Pyrimidopyrrole derivative and application thereof in medicine

Abstract

The invention relates to a pyrimidopyrrole derivative and application thereof in medicine, in particular to a compound shown in a general formula (I) or a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal of the compound, an intermediate and a preparation method of the compound, and application of the compound in BTK related diseases such as tumors or autoimmune system diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry and provides a pyrimidopyrrole derivative and its application in medicine, specifically relates to a compound described by general formula (I) or its stereoisomers, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and intermediates and preparation methods thereof, as well as the use of the pyrimidopyrrole derivative in BTK-related diseases such as tumors or autoimmune system diseases. Background Art

[0002] Bruton's tyrosine kinase (BTK) is a member of the Tec family of non-receptor protein tyrosine kinases and a key regulator in the B cell antigen receptor (BCR) signaling pathway, distributed in the lymphatic system, hematopoiesis and blood system. BTK mutations can cause activation of downstream tumor cell proliferation, differentiation and angiogenesis signaling pathways, leading to X-linked agammaglobulinemia, non-Hodgkin's lymphoma (NHL) and many B cell malignancies, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma and diffuse large B cell lymphoma. BTK is a target with good targeting and safety because it is mainly expressed in B cells and myeloid cells.

[0003] PROTAC (proteolysis targeting chimera) molecules are a class of bifunctional compounds that can simultaneously bind to target proteins and E3 ubiquitin ligases. Such compounds can be recognized by the proteasome of the cell, causing the degradation of the target protein, and can effectively reduce the content of the target protein in the cell. By introducing ligands that can bind to different target proteins into PROTAC molecules, PROTAC technology can be applied to the treatment of various diseases. This technology has also received widespread attention in recent years.

[0004] Therefore, it is necessary to develop new PROTAC drugs that are BTK inhibitors for the treatment of BTK-related tumor diseases. Summary of the invention

[0005] The object of the present invention is to provide a compound with novel structure, good efficacy, high bioavailability, greater safety, and the ability to inhibit or degrade BTK, for the treatment of BTK-related diseases such as autoimmune diseases, inflammatory diseases or cancer.

[0006] The compound of the invention has good pharmacokinetic properties and bioavailability, oral properties and good safety.

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

[0008]

[0009] In certain embodiments, B1 is selected from 5- to 6-membered heterocyclic groups;

[0010] In certain embodiments, B1 is selected from 5- to 6-membered heteroaryl groups;

[0011] In certain embodiments, B1 is selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, furyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl;

[0012] In certain embodiments, B4 is selected from phenyl, 5- to 6-membered heteroaryl groups;

[0013] In certain embodiments, B4 is selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, furyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl;

[0014] In certain embodiments, B4 is selected from phenyl, pyridyl;

[0015] In certain embodiments, X is selected from N or CH;

[0016] In certain embodiments, L1, L2, or L3 are each independently selected from a bond, C 1-8 alkylene, C 2-8 alkenylene, C 2-8 alkynylene, O, NR L , NR L CO, CO, C≡C, -C(=O)CH2-, wherein the alkylene, alkenylene, alkynylene are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, COOH, CN, NH2, =O, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, C 1-6 alkoxy, C 3-7 carbocyclic group, 4- to 6-membered heterocyclic group;

[0017] In certain embodiments, L1, L2, or L3 are each independently selected from a bond, C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, O, NR L , NR LCO, CO, -C(=O)CH2-, wherein the alkylene, alkenylene, alkynylene are optionally substituted by 1 to 4 substituents selected from deuterium, 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, C 1-4 alkoxy, C 3-6 cycloalkyl group, 4-6 membered heterocyclic group;

[0018] In certain embodiments, L1, L2 or L3 are each independently selected from a bond, C 1-4 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, O, NR L NR L CO, CO, -C(=O)CH2-, wherein the alkylene, alkenylene, alkynylene are optionally substituted by 1 to 4 substituents selected from deuterium, 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, C 1-4 alkoxy, C 3-6 cycloalkyl group, 4-6 membered heterocyclic group;

[0019] In certain embodiments, L1, L2 or L3 are each independently selected from a bond, O, NH, methylene, ethylene, vinylene, ethynylene, wherein the methylene, ethylene, vinylene, ethynylene are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH2, COOH, CN, =O, 1 to 4 substituents selected from deuterium, 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, C 1-4 alkoxy, C 3-6 cycloalkyl group, 4-6 membered heterocyclic group;

[0020] In certain embodiments, L1 or L3 is selected from a bond;

[0021] In certain embodiments, L2 is selected from -C(=O)CH2-, methylene or ethylene;

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

[0023] In certain embodiments, RL Selected from H or C 1-4 Alkyl;

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

[0025] In certain embodiments, Cy1 and Cy2 are each independently selected from a bond, a 3- to 7-membered monocyclic heterocyclic group, a 4- to 12-membered fused heterocyclic group, a 5- to 12-membered spiro heterocyclic group, a 5- to 12-membered bridged heterocyclic group, a C 3-7 membered monocyclic carbocyclic group, a 4- to 12-membered fused carbocyclic group, a 5- to 12-membered spiro carbocyclic group, a 5- to 12-membered bridged carbocyclic group, a 5- to 12-membered heteroaryl or a 6- to 10-membered aryl, and the aryl, heteroaryl, carbocyclic group, and heterocyclic group are optionally substituted by 1 to 4 R Cy substituents;

[0026] In certain embodiments, Cy1 and Cy2 are each independently selected from a 3- to 6-membered monocyclic heterocyclic group, a 4- to 10-membered fused heterocyclic group, a 5- to 11-membered spiro heterocyclic group, a 5- to 10-membered bridged heterocyclic group, a C 3-6 membered monocyclic carbocyclic group, a 4- to 10-membered fused carbocyclic group, a 5- to 11-membered spiro carbocyclic group, a 5- to 10-membered bridged carbocyclic group, a 5- to 10-membered heteroaryl or a 6- to 10-membered aryl, and the aryl, heteroaryl, carbocyclic group, and heterocyclic group are optionally substituted by 1 to 4 R Cy substituents;

[0027] In certain embodiments, Cy1 and Cy2 are each independently selected from one of the following substituted or unsubstituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, phenyl, cyclopropylcyclopropyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, cyclopropylcyclohexyl, cyclobutylcyclobutyl, cyclobutylcyclopentyl, cyclobutylcyclohexyl, cyclopentylcyclopentyl, cyclopentylcyclohexyl, cyclohexylcyclohexyl, cyclopropylspirocyclopropyl, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylazetidinyl, cyclopropylpyrrolidinyl, cyclopropylpiperidinyl, cyclobutylazetidinyl, cyclobutylpyrrolidinyl, cyclobutylpiperidinyl, cyclopentylazetidinyl, cyclopentylpyrrolidinyl, cyclopentylpiperidinyl, cyclohexylazetidinyl, cyclohexylpyrrolidinyl, cyclohexylpiperidinyl, azetidinylazetidinyl, azetidinylpyrrolidinyl, azetidinylpiperidinyl, pyrrolidinylazetidinyl, pyrrolidinylpyrrolidinyl, pyrrolidinylpiperidinyl, piperidinylazetidinyl, piperidinylpyrrolidinyl, piperidinylpiperidinyl, cyclobutylspiroazetidinyl, cyclobutylspiropyrrolidinyl, cyclobutylspiropiperidinyl, cyclopentylspiroazetidinyl, cyclopentylspiropyrrolidinyl, cyclopentylspiropiperidinyl, cyclohexylspiroazetidinyl, cyclohexylspiropyrrolidinyl, cyclohexylspiropiperidinyl, azetidinylspiroazetidinyl, azetidinylspiropyrrolidinyl, azetidinylspiropiperidinyl, pyrrolidinylspiroazetidinyl, pyrrolidinylspiropyrrolidinyl, pyrrolidinylspiropiperidinyl, piperidinylspiroazetidinyl, piperidinylspiropyrrolidinyl, piperidinylspiropiperidinyl; When substituted, it is optionally substituted by 1 to 4 R Cy ;

[0028] In certain embodiments, Cy1 and Cy2 are each independently selected from one of the following substituted or unsubstituted groups: When substituted, it is optionally substituted by 1 to 4 R Cy ;

[0029] In certain embodiments, Cy1 and Cy2 are each independently selected from one of the following substituted or unsubstituted groups: When substituted, it is optionally substituted by 1 to 4 RCy is replaced;

[0030] In certain embodiments, R Cy is independently selected from deuterium, F, Cl, Br, I, OH, ═O, NH2, CN, COOH, CONH2, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 -membered carbocyclic group, 4-6-membered heterocyclic group, -O-C 3-7 -membered carbocyclic group, -O-4-6-membered heterocyclic group, and the alkyl, alkoxy, heterocyclic group, and carbocyclic group are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, ═O, NH2, CN, CONH2, COOH, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 -membered carbocyclic group, 4-6-membered heterocyclic group;

[0031] In certain embodiments, R Cy is independently selected from deuterium, F, Cl, Br, I, OH, ═O, NH2, CN, COOH, CONH2, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 -membered carbocyclic group, 4-6-membered heterocyclic group, -O-C 3-6 -membered carbocyclic group, -O-4-6-membered heterocyclic group, and the alkyl, alkoxy, heterocyclic group, and carbocyclic group are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, ═O, NH2, CN, CONH2, COOH, C 1-4 alkyl, C 1-4 alkoxy, C 3-7 -membered carbocyclic group, 4-6-membered heterocyclic group;

[0032] In certain embodiments, R Cy is independently selected from deuterium, F, Cl, Br, I, OH, ═O, NH2, CN, COOH, CONH2, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, phenyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, pyridyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, -O-phenyl, and the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, phenyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, pyridyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, ═O, NH2, CN, CONH2, COOH, C 1-4 alkyl, C1-4 Alkoxy, C 3-7 substituted by a substituent of a carbocyclic group having C atoms, or a 4- to 6-membered heterocyclic group;

[0033] In certain embodiments, R Cy are each independently selected from deuterium, F, Cl, Br, I, OH, ═O, NH2, CN, COOH, CONH2, CF3, CHF2, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, methoxymethyl;

[0034] In certain embodiments, R Cy are each independently selected from deuterium, F, Cl, Br, I, OH, NH2, CN, CF3, CHF2, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, methoxymethyl;

[0035] In certain embodiments, R b1 , R b2 , R b3 , R b4 , R k1 , R k2 , R bL are each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH2, CN, COOH, CONH2, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 substituted by a substituent of a carbocyclic group having C atoms, or a 4- to 6-membered heterocyclic group, -O-C 3-7 substituted by a substituent of a carbocyclic group having C atoms, or a 4- to 6-membered heterocyclic group, -O-4- to 6-membered heterocyclic group, and the alkyl, alkoxy, heterocyclic group, and carbocyclic group are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, ═O, NH2, CN, CONH2, COOH, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 substituted by a substituent of a carbocyclic group having C atoms, or a 4- to 6-membered heterocyclic group;

[0036] In certain embodiments, R b1 , R b2 , R b3 , R b4 , R k1 , R k2 , R bL are each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH2, CN, COOH, CONH2, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 substituted by a substituent of a carbocyclic group having C atoms, or a 4- to 6-membered heterocyclic group, -O-C3-6 A C1-C6 alkyl group, a C1-C6 alkoxy group, a 3-6 membered carbocyclic group, or a 4-6 membered heterocyclic group, wherein the alkyl group, alkoxy group, heterocyclic group, and carbocyclic group are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, ═O, NH2, CN, CONH2, COOH, C 1-4 1-C6 alkyl, C 1-4 1-C6 alkoxy, C 3-7 3-6 membered carbocyclic group, or 4-6 membered heterocyclic group;

[0037] In certain embodiments, R b1 , R b2 , R b3 , R b4 , R k1 , R k2 , R bL are each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH2, CN, COOH, CONH2, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, phenyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, pyridyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, -O-phenyl, wherein the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, phenyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, pyridyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, ═O, NH2, CN, CONH2, COOH, C 1-4 1-C6 alkyl, C 1-4 1-C6 alkoxy, C 3-7 3-6 membered carbocyclic group, or 4-6 membered heterocyclic group;

[0038] In certain embodiments, R b1 , R b2 , R b3 , R b4 , R k1 , R k2 are each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH2, CN, COOH, CONH2, CF3, CHF2, CH2F, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl;

[0039] In certain embodiments, R bL are each independently selected from H, deuterium, methyl;

[0040] In certain embodiments, b1 is each independently selected from 0, 1, 2, 3, 4, 5, or 6;

[0041] In certain embodiments, each of b2 and b4 is independently selected from 0, 1, 2, 3, or 4;

[0042] In certain embodiments, b3 is independently selected from 0, 1, or 2;

[0043] In certain embodiments, each of p1 or p2 is independently selected from 0, 1, 2, 3, or 4;

[0044] In certain embodiments, selected from

[0045]

[0046] In certain embodiments, selected from

[0047] In certain embodiments, selected from one of the fragments shown in Table A;

[0048] Table A

[0049]

[0050]

[0051] Optionally, when Cy2 is selected from an unsubstituted 3- to 7-membered monocyclic heterocyclic group or an unsubstituted C 3-7 -membered monocyclic carbocyclic group, Cy1 is selected from a 4- to 12-membered fused heterocyclic group, a 5- to 12-membered spiro heterocyclic group, a 4- to 12-membered fused carbocyclic group, a 5- to 12-membered spiro carbocyclic group, and the carbocyclic group and heterocyclic group are optionally substituted with 1 to 4 R Cy groups.

[0052] As a first embodiment of the present invention, the compound represented by the foregoing general formula (I) or its stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0053] B1 is selected from a 5- to 6-membered heterocyclic group;

[0054] B4 is selected from a phenyl group, a 5- to 6-membered heteroaryl group;

[0055] X is selected from N or CH;

[0056] Each of L1, L2, or L3 is independently selected from a bond, C 1-8 -alkylene, C 2-8 -alkenylene, C 2-8 -alkynylene, O, NRL , NR L CO, CO, C≡C, -C(=O)CH2-, the alkylene, alkenylene, alkynylene are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, COOH, CN, NH2, =O, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, C 1-6 alkoxy, C 3-7 membered carbocyclic group, 4-6 membered heterocyclic group;

[0057] R L is selected from H or C 1-6 alkyl;

[0058] Cy1 and Cy2 are each independently selected from a bond, 3-7 membered monocyclic heterocyclic group, 4-12 membered fused heterocyclic group, 5-12 membered spiro heterocyclic group, 5-12 membered bridged heterocyclic group, C 3-7 membered monocyclic carbocyclic group, 4-12 membered fused carbocyclic group, 5-12 membered spiro carbocyclic group, 5-12 membered bridged carbocyclic group, 5-12 membered heteroaryl or 6-10 membered aryl, the aryl, heteroaryl, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R Cy ;

[0059] R Cy are each independently selected from deuterium, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 membered carbocyclic group, 4-6 membered heterocyclic group, -O-C 3-7 membered carbocyclic group, -O-4-6 membered heterocyclic group, the alkyl and alkoxy, heterocyclic group, carbocyclic group are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, =O, NH2, CN, CONH2, COOH, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 membered carbocyclic group, 4-6 membered heterocyclic group;

[0060] R b1 , R b2 , R b3 , R b4 , R k1 , R k2 , R bL are each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-6 alkyl, C 1-6 alkoxy, C3-7 a carbocyclic group having 3 to 7 carbon atoms, a 4- to 6-membered heterocyclic group, -O-C 3-7 a carbocyclic group having 3 to 7 carbon atoms, -O-a 4- to 6-membered heterocyclic group, and the alkyl group, alkoxy group, heterocyclic group, and carbocyclic group are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, =O, NH2, CN, CONH2, COOH, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 a carbocyclic group having 3 to 7 carbon atoms, a 4- to 6-membered heterocyclic group;

[0061] b1 are each independently selected from 0, 1, 2, 3, 4, 5, or 6;

[0062] b2 and b4 are each independently selected from 0, 1, 2, 3, or 4;

[0063] b3 are each independently selected from 0, 1, or 2;

[0064] p1 or p2 are each independently selected from 0, 1, 2, 3, or 4;

[0065] provided that when Cy2 is selected from an unsubstituted 3- to 7-membered monocyclic heterocyclic group or an unsubstituted C 3-7 a monocyclic carbocyclic group having 3 to 7 carbon atoms, Cy1 is selected from a 4- to 12-membered fused heterocyclic group, a 5- to 12-membered spiro heterocyclic group, a 4- to 12-membered fused carbocyclic group, a 5- to 12-membered spiro carbocyclic group, and the carbocyclic group and heterocyclic group are optionally substituted with 1 to 4 R Cy substituents.

