Nitrogen-containing heterocyclic ring derivative and composition and pharmaceutical application thereof

Abstract

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 co-crystal of the compound, an intermediate of the compound, and application of the compound in AR-related diseases such as cancers. And B-L-K (I).

Description

A nitrogen-containing heterocyclic derivative and its composition and pharmaceutical application Technical Field

[0001] The present invention relates to a compound of general formula (I) or its stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, as well as intermediates and preparation methods, and uses thereof in AR-related diseases such as cancer. Background Art

[0002] The androgen receptor (AR) is a nuclear hormone receptor structurally divided into an N-terminal activation domain (NTD), a DNA-binding domain (DBD), and a ligand-binding domain (LTD). It regulates the expression of genes that drive prostate cancer, making AR inhibition an effective treatment for prostate cancer. Currently available AR inhibitors, such as enzalutamide and bicalutamide, primarily exert their inhibitory effects by interacting with the AR ligand-binding domain (LTD). However, some patients develop resistance during treatment due to AR splice variants (AR-Vs) lacking the LTD. Preclinical studies have shown that AR splice variants can accelerate the progression of enzalutamide-resistant prostate cancer, making addressing AR resistance a key concern in clinical medicine.

[0003] Small molecule degraders are drugs that utilize the body's ubiquitin-proteasome system (UPS) to degrade target proteins. With their unique catalytic mechanisms, small molecule degraders can target difficult-to-drugged targets and address drug resistance. They are currently a hot topic in drug development for cancer, autoimmune diseases, and other diseases.

[0004] PROTAC (proteolysis targeting chimera) molecules are a class of bifunctional compounds that can simultaneously bind to target proteins and E3 ubiquitin ligases. These compounds can be recognized by the cell's proteasome, causing degradation of the target protein and effectively reducing the target protein's content in the cell. By introducing ligands that can bind to different target proteins into PROTAC molecules, PROTAC technology has become possible for the treatment of various diseases. This technology has also received widespread attention in recent years.

[0005] Molecular glues are small molecules that facilitate contact between target proteins and E3 ubiquitin ligases, inducing interaction between the two and ultimately leading to target protein degradation. Functionally, molecular glues primarily bridge the gap between target proteins and E3 ubiquitin ligases, enhancing their binding interface and promoting strong interactions (Nat. Commun., 2022, 13, 815). Compared to traditional small molecule inhibitors, molecular glues offer the advantages of catalytically driving target protein degradation and eliminating the need for binding pockets on the target protein, potentially targeting undruggable targets.

[0006] Therefore, it is necessary to develop novel androgen receptor splice variants (AR-Vs, especially AR-V7 mutants) inhibitors and PROTACs or other small molecule degraders of E3 ubiquitin ligases for the treatment of tumor diseases associated with androgen receptor splice variants.

[0007] Summary of the Invention

[0008] The purpose of the present invention is to provide a compound with novel structure, good efficacy, high bioavailability, greater safety, and the ability to inhibit and degrade AR and / or AR-Vs (especially AR-V7) for the treatment of AR-related diseases such as prostate cancer.

[0009] The present invention provides a compound or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein the compound is selected from the compound represented by general formula (I),

[0010] BLK (I);

[0011] In certain embodiments, L is selected from a bond or -C 1-50 Hydrocarbyl-, wherein 1 to 20 methylene units in the hydrocarbyl group are optionally replaced by -Ak- or -Cy-;

[0012] In certain embodiments, L is selected from a bond or -C 1-20 Hydrocarbyl-, wherein 1 to 20 methylene units in the hydrocarbyl group are optionally replaced by -Ak- or -Cy-;

[0013] In certain embodiments, L is selected from a bond or -C 1-10 Hydrocarbyl-, wherein 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) methylene units are optionally replaced by -Ak-, -Cy-;

[0014] In certain embodiments, each -Ak- is independently selected from Ak1, Ak2, Ak3, Ak4, or Ak5;

[0015] In certain embodiments, each -Ak- is independently selected from -(CH2) q -、-(CH2) q -O-, -O-(CH2) q -、-(CH2) q -S-, -S-(CH2) q -、-(CH2) q -NR L -、-NR L -(CH2) q -、-(CH2) q -NR L C(=O)-、-NR L (CH2) q C(=O)-、-(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -、-(C≡C) q -、-CH=CH-、-Si(R L )2-、-Si(OH)(R L )-、-Si(OH)2-、-P(=O)(OR L )-、-P(=O)(R L )-, -S-, -S(=O)-, -S(=O)2- or a bond, wherein the -CH2-, -CH=CH- are optionally substituted by 1 to 2 groups selected from halogen, OH, CN, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, halogen-substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 substituted by an alkyl substituent;

[0016] In certain embodiments, each -Cy- is independently selected from Cy1, Cy2, Cy3, Cy4, or Cy5;

[0017] In certain embodiments, each -Cy- is independently selected from a bond or one of the following groups which are optionally substituted: a 4-8 membered heteromonocyclyl, a 4-10 membered heterocycloalkyl, a 5-12 membered heterospirocyclyl, a 7-10 membered heterobridged cyclyl, a 3-7 membered monocycloalkyl, a 4-10 membered cycloalkyl, a 5-12 membered spirocycloalkyl, a 5-10 membered bridged cycloalkyl, a benzoC 4-6 Carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, or 6- to 10-membered aryl, when substituted, is replaced by 1 to 4 R L2Substitution, wherein the heterocyclic group, heteroaryl group, heteromonocyclic group, heterocyclic group, heterospirocyclic group or heterobridged ring group contains 1 to 4 heteroatoms selected from O, S and N, and when the heteroatom is selected from S, it is optionally substituted by 1 or 2 =O;

[0018] In certain embodiments, L is selected from the group consisting of -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, 5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak1-Ak2-Ak 3-Ak4-Ak5-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-, -Cy1 -Ak1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-A k3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak 2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4- Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3- Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, - Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Cy2 -Cy3-Cy4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-, -Cy1-Cy2 -Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy 3-Cy4-, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy 2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-,-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-、-Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-、 -Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-;、

[0019] In certain embodiments, L is selected from a bond, -Ak1-, -Cy1-, -Cy1-Ak1-, -Cy1-Ak1-Ak2-, -Cy1-Ak1-Ak2-Ak3-, -Cy1-Ak1-Ak2-Ak3-Ak4-, -Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-Ak3-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Cy2-Ak2-Ak3-, -Cy1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Ak2-Cy3-, -Cy1-Ak1-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Cy1-Cy2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Cy3-Ak3-, -Cy1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Ak2-Cy3-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-Ak3-Ak4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-, -Cy1-Ak1-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak2-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-Ak4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-, -Ak1-Cy2-, -Ak1-Cy2-Cy3-, -Ak1-Ak2-Cy3-, -Ak1-Ak2-Cy3-Cy4-, -Ak1-Cy2-Ak2-Cy3-, -Ak1-Cy2-Cy3-Ak3-Cy4-, -Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-, -Ak1-Cy2-Ak2-, -Ak1-Ak2-Ak3-Ak4-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak4-Ak5--Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4-, -Ak1-Cy2-Ak2-Ak3-;,

[0020] In certain embodiments, L is selected from a bond, -Ak1-Cy2-, -Ak1-Cy2-Cy3-, -Cy1-Ak1-, -Ak1-Cy2-Ak2-, -Cy1-Cy2-Cy3-, -Cy2-Cy3-, -Cy1-Ak1-Cy2-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Ak1-, -Cy1-, -Ak1-, -Ak1-Cy2-Ak2-Ak3-, -Ak1-Cy2-Ak2-Cy3-, -Ak1-Cy2-Ak2-Ak3-, -Ak1-Cy2-Ak2-Ak3-Ak4-, -NHCO-(CH2) s1 -, s1 is selected from 0, 1, 2, 3, 4, 5, 6 or 7;

[0021] In certain embodiments, L is selected from a bond, a group shown in Table L-1, Table L-2, or Table L-3, and the left side of the group is connected to B;

[0022] In certain embodiments, L is selected from a bond or a group shown in Table L-2, the left side of which is connected to B;

[0023] In certain embodiments, L is selected from the group shown in Table L-3, and the left side of the group is connected to B;

[0024] In certain embodiments, L is selected from

[0025] In certain embodiments, Cy1 is selected from the group consisting of L2 One of the following substituted groups: a 4-12 membered nitrogen-containing heterocyclic group, preferably a 4-7 membered nitrogen-containing heteromonocyclic group, a 4-10 membered nitrogen-containing heterocyclic group, a 5-12 membered nitrogen-containing heterospirocyclic group, or a 7-10 membered nitrogen-containing heterobridged ring group, wherein the nitrogen-containing heterocyclic group contains 1 to 4 (e.g., 1, 2, 3, or 4) heteroatoms selected from O, S, and N, and when the heteroatom is selected from S, it is optionally substituted with 1 or 2 =O;

[0026] In certain embodiments, Cy1 is selected from the group consisting of L2 substituted 4-6 membered nitrogen-containing heterocycle;

[0027] In certain embodiments, L is selected from

[0028] Table L-1 L Group

[0029] Table L-2

[0030] Table L-3

[0031] In certain embodiments, Ak1, Ak2, Ak3, Ak4, and Ak5 are each independently selected from -(CH2) q -、-(CH2) q -O-, -O-(CH2) q -、-(CH2) q -S-, -S-(CH2) q -、-(CH2) q -NR L -、-NR L -(CH2) q -、-(CH2) q -NR L C(=O)-、-(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -、-CH=CH-、-(C≡C) q - or bond, wherein said -CH2-, -CH=CH- are optionally replaced by 1 to 2 (e.g. 1 or 2) selected from halogen, OH, CN, NH2, C 1-4 Alkyl, C 1-4 Alkoxy, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 substituted by an alkyl substituent;

[0032] In certain embodiments, Ak1, Ak2, Ak3, Ak4, and Ak5 are each independently selected from -(CH2) q -、-(CH2) q -O-, -O-(CH2) q -、-(CH2) q -S-, -S-(CH2)q -、-(CH2) q -NR L -、-NR L -(CH2) q -、-(CH2) q -NR L C(=O)-、-(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -, -CH=CH-, -C≡C- or a bond, wherein the -CH2-, -CH=CH- are optionally substituted by 1 to 2 substituents selected from F, Cl, Br, I, OH, CN, NH2, CF3, hydroxymethyl, methyl, ethyl, methoxy or ethoxy;

[0033] In certain embodiments, Ak1, Ak2, Ak3, Ak4, and Ak5 are each independently selected from -O-, -OCH2-, -CH2O-, -OCH2CH2-, -CH2CH2O-, -SCH2-, -CH2S-, -CH=CH-, -CH=C(CN)-, -CH=C(F)-, -C(CN)=CH-, -C(F)=CH-, -C≡C-, -C(CH3)2-, -CH 2-, -CH2CH2-, -CH2CH2CH2-, -N(CH3)-, -NH-, -CH2N(CH3)-, -CH2NH-, -NHCH2-, -CH2CH2N(CH3 )-, -CH2CH2NH-, -NHCH2CH2-, -C(=O)-, -C(=O)CH2NH-, -CH2C(=O)NH-, -C(=O)NH- or -NHC(=O)-;

[0034] In certain embodiments, Ak1, Ak2, Ak3, and Ak4 are each independently selected from -C(=O)-, -O-, NH, -CH=CH-, -CH=C(CN)-, -CH=C(F)-, -C(CN)=CH-, -C(F)=CH-, -C≡C-, -C(CH3)2-, -CH2-, -CH2CH2-, -CH2CH2CH2-, and -NHCO-;

[0035] In certain embodiments, R L Each independently selected from H, C 1-6 Alkyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, phenyl or 5-6 membered heteroaryl, wherein the heterocyclyl or heteroaryl contains 1 to 4 heteroatoms selected from O, S and N;

[0036] In certain embodiments, R LEach independently selected from H or C 1-6 alkyl;

[0037] In certain embodiments, R L Each independently selected from H or C 1-4 alkyl;

[0038] In certain embodiments, R L each independently selected from H, methyl or ethyl;

[0039] In certain embodiments, Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from a bond or one of the following groups which are optionally substituted: a 4-7 membered heteromonocyclic group, a 4-10 membered heterocycloalkyl group, a 5-12 membered heterospirocyclic group, a 7-10 membered heterobridged cyclyl group, a 3-7 membered monocycloalkyl group, a 4-10 membered cycloalkyl group, a 5-12 membered spirocycloalkyl group, a 5-10 membered bridged cycloalkyl group, a benzoC 4-6 Carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, or 6- to 10-membered aryl, when substituted, is replaced by 1 to 4 R L2 Substitution, wherein the heterocyclic group, heteroaryl group, heteromonocyclic group, heterocyclic group, heterospirocyclic group or heterobridged ring group contains 1 to 4 heteroatoms selected from O, S and N, and when the heteroatom is selected from S, it is optionally substituted by 1 or 2 =O;

[0040] In certain embodiments, Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from a bond, a 4-7 membered nitrogen-containing heteromonocyclic group, a 4-10 membered nitrogen-containing heterocycloalkyl group, a 5-12 membered nitrogen-containing heterospirocyclic group, a 7-10 membered nitrogen-containing heterobridged cyclic group, a 3-7 membered monocycloalkyl group, a 4-10 membered cycloalkyl group, a 5-12 membered spirocycloalkyl group, a 5-10 membered bridged cycloalkyl group, a 5-10 membered heteroaryl group or a 6-10 membered aryl group, wherein the heteromonocyclic group, heterocycloalkyl group, heterobridged cyclic group, heterospirocyclic group, cycloalkyl group, aryl group or heteroaryl group is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, COOH, CN, NH2, =O, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 The alkoxy group is substituted by a substituent, wherein the heteromonocyclic group, heterocyclic group, heterobridged ring group, heterospirocyclic group or heteroaryl group contains 1 to 4 heteroatoms selected from O, S and N, and when the heteroatom is selected from S, it is optionally substituted by 1 or 2 =O;

[0041] In certain embodiments, Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from a bond or one of the following groups, which are substituted or unsubstituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azacyclohexenyl, piperidinyl, morpholinyl, piperazinyl, 1,4-diazepanyl, pyridyl, phenyl, cyclopropylcyclopropyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, cyclopropylcyclohexyl, cyclobutylcyclobutyl, cyclobutylcyclobutyl, cyclobutyl cyclopentyl, cyclobutyl and cyclohexyl, cyclopentyl and cyclopentyl, cyclopentyl and cyclohexyl, cyclohexyl and cyclohexyl, cyclopropyl spirocyclopropyl, cyclopropyl spirocyclobutyl, cyclopropyl spirocyclopentyl, cyclopropyl spirocyclohexyl, cyclobutyl spirocyclobutyl, cyclobutyl spirocyclopentyl, cyclobutyl spirocyclohexyl, cyclopentyl spirocyclopentyl, cyclopentyl spirocyclohexyl, cyclohexyl spirocyclohexyl, cyclopropyl and azetidinyl, cyclopropyl and pyrrolidinyl, cyclopropyl and piperidinyl, cyclobutyl and azetidinyl, cyclobutyl and Pyrrolidinyl, cyclobutylpiperidinyl, cyclopentylazetidinyl, cyclopentylpyrrolidinyl, cyclopentylpiperidinyl, cyclohexylazetidinyl, cyclohexylpyrrolidinyl, cyclohexylpiperidinyl, azetidinylazetidinyl, azetidinylpyrrolidinyl, azetidinylpiperidinyl, pyrrolidinylazetidinyl, pyrrolidinylpyrrolidinyl, pyrrolidinylpiperidinyl, piperidinylazetidinyl, piperidinylpyrrolidinyl, piperidinylpiperidinyl, cyclobutyl cyclopentylspiroazetidinyl, cyclobutylspiropyrrolidinyl, cyclobutylspiropiperidinyl, cyclopentylspiroazetidinyl, cyclopentylspiropyrrolidinyl, cyclopentylspiropiperidinyl, cyclohexylspiroazetidinyl, cyclohexylspiropyrrolidinyl, cyclohexylspiropiperidinyl, azetidinylspiroazetidinyl, azetidinylspiropyrrolidinyl, azetidinylspiropiperidinyl, pyrrolidinylspiroazetidinyl, pyrrolidinylspiropyrrolidinyl, pyrrolidinylspiropiperidinyl, piperidinylspiroazetidinyl, piperidinylspiropiperidinyl, When substituted, by 1 to 4 R L2 replace;

[0042] In certain embodiments, Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from a triazole group, wherein the triazole group is optionally substituted by one selected from F, Cl, Br, I, OH, NH2, COOH, CN, =O, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent;

[0043] In certain embodiments, Cy1, Cy2, Cy3, Cy4, or Cy5 are each independently selected from one of the following groups, which are substituted or unsubstituted: When substituted, it is substituted by 1 substituent selected from F, CF3, methyl, methoxy, =O, hydroxymethyl, COOH, CN, OH or NH2;

[0044] In certain embodiments, Cy1, Cy2, Cy3, Cy4, or Cy5 are each independently selected from a bond or one of the following groups, which may be substituted or unsubstituted: When substituted, by 1 to 4 R L2 replace;

[0045] In certain embodiments, R L2 Each independently selected from F, Cl, Br, I, OH, COOH, CN, NH2, NHC 1-4 Alkyl, N(C 1-4 alkyl)2,=O,C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -OC 1-4 Alkylene-OC 1-4 Alkyl, -OC 1-4 Alkylene-OC 3-10 Carbocyclic group, -C 1-4 Alkylene-OC 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkylene-OC 1-4 Alkylene-OC 3-10 Carbocyclic group, -OC 0-4 Alkylene-C 3-10 Carbocyclic group, -C 0-4 Alkylene-C 3-10 Carbocyclic group, -C 0-4 Alkylene-4 to 10 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, COOH, CN, NH2, NHC 1-4 Alkyl, N(C 1-4 alkyl)2,=O,C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy, halogen-substituted C 1-4 substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0046] In certain embodiments, R L2Each independently selected from F, Cl, Br, I, OH, NH2, NHCH3, N(CH3)2, COOH, CN, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -OC 1-2 Alkylene-OC 1-2 Alkyl, -OC 1-2 Alkylene-OC 3-6 Carbocyclic group, -C 1-2 Alkylene-OC 1-2 Alkylene-OC 1-2 Alkyl, -C 1-2 Alkylene-OC 1-2 Alkylene-OC 3-6 Carbocyclic group, -OC 0-2 Alkylene-C 3-6 Carbocyclic group, -C 0-2 Alkylene-C 3-6 Carbocyclic group, -C 0-2 Alkylene-4 to 6 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, COOH, CN, NH2, NHC 1-4 Alkyl, N(C 1-4 alkyl)2,=O,C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy, halogen-substituted C 1-4 substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0047] In certain embodiments, R L2Each is independently selected from F, Cl, Br, =O, COOH, CN, NHCH3, N(CH3)2, OH, NH2 or one of the following groups that are optionally substituted: methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, phenyl, morpholine, -CH2-cyclopropyl, -CH2-morpholine, -CH2-pyrazole, -OCH2-cyclopropyl, -O-cyclopropyl, -OCH2CH2-O-methyl, -OCH2CH2-O-cyclopropyl, -CH2OCH2CH2-O-methyl, -CH2OCH2CH2-O-cyclopropyl, when substituted, by 1 to 4 substituents selected from F, CHF2, CF3, OCHF2, OCF3, methyl, methoxy, =O, CH2OH, COOH, CN, NHCH3, N(CH3)2, OH, NH2;

[0048] In certain embodiments, Cy1, Cy2, and Cy3 are each independently selected from one of the following substituted or unsubstituted groups: When substituted, it is substituted with 1 to 4 substituents selected from F, CF3, OH, methyl, methoxy, =O, hydroxymethyl, COOH, CN or NH2;

[0049] In certain embodiments, B is selected from

[0050] In certain embodiments, B1 is selected from C 3-20 Carbocyclic group or 4-20 membered heterocyclic ring, said carbocyclic group or heterocyclic ring is optionally substituted by 1 to 4 R b1 Substituted, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0051] In certain embodiments, B2 is selected from C 3-20 Carbocyclic group or 4-20 membered heterocyclic ring, said carbocyclic group or heterocyclic ring is optionally substituted by 1 to 4 R b2 Substituted, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0052] In certain embodiments, B3 is selected from C 3-20 Carbocyclic group or 4-20 membered heterocyclic ring, said carbocyclic group or heterocyclic ring is optionally substituted by 1 to 4 R b3 Substituted, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0053] In certain embodiments, B1 is selected from C 3-14 Carbocyclic group or 4-14 membered heterocyclic ring, said carbocyclic group or heterocyclic ring is optionally substituted by 1 to 4 R b1Substituted, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0054] In certain embodiments, B2 is selected from C 3-14 Carbocyclic group or 4-14 membered heterocyclic ring, said carbocyclic group or heterocyclic ring is optionally substituted by 1 to 4 R b2 Substituted, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0055] In certain embodiments, B3 is selected from C 3-14 Carbocyclic group or 4-14 membered heterocyclic ring, said carbocyclic group or heterocyclic ring is optionally substituted by 1 to 4 R b3 Substituted, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0056] In certain embodiments, B3 is selected from a bond;

[0057] In certain embodiments, L1 is selected from a bond or

[0058] In certain embodiments, L2 is selected from a bond or

[0059] In certain embodiments, Y1, Y2, Y3, and Y4 are each independently selected from a bond, O, S, NR b5a ;

[0060] In certain embodiments, Q1, Q2, Q3, and Q4 are each independently selected from

[0061] In certain embodiments, Q1, Q2, Q3, and Q4 are each independently selected from -CH2-;

[0062] In certain embodiments, v1, v2, v3, and v4 are each independently selected from 0, 1, 2, 3, or 4;

[0063] In certain embodiments, L1 and L2 are each independently selected from a bond, -CH2-, -OCH2-, -SCH2-, -NHCH2-, -O-, -S-, -NH-;

[0064] In certain embodiments, B is selected from V is selected from a bond or L1, L1 and L2 are not bonds;

[0065] In certain embodiments, B is selected from

[0066] In certain embodiments, B is selected from

[0067] In certain embodiments, B is selected from

[0068] In certain embodiments, B is selected from

[0069] In certain embodiments, V is selected from a bond, O, S, NR b5a NR b5a -(Q2) v2 -、-(Q2) v2 -NR b5a 、O-(Q2) v2 -、-(Q2) v2 -O, -(Q2) v2 -;

[0070] In certain embodiments, V is selected from a bond, O, S, NR b5a NR b5a -C 1-4 Alkylene, C 1-4 Alkylene-NR b5a , OC 1-4 Alkylene, C 1-4 Alkylene-O, C 1-4 Alkylene, said alkylene is optionally substituted by 1 to 4 R b4 or R b5 replaced by;

[0071] In certain embodiments, V is selected from a bond, NH, NHC(CH3)2CH2, NHCH2C(CH3)2, CH2CH2, C(CH3)2CH2, CH2C(CH3)2, NHCH2CH2, NHCH2, OCH2, CH2NH, CHO, NHC(CH3)2, OC(CH3)2, C(CH3)2NH, C(CH3)2O, N(CH3)CH2, N(CH3)C(CH3)2, C(CH3)2N(CH3), CH2N(CH3), N(CH3), O, S;

[0072] In certain embodiments, v2 and v4 are each independently selected from 1, 2, 3, or 4;

[0073] In certain embodiments, Y1 and Y3 are each independently selected from a bond, O, S, NR b5a ;

[0074] In certain embodiments, Y2 and Y4 are each independently selected from O, S, NR b5a ;

[0075] In certain embodiments, Y1 and Y3 are each independently selected from a bond, O, S, or NH;

[0076] In certain embodiments, Y2 and Y4 are each independently selected from O, S, and NH;

[0077] In certain embodiments, R b5a Selected from H, C 1-4 Alkyl, -(CH2) n -R b22 、-C(=O)N(R b21 )2, -C(=O)R b22 、C 3-6 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclic group, wherein said -CH2-, alkyl, cycloalkyl, heterocyclic group, aryl or heteroaryl group is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, =O, -N(R b21 )2、CN、COOH、C 1-4 Alkyl, C 1-4 Alkoxy, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 3-6 substituted by a cycloalkyl, a 5-10 membered heteroaryl or a 4-10 membered heterocyclic group, wherein the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0078] In certain embodiments, R b5a Selected from H, C 1-4 Alkyl, -(CH2) n -R b22 The -CH2-, alkyl group is optionally replaced by 1 to 4 groups selected from F, Cl, Br, I, OH, =O, -N(R b21 )2、CN、COOH、C 1-4 Alkyl, C 1-4 Alkoxy, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 3-6 substituted by a cycloalkyl, 5-6 membered heteroaryl or 4-8 membered heterocyclic group, wherein the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S and N;

[0079] In certain embodiments, R b5a is selected from H, methyl, ethyl, cyclopropyl, wherein the methyl, ethyl, cyclopropyl is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, =O, NH2, N(CH3), CN, CF3, COOH, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0080] In certain embodiments, R b5a is selected from H, CF3, CHF2, CH2F, CH2OH, CH2CN, CH2NH2, methyl, ethyl, cyclopropyl;

[0081] In certain embodiments, B is selected from

[0082] In certain embodiments, B is selected from

[0083] In certain embodiments, B is selected from

[0084] In certain embodiments, B is selected from

[0085] In certain embodiments, b1, b2, and b3 are each independently selected from 0, 1, 2, 3, and 4;

[0086] In certain embodiments, b1, b2, and b3 are each independently selected from 0, 1, and 2;

[0087] In certain embodiments, B1 is selected from 4-7 membered heteromonocyclic group, 5-14 membered heterocyclyl, 5-12 membered heterospirocyclic group, 7-10 membered heterobridged cyclyl, C 4-7 Monocyclic alkyl, C 6-14 Cycloalkyl, C 6-12 Spiroalkyl, C 5-12 bridged cycloalkyl, 5-10 membered heteroaryl or 6-14 membered aryl, said B1 is optionally substituted by 1 to 4 R b2 Substitution, the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0088] In certain embodiments, B3 is selected from 4-7 membered heteromonocyclic group, 5-14 membered heterocyclyl, 5-12 membered heterospirocyclic group, 7-10 membered heterobridged cyclyl, C 4-7 Monocyclic alkyl, C 6-14 Cycloalkyl, C 6-12 Spiroalkyl, C 5-12 bridged cycloalkyl, 5-10 membered heteroaryl or 6-14 membered aryl, said B3 is optionally substituted by 1 to 4 R b3 Substitution, the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0089] In certain embodiments, B2 is selected from 4-7 membered heteromonocyclic group, 5-14 membered heterocyclyl, 5-12 membered heterospirocyclic group, 7-10 membered heterobridged cyclyl, C 4-7 Monocyclic alkyl, C 6-14Cycloalkyl, C 6-12 Spiroalkyl, C 5-12 bridged cycloalkyl, 5-10 membered heteroaryl or 6-14 membered aryl, said B2 is optionally substituted by 1 to 4 R b2 Substitution, the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0090] In certain embodiments, B1 is selected from 6-7 membered heteromonocyclic group, 5-14 membered heterocyclyl, 5-12 membered heterospirocyclic group, 7-10 membered heterobridged cyclyl, C 6-8 Monocarbocyclic group, C 6-14 Cycloalkyl, C 6-12 Spiroalkyl, C 5-12 Bridged cycloalkyl, benzo C 3-10 Carbocyclic group, benzo 3 to 10 membered heterocyclic group, C 12-18 tricyclic group, 12 to 18 membered heterotricyclic group, 5-10 membered heteroaryl group or 6-14 membered aryl group, wherein B1 is optionally replaced by 1 to 4 R b2 Substitution, the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0091] In certain embodiments, B3 is selected from 4-7 membered heteromonocyclic group, 5-14 membered heterocyclyl, 5-12 membered heterospirocyclic group, 7-10 membered heterobridged cyclyl, C 3-8 Monocarbocyclic group, C 6-14 Cycloalkyl, C 6-12 Spiroalkyl, C 5-12 Bridged cycloalkyl, benzo C 3-10 Carbocyclic group, benzo 3 to 10 membered heterocyclic group, C 12-18 tricyclic group, 12 to 18 membered heterotricyclic group, 5-10 membered heteroaryl group or 6-14 membered aryl group, wherein B3 is optionally substituted by 1 to 4 R b3 Substitution, the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0092] In certain embodiments, B2 is selected from 4-7 membered heteromonocyclic group, 5-14 membered heterocyclyl, 5-12 membered heterospirocyclic group, 7-10 membered heterobridged cyclyl, C 3-8 Monocarbocyclic group, C 6-14 Cycloalkyl, C 6-12 Spiroalkyl, C 5-12 Bridged cycloalkyl, benzo C 3-10 Carbocyclic group, benzo 3 to 10 membered heterocyclic group, C 12-18 tricyclic group, 12 to 18 membered heterotricyclic group, 5-10 membered heteroaryl group or 6-14 membered aryl group, wherein B2 is optionally substituted by 1 to 4 R b2 Substitution, the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0093] In certain embodiments, B1 is selected from one of the following groups, substituted or unsubstituted: cyclohexyl, phenyl, naphthyl, thiophene, furan, pyrrole, pyrazole, imidazole, pyridine, 2-pyridone, pyrimidine, pyrazine, pyridazine, quinoline, isoquinoline, quinazoline, 3,4-dihydro-1H-benzopyran, 1,2,3,4-tetrahydroquinoline, benzofuran, benzothiophene, benzopyrrole, benzoxazole, benzothiazole, benzimidazole, benzopyrazole, morpholine, cyclobutylspirocyclobutyl, cyclobutylspiroazetidinyl, cyclopentylcyclopentyl, cyclopentylpyrrolidinyl, carbazole, and when substituted, 1 to 4 R b1 replace;

[0094] In certain embodiments, B1 is selected from one of the following optionally substituted structures: When substituted, by 1 to 4 R b1 replace;

[0095] In certain embodiments, B1 is selected from B 1A ;

[0096] In certain embodiments, B1 is selected from substituted or unsubstituted phenyl or pyridine, which, when substituted, is optionally substituted with 1 to 4 R b1 replaced by;

[0097] In certain embodiments, B2 is selected from one of the following groups, substituted or unsubstituted: phenyl, cyclohexyl, piperidine, pyrazole, imidazole, triazole, thiazole, oxazole, isoxazole, thiophene, benzopyrrole, indole, benzimidazole, benzopyrazole, benzothiazole, pyrazolotetrahydropyrrole, 3-pyridazinone, 2-pyridone, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, cyclobutylspirocyclobutyl, cyclobutylspiroazetidinyl, cyclopentylcyclopentyl, cyclopentylpyrrolidinyl, When substituted, by 1 to 4 R b2 replace;

[0098] In certain embodiments, B2 is selected from one of the following groups, substituted or unsubstituted: phenyl, naphthyl, quinoline, pyrazole, pyridine, imidazole, triazole, thiazole, oxazole, isoxazole, thiophene, benzopyrrole, indole, benzimidazole, benzopyrazole, benzothiophene, benzothiazole, pyrazolotetrahydropyrrole, 3-pyridazinone, 2-pyridone, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, cyclobutylspirocyclobutyl, cyclobutylspiroazetidinyl, cyclopentylcyclopentyl, cyclopentylpyrrolidinyl, when substituted, by 1 to 4 R b2 replace;

[0099] In certain embodiments, B2 is selected from one of the following optionally substituted structures: When substituted, by 1 to 4 R b2 replace;

[0100] In certain embodiments, B2 is selected from B 2A ;

[0101] In certain embodiments, B2 is selected from pyrazole;

[0102] In certain embodiments, B2 is selected from The B2 is optionally replaced by 1 or 2 R b2 replace;

[0103] In certain embodiments, B 1A 、B 2A Each is independently selected from one of the following optionally substituted structures: When replaced, B 1A 1 to 4 R b1 Replace, B 2A 1 to 4 R b2 replace;

[0104] In certain embodiments, B3 is selected from one of the following groups, substituted or unsubstituted: oxetanyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, tetrahydrofuranyl, phenyl, pyridine, naphthyl, pyrazole, pyrrole, pyrrolidinyl, piperidine, piperazine, azacyclohexenyl, tetrahydropyranyl, imidazole, thiophene, thiazole, oxazole, isoxazole, triazole, 2-pyridone, benzopyrrole, benzopyrrolidine, benzothiophene, benzothiazole, benzopyrazole, benzimidazole, pyrazolotetrahydropyrrole, 3-pyridazinone, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, cyclobutylspirobutyl, cyclobutylspiroazetidinyl, cyclopentylcyclopentyl, cyclopentylpyrrolidinyl, cyclobutylspiropiperidinyl, When substituted, by 1 to 4 R b3 replace;

[0105] In certain embodiments, B3 is selected from one of the following optionally substituted structures: When substituted, by 1 to 4 R b3 replace;

[0106] In certain embodiments, B3 and B2 are connected via a carbon-nitrogen bond;

[0107] In certain embodiments, Selected from

[0108] In certain embodiments, Selected from

[0109] In certain embodiments, R b1 、R b2 Each independently selected from H, F, Cl, Br, I, ═O, ═S, OH, CN, NO2, COOH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, NH2, NHC 1-4 Alkyl, N(C 1-4 alkyl)2, -C(=O)NH2, -C(=O)NHC 1-4 Alkyl, -C(=O)N(C 1-4 alkyl)2, -C(=O)OC 1-4 Alkyl, -S(=O)2NH2, -S(=O)2N(C 1-4 alkyl)2, -S(=O)2NHC 1-4 Alkyl, -OR b22 、-C(=O)R b22 、-S(=O)2R b22 、-P(=O)(R b22 )2, -NHC(=O)R b22 、-N(C 1-4 alkyl)C(=O)R b22 、-NHS(=O)2R b22 、-N(C 1-4 alkyl)S(=O)2R b22 、-OC 3-12 Carbocyclic group, -NH-C 3-12 Carbocyclic group, -SC 3-12 Carbocyclic group, C 3-12 Carbocyclic group, C 6-10 Aryl, 5- to 12-membered heteroaryl, 4- to 12-membered heterocyclyl, -C 1-4 Alkylene-R b22 、-OC 1-4 Alkylene-R b22 、-C 1-4 Alkylene-OC 1-4 Alkylene-R b22 、-C 1-4 Alkylene-OC 1-4 Alkylene-OR b22The alkylene, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclyl, heterocyclyl, aryl or heteroaryl groups are optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, =O, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, CN, COOH, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 3-10 Carbocyclic group, C 3-10 is substituted by a carbocyclic group or a 4- to 10-membered heterocyclic group, wherein the heteroaryl group or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0110] In certain embodiments, R b1 Each independently selected from F, Cl, Br, I, =O, =S, OH, NH2, CN, NO2, -C(=O)CH3, -C(=O)NH2, -C(=O)NH-CH3, -C(=O)N(CH3)2, -S(=O)2NH2, -P(=O)2(CH3)2, -S(=O)2CH3, -O-cyclopropyl, -O-cyclobutyl, -S-cyclopropyl, -S- cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -NH-cyclopropyl, -NH-cyclobutyl, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, pyrrole, pyrazole, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolane, oxhexyl, morpholine, pyrrolidinyl and cyclopentyl, azetidinyl spirocyclohexyl, Phenyl, the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, pyrrole, pyrazole, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolane, oxhexyl, morpholine, pyrrolidinyl and cyclopentyl, azetidinyl spirocyclohexyl, The phenyl group is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, ═O, —N(R b21 )2、CN、COOH、C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 3-6substituted by a cycloalkyl, a 5-6 membered heteroaryl or a 4-6 membered heterocyclic group, wherein the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0111] In certain embodiments, R b1 Each independently selected from F, Cl, Br, I, =O, =S, OH, NH2, CN, NO2, -C(=O)CH3, -C(=O)NH2, -C(=O)NH-CH3, -C(=O)N(CH3)2, -S(=O)2NH2, -P(=O)2(CH3)2, -S(=O)2CH3, -O-cyclopropyl, -O-cyclobutyl, -S-cyclopropyl, -S- cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -NH-cyclopropyl, -NH-cyclobutyl, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, pyrrole, pyrazole, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolane, oxhexyl, morpholine, pyrrolidinyl and cyclopentyl, azetidinyl spirocyclohexyl, Phenyl, the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, pyrrole, pyrazole, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolane, oxhexyl, morpholine, pyrrolidinyl and cyclopentyl, azetidinyl spirocyclohexyl, Phenyl is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, CN, CHF2, CF3, NH2, N(CH3)2, methyl, methoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl;

[0112] In certain embodiments, R b21 Each independently selected from H or C 1-4 Alkyl, wherein the alkyl is optionally substituted by 1 to 4 groups selected from halogen, OH, =O, NH2, CN, CF3, COOH, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 substituted by an alkoxy substituent;

[0113] In certain embodiments, R b22 Each independently selected from H, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -NH-C 1-4 Alkyl, C 3-6Cycloalkyl, wherein the alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl is optionally substituted by 1 to 4 groups selected from halogen, OH, =O, NH2, CN, CF3, COOH, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 substituted by an alkoxy substituent;

