the mixture was allowed to react at room temperature for 1 h. Water and ethyl acetate were added for extraction, and the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 1 to 1 / 1) to obtain 4B (9.1 g, yield: 67%). LCMS m / z=215.0[M+H] +

[0084] Step 3: Manufacturing 4C 4B (6 g, 27.90 mmol) was dissolved in acetonitrile (200 mL), sodium hydride (2.2 g, 54.90 mmol) was added, and the mixture was stirred at room temperature for 45 min, 2-fluorosulfonyldifluoroacetic acid (8.94 g, 50.22 mmol) was added, and the mixture was reacted at room temperature for 2 h. Water and ethyl acetate were added for extraction, and the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 1 to 1 / 2) to obtain 4C (4.0 g, yield: 54%). LCMS m / z=265.0[M+H] +

[0085] Step 4: 4D Manufacturing 4C (1.0g, 3.77mmol) was dissolved in 1,4-dioxane (15mL), and bis(pinacolato)diboron (1.05g, 4.16mmol), Pd(dppf)Cl2·CH2Cl2 (0.31g, 0.38mmol) and potassium acetate (0.74g, 7.54mmol) were added in sequence, and the mixture was reacted at 90℃ overnight under nitrogen gas protection. The mixture was cooled to room temperature, and water and ethyl acetate were added for extraction. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 1 to 1 / 20) to obtain 4D (420mg, yield: 35%). LCMS m / z=313.0[M+H] +

[0086] Step 5: Preparation of compound 4 2G (100 mg, 0.21 mmol), 4D (85.21 mg, 0.27 mmol), Pd(dppf)Cl2·CH2Cl2 (17.15 mg, 0.021 mmol) and potassium carbonate (87.07 mg, 0.63 mmol) were placed in a 25 mL single-neck flask, 1,4-dioxane (4 mL) and water (1 mL) were added, the atmosphere was replaced with nitrogen gas three times, and the mixture was stirred at 90 °C for 3 h. The mixture was cooled to room temperature, and 20 mL of water and 20 mL of ethyl acetate were added for extraction. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10 to 1 / 1). The crude product obtained was further separated and purified by preparative HPLC (instrument: waters2767 preparative liquid, chromatography column: SunFire@Prep C18 (19 mm x 150 mm), mobile phase composition: mobile phase A: acetonitrile mobile phase B: water (containing 5 mM ammonium acetate)) to obtain compound 4 (20 mg, yield: 15%). LCMS m / z=620.3[M+H] + 1H NMR(400 MHz,DMSO-d6)δ 9.10(d,1H),8.85(s,1H),8.52(d,1H),8.03-7.63(m,2H),4.88-4.74(m,1H),4.39-4.26(m,2 H),1.95-1.79(m,7H),1.61-1.46(m,6H),1.32(d,6H),1.23-1.18(m,1H),1.13-0.92(m,3H). Example 5: [ka]

[0087] Step 1: Manufacturing 5A 2C (4g, 13.23mmol) was dissolved in DMF (20mL), NaH (0.79g, 19.84mmol, wt%=60%) was slowly added in an ice bath, and after stirring for 10min in an ice bath, 2-(trimethylsilyl)ethoxymethyl chloride (3.31g, 19.85mmol) was added, and the mixture was allowed to warm to room temperature and stirred for 30min. The reaction was quenched by adding 10mL of saturated aqueous ammonium chloride solution, and 20mL of ethyl acetate was added for extraction. The organic layer was washed with saturated saline (10mLx3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V)=1 / 10~1 / 3) to obtain 5A (5.2g, yield: 90%).

[0088] Step 2: Fabrication of 5B 5A (5.2 g, 12.02 mmol) was dissolved in THF (25 mL), and lithium borohydride (1.31 g, 59.86 mmol) was added at room temperature. After completion, the mixture was stirred at 60° C. for 2 h. The mixture was cooled to room temperature, and 10 mL of saturated aqueous ammonium chloride solution was slowly added dropwise to quench the reaction, and 20 ml of ethyl acetate was added for extraction. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 5B (5 g, yield: 100%). LCMS m / z=405.2[M+H] +

[0089] Step 3: Manufacturing 5C 5B (4.81 g, 11.89 mmol) was dissolved in DCM (30 mL), pyridine (1.41 g, 17.84 mmol) was added, trifluoromethanesulfonic anhydride (4.03 g, 14.29 mmol) was slowly added dropwise in an ice bath, the mixture was allowed to warm to room temperature, and stirred for 1 h. 30 mL of dichloromethane and 50 mL of water were added for extraction, and the organic layer was washed once with 30 mL of saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 5C.

[0090] Step 4: 5D Fabrication 1F (1.7 g, 9.91 mmol) and 5C from the previous step were dissolved in DMF (30 mL), and cesium carbonate (9.69 g, 29.73 mmol) was added under a water bath at room temperature. After completion, the mixture was stirred for 1 h, and 50 mL of ethyl acetate and 50 mL of water were added for extraction. The organic layer was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10 to 1 / 2) to obtain 5D (2.3 g, yield: 41%). LCMS m / z=558.2[M+H] +

[0091] Step 5: Fabrication of 5E 5D (1g, 1.79mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (0.69g, 3.56mmol) were dissolved in a mixed solvent of 1,4-dioxane (10mL) and water (2mL), XPhosG3 (0.15g, 0.18mmol) and potassium phosphate (0.76g, 3.58mmol) were added in sequence, and after completion, the mixture was replaced with nitrogen gas three times, heated to 90°C, and stirred overnight. The mixture was cooled to room temperature, extracted with 20ml of ethyl acetate and 10ml of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10 to 1 / 1) to obtain 5E (1.1g, yield: 91%).

[0092] Step 6: Fabrication of 5F 5E (1.1 g, 1.64 mmol) was dissolved in THF (15 mL), tetrabutylammonium fluoride (4.29 g, 16.4 mmol) was added, and the mixture was heated to 70°C and stirred for 6 h. The mixture was cooled to room temperature, and 20 mL of ethyl acetate and 20 mL of water were added for extraction. The organic layer was washed with saturated saline (10 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 3 to 1 / 0) to obtain 5F (0.8 g, yield 90%). LCMS m / z=542.2[M+H] +

[0093] Step 7: 5G Manufacturing Isopropanol-D7 (2g, 29.79mmol) was dissolved in DCM (20mL), triethylamine (6.03g, 59.59mmol) was added under ice bath, methanesulfonyl chloride (4.10g, 35.79mmol) was slowly added dropwise, and after completion, the mixture was allowed to warm to room temperature and stirred for 20min. 30mL of water and 30mL of dichloromethane were added for extraction, and the organic layer was washed with 20mL of saturated aqueous sodium bicarbonate and 20mL of aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 5G (4g).

[0094] Step 8: Preparation of Compound 5 5F (0.1g, 0.18mmol) and 5G (0.13g, 0.90mmol) were dissolved in DMF (5mL), and cesium carbonate (0.29g, 0.90mmol) and sodium iodide (0.027g, 0.18mmol) were added in sequence, and the mixture was stirred at 80°C overnight. The mixture was cooled to room temperature, and 20mL of ethyl acetate and 20mL of water were added for extraction. The organic layer was washed with saturated saline (10mLx3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5 to 1 / 1) to obtain compound 5 (60mg, yield: 56%). LCMS m / z=591.3[M+H] + 、1H NMR(400 MHz,DMSO-d6)δ 9.05(d,1H),8.72(s,1H),8.48(d,1H),7.93-7.85(m,1H),4.38-4.25(m,2H),3.86(s,3H),1. 96-1.82(m,6H),1.78-1.68(m,1H),1.62-1.45(m,6H),1.18-0.98(m,2H),0.97-0.81(m,2H). Example 6: [ka]

[0095] 5F (0.1g, 0.18mmol) and bromomethylcyclopropane (0.049g, 0.36mmol) were dissolved in DMF (5mL), cesium carbonate (0.12g, 0.36mmol) was added, and the mixture was stirred at 60°C for 3h. The mixture was cooled to room temperature, and 20mL of ethyl acetate and 20mL of water were added for extraction. The organic layer was washed with saturated saline (10mLx3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5 to 1 / 1) to obtain compound 6 (60mg, yield: 56%). LCMS m / z=596.3[M+H] + 1 H NMR(400 MHz,DMSO-d6)δ 9.04(d,1H),8.72(s,1H),8.48(d,1H),7.79-7.71(m,1H),4.39-4.24(m,2H),3.94(d,2H),3.86(s,3H),1.96-1.82(m,6H),1.79 -1.68(m,1H),1.61-1.45(m,6H),1.22-1.08(m,2H),1.05-0.98(m,1H),0.97-0.80(m,2H),0.59-0.49(m,2H),0.46-0.37(m,2H). Example 7: [ka]

[0096] Step 1: Fabricating 7A 2,2-Difluorocyclopropylmethanol (1g, 9.28mmol) was dissolved in DCM (20mL), triethylamine (1.88g, 18.54mmol) was added under ice bath, methanesulfonyl chloride (1.28g, 11.11mmol) was slowly added dropwise, the mixture was allowed to warm to room temperature, and stirred for 20min. 30mL of water and 30mL of dichloromethane were added for extraction, and the organic layer was washed with 20mL of saturated aqueous sodium bicarbonate solution and 20mL of aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 7A (1.6g).

