Compound for inhibiting or degrading Bcl6 and application of compound in medicine

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 and a pharmaceutical composition of the compound, and application of the compound in Bcl6 related diseases such as cancers. And B-L-K (I).

Description

A compound for inhibiting or degrading Bcl6 and its application in medicine 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 pharmaceutical compositions thereof, and their use in Bcl6-related diseases such as cancer. Background Art

[0002] Bcl6 is a transcriptional repressor that regulates the development and function of germinal center B cells. Overexpression of Bcl6 protein, driven by various factors including exon mutations, regulatory pathway mutations, somatic Bcl6 translocations, and promoter mutations, can lead to rapid proliferation of germinal center B cells, thereby promoting the development of B cell lymphomas. Furthermore, Bcl6 can inhibit cell cycle checkpoints, differentiation-related genes, and the DNA damage response. Preclinical studies have shown that loss of Bcl6 in lymphoma cells can lead to tumor progression arrest. Therefore, Bcl6 is a promising target for the treatment of various lymphomas.

[0003] 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.

[0004] Therefore, it is necessary to develop novel PROTAC drugs targeting Bcl6 proteins and E3 ubiquitin ligases for the treatment of Bcl6-related tumor diseases.

[0005] Summary of the Invention

[0006] 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 Bcl6, for the treatment of Bcl6-related diseases such as cancer.

[0007] The present invention provides a compound or its stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from the compound represented by general formula (I),

[0008] BLK(I);

[0009] In certain embodiments, the compound represented by general formula (I) is selected from the compound represented by general formula (II),

[0010] In certain embodiments, the compound represented by general formula (I) is selected from the compound represented by general formula (III),

[0011] In certain embodiments, L is selected from a bond or -C 1-50 Hydrocarbyl-, wherein 0 to 20 methylene units in the hydrocarbyl group are optionally further replaced by -Ak-, -Cy-;

[0012] In certain embodiments, L is selected from a bond or -C 1-20 Hydrocarbyl-, wherein 0 to 20 methylene units in the hydrocarbyl group are optionally further replaced by -Ak-, -Cy-;

[0013] In certain embodiments, L is selected from a bond or -C 1-10 Hydrocarbyl-, wherein 0 to 10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) methylene units are optionally further replaced by -Ak-, -Cy-;

[0014] In certain embodiments, each -Ak- is independently selected from Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, or Ak9;

[0015] In certain embodiments, each -Ak- is independently selected from -(CH2) q -、-(CH2) q -O-, -O-(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)(RL )-, -S-, -S(=O)-, -S(=O)2- or a bond, wherein the -CH2- is optionally replaced 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, Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, and Ak9 are each independently selected from -(CH2) q -、-(CH2) q -O-, -O-(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 -、-(C≡C) q - or bond, wherein the -CH2- is optionally replaced by 1 to 2 groups 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;

[0017] In certain embodiments, Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, and Ak9 are each independently selected from -(CH2) q -、-(CH2) q -O-, -O-(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 -、-(C≡C) q - or bond, wherein the -CH2- is optionally replaced by 1 to 2 groups selected from F, Cl, Br, I, OH, CN, NH2, CF3, hydroxymethyl, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0018] In certain embodiments, Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, and Ak9 are each independently selected from -(CH2) q -、-(CH2) q -O-, -O-(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 -、-(C≡C) q - or a bond, wherein the -CH2- is optionally substituted by 1 to 2 substituents selected from F, Cl, Br, I, OH, CN, NH2, CF3, hydroxymethyl, methyl, ethyl, methoxy or ethoxy;

[0019] In certain embodiments, Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, Ak9 are each independently selected from a bond, -O-, -OCH2-, -CH2O-, -OCH2CH2-, -CH2CH2O-, -C≡C-, -C(CH3)2-, -CF2-, -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)-;

[0020] In certain embodiments, Ak1 is selected from -CH2-, -O-, -CH2-CH2-;

[0021] 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;

[0022] In certain embodiments, R L Each independently selected from H or C 1-6 alkyl;

[0023] In certain embodiments, R L Each independently selected from H or C 1-4 alkyl;

[0024] In certain embodiments, R L Selected from H, methyl or ethyl;

[0025] In certain embodiments, each q is independently selected from 0, 1, 2, 3, 4, 5, or 6;

[0026] In certain embodiments, q is each independently selected from 0, 1, 2, 3, or 4;

[0027] In certain embodiments, q is each independently selected from 0, 1, 2, or 3;

[0028] In certain embodiments, each -Cy- is independently selected from Cy1, Cy2, Cy3, Cy4, or Cy5;

[0029] In certain embodiments, each -Cy- is independently selected from a bond, a 4-8 membered heteromonocyclic ring, a 4-10 membered heterocyclic ring, a 5-12 membered heterospirocyclic ring, a 7-10 membered heterobridged ring, a C 3-7 Monocyclic alkyl, C 4-10 Cycloalkyl, C 5-12 Spiroalkyl, C 7-10 Bridged cycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl, wherein the aryl, heteroaryl, cycloalkyl, heteromonocyclic, heterocyclic, heterospirocyclic or heterobridged ring is optionally substituted by 1 to 2 groups selected from halogen, 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 heteroaryl, heteromonocyclic, heterocyclic, heterospirocyclic or heterobridged ring 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;

[0030] In certain embodiments, Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from a bond, a 4-7 membered heteromonocyclic ring, a 4-10 membered heterocyclic ring, a 5-12 membered heterospirocyclic ring, a 7-10 membered heterobridged ring, a C 3-7 Monocyclic alkyl, C 4-10 Cycloalkyl, C 5-12 Membered spirocycloalkyl, C 7-10 cycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl, wherein the aryl, heteroaryl, cycloalkyl, heteromonocyclic, heterocyclic, heterospirocyclic or heterobridged ring is optionally substituted by 1 to 2 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 heteroaryl, heteromonocyclic, heterocyclic, heterospirocyclic or heterobridged ring 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;

[0031] In certain embodiments, Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from a bond, a 4-7 membered nitrogen-containing heteromonocycle, a 4-10 membered nitrogen-containing heterocyclic ring, a 5-12 membered nitrogen-containing heterospirocycle, a 7-10 membered nitrogen-containing heterobridged ring, a C 3-7 Monocyclic alkyl, C 4-10 Cycloalkyl, C 5-12 Spiroalkyl, C 7-10 Bridged cycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl, wherein the heteromonocyclic, heterocyclic, heterobridged, heterospirocyclic, cycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 2 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, heterocyclic, heterobridged, heterospirocyclic 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;

[0032] In certain embodiments, Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from a bond or a substituted or unsubstituted one of the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azacyclohexenyl, piperidinyl, morpholinyl, piperazinyl, 1,4-diazepanyl, phenyl, pyridinyl, cyclopropylcyclopropyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, cyclopropylcyclohexyl, cyclobutylcyclobutyl, cyclobutylcyclopentyl, cyclobutylcyclohexyl , 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, cyclobutyl and piperidinyl, cyclopentyl and azetidinyl, cyclopentyl pyrrolidinyl, cyclopentylpiperidinyl, cyclohexylazetidinyl, cyclohexylpyrrolidinyl, cyclohexylpiperidinyl, azetidinylazetidinyl, azetidinylpyrrolidinyl, azetidinylpiperidinyl, pyrrolidinylazetidinyl, pyrrolidinylpyrrolidinyl, pyrrolidinylpiperidinyl, piperidinylazetidinyl, piperidinylpyrrolidinyl, piperidinylpiperidinyl, cyclopropylspiroazetidinyl, cyclopropylspiropyrrolidinyl, cyclopropylspiropiperidinyl, cyclopropylspiropiperazinyl, cyclobutylspiroazetidinyl cyclobutyl, 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 spiropyrrolidinyl, piperidinyl spiropiperidinyl, cyclopropyl spiropiperazinyl, When substituted, it is optionally replaced by 1 to 4 groups 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;

[0033] 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, it is substituted with 1 to 4 substituents selected from F, CF3, OH, methyl, =O, hydroxymethyl, COOH, CN or NH2;

[0034] In certain embodiments, Cy1, Cy2, or Cy3 are each independently selected from a bond or one of the following groups, which may be substituted or unsubstituted: When substituted, it is substituted with 1 to 4 substituents selected from F, CF3, OH, methyl, =O, hydroxymethyl, COOH, CN or NH2;

[0035] In certain embodiments, Cy1 or Cy2 are each independently selected from one of the following groups, which are substituted or unsubstituted: When substituted, it is substituted with 1 to 4 substituents selected from F, CF3, OH, methyl, =O, hydroxymethyl, COOH, CN or NH2;

[0036] 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 -Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-A k3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy 3-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-Cy 4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy 3-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-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-、-Ak1-、-Ak1-Ak2-、-Ak1-Ak2-Ak3-、-Ak1-Ak2-Ak3-Ak4-、-Ak1-Ak2-Ak3-Ak4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9;、

[0037] In certain embodiments, L is selected from a bond, -Ak1-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-Ak3-Ak4-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-, -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-、-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-;

[0038] In certain embodiments, L is selected from -Cy1-Ak1-, -Cy1-Ak1-Ak2-, -Cy1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Ak1-Cy2-, -Cy1-Ak1-Cy2-Ak2-, -Cy1-Cy2-Cy3-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Ak1-Cy2-Cy3-;

[0039] In certain embodiments, L is selected from a bond or a group shown in Table L-1, wherein the left side of the group is connected to B;

[0040] In certain embodiments, L is selected from a bond or a group shown in Table L-2, wherein the left side of the group is connected to B;

[0041] Table L-1 L Group

[0042] Table L-2 L Group

[0043] In certain embodiments, L is selected from L1 or L2;

[0044] In certain embodiments, L1 is selected from -Cy1-, -Cy1-Cy2-, -Cy1-Ak1-, -Cy1-Ak1-Cy2-, -Cy1-Ak1-Cy2-Cy3-;

[0045] In certain embodiments, L2 is selected from -Cy1-, -Cy1-Ak1-, or -Cy1-Ak1-Cy2-;

[0046] In certain embodiments, L1 is selected from

[0047] In certain embodiments, L2 is selected from

[0048] In certain embodiments, B is selected from

[0049] In certain embodiments, B is selected from

[0050] In certain embodiments, X is selected from O, S, or CH2;

[0051] In certain embodiments, X is selected from O or S;

[0052] In certain embodiments, Y is selected from NR Y or O;

[0053] In certain embodiments, Y is selected from NH or O;

[0054] In certain embodiments, R Y Selected from H, C 1-6 Alkyl, C 3-10 Carbocyclic or 3 to 10 membered heterocyclic ring, wherein the alkyl, carbocyclic or heterocyclic ring is optionally substituted by 1 to 3 groups selected from halogen, OH, cyano, NH2, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 is substituted by a carbocyclic or 3- to 8-membered heterocyclic substituent, wherein the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;

[0055] In certain embodiments, in certain embodiments, R Y Selected from H, C 1-4 Alkyl, C 3-6 Carbocyclic or 3 to 6 membered heterocyclic rings, wherein the alkyl, carbocyclic or heterocyclic rings are optionally substituted by 1 to 3 groups selected from halogen, OH, cyano, NH2, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 is substituted by a carbocyclic or 3- to 8-membered heterocyclic substituent, wherein the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;

[0056] In certain embodiments, R Y Selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl is optionally substituted by 1 to 3 selected from halogen, OH, cyano, NH2, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4Alkyl, C 1-4 Alkoxy, C 3-6 is substituted by a carbocyclic or 3- to 6-membered heterocyclic substituent, wherein the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;

[0057] In certain embodiments, R Y Selected from H;

[0058] In certain embodiments, R 1 Selected from H, OH, -(CH2) t2 NR 1a R 1b 、C 1-6 Alkyl, C 1-6 Alkoxy, wherein the alkyl or alkoxy is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0059] In certain embodiments, R 1 Selected from H, OH, -(CH2) t2 NR 1a R 1b 、C 1-4 Alkyl, C 1-4 Alkoxy, wherein the alkyl or alkoxy is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0060] In certain embodiments, R 1 Selected from H, OH, NR 1a R 1b , methyl, ethyl, propyl, isopropyl, methoxy, wherein the methyl, ethyl, propyl, isopropyl, methoxy is optionally substituted by 1 to 3 groups selected from halogen, OH, cyano, NH2, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0061] In certain embodiments, R 1 Selected from H, OH, NR1a R 1b , methyl, ethyl, propyl, isopropyl, methoxy, wherein the methyl, ethyl, propyl, isopropyl, methoxy is optionally substituted by 1 to 3 substituents selected from F, Cl, Br, I, OH, cyano, NH2, methyl, ethyl, CF3;

[0062] In certain embodiments, R 1 is selected from H, OH, NH2, NH(CH3), N(CH3)2, NH(CH2CH3), N(CH2CH3)2, methyl, ethyl, propyl, isopropyl; in certain embodiments, R 1a 、R 1b Each independently selected from H, OH, NH2, C 1-4 Alkyl, C 2-6 Alkynyl, C 1-4 Alkoxy, the alkyl, alkynyl, alkoxy is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 substituted by a substituent of the alkynyl group;

[0063] In certain embodiments, R 1a 、R 1b The atoms to which it is connected together form a 3-10 membered ring;

[0064] In certain embodiments, R 1a 、R 1b Each independently selected from H, OH, NH2, methyl, ethyl, propyl, isopropyl, methoxy, propargyl, propynyl, said methyl, ethyl, propyl, isopropyl, methoxy, propargyl, propynyl optionally substituted by 1 to 3 selected from halogen, OH, cyano, NH2, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkynyl, substituted by a substituent;

[0065] In certain embodiments, R 1a 、R 1bEach is independently selected from H, OH, NH2, methyl, ethyl, propyl, isopropyl, methoxy, propargyl, and propynyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, propargyl, and propynyl are optionally substituted with 1 to 3 substituents selected from F, Cl, Br, I, OH, cyano, NH2, methyl, ethyl, methoxy, ethynyl, and CF3;

[0066] In certain embodiments, R 3a or R 4 Each independently selected from H, OH, NH2, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 Carbocyclic or 3 to 10 membered heterocyclic rings, wherein the alkyl, alkoxy, alkynyl, carbocyclic or heterocyclic rings are optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH(CH3), N(CH3)2, NH(CH2CH3), N(CH2CH3)2, NH2, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkynyl, C 3-6 Cycloalkyloxy, C 3-6 is substituted by a carbocyclic or 3- to 8-membered heterocyclic substituent, wherein the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;

[0067] In certain embodiments, R 3a or R 4 Each independently selected from H, OH, NH2, methyl, ethyl, propyl, propargyl, propynyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, propargyl, propynyl is optionally substituted by 1 to 3 selected from halogen, OH, cyano, NH2, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyloxy, C 2-4 Alkynyl, C 3-6 is substituted by a carbocyclic or 3- to 6-membered heterocyclic substituent, wherein the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;

[0068] In certain embodiments, R3a is selected from H, OH, NH2, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, propargyl, propynyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, propargyl, propynyl is optionally substituted with 1 to 3 substituents selected from F, Cl, Br, I, OH, cyano, NH2, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethynyl, methoxy, cyclopropyloxy; in certain embodiments, R 4 Each is independently selected from H, methyl, ethyl, and cyclopropyl;

[0069] In certain embodiments, R 3b or R 5 Each independently selected from H, halogen, cyano, NH2, NO2, OH, C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-6 Alkoxy, C 3-10 Carbocyclic or 3 to 10 membered heterocyclic ring, wherein the alkyl, alkoxy, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 is substituted by a carbocyclic or 3- to 8-membered heterocyclic substituent, wherein the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;

[0070] In certain embodiments, R 3b or R 5 Each independently selected from H, halogen, cyano, NH2, NO2, OH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Carbocyclic or 3 to 6 membered heterocyclic rings, wherein the alkyl, alkoxy, carbocyclic or heterocyclic rings are optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 is substituted by a carbocyclic or 3- to 6-membered heterocyclic substituent, wherein the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;

[0071] In certain embodiments, R 3b or R 5 Each independently selected from H, F, Cl, Br, I, cyano, NH2, OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, ethynyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, ethynyl is optionally substituted by 1 to 3 halogen, OH, cyano, NH2, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 is substituted by a carbocyclic or 3- to 6-membered heterocyclic substituent, wherein the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;

[0072] In certain embodiments, R 3b or R 5 Each independently selected from H, F, Cl, Br, I, cyano, NH2, OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl is optionally substituted by 1 to 3 selected from halogen, OH, cyano, NH2, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 is substituted by a carbocyclic or 3- to 6-membered heterocyclic substituent, wherein the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;

[0073] In certain embodiments, R 3b Each is independently selected from H, F, Cl, Br, I, OH, CN, methoxy, methyl, ethyl, and cyclopropyl;

[0074] In certain embodiments, R 3b Each is independently selected from H, F, Cl, Br, I, OH, methyl, ethyl, cyclopropyl;

[0075] In certain embodiments, R 5 Each independently selected from H, F, Cl, Br, I, cyano, NH2, OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, and ethynyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, and ethynyl are optionally substituted with 1 to 3 substituents selected from F, Cl, Br, I, OH, cyano, NH2, methyl, ethyl, and cyclopropyl;

[0076] In certain embodiments, R 5 Each independently selected from H, F, Cl, Br, I, cyano, NH2, OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, and cyclopropyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, and cyclopropyl are optionally substituted with 1 to 3 substituents selected from F, Cl, Br, I, OH, cyano, NH2, methyl, ethyl, and cyclopropyl;

[0077] In certain embodiments, t1 is selected from 1, 2, 3, 4, or 5; in certain embodiments, t1 is selected from 1, 2, or 3; in certain embodiments, t1 is selected from 1;

[0078] In certain embodiments, t2 is selected from 0, 1, 2, 3, 4, or 5; in certain embodiments, t2 is selected from 0, 1, 2, 3; in certain embodiments, t2 is selected from 0;

[0079] In certain embodiments, m is selected from 0, 1, 2, 3, or 4; In certain embodiments, m is selected from 0, 1, 2, or 3;

[0080] In certain embodiments, m is selected from 0 or 1;

[0081] In certain embodiments, n is selected from 0, 1, or 2; in certain embodiments, n is selected from 0 or 1;

[0082] In certain embodiments, B is selected from one of the structural fragments shown in Table B-1;

[0083] Table B-1

[0084] In some embodiments, B is selected from

[0085] In certain embodiments, K is selected from

[0086] In certain embodiments, each F1 is independently selected from C3-7 Monocyclic carbocyclic ring, C 4-14 Ring carbon ring, C 5-12 Spirocarbon ring, C 5-10 Bridged carbon ring, C 6-14 Aryl, 6-7 membered non-aromatic monocyclic ring, 5-14 membered hetero-bridged ring, 5-6 membered heteroaryl, 11-20 membered heterocyclic ring, phthalazine-1(2H)-one, benzo[d][1,2,3]triazine-4(3H)-one, benzothiophene, The heteromonocyclic, heterocyclic, heterospirocyclic, heterobridged or heteroaromatic ring contains 1 to 4 heteroatoms selected from O, S and N, provided that when F1 is selected from a 6-membered heteroaryl group, the right side connection site on the ring is a carbon atom;

[0087] In certain embodiments, represents a ring selected from an aromatic ring or a non-aromatic ring;

[0088] In certain embodiments, each of F1 is independently selected from cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, phenyl, naphthyl, pyridinyl, pyrazinyl, pyridazinyl, pyridazinonyl, pyrimidinyl, phthalazin-1(2H)-onyl, benzo[d][1,2,3]triazin-4(3H)-onyl, thienyl, benzothienyl, triazolyl,

[0089] is selected from a single bond or a double bond;

[0090] In certain embodiments, each of F1 is independently selected from cyclohexyl, piperidinyl, piperazinyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridazinonyl, phthalazin-1(2H)-onyl, benzo[d][1,2,3]triazin-4(3H)-onyl, thienyl, triazolyl,

[0091] In certain embodiments, F1 is selected from phenyl, 5-6 membered heteroaryl or 13-14 membered heterotricyclic ring;

[0092] In certain embodiments, F1 is selected from a 13-14 membered heterotricyclic ring;

[0093] In certain embodiments, F1 is selected from phenyl, pyrrolyl, pyrazolyl, triazolyl, pyridinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, triazinyl,

[0094] In certain embodiments, F1 is selected from

[0095] In certain embodiments, F1 is selected from phenyl;

[0096] In certain embodiments, F1 is selected from

[0097] In certain embodiments, each F2 is independently selected from C 3-7 Monocyclic non-aromatic carbocyclic ring, C 4-10 Non-aromatic carbon ring, C 5-12 Spirocarbon ring, C 5-10 Bridged carbon ring, C 12-14 Aryl, 4-7 membered non-aromatic monocyclic ring, 5-14 membered heterospirocyclic ring, 5-14 membered heterobridged ring, 11-20 membered heterocyclic ring, The heteromonocyclic, heterocyclic, heterospirocyclic, heterobridged or heteroaromatic ring contains 1 to 4 heteroatoms selected from O, S, and N; in certain embodiments, F2 is independently selected from In certain embodiments, each F2 is independently selected from

[0098] In certain embodiments, each of E1 is independently selected from an 8-15 membered heterocyclic ring; in certain embodiments, each of E1 is independently selected from

[0099] In certain embodiments, E2 is each independently selected from a benzene ring or a 5-6 membered heteroaryl ring;

[0100] In certain embodiments, E2 is each independently selected from a benzene ring, a pyridine ring, a pyrimidine ring, a thiazole ring, a thiophene ring, a furan ring;

[0101] In certain embodiments, each F is independently selected from C 3-7 Monocyclic carbocyclic ring, C 4-20 Ring carbon ring, C 5-20 Spirocarbon ring, C 5-20 Bridged carbocyclic ring, 4-7 membered heteromonocyclic ring, 4-20 membered heterocyclic ring, 5-20 membered heterospirocyclic ring, 5-20 membered heterobridged ring, wherein the heteromonocyclic ring, heterocyclic ring, heterospirocyclic ring, heterobridged ring or heteroaromatic ring contains 1 to 4 heteroatoms selected from O, S and N;

[0102] In certain embodiments, each F is independently selected from cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, 2-pyridonyl, pyrazolyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, benzothiazolyl, indolyl,

[0103] In certain embodiments, each F is independently selected from cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, 2-pyridonyl, pyrazolyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, benzothiazolyl, indolyl,

[0104] In certain embodiments, each E is independently selected from C 5-12 Carbocyclic ring, 5-12 membered heterocyclic ring, 5-12 membered heteroaromatic ring, wherein the heterocyclic ring or heteroaromatic ring contains 1 to 4 heteroatoms selected from O, S or N;

[0105] In certain embodiments, each E is independently selected from C 3-10 Carbocyclic ring, benzene ring, 4-12 membered heterocyclic ring, 5-12 membered heteroaromatic ring, wherein the heterocyclic ring or heteroaromatic ring contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, and N;

[0106] In certain embodiments, E is independently selected from a benzene ring, a naphthalene ring, a 5-6 membered heteroaromatic ring, wherein the heterocyclic ring or heteroaromatic ring contains 1 to 3 (e.g., 1, 2, 3) heteroatoms selected from O, S, and N;

[0107] In certain embodiments, each E is independently selected from a benzene ring, a naphthalene ring, a pyridine ring, a pyridazine ring, a pyrazine ring, a pyrimidine ring, a pyrrole ring, a pyrazole ring, an imidazole ring, a thiazole ring, a furan ring, a thiophene ring, an oxazole ring, an indoline ring, an isoindoline ring, a 1,2,3,4-tetrahydroquinoline ring, or a 1,2,3,4-tetrahydroisoquinoline ring;

[0108] In certain embodiments, E is each independently selected from a benzene ring, a naphthalene ring, a pyridine ring, a pyridazine ring, a pyrazine ring, a pyrimidine ring, a pyrrole ring, a pyrazole ring, an imidazole ring, a thiazole ring, a furan ring, a thiophene ring, or an oxazole ring;

[0109] In certain embodiments, E is each independently selected from a benzene ring, a naphthalene ring, a pyridine ring, a pyridazine ring, a pyrazine ring, a pyrimidine ring;

[0110] In certain embodiments, each E is independently selected from a benzene ring, a naphthalene ring, or a pyridine ring;

[0111] In certain embodiments, A is selected from C 3-10 Carbon ring, C 6-10 an aromatic ring, a 3-10 membered heterocyclic ring or a 5-10 membered heteroaromatic ring, wherein the heterocyclic ring or heteroaromatic ring contains 1 to 4 (e.g., 1, 2, 3 or 4) heteroatoms selected from O, S, and N;

[0112] In certain embodiments, A is selected from C 3-8a carbocyclic ring, a benzene ring, a naphthalene ring, a 4-7 membered heterocyclic ring or a 5-6 membered heteroaromatic ring, wherein the heterocyclic ring or heteroaromatic ring contains 1 to 4 (e.g., 1, 2, 3 or 4) heteroatoms selected from O, S and N;

[0113] In certain embodiments, A is selected from a benzene ring, a naphthalene ring, a pyridine ring, a pyridazine ring, a pyrazine ring, a pyrimidine ring, a pyrrole ring, a pyrazole ring, an imidazole ring, a thiazole ring, a furan ring, a thiophene ring, or an oxazole ring;

[0114] In certain embodiments, A is selected from a benzene ring, a naphthalene ring, or a pyridine ring;

[0115] In certain embodiments, each Q is independently selected from a bond, -O-, -S-, -CH2-, -NR q -、-CO-、-NR q CO-、-CONR 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 ring is substituted by an alkoxy substituent, wherein the heterocyclic ring contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, and N;

[0116] In certain embodiments, each Q is independently selected from a bond, -O-, -S-, -CH2-, -NR q -、-CO-、-NR q CO-、-CONR 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 ring is substituted by an alkoxy substituent, wherein the heterocyclic ring contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, and N;

[0117] In certain embodiments, each Q is independently 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),

[0118] In certain embodiments, Q1 is selected from -O-, -S-, -CH2-, NH, N(CH3) or -CO-;

[0119] In certain embodiments, R q Selected from H or C 1-6 Alkyl; in certain embodiments, Rq Selected from H or C 1-4 alkyl;

[0120] In certain embodiments, R q Selected from H, methyl, ethyl;

[0121] In certain embodiments, R k1 Each independently selected from H, D, F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, R k7a The alkyl, alkoxy, and cycloalkyl groups are optionally substituted by 1 to 4 (e.g., 1, 2, 3, or 4) groups selected from D, F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 , C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 substituted by a cycloalkyl substituent;

[0122] In certain embodiments, R k1 Selected from R k7a ;

[0123] In certain embodiments, R k3 Each independently selected from H, D, 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 D, 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;

[0124] In certain embodiments, R k1 、R k3 Each independently selected from H, D, F, Cl, Br, I, OH, =O, NH2, CF3, CN, COOH, CONH2, C 1-4 Alkyl or C 1-4 Alkoxy, R k7a , the alkyl or alkoxy group is optionally substituted by 1 to 4 substituents selected from D, F, Cl, Br, I, OH or NH2;

[0125] R k1、R k3 Each is independently selected from H, D, F, Cl, Br, I, OH, =O, NH2, CF3, CN, COOH, CONH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, ethynyl, cyclopropyl, azetidinyl, said methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, ethynyl, cyclopropyl, azetidinyl being optionally substituted with 1 to 4 substituents selected from D, F, Cl, Br, I, OH, NH2, CN, cyclopropyl, methoxy;

[0126] In certain embodiments, R k1 、R k3 Each independently selected from H, D, 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 D, F, Cl, Br, I, OH, NH2;

[0127] In certain embodiments, R k1 、R k3 each independently selected from H, D, 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 D, F, Cl, Br, I, OH, NH 2 ;

[0128] In certain embodiments, R k1 Each is independently selected from H, D, F, Cl, Br, I, OH, =O, NH2, CF3, CN, COOH, CONH2, methyl, ethyl, methoxy, ethoxy;

[0129] In certain embodiments, R k1 Each independently selected from H, D, F, Cl, Br;

[0130] In certain embodiments, both R k3 Together with the carbon atoms or ring skeletons directly connected to the two, they form C 3-8 Carbocyclic or 3-8 membered heterocyclic ring, or two R k1 Together with the carbon atoms or ring skeletons directly connected to the two, they form C 3-8 A carbocyclic ring or a 3-8 membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 (e.g., 1, 2, 3, 4) rings selected from F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C1-4 Alkyl or C 1-4 The heterocyclic ring is substituted by an alkoxy substituent, wherein the heterocyclic ring contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, and N;

[0131] In certain embodiments, either two R k3 Together with the carbon atoms or ring skeletons directly connected to the two, they form C 3-7 Carbocyclic or 3-7 membered heterocyclic ring, or two R k1 Together with the carbon atoms or ring skeletons directly connected to the two, they form C 3-7 Carbocyclic or 3-7 membered heterocyclic ring, wherein the carbocyclic or 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 The heterocyclic ring is substituted by an alkoxy substituent, and the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N;

[0132] In certain embodiments, both R k3 Together with the carbon atoms or ring skeletons directly connected to the two, they form C 3-6 Carbocyclic or 3-7 membered heterocyclic ring, or two R k1 Together with the carbon atoms or ring skeletons directly connected to the two, they form C 3-6 A carbocyclic ring or a 3-7 membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 (e.g., 1, 2, 3, 4) rings selected from F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl or C 1-4 The heterocyclic ring is substituted by an alkoxy substituent, wherein the heterocyclic ring contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, and N;

[0133] In certain embodiments, R k4 Each independently selected from H, 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;

[0134] In certain embodiments, R k4 Each independently selected from H, C 1-4 alkyl;

[0135] In certain embodiments, Rk4 Each independently selected from H, methyl, ethyl or propyl;

[0136] In certain embodiments, R k5 Each independently selected from C(CH3)2, CO, CH2, SO2, In certain embodiments, R k5 Each independently selected from CO, CH2, SO2 or

[0137] In certain embodiments, R k6 Each independently selected from CO, CH, SO, SO2, CH2, N or NR k7a ;

[0138] In certain embodiments, R k7 Each independently selected from C(CH3)2,CO,CH,N,CH2,O,S,NR k7a ;

[0139] 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;

[0140] In certain embodiments, R k7 Each is independently selected from CO, CH, N, CH2, O, S, N(CH3) or NH;

[0141] In certain embodiments, R k7 are each independently selected from CH2, O, N(CH3) or NH;

[0142] 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;

[0143] In certain embodiments, R k7aSelected 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;

[0144] In certain embodiments, R k7a Selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 substituted by a cycloalkyl substituent;

[0145] 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;

[0146] In certain embodiments, R k7a Selected from H, methyl, ethyl, isopropyl, cyclopropyl, oxetanyl, tetrahydropyranyl, -CH2CF3, -CH(CH3)CF3, -CH(CH3)-cyclopropyl, -CH2-cyclopropyl, -CH2-vinyl, -CH2-ethynyl, -CH2CH2-methoxy;

[0147] In certain embodiments, R k7a is selected from H, CF3, methyl, ethyl, cyclopropyl, -CH2-cyclopropyl;

[0148] In certain embodiments, R k7ais selected from H, CH3, CH2CH3, cyclopropyl;

[0149] In certain embodiments, R k8 are each independently selected from C, N or CH;

[0150] In certain embodiments, R k9 are each independently selected from a bond, C(CH3)2, CO, CH2, CH2CH2 or SO2;

[0151] In certain embodiments, R k9 Each independently selected from CO, SO2 or CH2;

[0152] In certain embodiments, R ka Selected from O, S or NH;

[0153] In certain embodiments, R kb Selected from a bond or CO;

[0154] In certain embodiments, R k10 Selected from CH2 or CO;

[0155] In certain embodiments, R k11 Selected from NH, O or CH2;

[0156] In certain embodiments, p1 or p2 are each independently selected from 0, 1, 2, 3, 4, or 5;

[0157] In certain embodiments, p1 or p2 are each independently selected from 0, 1, 2 or 3;

[0158] In certain embodiments, p1 is selected from 0, 1 or 2;

[0159] In certain embodiments, K is selected from one of the structural fragments shown in Table K-1;

[0160] In certain embodiments, K is selected from one of the structural fragments shown in Table K-2;

[0161] In certain embodiments, the compound is substituted with 1-30 D (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 D);

[0162] In certain embodiments, the compound is substituted with 1 to 20 D (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 D);

[0163] In certain embodiments, the compound is substituted with 1 to 15 D (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 D);

[0164] Table K-1

[0165] Table K-2

[0166] As a first embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0167] 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-;

[0168] Each -Ak- is independently selected from -(CH2) q -、-(CH2) q -O-, -O-(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- is optionally replaced by 1 to 2 groups selected from halogen, OH, CN, NH2, C 1-6Alkyl, 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;

[0169] q is each independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0170] 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;

[0171] Each -Cy- is independently selected from a bond, a 4-8 membered heteromonocyclic ring, a 4-10 membered heterocyclic ring, a 5-12 membered heterospirocyclic ring, a 7-10 membered heterobridged ring, a C 3-7 Monocyclic alkyl, C 4-10 Cycloalkyl, C 5-12 Spiroalkyl, C 7-10 Bridged cycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl, wherein the aryl, heteroaryl, cycloalkyl, heteromonocyclic, heterocyclic, heterospirocyclic or heterobridged ring is optionally substituted by 1 to 2 groups selected from halogen, 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 heteroaryl, heteromonocyclic, heterocyclic, heterospirocyclic or heterobridged ring 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;

[0172] B is selected from

[0173] X is selected from O, S or CH2;

[0174] Y is selected from NR Y or O;

[0175] R Y Selected from H, C 1-6 Alkyl, C 3-10 Carbocyclic or 3 to 10 membered heterocyclic ring, wherein the alkyl, carbocyclic or heterocyclic ring is optionally substituted by 1 to 3 groups selected from halogen, OH, cyano, NH2, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6is substituted by a carbocyclic or 3- to 8-membered heterocyclic substituent, wherein the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;

[0176] R 1 Selected from H, OH, -(CH2) t2 NR 1a R 1b 、C 1-6 Alkyl, C 1-6 Alkoxy, the alkyl, alkoxy is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0177] R 1a 、R 1b Each independently selected from H, OH, NH2, C 1-4 Alkyl, C 2-6 Alkynyl, C 1-4 Alkoxy, the alkyl, alkynyl, alkoxy is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 substituted by a substituent of the alkynyl group;

[0178] or R 1a 、R 1b The atoms to which it is connected together form a 3-10 membered ring;