[0114] In certain embodiments, R b21 Each independently selected from H, methyl, ethyl, isopropyl;

[0115] In certain embodiments, R b22 Each independently selected from H, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -NH-C 1-4 Alkyl, C 3-6 Cycloalkyl, wherein the alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, =O, NH2, CN, CF3, COOH, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 substituted by an alkoxy substituent;

[0116] In certain embodiments, R b22 Each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl;

[0117] In certain embodiments, R b22 Each independently selected from H, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl;

[0118] In certain embodiments, R b3 Each independently selected from halogen, =O, =S, OH, CN, NO2, COOH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, -(CH2) n -R b22 、-OR b22 、-SR b22 、-NH-R b22 、-(CH2) m1 -X-(CH2) m2 -R b24 、-N(R b21 )2、-C(=O)N(R b21)2, -C(=O)OR b21 、-C(=O)R b22 、-S(=O)2R b22 、-P(=O)(R b22 )2、-S(=O)2N(R b21 )2、-NR b21 C(=O)R b22 、-NR b21 S(=O)2R b22 、C 3-6 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclic group, wherein said -CH2-, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally substituted by 1 to 4 groups selected from halogen, OH, =O, -N(R b21 )2、CN、COOH、C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkynyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 3-6 substituted by a cycloalkyl, a 5-10 membered heteroaryl or a 4-10 membered heterocyclic group, wherein the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0119] In certain embodiments, R b3 Each independently selected from halogen, =O, =S, OH, CN, NO2, COOH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, -CH2-R b22 、-CH2CH2-R b22 、-OR b22 、-SR b22 、-NH-R b22 、-O-CH2CH2-R b24 、-S-CH2CH2-R b24 、-NH-CH2CH2-R b24 、-O-CH2-R b24 、-S-CH2-R b24 、-NH-CH2-R b24 、-CH2-O-CH2-R b24 、-CH2-S-CH2-R b24 、-CH2-NH-CH2-R b24 、-N(R b21)2、-C(=O)N(R b21 )2, -C(=O)OR b21 、-C(=O)R b22 、-S(=O)2R b22 、-P(=O)(R b22 )2、-S(=O)2N(R b21 )2、-NR b21 C(=O)R b22 、-NR b21 S(=O)2R b22 、C 3-6 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclic group, wherein said -CH2-, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally substituted by 1 to 4 groups selected from halogen, OH, =O, -N(R b21 )2、CN、COOH、C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkynyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 3-6 substituted by a cycloalkyl, 5-6 membered heteroaryl or 4-8 membered heterocyclic group, wherein the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S and N;

[0120] In certain embodiments, R b3Each is independently selected from F, Cl, Br, I, =O, =S, OH, NH2, CN, NO2, -C(=O)CH3, -C(=O)NH2, -C(=O)NH-CH3, -C(=O)N(CH3)2, -S(=O)2NH2, -P(=O)2(CH3)2, -S(=O)2CH3, -O-cyclopropyl, -O-cyclobutyl, -NH-cyclopropyl, -NH-cyclobutyl, -S-cyclopropyl, -S-cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-CH2-cyclopropyl, -O-CH2-cyclobutyl, -O-CH2CH2-methoxy, -O-CH2CH2-O- Cyclopropyl, -O-CH2CH2-O-cyclobutyl, -CH2-O-CH2CH2-methoxy, -CH2-O-CH2CH2-O-cyclopropyl, -CH2-O-CH2CH2-O-cyclobutyl, -CH2-O-CH2CH2-NH-methyl, -CH2-methoxy, -CH2-ethoxy, N(CH3)2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, pyrrole, pyrazole, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolane, oxhexyl, morpholine, pyrrolidinyl and cyclopentyl, azetidinyl spirocyclohexyl, Phenyl, the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, pyrrole, pyrazole, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolane, oxhexyl, morpholine, pyrrolidinyl and cyclopentyl, azetidinyl spirocyclohexyl, Phenyl is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, CN, CHF2, CF3, NH2, N(CH3)2, methyl, methoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl;

[0121] In certain embodiments, R b2each independently selected from H, F, Cl, Br, I, =O, =S, OH, NH2, NHCH3, N(CH3)2, CN, NO2, -C(=O)CH3, -C(=O)NH2, -C(=O)NH-CH3, -C(=O)N(CH3)2, -S(=O)2NH2, -P(=O)(CH3)2, -S(=O)2CH3 or one of the following groups that are optionally substituted: methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, triazolyl, azetidinyl, pyrrolidinyl, piperidinyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-morpholine, -CH2-pyrazole, -OCH2-cyclopropyl, -O-cyclopropyl, -O-cyclobutyl, -NH-cyclopropyl, -NH-cyclobutyl, -OCH2CH2-O-methyl, -OCH2CH2-O-cyclopropyl, -CH2OCH2CH2-O-methyl, -CH2OCH2CH2-O-cyclopropyl, -CH2OCH2CH2-NH-methyl, When substituted, it is substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, CN, CHF2, CH2F, CF3, NH2, NHCH3, N(CH3)2, CH2OH, methyl, ethyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, pyrazolyl, morpholinyl;

[0122] In certain embodiments, R b1 With R b3 、R b2 With R b3 Either one directly connects to form C 5-7 Carbocyclic group, 5 to 7 membered heterocyclic ring, wherein the carbocyclic group or heterocyclic ring is optionally substituted by 1 to 4 members selected from halogen, OH, -NH2, CN, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl or C 1-4 The heterocyclic group is substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, and N;

[0123] In certain embodiments, R b1 With R b3 、R b2 With R b3 Either one directly connects to form C5-7 Carbocyclyl, 5- to 7-membered heterocycle, wherein the carbocyclyl or heterocycle is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, I, OH, NH2, CN, CH2F, CHF2, CF3, methyl, ethyl, methoxy or ethoxy, and the heterocyclyl contains 1 to 3 heteroatoms selected from O, S, and N;

[0124] In certain embodiments, R b1 With R b3 、R b2 With R b3 Any one of them is directly connected to form a phenyl ring group, pyrrolidine, piperidine, piperazine, morpholine ring group, azacyclohexene, cyclohexene, cyclopentene, cyclopentane, or cyclohexane, wherein the pyrrolidine, piperidine, piperazine, morpholine ring group, azacyclohexene, cyclohexene, cyclopentene, cyclopentane, or cyclohexane is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, NH2, CN, CH2F, CHF2, CF3, methyl, ethyl, methoxy, or ethoxy;

[0125] In certain embodiments, R b4 、R b5 Each independently selected from H, F, Cl, Br, I, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, CN, COOH, NO2, -(CH2) m1 -R b23 、-(CH2) m1 -X-(CH2) m2 -R b24 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-12 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl or heterocyclic group is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, CN, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkynyl, C 3-8 substituted by a cycloalkyl or 3 to 8 heterocyclic substituent, wherein the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0126] In certain embodiments, R b4 、R b5 Each independently selected from H, F, Cl, Br, I, OH, NH2, CN, NO2, COOH, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 3-8 Cycloalkyl, OC 3-8 Cycloalkyl, NH-C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl or 3-8 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl or heterocyclic group is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, CN, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkynyl, C 3-6 substituted by a cycloalkyl or 3 to 8 heterocyclic substituent, wherein the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0127] In certain embodiments, R b4 、R b5 each independently selected from H, F, Cl, Br, I, OH, NH2, NHCH3, N(CH3)2, CN, NO2, COOH or one of the following groups that are optionally substituted: methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, triazolyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, oxhexyl, O-cyclopropyl, NH-cyclopropyl, morpholine, and when substituted, 1 to 4 selected from F, Cl, Br, I, OH, NH2, CN, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 substituted by a substituent of the alkynyl group;

[0128] In certain embodiments, any of R b4 、R b5 Together with the carbon atom it is connected to form C 3-8 Cycloalkyl or 3 to 8 membered heteromonocyclic ring, wherein the cycloalkyl or heteromonocyclic ring is optionally substituted by 1 to 4 rings selected from F, Cl, Br, I, OH, NH2, -N(R b21 )2.CN.C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkynyl, C 3-6 substituted by a cycloalkyl, a 5-6 membered heteroaryl or a 3 to 8 membered heterocyclic group, wherein the heteromonocyclic group, heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S and N;

[0129] In certain embodiments, any of R b4 、R b5 and the carbon atom to which it is attached together form one of the following optionally substituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetyl, oxetyl, oxetyl, when substituted, by 1 to 4 selected from F, Cl, Br, I, OH, NH2, -N(R b21 )2.CN.C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkynyl, C 3-6 substituted by a cycloalkyl, a 5-6 membered heteroaryl or a 3 to 8 membered heterocyclic group, wherein the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0130] In certain embodiments, R b23 Each independently selected from C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-10 Carbocyclic group or 4-10 membered heterocyclic group, wherein the carbocyclic group, alkenyl group, alkynyl group, heterocyclic group is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, =O, NH2, CN, CF3, COOH, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0131] In certain embodiments, R b23Each independently selected from vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, wherein the vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, =O, NH2, CN, CF3, COOH, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0132] In certain embodiments, R b24 Each independently selected from C 1-4 Alkoxy, NH-C 1-4 Alkyl, NH-C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, C 3-10 Carbocyclic or 4-10 membered heterocyclic, wherein the alkoxy, carbocyclic, cycloalkyl, cycloalkyloxy, heterocyclic is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, =O, NH2, CN, CF3, COOH, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0133] In certain embodiments, R b24 Each independently selected from methoxy, ethoxy, propoxy, isopropoxy, -O-cyclopropyl, -O-cyclobutyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, wherein the methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, =O, NH2, CN, CF3, COOH, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0134] In certain embodiments, each X is independently selected from NH, O, or S;

[0135] In certain embodiments, each m1 is independently selected from 0, 1, 2 or 3;

[0136] In certain embodiments, m2 is each independently selected from 0, 1, 2 or 3;

[0137] In certain embodiments, n is each independently selected from 0, 1, 2, 3, or 4;

[0138] In certain embodiments, B is selected from one of the structural fragments shown in Table B-1, Table B-2, or Table B-3, the right side of which is connected to L, and b1 and b2 are each independently selected from 0, 1, or 2:

[0139] Table B-1

[0140] Table B-2

[0141] Table B-3

[0142] In certain embodiments, each q is independently selected from 0, 1, 2, 3, 4, 5, or 6;

[0143] In certain embodiments, q is each independently selected from 0, 1, 2, 3, or 4;

[0144] In certain embodiments, q is each independently selected from 0, 1, 2, or 3;

[0145] In certain embodiments, q is each independently selected from 0, 1 or 2;

[0146] In certain embodiments, K is selected from K1, K2, K3, K4;

[0147] In certain embodiments, K1 is selected from

[0148] In certain embodiments, K1 is selected from

[0149] In certain embodiments, K2 is selected from

[0150] In certain embodiments, K2 is selected from

[0151] In certain embodiments, K3 is selected from In certain embodiments, K3 is selected from

[0152] In certain embodiments, K4 is selected from In certain embodiments, K4 is selected from

[0153] In certain embodiments, each E is independently selected from C 3-10 Carbocyclic group, C 6-10 Aryl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl, wherein the heterocyclyl or heteroaryl contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, and N;

[0154] In certain embodiments, each E is independently selected from C 3-10 Carbocyclyl, phenylcyclyl, 4-12 membered heterocyclyl, 5-12 membered heteroaryl, wherein the heterocyclyl or heteroaryl contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, and N;

[0155] In certain embodiments, E is independently selected from a phenyl ring group, a 5-6 membered heteroaryl group, wherein the heterocyclic group or heteroaryl group contains 1 to 3 (e.g., 1, 2, 3) heteroatoms selected from O, S, and N;

[0156] In certain embodiments, E is each independently selected from a benzene ring group, a pyridine ring group, a pyridazine ring group, a pyrazine ring group, a pyrimidine ring group, a pyrrole ring group, a pyrazole ring group, an imidazole ring group, a thiazole ring group, a furan ring group, a thiophene ring group, an oxazole ring group, an indoline ring group, an isoindoline ring group, a 1,2,3,4-tetrahydroquinoline ring group or a 1,2,3,4-tetrahydroisoquinoline ring;

[0157] In certain embodiments, E is independently selected from a benzene ring group, a pyridine ring group, a pyridazine ring group, a pyrazine ring group, a pyrimidine ring group, a pyrrole ring group, a pyrazole ring group, an imidazole ring group, a thiazole ring group, a furan ring group, a thiophene ring group or an oxazole ring;

[0158] In certain embodiments, E is independently selected from a benzene ring group, a pyridine ring group, a pyridazine ring group, a pyrazine ring group, a pyrimidine ring;

[0159] In certain embodiments, each E is independently selected from a phenyl ring group or a pyridine ring;

[0160] In certain embodiments, A is selected from C 3-10 Carbocyclic group, C6-10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the heterocyclyl or heteroaryl contains 1 to 4 (e.g., 1, 2, 3 or 4) heteroatoms selected from O, S, and N;

[0161] In certain embodiments, A is selected from C 3-8 a carbocyclyl, a phenylcyclyl, a 4-7 membered heterocyclyl or a 5-6 membered heteroaryl, wherein the heterocyclyl or heteroaryl contains 1 to 4 (e.g., 1, 2, 3 or 4) heteroatoms selected from O, S, and N;

[0162] In certain embodiments, A is selected from a benzene ring group, a pyridine ring group, a pyridazine ring group, a pyrazine ring group, a pyrimidine ring group, a pyrrole ring group, a pyrazole ring group, an imidazole ring group, a thiazole ring group, a furan ring group, a thiophene ring group, or an oxazole ring;

[0163] In certain embodiments, A is selected from a phenyl ring group or a pyridine ring;

[0164] In certain embodiments, each F is independently selected from C 3-20 Carbocyclic group, C 6-20 Aryl, 3-20 membered heterocyclyl or 5-20 membered heteroaryl, wherein the heterocyclyl or heteroaryl contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, and N;

[0165] In certain embodiments, each F is independently selected from C 3-7 Monocyclic carbocyclic group, C 4-10 Cyclic carbocyclic group, C 5-12 Spirocarbocyclic group, C 5-10 Bridged carbocyclic group, 4-7 membered heteromonocyclic group, 4-10 membered heterocyclic group, 8-15 membered heterotricyclic group, 5-12 membered heterospirocyclic group, 5-10 membered heterobridged ring group, C 6-14 Aryl, 5-10 membered heteroaryl, wherein the heteromonocyclic group, heterocyclic group, heterospirocyclic group, heterobridged ring group or heteroaryl group contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S and N;

[0166] In certain embodiments, each F is independently selected from C 3-7 Monocyclic carbocyclic group, C 4-10 Cyclic carbocyclic group, C 5-12 Spirocarbocyclic group, C 5-10 Bridged carbocyclic group, 4-7 membered heteromonocyclic group, 4-10 membered heterocyclic group, 8-15 membered tricyclic heterocyclic group, 12-17 membered tetracyclic heterocyclic group, 5-17 membered heterospirocyclic group, C 6-14 Aryl, 5-10 membered heteroaryl, The heteromonocyclic group, heterocyclic group, heterospirocyclic group, heterobridged ring group or heteroaryl group contains 1 to 4 heteroatoms selected from O, S or N;

[0167] In certain embodiments, F is independently selected from a benzene ring group, a pyridine ring group, a pyrimidine ring group, a pyrazine ring group, a pyridazine ring group,

[0168] In certain embodiments, F is independently selected from a benzene ring group, a pyridine ring group, a pyrimidine ring group, a pyrazine ring group, a pyridazine ring group,

[0169] In certain embodiments, each F is independently selected from cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, 6,7-dihydro-5H-cyclopenta[c]pyridinyl, 2,3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, 2-pyridone, benzoxazolyl, pyridoimidazolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzo pyridyl, benzopyrazinyl, benzopyrimidinyl, benzopyridazinyl, benzotriazinyl, pyrrolopyrrolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, pyrimidopyridinyl, pyrimidopyrazinyl, pyrimidopyridazinyl, pyrimidopyridinyl, pyridopyrazinyl, pyridopyrazinyl, pyridopyrazinyl, pyridopyrazinyl, indolopyridine, indolothiophene, indolofuran, Its left side is directly connected to L;

[0170] In certain embodiments, each Q is independently selected from a bond, -O-, -S-, -CH2-, -NR q -, -C(=O)-, -NR q C(=O)-, -C(=O)NR q - or 3-12 membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted by 1 to 4 (e.g. 1, 2, 3, 4) selected from F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl or C 1-4 The heterocyclic group is substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, and N;

[0171] In certain embodiments, each Q is independently selected from -O-, -S-, -CH2-, -NR q -, -C(=O)-, -NR q C(=O)-, -C(=O)NR q - or 4-7 membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted by 1 to 4 (e.g. 1, 2, 3, 4) selected from F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl or C 1-4 The heterocyclic group is substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, and N;

[0172] In certain embodiments, each Q is independently selected from a bond, C(=O), Qa, or Qb;

[0173] In certain embodiments, Qa is selected from a bond, CH2, NH, N(CH3), O, S, C(=O), NHC(=O), C(=O)NH, N(CH3)C(=O), C(=O)N(CH3),

[0174] In certain embodiments, Qb is selected from a bond, CH2, O, S, C(=O), NHC(=O), N(CH3)C(=O);

[0175] In certain embodiments, R q Selected from H or C 1-6 alkyl;

[0176] In certain embodiments, R q Selected from H or C 1-4 alkyl;

[0177] In certain embodiments, R q Selected from H, methyl, ethyl;

[0178] In certain embodiments, R k2 Each independently selected from a bond, -C(=O)-, -S(=O)2-, -S(=O)- or -C(R k3 )2-;

[0179] In certain embodiments, R k2 Each independently selected from -C(=O)-, -S(=O)2- or -C(R k3 )2-;

[0180] In certain embodiments, R k1 Each independently selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-6Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, R k7a The alkyl, alkoxy, cycloalkyl groups are optionally substituted by 1 to 4 (e.g., 1, 2, 3, 4) groups selected from F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 substituted by a cycloalkyl substituent;

[0181] In certain embodiments, R k1 Selected from R k7a ;

[0182] In certain embodiments, R k3 Each independently selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally substituted by 1 to 4 (e.g. 1, 2, 3, 4) selected from F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl or C 1-4 The heterocyclic group is substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, and N;

[0183] In certain embodiments, R k1 、R k3 Each independently selected from H, F, Cl, Br, I, OH, =O, NH2, CF3, CN, COOH, CONH2, C 1-4 Alkyl or C 1-4 Alkoxy, wherein the alkyl or alkoxy group is optionally substituted with 1 to 4 (e.g., 1, 2, 3 or 4) substituents selected from F, Cl, Br, I, OH, NH2;

[0184] In certain embodiments, R k1 、R k3 Each is independently selected from H, F, Cl, Br, I, OH, ═O, NH 2 , CF 3 , CN, COOH, CONH 2 , methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy group is optionally substituted with 1 to 4 (e.g., 1, 2, 3 or 4) substituents selected from F, Cl, Br, I, OH, NH 2 ;

[0185] In certain embodiments, both R k3and the carbon atoms or ring skeletons directly connected to the two, the two R k1 Together with the carbon atoms or ring skeletons directly connected to the two, they form C 3-8 A carbocyclic group or a 3-8 membered heterocyclic ring, wherein the carbocyclic group or heterocyclic ring is optionally substituted by 1 to 4 (e.g., 1, 2, 3, 4) selected from F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 , C 1-4 Alkyl or C 1-4 The heterocyclic group is substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, and N;

[0186] In certain embodiments, both R k3 and the carbon atoms or ring skeletons directly connected to the two, the two R k1 Together with the carbon atoms or ring skeletons directly connected to the two, they form C 3-6 A carbocyclic group or a 3-7 membered heterocyclic ring, wherein the carbocyclic group or heterocyclic ring is optionally substituted by 1 to 4 (e.g., 1, 2, 3, 4) selected from F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 , C 1-4 Alkyl or C 1-4 The heterocyclic group is substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, and N;

[0187] In certain embodiments, R k4 Each independently selected from H, OH, NH2, CN, CONH2, C 1-6 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, wherein the alkyl, cycloalkyl or heterocyclic group is optionally substituted by 1 to 4 (e.g. 1, 2, 3, 4) selected from F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl or C 1-4 The heterocyclic group is substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, and N;

[0188] In certain embodiments, R k4 Each independently selected from H, OH, NH2, CF3, CN, C 1-4 alkyl;

[0189] In certain embodiments, R k5 Each independently selected from C(CH3)2, CO, CH2, CH2CH2, SO2,

[0190] In certain embodiments, Rk5 Each independently selected from CO, CH2, SO2 or

[0191] In certain embodiments, R k6 Each independently selected from CO, CH, SO, SO2, CH2 or N;

[0192] In certain embodiments, R k7 Each independently selected from C(CH3)2,CO,CH,N,CH2,O,S,NR k7a ;

[0193] In certain embodiments, R k7 Each independently selected from C(CH3)2, CO, CH, N, CH2, O, S, N(CH3), N(CH2CH3), N(cyclopropyl) or NH;

[0194] In certain embodiments, R k7 Each is independently selected from CO, CH, N, CH2, O, S, N(CH3) or NH;

[0195] In certain embodiments, R k7 are each independently selected from CH2, O, N(CH3) or NH;

[0196] In certain embodiments, R k7a Selected from H, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, said alkyl, cycloalkyl, heterocycloalkyl being optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, NH2, CN, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 substituted by a cycloalkyl substituent;

[0197] In certain embodiments, R k7a Selected from H, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, said alkyl, cycloalkyl, heterocycloalkyl being optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, NH2, CN, CF3, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4Alkenyl, C 2-4 Alkynyl, C 3-6 substituted by a cycloalkyl substituent;

[0198] In certain embodiments, R k7a Selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, said alkyl, heterocycloalkyl or cycloalkyl being optionally substituted by 1 to 4 groups selected from halogen, OH, CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 substituted by a cycloalkyl substituent;

[0199] In certain embodiments, R k7a Selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, CN, CF3, C 1-4 Alkyl, C 1-4 Alkoxy, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, C 3-6 substituted by a cycloalkyl substituent;

[0200] In certain embodiments, R k7a Selected from H, CF3, methyl, ethyl, isopropyl, cyclopropyl, oxetanyl, tetrahydropyranyl, -CH2CF3, -CH(CH3)CF3, -CH(CH3)-cyclopropyl, -CH2-cyclopropyl, -CH2-vinyl, -CH2-ethynyl, -CH2CH2-methoxy;

[0201] In certain embodiments, R k7a is selected from H, CF3, methyl, ethyl, cyclopropyl, -CH2-cyclopropyl;

[0202] In certain embodiments, R k7a is selected from H, CH3, CH2CH3, cyclopropyl;

[0203] In certain embodiments, R k8 are each independently selected from C, N or CH;

[0204] In certain embodiments, R k9 are each independently selected from a bond, C(CH3)2, CO, CH2, CH2CH2 or SO2;

[0205] In certain embodiments, R k9 Each independently selected from CO, SO2 or CH2;

[0206] In certain embodiments, M1 is selected from a bond, -CH2-C(=O)NH-, or -C(=O)CH2NH-;

[0207] In certain embodiments, M2 is selected from -NHC(=O)-C 1-6 Alkyl, -NHC(=O)-C 3-6 Cycloalkyl or 4-10 membered heterocyclic group, wherein the alkyl, cycloalkyl or heterocyclic group is optionally substituted by 1 to 4 (e.g. 1, 2, 3, 4) selected from F, Cl, Br, I, =O, OH, NH2, C 1-4 Alkyl or C 1-4 The heterocyclic group is substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, and N;

[0208] In certain embodiments, M3 is selected from -NH- or -O-;

[0209] In certain embodiments, R k10 Selected from C 1-6 Alkyl, wherein the alkyl is optionally substituted by 1 to 4 (e.g., 1, 2, 3, 4) selected from F, Cl, Br, I, ═O, OH, C 1-6 Alkyl or C 3-6 substituted by a cycloalkyl substituent;

[0210] In certain embodiments, G is selected from C 6-10 Aryl or 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted by 1 to 4 (e.g., 1, 2, 3, 4) selected from F, Cl, Br, I, OH, =O, CF3, CN, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 The heteroaryl group is substituted by a cycloalkyl substituent, wherein the heteroaryl group contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from N, O, and S;

[0211] In certain embodiments, R k11 Each independently selected from H, F, Cl, Br, I, =O, OH, SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or -OC(=O)-C1-6 Alkyl, wherein the alkyl, alkoxy or alkylthio group is optionally substituted by 1 to 4 (e.g. 1, 2, 3, 4) groups selected from F, Cl, Br, I, OH, C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent;

[0212] In certain embodiments, R k12 、R k13 Each independently selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by 1 to 4 (e.g., 1, 2, 3, 4) groups selected from F, Cl, Br, I, ═O, OH, NH 2 , C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent;

[0213] In certain embodiments, R k14 5-6 membered heteroaryl, wherein the heteroaryl is optionally substituted by 1 to 4 (e.g. 1, 2, 3, 4) selected from F, Cl, Br, I, OH, =O, CF3, CN, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 The heteroaryl group is substituted by a cycloalkyl substituent, wherein the heteroaryl group contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from N, O, and S;

[0214] In certain embodiments, R k14 Selected from

[0215] In certain embodiments, K is selected from one of the structural fragments shown in Table K-1;

[0216] In certain embodiments, K is selected from one of the structural fragments shown in Table K-2;

[0217] Table K-1

[0218] Table K-2

[0219] In certain embodiments, n1, n2, and n3 are each independently selected from 0, 1, 2, or 3;

[0220] In certain embodiments, p1 or p2 are each independently selected from 0, 1, 2 or 3;

[0221] In certain embodiments, p1 or p2 are each independently selected from 0, 1, 2, 3, 4, or 5;

[0222] In certain embodiments, the compound represented by formula (I) is selected from one of the structures represented by (Ia) or (Ib);

[0223] The definitions of the various groups are the same as in the above embodiment;

[0224] In certain embodiments, the compound represented by formula (I) is selected from formula (Id),

[0225] R b4 、R b5 Each independently selected from H, methyl, ethyl, isopropyl;

[0226] Alternatively, R b4 、R b5 The carbon atoms connected thereto together form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group is optionally substituted by 1 to 4 groups selected from H, F, Cl, Br, I, OH, NH2, C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent;

[0227] B2 is selected from 5-6 membered heteroaryl or 6 membered aryl, preferably phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, said B2 is optionally substituted by 1 to 3 R b2 Substitution, the heteroaryl group contains 1 to 4 heteroatoms selected from O, S, and N;

[0228] B3 is selected from 4-7 membered heteromonocyclic group, 5-14 membered heterocyclic group, 5-12 membered heterospirocyclic group, 7-10 membered heterobridged ring group, C 4-7 Monocyclic alkyl, C 6-14 Cycloalkyl, C 6-12 Spiroalkyl, C 5-12 Bridged cycloalkyl, 5-6 membered heteroaryl or 6 membered aryl, preferably selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, said B3 is optionally substituted by 1 to 3 R b3 Substitution, the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0229] R d Selected from H, F, Cl, Br, I, OH, COOH, CN, NH2, C 1-4 Alkyl, halogen-substituted C1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 alkoxy;

[0230] The remaining groups are the same as in any of the above embodiments.

[0231] As a first embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0232] BLK(I);

[0233] L is selected from a bond or -C 1-50 Hydrocarbyl-, wherein 1 to 20 methylene units in the hydrocarbyl group are optionally replaced by -Ak- or -Cy-;

[0234] Each -Ak- is independently selected from -(CH2) q -、-(CH2) q -O-, -O-(CH2) q -、-(CH2) q -S-, -S-(CH2) q -、-(CH2) q -NR L -、-NR L -(CH2) q -、-(CH2) q -NR L C(=O)-、-NR L (CH2) q C(=O)-、-(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -、-(C≡C) q -、-CH=CH-、-Si(R L )2-、-Si(OH)(R L )-、-Si(OH)2-、-P(=O)(OR L )-、-P(=O)(R L )-, -S-, -S(=O)-, -S(=O)2- or a bond, wherein the -CH2-, -CH=CH- are optionally substituted by 1 to 2 groups selected from halogen, OH, CN, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, halogen-substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6substituted by an alkyl substituent;

[0235] q is each independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0236] R L Each independently selected from H, C 1-6 Alkyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, phenyl or 5-6 membered heteroaryl, wherein the heterocyclyl or heteroaryl contains 1 to 4 heteroatoms selected from O, S and N;

[0237] Each -Cy- is independently selected from a bond or one of the following groups which are optionally substituted: a 4-8 membered heteromonocyclic group, a 4-10 membered heterocycloalkyl group, a 5-12 membered heterospirocyclic group, a 7-10 membered heterobridged cyclyl group, a 3-7 membered monocycloalkyl group, a 4-10 membered cycloalkyl group, a 5-12 membered spirocycloalkyl group, a 5-10 membered bridged cycloalkyl group, a benzoC 4-6 Carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, or 6- to 10-membered aryl, when substituted, is replaced by 1 to 4 R L2 Substitution, wherein the heterocyclic group, heteroaryl group, heteromonocyclic group, heterocyclic group, heterospirocyclic group or heterobridged ring group contains 1 to 4 heteroatoms selected from O, S and N, and when the heteroatom is selected from S, it is optionally substituted by 1 or 2 =O;

[0238] R L2 Each independently selected from F, Cl, Br, I, OH, COOH, CN, NH2, NHC 1-4 Alkyl, N(C 1-4 alkyl)2,=O,C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -OC 1-4 Alkylene-OC 1-4 Alkyl, -OC 1-4 Alkylene-OC 3-10 Carbocyclic group, -C 1-4 Alkylene-OC 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkylene-OC 1-4 Alkylene-OC 3-10 Carbocyclic group, -OC 0-4 Alkylene-C 3-10 Carbocyclic group, -C 0-4 Alkylene-C 3-10 Carbocyclic group, -C 0-4Alkylene-4 to 10 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, COOH, CN, NH2, NHC 1-4 Alkyl, N(C 1-4 alkyl)2,=O,C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy substituents, halogen-substituted C 1-4 The heterocyclic group is substituted by an alkoxy group, and the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0239] B is selected from

[0240] B1 is selected from C 3-20 Carbocyclic group or 4-20 membered heterocyclic ring, said carbocyclic group or heterocyclic ring is optionally substituted by 1 to 4 R b1 Substituted, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0241] B2 is selected from C 3-20 Carbocyclic group or 4-20 membered heterocyclic ring, said carbocyclic group or heterocyclic ring is optionally substituted by 1 to 4 R b2 Substituted, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0242] B3 is selected from C 3-20 Carbocyclic group or 4-20 membered heterocyclic ring, said carbocyclic group or heterocyclic ring is optionally substituted by 1 to 4 R b3 Substituted, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0243] or B3 is selected from a bond;

[0244] L1 is selected from a bond or

[0245] L2 is selected from a bond or

[0246] Y1, Y2, Y3, Y4 are each independently selected from a bond, O, S, NR b5a ;

[0247] Q1, Q2, Q3, and Q4 are each independently selected from

[0248] v1, v2, v3, and v4 are each independently selected from 0, 1, 2, 3, or 4;

[0249] R b1 、R b2Each independently selected from H, F, Cl, Br, I, ═O, ═S, OH, CN, NO2, COOH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, NH2, NHC 1-4 Alkyl, N(C 1-4 alkyl)2, -C(=O)NH2, -C(=O)NHC 1-4 Alkyl, -C(=O)N(C 1-4 alkyl)2, -C(=O)OC 1-4 Alkyl, -S(=O)2NH2, -S(=O)2N(C 1-4 alkyl)2, -S(=O)2NHC 1-4 Alkyl, -OR b22 、-C(=O)R b22 、-S(=O)2R b22 、-P(=O)(R b22 )2, -NHC(=O)R b22 、-N(C 1-4 alkyl)C(=O)R b22 、-NHS(=O)2R b22 、-N(C 1-4 alkyl)S(=O)2R b22 、-OC 3-12 Carbocyclic group, -NH-C 3-12 Carbocyclic group, -SC 3-12 Carbocyclic group, C 3-12 Carbocyclic group, C 6-10 Aryl, 5- to 12-membered heteroaryl, 4- to 12-membered heterocyclyl, -C 1-4 Alkylene-R b22 、-OC 1-4 Alkylene-R b22 、-C 1-4 Alkylene-OC 1-4 Alkylene-R b22 、-C 1-4 Alkylene-OC 1-4 Alkylene-OR b22 The alkylene, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclyl, heterocyclyl, aryl or heteroaryl groups are optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, =O, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, CN, COOH, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 3-10 Carbocyclic group, C 3-10 is substituted by a carbocyclic group or a 4- to 10-membered heterocyclic group, wherein the heteroaryl group or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0250] R b3 Each independently selected from halogen, =O, =S, OH, CN, NO2, COOH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, -(CH2) n -R b22 、-OR b22 、-SR b22 、-NH-R b22 、-(CH2) m1 -X-(CH2) m2 -R b24 、-N(R b21 )2、-C(=O)N(R b21 )2, -C(=O)OR b21 、-C(=O)R b22 、-S(=O)2R b22 、-P(=O)(R b22 )2、-S(=O)2N(R b21 )2、-NR b21 C(=O)R b22 、-NR b21 S(=O)2R b22 、C 3-6 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclic group, wherein said -CH2-, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally substituted by 1 to 4 groups selected from halogen, OH, =O, -N(R b21 )2、CN、COOH、C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkynyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 3-6substituted by a cycloalkyl, a 5-10 membered heteroaryl or a 4-10 membered heterocyclic group, wherein the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0251] n is each independently selected from 0, 1, 2, 3 or 4;

[0252] R b21 Each independently selected from H or C 1-4 Alkyl, wherein the alkyl is optionally substituted by 1 to 4 groups selected from halogen, OH, =O, NH2, CN, CF3, COOH, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 substituted by an alkoxy substituent;

[0253] R b22 Each independently selected from H, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -NH-C 1-4 Alkyl, C 3-6 Cycloalkyl, wherein the alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl is optionally substituted by 1 to 4 groups selected from halogen, OH, =O, NH2, CN, CF3, COOH, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 substituted by an alkoxy substituent;

[0254] or R b1 With R b3 、R b2 With R b3 Either one directly connects to form C 5-7 Carbocyclic group, 5 to 7 membered heterocyclic ring, wherein the carbocyclic group or heterocyclic ring is optionally substituted by 1 to 4 members selected from halogen, OH, NH2, CN, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl or C 1-4 The heterocyclic group is substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, and N;

[0255] R b4 、R b5 Each independently selected from H, F, Cl, Br, I, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, CN, COOH, NO2, -(CH2) m1 -R b23 、-(CH2) m1 -X-(CH2)m2 -R b24 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-12 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl or heterocyclic group is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, CN, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkynyl, C 3-8 substituted by a cycloalkyl or 3 to 8 heterocyclic substituent, wherein the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0256] or any R b4 、R b5 Together with the carbon atom it is connected to form C 3-8 Cycloalkyl or 3 to 8 membered heteromonocyclic ring, wherein the cycloalkyl or heteromonocyclic ring is optionally substituted by 1 to 4 rings selected from F, Cl, Br, I, OH, NH2, -N(R b21 )2.CN.C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkynyl, C 3-6 substituted by a cycloalkyl, a 5-6 membered heteroaryl or a 3 to 8 membered heterocyclic group, wherein the heteromonocyclic group, heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S and N;

[0257] R b5a Selected from H, C 1-4 Alkyl, -(CH2) n -R b22 、-C(=O)N(R b21 )2, -C(=O)R b22 、C 3-6 Cycloalkyl, C 6-10Aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclic group, wherein said -CH2-, alkyl, cycloalkyl, heterocyclic group, aryl or heteroaryl group is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, =O, -N(R b21 )2、CN、COOH、C 1-4 Alkyl, C 1-4 Alkoxy, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 3-6 substituted by a cycloalkyl, a 5-10 membered heteroaryl or a 4-10 membered heterocyclic group, wherein the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0258] X is independently selected from NH, O or S;

[0259] m1 are each independently selected from 0, 1, 2 or 3;

[0260] m2 are each independently selected from 0, 1, 2 or 3;

[0261] R b23 Each independently selected from C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-10 Carbocyclic group or 4-10 membered heterocyclic group, wherein the carbocyclic group, alkenyl group, alkynyl group, heterocyclic group is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, =O, NH2, CN, CF3, COOH, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0262] R b24 Each independently selected from C 1-4 Alkoxy, NH-C 1-4 Alkyl, NH-C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, C 3-10 Carbocyclic or 4-10 membered heterocyclic, wherein the alkoxy, carbocyclic, cycloalkyl, cycloalkyloxy, heterocyclic is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, =O, NH2, CN, CF3, COOH, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0263] K is selected from K1, K2, K3, K4;

[0264] K1 is selected from

[0265] K2 is selected from

[0266] K3 is selected from

[0267] K4 is selected from

[0268] Q is independently selected from a bond, -O-, -S-, -CH2-, -NR q -, -C(=O)-, -NR q C(=O)-, -C(=O)NR q - or 3-12 membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted by 1 to 4 rings selected from F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 4 heteroatoms selected from O, S or N;

[0269] R q Selected from H or C 1-6 alkyl;

[0270] A is selected from C 3-10 Carbocyclic group, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the heterocyclyl or heteroaryl contains 1 to 4 heteroatoms selected from O, S or N;

[0271] F are each independently selected from C 3-20 Carbocyclic group, C 6-20 aryl, 3-20 membered heterocyclyl or 5-20 membered heteroaryl, wherein the heterocyclyl or heteroaryl contains 1 to 4 heteroatoms selected from O, S or N;

[0272] R k2 Each independently selected from a bond, -C(=O)-, -S(=O)2-, -S(=O)- or -C(R k3 )2-;

[0273] R k1 Each independently selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, R k7aThe alkyl, alkoxy or cycloalkyl group is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 substituted by a cycloalkyl substituent;

[0274] R k7a Selected from H, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, said alkyl, cycloalkyl, heterocycloalkyl being optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, NH2, CN, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 substituted by a cycloalkyl substituent;

[0275] R k3 Each independently selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 4 heteroatoms selected from O, S or N;

[0276] Or two R k3 and the carbon atoms or ring skeletons directly connected to the two, the two R k1 Together with the carbon atoms or ring skeletons directly connected to the two, they form C 3-8 Carbocyclic group or 3-8 membered heterocyclic ring, wherein the carbocyclic group or heterocyclic ring is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 4 heteroatoms selected from O, S or N;

[0277] R k4 Each independently selected from H, OH, NH2, CN, CONH2, C 1-6 Alkyl, C 3-8Cycloalkyl or 3-8 membered heterocyclic group, wherein the alkyl, cycloalkyl or heterocyclic group is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 4 heteroatoms selected from O, S or N;

[0278] M1 is selected from a bond, -CH2-C(=O)NH- or -C(=O)CH2NH-;

[0279] M2 is selected from -NHC(=O)-C 1-6 Alkyl, -NHC(=O)-C 3-6 Cycloalkyl or 4-10 membered heterocyclic group, wherein the alkyl, cycloalkyl or heterocyclic group is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, =O, OH, NH2, C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 4 heteroatoms selected from O, S or N;

[0280] M3 is selected from -NH- or -O-;

[0281] R k10 Selected from C 1-6 Alkyl, wherein the alkyl is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, ═O, OH, C 1-6 Alkyl or C 3-6 substituted by a cycloalkyl substituent;

[0282] R k11 Each independently selected from H, F, Cl, Br, I, =O, OH, SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or -OC(=O)-C 1-6 Alkyl, said alkyl, alkoxy or alkylthio group is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent;

[0283] R k12 、R k13 Each independently selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, ═O, OH, NH 2 , C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent;

[0284] Rk14 5-6 membered heteroaryl, wherein the heteroaryl is optionally substituted by 1 to 4 members selected from F, Cl, Br, I, OH, =O, CF3, CN, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 The heteroaryl group is substituted by a substituent of a cycloalkyl group, wherein the heteroaryl group contains 1 to 4 heteroatoms selected from N, O or S;

[0285] G is selected from C 6-10 Aryl or 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, =O, CF3, CN, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 The heteroaryl group is substituted by a substituent of a cycloalkyl group, wherein the heteroaryl group contains 1 to 4 heteroatoms selected from N, O or S;

[0286] n1, n2, n3 are each independently selected from 0, 1, 2 or 3;

[0287] p1 and p2 are each independently selected from 0, 1, 2, 3, 4 or 5.