[0097] Step 2: Preparation of compound 7 5F (0.1g, 0.18mmol) and 7A (0.067g, 0.36mmol) were dissolved in DMF (5mL), and cesium carbonate (0.12g, 0.36mmol) and sodium iodide (0.027g, 0.18mmol) were added in sequence, and the mixture was stirred at 60°C for 3h. The mixture was cooled to room temperature, and extracted with 20mL of ethyl acetate and 20mL of water. The organic layer was washed with saturated saline (10mLx3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5 to 1 / 1) to obtain compound 7 (65mg, yield: 57%). LCMS m / z=632.7[M+H] + 1 H NMR(400 MHz,DMSO-d6)δ 9.04(d,1H),8.72(s,1H),8.48(d,1H),7.73-7.67(m,1H),4.39-4.26(m,3H),4.19-4.08(m,1H),3.86(s,3H),2.28-2.15 (m,1H),1.96-1.83(m,6H),1.77-1.62(m,3H),1.59-1.45(m,6H),1.18-1.09(m,1H),1.06-0.97(m,1H),0.97-0.83(m,2H) Example 8: [ka]

[0098] 5F (0.1g, 0.18mmol) and 3-bromopropyne (0.043g, 0.36mmol) were dissolved in DMF (5mL), cesium carbonate (0.12g, 0.36mmol) was added, and the mixture was stirred at room temperature for 3h. 20mL of ethyl acetate and 20mL of water were added for extraction, and the organic layer was washed with saturated saline (10mLx3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5 to 1 / 1) to obtain compound 8 (90mg, yield: 86%). LCMS m / z=580.2[M+H] + 1 H NMR(400 MHz,DMSO-d6)δ 9.05(d,1H),8.72(s,1H),8.48(d,1H),7.76-7.69(m,1H),5.03(d,2H),4.41-4.24(m,2H),3.86(s,3H),3.53(t,1H) ,1.96-1.83(m,6H),1.79-1.69(m,1H),1.60-1.43(m,6H),1.18-1.09(m,1H),1.06-0.98(m,1H),0.98-0.82(m,2H). Example 9: [ka]

[0099] Step 1: Manufacturing 9A 4B (1 g, 4.65 mmol) was dissolved in acetonitrile (10 mL), and phosphorus oxychloride (7.13 g, 46.50 mmol) was slowly added at room temperature. After completion, the mixture was stirred at 80° C. for 4 h. The mixture was cooled to room temperature, and the reaction solution was poured into ice water. The pH of the aqueous solution was adjusted to alkaline with saturated sodium bicarbonate, and 30 mL of ethyl acetate was added for extraction. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 9A.

[0100] Step 2: Fabrication of 9B 2,2-Difluorocyclopropylmethanol (0.93g, 8.60mmol) was dissolved in THF (10mL), and sodium hydride (0.25g, 6.3mmol, wt%=60%) was slowly added in an ice bath. After completion, the mixture was stirred for 20min in an ice bath, and then 9A (1g, 4.28mmol) was slowly added, allowed to warm to room temperature, and stirred for 20min. The reaction was quenched by adding 10mL of saturated aqueous ammonium chloride solution, and extracted with 20mL of ethyl acetate and 20mL of water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 9B (1.4g). LCMS m / z=305.1[M+H] +

[0101] Step 3: Manufacturing 9C 9B (1.3 g, 4.26 mmol) was dissolved in THF (10 mL), and isopropylmagnesium chloride·tetrahydrofuran solution (3.2 mL, 6.39 mmol, 2N) was slowly added dropwise under ice bath, and the mixture was stirred at room temperature for 1.5 h. At 0 °C, 2 mL of THF solution of pinacol isopropoxyboronate (1.19 g, 6.39 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 1 h. The reaction was quenched by adding 20 mL of water, and 20 mL of ethyl acetate was added for extraction. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 1 to 1 / 10) to give 9C (0.23 g, yield: 15%). LCMS m / z=353.2[M+H] +

[0102] Step 4: Preparation of compound 9 2G (0.11 g, 0.23 mmol) and 9C (0.12 g, 0.34 mmol) were dissolved in a mixed solvent of 1,4-dioxane (4 mL) and water (1 mL), and XPhos G3 (0.019 g, 0.023 mmol) and potassium phosphate (0.098 g, 0.46 mmol) were added in that order. After completion, the atmosphere was replaced with nitrogen gas three times and the mixture was stirred at 90°C overnight. The mixture was cooled to room temperature, and extracted with 20 mL of ethyl acetate and 10 mL of water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10 to 1 / 1). The crude product was further separated and purified by preparative HPLC (instrument: waters 2767 preparative liquid, chromatography column: SunFire@Prep C18 (19 mm x 150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 5 mM ammonium acetate)) to obtain compound 9 (30 mg, yield: 20%). LCMS m / z=660.90[M+H] + 1 H NMR(400 MHz,DMSO-d6)δ 9.06(d,1H),8.71(d,1H),8.49(d,1H),7.91-7.84(m,1H),4.88-4.73(m,1H),4.68-4.14(m,4H),2.17-2.00(m,1H),1.94-1. 80(m,6H),1.78-1.69(m,1H),1.65-1.45(m,7H),1.43-1.28(m,7H),1.18-1.10(m,1H),1.05-0.91(m,2H),0.90-0.80(m,1H). Example 10: [ka]

[0103] Step 1: Manufacturing the 10A 5D (0.7 g, 1.25 mmol) was dissolved in DCM (4 mL), trifluoroacetic acid (4 mL) was added, and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, and 20 mL of dichloromethane was added to the residue, and 10 mL of saturated aqueous sodium bicarbonate was added and stirred for 10 min. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 10A.

[0104] Step 2: Fabrication of 10B 10A (0.1 g, 0.23 mmol) was dissolved in DMF (5 mL), bromomethylcyclopropane (0.062 g, 0.46 mmol) was added, and the mixture was stirred at 60 ° C for 3 h. The mixture was cooled to room temperature, 20 mL of ethyl acetate and 20 mL of water were added, and the mixture was layered by stirring. The organic layer was washed with saturated saline (10 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5 to 1 / 2) to obtain 10B (0.1 g, yield: 90%).

[0105] Step 3: Preparation of compound 10 10B (0.1 g, 0.21 mmol) and 4D (0.098 g, 0.32 mmol) were dissolved in a mixed solvent of 1,4-dioxane (4 mL) and water (1 mL), XPhos Pd G2 (0.017 g, 0.021 mmol) and potassium phosphate (0.089 g, 0.42 mmol) were added in sequence, and the mixture was purged with nitrogen gas three times and stirred at 90 ° C for 3 h. The mixture was cooled to room temperature, and extracted with 20 ml of ethyl acetate and 10 ml of water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10 to 1 / 1) to obtain compound 10 (90 mg, yield: 68%). LCMS m / z=632.90[M+H] + 1H NMR(400 MHz,DMSO-d6)δ 9.10(d,1H),8.85(s,1H),8.52(d,1H),8.05-7.62(m,2H),4.42-4.24(m,2H),3.93(d,2H),1.94-1.81(m,7H),1. 64-1.46(m,6H),1.27-1.18(m,2H),1.18-1.13(m,1H),1.06-0.93(m,2H),0.58-0.50(m,2H),0.45-0.37(m,2H). Example 11: [ka]

[0106] Step 1: Fabricating 11A 5D (0.100 g, 0.18 mmol) and 4D (0.084 g, 0.27 mmol) were dissolved in a mixed solvent of 1,4-dioxane (4 mL) and water (1 mL), potassium phosphate (0.076 g, 0.36 mmol) and XPhos Pd G2 (0.014 g, 0.018 mmol) were added in sequence, and the mixture was purged with nitrogen gas three times and stirred at 90 ° C overnight. The mixture was cooled to room temperature, and extracted with 20 mL of ethyl acetate and 10 mL of water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10 to 1 / 2) to obtain 11A (0.13 g, yield: 99%).

[0107] Step 2: Fabrication of 11B 11A (0.13 g, 0.18 mmol) was dissolved in DCM (4 mL), trifluoroacetic acid (4 mL) was added at room temperature, and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, and 20 mL of dichloromethane was added to the residue, and 10 mL of saturated aqueous sodium bicarbonate was added, and the mixture was stirred for 10 min. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 11B.

[0108] Step 3: Preparation of compound 11 11B (0.11g, 0.19mmol) and 3-bromopropyne (0.045g, 0.38mmol) were dissolved in DMF (5mL), cesium carbonate (0.12g, 0.38mmol) was added, and the mixture was stirred at room temperature for 3h. 20mL of ethyl acetate and 20mL of water were added for extraction, and the organic layer was washed with saturated saline (10mLx3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5 to 1 / 1) to obtain compound 11 (70mg, yield: 60%). LCMS m / z=616.80[M+H] + 1 H NMR(400 MHz,DMSO-d6)δ 9.10(d,1H),8.85(s,1H),8.52(d,1H),8.03-7.62(m,2H),5.02(d,2H),4.40-4.26(m,2H),3.51(t, 1H),1.95-1.81(m,7H),1.63-1.41(m,6H),1.30-1.20(m,1H),1.12-1.01(m,2H),1.01-0.92(m,1H). Example 12: [ka]

[0109] Step 1: Manufacturing the 12A (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (10 g, 41.49 mmol) was dissolved in THF (100 mL), and borane tetrahydrofuran solution (62 mL, 1 M) was slowly added dropwise at 0° C. and stirred at room temperature for 2 h. The mixture was quenched with methanol at 0° C. and concentrated under reduced pressure. The residue was extracted with ethyl acetate and water, and the organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 12A (9.42 g).

[0110] Step 2: Fabrication of 12B 12A (9.42 g, 41.44 mmol) was dissolved in DMSO (60 mL), 2-iodoacylbenzoic acid (12.76 g, 45.58 mmol) was added, and the mixture was stirred at room temperature for 2 h. 2-iodoacylbenzoic acid (6 g, 21.41 mmol) was added, and the mixture was reacted at 40 ° C for 1 h. 100 mL of ethyl acetate was added, and the mixture was stirred at room temperature for 10 min, filtered, and the filter cake was washed with ethyl acetate 3 × 30 mL, and 100 mL of saturated aqueous sodium thiosulfate solution was added to the filtrate, followed by stirring for 10 min, adding 50 mL of saturated aqueous sodium bicarbonate solution, extracting, and the organic phase was washed three times with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 1 ~ 1 / 5) to obtain 12B (8 g, yield: 85%).

[0111] Step 3: Manufacturing 12C At 0°C, (trifluoromethyl)trimethylsilane (4.73g, 33.29mmol) was added to a solution of 12B (5g, 22.19mmol) in tetrahydrofuran (50mL), stirred at 0°C for 10min, tetrabutylammonium fluoride (4.66mL, 4.66mmol, 1M solution in THF) was added, stirred at 0°C for 1h, then tetrabutylammonium fluoride (5mL, 5mmol, 1M solution in THF) was added, stirred at room temperature for 2h, quenched by adding saturated aqueous ammonium chloride (100mL), extracted with ethyl acetate (100mL x 3), combined organic phase, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 100-1 / 5) to obtain 12C (5.9g, yield: 90%). LCMS m / z=240.2[M-55] +

[0112] Step 4: Preparation of 12D hydrochloride 12C (1.73 g, 5.86 mmol) was dissolved in hydrochloric acid-dioxane solution (30 mL, 4 M) and stirred at room temperature for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure to give 12D hydrochloride (1.34 g).