[0179] R 3a or R 4 Each independently selected from H, OH, NH2, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 Carbocyclic or 3 to 10 membered heterocyclic rings, wherein the alkyl, alkoxy, alkynyl, carbocyclic or heterocyclic rings are optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH(CH3), N(CH3)2, NH(CH2CH3), N(CH2CH3)2, NH2, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 1-6 Alkoxy, C2-6 Alkynyl, C 3-6 Cycloalkyloxy, C 3-6 is substituted by a carbocyclic or 3- to 8-membered heterocyclic substituent, wherein the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;

[0180] R 3b or R 5 Each independently selected from H, halogen, cyano, NH2, NO2, OH, C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-6 Alkoxy, C 3-10 Carbocyclic or 3 to 10 membered heterocyclic ring, wherein the alkyl, alkoxy, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 is substituted by a carbocyclic or 3- to 8-membered heterocyclic substituent, wherein the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;

[0181] t1 is selected from 1, 2, 3, 4 or 5;

[0182] t2 is selected from 0, 1, 2, 3, 4 or 5;

[0183] m is selected from 0, 1, 2, 3 or 4;

[0184] n is selected from 0, 1 or 2;

[0185] K is selected from

[0186] F1 is each independently selected from C 3-7 Monocyclic carbocyclic ring, C 4-14 Ring carbon ring, C 5-12 Spirocarbon ring, C 5-10 Bridged carbon ring, C 6-14 Aryl, 6-7 membered non-aromatic monocyclic ring, 5-14 membered hetero-bridged ring, 5-6 membered heteroaryl, 11-20 membered heterocyclic ring, phthalazine-1(2H)-one, benzo[d][1,2,3]triazine-4(3H)-one, benzothiophene, The heteromonocyclic, heterocyclic, heterospirocyclic, heterobridged or heteroaromatic ring contains 1 to 4 heteroatoms selected from O, S and N, provided that when F1 is selected from a 6-membered heteroaryl group, the right side connection site on the ring is a carbon atom;

[0187] E are each independently selected from C 5-12 Carbocyclic ring, 5-12 membered heterocyclic ring, 5-12 membered heteroaromatic ring, wherein the heterocyclic ring or heteroaromatic ring contains 1 to 4 heteroatoms selected from O, S or N;

[0188] F2 are each independently selected from C 3-7 Monocyclic non-aromatic carbocyclic ring, C 4-10 Non-aromatic carbon ring, C 5-12 Spirocarbon ring, C 5-10 Bridged carbon ring, C 12-14 Aryl, 4-7 membered non-aromatic monocyclic ring, 5-14 membered heterospirocyclic ring, 5-14 membered heterobridged ring, 11-20 membered heterocyclic ring, The heteromonocyclic, heterocyclic, heterospirocyclic, heterobridged or heteroaromatic ring contains 1 to 4 heteroatoms selected from O, S and N;

[0189] represents a ring selected from an aromatic ring or a non-aromatic ring;

[0190] F are each independently selected from C 3-7 Monocyclic carbocyclic ring, C 4-20 Ring carbon ring, C 5-20 Spirocarbon ring, C 5-20 Bridged carbocyclic ring, 4-7 membered heteromonocyclic ring, 4-20 membered heterocyclic ring, 5-20 membered heterospirocyclic ring, 5-20 membered heterobridged ring, wherein the heteromonocyclic ring, heterocyclic ring, heterospirocyclic ring, heterobridged ring or heteroaromatic ring contains 1 to 4 heteroatoms selected from O, S and N;

[0191] A is selected from C 3-8 a carbocyclic ring, a benzene ring, a 4-7 membered heterocyclic ring or a 5-6 membered heteroaromatic ring, wherein the heterocyclic ring or heteroaromatic ring contains 1 to 4 heteroatoms selected from O, S or N;

[0192] Q1 is independently selected from -O-, -S-, -CH2-, -NR q -or-CO-;

[0193] Q is independently selected from a bond, -O-, -S-, -CH2-, -NR q -、-CO-、-NR q CO-、-CONR 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 ring contains 1 to 4 heteroatoms selected from O, S or N;

[0194] R q Selected from H or C 1-4 alkyl;

[0195] R k1 Each independently selected from H, D, F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, R k7a The alkyl, alkoxy, cycloalkyl group is optionally substituted by 1 to 4 groups selected from D, 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;

[0196] R k3 Each independently selected from H, D, F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 , 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 D, 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, and N;

[0197] Or two R k3 Together with the carbon atoms or ring skeletons directly connected to the two, they form C 3-8 Carbocyclic or 3-8 membered heterocyclic ring, or two R k1 Together with the carbon atoms or ring skeletons directly connected to the two, they form C 3-8 Carbocyclic or 3-8 membered heterocyclic ring, wherein the carbocyclic or 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 The heterocyclic ring is substituted by an alkoxy substituent, and the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N;

[0198] R k4 Each independently selected from H or C 1-4 alkyl;

[0199] R k5 Each independently selected from C(CH3)2, CO, CH2, SO2,

[0200] R k6Each independently selected from CO, CH, SO, SO2, CH2, N or NR k7a ;

[0201] R k7 Each independently selected from C(CH3)2,CO,CH,N,CH2,O,S,NR k7a ;

[0202] 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;

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

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

[0205] R ka Selected from O, S or NH;

[0206] R k10 Selected from CH2 or CO;

[0207] p1 or p2 are each independently selected from 0, 1, 2, 3, 4 or 5;

[0208] The compound is optionally substituted with 1 to 30 Ds.

[0209] As a second embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0210] 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-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -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-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-, -Ak1-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-Ak3-Ak4-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9;;

[0211] Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, Ak9 are each independently selected from -(CH2) q -, -(CH2) q -O-, -O-(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 -、-(C≡C) q - or bond, wherein the -CH2- is optionally replaced by 1 to 2 groups 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;

[0212] Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from a bond, a 4-7 membered heteromonocyclic ring, a 4-10 membered heterocyclic ring, a 5-12 membered heterospirocyclic ring, a 7-10 membered heterobridged ring, a C 3-7 Monocyclic alkyl, C 4-10 Cycloalkyl, C 5-12 Membered spirocycloalkyl, C 7-10 cycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl, wherein the aryl, heteroaryl, cycloalkyl, heteromonocyclic, heterocyclic, heterospirocyclic or heterobridged ring is optionally substituted by 1 to 2 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 heteroaryl, heteromonocyclic, heterocyclic, heterospirocyclic or heterobridged ring 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;

[0213] q is each independently selected from 0, 1, 2, 3 or 4;

[0214] R L Each independently selected from H or C 1-6 alkyl;

[0215] The remaining definitions are the same as those of the first embodiment of the present invention.

[0216] As a third embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0217] Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, and Ak9 are each independently selected from -(CH2) q -、-(CH2) q -O-, -O-(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 -、-(C≡C) q - or bond, wherein the -CH2- is optionally replaced by 1 to 2 groups selected from F, Cl, Br, I, OH, CN, NH2, CF3, hydroxymethyl, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0218] R L Each independently selected from H or C 1-4 alkyl;

[0219] Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from a bond, a 4-7 membered nitrogen-containing heteromonocycle, a 4-10 membered nitrogen-containing heterocyclic ring, a 5-12 membered nitrogen-containing heterospirocycle, a 7-10 membered nitrogen-containing heterobridged ring, a C 3-7 Monocyclic alkyl, C 4-10 Cycloalkyl, C 5-12 Spiroalkyl, C 7-10 Bridged cycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl, wherein the heteromonocyclic, heterocyclic, heterobridged, heterospirocyclic, cycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 2 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, heterocyclic, heterobridged, heterospirocyclic 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;

[0220] R Y Selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl is optionally substituted by 1 to 3 selected from halogen, OH, cyano, NH2, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 1-4 Alkoxy, C3-6 is substituted by a carbocyclic or 3- to 6-membered heterocyclic substituent, wherein the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;

[0221] R 1 Selected from H, OH, NR 1a R 1b , methyl, ethyl, propyl, isopropyl, methoxy, wherein the methyl, ethyl, propyl, isopropyl, methoxy is optionally substituted by 1 to 3 groups selected from halogen, OH, cyano, NH2, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0222] R 1a 、R 1b Each independently selected from H, OH, NH2, methyl, ethyl, propyl, isopropyl, methoxy, propargyl, propynyl, said methyl, ethyl, propyl, isopropyl, methoxy, propargyl, propynyl optionally substituted by 1 to 3 selected from halogen, OH, cyano, NH2, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkynyl, substituted by a substituent;

[0223] R 3a or R 4 Each independently selected from H, OH, NH2, methyl, ethyl, propyl, propargyl, propynyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, propargyl, propynyl is optionally substituted by 1 to 3 selected from halogen, OH, cyano, NH2, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkynyl, C 3-6 Cycloalkyloxy, C 3-6 is substituted by a carbocyclic or 3- to 6-membered heterocyclic substituent, wherein the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;

[0224] R 3bor R 5 Each independently selected from H, F, Cl, Br, I, cyano, NH2, OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, ethynyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, ethynyl is optionally substituted by 1 to 3 selected from halogen, OH, cyano, NH2, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 is substituted by a carbocyclic or 3- to 6-membered heterocyclic substituent, wherein the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;

[0225] F1 is independently selected from cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, phenyl, naphthyl, pyridinyl, pyrazinyl, pyridazinyl, pyridazinone, pyrimidinyl, phthalazin-1 (2H) -one, benzo [d] [1,2,3] triazin-4 (3H) -one, thienyl, benzothienyl, triazolyl,

[0226] is selected from a single bond or a double bond;

[0227] F2 are each independently selected from

[0228] F is independently selected from cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, 2-pyridonyl, pyrazolyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, benzothiazolyl, indolyl,

[0229] E or A are each independently selected from a benzene ring, a naphthalene ring or a pyridine ring;

[0230] E1 is each independently selected from

[0231] E2 is each independently selected from a benzene ring, a pyridine ring, a pyrimidine ring, a thiazole ring, a thiophene ring, or a furan ring;

[0232] R q Selected from H, methyl, ethyl;

[0233] R k1 、R k3 Each independently selected from H, D, F, Cl, Br, I, OH, =O, NH2, CF3, CN, COOH, CONH2, C 1-4 Alkyl or C 1-4 Alkoxy, R k7a , the alkyl or alkoxy group is optionally substituted by 1 to 4 substituents selected from D, F, Cl, Br, I, OH or NH2;

[0234] Or two R k3 Together with the carbon atoms or ring skeletons directly connected to the two, they form C 3-7 Carbocyclic or 3-7 membered heterocyclic ring, or two R k1 Together with the carbon atoms or ring skeletons directly connected to the two, they form C 3-7 Carbocyclic or 3-7 membered heterocyclic ring, wherein the carbocyclic or 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 The heterocyclic ring is substituted by an alkoxy substituent, and the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N;

[0235] R k4 Each independently selected from H, methyl, ethyl or propyl;

[0236] R k5 Each independently selected from CO, CH2, SO2 or

[0237] R k7a Selected from H, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, heterocyclic group or cycloalkyl group 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, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Substituted by a cycloalkyl substituent; R k9 Each independently selected from CO, SO2 or CH2;

[0238] R kb Selected from a bond or CO;

[0239] R k10 Selected from CH2 or CO;

[0240] R k11 Selected from NH, O or CH2;

[0241] The remaining definitions are the same as those of the first or second embodiment of the present invention.

[0242] As a fourth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0243] Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, and Ak9 are each independently selected from -(CH2) q -、-(CH2) q -O-, -O-(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 -、-(C≡C) q - or a bond, wherein the -CH2- is optionally substituted by 1 to 2 substituents selected from F, Cl, Br, I, OH, CN, NH2, CF3, hydroxymethyl, methyl, ethyl, methoxy or ethoxy;

[0244] R L Selected from H, methyl or ethyl;

[0245] q is each independently selected from 0, 1, 2 or 3;

[0246] 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, phenyl, pyridyl, cyclopropyl-cyclopropyl, cyclopropyl-cyclobutyl, cyclopropyl-cyclopentyl, cyclopropyl-cyclohexyl, cyclobutyl-cyclobutyl, cyclobutyl-cyclopentyl, cyclobutyl-cyclohexyl, cyclopentyl-cyclopentyl cyclohexyl, cyclopentyl and cyclohexyl, 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, cyclopropylspiroazetidinyl, cyclopropylspiropyrrolidinyl, cyclopropylspiropiperidinyl, cyclopropylspiropiperazinyl, cyclobutylspiroazetidinyl , cyclobutyl spiropyrrolidinyl, cyclobutyl spiropyrrolidinyl, cyclopentyl spiroazetidinyl, cyclopentyl spiropyrrolidinyl, cyclopentyl spiropyridinyl, cyclohexyl spiroazetidinyl, cyclohexyl spiropyrrolidinyl, cyclohexyl spiropyridinyl, azetidinyl spiroazetidinyl, azetidinyl spiropyrrolidinyl, azetidinyl spiropyridinyl, pyrrolidinyl spiroazetidinyl, pyrrolidinyl spiropyrrolidinyl, pyrrolidinyl spiropyridinyl, piperidinyl spiroazetidinyl, piperidinyl spiropyridinyl, piperidinyl spiropyridinyl, cyclopropyl spiropiperazinyl, When substituted, it is optionally replaced by 1 to 4 groups 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;

[0247] X is selected from O or S;

[0248] Y is selected from NH or O;

[0249] R 1 Selected from H, OH, NR 1a R 1b, methyl, ethyl, propyl, isopropyl, methoxy, wherein the methyl, ethyl, propyl, isopropyl, methoxy is optionally substituted by 1 to 3 substituents selected from F, Cl, Br, I, OH, cyano, NH2, methyl, ethyl, CF3;

[0250] R 1a 、R 1b Each is independently selected from H, OH, NH2, methyl, ethyl, propyl, isopropyl, methoxy, propargyl, and propynyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, propargyl, and propynyl are optionally substituted with 1 to 3 substituents selected from F, Cl, Br, I, OH, cyano, NH2, methyl, ethyl, methoxy, ethynyl, and CF3;

[0251] R 3a is selected from H, OH, NH2, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, propargyl, and propynyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, propargyl, and propynyl are optionally substituted with 1 to 3 substituents selected from F, Cl, Br, I, OH, cyano, NH2, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethynyl, cyclopropyloxy, and methoxy;

[0252] R 4 Each is independently selected from H, methyl, ethyl, and cyclopropyl;

[0253] R 3b Each is independently selected from H, F, Cl, Br, I, OH, CN, methoxy, methyl, ethyl, and cyclopropyl;

[0254] R 5 Each independently selected from H, F, Cl, Br, I, cyano, NH2, OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, and ethynyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, and ethynyl are optionally substituted with 1 to 3 substituents selected from F, Cl, Br, I, OH, cyano, NH2, methyl, ethyl, and cyclopropyl;

[0255] F1 is independently selected from cyclohexyl, piperidinyl, piperazinyl, phenyl, naphthyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, pyridazinone, phthalazin-1 (2H) -one, benzo [d] [1,2,3] triazin-4 (3H) -one, thienyl, triazolyl,

[0256] F2 are each independently selected from

[0257] F is independently selected from cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, 2-pyridone, pyrazolyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, benzothiazolyl, indolyl,

[0258] Q1 is selected from -O-, -S-, -CH2-, NH, N(CH3) or -CO-;

[0259] Q is selected from a bond, C(=O), CH2, NH, N(CH3), O, S, NHC(=O), C(=O)NH, N(CH3)C(=O), C(=O)N(CH3),

[0260] 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;

[0261] R k1 、R k3 Each independently selected from H, D, F, Cl, Br, I, OH, =O, NH2, CF3, CN, COOH, CONH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, ethynyl, cyclopropyl, azetidinyl, said methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, ethynyl, cyclopropyl, azetidinyl optionally substituted with 1 to 4 substituents selected from D, F, Cl, Br, I, OH, NH2, CN, cyclopropyl, methoxy; or two R k3 Together with the carbon atoms or ring skeletons directly connected to the two, they form C 3-6 Carbocyclic or 3-7 membered heterocyclic ring, or two R k1Together with the carbon atoms or ring skeletons directly connected to the two, they form C 3-6 Carbocyclic or 3-7 membered heterocyclic ring, wherein the carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 rings selected from D, 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 ring contains 1 to 4 heteroatoms selected from O, S or N;

[0262] p1 or p2 are each independently selected from 0, 1, 2 or 3;

[0263] The remaining definitions are the same as those of the first, second or third embodiment of the present invention.

[0264] As a fifth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0265] Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, Ak9 are each independently selected from a bond, -O-, -OCH2-, -CH2O-, -OCH2CH2-, -CH2CH2O-, -C≡C-, -C(CH3)2-, -CF2-, -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)-;

[0266] 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, it is substituted with 1 to 4 substituents selected from F, CF3, OH, methyl, =O, hydroxymethyl, COOH, CN or NH2;

[0267] B is selected from one of the structural fragments shown in Table B-1;

[0268] K is selected from one of the structural fragments shown in Table K-1 or K-2;

[0269] The remaining definitions are the same as those of the first, second, third or fourth embodiment of the present invention.

[0270] As a sixth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0271] L is selected from a bond, -Ak1-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-Ak3-Ak4-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-, -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-, -Akl-Cy2-Cy3-Ak3-Cy4-, -Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-, -Ak1-Cy2-Ak2-, -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-;,

[0272] The remaining definitions are the same as those of the first, second, third, fourth or fifth embodiment of the present invention.

[0273] As a seventh embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0274] L is selected from a bond or one of the structural fragments shown in Table L-1, wherein the left side of the group is connected to B;

[0275] The remaining definitions are the same as those of the first, second, third, fourth, fifth or sixth embodiment of the present invention.

[0276] As an eighth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0277] L is selected from a bond or one of the structural fragments shown in Table L-2, wherein the left side of the group is connected to B;

[0278] K is selected from one of the structural fragments shown in Table K-2;

[0279] The remaining definitions are the same as those of the first, second, third, fourth, fifth, sixth or seventh embodiment of the present invention.

[0280] As a ninth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, the compound of general formula (I) is selected from the compound of general formula (II),

[0281] wherein L1 is selected from -Cy1-, -Cy1-Ak1-, -Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Ak1-Cy2-Cy3-;

[0282] Ak1 is selected from -CH2-, -O-, -CH2-CH2-;

[0283] F1 is selected from phenyl, 5-6 membered heteroaryl or 13-14 membered heterocyclic ring;

[0284] The remaining definitions are the same as those of the first, second, third, fourth, fifth, sixth, seventh or eighth embodiment of the present invention.

[0285] As a tenth embodiment of the present invention, the compound represented by the aforementioned general formula (II) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0286] wherein L1 is selected from -Cy1-, -Cy1-Ak1-, -Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Ak1-Cy2-Cy3-;

[0287] Cy1, Cy2 or Cy3 are each independently selected from a bond or one of the following substituted or unsubstituted groups: When substituted, it is substituted with 1 to 4 substituents selected from F, CF3, OH, methyl, =O, hydroxymethyl, COOH, CN or NH2;

[0288] Ak1 is selected from -CH2-, -O-, -CH2-CH2-;

[0289] B is selected from one of the structural fragments shown in Table B-1;

[0290] F1 is selected from phenyl, pyrrolyl, pyrazolyl, triazolyl, pyridyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, triazinyl,

[0291] R k1 Each is independently selected from H, D, F, Cl, Br, I, OH, =O, NH2, CF3, CN, COOH, CONH2, methyl, ethyl, methoxy, ethoxy;

[0292] p1 is selected from 0, 1 or 2.

[0293] As an eleventh embodiment of the present invention, the compound represented by the aforementioned general formula (II) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, wherein:

[0294] L1 is selected from

[0295] The remaining definitions are the same as those in the tenth embodiment.

[0296] As a twelfth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or general formula (II) or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound represented by general formula (I) or general formula (II) is selected from the compound represented by general formula (III),

[0297] L2 is selected from -Cy1-, -Cy1-Ak1- or -Cy1-Ak1-Cy2-;

[0298] Cy1 and Cy2 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, =O, hydroxymethyl, COOH, CN or NH2;

[0299] Ak1 is selected from -CH2-, -O-, -CH2-CH2-;

[0300] R k1 Each independently selected from H, D, F, Cl, Br, I, OH, =O, NH2, CF3, CN, COOH, CONH2, methyl, ethyl, methoxy, ethoxy;

[0301] p1 is selected from 0, 1 or 2.

[0302] B is defined the same as in the first, second, third, fourth, fifth, sixth, seventh or eighth embodiment of the present invention.

[0303] As the thirteenth embodiment of the present invention, the compound represented by the aforementioned general formula (III) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0304] B is selected from

[0305] L2 is selected from

[0306] R k1 Each is independently selected from H, D, F, Cl, Br, I, OH, =O, NH2, CF3, CN, COOH, CONH2, methyl, ethyl, methoxy, ethoxy;

[0307] p1 is selected from 0, 1 or 2.

[0308] The present invention relates to the following compound or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures in Table S-1 below:

[0309] Table S-1

[0310] The present invention relates to a pharmaceutical composition comprising the above-mentioned compound of the present invention or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and a pharmaceutically acceptable carrier.

[0311] The present invention relates to the use of the above-mentioned compound of the present invention or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals in the preparation of drugs for treating diseases related to Bcl6 activity or expression.

[0312] The present invention relates to the use of the above-mentioned compound of the present invention or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals in the preparation of drugs for treating and inhibiting or degrading diseases related to Bcl6.

[0313] The present invention relates to the use of the above-mentioned compound of the present invention or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, wherein the disease is selected from cancer.

[0314] The present invention relates to a pharmaceutical composition or pharmaceutical formulation comprising a therapeutically effective amount of a compound of the present invention, or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, and a pharmaceutically acceptable excipient. The pharmaceutical composition may be in the form of a unit dosage form (the amount of the active ingredient in a unit dosage form is also referred to as the "drug strength").

[0315] The present invention also provides a method for treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of the present invention, or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, cocrystal, or pharmaceutical composition thereof. In some embodiments, the mammal of the present invention comprises a human.

[0316] As used herein, an "effective amount" or "therapeutically effective amount" refers to administering a sufficient amount of a compound disclosed herein to alleviate, to some extent, one or more symptoms of the disease or condition being treated (e.g., 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 a biological system. For example, an "effective amount" for therapeutic use is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease symptoms.Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-600 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, 10 0-600mg, 200-600mg, 1-500mg, 2-500mg, 3-500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25 -500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg, 90-500mg, 100-500 mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg, 400-500mg, 5-400mg, 10-400mg, 20-400 mg, 25-400mg, 30-400mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80-400mg, 90-400mg, 10 0-400mg, 125-400mg, 150-400mg, 200-400mg, 250-400mg, 300-400mg, 1-300mg, 2-300mg, 5-300mg, 10-3 00mg, 20-300mg, 25-300mg, 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-300mg, 80-300mg, 90-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-20 0mg, 30-200mg, 40-200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg;.

[0317] In some embodiments, the pharmaceutical composition includes but is not limited to 1-1500 mg, 1-600 mg, 20-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 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 of a compound of the invention or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

[0318] 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 cancer.

[0319] 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 1-1500 mg / day, wherein the daily dose can be a single dose or divided doses. In some embodiments, the daily dose includes but is not limited to 10-1500 mg / day, 10-800 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, or a combination thereof. 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, 100 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 400 mg / day, 600 mg / day, 800 mg / day, 1500 mg / day, 2000 mg / day.

[0320] 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 form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and the amount of the compound of the present invention or its stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is the same as the amount in the above-mentioned pharmaceutical composition.

[0321] The amount of the compound of the invention or its stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the present invention is in each case calculated as the free base.

[0322] Unless otherwise stated, the terms used in this specification and claims have the following meanings.

[0323] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0324] 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 further 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 and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl, bromine include 79 Br and 81 Br.

[0325] "Halogen" refers to F, Cl, Br or I.

[0326] "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 preferably substitution with 1 to 4 substituents selected from F, Cl, Br or I. "Halogen-substituted" is abbreviated as "halo".

[0327] "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.

[0328] "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.

[0329] "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.

[0330] "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 ring of the heterocycloalkyl can be oxidized to various oxidation states. The heterocycloalkyl group can be connected to a heteroatom or a carbon atom, the heterocycloalkyl group can be connected to an aromatic ring or a non-aromatic ring, and the heterocycloalkyl group can be connected to a bridged ring or a spiro ring. Non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolane, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl. The heterocycloalkyl group can be monovalent, divalent, trivalent or tetravalent.

[0331] "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.

[0332] "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, with a backbone comprising 2 to 10 carbon atoms, including but not limited to 2 to 6 carbon atoms in the backbone, and 2 to 4 carbon atoms in the backbone. Examples of alkynyl groups include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 5-pentynyl, 6-pentynyl, 7-pentynyl, 8-pentynyl, 9-pentynyl, 10-pentynyl, 11-pentynyl, 12-pentynyl, 13-pentynyl, 14-pentynyl, 15-pentynyl, 16-pentynyl, 17-pentynyl, 18-pentynyl, 19-pentynyl, 20-pentynyl, 21-pentynyl, 22-pentynyl, 23-pentynyl, 24-pentynyl, 25-pentynyl, 26-pentynyl, 27-pentynyl, 28-pentynyl, 29-pentynyl, 30-pentynyl, 31-pentynyl, 32-pentynyl, 33-pentynyl, 34-pentynyl, 35-pentynyl, 36-pentynyl, 37-pentynyl, 38-pentynyl, 39-pentynyl, 40-pentynyl, 41-pentynyl, 42-pentynyl, 43-pentynyl, 44-pentynyl, 45-pentynyl, 46-pentynyl, 47-pentynyl, 48-pentyn Alkynyl, 1-methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, and the like; an alkynyl group may be monovalent, divalent, trivalent, or tetravalent.

[0333] "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.

[0334] "Carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, which can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring, or a 10-15 membered tricyclic ring system. The carbocyclyl can be attached to the aromatic or non-aromatic ring, which can be optionally a monocyclic, bridged, or spirocyclic ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, a benzene ring, a naphthalene ring, "Carbocyclyl" or "carbocycle" can be monovalent, divalent, trivalent, or tetravalent.

[0335] "Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, which can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring or a 10-15 membered tricyclic ring system, and contains one or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S. The C, N, 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-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, py ... furanyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophenyl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptanyl, "Heterocyclyl" or "heterocycle" can be monovalent, divalent, trivalent or tetravalent.

[0336] "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 Non-limiting examples include: "Spirocycle" or "spirocyclyl" can be monovalent, divalent, trivalent or tetravalent.

[0337] "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.

[0338] "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 "Bridged ring" or "bridged ring group" may be monovalent, divalent, trivalent or tetravalent.

[0339] "Carbospirocycle," "spirocarbocyclyl," "spirocarbocyclyl," or "carbospirocyclyl" refers to a "spirocycle" whose ring system consists solely of carbon atoms. As used herein, "carbospirocycle," "spirocarbocyclyl," "spirocarbocyclyl," or "carbospirocyclyl" have the same definition as for spirocycle.

[0340] "Carbocyclyl," "carbocyclyl," "carbocyclyl," or "carbocyclyl" refers to a "carbocyclyl" ring system consisting solely of carbon atoms. As used herein, "carbocyclyl," "carbocyclyl," "carbocyclyl," or "carbocyclyl" has the same definition as for cyclyl.

[0341] "Carbon bridged ring," "bridged ring carbocyclic group," "bridged carbocyclic group," or "carbon bridged cyclic group" refers to a "bridged ring" in which the ring system consists only of carbon atoms. As used herein, "carbon bridged ring," "bridged ring carbocyclic group," "bridged carbocyclic group," or "carbon bridged cyclic group" has the same definition as for a bridged ring.

[0342] "Heteromonocycle", "monocyclic heterocyclyl" or "heteromonocyclyl" refers to a "heterocyclyl" or "heterocycle" of a monocyclic ring system. The heterocyclyl, "monocyclic heterocyclyl" or "heteromonocyclyl" appearing in this document has the same definition as heterocycle.

[0343] "Heterocyclic ring", "heterocyclic ring group", "heterocyclic ring heterocyclyl" or "heterocyclic ring group" refers to a "cyclic ring" containing a heteroatom. The heterocyclic ring, "heterocyclic ring group", "heterocyclic ring heterocyclyl" or "heterocyclic ring group" appearing in this article have the same definition as the cyclic ring.

[0344] "Heterospirocycle", "heterospirocyclyl", "spiroheterocyclyl" or "heterospirocyclyl" refers to a "spirocycle" containing a heteroatom. Heterospirocycle, "heterospirocyclyl", "spiroheterocyclyl" or "heterospirocyclyl" appearing herein have the same definition as spirocycle.

[0345] "Heterobridged ring", "heterobridged cyclic group", "bridged heterocyclic group" or "heterobridged cyclic group" refers to a "bridged ring" containing a heteroatom. The heterobridged ring, "heterobridged cyclic group", "bridged heterocyclic group" or "heterobridged cyclic group" appearing herein have the same definition as that of the bridged ring.

[0346] "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 benzene ring, naphthalene 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.

[0347] "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, n is 0, 1, 2), and the number of ring atoms in the heteroaromatic ring is but 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, benzopyrazolyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl and the like. 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, and 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.

[0348] "5-membered ring and 5-membered heteroaromatic ring" refers to a 5-membered fused heteroaromatic ring, at least one of the two fused 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, pyrazolopyrrole ring, pyrazolopyrazole ring, pyrrolofuran ring, pyrazolofuran ring, pyrrolothiophene ring, and pyrazolothiophene ring.

[0349] "5-membered and 6-membered heteroaromatic ring" refers to a 5-membered and 6-membered fused heteroaromatic ring, at least one of the two fused 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 heteroaromatic group, 6-membered heteroaromatic ring and 5-membered heteroaromatic ring.

[0350] "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 , ORd 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 It can form a five- or six-membered cycloalkyl or heterocyclic group. a With R d Each is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring or paracyclic group.

[0351] “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.

[0352] "Replaced by 1 to X substituents" means substituted by 1, 2, 3, ..., X substituents, where X is selected from any integer between 2 and 10. For example, "replaced by 1 to 4 substituents" means substituted by 1, 2, 3, or 4 substituents. For example, "replaced by 1 to 5 substituents" means substituted by 1, 2, 3, 4, or 5 substituents. For example, "the heterobridged ring is optionally substituted by 1 to 4 substituents selected from H or F" means that the heterobridged ring is optionally further substituted by 1, 2, 3, or 4 substituents selected from H or F.

[0353] XY-membered rings (where X is selected from an integer less than Y and greater than 3, and Y is selected from any integer between 4 and 12) include rings with X, X+1, X+2, X+3, X+4, and so on. Rings include heterocycles, carbocycles, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocycles, heteroplexes, heterospirocycles, and heterobridged rings. For example, "4-7-membered heteromonocycle" refers to a 4-, 5-, 6-, or 7-membered heteromonocycle, and "5-10-membered heteroplexes" refers to a 5-, 6-, 7-, 8-, 9-, or 10-membered heteroplexe.

[0354] "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.

[0355] "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.

[0356] "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.

[0357] "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.

[0358] "Excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrants.

[0359] "Prodrugs" refer to compounds of the present invention that can be converted into biologically active compounds through in vivo metabolism. Prodrugs of the present invention are prepared by modifying amino or carboxyl groups in compounds of the present invention. These modifications can be removed by conventional manipulation or in vivo to yield the parent compound. When the prodrugs of the present invention are administered to a mammalian subject, the prodrugs are cleaved to form free amino or carboxyl groups.

[0360] A "cocrystal" is a crystal formed by the active pharmaceutical ingredient (API) and cocrystal former (CCF) bound together by hydrogen bonds or other non-covalent bonds. Both the API and CCF are solid in their pure form at room temperature, and the components exist in a fixed stoichiometric ratio. A cocrystal is a multi-component crystal, encompassing both binary cocrystals formed between two neutral solids and multi-component cocrystals formed between a neutral solid and a salt or solvate.

[0361] "Animal" is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

[0362] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers, and conformational isomers.

[0363] "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.

[0364] “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. BRIEF DESCRIPTION OF THE DRAWINGS

[0365] FIG1 is a diagram of the asymmetric unit cell of the MicroED test of compound 46b. DETAILED DESCRIPTION

[0366] The technical solutions of the present invention are described in detail below in conjunction with the embodiments, but the protection scope of the present invention includes but is not limited to them.

[0367] 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).

[0368] MS was determined using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0369] HPLC determination was performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM);

[0370] MicroED was determined using a Thermo Scientific Glacios 200kV cryo-transmission electron microscope;

[0371] Thin layer chromatography silica gel plate using Yantai Huanghai HSGF 254 or Qingdao GF 254 Silica gel plates, the specifications of silica gel plates used in thin layer chromatography (TLC) are 0.15mm-0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm;

[0372] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier;

[0373] Boc: tert-butoxycarbonyl; Ts: p-toluenesulfonyl; Cbz: benzyloxycarbonyl; TMS: trimethylsilyl; DMF: N,N-dimethylformamide; DIPEA: N,N-diisopropylethylamine.

[0374] Preparation of intermediate A-5:

[0375] Step 1: Preparation of A-2

[0376] Tert-butyl piperazine-1-carboxylate (82 g, 0.44 mol) was dissolved in 500 mL of DMF, and cesium carbonate (215 g, 0.66 mol) was added. After stirring at room temperature for 20 min, compound A-1 (70 g, 0.44 mol) was added. The mixture was reacted at 50°C under nitrogen atmosphere for 16 h. The reaction solution was cooled to room temperature and quenched by adding 1.5 L of ice water. A large amount of yellow solid precipitated, which was filtered. The filter cake was washed twice with 500 mL of water and dried to obtain compound A-2 (135 g, yield: 95%).

[0377] LCMS m / z=326.1[M+1] + .

[0378] Step 2: Preparation of A-3

[0379] Under nitrogen, compound A-2 (83.0 g, 0.255 mol) was dissolved in 400 mL of acetonitrile and stirred in an ice bath for 20 min. 200 mL of 1,4-dioxane hydrochloride solution was added, and the mixture was allowed to warm to room temperature and react for 1 h. The reaction system was concentrated under reduced pressure to obtain the crude hydrochloride salt of A-3 (72 g).

[0380] LCMS m / z=226.1[M+1] + .

[0381] Step 3: Preparation of A-4

[0382] The hydrochloride salt of crude product A-3 (72 g) was dissolved in 800 mL of toluene. Sodium acetate (52 g, 0.64 mol) and 60 mL of acetic acid were added sequentially under nitrogen. After stirring at room temperature for 20 min, tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate (66 g, 0.28 mol) was added and the mixture was allowed to react at 100°C for 6 h. The reaction system was cooled to room temperature, filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to obtain the crude product. Under nitrogen, the crude product was dissolved in a mixture of 200 mL of ultra-dry methanol and 200 mL of ultra-dry 1,2-dichloroethane, and sodium cyanoborohydride (41.4 g, 1.275 mol) was added. The reaction was allowed to react at room temperature for 16 h. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:1) to obtain compound A-4 (65 g, two-step yield: 57%).

