CN116462679A

CN116462679A - Pyrazolopyrimidine derivative and application thereof in medicine

Info

Publication number: CN116462679A
Application number: CN202310030587.XA
Authority: CN
Inventors: 张晨; 王健民; 钱国飞; 余彦; 唐平明; 陈滕飞; 石荣华; 黄安邦; 李瑶; 严庞科
Original assignee: Sichuan Haisco Pharmaceutical Co Ltd
Current assignee: Tibet Haisike Pharmaceutical Co ltd
Priority date: 2022-01-18
Filing date: 2023-01-10
Publication date: 2023-07-21

Abstract

The invention relates to a compound shown in a general formula (I), a general formula (II) or a general formula (III) or a stereoisomer, a deuterated compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, an intermediate and a preparation method thereof, and application in preparing medicaments for treating diseases related to activity or expression quantity of USP 1.

Description

Pyrazolopyrimidine derivative and application thereof in medicine

Technical Field

The invention relates to a compound shown in a general formula (I) or a stereoisomer, a deuterated compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, an intermediate and a preparation method thereof, and application in preparing medicaments for treating diseases related to activity or expression quantity of USP 1.

Background

Protein ubiquitination of cells is a critical protein modification that regulates multiple cellular processes. Protein ubiquitination is controlled synergistically by E3 ubiquitin ligase and deubiquitinase (deubiquitinating enzymes, DUBs). DUBs can cleave the isopeptide bond between ubiquitin and modified protein, and are responsible for removing ubiquitin from the target protein and rescuing it from the degradation pathway; also participates in editing, maturation and recycling after degradation of ubiquitin molecules. Currently, over 100 deubiquitinating enzymes are known, and these proteins are subdivided into six subfamilies. The ubiquitin-specific protease (ubiquitinspecific protease, USP) subfamily is the largest of these, with 58 members currently known. USP is a cysteine protease containing a highly conserved catalytic domain, USP1 is one of the USP subfamilies in DUBs (cancer, 2020,12,1579;Molecular Cell,2018,72,925-941).

The Fanconi Anemia (FA) and DNA Translesion Synthesis (TLS) pathways were the earliest discovered pathways of DNA damage tolerance and repair regulated by reversible ubiquitination, USP1 could modulate the de-ubiquitination of specific proteins in the FA and TLS pathways to participate in regulating the DNA damage-repair pathway (Nature Chemical Biology,2014,10,298-304). USP1 plays an important role in tumor Cell DNA repair, and it has been reported that the deletion of USP1 results in reduced survival and replication fork degradation of BRCA 1-deficient cells (Molecular Cell,2018,72,925-941). UAF1 (USP 1-associated factor 1) as a cofactor for USP1, USP12 and USP46 may enhance their deubiquitinase activity by forming stable USP/UAF1 protein complexes; the USP1/UAF1 complex de-ubiquitinates a variety of substrates and is involved in the DNA repair process, tumor pathogenesis and modulation of antiviral innate immunity (Nat Commun,2020,11,6042). At present, no medicine aiming at USP1 protein is marketed, and the research of USP1 inhibitors has wide application prospect.

Disclosure of Invention

The invention aims to provide a compound capable of inhibiting USP1 or stereoisomers, deuterated matters, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or eutectic crystals thereof, intermediates and preparation methods thereof, and application of the compound in preparing medicaments for treating diseases related to the activity or expression quantity of USP 1.

The present invention provides a compound of formula (I) or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein

In some embodiments of the present invention, in some embodiments,selected from->

In certain embodiments, the compound of formula (I) is selected from compounds of formula (Ia),

in certain embodiments, R ¹ Selected from H, halogen, cyano, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, said alkyl, alkenyl, alkynyl, alkoxy optionally being substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Alkoxy, halogen substituted C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl-and cyano-substituted C _1-6 Substituted by alkyl;

in certain embodiments, R ¹ Selected from H, halogen, cyano, C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _1-4 Alkoxy, said alkyl, alkenyl, alkynyl, alkoxy optionally being substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl-and cyano-substituted C _1-4 Substituted by alkyl;

in certain embodiments, R ¹ Selected from H, F, cl, br, I, cyano, methyl or ethyl;

in certain embodiments, R ² Selected from C _6-10 Carbocycles or 5 to10 membered heterocycles, said carbocycle or heterocycle optionally being substituted with 1 to 4R ^2a Substitution;

in certain embodiments, R ² Selected from phenyl, pyridine, pyrimidine, pyrrole, pyrazole, imidazole, furan, thiophene, thiazole, oxazole, said phenyl, pyridine, pyrimidine, pyrrole, pyrazole, imidazole, furan, thiophene, thiazole, oxazole optionally being selected from 1 to 4 of R ^2a Substitution;

in certain embodiments, R ² Selected from pyrrole, pyrazole, imidazole, pyrimidine optionally substituted with 1 to 4 groups selected from H, F, cl, br, I, cyano, -SO ₂ -methyl, -SO ₂ -ethyl, -SO ₂ -propyl, -SO ₂ -isopropyl, -SO ₂ -cyclopropyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, piperazine, oxetanyl, oxolanyl, morpholin, -O-azetidine, -O-azetidinyl, -O-azetidine, -O-oxepinyl, -O-oxetanyl, -O-oxolanyl, -O-oxhexyl, -OCH ₂ -phenyl substituted with a substituent;

in certain embodiments, R ² Selected from the group consisting of

In certain embodiments, R ^2a Each independently selected from H, halogen, OH, =O, cyano, NH ₂ 、NH(C _1-6 Alkyl), N (C) _1-6 Alkyl group ₂ 、-SO ₂ -C _1-6 Alkyl, -SO ₂ -C _3-6 Cycloalkyl, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, -Z-C _3-6 Cycloalkyl or-Z-3 to 8 membered heterocycle, said alkyl, cycloalkyl, alkoxy, alkylthio, heterocycle optionally being substituted with 1 to 4 substituents selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Taking alkoxy groupsSubstituted by a substituent, said heterocycle containing from 1 to 4 heteroatoms selected from O, S, N;

in certain embodiments, R ^2a Each independently selected from H, halogen, OH, =O, cyano, NH ₂ 、NH(C _1-4 Alkyl), N (C) _1-4 Alkyl group ₂ 、-SO ₂ -C _1-4 Alkyl, -SO ₂ -C _3-6 Cycloalkyl, C _1-4 Alkyl, C _1-4 Alkoxy, C _1-4 Alkylthio, -Z-C _3-6 Cycloalkyl or-Z-3 to 6 membered heterocycle, said alkyl, cycloalkyl, alkoxy, alkylthio, heterocycle optionally being substituted with 1 to 4 substituents selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Substituted with an alkoxy substituent, said heterocycle containing 1 to 4 heteroatoms selected from O, S, N;

in certain embodiments, R ^2a Each independently selected from H, F, cl, br, I, cyano, or R ^2a Each independently selected from one of the following substituted or unsubstituted: -SO ₂ -methyl, -SO ₂ -ethyl, -SO ₂ -propyl, -SO ₂ -isopropyl, -SO ₂ -cyclopropyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, piperazine, oxetanyl, oxolanyl, morpholin, -O-azetidine, -O-azetidinyl, -O-azetidine, -O-oxepinyl, -O-oxetanyl, -O-oxolanyl, -O-oxhexyl, -OCH ₂ -phenyl, optionally substituted by 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Substituted with alkoxy;

in certain embodiments, Z is selected from a bond, O, S, NH, N (C _1-4 Alkyl), C (=o) NH, NHC (=o), OCH ₂ -、-CH ₂ O-、C _1-3 An alkylene group;

in certain embodiments, X ₁ 、X ₂ Each independently selected from N or CR ^x ；

In certain embodiments, X ₁ Selected from CH, X ₂ Selected from N;

in certain embodiments, R ^x Selected from H, halogen, cyano, C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyl, C _2-6 Alkynyl, said alkyl, alkoxy, alkenyl, alkynyl being optionally substituted with 1 to 4H, halogen, OH, =o, cyano, NH ₂ 、C _1-6 Alkyl, C _1-6 Alkoxy, halogen substituted C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl-and cyano-substituted C _1-6 Substituted by alkyl;

in certain embodiments, R ^x Selected from H, halogen, cyano, C _1-4 Alkyl, C _1-4 Alkoxy, C _2-4 Alkenyl, C _2-4 Alkynyl, said alkyl, alkoxy, alkenyl, alkynyl being optionally substituted with 1 to 4H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl-and cyano-substituted C _1-4 Substituted by alkyl;

in certain embodiments, R ^x Each independently selected from H, F, cl, br, I, cyano, methyl or ethyl;

in certain embodiments, R ³ 、R ⁴ Each independently selected from H, halogen, OH, cyano, NH ₂ 、C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, said alkyl, alkenyl, alkynyl, alkoxy optionally being substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Alkoxy, halogen substituted C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl-and cyano-substituted C _1-6 Alkyl, C _3-6 Cycloalkyl or a 3 to 8 membered heterocyclyl group substituted with 1 to 4 heteroatoms selected from O, S, N;

in certain embodiments, R ³ 、R ⁴ Each independently selected from H, halogen, OH, cyano, C _1-4 An alkyl group;

in certain embodiments, R ³ 、R ⁴ Each independently selected from H, F, cl, br, I, methyl, ethyl;

in certain embodiments, cy is selected from C _3-12 Non-aromatic carbocyclic ring, 4-to 12-membered non-aromatic heterocyclic ring, benzo C _4-6 Carbocycle, benzo 4 to 6 membered heterocycle, 5 membered heteroaryl ring, pyrimidine, pyrazine, 8 to 10 membered fused ring heteroaryl ring, said Cy optionally being substituted with 1 to 4 substituents selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Alkoxy, halogen substituted C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl-and cyano-substituted C _1-6 Alkyl, C _3-6 Cycloalkyl or a substituent of a 3 to 8 membered heterocyclic group, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;

in certain embodiments, cy is selected from C _4-6 Monocyclic cycloalkyl, C _5-11 Cycloalkyl radicals C _5-11 Spiro cycloalkyl, C _5-11 Bridged cycloalkyl, 4-to 7-membered monocyclic heterocycloalkyl, 6-to 11-membered fused-ring heterocycloalkyl, 6-to 11-membered spirocycloalkyl, 6-to 11-membered bridged-ring heterocycloalkyl, benzoC _4-6 Carbocycle, benzo 4 to 6 membered heterocycle, 5 membered heteroaryl ring, pyrimidine, pyrazine, 8 to 10 membered fused ring heteroaryl ring, said Cy optionally being substituted with 1 to 4 substituents selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl-and cyano-substituted C _1-4 Alkyl, C _3-6 Cycloalkyl or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;

in certain embodiments, cy is selected from cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.2]Octyl and bicyclo [1.1.1]Pentyl, cyclopentyl-cyclopentyl, cyclobutylspirohexyl, cyclobutylspiropentyl, azetidinyl, azaCyclohexyl, azetidinyl spirobutyl, azetidinyl spiropentyl, azetidinyl spirohexyl, azetidinyl spiroazetidinyl, azetidinyl spirohexyl,

Thiophene, furan, pyrrole, thiazole, oxazole, pyrazole, pyrazine, pyrimidine,Benzothiazole, benzothiophene, benzofuran, benzoxazole, benzopyrrole, benzopyrazole, benzimidazole, indolizine, pyridopyrrole, pyridoimidazole, pyridopyrazole, pyrimidoimidazole, pyrimidoizole, 2-pyridone, pyridotriazole, said Cy optionally being substituted with 1 to 4 substituents selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl-and cyano-substituted C _1-4 Alkyl, C _3-6 Cycloalkyl or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;

in certain embodiments, cy is selected from

Said Cy is optionally substituted with 1 to 4 groups selected from HF, cl, br, I, cyano, CH ₂ F、CHF ₂ 、CF ₃ Substituents for methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl;

in certain embodiments, cy is selected from

Said Cy is optionally substituted with 1 to 4 groups selected from H, F, cl, br, I, cyano, CH ₂ F、CHF ₂ 、CF ₃ Substituents for methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl;

in certain embodiments, R ⁵ Selected from C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, -Z-C _6-10 Carbocycle or-Z-5 to 10 membered heterocycle, said R ⁵ Optionally by 1 to 4R ^5a Substitution;

in certain embodiments, R ⁵ Selected from-Z-C _6-10 Carbocycle or-Z-5 to 10 membered heterocycle, said R ⁵ Optionally by 1 to 4R ^5a Substitution;

in certain embodiments, R ⁵ Selected from benzene ring, pyrazole, pyrrole, imidazole, triazole, pyridine, pyrimidine, pyrazine and pyridazine, wherein R is ⁵ Optionally by 1 to 4R ^5a Substitution;

in certain embodiments, R ⁵ Selected from pyrrole, pyrazole, imidazole optionally substituted with 1 to 4 groups selected from H, F, cl, br, I, cyano, CH ₂ F、CHF ₂ 、CF ₃ Substituents such as methyl, ethyl, propyl, isopropyl, methoxy, and ethoxy;

in certain embodiments, R ⁵ Selected from the group consisting of

In certain embodiments, R ^5a Each independently selected from H, halogen, OH, cyano, NH ₂ 、NHC _1-6 Alkyl, N (C) _1-6 Alkyl group ₂ 、C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkyl, 3-to 8-membered heterocycle, -CONHC _1-6 Alkyl, -CONHC _1-6 Alkoxy, -CONHC _3-6 Cycloalkyl, -CONH3 to 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, said alkyl, alkoxy, cycloalkyl, heterocycle optionally being substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、-C(＝O)NH ₂ 、-C(＝O)NHC _1-6 Alkyl, -C (=o) N (C) _1-6 Alkyl group ₂ 、C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Alkoxy, halogen substituted C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl-and cyano-substituted C _1-6 Alkyl, C _3-6 Cycloalkyl or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;

in certain embodiments, R ^5a Each independently selected from H, halogen, OH, cyano, NH ₂ 、C _1-4 Alkyl, C _1-4 Alkoxy, C _3-6 Cycloalkyl or a 3-to 6-membered heterocycle, said alkyl, alkoxy, cycloalkyl, heterocycle optionally being substituted with 1 to 4 substituents selected from H, halogen, OH, =o, cyano, NH ₂ 、-C(＝O)NH ₂ 、-C(＝O)NHC _1-4 Alkyl, -C (=o) N (C) _1-4 Alkyl group ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl-and cyano-substituted C _1-4 Alkyl, C _3-6 Cycloalkyl or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;

in certain embodiments, R ^5a Each independently selected from H, F, cl, br, I, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl optionally being substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Substituted with alkoxy;

in certain embodiments, the compound of formula (I) is not

In another aspect, the invention provides a compound of formula (II) or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein

In certain embodiments, ring a is selected fromLeft side and R ² Connecting;

in certain embodiments, ring a is selected from Left side and R ² Connecting;

in certain embodiments, X ₁ Selected from N or CR ⁸ ；

In certain embodiments, X ₁ Selected from N, CH or CF;

in certain embodiments, R ¹ 、R ⁸ 、R ⁹ Each independently selected from H, halogen, cyano, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, said alkyl, alkenyl, alkynyl, alkoxy optionally being substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Alkoxy, halogen substituted C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl-and cyano-substituted C _1-6 Substituted by alkyl;

in certain embodiments, R ¹ 、R ⁸ 、R ⁹ Each independently selected from H, halogen, cyano, C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _1-4 Alkoxy, said alkyl, alkenyl, alkynyl, alkoxy optionally being substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl-and cyano-substituted C _1-4 Substituted by alkyl;

in certain embodiments, R ¹ 、R ⁸ 、R ⁹ Each independently selected from H, F, cl, br, I, cyano, methyl or ethyl;

In certain embodiments, R ¹ Selected from H;

in certain embodiments, R ⁸ Selected from H, F, cl;

in certain embodiments, R ⁹ Selected from H;

in certain embodiments, Y is selected from O, S, S (=o),S(＝O) ₂ 、S(＝O) ₂ N(R ^y )、N(R ^y )、C _1-4 Alkylene, -OC _1-3 Alkylene-, -C _1-3 Alkylene group O-, -C _1-3 Alkylene S-, -SC _1-3 Alkylene-, -C _1-3 Alkylene S (=o) -, -S (=o) C _1-3 Alkylene-, -C _1-3 Alkylene group S (=o) ₂ -、-S(＝O) ₂ C _1-3 Alkylene-, -N (R) ^y )C _1-3 Alkylene-, -C _1-3 Alkylene N (R) ^y ) -said alkylene group optionally being 1 to 4 groups selected from H, halogen, = O, OH, cyano, C _1-6 Alkyl, halogen substituted C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Substituted cycloalkyl;

in certain embodiments, Y is selected from the group consisting of-OCH ₂ -、-OCH ₂ CH ₂ -、-CH ₂ CH ₂ -、-CH ₂ CH ₂ CH ₂ -、-NHCH ₂ -、-NHCH ₂ CH ₂ -、-SCH ₂ CH ₂ -、-NHC(＝O)-、-NHC(＝O)CH ₂ -、-N(CH ₃ )C(＝O)CH ₂ -, said-CH ₂ -optionally further 0 to 2 are selected from H, F, cl, br, I, = O, OH, cyano, CH ₂ F、CHF ₂ 、CF ₃ Substituents such as methyl, ethyl, propyl, isopropyl, methoxy, and ethoxy;

in certain embodiments, R ^y Each independently selected from H, C _1-6 Alkyl or C _3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being substituted with 1 to 4 substituents selected from H, halogen, = O, CF ₃ OH, cyano, NH ₂ 、C _1-6 Alkyl or C _1-6 Substituted with alkoxy;

in certain embodiments, R ^y Each independently selected from H, C _1-4 Alkyl or C _3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being substituted with 1 to 4 substituents selected from H, halogen, = O, CF ₃ OH, cyano, NH ₂ 、C _1-4 Alkyl or C _1-4 Substituted with alkoxy;

in some implementationsIn the scheme, R ^y Each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally being selected from 1 to 4 from H, halogen, = O, CF ₃ OH, cyano, NH ₂ 、C _1-4 Alkyl or C _1-4 Substituted with alkoxy;

in certain embodiments, R ^y Each independently selected from H, methyl, ethyl, isopropyl, cyclopropyl;

in certain embodiments, R ² Selected from C _6-10 Carbocycles or 5-to 10-membered heterocycles, said carbocycles or heterocycles optionally being substituted with 1 to 4R ^2a Substitution;

in certain embodiments, R ² Selected from phenyl, pyridine, pyrimidine, pyrrole, pyrazole, imidazole, furan, thiophene, thiazole, oxazole, said phenyl, pyridine, pyrimidine, pyrrole, pyrazole, imidazole, furan, thiophene, thiazole, oxazole optionally having 1 to 4R' s ^2a Substitution;

in certain embodiments, R ² Selected from pyrrole, pyrazole, imidazole, pyrimidine optionally substituted with 1 to 4 groups selected from F, cl, br, I, cyano, -SO ₂ -methyl, -SO ₂ -ethyl, -SO ₂ -propyl, -SO ₂ -isopropyl, -SO ₂ -cyclopropyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, piperazine, oxetanyl, oxolanyl, morpholin, -O-azetidine, -O-azetidinyl, -O-azetidine, -O-oxepinyl, -O-oxetanyl, -O-oxolanyl, -O-oxhexyl, -OCH ₂ -phenyl, pyrrole, pyrazole, imidazole, thiazole, thiophene, furan, oxazole,Is substituted by a substituent of (2);

in certain embodiments, R ² Selected from the group consisting of

In certain embodiments, R ^2a H, halogen, OH, =o, cyano, NH, independently of one another ₂ 、NH(C _1-6 Alkyl), N (C) _1-6 Alkyl group ₂ 、-SO ₂ -C _1-6 Alkyl, -SO ₂ -C _3-6 Cycloalkyl, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, -W-C _3-6 Cycloalkyl or-W-3 to 8 membered heterocycle, said alkyl, cycloalkyl, alkoxy, alkylthio, heterocycle optionally being substituted with 1 to 4 substituents selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Substituted with an alkoxy substituent, said heterocycle containing 1 to 4 heteroatoms selected from O, S, N;

In certain embodiments, R ^2a H, halogen, OH, =o, cyano, NH, independently of one another ₂ 、NH(C _1-4 Alkyl), N (C) _1-4 Alkyl group ₂ 、-SO ₂ -C _1-4 Alkyl, -SO ₂ -C _3-6 Cycloalkyl, C _1-4 Alkyl, C _1-4 Alkoxy, C _1-4 Alkylthio, -W-C _3-6 Cycloalkyl or-W-3 to 6 membered heterocycle, said alkyl, cycloalkyl, alkoxy, alkylthio, heterocycle optionally being substituted with 1 to 4 substituents selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Substituted with an alkoxy substituent, said heterocycle containing 1 to 4 heteroatoms selected from O, S, N;

in certain embodiments, R ^2a Each independently selected from H, F, cl, br, I, cyano, or R ^2a Each independently selected from one of the following substituted or unsubstituted: -SO ₂ -methyl, -SO ₂ -ethyl, -SO ₂ -propyl, -SO ₂ -isopropyl, -SO ₂ -cyclopropyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, methylthioEthylthio, propylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, piperazine, oxetanyl, oxolanyl, morpholinyl, O-azetidine, O-azetidinyl, O-azetidine, O-oxepinyl, O-oxetanyl, O-oxolanyl, O-oxepinyl, OCH ₂ -phenyl, pyrrole, pyrazole, imidazole, thiazole, thiophene, furan, oxazole, optionally substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Substituted with alkoxy;

in certain embodiments, R ^2a Each independently selected from H, F, cl, br, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl;

in certain embodiments, each W is independently selected from a bond, O, S, NH, N (C _1-4 Alkyl), C (=o) NH, NHC (=o), OCH ₂ -、-CH ₂ O-、C _1-3 An alkylene group;

in certain embodiments, W are each independently selected from the group consisting of bond, O, S, C (=o), S (=o) ₂ 、NH、N(CH ₃ )、C(＝O)NH、NHC(＝O)、-OCH ₂ -、-CH ₂ O-, methylene, ethylene;

In certain embodimentsWherein R is ³ 、R ⁴ Each independently selected from H, halogen, OH, cyano, C _1-4 An alkyl group;

in certain embodiments, R ³ 、R ⁴ Selected from H;

in certain embodiments, cy is selected from a benzene ring or a 6 membered heteroaryl ring, said Cy optionally being substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Alkoxy, halogen substituted C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl-and cyano-substituted C _1-6 Alkyl, C _3-6 Cycloalkyl or a 3 to 8 membered heterocyclyl, said heteroaryl or heterocycle containing 1 to 4 heteroatoms selected from O, S, N;

in certain embodiments, cy is selected from a benzene ring or a 6 membered heteroaryl ring, said Cy optionally being substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl-and cyano-substituted C _1-4 Alkyl, C _3-6 Cycloalkyl or a 3 to 8 membered heterocyclic ring, said heteroaryl or heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;

in certain embodiments, cy is selected from the group consisting of benzene ring, pyridine, pyrazine, pyrimidine, pyridazine, said Cy optionally being substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl-and cyano-substituted C _1-4 Alkyl, C _3-6 Cycloalkyl or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;

in certain embodiments, cy is selected fromSaid Cy is optionally substituted with 1 to 4 groups selected from H, F, cl, br, I, cyano, CH ₂ F、CHF ₂ 、CF ₃ Substituents for methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl;

in certain embodiments, ring B is selected from a 5 to 6 membered carbocycle or a 5 to 6 membered heterocycle, said ring B optionally being substituted with 1 to 4R ^5a A substitution, said heterocycle containing from 1 to 4 heteroatoms selected from O, S, N;

in certain embodiments, ring B is selected from 5 to 6 membered heteroaryl rings, optionally substituted with 1 to 4R ^5a A substitution, said heteroaryl ring containing 1 to 4 heteroatoms selected from O, S, N;

in certain embodiments, ring B is selected from pyrazole, pyrrole, imidazole, triazole, pyridine, pyrimidine, pyrazine, pyridazine, said ring B optionally being substituted with 1 to 4R ^5a Substitution;

in certain embodiments, ring B is selected from pyrazole, imidazole, optionally substituted with 1 to 4 groups selected from H, F, cl, br, I, cyano, CH ₂ F、CHF ₂ 、CF ₃ Substituents such as methyl, ethyl, propyl, isopropyl, methoxy, and ethoxy;

in certain embodiments, R ^5a Each independently selected from H, F, cl, br, I, cyano, CH ₂ F、CHF ₂ 、CF ₃ Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy;

in certain embodiments, R ⁶ 、R ⁷ Each independently selected from H, halogen, cyano, C _1-6 Alkyl, C _3-6 Cycloalkyl, 3-to 8-membered heterocyclyl, said alkyl, cycloalkyl, heterocyclyl optionally being substituted with 1 to 4 substituents selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Alkoxy, halogen substituted C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl-and cyano-substituted C _1-6 Alkyl, C _3-6 Cycloalkyl or a 3 to 8 membered heterocyclyl group substituted with 1 to 4 heteroatoms selected from O, S, N;

in certain embodiments, R ⁶ 、R ⁷ Each independently selected from H, halogen, C _1-4 Alkyl, C _3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, said alkyl, cycloalkyl, heterocyclyl optionally being substituted with 1 to 4 substituents selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl-and cyano-substituted C _1-4 Alkyl, C _3-6 Cycloalkyl or a 3 to 8 membered heterocyclyl group substituted with 1 to 4 heteroatoms selected from O, S, N;

in certain embodiments, R ⁶ 、R ⁷ Each independently selected from H, F, cl, br, I, cyano, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, said methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, and azetidinyl optionally being substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Substituted with alkoxy;

in certain embodiments, R ⁶ 、R ⁷ Together with the carbon atoms to which they are attached form C _3-6 Cycloalkyl, 3-to 8-membered heterocycle, said cycloalkyl or heterocycle optionally being substituted with 1 to 4 substituents selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Alkoxy, halogen substituted C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl-and cyano-substituted C _1-6 Alkyl, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;

in certain embodiments, R ⁶ 、R ⁷ Together with the carbon atoms to which they are attached form C _3-6 Cycloalkyl, 3-to 8-membered heterocycle, said cycloalkyl or heterocycle optionally being substituted with 1 to 4 substituents selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl-and cyano-substituted C _1-4 Alkyl, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;

in certain embodiments, R ⁶ 、R ⁷ Together with the carbon atoms to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, optionally substituted with 1 to 4H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Substituted with alkoxy;

in certain embodiments, R ⁶ 、R ⁷ Each independently selected from H, F, cl, br, I, cyano, methyl, ethyl, cyclopropyl;

in certain embodiments, R ⁶ 、R ⁷ Together with the carbon atom to which it is attached form a cyclopropyl group; or (b)

In another aspect, the invention provides a compound of formula (III) or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein

In certain embodiments, ring a is selected from 6 and 6 membered heterocycles, optionally further substituted with 0 to 7R ^a A substitution, said heterocycle containing from 1 to 5 heteroatoms selected from O, S, N;

in certain embodiments, ring a is selected fromSelected from-> Preferably +.>

In certain embodiments, X ₁ Selected from CH, X ₂ Selected from N;

in certain embodiments, ring a is selected fromIn certain embodiments, ring A is selected from +.>

In some embodiments of the present invention, in some embodiments,selected from single bond or double bond;

in certain embodiments, A ₁ Selected from C (R) ^a ) ₂ 、NR ^a Or c=o;

in certain embodiments, A ₁ Selected from C (R) ^a ) ₂ Or c=o;

in certain embodiments, A ₁ Selected from CH ₂ Or c=o;

in certain embodiments, A ₂ Selected from C (R) ^a ) ₂ 、CR ^a O, S, N or NR ^a ；

In certain embodiments, A ₂ Selected from C (R) ^a ) ₂ 、CR ^a Or O;

in certain embodiments, A ₂ Selected from CH ₂ CH or O;

in certain embodiments, R ^a Each independently selected from H, halogen, OH, =O, cyano, NH ₂ 、C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, C _3-6 Cycloalkyl or 3-to 8-membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl optionally being substituted with 1 to 4 substituents selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Alkoxy, halogen substituted C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl-and cyano-substituted C _1-6 Alkyl, C _3-6 Cycloalkyl or a 3 to 8 membered heterocyclyl group substituted with 1 to 4 heteroatoms selected from O, S, N;

in certain embodiments, R ^a Each independently selected from H, halogen, OH, =O, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _1-4 Alkoxy or C _3-6 Cycloalkyl, said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl optionally being substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano Radical, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl-and cyano-substituted C _1-4 Alkyl, C _3-6 Cycloalkyl or a 3 to 8 membered heterocyclyl group substituted with 1 to 4 heteroatoms selected from O, S, N;

in certain embodiments, R ^a Each independently selected from H, F, cl, br, I, methyl, ethyl, isopropyl or cyclopropyl;

in certain embodiments, R ^a Each independently selected from H, F, cl, br, I, methyl or ethyl;

in certain embodiments, R ^a Each independently selected from H or methyl;

in certain embodiments, two R' s ^a Atoms directly attached thereto forming C _3-6 Carbocyclyl or 3-6 membered heterocyclyl, optionally substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Alkoxy, halogen substituted C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl-and cyano-substituted C _1-6 Alkyl, C _3-6 Cycloalkyl or a 3 to 8 membered heterocyclyl group substituted with 1 to 4 heteroatoms selected from O, S, N;

in certain embodiments, two R' s ^a Atoms directly attached thereto forming C _3-6 Carbocyclyl or 3-6 membered heterocyclyl, optionally substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl-and cyano-substituted C _1-4 Alkyl, C _3-6 Cycloalkyl or a 3 to 8 membered heterocyclyl group substituted with 1 to 4 heteroatoms selected from O, S, N;

in certain embodiments, two R' s ^a Atoms directly attached thereto forming cyclopropyl groupsCyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl;

in certain embodiments, two R' s ^a An atom directly attached thereto forms a cyclopropyl group;

in certain embodiments, R ¹ Selected from H;

in some embodimentsIn the scheme, R ² Selected from pyrrole, pyrazole, imidazole, pyrimidine optionally substituted with 1 to 4 groups selected from H, F, cl, br, I, cyano, -SO ₂ -methyl, -SO ₂ -ethyl, -SO ₂ -propyl, -SO ₂ -isopropyl, -SO ₂ -cyclopropyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, piperazine, oxetanyl, oxolanyl, morpholin, -O-azetidine, -O-azetidinyl, -O-azetidine, -O-oxepinyl, -O-oxetanyl, -O-oxolanyl, -O-oxhexyl, -OCH ₂ -phenyl, pyrrole, pyrazole, imidazole, thiazole, thiophene, furan, oxazole,Is substituted by a substituent of (2);

in certain embodiments, R ² Selected from the group consisting of

In certain embodiments, R ^2a H, halogen, OH, =o, cyano, NH, independently of one another ₂ 、NH(C _1-6 Alkyl), N (C) _1-6 Alkyl group ₂ 、-SO ₂ -C _1-6 Alkyl, -SO ₂ -C _3-6 Cycloalkyl, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, -Z-C _3-6 Cycloalkyl or-Z-3 to 8 membered heterocycle, said alkyl, cycloalkyl, alkoxy, alkylthio, heterocycle optionally being substituted with 1 to 4 substituents selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Substituted with an alkoxy substituent, said heterocycle containing 1 to 4 heteroatoms selected from O, S, N;

in certain embodiments, R ^2a H, halogen, OH, =o, cyano, NH, independently of one another ₂ 、NH(C _1-4 Alkyl), N (C) _1-4 Alkyl group ₂ 、-SO ₂ -C _1-4 Alkyl, -SO ₂ -C _3-6 Cycloalkyl, C _1-4 Alkyl, C _1-4 Alkoxy, C _1-4 Alkylthio, -Z-C _3-6 Cycloalkyl or-Z-3 to 6 membered heterocycle, said alkyl, cycloalkyl, alkoxy, alkylthio, heterocycle optionally being substituted with 1 to 4 substituents selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Substituted with an alkoxy substituent, said heterocycle containing 1 to 4 heteroatoms selected from O, S, N;

in certain embodiments, R ^2a Each independently selected from H, F, cl, br, I, cyano, or R ^2a Each independently selected from one of the following substituted or unsubstituted: -SO ₂ -methyl, -SO ₂ -ethyl, -SO ₂ -propyl, -SO ₂ -isopropyl, -SO ₂ -cyclopropyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, piperazine, oxetanyl, oxolanyl, morpholin, -O-azetidine, -O-azetidinyl, -O-azetidine, -O-oxepinyl, -O-oxetanyl, -O-oxolanyl, -O-oxhexyl, -OCH ₂ -phenyl, pyrrole, pyrazole, imidazole, thiazole, thiophene, furan, oxazole, optionally substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Substituted with alkoxy;

in certain embodiments, R ³ 、R ⁴ Each independently selected from H, halogen, OH, cyano, NH ₂ 、C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, said alkyl,Alkenyl, alkynyl, alkoxy are optionally substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Alkoxy, halogen substituted C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl-and cyano-substituted C _1-6 Alkyl, C _3-6 Cycloalkyl or a 3 to 8 membered heterocyclyl group substituted with 1 to 4 heteroatoms selected from O, S, N;

in certain embodiments, R ³ 、R ⁴ Selected from H;

in certain embodiments, cy is selected from C _3-12 Carbocycle or 4 to 12 membered heterocycle, said Cy optionally being substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Alkoxy, halogen substituted C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl-and cyano-substituted C _1-6 Alkyl, C _3-6 Cycloalkyl or a substituent of a 3 to 8 membered heterocyclic group, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;

in certain embodiments, cy is selected from C _3-6 Monocyclic cycloalkyl, C _5-11 Cycloalkyl radicals C _5-11 Spiro cycloalkyl, C _5-11 Bridged cycloalkyl, 4-to 7-membered monocyclic heterocycloalkyl, 6-to 11-membered fused-ring heterocycloalkyl, 6-to 11-membered spirocycloalkyl, 6-to 11-membered bridged-ring heterocycloalkyl, benzene ring, benzoC _4-6 Carbocycle, benzo 4 to 6 membered heterocycle, 5 to 6 membered heteroaryl ring, 8 to 10 membered bicyclic heteroaryl ring, said Cy optionally being substituted with 1 to 4 substituents selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl, cyano substitutedC _1-4 Alkyl, C _3-6 Cycloalkyl or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;

in certain embodiments, cy is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.2] octyl, bicyclo [2.2.1] heptyl, bicyclo [1.1.1] pentyl, cyclopentyl, cyclobutylspirocyclohexyl, cyclobutylspiropentyl, azetidinyl, azacyclopentyl, azacyclohexyl, azacyclobutylspirobutyl, azabutylspiropentyl, azabutylspirohexyl, azabutylspiroazetidinyl, azabutylspirocyclohexyl,

Benzene ring, thiophene, furan, pyrrole, thiazole, oxazole, pyrazole, pyrazine, pyrimidine,/->Benzothiazole, benzothiophene, benzofuran, benzoxazole, benzopyrrole, benzopyrazole, benzimidazole, indolizine, pyridopyrrole, pyridoimidazole, pyridopyrazole, pyrimidoimidazole, pyrimidoizole, pyridotriazole, said Cy optionally being substituted with 1 to 4 substituents selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl-and cyano-substituted C _1-4 Alkyl, C _3-6 Cycloalkyl or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;

in certain embodiments, cy is selected from

in certain embodiments, R ⁵ Selected from-Z-C _3-10 Carbocycle or-Z-4 to 10 membered heterocycle, said R ⁵ Optionally by 1 to 4R ^5a Substitution;

in certain embodiments, R ⁵ Selected from pyrrole, pyrazole, imidazole optionally substituted with 1 to 4 groups selected from H, F, cl, br, I, cyano, CH ₂ F、CHF ₂ 、CF ₃ A methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl substituent;

in certain embodiments, R ⁵ Selected from the group consisting of

In certain embodiments, R ^5a Each independently selected from H, halogen, OH, cyano, NH ₂ 、NHC _1-6 Alkyl, N (C) _1-6 Alkyl group ₂ 、C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkyl group,3-to 8-membered heterocycle, -CONHC _1-6 Alkyl, -CONHC _1-6 Alkoxy, -CONHC _3-6 Cycloalkyl, -CONH3 to 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, said alkyl, alkoxy, cycloalkyl, heterocycle optionally being substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、-C(＝O)NH ₂ 、-C(＝O)NHC _1-6 Alkyl, -C (=o) N (C) _1-6 Alkyl group ₂ 、C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Alkoxy, halogen substituted C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl-and cyano-substituted C _1-6 Alkyl, C _3-6 Cycloalkyl or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;

in certain embodiments, R ^5a Each independently selected from H, F, cl, br, I, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, and azetidinyl, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, and azetidinyl being optionally substituted1 to 4 are selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Substituted with alkoxy;

In certain embodiments, m is selected from 0, 1, 2, or 3;

in certain embodiments, the compound of formula (III) is selected from compounds of formula (IIIa), the groups of which are defined as the same as the compounds of formula (III).

As a first embodiment of the present invention, the compound represented by the aforementioned general formula (I) or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,

R ¹ selected from H, halogen, cyano, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, said alkyl, alkenyl, alkynyl, alkoxy optionally being substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Alkoxy, halogen substituted C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl-and cyano-substituted C _1-6 Substituted by alkyl;

R ² selected from C _6-10 Carbocycles or 5-to 10-membered heterocycles, said carbocycles or heterocycles optionally being substituted with 1 to 4R ^2a Substitution;

R ^2a each independently selected from H, halogen, OH, =O, cyano, NH ₂ 、NH(C _1-6 Alkyl), N (C) _1-6 Alkyl group ₂ 、-SO ₂ -C _1-6 Alkyl, -SO ₂ -C _3-6 Cycloalkyl, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, -Z-C _3-6 Cycloalkyl or-Z-3 to 8 membered heterocycle, said alkyl, cycloalkyl, alkoxy, alkylthio, heterocycle optionally being substituted with 1 to 4 substituents selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Substituted with an alkoxy substituent, said heterocycle containing 1 to 4 heteroatoms selected from O, S, N;

z is selected from a bond, O, S, NH, N (C) _1-4 Alkyl), C (=o) NH, NHC (=o), OCH ₂ -、-CH ₂ O-、C _1-3 An alkylene group;

X ₁ 、X ₂ each independently selected from N or CR ^x ；

R ^x Selected from H, halogen, cyano, C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyl, C _2-6 Alkynyl, said alkyl, alkoxy, alkenyl, alkynyl being optionally substituted with 1 to 4H, halogen, OH, =o, cyano, NH ₂ 、C _1-6 Alkyl, C _1-6 Alkoxy, halogen substituted C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl-and cyano-substituted C _1-6 Substituted by alkyl;

R ³ 、R ⁴ each independently selected from H, halogen, OH, cyano, NH ₂ 、C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, said alkyl, alkenyl, alkynyl, alkoxy optionally being substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Alkoxy, halogen substituted C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl-and cyano-substituted C _1-6 Alkyl, C _3-6 Cycloalkyl or a 3 to 8 membered heterocyclyl group substituted with 1 to 4 heteroatoms selected from O, S, N;

cy is selected from C _3-12 Non-aromatic carbocyclic ring, 4-to 12-membered non-aromatic heterocyclic ring, benzo C _4-6 Carbocycle, benzo 4 to 6 membered heterocycle, 5 membered heteroaryl ring, pyrimidine, pyrazine, 8 to 10 membered fused ring heteroaryl ring, said Cy optionally being substituted with 1 to 4 substituents selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Alkoxy, halogen substituted C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl-and cyano-substituted C _1-6 Alkyl, C _3-6 Substituted by cycloalkyl or by substituents of 3-to 8-membered heterocyclic groups containing 1-4 hetero atoms selected from O, S, NA seed;

R ⁵ selected from C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, -Z-C _6-10 Carbocycle or-Z-5 to 10 membered heterocycle, said R ⁵ Optionally by 1 to 4R ^5a Substitution;

R ^5a each independently selected from H, halogen, OH, cyano, NH ₂ 、NHC _1-6 Alkyl, N (C) _1-6 Alkyl group ₂ 、C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkyl, 3-to 8-membered heterocycle, -CONHC _1-6 Alkyl, -CONHC _1-6 Alkoxy, -CONHC _3-6 Cycloalkyl, -CONH3 to 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, said alkyl, alkoxy, cycloalkyl, heterocycle optionally being substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、-C(＝O)NH ₂ 、-C(＝O)NHC _1-6 Alkyl, -C (=o) N (C) _1-6 Alkyl group ₂ 、C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Alkoxy, halogen substituted C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl-and cyano-substituted C _1-6 Alkyl, C _3-6 Cycloalkyl or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;

provided that the compound is not:

a compound represented by the general formula (II) or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,

Ring A is selected fromLeft side and R ² Connecting;

X ₁ selected from N or CR ⁸ ；

R ¹ 、R ⁸ 、R ⁹ Each independently selected from H, halogen, cyano, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, said alkyl, alkenyl, alkynyl, alkoxy optionally being substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Alkoxy, halogen substituted C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl-and cyano-substituted C _1-6 Substituted by alkyl;

R ^2a each independently selected from H, halogen, OH, =O, cyano, NH ₂ 、NH(C _1-6 Alkyl), N (C) _1-6 Alkyl group ₂ 、-SO ₂ -C _1-6 Alkyl, -SO ₂ -C _3-6 Cycloalkyl, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, -W-C _3-6 Cycloalkyl or-W-3 to 8 membered heterocycle, said alkyl, cycloalkyl, alkoxy, alkylthio, heterocycle optionally being substituted with 1 to 4 substituents selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Substituted with an alkoxy substituent, said heterocycle containing 1 to 4 heteroatoms selected from O, S, N;

y is selected from O, S, S (=O), S (=O) ₂ 、S(＝O) ₂ N(R ^y )、N(R ^y )、C _1-4 Alkylene, -OC _1-3 Alkylene-, -C _1-3 Alkylene group O-, -C _1-3 Alkylene S-, -SC _1-3 Alkylene-, -C _1-3 Alkylene S (=o) -, -S (=o) C _1-3 Alkylene-, -C _1-3 Alkylene group S (=o) ₂ -、-S(＝O) ₂ C _1-3 Alkylene-, -N (R) ^y )C _1-3 Alkylene-, -C _1-3 Alkylene N (R) ^y ) -said alkylene group optionally being 1 to 4 groups selected from H, halogen, = O, OH, cyano, C _1-6 Alkyl, halogen substituted C _1-6 Alkyl group、C _1-6 Alkoxy, C _3-6 Substituted cycloalkyl;

R ^y each independently selected from H, C _1-6 Alkyl or C _3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being substituted with 1 to 4 substituents selected from H, halogen, = O, CF ₃ OH, cyano, NH ₂ 、C _1-6 Alkyl or C _1-6 Substituted with alkoxy;

w are each independently selected from the group consisting of bond, O, S, C (=o), S (=o) ₂ 、NH、N(C _1-4 Alkyl), C (=O) NH,

NHC(＝O)、-OCH ₂ -、-CH ₂ O-、C _1-3 An alkylene group;

cy is selected from benzene ring or 6 membered heteroaryl ring, said Cy is optionally substituted with 1 to 4 groups selected from H, halogen, OH, =O, cyano, NH ₂ 、C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Alkoxy, halogen substituted C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl-and cyano-substituted C _1-6 Alkyl, C _3-6 Cycloalkyl or a 3 to 8 membered heterocyclyl, said heteroaryl or heterocycle containing 1 to 4 heteroatoms selected from O, S, N;

ring B is selected from a 5 to 6 membered carbocycle or a 5 to 6 membered heterocycle, said ring B optionally being substituted with 1 to 4R ^5a A substitution, said heterocycle containing from 1 to 4 heteroatoms selected from O, S, N;

R ^5a each independently selected from H, halogen, OH, cyano, NH ₂ 、NHC _1-6 Alkyl, N (C) _1-6 Alkyl group ₂ 、C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkyl, 3-to 8-membered heterocycle, -CONHC _1-6 Alkyl, -CONHC _1-6 Alkoxy, -CONHC _3-6 Cycloalkyl, -CONH-3 to 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, said alkyl, alkoxy, cycloalkyl, heterocycle optionally being substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、-C(＝O)NH ₂ 、-C(＝O)NHC _1-6 Alkyl, -C (=o) N (C) _1-6 Alkyl group ₂ 、C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Alkoxy, halogen substituted C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl-and cyano-substituted C _1-6 Alkyl, C _3-6 Cycloalkyl or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;

R ⁶ 、R ⁷ Each independently selected from H, halogen, cyano, C _1-6 Alkyl, C _3-6 Cycloalkyl, 3-to 8-membered heterocyclyl, said alkyl, cycloalkyl, heterocyclyl optionally being substituted with 1 to 4 substituents selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Alkoxy, halogen substituted C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl-and cyano-substituted C _1-6 Alkyl, C _3-6 Cycloalkyl or a 3 to 8 membered heterocyclyl group substituted with 1 to 4 heteroatoms selected from O, S, N;

alternatively, R ⁶ 、R ⁷ Together with the carbon atoms to which they are attached form C _3-6 Cycloalkyl, 3-to 8-membered heterocycle, said cycloalkyl or heterocycle optionally being substituted with 1 to 4 substituents selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Alkoxy, halogen substituted C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl group,Cyano-substituted C _1-6 Alkyl, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N; or (b)

A compound represented by the aforementioned general formula (III) or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,

ring A is selected from

Selected from single bond or double bond;

A ₁ selected from C (R) ^a ) ₂ 、NR ^a Or c=o;

A ₂ selected from C (R) ^a ) ₂ 、CR ^a O, S, N or NR ^a ；

R ^a Each independently selected from H, halogen, OH, =O, cyano, NH ₂ 、C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, C _3-6 Cycloalkyl or 3-to 8-membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl optionally being substituted with 1 to 4 substituents selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Alkoxy, halogen substituted C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl-and cyano-substituted C _1-6 Alkyl, C _3-6 Cycloalkyl or a 3 to 8 membered heterocyclyl group substituted with 1 to 4 heteroatoms selected from O, S, N;

alternatively, two R ^a Atoms directly attached thereto forming C _3-6 Carbocyclyl or 3-6 membered heterocyclyl, optionally substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Alkoxy, halogen substituted C _1-6 Alkyl, hydroxyC substituted by radicals _1-6 Alkyl-and cyano-substituted C _1-6 Alkyl, C _3-6 Cycloalkyl or a 3 to 8 membered heterocyclyl group substituted with 1 to 4 heteroatoms selected from O, S, N;

R ³ 、R ⁴ each independently selected from H, halogen, OH, cyano, NH ₂ 、C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, said alkyl, alkenyl, alkynyl, alkoxy optionally being substituted with 1 to 4 groups selected from H, haloPlain, OH, =o, cyano, NH ₂ 、C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Alkoxy, halogen substituted C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl-and cyano-substituted C _1-6 Alkyl, C _3-6 Cycloalkyl or a 3 to 8 membered heterocyclyl group substituted with 1 to 4 heteroatoms selected from O, S, N;

cy is selected from C _3-12 Carbocycle or 4 to 12 membered heterocycle, said Cy optionally being substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Alkoxy, halogen substituted C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl-and cyano-substituted C _1-6 Alkyl, C _3-6 Cycloalkyl or a substituent of a 3 to 8 membered heterocyclic group, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;

R ⁵ selected from-Z-C _3-10 Carbocycle or-Z-4 to 10 membered heterocycle, said R ⁵ Optionally by 1 to 4R ^5a Substitution;

R ^5a each independently selected from H, halogen, OH, cyano, NH ₂ 、NHC _1-6 Alkyl, N (C) _1-6 Alkyl group ₂ 、C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkyl, 3-to 8-membered heterocycle, -CONHC _1-6 Alkyl, -CONHC _1-6 Alkoxy, -CONHC _3-6 Cycloalkyl, -CONH3 to 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, said alkyl, alkoxy, cycloalkyl, heterocycle optionally being substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、-C(＝O)NH ₂ 、-C(＝O)NHC _1-6 Alkyl, -C (=o) N (C) _1-6 Alkyl group ₂ 、C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Alkoxy, halogen substituted C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl-and cyano-substituted C _1-6 Alkyl, C _3-6 Substituted by cycloalkyl or by substituents of 3-to 8-membered heterocyclic rings containing 1-4 optional groupsA heteroatom from O, S, N;

m is selected from 0, 1, 2 or 3.

As a second embodiment of the present invention, the compound represented by the aforementioned general formula (I) or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,

R ¹ selected from H, halogen, cyano, C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _1-4 Alkoxy, said alkyl, alkenyl, alkynyl, alkoxy optionally being substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl-and cyano-substituted C _1-4 Substituted by alkyl;

R ^2a each independently selected from H, halogen, OH, =O, cyano, NH ₂ 、NH(C _1-4 Alkyl), N (C) _1-4 Alkyl group ₂ 、-SO ₂ -C _1-4 Alkyl, -SO ₂ -C _3-6 Cycloalkyl, C _1-4 Alkyl, C _1-4 Alkoxy, C _1-4 Alkylthio, -Z-C _3-6 Cycloalkyl or-Z-3 to 6 membered heterocycle, said alkyl, cycloalkyl, alkoxy, alkylthio, heterocycle optionally being substituted with 1 to 4 substituents selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Substituted with an alkoxy substituent, said heterocycle containing 1 to 4 heteroatoms selected from O, S, N;

R ^x Selected from H, halogen, cyano, C _1-4 Alkyl, C _1-4 Alkoxy, C _2-4 Alkenyl, C _2-4 Alkynyl, said alkyl, alkoxy, alkenyl, alkynyl being optionally substituted with 1 to 4H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl-and cyano-substituted C _1-4 Substituted by alkyl;

R ³ 、R ⁴ each independently selected from H, halogen, OH, cyano, C _1-4 An alkyl group;

cy is selected from C _4-6 Monocyclic cycloalkyl, C _5-11 Cycloalkyl radicals C _5-11 Spiro cycloalkyl, C _5-11 Bridged cycloalkyl, 4-to 7-membered monocyclic heterocycloalkyl, 6-to 11-membered fused-ring heterocycloalkyl, 6-to 11-membered spirocycloalkyl, 6-to 11-membered bridged-ring heterocycloalkyl, benzoC _4-6 Carbocycle, benzo 4 to 6 membered heterocycle, 5 membered heteroaryl ring, pyrimidine, pyrazine, 8 to 10 membered fused ring heteroaryl ring, said Cy optionally being substituted with 1 to 4 substituents selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl-and cyano-substituted C _1-4 Alkyl, C _3-6 Cycloalkyl or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;

R ⁵ selected from-Z-C _6-10 Carbocycle or-Z-5 to 10 membered heterocycle, said R ⁵ Optionally by 1 to 4R ^5a Substitution;

R ^5a each independently selected from H, halogen, OH, cyano, NH ₂ 、C _1-4 Alkyl, C _1-4 Alkoxy, C _3-6 Cycloalkyl or a 3-to 6-membered heterocycle, said alkyl, alkoxy, cycloalkyl, heterocycle optionally being substituted with 1 to 4 substituents selected from H, halogen, OH, =o, cyano, NH ₂ 、-C(＝O)NH ₂ 、-C(＝O)NHC _1-4 Alkyl, -C (=o) N (C) _1-4 Alkyl group ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl-and cyano-substituted C _1-4 Alkyl, C _3-6 Cycloalkyl or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;

the definition of the rest substituents is the same as that of the first scheme of the invention; or (b)

R ^y each independently selected from H, C _1-4 Alkyl or C _3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being substituted with 1 to 4 substituents selected from H, halogen, = O, CF ₃ OH, cyano, NH ₂ 、C _1-4 Alkyl or C _1-4 Substituted with alkoxy;

R ¹ 、R ⁸ 、R ⁹ each independently selected from H, halogen, cyano, C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _1-4 Alkoxy, said alkyl, alkenyl, alkynyl, alkoxy optionally being substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl-and cyano-substituted C _1-4 Substituted by alkyl;

R ^2a each independently selected from H, halogen, OH, =O, cyano, NH ₂ 、NH(C _1-4 Alkyl), N (C) _1-4 Alkyl group ₂ 、-SO ₂ -C _1-4 Alkyl, -SO ₂ -C _3-6 Cycloalkyl, C _1-4 Alkyl, C _1-4 Alkoxy, C _1-4 Alkylthio, -W-C _3-6 Cycloalkyl or-W-3 to 6 membered heterocycle, said alkyl, cycloalkyl, alkoxy, alkylthio, heterocycle optionally being substituted with 1 to 4 substituents selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Substituted with an alkoxy substituent, said heterocycle containing 1 to 4 heteroatoms selected from O, S, N;

cy is selected from benzene ring or 6 membered heteroaryl ring, said Cy is optionally substituted with 1 to 4 groups selected from H, halogen, OH, =O, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl-and cyano-substituted C _1-4 Alkyl, C _3-6 Cycloalkyl or a 3 to 8 membered heterocyclic ring, said heteroaryl or heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;

ring B is selected from 5-to 6-membered heteroaromatic rings, said ring B optionally being substituted with 1 to 4R ^5a A substitution, said heteroaryl ring containing 1 to 4 heteroatoms selected from O, S, N;

R ⁶ 、R ⁷ each independently selected from H, halogen, C _1-4 Alkyl, C _3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, said alkyl, cycloalkyl, heterocyclyl optionally being substituted with 1 to 4 substituents selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl-and cyano-substituted C _1-4 Alkyl, C _3-6 Cycloalkyl or a 3 to 8 membered heterocyclyl group substituted with 1 to 4 heteroatoms selected from O, S, N;

alternatively, R ⁶ 、R ⁷ Together with the carbon atoms to which they are attached form C _3-6 Cycloalkyl, 3-to 8-membered heterocycle, said cycloalkyl or heterocycle optionally being substituted with 1 to 4 substituents selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl-and cyano-substituted C _1-4 Alkyl, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;

the definition of the rest substituents is the same as in the first embodiment of the invention; or (b)

A compound represented by the following general formula (IIIa) or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,

selected from single bond or double bond;

A ₁ selected from C (R) ^a ) ₂ 、NR ^a Or c=o;

A ₂ selected from C (R) ^a ) ₂ 、CR ^a O, S, N or NR ^a ；

R ^a Each independently selected from H, halogen, OH, =O, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _1-4 Alkoxy or C _3-6 Cycloalkyl, said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl optionally being substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl-and cyano-substituted C _1-4 Alkyl, C _3-6 Cycloalkyl or a 3 to 8 membered heterocyclyl group substituted with 1 to 4 heteroatoms selected from O, S, N;

alternatively, two R ^a Atoms directly attached thereto forming C _3-6 Carbocyclyl or 3-6 membered heterocyclyl, optionally substituted with 1 to 4 substituents selected from H, halogen Plain, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl-and cyano-substituted C _1-4 Alkyl, C _3-6 Cycloalkyl or a 3 to 8 membered heterocyclyl group substituted with 1 to 4 heteroatoms selected from O, S, N;

cy is selected from C _3-6 Monocyclic cycloalkyl, C _5-11 Cycloalkyl radicals C _5-11 Spiro cycloalkyl, C _5-11 Bridged cycloalkyl, 4-to 7-membered monocyclic heterocycloalkyl, 6-to 11-membered fused-ring heterocycloalkyl, 6-to 11-membered spirocycloalkyl, 6-to 11-membered bridged-ring heterocycloalkyl, benzene ring, benzoC _4-6 Carbocycles, benzo 4 to 6A membered heterocycle, a 5 to 6 membered heteroaryl ring, a 8 to 10 membered fused heteroaryl ring, said Cy optionally being substituted with 1 to 4 substituents selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl-and cyano-substituted C _1-4 Alkyl, C _3-6 Cycloalkyl or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;

m is selected from 0, 1, 2 or 3;

the remaining substituents are as defined in scheme one of the present invention.