[0113] Step 5: Manufacturing 12E 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.16 g, 10.95 mmol) was added to 12D hydrochloride (1.69 g, 7.30 mmol) and 4-(methoxycarbonyl)benzoic acid (1.45 g, 8.03 mmol) in N,N-dimethylformamide (30 mL). After stirring at room temperature for 5 min, N,N-diisopropylethylamine (2.83 g, 21.9 mmol) was added, and 200 mL of ethyl acetate and 100 mL of water were added and layered. The organic layer was dried under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 100 to 1 / 5) to obtain 12E (2.5 g, yield 95%). LCMS m / z=358.2[M+H] +

[0114] Step 6: Fabrication of 12F 12E (2.5 g, 7.00 mmol) was dissolved in dichloromethane (30 mL), and Dess-Martin oxidant (4.45 g, 10.5 mmol) was added in small portions at 0°C, and the mixture was allowed to react at room temperature for 3 h. The mixture was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 100 to 1 / 5) to obtain 12F (2 g, yield: 80%).

[0115] Step 7: Manufacturing the 12G Ammonium trifluoroacetate (33.12 g, 252.73 mmol) was added to 12F (2 g, 5.63 mmol) and reacted at 130° C. for 2 h. The mixture was cooled to room temperature, and extracted with 100 mL of water and ethyl acetate (100 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V)=1 / 100-1 / 2) to obtain 12G (1.4 g, yield: 73%). LCMS m / z=337.1[M+H] +

[0116] Step 8: Manufacturing the 12H At 0°C, diisobutylaluminum hydride (10.4mL, 10.4mmol, 1.0M solution in hexanes) was added dropwise to a solution (20mL) of 12G (1.4g, 4.16mmol) in tetrahydrofuran, and the mixture was allowed to warm to room temperature and react for 3h. 60mL of water and ethyl acetate (60mL x 3) were added for extraction, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 100 to 1 / 2) to obtain 12H (0.95g, yield: 74%). LCMS m / z=309.2[M+H] +

[0117] Step 9: Preparation of 12I 12H (0.95 g, 3.08 mmol) was dissolved in 10 mL of dichloromethane, and sulfinyl chloride (1.83 g, 15.40 mmol) was slowly added dropwise in an ice-water bath, followed by stirring for 2 h in an ice-water bath. The mixture was quenched by adding saturated sodium bicarbonate (20 mL), extracted with dichloromethane (30 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 12I (0.95 g). LCMS m / z=327.3[M+H] +

[0118] Step 10: Fabrication of 12J Cesium carbonate (1495.51 mg, 4.59 mmol) was added to a solution of 12I (500 mg, 1.53 mmol) and 1F (275.61 mg, 1.61 mmol) in N,N-dimethylformamide (10 mL) and reacted at room temperature for 3 h. Water and ethyl acetate were added for extraction, and the organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 1 to 2 / 1) to obtain 12J (330 mg, 46% yield). LCMS m / z=462.1[M+H] +

[0119] Step 11: Manufacturing 12 12J (100 mg, 0.22 mmol), 4D (103 mg, 0.33 mmol), XPhos Pd G2 (17.31 mg, 0.022 mmol) and potassium phosphate (140.10 mg, 0.66 mmol) were placed in a 25 mL one-neck flask, 1,4-dioxane (4 mL) and water (1 mL) were added, and the mixture was purged with nitrogen gas three times and stirred at 90 ° C for 3 h. The mixture was cooled to room temperature, and 20 mL of water and 20 mL of ethyl acetate were added for extraction. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 1 to 2 / 1) to obtain compound 12 (50 mg, yield: 37%). LCMS m / z=612.7[M+H] + 1 H NMR(400 MHz,DMSO-d6)δ 9.12(d,1H),8.84(s,1H),8.56(d,1H),8.03-7.59(m,3H),7.34(d,2H),5.90-5.72(m,2H),4.23(s,2H) ,2.95(s,2H),1.89-1.76(m,1H),1.21-1.14(m,1H),1.12-0.98(m,2H),0.98-0.89(m,1H),0.78(s,4H). Example 13: [ka]

[0120] Step 1: Fabrication of 13B 13A (7 g, 26.4 mmol) was dissolved in tetrahydrofuran (100 mL), and lithium borohydride (1.72 g, 79.2 mmol) was added in small portions at 0°C, and the reaction was allowed to proceed at room temperature for 3 h. Water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (40 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 100 to 1 / 10) to obtain 13B (6 g, yield: 96%). LCMS m / z=182.1[M-55] +

[0121] Step 2: Manufacturing 13C 13B (6 g, 25.3 mmol) was dissolved in dichloromethane (100 mL), and Dess-Martin oxidant (16.1 g, 37.95 mmol) was added in small portions at 0°C, and the reaction was allowed to proceed at room temperature for 3 h. The reaction was quenched by adding saturated sodium thiosulfate solution (50 mL), extracted with dichloromethane (30 mL x 3), and the organic phases were combined and dried over anhydrous sodium sulfate, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 100 to 1 / 10) to obtain 13C (3.2 g, yield 54%).

[0122] Step 3: 13D Fabrication At 0°C, (trifluoromethyl)trimethylsilane (2.9g, 20.4mmol) was added to a solution of 13C (3.2g, 13.6mmol) in tetrahydrofuran (50mL), stirred at 0°C for 10min, tetrabutylammonium fluoride (0.86mL, 0.86mmol, 1M solution in THF) was added, stirred at 0°C for 1h, then tetrabutylammonium fluoride (2mL, 2mmol, 1M solution in THF) was added, stirred at room temperature for 1h, quenched by adding saturated aqueous ammonium chloride (50mL), extracted with ethyl acetate (30mL x 3), combined organic phase, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 100-1 / 10) to obtain 13D (4g, yield: 96%).

[0123] Step 4: Preparation of 13E hydrochloride 13D (4 g, 13.1 mmol) was dissolved in hydrochloric acid-dioxane solution (50 mL, 4 M) and stirred at room temperature for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain 13E hydrochloride.

[0124] Step 5: Fabrication of 13F 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (7.23 g, 19 mmol) was added to 13E (2.6 g, 12.67 mmol) and 4-(methoxycarbonyl)benzoic acid (2.05 g, 11.4 mmol) in N,N-dimethylformamide (20 mL). After stirring at room temperature for 5 min, N,N-diisopropylethylamine (3.27 g, 25.34 mmol) was added, and 100 mL of ethyl acetate and 50 mL of water were added and layered. The organic layer was dried under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 100 to 1 / 5) to obtain 13F (3.3 g, yield 71%). LCMS m / z=368.4[M+H] +

[0125] Step 6: Fabricating 13G 13F (2.5 g, 6.81 mmol) was dissolved in dichloromethane (50 mL), and Dess-Martin oxidant (4.33 g, 10.21 mmol) was added little by little at 0 ° C., and the mixture was allowed to react for 3 h. Saturated sodium thiosulfate aqueous solution (50 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 100 ~ 1 / 10) to obtain 13G (2.4 g, yield: 96%).

[0126] Step 7: Fabrication of 13H Ammonium trifluoroacetate (20 g, 76.31 mmol) was added to a 1,4-dioxane solution (10 mL) of 13G (2.4 g, 6.57 mmol), and the mixture was reacted at 130° C. for 2 h. The mixture was cooled to room temperature, and extracted with 50 mL of water and ethyl acetate (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V)=1 / 100-1 / 10) to obtain 13H (1.1 g, yield: 48%). LCMS m / z=347.1[M+H] +

[0127] Step 8: Preparation of 13I At 0°C, diisobutylaluminum hydride (9.54mL, 9.54mmol, 1.0M solution in hexanes) was added dropwise to a tetrahydrofuran solution (55mL) of 13H (1.1g, 3.18mmol), and the mixture was allowed to react for 2h at 0°C. 50mL of water and ethyl acetate (30mL x 3) were added for extraction, the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 100 to 1 / 10) to obtain 13I (0.76g, yield: 75%). LCMS m / z=319.3[M+H] +

[0128] Step 9: Build 13J 13I (760 mg, 2.39 mmol) was dissolved in 20 mL of dichloromethane, and sulfinyl chloride (0.85 g, 7.17 mmol) was slowly added dropwise in an ice-water bath, followed by stirring for 2 h in an ice-water bath. The mixture was quenched by adding saturated sodium bicarbonate (20 mL), extracted with dichloromethane (30 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 13J (800 mg). LCMS m / z=337.3[M+H] +

[0129] Step 10: Fabrication of 13K Cesium carbonate (1.45g, 4.47mmol) was added to a solution of 13J (500mg, 1.49mol) and 1F (268mg, 1.56mmol) in N,N-dimethylformamide (10mL) and stirred at room temperature for 2h. Water and ethyl acetate were added for extraction, the organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 1 to 2 / 1) to obtain 13K (300mg, 43% yield). LCMS m / z=472.1[M+H] +

[0130] Step 11: Preparation of Compound 13 13K (0.1 g, 0.21 mmol) was dissolved in a mixed solvent of 1,4-dioxane (10 mL) and water (3 mL), and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (61 mg, 0.32 mmol), potassium phosphate (0.13 g, 0.60 mmol) and XPhos G2 (CAS: 1310584-14-5, 16.5 mg, 0.021 mmol) were added in sequence, and the mixture was stirred at 90 °C for 3 h under nitrogen gas protection. The mixture was cooled to room temperature, and 10 mL of ethyl acetate and 10 mL of water were added and layered. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5 to 1 / 1) to obtain 13 (60 mg, yield: 48.8%). LCMS m / z=586.2[M+H] + 1 H NMR(400 MHz,DMSO-d6)δ 9.07(d,1H),8.71(s,1H),8.54(d,1H),7.82(d,2H),7.37(d,2H),5.82(s,2H),4.93(t,2H),3.84 (s,3H),3.72(t,2H),1.73-1.64(m,1H),1.16-1.06(m,1H),1.05-0.96(m,1H),0.95-0.78(m,2H). Example 14: [ka]