[0383] LCMS m / z=445.2[M+1] + .

[0384] Step 4: Preparation of A-5

[0385] A-4 (55 g, 0.124 mol) was dissolved in 1000 mL of ethyl acetate, and 5.5 g of 10% palladium on carbon was added. The hydrogen atmosphere was replaced three times, and the mixture was reacted under a hydrogen balloon at room temperature for 16 h. The reaction system was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain A-5 (50.5 g, 98% yield).

[0386] LCMS m / z=415.2[M+1] + .

[0387] Compound A-5 was separated and purified by SFC to obtain chiral isomer A-5-P1 (23.15 g, SFC retention time 0.946 min; chiral HPLC retention time 20.460 min; [α] 20 D =+31.1 ° ) and isomer A-5-P2 (19.94 g, SFC preparation retention time of 1.883 min, chiral HPLC retention time of 17.221 min; [α] 20 D =-27.1 ° )(A-5-P1 and A-5-P2 are one of the structures of compounds A-5-a and A-5-b, and A-5-P1 and A-5-P2 are enantiomers of each other).

[0388] SFC chiral preparation method:

[0389] Instrument: Waters 150SFC; Preparative column model: Chiralpak IC-3 Column (250×30 mm, ID 50 mm, 10 μm particle size); Mobile phase: A is CO 2 ; B is isopropanol and acetonitrile solution containing 0.1% ammonia.

[0390] Elution conditions: 35% B isocratic elution; flow rate: 200 mL / min; column pressure: 100 bar; column temperature: 25°C; detection wavelength: 220 nm; post-processing: after preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain A-5-P1 and A-5-P2, respectively.

[0391] Chiral HPLC analysis conditions:

[0392] Instrument: Shimadzu LC-20A; Chiral column: CHIRALCEL OD-H, 4.6×250 mm, 5 μm; Mobile phase: n-hexane (containing 0.1% diethylamine)-isopropanol (v / v) = 70:30; Flow rate: 1 mL / min; Column temperature: 35°C; Detection wavelength: 210 nm;

[0393] Injection volume: 10 μL; run time: 30 min.

[0394] Optical rotation measurement method: Instrument model: Anton Paar MCP 4100; Measurement tube length: 1 dm; Detection solvent: methanol;

[0395] Sample amount: A-5-P1: 100.66 mg; A-5-P2: 104.50 mg;

[0396] Sample concentration: A-5-P1: 3.8024 mg / mL; A-5-P2: 3.8024 mg / mL.

[0397] Preparation of intermediate A-6-P1:

[0398] Note: The wavy lines in the structure of this application refer to configuration R or S;

[0399] A-5-P1 (0.50 g, 1.21 mmol), 3-bromopiperidine-2,6-dione (0.70 g, 3.65 mmol), sodium bicarbonate (0.61 g, 7.26 mmol) and Molecular sieves were added, 5 mL of DMF was added, and the reaction was carried out at 80°C for 2 h. The reaction solution was cooled to room temperature, poured into 20 mL of water, and extracted with ethyl acetate (20 mL × 3). 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 (petroleum ether / ethyl acetate (v / v) = 1:1) to obtain A-6-P1 (0.30 g, yield: 47%).

[0400] LCMS m / z=526.7[M+1] + .

[0401] Preparation of intermediate A-6-P2:

[0402] Note: The wavy lines in the structure of this application refer to configuration R or S;

[0403] A-5-P2 (2.62 g, 6.33 mmol) and 3-bromopiperidine-2,6-dione (3.65 g, 19 mmol) were placed in a sealed tube and dissolved in 20 mL of DMF. Sodium bicarbonate (3.19 g, 37.98 mmol) was added and reacted at 90°C for 16 h. The reaction system was cooled to room temperature and diluted with 100 mL of ethyl acetate. The organic phase was washed three times with 50 mL of water and then washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 75:1) to obtain compound A-6-P2 (2.5 g, yield: 75%).

[0404] LCMS m / z=526.2[M+1] + .

[0405] Example 1: Preparation of Compound 1

[0406] Step 1: Preparation of 1b

[0407] Under nitrogen atmosphere, 1a (0.50 g, 1.48 mmol) (synthesis method see WO2019060742), tert-butyl 4-(methyl(piperidin-4-yl)amino)piperidine-1-carboxylate (0.66 g, 2.22 mmol) (synthesis method see WO2021058017), RuPhos Pd G3 (CAS: 1445085-77-7) (0.25 g, 0.30 mmol) and RuPhos (CAS: 787618-22-8) (0.14 g, 0.30 mmol) were added to the reaction flask, 5 mL of toluene and 1 mol / L LiHMDS in THF solution (8.8 mL, 8.8 mmol) were added, and the reaction was carried out at 80 ° C for 1.5 h. The reaction solution was cooled to 0°C in an ice bath, and 10 mL of saturated aqueous ammonium chloride was added dropwise to quench the reaction system. The mixture was extracted with ethyl acetate (30 mL × 3). 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 (petroleum ether / ethyl acetate (v / v) = 1:1-1:2) to obtain 1b (0.19 g, yield: 23%).

[0408] LCMS m / z=555.4[M+1] + .

[0409] Step 2: Preparation of trifluoroacetate salt of 1c

[0410] 1b (0.13 g, 0.23 mmol), 0.5 mL of trifluoroacetic acid, and 2 mL of dichloromethane were added to a reaction flask and reacted at room temperature for 2 h. The reaction system was concentrated under reduced pressure to obtain the trifluoroacetic acid salt of crude product 1c (0.15 g).

[0411] LCMS m / z=455.3[M+1] + .

[0412] Step 3: Preparation of compound 1

[0413] To a reaction flask, the trifluoroacetic acid salt of the crude product 1c (0.15 g), sodium bicarbonate (0.097 g, 1.15 mmol), and 5 mL of DMSO were added. After stirring at room temperature for 0.5 h, 1D (0.090 g, 0.23 mmol) (synthesis method, see WO2021077010) and 0.19 mL of DIPEA were added and stirred at 100°C for 7 h. The reaction system was cooled to room temperature, poured into 50 mL of water, and filtered. The filter cake was collected and dissolved in 50 mL of a 2:1 (v / v) mixture of dichloromethane and methanol, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was then subjected to pre-HPLC (instrument and preparative column: SHIMADZULC-20AP preparative HPLC, Phenomenex C18 preparative column). Preparation method: The crude product was dissolved in acetonitrile and water and filtered through a 0.45 μm filter to prepare a sample solution. The mobile phase system was 10 mmol / L ammonium bicarbonate aqueous solution / acetonitrile. Gradient elution method was acetonitrile from 27% to 57% (elution time 10 min). The product was lyophilized to obtain compound 1 (25 mg, yield: 13%).

[0414] 1 H NMR(400MHz,DMSO-d6)δ11.03(s,1H),8.81(s,1H),8.03(s,1H),7.91(d,1H),7.71(dd,1H),7 .46(d,1H),7.04(s,1H),6.92(d,1H),6.81(d,1H),6.62(dd,1H),5.34–5.22(m,1H),4.90(s,2 H),4.59–4.45(m,2H),3.67(s,3H),3.65–3.54(m,2H),3.40–3.20(m,3H),2.97–2.75(m,4H),2 .75–2.55(m,5H),2.23–2.14(m,6H),2.05–1.92(m,1H),1.85–1.55(m,6H),1.50–1.32(m,2H).

[0415] LCMS m / z=811.3[M+1] + .

[0416] Example 2: Preparation of Compound 2

[0417] Compound 2 was obtained using 2a (synthesis method see WO2021158634) as raw material and referring to the synthesis method of Example 1.

[0418] 1 H NMR(400MHz,DMSO-d6)δ11.07(s,1H),8.82(s,1H),8.03(s,1H),7.94–7.88(m,1H), 7.71(dd,1H),7.52–7.41(m,1H),7.04(s,1H),7.01–6.82(m,3H),5.34(dd,1H),4.91 (s,2H),4.62–4.42(m,2H),3.67(s,3H),3.63(s,3H),3.19–3.05(m,2H),2.96–2.56 (m,9H),2.26–2.15(m,6H),2.08–1.92(m,1H),1.90–1.58(m,6H),1.52–1.31(m,2H).

[0419] LCMS m / z=811.9[M+1] + .

[0420] Example 3: Preparation of Compound 3

[0421] Compound 3 was obtained using 3a (synthesis method see WO2017197046) as raw material and referring to the synthesis method of Example 1.

[0422] 1 H NMR(400MHz,DMSO-d6)δ10.74(s,1H),8.80(s,1H),8.03(s,1H),7.94–7.87 (m,1H),7.71(dd,1H),7.50–7.41(m,1H),7.08–6.97(m,3H),6.94–6.82(m, 2H),4.90(s,2H),4.59–4.44(m,2H),3.77–3.60(m,6H),2.92–2.74(m,3H), 2.72–2.56(m,4H),2.49–2.37(m,1H),2.24–1.94(m,8H),1.84–1.30(m,8H).

[0423] LCMS m / z=741.3[M+1] + .

[0424] Example 4: Preparation of Compound 4

[0425] Note: The wavy lines in the structure of this application refer to configuration R or S;

[0426] Step 1: Preparation of trifluoroacetate salt of 4a

[0427] A-6-P2 (100 mg, 0.19 mmol), 1 mL of trifluoroacetic acid, and 2 mL of dichloromethane were added to the reaction flask and reacted at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetic acid salt of crude product 4a (100 mg).

[0428] Step 2: Preparation of compound 4

[0429] The trifluoroacetic acid salt (100 mg) of the crude product 4a, solid sodium bicarbonate (80 mg, 0.95 mmol), and 5 mL of DMSO were added to a reaction flask. After reacting at room temperature for 0.5 h, 4B (78 mg, 0.19 mmol) (synthesis method, see WO2021077010) and 0.16 mL of DIPEA were added and reacted at 100°C for 7 h. The reaction system was cooled to room temperature, and the reaction solution was subjected to Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid chromatography, preparative column model SunFire@Prep C18, 5 μm, i.d. × length = 19 mm × 250 mm). Preparation method: The crude product DMSO solution was filtered through a 0.45 μm filter membrane to prepare the sample solution. The mobile phase system was an aqueous solution of ammonium acetate (5 mmol / L) in acetonitrile. Gradient elution method: acetonitrile was gradient eluted from 10% to 70% (elution time 18 min), and lyophilized to obtain compound 4 (24 mg, yield: 16%).

[0430] LCMS m / z=797.2[M+1] + .

[0431] Example 5: Preparation of trifluoroacetate salt of compound 5

[0432] Note: The wavy lines in the structure of this application refer to configuration R or S;

[0433] Crude product 4a (100 mg, trifluoroacetic acid salt), sodium bicarbonate (80 mg, 0.95 mmol), and 5 mL of DMSO were added to a reaction flask. The mixture was allowed to react at room temperature for 0.5 h. 1D (75 mg, 0.19 mmol) and 0.16 mL of DIPEA were then added and the mixture was allowed to react at 100°C for 7 h. After cooling to room temperature, the reaction solution was subjected to pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, SunFire@Prep C18, 5 μm, i.d. x length = 19 mm x 250 mm). Preparation method: The crude product in DMSO was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was water (containing 0.1% trifluoroacetic acid) / acetonitrile. Gradient elution was performed: 10% to 50% acetonitrile (elution time 12 min). The trifluoroacetic acid salt of compound 5 (4.2 mg) was obtained by lyophilization.

[0434] LCMS m / z=782.2[M+1] + .

[0435] Example 6: Preparation of Compound 6

[0436] Note: The wavy lines in the structure of this application refer to configuration R or S;

[0437] Step 1: Preparation of trifluoroacetate salt of 6a

[0438] A-6-P1 (100 mg, 0.19 mmol), 1 mL of trifluoroacetic acid, and 2 mL of dichloromethane were added to the reaction flask and reacted at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetic acid salt of crude product 6a (100 mg).

[0439] Step 2: Preparation of compound 6

[0440] The trifluoroacetic acid salt (100 mg) of the crude product 6a, sodium bicarbonate (80 mg, 0.95 mmol), and 5 mL of DMSO were added to a reaction flask. The mixture was allowed to react at room temperature for 0.5 h. Then, 1D (75 mg, 0.19 mmol) and 0.16 mL of DIPEA were added and the reaction was continued at 100°C for 7 h. After cooling to room temperature, the reaction solution was subjected to pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, SunFire@Prep C18, 5 μm, i.d. x length = 19 mm x 250 mm). Preparation method: The crude product in DMSO was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was ammonium acetate (5 mmol / L) / acetonitrile. Gradient elution was performed: 10% to 70% acetonitrile (elution time 15 min). The mixture was lyophilized to afford compound 6 (15.0 mg, yield: 10%).

[0441] LCMS m / z=782.2[M+1] + .

[0442] Example 7: Preparation of trifluoroacetate salt of compound 7

[0443] Note: The wavy lines in the structure of this application refer to configuration R or S;

[0444] To the reaction flask were added the trifluoroacetic acid salt of the crude product 6a (100 mg), 0.31 mL of DIPEA, 50 mg of After 0.5 h of reaction at room temperature with 5 mL of DMSO and 4B (78 mg, 0.19 mmol), the mixture was allowed to react at 90°C for 7 h. After cooling to room temperature, the reaction solution was subjected to Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid chromatography, SunFire@Prep C18 preparative column model, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: The crude product in DMSO was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was water (containing 0.1% trifluoroacetic acid) / acetonitrile. Gradient elution method: Acetonitrile was gradiently eluted from 10% to 50% (elution time 15 min). The trifluoroacetic acid salt of compound 7 (10 mg, yield: 7%) was lyophilized.

[0445] LCMS m / z=797.2[M+1] + .

[0446] Example 8: Preparation of Compound 8

[0447] Step 1: Preparation of 8b

[0448] Under a nitrogen atmosphere, 8a (0.2 g, 0.75 mmol) (synthesis method see WO2017197046), tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (0.32 g, 1.13 mmol) (synthesis method see WO2020201080), RuPhos Pd G3 (0.13 g, 0.16 mmol) and RuPhos (0.07 g, 0.15 mmol) were added to a reaction flask, 5 mL of toluene and a THF solution of LiHMDS (4.5 mL, 1 mol / L) were added, and the reaction was carried out at 80 °C for 1.5 h. The reaction solution was cooled to 0°C, and saturated aqueous ammonium chloride solution (10 mL) was added dropwise to quench the reaction. The product was extracted with ethyl acetate (30 mL × 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 (dichloromethane / methanol (v / v) = 10:1) to obtain 8b (0.09 g, yield: 25%).

[0449] LCMS m / z=471.6[M+1] + .

[0450] Step 2: Preparation of 8c trifluoroacetate

[0451] 8b (0.09 g, 0.19 mmol), 1.0 mL of trifluoroacetic acid, and 2 mL of dichloromethane were added to a reaction flask and reacted at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the crude trifluoroacetic acid salt of 8c (0.09 g).

[0452] Step 3: Preparation of Compound 8

[0453] To a reaction flask, crude product 8c (90 mg) of trifluoroacetic acid salt, sodium bicarbonate (80 mg, 0.95 mmol), and 5 mL of DMSO were added. After stirring at room temperature for 0.5 h, 4B (78 mg, 0.19 mmol) (synthesis method, see WO2021077010) and 0.16 mL of DIPEA were added and reacted at 100°C for 7 h. The reaction system was cooled to room temperature and subjected to Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid chromatography, preparative column model SunFire@Prep C18, 5 μm, i.d. × length = 19 mm × 250 mm). Preparation method: The crude product DMSO solution was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was ammonium acetate aqueous solution (5 mmol / L) / acetonitrile. Gradient elution method: acetonitrile was gradient eluted from 10% to 70% (elution time 15 min), and lyophilized to obtain compound 8 (20 mg, yield: 14%).

[0454] 1 H NMR(400MHz,DMSO-d6)δ10.80(s,1H),9.09(s,1H),8.16(s,1H),8.01–7.93(m,1H),7.91(d,1H),7.7 2(dd,1H),7.52–7.46(m,1H),7.17(s,1H),7.14–7.06(m,2H),7.06–6.94(m,2H),4.60(s,2H),4.56–4 .42(m,2H),3.80–3.65(m,6H),3.64–3.52(m,2H),3.40–3.23(m,2H),3.15–2.97(m,4H),2.89–2.71(m ,2H),2.71–2.57(m,4H),2.50–2.42(m,1H),2.24–1.94(m,3H),1.92–1.79(m,2H),1.46–1.28(m,2H).

[0455] LCMS m / z=742.3[M+1] + .

[0456] Example 9: Preparation of Compound 9

[0457] Step 1: Preparation of 9b

[0458] Under nitrogen atmosphere, 9a (0.60 g, 1.78 mmol) (synthesis method see WO2021158634), tert-butyl 4-(piperazin-1-ylmethyl)piperidine-1-carboxylate (0.75 g, 2.65 mmol), RuPhos Pd G3 (0.30 g, 0.36 mmol) and RuPhos (0.17 g, 0.36 mmol) were added to a reaction flask, 10 mL of toluene and 1 mol / L LiHMDS in THF solution (10.6 mL, 10.6 mmol) were added, and the reaction was carried out at 80 ° C for 1.5 h. The reaction solution was cooled to 0°C in an ice bath, and 10 mL of saturated aqueous ammonium chloride was added dropwise to quench the reaction system. The mixture was extracted with ethyl acetate (30 mL × 3). 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) = 20:1-10:1) to obtain 9b (0.14 g, yield: 15%).

[0459] Step 2: Preparation of trifluoroacetate salt of 9c

[0460] 9b (0.07 g, 0.13 mmol), 1.0 mL of trifluoroacetic acid, and 2 mL of dichloromethane were added to a reaction flask and reacted at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the crude trifluoroacetic acid salt of 9c (0.07 g).

[0461] Step 3: Preparation of compound 9

[0462] To a reaction flask, crude product 9c (trifluoroacetic acid salt, 70 mg), sodium bicarbonate (55 mg, 0.65 mmol), and 5 mL of DMSO were added. After stirring at room temperature for 0.5 h, 4B (53 mg, 0.13 mmol) (synthesis method, see WO2021077010) and 0.11 mL of DIPEA were added and reacted at 100°C for 7 h. The reaction system was cooled to room temperature, and the reaction solution was subjected to pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid chromatography, preparative column model SunFire@Prep C18, 5 μm, i.d. × length = 19 mm × 250 mm). Preparation method: The crude product DMSO solution was filtered through a 0.45 μm filter membrane to prepare the sample solution. The mobile phase system was an aqueous solution of ammonium acetate (5 mmol / L) in acetonitrile. Gradient elution method: acetonitrile was gradient eluted from 10% to 70% (elution time 14 min), and lyophilized to obtain compound 9 (22 mg, yield: 21%).

[0463] 1 H NMR(400MHz,DMSO-d6)δ11.06(s,1H),8.80(s,1H),8.04(s,1H),7.99–7.89(m,2H),7.82–7.71(m,1H),7.54–7.44(m,1H),7.12(s,1H),7.03–6.8 4(m,3H),5.41–5.29(m,1H),4.58(s,2H),4.54–4.41(m,2H),3.68(s,3H) ,3.62(s,3H),3.10–2.55(m,14H),2.40–1.68(m,8H),1.14–0.96(m,2H).

[0464] LCMS m / z=812.3[M+1] + .

[0465] Example 10: Preparation of Compound 10

[0466] To a reaction flask, the trifluoroacetic acid salt of crude product 9c (70 mg), sodium bicarbonate (55 mg, 0.65 mmol), and 5 mL of DMSO were added. After stirring at room temperature for 0.5 h, 1D (51 mg, 0.13 mmol) (synthesis method, see WO2021077010) and 0.11 mL of DIPEA were added and stirred at 100°C for 7 h. The reaction system was cooled to room temperature, and the reaction solution was subjected to Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid chromatography, preparative column model: SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: The crude product DMSO solution was filtered through a 0.45 μm filter membrane to prepare the sample solution. The mobile phase system was an aqueous solution of ammonium acetate (5 mmol / L) in acetonitrile. Gradient elution method: acetonitrile was gradient eluted from 10% to 70% (elution time 18 min), and lyophilized to obtain compound 10 (20 mg, yield 19%).

[0467] 1 H NMR(400MHz,DMSO-d6)δ11.06(br.s,1H),8.80(s,1H),8.03(s,1H),7.94–7.85 (m,1H),7.78–7.67(m,1H),7.52–7.42(m,1H),7.06–6.82(m,4H),5.40–5.29(m, 1H),4.91(s,2H),4.56–4.42(m,2H),3.67(s,3H),3.62(s,3H),3.11–2.55(m,11 H),2.35–2.10(m,7H),2.06–1.93(m,1H),1.88–1.70(m,3H),1.15–0.97(m,2H).

[0468] LCMS m / z=797.3[M+1] + .

[0469] Example 11: Preparation of trifluoroacetic acid salt of compound 11

[0470] The trifluoroacetic acid salt of crude product 2c (0.11 g), sodium bicarbonate (0.09 g, 1.07 mmol), and 5 mL of DMSO were added to a reaction flask. After stirring at room temperature for 0.5 h, 4B (0.09 g, 0.22 mmol) (synthesis method, see WO2021077010) and 0.18 mL of DIPEA were added and reacted at 100°C for 7 h. The reaction system was cooled to room temperature, poured into 50 mL of water, filtered, and the filter cake was collected and dissolved in 50 mL of a dichloromethane / methanol (v / v = 2:1) mixture. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was then subjected to pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, preparative column model: SunFire@Prep C18, 5 μm, i.d. × length = 19 mm × 250 mm). Preparation method: The crude product DMSO solution was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: water (containing 0.1% TFA) / acetonitrile. Gradient elution method: acetonitrile gradient elution from 10% to 50% (elution time 15 min), and lyophilization to obtain trifluoroacetic acid salt of compound 11 (24 mg).

[0471] 1 H NMR(400MHz, DMSO-d6)δ11.08(s,1H),8.97(s,1H),8.10(s,1H),8.02–7.90(m,2H),7.78–7.70(m,1H),7.53–7.44(m,1H),7.13(s,1H), 7.04–6.86(m,3H),5.41–5.31(m,1H),4.70–4.56(m,4H),3.86–3.48(m,8H),3.28–3.15(m,2H),3.04–2.56(m,13H),2.25–1.47(m,9H).

[0472] LCMS m / z=827.0[M+1] + .

[0473] Example 12: Preparation of Compound 12

[0474] Step 1: Preparation of 12b

[0475] To a reaction flask, tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (0.18 g, 0.64 mmol) (synthesis method, see WO2020201080), 12a (0.12 g, 0.41 mmol) (synthesis method, see WO2020113233), 0.1 mL of glacial acetic acid, 3 mL of 1,2-dichloroethane, and 1 mL of DMSO were added. After stirring at room temperature for 0.5 h, sodium triacetoxyborohydride (0.18 g, 0.85 mmol) was added and the mixture was allowed to react at room temperature for 16 h. 10 mL of saturated aqueous sodium bicarbonate was added to the reaction system, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 10:1) to obtain 12b (95 mg, yield: 42%).

[0476] LCMS m / z=555.8[M+1] + .

[0477] Step 2: Preparation of trifluoroacetate salt of 12c

[0478] 12b (95 mg, 0.17 mmol), 0.5 mL of trifluoroacetic acid, and 2 mL of dichloromethane were added to a reaction flask and reacted at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetic acid salt of crude product 12c (90 mg).

[0479] Step 3: Preparation of compound 12

[0480] The trifluoroacetic acid salt (90 mg) of the crude product 12c, sodium bicarbonate (71 mg, 0.85 mmol), and 5 mL of DMSO were added to a reaction flask. After stirring at room temperature for 0.5 h, 4B (69 mg, 0.17 mmol) and 0.14 mL of DIPEA were added and the mixture was allowed to react at 100°C for 7 h. The reaction system was cooled to room temperature and the reaction solution was subjected to pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, SunFire@Prep C18, 5 μm, i.d. x length = 19 mm x 250 mm). Preparation method: The crude product DMSO solution was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was ammonium acetate (5 mmol / L) in aqueous solution / acetonitrile. Gradient elution was performed: 10% to 70% acetonitrile (elution time 12 min). The product was then lyophilized to obtain compound 12 (20 mg, yield: 14%).

[0481] 1H NMR(400MHz,DMSO-d6)δ8.83(s,1H),8.04(s,1H),7.99–7.89(m,2H),7.77–7.70(m, 1H),7.50–7.42(m,1H),7.12(s,1H),7.09–7.02(m,1H),6.99–6.91(m,1H),6.90–6.83(m,1H),5.44–5.30(m,1H),4.58(s ,2H),3.72–3.54(m,12H),2.96–2.56(m,8H),2.41–2.28(m,4H),2.18–1.90(m,5H),1.74–1.46(m,3H),1.14–0.98(m,2H).

[0482] LCMS m / z=826.3[M+1] + .

[0483] Example 13: Preparation of trifluoroacetate salt of compound 13

[0484] Step 1: Preparation of trifluoroacetate salt of 13b

[0485] In a 50 mL reaction flask, 13a (0.10 g, 0.21 mmol) (synthesis method, see WO2022133285), dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) were added sequentially and reacted at room temperature for 1 h. The reaction solution was concentrated under reduced pressure to obtain the crude trifluoroacetate salt of 13b (0.10 g).

[0486] Step 2: Preparation of trifluoroacetate salt of compound 13

[0487] To a 25 mL reaction flask, the trifluoroacetic acid salt of the crude product 13b (0.10 g), 1D (0.075 g, 0.19 mmol) (synthesis method, see WO2021077010), DIPEA (0.31 mL), and DMSO (5 mL) were added sequentially and reacted at 100°C for 7 h. The reaction system was cooled to room temperature, and the reaction solution was subjected to Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid chromatography, preparative column model SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was water (containing 0.1% trifluoroacetic acid) / acetonitrile. Gradient elution method: Acetonitrile was gradient eluted from 10% to 50% (elution time 12 min). The solution was then lyophilized to obtain the trifluoroacetic acid salt of compound 13 (15 mg).

[0488] 1H NMR(400MHz,DMSO-d6)δ10.77(s,1H),8.99(s,1H),8.08(s,1H),7.84(d,1H),7 .72(dd,1H),7.45(d,1H),7.15–7.06(m,3H),7.01–6.94(m,2H),4.93–4.87(m, 2H),4.53–4.39(m,2H),4.00–3.50(m,8H),3.25–2.83(m,8H),2.73–2.57(m,1H ),2.50–2.42(m,1H),2.24–1.94(m,6H),1.84–1.69(m,2H),1.27–1.07(m,2H).

[0489] LCMS m / z=727.3[M+1] + .

[0490] Example 14: Preparation of trifluoroacetate salt of compound 14

[0491] To a 25 mL reaction flask, the trifluoroacetic acid salt of the crude product 13b (0.10 g), 4B (0.078 g, 0.19 mmol), DIPEA (0.31 mL), and DMSO (5 mL) were added sequentially and reacted at 100°C for 7 h. The reaction system was cooled to room temperature, and the reaction solution was subjected to Pre-HPLC (instrument and preparative column: Waters 2767 Preparative HPLC, preparative column model: SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: The crude product DMSO solution was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was water (containing 0.1% trifluoroacetic acid) / acetonitrile. Gradient elution method: Acetonitrile was gradient eluted from 10% to 50% (elution time 13 min). The solution was then lyophilized to obtain the trifluoroacetic acid salt of compound 14 (20 mg).

[0492] 1H NMR(400MHz,DMSO-d6)δ10.78(s,1H),9.00–8.91(m,1H),8.08(s,1H),8.01–7.88(m, 2H),7.74(dd,1H),7.47(d,1H),7.16–7.06(m,3H),7.02–6.93(m,2H),4 .59(s,2H),4.55–4.40(m,2H),3.87–3.72(m,3H),3.68(s,3H),3.65–3. 54(m,2H),3.26–2.84(m,8H),2.71–2.58(m,4H),2.49–2.41(m,1H),2.2 3–2.08(m,2H),2.07–1.95(m,1H),1.85–1.71(m,2H),1.27–1.11(m,2H).

[0493] LCMS m / z=742.3[M+1] + .

[0494] Example 15: Preparation of Compound 15

[0495] Step 1: Preparation of 15b

[0496] To a reaction flask, 15A (synthesis method, see WO2017197046) (0.30 g, 1.12 mmol), 15a (synthesis method, see WO2022019597) (0.30 g, 1.11 mmol), and 10 mL of toluene were added. RuPhos (0.10 g, 0.21 mmol), RuPhos Pd G3 (0.19 g, 0.227 mmol), and a 1 mol / L LiHMDS solution in THF (6.72 mL, 6.72 mmol) were added sequentially under nitrogen. The reaction was allowed to react at 80°C for 1.5 h. The reaction solution was cooled to room temperature, and 15 mL of saturated aqueous ammonium chloride was added. The mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 10:1) to obtain 15b (0.23 g, yield: 45%).

[0497] LCMS m / z=457.6[M+1] + .

[0498] Step 2: Preparation of trifluoroacetate salt of 15c

[0499] 15b (0.28 g, 0.61 mmol), 1.5 mL of trifluoroacetic acid, and 5 mL of dichloromethane were added to a reaction flask and reacted at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the crude trifluoroacetic acid salt of 15c (0.30 g).

[0500] Step 3: Preparation of compound 15

[0501] The trifluoroacetic acid salt of crude product 15c (0.15 g), DIPEA (0.54 g, 4.2 mmol), and 5 mL of DMSO were added to a reaction flask. After stirring at room temperature for 0.5 h, 1D (0.15 g, 0.38 mmol) (synthesis method, see WO2021077010) was added and the reaction was allowed to proceed at 100°C for 7 h. The reaction system was cooled to room temperature, and the reaction solution was subjected to Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid chromatography, preparative column model SunFire@Prep C18, 5 μm, i.d. × length = 19 mm × 250 mm). Preparation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter membrane to prepare the sample solution. The mobile phase system was an aqueous solution of ammonium acetate (5 mmol / L) in acetonitrile. Gradient elution method: acetonitrile was gradient eluted from 10% to 70% (elution time 12 min), and lyophilized to obtain compound 15 (10 mg, yield: 4%).

[0502] 1 H NMR(400MHz,DMSO-d6)δ10.74(s,1H),8.82(s,1H),8.04(s,1H),7.94–7.86(m,1H), 7.70(dd,1H),7.46(d,1H),7.08–6.99(m,3H),6.93–6.82(m,2H),4.90(s,2H),4.60 –4.40(m,2H),3.76–3.64(m,4H),3.14–3.04(m,4H),2.92–2.77(m,2H),2.71–2.56( m,5H),2.49–2.39(m,2H),2.24–1.94(m,5H),1.89–1.75(m,2H),1.52–1.20(m,2H).

[0503] LCMS m / z=713.8[M+1] + .

[0504] Example 16: Preparation of Compound 16

[0505] The trifluoroacetic acid salt of crude product 15c (0.15 g), DIPEA (0.54 g, 4.2 mmol), and 5 mL of DMSO were added to a reaction flask. After stirring at room temperature for 0.5 h, 4B (0.15 g, 0.37 mmol) (synthesis method, see WO2021077010) was added and the reaction was allowed to proceed at 100°C for 7 h. The reaction system was cooled to room temperature, and the reaction solution was subjected to pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid chromatography, preparative column model SunFire@Prep C18, 5 μm, i.d. × length = 19 mm × 250 mm). Preparation method: The crude product DMSO solution was filtered through a 0.45 μm filter membrane to prepare the sample solution. The mobile phase system was an aqueous solution of ammonium acetate (5 mmol / L) in acetonitrile. Gradient elution method: acetonitrile was gradient eluted from 10% to 70% (elution time 12 min), and lyophilized to obtain compound 16 (15 mg, yield: 6%).

[0506] 1 H NMR(400MHz,DMSO-d6)δ10.75(s,1H),8.83(s,1H),8.07–7.89(m,3H),7.80–7. 72(m,1H),7.52–7.45(m,1H),7.18–6.98(m,3H),6.94–6.82(m,2H),4.63–4.42( m,4H),3.77–3.61(m,4H),3.15–3.03(m,4H),2.94–2.80(m,2H),2.73–2.56(m,8 H),2.55–2.38(m,2H),2.20–1.92(m,2H),1.90–1.80(m,2H),1.54–1.18(m,2H).

[0507] LCMS m / z=728.3[M+1] + .

[0508] Example 17: Preparation of trifluoroacetate salt of compound 17

[0509] Step 1: Preparation of trifluoroacetate salt of 17b

[0510] In a 50 mL reaction flask, 17a (0.22 g, 0.59 mmol) (synthesis method, see WO2022133285), dichloromethane (2 mL), and trifluoroacetic acid (1.0 mL) were added sequentially and reacted at room temperature for 1 h. The reaction system was concentrated under reduced pressure to obtain the crude trifluoroacetic acid salt of 17b (0.22 g).

[0511] Step 2: Preparation of trifluoroacetate salt of compound 17

[0512] To a 25 mL reaction flask, the trifluoroacetic acid salt of the crude product 17b (0.11 g), 1D (0.11 g, 0.28 mmol) (synthesis method, see WO2021077010), DIPEA (0.46 mL), and DMSO (5 mL) were added sequentially and reacted at 100°C for 7 h. The reaction system was cooled to room temperature, and the reaction solution was subjected to Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid chromatography, preparative column model SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: The crude product DMSO solution was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was water (containing 0.1% trifluoroacetic acid) / acetonitrile. Gradient elution method: Acetonitrile was gradient eluted from 10% to 50% (elution time 11 min). The solution was then lyophilized to obtain the trifluoroacetic acid salt of compound 17 (10 mg).

[0513] 1 H NMR(400MHz,DMSO-d6)δ10.75(s,1H),9.00(s,1H),8.11(s,1H),7.90(d,1H),7.71(dd,1H),7.48(d,1H),7.13–7.03(m,3H),7.00–6. 92(m,2H),4.91(s,2H),3.84–3.70(m,5H),3.68(s,3H),3.24–3.13(m,4H),2.71–2.56(m,1H),2.50–2.41(m,1H),2.24–1.95(m,5H).

[0514] LCMS m / z=630.2[M+1] + .

[0515] Example 18: Preparation of Compound 18

[0516] Compound 18 was obtained using compound 18a as the raw material by referring to the synthetic method of Example 15.