[0066] As a second embodiment of the present invention, a compound represented by the foregoing general formula (I) or a stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof

[0067] B1 is selected from a 5- to 6-membered heteroaryl group;

[0068] L1, L2, or L3 are each independently selected from a bond, C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, O, NR L NR L CO, CO, -C(=O)CH2-, and the alkylene, alkenylene, and alkynylene are optionally substituted with 1 to 4 substituents selected from deuterium, 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, C 1-4 alkoxy, C 3-6 a carbocyclic group having 3 to 7 carbon atoms, a 4- to 6-membered heterocyclic group;

[0069] R L Selected from H or C 1-4 Alkyl

[0070] Cy1 and Cy2 are each independently selected from a 3- to 6-membered monocyclic heterocyclic group, a 4- to 10-membered fused heterocyclic group, a 5- to 11-membered spiro heterocyclic group, a 5- to 10-membered bridged heterocyclic group, a C 3-6 -membered monocyclic carbocyclic group, a 4- to 10-membered fused carbocyclic group, a 5- to 11-membered spiro carbocyclic group, a 5- to 10-membered bridged carbocyclic group, a 5- to 10-membered heteroaryl group or a 6- to 10-membered aryl group, and the aryl group, heteroaryl group, carbocyclic group and heterocyclic group are optionally substituted by 1 to 4 R Cy substituents;

[0071] R Cy are each independently selected from deuterium, F, Cl, Br, I, OH, ═O, NH2, CN, COOH, CONH2, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 -membered carbocyclic group, a 4- to 6-membered heterocyclic group, -O-C 3-6 -membered carbocyclic group, -O-4- to 6-membered heterocyclic group, and the alkyl, alkoxy, heterocyclic group and carbocyclic group are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, ═O, NH2, CN, CONH2, COOH, C 1-4 alkyl, C 1-4 alkoxy, C 3-7 -membered carbocyclic group, a 4- to 6-membered heterocyclic group;

[0072] R b1 R b2 R b3 R b4 R k1 R k2 R bL are each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH2, CN, COOH, CONH2, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 -membered carbocyclic group, a 4- to 6-membered heterocyclic group, -O-C 3-6 -membered carbocyclic group, -O-4- to 6-membered heterocyclic group, and the alkyl, alkoxy, heterocyclic group and carbocyclic group are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, ═O, NH2, CN, CONH2, COOH, C 1-4 alkyl, C 1-4 alkoxy, C 3-7 -membered carbocyclic group, a 4- to 6-membered heterocyclic group;

[0073] The remaining definitions are the same as those of the first embodiment of the present invention.

[0074] As a third embodiment of the present invention, the compound represented by the foregoing general formula (I) or its stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0075] L1, L2 or L3 are each independently selected from a bond, C 1-4 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, O, NR L , NR L CO, CO, -C(=O)CH2-, and the alkylene, alkenylene and alkynylene are optionally substituted by 1 to 4 substituents selected from deuterium, 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, C 1-4 alkoxy, C 3-6 carbocyclic group having a certain number of carbon atoms, 4- to 6-membered heterocyclic group;

[0076] R L is selected from H, methyl or ethyl;

[0077] Cy1 and Cy2 are each independently selected from one of the following substituted or unsubstituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, phenyl, cyclopropyl-fused cyclopropyl, cyclopropyl-fused cyclobutyl, cyclopropyl-fused cyclopentyl, cyclopropyl-fused cyclohexyl, cyclobutyl-fused cyclobutyl, cyclobutyl-fused cyclopentyl, cyclobutyl-fused cyclohexyl, cyclopentyl-fused cyclopentyl, cyclopentyl-fused cyclohexyl, cyclohexyl-fused cyclohexyl, cyclopropyl-spiro cyclopropyl, cyclopropyl-spiro cyclobutyl, cyclopropyl-spiro cyclopentyl, cyclopropyl-spiro cyclohexyl, cyclobutyl-spiro cyclobutyl, cyclobutyl-spiro cyclopentyl, cyclobutyl-spiro cyclohexyl, cyclopentyl-spiro cyclopentyl, cyclopentyl-spiro cyclohexyl, cyclohexyl-spiro cyclohexyl, cyclopropyl-fused azetidinyl, cyclopropyl-fused pyrrolidinyl, cyclopropyl-fused piperidinyl, cyclobutyl-fused azetidinyl, cyclobutyl-fused pyrrolidinyl, cyclobutyl-fused piperidinyl, cyclopentyl-fused azetidinyl, cyclopentyl-fused pyrrolidinyl, cyclopentyl-fused piperidinyl, cyclohexyl-fused azetidinyl, cyclohexyl-fused pyrrolidinyl, cyclohexyl-fused piperidinyl, azetidinyl-fused azetidinyl, azetidinyl-fused pyrrolidinyl, azetidinyl-fused piperidinyl, pyrrolidinyl-fused azetidinyl, pyrrolidinyl-fused pyrrolidinyl, pyrrolidinyl-fused piperidinyl, piperidinyl-fused azetidinyl, piperidinyl-fused pyrrolidinyl, piperidinyl-fused piperidinyl, cyclobutyl-spiro azetidinyl, cyclobutyl-spiro pyrrolidinyl, cyclobutyl-spiro piperidinyl, cyclopentyl-spiro azetidinyl, cyclopentyl-spiro pyrrolidinyl, cyclopentyl-spiro piperidinyl, cyclohexyl-spiro azetidinyl, cyclohexyl-spiro pyrrolidinyl, cyclohexyl-spiro piperidinyl, azetidinyl-spiro azetidinyl, azetidinyl-spiro pyrrolidinyl, azetidinyl-spiro piperidinyl, pyrrolidinyl-spiro azetidinyl, pyrrolidinyl-spiro pyrrolidinyl, pyrrolidinyl-spiro piperidinyl, piperidinyl-spiro azetidinyl, piperidinyl-spiro pyrrolidinyl, piperidinyl-spiro piperidinyl;

[0078] When substituted, it is optionally substituted by 1 to 4 R Cy ;

[0079] R CyEach independently selected from deuterium, F, Cl, Br, I, OH, ═O, NH2, CN, COOH, CONH2, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, phenyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, pyridyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, -O-phenyl, and the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, phenyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, pyridyl are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, ═O, NH2, CN, CONH2, COOH, C 1-4 alkyl, C 1-4 alkoxy, C 3-7 substituents of a 3- to 6-membered carbocyclic group or a 4- to 6-membered heterocyclic group;

[0080] The remaining definitions are the same as those in the first or second embodiment of the present invention.

[0081] As a fourth embodiment of the present invention, the compound represented by the foregoing general formula (I) or its stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0082] B1 is selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, furyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl;

[0083] B4 is selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, furyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl;

[0084] L1, L2 or L3 are each independently selected from a bond, O, NH, methylene, ethylene, vinylene, ethynylene, and the methylene, ethylene, vinylene, ethynylene are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH2, COOH, CN, ═O, 1 to 4 substituents selected from deuterium, 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, C 1-4 alkoxy, C 3-6 substituents of a 3- to 6-membered carbocyclic group or a 4- to 6-membered heterocyclic group;

[0085] Cy1 and Cy2 are each independently selected from one of the following substituted or unsubstituted groups: When substituted, it is optionally substituted by 1 to 4 R Cy ;

[0086] R Cy is each independently selected from deuterium, F, Cl, Br, I, OH, ═O, NH2, CN, COOH, CONH2, CF3, CHF2, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, methoxymethyl;

[0087] R b1 , R b2 , R b3 , R b4 , R k1 , R k2 , R bL is each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH2, CN, COOH, CONH2, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, phenyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, pyridyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, -O-phenyl, and the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, phenyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, pyridyl are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, ═O, NH2, CN, CONH2, COOH, C 1-4 alkyl, C 1-4 alkoxy, C 3-7 carbocyclic group of 3 to 6 members, 4-6 membered heterocyclic group;

[0088] The remaining definitions are the same as those of the first, second or third embodiment of the present invention.

[0089] As the fifth embodiment of the present invention, the compound represented by the foregoing general formula (I) or its stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0090] L1 or L3 is selected from a bond;

[0091] L2 is selected from -C(═O)CH2-, methylene or ethylene;

[0092] Cy1 and Cy2 are each independently selected from one of the following substituted or unsubstituted groups: When substituted, it is optionally substituted by 1 to 4 Rs Cy ;

[0093] R Cy are each independently selected from deuterium, F, Cl, Br, I, OH, NH2, CN, CF3, CHF2, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, methoxymethyl;

[0094] R b1 , R b2 , R b3 , R b4 , R k1 , R k2 are each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, CF3, CHF2, CH2F, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl;

[0095] R bL are each independently selected from H, deuterium, methyl;

[0096] The remaining definitions are the same as those of the first, second, third or fourth embodiment of the present invention.

[0097] As the sixth embodiment of the present invention, the compound represented by the foregoing general formula (I) or its stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0098] is selected from

[0099] B4 is selected from phenyl or pyridyl;

[0100] is selected from one of the fragments shown in Table A;

[0101] is selected from

[0102] The present invention relates to a compound as described below, or a stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from one of the structures in Table E-1.

[0103] The present invention relates to a pharmaceutical composition comprising the above-mentioned compound, or a stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable carrier.

[0104] The present invention relates to the use of the above-mentioned compound, or a stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, or the above-mentioned pharmaceutical composition, in the preparation of a drug for inhibiting or degrading BTK.

[0105] The present invention relates to the use of the above-mentioned compound, or a stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, or the above-mentioned pharmaceutical composition, in the preparation of a drug for treating tumors or autoimmune diseases.

[0106] The present invention relates to a pharmaceutical composition or pharmaceutical preparation, wherein the pharmaceutical composition or pharmaceutical preparation comprises a therapeutically effective amount of the compound as described in the present invention, or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutical excipient. The pharmaceutical composition can be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as the "preparation specification").

[0107] The present invention also provides a method for treating a disease in a mammal, which comprises administering to the mammal a therapeutically effective amount of the compound as described in the present invention, or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, or a pharmaceutical composition. In some embodiments, the mammal in the present invention includes humans.

[0108] As used herein, the term "effective amount" or "therapeutically effective amount" means an amount of a compound disclosed herein that, to some extent, alleviates one or more symptoms of a disease or disorder being treated (e.g., cancer or an autoimmune disease). In some embodiments, the result is a reduction and / or mitigation of the signs, symptoms, or causes of the disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is an amount of a compound disclosed herein that provides a clinically significant reduction in the symptoms of the disease.Examples of a therapeutically effective amount include, but are not limited to, 1 - 1500 mg, 1 - 1000 mg, 1 - 800 mg, 1 - 600 mg, 2 - 600 mg, 3 - 600 mg, 4 - 600 mg, 5 - 600 mg, 6 - 600 mg, 10 - 600 mg, 20 - 600 mg, 25 - 600 mg, 30 - 600 mg, 40 - 600 mg, 50 - 600 mg, 60 - 600 mg, 70 - 600 mg, 75 - 600 mg, 80 - 600 mg, 90 - 600 mg, 100 - 600 mg, 200 - 600 mg, 1 - 500 mg, 2 - 500 mg, 3 - 500 mg, 4 - 500 mg, 5 - 500 mg, 6 - 500 mg, 10 - 500 mg, 20 - 500 mg, 25 - 500 mg, 30 - 500 mg, 40 - 500 mg, 50 - 500 mg, 60 - 500 mg, 70 - 500 mg, 75 - 500 mg, 80 - 500 mg, 90 - 500 mg, 100 - 500 mg, 125 - 500 mg, 150 - 500 mg, 200 - 500 mg, 250 - 500 mg, 300 - 500 mg, 400 - 500 mg, 5 - 400 mg, 10 - 400 mg, 20 - 400 mg, 25 - 400 mg, 30 - 400 mg, 40 - 400 mg, 50 - 400 mg, 60 - 400 mg, 70 - 400 mg, 75 - 400 mg, 80 - 400 mg, 90 - 400 mg, 100 - 400 mg, 125 - 400 mg, 150 - 400 mg, 200 - 400 mg, 250 - 400 mg, 300 - 400 mg, 1 - 300 mg, 2 - 300 mg, 5 - 300 mg, 10 - 300 mg, 20 - 300 mg, 25 - 300 mg, 30 - 300 mg, 40 - 300 mg, 50 - 300 mg, 60 - 300 mg, 70 - 300 mg, 75 - 300 mg, 80 - 300 mg, 90 - 300 mg, 100 - 300 mg, 125 - 300 mg, 150 - 300 mg, 200 - 300 mg, 250 - 300 mg, 1 - 200 mg, 2 - 200 mg, 5 - 200 mg, 10 - 200 mg, 20 - 200 mg, 25 - 200 mg, 30 - 200 mg, 40 - 200 mg, 50 - 200 mg, 60 - 200 mg, 70 - 200 mg, 75 - 200 mg, 80 - 200 mg, 90 - 200 mg, 100 - 200 mg, 125 - 200 mg, 150 - 200 mg;.

[0109] In some embodiments, the pharmaceutical composition comprises, but is not limited to, 1 - 1500 mg, 1 - 1000 mg, 1 - 800 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 the compound of the present invention or its stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals.

[0110] A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of the compound of the present invention or its stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, the therapeutically effective amount being preferably 1 - 1500 mg, and the disease being preferably a tumor or an autoimmune disease.

[0111] A method for treating a disease in a mammal, the method comprising administering to a subject a daily dose of 1 - 1500 mg / day of the compound of the present invention or its stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, the daily dose may be a single dose or divided doses. In some embodiments, the daily dose comprises, but is not limited to, 10 - 1500 mg / day, 10 - 1000 mg / day, 10 - 800 mg / day, 25 - 800 mg / day, 50 - 800 mg / day, 100 - 800 mg / day, 200 - 800 mg / day, 25 - 400 mg / day, 50 - 400 mg / day, 100 - 400 mg / day, 200 - 400 mg / day. In some embodiments, the daily dose comprises, but is not limited to, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 400 mg / day, 600 mg / day, 800 mg / day.

[0112] The present invention relates to a kit, which may include a composition in single-dose or multi-dose form. The kit contains the compound of the present invention or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and the amount of the compound of the present invention or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is the same as that in the above-mentioned pharmaceutical composition.

[0113] In the present invention, the amount of the compound of the present invention or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is converted in the form of free base in each case.

[0114] "Formulation specification" refers to the weight of the active ingredient contained in each vial, tablet or other unit formulation.

[0115] The compound of the present invention can be prepared by the following methods:

[0116] General synthetic method 1:

[0117]

[0118] The compound of general formula (M-1) reacts with the compound of general formula (M-2) through a substitution reaction to obtain the compound of general formula (M-3);

[0119] The compound of general formula (M-3) reacts with the compound of general formula (M-4) through a coupling reaction to obtain the compound of general formula (M-5);

[0120] The compound of general formula (M-5) reacts with the compound of general formula (M-6) through a coupling reaction to obtain the compound of general formula (M-7);

[0121] The compound of general formula (M-7) reacts with the compound of general formula (M-8) through a condensation reaction to obtain the compound of general formula (M-9);

[0122] After removing the protecting group R m from the compound of general formula (M-9), and then removing the protecting group of the N on the ring Cy1, it reacts with the compound of general formula (M-10) through reductive amination reaction to obtain the compound of general formula (I);

[0123] R m is an amino protecting group such as benzenesulfonyl;

[0124] The definitions of the remaining groups are the same as those defined in the specification and claims.