[0131] 13K (0.1g, 0.21mmol) was dissolved in a mixed solvent of 1,4-dioxane (10mL) and water (3mL), and 4D (98mg, 0.32mmol), potassium phosphate (0.13g, 0.6mmol) and XPhos G2 (CAS: 1310584-14-5, 17mg, 0.021mmol) were added in sequence, and the mixture was stirred at 90°C for 3h under nitrogen gas protection. The mixture was cooled to room temperature, and 10mL of ethyl acetate and 10mL of water were added and layered. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5 to 1 / 1) to obtain compound 14 (66mg, yield: 51%). LCMS m / z=622.7[M+H] + 1 H NMR(400 MHz,DMSO-d6)δ 9.12(d,1H),8.84(s,1H),8.57(d,1H),8.00-7.60(m,3H),7.37(d,2H),5.89-5.77(m,2 H),4.91(t,2H),3.71(t,2H),1.88-1.78(m,1H),1.21-1.12(m,1H),1.11-0.90(m,3H). Example 15: [ka]

[0132] Step 1: Manufacturing the 15A 10A (0.15g, 0.35mmol) and 5G (0.25g, 1.72mmol) were dissolved in DMF (5mL), and cesium carbonate (0.57g, 1.75mmol) and sodium iodide (0.052g, 0.35mmol) were added in sequence, and the mixture was stirred at 80°C overnight. The mixture was cooled to room temperature, and 20mL of ethyl acetate and 20mL of water were added for extraction. The organic layer was washed with saturated saline (10mLx3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5 to 1 / 2) to obtain compound 15A (0.1g, yield: 60%).

[0133] Step 2: Preparation of compound 15 15A (0.1 g, 0.21 mmol) and 4D (0.098 g, 0.32 mmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL), XPhosPd G2 (0.017 g, 0.021 mmol) and potassium phosphate (0.089 g, 0.42 mmol) were added in sequence, and the mixture was purged with nitrogen gas three times and stirred at 90 ° C for 3 h. The mixture was cooled to room temperature, extracted with 20 ml of ethyl acetate and 10 ml of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10 to 1 / 1) to obtain compound 15 (70 mg, yield: 53%). LCMS m / z=627.80[M+H] + 1 H NMR(400 MHz,DMSO-d6)δ 9.10(d,1H),8.85(s,1H),8.52(d,1H),8.04-7.62(m,2H),4.40-4.25(m,2H),1.93-1. 81(m,7H),1.63-1.43(m,6H),1.24-1.16(m,1H),1.12-1.02(m,2H),1.01-0.93(m,1H). Example 16: [ka]

[0134] Step 1: Manufacturing the 16A 1A (3 g, 11.10 mmol) was dissolved in 30 mL of DMF, sodium hydride (0.66 g, 16.5 mmol, wt% = 60%) was added under ice water bath, and the mixture was reacted at 0 ° C for 30 min, 2-(trimethylsilyl)ethoxymethyl chloride (2.77 g, 16.63 mmol) was added, and the mixture was reacted at room temperature for 1 h. Water was added to quench the reaction, and water and ethyl acetate were added, followed by extraction. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 1 to 1 / 5) to obtain 16A (3.9 g, yield: 87%). LCMS m / z=401.3[M+H] +

[0135] Step 2: Fabrication of 16B 16A (3.9 g, 9.74 mmol) was dissolved in 30 mL of THF, lithium borohydride (1.06 g, 48.7 mmol) was slowly added in small portions, and the mixture was stirred at 50° C. for 3 h. The mixture was cooled to room temperature, and the reaction was quenched by adding a saturated aqueous ammonium chloride solution in an ice-water bath, followed by extraction with water and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 16B (3.5 g, yield: 96%). LCMS m / z=373.4[M+H] +

[0136] Step 3: Manufacturing 16C 1F (0.5 g, 2.91 mmol), 16B (1.19 g, 3.20 mmol) and tri-n-butylphosphine (1.18 g, 5.82 mmol) were added to THF (10 mL), and diethyl azodicarboxylate (1.01 g, 5.82 mmol) was added dropwise at room temperature under nitrogen gas protection, and the mixture was stirred at room temperature for 1 h. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10 to 1 / 2) to obtain 16C (0.52 g, yield: 34%). LCMS m / z=526.60[M+H] +

[0137] Step 4: Fabrication of 16D 16C (0.2 g, 0.38 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (0.13 g, 0.67 mmol) were dissolved in a mixed solvent of 1,4-dioxane (4 mL) and water (1 mL), potassium phosphate (0.16 g, 0.76 mmol) and XPhos G3 (0.032 g, 0.038 mmol) were added in sequence, and the mixture was purged with nitrogen gas three times and stirred at 90 ° C for 3 h. The mixture was cooled to room temperature, and extracted with 20 ml of ethyl acetate and 10 ml of water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10 to 1 / 2) to obtain 16D (0.22 g, yield: 90%).

[0138] Step 5: Fabrication of 16E 16D (0.22 g, 0.34 mmol) was dissolved in DCM (4 mL), TFA (4 mL) was added, and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, 20 mL of dichloromethane was added, and the mixture was alkalized with 10 mL of saturated aqueous sodium bicarbonate solution. After separation, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 16E.

[0139] Step 6: Preparation of Compound 16 16E (0.090 g, 0.18 mmol) and 3-bromopropyne (0.043 g, 0.36 mmol) were dissolved in DMF (5 mL), cesium carbonate (0.12 g, 0.36 mmol) was added, and the mixture was stirred at room temperature for 3 h. 20 mL of ethyl acetate and 20 mL of water were added for extraction, and the organic layer was washed with saturated saline (10 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5 to 1 / 1) to obtain compound 16 (70 mg, yield 71%). LCMS m / z=548.2[M+H] + 1H NMR(400 MHz,DMSO-d6)δ 9.07(d,1H),8.71(s,1H),8.54(d,1H),8.04-8.01(m,1H),7.75-7.70(m,2H),7.42-7.37(m,2H),5.84(s,2H),4. 99(d,2H),3.84(s,3H),3.56(t,1H),1.74-1.65(m,1H),1.14-1.07(m,1H),1.04-0.96(m,1H),0.94-0.78(m,2H). Example 17: [ka]

[0140] 16E (0.090g, 0.18mmol) and 1-bromo-2-butyne (0.047g, 0.35mmol) were dissolved in DMF (5mL), cesium carbonate (0.12g, 0.36mmol) was added, and the mixture was stirred at room temperature for 3h. 20mL of ethyl acetate and 20mL of water were added for extraction, and the organic layer was washed with saturated saline (10mLx3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5 to 1 / 1) to obtain compound 17 (70mg, yield: 69%). LCMS m / z=562.2[M+H] + 1 H NMR(400 MHz,DMSO-d6)δ 9.08(d,1H),8.71(s,1H),8.54(d,1H),8.03-7.99(m,1H),7.75-7.69(m,2H),7.43-7.37(m,2H),5.84(s,2H),4.93- 4.88(m,2H),3.84(s,3H),1.75(t,3H),1.73-1.66(m,1H),1.15-1.07(m,1H),1.05-0.97(m,1H),0.94-0.82(m,2H). Example 18: [ka]

[0141] Step 1: Manufacturing the 18A 16C (0.3 g, 0.57 mmol) and 4D (0.44 g, 1.41 mmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL), XPhosPdG2 (0.045 g, 0.057 mmol) and potassium phosphate (0.36 g, 1.70 mmol) were added in sequence, and the mixture was purged with nitrogen gas three times and stirred at 90 ° C for 3 h. The mixture was cooled to room temperature, and extracted with 20 ml of ethyl acetate and 10 ml of water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10 to 1 / 1) to obtain 18A (0.35 g, yield: 91%). LCMS m / z=676.80[M+H] +

[0142] Step 2: Fabrication of 18B 18A (0.35 g, 0.52 mmol) was dissolved in DCM (4 mL), TFA (4 mL) was added, and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, 20 mL of dichloromethane was added, and the mixture was alkalized with 10 mL of saturated aqueous sodium bicarbonate solution. After separation, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 18B.

[0143] Step 3: Preparation of compound 18 18B (0.070 g, 0.13 mmol) and 3-bromopropyne (0.031 g, 0.26 mmol) were dissolved in DMF (5 mL), cesium carbonate (0.085 g, 0.26 mmol) was added, and the mixture was stirred at room temperature for 3 h. 20 mL of ethyl acetate and 20 mL of water were added for extraction, and the organic layer was washed with saturated saline (10 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5 to 1 / 1) to obtain compound 18 (30 mg, yield 40%). LCMS m / z=584.6[M+H] + 1H NMR(400 MHz,DMSO-d6)δ 9.13(d,1H),8.84(s,1H),8.57(d,1H),8.04-8.01(m,1H),7.99-7.62(m,3H),7.44-7.38(m,2H),5. 91-5.80(m,2H),4.97(d,2H),3.55(t,1H),1.88-1.78(m,1H),1.21-1.13(m,1H),1.10-0.89(m,3H). Example 19: [ka]

[0144] 18B (0.076 g, 0.14 mmol) and 1-bromo-2-butyne (0.037 g, 0.28 mmol) were dissolved in DMF (5 mL), cesium carbonate (0.091 g, 0.28 mmol) was added, and the mixture was stirred at room temperature for 3 h. 20 mL of ethyl acetate and 20 mL of water were added for extraction, and the organic layer was washed with saturated saline (10 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5 to 1 / 1) to obtain compound 19 (50 mg, yield: 60%). LCMS m / z=598.80[M+H] + 1 H NMR(400 MHz,DMSO-d6)δ 9.13(d,1H),8.85(s,1H),8.57(d,1H),8.02-8.00(m,1H),8.00-7.63(m,3H),7.44-7.38(m,2H),5.91- 5.80(m,2H),4.92-4.86(m,2H),1.88-1.80(m,1H),1.76(t,3H),1.23-1.14(m,1H),1.12-0.90(m,3H). Example 20: [ka]