[0517] 1H NMR(400MHz,DMSO-d6)δ10.74(s,1H),8.80(s,1H),8.03(s,1H),7.94–7.8 8(m,1H),7.71(dd,1H),7.45(d,1H),7.07–6.97(m,3H),6.93–6.83(m,2H) ,4.90(s,2H),4.60–4.45(m,2H),3.78–3.61(m,6H),2.84–2.51(m,5H),2. 49–2.40(m,1H),2.25–1.92(m,5H),1.85–1.65(m,4H),1.46–1.02(m,6H).

[0518] LCMS m / z=356.7[M / 2+1] + .

[0519] Example 19: Preparation of Compound 19

[0520] The trifluoroacetic acid salt of crude product 18c (0.15 g), DIPEA (0.39 g, 3.02 mmol), and 5 mL of DMSO were added to a reaction flask. After stirring at room temperature for 0.5 h, 4B (0.11 g, 0.27 mmol) was added and the reaction was continued at 100°C for 7 h. The reaction system was cooled to room temperature and the reaction solution was subjected to pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid chromatography, preparative column model SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: The crude product DMSO solution was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was ammonium acetate (5 mmol / L) in aqueous solution / acetonitrile. Gradient elution method: Acetonitrile was gradient eluted from 10% to 70% (elution time 12 min). The product was lyophilized to obtain compound 19 (15 mg, yield: 8%).

[0521] 1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),9.16(s,1H),8.10(s,1H),8.02–7.88(m,2H),7.74(dd,1H),7 .54–7.46(m,1H),7.34–6.95(m,5H),4.58(s,2H),4.55–4.42(m,2H),3.90–3.77(m,1H),3.73–3.57 (m,5H),3.25–2.95(m,2H),2.94–2.76(m,2H),2.74–2.57(m,4H),2.50–2.42(m,1H),2.27–2.10(m, 1H),2.07–1.95(m,1H),1.95–1.82(m,2H),1.82–1.70(m,2H),1.60–1.27(m,4H),1.25–1.05(m,2H).

[0522] Example 20: Preparation of trifluoroacetate salt of compound 20

[0523] To a 25 mL reaction vial, crude product 17b (0.11 g) of trifluoroacetic acid salt, 4B (0.11 g, 0.27 mmol), DIPEA (0.46 mL), and DMSO (5 mL) were added sequentially and reacted at 100°C for 7 h. The reaction system was cooled to room temperature and the reaction solution was subjected to Pre-HPLC (instrument and preparative column: Waters 2767 Preparative HPLC, SunFire@Prep C18, 5 μm, ID × length = 19 mm × 250 mm). Preparation method: The crude product DMSO solution was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was water (containing 0.1% trifluoroacetic acid) / acetonitrile. Gradient elution method: Acetonitrile was gradient eluted from 10% to 50% (elution time 13 min). The solution was then lyophilized to obtain the trifluoroacetic acid salt of compound 20 (18 mg).

[0524] 1 H NMR(400MHz,DMSO-d6)δ10.76(s,1H),9.21–9.07(m,1H),8.17–8.10(m,1H),8.03–7.92(m,2H),7.75(dd,1H),7.51(d,1H),7.18(s,1H),7.13 –7.04(m,2H),7.03–6.94(m,2H),4.60(s,2H),4.00–3.68(m,8H),3.28 –3.15(m,4H),2.72–2.57(m,4H),2.50–2.39(m,1H),2.22–1.94(m,2H).

[0525] LCMS m / z=645.2[M+1] + .

[0526] Example 21: Preparation of trifluoroacetate salt of compound 21

[0527] Step 1: Preparation of 21b

[0528] 21a (2.93 g, 10.34 mmol), potassium carbonate (6.49 g, 46.96 mmol), 21A (3.0 g, 9.41 mmol), L-proline (0.43 g, 3.73 mmol), and CuI (0.36 g, 1.89 mmol) were added to a reaction flask. DMSO (80 mL) was added, the nitrogen atmosphere was replaced three times, and the reaction was carried out at 90°C for 12 h. The reaction solution was cooled to room temperature, and ethyl acetate (100 mL) and water (100 mL) were added. The aqueous phase was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, 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) = 100:1 to 1:1) to obtain 21b (2.0 g, yield: 45%).

[0529] LCMS m / z=474.6[M+1] + .

[0530] Step 2: Preparation of 21c

[0531] 21b (1.50 g, 3.16 mmol), 21B (synthesis method see WO2021262812) (1.45 g, 3.47 mmol), Pd(dppf)Cl2·DCM (CAS: 95464-05-4) (0.26 g, 0.32 mmol) and cesium carbonate (2.06 g, 6.32 mmol) were added to a reaction flask, and 1,4-dioxane (10 mL) and water (2 mL) were added. The nitrogen was replaced three times and the reaction was carried out at 100°C for 20 h. The reaction solution was cooled to room temperature, and 100 mL of water and 100 mL of ethyl acetate were added. The liquid was separated, and the aqueous phase was extracted with ethyl acetate (20 mL×2). The organic phases were combined, 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 (petroleum ether / ethyl acetate (v / v) = 1:0-20:1) to obtain 21c (0.85 g, yield: 39%).

[0532] LCMS m / z=685.4[M+1] + .

[0533] Step 3: Preparation of 21d

[0534] 21c (450 mg, 0.66 mmol), 10% palladium on carbon (330 mg), and methanol (15 mL) were added sequentially to a reaction flask. The hydrogen atmosphere was replaced three times, and the reaction was allowed to proceed at 45°C under a hydrogen balloon for 20 h. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 21d (0.30 g).

[0535] LCMS m / z=507.3[M+1] + .

[0536] Step 4: Preparation of trifluoroacetate salt of 21e

[0537] The crude product 21d (150 mg) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (2 mL) was added, and the mixture was reacted at room temperature for 3 h. The reaction system was concentrated under reduced pressure to obtain the trifluoroacetic acid salt of the crude product 21e (160 mg).

[0538] LCMS m / z=407.5[M+1] + .

[0539] Step 5: Preparation of trifluoroacetate salt of compound 21

[0540] To a reaction flask, the trifluoroacetic acid salt of the crude product 21e (78 mg), DIPEA (200 mg, 1.55 mmol), and 15 mL of DMSO were added, followed by 4B (61 mg, 0.15 mmol) and the reaction was carried out at 100°C for 7 h. The reaction system was cooled to room temperature, and the crude product was subjected to Pre-HPLC (instrument and preparative column: Waters 2767 Preparative HPLC, SunFire@Prep C18, 5 μm, i.d. x length = 19 mm x 250 mm). Preparation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was water (containing 0.1% TFA) / acetonitrile. Gradient elution was performed: 10% acetonitrile to 50% (elution time 15 min). The product was then lyophilized to obtain the trifluoroacetic acid salt of compound 21 (15 mg).

[0541] 1H NMR(400MHz,DMSO-d6)δ10.86(s,1H),9.07(s,1H),8.15(s,1H),8.01–7.87(m,2H),7.72(dd, 1H),7.48(d,1H),7.17(s,1H),6.71–6.59(m,2H),4.59(s,2H),4.55–4.40(m,2H),4.10–4.00 (m,1H),3.87–3.75(m,2H),3.68(s,3H),3.63–3.51(m,2H),3.41–3.23(m,2H),3.14–2.97(m, 4H),2.86–2.71(m,3H),2.66(d,3H),2.56–2.51(m,1H),2.20–1.70(m,5H),1.37–1.15(m,2H).

[0542] LCMS m / z=778.8[M+1] + .

[0543] Example 22: Preparation of Compound 22

[0544] To a reaction flask, the trifluoroacetic acid salt (78 mg) of the crude product 21e, DIPEA (200 mg, 1.55 mmol), and 15 mL of DMSO were added. 1D (60 mg, 0.15 mmol) (synthesis method, see WO2021077010) was also added and the reaction was carried out at 100°C for 7 h. The reaction system was cooled to room temperature, and the reaction solution was subjected to pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, preparative column model SunFire@Prep C18, 5 μm, i.d. × length = 19 mm × 250 mm). Preparation method: The crude product DMSO solution was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was ammonium acetate (5 mmol / L) in water / acetonitrile. Gradient elution method: Acetonitrile was gradient eluted from 10% to 70% (elution time 12 min). The product was then lyophilized to obtain compound 22 (4.5 mg, yield: 4%).

[0545] 1H NMR(400MHz,DMSO-d6)δ10.85(s,1H),8.85(s,1H),8.04(s,1H),7.93–7.86(m,1H ),7.70(dd,1H),7.50–7.42(m,1H),7.05(s,1H),6.70–6.53(m,2H),4.91(s,2H),4 .09–3.98(m,1H),3.81–3.70(m,2H),3.66(s,3H),3.65–3.58(m,4H),2.85–2.64(m ,4H),2.44–2.30(m,4H),2.24–1.90(m,7H),1.85–1.67(m,3H),1.20–1.05(m,2H).

[0546] LCMS m / z=763.9[M+1] + .

[0547] Example 23: Preparation of Compound 23

[0548] Step 1: Preparation of 23b

[0549] To a reaction flask were added 23A (1.5 g, 13.02 mmol), potassium carbonate (3.6 g, 26.05 mmol), 23a (3.92 g, 13.03 mmol), L-proline (0.6 g, 5.21 mmol), and CuI (0.5 g, 2.63 mmol). DMSO (30 mL) was added, and the nitrogen atmosphere was replaced three times. The reaction was carried out at 50°C for 16 h. The reaction solution was cooled to room temperature, 50 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL × 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) = 3:2) to obtain 23b (2.5 g, yield: 67%).

[0550] LCMS m / z=288.3[M+1] + .

[0551] Step 2: Preparation of 23c

[0552] Under nitrogen, a reaction flask was charged with 23b (2.5 g, 8.70 mmol), 23B (synthesis method, see WO2021262812) (12.68 g, 30.34 mmol), Pd(dppf)Cl2·DCM (CAS: 95464-05-4) (0.71 g, 0.87 mmol), and cesium carbonate (11.31 g, 34.71 mmol). 40 mL of 1,4-dioxane and 8 mL of water were added, and the nitrogen atmosphere was replaced three times. The reaction was incubated at 100°C for 6 h. The reaction solution was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL x 3). 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 23c (3.2 g, yield: 74%).

[0553] LCMS m / z=499.3[M+1] + .

[0554] Step 3: Preparation of 23d

[0555] 23c (3.2 g, 6.42 mmol) and 10% palladium on carbon (3 g) were added to 100 mL of THF, the hydrogen atmosphere was replaced three times, and the mixture was allowed to react at room temperature under a hydrogen balloon for 16 h. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20:1) to obtain 23d (0.91 g, yield: 44%).

[0556] LCMS m / z=321.4[M+1] + .

[0557] Step 4: Preparation of 23e

[0558] 23d (0.30 g, 0.94 mmol) was dissolved in DMSO (3 mL), and 2-iodoacylbenzoic acid (0.42 g, 1.50 mmol) was added. The reaction was allowed to react at 50°C for 2 h. The reaction solution was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product 23e (0.28 g).

[0559] LCMS m / z=319.3[M+1] + .

[0560] Step 5: Preparation of 23f

[0561] The crude product 23e (0.28 g) was dissolved in 1,2-dichloroethane (30 mL), and tert-butyl piperazine-1-carboxylate (0.25 g, 1.34 mmol) and 0.33 mL of acetic acid were added. After stirring at room temperature for 1 h, sodium triacetoxyborohydride (0.56 g, 2.64 mmol) was added and the mixture was allowed to react at room temperature for 16 h. To the reaction solution was slowly added 50 mL of saturated aqueous sodium bicarbonate solution, and the mixture was extracted with 30 mL of dichloromethane. 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 (dichloromethane / methanol (v / v) = 10:1) to obtain 23f (0.33 g, yield: 50%).

[0562] LCMS m / z=489.3[M+1] + .

[0563] Step 6: Preparation of 23g of trifluoroacetate

[0564] 23f (330 mg, 0.676 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (2 mL) was added, and the mixture was reacted at room temperature for 3 h. The reaction solution was concentrated under reduced pressure to obtain 23 g of a crude trifluoroacetate salt (340 mg).

[0565] LCMS m / z=389.3[M+1] + .

[0566] Step 7: Preparation of compound 23

[0567] To a reaction flask, 23g of the crude product (150mg) of its trifluoroacetic acid salt, DIPEA (301mg, 2.33mmol), and 10mL of DMSO were added. 1D (100mg, 0.25mmol) (synthesis method, see WO2021077010) was also added, and the reaction was carried out at 100°C for 7h. The reaction system was cooled to room temperature, and the reaction solution was subjected to pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, SunFire@Prep C18, 5μm, i.d. x length = 19mm x 250mm). Preparation method: The DMSO solution of the crude product was filtered through a 0.45μm filter to prepare the sample solution. The mobile phase system was ammonium acetate (5mmol / L) in water / acetonitrile. Gradient elution method: Acetonitrile was gradient eluted from 10% to 70% (elution time 12min). The mixture was lyophilized to obtain compound 23 (24mg, yield: 13%).

[0568] 1H NMR(400MHz,DMSO-d6)δ10.78(s,1H),8.85(s,1H),8.05(s,1H),7.89(d,1H),7.7 0(dd,1H),7.45(d,1H),7.12–7.00(m,2H),6.77–6.63(m,2H),4.91(s,2H),3.93–3 .82(m,1H),3.77–3.55(m,9H),2.78–2.60(m,3H),2.58–2.45(m,1H),2.44–2.30(m ,4H),2.25–2.06(m,6H),2.03–1.90(m,1H),1.85–1.63(m,3H),1.28–1.08(m,2H).

[0569] LCMS m / z=745.3[M+1] + .

[0570] Example 24: Preparation of trifluoroacetate salt of compound 24

[0571] To a reaction flask, 23 g of the crude product (140 mg) of its trifluoroacetic acid salt, DIPEA (301 mg, 2.33 mmol), and 10 mL of DMSO were added. Then, 4B (100 mg, 0.24 mmol) was added and the reaction was carried out at 100°C for 7 h. The reaction system was cooled to room temperature, and the reaction solution was subjected to Pre-HPLC (instrument and preparative column: Waters 2767 Preparative HPLC, SunFire@Prep C18, 5 μm, ID x length = 19 mm x 250 mm). Preparation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile was gradient eluted from 10% to 50% (elution time 15 min). The solution was then lyophilized to obtain the trifluoroacetic acid salt of compound 24 (50 mg).

[0572] 1H NMR(400MHz,DMSO-d6)δ10.80(s,1H),9.07(s,1H),8.15(s,1H),8.00–7.86(m,2H),7.72(dd,1H ),7.48(d,1H),7.17(s,1H),7.13–7.03(m,1H),6.82–6.68(m,2H),4.62–4.38(m,4H),3.94–3.83 (m,1H),3.83–3.70(m,2H),3.68(s,3H),3.64–3.50(m,2H),3.40–3.22(m,2H),3.15–2.95(m,4H) ,2.80–2.60(m,6H),2.57–2.47(m,1H),2.25–1.89(m,3H),1.88–1.73(m,2H),1.43–1.20(m,2H).

[0573] LCMS m / z=760.8[M+1] + .

[0574] The trifluoroacetic acid salt of compound 24 was subjected to chiral resolution to obtain chiral isomer 1 and chiral isomer 2, respectively. The resolution conditions are as follows:

[0575] 1. Instrument: Waters 150Prep-SFC E; Column: Chiralcel AD column.

[0576] 2. Dissolve the sample in acetonitrile and filter with a 0.45 μm filter to prepare a sample solution.

[0577] 3. Preparative chromatographic conditions: a. Mobile phases consisted of systems A and B: Mobile phase A: CO2; Mobile phase B: a methanol / acetonitrile mixture containing 0.1% ammonia; b. Isocratic elution, mobile phase B content: 65%; c. Flow rate: 100 mL / min.

[0578] Chiral analysis method:

[0579] 1. Instrument: SHIMAZU LC-30AD; Chromatographic column: Chiral AD column.

[0580] 2. Analytical chromatographic conditions: a. Mobile phases consisted of a system A and B: Mobile phase A: CO2; Mobile phase B: 0.05% diethylamine in isopropanol and acetonitrile; b. Isocratic elution, mobile phase B content: 60%; c. Flow rate: 3 mL / min.

[0581] Peak time: chiral isomer 1: 1.028 min, chiral isomer 2: 1.431 min.

[0582] NMR characterization of chiral isomer 1:

[0583] 1 H NMR(400MHz,DMSO-d6)δ10.77(s,1H),8.84(s,1H),8.20–8.00(m,1H),7.98–7.87(m, 2H),7.74(dd,1H),7.47(d,1H),7.17–7.00(m,2H),6.75–6.62(m,2H),4.58(s,2H),3 .94–3.82(m,1H),3.76–3.58(m,9H),2.80–2.59(m,6H),2.56–2.45(m,1H),2.44–2.3 2(m,4H),2.25–2.05(m,3H),2.03–1.88(m,1H),1.86–1.64(m,3H),1.30–1.10(m,2H).

[0584] NMR characterization of chiral isomer 2:

[0585] 1 H NMR(400MHz,DMSO-d6)δ10.77(s,1H),8.84(s,1H),8.20–8.00(m,1H),7.98–7.87(m, 2H),7.74(dd,1H),7.47(d,1H),7.17–7.00(m,2H),6.75–6.62(m,2H),4.58(s,2H),3 .94–3.82(m,1H),3.76–3.58(m,9H),2.80–2.59(m,6H),2.56–2.45(m,1H),2.44–2.3 2(m,4H),2.25–2.05(m,3H),2.03–1.88(m,1H),1.86–1.64(m,3H),1.30–1.10(m,2H).

[0586] Example 25: Preparation of trifluoroacetate salt of compound 25

[0587] Step 1: Preparation of 25b

[0588] To a 50 mL reaction flask, 25a (0.3 g, 1.15 mmol) (synthesis method, see WO2019119138), 2,4-dichloropyrimidine (0.21 g, 1.41 mmol), DIPEA (0.45 g, 3.48 mmol), and DMF (5 mL) were added. The nitrogen atmosphere was replaced three times and the reaction was carried out at 80°C for 2 h. The reaction system was cooled to room temperature, and the precipitated solid was filtered. The filter cake was washed with 6 mL of a 2:1 dichloromethane / methanol (v / v) mixture and dried under reduced pressure to obtain 25b (0.23 g, yield: 54%).

[0589] LCMS m / z=374.1[M+1] + .

[0590] Step 2: Preparation of trifluoroacetate salt of compound 25

[0591] The trifluoroacetic acid salt of the crude product 8c (70 mg), 25b (71 mg, 0.19 mmol), DIPEA (0.12 g, 0.93 mmol), and DMSO (5 mL) were added to a reaction flask. The atmosphere was purged with nitrogen three times and the reaction was carried out at 100°C for 16 h. The reaction system was cooled to room temperature and the reaction solution was subjected to Pre-HPLC (instrument and preparative column: Waters 2767 Preparative HPLC, SunFire@Prep C18, 5 μm, ID × length = 19 mm × 250 mm). Preparation method: The crude product DMSO solution was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was water (containing 0.1% trifluoroacetic acid) / acetonitrile. Gradient elution method: Acetonitrile was gradient eluted from 10% to 50% (elution time 20 min). The solution was then lyophilized to obtain the trifluoroacetic acid salt of compound 25 (10.0 mg).

[0592] 1 H NMR(400MHz,DMSO-d6)δ9.36(s,1H),8.01–7.88(m,3H),7.67(dd,1H),7.46(d,1H),7.12(s,1H),7.07–6.99(m,2H),6.93–6.84(m,2H),6.0 5(d,1H),4.58(s,2H),3.76–3.62(m,10H),2.71–2.57(m,6H),2.49–2 .38(m,5H),2.26–1.94(m,4H),1.90–1.60(m,3H),1.33–1.12(m,2H).

[0593] LCMS m / z=355.0[M / 2+1] + .

[0594] Example 26: Preparation of Compound 26

[0595] Compound 26 was obtained using 26a (synthesis method see WO2021077010) as raw material and referring to the synthesis method of Example 25.

[0596] 1 H NMR(400MHz,DMSO-d6)δ10.75(s,1H),9.32(s,1H),7.93(d,1H),7.87(d,1H),7.66(dd,1H),7.44(d,1H),7.08–6.98(m,3H),6.93–6.84(m,2H) ,6.04(d,1H),4.91(s,2H),3.80–3.58(m,10H),2.72–2.57(m,3H),2.50 –2.35(m,5H),2.26–1.94(m,7H),1.90–1.61(m,3H),1.33–1.14(m,2H).

[0597] LCMS m / z=693.4[M+1] + .

[0598] Example 27: Preparation of trifluoroacetate salt of compound 27

[0599] Step 1: Preparation of 27b

[0600] To a reaction flask, 27a (5.00 g, 21.71 mmol), 4-bromo-1-fluoro-2-nitrobenzene (7.16 g, 32.55 mmol), cesium carbonate (21.22 g, 65.13 mmol), and 30 mL of DMSO were added and reacted at 110°C for 2 h. The reaction solution was cooled to room temperature, and 50 mL of ethyl acetate and 50 mL of water were added. The pH was adjusted to 5 with 3 mol / L hydrochloric acid. The layers were separated, and the aqueous phase was extracted with ethyl acetate (20 mL x 2). 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) = 1:1) to obtain 27b (7.6 g, yield: 81%).

[0601] Step 2: Preparation of 27c

[0602] To a reaction flask, 27b (6.60 g, 15.34 mmol), zinc powder (5.02 g, 77.234 mmol), ammonium chloride (8.21 g, 153.48 mmol), and 80 mL of ethanol were added and refluxed for 4 h. The reaction solution was cooled to room temperature, filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. 50 mL of ethyl acetate and 50 mL of water were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, 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 27c (2.30 g, yield: 39%).

[0603] Step 3: Preparation of 27d

[0604] To the reaction flask, 27c (1.40 g, 3.66 mmol), 20 mL of 1,4-dioxane and 5 mL of water were added respectively. Under nitrogen protection, 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4.58 g, 10.98 mmol) (synthesis method see WO2021262812), cesium carbonate (3.58 g, 10.99 mmol) and Pd(dppf)Cl2 (0.27 g, 0.37 mmol) were added. The nitrogen was replaced three times and the reaction was carried out at 100°C for 16 h. The reaction system was cooled to room temperature and filtered through a pad of celite. 50 mL of ethyl acetate and 50 mL of water were added to the filtrate, and the aqueous phase was extracted with ethyl acetate (20 mL×3). The organic phases were combined, 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 (petroleum ether:ethyl acetate (v / v) = 2:1) to obtain 27d (2.0 g, yield: 92%).

[0605] Step 4: Preparation of 27e

[0606] To a reaction flask, 27d (2.0 g, 3.37 mmol), 40 mL of THF, and 10% Pd / C (1.00 g) were added. The hydrogen atmosphere was replaced three times, and the mixture was allowed to react at room temperature under a hydrogen balloon for 16 h. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to afford 27e (0.85 g, 61% yield).

[0607] Step 5: Preparation of 27f

[0608] 27e (0.30 g, 0.72 mmol), 1.5 mL of trifluoroacetic acid, and 5 mL of dichloromethane were added to a reaction flask and allowed to react at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, triethylamine was added to adjust the pH to 7, and the solution was concentrated under reduced pressure. To the residue was added 6 mL of THF, followed by tert-butyl 4-formylpiperidine-1-carboxylate (0.20 g, 0.94 mmol), 0.5 mL of acetic acid, and sodium triacetoxyborohydride (0.31 g, 1.46 mmol). The reaction was allowed to react at room temperature for 16 h. 10 mL of ethyl acetate and 10 mL of saturated aqueous sodium bicarbonate were added to the reaction solution. The aqueous phase was extracted with ethyl acetate (5 mL x 3). The organic phases were combined, 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 (dichloromethane:methanol (v / v) = 20:1) to afford 27f (0.31 g, yield: 84%).

[0609] LCMS m / z=512.3[M+1] + .

[0610] Step 6: Preparation of 27g of trifluoroacetate

[0611] 27f (0.31 g, 0.61 mmol), 1.5 mL of trifluoroacetic acid, and 5 mL of dichloromethane were added to a reaction flask and reacted at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain 27 g of the crude trifluoroacetate salt (0.38 g).

[0612] Step 7: Preparation of trifluoroacetate salt of compound 27

[0613] To a reaction flask, 27 g of the crude product (trifluoroacetic acid salt, 0.19 g), DIPEA (0.47 g, 3.64 mmol), and 5 mL of DMSO were added. After stirring at room temperature for 0.5 h, 4B (0.12 g, 0.29 mmol) was added and the reaction was allowed to proceed at 100°C for 7 h. The reaction system was cooled to room temperature and the reaction solution was subjected to Pre-HPLC (instrument and preparative column: Waters 2767 Preparative HPLC, SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile was gradient eluted from 10% to 50% (elution time 15 min). The solution was then lyophilized to obtain the trifluoroacetic acid salt of compound 27 (66 mg).

[0614] 1H NMR(400MHz,DMSO-d6)δ10.81(s,2H),8.99(s,1H),8.09(s,1H),8.02–7.89(m,2H ),7.75(dd,1H),7.47(d,1H),7.12(s,1H),6.93–6.82(m,2H),6.76–6.69(m,1H),4 .59(s,2H),4.54–4.40(m,2H),4.00–3.62(m,8H),3.35–2.86(m,7H),2.74–2.58(m ,4H),2.54–2.42(m,1H),2.35–1.92(m,3H),1.89–1.71(m,2H),1.30–1.10(m,2H).

[0615] LCMS m / z=392.2[M / 2+1] + .

[0616] Example 28: Preparation of Compound 28

[0617] Step 1: Preparation of 28a

[0618] To a reaction flask, 27c (1.3 g, 3.40 mmol), iodomethane (1.45 g, 10.22 mmol), cesium carbonate (3.32 g, 10.19 mmol), and 30 mL of DMF were added and reacted at room temperature for 16 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 aqueous phase was extracted with ethyl acetate (10 mL x 2). 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) = 3:1) to obtain 28a (1.25 g, yield: 93%).

[0619] Step 2: Preparation of 28b

[0620] 28a (1.30 g, 3.28 mmol), 20 mL of 1,4-dioxane and 5 mL of water were added to the reaction flask respectively. Under nitrogen protection, 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4.11 g, 9.85 mmol) (synthesis method see WO2021262812), cesium carbonate (3.21 g, 9.85 mmol) and Pd(dppf)Cl2 (0.24 g, 0.33 mmol) were added. The nitrogen was replaced three times and the reaction was carried out at 100°C for 16 h. The reaction system was cooled to room temperature and filtered through a pad of celite. 50 mL of ethyl acetate and 50 mL of water were added to the filtrate, and the aqueous phase was extracted with ethyl acetate (20 mL×3). The organic phases were combined, 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 (petroleum ether:ethyl acetate (v / v) = 2:1) to obtain 28b (1.80 g, yield: 90%).

[0621] Step 3: Preparation of 28c

[0622] To a reaction flask, 28b (1.8 g, 2.97 mmol), 40 mL of THF, and 10% Pd / C (0.9 g) were added. The hydrogen atmosphere was replaced three times, and the mixture was allowed to react at room temperature under a hydrogen balloon for 16 h. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to afford 28c (0.90 g, 71% yield).

[0623] Step 4: Preparation of 28d

[0624] To a reaction flask, 28c (0.30 g, 0.70 mmol), 1.5 mL of trifluoroacetic acid, and 5 mL of dichloromethane were added and allowed to react at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, triethylamine was added to adjust the pH to 7, and the reaction was concentrated under reduced pressure. 6 mL of THF was added, followed by tert-butyl 4-formylpiperidine-1-carboxylate (0.19 g, 0.891 mmol), 0.5 mL of acetic acid, and sodium triacetoxyborohydride (0.30 g, 1.42 mmol). The reaction was allowed to react at room temperature for 16 h. 10 mL of ethyl acetate and 10 mL of saturated aqueous sodium bicarbonate were added to the reaction solution. The aqueous phase was extracted with ethyl acetate (5 mL x 3). The organic phases were combined, 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 (dichloromethane:methanol (v / v) = 20:1) to obtain 28d (0.30 g, yield: 82%).

[0625] LCMS m / z=526.3[M+1] + .

[0626] Step 5: Preparation of trifluoroacetate salt of 28e

[0627] 28d (0.30 g, 0.57 mmol), 1.5 mL of trifluoroacetic acid, and 5 mL of dichloromethane were added to a reaction flask and reacted at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the crude trifluoroacetic acid salt of 28e (0.36 g).

[0628] Step 6: Preparation of compound 28

[0629] The trifluoroacetic acid salt of crude product 28e (0.18 g), DIPEA (0.43 g, 3.30 mmol), and 5 mL of DMSO were added to a reaction flask. After stirring at room temperature for 0.5 h, 4B (0.11 g, 0.27 mmol) was added and the reaction was continued at 100°C for 7 h. The reaction system was cooled to room temperature and the reaction solution was subjected to pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, preparative column model SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: The crude product DMSO solution was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was ammonium acetate (5 mmol / L) in aqueous solution / acetonitrile. Gradient elution method: Acetonitrile was gradient eluted from 10% to 70% (elution time 12 min). The product was then lyophilized to obtain compound 28 (70 mg, yield: 33%).

[0630] 1 H NMR (400MHz, DMSO-d6) δ10.78(s,1H),8.79(s,1H),8.03(s,1H),7.98–7.88(m,2H),7.77(dd,1H),7. 47(d,1H),7.10(s,1H),6.98–6.92(m,1H),6.91–6.77(m,2H),4.63–4.41(m,4H),3.85–3.74(m,1H),3 .73–3.63(m,3H),3.58–3.47(m,1H),3.47–3.37(m,1H),3.25(s,3H),3.00–2.78(m,3H),2.76–2.58(m ,5H),2.56–2.43(m,2H),2.34–2.16(m,3H),2.14–1.95(m,3H),1.90–1.70(m,3H),1.15–0.97(m,2H).

[0631] LCMS m / z=399.5[M / 2+1] + .

[0632] Example 29: Preparation of Compound 29

[0633] To a reaction flask, add 27g of the crude product (0.19g) of its trifluoroacetic acid salt, DIPEA (0.47g, 3.64mmol), and 5mL of DMSO. After stirring at room temperature for 0.5h, add 1D (0.12g, 0.31mmol) (synthesis method, see WO2021077010) and react at 100°C for 7h. Cool the reaction system to room temperature, and the reaction solution is subjected to Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid chromatography, preparative column model SunFire@Prep C18, 5μm, inner diameter × length = 19mm × 250mm). Preparation method: Filter the crude product in DMSO through a 0.45μm filter to prepare the sample solution. The mobile phase system is an aqueous solution of ammonium acetate (5mmol / L) in acetonitrile. Gradient elution method: acetonitrile was gradient eluted from 10% to 70% (elution time 12 min), and lyophilized to obtain compound 29 (20 mg, yield: 8%).

[0634] 1 H NMR(400MHz,DMSO-d6)δ10.78(s,1H),10.46(s,1H),8.79(s,1H),8.03(s,1H),7.90(d,1H),7.72(dd,1H),7 .45(d,1H),7.02(s,1H),6.83–6.73(m,2H),6.66(s,1H),4.89(s,2H),4.55–4.40(m,2H),3.77–3.68(m,1H), 3.66(s,3H),3.63–3.51(m,1H),3.47–3.37(m,1H),3.30–3.22(m,1H),2.99–2.77(m,3H),2.75–2.57(m,2H), 2.50–2.41(m,1H),2.30–2.21(m,2H),2.18(s,3H),2.14–1.92(m,4H),1.90–1.65(m,3H),1.14–0.96(m,2H).

[0635] LCMS m / z=384.6[M / 2+1] + .

[0636] Example 30: Preparation of Compound 30

[0637] The trifluoroacetic acid salt (0.18 g) of the crude product 28e, DIPEA (0.43 g, 3.30 mmol), and 5 mL of DMSO were added to a reaction flask. After stirring at room temperature for 0.5 h, 30A (0.10 g, 0.26 mmol) (synthesis method, see WO2021077010) was added and the reaction was carried out at 100°C for 7 h. The reaction system was cooled to room temperature, and the reaction solution was subjected to pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid chromatography, preparative column model SunFire@Prep C18, 5 μm, i.d. × length = 19 mm × 250 mm). Preparation method: The crude product DMSO solution was filtered through a 0.45 μm filter membrane to prepare the sample solution. The mobile phase system was an aqueous solution of ammonium acetate (5 mmol / L) in acetonitrile. Gradient elution method: acetonitrile was gradient eluted from 10% to 70% (elution time 12 min), and lyophilized to obtain compound 30 (20 mg, yield: 10%).

[0638] 1 H NMR(400MHz,DMSO-d6)δ10.78(s,1H),8.79(s,1H),8.03(s,1H),7.90(d,1H),7.72(dd,1H),7.45(d,1H), 7.02(s,1H),6.98–6.92(m,1H),6.91–6.78(m,2H),4.89(s,2H),4.56–4.40(m,2H),3.85–3.75(m,1H),3. 66(s,3H),3.58–3.48(m,1H),3.42(dd,1H),3.37–3.28(m,1H),3.25(s,3H),3.02–2.77(m,3H),2.77–2.5 7(m,2H),2.55–2.42(m,1H),2.35–2.14(m,6H),2.14–1.95(m,3H),1.92–1.65(m,3H),1.14–0.95(m,2H).

[0639] LCMS m / z=391.7[M / 2+1] + .

[0640] Example 31: Preparation of trifluoroacetate salt of compound 31

[0641] The trifluoroacetate salt of compound 31 was obtained using compound 31a as raw material according to the synthesis method of Example 27.

[0642] 1H NMR(400MHz,DMSO-d6)δ10.81(s,2H),8.94(s,1H),8.08(s,1H),8.02–7.90(m,2 H),7.75(dd,1H),7.47(d,1H),7.12(s,1H),6.93–6.81(m,2H),6.73(s,1H),4.59 (s,2H),4.54–4.40(m,2H),4.05–3.45(m,8H),3.34–2.85(m,7H),2.74–2.57(m, 4H),2.55–2.40(m,1H),2.37–1.93(m,3H),1.88–1.70(m,2H),1.30–1.10(m,2H).

[0643] LCMS m / z=392.4[M / 2+1] + .

[0644] Example 32: Preparation of Trifluoroacetate Salt of Compound 32

[0645] The trifluoroacetate of compound 32 was prepared from compound 31c by referring to the synthesis method of Example 28.