[0125] In the groups and compounds of the present invention, carbon, hydrogen, oxygen, sulfur, nitrogen, or F, Cl, Br, I all include their isotope cases, and in the groups and compounds of the present invention, carbon, hydrogen, oxygen, sulfur, or nitrogen involved may be optionally replaced by one or more of their corresponding isotopes, where the isotopes of carbon include 12 C, 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called superheavy hydrogen), and the isotopes of oxygen include 16 O, 17 O and 18 O, the isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, the isotopes of nitrogen include 14 N and 15 N, the isotopes of fluorine include 17 F and 19 F, the isotopes of chlorine include 35 Cl and 37 Cl, the isotopes of bromine include 79 Br and 81 Br.

[0126] "Halogen" means F, Cl, Br, or I.

[0127] "Halogen-substituted" means substituted by F, Cl, Br, or I, including but not limited to being substituted by 1 to 10 substituents selected from F, Cl, Br, or I, being substituted by 1 to 6 substituents selected from F, Cl, Br, or I, preferably being substituted by 1 to 4 substituents selected from F, Cl, Br, or I. "Halogen-substituted" is abbreviated as "halogenated".

[0128] "Alkyl" means a substituted or unsubstituted straight-chain or branched-chain saturated aliphatic hydrocarbon group, including but not limited to alkyl groups having 1 to 20 carbon atoms, alkyl groups having 1 to 8 carbon atoms, alkyl groups having 1 to 6 carbon atoms, alkyl groups having 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 their various branched isomers; for the alkyl groups appearing herein, their definitions are consistent with this definition. An alkyl group can be monovalent, divalent, trivalent, or tetravalent.

[0129] "Alkylene" means a substituted or unsubstituted straight-chain and branched-chain divalent saturated hydrocarbon group, including -(CH2) v -(where v is an integer from 1 to 10), and examples of alkylene include but are not limited to methylene, ethylene, propylene, and butylene, etc.

[0130] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, usually having 3 to 10 carbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, etc. The cycloalkyl groups appearing in this text are defined as described above. Cycloalkyl can be monovalent, divalent, trivalent, or tetravalent.

[0131] "Heterocycloalkyl" refers to a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to groups having 3 to 10 atoms, 3 to 8 atoms, containing 1 to 3 heteroatoms selected from N, O, or S. Optionally substituted N and S in the ring of heterocycloalkyl can be oxidized to various oxidation states. Heterocycloalkyl can be attached to a heteroatom or a carbon atom, can be attached to an aromatic ring or a non-aromatic ring, and can be attached with a bridged ring or a spiro ring. Non-limiting examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl, dioxanyl, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl. Heterocycloalkyl can be monovalent, divalent, trivalent, or tetravalent.

[0132] "Alkenyl" refers to a substituted or unsubstituted straight-chain and branched-chain unsaturated hydrocarbon group, which has at least 1, usually 1, 2, or 3 carbon-carbon double bonds. The main chain includes but is not limited to 2 to 10, 2 to 6, or 2 to 4 carbon atoms. Examples of alkenyl 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, etc.; the alkenyl groups appearing in this text are defined in accordance with this definition. Alkenyl can be monovalent, divalent, trivalent, or tetravalent.

[0133] "Alkynyl" refers to a substituted or unsubstituted straight-chain or branched-chain unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, with the main chain including 2 to 10 carbon atoms, including but not limited to having 2 to 6 carbon atoms in the main chain, having 2 to 4 carbon atoms in the main chain. Examples of alkynyl include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, etc.; alkynyl can be monovalent, divalent, trivalent or tetravalent.

[0134] "Propargyl" refers to 1-propynyl and 2-propynyl.

[0135] "Alkoxy" refers to a substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropoxy and cyclobutoxy.

[0136] "Carbocyclic group" or "carbocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring. The aromatic or non-aromatic ring can be a 3- to 8-membered monocyclic, 4- to 12-membered bicyclic or 10- to 15-membered tricyclic system. The carbocyclic group can be attached to an aromatic or non-aromatic ring, and the aromatic or non-aromatic ring is optionally a monocyclic, bridged or spiro ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring, "Carbocyclic group" or "carbocycle" can be monovalent, divalent, trivalent or tetravalent.

[0137] "Heterocyclic group" or "heterocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring. The aromatic or non-aromatic ring can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, or a 10- to 15-membered tricyclic system, and contains one or more (including but not limited to 2, 3, 4, or 5) heteroatoms selected from N, O, or S. Optionally, the N and S atoms in the ring of the heterocyclic group can be oxidized to various oxidation states. The heterocyclic group can be attached to a heteroatom or a carbon atom, can be attached to an aromatic ring or a non-aromatic ring, and can be attached with a bridged ring or a spiro ring. Non-limiting examples include epoxyethyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithiolyl, dihydrofuryl, dihydropyranyl, dithiolanyl, tetrahydrofuryl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuryl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl, benzofuryl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecanyl, azadamantyl, oxaspiro[3.3]heptanyl, "Heterocyclic group" or "heterocycle" can be monovalent, divalent, trivalent, or tetravalent.

[0138] "Spiro ring" or "spiro group" refers to a polycyclic group in which a substituted or unsubstituted monocyclic ring shares one atom (called the spiro atom). The number of ring atoms in the spiro ring system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, and one or more of the rings can contain zero or more (including but not limited to 1, 2, 3, or 4) double bonds, and optionally can contain 1 to 5 heteroatoms selected from N, O, or S(=O) n of the heteroatoms. "Spiro ring" or "spiro group" can be monovalent, divalent, trivalent, or tetravalent.

[0139] "Fused ring" or "fused ring group" refers to a polycyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, where one or more rings may contain zero or more (including but not limited to 1, 2, 3, or 4) double bonds, and may be substituted or unsubstituted. Each ring in the fused ring system may contain from 0 to 5 heteroatoms or heteroatom-containing groups (including but not limited to selected from N, S(=O) n or O, where n is 0, 1, or 2). The number of ring atoms in the fused ring system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include:

[0140]

[0141] "Fused ring" or "fused ring group" can be monovalent, divalent, trivalent, or tetravalent.

[0142] "Bridged ring" or "bridged ring group" refers to a polycyclic group, substituted or unsubstituted, containing two non-directly connected atoms shared by any two rings, which may contain zero or more double bonds. Any ring in the bridged ring system may contain from 0 to 5 heteroatoms or heteroatom-containing groups (including but not limited to N, S(=O)n or O, where n is 0, 1, 2). The number of ring atoms includes but is not limited to 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include

[0143] Cubane, adamantane. "Bridged ring" or "bridged ring group" can be monovalent, divalent, trivalent, or tetravalent.

[0144] "Carbospirocycle", "spirocarbocyclic group", "spirocarbon group" or "carbospiro group" refers to a "spirocycle" whose ring system is composed only of carbon atoms. The "carbospirocycle", "spirocarbocyclic group", "spirocarbon group" or "carbospiro group" appearing in this article has the same definition as spirocycle.

[0145] "Carbofused ring", "fused carbocyclic group", "carbofused group" or "carbofused ring group" refers to a "fused ring" whose ring system is composed only of carbon atoms. The "carbofused ring", "fused carbocyclic group", "carbofused group" or "carbofused ring group" appearing in this article has the same definition as fused ring.

[0146] "Carbobridged ring", "bridged carbocyclic group", "carbobridged group" or "carbobridged ring group" refers to a "bridged ring" whose ring system is composed only of carbon atoms. The "carbobridged ring", "bridged carbocyclic group", "carbobridged group" or "carbobridged ring group" appearing in this article has the same definition as bridged ring.

[0147] "Heteromonocyclic", "monocyclic heterocyclic group" or "heteromonocyclic group" refers to a "heterocyclic group" or "heterocycle" of a monocyclic system. For the heterocyclic group, "monocyclic heterocyclic group" or "heteromonocyclic group" appearing in this article, their definitions are the same as those of heterocycles.

[0148] "Fused heterocycle", "fused heterocyclic group", "fused ring heterocyclic group" or "fused heterocyclic group" refers to a "fused ring" containing a heteroatom. For the fused heterocycle, "fused heterocyclic group", "fused ring heterocyclic group" or "fused heterocyclic group" appearing in this article, their definitions are the same as those of fused rings.

[0149] "Spiro heterocycle", "spiro heterocyclic group", "spiro ring heterocyclic group" or "spiro heterocyclic group" refers to a "spiro ring" containing a heteroatom. For the spiro heterocycle, "spiro heterocyclic group", "spiro ring heterocyclic group" or "spiro heterocyclic group" appearing in this article, their definitions are the same as those of spiro rings.

[0150] "Bridged heterocycle", "bridged heterocyclic group", "bridged ring heterocyclic group" or "bridged heterocyclic group" refers to a "bridged ring" containing a heteroatom. For the bridged heterocycle, "bridged heterocyclic group", "bridged ring heterocyclic group" or "bridged heterocyclic group" appearing in this article, their definitions are the same as those of bridged rings.

[0151] "Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a monocyclic or fused ring, and 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 can be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, and the ring connected to the parent structure is the aryl ring. Non-limiting examples include benzene ring, naphthalene ring, "Aryl" or "aromatic ring" can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the connection site is on the aryl ring.

[0152] "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 includes, but is not limited to, 5 to 15, 5 to 10 or 5 to 6. Non-limiting examples of heteroaryl include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, etc. The heteroaryl ring can be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, and the ring connected to the parent structure is the heteroaryl ring. Non-limiting examples include For the heteroaryl appearing in this article, its definition is the same as this definition. Heteroaryl can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the connection site is on the heteroaryl ring.

[0153] "5-membered ring and 5-membered heteroaromatic ring" refers to a 5-membered fused heteroaromatic ring, at least one of the two rings contains one or more heteroatoms (including but not limited to O, S or N), and the whole group is aromatic. Non-limiting examples include pyrrolopyrrole ring, pyrazolopyrrole ring, pyrazolopyrazole ring, pyrrolofuran ring, pyrazolofuran ring, pyrrolothiophene ring, and pyrazolothiophene ring.

[0154] "5- and 6-membered heteroaromatic ring" refers to a 5- and 6-membered fused heteroaromatic ring, where 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, 6-membered heteroaromatic ring and 5-membered heteroaromatic ring.

[0155] "Substituted" or "substituted" means substituted by one or more (including but not limited to 2, 3, 4 or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, cycloalkyl, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH2) m -C(=O)-R a 、-O-(CH2) m -C(=O)-R a 、-(CH2) m -C(=O)-NR b R c 、-(CH2) m S(=O) n R a 、-(CH2) m -Alkenyl-R a , OR d or -(CH2) m -alkynyl-R a (wherein m and n are 0, 1 or 2), arylthio, thiocarbonyl, silane or -NR b R c etc., where R b With R c is independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R 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, spiro or paracyclic groups.

[0156] "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.

[0157] "Substituted by 1 to X substituents selected from..." means substituted by 1, 2, 3... X substituents, where X is any integer between 1 and 10. For example, "substituted by 1 to 4 R k substituents" means substituted by 1, 2, 3, or 4 R k substituents. For example, "substituted by 1 to 5 substituents selected from..." means substituted by 1, 2, 3, 4, or 5 substituents selected from.... For example, "the hetero-bridged ring is optionally substituted by 1 to 4 substituents selected from D or F" means the hetero-bridged ring is optionally substituted by 1, 2, 3, or 4 substituents selected from D or F.

[0158] A ring of X - Y members (3 ≤ X < Y, where Y is any integer between 4 and 12) includes rings of X, X + 1, X + 2, X + 3, X + 4... Y members. The ring includes heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, hetero-monocyclic rings, hetero-fused rings, hetero-spiro rings, or hetero-bridged rings. For example, "a 4 - 7 membered hetero-monocyclic ring" means a 4 - membered, 5 - membered, 6 - membered, or 7 - membered hetero-monocyclic ring, and "a 5 - 10 membered hetero-fused ring" means a 5 - membered, 6 - membered, 7 - membered, 8 - membered, 9 - membered, or 10 - membered hetero-fused ring.

[0159] "Optionally" or "optionally" means that the subsequent described event or circumstance can but does not have to occur, and this description includes the cases where the event or circumstance occurs or does not occur. For example: "an alkyl group optionally substituted by F" means that the alkyl group can but does not have to be substituted by F, and the description includes the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.

[0160] "Pharmaceutically acceptable salt" or "its pharmaceutically acceptable salt" means a salt in which the compound of the present invention retains the biological effectiveness and characteristics of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, and the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0161] "Pharmaceutical composition" means a mixture formed by one or more compounds of the present invention, or their stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, and other chemical components, where "other chemical components" means pharmaceutically acceptable carriers, excipients, and / or one or more other therapeutic agents.

[0162] "Carrier" means a material that does not cause significant irritation to the organism and does not eliminate the biological activity and characteristics of the administered compound.

[0163] "Excipient" refers to an inert substance added to a pharmaceutical composition to facilitate the 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.

[0164] "Prodrug" refers to a compound of the present invention that can be metabolically converted in vivo into a biologically active compound. The prodrugs of the present invention are prepared by modifying the amino or carboxyl groups in the compounds of the present invention, and such modification can be removed by conventional operations or in vivo to obtain the parent compound. When the prodrugs of the present invention are administered to a mammalian individual, the prodrugs are cleaved to form free amino or carboxyl groups.

[0165] "Co-crystal" refers to a crystal formed by the binding of an active pharmaceutical ingredient (API) and a co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, where both the pure states of the API and the CCF are solids at room temperature, and there is a fixed stoichiometric ratio between the components. A co-crystal is a multi-component crystal, including binary co-crystals formed between two neutral solids and multi-component co-crystals formed between a neutral solid and a salt or solvate.

[0166] "Animal" refers to including mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

[0167] "Stereoisomer" refers to an isomer generated by the different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereoisomers, and conformational isomers.

[0168] "Tautomer" refers to a functional group isomer generated by the rapid movement of a certain atom in a molecule between two positions, such as keto-enol tautomerism and amide-imidol tautomerism, etc.

[0169] "IC 50 " is the concentration of a drug or inhibitor required to inhibit a specified biological process (or a certain component in the process, such as an enzyme, receptor, cell, etc.) by half. Detailed Description of the Invention

[0170] The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to this.

[0171] The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is in 10 -6(ppm) units. NMR measurements were performed using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic resonance spectrometers. The solvents for measurement were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS);

[0172] MS measurements were performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0173] HPLC measurements were performed using an Agilent 1260DAD high-performance liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5 μM);

[0174] Thin-layer chromatography silica gel plates used Yantai Huanghai HSGF 254 or Qingdao GF 254 Silica gel plates, and the specifications of the silica gel plates used for thin-layer chromatography (TLC) were 0.15 mm - 0.20 mm, and the specifications of the silica gel plates used for thin-layer chromatography separation and purification of products were 0.4 mm - 0.5 mm;

[0175] Column chromatography generally used Yantai Huanghai silica gel 200 - 300 mesh silica gel as the carrier.

[0176] The * beside the chemical bond represents that the configuration of the chiral atom is R or S.

[0177] Example 1: Synthesis of Compound 1

[0178]

[0179] First step: Synthesis of Compound 1B

[0180] Compound 1A (10.0 g, 44.83 mmol), 2-tert-butoxycarbonyl-2,7-diazaspiro[3.5]nonane (6.2 g, 53.80 mmol), and potassium carbonate (13.19 g, 58.28 mmol) were dissolved in 100 mL of acetonitrile and reacted at 80 °C overnight. Concentrate, and the residue was purified by column chromatography to obtain the target compound 1B (12.1 g, 62.86%).

[0181] Ms m / z (ESI): 348.2 [M+H] +

[0182] Second step: Synthesis of Compound 1C

[0183] Dissolve compound intermediate 1 (11 g, 26.21 mmol), Pd(dppf)Cl2 (2.14 g, 2.62 mmol), 1B (11.83 g, 34.07 mmol) and potassium carbonate (10.87 g, 78.63 mmol) in 180 mL of 1,4-dioxane and 20 mL of water, and react at 80 °C for 12 h. Concentrate, and purify the residue by column chromatography to obtain the target compound 1C (3.4 g, 58.94%).