[0145] 18B (0.1 g, 0.18 mmol) and isopropyl iodide (0.15 g, 0.90 mmol) were dissolved in acetonitrile (5 mL), cesium carbonate (0.29 g, 0.90 mmol) was added, and the mixture was stirred at 60 ° C for 16 h. The mixture was cooled to room temperature, and extracted with 20 mL of ethyl acetate and 20 mL of water. The organic layer was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5 to 1 / 1) to obtain compound 20 (70 mg, yield: 66%). LCMS m / z=588.7[M+H] + 1 H NMR(400 MHz,DMSO-d6)δ 9.13(d,1H),8.84(s,1H),8.58(d,1H),8.17-8.14(m,1H),8.00-7.61(m,1H),7.56-7.50(m,2H),7.41-7.35(m,2H) ,5.92-8.81(m,2H),4.48-4.36(m,1H),1.88-1.80(m,1H),1.40-1.34(m,6H),1.22-1.13(m,1H),1.11-0.87(m,3H). Example 21: [ka]

[0146] 12J (100 mg, 0.22 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (64.02 mg, 0.33 mmol), XPhos Pd G2 (17.31 mg, 0.022 mmol) and potassium phosphate (140.10 mg, 0.66 mmol) were placed in a 25 mL one-neck flask, 1,4-dioxane (4 mL) and water (1 mL) were added, the atmosphere was replaced with nitrogen gas three times, and the mixture was stirred at 90° C. for 3 hours. The mixture was cooled to room temperature, and extracted with 20 mL of water and 20 mL of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 1 to 2 / 1). The crude product was further separated and purified by preparative HPLC (instrument: waters 2767 preparative liquid, chromatography column: SunFire@Prep C18 (19 mm x 150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 5 mM ammonium acetate)) to obtain compound 21 (35 mg, yield: 27%). LCMS m / z=576.3[M+H] + 1 H NMR(400 MHz,DMSO-d6)δ 9.06(d,1H),8.71(s,1H),8.53(d,1H),7.81-7.75(m,2H),7.37-7.31(m,2H),5.80(s,2H),4.25(s,2H),3.83(s, 3H),2.97-2.93(m,2H),1.74-1.62(m,1H),1.14-1.06(m,1H),1.04-0.96(m,1H),0.94-0.80(m,2H),0.78(s,4H). Example 22: [ka]

[0147] Step 1: Manufacturing the 22A (2S,5S)-N-Boc-5-methylpyrrolidine-2-carboxylic acid (3 g, 13.09 mmol) was dissolved in THF (30 mL), and borane tetrahydrofuran solution (19.63 mL, 1 M) was slowly added dropwise at 0° C. and stirred at room temperature for 2 h. The mixture was quenched with methanol at 0° C. and concentrated under reduced pressure. The residue was extracted with ethyl acetate and water, and the organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 22A (2.8 g).

[0148] Step 2: Fabrication of 22B 22A (2.8 g, 13.01 mmol) was dissolved in DMSO (15 mL), 2-iodoacylbenzoic acid (4.01 g, 14.31 mmol) was added, and the mixture was stirred at 40 °C for 2 h. 60 mL of ethyl acetate was added, stirred at room temperature for 10 min, filtered, the filter cake was washed with ethyl acetate 3 x 10 ml, 60 mL of saturated aqueous sodium thiosulfate was added to the filtrate, stirred for 10 min, 30 mL of saturated aqueous sodium bicarbonate was added, extracted, the organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 1 to 1 / 5) to obtain 22B (2 g, yield: 72%).

[0149] Step 3: Manufacturing the 22C At 0°C, (trifluoromethyl)trimethylsilane (2g, 14.07mmol) was added to 22B (2g, 9.38mmol) in tetrahydrofuran (20mL). After stirring at 0°C for 10min, tetrabutylammonium fluoride (1.97mL, 1.97mmol, 1M solution in THF) was added. After stirring at room temperature for 2h, the mixture was quenched by adding saturated aqueous ammonium chloride solution (30mL). The mixture was extracted with ethyl acetate (50mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 100-1 / 5) to obtain 22C (2.46g, yield: 92%). LCMS m / z=228.1[M-55]+

[0150] Step 4: Preparation of the hydrochloride salt of 22D 22C (2.46 g, 8.68 mmol) was dissolved in hydrochloric acid-dioxane solution (20 mL, 4 M) and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give the hydrochloride salt of compound 22D (1.8 g).

[0151] Step 5: Manufacturing 22E HATU (5.61 g, 14.75 mmol) was added to 22D hydrochloride (1.8 g) and 4-(methoxycarbonyl)benzoic acid (1.86 g, 10.32 mmol) in DMF (20 mL). After stirring at room temperature for 5 min, DIPEA (3.81 g, 29.49 mmol) was added, and 100 mL of ethyl acetate and 100 mL of water were added and layered. The organic layer was dried under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 100 to 1 / 5) to obtain 22E (3 g, yield 88%). LCMS m / z=346.1[M+H] +

[0152] Step 6: Fabrication of 22F 22E (2 g, 5.79 mmol) was dissolved in dichloromethane (30 mL), and Dess-Martin oxidant (3.68 g, 8.69 mmol) was added in small portions at 0°C, and the mixture was allowed to react at room temperature for 3 h. The mixture was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 100 to 1 / 5) to obtain 22F (1.59 g, yield: 80%).

[0153] Step 7: Fabrication of 22G Ammonium trifluoroacetate (11 g, 83.94 mmol) was added to 22F (1.59 g, 4.63 mmol) and reacted at 130° C. for 2 h. The mixture was cooled to room temperature, and extracted with 50 mL of water and ethyl acetate (50 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V)=1 / 100-1 / 2) to obtain 22G (1.3 g, yield: 86%). LCMS m / z=325.1[M+H] +

[0154] Step 8: Manufacturing the 22H At 0°C, diisobutylaluminum hydride (10.02mL, 10.02mmol, 1.0M solution in hexanes) was added dropwise to a solution (20mL) of 22G (1.3g, 4.01mmol) in tetrahydrofuran, and the mixture was allowed to warm to room temperature and react for 3 hours. 60mL of water was added, and the mixture was extracted with ethyl acetate (60mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 100 to 1 / 2) to obtain 22H (1.1g, yield: 92%). LCMS m / z=297.2[M+H] +

[0155] Step 9: Preparation of 22I 22H (1.1 g, 3.71 mmol) was dissolved in 20 mL of dichloromethane, and sulfinyl chloride (2.21 g, 18.55 mmol) was slowly added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 2 h. The mixture was quenched by adding saturated aqueous sodium bicarbonate solution (30 mL), extracted with dichloromethane (30 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 22I (1 g). LCMS m / z=315.1[M+H] +

[0156] Step 10: Building the 22J Cesium carbonate (1554.16 mg, 4.77 mmol) was added to a solution of 22I (500 mg, 1.59 mmol) and 1F (286.42 mg, 1.67 mmol) in DMF (10 mL), and the mixture was allowed to react at room temperature for 3 h. Water and ethyl acetate were added for extraction, and the organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 1 to 2 / 1) to obtain compound 22J (310 mg, 43% yield). LCMS m / z=450.1[M+H] +

[0157] Step 11: Preparation of Compound 22 22J (150 mg, 0.33 mmol) was dissolved in a mixed solvent of 1,4-dioxane (4 mL) and water (1 mL), and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (96.03 mg, 0.49 mmol), potassium phosphate (210.15 mg, 0.99 mmol) and XPhos G2 (CAS: 1310584-14-5, 25.96 mg, 0.033 mmol) were added in sequence. The mixture was heated to 90°C under nitrogen gas protection and reacted for 3 h. The mixture was cooled to room temperature, 20 mL of ethyl acetate and 20 mL of water were added, layered, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5 to 2 / 1) to obtain compound 22 (100 mg, yield: 53%). LCMS m / z=564.60[M+H] + 1H NMR(400 MHz,DMSO-d6)δ 9.07(d,1H),8.71(s,1H),8.54(d,1H),7.80(d,2H),7.34(d,2H),5.81(s,2H),5.07-4.93(m,1H),3.86-3.79(m,3H),3.09-2.95(m,1H) ,2.94-2.79(m,2H),2.31-2.20(m,1H),1.73-1.62(m,1H),1.19-1.14(m,3H),1.14-1.06(m,1H),1.03-0.95(m,1H),0.95-0.78(m,2H). Example 23: [ka]

[0158] Step 1: Fabrication of 23B 23A (CAS number: 160033-52-3, 2 g, 8.73 mmol) was dissolved in THF (10 mL), and borane tetrahydrofuran solution (17 mL, 17 mmol, 1N) was added dropwise under ice bath, and the mixture was stirred at room temperature for 120 min. 10 mL of methanol was added dropwise to quench the reaction, and the mixture was concentrated under reduced pressure. 50 mL of ethyl acetate was added to the residue to dissolve it, and the organic layer was washed with 50 mL of saturated aqueous sodium bicarbonate solution and 50 mL of saturated saline solution in sequence. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 23B. LCMS m / z=160.1[M-55] + Step 2: Manufacturing 23C 23B (1.88 g, 8.73 mmol) was dissolved in DMSO (10 mL), 2-iodoacylbenzoic acid (2.93 g, 10.48 mmol) was added, and the mixture was stirred at room temperature for 30 min and at 40° C. for 30 min. The mixture was cooled to room temperature, 20 mL of ethyl acetate was added, filtered, 20 mL of saturated aqueous sodium thiosulfate solution was added to the filtrate, and the mixture was stirred for 20 min. Then, 10 mL of saturated aqueous sodium bicarbonate solution was added, and the mixture was stirred for 10 min. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 23C.