As a third embodiment of the present invention, the compound represented by the aforementioned general formula (I) or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,

selected from->

R ¹ Selected from H, F, cl, br, I, cyano, methyl or ethyl;

R ^x each independently selected from H, F, cl, br, I, cyano, methyl or ethyl;

R ² selected from phenyl, pyridine, pyrimidine, pyrrole, pyrazole, imidazole, furan, thiophene, thiazole, oxazole, said phenyl, pyridine, pyrimidine, pyrrole, pyrazole, imidazole, furan, thiophene, thiazole, oxazole optionally being selected from 1 to 4 of R ^2a Substitution;

R ^2a each independently selected from H, F, cl, br, I, cyano, or R ^2a Each independently selected from one of the following substituted or unsubstituted: -SO ₂ -methyl, -SO ₂ -ethyl, -SO ₂ -propyl, -SO ₂ -isopropyl, -SO ₂ -cyclopropyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, piperazine, oxetanyl, oxolanyl, morpholin, -O-azetidine, -O-azetidinyl, -O-azetidine, -O-oxepinyl, -O-oxetanyl, -O-oxolanyl, -O-oxhexyl, -OCH ₂ -phenyl, optionally substituted by 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Substituted with alkoxy;

R ³ 、R ⁴ each independently selected from H, F, cl, br, I, methyl, ethyl;

cy is selected from cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.2]Octyl and bicyclo [1.1.1]Pentyls, cyclopentylcyclopentyl, cyclobutylspirocyclohexyl, cyclobutylspirocyclopentyl, azetidinyl spirocyclobutyl, azetidinspirocyclopentyl, azetidinspirocyclohexyl, azetidinyl spirocyclohexyl, azetidinyl spiroazetidinyl azetidinyl, azetidinyl spiroazetidinylA hexyl radical,

Thiophene, furan, pyrrole, thiazole, oxazole, pyrazole, pyrazine, pyrimidine,/->Benzothiazole, benzothiophene, benzofuran, benzoxazole, benzopyrrole, benzopyrazole, benzimidazole, indolizine, pyridopyrrole, pyridoimidazole, pyridopyrazole, pyrimidoimidazole, pyrimidoizole, 2-pyridone, pyridotriazole, said Cy optionally being substituted with 1 to 4 substituents selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl-and cyano-substituted C _1-4 Alkyl, C _3-6 Cycloalkyl or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;

R ⁵ selected from benzene ring, pyrazole, pyrrole, imidazole, triazole, pyridine, pyrimidine, pyrazine and pyridazine, wherein R is ⁵ Optionally by 1 to 4R ^5a Substitution;

R ^5a each independently selected from H, F, cl, br, I, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl optionally being substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Substituted with alkoxy;

the definition of the rest substituents is the same as that of the scheme one or two of the invention; or (b)

R ¹ 、R ⁸ 、R ⁹ Each independently selected from H, F, cl, br, I, cyano, methyl or ethyl;

R ² selected from phenyl, pyridine, pyrimidine, pyrrole, pyrazole, imidazole, furan, thiophene, thiazole, oxazole, said phenyl, pyridine, pyrimidine, pyrrole, pyrazole, imidazole, furan, thiophene, thiazole, oxazole optionally having 1 to 4R' s ^2a Substitution;

R ^2a each independently selected from H, F, cl, br, I, cyano, or R ^2a Each independently selected from one of the following substituted or unsubstituted: -SO ₂ -methyl, -SO ₂ -ethyl, -SO ₂ -propyl, -SO ₂ -isopropyl, -SO ₂ -cyclopropyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, piperazine, oxetanyl, oxolanyl, morpholin, -O-azetidine, -O-azetidinyl, -O-azetidine, -O-oxepinyl, -O-oxetanyl, -O-oxolanyl, -O-oxhexyl, -OCH ₂ -phenyl, pyrrole, pyrazole, imidazole, thiazole, thiophene, furan, oxazole, optionally substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Substituted with alkoxy;

R ^y each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylHexyl is optionally substituted with 1 to 4 groups selected from H, halogen, = O, CF ₃ OH, cyano, NH ₂ 、C _1-4 Alkyl or C _1-4 Substituted with alkoxy;

R ³ 、R ⁴ each independently selected from H, F, cl, br, I, methyl, ethyl;

cy is selected from benzene ring, pyridine, pyrazine, pyrimidine, pyridazine, said Cy optionally being selected from H, halogen, OH, =O, cyano, NH by 1 to 4 ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl-and cyano-substituted C _1-4 Alkyl, C _3-6 Cycloalkyl or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;

ring B is selected from pyrazole, pyrrole, imidazole, triazole, pyridine, pyrimidine, pyrazine, pyridazine, said ring B optionally being substituted with 1 to 4R ^5a Substitution;

R ⁶ 、R ⁷ each independently selected from H, F, cl, br, I, cyano, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, said methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, and azetidinyl optionally being substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl group,C _1-4 Substituted with alkoxy;

alternatively, R ⁶ 、R ⁷ Together with the carbon atoms to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, optionally substituted with 1 to 4H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Substituted with alkoxy;

the definition of the rest substituents is the same as that of any one of the first and second schemes; or (b)

A compound represented by the general formula (IIIa) or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,

R ^a each independently selected from H, F, cl, br, I, methyl, ethyl, isopropyl or cyclopropyl;

Alternatively, two R ^a The atoms directly attached thereto form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl;

R ¹ selected from H, F, cl, br, I, cyano, methyl or ethyl;

R ^2a each independently selected from H, F, cl, br, I, cyano, or R ^2a Each independently selected from one of the following substituted or unsubstituted: -SO ₂ -methyl, -SO ₂ -ethyl, -SO ₂ -propyl, -SO ₂ -isopropyl, -SO ₂ -cyclopropyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, piperazine, oxetanyl, oxa-nylCyclohexyl, morpholine, -O-azetidinyl, -O-oxetanyl, -O-oxolanyl, -O-oxetanyl, -OCH ₂ -phenyl, pyrrole, pyrazole, imidazole, thiazole, thiophene, furan, oxazole, optionally substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Substituted with alkoxy;

R ³ 、R ⁴ each independently selected from H, F, cl, br, I, methyl, ethyl;

cy is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.2]Octyl and bicyclo [2.2.1]Heptyl and bicyclo [1.1.1]Pentyl, cyclopentyl-cyclopentyl, cyclobutylspirocyclohexyl, cyclobutylspirocyclopentyl, azetidinyl, azetidinspirocyclobutyl, azetidinspirocyclopentyl, azetidinspirocyclohexyl, azetidinspiroazetidinyl, azetidinyl spiroazetidinyl, azetidinspiropentyl, azetidinspiroazetidinyl,

benzene ring, thiophene, furan, pyrrole, thiazole, oxazole, pyrazole, pyrazine, pyrimidine,/-> Benzothiazole, benzothiophene, benzofuran, benzoxazole, benzopyrrole, benzopyrazole, benzimidazole, indolizine, pyridopyrrole, pyridoimidazole, pyridopyrazole, pyrimidoimidazole, pyridopyrazoleTriazole, said Cy optionally being selected from 1 to 4 of H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl-and cyano-substituted C _1-4 Alkyl, C _3-6 Cycloalkyl or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;

the remaining substituents are as defined in one or both of the schemes of the present invention.

As a fourth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, is selected from the compounds represented by the general formula (Ia),

R ² Selected from pyrrole, pyrazole, imidazole, pyrimidine optionally substituted with 1 to 4 groups selected from H, F, cl, br, I, cyano, -SO ₂ -methyl, -SO ₂ -ethyl, -SO ₂ -propyl, -SO ₂ -isopropyl, -SO ₂ -cyclopropyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, piperazine, oxetanyl, oxolanyl, morpholin, -O-azetidine, -O-azetidinyl, -O-azetidine, -O-oxepinyl, -O-oxetanyl, -O-oxolanyl, -O-oxhexyl, -OCH ₂ -phenyl substituted with a substituent;

cy is selected from

or Cy is selected from

R ⁵ selected from pyrrole, pyrazole, imidazole optionally substituted with 1 to 4 groups selected from H, F, cl, br, I, cyano, CH ₂ F、CHF ₂ 、CF ₃ Methyl, ethyl, propyl, isopropyl, methoxy, ethylSubstituted by substituents of oxo;

the definition of the rest substituents is the same as that of the first, second or third embodiment; or (b)

R ¹ 、R ⁹ selected from H;

R ⁸ selected from H, F, cl;

R ² selected from pyrrole, pyrazole, imidazole, pyrimidine optionally substituted with 1 to 4 groups selected from F, cl, br, I, cyano, -SO ₂ -methyl, -SO ₂ -ethyl, -SO ₂ -propyl, -SO ₂ -isopropyl, -SO ₂ -cyclopropyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, piperazine, oxetanyl, oxolanyl, morpholin, -O-azetidine, -O-azetidinyl, -O-azetidine, -O-oxepinyl, -O-oxetanyl, -O-oxolanyl, -O-oxhexyl, -OCH ₂ -phenyl, pyrrole, pyrazole, imidazole, thiazole, thiophene, furan, oxazole, Is substituted by a substituent of (2);

y is selected from-OCH ₂ -、-OCH ₂ CH ₂ -、-CH ₂ CH ₂ -、-CH ₂ CH ₂ CH ₂ -、-NHCH ₂ -、-NHCH ₂ CH ₂ -、-SCH ₂ CH ₂ -、-NHC(＝O)-、-NHC(＝O)CH ₂ -、-N(CH ₃ )C(＝O)CH ₂ -, said-CH ₂ -optionally 1 to 2 are selected from H, F, cl, br, I, = O, OH, cyano, CH ₂ F、CHF ₂ 、CF ₃ Substituents such as methyl, ethyl, propyl, isopropyl, methoxy, and ethoxy;

cy is selected fromSaid Cy is optionally substituted with 1 to 4 groups selected from H, F, cl, br, I, cyano, CH ₂ F、CHF ₂ 、CF ₃ Substituents for methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl;

ring B is selected from pyrazole, imidazole, optionally substituted with 1 to 4 groups selected from H, F, cl, br, I, cyano, CH ₂ F、CHF ₂ 、CF ₃ Substituents such as methyl, ethyl, propyl, isopropyl, methoxy, and ethoxy;

the definition of the rest substituents is the same as that of any one of the first, second and third schemes; or (b)

A ₁ selected from C (R) ^a ) ₂ Or c=o;

A ₂ selected from C (R) ^a ) ₂ 、CR ^a Or O;

R ¹ selected from H;

R ² selected from pyrrole, pyrazole, imidazole, pyrimidine optionally substituted with 1 to 4 groups selected from H, F, cl, br, I, cyano, -SO ₂ -methyl, -SO ₂ -ethyl, -SO ₂ -propyl, -SO ₂ -isopropyl, -SO ₂ -cyclopropyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, azetidinyl, azetidine, piperazine, oxetanyl, oxolanyl, morpholin, -O-azetidine, -O-azetidinyl, -O-azetidine, -O-oxetanylButyl, -O-oxo-pentyl, -O-oxo-hexyl, -OCH ₂ -phenyl, pyrrole, pyrazole, imidazole, thiazole, thiophene, furan, oxazole, Is substituted by a substituent of (2);

cy is selected from

R ⁵ selected from pyrrole, pyrazole, imidazole optionally substituted with 1 to 4 groups selected from H, F, cl, br, I, cyano, CH ₂ F、CHF ₂ 、CF ₃ A methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl substituent;

the remaining substituents are as defined in scheme one, two or three of the present invention.

As a fifth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, is selected from the compounds represented by the general formula (Ia),

R ² selected from the group consisting of

R ⁵ Selected from the group consisting of

The definition of the rest substituents is the same as that of the first, second, third or fourth embodiment; or (b)

ring A is selected from Left side and R ² Connecting;

R ² selected from the group consisting of

Selected from->

The definition of the rest substituents is the same as any one of the first, second, third or fourth embodiments of the invention; or (b)

selected from->

R ² Selected from the group consisting of

R ³ 、R ⁴ Each independently selected from H;

R ⁵ selected from the group consisting of

The remaining substituents are as defined in scheme one, two, three or four of the present invention.

The present invention relates to a compound or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from one of the following structures:

/>

The invention relates to a pharmaceutical composition comprising a compound of the invention or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable carrier.

The invention relates to an application of a compound or stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic thereof in preparing medicaments for treating diseases related to activity or expression quantity of USP1, preferably in preparing medicaments for treating tumor diseases.

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

The present invention also provides a method for treating a disease in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of the invention or a stereoisomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, or a pharmaceutical composition. In some embodiments, the mammal of the present invention comprises a human.

As used herein, an "effective amount" or "therapeutically effective amount" refers to the administration of a sufficient amount of a compound disclosed herein that will alleviate one or more symptoms of the disease or disorder being treated (e.g., USP1 activity or an expression level related disease 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 clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts include, but are not limited to, 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, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg, 90-500mg, 100-500mg, 125-500mg, 100-500mg 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, 10-300mg, 20-300mg, 25-300mg, 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-300mg, 80-300mg, 90-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250-300mg, 1-200mg, 1-300mg, 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 includes, but is not limited to, 1-1500mg, 1-1400mg, 1-1200mg, 1-600mg, 20-400mg, 25-200mg, 1mg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 125mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 300mg, 400mg, 480mg, 500mg of a compound of the invention or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof.

A method for treating a disease in a mammal, said method comprising administering to a subject a therapeutically effective amount of a compound of the invention, or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, preferably 1-1500mg, said disease being preferably a tumor.

A method for treating a disease in a mammal comprising administering a pharmaceutical compound of the invention, or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, to a subject 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 includes, but is not limited to, 10-1500 mg/day, 10-800 mg/day, 25-800 mg/day, 50-800 mg/day, 100-800 mg/day, 200-800 mg/day, 25-400 mg/day, 50-400 mg/day, 100-400 mg/day, 200-400 mg/day, and 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.

The present invention relates to a kit comprising a single or multiple dose form of a composition comprising a compound of the invention or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, in an amount equivalent to the amount of the compound of the invention or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof.

The amount of a compound of the invention or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof in the present invention is in each case converted in the form of the free base.

The synthesis method comprises the following steps:

R ^a1 selected from halogen or OH; r is R ^a2 Selected from halogen, preferably from Br, cl; r is R ^a3 Selected from amino protecting groups or H;

the definition of the rest groups is consistent with the specification;

the compound shown in the general formula (Ia-1) and the compound shown in the general formula (Ia-2) are subjected to substitution reaction to obtain the compound shown in the general formula (Ia-3), or the amino protecting group of the compound shown in the general formula (Ia-2) is firstly removed and then the compound shown in the general formula (Ia-1) is subjected to substitution reaction to obtain the compound shown in the general formula (Ia-3);

the compound of the general formula (Ia-3) is subjected to a coupling reaction to obtain the compound of the general formula (I).

The synthesis method II comprises the following steps:

R ^a1 、R ^a2 、R ^a3 the definition of the groups is consistent with the synthesis method;

the definition of the rest groups is consistent with the specification;

the compound of the general formula (Ia-2) is subjected to a coupling reaction to obtain a compound of the general formula (Ib-1);

the compound of the general formula (Ib-1) and the compound of the general formula (Ia-1) are subjected to substitution reaction to obtain the compound of the general formula (I), or the amino protecting group of the compound of the general formula (Ib-1) is firstly removed and then subjected to substitution reaction with the compound of the general formula (Ia-1) to obtain the compound of the general formula (I).

And a synthesis method III:

the definition of the rest groups is consistent with the specification;

the compound of the general formula (IIa-2) is subjected to a coupling reaction to obtain a compound of the general formula (IIa-3);

the compound of the general formula (IIa-3) and the compound of the general formula (IIa-1) are subjected to substitution reaction to obtain the compound of the general formula (II), or the amino protecting group of the compound of the general formula (IIa-3) is removed firstly and then the compound of the general formula (IIa-1) is subjected to substitution reaction to obtain the compound of the general formula (II).

When the compound of formula (III) is selected from the compounds of formula (IIIa), it can be obtained by the following synthetic method,

and a synthesis method:

The definition of the rest groups is consistent with the specification;

the compound of the general formula (IIIa-1) and the compound of the general formula (IIIa-2) are subjected to substitution reaction to obtain the compound of the general formula (IIIa-3), or an amino protecting group of the compound of the general formula (IIIa-2) is firstly removed and then the compound of the general formula (IIIa-1) is subjected to substitution reaction to obtain the compound of the general formula (IIIa-3);

the compound of formula (IIIa-3) is coupled to the compound of formula (IIIa).

Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

The carbon, hydrogen, oxygen, sulfur, nitrogen or F, cl, br, I referred to in the groups and compounds of the invention each include their isotopic condition, and the carbon, hydrogen, oxygen, sulfur or nitrogen referred to in the groups and compounds of the invention are optionally replaced by one or more of their corresponding isotopes, where the isotopes of carbon include ¹² C、 ¹³ C and C ¹⁴ Isotopes of C, hydrogen include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as super heavy hydrogen), isotopes of oxygen include ¹⁶ O、 ¹⁷ O and ¹⁸ isotopes of O, sulfur include ³² S、 ³³ S、 ³⁴ S and ³⁶ isotopes of S, nitrogen include ¹⁴ N and ¹⁵ isotopes of N, fluorine include ¹⁷ F and F ¹⁹ Isotopes of F, chlorine include ³⁵ Cl and Cl ³⁷ Isotopes of Cl, bromine include ⁷⁹ Br and ⁸¹ Br。

"halogen" means F, cl, br or I.

"halo substituted" means F, cl, br or I substituted, including but not limited to 1 to 10 substituents selected from F, cl, br or I, 1 to 6 substituents selected from F, cl, br or I, and 1 to 4 substituents selected from F, cl, br or I. "halo substituted" is simply referred to as "halo".

"alkyl" 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, 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 isomers thereof. Alkyl groups appearing herein are defined in accordance with the present definition. The alkyl group may be monovalent, divalent, trivalent, or tetravalent.

"alkylene" means a substituted or unsubstituted straight and branched chain divalent saturated hydrocarbon radical, including- (CH) ₂ ) _v - (v is an integer of 1 to 10), alkylene examples include, but are not limited to, methylene, ethylene, propylene, butylene and the like.

"cycloalkyl" 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, cycloheptyl, and the like. Cycloalkyl groups as herein presented are defined as described above. Cycloalkyl groups may be monovalent, divalent, trivalent, or tetravalent.

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

"alkenyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbon groups having at least 1, typically 1, 2 or 3 carbon-carbon double bonds, with the backbone including, but not limited to, 2 to 10, 2 to 6 or 2 to 4 carbon atoms, and alkenyl examples include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-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, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1, 3-pentadienyl, 1, 4-pentadienyl and the like. Alkenyl groups appear herein, the definition of which is consistent with the definition. Alkenyl groups may be monovalent, divalent, trivalent, or tetravalent.

"alkynyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbyl radicals having at least 1, typically 1, 2 or 3 carbon-carbon triple bonds, the backbone comprising 2 to 10 carbon atoms, including but not limited to 2 to 6 carbon atoms in the backbone, and alkynyl examples include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-methyl-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, 1-4-decynyl, and the like. Alkynyl groups may be monovalent, divalent, trivalent or tetravalent.

"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-pentoxy, n-hexoxy, cyclopropoxy and cyclobutoxy.

"carbocyclyl" 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 ring, a 4 to 12 membered bicyclic ring, or a 10 to 15 membered tricyclic ring system, to which carbocyclyl may be attached,the aromatic or non-aromatic ring is optionally a single ring, bridged ring or spiro ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring, "carbocyclyl" or "carbocycle" may be monovalent, divalent, trivalent, or tetravalent.

"heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring that may be a 3-to 8-membered monocyclic, 4-to 12-membered bicyclic, or 10-to 15-membered tricyclic ring system and that contains 1 or more (including but not limited to 2, 3, 4, or 5) heteroatoms selected from N, O or S, and N, S optionally substituted in the ring of the heterocyclyl can be oxidized to various oxidation states. The heterocyclic group may be attached to a heteroatom or carbon atom, the heterocyclic group may be attached to an aromatic or non-aromatic ring, the heterocyclic group may be attached to a bridged or spiro ring, non-limiting examples include an oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1, 3-dioxolanyl, 1, 4-dioxolanyl, 1, 3-dioxanyl, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1, 3-dithianyl, dihydrofuranyl, dihydropyranyl, dithianyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridinyl, benzodihydropyranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzothiazolyl, benzopyrimidinyl, piperazinyl, benzopyrimidinyl, benzoxazolyl, piperazinyl, benzopyrimidinyl, and the like Azabicyclo [3.2.1]Octyl and azabicyclo [5.2.0]Nonylalkyl oxatricyclo [5.3.1.1 ]]Dodecyl, azaadamantyl, oxaspiro [3.3 ]]Heptyl radical,

"heterocyclyl" or "heterocycle" may be monovalent, divalent, trivalent, or tetravalent.

"Spiro" or "spirocyclic group" refers to a polycyclic group having one atom (referred to as a spiro atom) shared between substituted or unsubstituted monocyclic rings, the number of ring atoms in the spirocyclic ring system including, but not limited to, 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more of the rings may contain 0 or more (including, but not limited to, 1, 2, 3, or 4) double bonds, and optionally may contain 0 to 5 members selected from N, O or S (=O) _n Is a heteroatom of (2).

"Spiro" or "spirocyclic group" may be monovalent, divalent, trivalent, or tetravalent.

"fused ring" or "fused ring group" refers to a polycyclic group wherein each ring in the system shares an adjacent pair of atoms with the other rings in the system, wherein one or more of the rings may contain 0 or more (including but not limited to 1, 2, 3, or 4) double bonds, and may be substituted or unsubstituted, and each ring in the ring system may contain 0 to 5 heteroatoms or heteroatom-containing groups (including but not limited to those selected from N, S (=o) _n Or O, n is 0, 1 or 2). The number of ring atoms in the fused ring system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, 5 to 10. Non-limiting examples include:

"fused" or "fused-ring" groups may be monovalent, divalent, trivalent, or tetravalent.

"bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms not directly attached, which may contain 0 or more double bonds, and any ring in the ring system may contain 0 to 5 groups selected from heteroatoms 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 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include

Cubane and adamantane. "bridged ring" or "bridged ring radical" can be monovalent, divalent, trivalent, or tetravalent.

"carbospiro", "spirocarbocyclyl" or "carbospirocyclyl" refers to a "spiro" ring system consisting of only carbon atoms. "carbospiro", "spirocarbocyclyl" or "carbospirocyclyl" as referred to herein are defined in accordance with spirocyclic rings.

"carbon-fused", "fused carbocyclyl" or "carbon-fused cyclic" refers to a "fused ring" in which the ring system has only carbon atoms. "carbo-cyclic", "carbocyclyl" or "carbo-cyclic" as used herein is defined as consistent with a carbo-cyclic group.

"carbon bridged ring", "bridged carbocyclyl" or "carbon bridged cyclyl" refers to a "bridged ring" in which the ring system has only carbon atoms. "carbobridged ring", "bridged ring carbocyclyl", "bridged carbocyclyl" or "carbobridged ring radical" as used herein is defined as being identical to a bridged ring.

"heteromonocyclic", "monocyclic heterocyclyl" or "heteromonocyclic" refers to a "heterocyclyl" or "heterocycle" of a monocyclic system, and the heterocyclic groups, "monocyclic heterocyclyl" or "heteromonocyclic" appearing herein are defined as identical to heterocycles.

"heterobicyclic", "heterobicyclic radical", "fused-to-heterocyclic radical" or "heterobicyclic radical" refers to a "fused ring" containing a heteroatom. The "heteroacene", "heteroacenyl", "fused-ring heterocyclyl" or "heteroacenyl" as presented herein are defined in accordance with the fused ring.

"Heterospiro", "spirocyclic heterocyclyl" or "Heterospiro" refers to a "spiro" containing heteroatoms. As used herein, a heterospiro, "spiroheterocyclyl," or "heterospiro" is defined as a spiro.

"heterobridged", "bridged heterocyclyl" or "heterobridged heterocyclyl" refers to a "bridged ring" that contains a heteroatom. The term "heterobridged ring," as used herein, refers to a bridged ring, or a bridged ring.

"aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a single ring or a fused ring, 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 may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring in which the ring attached to the parent structure is an aryl ring, non-limiting examples of which include benzene rings, naphthalene rings,

The "aryl" or "aromatic ring" may be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent or tetravalent, the attachment site is located on the aryl ring.