[0288] As a second embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0289] B is selected from

[0290] Or B is selected from V is selected from a bond or L1;

[0291] L1 and L2 are not bonds;

[0292] B1 is selected from 6-7 membered heteromonocyclic group, 5-14 membered heterocyclic group, 5-12 membered heterospirocyclic group, 7-10 membered heterobridged ring group, C 6-8 Monocarbocyclic group, C 6-14 Cycloalkyl, C 6-12 Spiroalkyl, C 5-12 Bridged cycloalkyl, benzo C 3-10 Carbocyclic group, benzo 3 to 10 membered heterocyclic group, C 12-18 tricyclic group, 12 to 18 membered heterotricyclic group, 5-10 membered heteroaryl group or 6-14 membered aryl group, wherein B1 is optionally replaced by 1 to 4 R b2Substitution, the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0293] B3 is selected from 4-7 membered heteromonocyclic group, 5-14 membered heterocyclic group, 5-12 membered heterospirocyclic group, 7-10 membered heterobridged ring group, C 3-8 Monocarbocyclic group, C 6-14 Cycloalkyl, C 6-12 Spiroalkyl, C 5-12 Bridged cycloalkyl, benzo C 3-10 Carbocyclic group, benzo 3 to 10 membered heterocyclic group, C 12-18 tricyclic group, 12 to 18 membered heterotricyclic group, 5-10 membered heteroaryl group or 6-14 membered aryl group, wherein B3 is optionally substituted by 1 to 4 R b3 Substitution, the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0294] B2 is selected from 4-7 membered heteromonocyclic group, 5-14 membered heterocyclic group, 5-12 membered heterospirocyclic group, 7-10 membered heterobridged ring group, C 3-8 Monocarbocyclic group, C 6-14 Cycloalkyl, C 6-12 Spiroalkyl, C 5-12 Member-bridged cycloalkyl, benzo C 3-10 Carbocyclic group, benzo 3 to 10 membered heterocyclic group, C 12-18 tricyclic group, 12 to 18 membered heterotricyclic group, 5-10 membered heteroaryl group or 6-14 membered aryl group, wherein B2 is optionally substituted by 1 to 4 R b2 Substitution, the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0295] R b4 、R b5 Each independently selected from H, F, Cl, Br, I, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 alkyl)2、CN、COOH、NO2、C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 3-8 Cycloalkyl, C 6-10 Aryl, OC 3-8 Cycloalkyl, NH-C 3-8 Cycloalkyl, 5-6 membered heteroaryl or 3-8 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl or heterocyclic group is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, NH2, NHC 1-4 Alkyl, N(C 1-4Alkyl)2, CN, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkynyl, C 3-6 substituted by a cycloalkyl or 3 to 8 heterocyclic substituent, wherein the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0296] R b5a Selected from H, C 1-4 Alkyl, -(CH2) n -R b22 The -CH2-, alkyl group is optionally replaced by 1 to 4 groups selected from F, Cl, Br, I, OH, =O, -N(R b21 )2、CN、COOH、C 1-4 Alkyl, C 1-4 Alkoxy, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 3-6 substituted by a cycloalkyl, 5-6 membered heteroaryl or 4-8 membered heterocyclic group, wherein the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S and N;

[0297] The remaining groups are defined the same as in the first embodiment of the present invention.

[0298] As a third embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0299] L is selected from -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-, -Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-,-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-, -Ak1-Cy1-Ak2-Ak3-Ak4-Ak 5-Cy2-Cy3-Cy4-, -Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Cy1- Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3- Cy4-, -Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Cy 3-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1 -Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4 -Ak5-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-A k4-Cy1-Cy2-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-;

[0300] Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from -(CH2) q -、-(CH2) q -O-, -O-(CH2) q -、-(CH2) q -S-, -S-(CH2) q -、-(CH2) q -NR L -、-NR L -(CH2) q -、-(CH2)q-NR L C(=O)-、-(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -、-CH=CH-、-(C≡C) q - or bond, wherein the -CH2-, -CH=CH- are optionally replaced by 1 to 2 selected from F, Cl, Br, I, OH, CN, NH2, C 1-4 Alkyl, C 1-4 Alkoxy, halogen-substituted C 1-4 Alkyl, hydroxy substituted C1-4 Alkyl, cyano substituted C 1-4 substituted by an alkyl substituent;

[0301] Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from a bond or one of the following groups which are optionally substituted: a 4-7 membered heteromonocyclic group, a 4-10 membered heterocycloalkyl group, a 5-12 membered heterospirocyclic group, a 7-10 membered heterobridged cyclic group, a 3-7 membered monocycloalkyl group, a 4-10 membered cycloalkyl group, a 5-12 membered spirocycloalkyl group, a 5-10 membered bridged cycloalkyl group, a benzoC 4-6 Carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, or 6- to 10-membered aryl, when substituted, is replaced by 1 to 4 R L2 Substitution, wherein the heterocyclic group, heteroaryl group, heteromonocyclic group, heterocyclic group, heterospirocyclic group or heterobridged ring group contains 1 to 4 heteroatoms selected from O, S and N, and when the heteroatom is selected from S, it is optionally substituted by 1 or 2 =O;

[0302] q is each independently selected from 0, 1, 2, 3 or 4;

[0303] R L Each independently selected from H or C 1-6 alkyl;

[0304] The remaining groups are defined in the same manner as in the first or second embodiment of the present invention.

[0305] As a fourth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal;

[0306] K2 is selected from

[0307] K3 is selected from

[0308] A is selected from C 3-8 a carbocyclyl, a phenylcyclyl, a 4-7 membered heterocyclyl or a 5-6 membered heteroaryl, wherein the heterocyclyl or heteroaryl contains 1 to 4 heteroatoms selected from O, S or N;

[0309] F are each independently selected from C 3-7 Monocyclic carbocyclic group, C 4-10 Cyclic carbocyclic group, C 5-12 Spirocarbocyclic group, C 5-10 Bridged carbocyclic group, 4-7 membered heteromonocyclic group, 4-10 membered heterocyclic group, 8-15 membered tricyclic heterocyclic group, 12-17 membered tetracyclic heterocyclic group, 5-17 membered heterospirocyclic group, C 6-14 Aryl, 5-10 membered heteroaryl, The heteromonocyclic group, heterocyclic group, heterospirocyclic group, heterobridged ring group or heteroaryl group contains 1 to 4 heteroatoms selected from O, S or N;

[0310] represents a ring selected from an aromatic ring group or a non-aromatic ring;

[0311] E are each independently selected from C 3-10 Carbocyclyl, phenylcyclyl, 4-12 membered heterocyclyl, 5-12 membered heteroaryl, wherein the heterocyclyl or heteroaryl contains 1 to 4 heteroatoms selected from O, S or N;

[0312] Q is independently selected from a bond, -O-, -S-, -CH2-, -NR q -, -C(=O)-, -NR q C(=O)-, -C(=O)NR q - or 4-7 membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted by 1 to 4 rings selected from F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 4 heteroatoms selected from O, S or N;

[0313] R q Selected from H or C 1-4 alkyl;

[0314] R k1 、R k3 Each independently selected from H, F, Cl, Br, I, OH, =O, NH2, CF3, CN, COOH, CONH2, C 1-4 Alkyl or C 1-4 Alkoxy, wherein the alkyl or alkoxy group is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH or NH2;

[0315] Or two R k3 and the carbon atoms or ring skeletons directly connected to the two, the two R k1 Together with the carbon atoms or ring skeletons directly connected to the two, they form C 3-6 Carbocyclic group or 3-7 membered heterocyclic ring, wherein the carbocyclic group or heterocyclic ring is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 4 heteroatoms selected from O, S or N;

[0316] R k4 Each independently selected from H, OH, NH2, CF3, CN or C 1-4 alkyl;

[0317] R k5 Each independently selected from C(CH3)2, C(=O), CH2, CH2CH2, S(=O)2,

[0318] R k6 Each is independently selected from C(=O), CH, S(=O), S(=O)2, CH2 or N;

[0319] R k7 Each independently selected from C(CH3)2, C(=O), CH, N, CH2, O, S, NR k7a ;

[0320] R k8 are each independently selected from C, N or CH;

[0321] R k9 are each independently selected from a bond, C(CH3)2, C(=O), CH2, CH2CH2 or S(=O)2;

[0322] R ka Selected from O, S or NH;

[0323] R k7a Selected from H, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, said alkyl, cycloalkyl, heterocycloalkyl being optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, NH2, CN, CF3, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 substituted by a cycloalkyl substituent;

[0324] R k14 Selected from

[0325] The remaining groups are defined the same as in the first, second, or third embodiment of the present invention.

[0326] As a fifth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0327] B is selected from

[0328] V is selected from a bond, O, S, NR b5a NR b5a -(Q2) v2 -、-(Q2) v2 -NR b5a 、O-(Q2) v2 -、-(Q2) v2 -O, -(Q2) v2 -;

[0329] v2 and v4 are each independently selected from 1, 2, 3 or 4;

[0330] Y1 and Y3 are each independently selected from a bond, O, S, NR b5a ;

[0331] Y2 and Y4 are each independently selected from O, S, NR b5a ;

[0332] Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from -(CH2) q -、-(CH2) q -O-, -O-(CH2) q -、-(CH2) q -S-, -S-(CH2) q -、-(CH2) q -NR L -、-NR L -(CH2) q -、-(CH2) q -NR L C(=O)-、-(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -, -CH=CH-, -C≡C- or a bond, wherein the -CH2-, -CH=CH- are optionally substituted by 1 to 2 substituents selected from F, Cl, Br, I, OH, CN, NH2, CF3, hydroxymethyl, methyl, ethyl, methoxy or ethoxy;

[0333] q is each independently selected from 0, 1, 2 or 3;

[0334] R L Each independently selected from H or C 1-4 alkyl;

[0335] K1 is selected from

[0336] K4 is selected from

[0337] Q is selected from a bond, C(=O);

[0338] Qa is selected from a bond, CH2, NH, N(CH3), O, S, C(=O), NHC(=O), C(=O)NH, N(CH3)C(=O), C(=O)N(CH3),

[0339] Qb is selected from a bond, CH2, O, S, C(=O), NHC(=O), N(CH3)C(=O);

[0340] E and A are each independently selected from a benzene ring group, a pyridine ring group, a pyridazine ring group, a pyrazine ring group, a pyrimidine ring group, a pyrrole ring group, a pyrazole ring group, an imidazole ring group, a thiazole ring group, a furan ring group, a thiophene ring group or an oxazole ring;

[0341] Each F is independently selected from cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, 6,7-dihydro-5H-cyclopenta[c]pyridinyl, 2,3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, 2-pyridone, benzoxazolyl, pyridoimidazolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzopyridinyl, benzopyrazinyl, benzopyrimidinyl, benzopyridazinyl, benzotriazinyl, pyrrolopyrrolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, pyrimidopyridinyl, pyrimidopyrazinyl, pyrimidopyridazinyl, pyrimidopyridinyl, pyridopyridinyl, pyridopyrazole, pyridopyrazinyl, pyridopyridazinyl, pyridazinopyrazinyl, pyrazinopyrazinyl, indolopyridine, indolothiophene, indolofuran, Its left side is directly connected to L;

[0342] R ka Selected from O, S or NH;

[0343] R k7 Each independently selected from C(CH3)2, CH2, O, N(CH3), N(CH2CH3), N(cyclopropyl) or NH;

[0344] R k7a Selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, CN, CF3, C 1-4 Alkyl, C 1-4 Alkoxy, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, C 3-6 substituted by a cycloalkyl substituent;

[0345] p1 or p2 are each independently selected from 0, 1, 2 or 3;

[0346] The remaining groups are defined the same as in any one of the second, third or fourth embodiments of the present invention.

[0347] As a sixth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0348] R L Selected from H, methyl or ethyl;

[0349] q is each independently selected from 0, 1 or 2;

[0350] Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from a bond or one of the following groups which are substituted or unsubstituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azacyclohexenyl, piperidinyl, morpholinyl, piperazinyl, 1,4-diazepanyl, pyridyl, phenyl, cyclopropyl and cyclopropyl, cyclopropyl and cyclobutyl, cyclopropyl and cyclopentyl, cyclopropyl and cyclohexyl, cyclobutyl and cyclobutyl, cyclobutyl and cyclopentyl, cyclo Butylcyclohexyl, cyclopentylcyclopentyl, cyclopentylcyclohexyl, cyclohexylcyclohexyl, cyclopropylspirocyclopropyl, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylazetidinyl, cyclopropylpyrrolidinyl, cyclopropylpiperidinyl, cyclobutylazetidinyl, cyclobutylpyrrolidinyl, Cyclobutylpiperidinyl, cyclopentylazetidinyl, cyclopentylpyrrolidinyl, cyclopentylpiperidinyl, cyclohexylazetidinyl, cyclohexylpyrrolidinyl, cyclohexylpiperidinyl, azetidinylazetidinyl, azetidinylpyrrolidinyl, azetidinylpiperidinyl, pyrrolidinylazetidinyl, pyrrolidinylpyrrolidinyl, pyrrolidinylpiperidinyl, piperidinylazetidinyl, piperidinylpyrrolidinyl, piperidinylpiperidinyl, cyclobutylspiroazacyclo Heterocyclobutyl, cyclobutyl spiropyrrolidinyl, cyclobutyl spiropiperidinyl, cyclopentyl spiroazetidinyl, cyclopentyl spiropyrrolidinyl, cyclopentyl spiropiperidinyl, cyclohexyl spiroazetidinyl, cyclohexyl spiropyrrolidinyl, cyclohexyl spiropiperidinyl, azetidinyl spiroazetidinyl, azetidinyl spiropyrrolidinyl, azetidinyl spiropiperidinyl, pyrrolidinyl spiroazetidinyl, pyrrolidinyl spiropyrrolidinyl, pyrrolidinyl spiropiperidinyl, piperidinyl spiroazetidinyl, piperidinyl spiropiperidinyl, When substituted, by 1 to 4 R L2 replace;

[0351] R L2 Each independently selected from F, Cl, Br, I, OH, NH2, NHCH3, N(CH3)2, COOH, CN, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -OC 1-2 Alkylene-OC 1-2 Alkyl, -OC 1-2 Alkylene-OC 3-6 Carbocyclic group, -C 1-2 Alkylene-OC 1-2 Alkylene-OC 1-2 Alkyl, -C1-2 Alkylene-OC 1-2 Alkylene-OC 3-6 Carbocyclic group, -OC 0-2 Alkylene-C 3-6 Carbocyclic group, -C 0-2 Alkylene-C 3-6 Carbocyclic group, -C 0-2 Alkylene-4 to 6 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, COOH, CN, NH2, NHC 1-4 Alkyl, N(C 1-4 alkyl)2,=O,C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy, halogen-substituted C 1-4 substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0352] B1 is selected from one of the following groups, substituted or unsubstituted: phenyl, naphthyl, thiophene, furan, pyrrole, pyrazole, imidazole, pyridine, 2-pyridone, pyrimidine, pyrazine, pyridazine, quinoline, isoquinoline, quinazoline, 3,4-dihydro-1H-benzopyran, 1,2,3,4-tetrahydroquinoline, benzofuran, benzothiophene, benzopyrrole, benzoxazole, benzothiazole, benzimidazole, benzopyrazole, morpholine, cyclobutylspirocyclobutyl, cyclobutylspiroazetidinyl, cyclopentylcyclopentyl, cyclopentylpyrrolidinyl, carbazole, and when substituted, 1 to 4 R b1 replace;

[0353] Or B1 is selected from one of the following optionally substituted structures: When substituted, by 1 to 4 R b1 replace;

[0354] Or B1 is selected from B 1A ;

[0355] B2 is selected from one of the following groups, substituted or unsubstituted: phenyl, naphthyl, quinoline, pyrazole, pyridine, imidazole, triazole, thiazole, oxazole, isoxazole, thiophene, benzopyrrole, indole, benzimidazole, benzopyrazole, benzothiophene, benzothiazole, pyrazolotetrahydropyrrole, 3-pyridazinone, 2-pyridone, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, cyclobutylspirocyclobutyl, cyclobutylspiroazetidinyl, cyclopentylcyclopentyl, cyclopentylpyrrolidinyl, when substituted, by 1 to 4 R b2 replace;

[0356] Or B2 is selected from one of the following optionally substituted structures: When substituted, by 1 to 4 R b2 replace;

[0357] Or B2 is selected from B 2A ;

[0358] B 1A 、B 2A Each is independently selected from one of the following optionally substituted structures: When replaced, B 1A 1 to 4 R b1 Replace, B 2A 1 to 4 R b2 replace;

[0359] B3 is selected from one of the following groups, substituted or unsubstituted: oxetanyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, tetrahydrofuranyl, phenyl, pyridine, naphthyl, pyrazole, pyrrole, pyrrolidinyl, piperidine, piperazine, azacyclohexenyl, tetrahydropyranyl, imidazole, thiophene, thiazole, oxazole, isoxazole, triazole, 2-pyridone, benzopyrrole, benzopyrrolidine, benzothiophene, benzothiazole, benzopyrazole, benzimidazole, pyrazolotetrahydropyrrole, 3-pyridazinone, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, cyclobutylspirobutyl, cyclobutylspiroazetidinyl, cyclopentylcyclopentyl, cyclopentylpyrrolidinyl, cyclobutylspiropiperidinyl, when substituted, by 1 to 4 R b3 replace;

[0360] Or B3 is selected from one of the following optionally substituted structures: When substituted, by 1 to 4 R b3 replace;

[0361] V is selected from a bond, O, S, NR b5a NR b5a -C 1-4 Alkylene, C 1-4 Alkylene-NR b5a , OC 1-4 Alkylene, C 1-4 Alkylene-O, C 1-4 Alkylene, said alkylene being optionally substituted by 1 to 4 R b4 or R b5 replaced by;

[0362] Rb1 Each independently selected from F, Cl, Br, I, =O, =S, OH, NH2, CN, NO2, -C(=O)CH3, -C(=O)NH2, -C(=O)NH-CH3, -C(=O)N(CH3)2, -S(=O)2NH2, -P(=O)2(CH3)2, -S(=O)2CH3, -O-cyclopropyl, -O-cyclobutyl, -S-cyclopropyl, -S- cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -NH-cyclopropyl, -NH-cyclobutyl, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, pyrrole, pyrazole, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolane, oxhexyl, morpholine, pyrrolidinyl and cyclopentyl, azetidinyl spirocyclohexyl, Phenyl, the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, pyrrole, pyrazole, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolane, oxhexyl, morpholine, pyrrolidinyl and cyclopentyl, azetidinyl spirocyclohexyl, Phenyl is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, CN, CHF2, CF3, NH2, N(CH3)2, methyl, methoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl;

[0363] R b3Each is independently selected from F, Cl, Br, I, =O, =S, OH, NH2, N(CH3)2, NHCH3, CN, NO2, -C(=O)CH3, -C(=O)NH2, -C(=O)NH-CH3, -C(=O)N(CH3)2, -S(=O)2NH2, -P(=O)2(CH3)2, -S(=O)2CH3, -O-cyclopropyl, -O-cyclobutyl, -NH-cyclopropyl, -NH-cyclobutyl, -S-cyclopropyl, -S-cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-CH2-cyclopropyl, -O-CH2-cyclobutyl, -O-CH2CH2-methoxy, - O-CH2CH2-O-cyclopropyl, -O-CH2CH2-O-cyclobutyl, -CH2-O-CH2CH2-methoxy, -CH2-O-CH2CH2-O-cyclopropyl, -CH2-O-CH2CH2-O-cyclobutyl, -CH2-O-CH2CH2-NH-methyl, -CH2-methoxy, -CH2-ethoxy, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, pyrrole, pyrazole, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, oxhexyl, morpholine, pyrrolidinyl and cyclopentyl, azetidinyl spirocyclohexyl, Phenyl, the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, pyrrole, pyrazole, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolane, oxhexyl, morpholine, pyrrolidinyl and cyclopentyl, azetidinyl spirocyclohexyl, Phenyl is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, CN, CHF2, CF3, NH2, N(CH3)2, methyl, methoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl;

[0364] R b2Each independently selected from H, F, Cl, Br, I, =O, =S, OH, NH2, NHCH3, N(CH3)2, CN, NO2, -C(=O)CH3, -C(=O)NH2, -C(=O)NH-CH3, -C(=O)N(CH3)2, -S(=O)2NH2, -P(=O)(CH3)2, -S(=O)2CH3 or one of the following groups that are optionally substituted: methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy , ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, triazolyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, oxhexyl, morpholine, pyrrolidinyl and cyclopentyl, azetidinyl spirocyclohexyl, cyclopropyl spirocyclobutyl, cyclobutyl spirocyclobutyl, cyclobutyl spirocyclopentyl, cyclobutyl spirocyclohexyl, cyclopentyl spirocyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-morpholine, -CH2-pyrazole, -OCH2- Cyclopropyl, -O-cyclopropyl, -O-cyclobutyl, -NH-cyclopropyl, -NH-cyclobutyl, -OCH2CH2-O-methyl, -OCH2CH2-O-cyclopropyl, -CH2OCH2CH2-O-methyl, -CH2OCH2CH2-O-cyclopropyl, -CH2OCH2CH2-NH-methyl, When substituted, it is substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, CN, CHF2, CH2F, CF3, NH2, NHCH3, N(CH3)2, CH2OH, methyl, ethyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, pyrazolyl, morpholinyl;

[0365] Alternatively, R b1 With R b3 、R b2 With R b3 Either one directly connects to form C 5-7 Carbocyclyl, 5- to 7-membered heterocycle, wherein the carbocyclyl or heterocycle is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, I, OH, -NH2, CN, CH2F, CHF2, CF3, methyl, ethyl, methoxy or ethoxy, and the heterocyclyl contains 1 to 3 heteroatoms selected from O, S, and N;

[0366] K is selected from one of the structural fragments shown in Table K-1;

[0367] The remaining groups are defined the same as in any one of the second, third, fourth or fifth embodiments of the present invention.

[0368] As a seventh embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0369] Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from a bond or one of the following groups which are substituted or unsubstituted: When substituted, by 1 to 4 R L2 replace;

[0370] R L2 Each is independently selected from F, Cl, Br, =O, COOH, CN, NHCH3, N(CH3)2, OH, NH2 or one of the following groups that are optionally substituted: methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, phenyl, morpholine, -CH2-cyclopropyl, -CH2-morpholine, -CH2-pyrazole, -OCH2-cyclopropyl, -O-cyclopropyl, -OCH2CH2-O-methyl, -OCH2CH2-O-cyclopropyl, -CH2OCH2CH2-O-methyl, -CH2OCH2CH2-O-cyclopropyl, when substituted, by 1 to 4 substituents selected from F, CHF2, CF3, OCHF2, OCF3, methyl, methoxy, =O, CH2OH, COOH, CN, NHCH3, N(CH3)2, OH, NH2;

[0371] B is selected from one of the structural fragments shown in Table B-1, Table B-2 or Table B-3, the right side of which is connected to L, and b1 and b2 are each independently selected from 0, 1 or 2;

[0372] K is selected from one of the structural fragments shown in Table K-2;

[0373] The remaining groups are defined the same as in any one of the second, third, fourth, fifth or sixth embodiments of the present invention.

[0374] As an eighth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0375] L is selected from a bond, -Ak1-, -Cy1-, -Cy1-Ak1-, -Cy1-Ak1-Ak2-, -Cy1-Ak1-Ak2-Ak3-, -Cy1-Ak1-Ak2-Ak3-Ak4-, -Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-Ak3-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Cy2-Ak2-Ak3-, -Cy1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Ak2-Cy3-, -Cy1-Ak1-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Cy1-Cy2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Cy3-Ak3-, -Cy1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Ak2-Cy3-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-Ak3-Ak4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-, -Cy1-Ak1-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak2-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-Ak4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-, -Ak1-Cy2-, -Ak1-Cy2-Cy3-, -Ak1-Ak2-Cy3-, -Ak1-Ak2-Cy3-Cy4-, -Ak1-Cy2-Ak2-Cy3-, -Ak1-Cy2-Cy3-Ak3-Cy4-, -Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-, -Ak1-Cy2-Ak2-, -Ak1-Ak2-Ak3-Ak4-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5--Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4-, -Ak1-Cy2-Ak2-Ak3-;,

[0376] Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from -O-, -OCH2-, -CH2O-, -OCH2CH2-, -CH2CH2O-, -CH=CH-, -CH=C(CN)-, -CH=C(F)-, -C(CN)=CH-, -C(F)=CH-, -C≡C-, -C(CH3)2-, -CH2-, -CH2CH2-, -CH2CH2CH2-, -N(CH3)-, -NH-, -CH2N(CH3)-, -CH2NH-, -NHCH2-, -CH2CH2N(CH3)-, -CH2CH2NH-, -NHCH2CH2-, -C(=O)-, -C(=O)CH2NH-, -CH2C(=O)NH-, -C(=O)NH- or -NHC(=O)-;

[0377] V is selected from bonds, NH, NHC(CH3)2CH2, NHCH2C(CH3)2, CH2CH2, C(CH3)2CH2, CH2C(CH3)2, NHCH2CH2, NHCH2, OCH2, CH2NH, CH2O, N HC(CH3)2, OC(CH3)2, C(CH3)2NH, C(CH3)2O, N(CH3)CH2, N(CH3)C(CH3)2, C(CH3)2N(CH3), CH2N(CH3), N(CH3), O, S;

[0378] The remaining groups are defined the same as in any one of the second, third, fourth, fifth or sixth embodiments of the present invention.

[0379] As a ninth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0380] L is selected from a bond or one of the structural fragments shown in Table L-1, Table L-2 or Table L-3, wherein the left side of the group is connected to B and the remaining groups are defined the same as in any one of the second, third, fourth, fifth or sixth embodiments of the present invention.

[0381] The present invention relates to the following compound or its stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures in Table E-1.

[0382] Table E-1

[0383] The present invention relates to a pharmaceutical composition comprising the above-mentioned compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier.

[0384] The present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier.

[0385] In some embodiments, the pharmaceutical composition of the present invention may be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as the "preparation strength").

[0386] As used herein, an "effective amount" or "therapeutically effective amount" refers to administering a sufficient amount of a compound disclosed herein that will alleviate to some extent one or more symptoms of the disease or condition being treated (e.g., inhibiting or degrading AR or AR splicing mutant-related diseases such as prostate cancer). In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired change in the biological system. For example, an "effective amount" for therapeutic use is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease symptoms.Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 mg, 6-600 mg, 10-600 mg, 20-600 mg, 25-600 mg, 30-600 mg, 40-600 mg, 50-600 mg, 60-600 mg, 70-600 mg, 75-600 mg, 80-600 mg, 90-600 mg, 100-600 mg, 200-600 mg, 1-500 mg, 2-500 mg, 3-500 mg, 4-500 mg, 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, 1 00-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg, 400-500mg, 5-400mg, 10-400mg, 20-400mg, 25-400mg, 30-400mg, 40- 400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80-400mg, 90-400mg, 100-400mg, 125-400mg, 150-400mg, 200-400mg, 250-400mg, 300-40 0mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300mg, 25-300mg, 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-300mg, 80-300m g, 90-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-2 00mg, 40-200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg, 80-1000mg, 80-800mg.

[0387] In some embodiments, the pharmaceutical composition includes but is not limited to 1-1000 mg, 20-800 mg, 40-800 mg, 40-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg , 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, 840 mg of a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

[0388] A method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein the therapeutically effective amount is preferably 1-1500 mg, and the disease is preferably a disease associated with the inhibition or degradation of AR or AR splicing mutants (such as prostate cancer).

[0389] A method for treating a disease in a mammal, comprising administering to a subject a compound of the present invention or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof at a daily dose of 1-1000 mg / day. The daily dose may be a single dose or divided doses. In some embodiments, the daily dose includes but is not limited to 10-1500 mg / day, 10-1000 mg / day, 10-800 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day. , 25-400 mg / day, 50-400 mg / day, 100-400 mg / day, 200-400 mg / day, in some embodiments, daily doses include but are not limited to 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 80 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 160 mg / day, 200 mg / day, 300 mg / day, 320 mg / day, 400 mg / day, 480 mg / day, 600 mg / day, 640 mg / day, 800 mg / day, 1000 mg / day.

[0390] The present invention relates to a kit, which may include a composition in single-dose or multi-dose form, wherein the kit contains a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and the amount of the compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is the same as the amount in the above-mentioned pharmaceutical composition.

[0391] The present invention relates to the use of the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or the above-mentioned pharmaceutical composition in the preparation of a drug for treating diseases related to the activity or expression of AR or AR splicing mutants.

[0392] The present invention relates to the use of the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, or the above-mentioned pharmaceutical composition in the preparation of a drug for treating diseases related to the inhibition or degradation of AR or AR splicing mutants.

[0393] The present invention relates to the use of the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, or the above-mentioned pharmaceutical composition, wherein the disease is selected from prostate cancer.

[0394] The amount of the compound of the invention or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof is in each case calculated as the free base.

[0395] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0396] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, nitrogen isotopes include 14 N and15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl, bromine include 79 Br and 81 Br.

[0397] "Halogen" refers to F, Cl, Br or I.

[0398] "Halogen-substituted" refers to substitution with F, Cl, Br or I, including but not limited to substitution with 1 to 10 substituents selected from F, Cl, Br or I, substitution with 1 to 6 substituents selected from F, Cl, Br or I, and substitution with 1 to 4 substituents selected from F, Cl, Br or I. "Halogen-substituted" is abbreviated as "halo".

[0399] "Alkyl" refers to a substituted or unsubstituted straight-chain or branched saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, and alkyl groups of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched chain isomers thereof; alkyl groups appearing herein have the same definition as this one. Alkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0400] "Hydrocarbyl" refers to a substituted or unsubstituted, linear or branched, saturated or unsaturated group consisting of carbon and hydrogen atoms. The hydrocarbyl group may be monovalent, divalent, trivalent or tetravalent.

[0401] "Alkylene" refers to substituted or unsubstituted straight-chain and branched divalent saturated hydrocarbon groups, including -(CH2) v -(v is an integer from 1 to 10), examples of alkylene include but are not limited to methylene, ethylene, propylene and butylene.

[0402] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon radical, typically having 3 to 10 carbon atoms, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Cycloalkyl groups as used herein are as defined above. Cycloalkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0403] "Heterocycloalkyl" refers to a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 10 atoms, 3 to 8 atoms, including 1 to 3 heteroatoms selected from N, O or S. The N and S optionally substituted in the heterocycloalkyl ring can be oxidized to various oxidation states. The heterocycloalkyl group can be attached to a heteroatom or a carbon atom, can be attached to an aromatic ring or a non-aromatic ring, can be connected to a bridged ring group or a spirocycle, and non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl. The heterocycloalkyl group can be monovalent, divalent, trivalent or tetravalent.

[0404] "Alkenyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbon groups having at least one, typically one, two or three carbon-carbon double bonds, with a backbone of 2 to 10, 2 to 6 or 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2- Methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, and 1,4-hexadiene; alkenyl groups appearing herein have the same definition as this one. Alkenyl groups may be monovalent, divalent, trivalent, or tetravalent.

[0405] "Alkynyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbon groups having at least one, typically one, two or three carbon-carbon triple bonds, including but not limited to 2 to 10 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms in the backbone chain. Examples of alkynyl groups include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1- Alkynyl groups include methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, and 4-decynyl. Alkynyl groups may be monovalent, divalent, trivalent, or tetravalent.

[0406] "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, cyclopropyloxy, and cyclobutyloxy.

[0407] "Carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring, the aromatic ring or non-aromatic ring can be a 3-8 membered monocyclic radical, a 4-12 membered bicyclic radical or a 10-15 membered tricyclic ring system, the carbocyclyl can be attached to the aromatic ring or the non-aromatic ring, the aromatic ring or non-aromatic ring is optionally a monocyclic radical, a bridged ring radical or a spirocyclic ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, phenyl ring, naphthyl ring, "Carbocyclyl" or "carbocycle" can be monovalent, divalent, trivalent, or tetravalent.

[0408] "Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring, which can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, or a 10- to 15-membered tricyclic ring system, and contains one or more (including but not limited to 2, 3, 4, or 5) heteroatoms selected from N, O, or S. The C, N, or S optionally substituted in the heterocyclyl ring can be oxidized to various oxidation states. The heterocyclic group can be connected to a heteroatom or a carbon atom, the heterocyclic group can be connected to an aromatic ring or a non-aromatic ring, and the heterocyclic group can be connected to a bridged ring or a spiro ring. Non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolane, 1,4-dioxolane, 1,3-dioxane, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, pyranyl, ... furanyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophenyl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptanyl, "Heterocyclyl" or "heterocycle" can be monovalent, divalent, trivalent or tetravalent.

[0409] "Spirocycle" or "spirocyclyl" refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called a spiro atom), and the number of ring atoms in the spirocycle system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more 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 atoms selected from N, O or S (=O) n of heteroatoms.

[0410] "Spirocycle" or "spirocyclyl" can be monovalent, divalent, trivalent or tetravalent.

[0411] "Parallel ring" or "parallel ring group" refers to a polycyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, wherein one or more rings may contain 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 parallel ring system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O) n or O, n is 0, 1 or 2). The number of ring atoms in the cyclic system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, and 5 to 10. Non-limiting examples include: "Bicyclic" or "bicyclic group" can be monovalent, divalent, trivalent or tetravalent.