[0646] 1 H NMR(400MHz,DMSO-d6)δ10.81(s,1H),9.07(s,1H),8.11(s,1H),8.04–7.86(m,2H),7.79– 7.69(m,1H),7.47(d,1H),7.12(s,1H),7.05(s,1H),6.99–6.90(m,2H),4.59(s,2H),4.52– 4.39(m,2H),4.03–3.71(m,5H),3.68(s,3H),3.37–2.88(m,10H),2.74–2.61(m,4H),2.58 –2.47(m,1H),2.37–2.13(m,2H),2.08–1.93(m,1H),1.90–1.72(m,2H),1.30–1.10(m,2H).

[0647] LCMS m / z=399.4[M / 2+1] + .

[0648] Example 33: Preparation of trifluoroacetate salt of compound 33

[0649] Step 1: Preparation of 33b

[0650] To a reaction flask, 33a (9.90 g, 51.53 mmol), bromomethylcyclopropane (10.43 g, 77.26 mmol), potassium carbonate (17.80 g, 128.8 mmol), and 100 mL of DMF were added and allowed to react at room temperature for 16 h. To the reaction solution, 100 mL of ethyl acetate and 100 mL of saturated sodium chloride were added. The pH was adjusted to 6 with 1 mol / L hydrochloric acid. The layers were separated, and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with 100 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product (12 g). The crude product (12 g), DIPEA (11.74 g, 90.83 mmol), HATU (18.99 g, 49.94 mmol), and 200 mL of dichloromethane were added to the reaction flask and allowed to react at room temperature for 2 h. To the reaction solution was added 100 mL of water, the mixture was separated, and the aqueous phase was extracted with dichloromethane (50 mL × 2). The organic phases were combined, 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) = 1:1) to give 33b (5.2 g, two-step yield: 41%).

[0651] LCMS m / z=247.0[M+1] + .

[0652] Step 2: Preparation of 33c

[0653] To a reaction flask, 33b (5.2 g, 21.14 mmol), triethylamine (4.45 g, 43.98 mmol), and 100 mL of ethanol were added. A 2 mol / L solution of trimethylsilylated diazomethane in n-hexane (22.00 mL, 44 mmol) was added dropwise under nitrogen. The mixture was allowed to react at room temperature for 3 h. 300 mL of ethyl acetate and 300 mL of saturated sodium chloride were added to the reaction solution. The layers were separated, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with 100 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) = 1:1) to afford 33c (3.1 g, 53% yield).

[0654] LCMS m / z=275.1[M+1] + .

[0655] Step 3: Preparation of 33d

[0656] To a reaction flask, 33c (3.1 g, 11.30 mmol) and 50 mL of dichloromethane were added. The mixture was cooled to 0°C under nitrogen atmosphere, and a 1 mol / L solution of boron tribromide in dichloromethane (33.90 mL, 33.90 mmol) was added dropwise. The reaction was allowed to react at room temperature for 2 h. 30 mL of dichloromethane was added to the reaction solution, and the layers were separated. The aqueous phase was extracted with dichloromethane (20 mL x 3). The organic phases were combined, 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 (petroleum ether:ethyl acetate (v / v) = 1:1) to afford 33d (2.3 g, 78% yield).

[0657] LCMS m / z=261.2[M+1] + .

[0658] Step 4: Preparation of 33e

[0659] To a reaction flask, 33d (2.1 g, 8.07 mmol), cesium carbonate (5.26 g, 16.14 mmol), 2-bromo-N-methylacetamide (1.47 g, 9.67 mmol), and 40 mL of DMF were added and reacted at room temperature for 2 h. The reaction solution was poured into 200 mL of ice water, filtered, and the filter cake was washed with 10 mL of water to obtain crude product 33e (9.0 g).

[0660] Step 5: Preparation of 33f

[0661] To a reaction flask, add the crude product 33e (9.0 g), 70 mL of dichloromethane, 70 mL of methanol, and 10% Pd / C (1.6 g). The hydrogen atmosphere is replaced three times, and the mixture is allowed to react at room temperature under a hydrogen balloon for 16 h. The reaction mixture is filtered through a pad of Celite, and the filtrate is concentrated under reduced pressure to afford the crude product 33f (2.1 g).

[0662] LCMS m / z=302.3[M+1] + .

[0663] Step 6: Preparation of 33g

[0664] To a reaction flask, crude product 33f (2.1 g), 2,4,5-trichloropyrimidine (1.53 g, 8.34 mmol), and 30 mL of DMF were added and reacted at 70°C for 2 h. The reaction solution was cooled to room temperature, poured into 150 mL of ice water, and filtered. The filter cake was washed with 20 mL of water and air-dried at 50°C to yield crude product 33 g (2.9 g).

[0665] Step 7: Preparation of trifluoroacetate salt of compound 33

[0666] The trifluoroacetic acid salt of crude product 8c (0.25 g), DIPEA (0.67 g, 5.18 mmol), and 5 mL of DMSO were added to a reaction flask. After stirring at room temperature for 0.5 h, 33 g (0.19 g) of the crude product was added and the mixture was reacted at 100°C for 7 h. The reaction system was cooled to room temperature and the reaction solution was subjected to pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid chromatography, preparative column model SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile was gradient eluted from 10% to 50% (elution time 15 min). The solution was then lyophilized to obtain the trifluoroacetic acid salt of compound 33 (200 mg).

[0667] 1 H NMR(400MHz,DMSO-d6)δ10.83–10.77(m,1H),9.16–9.06(m,1H),8.19–8.14(m,1H),8.0 5–7.91(m,2H),7.77–7.69(m,1H),7.65–7.58(m,1H),7.27–7.09(m,5H),4.65–4.40(m,4 H),4.30–4.18(m,2H),3.88–3.50(m,5H),3.45–3.22(m,2H),3.20–2.88(m,6H),2.74–2 .57(m,4H),2.55–2.43(m,1H),2.28–1.80(m,5H),1.60–1.18(m,3H),0.54–0.40(m,4H).

[0668] LCMS m / z=391.7[M / 2+1] + .

[0669] Example 34: Preparation of trifluoroacetate salt of compound 34

[0670] Step 1: Preparation of 34b

[0671] To a reaction flask, 34a (1.50 g, 7.81 mmol), 12 mL of acetone, and 6 mL of water were added. Under nitrogen, sodium azide (2.55 g, 39.2 mmol) was added and the mixture was allowed to react at room temperature for 16 h. The reaction solution was cooled to room temperature, and 30 mL of ethyl acetate and 50 mL of saturated sodium chloride were added. The layers were separated, and the aqueous phase was extracted with ethyl acetate (15 mL x 2). The organic phases were combined, washed with 50 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 34b (0.92 g).

[0672] Step 2: Preparation of 34c

[0673] To a reaction flask, crude product 34b (0.20 g), 1-Boc-4-ethynylpiperidine (0.33 g, 1.58 mmol), anhydrous copper sulfate (0.02 g, 0.125 mmol), sodium ascorbate (0.10 g, 0.505 mmol), 3 mL of THF, and 1 mL of water were added and allowed to react at room temperature for 3 h. The reaction system was filtered, and 10 mL of ethyl acetate and 10 mL of water were added to the filtrate. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phases were 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 (dichloromethane:methanol (v / v) = 10:1) to obtain 34c (0.45 g, yield: 78%).

[0674] Step 3: Preparation of 34d

[0675] To a reaction flask, 34c (0.45 g, 1.24 mmol), 2 mL of trifluoroacetic acid, and 5 mL of dichloromethane were added and allowed to react at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, the pH was adjusted to 7 with triethylamine, and the reaction was concentrated under reduced pressure. 10 mL of THF was added, followed by tert-butyl 4-formylpiperidine-1-carboxylate (0.29 g, 1.36 mmol), 0.5 mL of acetic acid, and sodium triacetoxyborohydride (0.53 g, 2.50 mmol). The reaction was allowed to react at room temperature for 16 h. 20 mL of ethyl acetate and 20 mL of saturated aqueous sodium bicarbonate were added to the reaction solution. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, 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 (dichloromethane:methanol (v / v) = 5:1) to afford 34d (0.38 g, yield: 67%).

[0676] Step 4: Preparation of trifluoroacetate salt of 34e

[0677] To a reaction flask, 34d (0.19 g, 0.41 mmol), 1 mL of trifluoroacetic acid, and 3 mL of dichloromethane were added and reacted at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the crude trifluoroacetic acid salt of 34e (0.23 g).

[0678] Step 5: Preparation of trifluoroacetate salt of compound 34

[0679] The trifluoroacetic acid salt of crude product 34e (0.38 g), DIPEA (0.62 g, 4.8 mmol), and 5 mL of DMSO were added to a reaction flask. After stirring at room temperature for 0.5 h, 4B (0.16 g, 0.39 mmol) was added and the reaction was continued at 100°C for 7 h. The reaction system was cooled to room temperature and the reaction solution was subjected to pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid chromatography, preparative column model SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: The crude product DMSO solution was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile was gradient eluted from 10% to 50% (elution time 15 min). The solution was then lyophilized to obtain the trifluoroacetic acid salt of compound 34 (60 mg).

[0680] 1 H NMR(400MHz,DMSO-d6)δ11.23(s,1H),9.09–8.97(m,1H),8.17–7.89(m,4H),7.88–7.68(m,1H),7.47(d,1H),7.12(s,1H),5.84–5.72( m,1H),4.60(s,2H),4.53–4.40(m,2H),3.74–3.55(m,5H),3.26–2.77(m,8H),2.75–2.55(m,5H),2.37–1.69(m,8H),1.30–1.05(m,2H).

[0681] LCMS m / z=732.9[M+1] + .

[0682] Example 35: Preparation of Compound 35

[0683] Step 1: Preparation of 35b

[0684] Compound 35a (synthesis method, see Bioorg. Med. Chem., 2016, 26, 5877) (1.50 g, 4.08 mmol), 35A (synthesis method, see WO2022171123) (3.41 g, 8.16 mmol), Pd(dppf)Cl2·DCM (0.33 g, 0.41 mmol) and cesium carbonate (2.66 g, 8.16 mmol) were added sequentially to a reaction flask, and 1,4-dioxane (30 mL) and water (3 mL) were added. The nitrogen atmosphere was replaced three times, and the reaction was carried out at 100°C for 20 h. The reaction system was cooled to room temperature, and 200 mL of water and 200 mL of ethyl acetate were added. The liquids were separated, and the aqueous phase was extracted with ethyl acetate (50 mL). The organic phases were combined, 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) = 1:0-9:1) to give 35b (2.36 g, yield: >99%).

[0685] Step 2: Preparation of 35c

[0686] 35b (0.95 g, 1.64 mmol) was dissolved in THF (30 mL), and 10% palladium on carbon (0.87 g) was added. The hydrogen atmosphere was replaced three times, and the mixture was reacted at 45°C under a hydrogen balloon for 20 h. The reaction solution was cooled to room temperature, filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (methanol:dichloromethane (v / v) = 0:1-5:95) to obtain 35c (0.60 g, yield: 92%).

[0687] LCMS m / z=400.4[M+1] + .

[0688] Step 3: Preparation of 35d

[0689] 35c (600 mg, 1.50 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (2 mL) was added, and the mixture was allowed to react at room temperature for 3 h. The reaction system was concentrated under reduced pressure, 5 mL of dichloromethane and 1 mL of triethylamine were added, and the mixture was concentrated under reduced pressure to give the crude product 35d (450 mg).

[0690] LCMS m / z=300.4[M+1] + .

[0691] Step 4: Preparation of 35e

[0692] The crude product 35d (0.45 g) was dissolved in dichloroethane (30 mL), and tert-butyl 4-formylpiperidine-1-carboxylate (0.48 g, 2.25 mmol) and 3 mL of acetic acid were added. After stirring at room temperature for 1 h, sodium triacetoxyborohydride (0.64 g, 3.0 mmol) was added and the mixture was allowed to react at room temperature for 16 h. 50 mL of saturated aqueous sodium bicarbonate was slowly added to the reaction solution, and the mixture was extracted twice with 50 mL of dichloromethane. The organic phase was washed with 100 mL of saturated aqueous sodium chloride, 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 obtain 35e (0.33 g, yield: 30%).

[0693] LCMS m / z=497.3[M+1] + .

[0694] Step 5: Preparation of trifluoroacetate salt of 35f

[0695] 35e (100 mg, 6.65 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, and the mixture was reacted at room temperature for 3 h. The reaction system was concentrated under reduced pressure to obtain the crude trifluoroacetate salt of 35f (100 mg).

[0696] LCMS m / z=397.3[M+1] + .

[0697] Step 6: Preparation of compound 35

[0698] To a reaction flask, the trifluoroacetic acid salt (100 mg) of the crude product 35f, DIPEA (200 mg, 1.55 mmol), and 15 mL of DMSO were added. 4B (80 mg, 0.20 mmol) was then added and the reaction was carried out at 100°C for 7 h. The reaction system was cooled to room temperature and the reaction solution was subjected to Pre-HPLC (instrument and preparative column: Waters 2767 Preparative HPLC, SunFire@Prep C18, 5 μm, i.d. x length = 19 mm x 250 mm). Preparation method: The crude product DMSO solution was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system consisted of aqueous ammonium acetate (5 mmol / L) / acetonitrile. Gradient elution was performed: 10% to 70% acetonitrile (elution time 12 min). The product was then lyophilized to afford compound 35 (10 mg, yield: 7%).

[0699] 1H NMR(400MHz,DMSO-d6)δ10.72(s,1H),8.80(s,1H),8.08–7.86(m,3H),7.77(dd,1H),7.47(d,1H),7.12(s,1H),6.90–6.70(m,3H),4. 64–4.38(m,4H),3.78–3.60(m,6H),2.97–2.55(m,12H),2.50–2.37(m,1H),2.22–1.92(m,5H),1.90–1.50(m,5H),1.14–0.94(m,2H).

[0700] LCMS m / z=768.3[M+1] + .

[0701] Example 36: Preparation of trifluoroacetate salt of compound 36

[0702] Step 1: Preparation of 36a and 36b

[0703] To a reaction flask, 33a (10 g, 52.05 mmol), cyclopropylboronic acid (8.94 g, 104.07 mmol), sodium carbonate (11.03 g, 104.07 mmol), 2,2'-bipyridine (8.13 g, 52.06 mmol), anhydrous copper acetate (9.45 g, 52.03 mmol) and 1,2-dichloroethane (200 mL) were added and the mixture was reacted at 70°C under air atmosphere for 16 h. The reaction solution was cooled to room temperature, and 200 mL of aqueous ammonium chloride solution was added. The pH was adjusted to 6 with 1 mol / L hydrochloric acid. The layers were separated, and the aqueous phase was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with 100 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 (first eluted with petroleum ether:ethyl acetate (v / v) = 2:1, then with dichloromethane:methanol (v / v) = 5:1) to give 36b (0.79 g, yield: 7%) and crude 36a (3.5 g), respectively.

[0704] Step 2: Preparation from 36a to 36b

[0705] To a reaction flask, crude product 36a (3.5 g), DIPEA (5.42 g, 41.93 mmol), HATU (7.98 g, 20.99 mmol), and 100 mL of dichloromethane were added and reacted at room temperature for 2 h. 100 mL of water was added to the reaction mixture, and the layers were separated. The aqueous phase was extracted with dichloromethane (50 mL x 2). The organic phases were combined, 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) = 2:1) to afford 36b (1.2 g, 10% yield over two steps based on compound 33a).

[0706] The trifluoroacetate of compound 36 was prepared from compound 36b by lyophilization in acidic solution (water (containing 0.1% TFA) / acetonitrile) according to the synthesis method of Example 33.

[0707] 1 H NMR(400MHz,DMSO-d6)δ10.78(s,1H),9.06(s,1H),8.15(s,1H),8.04–7.93(m,1H) ,7.93–7.84(m,1H),7.83–7.73(m,1H),7.72–7.63(m,1H),7.23–7.04(m,5H),4.64– 4.40(m,4H),3.86–3.50(m,5H),3.45–3.21(m,2H),3.17–2.82(m,7H),2.75–2.57( m,4H),2.55–2.40(m,1H),2.24–1.82(m,5H),1.55–1.20(m,4H),0.87–0.73(m,2H).

[0708] LCMS m / z=385.0[M / 2+1] + .

[0709] Example 37: Preparation of trifluoroacetate salt of compound 37

[0710] Step 1: Preparation of 37b

[0711] To a reaction flask, 37a (10.0 g, 52.05 mmol) and 100 mL of DMF were added separately. The mixture was cooled to 0°C, and 60% sodium hydride (3.12 g) was added portionwise. After reacting at room temperature for 30 min, 1-bromo-2-butyne (10.38 g, 78.05 mmol) was added dropwise. The reaction was continued at room temperature for 16 h. The reaction solution was poured into 300 mL of ice water, filtered, and the filter cake was washed with 100 mL of water. The filter cake was collected and dried under reduced pressure to obtain crude product 37b (8.20 g).

[0712] Step 2: Preparation of 37c

[0713] To a reaction flask, 37b (8.20 g, 33.58 mmol), 1,8-diazacyclo[5.4.0]undec-7-ene (1.02 g, 6.70 mmol), ethyl diazoacetate (4.84 g, 42.42 mmol), and 150 mL of ethanol were added. The mixture was allowed to react at room temperature for 3 h. Then, dimerized rhodium acetate (74 mg, 0.167 mmol) was added and allowed to react at room temperature for 16 h. The reaction mixture was filtered, and the filter cake was collected. The filter cake was washed with 50 mL of ethanol, collected, and dried under reduced pressure to yield crude product 37c (4.92 g).

[0714] Step 3: Preparation of 37d

[0715] In a reaction flask, the above crude product 37c (4.00 g), sodium hydroxide (1.94 g, 48.5 mmol) and 100 mL of water were added respectively, and the reaction was refluxed for 16 h. The reaction system was cooled to room temperature, and 1 mol / L hydrochloric acid was added to adjust the pH to 1. The reaction was filtered, and the filter cake was collected. The filter cake was washed with 50 mL of water, collected, and dried under reduced pressure to obtain a crude product 37d (4.03 g).

[0716] LCMS m / z=303.2[M+1] + .

[0717] Step 4: Preparation of 37e

[0718] The crude product 37d (4.03 g), lithium chloride (1.70 g, 40.1 mmol), 7 mL of water, and 70 mL of DMSO were added to a reaction flask, respectively, and the reaction was carried out at 130°C for 3 h. The reaction system was cooled to room temperature, poured into 300 mL of water, filtered, and the filter cake was collected. The filter cake was washed with 100 mL of water, collected, and dried under reduced pressure to obtain a crude product 37e (3.50 g).

[0719] The trifluoroacetate of compound 37 was prepared from compound 37e by lyophilization in acidic solution (water (containing 0.1% TFA) / acetonitrile) according to the synthesis method of Example 33.

[0720] 1H NMR(400MHz,DMSO-d6)δ10.76(s,1H),9.06(s,1H),8.16(s,1H),7.99–7.91(m,2H),7.73(dd,1H),7. 51(d,1H),7.17(s,1H),7.12–7.04(m,2H),7.01–6.90(m,2H),5.13–5.02(m,2H),4.60(s,2H),4.57–4 .42(m,2H),3.78–3.65(m,3H),3.63–3.51(m,2H),3.40–3.25(m,2H),3.17–2.98(m,4H),2.82–2.56(m ,6H),2.50–2.40(m,1H),2.20–1.95(m,3H),1.90–1.78(m,2H),1.78–1.73(m,3H),1.45–1.27(m,2H). LCMS m / z=780.3[M+1] + .

[0721] Example 38: Preparation of trifluoroacetate salt of compound 38

[0722] Step 1: Preparation of 38b

[0723] To a reaction flask, 38a (10.0 g, 52.05 mmol) and 100 mL of DMF were added separately. The mixture was cooled to 0°C, and 60% sodium hydride (3.12 g) was added portionwise. After reacting at room temperature for 30 min, 3-bromo-1-trimethylsilyl-1-propyne (14.92 g, 78.06 mmol) was added dropwise. The reaction was continued at room temperature for 16 h. The reaction solution was poured into 300 mL of ice water, filtered, and the filter cake was washed with 100 mL of water. The filter cake was collected and dried under reduced pressure to obtain crude product 38b (8.40 g).

[0724] Step 2: Preparation of 38c

[0725] To a reaction flask, crude product 38b (0.50 g) and 7 mL of ethanol were added. Triethylamine (0.37 g, 3.66 mmol) and a 2 mol / L trimethylsilyldiazomethane solution in n-hexane (1.81 mL, 3.62 mmol) were added with stirring, and the mixture was allowed to react at room temperature for 3 h. To the reaction mixture was added 30 mL of water, and the aqueous phase was extracted with ethyl acetate (30 mL x 2). The combined organic phases were 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 afford 38c (0.25 g, 24% yield based on compound 38a).

[0726] LCMS m / z=331.1[M+1] + .

[0727] Step 3: Preparation of 38d

[0728] To a reaction flask, 38c (0.25 g, 0.76 mmol) and 2 mL of dichloromethane were added, cooled to 0°C, and a 1 mol / L dichloromethane solution of boron tribromide (2.28 mL) was added dropwise. The reaction was allowed to react at room temperature for 2 h. 10 mL of saturated aqueous sodium bicarbonate was added to the reaction system, and the aqueous phase was extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with 50 mL of saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield crude product 38d (0.05 g).

[0729] The trifluoroacetate of compound 38 was prepared from compound 38d by referring to the synthesis method of Example 33, and then freeze-dried in acidic solution (water (containing 0.1% TFA) / acetonitrile).

[0730] 1 H NMR(400MHz,DMSO-d6)δ10.76(s,1H),9.07(s,1H),8.16(s,1H),8.02–7.90(m,2H),7.73(dd,1H), 7.52(d,1H),7.19(s,1H),7.13–7.04(m,2H),7.02–6.90(m,2H),5.18–5.10(m,2H),4.64–4.57(m, 2H),4.56–4.40(m,2H),3.80–3.65(m,3H),3.65–3.50(m,2H),3.40–3.25(m,3H),3.17–2.97(m,4H ),2.84–2.57(m,6H),2.50–2.41(m,1H),2.20–1.93(m,3H),1.90–1.77(m,2H),1.44–1.27(m,2H).

[0731] LCMS m / z=383.8[M / 2+1] + .

[0732] Example 39: Preparation of Compound 39

[0733] Step 1: Preparation of 39b

[0734] 39a (0.25 g, 0.82 mmol) (synthesis method, see WO2021113557) was dissolved in DMSO (3 mL), and 2-iodoacylbenzoic acid (0.37 g, 1.32 mmol) was added. The reaction was allowed to react at 55°C for 2 h. The reaction system was cooled to room temperature, water (100 mL) was added, and the mixture was extracted with 100 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product 39b (0.24 g).

[0735] LCMS m / z=302.3[M+1] + .

[0736] Step 2: Preparation of 39c

[0737] The crude product 39b (0.24 g) was dissolved in 1,2-dichloroethane (30 mL), and tert-butyl piperazine-1-carboxylate (0.22 g, 1.18 mmol) and 0.3 mL of acetic acid were added. The mixture was allowed to react at room temperature for 1 h, followed by the addition of sodium triacetoxyborohydride (0.56 g, 2.64 mmol) and the reaction was continued at room temperature for 16 h. To the reaction solution was slowly added 50 mL of saturated aqueous sodium bicarbonate solution, and the mixture was extracted with 30 mL of dichloromethane. 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 purified by silica gel column chromatography (dichloromethane / methanol (v:v) = 10:1) to afford 39c (0.20 g, 36% yield).

[0738] LCMS m / z=472.6[M+1] + .

[0739] Step 3: Preparation of trifluoroacetate salt of 39d

[0740] 39c (200 mg, 0.42 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (2 mL) was added, and the mixture was reacted at room temperature for 3 h. The reaction system was concentrated under reduced pressure to obtain the crude trifluoroacetate salt of 39d (200 mg).

[0741] LCMS m / z=372.3[M+1] + .

[0742] Step 4: Preparation of compound 39

[0743] To a reaction flask, the trifluoroacetic acid salt of crude product 39d (200 mg), DIPEA (140 mg, 1.08 mmol), and 10 mL of DMSO were added. Then, 4B (150 mg, 0.375 mmol) (synthesis method, see WO2021077010) was added and the reaction was carried out at 100°C for 7 h. The reaction system was cooled to room temperature, and the reaction solution was subjected to pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, preparative column model SunFire@Prep C18, 5 μm, i.d. x length = 19 mm x 250 mm). Preparation method: The crude product DMSO solution was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was ammonium acetate (5 mmol / L) in water / acetonitrile. Gradient elution method: Acetonitrile was gradient eluted from 10% to 70% (elution time 12 min). The mixture was lyophilized to obtain compound 39 (30 mg, yield: 11%).

[0744] 1 H NMR(400MHz,DMSO-d6)δ10.77(s,1H),8.84(s,1H),8.05(s,1H),7.98–7.86(m,3H), 7.74(dd,1H),7.47(d,1H),7.35(dd,1H),7.12(s,1H),6.77(d,1H),4.58(s,2H),4.3 4–4.17(m,2H),3.79–3.55(m,8H),2.85–2.60(m,6H),2.57–2.45(m,1H),2.45–2.30 (m,4H),2.25–2.10(m,3H),2.04–1.92(m,1H),1.88–1.70(m,3H),1.17–0.98(m,2H).

[0745] LCMS m / z=743.3[M+1] + .

[0746] Example 40: Preparation of trifluoroacetate salt of compound 40

[0747] The trifluoroacetate of compound 40 was prepared from compounds 40a and 40A by referring to the synthesis methods of Examples 23 and 24, and then freeze-dried in acidic solution (water (containing 0.1% TFA) / acetonitrile).

[0748] 1H NMR(400MHz,DMSO-d6)δ10.77(s,1H),9.05(s,1H),8.15(s,1H),8.00–7.91(m,1H),7. 91–7.84(m,1H),7.73(dd,1H),7.48(d,1H),7.19(s,1H),7.02–6.84(m,2H),6.51(t,1H ),4.63–4.42(m,4H),4.15–4.02(m,2H),3.84–3.60(m,6H),3.55–3.42(m,4H),3.33–2. 95(m,5H),2.72–2.56(m,4H),2.53–2.42(m,1H),2.24–2.06(m,1H),2.04–1.89(m,1H).

[0749] LCMS m / z=732.8[M+1] + .

[0750] Example 41: Preparation of trifluoroacetate salt of compound 41

[0751] The trifluoroacetate of compound 41 was prepared from compounds 41a and 41A by referring to the synthesis methods of Examples 23 and 24, and then freeze-dried in acidic solution (water (containing 0.1% TFA) / acetonitrile).

[0752] 1 H NMR(400MHz,DMSO-d6)δ10.79(s,1H),9.06(s,1H),8.15(s,1H),8.03–7.85(m,2H),7.72(dd ,1H),7.48(d,1H),7.18(s,1H),7.07–6.92(m,3H),4.59(s,2H),4.56–4.40(m,2H),3.85–3.7 6(m,1H),3.69(s,3H),3.65–3.52(m,2H),3.45–3.25(m,4H),3.20–2.95(m,4H),2.77–2.60(m ,6H),2.55–2.44(m,1H),2.27–2.10(m,1H),2.10–1.94(m,2H),1.94–1.80(m,2H),1.51–1.33 (m,2H).

[0753] LCMS m / z=760.3[M+1] + .

[0754] Example 42: Preparation of trifluoroacetate salt of compound 42

[0755] To a reaction flask, the trifluoroacetic acid salt of crude product 8c (0.17 g), DIPEA (0.30 g, 2.32 mmol), and 5 mL of DMSO were added. Compound 42A (0.20 g, 0.46 mmol) (synthesis method, see WO2022221673) was added and reacted at 100°C for 7 h. The reaction system was cooled to room temperature, and the reaction solution was subjected to pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, SunFire@Prep C18, 5 μm, i.d. x length = 19 mm x 250 mm). Preparation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was water (containing 0.1% TFA) / acetonitrile. Gradient elution was performed: 10% acetonitrile to 50% acetonitrile (elution time 15 min). The solution was then lyophilized to obtain the trifluoroacetic acid salt of compound 42 (150 mg).

[0756] 1 H NMR(400MHz,DMSO-d6)δ10.78(s,1H),9.05(s,1H),8.15(s,1H),8.00–7.86(m,2H),7. 75–7.60(m,2H),7.20–6.93(m,5H),5.60–5.00(m,1H),4.68–4.38(m,4H),3.82–3.51( m,5H),3.43–3.25(m,2H),3.20–2.97(m,4H),2.93–2.73(m,2H),2.72–2.58(m,4H),2. 51–2.42(m,1H),2.24–1.95(m,3H),1.94–1.80(m,2H),1.58(d,6H),1.48–1.31(m,2H).

[0757] LCMS m / z=385.8[M / 2+1] + .

[0758] Example 43: Preparation of Compound 43 Trifluoroacetate

[0759] Step 1: Preparation of 43a chiral isomers 1 and 2

[0760] The chiral separation of 43a (synthesis method see WO2022007866) was performed as follows:

[0761] 1. Instrument: SFC Prep 150AP; Chromatographic column: Daicel AD-H (19 mm × 250 mm).

[0762] 2. Dissolve the sample in methanol and filter with a 0.45 μm filter to prepare a sample solution.

[0763] 3. Preparative chromatographic conditions: a. Mobile phases consisted of A and B: Mobile phase A: CO2; Mobile phase B: methanol; b. Isocratic elution, mobile phase B content was 25%; c. Flow rate was 40 mL / min.

[0764] Peak time: chiral isomer 1: 4.65 min, chiral isomer 2: 5.85 min.

[0765] Chiral isomer 1 and chiral isomer 2 of compound 43a are one of the isomers of structure 43a-1 or 43a-2, respectively.

[0766] Step 2: Preparation of 43b

[0767] Chiral isomer 2 of 43a (0.55 g, 2.92 mmol) was dissolved in dichloromethane (30 mL), and Boc2O (1.27 g, 5.82 mmol) and DMAP (0.71 g, 5.81 mmol) were added. The reaction was allowed to react at room temperature for 16 h. The reaction system was washed with 0.5 mol / L hydrochloric acid (50 mL), 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 (ethyl acetate:petroleum ether (v / v) = 0:1-1:9) to obtain 43b (0.78 g, yield: 93%).

[0768] LCMS m / z=289.3[M+1] + .

[0769] Compound 43b is one of the isomers of structure 43b-1 or 43b-2.

[0770] Step 3: Preparation of 43c

[0771] 43b (0.78 g, 2.71 mmol) was dissolved in acetonitrile (20 mL), and NBS (0.53 g, 2.98 mmol) was added. The reaction was allowed to react 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 (ethyl acetate:petroleum ether (v / v) = 0:1-1:9) to afford 43c (0.85 g, yield: 86%).

[0772] LCMS m / z=367.3[M+1] + .

[0773] Compound 43c is one of the isomers of structure 43c-1 or 43c-2.

[0774] Step 4: Preparation of 43d

[0775] 43c (1.50 g, 4.10 mmol), 43A (2.89 g, 6.93 mmol) (synthesis method, see WO2022235945), Pd(dppf)Cl2·DCM (0.19 g, 0.23 mmol), and cesium carbonate (1.51 g, 4.63 mmol) were added to a reaction flask. 1,4-dioxane (30 mL) and water (3 mL) were added, and the mixture was reacted at 100°C under a nitrogen atmosphere for 20 h. The reaction system was cooled to room temperature, and 50 mL of water and 50 mL of ethyl acetate were added. The aqueous phase was extracted with 50 mL of ethyl acetate, 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 separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-9:1) to obtain 43d (0.55 g, yield: 23%).

[0776] Compound 43d is an isomer of structure 43d-1 or 43d-2.

[0777] Step 5: Preparation of 43e

[0778] 43d (0.55 g, 0.95 mmol) was dissolved in THF (20 mL), and 10% palladium on carbon (0.51 g) was added. The mixture was reacted at 45°C under a hydrogen balloon atmosphere for 20 h. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (MeOH / DCM (v / v) = 0:1-5:95) to obtain 43e (0.22 g, yield: 58%).

[0779] LCMS m / z=400.2[M+1] + .

[0780] Compound 43e is an isomer of structure 43e-1 or 43e-2.

[0781] Step 6: Preparation of 43f

[0782] 43e (110 mg, 0.276 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, and the mixture was allowed to react at room temperature for 3 h. The reaction system was concentrated under reduced pressure, 5 mL of dichloromethane and 1 mL of triethylamine were added, and the mixture was concentrated under reduced pressure to obtain crude product 43f (84 mg).

[0783] LCMS m / z=300.3[M+1] + .

[0784] Compound 43f is an isomer of structure 43f-1 or 43f-2.

[0785] Step 7: Preparation of 43g

[0786] The crude product 43f (0.084 g) was dissolved in 1,2-dichloroethane (30 mL), and tert-butyl 4-formylpiperidine-1-carboxylate (0.090 g, 0.42 mmol) and 3 mL of acetic acid were added. After stirring at room temperature for 1 h, sodium triacetoxyborohydride (0.12 g, 0.57 mmol) was added and the mixture was allowed to react at room temperature for 16 h. To the reaction solution was slowly added 50 mL of saturated aqueous sodium bicarbonate, and the mixture was extracted with 50 mL of dichloromethane. The organic phase was washed with 100 mL of saturated aqueous sodium chloride, 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 obtain 43f (0.13 g, yield: 62%).

[0787] LCMS m / z=497.3[M+1] + .

[0788] Compound 43g is one of the isomers of structure 43g-1 or 43g-2.

[0789] Step 8: Preparation of trifluoroacetate salt of 43h

[0790] 43g (130mg, 0.26mmol) was dissolved in dichloromethane (2mL), trifluoroacetic acid (1mL) was added, and the mixture was reacted at room temperature for 3h. The reaction system was concentrated under reduced pressure to obtain the trifluoroacetic acid salt of crude product 43h (130mg).

[0791] LCMS m / z=397.3[M+1] + .

[0792] Compound 43h is an isomer of structure 43h-1 or 43h-2.

[0793] Step 9: Preparation of trifluoroacetate salt of compound 43

[0794] To a reaction flask, the trifluoroacetic acid salt (120 mg) of the crude product 43h, DIPEA (300 mg, 2.32 mmol), and 10 mL of DMSO were added. Then, 4B (100 mg, 0.25 mmol) was added and the reaction was carried out at 100°C for 7 h. The reaction system was cooled to room temperature, and the crude product was subjected to Pre-HPLC (instrument and preparative column: Waters 2767 Preparative HPLC, SunFire@Prep C18, 5 μm, i.d. x length = 19 mm x 250 mm). Preparation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile was gradient eluted from 10% to 70% (elution time 12 min). The product was then lyophilized to obtain the trifluoroacetic acid salt of compound 43 (20 mg).