"heteroaryl" or "heteroaryl ring" refers to a substituted or unsubstituted aromatic hydrocarbon group and contains 1 to 5 optional heteroatoms or heteroatom-containing groups (including but not limited to N, O or S (=o) _n N is 0, 1, 2), the number of ring atoms in the heteroaromatic ring including, but not limited to, 5 to 15, 5 to 10, or 5 to 6. Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridone, imidazolyl, benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, and the like. The heteroaryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring in which the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include Heteroaryl groups as herein appear, the definition of which is consistent with the definition. Heteroaryl groups may be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent or tetravalent, the attachment sites are located on the heteroaryl ring.

"substituted" or "substituted" means substituted with 1 or more (including but not limited to 2, 3, 4, or 5) substituents including but not limited to H, F, cl, br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spirocyclic, and cyclic, hydroxyalkyl, =o, carbonyl, aldehyde, carboxylic acid, formate, - (CH) ₂ ) _m -C(＝O)-R ^a 、-O-(CH ₂ ) _m -C(＝O)-R ^a 、-(CH ₂ ) _m -C(＝O)-

NR ^b R ^c 、-(CH ₂ ) _m S(＝O) _n R ^a 、-(CH ₂ ) _m -alkenyl-R ^a 、OR ^d Or- (CH) ₂ ) _m -alkynyl-R ^a (wherein m, n is 0, 1 or 2), arylthio, thiocarbonyl, silane or-NR ^b R ^c Etc., wherein R is ^b And R is R ^c Independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally R ^b And R is R ^c Can form five-membered or six-membered cycloalkyl or heterocycleRadical R ^a And R is R ^d Each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spirocyclic, or fused ring.

"containing 1 to 5 heteroatoms selected from O, S, N" means containing 1, 2, 3, 4 or 5 heteroatoms selected from O, S, N.

"substituted with 0 to X substituents" means substituted with 0, 1, 2, 3 … X substituents, X being selected from any integer between 1 and 10. By "substituted with 0 to 4 substituents" is meant substituted with 0, 1, 2, 3 or 4 substituents. By "substituted with 0 to 5 substituents" is meant substituted with 0, 1, 2, 3, 4 or 5 substituents. By "the hetero-bridge ring is optionally substituted with 1 to 4 substituents selected from H or F" is meant that the hetero-bridge ring is optionally substituted with 0, 1, 2, 3 or 4 substituents selected from H or F.

The X-Y membered ring (X is selected from an integer of 3 or more and Y is selected from any integer of 4 to 12) includes X+1, X+2, X+3, X+4 … Y membered rings. The ring includes heterocyclic, carbocyclic, aromatic, aryl, heteroaryl, cycloalkyl, heteromonocyclic, heterobicyclic, heterospiro, or heterobridged rings. For example, "4-7 membered heteromonocyclic ring" means 4-, 5-, 6-or 7-membered heteromonocyclic ring, and "5-10 membered heteromonocyclic ring" means 5-, 6-, 7-, 8-, 9-or 10-membered heteromonocyclic ring.

"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. Such as: "alkyl optionally substituted with F" means that the alkyl may be, but is not necessarily, substituted with F, and is intended to include both cases where the alkyl is substituted with F and cases where the alkyl is not substituted with F.

"stereoisomers" refers to isomers arising from the spatial arrangement of atoms in a molecule, and include cis-trans isomers, enantiomers and conformational isomers.

"tautomer" refers to a functional group isomer produced by rapid movement of an atom in a molecule at two positions, such as keto-enol isomers and amide-imine alcohol isomers.

Detailed Description

The following examples illustrate the technical aspects of the present invention in detail, but the scope of the present invention is not limited thereto.

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (sum) Mass Spectrometry (MS). NMR shift (. Delta.) is given in units of 10-6 (ppm). NMR was performed using a (Bruker Avance III and Bruker Avance 300) magnetonuclear instrument with deuterated dimethyl sulfoxide (DMSO-d 6), deuterated chloroform (CDCl 3), deuterated methanol (CD 3 OD) and an internal standard of Tetramethylsilane (TMS);

MS measurement (Agilent 6120B (ESI) and Agilent 6120B (APCI));

HPLC was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18X14.6mm, 3.5. Mu.M);

the thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15mm-0.20mm, and the specification of the thin layer chromatography separation and purification product is 0.4mm-0.5mm;

Column chromatography generally uses tobacco stage yellow sea silica gel 200-300 mesh silica gel as carrier.

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 the companies of taan technology, an Naiji chemistry, shanzheimer, chengdalong chemical, shaoshan chemical technology, carbofuran technology, etc.

Tf: a trifluoromethanesulfonyl group; ts: p-toluenesulfonyl; TMS: trimethylsilyl group; SEM:THP:boc: a tert-butoxycarbonyl group; ms: />TBS:/>MTBE methyl tert-butyl ether; bn: -herba cistanches>DIPEA: n, N-diisopropylethylamine; DMAc: n, N-dimethylacetamide; DMF: n, N-dimethylformamide; DMSO: dimethyl sulfoxide; DCM: dichloromethane; cbz:>LDA: lithium diisopropylamide; pd (dppf) Cl ₂ 1,1' -bis (diphenylphosphino) ferrocene Palladium (II) dichloride (CAS number: 72287-26-4).

Example 1:

the first step: 5- (4- (trifluoromethyl) -1H-imidazol-2-yl) thiophene-2-carboxylic acid methyl ester (1B)

methyl 5-(4-(trifluoromethyl)-1H-imidazol-2-yl)thiophene-2-carboxylate

1, 1-dibromo-3, 3-trifluoroacetone (4.05 g,15.01 mmol), sodium acetate (1.37 g,16.51 mmol) and water (30 mL) were added to a 100mL reaction flask, and the mixture was stirred at 100℃for 1 hour after the addition. Cooled to room temperature, then a mixed solution of methyl 5-aldehyde thiophene-2-carboxylate (2.30 g,13.51 mmol) in methanol/ammonia (40 ml, v/v=1/1) was added, and after the addition was completed, the reaction was stirred at 100℃for 2 hours. Water (100 mL) was added to the reaction solution, ethyl acetate (100 mX1) L was extracted, the organic phase was dried over anhydrous sodium sulfate, suction filtration was performed, the filtrate was concentrated under reduced pressure, and then 1B (0.61 g, yield: 15%) was obtained by separation and purification through medium pressure preparation (PE/EA: 16% -30%).

LCMS m/z＝277.0[M+H] ⁺

¹ H NMR(400MHz,CD ₃ OD)δ7.79(d,1H),7.67(s,1H),7.56(d,1H),3.90(s,3H).

And a second step of: 5- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) thiophene-2-carboxylic acid methyl ester (1C)

methyl 5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)thiophene-2-carboxylate

1B (0.87 g,3.14 mmol), cesium carbonate (3.07 g,9.42 mmol), 2-iodopropane (1.60 g,9.42 mmol) and N, N-dimethylformamide (30 mL) were added to a 100mL reaction flask, and the reaction was stirred at 100℃for 4 hours. Cooled to room temperature, the reaction mixture was washed with 50mL of ethyl acetate, water (50 mL. Times.3), saturated sodium chloride solution (50 mL. Times.1), the organic phase was dried, filtered off with suction, concentrated under reduced pressure, and the preparation plate (PE/EA=20/1) was isolated and purified to give 1C (0.46 g, yield: 46%).

LCMS m/z＝319.0[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ8.25(d,1H),7.85(d,1H),7.56(d,1H),4.88-4.72(m,1H),3.86(s,3H),1.47(d,6H).

And a third step of: (5- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) thiophen-2-yl) methanol (1D)

(5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)thiophen-2-yl)methanol

1C (0.46 g,1.45 mmol) and tetrahydrofuran (3.0 mL) were added to a 50mL reaction flask, and after the addition was completed, the solution was stirred at 0deg.C and then diisobutylaluminum hydride/hexane solution (2.17 mL,1 mol/L) was added. After the addition was completed, the reaction was stirred at room temperature for 2 hours. To the reaction solution was added saturated sodium hydrogencarbonate solution (30 mL), and the emulsion was removed by suction filtration through celite, followed by extraction with ethyl acetate (30 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, suction-filtered, and the filtrate was concentrated under reduced pressure, followed by separation and purification by medium-pressure preparation (PE/ea=30-50%) to give 1D (0.30 g, yield: 71%).

LCMS m/z＝291.1[M+H] ⁺

¹ H NMR(400MHz,CDCl3)δ7.40(d,1H),7.21(d,1H),6.99(d,1H),4.85(s,2H),4.81-4.70(m,1H),2.33(br.s,1H),1.49(d,6H).

Fourth step: 2- (5- (chloromethyl) thiophen-2-yl) -1-isopropyl-4- (trifluoromethyl) -1H-imidazole (1E)

2-(5-(chloromethyl)thiophene-2-yl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole

1D (0.41 g,1.41 mmol) and methylene chloride (15.0 mL) were added to a 50mL reaction flask, and after the addition, the solution was stirred at 0℃and then thionyl chloride (0.5 g,4.23 mmol) was added dropwise, and the reaction was resumed at room temperature for 30 minutes. The reaction mixture was quenched by adding saturated sodium bicarbonate solution (50 mL), extracted with dichloromethane (50 mL. Times.2), the organic phases were combined and dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure to give 0.44g of 1E crude product, which was directly fed to the next reaction.

Fifth step: 6-chloro-1- ((5- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) thiophen-2-yl) methyl) -1H-pyrazolo [3,4-d ] pyrimidine (1F)

6-chloro-1-((5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)thiophene-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidine

1E (0.43 g,1.39 mmol), 6-chloro-1H-pyrazolo [3,4-D ] pyrimidine (0.21 g,1.39mmol, CAS: 23002-51-9), potassium carbonate (0.58 g,4.17 mmol) and N, N-dimethylformamide (10 mL) were added to the flask, and the reaction was stirred at room temperature overnight after the addition. Water (50 mL) was added to the reaction mixture, extraction was performed with ethyl acetate (50 mL. Times.3), the organic phases were combined and washed successively with water (50 mL. Times.3) and saturated brine (50 mL. Times.1), the organic phase was dried over anhydrous sodium sulfate, suction filtration was performed, and the filtrate was concentrated under reduced pressure, followed by isolation and purification by medium pressure preparation (PE/EA=2/1-EA) to give 1F (0.29 g, yield: 48.5%).

LCMS m/z＝427.0[M+H] ⁺

Sixth step: 6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1- ((5- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) thiophen-2-yl) methyl) -1H-pyrazolo [3,4-d ] pyrimidine (Compound 1)

6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-((5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)thiophene-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidine

To a 50mL single vial was added 1F (140 mg,0.33 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl) boronic acid (96 mg,0.49mol, CAS: 1798304-51-4), dissolved in a 1, 4-dioxane/water (10 mL, v/v=4/1) mixture, and Pd (dppf) Cl was then added thereto under nitrogen protection ₂ DCM (CAS: 95464-05-4) (27 mg,0.033 mmol) and potassium phosphate (210 mg,0.99 mmol), nitrogen replaced three times, and reacted overnight in an oil bath at 100deg.C. The reaction mixture was added with water (50 mL), extracted with ethyl acetate (50 mL. Times.2), and the organic phases were combined and dried over anhydrous sodium sulfateSuction filtration, concentration of the filtrate under reduced pressure, and purification by separation on a silica gel preparation plate (PE/ea=3/2) gave compound 1 (54 mg, yield: 30%).

LCMS m/z＝541.2[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ9.50(s,1H),8.72(s,1H),8.51(s,1H),8.12(d,1H),7.31(d,1H),7.26(d,1H),5.93(s,2H),4.77-4.65(m,1H),3.87(s,3H),1.73-1.63(m,1H),1.42(d,6H),1.10-1.04(m,2H),0.94-0.84(m,2H).

Example 2:

the first step: 3- (hydroxymethyl) bicyclo [1.1.1] pentane-1-carboxylic acid methyl ester (2A)

methyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate

3- (methoxycarbonyl) bicyclo [1.1.1] pentane-1-carboxylic acid (1 g,5.88 mmol) was dissolved in THF (10 mL), borane tetrahydrofuran solution (7 mL, 1M) was slowly added dropwise at 0deg.C, and the mixture was stirred overnight at room temperature. TLC monitored completion of the reaction, quenched by addition of methanol at 0deg.C, and concentrated under reduced pressure to give 2A (0.8 g, yield: 87%) which was used directly in the next step.

And a second step of: 3-formyl-bicyclo [1.1.1] pentane-1-carboxylic acid methyl ester (2B)

methyl 3-formylbicyclo[1.1.1]pentane-1-carboxylate

2A (0.8 g,5.12 mmol) was dissolved in DCM (10 mL), and dess-Martin oxidant (2.6 g,6.14 mmol) was added at room temperature and stirred at room temperature for 3h. The reaction was quenched by the addition of 10mL of saturated aqueous sodium bisulfite and extracted with 10mL of methylene chloride. 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) =1/3-1/1) to give 2B (0.46 g, yield: 58%).

And a third step of: 3- (4- (trifluoromethyl) -1H-imidazol-2-yl) bicyclo [1.1.1] pentane-1-carboxylic acid methyl ester (2C)

methyl 3-(4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[1.1.1]pentane-1-carboxylate

1, 1-dibromo-3, 3-trifluoroacetone (0.89 g,3.3mmol, CAS: 431-67-4) was placed in a 50mL single-necked flask, 5mL of water and sodium acetate (0.49 g,5.90 mmol) were added, and the mixture was stirred at 90℃for 0.5h. Cooled to room temperature, 10mL of methanol, 2B (0.49 g,2.98 mmol) and concentrated ammonia (5 mL) were added in this order and stirred overnight at room temperature. The mixture was filtered, and the cake was washed with 10mL of water, and the cake was dried under reduced pressure to give 2C (0.35 g, yield: 45%).

LCMS m/z＝261.1[M+H] ⁺

Fourth step: 3- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) bicyclo [1.1.1] pentane-1-carboxylic acid methyl ester (2D)

methyl 3-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[1.1.1]pentane-1-carboxylate

2C (0.3 g,1.15 mmol) was dissolved in 5mL DMSO at room temperature, isopropyl iodide (0.58 g,3.40 mmol) and cesium carbonate (0.75 g,2.30 mmol) were added sequentially and stirred at 90℃for 3h. Cooled to room temperature, 10mL of water and 10mL of ethyl acetate were added and extracted, and the organic layer was washed with saturated brine (10 mL. Times.3). The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 2D (0.32 g, yield: 92%).

¹ H NMR(400MHz,CDCl ₃ )δ7.24(s,1H),4.61-4.50(m,1H),3.72(s,3H),2.55(s,6H),1.45(d,6H).

Fifth step: (3- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) bicyclo [1.1.1] pent-1-yl) methanol (2E)

(3-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[1.1.1]pentan-1-yl)methanol

2D (0.32 g,1.06 mmol) was dissolved in 5mL THF, lithium borohydride (0.12 g,5.51 mmol) was added and stirred at 60℃for 1h. The reaction was quenched by cooling to room temperature, adding 5mL of saturated aqueous ammonium chloride, extracting with 5mL of water and 10mL of ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and used directly in the next step.

LCMS m/z＝275.1[M+H] ⁺

Sixth step: 6-chloro-1- ((3- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) bicyclo [1.1.1] pent-1-yl) methyl) -1H-pyrazolo [3,4-d ] pyrimidine (2F)

6-chloro-1-((3-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidine

2E (290 mg,1.06 mmol) was placed in a 50mL three-necked flask, 10mL THF was added for dissolution, 6-chloro-1H-pyrazolo [3,4-D ] pyrimidine (165 mg,1.07mmol, CAS: 23002-51-9) and triphenylphosphine (0.42 g,1.60 mmol) were sequentially added, nitrogen was replaced three times, diethyl azodicarboxylate (0.32 g,1.60 mmol) was added dropwise at room temperature, and stirring was continued for 1H after the addition. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate/petroleum ether (V/V) =1/3-1/1) to give 2F (0.34 g, yield: 77%).

LCMS m/z＝411.1[M+H] ⁺

Seventh step: trifluoroacetate salt of 6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1- ((3- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) bicyclo [1.1.1] pentan-1-yl) methyl) -1H-pyrazolo [3,4-d ] pyrimidine (compound 2)

6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-((3-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidine；trifluoroacetate

2F (0.15 g,0.37 mmol) was placed in a 50mL single neck flask and (4-cyclopropyl-6-methoxypyrimidin-5-yl) boronic acid (0.14 g,0.72 mmol), pd (dppf) Cl were added sequentially ₂ DCM (30 mg,0.037 mmol), potassium phosphate (0.24 g,1.11 mmol), 1, 4-dioxane (10 mL) and water (3 mL), after which nitrogen was replaced three times and stirred overnight at 95 ℃. After cooling to room temperature, 20mL of water and 20mL of ethyl acetate were added to extract, and 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) =1/3-1/0), and the obtained crude product was further purified by preparative HPLC (instrument: waters 2767 preparation liquid phase; column chromatography: sunfire@prep C18 (19 mm×150 mm), mobile phase composition: mobile phase a: acetonitrile mobile phase B: water (containing 0.1% trifluoroacetic acid)), to obtain the trifluoroacetate salt of compound 2 (50 mg).

LCMS m/z＝525.2[M+H] ⁺

¹ H NMR(400MHz,CD ₃ OD)δ9.45(s,1H),8.69(s,1H),8.45(s,1H),7.78(s,1H),4.77(s,2H),4.72–4.62(m,1H),3.95(s,3H),2.25(s,6H),1.78–1.68(m,1H),1.43(d,6H),1.24–1.17(m,2H),1.00–0.92(m,2H).

Example 3:

the first step: (2-Bromothiazol-5-yl) methanol (3A)

(2-bromothiazol-5-yl)methanol

Methyl 2-bromothiazole-5-carboxylate (4.4 g,20 mmol) was dissolved in 100mL of methanol at 0deg.C, sodium borohydride (3.78 g,100 mmol) was added, and the mixture was stirred at room temperature for 1h. Cooled to room temperature, quenched with 50mL of water, 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 give 3A (2.82 g, yield: 73.1%).

LCMS m/z＝194.0[M+H] ⁺

¹ H NMR(400MHz,CDCl ₃ )δ7.36(s,1H),4.76(s,2H),2.42(br.s,1H).

And a second step of: 5- (hydroxymethyl) thiazole-2-carbaldehyde (3B)

5-(hydroxymethyl)thiazole-2-carbaldehyde

N-butyllithium (6.1mL,15.29mmol,2.5M solution in Hexanes) was added to a solution of 3A (1.35 g,6.95 mmol) in tetrahydrofuran (100 mL) at-78℃under nitrogen protection, after stirring for 10 minutes at-78℃N, N-dimethylformamide (1.12 g,15.29 mmol) was added, the system was gradually warmed to room temperature and stirred for 1 hour, 3N hydrochloric acid (5.1 mL,15.3 mmol) was added immediately after the addition of saturated sodium bicarbonate (60 mL), the mixture was moved to room temperature, 50mL of water and 100mL of ethyl acetate were added to extract, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether (V/V) =1/10-1/1) to give 3B (0.5 g, yield: 50.3%).

¹ H NMR(400MHz,DMSO-d ₆ )δ9.89(s,1H),8.10(s,1H),5.88(t,1H),4.82-4.78(m,2H).

And a third step of: (2- (4- (trifluoromethyl) -1H-imidazol-2-yl) thiazol-5-yl) methanol (3C)

(2-(4-(trifluoromethyl)-1H-imidazol-2-yl)thiazol-5-yl)methanol

Sodium acetate (0.31 g,3.77 mmol) was added to a solution of 1, 1-dibromo-3, 3-trifluoroacetone (1.04 g,3.82 mmol) in water (5 mL), heated at 100℃for 1h, cooled to room temperature, 3B (0.5 g,3.49 mmol) in methanol (18 mL) and aqueous ammonia (4.4 mL) were added, after stirring at room temperature for 40min, the reaction was continued at 100℃for 2h, quenched with water (50 mL), extracted with ethyl acetate (60 mL. Times.3), the organic phases were combined, 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) =1/10-1/1) to give 3C (0.38 g, yield: 43.7%).

LCMS m/z＝250.0[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ13.75(s,1H),7.93(s,1H),7.80(s,1H),5.68(t,1H),4.73(d,2H).

Fourth step: 2- (4- (trifluoromethyl) -1H-imidazol-2-yl) thiazole-5-carbaldehyde (3D)

2-(4-(trifluoromethyl)-1H-imidazol-2-yl)thiazole-5-carbaldehyde

Dess-martin reagent (1.93 g,4.56 mmol) was added to a solution of 3C (0.38 g,1.52 mmol) in dichloromethane (10 mL) and ethyl acetate (10 mL), stirred at room temperature for 2h, extracted with 20mL water and 100mL ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3D (0.35 g) which was used directly in the next step.

Fifth step: 2- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) thiazole-5-carbaldehyde (3E)

2-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)thiazole-5-carbaldehyde

3D (0.35 g,1.42 mmol) was mixed in N, N-dimethylformamide (5 mL), cesium carbonate (1.39 g,4.27 mmol) and 2-iodopropane (0.73 g,4.3 mmol) were added in sequence and stirred at 90℃for 8h. After addition of 20mL of dichloromethane and 8mL of water, the layers were separated, the organic layer was dried under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: dichloromethane/methanol V/V) =100/1-100/2) to give 3E (330 mg, yield: 80.34%).

LCMS m/z＝290.1[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ10.11(s,1H),8.82(s,1H),8.44(s,1H),5.85–5.72(m,1H),1.50(d,6H).

Sixth step: (2- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) thiazol-5-yl) methanol (3F)

(2-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)thiazol-5-yl)methanol

3E (0.33 g,1.14 mmol) was dissolved in 100mL of methanol at 0deg.C, sodium borohydride (0.13 g,3.43 mmol) was added, and the mixture was stirred at room temperature for 1h. Cooled to room temperature, quenched with 10mL of water, 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 give 3F (0.26 g, yield: 78.3%).

LCMS m/z＝292.1[M+H] ⁺

Seventh step: 6-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d ] pyrimidine (3G)

6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine

Para-toluenesulfonic acid (620 mg,3.26 mmol) was added to a solution of 6-chloro-1H-pyrazolo [3,4-d ] pyrimidine (5 g,32.35mmol, CAS: 23002-51-9) in methylene chloride (100 mL), and after stirring at room temperature for 5min, 3, 4-dihydro-2H-pyran ((8.16 g,97 mmol)) was added and the reaction was stirred at room temperature for 2 hours. After 200mL of dichloromethane and 80mL of water were added, the layers were separated, the organic layer was dried under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate V/V) =50/1-20/1) to give 3G (7.5G, yield 97.14%)

LCMS m/z＝239.2[M+H] ⁺

Eighth step: 6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d ] pyrimidine (3H)

6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine

To a 50mL single vial was added (4-cyclopropyl-6-methoxypyrimidin-5-yl) boronic acid (2.5G, 12.89 mmol) and 3G (3.08G, 12.89 mmol) under nitrogen, dissolved in 100mL dioxane and 20mL water, methanesulfonic acid (2-dicyclohexylphosphino-2 ',4',6 '-tri-isopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (1.09G, 1.29 mmol) and potassium heptahydrate (13.08G, 38.67 mmol) were added, the nitrogen was replaced three times, the oil bath at 100℃was reacted for 16h, the temperature was lowered to room temperature, and the reaction solution was poured into water (100 mL) and extracted three times with ethyl acetate (60 mL. Times 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) =1/100-1/10) to give 3H (2.3 g, yield 50.64%).

LCMS m/z＝353.2[M+H] ⁺

Ninth step: 6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine (3I)

6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidine

Trifluoroacetic acid (10 mL) was added to a solution of 3H (2.3 g,6.53 mmol) in dichloromethane (5 mL), stirred at room temperature for 18H, concentrated under reduced pressure, the residue was diluted with dichloromethane (20 mL), saturated sodium bicarbonate (50 mL) was added to adjust ph=8, the organic layer was dried under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: dichloromethane/methanol V/V) =100/1-100/2) to give 3I (1.5 g, yield 85.63%).

LCMS m/z＝269.1[M+H] ⁺

1H NMR(400MHz,DMSO-d ₆ )δ14.16(s,1H),9.48(s,1H),8.70(s,1H),8.43(s,1H),3.84(s,3H),1.67-1.59(m,1H),1.14–1.01(m,2H),0.91-0.83(m,2H)

Tenth step: 5- ((6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) methyl) -2- (1-isopropyl-4- (trifluoromethyl)) -1H-imidazol-2-yl) thiazole (compound 3)

5-((6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-2-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)thiazole

3F (200 mg,0.69 mmol) and 3I (200 mg,0.75 mmol) were placed in a 50mL three-necked flask, 10mL THF was added for dissolution, triphenylphosphine (0.27 g,1.03 mmol) was sequentially added, nitrogen was replaced three times, diethyl azodicarboxylate (0.18 g,1.03 mmol) was added dropwise at room temperature, and stirring was continued for 1h. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate/petroleum ether (V/V) =1/3-1/1) to give compound 3 (0.1 g, yield: 26.76%).

LCMS m/z＝542.2[M+H] ⁺

1H NMR(400MHz,DMSO-d ₆ )δ9.50(s,1H),8.73(s,1H),8.52(s,1H),8.27(s,1H),8.07(s,1H),6.03(s,2H),5.77–5.60(m,1H),3.89(s,3H),1.74–1.64(m,1H),1.44(d,6H),1.14–1.04(m,2H),0.99–0.86(m,2H).

Example 4:

the first step: 4- (hydroxymethyl) bicyclo [2.2.2] octane-1-carboxylic acid methyl ester (4A)

methyl 4-(hydroxymethyl)bicyclo[2.2.2]octane-1-carboxylate

4- (methoxycarbonyl) bicyclo [2.2.2] octane-1-carboxylic acid (5 g,23.58 mmol) was dissolved in THF (60 mL), and a borane tetrahydrofuran solution (47 mL, 1M) was slowly added dropwise at 0deg.C, and the mixture was stirred overnight at room temperature. TLC monitored completion of the reaction, quenching with methanol at 0deg.C, concentrating under reduced pressure, and purifying the residue by silica gel column chromatography (ethyl acetate/petroleum ether (V/V) =1/20-1/2) to give 4A (3.8 g, yield: 81%).

And a second step of: 4-formyl-bicyclo [2.2.2] octane-1-carboxylic acid methyl ester (4B)

methyl 4-formylbicyclo[2.2.2]octane-1-carboxylate

4A (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 portions at 0deg.C and allowed to react for 3h at room temperature. TLC monitoring the reaction completion, concentration under reduced pressure, and purification of the residue by silica gel column chromatography (ethyl acetate/petroleum ether (V/V) =1/20-1/2) gave 4B (3.02 g, yield: 80%).