[0412] "Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected, and may contain zero or more double bonds. Any ring in the bridged ring system may contain zero to five atoms selected from heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O)n or O, where n is 0, 1, or 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

[0413] "Bridged ring" or "bridged ring group" may be monovalent, divalent, trivalent or tetravalent.

[0414] "Carbospirocycle," "spirocarbocyclyl," "spirocarbocyclyl," or "carbospirocyclyl" refers to a "spirocycle" wherein the ring system consists of only carbon atoms.

[0415] "Carbocyclyl," "carbocyclyl," "carbocyclyl," or "carbocyclyl" refers to a "carbocyclyl" ring system consisting of only carbon atoms.

[0416] "Carbobridged ring," "bridged carbocyclic group," "bridged carbocyclic group," or "carbon-bridged cyclic group" refers to a "bridged ring" in which the ring system consists of only carbon atoms.

[0417] "Heteromonocycle", "monocyclic heterocyclyl" or "heteromonocyclyl" refers to a monocyclic ring system of "heterocyclyl" or "heterocycle".

[0418] "Heterocyclo", "cycloheterocyclyl" or "heterocyclo" refers to a cycloheterocyclic ring containing a heteroatom.

[0419] "Heterospirocycle," "spiroheterocyclyl," or "heterospirocyclyl" refers to a spirocycle containing a heteroatom.

[0420] "Heterobridged ring," "bridged heterocyclyl," or "heterobridged cyclyl" refers to a "bridged ring" containing a heteroatom.

[0421] "Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a single ring or a fused ring, wherein the number of ring atoms in the aromatic ring includes, but is 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, wherein the ring connected to the parent structure is the aryl ring, non-limiting examples of which include phenyl ring, naphthyl ring, "Aryl" or "aromatic ring" can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the aryl ring.

[0422] "Heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, O or S(=O)n, where n is 0, 1, or 2), and the number of ring atoms in the heteroaromatic ring includes but is not limited to 5 to 15, 5 to 10, or 5 to 6. Non-limiting examples of heteroaryl include but are not limited to pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, pyridone, pyrazinone, The heteroaryl ring may be fused to a saturated or unsaturated carbocyclic ring or heterocyclic ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples include When heteroaryl appears in this document, its definition is consistent with this definition. Heteroaryl can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the attachment point is located on the heteroaryl ring.

[0423] "5-membered ring and 5-membered heteroaryl" refers to a 5-membered fused heteroaryl group, at least one of the two rings contains one or more heteroatoms (including but not limited to O, S or N), and the entire group is aromatic. Non-limiting examples include pyrrolopyrrole ring group, pyrazolopyrrole ring group, pyrazolopyrazole ring group, pyrrolofuran ring group, pyrazolofuran ring group, pyrrolothiophene ring group, and pyrazolothiophene ring.

[0424] "5-membered and 6-membered heteroaryl" refers to a 5-membered and 6-membered fused heteroaryl group, wherein at least one of the two rings contains one or more heteroatoms (including but not limited to O, S or N), and the entire group is aromatic. Non-limiting examples include benzo-5-membered heteroaryl, 6-membered heteroaryl and 5-membered heteroaryl.

[0425] "Substituted" or "substituted" refers to substitution by one or more (including but not limited to 2, 3, 4 or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, cycloalkyl, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH2), m -C(=O)-R a 、-O-(CH2) m -C(=O)-R a 、-(CH2) m -C(=O)-NR b R c 、-(CH2) m S(=O) n R a 、-(CH2) m -alkenyl-R a , OR d or -(CH2) m -alkynyl-R a (wherein m and n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR b R c etc., where R b With R c R is independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, b With R c Can form a five- or six-membered cycloalkyl or heterocyclic group, R a With R d Each is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring or paracyclic group.

[0426] “Containing 1 to 5 heteroatoms selected from O, S, and N” means containing 1, 2, 3, 4, or 5 heteroatoms selected from O, S, and N.

[0427] "1 to X substituents selected from..." means substituted by 1, 2, 3, ..., X substituents selected from ..., where X is any integer from 1 to 10. For example, "1 to 4 R k "Substituted" means replaced by 1, 2, 3 or 4 R k Substitution. For example, "substituted by 1 to 5 substituents selected from..." means substituted by 1, 2, 3, 4, or 5 substituents selected from..." For example, "a heterobridged ring is optionally substituted by 1 to 4 substituents selected from H or F" means that the heterobridged ring is optionally substituted by 1, 2, 3, or 4 substituents selected from H or F.

[0428] An XY-membered ring (X and Y are integers, and 3≤X<Y, X<Y≤20 is selected from any integer between 4 and 20) includes rings with X, X+1, X+2, X+3, X+4, ..., Y members. Rings include heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heterocyclic rings, heterospirocyclic rings, or heterobridged rings. For example, "4-7 membered heteromonocyclic ring" refers to a 4-, 5-, 6-, or 7-membered heteromonocyclic ring, and "5-10 membered heterocyclic ring" refers to a 5-, 6-, 7-, 8-, 9-, or 10-membered heterocyclic ring.

[0429] C x-y Carbocycles (including aryl, cycloalkyl, monocyclic carbocyclic, spirocyclic carbocyclic, cyclic carbocyclic or bridged carbocyclic) include C x 、C x+1 、C x+2 、C x+3 、C x+4 ….C y A ring of 1 member (x is an integer, and 3≤x<y, y is selected from any integer between 4 and 20), for example, C 3-6 "Cycloalkyl" refers to a C3, C4, C5 or C6 cycloalkyl group.

[0430] When a group has one or more bondable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are hydrogen atoms at the bondable sites, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of chemical bonds connected, and the group will become a group with the corresponding valence. For example Indicates that any linkable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Also included For example Indicates that the R group on the piperidinyl group can be located on C, can be located on N, and at least includes

[0431] When the listed linking groups do not specify their connection direction, their connection directions include connection from left to right and from right to left in the reading order, for example, when ALB, L is selected from -MW-, it includes AMWB and AWMB.

[0432] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not. For example, "alkyl optionally substituted with F" means that the alkyl group may but need not be substituted with F, and the description includes instances where the alkyl group is substituted with F and instances where the alkyl group is not substituted with F.

[0433] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, or the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0434] "Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, or stereoisomers, tautomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals thereof, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0435] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0436] "Carrier" refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

[0437] "Animal" is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

[0438] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers, and conformational isomers.

[0439] "Tautomers" refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions, such as keto-enol isomers and amide-imino alcohol isomers.

[0440] “IC 50 "It is the concentration of a drug or inhibitor required to inhibit a specified biological process (or a component of the process such as an enzyme, receptor, cell, etc.) by half. DETAILED DESCRIPTION

[0441] The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.

[0442] The compounds used in the reactions described herein were prepared using organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or compounds described in the chemical literature. "Commercially available chemicals" were obtained from reputable commercial sources, including suppliers such as Titan Technology, Anage Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and J&K Technology.

[0443] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0444] MS was determined using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0445] HPLC determination was performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM);

[0446] Thin layer chromatography silica gel plates used were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of silica gel plates used for thin layer chromatography (TLC) were 0.15 mm to 0.20 mm, and the specifications used for thin layer chromatography separation and purification products were 0.4 mm to 0.5 mm.

[0447] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0448] SEM: THP: Boc: tert-butoxycarbonyl; Ms: TBS: Bn: DIPEA: N,N-diisopropylethylamine; DMF: N,N-dimethylformamide; DMAc: N,N-dimethylacetamide; DMSO: dimethyl sulfoxide; DCM: dichloromethane; Cbz: NMP: N-methylpyrrolidone; TEA: triethylamine; MsCl: methanesulfonyl chloride.

[0449] Synthesis of intermediate 1:

[0450] Step 1: Preparation of 1B hydrochloride

[0451] 1A (90 g, 0.50 mol) was dissolved in 500 mL of 2 mol / L hydrochloric acid and ethyl acetate solution and reacted at room temperature for 5 h. The reaction system was concentrated under reduced pressure to obtain the crude hydrochloride of 1B (59 g).

[0452] LCMS m / z=82.3[M+1] +

[0453] Step 2: Preparation of Intermediate 1

[0454] The crude hydrochloride of 1B (59 g) was dissolved in 500 mL of DMSO, and sodium bicarbonate (42 g, 0.50 mol) was added. After stirring at room temperature for 10 min, 100 mL of DIPEA and 1C (165.6 g, 0.60 mol) were added, and the mixture was reacted at 85°C for 5 h. The reaction solution was cooled to room temperature, 5 L of water was added, and the solid was collected by filtration and washed with 500 mL of water. The solid was then air-dried to obtain crude intermediate 1 (40 g).

[0455] Example 1: Preparation of Compound 1

[0456] Step 1: Preparation of 1b

[0457] 1a (1.0 g, 3.4 mmol) (synthesis method, see WO2012123745), 1A (0.92 g, 5.1 mmol), TEA (2.06 g, 20.4 mmol), cuprous iodide (130 mg, 0.68 mmol), and (PPh3)2PdCl2 (240 mg, 0.34 mmol) were added to a reaction flask. Under nitrogen, 5 mL of DMF was added, and the temperature was raised to 50°C for 0.5 h. The reaction solution was cooled to room temperature and added to 50 mL of ethyl acetate. The organic phase was washed with saturated sodium chloride solution (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-1:2) to obtain 1b (1.0 g, yield: 85%).

[0458] Step 2: Preparation of 1c

[0459] 1b (1.0 g, 2.88 mmol) and sodium carbonate (0.61 g, 5.76 mmol) were added to 10 mL of DMF and heated to 85°C for 1.5 h. The reaction solution was cooled to room temperature, added to 100 mL of ethyl acetate, washed with saturated sodium chloride solution (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-1:2) to obtain 1c (0.6 g, yield: 84%).

[0460] LCMS m / z=248.2[M+1] +

[0461] Step 3: Preparation of 1e

[0462] 1c (0.58 g, 2.33 mmol), 1d (0.95 g, 2.33 mmol) (synthesis method, see Journal of Organic Chemistry, 2003, 68, 8075-8079), cuprous iodide (89 mg, 0.47 mmol), and (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (CAS: 87583-89-9) (0.71 g, 4.99 mmol) were added to a reaction flask. Under nitrogen, 10 mL of DMF was added, and the temperature was raised to 100°C for 2 h. The reaction solution was cooled to room temperature and added to 50 mL of ethyl acetate. The solution was washed with saturated sodium chloride solution (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-1:2) to obtain 1e (0.6 g, yield: 49%).

[0463] LCMS m / z=526.1[M+1] +

[0464] Step 4: Preparation of compound 1

[0465] 1e (0.2 g, 0.38 mmol) and p-toluenesulfonic acid (0.19 g, 1.10 mmol) were dissolved in 5 mL of acetonitrile and reacted at room temperature for 12 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The above crude product, 1f (0.1 g, 0.36 mmol), and DIPEA (0.29 g, 2.24 mmol) were dissolved in 5 mL of DMF and heated to 80°C for 5 h. The reaction solution was cooled to room temperature and 100 mL of ethyl acetate was added. The organic phase was washed with saturated sodium chloride solution (50 mL × 3), dried over anhydrous sodium sulfate, and the crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-1:2) to obtain compound 1 (0.1 g, yield: 39%).

[0466] 1 H NMR (400MHz, CDCl3) δ8.05(s,1H),7.98(s,1H),7.90(s,1H),7.86(s,1H),7.80–7.64(m,4H),6.86–6.78(m,1H),6.57(dd ,1H),5.01–4.89(m,1H),4.45–4.30(m,2H),4.17–4.03(m,2H),3.94–3.76(m,1H),2.98–2.63(m,3H),2.23–2.06(m,1H).

[0467] LCMS m / z=682.1[M+1] +

[0468] Example 2: Preparation of trifluoroacetate salt of compound 2

[0469] Step 1: Preparation of 2b

[0470] 2a (5.0 g, 25.57 mmol) was added to 50 mL of water, and 15 mL of concentrated sulfuric acid was slowly added. The reaction mixture was allowed to react at 60°C for 1 h. The reaction mixture was cooled to 0°C, and 5 mL of an aqueous solution of sodium nitrite (1.76 g, 25.51 mmol) was added dropwise. The mixture was stirred at 0-5°C for 30 min. The reaction mixture was heated to 40°C, and 10 mL of an aqueous solution of potassium iodide (8.49 g, 51.14 mmol) was added dropwise. The reaction mixture was allowed to react at 50°C for 1 h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (50 mL x 3). The organic phases were combined and washed with 1 mol / L aqueous hydrochloric acid (50 mL), then with 50 mL of saturated aqueous sodium thiosulfate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-100:1) to obtain 2b (5.0 g, yield: 64%).

[0471] Step 2: 2D preparation

[0472] 2c (5.0 g, 49.93 mmol) was dissolved in 50 mL of acetic acid, and iodine (12.67 g, 49.92 mmol) was added at room temperature. The reaction mixture was allowed to react at room temperature for 12 h. The reaction solution was added to 200 mL of water, and the pH was adjusted to 8 with solid potassium carbonate. The mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with 50 mL of saturated sodium thiosulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-5:1) to obtain 2d (2.0 g, yield: 18%).

[0473] Step 3: Preparation of 2e

[0474] 2d (2.0 g, 8.85 mmol) and 1-chloro-2-isocyanatoethane (0.95 g, 9.0 mmol) were added to 20 mL of acetonitrile and refluxed at 90°C for 2 h. The reaction solution was cooled to room temperature, 5 mL of methanol was added, and the mixture was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-2:1) to obtain 2e (2.0 g, yield: 73%).

[0475] Step 4: Preparation of 2f

[0476] 2e (2.0 g, 6.03 mmol) and potassium carbonate (1.25 g, 9.04 mmol) were added to 20 mL of acetonitrile and refluxed at 80°C for 12 h. The reaction solution was cooled to room temperature, 5 mL of methanol was added, and the mixture was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-1:2) to obtain 2f (1.5 g, yield: 84%).

[0477] LCMS m / z=296.2[M+1] +

[0478] Step 5: Preparation of 2g

[0479] 2f (1.0 g, 3.39 mmol), 1A (0.92 g, 5.08 mmol), TEA (2.06 g, 20.36 mmol), cuprous iodide (130 mg, 0.68 mmol), and (PPh3)2PdCl2 (240 mg, 0.34 mmol) were added to a reaction flask. 5 mL of DMF was added under nitrogen, and the temperature was raised to 50°C for 0.5 h. The reaction solution was cooled to room temperature and added to 50 mL of ethyl acetate. The organic phase was washed with saturated sodium chloride solution (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-1:2) to obtain 2g (0.8 g, yield: 68%).

[0480] LCMS m / z=349.3[M+1] +

[0481] Step 6: Preparation of 2h

[0482] 2g (0.6g, 1.72mmol), 2b (0.6g, 1.96mmol), cuprous iodide (59mg, 0.31mmol), and (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (0.6g, 4.22mmol) were added to a reaction flask. Under nitrogen, 6mL of DMF was added, and the temperature was raised to 100°C for 2h. The reaction solution was cooled to room temperature and added to 50mL of ethyl acetate. The organic phase was washed with saturated sodium chloride solution (50mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-1:2) to obtain 2h (0.6g, yield: 66%).

[0483] LCMS m / z=527.1[M+1] +

[0484] Step 7: Preparation of trifluoroacetate salt of compound 2

[0485] 2h (0.2 g, 0.38 mmol) and p-toluenesulfonic acid (0.26 g, 1.51 mmol) were dissolved in 10 mL of acetonitrile and allowed to react at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product, 1f (0.1 g, 0.36 mmol), and DIPEA (0.3 g, 2.32 mmol) were dissolved in 5 mL of DMF and heated to 80°C for 5 h. The reaction mixture was cooled to room temperature and 100 mL of ethyl acetate was added. The organic phase was washed with saturated sodium chloride (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was then subjected to pre-HPLC (instrument and preparative column: Glison GX-281 preparative HPLC, Sunfire C18 preparative column, 5 μm, inner diameter x length = 30 mm x 150 mm). Preparation method: The crude product was dissolved in methanol and dimethyl sulfoxide and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile / water (containing 0.1% TFA). Gradient elution method: acetonitrile was gradient eluted from 5% to 60% (elution time 15 min), and lyophilized to obtain trifluoroacetate salt of compound 2 (0.05 g).

[0486] 1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),8.05(s,1H),7.90–7.79(m,2H),7.74–7.62(m,2H),6.90–6.82(m,1H),6.71(dd,1H),5.13 –5.01(m,1H),4.45–4.32(m,2H),4.32–4.15(m,2H),4.15–3.90(m,5H),2.98–2.80(m,1H),2.69–2.50(m,2H),2.09–1.96(m,1H).

[0487] LCMS m / z=683.0[M+1] +

[0488] Example 3: Preparation of Compound 3

[0489] Step 1: Preparation of 3b

[0490] 3a (4.1 g, 19.80 mmol) and 4-iodo-1H-pyrazole (4.22 g, 21.75 mmol) were dissolved in 40 mL of acetonitrile, and solid cesium carbonate (9.68 g, 29.70 mmol) was added. The mixture was reacted at 80°C for 3 h. The reaction solution was cooled to room temperature, and 30 mL of water and 100 mL of ethyl acetate were added. The layers were separated, and the organic phase was washed with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was then purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1:9) to obtain 3b (2.40 g, yield: 38%).

[0491] Step 2: Preparation of 3c

[0492] Dissolve 3b (2.30 g, 7.18 mmol) in 20 mL of tetrahydrofuran, add 4 mL of water, and then add lithium hydroxide monohydrate (0.6 g, 14.3 mmol). React at room temperature for 30 min. Add 1 mol / L dilute hydrochloric acid dropwise to the reaction solution to adjust the pH to 6. Add 50 mL of ethyl acetate, separate the layers, and wash the organic phase with 20 mL of saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product 1 (2.0 g). Dissolve 4-(trifluoromethyl)benzene-1,2-diamine (1.0 g, 5.7 mmol) in 10 mL of pyridine, add the crude product 1 (1.6 g) and triphenyl phosphite (5.3 g, 17.1 mmol), and heat to 200°C and microwave for 20 min. The reaction solution was cooled to room temperature, and 80 mL of ethyl acetate was added. The organic phase was washed with water (100 mL × 3), then washed with 50 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 68:32) to obtain 3c (0.3 g, yield: 12%).

[0493] LCMS m / z=433.2[M+1] +

[0494] Step 3: Preparation of compound 3

[0495] 3c (100 mg, 0.23 mmol) was added to a 50 mL single-necked bottle, followed by 8 mL of dry DMF, crude intermediate 1 (116 mg) and triethylamine (70 mg, 0.69 mmol), the nitrogen atmosphere was replaced three times, (PPh3)2PdCl2 (16 mg, 0.023 mmol) and cuprous iodide (8 mg, 0.042 mmol) were added, the nitrogen atmosphere was replaced three times, and the reaction was carried out at 50°C for 2 h. The reaction system was cooled to room temperature, 100 mL of saturated aqueous ammonium chloride was slowly added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated aqueous sodium chloride (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 12:88) to obtain compound 3 (50 mg, yield: 34%).

[0496] 1 H NMR(400MHz, CDCl3)δ8.31(s,1H),8.20–7.30(m,6H),6.84–6.72(m,1H),6.54(dd,1H),5.00–4.88(m,1H),4.4 0–4.28(m,2H),4.10–3.97(m,2H),3.88–3.72(m,1H),3.34–3.07(m,2H),3.05–2.62(m,5H),2.43–2.06(m,3H).

[0497] LCMS m / z=642.4[M+1] +

[0498] Example 5: Preparation of Compound 5

[0499] Step 1: Preparation of 5b: 5a (4.1 g, 19.80 mmol) and 4-iodo-1H-pyrazole (4.22 g, 21.75 mmol) were dissolved in 40 mL of acetonitrile, and cesium carbonate (9.68 g, 29.70 mmol) was added. The mixture was reacted at 80°C for 3 h. The reaction solution was cooled to room temperature, and 30 mL of water and 100 mL of ethyl acetate were added. The layers were separated, and the organic phase was washed with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was then purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1:9) to obtain 5b (2.40 g, yield: 38%).

[0500] Step 2: Preparation of 5c

[0501] 5b (2.30 g, 7.18 mmol) was dissolved in 20 mL of tetrahydrofuran, and 4 mL of water and lithium hydroxide monohydrate (0.6 g, 14.3 mmol) were added. The mixture was allowed to react at room temperature for 30 min. 1 mol / L dilute hydrochloric acid was added dropwise to adjust the pH to 6. 50 mL of ethyl acetate was added, and the layers were separated. The organic phase was washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product (2.0 g). The crude product (2.0 g) was cooled to 0°C, and 40 mL of 1.0 mol / L borane solution in tetrahydrofuran was slowly added. The reaction was allowed to react at room temperature for 16 h. The reaction mixture was cooled to 0°C, and methanol was slowly added dropwise until no bubbles formed. The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3:1) to obtain 5c (1.1 g, yield: 55%).

[0502] LCMS m / z=279.1[M+1] +

[0503] Step 3: Preparation of 5d

[0504] 5c (0.4 g, 1.44 mmol) was dissolved in 15 mL of dichloromethane, and triethylamine (0.44 g, 4.35 mmol) was added. The mixture was cooled to 0°C, and MsCl (0.2 g, 1.75 mmol) was slowly added dropwise. The reaction mixture was allowed to react at room temperature for 16 h. 50 mL of water was added to the reaction system, and the mixture was extracted with 100 mL of ethyl acetate. The organic phase was washed with 50 mL of saturated sodium bicarbonate solution, followed by 50 mL of 0.5 mol / L hydrochloric acid, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3:1) to obtain 5d (0.5 g, yield: 98%).

[0505] LCMS m / z=357.0[M+1] +

[0506] Step 4: Preparation of 5e

[0507] 5-(Trifluoromethyl)-1H-indazole (0.2 g, 1.07 mmol) was dissolved in 5 mL of DMF, and cesium carbonate (0.70 g, 2.15 mmol) was added. The temperature was raised to 90°C, and 5d (0.46 g, 1.29 mmol) was slowly added portionwise. The reaction was allowed to react at 90°C for 16 h. The reaction system was cooled to room temperature, 50 mL of water was added, and the mixture was extracted with 100 mL of ethyl acetate. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 5:1) to obtain 5e (0.25 g, yield: 52%).

[0508] Step 5: Preparation of compound 5

[0509] 5e (0.15 g, 0.34 mmol), crude intermediate 1 (0.14 g), TEA (0.10 g, 0.99 mmol), CuI (7 mg, 0.037 mmol), and PdCl2(PPh3)2 (24 mg, 0.034 mmol) were added to a reaction flask. Under nitrogen protection, 5 mL of DMF was added and the reaction was carried out at 50°C for 1 h. The reaction solution was cooled to room temperature, 50 mL of water was added, and the mixture was filtered. The filter cake was washed with 10 mL of water and dissolved in 100 mL of DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:1) to obtain compound 5 (0.12 g, yield: 54%).

[0510] 1H NMR (400MHz, CDCl3) δ8.13–8.04(m,2H),7.96(s,1H),7.69–7.62(m,1H),7.59 –7.53(m,1H),7.40–7.33(m,1H),6.80–6.74(m,1H),6.72–6.62(m,2H),6.51( dd,1H),4.99–4.87(m,1H),4.83(s,2H),4.34–4.20(m,2H),4.00–3.87(m,2H) ,3.75–3.60(m,1H),2.95–2.65(m,5H),2.65–2.46(m,2H),2.26–2.00(m,3H).

[0511] LCMS m / z=656.6[M+1] +

[0512] Example 6: Preparation of Compound 6

[0513] Step 1: Preparation of 6b

[0514] Compound 6a (1.00 g, 4.12 mmol) and 6A (1.01 g, 4.5 mmol) were dissolved in tetrahydrofuran (50 mL). 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (CAS: 161265-03-8) (0.24 g, 0.415 mmol), potassium phosphate (2.62 g, 12.34 mmol), and palladium acetate (0.05 g, 0.22 mmol) were added. The nitrogen atmosphere was replaced three times, and the reaction was carried out at 80°C for 16 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 4:1) to obtain 6b (1.00 g, 71% yield).

[0515] Step 2: Preparation of 6c

[0516] To a 250 mL reaction flask, 6b (1.00 g, 2.92 mmol), 1c (0.72 g, 2.91 mmol), CuI (0.11 g, 0.58 mmol), trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (CAS: 67579-81-1) (0.17 g, 1.2 mmol), potassium phosphate (1.86 g, 8.76 mmol), and DMF (30 mL) were added sequentially and reacted at 100°C for 16 h. The reaction solution was cooled to room temperature, and 100 mL of ethyl acetate was added. The organic phase was washed with water (100 mL × 3) and 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3:1) to obtain 6c (0.72 g, 49% yield).

[0517] Step 3: Preparation of 6d

[0518] In a 50 mL reaction flask, 6c (0.50 g, 0.98 mmol) was dissolved in 20 mL of acetonitrile, and p-toluenesulfonic acid monohydrate (0.51 g, 2.68 mmol) was added. The mixture was allowed to react at 25°C for 16 h. The reaction solution was adjusted to pH 9 with saturated aqueous sodium bicarbonate solution and extracted with 30 mL of dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield crude product 6d (0.38 g).

[0519] LCMS m / z=409.4[M+1] +

[0520] Step 4: Preparation of compound 6

[0521] To a 50 mL reaction flask, the crude product 6d (0.15 g), 1f (0.12 g, 0.43 mmol), DIPEA (0.10 g, 0.77 mmol), and DMSO (10 mL) were added sequentially and reacted at 90°C for 3 h. The reaction solution was cooled to room temperature and 10 mL of water was added. A yellow solid precipitated and was filtered. The filter cake was washed with water (5 mL × 3) and then dissolved in a 10:1 dichloromethane / methanol (v / v) mixture. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 15:1) to obtain compound 6 (0.13 g, 25% yield).

[0522] 1H NMR (400MHz, CDCl3) δ8.56–8.46(m,2H),7.92(s,1H),7.85–7.61(m,5H),6.86–6.79(m,1H),6.58(dd,1H),5.0 0–4.89(m,1H),4.42–4.31(m,2H),4.18–4.05(m,2H),3.94–3.79(m,1H),3.04–2.60(m,3H),2.22–2.08(m,1H).

[0523] Example 7: Preparation of Compound 7

[0524] Step 1: Preparation of 7b

[0525] In a 1 L reaction flask, crude intermediate 1 (10.00 g) and 7a (8.72 g, 29.65 mmol) were dissolved in DMF (200 mL). PdCl2(PPh3)2 (2.08 g, 2.96 mmol), CuI (1.13 g, 5.93 mmol), and TEA (18.00 g, 177.88 mmol) were added. The nitrogen atmosphere was replaced three times and the reaction was carried out at 55°C for 1 h. The reaction solution was cooled to room temperature, 500 mL of ethyl acetate and 100 mL of water were added, and a flocculent solid precipitated. The solid was filtered and the filtrate was allowed to stand for stratification. The organic phase was washed with water (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by slurrying with 50 mL of a mixed solvent of dichloromethane / methyl tert-butyl ether (v / v) = 1:5 and filtered to obtain crude product 7b (7.00 g).

[0526] LCMS m / z=504.7[M+1] +

[0527] Step 2: Preparation of 7c

[0528] The crude product 7b (2.00 g) was dissolved in dichloromethane (30 mL), and trifluoroacetic acid (30 mL) was added at room temperature. The reaction was allowed to react at 25°C for 2 h. The reaction system was concentrated under reduced pressure, and 200 mL of dichloromethane was added. The pH was adjusted to 9 with saturated aqueous sodium bicarbonate solution. The layers were separated, and the aqueous phase was extracted with dichloromethane (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 12:1) to obtain 7c (1.54 g, two-step yield: 45% based on compound 7a).

[0529] LCMS m / z=404.1[M+1] +

[0530] Step 3: Preparation of 7f

[0531] To a sealed glass tube, add 7d (2.00 g, 8.23 ​​mmol) and 7e (15 mL), and the reaction was sealed at 50°C for 16 h. The reaction system was cooled to room temperature, and 100 mL of ethyl acetate was added. The reaction was washed with water (50 mL × 3) and 50 mL of saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product 7f (1.95 g).

[0532] LCMS m / z=249.1[M+1] +

[0533] Step 4: Preparation of compound 7

[0534] To a 50 mL reaction flask, the crude product 7f (0.025 g), 7c (0.04 g, 0.099 mmol), CuI (0.004 g, 0.021 mmol), trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (CAS: 67579-81-1) (0.006 g, 0.042 mmol), potassium phosphate (0.063 g, 0.297 mmol), and DMF (10 mL) were added sequentially and reacted at 100°C for 16 h. The reaction solution was cooled to room temperature, ethyl acetate (50 mL) was added, and the mixture was washed with water (50 mL × 3) and 50 mL of saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was isolated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:1) to obtain compound 7 (0.015 g, yield: 27%).

[0535] 1 H NMR (400MHz, CDCl3) δ8.25(s,1H),7.93(s,1H),7.72–7.63(m,2H),6.85–6.78(m,1H),6.72–6.52(m,2H),4.98–4. 89(m,1H),4.36(t,2H),4.09(t,2H),3.88–3.77(m,5H),3.54–3.45(m,4H),2.95–2.64(m,3H),2.19–2.08(m,1H).

[0536] Example 8: Preparation of Compound 8

[0537] Step 1: Preparation of 8c

[0538] 8a (0.20 g, 0.65 mmol) and 8b (0.13 g, 0.65 mmol) were added to a sealed glass tube, followed by toluene (3 mL) and methanol (3 mL). Tetrakis(triphenylphosphine)palladium (0.015 g, 0.013 mmol) and sodium carbonate (0.14 g, 1.32 mmol) were also added. The atmosphere was purged with nitrogen three times and the reaction was carried out at 110°C for 2 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether) to obtain 8c (0.115 g, 53% yield).

[0539] Step 2: Preparation of compound 8

[0540] To a 50 mL reaction flask, 8c (0.11 g, 0.33 mmol), 7c (0.133 g, 0.33 mmol), CuI (0.013 g, 0.068 mmol), trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (CAS: 67579-81-1) (0.019 g, 0.13 mmol), potassium phosphate (0.21 g, 0.99 mmol), and DMF (15 mL) were added sequentially and reacted at 100°C for 16 h. The reaction solution was cooled to room temperature, ethyl acetate (100 mL) was added, and the mixture was washed with water (100 mL × 3) and 50 mL of saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:1) to obtain compound 8 (0.025 g, 12% yield).

[0541] 1 H NMR(400MHz, CDCl3)δ8.07(s,1H),7.92(s,1H),7.82–7.73(m,4H),7.68(d,1H),7.63–7.45(m,4H),6.85–6.81(m,1H),6.58 (dd,1H),5.00–4.89(m,1H),4.45–4.33(m,2H),4.17–4.05(m,2H),3.92–3.80(m,1H),2.98–2.65(m,3H),2.20–2.09(m,1H).

[0542] Example 9: Preparation of Compound 9

[0543] Compound 9 was prepared using compounds 9a and 9b as raw materials according to the synthetic method of Example 8.

[0544] ' 1H NMR(400MHz, CDCl3)δ8.05(s,1H),7.93(s,1H),7.82–7.47(m,8H),7.42–7.36(m,1H),6.84–6.80(m,1H),6.57(dd,1H ),4.98–4.89(m,1H),4.45–4.30(m,2H),4.17–4.05(m,2H),3.93–3.76(m,1H),2.96–2.69(m,3H),2.18–2.08(m,1H).

[0545] LCMS m / z=658.0[M+1] +

[0546] Example 10: Preparation of Compound 10

[0547] Step 1: Preparation of 10b

[0548] In a 250 mL reaction flask, 10a (5.00 g, 25.77 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL) and cooled to 0°C. 60% sodium hydride (1.55 g) was added portionwise and the reaction continued at 0°C for 1 h. 2-(Trimethylsilyl)ethoxymethyl chloride (5.17 g, 31.00 mmol) was then added dropwise and the reaction continued at 25°C for 2 h. To the reaction solution were added 30 mL of water and 200 mL of ethyl acetate. The organic phase was washed with water (30 mL × 3) and then with 30 mL of saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10:1) to obtain 10b (6.97 g, 83% yield).

[0549] LCMS m / z=325.0[M+1] +

[0550] Step 2: Preparation of 10c

[0551] To a 100 mL reaction flask, compound 10b (0.51 g, 1.57 mmol), 7c (0.58 g, 1.44 mmol), CuI (0.14 g, 0.735 mmol), trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (CAS: 67579-81-1) (0.20 g, 1.41 mmol), potassium phosphate (0.92 g, 4.33 mmol), and DMF (20 mL) were added sequentially. The atmosphere was purged with nitrogen three times and the reaction was carried out at 120°C for 8 h. The reaction solution was cooled to room temperature, ethyl acetate (300 mL) was added, and the mixture was washed with water (100 mL × 3) and 50 mL of saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:1) to obtain 10c (0.43 g, 50% yield).

[0552] Step 3: Preparation of 10d

[0553] To a 100 mL reaction flask, 10c (0.43 g, 0.72 mmol) and dichloromethane (10 mL) were added dropwise, followed by the addition of trifluoroacetic acid (10 mL) at 25°C for 1 h. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to 9 with aqueous sodium bicarbonate solution to precipitate a yellow solid. The solid was filtered, and the filter cake was washed three times with 10 mL of water and then dissolved in a mixture of dichloromethane and methanol (v / v) = 10:1, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 10:1) to afford 10d (0.25 g, 74% yield).

[0554] LCMS m / z=470.2[M+1] +

[0555] Step 4: Preparation of 10f

[0556] To a 100 mL reaction flask, 10e (2.00 g, 8.20 mmol), cyclopropylboronic acid (1.06 g, 12.34 mmol), potassium phosphate (9.04 g, 42.59 mmol), tricyclohexylphosphine (0.46 g, 1.64 mmol), and palladium acetate (0.31 g, 1.38 mmol) were added sequentially. Toluene (20 mL) and water (1 mL) were then added. The nitrogen atmosphere was replaced three times, and the reaction was incubated at 100°C under nitrogen for 16 h. The reaction solution was cooled to room temperature, and a solid precipitated. 200 mL of water was added, and the mixture was extracted with 300 mL of ethyl acetate. The organic phase was washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 4:1) to obtain 10f (1.15 g, 89% yield).

[0557] LCMS m / z=159.2[M+1] +

[0558] Step 5: Preparation of 10g

[0559] To a 100 mL reaction flask, 10f (0.50 g, 3.16 mmol) and acetonitrile (15 mL) were added. The mixture was cooled to 0°C, and isoamyl nitrite (0.52 g, 4.44 mmol) was added. After the reaction was continued at 0°C for 10 min, copper bromide (0.90 g, 4.03 mmol) was added, and the reaction was continued at 25°C for 16 min. 50 mL of water and 200 mL of ethyl acetate were added to the reaction solution, which was then washed with water (50 mL × 3) and 30 mL of saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10:1) to obtain 10 g (0.70 g, 99% yield).

[0560] Step 6: Preparation of compound 10

[0561] To a 100 mL reaction flask, 10 g (0.044 g, 0.20 mmol), 10d (0.096 g, 0.20 mmol), CuI (0.008 g, 0.042 mmol), trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (CAS: 67579-81-1) (0.011 g, 0.077 mmol), potassium phosphate (0.13 g, 0.61 mmol), and DMF (10 mL) were added sequentially. The atmosphere was purged with nitrogen three times and the reaction was carried out at 110°C for 16 h. The reaction solution was cooled to room temperature, ethyl acetate (100 mL) was added, and the mixture was washed with water (50 mL × 3) and 30 mL of saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:1) to obtain compound 10 (0.025 g, 20% yield).

[0562] 1H NMR (400MHz, CDCl3) δ8.20–8.15(m,1H),8.02–7.95(m,2H),7.84(s,1H),7.73(s,1H) ,7.68(d,1H),7.62–7.54(m,2H),7.41–7.36(m,1H),6.85–6.78(m,1H),6.57(dd,1H), 5.00–4.89(m,1H),4.45–4.30(m,2H),4.15–4.03(m,2H),3.92–3.77(m,1H),2.99–2.6 5(m,3H),2.18–2.08(m,1H),2.06–1.94(m,1H),1.10–1.00(m,2H),0.80–0.72(m,2H).

[0563] Example 11: Preparation of Compound 11

[0564] Step 1: Preparation of 11b

[0565] In a 100 mL reaction flask, 11a (2.00 g, 8.33 mmol) was dissolved in hydrochloric acid (15 mL), cooled to 0°C, and sodium nitrite (0.63 g, 9.13 mmol) was added. After reacting at 0°C for 1.5 h, 10 mL of an aqueous solution of potassium iodide (4.15 g, 25.00 mmol) was added and the reaction was continued at 25°C for 16 h. The reaction solution was poured into 20 mL of a 6 mol / L aqueous sodium hydroxide solution and extracted with 30 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (pure petroleum ether) to obtain 11b (2.31 g, 79% yield).