[0184] Ms m / z(ESI): 595.1[M+H] +

[0185] Step 3: Synthesis of compound 1D

[0186] Dissolve compound 1C (1 g, 1.68 mmol), Pd(dppf)Cl2 (0.14 g, 0.17 mmol), intermediate 2 (0.48 g, 1.85 mmol) and potassium carbonate (0.7 g, 5.04 mmol) in 20 mL of 1,4-dioxane and 4 mL of water, and react at 100 °C for 12 h. Concentrate, and purify the residue by column chromatography to obtain the light yellow solid compound 1D (0.81 g, 69.47%).

[0187] Ms m / z(ESI): 694.3[M+H] +

[0188] Step 4: Synthesis of compound 1E

[0189] Dissolve compound intermediate 3 (0.32 g, 1.88 mmol), 1D (0.65 g, 0.94 mmol), N-methylimidazole 1 (0.23 g, 2.82 mmol) in 10 mL of DMF, and slowly add TCFH (0.53 g, 1.88 mmol) at room temperature and react overnight. Dilute with water, extract the reaction with EA, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, and purify by column chromatography to obtain the target compound 1E (510 mg, 64.35%).

[0190] Ms m / z(ESI): 846.2[M+H] +

[0191] Step 5: Synthesis of compound 1F

[0192] Dissolve compound 1E (250 mg, 0.30 mmol) in 15 mL of a 4% sodium hydroxide methanol solution, stir at room temperature for 2 hours, extract the reaction with ethyl acetate, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, and purify by column chromatography to obtain compound 1F (200 mg, 95.89%).

[0193] Step 6: Synthesis of Compound 1G

[0194] Dissolve Compound 1F (200 mg, 0.28 mmol) in 6 mL of DCM. Slowly add 3 mL of 1,4 - dioxane hydrochloride solution at room temperature, stir for 2 hours, add saturated sodium bicarbonate aqueous solution, adjust the pH to about 8, concentrate, dissolve in dichloromethane solution with 5% methanol, filter to collect the filtrate, and concentrate the filtrate to obtain Compound 1G (150 mg, 87.4%), which is directly used for the next step.

[0195] Step 7: Synthesis of Compound 1

[0196] Dissolve Compound 1G (0.15 g, 0.25 mmol) and Intermediate C (90 mg, 0.30 mmol) in 10 mL of chloroform and 2 mL of methanol, then add 0.3 mL of acetic acid, stir at room temperature for 2 hours, slowly add sodium triacetoxyborohydride (0.16 g, 0.75 mmol), directly add silica gel for sample mixing, and purify by column chromatography to obtain the target compound 1 (51 mg, 23.11%).

[0197] Ms m / z(ESI): 891.2[M + H] +

[0198] 1 H NMR(400MHz, DMSO - d6)δ12.53(br.s,1H),10.23(s,1H),9.92(d,1H),8.78(d,1H),8.75(s,1H),8.14(dd,1H),8.08(d,1H),8.03(s,1H),7.66(d,1H),7.26(s,1H),7.12(d,2H),6.98–6.93(m,3H),5.43–5.31(m,1H),3.77–3.51(m,8H),3.04–2.93(m,4H),2.71–2.56(m,4H),2.53(s,3H),2.38–2.30(m,2H),1.79–1.67(m,6H),1.55(d,3H),1.46–1.39(m,1H),1.37(s,9H),1.28–1.14(m,2H).

[0199] Example 2: Synthesis of Compound 2

[0200]

[0201] Referring to the synthesis route and experimental operation method of Compound 1, Compound 2 (54 mg) was obtained

[0202] LCMS m / z = 877.6 [M+1] +

[0203] 1 H NMR (400 MHz, CD3OD) δ 8.71 (s, 1H), 8.60 (d, 1H), 8.03 (dd, 1H), 7.96–7.88 (m, 2H), 7.65 (d, 1H), 7.15 (d, 2H), 7.02 (s, 1H), 6.99–6.93 (m, 2H), 6.68 (d, 1H), 5.51 (q, 1H), 3.80–3.74 (m, 2H), 3.71–3.61 (m, 4H), 3.59–3.53 (m, 2H), 3.12–3.04 (m, 4H), 2.80–2.75 (m, 2H), 2.74–2.64 (m, 4H), 2.62–2.54 (m, 5H), 1.90–1.81 (m, 2H), 1.78–1.67 (m, 1H), 1.63 (d, 3H), 1.41 (s, 9H), 1.39–1.27 (m, 2H).

[0204] Example 3: Synthesis of Compound 3

[0205]

[0206] Step 1: Synthesis of Compound 3B

[0207] Dissolve the substrate 3A (17 g, 67.7 mmol) and pyridine (10.7 g, 135.4 mmol) in 100 mL of tetrahydrofuran, slowly add the acid anhydride (10.4 g, 101.6 mmol), and react at 80 °C overnight. Concentrate the reaction solution, and obtain the pure product 3B (19 g, 96%) by silica gel column chromatography.

[0208] Step 2: Synthesis of Compound 3C

[0209] Add the ethyl acetate solution of hydrochloric acid (2N, 130 mL, 260 mmol) to the substrate 3B (19 g, 64.9 mmol), stir and react at room temperature for 4 hours. Dilute the reaction solution with petroleum ether, and obtain the white solid 3C (14.1 g, 95%) by filtration, washing and drying.

[0210] Ms m / z (ESI): 194.3 [M+H] +

[0211] Step 3: Synthesis of Compound 3D

[0212] Intermediate 3C (14.1 g, 61.6 mmol), p-nitrofluorobenzene (8.7 g, 61.6 mmol) and potassium carbonate (21.3 g, 154 mmol) were added to 100 mL of DMF, and then the mixture was reacted overnight at 110 °C. The reaction solution was concentrated, and the resulting oily residue was extracted twice with ethyl acetate. The obtained organic phase was washed, dried, concentrated, and the residue was purified by silica gel column chromatography to obtain yellow solid 3D (12.1 g, 63%).

[0213] Ms m / z(ESI): 315.1 [M+H] +

[0214] Step 4: Synthesis of Compound 3E

[0215] Intermediate 3D (11.1 g, 35.4 mmol), ammonium chloride (18.8 g, 354 mmol) and 20 mL of water were added to 100 mL of ethanol, and then iron powder (9.9 g, 176.8 mmol) was slowly added with stirring and the mixture was reacted at 80 °C for 1 hour. The reaction solution was concentrated, then dichloromethane was added to the obtained solid residue and stirred for 10 minutes. The resulting mixture was filtered, washed and concentrated, and the residue was purified by silica gel column chromatography to obtain intermediate 3E (9.6 g, 96%).

[0216] Step 5: Synthesis of Compound 3F

[0217] The obtained intermediate 3E (9.6 g, 33.8 mmol) and acrylic acid (3.7 g, 50.7 mmol) were dissolved in 80 mL of toluene and reacted overnight at 90 °C. Then, 80 mL of acetic acid and urea (10.1 g, 169 mmol) were added to the reaction solution and reacted at 110 °C for 24 hours. The crude oil obtained after concentrating the reaction solution was extracted, washed, dried and concentrated with ethyl acetate, and the residue was purified by silica gel column chromatography to obtain intermediate 3F (8.3 g, 64%).

[0218] Ms m / z(ESI): 382.2 [M+H] +

[0219] Step 6: Synthesis of Compound 3G

[0220] 100 mL of 4% sodium hydroxide methanol solution was added to intermediate 3F (8.3 g, 21.8 mmol), and the mixture was stirred at room temperature for half an hour. The reaction solution was appropriately concentrated and adjusted to pH neutral with hydrochloric acid methanol solution. The obtained mixture was filtered, washed and dried to obtain white solid 3G (5.9 g, 80%).

[0221] Ms m / z(ESI): 340.2 [M+H] +

[0222] Step 7: Synthesis of Compound 3H

[0223] Under ice bath conditions, 20 mL of dichloromethane and Dess-Martin periodinane (1.06 g, 2.5 mmol) were slowly added to intermediate 3G (339 mg, 1.0 mmol), and the reaction was carried out for one hour. The reaction mixture was filtered and concentrated, and the residue was purified by silica gel column chromatography to obtain compound 3H (250 mg, 75%).

[0224] Step 8: Synthesis of Compound 3

[0225] Compound 3H (150 mg, 0.45 mmol) and intermediate 4 (250 mg, 0.45 mmol) were dissolved in a mixed solvent of 4 mL of 1,2-dichloroethane and 2 mL of methanol, and two drops of acetic acid were added thereto. The reaction was carried out at room temperature for one hour, and then sodium triacetoxyborohydride (273 mg, 1.35 mmol) was added to the reaction and reacted overnight. The reaction solution was filtered and concentrated, and the residue was purified by silica gel column chromatography to obtain 50 mg of crude product 3. The crude product was purified by preparative liquid chromatography (instrument: Waters 2545; preparative column: Waters XSelect CSH 5 μm (19 mm × 250 mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% ammonium acetate)) to obtain the target compound 3 (10 mg, 2.5%).

[0226] Ms m / z (ESI): 887.4 [M+H] +

[0227] 1 H NMR (400 MHz, DMSO-d6) δ 12.56 (s, 1H), 10.24 (s, 1H), 9.91 (d, 1H), 8.81 (d, 1H), 8.76 (s, 1H), 8.18 (dd, 1H), 8.09 (d, 1H), 8.04 (s, 1H), 7.66 (d, 1H), 7.29 (s, 1H), 7.16 (d, 2H), 7.02–6.93 (m, 3H), 5.42–5.34 (m, 1H), 3.93–3.84 (m, 1H), 3.75–3.67 (m, 3H), 3.66–3.54 (m, 4H), 3.09 (dd, 1H), 2.92–2.82 (m, 1H), 2.71–2.65 (m, 2H), 2.65–2.56 (m, 2H), 2.53 (s, 3H), 2.46–2.36 (m, 4H), 2.13–2.05 (m, 1H), 1.56–1.54 (d, 3H), 1.37 (s, 9H), 1.32–1.24 (m, 2H).

[0228] Example 4: Preparation of Compound 4

[0229]

[0230] First Step: Preparation of 4B

[0231] Dissolve 1 - tert - butoxycarbonyl - 4 - fluoro - 4 - (hydroxymethyl)piperidine (20 g, 85.73 mmol) in 80 mL of dichloromethane, add 25 mL of trifluoroacetic acid, and stir at room temperature for 3 hours. After concentration under reduced pressure, the target compound 4B (11 g, crude product) is obtained and directly used in the next step without purification.

[0232] LCMS m / z = 134.1 [M + H] +

[0233] Second Step: Preparation of 4C

[0234] Dissolve the above - mentioned crude product 4B (11 g, 82.61 mmol) in 100 mL of N,N - dimethylformamide, add p - nitrofluorobenzene (11 g, 77.96 mmol), anhydrous potassium carbonate (32.32 g, 233.88 mmol), and stir at 80 °C for 16 hours. Cool the reaction solution to room temperature, add water (150 mL), extract the aqueous phase with ethyl acetate (200 mL × 2), combine the ethyl acetate layers, wash the ethyl acetate layers successively with water (150 mL × 2) and saturated aqueous NaCl solution (150 mL), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is purified by silica gel column chromatography to obtain 4C (15.6 g, overall yield of two steps 71.56%).

[0235] LCMS m / z = 255.1 [M + H] +

[0236] Third Step: Preparation of 4D

[0237] Dissolve dimethyl sulfoxide (2.75 g, 29.5 mmol) in 30 mL of dichloromethane. Under a nitrogen atmosphere, slowly add oxalyl chloride (3.74 g, 29.5 mmol) dropwise at - 78 °C. After dropping, keep stirring at - 78 °C for 30 min. Slowly add 4 mL of a mixed solvent of dichloromethane and dimethyl sulfoxide of 4C (1.5 g, 5.9 mmol) dropwise. After dropping, keep stirring at - 78 °C for 1 hour. Slowly add triethylamine (2.99 g, 29.5 mmol) dropwise. After dropping, slowly warm up to room temperature and stir for 1 hour. Add water (40 mL), extract and separate the layers. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is purified by silica gel column chromatography to obtain compound 4D (1.4 g, yield 94.08%).

[0238] LCMS m / z = 285.1 [M + MeOH + H] +

[0239] Step 4: Preparation of 4F

[0240] Dissolve 4E (1 g, 1.24 mmol) in 8 mL of dichloromethane, add 2 mL of trifluoroacetic acid, and stir at room temperature for 3 hours. After concentration under reduced pressure, the trifluoroacetate salt of the target compound 4F (0.8 g, crude product) is obtained and used directly in the next step without purification.

[0241] LCMS m / z = 706.5 [M + H] +

[0242] Step 5: Preparation of 4G

[0243] Dissolve the above-mentioned crude trifluoroacetate salt of 4F (0.8 g, 1.13 mmol) in 15 mL of N,N-dimethylacetamide, add compound 4D (0.57 g, 2.26 mmol), 0.1 mL of acetic acid, stir at room temperature for 1 hour, and add sodium triacetoxyborohydride (1.2 g, 5.65 mmol) in batches. After addition, stir at room temperature for 16 hours. Add water (40 mL) to the reaction solution, and extract with ethyl acetate (40 mL × 2). Combine the ethyl acetate layers, and wash the ethyl acetate layers successively with water (40 mL × 2) and saturated aqueous NaCl solution (40 mL). Dry the organic phase over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 4G (0.82 g, two-step yield 70.09%).

[0244] LCMS m / z = 471.8 [M / 2 + H] +

[0245] Step 6: Preparation of 4H

[0246] Dissolve 4G (0.82 g, 0.87 mmol) in a mixed solvent of 15 mL of absolute ethanol and 3 mL of water, add ammonium chloride (0.47 g, 8.7 mmol) and iron powder (0.29 g, 5.22 mmol) in sequence. After addition, stir at 80 °C for 3 hours. Cool the reaction solution to room temperature, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 4H (0.61 g, yield 76.84%).

[0247] LCMS m / z = 456.8 [M / 2 + H] +

[0248] Step 7: Preparation of 4I

[0249] Dissolve 4H (0.61 g, 8.7 mmol) in 10 mL of toluene, add 0.3 mL of acrylic acid, and stir at 90 °C for 16 hours. Cool the reaction solution to room temperature, add urea (0.89 g, 14.82 mmol) and glacial acetic acid (4.35 mL, 76.06 mmol) in sequence. After addition, stir at 110 °C for 16 hours. Cool the reaction solution to room temperature, concentrate under reduced pressure, adjust the pH of the residue to 8 with an aqueous solution of saturated NaHCO₃, extract with ethyl acetate (50 mL × 2), combine the ethyl acetate layers, dry the ethyl acetate layer with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and subject the residue to silica gel column chromatography to obtain 4H (0.15 g, yield 22.22%).

[0250] LCMS m / z = 505.5 [M / 2 + H] +

[0251] Step 8: Preparation of Compound 4

[0252] Dissolve 4I (0.15 g, 8.7 mmol) in 2 mL of methanol, add 4 mL of 4% NaOH-MeOH solution, and stir at room temperature for 30 min. Concentrate under reduced pressure, and subject the residue to silica gel column chromatography to obtain Compound 4 (35 mg, yield 27.10%)

[0253] LCMS m / z = 869.7 [M + H] +

[0254] 1 H NMR (400 MHz, CD₃OD) δ 8.73 (s, 1H), 8.64 (d, 1H), 8.08–8.02 (m, 1H), 7.97–7.89 (m, 2H), 7.66 (d, 1H), 7.21 (d, 2H), 7.08–7.02 (m, 3H), 6.92 (d, 1H), 5.52 (q, 1H), 3.81 (t, 2H), 3.68–3.60 (m, 4H), 3.56–3.46 (m, 2H), 3.16–3.06 (m, 2H), 2.80 (t, 2H), 2.74–2.67 (m, 4H), 2.65 (s, 1H), 2.60 (s, 3H), 2.59 (s, 1H), 2.12–2.04 (m, 2H), 1.94–1.82 (m, 2H), 1.64 (d, 3H), 1.42 (s, 9H).

[0255] Resolution of Intermediate Compound 3G

[0256]

[0257] Compound 3G (1.0 g) was resolved by chiral HPLC to give 3G-1 (346.9 mg, retention time: 1.809 min) and 3G-2 (343.7 mg, retention time: 2.138 min). When 3G-1 is in the S configuration, 3G-2 is in the R configuration; conversely, when 3G-1 is in the R configuration, 3G-2 is in the S configuration.