[0159] Step 3: 23D Fabrication 23C (1.88 g, 8.82 mmol) was dissolved in THF (20 mL), (trifluoromethyl)trimethylsilane (1.88 g, 13.23 mmol) was added, and 2.65 mL of tetrabutylammonium fluoride (0.69 g, 2.65 mmol, 1N) in tetrahydrofuran was slowly added dropwise under ice bath, and stirred at room temperature for 2 h. Saturated ammonium chloride aqueous solution was added (10 mL) to quench, and extracted with ethyl acetate (20 mL x 2). The organic phase was combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10 to 1 / 2) to obtain 23D (2 g, yield: 80%). LCMS m / z=228.1[M-55] +

[0160] Step 4: Preparation of 23E hydrochloride 23D (2 g, 7.06 mmol) was dissolved in DCM (5 mL), hydrochloric acid-dioxane solution (10 mL, 4 M) was added, and the mixture was stirred at room temperature for 2 h. After concentration under reduced pressure, 20 mL of methyl tert-butyl ether was added, and the mixture was stirred for 10 min and filtered to obtain 23E hydrochloride (1.16 g, yield: 75%).

[0161] Step 5: Fabrication of 23F HATU (2.42 g, 6.36 mmol) was added to a solution of 23E hydrochloride (1.16 g, 5.30 mmol) and monomethyl terephthalate (0.95 g, 5.30 mmol) in DMF (15 mL), stirred at room temperature for 5 min, DIPEA (1.37 g, 10.60 mmol) was added, and stirred for 20 min. 30 mL of ethyl acetate was added, washed with saturated saline (20 mL x 3), the organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10 to 1 / 2) to obtain 23F (1.8 g, yield: 98%). LCMS m / z=346.1[M+H] +

[0162] Step 6: Fabrication of 23G 23F (1.8 g, 5.21 mmol) was dissolved in DCM (20 mL), and Dess-Martin oxidant (2.65 g, 6.25 mmol) was added little by little at 0°C, and the mixture was allowed to react at room temperature for 3 hours. 20 mL of saturated aqueous sodium thiosulfate solution was added, and the mixture was stirred for 20 min, followed by addition of 20 mL of saturated aqueous sodium bicarbonate solution, and the mixture was stirred for 10 min. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 100 to 1 / 2) to obtain 23G (1.5 g, yield: 84%).

[0163] Step 7: Fabrication of 23H Ammonium trifluoroacetate (8.59 g, 65.55 mmol) was added to 23G (1.5 g, 4.37 mmol) and reacted at 130° C. for 1.5 h. The mixture was cooled to room temperature, and extracted with 30 mL of water and ethyl acetate (20 mL×2). The organic phases were combined and dried over anhydrous sodium sulfate, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V)=1 / 100-1 / 2) to obtain 23H (1 g, yield: 70%). LCMS m / z=325.3[M+H] +

[0164] Step 8: Preparation of 23I A solution of diisobutylaluminum hydride (7.7mL, 7.7mmol, 1N) in THF was added dropwise to a solution of 23H (1g, 3.08mmol) in THF (10mL) at 0°C, and the mixture was allowed to react for 3 hours at room temperature. The reaction was quenched by adding 10mL of saturated aqueous ammonium chloride solution, and extracted by adding 30mL of water and 60mL of ethyl acetate. The mixture was left to stand for 20min to precipitate a solid, and then filtered. The filtrate was separated, and the organic phase was washed once with 20mL of saturated saline, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 100-1 / 2) to obtain 23I (0.54g, yield: 59%). LCMS m / z=297.3[M+H] +

[0165] Step 9: Building the 23J 23I (0.54 g, 1.82 mmol) was dissolved in DCM (4 mL), and sulfinyl chloride (1.08 g, 9.1 mmol) was slowly added dropwise in an ice-water bath, and the mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure, and the residue was alkalized with saturated aqueous sodium bicarbonate (10 mL), extracted with dichloromethane (30 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 23J.

[0166] Step 10: Fabrication of 23K Compound 1F (0.11 g, 0.64 mmol) and 23J (0.24 g, 0.76 mmol) were dissolved in DMF (5 mL), and cesium carbonate (0.42 g, 1.28 mmol) was added at room temperature, and the mixture was stirred at 40 ° C for 1 h. The mixture was cooled to room temperature, and extracted with 20 mL of ethyl acetate and 20 mL of water. The organic layer was washed with saturated saline (10 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5 to 1 / 2) to obtain compound 23K (0.14 g, yield: 48%). LCMS m / z=450.3[M+H] +

[0167] Step 11: Preparation of Compound 23 Compound 23K and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (0.12 g, 0.62 mmol) were dissolved in 1,4-Dioxane (4 mL) and water (1 mL), and XPhos Pd G2 (0.024 g, 0.031 mmol) and potassium phosphate (0.20 g, 0.93 mmol) were added in sequence. After completion, the mixture was replaced with nitrogen gas three times, heated to 95 ° C, and stirred for 3 h. The mixture was cooled to room temperature, extracted with 20 ml of ethyl acetate and 10 ml of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10 to 1 / 1) to obtain compound 23 (0.14 g, yield: 80%). LCMS m / z=564.5[M+H]+ 1 H NMR(400 MHz,DMSO-d6)δ 9.07(d,1H),8.71(s,1H),8.54(d,1H),7.83-7.76(m,2H),7.37-7.29(m,2H),5.81(s,2H),5.07-4.95(m,1H),3.83(d,3H),3.07-2.94(m, 1H),2.92-2.80(m,2H),2.31-2.21(m,1H),1.72-1.62(m,1H),1.18-1 .13(m,3H),1.13-1.04(m,1H),1.03-0.95(m,1H),0.94-0.77(m,2H). Biological Test Examples

[0168] Test Example 1: USP1 / UAF1 enzyme inhibitory activity Using ubiquitin rhodamine 110 as a substrate, the activity of deubiquitinase USP1 / UAF1 after drug treatment was detected. The total test system was 20 μl, and the test buffer was 50 mM Tris-HCl, pH 7.8, 0.5 mM EDTA, 0.01% Bovine Serum Albumin, 1 mM DTT, 0.01% Tween-20. At the start of the test, 0.5 nM USP1 / UAF1 (Bio-Techne, E-568-050) protein was added to a 384-well plate (PerkinElmer, 6008269), followed by gradient dilution of the test compound, incubated at room temperature for 10 min, and then 500 nM ubiquitin rhodamine 110 (Bio-Techne, U-555-050) was added and incubated at room temperature for 20 min. Enspire TM Detection was performed using a Multilabel Reader microplate reader (PerkinElmer) at excitation light of 485 nM / emission light of 535 nM. IC was measured using GraphPad Prism (Softbank). 50 values ​​were calculated.

[0169] [Table 2] Conclusion: The compounds of the present invention have good inhibitory effects on USP1 / UAF1 enzyme activity.

[0170] Test Example 2: Pharmacokinetic study in beagle dogs Experimental objective: The test substance was administered to beagle dogs by intravenous and oral gavage at a single dose, and the concentration of the test substance in the plasma of the beagle dogs was measured to evaluate the pharmacokinetic properties of the test substance in the beagle dogs.

[0171] Test animals: male beagle dogs, approximately 8-11 kg, purchased from Beijing Masu Biotechnology Co., Ltd.

[0172] Test method: On the day of the test, beagle dogs were randomly divided into groups according to weight. One day before administration, they were fasted for 14-18 hours without water prohibition, and fed 4 hours after administration. The dosage was administered according to the information in the table below.

[0173] [Table 3] Solvent for intravenous administration: 5% DMA + 5% Solutol + 90% Saline Solvent for intragastric administration: 0.5% MC (DMA: dimethylacetamide, Solutol: polyethylene glycol-15-hydroxyhydroxystearate, Saline: physiological saline, MC: methylcellulose solution,)

[0174] Sampling: Blood was collected from the jugular vein or limb vein before and after administration and placed in an EDTAK2 centrifuge tube. Plasma was collected by centrifugation at 5000 rpm and 4° C. for 10 minutes.

[0175] Blood sampling time points: 0, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 24 h, 48 h, 72 h. All samples were stored below -60°C before analytical detection. Quantitative analysis of samples was performed by LC-MS / MS.

[0176] [Table 4] Conclusion: The compound synthesized by the technology of the present invention has good oral absorbability in beagle dogs, and the oral absorbability is superior to that of the control compound A, where the control compound A is [ka] For its manufacturing method, please refer to WO2020132269.

[0177] Test Example 3: Clonogenic test of MDA-MB-436 cells In this test, MDA-MB-436 cells were used, and the clone formation ability of the cells was detected after treatment with the test compound. At the start of the test, 500 MDA-MB-436 cells (ATCC, HTB-130) were added to a 96-well plate (Corning, 3599) and allowed to adhere overnight. The next day, gradient diluted compounds were added and the cells were cultured in a 37°C, CO2-free incubator. On the 7th day, the old medium was discarded and gradient diluted test compounds were newly added. On the 14th day, the 96-well plate was removed, the culture medium was discarded, and the cell clones were detected using a Crystal violet Assay kit. OD was measured using a PHERAstar FSX microplate reader (BMG LABTECH). 570 Detected at nM position. IC 50 values ​​were calculated.

[0178] [Table 5] Conclusion: The compounds of the present invention have good inhibitory effects on the clonogenesis of MDA-MB-436 cells.

[0179] Test Example 4: Pharmacokinetics test in mice Test animals: male ICR mice, 25-30 g, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0180] Experimental design: On the day of the experiment, ICR mice were randomly divided into groups according to weight. One day before administration, they were fasted for 12-14 h without water prohibition, and fed 4 h after administration.

[0181] [Table 6] (DMA: dimethylacetamide, Solutol: polyethylene glycol-15-hydroxyhydroxystearate, Saline: physiological saline, MC: methylcellulose)

[0182] Blood was collected from the orbit before and after administration at the specified time points, and then placed in an EDTAK2 centrifuge tube and centrifuged at 5,000 rpm for 4 h. o The samples were centrifuged at 4°C for 10 min, and plasma was collected. The blood was collected at 0, 5, 15, 30 min, 1 h, 2 h, 4 h, 7 h, and 24 h for both the intravenous and gavage groups. All samples were stored at -60 °C for 10 min before analysis. o C and samples were quantitatively analyzed using LC-MS / MS.

[0183] [Table 7] Conclusion: The compound synthesized by the technology of the present invention has good oral absorbability in mice.