[0795] 1 H NMR(400MHz,DMSO-d6)δ10.76(s,1H),8.95(s,1H),8.08(s,1H),8.03–7.89(m,2H),7.80–7.70(m,1H) ,7.50–7.42(m,1H),7.14–7.07(m,1H),6.95–6.80(m,3H),4.63–4.55(m,2H),4.55–4.42(m,2H),4.13– 4.02(m,1H),3.74–3.54(m,6H),3.35–3.20(m,1H),3.17–2.73(m,8H),2.72–2.57(m,5H),2.49–2.40( m,1H),2.25–2.05(m,2H),2.05–1.91(m,2H),1.87–1.70(m,2H),1.70–1.54(m,1H),1.30–1.07(m,2H).

[0796] Compound 43 is one of the isomers of compound 43-1 or 43-2.

[0797] Example 44: Preparation of Compound 44 Trifluoroacetate

[0798] Step 1: Preparation of 44b

[0799] Compound 44a (2.8 g, 13.58 mmol) (synthesis method, see Bioorganic & Medicinal Chemistry Letters, 2016, 26, 5877-5882) was dissolved in dichloromethane (50 mL), and Boc2O (5.93 g, 27.17 mmol) and DMAP (3.32 g, 27.18 mmol) were added. The reaction was allowed to react at room temperature for 16 h. The reaction system was washed with 0.5 mol / L hydrochloric acid (50 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) = 0:1-1:9) to obtain the racemate of 44b (3.4 g, yield: 82%).

[0800] The racemate of 44b was subjected to chiral separation as follows:

[0801] 1. Instrument: SFC Prep 150AP; Chromatographic column: Daicel IC-H (19 mm × 250 mm).

[0802] 2. Dissolve the sample in methanol and filter with a 0.45 μm filter to prepare a sample solution.

[0803] 3. Preparative chromatographic conditions: a. Mobile phases consisted of a system of A and B: mobile phase A: CO2; mobile phase B: methanol / isopropanol (v / v) = 1:1; b. Isocratic elution, mobile phase B content was 20%; c. Flow rate was 40 mL / min.

[0804] Peak time: chiral isomer 1 (compound 44b): 5.7 min, chiral isomer 2 (compound 46a): 6.47 min.

[0805] According to the MicroED structure determination of compound 46b, compound 44b is R-configuration and compound 46a is S-configuration.

[0806] LCMS m / z=307.3[M+1] + .

[0807] Step 2: Preparation of 44c

[0808] 44b (1.8 g, 5.88 mmol) was dissolved in acetonitrile (50 mL), and NBS (1.05 g, 5.90 mmol) was added. The reaction was allowed to react 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 (ethyl acetate:petroleum ether (v / v) = 0:1-1:9) to afford 44c (1.6 g, yield: 71%).

[0809] LCMS m / z=385.3[M+1] + .

[0810] Step 3: Preparation of 44d

[0811] 44c (0.77 g, 2.0 mmol), 44A (1.67 g, 4.0 mmol) (synthesis method, see WO2022235945), Pd(dppf)Cl2·DCM (0.16 g, 0.20 mmol), and cesium carbonate (1.30 g, 4.0 mmol) were added to a reaction flask. 1,4-dioxane (30 mL) and water (3 mL) were added, and the mixture was reacted at 100°C under a nitrogen atmosphere for 20 h. The reaction system was cooled to room temperature, and 50 mL of water and 50 mL of ethyl acetate were added. The aqueous phase was extracted with 50 mL of ethyl acetate, 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 separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-9:1) to obtain 44d (0.70 g, yield: 59%).

[0812] Step 4: Preparation of 44e

[0813] 44d (0.70 g, 1.18 mmol) was dissolved in THF (20 mL), and 10% palladium on carbon (0.63 g) was added. The mixture was reacted at 45°C under a hydrogen balloon atmosphere for 20 h. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (MeOH:DCM (v / v) = 0:1-5:95) to obtain 44e (0.25 g, yield: 51%).

[0814] LCMS m / z=418.1[M+1] + .

[0815] Step 5: Preparation of 44f

[0816] 44e (250 mg, 0.6 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the mixture was allowed to react at room temperature for 3 h. The reaction system was concentrated under reduced pressure, 5 mL of dichloromethane and 1 mL of triethylamine were added, and the mixture was concentrated under reduced pressure to obtain crude product 44f (190 mg).

[0817] LCMS m / z=318.3[M+1] + .

[0818] Step 6: Preparation of 44g

[0819] The crude product 44f (0.19 g) was dissolved in 1,4-dichloroethane (30 mL), and tert-butyl 4-formylpiperidine-1-carboxylate (0.20 g, 0.93 mmol) and 3 mL of acetic acid were added. After stirring at room temperature for 1 h, sodium triacetoxyborohydride (0.40 g, 1.89 mmol) was added and the mixture was allowed to react at room temperature for 16 h. 10 mL of saturated aqueous sodium bicarbonate was slowly added to the reaction system, and the mixture was extracted with 50 mL of dichloromethane. The organic phase was washed with 100 mL of saturated aqueous sodium chloride, 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 obtain 44f (0.30 g, yield: 63%).

[0820] LCMS m / z=515.3[M+1] + .

[0821] Step 7: 44h preparation

[0822] Dissolve 44g (300mg, 0.58mmol) in dichloromethane (2mL), add trifluoroacetic acid (2mL), and react at room temperature for 3h. Concentrate the reaction system under reduced pressure, adjust the pH to 9 with saturated aqueous sodium bicarbonate solution, and extract with dichloromethane (100mL x 2). Dry the organic phase over anhydrous sodium sulfate and concentrate under reduced pressure to obtain crude product 44h (180mg).

[0823] LCMS m / z=415.3[M+1] + .

[0824] Step 8: Preparation of trifluoroacetate salt of compound 44

[0825] To a reaction flask, crude product 44h (91 mg), DIPEA (85 mg, 0.66 mmol), and 10 mL of DMSO were added, followed by 4B (90 mg, 0.23 mmol) and allowed to react at 100°C for 7 h. The reaction system was cooled to room temperature, and the crude product was subjected to Pre-HPLC (instrument and preparative column: Waters 2767 Preparative HPLC, SunFire@Prep C18, 5 μm, i.d. x length = 19 mm x 250 mm). Preparation method: The crude product solution in DMSO was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was water (containing 0.1% TFA) / acetonitrile. Gradient elution was performed: 10% to 70% acetonitrile (elution time 12 min). The product was then lyophilized to obtain compound 44 trifluoroacetate (80 mg).

[0826] 1 H NMR(400MHz,DMSO-d6)δ10.79(s,1H),8.98(s,1H),8.09(s,1H),8.02–7.89(m,2H),7.74(dd,1H),7.50– 7.43(m,1H),7.12(s,1H),6.87(d,1H),6.79(d,1H),4.59(s,2H),4.54–4.40(m,2H),4.14–4.00(m,1H),3 .93–3.80(m,1H),3.73–3.55(m,5H),3.40–3.27(m,1H),3.20–2.80(m,7H),2.80–2.58(m,6H),2.58–2.5 0(m,1H),2.27–2.05(m,2H),2.05–1.87(m,2H),1.87–1.70(m,2H),1.70–1.53(m,1H),1.28–1.06(m,2H).

[0827] LCMS m / z=786.3[M+1] + .

[0828] Example 45: Preparation of Compound 45 Trifluoroacetate

[0829] Step 1: Preparation of 45a

[0830] Chiral isomer 1 of 43a (0.6 g, 3.19 mmol) was dissolved in dichloromethane (30 mL), and Boc2O (1.39 g, 6.4 mmol) and DMAP (0.39 g, 3.2 mmol) were added. The reaction was allowed to react at room temperature for 16 h. The reaction system was washed with 0.5 mol / L hydrochloric acid (50 mL), and the organic phase was 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) = 0:1-1:9) to afford 45a (0.8 g, yield: 87%).

[0831] Compound 45a is one of the isomers of structure 43b-1 or 43b-2.

[0832] Step 2: Preparation of 45b

[0833] 45a (0.78 g, 2.70 mmol) was dissolved in acetonitrile (20 mL), and NBS (0.53 g, 2.98 mmol) was added. The reaction was allowed to react 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 (ethyl acetate:petroleum ether (v / v) = 0:1-1:9) to afford 45b (0.86 g, yield: 87%).

[0834] LCMS m / z=367.5[M+1] + .

[0835] Compound 45b is one of the isomers of structure 43c-1 or 43c-2.

[0836] Step 3: Preparation of 45c

[0837] 45b (0.85 g, 2.32 mmol), 45A (2.89 g, 6.93 mmol), Pd(dppf)Cl2·DCM (0.19 g, 0.23 mmol), and cesium carbonate (1.51 g, 4.63 mmol) were added to a reaction flask, followed by 1,4-dioxane (30 mL) and water (3 mL). The mixture was reacted at 100°C under a nitrogen atmosphere for 20 h. The reaction system was cooled to room temperature, and 50 mL of water and 50 mL of ethyl acetate were added. The aqueous phase was extracted with 50 mL of ethyl acetate, 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 purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-9:1) to afford 45c (0.9 g, yield: 67%).

[0838] Compound 45c is an isomer of structure 43d-1 or 43d-2.

[0839] Step 4: Preparation of 45d

[0840] 45c (0.7 g, 1.21 mmol) was dissolved in THF (20 mL), and 10% palladium on carbon (0.51 g) was added. The mixture was reacted at 45°C under a hydrogen balloon atmosphere for 20 h. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (MeOH:DCM (v / v) = 0:1-5:95) to obtain 45d (0.4 g, yield: 83%).

[0841] Compound 45d is an isomer of structure 43e-1 or 43e-2.

[0842] Step 5: Preparation of 45e

[0843] 45d (120 mg, 0.3 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, and the mixture was allowed to react at room temperature for 3 h. The reaction system was concentrated under reduced pressure, 5 mL of dichloromethane and 1 mL of triethylamine were added, and the mixture was concentrated under reduced pressure to obtain crude product 45e (90 mg).

[0844] LCMS m / z=300.3[M+1] + .

[0845] Compound 45e is an isomer of structure 43f-1 or 43f-2.

[0846] Step 6: Preparation of 45f

[0847] The crude product 45e (0.09 g) was dissolved in 1,2-dichloroethane (20 mL), and tert-butyl 4-formylpiperidine-1-carboxylate (0.090 g, 0.42 mmol) and 1.5 mL of acetic acid were added. After stirring at room temperature for 1 h, sodium triacetoxyborohydride (0.12 g, 0.57 mmol) was added and the mixture was allowed to react at room temperature for 16 h. To the reaction solution was slowly added 50 mL of saturated aqueous sodium bicarbonate, and the mixture was extracted with 50 mL of dichloromethane. The organic phase was washed with 100 mL of saturated aqueous sodium chloride, 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 obtain 45f (0.13 g, yield: 62%).

[0848] LCMS m / z=497.3[M+1] + .

[0849] Compound 45f is one of the isomers of structure 43g-1 or 43g-2.

[0850] Step 7: Preparation of 45g trifluoroacetate

[0851] 45f (130 mg, 0.26 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, and the mixture was reacted at room temperature for 3 h. The reaction system was concentrated under reduced pressure to obtain 45 g of a crude trifluoroacetate salt (100 mg).

[0852] LCMS m / z=397.3[M+1] + .

[0853] Compound 45g is one of the isomers of structure 43h-1 or 43h-2.

[0854] Step 8: Preparation of trifluoroacetate salt of compound 45

[0855] To a reaction flask, 45 g of the crude product (100 mg) of its trifluoroacetic acid salt, DIPEA (78 mg, 0.60 mmol), and 10 mL of DMSO were added. Then, 4B (80 mg, 0.20 mmol) was added and the reaction was carried out at 100°C for 7 h. The reaction system was cooled to room temperature, and the crude product was subjected to Pre-HPLC (instrument and preparative column: Waters 2767 Preparative HPLC, SunFire@Prep C18, 5 μm, ID x length = 19 mm x 250 mm). Preparation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was water (containing 0.1% TFA) / acetonitrile. Gradient elution was performed: 10% to 70% acetonitrile (elution time 12 min). The product was then lyophilized to obtain compound 45 trifluoroacetic acid salt (20 mg).

[0856] 1 H NMR(400MHz,DMSO-d6)δ10.75(s,1H),9.01(s,1H),8.09(s,1H),8.03–7.89(m,2H),7.80–7.70(m,1H) ,7.50–7.42(m,1H),7.14–7.07(m,1H),6.95–6.80(m,3H),4.63–4.55(m,2H),4.55–4.42(m,2H),4.13– 4.02(m,1H),3.74–3.54(m,6H),3.35–3.20(m,1H),3.17–2.73(m,8H),2.72–2.57(m,5H),2.49–2.40( m,1H),2.25–2.05(m,2H),2.05–1.91(m,2H),1.87–1.70(m,2H),1.70–1.54(m,1H),1.30–1.07(m,2H).

[0857] Compound 45 is one of the isomers of compound 43-1 or 43-2.

[0858] Example 46: Preparation of Compound 46 Trifluoroacetate

[0859] Step 1: Preparation of 46b

[0860] 46a (1.4 g, 4.57 mmol) was dissolved in acetonitrile (50 mL), and NBS (0.81 g, 4.55 mmol) was added. The reaction was allowed to react 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 (ethyl acetate:petroleum ether (v / v) = 0:1-1:9) to afford 46b (1.6 g, yield: 92%).

[0861] LCMS m / z=385.3[M+1] + .

[0862] The MicroED structure of compound 46b was determined to be S-configuration.

[0863] Step 2: Preparation of 46c

[0864] 46b (1.6 g, 4.16 mmol), 46A (3.46 g, 8.29 mmol), Pd(dppf)Cl2·DCM (0.34 g, 0.42 mmol), and cesium carbonate (2.70 g, 8.3 mmol) were added to a reaction flask, followed by 1,4-dioxane (50 mL) and water (5 mL). The reaction was incubated at 100°C under a nitrogen atmosphere for 20 h. The reaction system was cooled to room temperature, and 50 mL of water and 50 mL of ethyl acetate were added. The aqueous phase was extracted with ethyl acetate (50 mL), 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 purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-9:1) to afford 46c (1.4 g, yield: 56%).

[0865] Step 3: Preparation of 46d

[0866] 46c (1.4 g, 2.35 mmol) was dissolved in THF (50 mL), and 10% palladium on carbon (1.25 g) was added. The mixture was reacted at 45°C under a hydrogen balloon atmosphere for 20 h. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (MeOH:DCM (v / v) = 0:1-5:95) to obtain 46d (0.85 g, yield: 87%).

[0867] LCMS m / z=418.1[M+1] + .

[0868] Step 4: Preparation of 46e

[0869] 46d (620 mg, 1.49 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (3 mL) was added, and the mixture was allowed to react at room temperature for 3 h. The reaction system was concentrated under reduced pressure, 5 mL of dichloromethane and 1 mL of triethylamine were added, and the mixture was concentrated under reduced pressure to give crude product 46e (460 mg).

[0870] LCMS m / z=318.3[M+1] + .

[0871] Step 5: Preparation of 46f

[0872] The crude product 46e (0.46 g) was dissolved in 1,2-dichloroethane (30 mL), and tert-butyl 4-formylpiperidine-1-carboxylate (0.46 g, 2.14 mmol) and 3 mL of acetic acid were added. After stirring at room temperature for 1 h, sodium triacetoxyborohydride (0.92 g, 4.34 mmol) was added and the mixture was allowed to react at room temperature for 16 h. 20 mL of saturated aqueous sodium bicarbonate was slowly added to the reaction solution, and the mixture was extracted with 50 mL of dichloromethane. The organic phase was washed with 100 mL of saturated aqueous sodium chloride, 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 obtain 46f (0.70 g, yield: 64%).

[0873] LCMS m / z=515.3[M+1] + .

[0874] Step 6: Preparation of 46g

[0875] 46f (700 mg, 1.36 mmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (2 mL) was added. The reaction was allowed to react at room temperature for 3 h. The reaction system was concentrated under reduced pressure, and the pH was adjusted to 9 with saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 46 g (520 mg) of the crude product.

[0876] LCMS m / z=415.3[M+1] + .

[0877] Step 7: Preparation of trifluoroacetate salt of compound 46

[0878] To a reaction flask, 46 g (90 mg) of the crude product, DIPEA (85 mg, 0.66 mmol), and 10 mL of DMSO were added. Then, 4B (90 mg, 0.23 mmol) was added and the reaction was carried out at 100°C for 7 h. The reaction system was cooled to room temperature, and the crude product was subjected to Pre-HPLC (instrument and preparative column: Waters 2767 Preparative HPLC, SunFire@Prep C18, 5 μm, ID x length = 19 mm x 250 mm). Preparation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile was gradient eluted from 10% to 50% (elution time 15 min). The product was then lyophilized to obtain the trifluoroacetate salt of compound 46 (70 mg).

[0879] 1 H NMR(400MHz,DMSO-d6)δ10.79(s,1H),8.98(s,1H),8.09(s,1H),8.02–7.90(m,2H),7.74(dd,1H),7.51– 7.43(m,1H),7.12(s,1H),6.87(d,1H),6.79(d,1H),4.59(s,2H),4.54–4.41(m,2H),4.13–4.00(m,1H),3 .92–3.80(m,1H),3.73–3.54(m,5H),3.40–3.27(m,1H),3.20–2.80(m,7H),2.80–2.58(m,6H),2.58–2.5 0(m,1H),2.27–2.05(m,2H),2.05–1.87(m,2H),1.87–1.70(m,2H),1.70–1.53(m,1H),1.30–1.06(m,2H).

[0880] LCMS m / z=786.3[M+1] + .

[0881] Example 47: Preparation of Compound 47

[0882] Step 1: Preparation of 47b

[0883] To a reaction flask, 47a (2.00 g, 7.19 mmol) (synthesis method reference CN112538083), HATU (4.10 g, 10.78 mmol), and 30 mL of DMF were added. After stirring at room temperature for 2 min, deuterated methylamine hydrochloride (1.52 g, 21.55 mmol) and DIPEA (2.79 g, 21.59 mmol) were added and reacted at room temperature for 16 h. The reaction system was poured into 200 mL of water, filtered, and the filter cake was dried under reduced pressure to obtain crude product 47b (1.03 g).

[0884] Step 2: Preparation of 47c

[0885] To a reaction flask, crude product 47b (1.03 g), 10% palladium on carbon (0.6 g), 30 mL of dichloromethane, and 30 mL of methanol were added and reacted at room temperature under a hydrogen balloon for 16 h. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to afford crude product 47c (0.62 g).

[0886] LCMS m / z=265.2[M+1] + .

[0887] Step 3: Preparation of 47d

[0888] To a reaction flask, crude product 47c (0.62 g), 2,4,5-trichloropyrimidine (0.47 g, 2.56 mmol), triethylamine (0.48 g, 4.74 mmol), and 5 mL of DMF were added and reacted at 70°C for 2 h. The reaction system was cooled to room temperature, poured into 50 mL of water, and filtered. The filter cake was washed with 20 mL of water and dried under reduced pressure to afford crude product 47d (0.70 g).

[0889] Step 4: Preparation of compound 47

[0890] Crude product 8c (90 mg) (trifluoroacetic acid salt), sodium bicarbonate (80 mg, 0.95 mmol), and 5 mL (DMSO) were added to a reaction flask. After stirring at room temperature for 0.5 h, crude product 47d (78 mg) and DIPEA (0.12 g, 0.93 mmol) were added and reacted at 100°C for 7 h. The reaction system was cooled to room temperature and subjected to Pre-HPLC (instrument and preparative column: Waters 2767 Preparative HPLC, SunFire@Prep C18, 5 μm, i.d. x length = 19 mm x 250 mm). Preparation method: The crude product DMSO solution was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system consisted of aqueous ammonium acetate (5 mmol / L) / acetonitrile. Gradient elution was performed: 10% to 70% acetonitrile (elution time 15 min). The product was then lyophilized to afford compound 47 (20 mg, 3% yield based on compound 47a).

[0891] 1 H NMR(400MHz,DMSO-d6)δ10.75(s,1H),8.85(s,1H),8.05(s,1H),7.97–7.87(m,2H),7.74(dd,1H),7.47(d,1H),7.12(s,1H),7.06–6.99(m,2H),6. 92–6.84(m,2H),4.58(s,2H),3.76–3.57(m,10H),2.70–2.56(m,3H),2.4 9–2.29(m,5H),2.23–1.97(m,4H),1.85–1.63(m,3H),1.29–1.11(m,2H).

[0892] LCMS m / z=745.3[M+1] + .

[0893] Example 48: Preparation of Compound 48

[0894] Step 1: Preparation of 48b

[0895] To a reaction flask, 48a (20.0 g, 104.10 mmol) and 200 mL of DMF were added. 60% sodium hydride (4.16 g) was added portionwise at 0°C. After reacting at room temperature for 30 min, deuterated iodomethane (15.09 g, 104.10 mmol) was added dropwise. The reaction was continued at room temperature for 16 h. The reaction solution was poured into 1.0 L of ice water and filtered. The filter cake was washed with 300 mL of water and dried under reduced pressure to obtain crude product 48b (10.2 g).

[0896] Step 2: Preparation of 48c

[0897] To a reaction flask, crude product 48b (12.5 g), DBU (1.82 g, 11.95 mmol), ethyl diazoacetate (8.61 g, 75.46 mmol), and 200 mL of ethanol were added and reacted at room temperature for 3 h. Rhodium diacetate (0.13 g, 0.29 mmol) was added and reacted at room temperature for 16 h. The reaction system was filtered, and the filter cake was washed with 50 mL of ethanol and dried under reduced pressure to yield crude product 48c (14.5 g).

[0898] Step 3: Preparation of 48d

[0899] To a reaction flask, crude product 48c (14.5 g), sodium hydroxide (9.82 g, 245.5 mmol), and 200 mL of water were added and refluxed for 16 h. The reaction system was cooled to room temperature, the pH was adjusted to 1 with 1 mol / L hydrochloric acid, and filtered. The filter cake was washed with 50 mL of water and dried under reduced pressure to afford crude product 48d (11.5 g).

[0900] LCMS m / z=266.2[M-1] – .

[0901] Step 4: Preparation of 48e

[0902] To a reaction flask, crude product 48d (11.5 g), LiCl (5.47 g, 129.04 mmol), 10 mL of water, and 200 mL of DMSO were added and reacted at 130°C for 3 h. The reaction system was cooled to room temperature, poured into 500 mL of water, and filtered. The filter cake was washed with 100 mL of water and dried under reduced pressure to afford crude product 48e (7.4 g).

[0903] Step 5: Preparation of 48f

[0904] To a reaction flask, crude product 48e (1.0 g), 2-bromo-N-methylacetamide (0.82 g, 5.40 mmol), and cesium carbonate (2.92 g, 8.96 mmol) were added, followed by 15 mL of DMF. The mixture was allowed to react at room temperature for 2 h. The reaction mixture was poured into 100 mL of water and filtered. The filter cake was washed sequentially with 50 mL of water and 5 mL of ethanol, and then dried under reduced pressure to afford crude product 48f (1.20 g).

[0905] Step 6: Preparation of 48g

[0906] Crude product 48f (1.20 g), 10% palladium on carbon (0.6 g), 30 mL of dichloromethane, and 30 mL of methanol were added to a reaction flask, and the mixture was reacted under a hydrogen balloon at room temperature for 16 h. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to afford crude product 48 g (0.56 g).

[0907] LCMS m / z=265.2[M+1] + .

[0908] Step 7: 48h preparation

[0909] To a reaction flask, add 48 g (0.56 g) of the crude product, 2,4,5-trichloropyrimidine (0.43 g, 2.34 mmol), triethylamine (0.43 g, 4.25 mmol), and 5 mL of DMF. React at 70°C for 2 h. Cool the reaction mixture to room temperature, pour into 50 mL of water, filter, and wash the filter cake with 20 mL of water. Dry under reduced pressure to obtain the crude product 48h (0.71 g).

[0910] LCMS m / z=411.1[M+1] + .

[0911] Step 8: Preparation of Compound 48

[0912] To a reaction flask, the trifluoroacetic acid salt (90 mg) of crude product 8c, sodium bicarbonate (80 mg, 0.95 mmol), and 5 mL of DMSO were added. After stirring at room temperature for 0.5 h, crude product 48h (78 mg) and DIPEA (0.12 g, 0.93 mmol) were added and reacted at 100°C for 7 h. The reaction system was cooled to room temperature and subjected to Pre-HPLC (instrument and preparative column: Waters 2767 Preparative HPLC, SunFire@Prep C18, 5 μm, i.d. x length = 19 mm x 250 mm). Preparation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was ammonium acetate (5 mmol / L) / acetonitrile. Gradient elution method: acetonitrile was gradient eluted from 10% to 70% (elution time 15 min), and lyophilized to obtain compound 48 (8 mg, eight-step yield based on compound 48a: 0.6%).

[0913] 1 H NMR(400MHz,DMSO-d6)δ10.75(s,1H),8.84(s,1H),8.05(s,1H),7.97–7.87(m,2H),7.74(dd,1H),7.47(d,1H),7.12(s,1H),7.06–6.99(m,2H),6 .92–6.84(m,2H),4.58(s,2H),3.76–3.57(m,7H),2.70–2.56(m,6H),2.4 9–2.29(m,5H),2.23–1.96(m,4H),1.85–1.63(m,3H),1.29–1.11(m,2H).

[0914] LCMS m / z=373.2[M / 2+1] + .

[0915] Example 49: Preparation of Compound 49

[0916] Step 1: Preparation of 49a

[0917] To a reaction flask, crude product 48e (3.0 g), ethyl bromoacetate (2.69 g, 16.11 mmol), cesium carbonate (8.76 g, 26.89 mmol), and 50 mL of DMF were added and reacted at room temperature for 3 h. The reaction system was poured into 200 mL of water, filtered, and the filter cake was dried under reduced pressure to afford crude product 49a (4.00 g).

[0918] Step 2: Preparation of 49b

[0919] To a reaction flask, crude product 49a (4.00 g), lithium hydroxide (1.56 g, 65.14 mmol), 72 mL of methanol, and 18 mL of water were added and reacted at room temperature for 2 h. The reaction solution was poured into 200 mL of water, the pH was adjusted to 1 with 1 mol / L hydrochloric acid, and the mixture was filtered. The filter cake was dried under reduced pressure to afford crude product 49b (2.35 g).

[0920] Step 3: Preparation of 49c

[0921] To a reaction flask, crude product 49b (1.50 g), HATU (3.04 g, 8.00 mmol), and 30 mL of DMF were added. After stirring at room temperature for 2 min, deuterated methylamine hydrochloride (1.13 g, 16.02 mmol) and DIPEA (2.07 g, 16.02 mmol) were added and allowed to react at room temperature for 16 h. The reaction system was poured into 200 mL of water, filtered, and the filter cake was dried under reduced pressure to afford crude product 49c (1.06 g).

[0922] Step 4: Preparation of 49d

[0923] To a reaction flask, crude product 49c (1.20 g), 10% palladium on carbon (0.5 g), 30 mL of dichloromethane, and 30 mL of methanol were added and reacted at room temperature under a hydrogen balloon for 16 h. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to afford crude product 49d (0.60 g).

[0924] LCMS m / z=268.2[M+1] + .

[0925] Step 5: Preparation of 49e

[0926] To a reaction flask, crude product 49d (0.60 g), 2,4,5-trichloropyrimidine (0.45 g, 2.45 mmol), triethylamine (0.45 g, 4.45 mmol), and 5 mL of DMF were added and reacted at 70°C for 2 h. The reaction solution was cooled to room temperature, poured into 50 mL of water, and filtered. The filter cake was washed with 20 mL of water and dried under reduced pressure to afford crude product 49e (0.70 g).

[0927] Step 6: Preparation of compound 49

[0928] To a reaction flask, the trifluoroacetic acid salt (90 mg) of crude product 8c, sodium bicarbonate (80 mg, 0.95 mmol), and 5 mL of DMSO were added. After stirring at room temperature for 0.5 h, crude product 49e (79 mg) and DIPEA (0.12 g, 0.93 mmol) were added and reacted at 100°C for 7 h. The reaction system was cooled to room temperature and subjected to Pre-HPLC (instrument and preparative column: Waters 2767 Preparative HPLC, SunFire@Prep C18, 5 μm, i.d. x length = 19 mm x 250 mm). Preparation method: The crude product DMSO solution was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was ammonium acetate (5 mmol / L) / acetonitrile. Gradient elution method: acetonitrile was gradient eluted from 10% to 70% (elution time 15 min), and lyophilized to obtain compound 49 (100 mg, two-step yield 70% based on compound 8b).

[0929] 1 H NMR(400MHz, DMSO-d6)δ10.75(s,1H),8.84(s,1H),8.05(s,1H),7.97–7.87(m,2H),7.74(dd,1H),7.47(d,1H),7.12(s,1H),7.06–6.99(m, 2H),6.92–6.84(m,2H),4.58(s,2H),3.76–3.57(m,7H),2.70–2.56(m ,3H),2.49–2.29(m,5H),2.23–1.96(m,4H),1.85–1.63(m,3H),1.29– 1.11(m,2H).

[0930] LCMS m / z=748.6[M+1] + .

[0931] Example 50: Preparation of Compound 50

[0932] To a reaction flask, the trifluoroacetic acid salt (57 mg) of crude product 35f, DIPEA (47 mg, 0.36 mmol), and 5 mL of DMSO were added. Then, crude product 38g (52 mg) was added and reacted at 100°C for 7 h. The reaction system was cooled to room temperature, and the crude product was subjected to pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, SunFire@Prep C18, 5 μm, i.d. x length = 19 mm x 250 mm). Preparation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system consisted of aqueous ammonium acetate (5 mmol / L) / acetonitrile. Gradient elution was performed: 10% to 70% acetonitrile (elution time 12 min). The product was then lyophilized to afford compound 50 (35 mg, two-step yield: 35% based on compound 38f).

[0933] 1 H NMR(400MHz,DMSO-d6)δ10.72(s,1H),8.82(s,1H),8.04(s,1H),8.00–7.90(m,2H),7.78(dd,1H), 7.51(d,1H),7.12(s,1H),6.87–6.80(m,1H),6.80–6.72(m,2H),5.20–5.05(m,2H),4.65–4.40(m, 4H),3.78–3.58(m,2H),3.29–3.23(m,1H),2.97–2.71(m,6H),2.71–2.53(m,6H),2.48–2.38(m,1H) ),2.24–2.13(m,2H),2.13–1.93(m,3H),1.90–1.69(m,5H),1.67–1.52(m,1H),1.11–0.95(m,2H).

[0934] LCMS m / z=792.3[M+1] + .

[0935] Example 51: Preparation of Compound 51

[0936] To a reaction flask, the trifluoroacetic acid salt (57 mg) of crude product 35f, DIPEA (47 mg, 0.36 mmol), and 5 mL of DMSO were added, followed by crude product 36g (50 mg) and allowed to react at 100°C for 7 h. The reaction system was cooled to room temperature, and the crude product was subjected to pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, SunFire@Prep C18, 5 μm, i.d. x length = 19 mm x 250 mm). Preparation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system consisted of aqueous ammonium acetate (5 mmol / L) / acetonitrile. Gradient elution was performed: 10% to 70% acetonitrile (elution time 12 min). The product was then lyophilized to afford compound 51 (25 mg, 17% yield based on 36d over four steps).

[0937] 1 H NMR(400MHz,DMSO-d6)δ10.72(s,1H),8.77(s,1H),8.03(s,1H),7.97–7.87(m,2H),7.78–7.67( m,2H),7.03(s,1H),6.87–6.80(m,1H),6.80–6.72(m,2H),4.57–4.40(m,4H),3.79–3.60(m,2H) ,3.05–2.96(m,1H),2.96–2.71(m,6H),2.71–2.53(m,6H),2.48–2.39(m,1H),2.20–1.92(m,5H) ,1.91–1.68(m,5H),1.67–1.51(m,1H),1.35–1.27(m,2H),1.12–0.95(m,2H),0.83–0.73(m,2H).

[0938] LCMS m / z=794.3[M+1] + .

[0939] Example 52: Preparation of Compound 52 Trifluoroacetate

[0940] To a reaction flask, 23 g of the trifluoroacetic acid salt (47 mg) of the crude product, DIPEA (160 mg, 1.24 mmol), and 5 mL of DMSO were added, followed by 38 g (50 mg) of the crude product, and the reaction was carried out at 100°C for 7 h. The reaction system was cooled to room temperature, and the crude product was subjected to Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid chromatography, preparative column model: SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile was gradient eluted from 10% to 50% (elution time 15 min). The product was then lyophilized to obtain the trifluoroacetic acid salt of compound 52 (40 mg).

[0941] 1 H NMR (400MHz, DMSO-d6) δ10.79(s,1H),9.08(s,1H),8.16(s,1H),8.00–7.92(m,2H),7.74(dd,1H),7. 52(d,1H),7.19(s,1H),7.12–7.04(m,1H),6.80–6.69(m,2H),5.18–5.09(m,2H),4.60(s,2H),4.56–4 .43(m,2H),3.93–3.84(m,1H),3.83–3.69(m,2H),3.64–3.50(m,2H),3.41–3.24(m,3H),3.15–2.96(m ,4H),2.82–2.60(m,6H),2.56–2.50(m,1H),2.23–1.89(m,3H),1.88–1.73(m,2H),1.38–1.20(m,2H).

[0942] LCMS m / z=784.3[M+1] + .

[0943] Example 53: Preparation of Compound 53 Trifluoroacetate

[0944] To a reaction flask, 23 g of the trifluoroacetic acid salt (47 mg), DIPEA (47 mg, 0.36 mmol), and 5 mL of DMSO were added, followed by 36 g (50 mg) of the crude product, and the reaction was carried out at 100°C for 7 h. The reaction system was cooled to room temperature, and the crude product was subjected to Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid chromatography, preparative column model: SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile was gradient eluted from 10% to 50% (elution time 15 min). The product was then lyophilized to obtain the trifluoroacetic acid salt of compound 53 (50 mg).

[0945] 1 H NMR (400MHz, DMSO-d6) δ10.79(s,1H),9.04(s,1H),8.15(s,1H),7.98–7.91(m,1H),7.90–7.84(m,1H) ),7.82–7.74(m,1H),7.68(dd,1H),7.14–7.03(m,2H),6.80–6.70(m,2H),4.60–4.40(m,4H),3.94–3. 83(m,1H),3.82–3.70(m,2H),3.65–3.50(m,2H),3.41–3.23(m,2H),3.15–2.95(m,5H),2.81–2.62(m ,6H),2.56–2.49(m,1H),2.22–1.88(m,3H),1.88–1.74(m,2H),1.40–1.20(m,4H),0.85–0.73(m,2H).