And a third step of: 4- (4- (trifluoromethyl) -1H-imidazol-2-yl) bicyclo [2.2.2] octane-1-carboxylic acid methyl ester (4C)

methyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octane-1-carboxylate

1, 1-dibromo-3, 3-trifluoroacetone (4.98 g,18.49mmol, CAS: 431-67-4) was placed in a 250mL single-necked flask, and 30mL of water and sodium acetate (1.89 g,23.09 mmol) were added to react at 90℃for 1 hour. Cooled to room temperature, 60mL of methanol, 4B (3.02 g,15.39 mmol) and concentrated ammonia (15 mL) were added in this order and reacted at 90℃for 2h. Cooled to room temperature, the reaction solution was poured into 200mL of water, filtered, and the cake was washed with water (2X 10 mL), and dried under reduced pressure to give 4C (2.9 g, yield: 62%).

LCMS m/z＝303.1[M+H] ⁺

Fourth step: 4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) bicyclo [2.2.2] octane-1-carboxylic acid methyl ester (4D)

methyl 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octane-1-carboxylate

4C (2.0 g,6.62 mmol) was dissolved in 30mL DMF at room temperature, isopropyl iodide (4.50 g,26.48 mmol) and cesium carbonate (6.47 g,19.86 mmol) were added sequentially and reacted overnight at 90 ℃. Cooled to room temperature, extracted with water and ethyl acetate, and the organic layer was washed 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) =1/20-1/1) to give 4D (1.2 g, yield: 52%).

LCMS m/z＝345.2[M+H] ⁺

Fifth step: (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) bicyclo [2.2.2] oct-1-yl) methanol (4E)

(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methanol

4D (1.2 g,3.48 mmol) was dissolved in 20mL THF, lithium borohydride (0.38 g,17.40 mmol) was added and stirred at 60℃for 2h. Cooled to room temperature, quenched with saturated aqueous ammonium chloride, extracted with water and ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 4E (0.9 g, yield: 81%) which was used directly in the next step.

LCMS m/z＝317.2[M+H] ⁺

Sixth step: trifluoroacetate salt of 6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1- ((4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) -1H-pyrazolo [3,4-d ] pyrimidine (compound 4)

6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidine；2,2,2-trifluoroacetic acid

4E (200 mg,0.63 mmol) was placed in a 50mL three-necked flask, 10mL of toluene was added for dissolution, 3I (185.91 mg,0.69 mmol) and tributylphosphine (0.64 g,3.15 mmol) were sequentially added, nitrogen was replaced three times, and diethyl azodicarboxylate (0.60 g,3.45 mmol) was added dropwise at room temperature for reaction at 100℃for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (V/V) =1/20-pure ethyl acetate), and the obtained crude product was separated and purified by a silica gel preparation plate (PE/ea=1/9) to obtain 30mg of crude product, and the obtained crude product was further subjected to preparative HPLC (instrument: waters 2767 preparation liquid phase; chromatographic column: sunfire@prep C18 (19 mm×150 mm)), and mobile phase composition: mobile phase a: acetonitrile mobile phase B: water (containing 0.1% trifluoroacetic acid)) to obtain the trifluoroacetate salt of compound 4 (12 mg, yield: 2.4%).

LCMS m/z＝567.3[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ9.47(s,1H),8.71(s,1H),8.46(s,1H),7.91–7.86(m,1H),4.87–4.74(m,1H),4.27(s,2H),3.84(s,3H),1.93–1.80(m,6H),1.70–1.62(m,1H),1.60–1.48(m,6H),1.33(d,6H),1.11–1.04(m,2H),0.90–0.83(m,2H).

6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1- ((4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) -1H-pyrazolo [3,4-d ] pyrimidine (Compound 4)

6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidine

Compound 4E (600 mg,1.90 mmol) was placed in a 50mL three-necked flask, 10mL of toluene was added for dissolution, compound 3I (560.68 mg,2.09 mmol) and tributylphosphine (1.92 g,9.5 mmol) were sequentially added, nitrogen was replaced three times, diethyl azodicarboxylate (1.81 g,10.40 mmol) was added dropwise at room temperature, and the temperature was raised to 100℃for reaction overnight. The reaction solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (V/V) =1/20-pure ethyl acetate), the obtained crude product was separated and purified by a silica gel preparation plate (PE/ea=1/9) to obtain a crude product, which was further prepared under medium pressure (mobile phase composition: mobile phase a-acetonitrile, mobile phase B-water (containing 0.1% trifluoroacetic acid)) to obtain the trifluoroacetate salt of the title compound 4, the preparation solution was concentrated, treated with a saturated aqueous sodium bicarbonate solution, extracted with methylene chloride, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the compound 4 (130 mg, yield: 12%).

LCMS m/z＝567.3[M+H] ⁺

¹ H NMR(400MHz,CD ₃ OD)δ9.37(s,1H),8.64(s,1H),8.36(s,1H),7.63-7.60(m,1H),4.93–4.83(m,1H),4.34(s,2H),3.92(s,3H),2.03–1.93(m,6H),1.72–1.62(m,7H),1.41(d,6H),1.20–1.15(m,2H),0.94–0.89(m,2H).

Example 5:

the first step: 5- (4- (trifluoromethyl) -1H-imidazol-2-yl) pyrazine-2-carboxamide (5A)

5-(4-(trifluoromethyl)-1H-imidazol-2-yl)pyrazine-2-carboxamide

1, 1-dibromo-3, 3-trifluoroacetone (3.90 g,14.45mmol, CAS: 431-67-4) was placed in a 250mL single-necked flask, and 20mL of water and sodium acetate (1.48 g,18.06 mmol) were added to react at 90℃for 1 hour. Cooled to room temperature, 40mL of methanol, methyl 5-formylpyrazine-2-carboxylate (2.00 g,12.04 mmol) and concentrated ammonia (10 mL) were added in this order and reacted at 90℃for 2h. Cooled to room temperature, extracted with water and ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 5A (1.6 g, yield: 51%) which was used directly in the next step.

LCMS m/z＝258.1[M+H] ⁺

And a second step of: 5- (4- (trifluoromethyl) -1H-imidazol-2-yl) pyrazine-2-carboxylic acid methyl ester (5B)

methyl 5-(4-(trifluoromethyl)-1H-imidazol-2-yl)pyrazine-2-carboxylate

5A (1.6 g,6.62 mmol) was dissolved in 20mL of methanol at room temperature, 4mL of concentrated hydrochloric acid was added, and the reaction was refluxed overnight. Cooled to room temperature, extracted with water and ethyl acetate, and the organic layer was washed 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) =1/20-1/1) to give 5B (0.6 g, yield: 35%).

LCMS m/z＝273.1[M+H] ⁺

And a third step of: 5- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) pyrazine-2-carboxylic acid methyl ester (5C)

methyl 5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyrazine-2-carboxylate

5B (0.4 g,1.47 mmol) was dissolved in 10mL DMF at room temperature, isopropyl iodide (0.75 g,4.41 mmol) and cesium carbonate (1.44 g,4.41 mmol) were added sequentially and reacted overnight at 90 ℃. Cooled to room temperature, extracted with water and ethyl acetate, and the organic layer was washed 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) =1/20-1/1) to give 5C (240 mg, yield: 52%).

LCMS m/z＝315.1[M+H] ⁺

Fourth step: (5- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) pyrazin-2-yl) methanol (5D)

(5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyrazin-2-yl)methanol

5C (240 mg,0.76 mmol) was dissolved in 10mL THF, lithium borohydride (100 mg,4.59 mmol) was added and stirred at 50deg.C for 3h. Cooled to room temperature, quenched with saturated aqueous ammonium chloride, extracted with water and ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 5D (120 mg, yield: 55%) which was used directly in the next step.

LCMS m/z＝287.1[M+H] ⁺

Fifth step: 6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1- ((5- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) pyrazin-2-yl) methyl) -1H-pyrazolo [3,4-d ] pyrimidine (Compound 5)

6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-((5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyrazin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidine

5D (110 mg,0.38 mmol) was placed in a 50mL three-necked flask, 5mL THF was added for dissolution, 3I (107.04 mg,0.40 mmol) and triphenylphosphine (199.34 mg,0.76 mmol) were sequentially added, nitrogen was replaced three times, diethyl azodicarboxylate (132.35 mg,0.76 mmol) was added dropwise at room temperature, and the reaction was carried out at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (V/V) =1/20-pure ethyl acetate), the obtained crude product was further subjected to preparative HPLC (instrument: waters 2767 for preparing a liquid phase; chromatographic column: sunfire@prep C18 (19 mm×150 mm), mobile phase composition: mobile phase a: acetonitrile mobile phase B: water (containing 0.1% trifluoroacetic acid)) for separating and purifying to obtain trifluoroacetate salt of compound 5, the obtained preparation was dried, then saturated sodium bicarbonate solution (10 mL) was added, and extraction was performed with dichloromethane (10 mL), and the organic phase was dried to obtain compound 5 (36 mg, yield: 17%).

LCMS m/z＝537.2[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ9.51(s,1H),9.08(d,1H),8.76(d,1H),8.69(s,1H),8.52(s,1H),8.35–8.29(m,1H),5.97(s,2H),5.56–5.40(m,1H),3.84(s,3H),1.71–1.58(m,1H),1.45(d,6H),1.06–0.99(m,2H),0.86-0.79(m,2H).

Example 6:

the first step: n- (2, 3-dihydro-1H-inden-4-yl) acetamide (6A)

N-(2,3-dihydro-1H-inden-4-yl)acetamide

The compound 2, 3-dihydro-1H-inden-4-amine (10 g,75.07 mmol) was dissolved in ethanol (150 mL), and acetic anhydride (14.06 mL,150.14 mmol) was added and reacted at room temperature for 1 hour. TLC monitoring the completion of the reaction under reduced pressure concentrating, adding saturated aqueous sodium hydrogencarbonate and ethyl acetate, stirring and layering, drying the organic phase over anhydrous sodium sulfate, concentrating under reduced pressure, purifying the residue by silica gel column chromatography (ethyl acetate/petroleum ether (V/V) =1/20-1/2) to give compound 6A (12.7 g, yield: 96%).

And a second step of: n- (7-bromo-2, 3-dihydro-1H-inden-4-yl) acetamide (6B)

N-(7-bromo-2,3-dihydro-1H-inden-4-yl)acetamide

Compound 6A (10 g,57.07 mmol) was dissolved in acetic acid (150 mL), and bromine (3.22 mL,62.78 mmol) was slowly added dropwise with stirring at room temperature, and reacted at room temperature for 2 minutes. The reaction solution was poured into water, filtered, and the residue was washed twice with water and dried to give product 6B (13.8 g, yield: 95%).

And a third step of: 7-bromo-2, 3-dihydro-1H-inden-4-amine (6C)

7-bromo-2,3-dihydro-1H-inden-4-amine

Compound 6B (13.8 g,54.31 mmol) was added to 50mL of water, followed by concentrated hydrochloric acid (50 mL, 12N) and the temperature was raised to 100deg.C for 4 hours. Cooled to room temperature, ice-water bath adjusted to pH to alkaline, filtered, and the solid was washed twice with water and dried to give Compound 6C (11 g, yield: 95%).

LCMS m/z＝212.0[M+H] ⁺

Fourth step: 4, 7-dibromo-2, 3-dihydro-1H-indene (6D)

4,7-dibromo-2,3-dihydro-1H-indene

Compound 6C (5 g,23.57 mmol) was dissolved in 80mL of acetonitrile at room temperature, isobutyl nitrite (6 g,58.21 mmol) and cuprous bromide (6 g,41.70 mmol) were added, reacted overnight at room temperature, then warmed to 80℃for 4 hours. Cooled to room temperature, water and ethyl acetate were added, the layers were stirred and separated, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (V/V) =0/100-1/50) to give compound 6D (4 g, yield: 61%).

Fifth step: 7-bromo-2, 3-dihydro-1H-indene-4-carbaldehyde (6E)

7-bromo-2,3-dihydro-1H-indene-4-carbaldehyde

Compound 6D (4 g,14.49 mmol) was dissolved in 40mL THF, isopropyl magnesium chloride (14.49 mL, 2M) was added at 0deg.C, after 30 minutes of reaction at 0deg.C, n-butyllithium (6.5 mL, 2.5M) was added and then reacted at 0deg.C for 2 hours, DMF (1.59 g,21.73 mmol) was added at 0deg.C, stirred for 30 minutes, then water was added to quench the reaction, water and ethyl acetate were added to stir and the layers were separated, 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) =0/100-1/3) to give compound 6E (1.3 g, yield: 39%).

Sixth step: 2- (7-bromo-2, 3-dihydro-1H-inden-4-yl) -4- (trifluoromethyl) -1H-imidazole (6F)

2-(7-bromo-2,3-dihydro-1H-inden-4-yl)-4-(trifluoromethyl)-1H-imidazole

1, 1-dibromo-3, 3-trifluoroacetone (1.72 g,6.36 mmol), sodium acetate (569 mg,6.94 mmol) and water (20 mL) were charged into a 100mL reaction flask, and after the completion of the addition, the reaction was stirred at 100℃for 1 hour. Cooled to room temperature, then a mixed solution of compound 6E (1.30 g,5.78 mmol) in methanol/ammonia (50 ml, v/v=1/1) was added, and after the addition was completed, the reaction was stirred at 100 ℃ for 2 hours. Water (60 mL) was added to the reaction mixture, ethyl acetate (60 mX2) was used for extraction, the organic phase was dried over anhydrous sodium sulfate, suction filtration was performed, and the filtrate was concentrated under reduced pressure and then purified by medium-pressure preparation (PE/EA: 16% -30%) to give Compound 6F (0.9 g, yield: 52%).

LCMS m/z＝331.0[M+H] ⁺

Seventh step: 2- (7-bromo-2, 3-dihydro-1H-inden-4-yl) -1-isopropyl-4- (trifluoromethyl) -1H-imidazole (6G)

2-(7-bromo-2,3-dihydro-1H-inden-4-yl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole

In a 100mL reaction flask, compound 6F (0.9 g,2.72 mmol), cesium carbonate (2.66 g,8.16 mmol), 2-iodopropane (1.39 g,8.16 mmol) and N, N-dimethylformamide (10 mL) were added, and after the addition, the reaction was stirred at 90℃for 4 hours. After cooling to room temperature, the reaction mixture was washed with 60mL of ethyl acetate (30 mL. Times.2) and saturated aqueous sodium chloride (50 mL. Times.1), the organic phase was dried, filtered off with suction, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (V/V) =0/100-1/20) to give compound 6G (0.76G, yield: 75%).

Eighth step: 7- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) -2, 3-dihydro-1H-indene-4-carboxylic acid ethyl ester (6H)

ethyl7-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2,3-dihydro-1H-indene-4-carboxylate

Compound 6G (0.56G, 1.5 mmol) was dissolved in ethanol (15 mL) and Pd (dppf) Cl was added ₂ DCM (0.12 g,0.15 mmol), triethylamine (0.45 g,4.47 mmol), carbon monoxide substitution 3 times, carbon monoxide atmosphere (balloon pressure), stirring overnight at 90 ℃, concentrating under reduced pressure,the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (V/V) =0/100-1/20) to give compound 6H (0.19 g, yield: 35%).

LCMS m/z＝367.1[M+H] ⁺

Ninth step: (7- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) -2, 3-dihydro-1H-inden-4-yl) methanol (6I)

(7-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2,3-dihydro-1H-inden-4-yl)methanol

In a 50mL reaction flask, compound 6H (0.19 g,0.52 mmol) and tetrahydrofuran (10 mL) were added, and after the addition was completed, the solution was stirred at 0℃and then diisobutylaluminum hydride/hexane solution (1.5 mL,1 mol/L) was added. After the addition was completed, the reaction was stirred at room temperature for 2 hours. To the reaction solution was added saturated aqueous sodium hydrogencarbonate (20 mL), and the emulsion was removed by suction filtration through celite, followed by extraction with ethyl acetate (30 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, suction-filtered, and the filtrate was concentrated under reduced pressure and then purified by medium-pressure preparation (petroleum ether/ethyl acetate=30-50%) to give 6I (0.12 g, yield: 71%).

LCMS m/z＝325.2[M+H] ⁺

Tenth step: (7- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) -2, 3-dihydro-1H-inden-4-yl) methyl methanesulfonate (6J)

(7-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2,3-dihydro-1H-inden-4-yl)methyl methanesulfonate

Methanesulfonyl chloride (64 mg,0.56 mmol) was added to a solution of compound 6I (0.12 g,0.37 mmol) and triethylamine (0.11 g,1.09 mmol) in dichloromethane (15 mL) at 0deg.C and stirred at room temperature for 1 hour. Quench by adding 20mL of saturated aqueous sodium bicarbonate solution and extract three times with dichloromethane (20 mL. Times.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) =1/100-1/20) to give compound 6J (0.11 g, yield 74%).

LCMS m/z＝403.1[M+H] ⁺

Eleventh step: 6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1- (7- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) -2, 3-dihydro-1H-inden-4-yl) methyl) -1H-pyrazolo [3,4-d ] pyrimidine (Compound 6)

6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-((7-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2,3-dihydro-1H-inden-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidine

Cesium carbonate (240 mg,0.75 mmol) and sodium iodide (110 mg,0.75 mmol) were added to a solution of compound 6J (0.1 g,0.25 mmol) and compound 3I (67 mg,0.25 mmol) in dimethyl sulfoxide (5 mL), respectively, under nitrogen protection, after stirring at 80 ℃ for 60 minutes, 20mL dichloromethane and 8mL water were added, the organic layer was dried under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: dichloromethane/methanol V/V) =100/1-100/3 to give compound 6 (42 mg, yield: 29%).

LCMS m/z＝575.2[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ9.50(s,1H),8.71(s,1H),8.50(s,1H),8.14-8.09(m,1H),7.16(d,1H),7.09(d,1H),5.72(s,2H),4.21–4.11(m,1H),3.85(s,3H),2.92(t,2H),2.73(t,2H),2.01–1.93(m,2H),1.66-1.61(m,1H),1.32(d,6H),1.09-1.05(m,2H),0.88–0.83(m,2H).

Example 7:

the first step: 1-isopropyl-4- (trifluoromethyl) -1H-imidazole (7B)

1-isopropyl-4-(trifluoromethyl)-1H-imidazole

The compound 4- (trifluoromethyl) -1H-imidazole (10.0 g,73.49 mmol) was dissolved in N, N-dimethylformamide (100 mL), and potassium carbonate (20.31 g,146.98 mmol) and 2-iodopropane (14.99 g,88.19 mmol) were added, and after the addition, the temperature was raised to 50℃for 16 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, 200mL of ethyl acetate was added to dilute the reaction solution, the organic phase was washed three times with water, and 1 time with saturated aqueous sodium chloride, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to flash column chromatography (petroleum ether/ethyl acetate=3/1) to give compound 7B (7.5 g, yield: 57%)

LCMS m/z＝179.1[M+H] ⁺

And a second step of: 2-bromo-1-isopropyl-4- (trifluoromethyl) -1H-imidazole (7C)

2-bromo-1-isopropyl-4-(trifluoromethyl)-1H-imidazole

Compound 7B (6.5 g,36.48 mmol) was dissolved in carbon tetrachloride (70 mL), azodiisobutyronitrile (1.2 g,7.3 mmol) and N-bromosuccinimide (8.44 g,47.42 mmol) were added, and after the addition was completed, the temperature was raised to 60℃and reacted for 16 hours. After the completion of the reaction, cooled to room temperature, insoluble matter was removed by filtration, the cake was washed with ethyl acetate, the filtrate was collected, concentrated under reduced pressure, and flash column chromatography (petroleum ether/ethyl acetate=9/1) was performed to give compound 7C (5.7 g, yield: 61%)

LCMS m/z＝257.0[M+H] ⁺

And a third step of: 4-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiophene-2-carboxylic acid methyl ester (7E)

Methyl 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate

The compound methyl 5-bromo-4-methylthiophene-2-carboxylate (2.0 g,8.48 mmol) and pinacol diboronate (2.15 g,8.48 mmol) were dissolved in ultra-dry 1, 4-dioxane (60 mL) and potassium acetate (2.5 g,25.44 mmol) and Pd (dppf) Cl were added ₂ DCM (0.69 g,0.85 mmol), and nitrogen was reacted three times at 100℃for 6 hours. Cooled to room temperature, and insoluble matter was removed by filtration through celite to give a filtrate containing compound 7E which was used directly in the next step.

LCMS m/z＝283.1[M+H] ⁺

Fourth step: 5- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) -4-methylthiophene-2-carboxylic acid methyl ester (7F)

methyl 5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-4-methylthiophene-2-carboxylate

To the filtrate containing 7E in the previous step, 7C (2.18 g,8.48 mmol) Pd (dppf) Cl was added ₂ DCM (0.69 g,0.85 mmol) and potassium carbonate (3.52 g,25.44 mmol), and 6mL of water was added and the reaction was continued at 90℃for 16 hours after three nitrogen substitutions. After the reaction, the solvent is removed by vacuum concentration, ethyl acetate and water are added, extraction is carried out, the organic phase is collected, and after drying, the organic phase is concentrated by vacuum concentration and flash column chromatography is carried out(petroleum ether/ethyl acetate=3/1) to give compound 7F (350 mg, two-step yield: 12%).

LCMS m/z＝333.1[M+H] ⁺

Fifth step: (5- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) -4-methylthiophene-2-yl) methanol (7G)

(5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-4-methylthiophen-2-yl)methanol

Compound 7F (300 mg,0.90 mmol) was dissolved in THF (15 mL), lithium borohydride (196 mg,9 mmol) was added under ice-water bath, the temperature was raised to room temperature for 16 hours, saturated aqueous ammonium chloride solution was slowly added under ice-water bath until no bubbling occurred, 20mL ethyl acetate was added, water was washed 3 times, saturated aqueous sodium chloride solution was washed 1 time, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and flash column chromatography (petroleum ether/ethyl acetate=1/1) was performed to give compound 7G (250 mg, yield: 91%).

LCMS m/z＝305.1[M+H] ⁺

Sixth step: trifluoroacetate salt of 6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1- ((5- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) -4-methylthiophene-2-yl) methyl) -1H-pyrazolo [3,4-d ] pyrimidine (compound 7)

6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-((5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-4-methylthiophen-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidine；TFA

Compound 7G (130 mg,0.43 mmol) was dissolved in toluene (6 mL), 6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine (3I) (110 mg,0.41 mmol), tributyl phosphorus (260 mg,1.29 mmol), diethyl azodicarboxylate (220 mg,1.26 mmol) was added sequentially, nitrogen was replaced three times after the addition, and the temperature was raised to 100℃for 16 hours. To the reaction solution was added 20mL of ethyl acetate to dilute the reaction solution, washing with water 3 times, washing with saturated aqueous sodium chloride solution 1 time, drying over anhydrous sodium sulfate, concentrating under reduced pressure, and flash column chromatography (petroleum ether/ethyl acetate=1/1) to give a crude product of compound 7, which was further purified by reverse phase column (mobile phase: acetonitrile/0.1% trifluoroacetic acid) to give trifluoroacetate salt (30 mg) of compound 7.

LCMS m/z＝555.2[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ9.50(s,1H),8.71(s,1H),8.51(s,1H),8.20-8.16(m,1H),7.09(s,1H),5.88(s,2H),4.28–4.18(m,1H),3.84(s,3H),2.05(s,3H),1.69–1.59(m,1H),1.33(d,6H),1.10–1.01(m,2H),0.86-0.79(m,2H).

Example 8:

the first step: 3-hydroxy-4- (4- (trifluoromethyl) -1H-imidazol-2-yl) benzoic acid methyl ester (8B)

methyl 3-hydroxy-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate

The compound 1, 1-dibromo-3, 3-trifluoroacetone (8.32 g,30.82 mmol) was added to a reaction flask, water (20 mL) was added, and sodium acetate (2.56 g,31.15 mmol) was added to react at 100℃for 1 hour. The reaction mixture was cooled to room temperature, and a methanol solution (120 mL) of methyl 4-formyl-3-hydroxybenzoate (8A) (5.00 g,27.78 mmol) and aqueous ammonia (26.90 g,767.46 mmol) was added thereto, followed by stirring at room temperature for reaction at 100℃for 1 hour. The reaction solution was cooled to room temperature, 200mL of methylene chloride was added to dilute the reaction solution, washed 3 times with water, washed 1 time with saturated aqueous sodium chloride, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to flash column chromatography (methylene chloride/methanol=15/1) to give a crude product, which was further purified by reverse phase column chromatography (acetonitrile/0.1% aqueous trifluoroacetic acid=1/1) to give compound 8B (0.45 g, yield: 6%).

LCMS m/z＝287.1[M+H] ⁺

And a second step of: 2- (trifluoromethyl) -5,6-Dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] oxaza-9-carboxylic acid methyl ester (8C)

methyl 2-(trifluoromethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate

Compound 8B (0.3995 g,1.38 mmol) was dissolved in DMF (10 mL), cesium carbonate (1.80 g,5.52 mmol) was added, 1, 2-dibromoethane (1.04 g,5.52 mmol) was added dropwise, the reaction was stirred at 90℃for 3 hours, the reaction solution was cooled to room temperature, 200mL of ethyl acetate was diluted, washed with water 3 times, saturated sodium chloride aqueous solution was washed 1 time, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and flash column chromatography (petroleum ether/ethyl acetate=3/1) gave compound 8C (0.16 g, yield: 37%).

LCMS m/z＝313.1[M+H] ⁺

And a third step of: (2- (trifluoromethyl) -5,6-Dihydrobenzo [ f ] imidazo [1,2-D ] [1,4] oxazepin-9-yl) methanol (8D) (2- (trifluoromethyl) -5, 6-dihydrozo [ f ] imidzo [1,2-D ] [1,4] oxazepin-9-yl) methanol

Compound 8C (0.20 g,0.64 mmol) was dissolved in THF (10 mL), lithium borohydride (0.07 g,3.20 mmol) was added at room temperature, the temperature was raised to 50℃and the reaction was stirred for 4 hours, the reaction solution was cooled to room temperature, saturated aqueous ammonium chloride solution was added to quench the reaction, 100mL of ethyl acetate was diluted, water was washed 3 times, saturated aqueous sodium chloride solution was washed 1 time, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and flash column chromatography (petroleum ether/ethyl acetate=1/1) gave compound 8D (0.136 g, yield: 75%).

LCMS m/z＝285.1[M+H] ⁺

Fourth step: 9- (chloromethyl) -2- (trifluoromethyl) -5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] oxaza (8E)

9-(chloromethyl)-2-(trifluoromethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

Compound 8D (0.10 g,0.35 mmol) was dissolved in DCM (5 mL), DMF (0.003g, 0.035 mmol) was added, and sulfoxide chloride (0.083 g,0.70 mmol) was added dropwise, and the reaction was stirred at room temperature for 2 hours, and the reaction solution was concentrated under reduced pressure to give compound 8E (0.105 g) which was directly used in the next reaction.