Claims

1. A compound or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharma- ceutically acceptable salt, or co-crystal thereof, wherein the compound is selected from the compounds according to general formula (I): 【Chemistry 1】 In the formula, ring A is 【Chemistry 2】 The left side is R. ２ is connected to R １ and R ９ are each independently H, a halogen, a cyano group, or C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group and C １－６ alkoxy groups, wherein the alkyl, alkenyl, alkynyl or alkoxy groups are optionally selected from H, halogen, OH, ═O, cyano, NH ２ , C １－６ Alkyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, halogen-substituted C １－６ C substituted with alkyl or hydroxyl groups １－６ C substituted with an alkyl group or a cyano group １－６ is further substituted with 0 to 4 substituents selected from alkyl groups; R ８ is a halogen, a cyano group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group and C １－６ alkoxy groups, wherein the alkyl, alkenyl, alkynyl or alkoxy groups are optionally selected from H, halogen, OH, ═O, cyano, NH ２ , C １－６ Alkyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, halogen-substituted C １－６ C substituted with alkyl or hydroxyl groups １－６ C substituted with an alkyl group or a cyano group １－６ is further substituted with 0 to 4 substituents selected from alkyl groups; R ２ is C ６－１０ A carbocycle or a 5- to 10-membered heterocycle, said carbocycle or heterocycle optionally comprising 0 to 4 R ２ａ is further substituted with R ２ａ are each independently H, a halogen, OH, ═O, a cyano group, or NH ２ , NH(C １－６ Alkyl), N(C １－６ Alkyl) ２ , -SO ２ -C １－６ Alkyl, -SO ２ -C ３－６ Cycloalkyl, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkylthio group, -Z-C ３－６ cycloalkyl or -Z-3 to 8 membered heterocycle, wherein the alkyl group, cycloalkyl group, alkoxy group, alkylthio group or heterocycle is optionally selected from H, D, halogen, OH, ═O, cyano group, NH ２ , C １－６ Alkyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group or C ３－６ is further substituted with 0-4 substituents selected from cycloalkyl groups, said heterocycle containing 1-4 heteroatoms selected from O, S and N; R ３ and R ４ are each independently H, a halogen, OH, a cyano group, or NH ２ , C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group or C １－６ alkoxy groups, wherein the alkyl, alkenyl, alkynyl or alkoxy groups are optionally selected from H, halogen, OH, ═O, cyano, NH ２ , C １－６ Alkyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, halogen-substituted C １－６ C substituted with alkyl or hydroxyl groups １－６ C substituted with alkyl or cyano groups １－６ Alkyl group, C ３－６ is further substituted with 0-4 substituents selected from a cycloalkyl group or a 3-8 membered heterocyclic group, said heterocyclic group containing 1-4 heteroatoms selected from O, S and N; Cy is C ３－１２ Carbocycle or 4-12 membered heterocycle, wherein Cy is optionally H, halogen, OH, ═O, cyano, NH ２ , C １－６ Alkyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, halogen-substituted C １－６ C substituted with alkyl or hydroxyl groups １－６ C substituted with alkyl or cyano groups １－６ Alkyl group, C ３－６ is further substituted with 0-4 substituents selected from a cycloalkyl group or a 3-8 membered heterocyclic group, said heterocyclic ring containing 1-4 heteroatoms selected from O, S and N; R ５ is -Z-C ３－１２ Carbocyclic ring or -Z-4 to 12 membered heterocyclic ring, ５ optionally, 0 to 4 R ５ａ is further substituted with R ５ａ are each independently H, a halogen, OH, a cyano group, or NH ２ , N.H.C. １－６ Alkyl group, N(C １－６ Alkyl) ２ , C １－６ Alkyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, -C １－４ Alkylene-C ３－６ Cycloalkyl, -C １－４ Alkylene-3 to 6 membered heterocycle, C ３－６ Cycloalkyl group, 3- to 8-membered heterocycle, -CONHC １－６ Alkyl, -CONHC １－６ Alkoxy, -CONHC ３－６ Cycloalkyl, -CONH 3-8 membered heterocycle, -NHCO-C １－６ Alkyl, -NHCO-C １－６ Alkoxy, -NHCO-C ３－６ cycloalkyl or -NHCO-3 to 8 membered heterocycle, wherein the alkyl group, alkylene group, alkynyl group, alkoxy group, cycloalkyl group or heterocycle is optionally selected from H, D, halogen, OH, =O, cyano group, NH ２ , -C(=O)NH ２ , -C(=O)NHC １－６ Alkyl, -C(=O)N(C １－６ Alkyl) ２ , C １－６ Alkyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, halogen-substituted C １－６ C substituted with alkyl or hydroxyl groups １－６ C substituted with alkyl or cyano groups １－６ Alkyl group, C ３－６ Cycloalkyl groups, halogen-substituted C ３－６ is further substituted with 0-4 substituents selected from a cycloalkyl group or a 3-8 membered heterocycle, said heterocycle containing 1-4 heteroatoms selected from O, S and N; Z is a bond, O, S, NH, N(C １－４ alkyl), C(=O)NH, NHC(=O), -OCH ２ --, --CH ２ O- or C １－３ 2. A compound or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharma- ceutically acceptable salt, or co-crystal thereof, wherein the compound is selected from the group consisting of an alkylene group, an aryl ...

2. The compound of general formula (I) is selected from the compounds of general formula (Ia): 【Chemistry 3】 In the formula, R １ and R ９ are each independently H, a halogen, a cyano group, or C １－４ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group and C １－４ alkoxy groups, wherein the alkyl, alkenyl, alkynyl or alkoxy groups are optionally selected from H, halogen, OH, ═O, cyano, NH ２ , C １－４ Alkyl group, C ２－４ Alkynyl group, C １－４ Alkoxy group, halogen-substituted C １－４ C substituted with alkyl or hydroxyl groups １－４ C substituted with an alkyl group or a cyano group １－４ is further substituted with 0 to 4 substituents selected from alkyl groups; R ８ is a halogen, a cyano group, C １－４ Alkyl group, C ２－４ Alkynyl group and C １－４ alkoxy groups, said alkyl, alkynyl or alkoxy groups being optionally selected from H, halogen, OH, cyano, NH ２ , C １－４ Alkyl group, C ２－４ Alkynyl group and C １－４ is further substituted with 0 to 4 substituents selected from an alkoxy group; R ２ａ are each independently H, a halogen, OH, ═O, a cyano group, or NH ２ , NH(C １－４ Alkyl), N(C １－４ Alkyl) ２ , -SO ２ -C １－４ Alkyl, -SO ２ -C ３－６ Cycloalkyl, C １－４ Alkyl group, C １－４ Alkoxy group, C １－４ Alkylthio group, -Z-C ３－６ cycloalkyl or -Z-3 to 6 membered heterocycle, wherein the alkyl group, cycloalkyl group, alkoxy group, alkylthio group or heterocycle is optionally selected from H, D, halogen, OH, ═O, cyano group, NH ２ , C １－４ Alkyl group, C ２－４ Alkynyl group, C １－４ Alkoxy group or C ３－６ is further substituted with 0-4 substituents selected from cycloalkyl groups, said heterocycle containing 1-4 heteroatoms selected from O, S and N; R ３ and R ４ are each independently H, a halogen, OH, a cyano group, or C １－４ alkyl groups, Cy is C ３－６ Monocyclic cycloalkyl groups, C ５－１１ Fused-ring cycloalkyl groups, C ５－１１ Spirocyclic cycloalkyl groups, C ５－１１ Bridged ring cycloalkyl group, 4- to 7-membered monocyclic heterocycloalkyl group, 6- to 11-membered condensed ring heterocycloalkyl group, 6- to 11-membered spiro ring heterocycloalkyl group, 6- to 11-membered bridged ring heterocycloalkyl group, benzene ring, Benzo C ４－６ Cy is optionally selected from H, halogen, OH, ═O, cyano, NH ２ , C １－４ Alkyl group, C ２－４ Alkynyl group, C １－４ Alkoxy group, halogen-substituted C １－４ C substituted with alkyl or hydroxyl groups １－４ C substituted with alkyl or cyano groups １－４ Alkyl group, C ３－６ is further substituted with 0-4 substituents selected from a cycloalkyl group or a 3-8 membered heterocycle, said heterocycle containing 1-4 heteroatoms selected from O, S and N; R ５ is -Z-C ６－１２ Carbocyclic ring or -Z-5 to 12 membered heterocyclic ring, ５ optionally, 0 to 4 R ５ａ is further substituted with R ５ａ are each independently H, a halogen, OH, a cyano group, or NH ２ , C １－４ Alkyl group, C ２－４ Alkynyl group, C １－４ Alkoxy group, -C １－２ Alkylene-C ３－６ Cycloalkyl, -C １－２ Alkylene-3 to 6 membered heterocycle, C ３－６ A cycloalkyl group or a 3- to 6-membered heterocycle, wherein the alkyl group, alkylene group, alkynyl group, alkoxy group, cycloalkyl group or heterocycle is optionally selected from H, D, halogen, OH, ═O, cyano group, NH ２ , -C(=O)NH ２ , -C(=O)NHC １－４ Alkyl, -C(=O)N(C １－４ Alkyl) ２ , C １－４ Alkyl group, C ２－４ Alkynyl group, C １－４ Alkoxy group, halogen-substituted C １－４ C substituted with alkyl or hydroxyl groups １－４ C substituted with alkyl or cyano groups １－４ Alkyl group, C ３－６ Cycloalkyl groups, halogen-substituted C ３－６ 2. The compound of claim 1, further substituted with 0-4 substituents selected from a cycloalkyl group or a 3-8 membered heterocycle, said heterocycle containing 1-4 heteroatoms selected from O, S and N, or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharma- ceutically acceptable salt, or co-crystal thereof.