[0566] Step 2: Preparation of 11c

[0567] In a sealed glass tube, 11b (2.30 g, 6.55 mmol), PdCl2(PPh3)2 (0.46 g, 0.66 mmol), CuI (0.25 g, 1.31 mmol), TEA (3.98 g, 39.33 mmol), and a 1 mol / L propyne solution in tetrahydrofuran (7.21 mL, 7.21 mmol) were added sequentially. DMF (10 mL) was added, and the nitrogen atmosphere was replaced three times. The reaction was sealed and incubated at 25°C under nitrogen for 2 h. Ethyl acetate (100 mL) was added to the reaction solution, and the mixture was washed with water (100 mL × 3) and 50 mL of saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether) to obtain 11c (0.88 g, 51% yield).

[0568] Step 3: Preparation of compound 11

[0569] To a 100 mL reaction flask, 11c (0.053 g, 0.20 mmol), 10d (0.096 g, 0.20 mmol), CuI (0.008 g, 0.042 mmol), trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (CAS: 67579-81-1) (0.011 g, 0.077 mmol), potassium phosphate (0.13 g, 0.61 mmol), and DMF (10 mL) were added sequentially. The atmosphere was purged with nitrogen three times and the reaction was carried out at 110°C for 16 h. The reaction solution was cooled to room temperature, ethyl acetate (100 mL) was added, and the mixture was washed with water (50 mL × 3) and 50 mL of saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:1) to obtain compound 11 (0.011 g, 8% yield).

[0570] 1 H NMR(400MHz, CDCl3)δ8.65(s,1H),7.92–7.87(m,2H),7.82(d,1H),7.77–7.72(m,2H),7.67(s,1H),7.64–7.53(m,2H),6.78–6.73(m, 1H),6.50(dd,1H),4.93–4.83(m,1H),4.38–4.26(m,2H),4.10–3.96(m,2H),3.86–3.70(m,1H),2.90–2.57(m,3H),2.15–1.98(m,4H).

[0571] Example 12: Preparation of Compound 12

[0572] Step 1: Preparation of 12b

[0573] In a 50 mL reaction flask, 12a (2.00 g, 8.91 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL), cooled to 0°C, and borane tetrahydrofuran complex (1.15 g, 13.38 mmol) was added dropwise. The mixture was reacted at 25°C for 16 h. 20 mL of saturated aqueous ammonium chloride and 300 mL of ethyl acetate were added to the reaction solution. The mixture was washed with water (20 mL × 3) and 30 mL of saturated aqueous sodium chloride. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product 12b (1.87 g).

[0574] Step 2: Preparation of 12c

[0575] To a 50 mL reaction flask, crude product 12b (0.50 g) and dichloromethane (15 mL) were added, along with DMF (0.017 g) and SOCl2 (0.56 g). The mixture was allowed to react at 25°C for 2 h. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10:1) to afford 12c (376 mg, two-step yield: 69% based on compound 12a).

[0576] Step 3: Preparation of compound 12

[0577] To a 50 mL reaction flask, 10d (0.096 g, 0.20 mmol), cesium carbonate (0.11 g, 0.34 mmol), and DMF (10 mL) were added sequentially. The mixture was cooled to 0°C, and 12c (0.04 g, 0.17 mmol) was added. The reaction mixture was allowed to react at 25°C for 3 h. 20 mL of water and 100 mL of ethyl acetate were added to the reaction solution, which was then washed with water (30 mL × 3) and 30 mL of saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by prep-TLC (petroleum ether / ethyl acetate (v / v) = 1:1) to afford compound 12 (34 mg, 26% yield).

[0578] 1 H NMR (400MHz, CDCl3) δ7.93(s,1H),7.76–7.66(m,3H),7.65–7.56(m,3H),7.47–7.40(m,1H),7.18–7.11(m,1H),6.76–6.72(m,1H),6.49( dd,1H),5.41(s,2H),4.91–4.81(m,1H),4.35–4.24(m,2H),4.07–3.96(m,2H),3.83–3.69(m,1H),2.90–2.55(m,3H),2.14–2.00(m,1H).

[0579] LCMS m / z=662.8[M+1] +

[0580] Example 13: Preparation of Compound 13

[0581] Step 1: Preparation of 13c

[0582] DMF (3 mL) was added to 13a (0.30 g, 2.04 mmol), followed by the addition of 13b (0.58 g, 2.49 mmol) and potassium carbonate (0.86 g, 6.22 mmol) with stirring at room temperature. The nitrogen atmosphere was replaced three times, and the reaction was carried out at 80°C for 2 h. The reaction solution was cooled to room temperature, and 20 mL of ethyl acetate and 20 mL of water were added. The organic phase was separated and washed with saturated sodium chloride solution (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1:20-1:10) to obtain 13c (0.65 g, 89% yield).

[0583] Step 2: Preparation of 13e

[0584] To a 50 mL reaction flask, 13c (0.70 g, 1.94 mmol), 1c (0.57 g, 2.30 mmol), CuI (0.074 g, 0.39 mmol), trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (CAS: 67579-81-1) (0.11 g, 0.77 mmol), potassium phosphate (1.23 g, 5.79 mmol), and DMF (10 mL) were added sequentially. The atmosphere was purged with nitrogen three times and microwaved at 130°C for 5 h. The reaction solution was cooled to room temperature, and 50 mL of ethyl acetate and 50 mL of water were added. The organic phase was separated and washed with saturated sodium chloride solution (30 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1:20-1:3) to afford 13e (0.05 g, 5% yield).

[0585] Step 3: Preparation of p-toluenesulfonate of 13f

[0586] Acetonitrile (3 mL) was added to 13e (0.05 g, 0.095 mmol), and p-toluenesulfonic acid (0.05 g, 0.29 mmol) was added with stirring at room temperature, and the mixture was reacted at 25° C. for 15 h. The reaction solution was concentrated under reduced pressure to obtain the p-toluenesulfonic acid salt of crude 13f (0.04 g).

[0587] Step 4: Preparation of compound 13

[0588] DMF (5 mL) was added to the p-toluenesulfonate salt (0.035 g) of the crude product 13f. 1f (0.023 g, 0.083 mmol) and DIPEA (0.074 g, 0.57 mmol) were added with stirring at room temperature. The nitrogen atmosphere was replaced three times, and the mixture was stirred at 80°C for 3 h. The reaction solution was cooled to room temperature, and 20 mL of ethyl acetate and 20 mL of water were added. The organic phase was separated and washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1:10-1:1) to obtain compound 13 (0.006 g, yield: 11%).

[0589] 1 H NMR(400MHz, CDCl3)δ8.30(s,1H),7.97(s,1H),7.84–7.63(m,4H),7.47–7.41(m,1H),7.28–7.23(m,1H),6.86–6.80(m,1H),6. 57(dd,1H),5.00–4.88(m,1H),4.45–4.32(m,2H),4.18–4.06(m,2H),3.92–3.79(m,1H),2.98–2.64(m,3H),2.20–2.08(m,1H).

[0590] Example 14: Preparation of Compound 14

[0591] Step 1: Preparation of 14b

[0592] 1,4-Dioxane (15 mL) was added to cyclopent-2-en-1-one (0.50 g, 6.09 mmol), 14a (2.05 g, 9.14 mmol), and (1,5-cyclooctadiene)rhodium(I) chloride dimer (CAS: 12092-47-6) (0.09 g, 0.18 mmol). A solution of sodium carbonate (1.03 g, 9.72 mmol) in water (5 mL) was added with stirring at room temperature. The atmosphere was purged with nitrogen three times, and the reaction was continued at 90°C for 4 h. The reaction solution was cooled to room temperature, and 30 mL of ethyl acetate and 30 mL of water were added. The organic phase was separated and washed with saturated sodium chloride solution (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1:20-1:10) to obtain 14b (0.80 g, 50% yield).

[0593] Step 2: Preparation of 14c

[0594] Methanol (15 mL) was added to 14b (0.80 g, 3.05 mmol), cooled to 0°C, and sodium borohydride (0.23 g, 6.08 mmol) was added. The reaction mixture was allowed to react at 25°C for 2 h. The reaction mixture was cooled to 0°C, and 10 mL of saturated aqueous ammonium chloride was added. 30 mL of ethyl acetate and 20 mL of water were added. The organic phase was separated and washed with 20 mL of saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1:20-1:3) to obtain crude product 1 (0.40 g). Dichloromethane (10 mL) was added to crude product 1 (0.25 g), cooled to 0°C, and methylsulfonyl chloride (0.22 g, 1.92 mmol) and triethylamine (0.29 g, 2.87 mmol) were added. The reaction mixture was allowed to react at 25°C for 2 h. The reaction solution was cooled to 0°C, saturated sodium bicarbonate (10 mL), dichloromethane (30 mL), and water (20 mL). The organic phase was separated and washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1:20-1:4) to obtain crude product 2 (0.40 g). In a 50 mL reaction flask, the above crude product 2 (0.27 g), 1c (0.23 g, 0.93 mmol), cesium carbonate (0.77 g, 2.36 mmol), and DMF (10 mL) were added in sequence and reacted at 80°C for 5 h. The reaction solution was cooled to room temperature, 30 mL of ethyl acetate and 30 mL of water were added, and the organic phase was separated. The organic phase was washed with saturated aqueous sodium chloride solution (30 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1:20-1:4) to obtain 14c (0.27 g, yield: 59%).

[0595] Step 3: Preparation of p-toluenesulfonate of 14d

[0596] Acetonitrile (10 mL) was added to 14c (0.25 g, 0.51 mmol), and p-toluenesulfonic acid (0.26 g, 1.51 mmol) was added with stirring at room temperature. The mixture was reacted at 25°C for 15 h. The reaction solution was concentrated under reduced pressure to obtain the p-toluenesulfonate salt of crude 14d (0.18 g).

[0597] Step 4: Preparation of compound 14

[0598] DMF (10 mL) was added to the p-toluenesulfonate salt (0.18 g) of the crude product 14d. 1f (0.13 g, 0.47 mmol) and DIPEA (0.42 g, 3.25 mmol) were added with stirring at room temperature. The nitrogen atmosphere was replaced three times, and the reaction was carried out at 80°C for 5 h. The reaction solution was cooled to room temperature, and 20 mL of ethyl acetate and 20 mL of water were added. The organic phase was separated and washed with saturated sodium chloride solution (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1:10-1:1). The crude product was purified by prep-TLC (DCM:MeOH (v / v) = 35:1) to obtain compound 14 (0.02 g, 7% yield).

[0599] 1 H NMR(400MHz, CDCl3)δ7.97(s,1H),7.72–7.56(m,4H),7.56–7.36(m,2H),6.84–6.78(m,1H),6.55(dd,1H),4.99–4.81(m ,2H),4.43–4.30(m,2H),4.14–4.02(m,2H),3.98–3.75(m,2H),2.96–2.65(m,3H),2.62–2.07(m,6H),1.89–1.74(m,1H).

[0600] Example 15: Preparation of Compound 15

[0601] Step 1: Preparation of 15c

[0602] In a 50 mL reaction flask, 15a (1.00 g, 5.04 mmol), 15b (0.48 g, 5.51 mmol), cesium carbonate (3.28 g, 10.07 mmol), and DMF (20 mL) were added sequentially and reacted at 80°C for 3 h. The reaction solution was cooled to room temperature, and 50 mL of ethyl acetate and 50 mL of water were added. The organic phase was separated and washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1:20-1:4) to obtain 15c (0.55 g, yield: 41%).

[0603] Step 2: Preparation of 15d

[0604] Dichloromethane (15 mL) was added to 15c (0.55 g, 2.07 mmol), cooled to 0°C, and methylsulfonyl chloride (0.47 g, 4.10 mmol) and triethylamine (0.63 g, 6.22 mmol) were added. The reaction was allowed to react at 25°C for 2 h. The reaction solution was cooled to 0°C, and 10 mL of saturated aqueous sodium bicarbonate solution was added. 40 mL of dichloromethane and 20 mL of water were added. The organic phase was separated and washed with 20 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1:20-1:4) to obtain 15d (0.61 g, yield: 86%).

[0605] Step 3: Preparation of 15e

[0606] To a 50 mL reaction flask, 15d (0.20 g, 0.58 mmol), 1c (0.17 g, 0.69 mmol), cesium carbonate (0.57 g, 1.75 mmol), and DMF (10 mL) were added sequentially and reacted at 80°C for 5 h. The reaction solution was cooled to room temperature, and 30 mL of ethyl acetate and 30 mL of water were added. The organic phase was separated and washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1:20-1:4) to obtain 15e (0.27 g, 94% yield).

[0607] Step 4: Preparation of p-toluenesulfonate of 15f

[0608] Acetonitrile (10 mL) was added to 15e (0.27 g, 0.55 mmol), and p-toluenesulfonic acid (0.28 g, 1.63 mmol) was added with stirring at room temperature, and the mixture was reacted at 25°C for 15 h. The reaction solution was concentrated under reduced pressure to obtain the p-toluenesulfonic acid salt of crude 15f (0.22 g).

[0609] Step 5: Preparation of compound 15

[0610] DMF (10 mL) was added to the p-toluenesulfonate salt (0.15 g) of the crude product 15f. 1f (0.11 g, 0.399 mmol) and DIPEA (0.49 g, 3.79 mmol) were added with stirring at room temperature. The nitrogen atmosphere was replaced three times, and the reaction was carried out at 80°C for 5 h. The reaction solution was cooled to room temperature, 20 mL of ethyl acetate and 20 mL of water were added, and the organic phase was separated and washed with saturated sodium chloride solution (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1:10-1:1). The crude product was purified by prep-TLC (DCM:MeOH (v / v) = 35:1) to obtain compound 15 (0.05 g, yield: 19%).

[0611] 1 H NMR(400MHz, CDCl3)δ8.14(s,1H),7.74–7.50(m,4H),7.44–7.33(m,1H),6.93–6.84(m,1H),6.84–6.75(m,1H),6.54(dd,1H),5.0 7–4.88(m,2H),4.44–4.27(m,2H),4.15–3.70(m,6H),3.64–3.47(m,1H),3.00–2.64(m,3H),2.60–2.35(m,2H),2.20–2.05(m,1H).

[0612] LCMS m / z=651.2[M+1] +

[0613] Example 16: Preparation of Compound 16

[0614] Step 1: Preparation of 16c

[0615] In a glass microwave tube, 16a (1.00 g, 3.26 mmol), 16b (0.28 g, 3.29 mmol), CuI (0.13 g, 0.68 mmol), trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (CAS: 67579-81-1) (0.19 g, 1.34 mmol), potassium phosphate (2.10 g, 9.90 mmol), and DMF (20 mL) were added sequentially. The atmosphere was purged with nitrogen three times and microwaved at 140°C for 5 h. The reaction solution was cooled to room temperature, and 50 mL of ethyl acetate and 50 mL of water were added. The organic phase was separated and washed with saturated sodium chloride solution (30 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1:20-1:3) to afford 16c (0.35 g, 41% yield).

[0616] Step 2: Preparation of 16d

[0617] Anhydrous tetrahydrofuran (15 mL) was added to 16c (0.30 g, 1.14 mmol), and the nitrogen atmosphere was replaced three times. Lithium bistrimethylsilylamide (0.38 g, 2.27 mmol) was added at -78°C. The reaction was continued at -78°C for 1 h, followed by the addition of N-bromosuccinimide (0.24 g, 1.35 mmol). The mixture was stirred at -78°C for 3 h. 20 mL of saturated aqueous ammonium chloride was added to the reaction solution, followed by 30 mL of ethyl acetate and 20 mL of water. The organic phase was separated, washed with 20 mL of saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1:20 to 1:4) to afford 16d (0.11 g, 28% yield).

[0618] Step 3: Preparation of compound 16

[0619] To a 25 mL reaction flask, 16d (0.10 g, 0.29 mmol), 7c (0.12 g, 0.30 mmol), cesium carbonate (0.28 g, 0.86 mmol), and DMF (5 mL) were added sequentially and reacted at 60°C for 3 h. The reaction solution was cooled to room temperature, and 30 mL of ethyl acetate and 30 mL of water were added. The organic phase was separated and washed with saturated sodium chloride solution (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1:10-1:1). The resulting crude product was purified by prep-TLC (DCM:MeOH (v / v) = 20:1) to obtain compound 16 (0.05 g, yield: 26%).

[0620] 1H NMR(400MHz, CDCl3)δ8.09(s,1H),7.80–7.72(m,2H),7.70–7.56(m,3H),7.54–7.44(m,1H),6.84–6.77(m,1H),6.55(dd,1H),5.13–5.02(m ,1H),5.01–4.86(m,1H),4.42–4.30(m,2H),4.12–4.03(m,2H),4.03– 3.90(m,2H),3.88–3.75(m,1H),2.98–2.65(m,5H),2.18–2.08(m,1H).

[0621] LCMS m / z=665.1[M+1] +

[0622] Example 17: Preparation of Compound 17

[0623] Compound 17 was prepared using compounds 17a and 10d as raw materials according to the synthetic method of Example 10.

[0624] ' 1 H NMR(400MHz, CDCl3)δ8.42–8.34(m,1H),8.19(s,1H),8.14(d,1H),8.10(s,1H),8.02(d,1H),7.95(s,1H),7.89(s,1H),7.85–7.61(m,5H),6.86 –6.80(m,1H),6.57(dd,1H),4.99–4.88(m,1H),4.45–4.32(m,2H),4.17 –4.05(m,2H),3.93–3.77(m,1H),2.97–2.65(m,3H),2.19–2.07(m,1H).

[0625] LCMS m / z=621.2[M+1] +

[0626] Example 18: Preparation of Compound 18

[0627] Compound 18 was obtained using compound 18a as the raw material by referring to the synthetic method of Example 10.

[0628] ' 1H NMR (400MHz, CDCl3) δ8.22(s,1H),7.92(s,1H),7.86(s,1H),7.78(s,1H),7.69–7. 58(m,3H),7.55–7.51(m,1H),7.24–7.19(m,1H),6.75(d,1H),6.50(dd,1H),4.92– 4.82(m,1H),4.35–4.27(m,2H),4.07–3.97(m,2H),3.83–3.69(m,1H),2.89–2.58( m,3H),2.12–2.02(m,1H),2.02–1.91(m,1H),1.08–1.00(m,2H),0.85–0.70(m,2H).

[0629] Example 19: Preparation of Compound 19

[0630] Step 1: Preparation of 19b

[0631] To a 50 mL reaction flask, 19a (0.50 g, 2.52 mmol), 19A (0.25 g, 2.47 mmol), cesium carbonate (1.64 g, 5.03 mmol), and DMF (10 mL) were added sequentially and reacted at 80°C for 3 h. The reaction solution was cooled to room temperature, and 50 mL of ethyl acetate and 50 mL of water were added. The organic phase was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1:20-1:4) to obtain 19b (0.06 g, yield: 9%).

[0632] Step 2: Preparation of 19c

[0633] Dichloromethane (5 mL) was added to 19b (0.06 g, 0.21 mmol), cooled to 0°C, and methylsulfonyl chloride (0.048 g, 0.42 mmol) and triethylamine (0.064 g, 0.63 mmol) were added. The reaction was allowed to react at 25°C for 2 h. The reaction system was cooled to room temperature, and 10 mL of saturated aqueous sodium bicarbonate solution was added, followed by 10 mL of dichloromethane and 10 mL of water. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1:20-1:4) to obtain 19c (0.058 g, yield: 77%).

[0634] Step 3: Preparation of compound 19

[0635] To a 25 mL reaction flask, 19c (0.061 g, 0.17 mmol), 7c (0.07 g, 0.17 mmol), cesium carbonate (0.17 g, 0.52 mmol), and DMF (4 mL) were added sequentially and reacted at 80°C for 5 h. The reaction solution was cooled to room temperature, and 20 mL of ethyl acetate and 10 mL of water were added. The organic phase was washed with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1:10-1:1) to obtain compound 19 (0.02 g, yield: 18%).

[0636] 1 H NMR(400MHz, CDCl3)δ8.02(s,1H),7.74–7.57(m,4H),7.52–7.42(m,1H),7.15–7.07(m,1H),6.86–6.77(m,1H),6.55(dd,1H),4.9 9–4.89(m,1H),4.43–4.20(m,3H),4.15–4.00(m,2H),3.90–3.75(m,1H),3.66–3.50(m,2H),3.04–2.60(m,5H),2.35–2.06(m,5H).

[0637] LCMS m / z=665.2[M+1] +

[0638] Example 20: Preparation of Compound 20

[0639] Step 1: Preparation of 20b

[0640] To a 25 mL reaction flask, 20a (0.10 g, 0.48 mmol), 20A (41.82 mg, 0.48 mmol), and 1,2-dichloroethane (5 mL) were added sequentially. After stirring at room temperature for 5 min, sodium triacetoxyborohydride (152.60 mg, 0.72 mmol) was added and the mixture was allowed to react at room temperature for 3 h. 20 mL of ethyl acetate and 10 mL of saturated aqueous sodium bicarbonate were added. The organic phase was washed with 10 mL of saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1:20 to 1:1) to obtain 20b (83 mg, 62% yield).

[0641] Step 2: Preparation of 20c

[0642] Dichloromethane (5 mL) was added to 20b (0.08 g, 0.29 mmol), cooled to 0°C, and methylsulfonyl chloride (0.066 g, 0.58 mmol) and triethylamine (0.088 g, 0.87 mmol) were added. The mixture was allowed to react at 25°C for 2 h. The reaction solution was cooled to 0°C, and 10 mL of saturated aqueous sodium bicarbonate solution, 10 mL of dichloromethane, and 10 mL of water were added. The organic phase was separated, washed with 20 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1:20-1:3) to obtain 20c (0.09 g, yield: 87%).

[0643] Step 3: Preparation of compound 20

[0644] To a 25 mL reaction flask, 20c (0.061 g, 0.17 mmol), 7c (0.07 g, 0.17 mmol), cesium carbonate (0.17 g, 0.52 mmol), and DMF (4 mL) were added sequentially and reacted at 80°C for 5 h. The reaction solution was cooled to room temperature, and 20 mL of ethyl acetate and 10 mL of water were added. The organic phase was washed with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1:10-1:1). The resulting crude product was then purified by prep-HPLC (dichloromethane:methanol (v / v) = 30:1) to obtain compound 20 (0.02 g, yield: 18%).

[0645] 1 H NMR(400MHz, CDCl3)δ9.07(s,1H),7.78–7.42(m,6H),6.84–6.76(m,1H),6.55(dd,1H),5.00–4.84(m ,2H),4.45–4.30(m,2H),4.13–4.02(m,2H),3.95–3.75(m,3H),3.15–2.40(m,8H),2.23–2.07(m,2H).

[0646] LCMS m / z=665.8[M+1] +

[0647] Example 21: Preparation of Compound 21

[0648] Compound 21 was obtained using compounds 21a and 21A as raw materials by referring to the synthetic method of Example 20.

[0649] 1H NMR(400MHz, CDCl3)δ7.98(s,1H),7.77–7.41(m,6H),6.84–6.76(m,1H),6.59–6.50(m,1H),4.99–4.87 (m,1H),4.44–4.27(m,2H),4.25–4.00(m,3H),3.88–3.64(m,3H),3.15–2.65(m,4H),2.49–1.93(m,8H).

[0650] LCMS m / z=679.3[M+1] +

[0651] Example 22: Preparation of Compound 22

[0652] To a 25 mL reaction flask, 22a (10.25 mg, 0.052 mmol), 10d (20 mg, 0.043 mmol), cesium carbonate (28.02 mg, 0.086 mmol), and DMF (3 mL) were added sequentially and reacted at 80°C for 3 h. The reaction solution was cooled to room temperature, and 20 mL of ethyl acetate and 10 mL of water were added. The layers were separated, and the organic phase was washed with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by prep-TLC (DCM:MeOH (v / v) = 30:1) to obtain compound 22 (0.01 g, 36% yield).

[0653] 1 H NMR(400MHz, CDCl3)δ8.32(s,1H),8.10–7.95(m,2H),7.90–7.60(m,6H),6.86–6.78(m,1H),6.62–6.52(m,1H),4 .99–4.89(m,1H),4.45–4.30(m,2H),4.18–4.02(m,2H),3.94–3.76(m,1H),3.04–2.61(m,3H),2.22–2.06(m,1H).

[0654] Example 23: Preparation of Compound 23

[0655] Step 1: Preparation of 23b

[0656] In a 50 mL reaction flask, 23a (0.5 g, 2.52 mmol), 23A (0.61 g, 2.54 mmol), and potassium carbonate (0.7 g, 5.07 mmol) were added, along with 10 mL of DMSO. The reaction was allowed to proceed at 100°C for 4 h. The reaction solution was cooled to room temperature, added to 50 mL of ethyl acetate, and washed with saturated sodium chloride solution (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-1:2) to afford 23b (0.5 g, 48% yield).

[0657] LCMS m / z=418.5[M+1] +

[0658] Step 2: Preparation of 23c

[0659] 23b (0.5 g, 1.20 mmol), 1c (0.29 g, 1.17 mmol), CuI (45 mg, 0.24 mmol), and (1S,2S)-(+)-N,N''-dimethyl-1,2-cyclohexanediamine (CAS: 87583-89-9) (0.36 g, 2.53 mmol) were added to a reaction flask. Under nitrogen, 10 mL of DMF was added, and the reaction was carried out at 100°C for 2 h. The reaction solution was cooled to room temperature, added to 50 mL of ethyl acetate, washed with saturated sodium chloride solution (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-1:2) to obtain 23c (0.4 g, yield: 59%).

[0660] LCMS m / z=585.2[M+1] +

[0661] Step 3: Preparation of p-toluenesulfonate of 23d

[0662] 23c (0.2 g, 0.34 mmol) and p-toluenesulfonic acid (0.19 g, 1.10 mmol) were dissolved in 5 mL of acetonitrile and reacted at room temperature for 12 h. The reaction system was concentrated under reduced pressure to obtain the p-toluenesulfonic acid salt of crude product 23d (0.2 g).

[0663] LCMS m / z=485.2[M+1] +

[0664] Step 4: Preparation of compound 23

[0665] The p-toluenesulfonate salt of the crude product 23d (0.2 g), 1f (0.094 g, 0.34 mmol), and DIPEA (0.26 g, 2.01 mmol) were dissolved in 5 mL of DMF and reacted at 90°C for 2 h. The reaction system was cooled to room temperature and added to 100 mL of ethyl acetate. The mixture was washed with saturated sodium chloride solution (50 mL x 3) and dried over anhydrous sodium sulfate. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-1:2) to obtain compound 23 (0.05 g, yield: 20%).

[0666] 1 H NMR(400MHz, CDCl3)δ8.02(s,1H),7.98(s,1H),7.91–7.86(m,1H),7.77(s,1H) ,7.72(dd,1H),7.70–7.65(m,2H),7.60–7.53(m,1H),7.41(dd,1H),6.84–6.80( m,1H),6.60–6.53(m,2H),4.98–4.88(m,1H),4.43–4.32(m,2H),4.15–4.04(m,2 H),3.90–3.76(m,1H),2.96–2.64(m,3H),2.20–2.06(m,1H),1.62–1.52(m,6H).

[0667] LCMS m / z=741.2[M+1] +

[0668] Example 24: Preparation of Compound 24

[0669] Step 1: Preparation of 24b

[0670] In a 100 mL reaction flask, 24a (3.00 g, 23.79 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), cooled to 0°C, and 60% sodium hydride (1.14 g) was added. After stirring at 0°C for 1 h, 2-(trimethylsilyl)ethoxymethyl chloride (4.36 g, 26.15 mmol) was added dropwise. The reaction was allowed to react at room temperature for 3 h. 50 mL of water and 500 mL of ethyl acetate were added to the reaction system. The mixture was washed with water (50 mL × 3) and 50 mL of saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10:1) to obtain 24b (3.87 g, 64% yield).

[0671] LCMS m / z=257.1[M+1] +

[0672] Step 2: Preparation of 24c

[0673] In a 100 mL reaction flask, 24b (2.00 g, 7.81 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL). Lithium aluminum hydride (0.44 g, 11.59 mmol) was added at 0°C and reacted for 3 h. 20 mL of water and 200 mL of ethyl acetate were added to the reaction system, and the mixture was washed with water (50 mL × 3) and 50 mL of saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 5:1) to obtain 24c (1.75 g, 98% yield).

[0674] LCMS m / z=229.1[M+1] +

[0675] Step 3: Preparation of 24d

[0676] To a 50 mL reaction flask, 24c (0.5 g, 2.19 mmol), triethylamine (0.45 g, 4.45 mmol), and methanesulfonyl chloride (0.37 g, 3.23 mmol) were added sequentially at 0°C and allowed to react for 16 h. The reaction solution was quenched with 20 mL of saturated aqueous ammonium chloride and extracted with 100 mL of ethyl acetate. The organic phase was washed with 20 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10:1) to afford 24d (0.28 g, 52% yield).

[0677] Step 4: Preparation of 24e

[0678] To a 50 mL reaction flask, 7c (0.28 g, 0.69 mmol), cesium carbonate (0.37 g, 1.14 mmol), and DMF (15 mL) were added sequentially, followed by the dropwise addition of 24d (0.14 g, 0.57 mmol), and the reaction was carried out at 25°C for 2 h. 25 mL of water and 100 mL of ethyl acetate were added to the reaction system, and the mixture was washed with water (25 mL × 3) and 25 mL of saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:1) to afford 24e (0.10 g, 29% yield).

[0679] LCMS m / z=614.8[M+1] +

[0680] Step 5: Preparation of 24f

[0681] In a 50 mL reaction flask, 24e (0.15 g, 0.24 mmol) and dichloromethane (10 mL) were added sequentially, followed by the dropwise addition of trifluoroacetic acid (10 mL). The reaction was allowed to react at 25°C for 1 h. The reaction solution was concentrated under reduced pressure, and 100 mL of dichloromethane was added. The pH was adjusted to 9 with saturated aqueous sodium bicarbonate solution, and the mixture was extracted with 100 mL of dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 12:1) to afford 24f (0.10 g, 86% yield).

[0682] LCMS m / z=484.7[M+1] +

[0683] Step 6: Preparation of compound 24

[0684] To a 50 mL reaction flask, 24f (0.046 g, 0.095 mmol), cesium carbonate (0.057 g, 0.17 mmol), and DMF (5 mL) were added sequentially. 24A (0.02 g, 0.087 mmol) (synthesis method, see WO2007018314) was added dropwise, and the reaction was allowed to proceed at 25°C for 2 h. 10 mL of water and 100 mL of ethyl acetate were added to the reaction system, and the mixture was washed with water (10 mL × 3) and 10 mL of saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was isolated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:1) to obtain compound 24 (0.036 g, 61% yield).

[0685] 1 H NMR (400MHz, CDCl3) δ7.74–7.54(m,6H),7.52–7.43(m,1H),7.28–7.24(m,1H),7.09(d,1H),6.77(s,1H),6.55(dd,1H),5.44(s,2H), 5.00–4.82(m,3H),4.42–4.30(m,2H),4.14–4.01(m,2H),3.89–3.72(m,1H),3.04–2.85(m,1H),2.85–2.64(m,2H),2.14–2.00(m,1H).

[0686] LCMS m / z=676.2[M+1] +

[0687] Example 25: Preparation of Compound 25

[0688] Step 1: Preparation of 25b

[0689] DMF (5 mL) was added to 25a (0.20 g, 0.85 mmol), and NBS (0.15 g, 0.84 mmol) was slowly added with stirring at room temperature. The reaction mixture was allowed to react at room temperature for 1 h. 20 mL of ethyl acetate and 20 mL of water were added to the reaction solution, and the layers were separated. The organic phase was washed with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1:20-1:10) to obtain 25b (0.20 g, yield: 76%).

[0690] Step 2: Preparation of 25c

[0691] In a microwave tube, 25b (0.20 g, 0.64 mmol), 1c (0.16 g, 0.64 mmol), CuI (0.024 g, 0.13 mmol), trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (0.036 g, 0.25 mmol), potassium phosphate (0.41 g, 1.93 mmol), and DMF (4 mL) were added sequentially and microwave-treated at 140°C for 5 h. The reaction mixture was cooled to room temperature, and 30 mL of ethyl acetate and 30 mL of water were added. The layers were separated, and the organic phase was washed with saturated sodium chloride solution (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1:20-1:3) to afford 25c (0.03 g, 10% yield).

[0692] Step 3: Preparation of p-toluenesulfonate of 25d

[0693] Acetonitrile (3 mL) was added to 25c (0.04 g, 0.083 mmol), and p-toluenesulfonic acid (0.043 g, 0.25 mmol) was added with stirring at room temperature, and the mixture was reacted at 25°C for 15 h. The reaction solution was concentrated under reduced pressure to obtain the p-toluenesulfonic acid salt of crude 25d (0.02 g).

[0694] Step 4: Preparation of compound 25

[0695] DMF (3 mL) was added to the p-toluenesulfonate salt (0.03 g) of the crude product 25d. 1f (0.022 g, 0.08 mmol) and DIPEA (0.10 g, 0.77 mmol) were added with stirring at room temperature. The nitrogen atmosphere was replaced three times, and the reaction was carried out at 80°C for 3 h. The reaction solution was cooled to room temperature, and 20 mL of ethyl acetate and 20 mL of water were added. The layers were separated, and the organic phase was washed with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1:10 to 1:1) to obtain compound 25 (0.006 g, yield: 12%).

[0696] 1 H NMR(400MHz, CDCl3)δ8.49(s,1H),8.39–8.32(m,2H),8.10(s,1H),8.01(s,1H),7.82(s, 1H),7.77(dd,1H),7.73–7.62(m,2H),7.58–7.48(m,2H),6.82–6.74(m,1H),6.55(dd,1H),4.99–4.90( m,1H),4.45–4.32(m,2H),4.17–4.05(m,2H),3.94–3.80(m,1H),2.97–2.65(m,3H),2.21–2.06(m,1H).

[0697] Example 26: Preparation of Compound 26

[0698] Compound 26 was obtained using compounds 26a and 26A as raw materials according to the synthetic method of Example 19.

[0699] 1 H NMR (400MHz, CDCl3) δ8.20–7.28(m,6H),6.86–6.76(m,1H),6.63–6.40(m,2H),5.01–4.89(m,1H) ,4.45–4.30(m,3H),4.30–4.02(m,5H),4.01–3.73(m,3H),3.28–2.60(m,4H),2.18–2.06(m,1H).

[0700] Example 27: Preparation of Compound 27

[0701] Step 1: Preparation of 27b

[0702] In a 25 mL reaction flask, 27a (0.20 g, 1.01 mmol), the hydrochloride salt of 27A (0.14 g), cesium carbonate (0.99 g, 3.04 mmol), and DMF (5 mL) were added sequentially and reacted at 80°C for 15 h. The reaction solution was cooled to room temperature, and 30 mL of ethyl acetate and 20 mL of water were added. The layers were separated, and the organic phase was washed with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1:20-1:4) to obtain 27b (0.06 g, yield: 24%).

[0703] Step 2: Preparation of 27c

[0704] Dichloromethane (5 mL) was added to 27b (0.06 g, 0.24 mmol), cooled to 0°C, and methanesulfonyl chloride (0.055 g, 0.48 mmol) and triethylamine (0.073 g, 0.72 mmol) were added. The mixture was allowed to react at 25°C for 2 h. The reaction solution was cooled to 0°C, and 20 mL of saturated aqueous sodium bicarbonate solution was added. 20 mL of dichloromethane and 10 mL of water were added, and the layers were separated. The organic phase was washed with 20 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1:20-1:4) to obtain 27c (0.065 g, yield: 82%).

[0705] Step 3: Preparation of compound 27

[0706] In a 25 mL reaction flask, 27c (0.066 g, 0.20 mmol), 7c (0.80 g, 0.20 mmol), cesium carbonate (0.20 g, 0.61 mmol), and DMF (4 mL) were added sequentially and reacted at 80°C for 15 h. The reaction solution was cooled to room temperature, and 20 mL of ethyl acetate and 10 mL of water were added. The layers were separated, and the organic phase was washed with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1:10-1:1) to obtain compound 27 (0.025 g, yield: 20%).

[0707] 1 H NMR(400MHz, CDCl3)δ8.07(s,1H),7.76–7.60(m,3H),7.52–7.45(m,1H),7. 42–7.34(m,1H),6.84–6.77(m,1H),6.62–6.51(m,2H),5.23–5.10(m,1H),5 .00–4.88(m,1H),4.70–4.58(m,2H),4.52–4.41(m,2H),4.40–4.28(m,2H), 4.12–4.01(m,2H),3.88–3.74(m,1H),3.00–2.64(m,3H),2.20–2.05(m,1H).