LCMS m/z＝303.1[M+H] ⁺

Fifth step: 6-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d ] pyrimidine (8G)

6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine

Para-toluenesulfonic acid (620 mg,3.26 mmol) was added to a solution of 6-chloro-1H-pyrazolo [3,4-d ] pyrimidine (8F) (5 g,32.35mmol, CAS: 23002-51-9) in methylene chloride (100 mL), and after stirring at room temperature for 5min, 3, 4-dihydro-2H-pyran ((8.16 g,97 mmol)) was added and the reaction was stirred at room temperature for 2 hours. After 200mL of dichloromethane and 80mL of water were added, the layers were separated, the organic layer was dried under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate V/V) =50/1-20/1) to give compound 8G (7.5G, yield 97.14%)

LCMS m/z＝239.2[M+H] ⁺

Sixth step: 6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d ] pyrimidine (8H)

To a 50mL single vial was added (4-cyclopropyl-6-methoxypyrimidin-5-yl) boronic acid (2.5G, 12.89 mmol) and 8G (3.08G, 12.89 mmol) under nitrogen protection, dissolved in 100mL dioxane and 20mL water, methanesulfonic acid (2-dicyclohexylphosphino-2 ',4',6 '-tri-isopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (1.09G, 1.29 mmol) and potassium heptahydrate (13.08G, 38.67 mmol) were added, the nitrogen was replaced three times, the oil bath at 100℃was reacted for 16h, the temperature was lowered to room temperature, and the reaction solution was poured into water (100 mL), and ethyl acetate (60 mL. Times.3) was extracted three times. 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) =1/100-1/10) to give compound 8H (2.3 g, yield 50.64%).

LCMS m/z＝353.2[M+H] ⁺

Seventh step: 6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1H-pyrazolo [3,4-d ] pyrimidine (8I)

6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidine

Trifluoroacetic acid (10 mL) was added to a solution of 8H (2.3 g,6.53 mmol) in dichloromethane (5 mL), stirred at room temperature for 18 hours, then concentrated under reduced pressure, the residue was diluted with dichloromethane (20 mL), saturated aqueous sodium bicarbonate (50 mL) was added to adjust ph=8, the organic layer was dried under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: dichloromethane/methanol V/V) =100/1-100/2) to give compound 8I (1.5 g, yield 85.63%).

LCMS m/z＝269.1[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ14.16(s,1H),9.48(s,1H),8.70(s,1H),8.43(s,1H),3.84(s,3H),1.67-1.59(m,1H),1.14–1.01(m,2H),0.91-0.83(m,2H).

Eighth step: 9- ((6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) methyl) -2- (trifluoromethyl) -5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] oxazapine (compound 8)

9-((6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-2-(trifluoromethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

Compound 8E (0.092 g,0.34 mmol) and compound 8I (0.10 g,0.34 mmol) were dissolved in DMF (5 mL), potassium carbonate (0.12 g,0.85 mmol) was added and the reaction stirred at room temperature for 16 hours. 100mL of ethyl acetate was used to dilute the reaction solution, washed 3 times with water, washed 1 time with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to flash column chromatography (petroleum ether/ethyl acetate=1/2) to give compound 8, (0.06 g, yield: 32%).

LCMS m/z＝535.2[M+H] ⁺

¹ H NMR(400MHz,CDCl ₃ )δ9.34(s,1H),8.75(s,1H),8.47(d,1H),8.24(s,1H),7.31–7.27(m,1H),7.13(dd,1H),7.02(d,1H),5.69(s,2H),4.46–4.33(m,4H),3.98(s,3H),1.81–1.69(m,1H),1.42–1.31(m,2H),1.04–0.90(m,2H).

Example 9:

the first step: 3-Nitro-4- (4- (trifluoromethyl) -1H-imidazol-2-yl) benzoic acid methyl ester

methyl 3-nitro-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate

The compound 1, 1-dibromo-3, 3-trifluoroacetone (7.10 g,26.31 mmol) was placed in a 100mL single-necked flask, water (10 mL) and sodium acetate (3.93 g,47.90 mmol) were added, and the mixture was heated to 90℃and stirred for 0.5h. Cooled to room temperature, 20mL of methanol, methyl 4-aldehyde-3-nitrobenzoate (5 g,23.92 mmol) and concentrated ammonia (10 mL) were added in this order and stirred overnight at room temperature. Concentrated to half volume under reduced pressure, extracted with 50mL ethyl acetate and 50mL water, and the organic layer was washed once with 50mL saturated brine. 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) =1/10-2/1) to give compound 9A (2.2 g, yield: 29%).

LCMS m/z＝316.0[M+H] ⁺

And a second step of: 3-Nitro-4- (4- (trifluoromethyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazol-2-yl) benzoic acid methyl ester (9B)

methyl 3-nitro-4-(4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)benzoate

Compound 9A (1.5 g,4.76 mmol) was dissolved in THF (10 mL), sodium hydride (0.23 g,5.71mmol, wt% = 60%) was added under ice-bath, 2- (trimethylsilyl) ethoxymethyl chloride (0.95 g,5.71 mmol) was added after stirring for 20 min, and the mixture was allowed to warm to room temperature and stirred for 1 hour. 10mL of saturated aqueous ammonium chloride solution was added, extraction was performed with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate/petroleum ether (V/V) =1/10-1/1) to give compound 9B (1.5 g, yield: 70%).

And a third step of: (3-nitro-4- (4- (trifluoromethyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazol-2-yl) phenyl) methanol (9C)

(3-nitro-4-(4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)phenyl)methanol

Compound 9B (1.5 g,3.37 mmol) was dissolved in diethyl ether (10 mL), cooled to 0deg.C under nitrogen, and a solution of diisobutylaluminum hydride (10.1 mL,10.1mmol, 1N) in n-hexane was slowly added. After the addition, the mixture was warmed to room temperature and stirred for 2 hours. The reaction was quenched by adding 10mL of an aqueous ammonium chloride solution, extracted with 10mL of water and 20mL of ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give Compound 9C (1.4 g, yield: 100%).

LCMS m/z＝418.1[M+H] ⁺

Fourth step: 6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1- (3-nitro-4- (4- (trifluoromethyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazol-2-yl) benzyl) -1H-pyrazolo [3,4-D ] pyrimidine (9D)

6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(3-nitro-4-(4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine

Compound 9C (1.3 g,3.11 mmol), compound 8I (0.92 g,3.42 mmol) and tri-n-butylphosphine (0.95 g,4.70 mmol) were mixed and dissolved in THF (10 mL), replaced with nitrogen three times, and diethyl azodicarboxylate (0.81 g,4.67 mmol) was slowly added at room temperature and stirred at room temperature for 1 hour. The solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (V/V) =1/10-1/1) to give compound 9D (1.1 g, yield: 53%)

LCMS m/z＝668.2[M+H] ⁺

Fifth step: 6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1- (3-nitro-4- (4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -1H-pyrazolo [3,4-d ] pyrimidine (9E)

6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(3-nitro-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine

Compound 9D (1.1 g,1.65 mmol) was dissolved in trifluoroacetic acid (10 mL) and stirred overnight at room temperature. The residue was dissolved in 20mL of methylene chloride and adjusted to pH >8 with saturated aqueous sodium bicarbonate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 9E which was used directly in the next step.

Sixth step: tert-butyl 2- (2- (4- ((6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) methyl) -2-nitrophenyl) -4- (trifluoromethyl) -1H-imidazol-1-yl) acetate (9F)

tert-butyl 2-(2-(4-((6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-2-nitrophenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)acetate

The crude compound 9E (0.85 g) was dissolved in acetonitrile (10 mL), tert-butyl bromoacetate (0.37 g,1.90 mmol) and cesium carbonate (0.77 g,2.37 mmol) were added sequentially, and the mixture was heated to 60℃and stirred for 20 minutes. Cooled to room temperature, filtered, and the filtrate was 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 give compound 9F (0.57 g, two-step yield: 53%).

Seventh step: tert-butyl 2- (2- (2-amino-4- ((6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) methyl)) phenyl) -4- (trifluoromethyl) -1H-imidazol-1-yl) acetate (9G)

tert-butyl 2-(2-(2-amino-4-((6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)acetate

Compound 9F (0.57 g,0.87 mmol) and ammonium chloride (0.93 g,17.38 mmol) were dissolved in a mixed solvent of THF (10 mL) and water (3 mL), zinc powder (1.14 g,17.43 mmol) was added, and the mixture was heated to 70℃and stirred for 6 hours. Cooled to room temperature, filtered, the filter cake was washed with 40mL of dichloromethane, the filtrates were combined, 10mL of concentrated aqueous ammonia and 10mL of water were sequentially added for washing, and the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was used directly in the next step.

LCMS m/z＝622.2[M+H] ⁺

Eighth step: 9- ((6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) methyl) -2- (trifluoromethyl) -5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazepin-6 (7H) -one (compound 9)

9-((6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-2-(trifluoromethyl)-5H-benzo[f]imidazo[1,2-d][1,4]diazepin-6(7H)-one

Compound 9G (0.54G, 0.87 mmol) was dissolved in trifluoroacetic acid (5 mL) and stirred at room temperature for 5 hours. After concentration under reduced pressure, the residue was dissolved in 20mL of methylene chloride, washed with 20mL of saturated aqueous sodium hydrogencarbonate solution, and 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) =1/5-2/1) to give compound 9 (0.35 g, yield: 73%).

LCMS m/z＝548.2[M+H] ⁺

¹ H NMR(400MHz,CDCl ₃ )δ9.36(s,1H),8.70(s,1H),8.26(s,1H),8.03(d,1H),8.00(s,1H),7.41-7.39(m,1H),7.38-7.34(m,1H),7.10(s,1H),5.75(s,2H),4.57(s,2H),3.94(s,3H),1.72-1.63(m,1H),1.31-1.23(m,2H),0.93-0.85(m,2H).

Example 10:9- ((6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) methyl) -7-methyl-2- (trifluoromethyl) -5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazepin-6 (7H) -one (compound 10)

9-((6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-7-methyl-2-(trifluoromethyl)-5H-benzo[f]imidazo[1,2-d][1,4]diazepin-6(7H)-one

Compound 9 (0.082 g,0.15 mmol) was dissolved in DMF (2 mL), followed by addition of potassium carbonate (0.041 g,0.30 mmol) and methyl iodide (0.043 g,0.30 mmol) and stirring at room temperature for 2h. 20mL of ethyl acetate and 20mL of water were added to the mixture to extract the mixture, the organic layer was washed with saturated brine (10 mL. Times.3), 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) =1/5-2/1) to give compound 10 (70 mg, yield: 83%).

LCMS m/z＝562.2[M+H] ⁺

¹ H NMR(400MHz,CDCl ₃ )δ9.36(s,1H),8.70(s,1H),8.26(s,1H),7.94(d,1H),7.44-7.41(m,2H),7.42-7.38(m,1H),5.78(s,2H),4.70-4.30(m,2H),3.93(s,3H),3.35(s,3H),1.69 -1.62(m,1H),1.30-1.25(m,2H),0.93-0.84(m,2H).

Example 11:

the first step: 4- (4- (trifluoromethyl) -1H-imidazol-2-yl) benzoic acid methyl ester (11A)

methyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate

Sodium acetate (4.15 g,50.55 mmol) was added to a solution of 1, 1-dibromo-3, 3-trifluoroacetone (12.4 g,45.95 mmol) in water (24 mL), heated at 100℃for 1 hour, cooled to room temperature, a solution of methyl 4-formylbenzoate (8.3 g,50.55 mmol) in methanol (180 mL) and aqueous ammonia (44 mL) was added, stirred at room temperature for 40 minutes and then warmed to 100℃for further reaction for 2 hours, cooled to room temperature, quenched with water (50 mL), extracted with ethyl acetate (60 mL. Times.3), the organic phases were combined, 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) =1/10-1/1) to give compound 11A (8 g, yield: 64%).

LCMS m/z＝271.1[M+H] ⁺

And a second step of: 4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzoic acid methyl ester (11B)

methyl 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate

Compound 11A (17 g,62.91 mmol) was dissolved in 200mL DMF at room temperature, isopropyl iodide (32.08 g,188.73 mmol) and cesium carbonate (61.49 g,188.75 mmol) were added sequentially and the temperature was raised to 90℃for reaction overnight. Cooled to room temperature, extracted with water and ethyl acetate, and the organic layer was washed 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) =1/20-1/1) to give compound 11B (11.8 g, yield: 60%).

LCMS m/z＝313.1[M+H] ⁺

And a third step of: (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) methanol (11C)

(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol

Compound 11B (11.8 g,37.79 mmol) was dissolved in 150mL THF, lithium borohydride (4.12 g,188.95 mmol) was added, and the mixture was stirred for 2 hours at 50 ℃. Cooled to room temperature, quenched by addition of saturated aqueous ammonium chloride in an ice-water bath, extracted with water and ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 11C (10 g, yield: 93%) which was used directly in the next step.

LCMS m/z＝285.1[M+H]+

Fourth step: hydrochloride of 2- (4- (chloromethyl) phenyl) -1-isopropyl-4- (trifluoromethyl) -1H-imidazole (11D)

2-(4-(chloromethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole；HCl

Compound 11C (0.5 g,1.76 mmol) was dissolved in DCM (10 mL), and thionyl chloride (1.05 g,8.82 mmol) was added at room temperature and stirred for 2 hours. Concentrating under reduced pressure to give the hydrochloride of the compound 11D, which was used directly in the next step.

Fifth step: 4-amino-2-chloropyrimidin-5-ol (11E)

4-amino-2-chloropyrimidin-5-ol

The compound 2-chloro-4-amino-5-methoxypyrimidine (0.78 g,4.89mmol, CAS:99979-77-8) was dissolved in 1, 2-dichloroethane (10 mL) and boron tribromide (5.19 g,20.72 mmol) was added at room temperature. The temperature was raised to 70℃and stirred overnight. The reaction was quenched by slowly dropping 10mL of methanol under stirring in an ice-water bath, 20mL of methylene chloride was added, the reaction mixture was washed with 30mL of saturated aqueous sodium bicarbonate solution, the organic layer was washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was slurried with 10mL of diethyl ether, filtered, and dried under reduced pressure to give compound 11E (0.62 g, yield: 87%).

LCMS m/z＝146.0[M+H] ⁺

Sixth step: 2- ((4-amino-2-chloropyrimidin-5-yl) oxy) acetic acid tert-butyl ester (11F)

tert-butyl 2-((4-amino-2-chloropyrimidin-5-yl)oxy)acetate

Compound 11E (0.4 g,2.75 mmol) was dissolved in DMF (5 mL) and cesium carbonate (1.34 g,4.13 mmol) and tert-butyl 2-bromoacetate (0.64 g,3.27 mmol) were added sequentially at room temperature and stirred at room temperature for 1 hour after addition. After adding 20mL of ethyl acetate and 20mL of water and stirring, the layers were separated, the organic layer was washed with saturated brine (20 ml×3), 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) =1/10-1/3) to give compound 11F (0.4 g, yield: 56%).

Seventh step: 2-chloro-6H-pyrimido [5,4-b ] [1,4] oxazin-7 (8H) -one (11G)

2-chloro-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one

Compound 11F (0.32 g,1.23 mmol) was dissolved in trifluoroacetic acid (2 mL), stirred at room temperature for 2 hours, concentrated under reduced pressure to remove the solvent, acetic anhydride (2 mL) was added, and the mixture was heated to 120℃and stirred for 2 hours. Cooled to room temperature, 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 give compound 11G (0.11G, yield 48%).

LCMS m/z＝183.9[M-H] ^-

Eighth step: 2-chloro-8- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -6H-pyrimidinyl [5,4-b ] [1,4] oxazin-7 (8H) -one (11H)

2-chloro-8-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one

Compound 11G (0.11G, 0.59 mmol) and 11D hydrochloride (0.24G, 0.71 mmol) were dissolved in DMF (5 mL), cesium carbonate (0.29G, 0.89 mmol) was added, and the mixture was warmed to 70℃and stirred for 3 hours. Cooled to room temperature, 20mL of ethyl acetate and 20mL of water were added, and the mixture was stirred and then separated, and the organic layer was washed with saturated brine (20 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the meal residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (V/V) =1/10-1/1) to give compound 11H (0.15 g, yield: 56%).

LCMS m/z＝452.0[M+H] ⁺

Ninth step: 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -8- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -6H-pyrimidine [5,4-b ] [1,4] oxazin-7 (8H) -one (Compound 11)

2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one

Compound 11H (0.078G, 0.17 mmol) was dissolved in a mixed solvent of 1, 4-dioxane (4 mL) and water (1 mL), and (4-cyclopropyl-6-methoxypyrimidin-5-yl) boric acid (0.066G, 0.34 mmol), potassium phosphate (0.072G, 0.34 mmol) and XPhos G3 (CAS: 1445085-55-1,0.014G,0.017 mmol) were added sequentially, and the mixture was stirred overnight at 90℃under nitrogen. Cooled to room temperature, 10mL of ethyl acetate and 10mL of water were added to stir and the mixture was separated, 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) =1/5-2/1) to give compound 11 (60 mg, yield: 62%).

LCMS m/z＝566.1[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ8.63(s,1H),8.53(s,1H),8.17–8.12(m,1H),7.53–7.43(m,4H),5.25(s,2H),5.05(s,2H),4.49–4.36(m,1H),3.81(s,3H),1.73–1.63(m,1H),1.39(d,6H),1.03–0.95(m,2H),0.80–0.71(m,2H).

Example 12:

the first step: 3- (4-amino-2- (methylthio) pyrimidin-5-yl) acrylic acid ethyl ester (12A)

ethyl 3-(4-amino-2-(methylthio)pyrimidin-5-yl)acrylate

The compound triethyl phosphorylacetate (3.18 g,14.18mmol, CAS: 867-13-0) was dissolved in THF (20 mL), sodium hydride (0.56 g,14.1 mmol) was slowly added under ice-bath, and stirred under ice-water bath for 20 minutes after the addition. A solution of 4-amino-2-methylsulfonylpyrimidine-5-carbaldehyde (2 g,11.82mmol, CAS 770-31-0) in THF (10 mL) was slowly added in an ice-water bath and after the addition was completed, the temperature was naturally raised to room temperature and stirred for 30 minutes. The reaction was quenched by cooling to 0℃and then adding 10mL of saturated aqueous ammonium chloride, and then adding 20mL of ethyl acetate and 20mL of water, and the layers were separated by stirring, and the organic layer was washed 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) =1/10-1/2) to give compound 12A (2.2 g, yield: 78%).

LCMS m/z＝240.1[M+H] ⁺

And a second step of: 2- (methylthio) pyrido [2,3-d ] pyrimidin-7 (8H) -one (12B)

2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

Compound 12A (1 g,4.18 mmol) was dissolved in ethanol (10 mL) and sodium hydride (0.20 g,5.02 mmol) was slowly added and after the addition was complete, the temperature was raised to 80℃and stirred for 2h. Cooling to room temperature, adding 30mL of aqueous solution to quench the reaction, adding 20mL of ethyl acetate to extract and separate layers, discarding the organic layer, adjusting the pH of the aqueous phase to be 3-4 by using 1N dilute hydrochloric acid, and precipitating a large amount of solid. The mixture was filtered, and the cake was washed with 10mL of water, and the cake was dried under reduced pressure to give Compound 12B (0.5 g, yield: 62%) which was used directly in the next step.

And a third step of: 8- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -2- (methylthio) pyrido [2,3-d ] pyrimidin-7 (8H) -one (12C)

8-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

Compound 12B (0.2 g,1.04 mmol) and the hydrochloride salt of compound 11D (0.42 g) were dissolved in DMF (5 mL), cesium carbonate (0.68 g,2.09 mmol) and sodium iodide (0.16 g,1.04 mmol) were added sequentially, and stirred at 100deg.C for 2 hours. Cooled to room temperature, 20mL of ethyl acetate and 20mL of water were added and the layers were stirred, and the organic layer was washed with saturated brine (10 ml×3), 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 give compound 12C (0.25 g, yield: 52%).

LCMS m/z＝460.1[M+H] ⁺

Fourth step: 2-chloro-8- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) pyrido [2,3-D ] pyrimidin-7 (8H) -one (12D)

2-chloro-8-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrido[2,3-d]pyrimidin-7(8H)-one

Compound 12C (0.080 g,0.17 mmol) was dissolved in THF (5 mL), m-chloroperoxybenzoic acid (0.056 g,0.32 mmol) was added at room temperature, the reaction was stirred for 2 hours, 10mL of saturated aqueous sodium thiosulfate solution was added, stirring was performed for 30 minutes, 20mL of ethyl acetate was added for extraction, the organic layer was washed with saturated aqueous sodium bicarbonate solution (20 mL. Times.2), the organic layer was concentrated under reduced pressure, the residue was dissolved in a mixed solvent of THF (4 mL) and water (1 mL), sodium hydroxide (0.014 g,0.34 mmol) was added at room temperature, stirring was performed for 10 minutes, and pH=3-4 was adjusted with 1N diluted hydrochloric acid. Filtering after separating out solid, and drying the filter cake under reduced pressure. Acetonitrile (5 mL) and phosphorus oxychloride (0.13 g,0.85 mmol) were added to the filter cake, and the mixture was stirred at 90℃for 2 hours. Cooled to room temperature, concentrated under reduced pressure, added with 20mL of methylene chloride and 20mL of saturated aqueous sodium hydrogencarbonate, stirred for 5 minutes, and then separated, and the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 12D (40 mg, yield: 52%).

LCMS m/z＝448.2[M+H] ⁺

Fifth step: trifluoroacetate salt of 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -8- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) pyrido [2,3-d ] pyrimidin-7 (8H) -one (compound 12)

2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrido[2,3-d]pyrimidin-7(8H)-one；trifluoroacetic acid

Compound 12D (0.040G, 0.089 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl) boronic acid (0.035G, 0.18 mmol) were dissolved in a mixed solvent of 1, 4-dioxane (4 mL) and water (1 mL), followed by the addition of potassium phosphate (0.057G, 0.27 mmol) and XPhos G3 (0.0075G, 0.0089 mmol). The nitrogen was replaced three times, warmed to 90 ℃ and stirred overnight. Cooled to room temperature, extracted with 20mL of water and 20mL of ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate/petroleum ether (V/V) =1/5-1/0). The crude product obtained was further purified by preparative HPLC (instrument: waters 2767 for liquid phase; chromatographic column: sunFire@PrepC18 (19 mm. Times.150 mm); mobile phase composition: mobile phase A: acetonitrile mobile phase B: water (containing 0.1% trifluoroacetic acid)) to give the trifluoroacetate salt of compound 12 (15 mg).

LCMS m/z＝562.2[M+H] ⁺

¹ H NMR(400MHz,CD ₃ OD)δ9.18(s,1H),8.63(s,1H),8.10(d,1H),7.98–7.91(m,1H),7.59–7.44(m,4H),6.90(d,1H),5.73(s,2H),4.57–4.44(m,1H),3.91(s,3H),1.81–1.71(m,1H),1.43(d,6H),1.16–1.08(m,2H),0.86–0.77(m,2H).

Example 13:

the first step: 2- (4- (chloromethyl) phenyl) -1-isopropyl-4- (trifluoromethyl) -1H-imidazole (11D)

2-(4-(chloromethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole

Compound 11C (0.4 g,1.41 mmol) was dissolved in DCM (2 mL), and thionyl chloride (0.82 g,6.9 mmol) was added at room temperature and stirred for 2 hours. Concentrated under reduced pressure, 10mL of ethyl acetate and 10mL of saturated sodium bicarbonate were added thereto, and the mixture was stirred and then separated, and the organic layer was washed with saturated brine (10 mL. Times.3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 11D (0.42 g) which was used directly in the next step.

And a second step of: 2-chloro-7, 8-dihydro-6H-pyrimido [5,4-b ] [1,4] oxazine (13A)

2-chloro-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine

Compound 11E (0.23 g,1.58 mmol) was dissolved in DMF (15 mL), 1, 2-dibromoethane (0.30 g,1.58 mmol) was added dropwise, potassium carbonate (0.65 g,4.74 mmol) was added again, the temperature was raised to 90℃and stirred for 4 hours, the reaction solution was cooled to room temperature, 50mL of ethyl acetate was added to dilute the reaction solution, water was washed 3 times, saturated brine was washed 1 time, the organic phase was dried over anhydrous sodium sulfate, concentrated in vacuo, and the crude product was purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate=1/1) to give compound 13A (80 mg, yield: 29%).

LCMS m/z＝172.1[M+H] ⁺

And a third step of: 2-chloro-8- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -7, 8-dihydro-6H-pyrimido [5,4-B ] [1,4] oxazine (13B)

2-chloro-8-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine

Compound 13A (80 mg,0.47 mmol) and 11D (142 mg,0.47 mmol) were dissolved in DMF (3 mL), cesium carbonate (306 mg,0.94 mmol) was added and stirred overnight at room temperature. 20mL of ethyl acetate and 10mL of saturated brine were added, the mixture was stirred and then separated, the organic layer was washed with saturated brine (10 mL. Times.3), 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 give compound 13B (180 mg, yield: 87%).

LCMS m/z＝438.1[M+H] ⁺

Fourth step: 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -8- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -7, 8-dihydro-6H-pyrimido [5,4-b ] [1,4] oxazine (Compound 13)

2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine

Compound 13B (180 mg,0.41 mmol) was dissolved in a mixed solvent of 1, 4-dioxane (20 mL) and water (3 mL), and (4-cyclopropyl-6-methoxypyrimidin-5-yl) boric acid (120 mg,0.61 mmol), potassium phosphate (260 mg,1.23 mmol) and XPhos G3 (CAS: 1445085-55-1,35mg,0.041 mmol) were added sequentially, and the mixture was heated to 90℃under nitrogen and stirred overnight. Cooled to room temperature, 20mL of ethyl acetate and 10mL of water were added and stirred to separate the layers, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, the residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether (V/V) =0/1-1/2), the crude product obtained was further purified by preparative HPLC (apparatus: waters 2767 for preparing a liquid phase; column: sunfire@prep C18 (19 mm×150 mm), mobile phase composition: mobile phase a: acetonitrile mobile phase B: water (containing 0.1% trifluoroacetic acid)), the prepared solution was treated with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (20 mL) and separated, the organic phase was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure and then a small amount of acetonitrile/water was added to freeze-dry to give compound 13 (100 mg, yield: 44%).

LCMS m/z＝552.3[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ8.59(s,1H),8.19–8.13(m,1H),7.96(s,1H),7.59–7.49(m,2H),7.48–7.40(m,2H),4.88(s,2H),4.50-4.40(m,1H),4.30(t,2H),3.84(s,3H),3.61(t,2H),1.82–

1.70(m,1H),1.40(d,6H),1.02–0.93(m,2H),0.86–0.75(m,2H).