[0946] LCMS m / z=786.3[M+1] + .

[0947] Example 54: Preparation of Compound 54 Trifluoroacetate

[0948] The trifluoroacetic acid salt of the crude product 35f (61 mg), DIPEA (54 mg, 0.42 mmol), and 5 mL of DMSO were added to a reaction flask. Then, 42A (61 mg, 0.14 mmol) was added and the reaction was carried out at 100°C for 7 h. The reaction system was cooled to room temperature, and the crude product was subjected to Pre-HPLC (instrument and preparative column: Waters 2767 Preparative HPLC, preparative column model: SunFire@Prep C18, 5 μm, i.d. x length = 19 mm x 250 mm). Preparation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile was gradient eluted from 10% to 50% (elution time 15 min). The product was then lyophilized to obtain the trifluoroacetic acid salt of compound 54 (25 mg).

[0949] 1 H NMR(400MHz,DMSO-d6)δ10.75(s,1H),8.95(s,1H),8.08(s,1H),8.03–7.90(m,2H),7.76–7.63( m,2H),7.03(s,1H),6.96–6.78(m,3H),5.55–5.15(m,1H),4.60–4.42(m,4H),4.15–4.00(m,1H) ,3.75–3.54(m,3H),3.35–3.21(m,1H),3.18–2.74(m,8H),2.74–2.57(m,5H),2.50–2.41(m,1H) ,2.27–2.05(m,2H),2.05–1.92(m,2H),1.89–1.70(m,2H),1.70–1.50(m,7H),1.28–1.10(m,2H).

[0950] LCMS m / z=796.3[M+1] + .

[0951] Example 55: Preparation of Compound 55 Trifluoroacetate

[0952] The trifluoroacetate of compound 55 was prepared from compound 55a by acidic preparation (trifluoroacetic acid aqueous solution (0.1% TFA) / acetonitrile) and lyophilization according to the synthesis method of Example 8.

[0953] 1H NMR(400MHz,DMSO-d6)δ10.80(s,1H),9.07(s,1H),8.15(s,1H),7.99–7.88(m,2H),7.71(dd,1H), 7.48(d,1H),7.24–7.13(m,2H),6.94–6.80(m,2H),6.70–6.60(m,1H),4.59(s,2H),4.56–4.42(m, 2H),3.83–3.65(m,6H),3.64–3.51(m,2H),3.39–3.25(m,2H),3.15–2.97(m,4H),2.82–2.57(m,6H ),2.55–2.42(m,1H),2.28–2.13(m,1H),2.13–1.95(m,2H),1.93–1.75(m,2H),1.45–1.25(m,2H).

[0954] LCMS m / z=742.2[M+1] + .

[0955] Example 56: Preparation of Compound 56 Trifluoroacetate

[0956] To a reaction flask, the crude product 44h (91 mg), DIPEA (280 mg, 2.17 mmol), and 10 mL of DMSO were added, followed by 42A (96 mg, 0.22 mmol), and the reaction was carried out at 100°C for 7 h. The reaction system was cooled to room temperature, and the reaction solution was subjected to Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid chromatography, preparative column model: SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: The crude product DMSO solution was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was water (containing 0.1% trifluoroacetic acid) / acetonitrile. Gradient elution method: Acetonitrile was gradient eluted from 10% to 70% (elution time 12 min). The trifluoroacetate salt of compound 56 (60 mg) was obtained by lyophilization.

[0957] 1H NMR(400MHz,DMSO-d6)δ10.80(s,1H),9.00(s,1H),8.09(s,1H),8.04–7.90(m,2H),7.75–7.64(m,2H),7.03(s ,1H),6.88(d,1H),6.80(d,1H),5.70–4.90(m,1H),4.56(s,2H),4.54–4.42(m,2H),4.15–4.00(m,1H),3.92–3. 80(m,1H),3.70–3.53(m,2H),3.42–3.25(m,1H),3.18–3.00(m,4H),3.00–2.80(m,3H),2.80–2.57(m,6H),2.5 7–2.50(m,1H),2.28–2.05(m,2H),2.05–1.87(m,2H),1.87–1.70(m,2H),1.70–1.50(m,7H),1.29–1.10(m,2H).

[0958] LCMS m / z=814.2[M+1] + .

[0959] Example 57: Preparation of Compound 57 Trifluoroacetate

[0960] To a reaction flask, 46 g (91 mg) of the crude product, DIPEA (280 mg, 2.17 mmol), and 10 mL of DMSO were added. Then, 42A (96 mg, 0.22 mmol) was added and the reaction was carried out at 100°C for 7 h. The reaction system was cooled to room temperature, and the crude product was subjected to Pre-HPLC (instrument and preparative column: Waters 2767 Preparative HPLC, SunFire@Prep C18, 5 μm, ID x length = 19 mm x 250 mm). Preparation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was water (containing 0.1% trifluoroacetic acid) / acetonitrile. Gradient elution method: Acetonitrile was gradient eluted from 10% to 70% (elution time 12 min). The trifluoroacetate salt of compound 57 (50 mg) was lyophilized.

[0961] 1H NMR (400MHz, CD3OD) δ8.06(s,1H),8.04–7.99(m,1H),7.84–7.75(m,1H),7.72–7.64(m,1H),7.22(s,1H),6.98–6. 88(m,1H),6.73(d,1H),5.75–5.05(m,1H),4.62(s,2H),4.56–4.44(m,2H),4.18–4.04(m,1H),3.95–3.85(m,1H),3 .81–3.62(m,2H),3.44–3.34(m,1H),3.30–3.05(m,6H),3.05–2.92(m,1H),2.92–2.80(m,4H),2.80–2.62(m,3H), 2.40–2.17(m,2H),2.17–2.02(m,2H),2.01–1.88(m,2H),1.86–1.75(m,1H),1.75–1.67(m,6H),1.48–1.32(m,2H).

[0962] LCMS m / z=814.2[M+1] + .

[0963] The trifluoroacetic acid salt of compound 57 was subjected to chiral resolution to obtain the trifluoroacetic acid salt of chiral isomer 1 and chiral isomer 2, respectively. The resolution conditions are as follows:

[0964] 1. Instrument: Waters 150Prep-SFC A; Column: Chiralcel OJ column.

[0965] 2. Dissolve the sample in acetonitrile and filter with a 0.45 μm filter to prepare a sample solution.

[0966] 3. Preparative chromatographic conditions: a. Mobile phases consisted of A and B: Mobile phase A: CO2; Mobile phase B: a methanol / acetonitrile mixed solvent; b. Isocratic elution, mobile phase B content was 40%; c. Flow rate was 100 mL / min.

[0967] Chiral analysis method:

[0968] 1. Instrument: SHIMAZU LC-20AD; Chromatographic column: Whelk column.

[0969] 2. Analytical chromatographic conditions: a. Mobile phases consisted of a system of A and B: Mobile phase A: n-hexane; Mobile phase B: a solution of isopropanol and acetonitrile containing 0.1% isopropylamine; b. Isocratic elution, mobile phase B content was 80%; c. Flow rate was 1 mL / min.

[0970] Peak time: chiral isomer 1: 1.963 min, chiral isomer 2: 3.594 min.

[0971] NMR characterization of trifluoroacetate salt of chiral isomer 1:

[0972] 1 H NMR (400MHz, DMSO-d6) δ10.77(s,1H),8.85(s,1H),8.06(s,1H),8.02–7.88(m,2H),7.76–7.60(m,2H),7. 03(s,1H),6.94–6.70(m,2H),5.55–4.95(m,1H),4.63–4.37(m,4H),4.18–3.97(m,1H),3.92–3.77(m,1H) ,3.70–3.52(m,2H),3.45–3.22(m,1H),3.17–2.98(m,4H),2.98–2.80(m,3H),2.80–2.59(m,6H),2.57–2. 50(m,1H),2.25–2.05(m,2H),2.05–1.87(m,2H),1.87–1.70(m,2H),1.68–1.50(m,7H),1.30–1.10(m,2H).

[0973] NMR characterization of chiral isomer 2:

[0974] 1 H NMR(400MHz,DMSO-d6)δ10.75(s,1H),8.77(s,1H),8.03(s,1H),7.98–7.85(m,2H),7.78– 7.62(m,2H),7.02(s,1H),6.78(d,1H),6.61(d,1H),5.55–5.05(m,1H),4.58–4.42(m,4H), 3.86–3.76(m,1H),3.75–3.64(m,1H),3.02–2.79(m,5H),2.79–2.52(m,7H), 2.50–2.42(m,1H),2.25–1.68(m,10H),1.66–1.49(m,7H),1.13–0.95(m,2H).

[0975] Example 58: Preparation of Compound 58 Trifluoroacetate

[0976] Step 1: Preparation of 58b

[0977] The crude products 46e (0.24 g) and 58a (0.46 g, 1.14 mmol) (synthesis method, see WO2022221673) were dissolved in acetonitrile (10 mL), triethylamine (0.38 g, 3.76 mmol) was added, and the mixture was stirred at 25°C for 20 h. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0:1-1:9) to obtain 58b (0.30 g, yield: 46%).

[0978] LCMS m / z=571.2[M+1] + .

[0979] Step 2: Preparation of 58c

[0980] 58b (300 mg, 0.53 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The reaction was allowed to react at room temperature for 3 h. The reaction system was concentrated under reduced pressure, and the pH was adjusted to 9 with saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product 58c (150 mg).

[0981] LCMS m / z=471.3[M+1] + .

[0982] Step 3: Preparation of trifluoroacetate salt of compound 58

[0983] To a reaction flask, crude product 58c (61 mg), DIPEA (170 mg, 1.32 mmol), and 10 mL of DMSO were added, followed by 42A (55 mg, 0.13 mmol), and the reaction was carried out at 100°C for 20 h. The reaction system was cooled to room temperature, and the crude product was subjected to Pre-HPLC (instrument and preparative column: Waters 2767 Preparative HPLC, SunFire@Prep C18, 5 μm, i.d. x length = 19 mm x 250 mm). Preparation method: The crude product solution in DMSO was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was water (containing 0.1% TFA) / acetonitrile. Gradient elution was performed: 10% acetonitrile to 50% (elution time 15 min). The product was then lyophilized to obtain the trifluoroacetate salt of compound 58 (40 mg).

[0984] 1H NMR(400MHz,DMSO-d6)δ10.78(s,1H),8.96(s,1H),8.07(s,1H),8.00–7.90(m,2H),7.73–7 .62(m,2H),7.03(s,1H),6.87(d,1H),6.80(d,1H),5.52–5.15(m,1H),4.54(s,2H),4.38–4. 25(m,1H),4.18–4.03(m,3H),3.97–3.80(m,2H),3.65–3.43(m,3H),3.34–3.18(m,3H),3.05 –2.85(m,2H),2.82–2.50(m,10H),2.36–1.77(m,7H),1.71–1.50(m,7H),1.49–1.33(m,2H).

[0985] LCMS m / z=870.3[M+1] + .

[0986] Example 59: Preparation of Compound 59 Trifluoroacetate

[0987] Step 1: Preparation of 59b

[0988] Compound 59a (1.28 g, 3.48 mmol) (synthesis method, see Bioorg. Med. Chem. Lett. 2016, 26, 5877-5882), cesium carbonate (2.27 g, 6.97 mmol), palladium acetate (0.16 g, 0.71 mmol), XantPhos (0.20 g, 0.35 mmol), and 59A (0.89 g, 4.91 mmol) were added to a 1,4-dioxane solution (40 mL) and reacted at 105°C under a nitrogen atmosphere for 3 h. The reaction system was cooled to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate (80 mL × 3). The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-7:3) to obtain 59b (1.30 g, 80% yield).

[0989] LCMS m / z=468.4[M+1] + .

[0990] Step 2: Preparation of 59c

[0991] 59b (1.30 g, 2.78 mmol) was added to methanol (10 mL), followed by 10% palladium on carbon (1.33 g) and ammonium acetate (1.32 g, 17.13 mmol). The mixture was reacted at room temperature under a hydrogen balloon for 12 h. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-1:1) to afford 59c (0.76 g, 90% yield).

[0992] LCMS m / z=304.4[M+1] + .

[0993] Step 3: Preparation of 59d

[0994] 59c (0.76 g, 2.55 mmol), 59B (0.75 g, 7.49 mmol), and DIPEA (0.97 g, 7.50 mmol) were added sequentially to ethanol (50 mL) and reacted at 100°C for 48 h. The reaction system was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0:1-6:94) to afford 59d (0.70 g, 68% yield).

[0995] LCMS m / z=404.2[M+1] + .

[0996] Step 4: Preparation of 59e

[0997] 59d (700 mg, 1.74 mmol) and DIPEA (671 mg, 5.19 mmol) were added to THF (20 mL), and triphosgene (565 mg, 1.90 mmol) was slowly added. The reaction was allowed to react at room temperature for 1 h. Aqueous ammonia (5 mL) was added to the reaction system, and the reaction was continued at 50°C for 2 h. The reaction system was cooled to room temperature, and water (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL x 2). The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0:1-1:9) to obtain 59e (700 mg, yield: 90%).

[0998] Step 5: Preparation of 59f

[0999] 59f (0.70 g, 1.57 mmol) was added to acetonitrile (30 mL), followed by a 40% benzyltrimethylammonium hydroxide solution in methanol (2 mL). The reaction was allowed to proceed at 60°C for 2 h. The reaction system was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0:1-8:92) to afford 59f (530 mg, 84% yield).

[1000] LCMS m / z=401.4[M+1] + .

[1001] Step 6: Preparation of 59g

[1002] To a reaction flask, 59f (0.18 g, 0.45 mmol), 1 mL of trifluoroacetic acid, and 3 mL of dichloromethane were added and allowed to react at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, triethylamine was added to adjust the pH to 7, and the residue was dissolved in 10 mL of THF. 4-Formylpiperidine-1-carboxylic acid tert-butyl ester (0.12 g, 0.56 mmol), 0.3 mL of acetic acid, and sodium triacetoxyborohydride (0.19 g, 0.90 mmol) were added sequentially, and the reaction was allowed to react at room temperature for 16 h. 12 mL of ethyl acetate and 12 mL of saturated sodium bicarbonate were added to the reaction solution. The aqueous phase was extracted with ethyl acetate (5 mL x 3). The organic phase was washed with 5 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 (dichloromethane:methanol (v / v) = 20:1) to obtain 59f (0.20 g, yield: 89%).

[1003] LCMS m / z=498.2[M+1] + .

[1004] Step 7: Preparation of 59h trifluoroacetate

[1005] 59g (0.20g, 0.40mmol), 1mL trifluoroacetic acid, and 3mL dichloromethane were added to the reaction flask and reacted at room temperature for 2h. The reaction solution was concentrated under reduced pressure to obtain the crude trifluoroacetic acid salt of 59h (0.20g).

[1006] Step 8: Preparation of trifluoroacetate salt of compound 59

[1007] The trifluoroacetic acid salt of crude product 59h (0.20 g), DIPEA (0.25 g, 1.93 mmol), and 5 mL of DMSO were added to a reaction flask. After stirring at room temperature for 0.5 h, 4B (0.13 g, 0.33 mmol) was added and the reaction was continued at 100°C for 7 h. The reaction system was cooled to room temperature and the reaction solution was subjected to pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid chromatography, preparative column model SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: The crude product DMSO solution was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile was gradient eluted from 10% to 50% (elution time 15 min). The solution was then lyophilized to obtain the trifluoroacetic acid salt of compound 59 (130 mg).

[1008] 1 H NMR (400MHz, DMSO-d6) δ10.24(s,1H),9.08(s,1H),8.11(s,1H),8.03–7.87(m,2H),7.78–7.69( m,1H),7.53–7.42(m,1H),7.12(s,1H),7.06–6.88(m,3H),4.65–4.55(m,2H),4.54–4.35(m,2H) ,4.17–4.02(m,1H),3.75–3.55(m,7H),3.40–3.23(m,1H),3.23–2.75(m,8H),2.75–2.60(m,6H) ,2.28–2.10(m,1H),2.08–1.93(m,1H),1.90–1.72(m,2H),1.72–1.56(m,1H),1.31–1.11(m,2H).

[1009] LCMS m / z=385.3[M / 2+1] + .

[1010] Example 60: Preparation of Compound 60 Trifluoroacetate

[1011] Step 1: Preparation of 60b

[1012] To a reaction flask, 60a (10 g, 49.26 mmol), 1-tert-butyloxycarbonylpiperazine (9.18 g, 49.29 mmol), potassium carbonate (8.17 g, 59.18 mmol), and 100 mL of DMSO were added and reacted at 95°C under nitrogen for 12 h. The reaction solution was cooled to room temperature, and 200 mL of ethyl acetate and 200 mL of water were added. 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 purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1) to obtain 60b (6.0 g, yield: 33%).

[1013] LCMS m / z=369.1[M+1] + .

[1014] Step 2: Preparation of 60c

[1015] To a reaction flask, 60b (6.0 g, 16.3 mmol), p-toluenesulfonyl hydrazide (3.03 g, 16.27 mmol), and 60 mL of ethanol were added and reacted at room temperature under nitrogen for 2 h. The reaction solution was concentrated under reduced pressure to obtain crude product 60c (5.0 g).

[1016] LCMS m / z=537.1[M+1] +.

[1017] Step 3: Preparation of 60d

[1018] To a reaction flask, crude product 60c (4.0 g) and 20 mL of toluene were added. 60% sodium hydride (0.36 g) was added portionwise under nitrogen. The mixture was allowed to react at room temperature for 20 minutes under nitrogen, and then at 135°C for 2 hours. The reaction mixture was cooled to room temperature, and 100 mL of ethyl acetate and 100 mL of water were added. The organic phase was washed with saturated sodium chloride solution (50 mL) 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 60d (1.6 g, 35% yield over two steps based on 60b).

[1019] LCMS m / z=353.3[M+1] + .

[1020] Step 4: Preparation of 60e

[1021] To the reaction flask, 60d (1.6 g, 4.54 mmol), 20 mL of 1,4-dioxane and 5 mL of water were added respectively. Under nitrogen protection, 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (3.78 g, 9.06 mmol) (synthesis method see WO2021262812), cesium carbonate (4.43 g, 13.60 mmol) and Pd(dppf)Cl2 (0.33 g, 0.45 mmol) were added. The reaction was carried out at 100 ° C under nitrogen atmosphere for 16 h. The reaction system was cooled to room temperature and filtered through a pad of celite. 50 mL of ethyl acetate and 50 mL of water were added to the filtrate, and the aqueous phase was extracted with ethyl acetate (20 mL×3). 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 (petroleum ether:ethyl acetate (v / v)=3:1) to obtain 60e (1.80 g, yield: 70%).

[1022] Step 5: Preparation of 60f

[1023] To a reaction flask, 60e (1.8 g, 3.19 mmol), 40 mL of THF, and 10% Pd / C (1.02 g) were added and reacted at room temperature under a hydrogen balloon for 16 h. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to afford 60f (0.9 g, 73% yield).

[1024] LCMS m / z=386.1[M+1] +

[1025] Step 6: Preparation of 60g

[1026] To a reaction flask, 60f (0.9 g, 2.34 mmol), 3 mL of trifluoroacetic acid, and 9 mL of dichloromethane were added and allowed to react at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, triethylamine was added to adjust the pH to 7, and the solution was concentrated under reduced pressure. The residue was dissolved in 30 mL of THF, and tert-butyl 4-formylpiperidine-1-carboxylate (0.54 g, 2.53 mmol), 1 mL of acetic acid, and sodium triacetoxyborohydride (0.99 g, 4.67 mmol) were added sequentially. The reaction was allowed to react at room temperature for 16 h. 30 mL of ethyl acetate and 30 mL of saturated sodium bicarbonate were added to the reaction solution. The aqueous phase was extracted with ethyl acetate (15 mL x 3). The organic phase was washed with 10 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 (dichloromethane:methanol (v / v) = 20:1) to obtain 60g (1.01 g, yield: 89%).

[1027] LCMS m / z=483.6[M+1] + .

[1028] Step 7: Preparation of 60h trifluoroacetate

[1029] 60g (0.15g, 0.31mmol), 1mL trifluoroacetic acid, and 3mL dichloromethane were added to the reaction flask and reacted at room temperature for 2h. The reaction solution was concentrated under reduced pressure to obtain the crude trifluoroacetic acid salt of 60h (0.20g).

[1030] Step 8: Preparation of trifluoroacetate salt of compound 60

[1031] The trifluoroacetic acid salt of the crude product 60h (0.20 g), DIPEA (0.26 g, 2.01 mmol), and 5 mL of DMSO were added to a reaction flask. After stirring at room temperature for 0.5 h, 4B (0.11 g, 0.28 mmol) was added and the reaction was allowed to proceed at 100°C for 7 h. The reaction system was cooled to room temperature and the reaction solution was subjected to Pre-HPLC (instrument and preparative column: Waters 2767 Preparative HPLC, SunFire@Prep C18, 5 μm, ID × length = 19 mm × 250 mm). Preparation method: The crude product DMSO solution was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile was gradient eluted from 10% to 50% (elution time 15 min). The solution was then lyophilized to obtain the trifluoroacetic acid salt of compound 60 (43 mg).

[1032] 1H NMR(400MHz,DMSO-d6)δ10.74(s,1H),8.96(s,1H),8.08(s,1H),8.02–7.88(m,2H),7.74(dd,1H),7 .46(d,1H),7.11(s,1H),7.02–6.95(m,1H),6.95–6.87(m,1H),6.62(d,1H),4.59(s,2H),4.54–4.40 (m,2H),3.94–3.80(m,2H),3.76–3.62(m,4H),3.62–3.42(m,2H),3.35–3.20(m,1H),3.15–2.77(m, 7H),2.72–2.55(m,5H),2.50–2.38(m,1H),2.24–1.91(m,3H),1.84–1.66(m,2H),1.24–1.06(m,2H).

[1033] LCMS m / z=377.8[M / 2+1] +

[1034] Example 61: Preparation of Compound 61 Trifluoroacetate

[1035] To a reaction flask, crude product 58c (52 mg), DIPEA (140 mg, 1.08 mmol), and 3 mL of DMSO were added, followed by 61A (45 mg, 0.107 mmol) (synthesis method, see WO2022221673), and the reaction was carried out at 100°C for 20 h. The reaction system was cooled to room temperature, and the reaction solution was subjected to pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid chromatography, preparative column model SunFire@Prep C18, 5 μm, i.d. x length = 19 mm x 250 mm). Preparation method: The crude product DMSO solution was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile was gradient eluted from 10% to 50% (elution time 15 min). The solution was then lyophilized to obtain the trifluoroacetate salt of compound 61 (40 mg).

[1036] 1H NMR(400MHz,DMSO-d6)δ10.78(s,1H),8.94(s,1H),8.07(s,1H),8.00–7.92(m,2H),7.71(dd,1 H),7.52(d,1H),7.09(s,1H),6.87(d,1H),6.80(d,1H),4.60–4.54(m,2H),4.40–4.25(m,3H),4 .18–4.03(m,3H),3.95–3.79(m,2H),3.63–3.42(m,3H),3.32–3.16(m,3H),3.04–2.85(m,2H),2 .80–2.50(m,10H),2.36–1.77(m,7H),1.70–1.54(m,1H),1.48–1.32(m,2H),1.29–1.19(m,3H).

[1037] LCMS m / z=856.3[M+1] + .

[1038] Example 62: Preparation of Compound 62 Trifluoroacetate

[1039] To a reaction flask, the crude product 44h (50 mg), DIPEA (160 mg, 1.24 mmol), and 10 mL of DMSO were added. The crude product 48h (50 mg) was then added and reacted at 100°C for 7 h. The reaction system was cooled to room temperature, and the crude product was subjected to Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid chromatography, preparative column model: SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: The crude product DMSO solution was filtered through a 0.45 μm filter to prepare a sample solution. The mobile phase system was water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile was gradient eluted from 10% to 50% (elution time 15 min). The product was then lyophilized to obtain the trifluoroacetate salt of compound 62 (20 mg).

[1040] 1H NMR(400MHz,DMSO-d6)δ10.79(s,1H),8.97(s,1H),8.08(s,1H),7.98–7.91(m,2H),7.74(dd,1H),7.47(d, 1H),7.12(s,1H),6.87(d,1H),6.79(d,1H),4.59(s,2H),4.54–4.42(m,2H),4.15–4.00(m,1H),3.92–3.80 (m,1H),3.68(s,3H),3.66–3.56(m,2H),3.41–3.28(m,1H),3.18–2.80(m,7H),2.80–2.59(m,3H),2.56–2. 51(m,1H),2.27–2.05(m,2H),2.05–1.87(m,2H),1.87–1.70(m,2H),1.70–1.53(m,1H),1.30–1.07(m,2H).

[1041] LCMS m / z=789.2[M+1] + .

[1042] Example 63: Preparation of Compound 63 Trifluoroacetate

[1043] To a reaction flask, crude product 44h (50 mg), DIPEA (160 mg, 1.24 mmol), and 10 mL of DMSO were added, followed by crude product 49e (50 mg), and the reaction was continued at 100°C for 7 h. The reaction system was cooled to room temperature, and the crude product was subjected to Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, preparative column model: SunFire@Prep C18, 5 μm, i.d. x length = 19 mm x 250 mm). Preparation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter to prepare a sample solution. The mobile phase system was water (containing 0.1% TFA) / acetonitrile. Gradient elution was performed: 10% acetonitrile to 50% acetonitrile (elution time: 15 min). The product was then lyophilized to obtain the trifluoroacetate salt of compound 63 (30 mg).

[1044] 1H NMR(400MHz,DMSO-d6)δ10.79(s,1H),8.97(s,1H),8.08(s,1H),7.98–7.90(m,2H),7.74(dd,1H), 7.46(d,1H),7.12(s,1H),6.87(d,1H),6.79(d,1H),4.59(s,2H),4.55–4.39(m,2H),4.13–4.00(m, 1H),3.93–3.79(m,1H),3.69–3.55(m,2H),3.42–3.26(m,1H),3.20–2.58(m,10H),2.57–2.51(m,1 H),2.28–2.05(m,2H),2.05–1.87(m,2H),1.87–1.70(m,2H),1.70–1.53(m,1H),1.30–1.05(m,2H).

[1045] LCMS m / z=792.2[M+1] + .

[1046] Example 64: Preparation of Compound 64 Trifluoroacetate

[1047] To a reaction flask, crude product 44h (50 mg), DIPEA (160 mg, 1.24 mmol), and 10 mL of DMSO were added, followed by crude product 47d (50 mg), and the reaction was carried out at 100°C for 7 h. The reaction system was cooled to room temperature, and the crude product was subjected to Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid chromatography, preparative column model: SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: The crude product DMSO solution was filtered through a 0.45 μm filter to prepare a sample solution. The mobile phase system was water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile was gradient eluted from 10% to 50% (elution time 15 min). The trifluoroacetate salt of compound 64 (25 mg) was lyophilized.

[1048] 1H NMR(400MHz,DMSO-d6)δ10.79(s,1H),8.97(s,1H),8.08(s,1H),7.98–7.91(m,2H),7.74(dd,1H),7.4 7(d,1H),7.12(s,1H),6.87(d,1H),6.79(d,1H),4.59(s,2H),4.55–4.40(m,2H),4.13–4.00(m,1H),3 .91–3.80(m,1H),3.68(s,3H),3.66–3.55(m,2H),3.44–3.26(m,1H),3.18–2.58(m,10H),2.56–2.51( m,1H),2.28–2.05(m,2H),2.05–1.88(m,2H),1.88–1.70(m,2H),1.70–1.52(m,1H),1.29–1.08(m,2H).

[1049] LCMS m / z=789.2[M+1] + .

[1050] Example 65: Preparation of Compound 65 Trifluoroacetate

[1051] To a reaction flask, 46 g (50 mg) of the crude product, DIPEA (160 mg, 1.24 mmol), and 10 mL of DMSO were added. The crude product (48h) (50 mg) was then added and reacted at 100°C for 7 h. The reaction system was cooled to room temperature, and the crude product was subjected to Pre-HPLC (instrument and preparative column: Waters 2767 Preparative HPLC, SunFire@Prep C18, 5 μm, ID x length = 19 mm x 250 mm). Preparation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter to prepare a sample solution. The mobile phase system was water (containing 0.1% TFA) / acetonitrile. Gradient elution was performed: 10% to 50% acetonitrile (elution time 15 min). The product was then lyophilized to obtain the trifluoroacetate salt of compound 65 (50 mg).

[1052] 1H NMR(400MHz,DMSO-d6)δ10.79(s,1H),9.02–8.88(m,1H),8.08(s,1H),8.02–7.90(m,2H),7.74(dd,1H), 7.46(d,1H),7.11(s,1H),6.87(d,1H),6.79(d,1H),4.59(s,2H),4.54–4.41(m,2H),4.13–4.02(m,1H),3 .92–3.77(m,1H),3.68–3.54(m,2H),3.42–3.26(m,1H),3.18–2.80(m,7H),2.80–2.57(m,6H),2.56–2.5 1(m,1H),2.27–2.05(m,2H),2.05–1.87(m,2H),1.87–1.70(m,2H),1.70–1.53(m,1H),1.28–1.05(m,2H).

[1053] LCMS m / z=789.2[M+1] + .

[1054] Example 66: Preparation of Compound 66 Trifluoroacetate

[1055] To a reaction flask, the crude product 46 g (50 mg), DIPEA (160 mg, 1.24 mmol), and 10 mL of DMSO were added, followed by the crude product 49e (50 mg), and the reaction was carried out at 100°C for 7 h. The reaction system was cooled to room temperature, and the crude product was subjected to Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid chromatography, preparative column model: SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter to prepare a sample solution. The mobile phase system was water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile was gradient eluted from 10% to 50% (elution time 15 min). The product was then lyophilized to obtain the trifluoroacetate salt of compound 66 (45 mg).

[1056] 1H NMR(400MHz,DMSO-d6)δ10.79(s,1H),8.97(s,1H),8.08(s,1H),7.98–7.90(m,2H),7.74(dd,1H),7.46( d,1H),7.14–7.09(m,1H),6.87(d,1H),6.79(d,1H),4.59(s,2H),4.53–4.41(m,2H),4.14–4.01(m,1H),3 .93–3.77(m,1H),3.70–3.53(m,2H),3.42–3.26(m,1H),3.18–2.80(m,7H),2.80–2.57(m,3H),2.57–2.5 0(m,1H),2.27–2.05(m,2H),2.05–1.87(m,2H),1.87–1.70(m,2H),1.70–1.53(m,1H),1.30–1.08(m,2H).

[1057] LCMS m / z=792.2[M+1] + .

[1058] Example 67: Preparation of Compound 67 Trifluoroacetate

[1059] To a reaction flask, the crude product 46 g (50 mg), DIPEA (160 mg, 1.24 mmol), and 10 mL of DMSO were added, followed by the crude product 47d (50 mg), and the reaction was carried out at 100°C for 7 h. The reaction system was cooled to room temperature, and the crude product was subjected to Pre-HPLC (instrument and preparative column: Waters 2767 Preparative HPLC, SunFire@Prep C18, 5 μm, ID × length = 19 mm × 250 mm). Preparation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter to prepare a sample solution. The mobile phase system was water (containing 0.1% TFA) / acetonitrile. Gradient elution was performed: 10% acetonitrile to 50% acetonitrile (elution time 15 min). The product was then lyophilized to obtain the trifluoroacetate salt of compound 67 (50 mg).

[1060] 1H NMR(400MHz,DMSO-d6)δ10.82(s,1H),9.06–8.94(m,1H),8.09(s,1H),8.02–7.89(m,2H),7.7 4(dd,1H),7.47(d,1H),7.11(s,1H),6.88(d,1H),6.80(d,1H),4.60(s,2H),4.54–4.42(m,2H ),4.13–4.01(m,1H),3.91–3.79(m,1H),3.68(s,3H),3.65–3.56(m,2H),3.40–3.26(m,1H),3 .20–2.80(m,7H),2.80–2.58(m,3H),2.57–2.50(m,1H),2.28–2.05(m,2H),2.05–1.88(m,2H), 1.88–1.70(m,2H),1.70–1.52(m,1H),1.29–1.05(m,2H).

[1061] LCMS m / z=789.2[M+1] + .

[1062] Example 68: Preparation of Compound 68 Trifluoroacetate

[1063] To a reaction flask, 23 g of the crude product (trifluoroacetic acid salt, 0.19 g), DIPEA (0.39 g, 3.02 mmol), and 5 mL of DMSO were added. Compound 61A (0.089 g, 0.21 mmol) (synthesis method, see WO2022221673) was added and reacted at 100°C for 7 h. The reaction system was cooled to room temperature, and the reaction solution was subjected to pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, SunFire@Prep C18, 5 μm, i.d. x length = 19 mm x 250 mm). Preparation method: The crude product solution in DMSO was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was water (containing 0.1% TFA) / acetonitrile. Gradient elution was performed: 10% acetonitrile to 50% acetonitrile (elution time 15 min). The solution was then lyophilized to obtain the trifluoroacetic acid salt of compound 68 (55 mg).

[1064] 1H NMR(400MHz,DMSO-d6)δ10.79(s,1H),9.06(s,1H),8.15(s,1H),8.03–7.90(m,2H),7.72(dd,1H), 7.53(d,1H),7.15(s,1H),7.09(t,1H),6.81–6.70(m,2H),4.58(s,2H),4.55–4.42(m,2H),4.33(q ,2H),3.95–3.83(m,1H),3.83–3.70(m,2H),3.67–3.51(m,2H),3.44–3.25(m,2H),3.17–2.95(m,4 H),2.83–2.62(m,6H),2.57–2.50(m,1H),2.24–1.90(m,3H),1.88–1.75(m,2H),1.40–1.17(m,5H).

[1065] LCMS m / z=388.0[M / 2+1] + .

[1066] Example 69: Preparation of Compound 69 Trifluoroacetate

[1067] The trifluoroacetic acid salt of crude product 8c (0.084 g), DIPEA (0.12 g, 0.93 mmol), and 5 mL of DMSO were added to a reaction flask. Compound 61A (0.08 g, 0.19 mmol) was then added and reacted at 100°C for 7 h. The reaction system was cooled to room temperature and the reaction solution was subjected to pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, SunFire@Prep C18, 5 μm, i.d. x length = 19 mm x 250 mm). Preparation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was water (containing 0.1% TFA) / acetonitrile. Gradient elution was performed: 10% acetonitrile to 50% (elution time 15 min). The mixture was then lyophilized to obtain the trifluoroacetic acid salt of compound 69 (20 mg).