[0258] The resolution conditions are as follows:

[0259] Instrument: Waters 150Prep-SFC; Column: Chiral AS column; Mobile phase: A for CO2; B for methanol solution of 0.1% ammonia water; Elution conditions: Elute with A solution containing 40% B; Flow rate: 100 mL / min; Pressure: 100 bar; Column temperature: room temperature

[0260] Detection wavelength: 220 nm;

[0261] Chiral HPLC conditions:

[0262] Instrument: SHIMADZU LC-30AD sf; Column: Chiral AS column; Mobile phase: A for CO2; B for methanol solution of 0.05% diethylamine; Elution conditions: Elute with A solution containing 5-40% B; Flow rate: 3 mL / min; Pressure: 100 bar; Column temperature: room temperature; Detection wavelength: 220 nm; Isomer 3G-1:

[0263] LCMS m / z = 340.0 [M+H] +

[0264] 1 1H NMR (400 MHz, CD3OD) δ 7.23–7.18 (m, 2H), 7.03–6.97 (m, 2H), 3.97 (dd, 1H), 3.85–3.70 (m, 4H), 3.59–3.49 (m, 1H), 3.09–2.94 (m, 1H), 2.90–2.81 (m, 1H), 2.78 (t, 2H), 2.18–1.99 (m, 2H), 1.75–1.61 (m, 1H). Isomer 3G-2:

[0265] LCMS m / z = 340.0 [M+H] +

[0266] 11H NMR (400 MHz, CD3OD) δ 7.25–7.17 (m, 2H), 7.04–6.96 (m, 2H), 3.97 (dd, 1H), 3.85–3.70 (m, 4H), 3.59–3.49 (m, 1H), 3.09–2.94 (m, 1H), 2.90–2.81 (m, 1H), 2.79 (t, 2H), 2.20–2.00 (m, 2H), 1.75–1.59 (m, 1H). Example 5: Synthesis of Compound 5

[0267]

[0268] Step 1: Synthesis of Compound 5A

[0269] Dissolve Compound 3G-1 (1.017 g, 3 mmol), triphenylphosphine (1.57 g, 6 mmol) and imidazole (0.408 g, 6 mmol) in 20 mL of tetrahydrofuran. Subsequently, add iodine (1.53 g, 6 mmol) to the reaction mixture. Place the reaction at 50 °C for 1 h. Filter and concentrate the reaction solution. The residue is purified by silica gel column chromatography to obtain the crude product of intermediate 5A (1.9 g, 88%).

[0270] LCMS m / z = 450.0 [M+H] +

[0271] Step 2: Synthesis of Compound 5B

[0272] Add Compound 5A (220 mg, 0.3 mmol), intermediate 5 (212 mg, 0.3 mmol), potassium carbonate (83 mg, 0.6 mmol) and 10 mL of DMF to the reaction flask successively and react at 80 °C for 4 h. Subsequently, dilute the reaction solution with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate and purify by silica gel column chromatography to obtain the crude product of 5B (140 mg).

[0273] LCMS m / z = 1027.6 [M+H] +

[0274] Step 3: Synthesis of Compound 5

[0275] Add the crude product of 5B (140 mg) to 4 mL of a 4% sodium hydroxide methanol solution and react at room temperature for 30 min. The reaction solution is purified twice by silica gel column chromatography and preparative TLC to obtain Compound 5 (42 mg, overall yield of two steps 16%).

[0276] LCMS m / z = 887.6 [M+H] +

[0277] 11H NMR (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 10.22 (s, 1H), 9.93 (d, 1H), 8.81 (s, 1H), 8.76 (s, 1H), 8.18 (d, 1H), 8.09 (d, 1H), 8.04 (s, 1H), 7.66 (d, 1H), 7.29 (s, 1H), 7.15 (d, 2H), 6.96 (d, 1H), 6.60 (d, 2H), 5.42–5.33 (m, 1H), 3.88–3.65 (m, 5H), 3.61 (s, 4H), 3.28 (s, 5H), 3.11 (t, 1H), 2.90–2.75 (m, 1H), 2.68 (t, 2H), 2.53 (s, 4H), 1.95–1.84 (m, 1H), 1.74–1.62 (m, 1H), 1.55 (d, 3H), 1.37 (s, 9H).

[0278] Example 6: Synthesis of Compound 6

[0279]

[0280] First step: Synthesis of Compound 6A

[0281] Compound 3G-2 (1.017 g, 3 mmol), triphenylphosphine (1.57 g, 6 mmol) and imidazole (0.408 g, 6 mmol) were dissolved in 20 mL of tetrahydrofuran. Subsequently, iodine (1.53 g, 6 mmol) was added to the reaction mixture, and the reaction was carried out at 50 °C for 1 h. The reaction solution was filtered and concentrated, and the residue was purified by silica gel column chromatography to obtain the crude product of 6A (1.8 g, 82%).

[0282] LCMS m / z = 450.0 [M+H] +

[0283] Second step: Synthesis of Compound 6B

[0284] Compound 6A (220 mg, 0.3 mmol), intermediate 5 (212 mg, 0.3 mmol), potassium carbonate (83 mg, 0.6 mmol) and 10 mL of DMF were successively added to the reaction flask and reacted at 80 °C for 4 h. Subsequently, the reaction solution was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to obtain the crude product of 6B (125 mg).

[0285] LCMS m / z = 1027.6 [M+H] +

[0286] Third step: Synthesis of Compound 6

[0287] The crude product of 6B (125 mg) was added to 4 ml of a 4% sodium hydroxide methanol solution, and the reaction was carried out at room temperature for 30 min. The reaction solution was purified twice by silica gel column chromatography and preparative TLC to obtain compound 6 (28 mg, overall yield of two steps: 11%).

[0288] LCMS m / z = 887.6 [M+H] +

[0289] 1 H NMR (400 MHz, DMSO-d6) δ 12.58 (s, 1H), 10.22 (s, 1H), 9.93 (d, 1H), 8.82 (s, 1H), 8.76 (s, 1H), 8.19 (d, 1H), 8.09 (d, 1H), 8.04 (s, 1H), 7.66 (d, 1H), 7.29 (s, 1H), 7.15 (d, 2H), 6.97 (d, 1H), 6.60 (d, 2H), 5.43–5.32 (m, 1H), 3.88–3.66 (m, 5H), 3.61 (s, 4H), 3.28 (s, 5H), 3.11 (t, 1H), 2.89–2.75 (m, 1H), 2.68 (t, 2H), 2.53 (s, 4H), 1.96–1.82 (m, 1H), 1.76–1.62 (m, 1H), 1.55 (d, 3H), 1.37 (s, 9H).

[0290] Compound 5 and compound 6 are respectively one of the following structures: when compound 5 is M-1, compound 6 is M-2; conversely, when compound 5 is M-2, compound 6 is M-1.

[0291]

[0292] Example 7: Synthesis of compound 7

[0293]

[0294] Referring to the synthesis route and experimental operation method of compound 1, compound 7 (46 mg) was obtained

[0295] LCMS m / z = 863.4 [M+H] +

[0296] 11H NMR (400 MHz, CD3OD) δ 8.71 (s, 1H), 8.61 (d, 1H), 8.04 (dd, 1H), 7.94–7.90 (m, 2H), 7.53 (d, 1H), 7.16 (d, 2H), 7.03 (s, 1H), 6.97 (d, 2H), 6.70 (d, 1H), 4.70 (s, 2H), 3.77 (t, 2H), 3.72–3.63 (m, 4H), 3.60–3.54 (m, 2H), 3.15–3.04 (m, 4H), 2.78 (t, 2H), 2.75–2.66 (m, 4H), 2.58 (d, 2H), 2.53 (s, 3H), 1.87 (d, 2H), 1.78–1.68 (m, 1H), 1.49 (s, 9H), 1.38–1.28 (m, 2H).

[0297] Example 8: Synthesis of Compound 8

[0298]

[0299] Referring to the synthetic route and preparation method of Compound 5, the target compound 8 (48 mg) was obtained.

[0300] LCMS m / z = 913.7 [M+H] +

[0301] 1 1H NMR (400 MHz, CD3OD) δ 8.71 (s, 1H), 8.59 (d, 1H), 8.01 (dd, 1H), 7.99–7.88 (m, 2H), 7.65 (d, 1H), 7.01 (s, 1H), 6.95 (d, 2H), 6.66 (d, 1H), 6.41 (d, 2H), 5.51 (q, 1H), 3.77–3.49 (m, 9H), 3.11–3.01 (m, 3H), 2.83–2.62 (m, 7H), 2.61–2.50 (m, 5H), 2.00–1.90 (m, 1H), 1.80–1.68 (m, 1H), 1.63 (d, 3H), 1.41 (s, 9H).

[0302] Example 9: Synthesis of Compound 9

[0303]

[0304] Step 1: Synthesis of Compound 9A

[0305] 8A (183 mg, 0.25 mmol), compound 6A (135 mg, 0.3 mmol), potassium carbonate (69 mg, 0.5 mmol) and 5 mL of DMF were successively added to a reaction flask and reacted at 80 °C for 4 h. Subsequently, the reaction solution was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to obtain the crude product of 9A (80 mg).

[0306] LCMS m / z = 1053.7 [M+H] +

[0307] Step 2: Synthesis of compound 9

[0308] The crude product of 9A (80 mg) was dissolved in 3 ml of tetrahydrofuran, and 0.5 ml of a tetrahydrofuran solution of tetrabutylammonium fluoride (1 M) was added thereto, and the mixture was reacted at room temperature for 30 min. The reaction solution was purified twice by preparative TLC and preparative HPLC to obtain compound 9 (32 mg, overall yield of two steps 15%). LCMS m / z = 913.7 [M+H] +

[0309] 1 1H NMR (400 MHz, CD3OD) δ 8.71 (s, 1H), 8.60 (d, 1H), 8.01 (dd, 1H), 7.97–7.89 (m, 2H), 7.65 (d, 1H), 7.02 (s, 1H), 6.96 (d, 2H), 6.67 (d, 1H), 6.42 (d, 2H), 5.51 (q, 1H), 3.82–3.50 (m, 9H), 3.12–3.01 (m, 3H), 2.85–2.63 (m, 7H), 2.60–2.50 (m, 5H), 2.01–1.91 (m, 1H), 1.82–1.70 (m, 1H), 1.63 (d, 3H), 1.41 (s, 9H).

[0310] Compound 8 and compound 9 are respectively one of the following structures: When compound 8 is Q-1, compound 9 is Q-2; conversely, when compound 8 is Q-2, compound 9 is Q-1.

[0311]

[0312] Example 10: Synthesis of compound 10

[0313]

[0314] Referring to the synthesis route and experimental operation method of compound 5, the trifluoroacetate of compound 10 (15 mg) was obtained.

[0315] Preparation method: Instrument: SHIMADZU LC-20AP; Chromatographic column: C18; Mobile phase: A is 0.1% aqueous TFA solution; B is acetonitrile; Elution conditions: Gradient elution with A solution of 15% to 45% B; Flow rate: 25 mL / min; Column temperature: Room temperature; Detection wavelength: 210 & 254 nm;

[0316] LCMS m / z = 873.4 [M+1] +

[0317] 1 H NMR (400 MHz, CD3OD) δ 8.92 (s, 1H), 8.80 (d, 1H), 8.20 (dd, 1H), 7.95–7.89 (m, 2H), 7.65 (d, 1H), 7.36 (s, 1H), 7.20 (d, 2H), 7.09 (d, 1H), 6.65 (d, 2H), 4.73 (s, 2H), 3.89–3.65 (m, 6H), 3.47–3.35 (m, 5H), 3.34–3.31 (m, 4H), 3.25–3.17 (m, 1H), 2.89–2.73 (m, 3H), 2.58 (s, 3H), 2.32–2.16 (m, 1H), 2.14–1.99 (m, 1H), 1.50 (s, 9H).

[0318] Example 11: Synthesis of Compound 11

[0319]

[0320] Referring to the synthesis route and experimental operation method of Compound 6, the trifluoroacetate salt of Compound 11 (28 mg) was obtained.

[0321] Preparation method: Instrument: SHIMADZU LC-20AP; Chromatographic column: C18; Mobile phase: A is 0.1% aqueous TFA solution; B is acetonitrile; Elution conditions: Gradient elution with A solution of 15% to 45% B; Flow rate: 25 mL / min; Column temperature: Room temperature; Detection wavelength: 210 & 254 nm;

[0322] LCMS m / z = 873.4 [M+1] +

[0323] 11H NMR (400 MHz, CD3OD) δ 8.92 (s, 1H), 8.80 (d, 1H), 8.20 (dd, 1H), 7.95–7.89 (m, 2H), 7.65 (d, 1H), 7.31 (s, 1H), 7.20 (d, 2H), 7.09 (d, 1H), 6.65 (d, 2H), 4.72 (s, 2H), 3.91–3.66 (m, 6H), 3.47–3.31 (m, 9H), 3.24–3.17 (m, 1H), 2.86–2.75 (m, 3H), 2.57 (s, 3H), 2.33–2.19 (m, 1H), 2.14–2.00 (m, 1H), 1.49 (s, 9H).

[0324] Compound 10 and Compound 11 are respectively one of the following structures: When Compound 10 is N-1, Compound 11 is N-2; conversely, when Compound 10 is N-2, Compound 11 is N-1.

[0325]

[0326] Example 12: Synthesis of Compound 12

[0327]

[0328] Referring to the synthesis route and experimental operation method of Compound 5, Compound 12 (21 mg) was obtained. Preparation method: Instrument: SHIMADZU LC-20AP; Chromatographic column: C18; Mobile phase: A is 10 mmol / L ammonium bicarbonate aqueous solution; B is acetonitrile; Elution conditions: Gradient elution with A solution of 50% to 70% B; Flow rate: 75 mL / min; Column temperature: Room temperature; Detection wavelength: 210 & 254 nm;

[0329] LCMS m / z = 899.4 [M+1] +

[0330] 11H NMR (400 MHz, CD3OD) δ 8.71 (s, 1H), 8.60 (d, 1H), 8.02 (dd, 1H), 7.96–7.90 (m, 2H), 7.53 (d, 1H), 7.03 (s, 1H), 6.94 (d, 2H), 6.69 (d, 1H), 6.42 (d, 2H), 4.70 (s, 2H), 3.79–3.71 (m, 3H), 3.70–3.61 (m, 1H), 3.60–3.50 (m, 5H), 3.12–3.01 (m, 3H), 2.82–2.58 (m, 7H), 2.58–2.50 (m, 5H), 2.00–1.89 (m, 1H), 1.79–1.67 (m, 1H), 1.49 (s, 9H).

[0331] Example 13: Synthesis of Compound 13

[0332]

[0333] Referring to the synthetic route and experimental operation method of Compound 6, Compound 13 (18 mg) was obtained. Preparation method: Instrument: SHIMADZU LC-20AP; Chromatographic column: C18; Mobile phase: A is 10 mmol / L aqueous ammonium bicarbonate solution; B is acetonitrile; Elution conditions: Gradient elution with A solution of 50% to 70% B; Flow rate: 75 mL / min; Column temperature: Room temperature; Detection wavelength: 210 & 254 nm;

[0334] LCMS m / z = 899.4 [M+1] +

[0335] 1 1H NMR (400 MHz, CD3OD) δ 8.71 (s, 1H), 8.60 (d, 1H), 8.02 (dd, 1H), 7.96–7.89 (m, 2H), 7.53 (d, 1H), 7.02 (s, 1H), 6.94 (d, 2H), 6.68 (d, 1H), 6.41 (d, 2H), 4.70 (s, 2H), 3.79–3.70 (m, 3H), 3.70–3.60 (m, 1H), 3.59–3.47 (m, 5H), 3.11–3.00 (m, 3H), 2.79–2.57 (m, 7H), 2.57–2.49 (m, 5H), 1.98–1.88 (m, 1H), 1.77–1.66 (m, 1H), 1.49 (s, 9H).

[0336] Compound 12 and Compound 13 are respectively one of the following structures: When Compound 12 is P-1, Compound 13 is P-2; conversely, when Compound 12 is P-2, Compound 13 is P-1.