Example 14:

the first step: (E) -3- (4-amino-2-chloropyrimidin-5-yl) but-2-enoic acid ethyl ester (14A)

ethyl(E)-3-(4-amino-2-chloropyrimidin-5-yl)but-2-enoate

4-amino-2-chloro-5-iodopyrimidine (1 g,3.93 mmol) and pinacol (Z) - (4-ethoxy-4-oxo-2-buten-2-yl) borate (1.13 g,4.72 mmol) were dissolved in DMF (10 mL) and water (2.5 mL), sodium carbonate (1.25 g,11.79 mmol) and Pd (dppf) Cl were added ₂ (0.28 g,0.39 mmol), nitrogen was replaced three times, and the temperature was raised to 100℃under nitrogen protection for 3 hours. Cooled to room temperature, extracted with water and ethyl acetate, and the organic layer was washed 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) =1/50-1/2) to give 14A (0.77 g, yield: 81%).

LCMS m/z＝242.1[M+H] ⁺

And a second step of: 2-chloro-5-methylpyrido [2,3-d ] pyrimidin-7 (8H) -one (14B)

2-chloro-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one

14A (720 mg,2.98 mmol) was dissolved in DMF (30 mL), cesium carbonate (1.94 g,5.95 mmol) was added and reacted at room temperature for 5 hours. Water and ethyl acetate were added to the reaction solution to extract, the organic layer was washed with saturated brine, the organic layer was dried over anhydrous sodium sulfate, and concentrated to dryness, and the residue was purified by silica gel column chromatography (methanol/dichloromethane (V/V) =1/100-1/10) to give 14B (530 mg, yield: 90%).

LCMS m/z＝194.1[M-H] ^-

And a third step of: 2-chloro-8- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -5-methylpyrido [2,3-d ] pyrimidin-7 (8H) -one (14C)

2-chloro-8-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one

Compound 14B (100 mg,0.51 mmol) and compound 11D (169.83 mg,0.56 mmol) were dissolved in DMF (4 mL), cesium carbonate (332.34 mg,1.02 mmol) and sodium iodide (76.44 mg,0.51 mmol) were added, and the temperature was raised to 100℃for 2 hours. Cooled to room temperature, the reaction solution was poured into water, extracted with ethyl acetate, 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) =0/100-60/100) to give 14C (100 mg, yield: 42%).

LCMS m/z＝462.1[M+H] ⁺

Fourth step: 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -8- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -5-methylpyrido [2,3-d ] pyrimidin-7 (8H) -one (compound 14)

2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one

Compound 14C (100 mg,0.22 mmol) was dissolved in a mixed solvent of 1, 4-dioxane (4 mL) and water (1 mL), and (4-cyclopropyl-6-methoxypyrimidin-5-yl) boric acid (85.36 mg,0.44 mmol), potassium phosphate (93.40 mg,0.44 mmol) and XPhos G3 (CAS: 1445085-55-1,18.62mg,0.022 mmol) were added sequentially, and the mixture was stirred overnight at 90℃under nitrogen. Cooled to room temperature, 10mL of ethyl acetate and 10mL of water were added to stir and separate the layers, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/dichloromethane (V/V) =0/100-1/10), to give crude product, which was purified by silica gel column chromatography (ethyl acetate/petroleum ether (V/V) =0/100-1/10) to give compound 14 (13 mg, yield: 10%).

LCMS m/z＝576.2[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ9.33(s,1H),8.68(s,1H),8.17–8.12(m,1H),7.52–7.43(m,2H),7.42–7.33(m,2H),6.76(s,1H),5.56(s,2H),4.51–4.33(m,1H),3.82(s,3H),2.58(s,3H),1.75–1.65(m,1H),1.37(d,6H),1.04–0.96(m,2H),0.77–0.69(m,2H).

Example 15:

the first step: 2-chloro-6, 6-dimethyl-6H-pyrimido [5,4-b ] [1,4] oxazin-7 (8H) -one (15A)

2-chloro-6,6-dimethyl-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one

Compound 11E (0.1 g,0.69 mmol) was dissolved in acetonitrile (5 mL), and potassium carbonate (0.19 g,1.38 mmol) and methyl 2-bromoisobutyrate (0.37 g,2.07 mmol) were added sequentially at room temperature, and after the addition, the mixture was stirred at 60℃for 24 hours. Cooled to room temperature, 20mL of ethyl acetate and 20mL of water were added, and the mixture was stirred and then separated, and the organic layer was washed with saturated brine (20 mL. Times.3), 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) =1/10-1/3) to give compound 15A (0.06 g, yield: 41%).

LCMS m/z＝214.1[M+H] ⁺

And a second step of: 2-chloro-8- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -6, 6-dimethyl-6H-pyrimidinyl [5,4-B ] [1,4] oxazin-7 (8H) -one (15B)

2-chloro-8-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one

Compound 15A (0.06 g,0.28 mmol) and 11D (0.12 g,0.35 mmol) were dissolved in DMF (3 mL), cesium carbonate (0.14 g,0.42 mmol) was added, and the mixture was stirred at 70℃for 3 hours. After cooling to room temperature, 20mL of ethyl acetate and 20mL of water were added and stirred, the layers were separated, and the organic layer was washed with saturated brine (20 mL. Times.3), 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 give compound 15B (0.09 g, yield: 67%).

LCMS m/z＝480.1[M+H] ⁺

And a third step of: 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -8- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -6, 6-dimethyl-6H-pyrimido [5,4-b ] [1,4] oxazin-7 (8H) -one (Compound 15)

2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one

Compound 15B (0.09G, 0.19 mmol) was dissolved in a mixed solvent of 1, 4-dioxane (4 mL) and water (1 mL), and (4-cyclopropyl-6-methoxypyrimidin-5-yl) boric acid (0.066G, 0.34 mmol), potassium phosphate (0.12G, 0.57 mmol) and XPhos G3 (CAS: 1445085-55-1,0.016G,0.019 mmol) were added sequentially, and the mixture was stirred overnight at 90℃under nitrogen. Cooled to room temperature, 10mL of ethyl acetate and 10mL of water were added and stirred for delamination, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether (V/V) =1/5-2/1), and the crude product obtained was further subjected to preparative HPLC (apparatus: waters AutoP preparation liquid phase; column: sunfire@prep C18 (19 mm×250 mM), mobile phase composition: mobile phase a: acetonitrile mobile phase B: water (containing 5mM ammonium acetate), separated and purified, and lyophilized to give compound 15 (10 mg, yield: 9%).

LCMS m/z＝594.3[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ8.64(s,1H),8.57(s,1H),8.16(s,1H),7.55–7.47(m,2H),7.45–7.38(m,2H),5.25(s,2H),4.52–4.34(m,1H),3.82(s,3H),1.80–1.68(m,1H),1.59(s,6H),1.39(d,6H),1.04–0.94(m,2H),0.83–0.70(m,2H).

Example 16:

the first step: 4- (hydroxymethyl) bicyclo [2.2.2] octane-1-carboxylic acid methyl ester (16A)

methyl 4-(hydroxymethyl)bicyclo[2.2.2]octane-1-carboxylate

4- (methoxycarbonyl) bicyclo [2.2.2] octane-1-carboxylic acid (5 g,23.58 mmol) was dissolved in THF (60 mL), and a borane tetrahydrofuran solution (47 mL, 1M) was slowly added dropwise at 0deg.C, and the mixture was stirred overnight at room temperature. TLC monitored completion of the reaction, quenching with methanol at 0deg.C, concentrating under reduced pressure, and purifying the residue by silica gel column chromatography (ethyl acetate/petroleum ether (V/V) =1/20-1/2) to give 16A (3.8 g, yield: 81%).

And a second step of: 4-formyl-bicyclo [2.2.2] octane-1-carboxylic acid methyl ester (16B)

methyl 4-formylbicyclo[2.2.2]octane-1-carboxylate

16A (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 portions at 0deg.C and allowed to react for 3 hours at room temperature. TLC monitoring the reaction completion, concentration under reduced pressure, and purification of the residue by silica gel column chromatography (ethyl acetate/petroleum ether (V/V) =1/20-1/2) gave 16B (3.02 g, yield: 80%).

And a third step of: 4- (4- (trifluoromethyl) -1H-imidazol-2-yl) bicyclo [2.2.2] octane-1-carboxylic acid methyl ester (16C)

1, 1-dibromo-3, 3-trifluoroacetone (4.98 g,18.49mmol, CAS: 431-67-4) was placed in a 250mL single-necked flask, and 30mL of water and sodium acetate (1.89 g,23.09 mmol) were added to react at 90℃for 1 hour. Cooled to room temperature, 60mL of methanol, 6B (3.02 g,15.39 mmol) and concentrated ammonia (15 mL) were added in this order and reacted at 90℃for 2 hours. Cooled to room temperature, the reaction solution was poured into 200mL of water, filtered, and the cake was washed with water (2X 10 mL), and dried under reduced pressure to give 6C (2.9 g, yield: 62%).

LCMS m/z＝303.1[M+H] ⁺

Fourth step: 4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) bicyclo [2.2.2] octane-1-carboxylic acid methyl ester (16D)

16C (2.0 g,6.62 mmol) was dissolved in 30mL DMF at room temperature, isopropyl iodide (4.50 g,26.48 mmol) and cesium carbonate (6.47 g,19.86 mmol) were added sequentially and reacted overnight at 90 ℃. Cooled to room temperature, extracted with water and ethyl acetate, and the organic layer was washed 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) =1/20-1/1) to give 16D (1.2 g, yield: 52%).

LCMS m/z＝345.2[M+H] ⁺

Fifth step: (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) bicyclo [2.2.2] oct-1-yl) methanol (16E)

16D (1.2 g,3.48 mmol) was dissolved in 20mL THF, lithium borohydride (0.38 g,17.40 mmol) was added and stirred at 60℃for 2 hours. Cooled to room temperature, quenched with saturated aqueous ammonium chloride, extracted with water and ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 16E (0.9 g, yield: 81%).

LCMS m/z＝317.2[M+H] ⁺

Sixth step: (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) bicyclo [2.2.2] oct-1-yl) methyl methanesulfonate (16F)

(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl methanesulfonate

Methanesulfonyl chloride (64 mg,0.56 mmol) was added to a solution of compound 16E (0.12 g,0.37 mmol) and triethylamine (0.11 g,1.09 mmol) in dichloromethane (15 mL) at 0deg.C and stirred at room temperature for 1 hour. Quench by adding 20mL of saturated aqueous sodium bicarbonate solution and extract with dichloromethane (20 mL. Times.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) =1/100-1/20) to give compound 16F (0.11 g, yield 74%).

LCMS m/z＝395.1[M+H] ⁺

Seventh step: 8- ((4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) -2- (methylsulfanyl) pyrido [2,3-d ] pyrimidin-7 (8H) -one (16G)

8-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

16F (300 mg,0.76 mmol) and 12B (161.54 mg,0.84 mmol) were dissolved in DMF (5 mL), cesium carbonate (742.87 mg,2.28 mmol) and sodium iodide (113.92 mg,0.76 mmol) were added, and then heated to 140℃for reaction for 5h. Cooled to room temperature, extracted with water and ethyl acetate, and the organic layer was washed 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) =1/50-1/1) to give 16G (320 mg, yield: 85%).

LCMS m/z＝492.3[M+H] ⁺

Eighth step: 2-chloro-8- ((4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) pyrido [2,3-d ] pyrimidin-7 (8H) -one (16H)

2-chloro-8-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one

Compound 16G (280 mg,0.57 mmol) was dissolved in THF (5 mL), m-chloroperoxybenzoic acid (196.73 mg,1.14 mmol) was added at room temperature, stirred for 2 hours, 10mL of saturated aqueous sodium thiosulfate was added, stirred for 30 minutes, 20mL of ethyl acetate was added for extraction, the organic layer was washed with saturated aqueous sodium bicarbonate (20 mL. Times.2), the residue after concentration of the organic layer under reduced pressure was dissolved in a mixed solvent of THF (4 mL) and water (1 mL), sodium hydroxide (45.60 mg,1.14 mmol) was added at room temperature, stirred for 30 minutes, pH was adjusted to acidity with 1N diluted hydrochloric acid, extracted with water and ethyl acetate, the organic layer was washed with saturated aqueous sodium chloride solution, the residue after concentration of the organic layer under reduced pressure was dissolved in acetonitrile (5 mL), phosphorus oxychloride (436.99 mg,2.85 mmol) was added, and stirred for 2 hours at 90 ℃. Cooled to room temperature, concentrated under reduced pressure, added with 20mL of methylene chloride and 20mL of saturated aqueous sodium hydrogencarbonate, stirred for 5 minutes, and then separated, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 16H (160 mg, yield: 58%).

LCMS m/z＝480.1[M+H] ⁺

Ninth step: 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -8- ((4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) pyrido [2,3-d ] pyrimidin-7 (8H) -one (compound 16)

2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one

Compound 16H (150 mg,0.31 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl) boronic acid (120.28 mg,0.62 mmol) were dissolved in a mixed solvent of 1, 4-dioxane (4 mL) and water (1 mL), followed by the addition of potassium phosphate (131.61 mg,0.62 mmol) and XPhos G3 (26.24 mg,0.031 mmol). The nitrogen was replaced three times, warmed to 90 ℃ and stirred overnight. Cooled to room temperature, 20mL of water and 20mL of ethyl acetate were added to extract, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/dichloromethane (V/V) =1/100-1/10), and the obtained crude product was purified again by silica gel column chromatography (ethyl acetate/petroleum ether (V/V) =1/100-60/100) to obtain compound 6 (26 mg, yield: 14%).

LCMS m/z＝594.3[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ9.21(s,1H),8.71(s,1H),8.07(d,1H),7.90–7.85(m,1H),6.84(d,1H),4.93–4.71(m,1H),4.24(s,2H),3.85(s,3H),1.91–1.77(m,6H),1.68–1.59(m,1H),1.58–1.47(m,6H),1.32(d,6H),1.11–1.04(m,2H),0.92–0.85(m,2H).

Example 17:

the first step: 4- (5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl) benzoic acid methyl ester (17A)

methyl 4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate

Methyl 4-hydrazinobenzoate hydrochloride (2.02 g,10.0 mmol) and hexafluoroisopropanol (10 mL) were added to the flask, 1-trifluoro-2, 4-pentanedione (1.54 g,10.0 mmol) was added, triethylamine (2.23 g,22.00 mmol) was slowly added dropwise to the flask under nitrogen protection in an ice bath, and the mixture was allowed to react overnight at room temperature. The reaction was quenched with water (50 mL), extracted with ethyl acetate (60 ml×3), 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) =1/10-1/5) to give compound 17A (2.4 g, yield: 84%).

LCMS m/z＝285.1[M+H] ⁺

And a second step of: (4- (5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl) phenyl) methanol (17B)

(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol

Compound 17A (2.4 g,8.44 mmol) was dissolved in 50mL THF and lithium borohydride (1.84 g,84.4 mmol) was added slowly under ice water bath, and after the addition was complete, the temperature was raised to 50deg.C and stirred for 4 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, the reaction flask was placed in an ice-water bath, a saturated aqueous ammonium chloride solution was slowly added to quench the reaction, 20mL of water was added, ethyl acetate (60 mL. Times.3) was added to extract, an organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give Compound 17B (2.0 g, yield: 92%).

LCMS m/z＝257.2[M+H] ⁺

And a third step of: 1- (4- (chloromethyl) phenyl) -5-methyl-3- (trifluoromethyl) -1H-pyrazole (17C)

1-(4-(chloromethyl)phenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole

Thionyl chloride (8 mL,110.28 mmol) was added to a solution of compound 7B (1.0 g,3.9 mmol) in methylene chloride (10 mL), the reaction was completed after stirring at room temperature for 5 hours, concentrated in vacuo, saturated aqueous sodium bicarbonate and ethyl acetate were added to the resulting crude product, the organic phase was collected after separation, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 17C (1.0 g, yield: 93%).

LCMS m/z＝275.0[M+H] ⁺

Fourth step: 8- (4- (5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl) benzyl) -2- (methylthio) pyrido [2,3-D ] pyrimidin-7 (8H) -one (17D)

8-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

Compound 12B (0.25 g,1.29 mmol) and compound 17C (0.35 g,1.29 mmol) were dissolved in DMF (6 mL), cesium carbonate (0.84 g,2.58 mmol) and sodium iodide (0.19 g,1.29 mmol) were added sequentially, and the mixture was stirred at 100℃for 2 hours. Cooled to room temperature, 20mL of ethyl acetate and 20mL of water were added and the mixture was stirred and separated, and the organic layer was washed with saturated brine (10 mL. Times.3), 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 give compound 17D (0.5 g, yield: 90%).

LCMS m/z＝432.1[M+H] ⁺

Fifth step: 2-chloro-8- (4- (5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl) benzyl) pyrido [2,3-d ] pyrimidin-7 (8H) -one (17E)

2-chloro-8-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)pyrido[2,3-d]pyrimidin-7(8H)-one

Compound 17D (0.5 g,1.16 mmol) was dissolved in THF (10 mL), m-chloroperoxybenzoic acid (0.4 g,2.32 mmol) was added at room temperature, the reaction was stirred for 2 hours, 20mL of saturated aqueous sodium thiosulfate solution was added, stirring was performed for 30 minutes, 20mL of ethyl acetate was added for extraction, the organic layer was washed with saturated aqueous sodium bicarbonate solution (20 mL. Times.2), the organic layer was concentrated under reduced pressure, the residue was dissolved in a mixed solvent of THF (12 mL) and water (4 mL), sodium hydroxide (0.093 g,2.32 mmol) was added at room temperature, stirring was performed for 10 minutes, and pH=3-4 was adjusted with 1N diluted hydrochloric acid. Filtering after separating out solid, and drying the filter cake under reduced pressure. Acetonitrile (10 mL) and phosphorus oxychloride (0.89 g,5.80 mmol) were added to the filter cake, and the mixture was stirred at 90℃for 2 hours. Cooled to room temperature, concentrated under reduced pressure, added with 20mL of methylene chloride and 20mL of saturated aqueous sodium hydrogencarbonate, stirred for 5 minutes, and then separated, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 17E (300 mg, yield: 61%).

LCMS m/z＝420.1[M+H] ⁺

Sixth step: 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -8- (4- (5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl) benzyl) pyrido [2,3-d ] pyrimidin-7 (8H) -one (compound 17)

2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)pyrido[2,3-d]pyrimidin-7(8H)-one

Compound 17E (0.15G, 0.36 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl) boronic acid (0.14G, 0.72 mmol) were dissolved in a mixed solvent of 1, 4-dioxane (6 mL) and water (1.5 mL), followed by the addition of potassium phosphate (0.15G, 0.72 mmol) and XPhos G3 (0.03G, 0.036 mmol). The nitrogen was replaced three times, warmed to 90 ℃ and stirred overnight. Cooled to room temperature, extracted with 20mL of water and 20mL of ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate/petroleum ether (V/V) =1/5-1/0). The crude product obtained was further subjected to preparative HPLC (instrument: GILSON GX-281 preparation liquid; chromatographic column: porosill 120 HPH-C18.2X105 mm,4 μm; mobile phase composition: mobile phase A: acetonitrile mobile phase B: water (0.05% ammonia water)), separation and purification, and lyophilization to give compound 17 (40 mg, yield: 21%).

LCMS m/z＝534.1[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ9.29(s,1H),8.69(s,1H),8.16(d,1H),7.54–7.38(m,4H),6.91(d,1H),6.73(s,1H),5.58(s,2H),3.83(s,3H),2.30(s,3H),1.79–1.65(m,1H),1.06–0.96(m,2H),0.82–0.70(m,2H).

Example 18:

the first step: 2-chloro-6, 6-dimethyl-7, 8-dihydro-6H-pyrimido [5,4-b ] [1,4] oxazine (18A)

2-chloro-6,6-dimethyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine

Compound 15A (0.3 g,1.40 mmol) was dissolved in THF (10 mL), lithium aluminum hydride solid (0.11 g,2.90 mmol) was added at room temperature, nitrogen was replaced three times, and the temperature was raised to 60℃and stirred for 2h. Cooled to room temperature, quenched by slowly adding 10mL of water, extracted with 20mL of ethyl acetate, and the organic layer was washed once with 10mL of saturated brine, 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) =1/10-1/2) to give compound 18A (0.12 g, yield: 43%).

LCMS m/z＝200.20[M+H] ⁺

And a second step of: 2-chloro-8- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -6, 6-dimethyl-7, 8-dihydro-6H-pyrimidinyl [5,4-B ] [1,4] oxazine (18B)

2-chloro-8-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine

Compound 18A (0.12 g,0.60 mmol) and 11D (0.20 g,0.66 mmol) were dissolved in DMF (5 mL), cesium carbonate (0.39 g,1.19 mmol) was added at room temperature and stirred overnight at room temperature. 20mL of water and 20mL of ethyl acetate were added to extract, the organic layer was washed with saturated brine (10 mL. Times.3), 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) =1/10-1/2) to give compound 18B (0.2 g, yield: 72%).

LCMS m/z＝466.20[M+H] ⁺

And a third step of: 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -8- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -6, 6-dimethyl-7, 8-dihydro-6H-pyrimido [5,4-b ] [1,4] oxazine (Compound 18)

2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,6-dimethyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine

Compound 18B (0.2G, 0.43 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl) boronic acid (0.17G, 0.86 mmol) were dissolved in a mixed solvent of 1, 4-dioxane (4 mL) and water (1 mL), followed by the addition of potassium phosphate (0.18G, 0.86 mmol) and XPhos G3 (0.036G, 0.043 mmol). The nitrogen was replaced three times, warmed to 90 ℃ and stirred overnight. Cooled to room temperature, 20mL of water and 20mL of ethyl acetate were added to extract, and 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) =1/5-1/0) to give compound 18 (0.11 g, yield: 44%).

LCMS m/z＝580.3[M+H] ⁺

¹ H NMR(400MHz,CD ₃ OD)δ8.54(s,1H),7.92–7.88(m,1H),7.85(s,1H),7.56–7.50(m,4H),4.97(s,2H),4.60–4.45(m,1H),3.94(s,3H),3.41(s,2H),1.85–1.76(m,1H),1.45(d,6H),1.34(s,6H),1.14–1.08(m,2H),0.93–0.86(m,2H).

Example 19:

the first step: 2-chloro-8- (4- (5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl) benzyl) -7, 8-dihydro-6H-pyrimidinyl [5,4-b ] [1,4] oxazine (9A)

2-chloro-8-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine

Compound 13A (300 mg,1.7 mmol) and 17C (528.74 mg,1.93 mmol) were dissolved in DMF (10 mL), cesium carbonate (1710.56 mg,5.25 mmol) was added and reacted overnight at room temperature. Ethyl acetate and water were added and stirred, the layers were separated, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (V/V) =1/100-1/1) to give compound 19A (550 mg, yield: 76%).

LCMS m/z＝410.1[M+H] ⁺

And a second step of: 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -8- (4- (5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl) benzyl) -7, 8-dihydro-6H-pyrimido [5,4-b ] [1,4] oxazine (Compound 19)

2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine

Compound 19A (500 mg,1.22 mmol) was dissolved in a mixed solvent of 1, 4-dioxane (10 mL) and water (2.5 mL), and (4-cyclopropyl-6-methoxypyrimidin-5-yl) boric acid (359.05 mg,1.83 mmol), potassium phosphate (776.91 mg,3.66 mmol) and XPhos G3 (CAS: 1445085-55-1,103.27mg,0.12 mmol) were sequentially added, and the mixture was reacted overnight at 90℃under nitrogen blanket by three times replacing nitrogen. Cooled to room temperature, ethyl acetate and water were added and the layers were stirred and separated, and 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) =1/100-1/5) to give compound 19 (380 mg, yield: 59%).

LCMS m/z＝524.2[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ8.59(s,1H),7.96(s,1H),7.59–7.43(m,4H),6.75(s,1H),4.89(s,2H),4.29(t,2H),3.84(s,3H),3.61(t,2H),2.33(s,3H),1.82–1.71(m,1H),1.02–0.95(m,2H),0.87–0.77(m,2H).

Example 20:

the first step: 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -5-methylpyrido [2,3-d ] pyrimidin-7 (8H) -one (20A)

2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one

Compound 14B (1.9G, 9.71 mmol) was dissolved in a mixed solvent of 1, 4-dioxane (30 mL) and water (7.5 mL), and (4-cyclopropyl-6-methoxypyrimidin-5-yl) boric acid (2.83G, 14.57 mmol), potassium phosphate (6.18G, 29.13 mmol) and XPhos G3 (CAS: 1445085-55-1,0.82G,0.97 mmol) were sequentially added, replaced with nitrogen three times, and the temperature was raised to 90℃under nitrogen protection for 2 hours. Cooled to room temperature, ethyl acetate and water were added and the layers were stirred and separated, and the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/dichloromethane (V/V) =0/100-1/10) to give 20A (2.3 g, yield: 76%).

LCMS m/z＝310.3[M+H] ⁺

And a second step of: 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -8- ((4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) -5-methylpyrido [2,3-d ] pyrimidin-7 (8H) -one (compound 20)

2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one

20A (200 mg,0.65 mmol) and 16F (282.03 mg,0.72 mmol) were dissolved in DMF (5 mL), cesium carbonate (423.57 mg,1.3 mmol) and sodium iodide (97.43 mg,0.65 mmol) were added, and then heated to 130℃for reaction for 5h. Cooled to room temperature, extracted with water and ethyl acetate, the organic layer was washed 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) =1/100-2/1), and the crude product obtained was further subjected to preparative HPLC (apparatus: waters AutoP preparation liquid phase; column: sunfire@prep C18 (19 mm×250 mM; mobile phase composition: mobile phase a: acetonitrile mobile phase B: water (containing 5mM ammonium acetate)) to obtain compound 20 (50 mg, yield: 12%) by freeze-drying after separation and purification.

LCMS m/z＝608.5[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ9.25(s,1H),8.72(s,1H),7.91–7.84(m,1H),6.72–6.68(m,1H),4.92–4.73(m,1H),4.40–4.04(m,2H),3.85(s,3H),2.54(s,3H),1.90–1.76(m,6H),1.67–1.58(m,1H),1.57–1.45(m,6H),1.32(d,6H),1.12–1.04(m,2H),0.93–0.83(m,2H).

Example 21:2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -5-methyl-8- (4- (5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl) benzyl) pyrido [2,3-d ] pyrimidin-7 (8H) -one (compound 21)

2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-methyl-8-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)pyrido[2,3-d]pyrimidin-7(8H)-one

Compound 20A (200 mg,0.65 mmol) and 17C (196.39 mg,0.72 mmol) were dissolved in DMF (5 mL), cesium carbonate (424 mg,1.3 mmol) was added and the temperature was raised to 70℃for 2h. Ethyl acetate and water were added and stirred, the layers were separated, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (V/V) =1/100-2/1) to give compound 21 (210 mg, yield: 59%).

LCMS m/z＝548.7[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ9.33(s,1H),8.69(s,1H),7.56–7.34(m,4H),6.78-6.75(m,1H),6.73(s,1H),5.57(s,2H),3.82(s,3H),2.61-2.55(m,3H),2.30(s,3H),1.76–1.66(m,1H),1.05–0.98(m,2H),0.81–0.72(m,2H).