[0708] Example 29: Preparation of Compound 29

[0709] Step 1: Preparation of 29b

[0710] 29a (4.1 g, 19.80 mmol) and 4-iodo-1H-pyrazole (4.22 g, 21.75 mmol) were dissolved in 40 mL of acetonitrile, and cesium carbonate (9.68 g, 29.70 mmol) was added. The mixture was reacted at 80°C for 3 h. The reaction solution was cooled to room temperature, and 30 mL of water and 100 mL of ethyl acetate were added. The layers were separated, and the organic phase was washed with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was then purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1:9) to obtain 29b (2.40 g, yield: 38%).

[0711] 1 H NMR (400MHz, CDCl3) δ7.55(s,2H),4.19(q,2H),2.95–2.70(m,4H),2.26–1.96(m,2H),1.23(t,3H).

[0712] LCMS m / z=321.1[M+1] + .

[0713] Step 2: Preparation of 29c

[0714] 29b (2.30 g, 7.18 mmol) was dissolved in THF (20 mL), and 4 mL of water and lithium hydroxide monohydrate (0.6 g, 14.3 mmol) were added. The mixture was allowed to react at room temperature for 30 min. 1 mol / L hydrochloric acid was added dropwise to adjust the pH to 6. 50 mL of ethyl acetate was added, and the mixture was separated. The organic phase was washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford crude product 1 (2.0 g). Crude product 1 (0.51 g) was dissolved in DCM (10 mL), and 1-chloro-N,N,2-trimethylpropenamine (0.35 g, 2.62 mmol) was slowly added dropwise. The mixture was allowed to react at room temperature for 2 h. TEA (0.53 g, 5.24 mmol) and 2-chloro-4-(trifluoromethyl)aniline (0.34 g, 1.74 mmol) were added to the reaction mixture, and the mixture was allowed to react at room temperature for 3 h. To the reaction solution was added 20 mL of saturated aqueous sodium bicarbonate solution, and the mixture was extracted with 100 mL of ethyl acetate. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1:3) to obtain 29c (0.45 g, yield: 52%).

[0715] Step 3: Preparation of 29d

[0716] 29c (2.0 g, 4.26 mmol) was dissolved in 10 mL of THF, cooled to 0°C, and 1 mol / L borane solution in tetrahydrofuran (8.5 mL, 8.5 mmol) was added. The reaction was allowed to react at room temperature for 18 h. The reaction solution was cooled to 0°C, and 5 mL of methanol, 40 mL of ethyl acetate, and 30 mL of water were added. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10:1-3:1) to obtain 29d (1.5 g, yield: 77%).

[0717] LCMS m / z=456.4[M+1] +

[0718] Step 4: Preparation of compound 29

[0719] 29d (0.32 g, 0.70 mmol), crude intermediate 1 (0.35 g), TEA (0.21 g, 2.08 mmol), CuI (27 mg, 0.14 mmol), and PdCl2(PPh3)2 (98 mg, 0.14 mmol) were added to a reaction flask, 8 mL of DMF was added under nitrogen protection, and the reaction was carried out at 55°C for 3 h. The reaction solution was cooled to room temperature, 40 mL of water was added, and the mixture was filtered. The filter cake was washed with 10 mL of water and dissolved in 100 mL of a mixed solvent of DCM / MeOH (v / v) = 5:1, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:1.5) to obtain compound 29 (88 mg, yield: 19%).

[0720] 1 H NMR(400MHz, CDCl3)δ8.03(s,1H),7.70–7.60(m,2H),7.53(s,1H),7.48–7.42(m,1H),7.29(dd,1H),6.82–6.77(m,1H),6.54(dd,1H),6.45(d,1H), 5.12–4.88(m,2H),4.39–4.27(m,2H),4.10–3.98(m,2H),3.85–3.72(m,1 H),3.65(d,2H),2.95–2.55(m,5H),2.53–2.37(m,2H),2.23–1.97(m,3H).

[0721] LCMS m / z=665.2[M+1] +

[0722] Example 30: Preparation of Compound 30

[0723] Compound 30 was prepared using compounds 30a and 30A as raw materials according to the synthetic method of Example 23.

[0724] 1 H NMR (400MHz, CDCl3) δ8.04–7.95(m,2H),7.92(d,1H),7.79–7.72(m,2H),7.71–7.65(m,2H),7.60–7.54(m,1H),7.41(dd,1H),6.82(d,1H),6.61–6 .53(m,2H),4.99–4.90(m,1H),4.44–4.32(m,2H),4.16–4.05(m,2H),3.9 2–3.77(m,1H),2.98–2.65(m,3H),2.20–2.07(m,1H),1.58–1.53(m,6H).

[0725] Example 31: Preparation of Compound 31

[0726] Step 1: Preparation of 31b

[0727] To a 50 mL reaction flask, sodium nitrite (0.18 g, 2.61 mmol) was added, and concentrated sulfuric acid (1.17 g) was slowly added dropwise at 0°C. After stirring for 10 min, glacial acetic acid (0.59 g, 9.83 mmol) was added. After reacting at 25°C for 1 h, a solution of 31a (0.50 g, 2.17 mmol) in glacial acetic acid (0.57 mL) was added dropwise. After reacting at 25°C for 1 h, a solution of potassium iodide (3.65 g, 22.00 mmol) in water (5 mL) was added. The reaction was continued at 25°C for 3 h. The reaction system was adjusted to pH 10 with 1 mol / L sodium hydroxide solution and extracted with 50 mL of ethyl acetate. The organic phase was washed with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (pure petroleum ether) to obtain 31b (0.28 g, 38% yield).

[0728] Step 2: Preparation of 31c

[0729] To a 50 mL reaction flask, 31b (0.50 g, 1.47 mmol), 31A (0.19 g, 1.51 mmol), potassium carbonate (0.61 g, 4.41 mmol), and DMF (15 mL) were added sequentially and reacted at 90°C for 4 h. The reaction system was cooled to room temperature, and 10 mL of water and 200 mL of ethyl acetate were added. The organic phase was washed three times with 50 mL of water and then with 30 mL of saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10:1) to obtain 31c (0.09 g, 18% yield).

[0730] Step 3: Preparation of 31d

[0731] In a 50 mL reaction flask, 31c (0.12 g, 0.35 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL). Lithium aluminum hydride (0.02 g, 0.53 mmol) was added at 0°C, and the reaction was continued at 0°C for 3 h. 10 mL of water and 100 mL of ethyl acetate were added to the reaction system. The organic phase was washed three times with 50 mL of water and then with 30 mL of saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 5:1) to obtain 31d (0.08 g, 74% yield).

[0732] LCMS m / z=311.0[M+1] +

[0733] Step 4: Preparation of 31e

[0734] In a 50 mL reaction flask, 31d (0.08 g, 0.26 mmol) was dissolved in dichloromethane (5 mL), and thionyl chloride (0.093 g, 0.78 mmol) was added at 0°C. The reaction was allowed to react for 1 h at 0°C. The reaction solution was concentrated under reduced pressure to obtain crude product 31e (0.085 g).

[0735] Step 5: Preparation of compound 31

[0736] To a 50 mL reaction flask, 7c (0.10 g, 0.248 mmol), cesium carbonate (0.17 g, 0.52 mmol), and DMF (5 mL) were added sequentially, followed by the dropwise addition of the crude product 31e (0.085 g), and the reaction was continued at 25°C for 2 h. 10 mL of water and 100 mL of ethyl acetate were added to the reaction system, and the organic phase was washed three times with 50 mL of water and then with 30 mL of saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:1) to obtain compound 31 (0.03 g, 17% yield).

[0737] 1 H NMR (400MHz, CDCl3) δ8.10–7.47(m,7H),6.84–6.78(m,1H),6.61–6.52(m,1H),5.35–4.85(m,3H) ,4.44–4.30(m,2H),4.14–4.02(m,2H),3.90–3.75(m,1H),3.10–2.66(m,3H),2.20–2.04(m,1H).

[0738] LCMS m / z=696.1[M+1] +

[0739] Example 32: Preparation of trifluoroacetate salt of compound 32

[0740] The trifluoroacetate salt of compound 32 was prepared from compounds 32a and 32A by referring to the synthesis method of Example 23, and was obtained by acidic preparation (acetonitrile / water (containing 0.1% TFA)) and lyophilization.

[0741] ' 1 H NMR(400MHz, CDCl3)δ7.99(s,2H),7.84(d,1H),7.79(s,1H),7.75–7.64(m,3H),7.55(dd,1H),7.47(dd,1H),7.04(d,1H),6.87–6.79(m,1H), 6.57(dd,1H),5.00–4.89(m,1H),4.45–4.32(m,2H),4.17–4.05(m,2H) ,3.93–3.77(m,1H),3.00–2.64(m,3H),2.20–2.06(m,1H),1.53(s,6H).

[0742] Example 33: Preparation of Compound 33

[0743] Step 1: Preparation of 33a

[0744] 33A (4.0 g, 20.15 mmol), 33B (3.91 g, 20.16 mmol), and potassium carbonate (2.78 g, 20.12 mmol) were added to 20 mL of DMSO and reacted at 100°C for 16 h. The reaction system was cooled to room temperature and added to 100 mL of ethyl acetate. The organic phase was washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-10:1) to obtain 33a (7.51 g, yield: >99%).

[0745] Step 2: Preparation of 33b

[0746] 33a (1.0 g, 2.68 mmol) and N-Boc-4-aminophenylboronic acid pinacol ester (CAS: 330793-01-6) (0.86 g, 2.69 mmol) were added to a reaction flask. Under nitrogen, 10 mL of DME and 3 mL of water were added, followed by Pd(PPh) (62 mg, 0.054 mmol) and CsCO (2.18 g, 6.69 mmol). The nitrogen atmosphere was replaced three times, and the reaction was microwaved at 90°C for 4 h. The reaction solution was cooled to room temperature, added to 50 mL of ethyl acetate, washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was isolated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-1:2) to afford 33b (0.8 g, yield: 68%).

[0747] LCMS m / z=438.2[M+1] +

[0748] Step 3: Preparation of 33c

[0749] 33b (0.8 g, 1.83 mmol) was dissolved in 10 mL of dichloromethane and 5 mL of trifluoroacetic acid and reacted at room temperature for 6 h. The reaction system was concentrated under reduced pressure, 50 mL of ethyl acetate was added, and the mixture was washed with 50 mL of saturated aqueous sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-1:2) to obtain 33c (0.4 g, yield: 65%).

[0750] Step 4: Preparation of 33d

[0751] 33c (0.4 g, 1.18 mmol) was added to 5 mL of water, followed by the slow addition of concentrated sulfuric acid (0.8 mL) and the reaction was carried out at 60°C for 1 h. The reaction system was cooled to 0°C, and 5 mL of an aqueous solution of sodium nitrite (0.081 g, 1.17 mmol) was added dropwise. The reaction was continued at 5°C for 30 min. Then, 2 mL of an aqueous solution of KI (0.39 g, 2.35 mmol) was added dropwise at 40°C and the reaction was continued at 50°C for 1 h. The reaction system was cooled to room temperature and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with 50 mL of a 1 mol / L aqueous hydrochloric acid solution and 50 mL of a saturated aqueous sodium thiosulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-2:1) to afford 33d (0.2 g, yield: 38%).

[0752] LCMS m / z=449.3[M+1]+

[0753] Step 5: Preparation of compound 33

[0754] 33d (0.05 g, 0.11 mmol), the crude intermediate 1 (0.056 g), TEA (0.067 g, 0.66 mmol), CuI (4.2 mg, 0.022 mmol), and PdCl2(PPh3)2 (7.7 mg, 0.011 mmol) were added to a reaction flask, 2 mL of DMF was added under nitrogen protection, and the reaction was carried out at 55°C for 2 h. The reaction solution was cooled to room temperature, 50 mL of water was added, and the filter cake was washed with 10 mL of water. The filter cake was dissolved in 20 mL of DCM and dried over anhydrous sodium sulfate. The crude product was separated and purified by silica gel column chromatography (petroleum ether / dichloromethane / ethyl acetate (v / v) = 1:1:2) to obtain compound 33 (0.03 g, yield: 42%).

[0755] 1 H NMR(400MHz, CDCl3)δ8.25(s,1H),8.05(s,1H),7.94(s,1H),7.88–7.79(m,2H),7.73–7.63(m,2H),7.55–7.42(m,4H),6.83(d,1H) ,6.58(dd,1H),4.98–4.89(m,1H),4.45–4.35(m,2H),4.17–4.07(m,2H),3.94–3.82(m,1H),2.97–2.65(m,3H),2.20–2.06(m,1H).

[0756] LCMS m / z=658.1[M+1] +

[0757] Example 34: Preparation of Compound 34

[0758] Step 1: Preparation of 34b

[0759] 34a (0.2 g, 0.904 mmol) (synthesis method, see WO2018066545) was dissolved in 2 mL of DMF, and 60% sodium hydride (5.3 mg) was added at room temperature. After reacting at room temperature for 15 minutes, 4-iodobenzyl bromide (0.32 g, 1.08 mmol) was added and reacted at room temperature for 2 hours. The reaction system was added to 50 mL of ethyl acetate, washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-1:2) to obtain 34b (0.2 g, yield: 51%).

[0760] Step 2: Preparation of compound 34

[0761] 34b (0.2 g, 0.46 mmol), the crude intermediate 1 (0.23 g), TEA (0.28 g, 2.77 mmol), CuI (18 mg, 0.095 mmol), and PdCl2(PPh3)2 (32 mg, 0.046 mmol) were added to a reaction flask, 2 mL of DMF was added under nitrogen, and the reaction was carried out at 55°C for 2 h. The reaction solution was cooled to room temperature, 50 mL of water was added, and the mixture was filtered. The filter cake was washed with 10 mL of water, dissolved in 20 mL of DCM, and dried over anhydrous sodium sulfate. The crude product was separated and purified by silica gel column chromatography (petroleum ether / dichloromethane / ethyl acetate (v / v) = 1:1:2) to obtain compound 34 (0.05 g, yield: 17%).

[0762] 1 H NMR(400MHz, CDCl3)δ7.92(s,1H),7.76–7.62(m,3H),7.56–7.48(m,2H),7.46–7.36(m,2H),6.88(d,2H),6.82(d,1H),6.56(dd,1H),5.1 0(s,2H),4.99–4.87(m,1H),4.43–4.33(m,2H),4.16–4.05(m,2H),3.92–3.77(m,1H),2.97–2.65(m,3H),2.36(s,3H),2.24–2.06(m,4H).

[0763] Example 35: Preparation of Compound 35

[0764] Step 1: Preparation of 35b

[0765] To a 25 mL reaction flask, 35A (0.18 g, 0.86 mmol), 35a (0.21 g, 0.84 mmol) (synthesis method, see WO2020211822), and 1,2-dichloroethane (6 mL) were added sequentially. After stirring at room temperature for 5 minutes, sodium triacetoxyborohydride (0.27 g, 1.27 mmol) was added and the reaction was allowed to proceed at room temperature for 16 hours. To the reaction solution were added 30 mL of ethyl acetate and 10 mL of saturated aqueous sodium bicarbonate solution. The organic phase was washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1:20-1:4) to obtain 35b (0.16 g, 43% yield).

[0766] Step 2: Preparation of compound 35

[0767] To a 25 mL reaction flask, 35b (66.24 mg, 0.15 mmol), the crude intermediate 1 (50 mg), PdCl2(PPh3)2 (10.53 mg, 0.015 mmol), CuI (5.71 mg, 0.030 mmol), TEA (91.07 mg, 0.90 mmol), and DMF (5 mL) were added sequentially and reacted at 55°C under nitrogen for 1 h. The reaction solution was cooled to room temperature, and 20 mL of ethyl acetate and 10 mL of water were added. The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1:10-1:1). The resulting crude product was further separated and purified by prep-TLC (ethyl acetate / petroleum ether (v / v) = 2:1) to obtain compound 35 (0.015 g, yield: 15%).

[0768] 1 H NMR(400MHz, CDCl3)δ8.11(s,1H),7.74–7.48(m,6H),6.85–6.77(m,1H),6.56(dd,1H),5.04–4.88(m,2H),4.4 4–4.27(m,2H),4.14–4.02(m,2H),3.99–3.75(m,5H),3.73–3.57(m,2H),2.97–2.63(m,3H),2.20–2.06(m,1H).

[0769] Example 36: Preparation of Compound 36

[0770] Step 1: Preparation of 36B

[0771] Under nitrogen, 36A (2.0 g, 15.4 mmol) was added to a 100 mL three-necked flask. Dry dichloromethane (40 mL) and triethylamine (3.1 g, 30.64 mmol) were added. The mixture was cooled to 0°C, and methanesulfonyl chloride (2.1 g, 18.33 mmol) was slowly added. The reaction was allowed to react at room temperature for 16 h. Dichloromethane (30 mL) and saturated aqueous sodium bicarbonate (10 mL) were added to the reaction system. The organic phase was separated and washed with saturated sodium bicarbonate (100 mL x 2), water (800 mL x 2), and saturated aqueous sodium chloride (80 mL x 2). The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product 36B (2.7 g).

[0772] LCMS m / z=209.1[M+1] +

[0773] Step 2: Preparation of 36b and 36b′

[0774] The crude product 36B (1.0 g) and potassium carbonate (1.24 g, 8.97 mmol) were added to a 100 mL single-necked flask, followed by dry DMF (15 mL) and 36a (0.87 g, 4.48 mmol). The reaction was allowed to react at 85°C for 16 h. The reaction system was cooled to room temperature and slowly poured into water (200 mL). The mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 89:11) to give 36b (0.46 g, yield: 33%) and 36b′ (0.33 g, yield: 24%), respectively.

[0775] 36b and 36b' are one of the isomers of structure 36b-A or 36b-B, respectively.

[0776] Step 3: Preparation of 36c

[0777] 36b (0.46 g, 1.5 mmol) was dissolved in a mixture of tetrahydrofuran (12 mL) and water (3 mL), and lithium hydroxide monohydrate (315 mg, 7.51 mmol) was added. The mixture was reacted at room temperature for 16 h. The pH of the reaction system was adjusted to 5 with 0.5 mol / L hydrochloric acid solution and extracted with ethyl acetate (40 mL × 3). The organic phase was washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 42:58) to obtain a crude product (0.31 g). The crude product (310 mg) was added to a 50 mL single-necked flask, followed by dry dichloromethane (20 mL) and 1-chloro-N,N,2-trimethylpropenamine (213 mg, 1.59 mmol). The mixture was allowed to react at room temperature for 1 h. Triethylamine (321 mg, 3.17 mmol) and 2-chloro-4-(trifluoromethyl)aniline (206 mg, 1.05 mmol) were then added sequentially, and the reaction was continued at room temperature for 1 h. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 87:13) to afford 36c (200 mg, 41% yield).

[0778] LCMS m / z=470.1[M+1] +

[0779] 36c is one of the isomers of structure 36c-A or 36c-B.

[0780] Step 4: Preparation of 36d

[0781] 36c (200 mg, 0.43 mmol) was added to a 50 mL single-necked flask, followed by dry tetrahydrofuran (4 mL). The nitrogen atmosphere was replaced three times, and a 1 mol / L borane solution in tetrahydrofuran (0.86 mL) was added. The reaction was allowed to react at room temperature for 16 h. 10 mL of methanol was added to the reaction system, and the pH was adjusted to 5 with 0.5 mol / L hydrochloric acid. The mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 42:58) to afford 36d (0.1 g, yield: 51%).

[0782] LCMS m / z=456.1[M+1] +

[0783] 36d is one of the isomers of structure 36d-A or 36d-B.

[0784] Step 5: Preparation of compound 36

[0785] 36d (100 mg, 0.22 mmol) was added to a 50 mL single-necked bottle, followed by dry DMF (10 mL). The crude intermediate 1 (110 mg) and triethylamine (66 mg, 0.65 mmol) were then added, the nitrogen atmosphere was replaced three times, PdCl2(PPh3)2 (16 mg, 0.023 mmol) and CuI (7 mg, 0.037 mmol) were added, the nitrogen atmosphere was replaced three times, and the reaction was carried out at 60°C for 3 h. The reaction system was cooled to room temperature, saturated aqueous ammonium chloride (80 mL) was slowly added, and the mixture was extracted with ethyl acetate (60 mL × 3). The organic phase was washed with saturated aqueous sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 22:78) to give compound 36 (70 mg, yield: 48%).

[0786] 1 H NMR(400MHz, CDCl3)δ7.98(s,1H),7.75–7.63(m,1H),7.60(s,1H),7.53–7.47 (m,2H),7.42–7.33(m,1H),6.80(d,1H),6.66(d,1H),6.55(dd,1H),4.99–4.8 8(m,1H),4.75–4.57(m,2H),4.41–4.30(m,2H),4.12–4.01(m,2H),3.88–3.75 (m,1H),3.37(t,2H),2.99–2.63(m,5H),2.58–2.28(m,3H),2.20–2.07(m,1H).

[0787] LCMS m / z=665.1[M+1] +

[0788] Compound 36 is one of the isomers of structure 36-A or 36-B.

[0789] Example 37: Preparation of Compound 37

[0790] Step 1: Preparation of 37c

[0791] Compound 36b′ (0.33 g, 1.08 mmol) was dissolved in a mixture of tetrahydrofuran (12 mL) and water (3 mL), and lithium hydroxide monohydrate (226.8 mg, 5.41 mmol) was added. The mixture was reacted at room temperature for 16 h. The pH of the reaction system was adjusted to 5 with 0.5 mol / L hydrochloric acid solution and extracted with ethyl acetate (40 mL × 3). The organic phase was washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 42:58) to obtain a crude product (0.22 g). The crude product (220 mg) was added to a 50 mL single-necked flask, followed by dry dichloromethane (20 mL) and 1-chloro-N,N,2-trimethylpropenamine (151 mg, 1.13 mmol). The mixture was allowed to react at room temperature for 1 h. Triethylamine (228 mg, 2.25 mmol) and 2-chloro-4-(trifluoromethyl)aniline (147 mg, 0.75 mmol) were then added sequentially, and the reaction was continued at room temperature for 1 h. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 87:13) to afford 37a (110 mg, 31% yield).

[0792] LCMS m / z=470.1[M+1] +

[0793] 37a is one of the isomers of structure 36c-A or 36c-B.

[0794] Step 2: Preparation of 37b

[0795] 37a (110 mg, 0.23 mmol) was added to a 50 mL single-necked flask, followed by dry tetrahydrofuran (4 mL). The nitrogen atmosphere was replaced three times, and 1 mol / L borane in tetrahydrofuran (0.47 mL) was added. The reaction was allowed to react at room temperature for 16 h. 8 mL of methanol was added to the reaction system, and the pH was adjusted to 5 by adding 0.5 mol / L hydrochloric acid solution. The mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 42:58) to obtain 37b (0.017 g, yield: 16%).

[0796] LCMS m / z=456.1[M+1] +

[0797] 37b is one of the isomers of structure 36d-A or 36d-B.

[0798] Step 3: Preparation of compound 37

[0799] 37b (17 mg, 0.037 mmol) was added to a 50 mL single-necked flask, followed by dry DMF (5 mL). The crude intermediate 1 (19 mg) and triethylamine (11 mg, 0.11 mmol) were then added, the nitrogen atmosphere was replaced three times, PdCl2(PPh3)2 (3 mg, 0.0043 mmol) and CuI (2 mg, 0.0105 mmol) were added, the nitrogen atmosphere was replaced three times, and the reaction was carried out at 60°C for 3 h. The reaction system was cooled to room temperature, and saturated aqueous ammonium chloride (50 mL) was slowly added. The mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was washed with saturated aqueous sodium chloride (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 22:78) to give compound 37 (5 mg, yield: 20%).

[0800] 1 H NMR(400MHz, CDCl3)δ7.99(s,1H),7.67(d,1H),7.61(s,1H),7.56–7.48(m ,2H),7.39(dd,1H),6.80(d,1H),6.69(d,1H),6.55(dd,1H),4.98–4.80(m, 2H),4.61(br.s,1H),4.40–4.30(m,2H),4.12–4.02(m,2H),3.86–3.74(m, 1H),3.38(d,2H),2.98–2.62(m,6H),2.50–2.31(m,2H),2.20–2.07(m,1H).

[0801] LCMS m / z=665.1[M+1] +

[0802] Compound 37 is one of the isomers of structure 36-A or 36-B.

[0803] Example 38: Preparation of Compound 38

[0804] Step 1: Preparation of 38b

[0805] 38a (2.0 g, 9.66 mmol) and potassium carbonate (4 g, 28.94 mmol) were added to a 100 mL single-necked bottle, followed by dry DMF (30 mL) and 38A (1.89 g, 9.74 mmol). The reaction was allowed to react at 85°C for 16 h. The reaction system was cooled to room temperature and slowly poured into water (300 mL). The mixture was extracted with ethyl acetate (80 mL × 3). The organic phase was washed with saturated sodium chloride solution (80 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 92:8) to obtain 38b (0.7 g, yield: 23%).

[0806] LCMS m / z=321.1[M+1] +

[0807] Step 2: Preparation of 38c

[0808] 38b (0.7 g, 2.19 mmol) was dissolved in a mixture of tetrahydrofuran (16 mL) and water (4 mL), and lithium hydroxide monohydrate (460 mg, 10.96 mmol) was added. The reaction was allowed to react at room temperature for 16 h. The pH of the reaction system was adjusted to 5 with 0.5 mol / L hydrochloric acid solution and extracted with ethyl acetate (60 mL × 3). The organic phase was washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 47:53) to obtain a crude product (0.51 g). The crude product (300 mg) was added to a 50 mL single-necked flask, followed by dry dichloromethane (10 mL). N,N,N''N''tetramethylchloroformamidine hexafluorophosphate (428 mg, 1.53 mmol) and 2-chloro-4-(trifluoromethyl)aniline (199 mg, 1.02 mmol) were then added sequentially. N-methylimidazole (418 mg, 5.09 mmol) was then added, and the mixture was allowed to react at room temperature for 16 h. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 89:11) to afford 38c (200 mg, 42% yield).

[0809] LCMS m / z=470.1[M+1] +

[0810] Step 3: Preparation of 38d

[0811] 38c (200 mg, 0.43 mmol) was added to a 50 mL single-necked flask, followed by dry tetrahydrofuran (4 mL). The nitrogen atmosphere was replaced three times, and 1 mol / L borane in tetrahydrofuran (0.86 mL) was added. The reaction was allowed to react at room temperature for 16 h. 5 mL of methanol was added to the reaction system, and the pH was adjusted to 5 by adding 0.5 mol / L hydrochloric acid solution. The mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 42:58) to obtain 38d (80 mg, yield: 41%).

[0812] LCMS m / z=456.1[M+1] +

[0813] Step 4: Preparation of compound 38

[0814] 38d (80 mg, 0.176 mmol) was added to a 50 mL single-necked bottle, followed by dry DMF (10 mL). The crude intermediate 1 (91 mg) and triethylamine (55 mg, 0.54 mmol) were then added, the nitrogen atmosphere was replaced three times, PdCl2(PPh3)2 (13 mg, 0.0185 mmol) and CuI (6 mg, 0.0315 mmol) were added, the nitrogen atmosphere was replaced three times, and the reaction was carried out at 60°C for 2 h. The reaction system was cooled to room temperature, saturated aqueous ammonium chloride (80 mL) was slowly added, and the mixture was extracted with ethyl acetate (60 mL × 3). The organic phase was washed with saturated aqueous sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 31:69) to give compound 38 (50 mg, yield: 43%).

[0815] 1H NMR(400MHz, CDCl3)δ7.98(s,1H),7.70–7.64(m,1H),7.61(s,1H),7.53–7.45(m,2H), 7.38–7.31(m,1H),6.81(d,1H),6.63–6.52(m,2H),4.98–4.89(m,1H),4.52–4.30(m,3H ),4.12–4.00(m,2H),3.88–3.75(m,1H),3.44–3.32(m,1H),3.32–3.20(m,1H),3.16–3. 01(m,1H),2.96–2.65(m,3H),2.57–2.30(m,2H),2.23–2.07(m,2H),1.80–1.62(m,1H).

[0816] LCMS m / z=665.1[M+1] +

[0817] Example 39: Preparation of Compound 39

[0818] Compound 39 was prepared using compound 33a and 3-(Boc-amino)phenylboronic acid pinacol ester as raw materials, referring to the synthetic method of Example 33.

[0819] 1 H NMR (400MHz, CDCl3) δ8.25(s,1H),8.04(s,1H),7.94(s,1H),7.87–7.79(m,2H),7.74–7.59(m,3H),7.55–7.47(m,1H),7.41–7.32(m,2H),6. 83(d,1H),6.58(dd,1H),4.99–4.88(m,1H),4.46–4.32(m,2H),4.20– 4.08(m,2H),3.94–3.80(m,1H),2.96–2.65(m,3H),2.19–2.07(m,1H).

[0820] LCMS m / z=658.2[M+1] +

[0821] Example 40: Preparation of Compound 40

[0822] Step 1: Preparation of 40b

[0823] 40a (1 g, 8.61 mmol) was dissolved in dimethyl sulfoxide (20 mL), cooled to 0°C, and 60% sodium hydride (62 mg) was added. The reaction was allowed to react at room temperature for 1 h. The reaction system was cooled to 0°C, 2-chloro-1-fluoro-4-(trifluoromethyl)benzene (1.7 g, 8.56 mmol) was added, and the reaction was allowed to react at room temperature for 2 h. Water (200 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated sodium chloride solution (40 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 74:26) to obtain 40b (360 mg, yield: 14%).

[0824] LCMS m / z=295.1[M+1] +

[0825] Step 2: Preparation of 40c

[0826] 40b (360 mg, 1.22 mmol) was added to a 100 mL single-necked flask, followed by dry dichloromethane (20 mL) and triethylamine (360 mg, 3.56 mmol). The mixture was cooled to 0°C, and methanesulfonyl chloride (205 mg, 1.79 mmol) was slowly added dropwise. The reaction was allowed to react at room temperature for 2 h. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 90:10) to afford 40c (0.31 g, 68% yield).

[0827] LCMS m / z=373.1[M+1] +

[0828] Step 3: Preparation of 40d

[0829] 40c (310 mg, 0.83 mmol) was added to a 100 mL single-necked flask, followed by dry DMF (10 mL), potassium carbonate (345 mg, 2.5 mmol), and 4-iodo-1H-pyrazole (161 mg, 0.83 mmol). The reaction was allowed to react at 85°C for 16 h. The reaction system was cooled to room temperature and added to water (120 mL). The mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 87:13) to obtain 40d (0.31 g, yield: 79%).

[0830] LCMS m / z=471.1[M+1] +

[0831] 40d is one of the isomers of structure 40d-A or 40d-B.

[0832] Step 4: Preparation of compound 40

[0833] 40d (130 mg, 0.277 mmol) was added to a 50 mL single-necked bottle, and dry DMF (10 mL) was added. The above-mentioned crude intermediate 1 (136 mg) and triethylamine (52 mg, 0.51 mmol) were added, and the nitrogen atmosphere was replaced three times. PdCl2(PPh3)2 (19 mg, 0.027 mmol) and CuI (8 mg, 0.042 mmol) were added, and the nitrogen atmosphere was replaced three times. The reaction was carried out at 60°C for 3 h. The reaction system was cooled to room temperature, and saturated aqueous ammonium chloride (50 mL) was slowly added. The mixture was extracted with ethyl acetate (40 mL × 3). The organic phase was washed with saturated aqueous sodium chloride (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 28:72). The crude product was prepared by Prep-HPLC (instrument: Waters 2767 preparative liquid phase; chromatographic column: SunFire@PrepC18 (19 × 250 nm); mobile phase A: acetonitrile; mobile phase B: water (containing 5 mmol / L ammonia water); gradient elution: mobile phase A content from 40-90%; flow rate: 12 mL / min; column temperature: room temperature; detection wavelength: 210 nm; the sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution; elution time: 15 min) and lyophilized to give compound 40 (30 mg, yield: 16%).

[0834] 1 H NMR(400MHz, CDCl3)δ8.09(s,1H),7.72–7.53(m,4H),7.48(dd,1H),7.01(d,1H),6.81(d,1H),6.55(dd,1H),4.99–4.88(m,1H),4. 80–4.70(m,1H),4.42–4.18(m,3H),4.14–4.01(m,2H),3.90–3.73(m,1H),2.95–2.64(m,3H),2.32–1.98(m,7H),1.85–1.69(m,2H).

[0835] Example 41: Preparation of Compound 41

[0836] Step 1: Preparation of 41b

[0837] 41a (1.17 g, 3.4 mmol) (synthesis method, see WO2016058544), 1A (0.92 g, 5.08 mmol), TEA (2.06 g, 20.4 mmol), CuI (130 mg, 0.68 mmol), and PdCl2(PPh3)2 (240 mg, 0.34 mmol) were added to 5 mL of DMF under nitrogen protection and reacted at 50°C for 0.5 h. The reaction solution was cooled to room temperature and added to 50 mL of ethyl acetate. The solution was washed with saturated sodium chloride solution (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-1:2) to obtain 41b (1.0 g, yield: 74%).

[0838] Step 2: Preparation of 41c

[0839] 41b (1.0 g, 2.52 mmol) and sodium carbonate (0.53 g, 5.0 mmol) were added to 10 mL of DMF, followed by 2 mL of water, and the reaction was carried out at 85°C for 1.5 h. The reaction solution was cooled to room temperature, added to 100 mL of ethyl acetate, washed with saturated aqueous sodium chloride solution (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-1:2) to obtain 41c (0.6 g, yield: 80%).

[0840] Step 3: Preparation of 41d

[0841] 41c (0.4 g, 1.35 mmol), 33a (0.5 g, 1.34 mmol), CuI (13 mg, 0.068 mmol), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (0.095 g, 0.67 mmol), and potassium carbonate (0.28 g, 2.03 mmol) were added to 10 mL of DMF under nitrogen and reacted at 100°C for 2 h. The reaction solution was cooled to room temperature, added to 50 mL of ethyl acetate, washed with saturated sodium chloride solution (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-1:2) to obtain 41d (0.4 g, yield: 55%).

[0842] Step 4: Preparation of p-toluenesulfonate salt of 41e

[0843] 41d (0.2 g, 0.37 mmol) and p-toluenesulfonic acid monohydrate (0.21 g, 1.10 mmol) were dissolved in 5 mL of acetonitrile and reacted at room temperature for 3 h. The reaction system was concentrated under reduced pressure to obtain the crude p-toluenesulfonate salt of 41e (0.16 g).

[0844] Step 5: Preparation of compound 41

[0845] The p-toluenesulfonate salt of the crude product 41e (0.16 g), 1f (0.12 g, 0.43 mmol), and DIPEA (0.29 g, 2.24 mmol) were dissolved in 5 mL of DMF and reacted at 80°C for 5 h. The reaction system was cooled to room temperature, added to 100 mL of ethyl acetate, washed with saturated sodium chloride solution (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-1:2) to obtain compound 41 (0.05 g, yield: 17%).

[0846] 1 H NMR (400MHz, CDCl3) δ8.46(s,1H),8.22(s,1H),8.00(s,1H),7.93–7.82(m,3H),7.75–7.62(m,3H),7.58–7.47(m,1H),7.37–7.29(m,1H),6. 85(d,1H),6.59(dd,1H),4.99–4.90(m,1H),4.53–4.40(m,2H),4.30– 4.17(m,2H),4.07–3.94(m,1H),2.97–2.64(m,3H),2.20–2.07(m,1H).

[0847] Example 42: Preparation of Compound 42

[0848] Step 1: Preparation of 42b

[0849] 42a (1.15 g, 4.96 mmol) was dissolved in 10 mL of 1,4-dioxane, and 42A (1.25 g, 5.94 mmol) was added. 1 mL of methanesulfonic acid was added, and the reaction was carried out at 100°C for 16 h. The reaction system was cooled to room temperature, and saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to 9. The reaction system was extracted with 50 mL of ethyl acetate. The organic phase was washed with 30 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-9:1) to obtain 42b (1.0 g, 48% yield).

[0850] LCMS m / z=423.2[M+1] +

[0851] Step 2: Preparation of compound 42

[0852] 42b (0.5 g, 1.18 mmol) and the crude intermediate 1 (0.52 g) were dissolved in 10 mL of DMF, and TEA (0.36 g, 3.56 mmol) was added. Under nitrogen, CuI (0.034 g, 0.18 mmol) and PdCl2(PPh3)2 (0.12 g, 0.17 mmol) were added and reacted at 50°C for 2 h. The reaction system was cooled to room temperature, 10 mL of water was added, and the mixture was stirred at room temperature for 5 min. The reaction mixture was filtered, and the filter cake was washed with 5 mL of water. The filter cake was collected and dissolved in 50 mL of dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 4:1-1:4) to obtain compound 42 (0.2 g, yield: 27%).