[0337]

[0338] Preparation of Example 14:

[0339]

[0340] Referring to the synthetic route and experimental operation method of Compound 1, Compound 14 (20 mg, 9%) was obtained. Preparation method: Instrument: SHIMADZU LC-20AP; Chromatographic column: C18; Mobile phase: A is 10 mmol / L aqueous ammonium bicarbonate solution; B is acetonitrile; Elution conditions: Gradient elution with A solution of 50% to 70% B; Flow rate: 75 mL / min; Column temperature: Room temperature; Detection wavelength: 210 & 254 nm;

[0341] LCMS m / z = 877.2 [M+H] +

[0342] 1 H NMR (400 MHz, CD3OD) δ 8.71 (s, 1H), 8.63 (d, 1H), 8.03 (dd, 1H), 7.95–7.90 (m, 2H), 7.53 (d, 1H), 7.19 (d, 2H), 7.05–6.97 (m, 3H), 6.94 (d, 1H), 4.70 (s, 2H), 3.80 (t, 2H), 3.75–3.68 (m, 2H), 3.66–3.53 (m, 8H), 2.84–2.76 (m, 4H), 2.76–2.67 (m, 2H), 2.53 (s, 3H), 1.93–1.87 (m, 4H), 1.87–1.79 (m, 2H), 1.76–1.65 (m, 1H), 1.49 (s, 9H), 1.46–1.34 (m, 2H).

[0343] Example 15: Synthesis of Compound 15

[0344]

[0345] Compound 1G (0.25 g, 0.41 mmol) and 15A (150 mg, 0.49 mmol) were dissolved in 10 mL of chloroform and 10 mL of methanol, then 0.3 mL of acetic acid was added. The mixture was stirred at room temperature for 1 hour, and sodium triacetoxyborohydride (0.17 g, 0.82 mmol) was slowly added. The mixture was stirred at 50 °C overnight. Subsequently, the reaction solution was diluted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative HPLC. (Instrument and preparative column: SHIMADZU LC-20AP preparative liquid phase was used, and the preparative column model was Phenomenex C18, 5 μm, inner diameter * length = 19 mm * 150 mm). Preparation method: The reaction solution was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile / water (containing 10 mmol / L ammonium bicarbonate). Gradient elution method: Acetonitrile was eluted from 32% to 62% (elution time 15 min). The prepared solution was freeze-dried to obtain the target compound 15 (31 mg, 8.42%).

[0346] Ms m / z(ESI): 892.2[M+H] +

[0347] 1 H NMR(400 MHz, CD3OD) δ 8.71(s, 1H), 8.61(d, 1H), 8.06(d, 1H), 8.00(dd, 1H), 7.95–7.88(m, 2H), 7.65(d, 1H), 7.50–7.40(m, 2H), 7.01(s, 1H), 6.90(d, 1H), 5.51(q, 1H), 4.02–3.94(m, 2H), 3.79–3.70(m, 5H), 3.65–3.56(m, 4H), 2.97–2.90(m, 2H), 2.82–2.72(m, 4H), 2.59(s, 3H), 1.93–1.81(m, 6H), 1.80–1.71(m, 1H), 1.63(d, 3H), 1.48–1.35(m, 11H).

[0348] Example 16: Preparation of Compound 16

[0349]

[0350] First step: Preparation of 16B

[0351] Dissolve 2,3-difluoro-5-bromopyridine (16A) (15 g, 77.33 mmol) in 80 mL of N,N-dimethylformamide, add cis-2-Boc-hexahydropyrrolo[3,4-c]pyrrole (19.7 g, 92.80 mmol) and triethylamine (19.99 g, 154.66 mmol). After addition, react at 80 °C for 16 hours. Cool the reaction to room temperature, add water (120 mL) to the reaction solution, and extract with ethyl acetate (120 mL × 2). Combine the ethyl acetate layers, and wash the ethyl acetate layers successively with water (150 mL × 2) and saturated aqueous NaCl solution (150 mL). Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is purified by silica gel column chromatography to obtain compound 16B (27.2 g, yield 91.07%).

[0352] LCMS m / z = 386.1 [M+H] +

[0353] Step 2: Preparation of 16C

[0354] Dissolve 16B (23.1 g, 59.80 mmol) in a mixed solvent of 150 mL of 1,4-dioxane and 10 mL of water. Successively add bis(pinacolato)diboron (22.78 g, 89.70 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (7.33 g, 8.97 mmol), and potassium acetate (11.74 g, 119.6 mmol). React at 100 °C for 16 hours under a nitrogen atmosphere. Cool the reaction to room temperature, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 16C (19.3 g, yield: 91.90%).

[0355] LCMS m / z = 352.1 [M+H] +

[0356] Steps 3 to 8: Preparation of compound 16

[0357] Refer to the synthesis method of compound 1 to obtain compound 16 (52 mg, yield 14.76%).

[0358] (Instrument and preparation column: SHIMADZU LC-20AP preparative liquid phase, the preparation column model is Phenomenex C18, 5 μm, inner diameter * length = 19 mm * 150 mm), mobile phase system: acetonitrile / water (containing 10 mmol / L ammonium bicarbonate). Gradient elution method: Gradient elution of acetonitrile from 32% to 62% for 62% (elution time 15 min). The prepared solution is lyophilized to obtain the target compound 16 (31 mg, 8.42%).

[0359] LCMS m / z = 895.4 [M+H] +

[0360] 1 H NMR (400 MHz, CD3OD) δ 8.73 (s, 1H), 8.50–8.46 (m, 1H), 7.97–7.85 (m, 3H), 7.68–7.62 (m, 1H), 7.17–7.10 (m, 3H), 6.98–6.90 (m, 2H), 5.55–5.47 (m, 1H), 3.80–3.73 (m, 4H), 3.73–3.63 (m, 4H), 3.17–3.08 (m, 2H), 3.06–2.99 (m, 2H), 2.81–2.75 (m, 2H), 2.74–2.64 (m, 4H), 2.62–2.56 (m, 5H), 1.91–1.82 (m, 2H), 1.78–1.69 (m, 1H), 1.63 (d, 3H), 1.42 (s, 9H), 1.38–1.28 (m, 2H).

[0361] Preparation of Example 17:

[0362]

[0363] First step: Synthesis of Compound 17B

[0364] 3-Fluoro-4-bromoiodobenzene (9 g, 30 mmol), copper(I) iodide (1.14 g, 6 mmol), L-proline (1.38 g, 12 mmol), potassium carbonate (8.26 g, 60 mmol) and 60 mL of DMF were successively added to a reaction flask, and then 4-(dimethoxymethyl)piperidine (4.8 g, 30 mmol) was added. After displacing nitrogen three times, the reaction was carried out at 90 °C for 16 hours. The reaction solution was concentrated, diluted with ethyl acetate, and washed with water three times. The obtained organic phase was concentrated and purified by silica gel column chromatography to obtain intermediate 17B (4.5 g, 45%).

[0365] LCMS m / z = 332.1 334.1 [M+H] +

[0366] Second step: Synthesis of Compound 17C

[0367] Compound 17B (3.3 g, 10 mmol), dihydrouracil (3.42 g, 30 mmol), EPhos Pd G4 (460 mg, 0.5 mmol), EPhos (268 mg, 0.5 mmol), cesium carbonate (9.8 g, 30 mmol) and 20 mL of dioxane were successively added to the reaction flask. After being purged with nitrogen three times, the reaction was carried out at 100 °C overnight. The reaction solution was directly concentrated and purified by silica gel column chromatography to obtain intermediate 17C (490 mg, 14%).

[0368] LCMS m / z = 366.2 [M+H] +

[0369] Step 3: Synthesis of compound 17D

[0370] Compound 17C (438 mg, 1.2 mmol) was dissolved in 4 mL of tetrahydrofuran. Subsequently, 4 mL of hydrochloric acid (4 M) was added thereto and the reaction was carried out at room temperature for half an hour. The reaction solution was extracted with ethyl acetate three times. The obtained organic phase was dried, concentrated and purified by silica gel column chromatography to obtain intermediate 17D (302 mg, 79%).

[0371] LCMS m / z = 320.6 [M+H] +

[0372] Step 4: Synthesis of compound 17

[0373] Compound 17D (32 mg, 0.1 mmol) and 17E (60 mg, 0.1 mmol) were dissolved in 4 mL of dichloromethane. DIPEA (104 mg, 0.8 mmol) was added thereto and stirred for half an hour. Subsequently, sodium triacetoxyborohydride (64 mg, 0.3 mmol) was added and the reaction was carried out overnight. The reaction solution was directly concentrated and purified by silica gel column chromatography to obtain the crude product of compound 17. The crude product was purified by preparative HPLC. (Instrument and preparative column: SHIMADZU LC-20AP preparative liquid phase was used, and the preparative column model was Phenomenex C18, 5 μm, inner diameter * length = 19 mm * 150 mm), mobile phase system: acetonitrile / water (containing 10 mmol of ammonium bicarbonate). Gradient elution method: acetonitrile was eluted from 32% to 62% with a gradient of 62% (elution time 15 min). After the preparative solution was freeze-dried, the pure product 17 (35 mg, 39%) was obtained.

[0374] LCMS m / z = 895.3 [M+H] +

[0375] 11H NMR (400 MHz, DMSO-d6) δ 12.53 (s, 1H), 10.32 (s, 1H), 9.91 (d, 1H), 8.78 (d, 1H), 8.75 (s, 1H), 8.15 (dd, 1H), 8.08 (d, 1H), 8.04 (d, 1H), 7.66 (d, 1H), 7.25 (s, 1H), 7.14 (t, 1H), 6.76 (dd, 1H), 6.71 (dd, 1H), 6.62 (d, 1H), 5.41–5.34 (m, 1H), 3.75–3.66 (m, 4H), 3.59 (t, 2H), 3.36–3.26 (m, 5H), 2.95–2.88 (m, 2H), 2.73–2.64 (m, 4H), 2.56–2.52 (m, 6H), 2.27 (d, 2H), 1.76 (d, 2H), 1.66–1.60 (m, 1H), 1.55 (d, 3H), 1.37 (s, 9H);

[0376] Preparation of Example 18:

[0377]

[0378] First step: Synthesis of Compound 18C

[0379] Using Compound 18A as the starting material, Compound 18C was synthesized according to the method of Patent (WO 2021 / 053495).

[0380] LCMS m / z = 307.0 305.0 [M+H] +

[0381] Second step: Synthesis of Compound 18D

[0382] Compound 18C (3.05 g, 10 mmol), 4-(dimethoxymethyl)piperidine (4.8 g, 30 mmol), palladium acetate (225 mg, 1 mmol), t-BuXPhos (850 mg, 2 mmol), cesium carbonate (9.8 g, 30 mmol) and 25 mL of dioxane were successively added to the reaction flask and reacted at 90 °C overnight. The reaction mixture was directly concentrated and purified by silica gel column chromatography to obtain Intermediate 18D (620 mg, 17%).

[0383] LCMS m / z = 384.3 [M+H] +

[0384] Third step: Synthesis of Compound 18E

[0385] Compound 18C (575 mg, 1.5 mmol) was dissolved in 4 mL of tetrahydrofuran, and then 4 mL of hydrochloric acid (4 M) was added thereto and reacted at room temperature for half an hour. The reaction solution was extracted three times with ethyl acetate, and the obtained organic phase was dried, concentrated, and subjected to silica gel column chromatography to obtain intermediate 18D (420 mg, 83%).

[0386] LCMS m / z = 338.2 [M+H] +

[0387] Step 4: Synthesis of Compound 18

[0388] Compound 18D (34 mg, 0.1 mmol) and 17E (60 mg, 0.1 mmol) were dissolved in 4 mL of dichloromethane, and DIPEA (104 mg, 0.8 mml) was added thereto and stirred for half an hour. Then, sodium triacetoxyborohydride (64 mg, 0.3 mmol) was added and the reaction was carried out overnight. The reaction solution was directly concentrated and subjected to preparative TLC to obtain the crude product of compound 18, and the crude product was purified by preparative HPLC. (Instrument and preparative column: SHIMADZU LC-20AP preparative liquid phase was used, and the preparative column model was Phenomenex C18, 5 μm, inner diameter * length = 19 mm * 150 mm), mobile phase system: acetonitrile / water (containing 10 mmol ammonium bicarbonate). Gradient elution method: acetonitrile was eluted from 32% to 62% with a gradient of 62% (elution time 15 min), and the prepared solution was freeze-dried to obtain pure compound 18 (32 mg, 35%).

[0389] LCMS m / z = 913.3 [M+H] +

[0390] 1 H NMR (400 MHz, DMSO-d6) δ 12.53 (s, 1H), 10.46 (s, 1H), 9.91 (d, 1H), 8.78 (d, 1H), 8.75 (s, 1H), 8.15 (dd, 1H), 8.08 (d, 1H), 8.04 (s, 1H), 7.66 (d, 1H), 7.24 (s, 1H), 6.70–6.60 (m, 3H), 5.42–5.34 (m, 1H), 3.79–3.68 (m, 4H), 3.58 (t, 2H), 3.34–3.24 (m, 5H) 2.92 (s, 3H), 2.74 (t, 2H), 2.67 (t, 3H), 2.56–2.52 (m, 6H), 2.26 (d, 2H), 1.75 (d, 2H), 1.68–1.60 (m, 1H), 1.55 (d, 3H), 1.37 (s, 9H).

[0391] Example 19: Preparation of Compound 19

[0392]

[0393] Step 1: Preparation of 19C

[0394] Dissolve 19A (2.5 g, 7.91 mmol), 19B (2.90 g, 7.91 mmol), cesium fluoride (3.00 g, 19.78 mmol), and Pd(dtbpf)Cl2 (0.51 g, 0.79 mmol) in 20 mL of 1,4 - dioxane. Replace the atmosphere with nitrogen three times, and then heat the mixture to 50 °C under a nitrogen atmosphere and react for 1.5 hours. Cool the reaction solution to room temperature, add water (20 mL), extract twice with ethyl acetate (20 mL × 2), combine the organic phases, wash the combined organic phases twice with water (20 mL × 2) and once with a saturated aqueous NaCl solution (20 mL × 1), dry the organic phase over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 19C (1.5 g, yield 46.59%).

[0395] LCMS m / z = 408.1 [M + H] +

[0396] Step 2: Preparation of 19D

[0397] Dissolve 19C (1.5 g, 3.68 mmol) in methanol, add Pd / C (0.15 g), and react under a hydrogen atmosphere for 2 hours. Filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 19D (1.2 g, yield 80.0%).

[0398] LCMS m / z = 410.1 [M + H] +

[0399] Step 3: Preparation of 19E

[0400] Dissolve 19D (1.2 g, 2.94 mmol) in dichloromethane (10 mL), add trifluoroacetic acid (1.95 g, 17.08 mmol), and react at room temperature for 1 hour. Concentrate the reaction mixture under reduced pressure to remove the reaction solvent to obtain 19E (0.8 g, yield 88.24%).

[0401] LCMS m / z = 310.1 [M + H] +

[0402] Step 4: Synthesis of Compound 19G

[0403] Compound 19F (10.0 g, 44.83 mmol), 4-hydroxymethylpiperidine (6.2 g, 53.80 mmol) and potassium carbonate (18.59 g, 134.49 mmol) were dissolved in 100 mL of acetonitrile and reacted overnight at 90 °C. After concentration, the residue was purified by column chromatography to obtain Compound 19G (12.1 g, 84.82%).

[0404] Ms m / z (ESI): 319.2 [M+H] +

[0405] Step 5: Synthesis of Compound 19H

[0406] Compound 19G (4.5 g, 14.30 mmol), Pd(dppf)Cl2 (0.97 g, 1.19 mmol), Intermediate 19G-1 (5.0 g, 11.92 mmol) and potassium carbonate (4.94 g, 35.76 mmol) were dissolved in 60 mL of 1,4-dioxane and 6 mL of water and reacted at 80 °C for 12 h. After concentration, the residue was purified by column chromatography to obtain Compound 19H (3.4 g, 58.94%).