Example 22:

the first step: 2-chloro-6, 6-dimethyl-8- (4- (5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl) benzyl) -6H-pyrimidinyl [5,4-b ] [1,4] oxazin-7 (8H) -one (22A)

2-chloro-6,6-dimethyl-8-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one

Compound 15A (0.06 g,0.28 mmol) and 17C (0.10 g,0.36 mmol) were dissolved in DMF (3 mL), cesium carbonate (0.14 g,0.42 mmol) was added, and the mixture was stirred at 70℃for 3 hours. After cooling to room temperature, 20mL of ethyl acetate and 20mL of water were added and stirred, the layers were separated, and the organic layer was washed with saturated brine (20 mL. Times.3), 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 give compound 22A (0.10 g, yield: 79%).

LCMS m/z＝452.1[M+H] ⁺

And a second step of: 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -6, 6-dimethyl-8- (4- (5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl) benzyl) -6H-pyrimido [5,4-b ] [1,4] oxazin-7 (8H) -one (Compound 22)

2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-8-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one

Compound 22A (0.10G, 0.22 mmol) was dissolved in a mixed solvent of 1, 4-dioxane (4 mL) and water (1 mL), and (4-cyclopropyl-6-methoxypyrimidin-5-yl) boric acid (0.077G, 0.40 mmol), sodium bicarbonate (0.037G, 0.44 mmol) and XPhos G3 (CAS: 1445085-55-1,0.019G,0.022 mmol) were added sequentially, and the mixture was stirred at 95℃under nitrogen. Cooled to room temperature, 10mL of ethyl acetate and 10mL of water were added to stir and the layers were separated, 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) =1/5-1/1), followed by lyophilization to give compound 22 (70 mg, yield: 56%).

LCMS m/z＝566.2[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ8.64(s,1H),8.57(s,1H),7.55–7.40(m,4H),6.74(s,1H),5.26(s,2H),3.82(s,3H),2.31(s,3H),1.81–1.71(m,1H),1.59(s,6H),1.03–0.95(m,2H),0.83–0.74(m,2H).

Example 23:

the first step: 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -6, 6-dimethyl-6H-pyrimido [5,4-b ] [1,4] oxazin-7 (8H) -one (23A)

2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,6-dimethyl-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one

Compound 15A (0.30G, 1.40 mmol) was dissolved in a mixed solvent of 1, 4-dioxane (12 mL) and water (3 mL), and (4-cyclopropyl-6-methoxypyrimidin-5-yl) boric acid (0.49G, 2.52 mmol), sodium bicarbonate (0.24G, 2.80 mmol) and XPhos G3 (CAS: 1445085-55-1,0.12G,0.14 mmol) were added sequentially, and the mixture was heated to 95℃under nitrogen and stirred for 3 hours. Cooled to room temperature, 10mL of ethyl acetate and 10mL of water were added to stir and the layers were separated, 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) =1/10-1/2) to give compound 23A (360 mg, yield: 79%).

LCMS m/z＝328.1[M+H] ⁺

And a second step of: 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -8- ((4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) bicyclo [2.2.2] oct-1-yl) methyl) -6, 6-dimethyl-6H-pyrimido [5,4-b ] [1,4] oxazin-7 (8H) -one (Compound 23)

2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-6,6-dimethyl-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one

23A (0.20 g,0.61 mmol) and 16F (0.26 g,0.67 mmol) were dissolved in DMF (10 mL), cesium carbonate (0.40 g,1.22 mmol) and sodium iodide (0.091 g,0.61 mmol) were added, and the mixture was stirred at 130℃for 6 hours. After cooling to room temperature, 20mL of ethyl acetate and 20mL of water were added and stirred and then the layers were separated, the organic layer was washed with saturated brine (20 mL. Times.3), 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), and the crude product obtained was further subjected to preparative HPLC (instrument: waters AutoP preparative liquid phase; chromatographic column: sunFire@PrepC18 (19 mM. Times.250 mM); mobile phase composition: mobile phase A: acetonitrile mobile phase B: water (containing 5mM ammonium acetate)) to obtain compound 23 (65 mg, yield: 17%) by freeze-drying.

LCMS m/z＝626.7[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ8.67(s,1H),8.51(s,1H),7.90–7.84(m,1H),4.91–4.73(m,1H),3.90(s,2H),3.85(s,3H),1.94–1.77(m,6H),1.75–1.65(m,1H),1.62–1.42(m,12H),1.33(d,6H),1.10–1.01(m,2H),0.95–0.84(m,2H).

Biological test case

Test example 1: USP1/UAF1 enzymatic inhibitory Activity

Ubiquitin rhodamine 110 is used as a substrate, and the activity of deubiquitinase USP1/UAF1 after drug treatment is detected. The total assay system was 20. Mu.l, and the assay buffer was 50mM Tris-HCl, pH 7.8,0.5mM EDTA,0.01%Bovine Serum Albumin,l mM DTT,0.01%Tween-20. At the beginning of the assay, 0.5nM of USP1/UAF1 (Bio-Techne, E-568-050) protein was added to 384 well plates (Perkinelmer, 6008269), followed by incubation at room temperature for 10min with gradient dilutions of the test compound, 500nM of ubiquitin rhodamine 110 (Bio-Techne, U-555-050) and incubation at room temperature for 20min. Using Enspire ^TM Multilabel Reader microplate reader (Perkinelmer) was tested at 485nM excitation/535 nM emission. Calculating IC by using GraphPad Prism software ₅₀ Values.

TABLE 1 results of test Compounds for the enzymatic inhibitory Activity of USP1/UAF1

Numbering of compounds	IC ₅₀ (nM)
		Trifluoroacetate salt of Compound 4	A
Compound 6	A
		Compound 8	A
Compound 11	A
		Compound 12Trifluoroacetate salt	A
Compound 13	A
		Compound 14	A
Compound 15	A
		Compound 16	A
Compound 17	A
		Compound 18	A
Compound 19	A
		Compound 20	A
Compound 21	A
		Compound 22	A

Note that: a < 20nM

Conclusion: the compound has good inhibition effect on the enzymatic activity of USP1/UAF 1.

Test example 2: MDA-MB-436 cell clone formation assay

The ability of the test to determine cell clone formation was measured using MDA-MB-436 cells, after treatment with the test compound. At the beginning of the assay, MDA-MB-436 cells (ATCC, HTB-130) were added to 96-well plates (Corning, 3599), 500 cells per well, and attached overnight; the next day the gradient diluted compound was added and placed at 37℃without CO ₂ On day 7, old medium was discarded, and the test compound was added in gradient dilution again, and by day 14, 96-well plates were removed, medium was discarded, and cell clones were examined using Crystal violet Assay kit. At OD using PHERAstar FSX microplate reader (BMG LABECH) ₅₇₀ Detection at nM. Calculating IC by using GraphPad Prism software ₅₀ Values.

TABLE 2 results of test Compounds for MDA-MB-436 cell clone inhibitory Activity

Numbering of compounds	IC ₅₀ (nM)
		Trifluoroacetate salt of Compound 4	A
Trifluoroacetate salt of Compound 12	A
		Compound 13	A
Compound 15	A

Note that: a is less than 100nM,

conclusion: the compound has good inhibition effect on MDA-MB-436 cell clone formation.

Test example 3: beagle pharmacokinetic testing

The purpose of the experiment is as follows: the concentration of the test substance in the beagle plasma was measured by administering the test substance to the beagle by intravenous and intragastric administration at a single dose, and the in vivo pharmacokinetic profile of the test substance was evaluated.

Test animals: about 8-11 kg of male beagle dogs are purchased from Beijing Mas Biotechnology Co., ltd.

The test method comprises the following steps: on the day of the trial, beagle dogs were randomly grouped by body weight. The water is not forbidden for 14-18 h after 1 day of feeding, and the feed is fed for 4h after the feeding. Dosing was according to the information in the table below.

Intravenous administration vehicle: 5% DMA+5% Solutol+90% Saline; gastric lavage dosing vehicle: 0.5% MC

( DMA: dimethylacetamide; solutol: polyethylene glycol-15-hydroxystearate; saline: physiological saline; MC: a methylcellulose solution; )

Sampling: blood was taken through the jugular vein or the limb vein before and after administration and placed in an EDTAK2 centrifuge tube. The plasma was collected by centrifugation at 5000rpm at 4℃for 10 min.

Blood collection time point: 0,5min,15min,30min,1h,2h,4h,6h,8h,10h,12h,24h,48h,72h. All samples were stored at-80 ℃ prior to analytical testing. The samples were quantitatively analyzed by LC-MS/MS.

Table 3 pharmacokinetic parameters of test compounds in beagle plasma

Test compounds	Administration mode	AUC _0-t (h.ng.mL ^-1 )	F(％)
				Compound 4	i.g.(5mg/kg)	6581	70.9
Control Compound A	i.g.(5mg/kg)	994	15.8

* And (3) injection: (lavage) administration of the compound.

Conclusion: the compound synthesized by the technology has good oral absorption performance in beagle dogs, and the oral performance is superior to that of a control compound A.

Claims

1. A compound or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from the group consisting of compounds of formula (I), formula (II) and formula (III),

wherein the compound of formula (I) is as follows:

R ¹ selected from H, halogen, cyano, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, said alkyl, alkenyl, alkynyl, alkoxy optionally being substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano、NH ₂ 、C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Alkoxy, halogen substituted C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl-and cyano-substituted C _1-6 Substituted by alkyl;

X ₁ 、X ₂ each independently selected from N or CR ^x ；

cy is selected from C _3-12 Non-aromatic carbocyclic ring, 4-to 12-membered non-aromatic heterocyclic ring, benzo C _4-6 Carbocycle, benzo 4 to 6 membered heterocycle, 5 membered heteroaryl ring, pyrimidine, pyrazine, 8 to 10 membered fused ring heteroaryl ring, said Cy optionally being substituted with 1 to 4 substituents selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Alkoxy, halogen substituted C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl-and cyano-substituted C _1-6 Alkyl, C _3-6 Cycloalkyl or a substituent of a 3 to 8 membered heterocyclic group, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;

provided that the compound of formula (I) is not:

the compounds of formula (II) are shown below:

ring A is selected fromLeft side and R ² Connecting;

X ₁ selected from N or CR ⁸ ；

y is selected from O, S, S (=O), S (=O) ₂ 、S(＝O) ₂ N(R ^y )、N(R ^y )、C _1-4 Alkylene, -OC _1-3 Alkylene-, -C _1-3 Alkylene group O-, -C _1-3 Alkylene S-, -SC _1-3 Alkylene-, -C _1-3 Alkylene S (=o) -, -S (=o) C _1-3 Alkylene-, -C _1-3 Alkylene group S (=o) ₂ -、-S(＝O) ₂ C _1-3 Alkylene-, -N (R) ^y )C _1-3 Alkylene-, -C _1-3 Alkylene N (R) ^y ) -said alkylene group optionally being 1 to 4 groups selected from H, halogen, = O, OH, cyano, C _1-6 Alkyl, halogen substituted C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Substituted cycloalkyl;

NHC(＝O)、-OCH ₂ -、-CH ₂ O-、C _1-3 An alkylene group;

R ³ 、R ⁴ each independently selected from H, halogen, OH, cyano, NH ₂ 、C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 An alkoxy group, an amino group,said alkyl, alkenyl, alkynyl, alkoxy is optionally substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Alkoxy, halogen substituted C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl-and cyano-substituted C _1-6 Alkyl, C _3-6 Cycloalkyl or a 3 to 8 membered heterocyclyl group substituted with 1 to 4 heteroatoms selected from O, S, N;

alternatively, R ⁶ 、R ⁷ Together with the carbon atoms to which they are attached form C _3-6 Cycloalkyl, 3-to 8-membered heterocycle, said cycloalkyl or heterocycle optionally being substituted with 1 to 4 substituents selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Alkoxy, halogen substituted C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl-and cyano-substituted C _1-6 Alkyl, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;

the compounds of formula (III) are shown below:

ring A is selected from

Selected from single bond or double bond;

A ₁ selected from C (R) ^a ) ₂ 、NR ^a Or c=o；

A ₂ Selected from C (R) ^a ) ₂ 、CR ^a O, S, N or NR ^a ；

alternatively, two R ^a Atoms directly attached thereto forming C _3-6 Carbocyclyl or 3-6 membered heterocyclyl, optionally substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Alkoxy, halogen substituted C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl-and cyano-substituted C _1-6 Alkyl, C _3-6 Cycloalkyl or a 3 to 8 membered heterocyclyl group substituted with 1 to 4 heteroatoms selected from O, S, N;

R ² selected from C _6-10 Carbocycle or 5-to 10-membered heterocycle, said carbonThe ring or heterocycle optionally being substituted with 1 to 4R ^2a Substitution;

cy is selected from C _3-12 Carbocycle or 4 to 12 membered heterocycle, said Cy optionally being substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Alkoxy, halogen substituted C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl-and cyano-substituted C _1-6 Alkyl, C _3-6 Substituted by cycloalkyl or by substituents of 3-to 8-membered heterocyclic groups containing 1-4 optional groupsA heteroatom from O, S, N;

m is selected from 0, 1, 2 or 3.

2. The compound of claim 1, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,

the definition of the compounds of the general formula (I) is as follows:

R ¹ selected from H, halogen, cyano, C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _1-4 Alkoxy, said alkyl, alkenyl, alkynyl, alkoxy optionally being substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl groupCyano-substituted C _1-4 Substituted by alkyl;

cy is selected from C _4-6 Monocyclic cycloalkyl, C _5-11 Cycloalkyl radicals C _5-11 Spiro cycloalkyl, C _5-11 Bridged cycloalkyl, 4-to 7-membered monocyclic heterocycloalkyl, 6-to 11-membered fused-ring heterocycloalkyl, 6-to 11-membered spirocycloalkyl, 6-to 11-membered bridged-ring heterocycloalkyl, benzoC _4-6 Carbocycle, benzo 4 to 6 membered heterocycle, 5 membered heteroaryl ring, pyrimidine, pyrazine, 8 to 10 membered fused ring heteroaryl ring, said Cy optionally being substituted with 1 to 4 substituents selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl-and cyano-substituted C _1-4 Alkyl group,C _3-6 Cycloalkyl or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, N; r is R ⁵ Selected from-Z-C _6-10 Carbocycle or-Z-5 to 10 membered heterocycle, said R ⁵ Optionally by 1 to 4R ^5a Substitution;

R ^5a each independently selected from H, halogen, OH, cyano, NH ₂ 、C _1-4 Alkyl, C _1-4 Alkoxy, C _3-6 Cycloalkyl or a 3-to 6-membered heterocycle, said alkyl, alkoxy, cycloalkyl, heterocycle optionally being substituted with 1 to 4 substituents selected from H, halogen, OH, =o, cyano, NH ₂ 、-C(＝O)NH ₂ 、-C(＝O)NHC _1-4 Alkyl, -C (=o) N (C) _1-4 Alkyl group ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl-and cyano-substituted C _1-4 Alkyl, C _3-6 Cycloalkyl or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, N; or (b)

The general formula (II) is defined as follows,

R ^5a each independently selected from H, halogen, OH, cyano, NH ₂ 、C _1-4 Alkyl, C _1-4 Alkoxy, C _3-6 Cycloalkyl or a 3-to 6-membered heterocycle, said alkyl, alkoxy, cycloalkyl, heterocycle optionally being substituted with 1 to 4 substituents selected from H, halogen, OH, =o, cyano, NH ₂ 、-C(＝O)NH ₂ 、-C(＝O)NHC _1-4 Alkyl, -C (=o) N (C) _1-4 Alkyl group ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl-and cyano-substituted C _1-4 Alkyl, C _3-6 Substituents of cycloalkyl or 3-to 8-membered heterocyclic ringSubstituted, said heterocycle containing from 1 to 4 heteroatoms selected from O, S, N;

alternatively, R ⁶ 、R ⁷ Together with the carbon atoms to which they are attached form C _3-6 Cycloalkyl, 3-to 8-membered heterocycle, said cycloalkyl or heterocycle optionally being substituted with 1 to 4 substituents selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl-and cyano-substituted C _1-4 Alkyl, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N; or (b)

The general formula (III) is selected from compounds shown in the general formula (IIIa), and is defined as follows,

selected from single bond or double bond;

A ₁ selected from C (R) ^a ) ₂ 、NR ^a Or c=o;

A ₂ selected from C (R) ^a ) ₂ 、CR ^a O, S, N or NR ^a ；

R ^a Each independently selected from H, halogenPlain, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _1-4 Alkoxy or C _3-6 Cycloalkyl, said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl optionally being substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl-and cyano-substituted C _1-4 Alkyl, C _3-6 Cycloalkyl or a 3 to 8 membered heterocyclyl group substituted with 1 to 4 heteroatoms selected from O, S, N;

alternatively, two R ^a Atoms directly attached thereto forming C _3-6 Carbocyclyl or 3-6 membered heterocyclyl, optionally substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl-and cyano-substituted C _1-4 Alkyl, C _3-6 Cycloalkyl or a 3 to 8 membered heterocyclyl group substituted with 1 to 4 heteroatoms selected from O, S, N;

R ^2a each independently selected from H, halogen, OH, =O, cyano, NH ₂ 、NH(C _1-4 Alkyl), N (C) _1-4 Alkyl group ₂ 、-SO ₂ -C _1-4 Alkyl, -SO ₂ -C _3-6 Cycloalkyl, C _1-4 Alkyl, C _1-4 Alkoxy, C _1-4 Alkylthio group,-Z-C _3-6 Cycloalkyl or-Z-3 to 6 membered heterocycle, said alkyl, cycloalkyl, alkoxy, alkylthio, heterocycle optionally being substituted with 1 to 4 substituents selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Substituted with an alkoxy substituent, said heterocycle containing 1 to 4 heteroatoms selected from O, S, N;

cy is selected from C _3-6 Monocyclic cycloalkyl, C _5-11 Cycloalkyl radicals C _5-11 Spiro cycloalkyl, C _5-11 Bridged cycloalkyl, 4-to 7-membered monocyclic heterocycloalkyl, 6-to 11-membered fused-ring heterocycloalkyl, 6-to 11-membered spirocycloalkyl, 6-to 11-membered bridged-ring heterocycloalkyl, benzene ring, benzoC _4-6 Carbocycle, benzo 4 to 6 membered heterocycle, 5 to 6 membered heteroaryl ring, 8 to 10 membered bicyclic heteroaryl ring, said Cy optionally being substituted with 1 to 4 substituents selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl-and cyano-substituted C _1-4 Alkyl, C _3-6 Cycloalkyl or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;

m is selected from 0, 1, 2 or 3.

3. The compound according to claim 2, or a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof,

the general formula (I) is defined as follows

Selected from->

R ¹ Selected from H, F, cl, br, I, cyano, methyl or ethyl;

R ^x each independently selected from H, F, cl, br, I, cyano, methyl or ethyl;

R ^2a each independently selected from H, F, cl, br, I, cyano, or R ^2a Each independently selected from one of the following substituted or unsubstituted: -SO ₂ -methyl, -SO ₂ -ethyl, -SO ₂ -propyl, -SO ₂ -isopropyl, -SO ₂ -cyclopropyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, piperazine, oxetanyl, oxolanyl, morpholin, -O-azetidine, -O-azetidinyl, -O-azetidine, -O-oxetanyl, -O-oxa-e Cyclopentyl, -O-oxetanyl, -OCH ₂ -phenyl, optionally substituted by 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Substituted with alkoxy;

R ³ 、R ⁴ each independently selected from H, F, cl, br, I, methyl, ethyl;

cy is selected from cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.2]Octyl and bicyclo [1.1.1]Pentyl, cyclopentyl-cyclopentyl, cyclobutylspirocyclohexyl, cyclobutylspirocyclopentyl, azetidinyl, azetidinspirocyclobutyl, azetidinspirocyclopentyl, azetidinspirocyclohexyl, azetidinspiroazetidinyl, azetidinyl spiroazetidinyl, azetidinspiropentyl, azetidinspiroazetidinyl,

R ^5a each independently selected from H, F, cl, br, I, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl optionally being substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Substituted with alkoxy; or (b)

The general formula (II) is defined as follows

R ^2a each independently selected from H, F, cl, br, I, cyano, or R ^2a Each independently selected from one of the following substituted or unsubstituted: -SO ₂ -methyl, -SO ₂ -ethyl, -SO ₂ -propyl, -SO ₂ -isopropyl, -SO ₂ -cyclopropyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, piperazine, oxetanyl, morpholin, -O-azetidinyl, -O-azaCyclopentyl, -O-azacyclohexyl, -O-oxetanyl, -O-oxolanyl, -OCH ₂ -phenyl, pyrrole, pyrazole, imidazole, thiazole, thiophene, furan, oxazole, optionally substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Substituted with alkoxy;

R ^y each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally being selected from 1 to 4 from H, halogen, = O, CF ₃ OH, cyano, NH ₂ 、C _1-4 Alkyl or C _1-4 Substituted with alkoxy;

R ³ 、R ⁴ each independently selected from H, F, cl, br, I, methyl, ethyl;

R ^5a each independently selected from H, F, cl, br, I, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl optionally being 1 to 4 members selected from H, halogen, OH, = O, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Substituted with alkoxy;

R ⁶ 、R ⁷ each independently selected from H, F, cl, br, I, cyano, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, said methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, and azetidinyl optionally being substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Substituted with alkoxy;

alternatively, R ⁶ 、R ⁷ Together with the carbon atoms to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, optionally substituted with 1 to 4H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Substituted with alkoxy; or (b)

The general formula (IIIa) is defined as follows,

R ¹ Selected from H, F, cl, br, I, cyano, methyl or ethyl;

R ^2a each independently selected from H, F, cl, br, I, cyano, or R ^2a Each independently selected from one of the following substituted or unsubstituted: -SO ₂ -methyl, -SO ₂ -ethyl group、-SO ₂ -propyl, -SO ₂ -isopropyl, -SO ₂ -cyclopropyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, piperazine, oxetanyl, oxolanyl, morpholin, -O-azetidine, -O-azetidinyl, -O-azetidine, -O-oxepinyl, -O-oxetanyl, -O-oxolanyl, -O-oxhexyl, -OCH ₂ -phenyl, pyrrole, pyrazole, imidazole, thiazole, thiophene, furan, oxazole, optionally substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Substituted with alkoxy;

R ³ 、R ⁴ each independently selected from H, F, cl, br, I, methyl, ethyl;

benzene ring, thiophene, furan, pyrrole, thiazole, oxazole, pyrazole, pyrazine, pyrimidine,/-> Benzothiazole, benzothiophene, benzofuran, benzoxazole, benzopyrrole, benzopyrazole, benzimidazole, indolizine, pyridopyrrole, pyridoimidazole, pyridopyrazole, pyrimidoimidazole, pyrimidoizole, pyridotriazole, said Cy optionally being substituted with 1 to 4 substituents selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl-and cyano-substituted C _1-4 Alkyl, C _3-6 Cycloalkyl or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;

R ^5a each independently selected from H, F, cl, br, I, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl optionally being substituted with 1 to 4 groups selected from H, halogen, OH, =o, cyano, NH ₂ 、C _1-4 Alkyl, C _2-4 Alkynyl, C _1-4 The substituent of the alkoxy group is substituted.

4. The compound according to claim 3, or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,

the compound is selected from compounds shown in a general formula (Ia), and the definition is as follows:

cy is selected from />

or Cy is selected from

R ⁵ selected from pyrrole, pyrazole, imidazole optionally substituted with 1 to 4 groups selected from H, F, cl, br, I, cyano, CH ₂ F、CHF ₂ 、CF ₃ Substituents such as methyl, ethyl, propyl, isopropyl, methoxy, and ethoxy; or (b)

The general formula (II) is defined as follows:

R ¹ 、R ⁹ selected from H;

R ⁸ selected from H, F, cl;

y is selected from-OCH ₂ -、-OCH ₂ CH ₂ -、-CH ₂ CH ₂ -、-CH ₂ CH ₂ CH ₂ -、-NHCH ₂ -、-NHCH ₂ CH ₂ -、-SCH ₂ CH ₂ -、-NHC(＝O)-、-NHC(＝O)CH ₂ -、-N(CH ₃ )C(＝O)CH ₂ -, said-CH ₂ -optionally further 0 to 2 are selected from H, F, cl, br, I, = O, OH, cyano, CH ₂ F、CHF ₂ 、CF ₃ Substituents such as methyl, ethyl, propyl, isopropyl, methoxy, and ethoxy;

ring B is selected from pyrazole, imidazole, optionally substituted with 1 to 4 groups selected from H, F, cl, br, I, cyano, CH ₂ F、CHF ₂ 、CF ₃ Substituents such as methyl, ethyl, propyl, isopropyl, methoxy, and ethoxy; or (b)

The general formula (IIIa) is defined as follows:

A ₁ selected from C (R) ^a ) ₂ Or c=o;

A ₂ selected from C (R) ^a ) ₂ 、CR ^a Or O;

R ¹ selected from H;

R ² selected from pyrrole, pyrazole, imidazole, pyrimidine optionally substituted with 1 to 4 groups selected from H, F, cl, br, I, cyano, -SO ₂ -methyl, -SO ₂ -ethyl, -SO ₂ -propyl, -SO ₂ -isopropyl, -SO ₂ -cyclopropyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, and azetidinylPiperazine, oxetane, morpholine, -O-azetidine-O-azacyclohexyl, -O-oxetanyl, -O-oxolanyl, -OCH ₂ -phenyl, pyrrole, pyrazole, imidazole, thiazole, thiophene, furan, oxazole, Is substituted by a substituent of (2);

cy is selected from

R ⁵ selected from pyrrole, pyrazole, imidazole optionally substituted with 1 to 4 groups selected from H, F, cl, br, I, cyano, CH ₂ F、CHF ₂ 、CF ₃ A methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl substituent.

5. The compound of claim 4, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,

the general formula (I) is defined as follows:

R ² selected from the group consisting of

R ⁵ Selected from the group consisting ofOr (b)

The general formula (II) is defined as follows:

ring A is selected from Left side and R ² Connecting;

R ² selected from the group consisting of

Selected from-> Or (b)

The general formula (IIIa) is defined as follows:

selected from->/>

R ² Selected from the group consisting of

R ³ 、R ⁴ Each independently selected from H;

R ⁵ selected from the group consisting of

6. The compound of claim 1, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein the compound is selected from one of the following structures:

/>

7. a pharmaceutical composition comprising a compound of any one of claims 1-6, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, and a pharmaceutically acceptable carrier.

8. The use of a compound according to any one of claims 1-6, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, for the manufacture of a medicament for the treatment of a disease associated with USP1 activity or expression level.

9. The use according to claim 8, wherein the disease is selected from the group consisting of tumors.