3. R １ and R ９ are each independently selected from H, F, Cl, Br, I, a cyano group, a methyl group, or an ethyl group; R ８ is selected from F, Cl, Br, I, CN, a methyl group, an ethyl group, an ethynyl group, a methoxy group or an ethoxy group, R ２ is selected from a phenyl group, a pyridine, a pyrimidine, a pyrrole, a pyrazole, an imidazole, a furan, a thiophene, a thiazole or an oxazole, and the phenyl group, the pyridine, the pyrimidine, the pyrrole, the pyrazole, the imidazole, the furan, the thiophene, the thiazole or the oxazole is optionally selected from 0 to 4 R ２ａ or Or R ２ teeth, 【Chemistry 4】 wherein R ２ optionally, 0 to 4 R ２ａ is further substituted with R ２ａ are each independently selected from H, F, Cl, Br, I, or a cyano group, or R ２ａ are each independently a substituted or unsubstituted group: ２ -Methyl, -SO ２ -Ethyl, -SO ２ -propyl, -SO ２ -isopropyl, -SO ２ -cyclopropyl, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, propoxy group, methylthio group, ethylthio group, propylthio group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, azetidinyl group, azacyclopentyl group, azacyclohexyl group, piperazine, oxetanyl group, oxacyclopentyl group, oxacyclohexyl group, morpholine, -O-azetidinyl, -O-azacyclopentyl, -O-azacyclohexyl, -O-oxetanyl, -O-oxacyclopentyl, -O-oxacyclohexyl, -OCH ２ -phenyl, -OCH ２ -Cyclopropyl, -OCH ２ -Cyclobutyl, -OCH ２ -Cyclopentyl, -OCH ２ - selected from one of cyclohexyl, pyrrole, pyrazole, imidazole, thiazole, thiophene, furan, oxazole, optionally, when substituted, H, D, halogen, OH, =O, cyano group, NH ２ , C １－４ Alkyl group, C ２－４ Alkynyl group, C １－４ Alkoxy group, C ３－６ is further substituted with 0 to 4 substituents selected from cycloalkyl groups; R ３ and R ４ are each independently selected from H, F, Cl, Br, I, a methyl group, and an ethyl group; Cy is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a bicyclo[2.2.2]octyl group, a bicyclo[1.1.1]pentanyl group, a cyclopentyl-fused cyclopentyl group, a cyclobutyl-spiro-cyclohexyl group, a cyclobutyl-spiro-cyclopentyl group, an azetidinyl group, an azacyclopentyl group, an azacyclohexyl group, an azetidinyl-spiro-cyclobutyl group, an azetidinyl-spiro-cyclopentyl group, an azetidinyl-spiro-cyclohexyl group, an azetidinyl-spiro-azetidinyl group, an azetidinyl-spiro-azacyclopentyl group, an azetidinyl-spiro-azacyclohexyl group, 【Chemistry 5】 Benzene ring, thiophene, furan, pyrrole, thiazole, oxazole, pyrazole, pyrazine, pyrimidine, 【Chemistry 6】 benzothiazole, benzothiophene, benzofuran, benzoxazole, benzopyrrole, benzopyrazole, benzimidazole, indolizine, pyridopyrrole, pyridoimidazole, pyridopyrazole, pyrimidoimidazole, pyrimidopyrazole, pyridotriazole or 2-pyridone, wherein Cy is optionally H, halogen, OH, ═O, a cyano group, NH ２ , C １－４ Alkyl group, C ２－４ Alkynyl group, C １－４ Alkoxy group, halogen-substituted C １－４ C substituted with alkyl or hydroxyl groups １－４ C substituted with alkyl or cyano groups １－４ Alkyl group, C ３－６ is further substituted with 0-4 substituents selected from a cycloalkyl group or a 3-8 membered heterocycle, said heterocycle containing 1-4 heteroatoms selected from O, S and N; R ５ is selected from a benzene ring, pyrazole, pyrrole, imidazole, triazole, pyridine, pyrimidine, pyrazine, or pyridazine, ５ optionally, 0 to 4 R ５ａ or Or R ５ teeth, 【Chemistry 7】 wherein R ５ optionally, 0 to 4 R ５ａ is further substituted with R ５ａ each independently represents H, F, Cl, Br, I, a cyano group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a propargyl group, a butynyl group, a methoxy group, an ethoxy group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an oxetanyl group, an oxacyclopentyl group, an oxacyclohexyl group, an azetidinyl group, an azacyclopentyl group, an azacyclohexyl group, -CH ２ -Cyclopropyl, -CH ２ -Cyclobutyl, -CH ２ -Cyclopentyl, -CH ２ -Cyclohexyl, -CH ２ -oxetanyl, -CH ２ -oxacyclopentyl, -CH ２ -oxacyclohexyl, -CH ２ -Azetidinyl, -CH ２ -azacyclopentyl or -CH ２ -azacyclohexyl, wherein the methyl, ethyl, propyl, isopropyl, propargyl, butynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxacyclopentyl, oxacyclohexyl, azetidinyl, azacyclopentyl or azacyclohexyl group is optionally selected from H, D, halogen, OH, =O, cyano, NH ２ , C １－４ Alkyl group, C ２－４ Alkynyl group, C １－４ Alkoxy group, C ３－６ Cycloalkyl group or halogen-substituted C ３－６ 3. The compound of claim 2, or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharma- ceutically acceptable salt, or co-crystal thereof, further substituted with 0 to 4 substituents selected from cycloalkyl groups.

4. R １ and R ９ is H, R ８ is selected from F, Cl, Br, CN, a methyl group, an ethynyl group or a methoxy group, R ２ pyrrole, pyrazole, imidazole, pyrimidine, 【Chemistry 8】 The pyrrole, pyrazole, imidazole, pyrimidine, 【Chemistry 9】 is optionally H, F, Cl, Br, I, a cyano group, -SO ２ -Methyl, -SO ２ -Ethyl, -SO ２ -propyl, -SO ２ -isopropyl, -SO ２ -Cyclopropyl, CH ２ F, C.H.F. ２ , C.F. ３ , -OCH ２ F, -OCHF ２ , -OCF ３ , methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, propoxy group, -OCD ３ , methylthio group, ethylthio group, propylthio group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, azetidinyl group, azacyclopentyl group, azacyclohexyl group, piperazine, oxetanyl group, oxacyclopentyl group, oxacyclohexyl group, morpholine, -O-azetidinyl, -O-azacyclopentyl, -O-azacyclohexyl, -O-oxetanyl, -O-oxacyclopentyl, -O-oxacyclohexyl, -OCH ２ -phenyl, -OCH ２ -Cyclopropyl, -OCH ２ -Cyclobutyl, -OCH ２ -Cyclopentyl, -OCH ２ -cyclohexyl, 【Chemistry 10】 Pyrrole, pyrazole, imidazole, thiazole, thiophene, furan, oxazole, 【Chemistry 11】 is further substituted with 0 to 4 substituents selected from Cy is 【Chemistry 12】 wherein Cy is optionally selected from H, F, Cl, Br, I, a cyano group, CH ２ F, C.H.F. ２ , C.F. ３ , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or cyclopropyl; Or Cy is 【Chemistry 13】 wherein Cy is optionally selected from H, F, Cl, Br, I, a cyano group, CH ２ F, C.H.F. ２ , C.F. ３ , further substituted with 0 to 4 substituents selected from methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, or cyclopropyl groups; R ５ is selected from pyrrole, pyrazole or imidazole, said pyrrole, pyrazole or imidazole optionally being selected from H, F, Cl, Br, I, a cyano group, CH ２ F, C.H.F. ２ , C.F. ３ , C.D. ３ , methyl group, ethyl group, propyl group, isopropyl group, -CH ２ CH ２ F, a methoxy group, an ethoxy group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an oxetanyl group, an oxacyclopentyl group, an oxacyclohexyl group, an azetidinyl group, an N-methylazetidinyl group, an azacyclopentyl group, an azacyclohexyl group, 【Chemistry 14】 -CH ２ -Cyclopropyl, -CH ２ -Cyclobutyl, -CH ２ -Cyclopentyl, -CH ２ -Cyclohexyl, -CH ２ -oxetanyl, -CH ２ -oxacyclopentyl, -CH ２ -oxacyclohexyl, -CH ２ -Azetidinyl, -CH ２ -azacyclopentyl, -CH ２ -azacyclohexyl, 【Chemistry 15】 or propargyl groups; Or R ５ teeth, 【Chemistry 16】 wherein R ５ is optionally H, F, Cl, Br, I, a cyano group, CH ２ F, C.H.F. ２ , C.F. ３ , C.D. ３ , methyl group, ethyl group, propyl group, isopropyl group, -CH ２ CH ２ F, a methoxy group, an ethoxy group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an oxetanyl group, an oxacyclopentyl group, an oxacyclohexyl group, an azetidinyl group, an N-methylazetidinyl group, an azacyclopentyl group, an azacyclohexyl group, 【Chemistry 17】 -CH ２ -Cyclopropyl, -CH ２ -Cyclobutyl, -CH ２ -Cyclopentyl, -CH ２ -Cyclohexyl, -CH ２ -oxetanyl, -CH ２ -oxacyclopentyl, -CH ２ -oxacyclohexyl, -CH ２ -Azetidinyl, -CH ２ -azacyclopentyl, -CH ２ -azacyclohexyl, 【Chemistry 18】 or a propargyl group; or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharma- ceutically acceptable salt, or co-crystal thereof.

5. R ２ teeth, 【Chemistry 19】 is selected from R ５ teeth, 【Chemistry 20】 Selected from or Or R ５ teeth, 【Chemistry 21】 【Chemical 22】 is selected from R ８ is selected from F, Cl, or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharma- ceutically acceptable salt, or co-crystal thereof.

6. The compound of claim 1, or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharma- ceutically acceptable salt, or co-crystal thereof, wherein the compound is selected from one of the structures shown in Table E.

7. A pharmaceutical composition comprising the compound of any one of claims 1 to 6 or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharma- ceutically acceptable salt, or co-crystal thereof, and a pharma- ceutically acceptable carrier.

8. 7. A pharmaceutical composition or formulation comprising 1 to 1500 mg of a compound according to any one of claims 1 to 6 or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharma- ceutically acceptable salt or co-crystal thereof and a pharmaceutical excipient.

9. Use of the compound according to any one of claims 1 to 6 or a stereoisomer, tautomer, deuterated product, solvate, prodrug, metabolite, pharma- ceutically acceptable salt or cocrystal thereof in the manufacture of a medicament for treating a disease associated with the activity or expression level of USP1.

10. The application according to claim 9, characterized in that the disease is selected from tumors.

11. 10. A method for treating a disease in a mammal, said method comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 6 or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharma- ceutically acceptable salt or co-crystal thereof, wherein the therapeutically effective amount is preferably 1 to 1500 mg, and wherein the disease is preferably a tumor.

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