[0407] Ms m / z (ESI): 484.1 [M+H] +

[0408] Step 6: Synthesis of Compound 19I

[0409] Compound 19H (2.7 g, 5.58 mmol), Pd(dppf)Cl2 (0.19 g, 0.23 mmol), Intermediate 19H-1 (1.75 g, 6.70 mmol) and potassium carbonate (2.7 g, 19.53 mmol) were dissolved in 30 mL of 1,4-dioxane and 3 mL of water and reacted at 100 °C for 2 h. After concentration, the residue was purified by column chromatography to obtain Compound 19I (1.9 g, 58.43%).

[0410] Ms m / z (ESI): 582.2 [M+H] +

[0411] Step 7: Synthesis of Compound 19J

[0412] Dissolve compound intermediate 19I-1 (699 mg, 4.11 mmol) in 10 mL of DCM. Slowly add 1-chloro-N,N,2-trimethylpropenylamine (550 mg, 4.11 mmol) at 0 °C. Warm up to room temperature and stir for 30 minutes. Slowly add the above liquid to a dichloromethane mixed solution of 19I (0.9 g, 1.58 mmol) and triethylamine (420 mg, 4.11 mmol) at room temperature and react for 2 hours. Extract the reaction with ethyl acetate, wash with saturated sodium chloride, dry over anhydrous sodium sulfate, and purify by column chromatography to obtain compound 19J (600 mg, 59.60%).

[0413] Ms m / z(ESI): 735.3[M+H] +

[0414] Step 8: Synthesis of compound 19K

[0415] Dissolve compound 19J (500 mg, 0.68 mmol) in 15 mL of a methanol solution of 4% sodium hydroxide. Stir at room temperature for 2 hours. Extract the reaction with ethyl acetate, wash with saturated sodium chloride, dry over anhydrous sodium sulfate, and purify by column chromatography to obtain compound 19K (320 mg, 65.62%).

[0416] Step 9: Synthesis of compound 19L

[0417] Dissolve compound 19K (320 mg, 0.54 mmol) in 10 mL of DMSO solution. Add IBX (760 mg, 2.7 mmol) under nitrogen protection at room temperature and stir for 12 hours. Extract the reaction with ethyl acetate, wash with saturated sodium chloride, dry over anhydrous sodium sulfate, and purify by column chromatography to obtain compound 19L (285 mg, 89.05%)

[0418] Step 10: Preparation of compound 19

[0419] 19 L (52 mg, 0.17 mmol) was added to a 50 mL single-necked flask, and 1,2-dichloroethane (5 mL), methanol (5 mL), intermediate 19F (100 mg, 0.17 mmol), and 0.04 mL of acetic acid were added. After stirring at room temperature for 4 h, sodium triacetoxyborohydride (43 mg, 0.2 mmol) was added, and the reaction was carried out at room temperature for 2 h. The reaction system was concentrated under reduced pressure, water (50 mL) was added, and extraction was carried out with a mixed solvent of dichloromethane and methanol (v / v) = 10:1 (20 mL × 3). The organic phase was washed with saturated sodium chloride aqueous solution (20 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound 19 (20 mg, 13.23%). Chiral resolution gave compound 19-P1 (7 mg, preparative retention time: 1.903 min) and compound 19-P2 (7 mg, preparative retention time: 4.530 min); Preparation instrument: SHIMADZU LC-20AP; Preparation column model: Chiral IA column; Mobile phase: A was n-hexane; B was an ethanol and acetonitrile solvent with 0.1% isopropylamine; Elution conditions: Isocratic elution with 80% B in A solution; Flow rate: 60 mL / min; Column temperature: Room temperature; Detection wavelength: 220 nm. When 19-1 is in the S configuration, then 19-2 is in the R configuration; conversely, when 19-1 is in the R configuration, then 19-2 is in the S configuration.

[0420] Compound 19-P1:

[0421] 1 H NMR (400 MHz, CD3OD) δ 8.91 (s, 1H), 8.68 (d, 1H), 8.17 (dd, 1H), 7.98–7.92 (m, 1H), 7.92–7.88 (m, 1H), 7.76 (d, 1H), 7.45–7.36 (m, 4H), 7.32 (s, 1H), 7.07 (d, 1H), 5.56–5.47 (m, 1H), 4.55–4.45 (m, 2H), 4.00–3.85 (m, 3H), 3.67–3.59 (m, 1H), 3.46–3.33 (m, 2H), 3.17–3.00 (m, 5H), 2.86–2.79 (m, 2H), 2.65 (s, 3H), 2.56–2.41 (m, 1H), 2.31–2.14 (m, 2H), 2.02–1.91 (m, 2H), 1.64 (d, 3H), 1.49–1.34 (s, 11H).

[0422] LCMS m / z = 886.6 [M+H] +

[0423] Compound 19-P1:

[0424] 1 1H NMR (400 MHz, CD3OD) δ 8.90 (s, 1H), 8.68 (d, 1H), 8.16 (dd, 1H), 7.97–7.92 (m, 1H), 7.92–7.88 (m, 1H), 7.76 (d, 1H), 7.45–7.36 (m, 4H), 7.31 (s, 1H), 7.07 (d, 1H), 5.55–5.47 (m, 1H), 4.55–4.44 (m, 2H), 3.98–3.85 (m, 3H), 3.65–3.56 (m, 1H), 3.46–3.33 (m, 2H), 3.16–3.02 (m, 5H), 2.85–2.77 (m, 2H), 2.55–2.40 (m, 3H), 2.29–2.13 (m, 1H), 2.13 (s, 2H), 2.02–1.91 (m, 2H), 1.64 (d, 3H), 1.47–1.32 (m, 11H).

[0425] LCMS m / z = 886.6 [M+H] +

[0426]

[0427] Biological Test Example

[0428] 1. Cell Proliferation Inhibition Experiment

[0429] When SU-DHL-4 cells grow to 5×10 6 cells / mL and Mino cells grow to 2×10 6 cells / mL, the cells are plated. Use a pipette to mix the cells in the culture dish / flask, transfer them to a 15 mL (50 mL) sterile centrifuge tube, centrifuge at 1500 rpm for 3 minutes, take out after centrifugation, and discard the supernatant. Add 5 mL of medium to the centrifuge tube to resuspend the cells and count. According to the counting results, dilute SU-DHL-4 cells to 20,000 cells / 90 μL and Mino cells to 5000 cells / 90 μL, and use a multi-channel pipette to plate the cells, 90 μL per well. Pay attention to mixing the cells in the sample addition slot while plating, and label the cell information on the 96-well plate.

[0430] SU-DHL-4 cells: P13I and the test compound stock solution at 10 mM, starting dosing concentration at 10,000 nM, diluted 9-fold in 3-fold increments. Compound concentrations: 10,000, 3333.33, 1111.11, 370.37, 123.46, 41.15, 13.72, 4.57, 1.52 nM. Dilution method: 5 μL of the compound stock solution + 495 μL of culture medium in the first well, and 80 μL of culture medium containing 1% DMSO + 40 μL of the dilution from the previous well in wells 2 - 9.

[0431] Mino cells: P13I and the test compound stock solution at 10 mM, starting dosing concentration at 10,000 nM, diluted 6-fold in 5-fold increments. Dosing concentrations: 10,000, 2000, 400, 80, 16, 3.2 nM. Dilution method: 5 μL of the compound stock solution + 495 μL of culture medium in the first well, and 80 μL of culture medium containing 1% DMSO + 20 μL of the dilution from the previous well in wells 2 - 6.

[0432] Add 10 μL / well of the compound to the 96-well plate seeded with cells. Set 3 replicates for each concentration, and the last column is the DMSO vehicle control group. Continue culturing at 37°C and 5% CO2 for 72 hours.

[0433] After 72 hours, add 100 μL of the detection reagent (Cell Viability Assay, Promega, G7573) to each well, mix for 2 minutes, incubate at room temperature for 10 minutes, and measure the chemiluminescence readings using a microplate reader.

[0434] Cell proliferation inhibition assay (IC 50 ): Using origin9.2 software, calculate the IC 50 value of the compound inhibiting cell proliferation.

[0435] Conclusion: The compounds synthesized using the technology of the present invention, such as the compounds in the examples, have good inhibitory effects on the proliferation of Mino cells (mantle cell lymphoma cells).

[0436] 2. TMD-8 cell proliferation inhibition activity test:

[0437] TMD-8 is a human lymphoma cell line that expresses the BTK protein and is used to evaluate the efficacy of the compound. The culture medium for TMD-8 cells is RPMI-1640 + 10% FBS + 1% penicillin-streptomycin, and they are cultured in an incubator at 37°C and 5% CO2. Seed the 96-well culture plate (Biosharp, BS-MP-96W) with 3000 cells / well. After seeding, add compounds at different concentrations with a final volume of 100 μL / well, and culture in an incubator at 37°C and 5% CO2 for 72 hours. After the culture is completed, add 50 μL of the detection solution ( Promega, G7573), mix for 2 minutes, incubate at room temperature for 10 minutes, and detect the chemiluminescence reading using a microplate reader (Molecular Devices, SpectraMax Paradigm). Calculate the inhibition rate of the compound on cell proliferation according to Equation (1), where RLU compound is the reading value of the compound well, RLU control is the reading value of the DMSO control well, and RLU blank is the reading value of the cell-free well. Analyze the data using Graphpad Prism 8.0 software, fit a four-parameter equation to generate a concentration-response curve, and calculate the IC 50 value of the compound inhibiting cell proliferation.

[0438] Inh% = 100% - (RLU compound - RLU blank ) / (RLU control - RLU blank ) * 100% Equation (1)

[0439] Conclusion: The compounds synthesized using the technology of the present invention, such as the example compounds, have a good inhibitory effect on the proliferation of TMD-8 cells. 3. Detection of BTK degradation in Mino cells

[0440] Mino is a human mantle cell lymphoma cell line, purchased from ATCC, and the culture conditions are: RPMI-1640 + 15% FBS + 1% double antibody, cultured in an incubator at 37℃ and 5% CO2. Plate the cells in a 6-well plate at 5×10 5 cells / well. After plating, add the compound at a concentration of 10 nM or 50 nM, and culture in an incubator at 37℃ and 5% CO2 for 6 hours. After the culture is completed, collect the cells, add RIPA lysis buffer (beyotime, Cat.P0013B), lyse on ice for 15 minutes, centrifuge at 12000 rpm at 4℃ for 10 minutes, collect the supernatant protein sample, perform protein quantification using a BCA kit (Beyotime, Cat.P0009), dilute the protein to 0.2 mg / mL, and detect the expression of BTK (CST, Cat.8547S) and the internal reference β-Actin (CST, Cat.3700S) using an automatic Western blot quantitative analyzer (Proteinsimple). Use the "Compass for SW" software to calculate the relative peak area of BTK when the internal reference area is 10000. Calculate the degradation rate of BTK at a drug concentration of 10 nM or 50 nM according to Equation (1), where BTK treat is the relative peak area of the drug administration group, and BTK solvent is the relative peak area of the solvent control group.

[0441] BTK Deg. % = 100% - (BTK treat / BTK solvent × 100%) Equation 2

[0442] BTK degradation rate in Mino cells

[0443] Compound Number Degradation Rate at 10 nM Compound Number Degradation Rate at 10 nM Compound 1 A Trifluoroacetate Salt of Compound 11 A Compound 2 A Compound 12 A Compound 3 A Compound 13 A Compound 7 A Compound 14 A Compound 8 A Compound 15 A Compound 9 A Compound 16 A Trifluoroacetate Salt of Compound 10 A Compound 17 A

[0444] A > 75%

[0445] Conclusion: The compounds synthesized using the technology of the present invention, such as the example compounds, have good degradation activity against BTK protein in Mino cells.

[0446] 4. Mouse Pharmacokinetics Test

[0447] 1.1 Test animals: Male ICR mice, 20 - 25 g, 6 mice / compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0448] 1.2 Test design: On the day of the test, the mice were randomly grouped according to body weight. They were fasted but given water ad libitum for 12 - 14 h one day before dosing, and fed 4 h after dosing.

[0449] Dosing Information

[0450]

[0451] Note: Intravenous dosing vehicle: 5% DMA + 5% Solutol + 90% Saline;

[0452] Gavage dosing vehicle: 5% DMSO + 5% Solutol + 10% PEG400 + 80% (20% SBE - CD)

[0453] (DMA: Dimethylacetamide; DMSO: Dimethyl sulfoxide; Solutol: Polyethylene glycol - 15 - hydroxystearate; Saline: Normal saline; PEG400: Polyethylene glycol 400; SBE - β - CD: Sulfobutyl - β - cyclodextrin;)

[0454] Blood (0.06 mL) was collected from the orbital sinus under isoflurane anesthesia before and after dosing, placed in an EDTAK2 centrifuge tube, centrifuged at 5000 rpm at 4 °C for 10 min, and plasma was collected. The blood sampling time points for both the intravenous group and the gavage group were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 24 h. Before analysis and detection, all samples were stored at -80 °C, and the samples were quantitatively analyzed by LC - MS / MS.

[0455] Pharmacokinetic parameters of the test compound in mouse plasma

[0456] Test Compound CL (mL / min / kg) (i.v.) <![CDATA[AUC 0-t (hr*ng / mL)(i.g.)]]> <![CDATA[T 1 / 2 (h)(i.g.)]]> Compound 6 0.432 132056 8.84 Trifluoroacetate Salt of Compound 11 0.144 223791 10.0 Control Compound A 0.967 46631 6.06

[0457] Conclusion: The compounds of the present invention, such as compound 6 and 11, have good oral absorption properties in mice.

[0458] 5. Rat Pharmacokinetics Test

[0459] Test animals: Male SD rats, about 220 g, 6 - 8 weeks old, 6 rats / compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0460] Test design: On the day of the test, 6 SD rats / compound were randomly grouped by body weight. Fast for 12 - 14 h without water deprivation 1 day before dosing, and give food 4 h after dosing.

[0461] Drug Administration Information

[0462]

[0463] Note: Solvent for intravenous administration: 5% DMA + 5% Solutol + 90% Saline;

[0464] Solvent for gavage administration: 5% DMSO + 5% Solutol + 10% PEG400 + 80% (20% SBE - CD)

[0465] (DMA: Dimethylacetamide; DMSO: Dimethyl sulfoxide; Solutol: Polyethylene glycol - 15 - hydroxystearate; Saline: Normal saline; PEG400: Polyethylene glycol 400; SBE - β - CD: Sulfobutyl - β - cyclodextrin; )

[0466] Collect 0.10 mL of blood from the orbital cavity under isoflurane anesthesia before and after dosing, place it in an EDTAK2 centrifuge tube, centrifuge at 5000 rpm at 4°C for 10 min, and collect the plasma. The blood sampling time points for both the intravenous group and the gavage group are: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 24 h. Before analysis and detection, all samples are stored at - 80°C, and LC - MS / MS is used for quantitative analysis of the samples.

[0467] Test the pharmacokinetic parameters of the compounds in rat plasma

[0468] Test Compound CL (mL / min / kg) (i.v.) <![CDATA[AUC 0-t (hr*ng / mL)(i.g.)]]> <![CDATA[T 1 / 2 (h)(i.g.)]]> Compound 6 0.113 578750 19.1 Compound 11 0.199 145848 20.2 Control Compound A 0.906 66226 11.6

[0469] Conclusion: The compounds of the present invention, such as compound 6 and 11, have good oral absorption properties in rats.

[0470] 6. Human CD34+ Hematopoietic Stem Cell Proliferation Inhibition Experiment

[0471] Human CD34+ hematopoietic stem cells (TPCS, Cat. hmPB34-P-2CW) are stem cells that are positive for CD34 expression and are obtained by immunomagnetic bead sorting from human PBMCs. The culture conditions are as follows: DPBS (Gibco, Cat. 14190-144) + StemSpan SFEMII (STEMCELL, Cat. 9655) + 1X StemSpan CD34+ Expansion Supplement (STEMCELL, Cat. 2691). First, add 40 nL of DMSO, the positive reference talazoparib, or the test compound to a 384-well plate (Corning, Cat. 3764) respectively, and then add the cell suspension, 400 cells / 40 μl / well, so that the final concentration in each well is 0.1% DMSO, 3 μM talazoparib, or different concentrations of the compound. Centrifuge at 1000 rpm for 1 minute at room temperature, and then culture in an incubator at 37 °C and 5% CO2 for 7 days. After the culture is completed, directly add 20 μL of CellTiter-Glo Reagent (Promega, Cat. G7573) to each well, centrifuge at 1000 rpm for 1 minute at room temperature, and then incubate in the dark for 20 minutes. After the incubation is completed, use an Envision multimode microplate reader (PerkinElmer, Cat. 2104) to read and record the chemiluminescence signal CFU. Calculate the proliferation inhibition rate of the compound at different concentrations on the cells according to formula (1), CFU high control is the average signal value of the DMSO group, CFU low control is the average signal value of the talazoparib group, CFU compound is the average signal value of the compound group. The data processed according to formula (1) is used with XLfit or GraphPad Prism software, and four parameters are used for curve fitting to calculate the concentration IC of the compound when the inhibition rate is 50% 50 value.