[0853] 1 H NMR (400MHz, DMSO-d6) δ13.90–13.50(m,1H),11.06(s,1H),8.55–8.15(m,2H),8.14–7.55(m,5H),6.91(d,1H),6.75(dd ,1H),5.13–5.03(m,1H),4.52–4.38(m,2H),4.19–3.92(m,3H),2.97–2.80(m,1H),2.67–2.50(m,2H),2.10–1.97(m,1H).

[0854] LCMS m / z=632.6[M+1] +

[0855] Example 43: Preparation of Compound 43

[0856] Step 1: Preparation of 43b

[0857] 43a (1.0 g, 4.79 mmol) was dissolved in 10 mL of 1,4-dioxane, and 43A (1.35 g, 5.77 mmol) was added. 1 mL of methanesulfonic acid was added, and the reaction was carried out at 100°C for 16 h. The reaction system was cooled to room temperature, and saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to 9. The reaction system was extracted with 50 mL of ethyl acetate. The organic phase was washed with 30 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-9:1) to obtain 43b (0.86 g, 43% yield).

[0858] LCMS m / z=423.0[M+1] +

[0859] Step 2: Preparation of compound 43

[0860] 43b (0.45 g, 1.07 mmol) and the crude intermediate 1 (0.46 g) were dissolved in 10 mL of DMF, and TEA (0.32 g, 3.16 mmol) was added. Under nitrogen, CuI (0.03 g, 0.16 mmol) and PdCl2(PPh3)2 (0.11 g, 0.16 mmol) were added, and the reaction was carried out at 50°C for 2 h. The reaction system was cooled to room temperature, 10 mL of water was added, and the mixture was stirred at room temperature for 5 min. The mixture was then filtered, and the filter cake was washed with 5 mL of water. The filter cake was collected and dissolved in 50 mL of dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 4:1-1:4) to obtain compound 43 (0.18 g, yield: 27%).

[0861] 1 H NMR(400MHz,DMSO-d6)δ13.13–12.98(m,1H),11.06(s,1H),8.20–8.13(m,1H),8.12–8.07(m,1H),7.96–7.55(m,4H),7.36(dd,1H),6.89(d,1H),6 .74(dd,1H),5.13–5.02(m,1H),4.50–4.37(m,2H),4.17–4.05(m,2H),4. 03–3.90(m,1H),2.97–2.81(m,1H),2.66–2.50(m,2H),2.08–1.96(m,1H).

[0862] LCMS m / z=632.1[M+1] +

[0863] Example 44: Preparation of Compound 44

[0864] Step 1: Preparation of 44b

[0865] 44a (1.0 g, 4.1 mmol), di-tert-butyl dicarbonate (1.79 g, 8.20 mmol), TEA (0.82 g, 8.10 mmol), and DMAP (0.1 g, 0.82 mmol) were dissolved in 20 mL of dichloromethane and reacted at room temperature for 12 h. The reaction system was added to 50 mL of dichloromethane, and the organic phase was washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-9:1) to obtain crude product 1 (1.2 g). The above crude product 1 (1.17 g), tert-butyl 3-ethynylazetidine-1-carboxylate (0.92 g, 5.08 mmol), TEA (2.06 g, 20.36 mmol), CuI (130 mg, 0.68 mmol) and PdCl2(PPh3)2 (240 mg, 0.34 mmol) were added to a reaction flask, 5 mL of DMF was added under nitrogen protection, and the reaction was carried out at 50°C for 0.5 h. The reaction solution was cooled to room temperature and added to 50 mL of ethyl acetate. The organic phase was washed with saturated sodium chloride aqueous solution (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-1:2) to obtain crude product 2 (1.1 g). The crude product 2 (1.0 g) and sodium carbonate (0.53 g, 5.0 mmol) were added to 10 mL of DMF, followed by 2 mL of water, and the reaction was carried out at 85°C for 12 h. The reaction solution was cooled to room temperature, added to 100 mL of ethyl acetate, washed with saturated aqueous sodium chloride solution (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-1:2) to obtain 44b (0.6 g, yield: 56%).

[0866] Step 2: Preparation of 44c

[0867] 44b (0.4 g, 1.35 mmol), 33a (0.5 g, 1.34 mmol), CuI (13 mg, 0.068 mmol), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (0.095 g, 0.67 mmol), and potassium carbonate (0.28 g, 2.03 mmol) were added to a reaction flask. 10 mL of DMF was added under nitrogen, and the reaction was carried out at 100°C for 2 h. The reaction solution was cooled to room temperature and added to 50 mL of ethyl acetate. The organic phase was washed with saturated sodium chloride solution (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was isolated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-1:2) to obtain 44c (0.4 g, yield: 55%).

[0868] Step 3: Preparation of p-toluenesulfonic acid of 44d

[0869] Compound 44c (0.2 g, 0.37 mmol) and p-toluenesulfonic acid monohydrate (0.21 g, 1.10 mmol) were dissolved in 5 mL of acetonitrile and reacted at room temperature for 3 h. The reaction system was concentrated under reduced pressure to obtain the p-toluenesulfonic acid salt of crude compound 44d (0.173 g).

[0870] LCMS m / z=442.4[M+1] +

[0871] Step 4: Preparation of compound 44

[0872] The p-toluenesulfonate salt of the crude product 44d (0.173 g), 1f (0.12 g, 0.43 mmol), and DIPEA (0.29 g, 2.24 mmol) were dissolved in 5 mL of DMF and reacted at 80°C for 5 h. The reaction system was cooled to room temperature and added to 100 mL of ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-1:2) to obtain compound 44 (0.06 g, yield: 20%).

[0873] 1 H NMR (400MHz, CDCl3) δ8.43(s,1H),8.27(s,1H),8.19(s,1H),7.96(s,1H),7.92–7.83(m,2H),7.74–7.66(m,2H),7.64–7.57(m,1H),7.48–7. 39(m,1H),7.38–7.31(m,1H),6.89–6.84(m,1H),6.61(dd,1H),4.99– 4.89(m,1H),4.53–4.40(m,2H),4.27–4.16(m,2H),4.05–3.93(m,1H), 2.98–2.65(m,3H),2.19–2.08(m,1H).

[0874] Example 45: Preparation of Compound 45

[0875] Step 1: Preparation of 45b

[0876] In a 50 mL reaction flask, 45a (1.0 g, 6.43 mmol), 3,3-dimethyl-5-nitroindolin-2-one (1.32 g, 6.40 mmol), and potassium carbonate (1.77 g, 12.81 mmol) were added, along with 10 mL of DMSO. The mixture was reacted at 100°C for 4 h. The reaction solution was cooled to room temperature and added to 50 mL of ethyl acetate. The organic phase was washed with saturated sodium chloride solution (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-1:2) to obtain 45b (1.5 g, yield: 69%).

[0877] Step 2: Preparation of 45c

[0878] 45b (1.0 g, 2.93 mmol) was dissolved in 20 mL of ethanol and 10 mL of saturated aqueous ammonium chloride solution, and iron powder (1.64 g, 29.29 mmol) was added. The reaction was allowed to react at room temperature for 6 h. The reaction system was concentrated under reduced pressure, and 50 mL of ethyl acetate and 50 mL of water were added. The reaction mixture was filtered, and the filtrate was separated. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product 45c (0.7 g).

[0879] LCMS m / z=312.1[M+1] +

[0880] Step 3: Preparation of 45d

[0881] The crude product 45c (0.37 g) was added to 5 mL of water, and 0.8 mL of concentrated sulfuric acid was slowly added, and the reaction was carried out at 60°C for 1 h. The reaction system was cooled to 0°C, and 5 mL of an aqueous solution of sodium nitrite (0.081 g, 1.17 mmol) was added dropwise. After reacting at 5°C for 30 min, 2 mL of an aqueous solution of KI (0.39 g, 2.35 mmol) was added dropwise at 40°C, and the reaction was carried out at 50°C for 1 h. The reaction system was cooled to room temperature and extracted with ethyl acetate (50 mL × 3). The organic phase was washed sequentially with 1 mol / L aqueous hydrochloric acid (50 mL) and saturated aqueous sodium thiosulfate (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-2:1) to obtain 45d (0.2 g, two-step yield: 31% based on compound 45b).

[0882] LCMS m / z=423.4[M+1] +

[0883] Step 4: Preparation of compound 45

[0884] 45d (0.046 g, 0.11 mmol), the crude intermediate 1 (0.056 g), TEA (0.067 g, 0.66 mmol), CuI (4.2 mg, 0.022 mmol), and PdCl2(PPh3)2 (7.7 mg, 0.011 mmol) were added to a reaction flask, 2 mL of DMF was added under nitrogen, and the reaction was carried out at 55°C for 2 h. The reaction solution was cooled to room temperature, 50 mL of water was added, and the reaction was filtered. The filter cake was washed with 10 mL of water, dissolved in 20 mL of DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / dichloromethane / ethyl acetate (v / v) = 1:1:2) to obtain compound 45 (0.02 g, yield: 29%).

[0885] 1 H NMR(400MHz, CDCl3)δ7.98(s,1H),7.87–7.77(m,1H),7.73–7.65(m,2H),7.52(dd,1H),7.39–7.30(m,2H),6.95–6.88(m,1H),6.85–6.81(m,1H) ,6.58(dd,1H),4.99–4.90(m,1H),4.44–4.35(m,2H),4.18–4.07(m,2H) ,3.93–3.80(m,1H),2.96–2.66(m,3H),2.20–2.09(m,1H),1.48(s,6H).

[0886] Example 46: Preparation of Compound 46

[0887] Step 1: Preparation of 46b

[0888] To a reaction flask, 46a (1.0 g, 3.27 mmol) (synthesis method, see WO2022003557), 4-iodopyrazole (0.61 g, 3.14 mmol), and potassium carbonate (0.87 g, 6.30 mmol) were dissolved in 10 mL of DMF and reacted at 80°C for 4 h. The reaction solution was cooled to room temperature and added to 50 mL of ethyl acetate. The organic phase was washed with saturated sodium chloride solution (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-1:2) to obtain 46b (0.4 g, yield: 32%).

[0889] Step 2: Preparation of trifluoroacetate salt of 46c

[0890] 46b (0.4 g, 0.99 mmol) was dissolved in 5 mL of dichloromethane and 5 mL of trifluoroacetic acid and reacted at room temperature for 2 h. The reaction system was concentrated under reduced pressure to obtain the crude trifluoroacetic acid salt of 46c (0.23 g).

[0891] Step 3: Preparation of 46d

[0892] The trifluoroacetate salt of the crude product 46c (0.23 g), 3-chloro-4-fluorobenzotrifluoride (0.2 g, 1.0 mmol), and potassium carbonate (0.55 g, 3.98 mmol) were dissolved in 5 mL of DMF and reacted at 80°C for 4 h. The reaction solution was cooled to room temperature and added to 50 mL of ethyl acetate. The organic phase was washed with saturated sodium chloride solution (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-1:2) to obtain 46d (0.04 g, yield: 8%).

[0893] LCMS m / z=482.1[M+1] +

[0894] Step 4: Preparation of compound 46

[0895] 46d (0.04 g, 0.083 mmol), the crude intermediate 1 (0.042 g), TEA (0.05 g, 0.49 mmol), CuI (3.2 mg, 0.017 mmol), and PdCl2(PPh3)2 (5.8 mg, 0.0083 mmol) were added to a reaction flask. Under nitrogen protection, 2 mL of DMF was added and the reaction was carried out at 55°C for 2 h. The reaction solution was cooled to room temperature, 50 mL of water was added, and the reaction was filtered. The filter cake was washed with 10 mL of water and dissolved in 20 mL of DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / dichloromethane / ethyl acetate (v / v) = 1:1:2) to obtain compound 46 (0.02 g, yield: 35%).

[0896] 1H NMR(400MHz, CDCl3)δ7.93(s,1H),7.71–7.63(m,1H),7.62–7.51(m,3H),7.47–7.4 0(m,1H),7.04(d,1H),6.84–6.76(m,1H),6.55(dd,1H),5.02–4.88(m,2H),4.43–4 .26(m,2H),4.13–4.00(m,2H),3.88–3.75(m,1H),3.48–3.38(m,2H),3.25–3.10(m ,2H),3.07–2.95(m,2H),2.95–2.65(m,3H),2.50–2.35(m,2H),2.23–2.06(m,3H).

[0897] LCMS m / z=691.3[M+1] +

[0898] Example 47: Preparation of Compound 47

[0899] Step 1: Preparation of 47B

[0900] 47A (1.0 g, 4.81 mmol), di-tert-butyl dicarbonate (1.16 g, 5.32 mmol), and TEA (0.73 g, 7.21 mmol) were dissolved in 50 mL of tetrahydrofuran and reacted at room temperature for 12 h. The reaction system was added to 100 mL of water and extracted with ethyl acetate (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-9:1) to obtain 47B (1.3 g, yield: 88%).

[0901] Step 2: Preparation of 47C

[0902] 47B (1.05 g, 3.4 mmol), 1A (0.92 g, 5.08 mmol), TEA (2.06 g, 20.36 mmol), CuI (130 mg, 0.68 mmol), and PdCl2(PPh3)2 (240 mg, 0.34 mmol) were added to a reaction flask. 10 mL of DMF was added under nitrogen, and the reaction was carried out at 50°C for 0.5 h. The reaction solution was cooled to room temperature and added to 50 mL of ethyl acetate. The organic phase was washed with saturated sodium chloride solution (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-1:2) to obtain 47C (1.05 g, yield: 85%).

[0903] Step 3: Preparation of 47a

[0904] 47C (0.91 g, 2.52 mmol) and sodium carbonate (0.53 g, 5.0 mmol) were added to 10 mL of DMF, followed by 2 mL of water, and the reaction was carried out at 85°C for 12 h. The reaction solution was cooled to room temperature and added to 100 mL of ethyl acetate. The organic phase was washed with saturated sodium chloride solution (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-1:2) to obtain 47a (0.5 g, yield: 76%).

[0905] LCMS m / z=262.2[M+1] +

[0906] Step 4: Preparation of 47b

[0907] 47a (0.35 g, 1.34 mmol), 1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-iodo-1H-pyrazole (0.55 g, 1.35 mmol) (synthesis method, see J. Org. Chem., 2003, 68, 8075-8079), CuI (13 mg, 0.068 mmol), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (0.095 g, 0.67 mmol) and potassium carbonate (0.28 g, 2.03 mmol) were added to a reaction flask, 10 mL of DMF was added under nitrogen protection, and the reaction was carried out at 100°C for 2 h. The reaction solution was cooled to room temperature and added to 50 mL of ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-1:2) to obtain 47b (0.5 g, yield: 69%).

[0908] LCMS m / z=540.1[M+1] +

[0909] Step 5: Preparation of p-toluenesulfonate salt of 47c

[0910] 47b (0.2 g, 0.37 mmol) and p-toluenesulfonic acid monohydrate (0.21 g, 1.10 mmol) were dissolved in 5 mL of acetonitrile and reacted at room temperature for 3 h. The reaction system was concentrated under reduced pressure to obtain the p-toluenesulfonic acid salt of crude 47c (0.16 g).

[0911] LCMS m / z=440.0[M+1] +

[0912] Step 6: Preparation of compound 47

[0913] The p-toluenesulfonate salt of the crude product 47c (0.16 g), 1f (0.12 g, 0.43 mmol), and DIPEA (0.29 g, 2.24 mmol) were dissolved in 5 mL of DMF and reacted at 80°C for 5 h. The reaction system was cooled to room temperature, and 100 mL of ethyl acetate was added. The organic phase was washed with saturated sodium chloride solution (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-1:2) to obtain compound 47 (0.05 g, yield: 17%).

[0914] 1 H NMR(400MHz, CDCl3)δ8.01(s,2H),7.87(s,1H),7.80–7.64(m,4H),6.86–6.80(m,1H),6.62–6.53(m,1H),4.99–4.89 (m,1H),4.45–4.32(m,2H),4.15–4.03(m,2H),3.95–3.80(m,1H),2.98–2.65(m,3H),2.37(s,3H),2.19–2.07(m,1H).

[0915] LCMS m / z=696.0[M+1] +

[0916] Example 48: Preparation of Compound 48 Trifluoroacetate

[0917] Step 1: Preparation of 48b

[0918] 48a (0.68 g, 3 mmol) was added to 20 mL of DMF, and 60% sodium hydride (0.096 g) was added at 0°C. After reacting at room temperature for 1 h, 3-chloro-4-fluorobenzotrifluoride (0.6 g, 3.02 mmol) was added and the reaction was continued at 25°C for 16 h. 100 mL of ethyl acetate was added to the reaction system, and the organic phase was washed with 200 mL of purified water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1) to obtain 48b (1.1 g, yield: 90%).

[0919] Step 2: Preparation of 48c

[0920] 48b (1.1 g, 2.7 mmol) was added to 20 mL of dichloromethane, followed by 5 mL of trifluoroacetic acid, and the mixture was allowed to react at 25°C for 2 h. The reaction solution was concentrated under reduced pressure, and 100 mL of dichloromethane was added. The organic phase was washed with 50 mL of saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 48c (0.8 g, yield: 97%).

[0921] Step 3: Preparation of 48d

[0922] 48c (0.8 g, 2.62 mmol) was added to 40 mL of dichloroethane, followed by 4-iodobenzaldehyde (0.63 g, 2.72 mmol). The mixture was allowed to react at room temperature for 2 h, followed by sodium triacetoxyborohydride (0.84 g, 3.96 mmol) and the reaction was continued at 25°C for 15 h. 50 mL of dichloromethane was added to the reaction system, and the organic phase was washed with 50 mL of saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:1) to afford 48d (1.0 g, yield: 73%).

[0923] LCMS m / z=522.0[M+1] +

[0924] Step 4: Preparation of trifluoroacetate salt of compound 48

[0925] 48d (0.26 g, 0.5 mmol) was dissolved in 8 mL of DMF, and the crude intermediate 1 (0.34 g), TEA (0.5 g, 4.94 mmol), CuI (0.019 g, 0.1 mmol), and PdCl2(PPh3)2 (0.07 g, 0.1 mmol) were added sequentially. The atmosphere was purged with nitrogen three times, and the reaction was carried out at 60°C for 1 h. The reaction solution was cooled to room temperature, 40 mL of water was added, and the reaction mixture was filtered. The filter cake was washed with 20 mL of water and then dissolved in 100 mL of DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:3). The crude product was then purified by Pre-HPLC (instrument and preparative column: Glison GX-281 preparative liquid chromatography, preparative column model: Sunfire C18, 5 μm, i.d. × length = 30 mm × 150 mm). Preparation: The crude product was dissolved in methanol and dimethyl sulfoxide and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase: acetonitrile / water (containing 0.1% TFA). Gradient elution: 5% to 60% acetonitrile (elution time 15 min). Lyophilization afforded the trifluoroacetic acid salt of compound 48 (90 mg).

[0926] 1 H NMR(400MHz, CDCl3)δ8.19(s,1H),7.77(d,1H),7.73–6.93(m,7H),6.83–6.76(m,1H),6. 59(dd,1H),4.98–4.89(m,1H),4.73–3.77(m,10H),2.95–2.65(m,3H),2.60–1.85(m,9H).

[0927] LCMS m / z=731.2[M+1] +

[0928] Example 49: Preparation of Compound 49

[0929] Step 1: Preparation of 49b-1 and 49b-2

[0930] 49a (0.8 g, 5.47 mmol) was dissolved in 40 mL of DMF, and cesium carbonate (3.54 g, 10.86 mmol) was added. 49A (1.50 g, 5.97 mmol) was added in four batches at 90°C (addition time 6 h), and the reaction was continued at 90°C for 16 h. The reaction system was cooled to room temperature, 100 mL of water was added, and the mixture was extracted with 100 mL of ethyl acetate. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 3:1) to obtain 49b-1 (0.6 g, yield: 36%) and 49b-2 (0.2 g, yield: 12%), respectively.

[0931] Step 2: Preparation of 49d

[0932] Compound 49c (2.96 g, 10.0 mmol) and cyclopropylboronic acid (5.16 g, 60.07 mmol) were dissolved in 70 mL of 1,4-dioxane and 15 mL of water. Potassium phosphate (12.76 g, 60.11 mmol) was added, followed by bistricyclohexylphosphine palladium dichloride (2.22 g, 3.01 mmol) under a nitrogen atmosphere. The reaction was allowed to react at 100°C for 16 h. The reaction system was cooled to room temperature, 80 mL of water was added, and the mixture was extracted with 100 mL of ethyl acetate. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to afford 49d (2.1 g, 96% yield).

[0933] LCMS m / z=219.2[M+1] +

[0934] Step 3: Preparation of 49e

[0935] 49d (0.5 g, 2.29 mmol) was dissolved in 10 mL of methanol, 0.2 g of 10% Pd / C was added, and the mixture was reacted at room temperature under a hydrogen balloon atmosphere for 4 h. The reaction system was filtered and the filtrate was concentrated under reduced pressure to obtain crude product 49e (0.4 g).

[0936] Step 4: Preparation of 49f

[0937] The crude product 49e (0.12 g) and 49b-1 (0.10 g, 0.33 mmol) were dissolved in 8 mL of ethanol and 8 mL of toluene and reacted at 100°C under a nitrogen atmosphere for 16 h. The reaction system was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 2:1) to afford 49f (0.11 g, 71% yield).

[0938] LCMS m / z=470.3[M+1] +

[0939] Step 5: Preparation of 49g p-toluenesulfonate

[0940] 49f (0.1 g, 0.21 mmol) was dissolved in 10 mL of acetonitrile, and p-toluenesulfonic acid monohydrate (0.24 g, 1.26 mmol) was added and reacted at 35°C for 4 h. The reaction system was cooled to room temperature and concentrated under reduced pressure to obtain 49 g of crude p-toluenesulfonate (0.33 g).

[0941] LCMS m / z=370.3[M+1] +

[0942] Step 6: Preparation of compound 49

[0943] The p-toluenesulfonate salt (0.33 g) of the crude product (49 g) was dissolved in 5 mL of DMSO, and DIPEA (0.21 g, 1.62 mmol) and 1f (83 mg, 0.30 mmol) were added. The reaction was allowed to react at 80°C for 3 h. The reaction system was cooled to room temperature, 35 mL of water was added, and the mixture was filtered. The filter cake was washed with 10 mL of water and then dissolved in 100 mL of DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 15:1) to obtain compound 49 (40 mg, yield: 21%).

[0944] 1H NMR(400MHz,DMSO-d6)δ12.9–12.4(m,1H),11.07(s,1H),8.74–8.20(m,3H),7.94–7 .84(m,1H),7.72(d,1H),7.15–6.90(m,2H),6.87–6.77(m,1H),6.51–6.42(m,1H),6. 08–5.92(m,1H),5.15–5.02(m,1H),4.75–4.60(m,2H),4.57–4.42(m,2H),3.00–2.80 (m,1H),2.70–2.45(m,3H),2.14–1.90(m,2H),1.12–0.75(m,6H),0.73–0.60(m,2H).

[0945] LCMS m / z=626.4[M+1] +

[0946] Example 50: Preparation of Compound 50

[0947] Compound 50 was obtained using compounds 49e and 49b-2 as raw materials by referring to the synthetic method of Example 49.

[0948] 1 H NMR(400MHz,DMSO-d6)δ12.66–12.40(m,1H),11.07(s,1H),8.78(s,1H),8.72–8.44(m,1H ),8.24–8.04(m,1H),7.78(d,1H),7.73(d,1H),7.15–6.93(m,2H),6.83(dd,1H),6.50–6.4 3(m,1H),5.88–5.76(m,1H),5.14–5.03(m,1H),4.75–4.62(m,2H),4.60–4.50(m,2H),2.99 –2.80(m,1H),2.67–2.50(m,3H),2.14–1.86(m,2H),1.14–0.75(m,6H),0.71–0.60(m,2H).

[0949] Example 51: Preparation of Compound 51

[0950] Step 1: Preparation of 51b

[0951] 51a (2.2 g, 9.88 mmol) was dissolved in 20 mL of methanol, and sodium borohydride (0.37 g, 9.78 mmol) was added at 0°C. The mixture was allowed to react at room temperature for 0.5 h. 50 mL of ethyl acetate and 50 mL of water were added to the reaction solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10:1 to 1:1) to obtain 51b (2.05 g, yield: 92%).

[0952] Step 2: Preparation of 51c

[0953] 51b (0.15 g, 0.67 mmol) was dissolved in 5 mL of THF, and triphenylphosphine (0.26 g, 0.99 mmol) and 3-fluoro-5-iodophenol (0.16 g, 0.67 mmol) were added. DEAD (0.21 g, 1.21 mmol) was added at 0°C, and the mixture was allowed to react at room temperature for 19 h. 50 mL of ethyl acetate and 50 mL of water were added to the reaction solution, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10:1 to 1:1) to obtain 51c (0.13 g, yield: 44%).

[0954] Step 3: Preparation of Compound 51

[0955] Compound 51 was obtained using compound 51c as the starting material by referring to the synthetic method of Example 48.

[0956] 1 H NMR (400MHz, CDCl3) δ7.94(s,1H),7.71–7.62(m,2H),7.61–7.54(m,1H),7.53–7.46(m,1H),6.84–6.78(m,1H),6.74–6.63(m,2H),6.56( dd,1H),6.51–6.43(m,1H),5.66(q,1H),4.98–4.89(m,1H),4.42–4.32(m,2H),4.13–4.02(m,2H),3.88–3.76(m,1H),2.95–2.66(m,3H), 2.18–2.07(m,1H),1.62(d,3H).

[0957] Example 52: Preparation of Compound 52

[0958] Step 1: Preparation of 52b

[0959] Under nitrogen, 52a (0.5 g, 2.54 mmol), 52A (1.01 g, 3.81 mmol), and triphenylphosphine (1.33 g, 5.07 mmol) were added to 10 mL of tetrahydrofuran. DIAD (1.54 g, 7.62 mmol) was added dropwise at 0°C and allowed to react at room temperature for 3 h. The reaction system was added to 50 mL of water and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:0-1:1) to afford 52b (0.5 g, 44% yield).

[0960] Step 2: Preparation of compound 52

[0961] Compound 52 was obtained using compound 52b as the starting material by referring to the synthetic method of Example 51.

[0962] 1 H NMR(400MHz, CDCl3)δ7.98(s,1H),7.74–7.66(m,1H),7.66–7.58(m,1H),7.48–7.3 9(m,1H),7.34–7.27(m,1H),7.15(dd,1H),6.99–6.90(m,1H),6.88–6.80(m,1H),6. 71(d,1H),6.59(dd,1H),5.75(q,1H),4.98–4.90(m,1H),4.47–4.37(m,2H),4.17– 4.05(m,2H),3.98–3.85(m,1H),2.96–2.65(m,3H),2.18–2.08(m,1H),1.71(d,3H).

[0963] Example 53: Preparation of Compound 53

[0964] Step 1: Preparation of 53b

[0965] 53a (0.24 g, 1.01 mmol) was dissolved in 10 mL of DMF, and potassium carbonate (0.28 g, 2.03 mmol) and 53A (0.24 g, 1.21 mmol) were added. The reaction was carried out at 90°C for 12 h. The reaction system was cooled to room temperature, and 30 mL of ethyl acetate and 50 mL of purified water were added. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 4:1) to obtain 53b (0.4 g, yield: 95%).

[0966] Step 3: Preparation of Compound 53

[0967] Compound 53 was obtained using compound 53b as the starting material by referring to the synthetic method of Example 52.

[0968] 1 H NMR(400MHz, CDCl3)δ8.18(s,1H),7.73–7.65(m,1H),7.65–7.55(m,1H),7 .49–7.40(m,1H),7.07–6.97(m,1H),6.92–6.81(m,1H),6.78–6.68(m,2H) ,6.68–6.58(m,1H),6.48(dd,1H),4.92–4.82(m,1H),4.35–4.23(m,2H),4 .07–3.95(m,2H),3.82–3.67(m,1H),2.90–2.55(m,3H),2.14–1.97(m,1H).

[0969] Example 54: Preparation of Compound 54

[0970] Step 1: Preparation of 54b

[0971] 54a (3 g, 13.48 mmol) was dissolved in 45 mL of chloroform, and bromine (2.1 g, 13.14 mmol) was added at 0°C. The reaction was allowed to react at room temperature for 16 h. 60 mL of dichloromethane was added to the reaction system, and the organic phase was washed with 100 mL of saturated aqueous sodium bicarbonate and 50 mL of saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 87:13) to afford 54b (1.5 g, yield: 37%).

[0972] LCMS m / z=301.1[M+1] +

[0973] Step 2: Preparation of 54c

[0974] 29b (2.30 g, 7.18 mmol) was dissolved in THF (20 mL), and 4 mL of water and lithium hydroxide monohydrate (0.6 g, 14.3 mmol) were added. The mixture was allowed to react at room temperature for 30 min. 1 mol / L hydrochloric acid was added dropwise to adjust the pH to 6. 50 mL of ethyl acetate was added, and the layers were separated. The organic phase was washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 1 (2.0 g). Crude product 1 (1.74 g) was added to a 100 mL single-necked flask, followed by dry dichloromethane (20 mL) and DIPEA (1.54 g, 11.91 mmol). 54b (1.2 g, 4.0 mmol) was slowly added dropwise at 0°C and allowed to react at room temperature for 16 h. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 73:27) to obtain crude product (1.0 g). The above crude product (1 g) was dissolved in 30 mL of toluene, and ammonium acetate (1.5 g, 19.46 mmol) was added and reacted at 90° C. for 16 h. The reaction system was cooled to room temperature and concentrated under reduced pressure. Dichloromethane (100 mL) and 100 mL of purified water were added. The organic phase was washed with 50 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 7:3). The crude product was prepared by Prep-HPLC (instrument: Waters 2767 preparative liquid phase; chromatographic column: SunFire@PrepC18 (19×250 nm); mobile phase A: acetonitrile; mobile phase B: water (containing 5 mmol / L ammonium acetate); gradient elution: mobile phase A content from 60-90%; flow rate: 12 mL / min; column temperature: room temperature; detection wavelength: 210 nm; the sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution; elution time: 18 min) to give 54c (45 mg, yield: 2%).

[0975] LCMS m / z=493.2[M+1] +

[0976] Step 3: Preparation of Compound 54

[0977] 54c (45 mg, 0.091 mmol) was added to a 50 mL single-necked bottle, followed by dry DMF (8 mL), the crude intermediate 1 (47 mg) and TEA (28 mg, 0.277 mmol), and PdCl2(PPh3)2 (12 mg, 0.017 mmol) and CuI (7 mg, 0.037 mmol) were added under nitrogen atmosphere. The reaction was allowed to react at 50°C for 2 h. The reaction system was cooled to room temperature, and saturated aqueous ammonium chloride (80 mL) was slowly added. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated aqueous sodium chloride (60 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 27:73) to obtain compound 54 (20 mg, yield: 31%).

[0978] 1 H NMR(400MHz, CDCl3)δ9.62(s,1H),8.48–8.30(m,1H),8.17–8.02(m,1H),7.85–7.40(m,6H),6.84–6.75(m,1H),6.54(dd,1H),4.9 9–4.88(m,1H),4.40–4.29(m,2H),4.11–4.00(m,2H),3.88–3.72(m,1H),3.24–3.08(m,2H),2.98–2.65(m,5H),2.35–2.00(m,3H).

[0979] LCMS m / z=702.2[M+1] +

[0980] Example 55: Preparation of Compound 55

[0981] Step 1: Preparation of 55b

[0982] To a reaction flask, 55a (0.5 g, 2.11 mmol) (synthesis method, see WO2021262596), 55A (0.97 g, 3.17 mmol), tetrakis(triphenylphosphine)palladium (0.24 g, 0.21 mmol), and potassium carbonate (0.58 g, 4.2 mmol) were dissolved in 20 mL of 1,4-dioxane and 4 mL of water. The mixture was reacted at 100°C for 12 h. The reaction solution was cooled to room temperature and added to 50 mL of ethyl acetate. The organic phase was washed with saturated sodium chloride solution (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:0-1:2) to obtain 55b (0.5 g, yield: 82%).

[0983] LCMS m / z=290.1[M+1] +

[0984] Step 2: Preparation of 55c

[0985] 55b (0.5 g, 1.73 mmol), CuI (0.49 g, 2.57 mmol), KI (0.43 g, 2.59 mmol), and isoamyl nitrite (0.36 g, 3.07 mmol) were dissolved in 70 mL of acetonitrile and reacted at 70°C for 2 h. The reaction system was concentrated under reduced pressure and added to 50 mL of ethyl acetate and 50 mL of water. The reaction mixture was filtered, and the aqueous phase was extracted with 50 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:0-1:2) to afford 55c (0.2 g, yield: 29%).

[0986] Step 3: Preparation of Compound 55

[0987] 55c (0.044 g, 0.11 mmol), the crude intermediate 1 (0.056 g), TEA (0.067 g, 0.66 mmol), CuI (4.2 mg, 0.022 mmol), and PdCl2(PPh3)2 (7.7 mg, 0.011 mmol) were added to a reaction flask, 2 mL of DMF was added under a nitrogen atmosphere, and the reaction was carried out at 55°C for 2 h. The reaction solution was cooled to room temperature, 50 mL of water was added, and the reaction was filtered. The filter cake was washed with 10 mL of water, dissolved in 20 mL of DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether: dichloromethane: ethyl acetate (v / v) = 1:1:2) to obtain compound 55 (0.025 g, yield: 37%).

[0988] 1 H NMR(400MHz, CDCl3)δ8.01(s,1H),7.75(s,1H)7.68(d,1H),7.63–7.55(m,1H),7.48–7.40(m,1H),7.32–7.24(m,1H),7.23–7.08(m,2H),6.86– 6.79(m,1H),6.57(dd,1H),4.99–4.89(m,1H),4.45–4.32(m,2H),4.18 –4.05(m,2H),3.94–3.80(m,1H),2.97–2.62(m,3H),2.22–2.07(m,1H).

[0989] LCMS m / z=610.0[M+1] +

[0990] Example 56: Preparation of Compound 56

[0991] Compound 56 was obtained using compounds 34a and 56a as raw materials according to the synthetic method of Example 34.

[0992] 1 H NMR(400MHz, CDCl3)δ7.94(s,1H),7.75–7.65(m,3H),7.57–7.49(m,2H),7.23–7.11(m,2H),6.82(d,1H),6.57(dd,1H),6.45(t,1H),5.13(s,2H ),4.98–4.89(m,1H),4.43–4.32(m,2H),4.15–4.05(m,2H),3.92–3.76( m,1H),2.95–2.65(m,3H),2.37(s,3H),2.19(s,3H),2.17–2.08(m,1H).

[0993] Example 57: Preparation of Compound 57

[0994] Compound 57 was obtained using compounds 34a and 57a as raw materials according to the synthetic method of Example 34.

[0995] 1 H NMR(400MHz, CDCl3)δ7.94(s,1H),7.76–7.64(m,3H),7.56–7.49(m,2H),7.41(t,1H),6.82(d,1H),6.73–6.61(m,2H),6.57(dd,1H),5.09(s,2H ),4.98–4.89(m,1H),4.44–4.35(m,2H),4.17–4.06(m,2H),3.95–3.82( m,1H),2.95–2.65(m,3H),2.36(s,3H),2.19(s,3H),2.17–2.08(m,1H).

[0996] Example 58: Preparation of Compound 58

[0997] Step 1: Preparation of 58b

[0998] 58A (2.40 g, 7.83 mmol) was dissolved in a mixture of 20 mL of 1,4-dioxane and 2 mL of water. 58a (2.05 g, 7.82 mmol), Pd(dppf)Cl2·DCM (0.64 g, 0.79 mmol), and potassium phosphate (3.32 g, 15.64 mmol) were added. The nitrogen atmosphere was replaced three times, and the reaction was carried out at 80°C for 19 h. The reaction system was cooled to room temperature, and 100 mL of ethyl acetate and 100 mL of water were added. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10:1 to 1:1) to obtain 58b (2.1 g, yield: 85%).

[0999] LCMS m / z=315.2[M+1] +

[1000] Step 2: Preparation of 58c

[1001] 15 mL of methylmagnesium bromide (3 mol / L tetrahydrofuran solution) was added to 5 mL of ultra-dry tetrahydrofuran, cooled to 0°C, and a solution of 58b (1.18 g, 3.76 mmol) in ultra-dry tetrahydrofuran (10 mL) was added dropwise. The mixture was allowed to react at 0°C for 3 h. 50 mL of saturated aqueous ammonium chloride was added dropwise to the reaction solution at 0°C, and the mixture was extracted with 150 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10:1-5:1) to obtain crude product 58c (1.21 g).

[1002] Step 3: Preparation of 58d

[1003] 4-Iodopyrazole (0.55 g, 2.84 mmol) was dissolved in 5 mL of THF, and triphenylphosphine (1.13 g, 4.31 mmol) and the crude product 58c (0.91 g) were added. DEAD (0.87 g, 5.0 mmol) was added at 0°C, and the reaction was continued at 60°C for 19 h. The reaction solution was cooled to room temperatur...