[1068] 1H NMR(400MHz,DMSO-d6)δ10.80(s,1H),9.08(s,1H),8.16(s,1H),8.04–7.96(m,1H),7.96–7.91( m,1H),7.72(dd,1H),7.53(d,1H),7.19–7.02(m,5H),4.65–4.41(m,4H),4.33(q,2H),3.84–3.66 (m,3H),3.66–3.52(m,2H),3.44–3.25(m,2H),3.18–2.96(m,4H),2.96–2.76(m,2H),2.73–2.57( m,4H),2.50–2.42(m,1H),2.24–1.95(m,3H),1.95–1.82(m,2H),1.51–1.34(m,2H),1.25(t,3H).

[1069] LCMS m / z=379.0[M / 2+1] + .

[1070] Example 70: Preparation of Compound 70 Trifluoroacetate

[1071] Compound 70 trifluoroacetate was prepared from 44f and 58a by referring to the synthesis method of Example 58 and lyophilized in acidic preparation [water (containing 0.1% TFA) / acetonitrile].

[1072] 1 H NMR(400MHz,DMSO-d6)δ10.79(s,1H),9.00(s,1H),8.08(s,1H),8.00–7.90(m,2H),7.73–7 .62(m,2H),7.03(s,1H),6.87(d,1H),6.80(d,1H),5.55–5.15(m,1H),4.55(s,2H),4.37–4. 25(m,1H),4.20–4.03(m,3H),3.97–3.80(m,2H),3.65–3.43(m,3H),3.34–3.18(m,3H),3.05 –2.85(m,2H),2.82–2.50(m,10H),2.36–1.77(m,7H),1.71–1.50(m,7H),1.49–1.33(m,2H).

[1073] LCMS m / z=870.3[M+1] + .

[1074] Example 71: Preparation of Compound 71 Trifluoroacetate

[1075] The trifluoroacetate salt of compound 71 was prepared from compounds 58c and 49e by lyophilization in acidic solution [water (containing 0.1% TFA) / acetonitrile] according to the synthesis method of Example 58.

[1076] 1 H NMR(400MHz,DMSO-d6)δ10.82(s,1H),9.06(s,1H),8.09(s,1H),7.99–7.89(m,2H),7.71(dd,1H ),7.47(d,1H),7.11(s,1H),6.93–6.75(m,2H),4.58(s,2H),4.38–4.23(m,1H),4.20–4.01(m,3H ),3.97–3.78(m,2H),3.65–3.43(m,3H),3.34–3.15(m,3H),3.05–2.86(m,2H),2.83–2.50(m,7H) ,2.38–2.21(m,2H),2.21–2.05(m,1H),2.05–1.76(m,4H),1.70–1.52(m,1H),1.48–1.32(m,2H).

[1077] LCMS m / z=425.1[M / 2+1] + .

[1078] Example 72: Preparation of Compound 72 Trifluoroacetate

[1079] Compound 72 trifluoroacetate was prepared from compounds 58c and 47d by lyophilization in acidic solution [water (containing 0.1% trifluoroacetic acid) / acetonitrile] according to the synthesis method of Example 58.

[1080] 1H NMR(400MHz,DMSO-d6)δ10.82(s,1H),8.98(s,1H),8.07(s,1H),7.98–7.90(m,2H),7.71(dd,1H),7 .48(d,1H),7.11(s,1H),6.92–6.77(m,2H),4.59(s,2H),4.36–4.25(m,1H),4.20–4.04(m,3H),3.93 –3.80(m,2H),3.68(s,3H),3.63–3.44(m,3H),3.32–3.15(m,3H),3.05–2.85(m,2H),2.83–2.50(m, 7H),2.37–2.21(m,2H),2.21–2.05(m,1H),2.05–1.76(m,4H),1.70–1.53(m,1H),1.48–1.32(m,2H).

[1081] LCMS m / z=845.3[M+1] + .

[1082] Example 73: Preparation of Compound 73 Trifluoroacetate

[1083] Compound 73 trifluoroacetate was prepared from compounds 58c and 48h by lyophilization in acidic solution [water (containing 0.1% TFA) / acetonitrile] according to the synthesis method of Example 58.

[1084] 1 H NMR(400MHz,DMSO-d6)δ10.81(s,1H),9.10–8.96(m,1H),8.10–8.05(m,1H),8.01–7.91(m,2H),7.7 1(dd,1H),7.47(d,1H),7.11(s,1H),6.93–6.76(m,2H),4.58(s,2H),4.37–4.25(m,1H),4.18–4.02( m,3H),3.95–3.80(m,2H),3.64–3.44(m,3H),3.34–3.15(m,3H),3.04–2.85(m,2H),2.82–2.50(m,1 0H),2.37–2.20(m,2H),2.20–2.05(m,1H),2.05–1.77(m,4H),1.72–1.52(m,1H),1.50–1.32(m,2H).

[1085] LCMS m / z=423.5[M / 2+1] + .

[1086] Example 74: Preparation of Compound 74 Trifluoroacetate

[1087] Compound 74 trifluoroacetate was prepared from compounds 70b and 61A by lyophilization in acidic solution [water (containing 0.1% TFA) / acetonitrile] according to the synthesis method of Example 58.

[1088] 1 H NMR (400MHz, DMSO-d6) δ10.80(s,1H),8.97(s,1H),8.10–8.04(m,1H),8.02–7.92(m,2H),7.79–7.63(m, 1H),7.61–7.48(m,1H),7.09(s,1H),6.92–6.75(m,2H),4.58(s,2H),4.40–4.23(m,3H),4.20–4.03(m,3 H),3.97–3.77(m,2H),3.63–3.42(m,3H),3.34–3.15(m,3H),3.05–2.85(m,2H),2.82–2.50(m,10H),2.3 7–2.21(m,2H),2.21–2.05(m,1H),2.05–1.75(m,4H),1.70–1.53(m,1H),1.48–1.32(m,2H),1.24(t,3H).

[1089] LCMS m / z=856.3[M+1] + .

[1090] Example 75: Preparation of Compound 75 Trifluoroacetate

[1091] Step 1: Preparation of 75b

[1092] 75a (2.0 g, 8.40 mmol), N-Boc-ethylenediamine (1.35 g, 8.43 mmol), and DIPEA (3.26 g, 25.22 mmol) were added to a reaction flask, followed by DMSO (20 mL). The reaction was allowed to react at 50°C for 3 h. The reaction system was cooled to room temperature, and 100 mL of water and 50 mL of ethyl acetate were added. The organic phase was washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 75b (3.2 g).

[1093] Step 2: Preparation of 75c

[1094] The crude product 75b (3.1 g), iron powder (4.58 g, 81.79 mmol), and ammonium chloride (4.39 g, 82.07 mmol) were added to a reaction flask, followed by methanol (150 mL) and reaction at 70°C for 20 h. The reaction system was cooled to room temperature, filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (methanol:dichloromethane (v / v) = 0:1-1:9) to afford 75c (2.7 g, 96% yield over two steps based on compound 75a).

[1095] Step 3: Preparation of 75d

[1096] 75c (2.7 g, 7.75 mmol) and TEA (2.35 g, 23.22 mmol) were dissolved in 25 mL of dichloromethane, and chloroacetyl chloride (1.31 g, 11.6 mmol) was added dropwise. The mixture was allowed to react at room temperature for 20 h. 50 mL of water was added to the reaction solution, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 75d (3.2 g, 98% yield).

[1097] LCMS m / z=424.2[M+1] + .

[1098] Step 4: Preparation of 75e

[1099] 75d (3.5 g, 8.27 mmol) was added to acetic acid (50 mL) and reacted at 40°C for 7 h. The reaction system was cooled to 0°C, and 25% aqueous ammonia was added to adjust the pH to 8. The mixture was extracted with 100 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 (methanol:dichloromethane (v / v) = 0:1-1:9) to obtain 75e (3.0 g, yield: 89%).

[1100] Step 5: Preparation of 75f hydrochloride

[1101] Dissolve 75e (3.0 g, 7.38 mmol) in dichloromethane (50 mL), add 50 mL of 4 mol / L hydrochloric acid in 1,4-dioxane, and react at room temperature for 20 h. Concentrate the reaction mixture under reduced pressure to obtain the crude product 75f hydrochloride (3.12 g).

[1102] Step 6: Preparation of 75g

[1103] The crude product 75f hydrochloride (3.0 g), potassium carbonate (3.48 g, 25.18 mmol), and KI (0.3 g, 1.81 mmol) were added to a reaction flask, followed by acetonitrile (50 mL) and the reaction was carried out at 80°C for 7 h. The reaction system was cooled to room temperature, and 20 mL of a 1:4 methanol / dichloromethane (v / v) solvent mixture was added. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (methanol:dichloromethane (v / v) = 0:1-1:9) to obtain 75g (0.50 g, two-step yield: 26% based on compound 75e).

[1104] Step 7: 75h preparation

[1105] Dissolve 75g (0.50g, 1.85mmol) in dichloromethane (10mL), add Boc anhydride (0.81g, 3.71mmol) and DMAP (0.45g, 3.68mmol), and react at room temperature for 16h. The reaction system is washed with 20mL of 0.5mol / L hydrochloric acid, and the organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product is separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether (v / v) = 0:1-1:9) to obtain 75h (0.2g, yield: 29%).

[1106] Step 8: Preparation of 75i

[1107] 75h (0.20 g, 0.54 mmol), 2,6-bis(benzyloxypyridine-3-boronic acid pinacol ester (0.34 g, 0.81 mmol), Pd(dppf)Cl2·DCM (0.044 g, 0.054 mmol), and cesium carbonate (0.35 g, 1.07 mmol) were added sequentially to a reaction flask. 1,4-Dioxane (10 mL) and water (1 mL) were added, and the mixture was reacted at 100°C under a nitrogen atmosphere for 20 h. After cooling to room temperature, 50 mL of water and 50 mL of ethyl acetate were added. 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) = 1:0-9:1) to afford 75i (0.23 g, yield: 73%).

[1108] LCMS m / z=581.2[M+1] + .

[1109] Step 9: Preparation of 75j

[1110] 75i (0.23 g, 0.396 mmol) was dissolved in THF (10 mL), and 10% palladium on carbon (0.20 g) was added. The mixture was reacted at 45°C under a hydrogen balloon atmosphere for 20 h. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to afford crude product 75j (0.16 g).

[1111] LCMS m / z=403.5[M+1] + .

[1112] Step 10: Preparation of 75k

[1113] The crude product 75j (250 mg) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, and the mixture was allowed to react at room temperature for 3 h. The reaction system was concentrated under reduced pressure, 5 mL of dichloromethane and 1 mL of triethylamine were added, and the mixture was concentrated under reduced pressure to obtain the crude product 75k (120 mg).

[1114] LCMS m / z=303.3[M+1] + .

[1115] Step 11: Preparation of 75L

[1116] The crude product 75k (0.12 g) was dissolved in 1,2-dichloroethane (5 mL), and tert-butyl 4-formylpiperidine-1-carboxylate (0.077 g, 0.36 mmol) and 1 mL of acetic acid were added. After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (0.13 g, 0.61 mmol) was added and the mixture was allowed to react at room temperature for 16 hours. To the reaction solution was slowly added 30 mL of saturated aqueous sodium bicarbonate solution, and the mixture was extracted with 50 mL of dichloromethane. The organic phase was washed with 100 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 (dichloromethane:methanol (v / v) = 10:1) to obtain 75l (0.06 g, yield: 33%).

[1117] LCMS m / z=500.2[M+1] + .

[1118] Step 12: Preparation of 75m

[1119] Dissolve 75l (60 mg, 0.12 mmol) in dichloromethane (2 mL), add trifluoroacetic acid (1 mL), and react at room temperature for 3 h. The reaction system is concentrated under reduced pressure, and the pH is adjusted to 9 with saturated sodium bicarbonate aqueous solution. Extract with dichloromethane (20 mL x 2), and the organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product 75m (48 mg).

[1120] LCMS m / z=400.3[M+1] + .

[1121] Step 13: Preparation of trifluoroacetate salt of compound 75

[1122] To a reaction flask, crude product 75m (48 mg), DIPEA (160 mg, 1.24 mmol), and 3 mL of DMSO were added, followed by 42A (52 mg, 0.12 mmol), and the reaction was carried out at 100°C for 7 h. The reaction system was cooled to room temperature, and the crude product was subjected to Pre-HPLC (instrument and preparative column: Waters 2767 Preparative HPLC, SunFire@Prep C18, 5 μm, ID x length = 19 mm x 250 mm). Preparation method: The crude product solution in DMSO was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was water (containing 0.1% TFA) / acetonitrile. Gradient elution was performed: 10% to 70% acetonitrile (elution time 12 min). The product was then lyophilized to obtain compound 75 trifluoroacetate (25 mg).

[1123] 1 H NMR(400MHz,CD3OD)δ8.05(s,1H),8.00–7.93(m,1H),7.84–7.75(m,1H),7.70–7.57(m,1H) ,7.30–7.12(m,1H),6.89(d,1H),6.70(d,1H),5.70–5.10(m,1H),4.65–4.53(m,2H),4.51–4 .38(m,2H),4.15–4.00(m,1H),3.95–3.82(m,1H),3.79–3.55(m,1H),3.45–3.31(m,1H),3.2 6–3.05(m,7H),3.01–2.58(m,5H),2.40–1.86(m,5H),1.74–1.62(m,6H),1.48–1.30(m,2H).

[1124] Example 76: Preparation of Compound 76 Trifluoroacetate

[1125] Step 1: Preparation of 76b

[1126] To a reaction flask, 76a (3.0 g, 11.03 mmol) and 30 mL of DMSO were added. 60% sodium hydride (0.66 g) was added portionw...

Claims

1. A compound or a stereoisomer, tautomer, 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 -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- is optionally replaced 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, a 4-8 membered heteromonocyclic ring, a 4-10 membered heterocyclic ring, a 5-12 membered heterospirocyclic ring, a 7-10 membered heterobridged ring, a C 3-7 Monocyclic alkyl, C 4-10 Cycloalkyl, C 5-12 Spiroalkyl, C 7-10 Bridged cycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl, wherein the aryl, heteroaryl, cycloalkyl, heteromonocyclic, heterocyclic, heterospirocyclic or heterobridged ring is optionally substituted by 1 to 2 groups selected from halogen, 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 heteroaryl, heteromonocyclic, heterocyclic, heterospirocyclic or heterobridged ring 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; B is selected from X is selected from O, S or CH2; Y is selected from NR Y or O; R Y Selected from H, C 1-6 Alkyl, C 3-10 Carbocyclic or 3 to 10 membered heterocyclic ring, wherein the alkyl, carbocyclic or heterocyclic ring is optionally substituted by 1 to 3 groups selected from halogen, OH, cyano, NH2, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 is substituted by a carbocyclic or 3- to 8-membered heterocyclic substituent, wherein the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N; R 1 Selected from H, OH, -(CH2) t2 NR 1a R 1b 、C 1-6 Alkyl, C 1-6 Alkoxy, the alkyl, alkoxy is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent; R 1a 、R 1b Each independently selected from H, OH, NH2, C 1-4 Alkyl, C 2-6 Alkynyl, C 1-4 Alkoxy, the alkyl, alkynyl, alkoxy is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 substituted by a substituent of the alkynyl group; or R 1a 、R 1b The atoms to which it is connected together form a 3-10 membered ring; R 3a or R 4 Each independently selected from H, OH, NH2, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 Carbocyclic or 3 to 10 membered heterocyclic rings, wherein the alkyl, alkoxy, alkynyl, carbocyclic or heterocyclic rings are optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH(CH3), N(CH3)2, NH(CH2CH3), N(CH2CH3)2, NH2, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkynyl, C 3-6 Cycloalkyloxy, C 3-6 is substituted by a carbocyclic or 3- to 8-membered heterocyclic substituent, wherein the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N; R 3b or R 5 Each independently selected from H, halogen, cyano, NH2, NO2, OH, C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-6 Alkoxy, C 3-10 Carbocyclic or 3 to 10 membered heterocyclic ring, wherein the alkyl, alkoxy, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 is substituted by a carbocyclic or 3- to 8-membered heterocyclic substituent, wherein the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N; t1 is selected from 1, 2, 3, 4 or 5; t2 is selected from 0, 1, 2, 3, 4 or 5; m is selected from 0, 1, 2, 3 or 4; n is selected from 0, 1 or 2; K is selected from F1 is each independently selected from C 3-7 Monocyclic carbocyclic ring, C 4-14 Ring carbon ring, C 5-12 Spirocarbon ring, C 5-10 Bridged carbon ring, C 6-14 Aryl, 6-7 membered non-aromatic monocyclic ring, 5-14 membered hetero-bridged ring, 5-6 membered heteroaryl, 11-20 membered heterocyclic ring, phthalazine-1(2H)-one, benzo[d][1,2,3]triazine-4(3H)-one, benzothiophene, The heteromonocyclic, heterocyclic, heterospirocyclic, heterobridged or heteroaryl group contains 1 to 4 heteroatoms selected from O, S and N, provided that when F1 is selected from a 6-membered heteroaryl group, the right side connection site on the ring is a carbon atom; E are each independently selected from C 5-12 Carbocyclic ring, 5-12 membered heterocyclic ring, 5-12 membered heteroaromatic ring, wherein the heterocyclic ring or heteroaromatic ring contains 1 to 4 heteroatoms selected from O, S or N; F2 are each independently selected from C 3-7 Monocyclic non-aromatic carbocyclic ring, C 4-10 Non-aromatic carbon ring, C 5-12 Spirocarbon ring, C 5-10 Bridged carbon ring, C 12-14 Aryl, 4-7 membered non-aromatic monocyclic ring, 5-14 membered heterospirocyclic ring, 5-14 membered heterobridged ring, 11-20 membered heterocyclic ring, The heteromonocyclic, heterocyclic, heterospirocyclic, heterobridged or heteroaromatic ring contains 1 to 4 heteroatoms selected from O, S and N; represents a ring selected from an aromatic ring or a non-aromatic ring; F are each independently selected from C 3-7 Monocyclic carbocyclic ring, C 4-20 Ring carbon ring, C 5-20 Spirocarbon ring, C 5-20 Bridged carbocyclic ring, 4-7 membered heteromonocyclic ring, 4-20 membered heterocyclic ring, 5-20 membered heterospirocyclic ring, 5-20 membered heterobridged ring, wherein the heteromonocyclic ring, heterocyclic ring, heterospirocyclic ring, heterobridged ring or heteroaromatic ring contains 1 to 4 heteroatoms selected from O, S and N; A is selected from C 3-8 a carbocyclic ring, a benzene ring, a 4-7 membered heterocyclic ring or a 5-6 membered heteroaromatic ring, wherein the heterocyclic ring or heteroaromatic ring contains 1 to 4 heteroatoms selected from O, S or N; Q1 is independently selected from -O-, -S-, -CH2-, -NR q -or-CO-; Q is independently selected from a bond, -O-, -S-, -CH2-, -NR q -、-CO-、-NR q CO-、-CONR 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 ring contains 1 to 4 heteroatoms selected from O, S or N; R q Selected from H or C 1-4 alkyl; R k1 Each independently selected from H, D, 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, cycloalkyl group is optionally substituted by 1 to 4 groups selected from D, 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; R k3 Each independently selected from H, D, 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 D, 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, and N; Or two R k3 Together with the carbon atoms or ring skeletons directly connected to the two, they form C 3-8 Carbocyclic or 3-8 membered heterocyclic ring, or two R k1 Together with the carbon atoms or ring skeletons directly connected to the two, they form C 3-8 Carbocyclic or 3-8 membered heterocyclic ring, wherein the carbocyclic or 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 The heterocyclic ring is substituted by an alkoxy substituent, and the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N; R k4 Each independently selected from H or C 1-4 alkyl; R k5 Each independently selected from <h2 style=";text-align:left;direction:ltr">C(CH3)2, CO, CH2, SO2,<h2 style=";text-align:left;direction:ltr"> R k6 Each independently selected from CO, CH, SO, SO2, CH2, N or NR k7a ; R k7 Each independently selected from C(CH3)2、CO、CH、N、CH2、O、S、NR k7a ; 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 k8 are each independently selected from C, N or CH; R k9 are each independently selected from a bond, C(CH3)2, CO, CH2, CH2CH2 or SO2; R ka Selected from O, S or NH; R k10 Selected from CH2 or CO; p1 or p2 are each independently selected from 0, 1, 2, 3, 4 or 5; The compound is optionally substituted with 1 to 30 Ds.

2. The compound according to claim 1 or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, 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-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -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-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-、-Ak1-、-Ak1-Ak2-、-Ak1-Ak2-Ak3-、-Ak1-Ak2-Ak3-Ak4-、-Ak1-Ak2-Ak3-Ak4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9;、 Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, and Ak9 are each independently selected from -(CH2) q -、-(CH2) q -O-, -O-(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 -、-(C≡C) q - or bond, wherein the -CH2- is optionally replaced by 1 to 2 groups 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; Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from a bond, a 4-7 membered heteromonocyclic ring, a 4-10 membered heterocyclic ring, a 5-12 membered heterospirocyclic ring, a 7-10 membered heterobridged ring, a C 3-7 Monocyclic alkyl, C 4-10 Cycloalkyl, C 5-12 Membered spirocycloalkyl, C 7-10 5- to 10-membered cycloalkyl, 5- to 10-membered heteroaryl or 6- to 10-membered aryl, wherein the aryl, heteroaryl, cycloalkyl, heteromonocyclic, heterocyclic, heterospirocyclic or heterobridged ring is optionally 1 to 2 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 heteroaryl, heteromonocyclic, heterocyclic, heterospirocyclic or heterobridged ring 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.

3. The compound according to claim 2, or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein: Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, and Ak9 are each independently selected from -(CH2) q -、-(CH2) q -O-, -O-(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 -、-(C≡C) q - or bond, wherein the -CH2- is optionally replaced by 1 to 2 groups selected from F, Cl, Br, I, OH, CN, NH2, CF3, hydroxymethyl, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; R L Each independently selected from H or C 1-4 alkyl; Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from a bond, a 4-7 membered nitrogen-containing heteromonocycle, a 4-10 membered nitrogen-containing heterocyclic ring, a 5-12 membered nitrogen-containing heterospirocycle, a 7-10 membered nitrogen-containing heterobridged ring, a C 3-7 Monocyclic alkyl, C 4-10 Cycloalkyl, C 5-12 Spiroalkyl, C 7-10 Bridged cycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl, wherein the heteromonocyclic, heterocyclic, heterobridged, heterospirocyclic, cycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 2 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, heterocyclic, heterobridged, heterospirocyclic 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; R Y Selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl is optionally substituted by 1 to 3 selected from halogen, OH, cyano, NH2, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 is substituted by a carbocyclic or 3- to 6-membered heterocyclic substituent, wherein the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N; R 1 Selected from H, OH, NR 1a R 1b , methyl, ethyl, propyl, isopropyl, methoxy, wherein the methyl, ethyl, propyl, isopropyl or methoxy is optionally substituted by 1 to 3 groups selected from halogen, OH, cyano, NH2, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; R 1a 、R 1b Each independently selected from H, OH, NH2, methyl, ethyl, propyl, isopropyl, methoxy, propargyl, propynyl, said methyl, ethyl, propyl, isopropyl, methoxy, propargyl, propynyl optionally substituted by 1 to 3 selected from halogen, OH, cyano, NH2, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkynyl, substituted by a substituent; R 3a or R 4 Each independently selected from H, OH, NH2, methyl, ethyl, propyl, propargyl, propynyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, propargyl, propynyl is optionally substituted by 1 to 3 selected from halogen, OH, cyano, NH2, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyloxy, C 2-4 Alkynyl, C 3-6 is substituted by a carbocyclic or 3- to 6-membered heterocyclic substituent, wherein the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N; R 3b or R 5 Each independently selected from H, F, Cl, Br, I, cyano, NH2, OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, ethynyl, the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, ethynyl are optionally substituted by 1 to 3 groups selected from halogen, OH, cyano, NH2, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 is substituted by a carbocyclic or 3- to 6-membered heterocyclic substituent, wherein the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N; F1 is independently selected from cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, phenyl, naphthyl, pyridinyl, pyrazinyl, pyridazinyl, pyridazinone, pyrimidinyl, phthalazin-1 (2H) -one, benzo [d] [1,2,3] triazin-4 (3H) -one, thienyl, benzothienyl, triazolyl, is selected from a single bond or a double bond; F2 are each independently selected from F is independently selected from cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, 2-pyridonyl, pyrazolyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, benzothiazolyl, indolyl, E or A are each independently selected from a benzene ring, a naphthalene ring or a pyridine ring; E1 is each independently selected from E2 is each independently selected from a benzene ring, a pyridine ring, a pyrimidine ring, a thiazole ring, a thiophene ring, or a furan ring; R q Selected from H, methyl, ethyl; R k1 、R k3 Each independently selected from H, D, F, Cl, Br, I, OH, =O, NH2, CF3, CN, COOH, CONH2, C 1-4 Alkyl or C 1-4 Alkoxy, R k7a , the alkyl or alkoxy group is optionally substituted by 1 to 4 substituents selected from D, F, Cl, Br, I, OH or NH2; Or two R k3 Together with the carbon atoms or ring skeletons directly connected to the two, they form C 3-7 Carbocyclic or 3-7 membered heterocyclic ring, or two R k1 Together with the carbon atoms or ring skeletons directly connected to the two, they form C 3-7 Carbocyclic or 3-7 membered heterocyclic ring, wherein the carbocyclic or 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 The heterocyclic ring is substituted by an alkoxy substituent, and the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N; R k4 Each independently selected from H, methyl, ethyl or propyl; R k5 Each independently selected from CO, CH2, SO2 or R k7a Selected from H, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, heterocyclic group or cycloalkyl group 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, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 substituted by a cycloalkyl substituent; R k9 Each independently selected from CO, SO2 or CH2; R kb Selected from a bond or CO; R k10 Selected from CH2 or CO; R k11 is selected from NH, O or CH2.

4. The compound according to claim 3, or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein: Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, and Ak9 are each independently selected from -(CH2) q -、-(CH2) q -O-, -O-(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 -、-(C≡C) q - or a bond, wherein the -CH2- is optionally substituted by 1 to 2 substituents selected from F, Cl, Br, I, OH, CN, NH2, CF3, hydroxymethyl, methyl, ethyl, methoxy or ethoxy; R L Selected from H, methyl or ethyl; q is each independently selected from 0, 1, 2 or 3; 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, phenyl, pyridyl, cyclopropylcyclopropyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, cyclopropylcyclohexyl, cyclobutylcyclobutyl, Cyclobutylcyclopentyl, cyclobutylcyclohexyl, cyclopentylcyclopentyl, cyclopentylcyclohexyl, cyclohexylcyclohexyl, cyclopropylspirocyclopropyl, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylazetidinyl, cyclopropylpyrrolidinyl, cyclopropylpiperidinyl, cyclobutyl azetidinyl, cyclobutylpyrrolidinyl, cyclobutylpiperidinyl, cyclopentylazetidinyl, cyclopentylpyrrolidinyl, cyclopentylpiperidinyl, cyclohexylazetidinyl, cyclohexylpyrrolidinyl, cyclohexylpiperidinyl, azetidinylazetidinyl, azetidinylpyrrolidinyl, azetidinylpiperidinyl, pyrrolidinylazetidinyl, pyrrolidinylpyrrolidinyl, pyrrolidinylpiperidinyl, piperidinylazetidinyl, pyrrolidinylpyrrolidinyl, pyrrolidinylpiperidinyl, piperidinylazetidinyl butyl, piperidinyl and pyrrolidinyl, piperidinyl and piperidinyl, cyclopropyl spiroazetidinyl, cyclopropyl spiropyrrolidinyl, cyclopropyl spiropiperidinyl, cyclopropyl spiropiperazinyl, cyclobutyl spiroazetidinyl, cyclobutyl spiropyrrolidinyl, cyclobutyl spiropiperidinyl, cyclopentyl spiroazetidinyl, cyclopentyl spiropyrrolidinyl, cyclopentyl spiropiperidinyl, cyclohexyl spiroazetidinyl, cyclohexyl spiropyrrolidinyl, cyclohexyl spiropiperidinyl, azetidinyl spiroazetidinyl, nitrogen Heterobutyl spiropyrrolidinyl, azetidinyl spiropiperidinyl, pyrrolidinyl spiroazetidinyl, pyrrolidinyl spiropyrrolidinyl, pyrrolidinyl spiropiperidinyl, piperidinyl spiroazetidinyl, piperidinyl spiropyrrolidinyl, piperidinyl spiropiperidinyl, cyclopropyl spiropiperazinyl, When substituted, it is optionally replaced by 1 to 4 groups 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; X is selected from O or S; Y is selected from NH or O; R 1 Selected from H, OH, NR 1a R 1b , methyl, ethyl, propyl, isopropyl, methoxy, wherein the methyl, ethyl, propyl, isopropyl or methoxy is optionally substituted by 1 to 3 substituents selected from F, Cl, Br, I, OH, cyano, NH2, methyl, ethyl, CF3; R 1a 、R 1b Each is independently selected from H, OH, NH2, methyl, ethyl, propyl, isopropyl, methoxy, propargyl, and propynyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, propargyl, and propynyl are optionally substituted with 1 to 3 substituents selected from F, Cl, Br, I, OH, cyano, NH2, methyl, ethyl, methoxy, ethynyl, and CF3; R 3a is selected from H, OH, NH2, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, propargyl, and propynyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, propargyl, and propynyl are optionally substituted with 1 to 3 substituents selected from F, Cl, Br, I, OH, cyano, NH2, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethynyl, methoxy, and cyclopropyloxy; R 4 Each is independently selected from H, methyl, ethyl, and cyclopropyl; R 3b Each is independently selected from H, F, Cl, Br, I, OH, CN, methoxy, methyl, ethyl, and cyclopropyl; R 5 Each independently selected from H, F, Cl, Br, I, cyano, NH2, OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, and ethynyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, and ethynyl are optionally substituted with 1 to 3 substituents selected from F, Cl, Br, I, OH, cyano, NH2, methyl, ethyl, and cyclopropyl; F1 is independently selected from cyclohexyl, piperidinyl, piperazinyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridazinone, phthalazin-1 (2H) -one, benzo [d] [1,2,3] triazin-4 (3H) -one, thienyl, triazolyl, F2 are each independently selected from F is independently selected from cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, 2-pyridonyl, pyrazolyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, benzothiazolyl, indolyl, Q1 is selected from -O-, -S-, -CH2-, NH, N(CH3) or -CO-; Q is selected from a bond, C(=O), CH2, NH, N(CH3), O, S, NHC(=O), C(=O)NH, N(CH3)C(=O), C(=O)N(CH3), R k7a Selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, alkyne Propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl are 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; R k1 、R k3 Each is independently selected from H, D, F, Cl, Br, I, OH, =O, NH2, CF3, CN, COOH, CONH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, ethynyl, cyclopropyl, azetidinyl, said methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, ethynyl, cyclopropyl, azetidinyl being optionally substituted with 1 to 4 substituents selected from D, F, Cl, Br, I, OH, NH2, CN, cyclopropyl, methoxy; Or two R k3 Together with the carbon atoms or ring skeletons directly connected to the two, they form C 3-6 Carbocyclic or 3-7 membered heterocyclic ring, or 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 ring, wherein the carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 rings selected from D, 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 ring contains 1 to 4 heteroatoms selected from O, S or N; p1 and p2 are each independently selected from 0, 1, 2 or 3.

5. The compound according to claim 4, or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein: Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, Ak9 are each independently selected from a bond, -O-, -OCH2-, -CH2O-, -OCH2CH2-, -CH2CH2O-, -C≡C-, -C(CH3)2-, -CF2-, -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)-; 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, it is substituted with 1 to 4 substituents selected from F, CF3, OH, methyl, =O, hydroxymethyl, COOH, CN or NH2; B is selected from one of the structural fragments shown in Table B-1; K is selected from one of the structural fragments shown in Table K-1 or K-2.

6. The compound according to claim 5, or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein: L is selected from a bond, -Ak1-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-Ak3-Ak4-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-, -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-, -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-。、 7. The compound according to claim 6, or a stereoisomer, tautomer, 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, wherein the left side of the group is connected to B.

8. The compound according to claim 6, or a stereoisomer, tautomer, 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-2, wherein the left side of the group is connected to B; K is selected from one of the structural fragments shown in Table K-2.

9. The compound according to claim 1 or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: The compound of general formula (I) is selected from the compounds of general formula (II), L1 is selected from -Cy1-, -Cy1-Ak1-, -Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Ak1-Cy2-Cy3-; Ak1 is selected from -CH2-, -O-, -CH2-CH2-; The definitions of Cy1, Cy2, and Cy3 are the same as those in claim 5; F1 is selected from phenyl, 5-6 membered heteroaryl or 13-14 membered heterotricyclic ring; B has the same meaning as in claim 1; R k1 , p1 is defined the same as in claim 4.

10. The compound according to claim 1 or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: The compound of general formula (I) is selected from the compounds of general formula (III), B has the same meaning as in claim 1; L2 is selected from -Cy1-, -Cy1-Ak1- or -Cy1-Ak1-Cy2-; Cy1 and Cy2 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, =O, hydroxymethyl, COOH, CN or NH2; Ak1 is selected from -CH2-, -O-, -CH2-CH2-; R k1 Each is independently selected from H, D, F, Cl, Br, I, OH, =O, NH2, CF3, CN, COOH, CONH2, methyl, ethyl, methoxy, ethoxy; p1 is selected from 0, 1 or 2.

11. The compound of claim 1 or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein the compound is selected from one of the structures in Table S-1.

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

13. A pharmaceutical composition or pharmaceutical formulation comprising 1-1500 mg of a compound according to any one of claims 1-11 or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof and a pharmaceutically acceptable excipient.

14. Use of the compound according to any one of claims 1 to 11, or its stereoisomers, tautomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, or the pharmaceutical composition according to any one of claims 12 to 13, in the preparation of a medicament for treating a disease associated with Bcl6 activity or expression.

15. Use of the compound according to any one of claims 1 to 11, or its stereoisomers, tautomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, or the pharmaceutical composition according to any one of claims 12 to 13, in the preparation of a medicament for treating diseases associated with the inhibition or degradation of Bcl6.

16. The use according to claim 14 or 15, wherein the disease is selected from cancer.

17. A method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 11, or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, or a pharmaceutical composition according to any one of claims 12 to 13, wherein the therapeutically effective amount is preferably 1 to 1500 mg, and the disease is preferably cancer.

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