Claims

1. A compound or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein: The compound is selected from the compounds represented by general formula (I), BLK (I); L is selected from a bond or -C 1-50 Hydrocarbyl-, wherein 1 to 20 methylene units in the hydrocarbyl group are optionally replaced by -Ak- or -Cy-; Each -Ak- is independently selected from -(CH2) q -、-(CH2) q -O-, -O-(CH2) q -、-(CH2) q -S-, -S-(CH2) q -、-(CH2) q -NR L -、-NR L -(CH2) q -、-(CH2) q -NR L C(=O)-、-NR L (CH2) q C(=O)-、-(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -、-(C≡C) q -、-CH=CH-、-Si(R L )2-、-Si(OH)(R L )-、-Si(OH)2-、-P(=O)(OR L )-、-P(=O)(R L )-, -S-, -S(=O)-, -S(=O)2- or a bond, wherein the -CH2-, -CH=CH- are optionally substituted by 1 to 2 groups selected from halogen, OH, CN, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, halogen-substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 substituted by an alkyl substituent; q is each independently selected from 0, 1, 2, 3, 4, 5 or 6; R L Each independently selected from H, C 1-6 Alkyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, phenyl or 5-6 membered heteroaryl, wherein the heterocyclyl or heteroaryl contains 1 to 4 heteroatoms selected from O, S and N; Each -Cy- is independently selected from a bond or one of the following groups which are optionally substituted: a 4-8 membered heteromonocyclic group, a 4-10 membered heterocycloalkyl group, a 5-12 membered heterospirocyclic group, a 7-10 membered heterobridged cyclyl group, a 3-7 membered monocycloalkyl group, a 4-10 membered cycloalkyl group, a 5-12 membered spirocycloalkyl group, a 5-10 membered bridged cycloalkyl group, a benzoC 4-6 Carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, or 6- to 10-membered aryl, when substituted, is replaced by 1 to 4 R L2 Substitution, wherein the heterocyclic group, heteroaryl group, heteromonocyclic group, heterocyclic group, heterospirocyclic group or heterobridged ring group contains 1 to 4 heteroatoms selected from O, S and N, and when the heteroatom is selected from S, it is optionally substituted by 1 or 2 =O; R L2 Each independently selected from F, Cl, Br, I, OH, COOH, CN, NH2, NHC 1-4 Alkyl, N(C 1-4 alkyl)2,=O,C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -OC 1-4 Alkylene-OC 1-4 Alkyl, -OC 1-4 Alkylene-OC 3-10 Carbocyclic group, -C 1-4 Alkylene-OC 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkylene-OC 1-4 Alkylene-OC 3-10 Carbocyclic group, -OC 0-4 Alkylene-C 3-10 Carbocyclic group, -C 0-4 Alkylene-C 3-10 Carbocyclic group, -C 0-4 Alkylene-4 to 10 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, COOH, CN, NH2, NHC 1-4 Alkyl, N(C 1-4 alkyl)2,=O,C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy, halogen-substituted C 1-4 substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N; B is selected from B1 is selected from C 3-20 Carbocyclic group or 4-20 membered heterocyclic ring, said carbocyclic group or heterocyclic ring is optionally substituted by 1 to 4 R b1 Substituted, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N; B2 is selected from C 3-20 Carbocyclic group or 4-20 membered heterocyclic ring, said carbocyclic group or heterocyclic ring is optionally substituted by 1 to 4 R b2 Substituted, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N; B3 is selected from C 3-20 Carbocyclic group or 4-20 membered heterocyclic ring, said carbocyclic group or heterocyclic ring is optionally substituted by 1 to 4 R b3 Substituted, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N; or B3 is selected from a bond; L1 is selected from a bond or L2 is selected from a bond or Y1, Y2, Y3, Y4 are each independently selected from a bond, O, S, NR b5a ; Q1, Q2, Q3, and Q4 are each independently selected from v1, v2, v3, and v4 are each independently selected from 0, 1, 2, 3, or 4; R b1 、R b2 Each independently selected from H, F, Cl, Br, I, ═O, ═S, OH, CN, NO2, COOH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, NH2, NHC 1-4 Alkyl, N(C 1-4 alkyl)2, -C(=O)NH2, -C(=O)NHC 1-4 Alkyl, -C(=O)N(C 1-4 alkyl)2, -C(=O)OC 1-4 Alkyl, -S(=O)2NH2, -S(=O)2N(C 1-4 alkyl)2, -S(=O)2NHC 1-4 Alkyl, -OR b22 、-C(=O)R b22 、-S(=O)2R b22 、-P(=O)(R b22 )2, -NHC(=O)R b22 、-N(C 1-4 alkyl)C(=O)R b22 、-NHS(=O)2R b22 、-N(C 1-4 alkyl)S(=O)2R b22 、-OC 3-12 Carbocyclic group, -NH-C 3-12 Carbocyclic group, -SC 3-12 Carbocyclic group, C 3-12 Carbocyclic group, C 6-10 Aryl, 5- to 12-membered heteroaryl, 4- to 12-membered heterocyclyl, -C 1-4 Alkylene-R b22 、-OC 1-4 Alkylene-R b22 、-C 1-4 Alkylene-OC 1-4 Alkylene-R b22 、-C 1-4 Alkylene-OC 1-4 Alkylene-OR b22 The alkylene, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclyl, heterocyclyl, aryl or heteroaryl groups are optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, =O, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, CN, COOH, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 3-10 Carbocyclic group, C 3-10 is substituted by a carbocyclic group or a 4- to 10-membered heterocyclic group, wherein the heteroaryl group or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N; R b3 Each independently selected from halogen, =O, =S, OH, CN, NO2, COOH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, -(CH2) n -R b22 、-OR b22 、-SR b22 、-NH-R b22 、-(CH2) m1 -X-(CH2) m2 -R b24 、-N(R b21 )2、-C(=O)N(R b21 )2, -C(=O)OR b21 、-C(=O)R b22 、-S(=O)2R b22 、-P(=O)(R b22 )2、-S(=O)2N(R b21 )2、-NR b21 C(=O)R b22 、-NR b21 S(=O)2R b22 、C 3-6 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclic group, wherein said -CH2-, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally substituted by 1 to 4 groups selected from halogen, OH, =O, -N(R b21 )2、CN、COOH、C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkynyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 3-6 substituted by a cycloalkyl, a 5-10 membered heteroaryl or a 4-10 membered heterocyclic group, wherein the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N; n is each independently selected from 0, 1, 2, 3 or 4; R b21 Each independently selected from H or C 1-4 Alkyl, wherein the alkyl is optionally substituted by 1 to 4 groups selected from halogen, OH, =O, NH2, CN, CF3, COOH, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 substituted by an alkoxy substituent; R b22 Each independently selected from H, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -NH-C 1-4 Alkyl, C 3-6 Cycloalkyl, wherein the alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl is optionally substituted by 1 to 4 groups selected from halogen, OH, =O, NH2, CN, CF3, COOH, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 substituted by an alkoxy substituent; or R b1 With R b3 、R b2 With R b3 Either one directly connects to form C 5-7 Carbocyclic group, 5 to 7 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from halogen, OH, NH2, CN, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl or C 1-4 The heterocyclic group is substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, and N; R b4 、R b5 Each independently selected from H, F, Cl, Br, I, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, CN, COOH, NO2, -(CH2) m1 -R b23 、-(CH2) m1 -X-(CH2) m2 -R b24 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-12 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl or heterocyclic group is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, CN, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkynyl, C 3-8 substituted by a cycloalkyl or 3 to 8 heterocyclic substituent, wherein the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N; or any R b4 、R b5 Together with the carbon atom it is connected to form C 3-8 Cycloalkyl or 3 to 8 membered heteromonocyclic group, wherein the cycloalkyl or heteromonocyclic group is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, NH2, -N(R b21 )2.CN.C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkynyl, C 3-6 substituted by a cycloalkyl, a 5-6 membered heteroaryl or a 3 to 8 membered heterocyclic group, wherein the heteromonocyclic group, heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S and N; R b5a Selected from H, C 1-4 Alkyl, -(CH2) n -R b22 、-C(=O)N(R b21 )2, -C(=O)R b22 、C 3-6 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclic group, wherein said -CH2-, alkyl, cycloalkyl, heterocyclic group, aryl or heteroaryl group is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, =O, -N(R b21 )2、CN、COOH、C 1-4 Alkyl, C 1-4 Alkoxy, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 3-6 substituted by a cycloalkyl, a 5-10 membered heteroaryl or a 4-10 membered heterocyclic group, wherein the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N; X is independently selected from NH, O or S; m1 are each independently selected from 0, 1, 2 or 3; m2 are each independently selected from 0, 1, 2 or 3; R b23 Each independently selected from C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-10 Carbocyclic group or 4-10 membered heterocyclic group, wherein the carbocyclic group, alkenyl group, alkynyl group, heterocyclic group is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, =O, NH2, CN, CF3, COOH, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N; R b24 Each independently selected from C 1-4 Alkoxy, NH-C 1-4 Alkyl, NH-C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, C 3-10 Carbocyclic or 4-10 membered heterocyclic, wherein the alkoxy, carbocyclic, cycloalkyl, cycloalkyloxy, heterocyclic is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, =O, NH2, CN, CF3, COOH, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N; K is selected from K1, K2, K3, K4; K1 is selected from K2 is selected from K3 is selected from K4 is selected from Q is independently selected from a bond, -O-, -S-, -CH2-, -NR q -, -C(=O)-, -NR q C(=O)-, -C(=O)NR q - or 3-12 membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 4 heteroatoms selected from O, S or N; R q Selected from H or C 1-6 alkyl; A is selected from C 3-10 Carbocyclic group, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the heterocyclyl or heteroaryl contains 1 to 4 heteroatoms selected from O, S or N; F are each independently selected from C 3-20 Carbocyclic group, C 6-20 aryl, 3-20 membered heterocyclyl or 5-20 membered heteroaryl, wherein the heterocyclyl or heteroaryl contains 1 to 4 heteroatoms selected from O, S or N; R k2 Each independently selected from a bond, -C(=O)-, -S(=O)2-, -S(=O)- or -C(R k3 )2-; R k1 Each independently selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, R k7a The alkyl, alkoxy or cycloalkyl group is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 substituted by a cycloalkyl substituent; R k7a Selected from H, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, said alkyl, cycloalkyl, heterocycloalkyl being optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, NH2, CN, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 substituted by a cycloalkyl substituent; R k3 Each independently selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 4 heteroatoms selected from O, S or N; Or two R k3 and the carbon atoms or ring skeletons directly connected to the two, the two R k1 and the carbon atoms directly connected to them or The ring skeleton together forms C 3-8 Carbocyclic or 3-8 membered heterocyclic, said carbocyclic or heterocyclic group is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 4 heteroatoms selected from O, S or N; R k4 Each independently selected from H, OH, NH2, CN, CONH2, C 1-6 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, wherein the alkyl, cycloalkyl or heterocyclic group is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 4 heteroatoms selected from O, S or N; M1 is selected from a bond, -CH2-C(=O)NH- or -C(=O)CH2NH-; M2 is selected from -NHC(=O)-C 1-6 Alkyl, -NHC(=O)-C 3-6 Cycloalkyl or 4-10 membered heterocyclic group, wherein the alkyl, cycloalkyl or heterocyclic group is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, =O, OH, NH2, C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 4 heteroatoms selected from O, S or N; M3 is selected from -NH- or -O-; R k10 Selected from C 1-6 Alkyl, wherein the alkyl is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, ═O, OH, C 1-6 Alkyl or C 3-6 substituted by a cycloalkyl substituent; R k11 Each independently selected from H, F, Cl, Br, I, =O, OH, SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or -OC(=O)-C 1-6 Alkyl, said alkyl, alkoxy or alkylthio group is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent; R k12 、R k13 Each independently selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, ═O, OH, NH 2 , C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent; R k14 5-6 membered heteroaryl, wherein the heteroaryl is optionally substituted by 1 to 4 members selected from F, Cl, Br, I, OH, =O, CF3, CN, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 The heteroaryl group is substituted by a substituent of a cycloalkyl group, wherein the heteroaryl group contains 1 to 4 heteroatoms selected from N, O or S; G is selected from C 6-10 Aryl or 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, =O, CF3, CN, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 The heteroaryl group is substituted by a substituent of a cycloalkyl group, wherein the heteroaryl group contains 1 to 4 heteroatoms selected from N, O or S; n1, n2, n3 are each independently selected from 0, 1, 2 or 3; p1 and p2 are each independently selected from 0, 1, 2, 3, 4 or 5.

2. The compound according to claim 1 or its stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: B is selected from Or B is selected from V is selected from a bond or L1; L1 and L2 are not bonds; B1 is selected from 6-7 membered heteromonocyclic group, 5-14 membered heterocyclic group, 5-12 membered heterospirocyclic group, 7-10 membered heterobridged ring group, C 6-8 Monocarbocyclic group, C 6-14 Cycloalkyl, C 6-12 Spiroalkyl, C 5-12 Bridged cycloalkyl, benzo C 3-10 Carbocyclic group, benzo 3 to 10 membered heterocyclic group, C 12-18 tricyclic group, 12 to 18 membered heterotricyclic group, 5-10 membered heteroaryl group or 6-14 membered aryl group, said B1 is optionally substituted by 1 to 4 R b2 Substitution, the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N; B3 is selected from 4-7 membered heteromonocyclic group, 5-14 membered heterocyclic group, 5-12 membered heterospirocyclic group, 7-10 membered heterobridged ring group, C 3-8 Monocarbocyclic group, C 6-14 Cycloalkyl, C 6-12 Membered spirocycloalkyl, C 5-12 Member-bridged cycloalkyl, benzo C 3-10 Carbocyclic group, benzo 3 to 10 membered heterocyclic group, C 12-18 tricyclic group, 12 to 18 membered heterotricyclic group, 5-10 membered heteroaryl group or 6-14 membered aryl group, wherein B3 is optionally substituted by 1 to 4 R b3 Substitution, the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N; B2 is selected from 4-7 membered heteromonocyclic group, 5-14 membered heterocyclic group, 5-12 membered heterospirocyclic group, 7-10 membered heterobridged ring group, C 3-8 Monocarbocyclic group, C 6-14 Cycloalkyl, C 6-12 Membered spirocycloalkyl, C 5-12 Member-bridged cycloalkyl, benzo C 3-10 Carbocyclic group, benzo 3 to 10 membered heterocyclic group, C 12-18 tricyclic group, 12 to 18 membered heterotricyclic group, 5-10 membered heteroaryl group or 6-14 membered aryl group, wherein B2 is optionally substituted by 1 to 4 R b2 Substitution, the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N; R b4 、R b5 Each independently selected from H, F, Cl, Br, I, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 alkyl)2、CN、COOH、NO2、C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 3-8 Cycloalkyl, C 6-10 Aryl, OC 3-8 Cycloalkyl, NH-C 3-8 Cycloalkyl, 5-6 membered heteroaryl or 3-8 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl or heterocyclic group is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, CN, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkynyl, C 3-6 substituted by a cycloalkyl or 3 to 8 heterocyclic substituent, wherein the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N; R b5a Selected from H, C 1-4 Alkyl, -(CH2) n -R b22 The -CH2-, alkyl group is optionally replaced by 1 to 4 groups selected from F, Cl, Br, I, OH, =O, -N(R b21 )2、CN、COOH、C 1-4 Alkyl, C 1-4 Alkoxy, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 3-6 The alkyl group is substituted by a cycloalkyl group, a 5-6 membered heteroaryl group or a 4-8 membered heterocyclic group, wherein the heteroaryl group or heterocyclic group contains 1 to 4 heteroatoms selected from O, S and N.

3. The compound according to claim 2, or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein: L is selected from -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-, -Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5--Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-、 -Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2- Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy 2-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2 -Cy3-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-; Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from -(CH2) q -、-(CH2) q -O-, -O-(CH2) q -、-(CH2) q -S-, -S-(CH2) q -、-(CH2) q -NR L -、-NR L -(CH2) q -、-(CH2)q-NR L C(=O)-、-(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -、-CH=CH-、-(C≡C) q - or bond, wherein the -CH2-, -CH=CH- are optionally replaced by 1 to 2 selected from F, Cl, Br, I, OH, CN, NH2, C 1-4 Alkyl, C 1-4 Alkoxy, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 substituted by an alkyl substituent; Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from a bond or one of the following groups which are optionally substituted: a 4-7 membered heteromonocyclic group, a 4-10 membered heterocycloalkyl group, a 5-12 membered heterospirocyclic group, a 7-10 membered heterobridged cyclic group, a 3-7 membered monocycloalkyl group, a 4-10 membered cycloalkyl group, a 5-12 membered spirocycloalkyl group, a 5-10 membered bridged cycloalkyl group, a benzoC 4-6 Carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, or 6- to 10-membered aryl, when substituted, is replaced by 1 to 4 R L2 Substitution, wherein the heterocyclic group, heteroaryl group, heteromonocyclic group, heterocyclic group, heterospirocyclic group or heterobridged ring group contains 1 to 4 heteroatoms selected from O, S and N, and when the heteroatom is selected from S, it is optionally substituted by 1 or 2 =O; q is each independently selected from 0, 1, 2, 3 or 4; R L Each independently selected from H or C 1-6 alkyl.

4. The compound according to claim 3, or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein: K2 is selected from K3 is selected from A is selected from C 3-8 Carbocyclyl, phenyl, 4-7 membered heterocyclyl, or 5-6 membered heteroaryl, wherein the heterocyclyl or heteroaryl contains 1 to 4 heteroatoms selected from O, S or N; F are each independently selected from C 3-7 Monocyclic carbocyclic group, C 4-10 Cyclic carbocyclic group, C 5-12 Spirocarbocyclic group, C 5-10 Bridged carbocyclic group, 4-7 membered heteromonocyclic group, 4-10 membered heterocyclic group, 8-15 membered tricyclic heterocyclic group, 12-17 membered tetracyclic heterocyclic group, 5-17 membered heterospirocyclic group, C 6-14 Aryl, 5-10 membered heteroaryl, The heteromonocyclic group, heterocyclic group, heterospirocyclic group, heterobridged ring group or heteroaryl group contains 1 to 4 heteroatoms selected from O, S or N; represents a ring selected from an aromatic ring or a non-aromatic ring; E are each independently selected from C 3-10 Carbocyclyl, phenyl, 4-12 membered heterocyclyl, 5-12 membered heteroaryl, wherein the heterocyclyl or heteroaryl contains 1 to 4 heteroatoms selected from O, S or N; Q is independently selected from a bond, -O-, -S-, -CH2-, -NR q -, -C(=O)-, -NR q C(=O)-, -C(=O)NR q - or 4-7 membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 4 heteroatoms selected from O, S or N; R q Selected from H or C 1-4 alkyl; R k1 、R k3 Each independently selected from H, F, Cl, Br, I, OH, =O, NH2, CF3, CN, COOH, CONH2, C 1-4 Alkyl or C 1-4 Alkoxy, wherein the alkyl or alkoxy group is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH or NH2; Or two R k3 and the carbon atoms or ring skeletons directly connected to the two, the two R k1 Together with the carbon atoms or ring skeletons directly connected to the two, they form C 3-6 Carbocyclic or 3-7 membered heterocyclic, said carbocyclic or heterocyclic, optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 4 heteroatoms selected from O, S or N; R k4 Each independently selected from H, OH, NH2, CF3, CN or C 1-4 alkyl; R k5 Each independently selected from C(CH3)2、C(=O)、CH2、CH2CH2、S(=O)2、 R k6 Each is independently selected from C(=O), CH, S(=O), S(=O)2, CH2 or N; R k7 Each independently selected from C(CH3)2、C(=O)、CH、N、CH2、O、S、NR k7a ; R k8 are each independently selected from C, N or CH; R k9 are each independently selected from a bond, C(CH3)2, C(=O), CH2, CH2CH2 or S(=O)2; R ka Selected from O, S or NH; R k7a Selected from H, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, said alkyl, cycloalkyl, heterocycloalkyl being optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, NH2, CN, CF3, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 substituted by a cycloalkyl substituent; R k14 Selected from 5. The compound according to claim 4, or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein: B is selected from V is selected from a bond, O, S, NR b5a NR b5a -(Q2) v2 -、-(Q2) v2 -NR b5a 、-O-(Q2) v2 -、-(Q2) v2 -O-, -(Q2) v2 -; v2 and v4 are each independently selected from 1, 2, 3 or 4; Y1 and Y3 are each independently selected from a bond, O, S, NR b5a ; Y2 and Y4 are each independently selected from O, S, NR b5a ; Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from -(CH2) q -、-(CH2) q -O-, -O-(CH2) q -、-(CH2) q -S-, -S-(CH2) q -、-(CH2) q -NR L -、-NR L -(CH2) q -、-(CH2) q -NR L C(=O)-、-(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -, -CH=CH-, -C≡C- or a bond, wherein the -CH2-, -CH=CH- are optionally substituted by 1 to 2 substituents selected from F, Cl, Br, I, OH, CN, NH2, CF3, hydroxymethyl, methyl, ethyl, methoxy or ethoxy; q is each independently selected from 0, 1, 2 or 3; R L Each independently selected from H or C 1-4 alkyl; K1 is selected from K4 is selected from Q is selected from a bond, C(=O); Qa is selected from a bond, CH2, NH, N(CH3), O, S, C(=O), NHC(=O), C(=O)NH, N(CH3)C(=O), C(=O)N(CH3), Qb is selected from a bond, CH2, O, S, C(=O), NHC(=O), N(CH3)C(=O); E and A are each independently selected from a benzene ring group, a pyridine ring group, a pyridazine ring group, a pyrazine ring group, a pyrimidine ring group, a pyrrole ring group, a pyrazole ring group, an imidazole ring group, a thiazole ring group, a furan ring group, a thiophene ring group or an oxazole ring group; Each F is independently selected from cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, 6,7-dihydro-5H-cyclopenta[c]pyridinyl, 2,3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, 2-pyridone, benzoxazolyl, pyridoimidazolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzopyridinyl, benzo pyrimidinyl, benzopyrimidinyl, benzopyridazinyl, benzotriazinyl, pyrrolopyrrolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, pyrazolopyridinyl, pyrimidopyridinyl, pyrimidopyrazinyl, pyrimidopyridazinyl, pyrimidopyridinyl, pyridopyridinyl, pyridopyrazinyl, pyridopyrazinyl, pyridopyrazinyl, pyridopyridazinyl, pyridazinopyrazinyl, pyrazinopyrazinyl, indolopyridinyl, indolothienyl, indolofuranyl, Its left side is directly connected to L; R ka Selected from O, S or NH; R k7 Each independently selected from C(CH3)2, CH2, O, N(CH3), N(CH2CH3), N(cyclopropyl) or NH; R k7a is selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, CN, CF3, C 1-4 Alkyl, C 1-4 Alkoxy, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, C 3-6 substituted by a cycloalkyl substituent; p1 and p2 are each independently selected from 0, 1, 2 or 3.

6. The compound according to claim 5, or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein: R L Selected from H, methyl or ethyl; q is each independently selected from 0, 1 or 2; Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from a bond or one of the following groups which are substituted or unsubstituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azacyclohexenyl, piperidinyl, morpholinyl, piperazinyl, 1,4-diazepanyl, pyridyl, phenyl, cyclopropyl and cyclopropyl, cyclopropyl and cyclobutyl, cyclopropyl and cyclopentyl, cyclopropyl and cyclohexyl, cyclobutyl and cyclobutyl, cyclobutyl and cyclopentyl, cyclo Butylcyclohexyl, cyclopentylcyclopentyl, cyclopentylcyclohexyl, cyclohexylcyclohexyl, cyclopropylspirocyclopropyl, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylazetidinyl, cyclopropylpyrrolidinyl, cyclopropylpiperidinyl, cyclobutylazetidinyl, cyclobutylpyrrolidinyl, Cyclobutylpiperidinyl, cyclopentylazetidinyl, cyclopentylpyrrolidinyl, cyclopentylpiperidinyl, cyclohexylazetidinyl, cyclohexylpyrrolidinyl, cyclohexylpiperidinyl, azetidinylazetidinyl, azetidinylpyrrolidinyl, azetidinylpiperidinyl, pyrrolidinylazetidinyl, pyrrolidinylpyrrolidinyl, pyrrolidinylpiperidinyl, piperidinylazetidinyl, piperidinylpyrrolidinyl, piperidinylpiperidinyl, cyclobutylspiroazacyclo Heterocyclobutyl, cyclobutyl spiropyrrolidinyl, cyclobutyl spiropiperidinyl, cyclopentyl spiroazetidinyl, cyclopentyl spiropyrrolidinyl, cyclopentyl spiropiperidinyl, cyclohexyl spiroazetidinyl, cyclohexyl spiropyrrolidinyl, cyclohexyl spiropiperidinyl, azetidinyl spiroazetidinyl, azetidinyl spiropyrrolidinyl, azetidinyl spiropiperidinyl, pyrrolidinyl spiroazetidinyl, pyrrolidinyl spiropyrrolidinyl, pyrrolidinyl spiropiperidinyl, piperidinyl spiroazetidinyl, piperidinyl spiropiperidinyl, When substituted, by 1 to 4 R L2 replace; R L2 Each independently selected from F, Cl, Br, I, OH, NH2, NHCH3, N(CH3)2, COOH, CN, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -OC 1-2 Alkylene-OC 1-2 Alkyl, -OC 1-2 Alkylene-OC 3-6 Carbocyclic group, -C 1-2 Alkylene-OC 1-2 Alkylene-OC 1-2 Alkyl, -C 1-2 Alkylene-OC 1-2 Alkylene-OC 3-6 Carbocyclic group, -OC 0-2 Alkylene-C 3-6 Carbocyclic group, -C 0-2 Alkylene-C 3-6 Carbocyclic group, -C 0-2 Alkylene-4 to 6 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, COOH, CN, NH2, NHC 1-4 Alkyl, N(C 1-4 alkyl)2,=O,C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy, halogen-substituted C 1-4 substituted by an alkoxy substituent, wherein the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N; B1 is selected from one of the following groups, substituted or unsubstituted: phenyl, naphthyl, thiophene, furan, pyrrole, pyrazole, imidazole, pyridine, 2-pyridone, pyrimidine, pyrazine, pyridazine, quinoline, isoquinoline, quinazoline, 3,4-dihydro-1H-benzopyran, 1,2,3,4-tetrahydroquinoline, benzofuran, benzothiophene, benzopyrrole, benzoxazole, benzothiazole, benzimidazole, benzopyrazole, morpholine, cyclobutylspirocyclobutyl, cyclobutylspiroazetidinyl, cyclopentylcyclopentyl, cyclopentylpyrrolidinyl, carbazole, and when substituted, 1 to 4 R b1 replace; Or B1 is selected from one of the following optionally substituted structures: When substituted, by 1 to 4 R b1 replace; Or B1 is selected from B 1A ; B2 is selected from one of the following groups, substituted or unsubstituted: phenyl, naphthyl, quinoline, pyrazole, pyridine, imidazole, triazole, thiazole, oxazole, isoxazole, thiophene, benzopyrrole, indole, benzimidazole, benzopyrazole, benzothiophene, benzothiazole, pyrazolotetrahydropyrrole, 3-pyridazinone, 2-pyridone, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, cyclobutylspirocyclobutyl, cyclobutylspiroazetidinyl, cyclopentylcyclopentyl, cyclopentylpyrrolidinyl, when substituted, by 1 to 4 R b2 replace; Or B2 is selected from one of the following optionally substituted structures: When substituted, by 1 to 4 R b2 replace; Or B2 is selected from B 2A ; B 1A 、B 2A Each is independently selected from one of the following optionally substituted structures: When replaced, B 1A 1 to 4 R b1 Replace, B 2A 1 to 4 R b2 replace; B3 is selected from one of the following groups, substituted or unsubstituted: oxetanyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, tetrahydrofuranyl, phenyl, pyridine, naphthyl, pyrazole, pyrrole, pyrrolidinyl, piperidine, piperazine, azacyclohexenyl, tetrahydropyranyl, imidazole, thiophene, thiazole, oxazole, isoxazole, triazole, 2-pyridone, benzopyrrole, benzopyrrolidine, benzothiophene, benzothiazole, benzopyrazole, benzimidazole, pyrazolotetrahydropyrrole, 3-pyridazinone, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, cyclobutylspirobutyl, cyclobutylspiroazetidinyl, cyclopentylcyclopentyl, cyclopentylpyrrolidinyl, cyclobutylspiropiperidinyl, when substituted, by 1 to 4 R b3 replace; Or B3 is selected from one of the following optionally substituted structures: When substituted, by 1 to 4 R b3 replace; V is selected from a bond, O, S, NR b5a NR b5a -C 1-4 Alkylene, C 1-4 Alkylene-NR b5a , OC 1-4 Alkylene, C 1-4 Alkylene-O, C 1-4 Alkylene, said alkylene being optionally substituted by 1 to 4 R b4 or R b5 replaced by; R b1 Each independently selected from F, Cl, Br, I, =O, =S, OH, NH2, CN, NO2, -C(=O)CH3, -C(=O)NH2, -C(=O)NH-CH3, -C(=O)N(CH3)2, -S(=O)2NH2, -P(=O)2(CH3)2, -S(=O)2CH3, -O-cyclopropyl, -O-cyclobutyl, -S-cyclopropyl, -S- cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -NH-cyclopropyl, -NH-cyclobutyl, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, pyrrole, pyrazole, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolane, oxhexyl, morpholine, pyrrolidinyl and cyclopentyl, azetidinyl spirocyclohexyl, Phenyl, the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, pyrrole, pyrazole, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolane, oxhexyl, morpholine, pyrrolidinyl and cyclopentyl, azetidinyl spirocyclohexyl, Phenyl is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, CN, CHF2, CF3, NH2, N(CH3)2, methyl, methoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl; R b3 Each is independently selected from F, Cl, Br, I, =O, =S, OH, NH2, N(CH3)2, NHCH3, CN, NO2, -C(=O)CH3, -C(=O)NH2, -C(=O)NH-CH3, -C(=O)N(CH3)2, -S(=O)2NH2, -P(=O)2(CH3)2, -S(=O)2CH3, -O-cyclopropyl, -O-cyclobutyl, -NH-cyclopropyl, -NH-cyclobutyl, -S-cyclopropyl, -S-cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-CH2-cyclopropyl, -O-CH2-cyclobutyl, -O-CH2CH2-methoxy, - O-CH2CH2-O-cyclopropyl, -O-CH2CH2-O-cyclobutyl, -CH2-O-CH2CH2-methoxy, -CH2-O-CH2CH2-O-cyclopropyl, -CH2-O-CH2CH2-O-cyclobutyl, -CH2-O-CH2CH2-NH-methyl, -CH2-methoxy, -CH2-ethoxy, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, pyrrole, pyrazole, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, oxhexyl, morpholine, pyrrolidinyl and cyclopentyl, azetidinyl spirocyclohexyl, Phenyl, the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, pyrrole, pyrazole, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolane, oxhexyl, morpholine, pyrrolidinyl and cyclopentyl, azetidinyl spirocyclohexyl, Phenyl is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, CN, CHF2, CF3, NH2, N(CH3)2, methyl, methoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl; R b2 each independently selected from H, F, Cl, Br, I, =O, =S, OH, NH2, NHCH3, N(CH3)2, CN, NO2, -C(=O)CH3, -C(=O)NH2, -C(=O)NH-CH3, -C(=O)N(CH3)2, -S(=O)2NH2, -P(=O)(CH3)2, -S(=O)2CH3 or one of the following groups that are optionally substituted: methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, triazolyl, azetidinyl, pyrrolidinyl, piperidinyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-morpholine, -CH2-pyrazole, -OCH2-cyclopropyl, -O-cyclopropyl, -O-cyclobutyl, -NH-cyclopropyl, -NH-cyclobutyl, -OCH2CH2-O-methyl, -OCH2CH2-O-cyclopropyl, -CH2OCH2CH2-O-methyl, -CH2OCH2CH2-O-cyclopropyl, -CH2OCH2CH2-NH-methyl, When substituted, it is replaced by 1 to 4 groups selected from F, Cl, Br, I, OH, CN, CHF2, CH2F, CF3, NH2, NHCH3, N(CH3)2, substituted by CH2OH, methyl, ethyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, pyrazolyl, or morpholinyl; Alternatively, R b1 With R b3 、R b2 With R b3 Either one directly connects to form C 5-7 Carbocyclyl, 5- to 7-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, I, OH, -NH2, CN, CH2F, CHF2, CF3, methyl, ethyl, methoxy or ethoxy, and the heterocyclyl contains 1 to 3 heteroatoms selected from O, S, and N; K is selected from one of the structural fragments shown in Table K-1.

7. The compound according to claim 6, or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein: Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from a bond or one of the following groups which are substituted or unsubstituted: When substituted, by 1 to 4 R L2 replace; R L2 Each is independently selected from F, Cl, Br, =O, COOH, CN, NHCH3, N(CH3)2, OH, NH2 or one of the following groups that are optionally substituted: methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, phenyl, morpholine, -CH2-cyclopropyl, -CH2-morpholine, -CH2-pyrazole, -OCH2-cyclopropyl, -O-cyclopropyl, -OCH2CH2-O-methyl, -OCH2CH2-O-cyclopropyl, -CH2OCH2CH2-O-methyl, -CH2OCH2CH2-O-cyclopropyl, when substituted, by 1 to 4 substituents selected from F, CHF2, CF3, OCHF2, OCF3, methyl, methoxy, =O, CH2OH, COOH, CN, NHCH3, N(CH3)2, OH, NH2; B is selected from one of the structural fragments shown in Table B-1, Table B-2 or Table B-3, the right side of which is connected to L, and b1 and b2 are each independently selected from 0, 1 or 2; K is selected from one of the structural fragments shown in Table K-2.

8. The compound according to claim 7, or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein: L is selected from a bond, -Ak1-, -Cy1-, -Cy1-Ak1-, -Cy1-Ak1-Ak2-, -Cy1-Ak1-Ak2-Ak3-, -Cy1-Ak1-Ak2-Ak3-Ak4-, -Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-Ak3-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Cy2-Ak2-Ak3-, -Cy1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Ak2-Cy3-, -Cy1-Ak1-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Cy1-Cy2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Cy3-Ak3-, -Cy1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Ak2-Cy3-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-Ak3-Ak4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-, -Cy1-Ak1-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak2-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-Ak4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-, -Ak1-Cy2-, -Ak1-Cy2-Cy3-, -Ak1-Ak2-Cy3-, -Ak1-Ak2-Cy3-Cy4-, -Ak1-Cy2-Ak2-Cy3-, -Ak1-Cy2-Cy3-Ak3-Cy4-, -Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-, -Ak1-Cy2-Ak2-, -Ak1-Ak2-Ak3-Ak4-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5--Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-、-Ak1-Cy2-Ak2-Ak3-Ak4-、-Ak1-Cy2-Ak2-Ak3-;、 Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from -O-, -OCH2-, -CH2O-, -OCH2CH2-, -CH2CH2O-, -CH=CH-, -CH=C(CN)-, -CH=C(F)-, -C(CN)=CH-, -C(F)=CH-, -C≡C-, -C(CH3)2-, -CH2-, -CH2CH2-, -CH2CH2CH2-, -N(CH3)-, -NH-, -CH2N(CH3)-, -CH2NH-, -NHCH2-, -CH2CH2N(CH3)-, -CH2CH2NH-, -NHCH2CH2-, -C(=O)-, -C(=O)CH2NH-, -CH2C(=O)NH-, -C(=O)NH- or -NHC(=O)-; V is selected from bonds, NH, NHC(CH3)2CH2, NHCH2C(CH3)2, CH2CH2, C(CH3)2CH2, CH2C(CH3)2, NHCH2CH2, NHCH2, OCH2, CH2NH, CH2O, N HC(CH3)2, OC(CH3)2, C(CH3)2NH, C(CH3)2O, N(CH3)CH2, N(CH3)C(CH3)2, C(CH3)2N(CH3), CH2N(CH3), N(CH3), O, S.

9. The compound according to claim 8, or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein: L is selected from a bond or one of the structural fragments shown in Table L-1, L-2 or L-3, wherein the left side of the group is connected to B.

10. The compound according to claim 1, or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein the compound is selected from one of the structures shown in Table E-1.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition comprises 1 to 1500 mg of the compound according to any one of claims 1 to 10 or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

12. Use of the compound according to any one of claims 1 to 10, or its stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, or the pharmaceutical composition according to claim 10, in the preparation of a medicament for treating a disease associated with the activity or expression of AR or an AR splice mutant.

13. Use of the compound according to any one of claims 1 to 10, or its stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, or the pharmaceutical composition according to claim 10, in the preparation of a medicament for treating a disease associated with the inhibition or degradation of AR or an AR splice mutant.

14. The use according to claim 12 or 13, characterized in that The disease is selected from prostate cancer.

15. A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 10, or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, wherein the therapeutically effective amount is preferably 1 to 1500 mg, and the disease is preferably a disease related to the activity or expression of AR or an AR splice mutant.