[0472] Inhibiton%=(CFU high control -CFU compound ) / (CFU high control -CFU low control )×100%(Formula 1)

[0473] Conclusion: The compounds of the present invention, such as the compounds of the examples, have weak inhibition on the proliferation of human CD34+ hematopoietic stem cells.

[0474] 7. hERG Potassium Channel Function Test

[0475] Experimental Platform: Electrophysiological Manual Patch Clamp System

[0476] Cell Line: Chinese Hamster Ovary (CHO) cell line stably expressing hERG potassium channel

[0477] Experimental Method: For CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channel, the hERG potassium channel current was recorded using the whole-cell patch clamp technique at room temperature. The glass microelectrode was pulled from a glass electrode blank (BF150-86-10, Sutter) by a puller. The tip resistance after perfusion with the electrode internal solution was about 2 - 5 MΩ. The glass microelectrode was inserted into the amplifier probe and then connected to the patch clamp amplifier. The clamping voltage and data recording were controlled and recorded by pClamp 10 software through a computer. The sampling frequency was 10 kHz and the filtering frequency was 2 kHz. After obtaining the whole-cell recording, the cell was clamped at -80 mV. The step voltage to induce the hERG potassium current (IhERG) was a 2-s depolarizing voltage from -80 mV to +20 mV, then repolarized to -50 mV, and returned to -80 mV after 1 s. This voltage stimulation was given every 10 s. After determining that the hERG potassium current was stable (at least 1 minute), the drug administration process was started. Each test concentration of the compound was given for at least 1 minute, and at least 2 cells were tested for each concentration (n≥2).

[0478] Data Processing: Data analysis and processing were performed using pClamp 10, GraphPad Prism 5, and Excel software. The inhibition degree of different compound concentrations on the hERG potassium current (the peak value of the hERG tail current induced at -50 mV) was calculated using the following formula:

[0479] Inhibition%=[1–(I / Io)]×100%

[0480] Where, Inhibition% represents the inhibition percentage of the compound on the hERG potassium current, and I and Io represent the amplitudes of the hERG potassium current after and before drug administration, respectively.

[0481] Compound IC 50 Calculated by fitting using the following equation with GraphPad Prism 5 software:

[0482] Y=Bottom+(Top - Bottom) / (1+10^((LogIC 50 -X)×HillSlope))

[0483] Among them, X is the Log value of the test sample detection concentration, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages respectively.

[0484] Conclusion: The compounds of the present invention, such as the compounds of the examples, have no obvious hERG inhibitory activity.

[0485] 8. Beagle dog pharmacokinetics test

[0486] Test animals: Male Beagle dogs, about 8 - 11 kg, 5 - 6 per compound, purchased from Beijing Mas Biotechnology Co., Ltd.

[0487] Test method: On the test day, 5 - 6 Beagle dogs per compound were randomly grouped by body weight. They were fasted but allowed to drink water for 12 - 14 h one day before dosing, and fed 4 h after dosing.

[0488] Dosing information

[0489]

[0490] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline;

[0491] Gavage administration solvent: 5% DMSO + 5% Solutol + 10% PEG400 + 80% (20% SBE - CD)

[0492] (DMA: Dimethylacetamide; DMSO: Dimethyl sulfoxide; Solutol: Polyethylene glycol - 15 - hydroxystearate; Saline: Normal saline; PEG400: Polyethylene glycol 400; SBE - β - CD: Sulfobutyl - β - cyclodextrin; )

[0493] Blood samples of 1 ml were taken from the jugular vein or limb veins before and after dosing and placed in EDTAK2 centrifuge tubes. Centrifuged at 5000 rpm at 4°C for 10 min to collect plasma. The blood sampling time points for both the intravenous and gavage groups in groups G1 and G2 were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24 h, 48, 72 h. The blood sampling time points for both the intravenous and gavage groups in groups G3 and G4 were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24 h. Before analysis and detection, all samples were stored at - 80°C, and the samples were quantitatively analyzed by LC - MS / MS.

[0494] Conclusion: The compounds of the present invention, such as the compounds of the examples, have good oral absorption performance in Beagle dogs.

[0495] 9. Monkey pharmacokinetics test

[0496] Test animals: Male cynomolgus monkeys, 3 - 5 kg, 3 - 6 years old, 4 - 6 monkeys per compound. Purchased from Suzhou Xishan Biotechnology Co., Ltd.

[0497] Test method: On the test day, 4 - 6 monkeys per compound were randomly grouped by body weight. One day before dosing, they were fasted for 14 - 18 h with water available, and fed 4 h after dosing.

[0498] Dosing information

[0499]

[0500] Note: Solvent for intravenous administration: 5% DMA + 5% Solutol + 90% Saline;

[0501] Solvent for gavage administration: 5% DMSO + 5% Solutol + 10% PEG400 + 80% (20% SBE - CD)

[0502] (DMA: Dimethylacetamide; DMSO: Dimethyl sulfoxide; Solutol: Polyethylene glycol - 15 - hydroxystearate; Saline: Normal saline; PEG400: Polyethylene glycol 400; SBE - β - CD: Sulfobutyl - β - cyclodextrin; )

[0503] 1.0 mL of blood was collected from the limb veins before and after dosing and placed in an EDTAK2 centrifuge tube. Centrifuged at 5000 rpm at 4 °C for 10 min to collect plasma. The blood sampling time points for both the intravenous group and the gavage group were: 0, 5 min, 15 min, 30 min, 1, 2, 4, 6, 8, 10, 12, 24 h. Before analysis and detection, all samples were stored at - 80 °C, and LC - MS / MS was used for quantitative analysis of the samples.

[0504] Conclusion: The compounds of the present invention, such as the compounds of the examples, have good oral absorption performance in monkeys.

[0505] 10. Liver microsome stability test

[0506] In this experiment, liver microsomes of five species including humans, dogs, rats, and mice were used as an in vitro model to evaluate the metabolic stability of the test substance.

[0507] At 37 °C, 1 μM of the test substance was incubated with microsomal protein and coenzyme NADPH. At a certain reaction time (5, 10, 20, 30, 60 min), ice - cold acetonitrile containing internal standard was added to terminate the reaction. The concentration of the test substance in the sample was detected by LC - MS / MS method, and the T was obtained from the ln value of the remaining rate of the drug in the incubation system and the incubation time 1 / 2 , and the intrinsic clearance rate of liver microsomes CL int(mic) and the intrinsic clearance rate of the liver CL int(Liver) .

[0508] Test results:

[0509]

[0510] Conclusion: The compound of the present invention has good stability in mouse liver microsomes. Compared with the control compound A, it has a longer half-life and slower clearance.

Claims

1. A compound or a stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, the compound being selected from the compounds represented by general formula (I), wherein: B1 is selected from a 5-6 membered heterocyclic group; B4 is selected from phenyl, 5-6 membered heteroaryl; X is selected from N or CH; L1, L2 or L3 are each independently selected from a bond, C 1-8 Alkylene, C 2-8 Alkenylene, C 2-8 Alkynylidene, O, NR L NR L CO, CO, C≡C, -C(=O)CH2-, wherein the alkylene, alkenylene, alkynylene is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, COOH, CN, NH2, =O, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 substituted by a substituent of a 4- to 6-membered carbocyclic group or a 4- to 6-membered heterocyclic group; R L Select from H or C 1-6 alkyl; Cy1 and Cy2 are each independently selected from a bond, a 3-7 membered monocyclic heterocyclic group, a 4-12 membered cyclic heterocyclic group, a 5-12 membered spirocyclic heterocyclic group, a 5-12 membered bridged heterocyclic group, a C 3-7 1 to 4 R Cy replaced by; R Cy Each independently selected from deuterium, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 4-6 membered carbocyclic group, 4-6 membered heterocyclic group, -OC 3-7 The alkyl and alkoxy, heterocyclic group, and carbocyclic group are optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, =O, NH2, CN, CONH2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 substituted by a substituent of a 4- to 6-membered carbocyclic group or a 4- to 6-membered heterocyclic group; R b1 , R b2 , R b3 , R b4 , R k1 , R k2 , R bL Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 4-6 membered carbocyclic group, 4-6 membered heterocyclic group, -OC 3-7 The alkyl and alkoxy, heterocyclic group, and carbocyclic group are optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, =O, NH2, CN, CONH2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 substituted by a substituent of a 4- to 6-membered carbocyclic group or a 4- to 6-membered heterocyclic group; b1 is each independently selected from 0, 1, 2, 3, 4, 5 or 6; b2, b4 are each independently selected from 0, 1, 2, 3 or 4; b3 are each independently selected from 0, 1 or 2; p1 or p2 are each independently selected from 0, 1, 2, 3 or 4; Provided that, when Cy2 is selected from an unsubstituted 3-7 membered monocyclic heterocyclic group or an unsubstituted C 3-7 When the carbonyl group is a monocyclic carbocyclic group, Cy1 is selected from a 4-12-membered cyclic heterocyclic group, a 5-12-membered spirocyclic heterocyclic group, a 4-12-membered cyclic carbocyclic group, a 5-12-membered spirocyclic carbocyclic group, and the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R Cy replaced.

2. The compound according to claim 1 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: B1 is selected from 5-6 membered heteroaryl; L1, L2 or L3 are each independently selected from a bond, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, O, NR L NR L CO, CO, -C(=O)CH2-, wherein the alkylene, alkenylene, alkynylene is optionally substituted by 1 to 4 deuterium, 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, C 1-4 Alkoxy, C 3-6 substituted by a substituent of a 4- to 6-membered carbocyclic group or a 4- to 6-membered heterocyclic group; R L Select from H or C 1-4 alkyl; Cy1 and Cy2 are each independently selected from a 3-6 membered monocyclic heterocyclic group, a 4-10 membered cyclic heterocyclic group, a 5-11 membered spirocyclic heterocyclic group, a 5-10 membered bridged heterocyclic group, a C 3-6 4-10 membered monocyclic carbocyclic group, 4-10 membered cyclic carbocyclic group, 5-11 membered spirocyclic carbocyclic group, 5-10 membered bridged carbocyclic group, 5-10 membered heteroaryl group or 6-10 membered aryl group, wherein the aryl group, heteroaryl group, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R Cy replaced by; R Cy Each independently selected from deuterium, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 4-6 membered carbocyclic group, 4-6 membered heterocyclic group, -OC 3-6 The alkyl and alkoxy, heterocyclic group, and carbocyclic group are optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, =O, NH2, CN, CONH2, COOH, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-7 substituted by a substituent of a 4- to 6-membered carbocyclic group or a 4- to 6-membered heterocyclic group; R b1 , R b2 , R b3 , R b4 , R k1 , R k2 , R bL Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 4-6 membered carbocyclic group, 4-6 membered heterocyclic group, -OC 3-6 The alkyl and alkoxy, heterocyclic group, and carbocyclic group are optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, =O, NH2, CN, CONH2, COOH, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-7 The group may be substituted by a substituent of a 4- to 6-membered carbocyclic group or a 4- to 6-membered heterocyclic group.

3. The compound according to claim 2 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: L1, L2 or L3 are each independently selected from a bond, C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylidene, O, NR L NR L CO, CO, -C(=O)CH2-, wherein the alkylene, alkenylene, alkynylene is optionally substituted by 1 to 4 deuterium, 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, C 1-4 Alkoxy, C 3-6 substituted by a substituent of a 4- to 6-membered carbocyclic group or a 4- to 6-membered heterocyclic group; R L is selected from H, methyl or ethyl; Cy1 and Cy2 are each independently selected from one of the following substituted or unsubstituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, phenyl, cyclopropyl-cyclopropyl, cyclopropyl-cyclobutyl, cyclopropyl-cyclopentyl, cyclopropyl-cyclohexyl, cyclobutyl-cyclobutyl, cyclobutyl-cyclopentyl, cyclobutyl-cyclohexyl, cyclopentyl-cyclopentyl, cyclopentyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclohexyl-cyclopentyl, cyclopentyl-cyclopentyl, cyclopentyl-cyclohexyl, cyclohex ...hexyl, cyclohexyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclohex cyclohexyl, cyclobutylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylazetidinyl, cyclopropylpyrrolidinyl, cyclopropylpiperidinyl, cyclobutylazetidinyl, cyclobutylpyrrolidinyl, cyclobutylpiperidinyl, cyclopentylazetidinyl, cyclopentyl ...propylazetidinyl, cyclopentylspirocyclohexyl, cyclopropylazetidinyl, cyclopropylpyrrolidinyl, cyclobutylpiperidinyl, cyclopentylazetidinyl, cyclopentylspirocyclohexyl, cyclopropylazetidinyl, cyclopropylpyrrolidinyl, cyclobutylpiperidinyl, cyclopentylazetidinyl, cyclopentylspirocyclohexyl, cyclopropylazetidinyl, cyclopropylpyrrolidinyl, cyclopropylpiperidinyl, cyclopropylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclopropyl pyrrolidinyl, cyclopentylpiperidinyl, cyclohexylazetidinyl, cyclohexylpyrrolidinyl, cyclohexylpiperidinyl, azetidinylazetidinyl, azetidinylpyrrolidinyl, azetidinylpiperidinyl, pyrrolidinylazetidinyl, pyrrolidinylpyrrolidinyl, pyrrolidinylpiperidinyl, piperidinylazetidinyl, piperidinylpyrrolidinyl, piperidinylpiperidinyl, cyclobutylspiroazetidinyl, cyclobutylspiropyrrolidinyl, cyclo butylspiropiperidinyl, cyclopentylspiroazetidinyl, cyclopentylspiropyrrolidinyl, cyclopentylspiropiperidinyl, cyclohexylspiroazetidinyl, cyclohexylspiropyrrolidinyl, cyclohexylspiropiperidinyl, azetidinylspiroazetidinyl, azetidinylspiropyrrolidinyl, azetidinylspiropiperidinyl, pyrrolidinylspiroazetidinyl, pyrrolidinylspiropyrrolidinyl, pyrrolidinylspiropiperidinyl, piperidinylspiroazetidinyl, piperidinylspiropyrrolidinyl, piperidinylspiropiperidinyl, When substituted, it is optionally substituted with 1 to 4 R Cy replaced by; R Cy each independently selected from deuterium, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, phenyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, pyridinyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, -O-phenyl, wherein the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, phenyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, pyridinyl is optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, =O, NH2, CN, CONH2, COOH, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-7 The group may be substituted by a substituent of a 4- to 6-membered carbocyclic group or a 4- to 6-membered heterocyclic group.

4. The compound according to claim 3 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: B1 is selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, furanyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl; B4 is selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, furanyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl; L1, L2 or L3 are each independently selected from a bond, O, NH, methylene, ethylene, vinylene, ethynylene, wherein the methylene, ethylene, vinylene, ethynylene are optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, NH2, COOH, CN, =O, 1 to 4 selected from deuterium, 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, C 1-4 Alkoxy, C 3-6 substituted by a substituent of a 4- to 6-membered carbocyclic group or a 4- to 6-membered heterocyclic group; Cy1 and Cy2 are each independently selected from one of the following substituted or unsubstituted groups: When substituted, it is optionally substituted with 1 to 4 R Cy replaced by; R Cy Each is independently selected from deuterium, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, CF3, CHF2, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, methoxymethyl; R b1 , R b2 , R b3 , R b4 , R k1 , R k2 , R bL each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, phenyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, pyridinyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, -O-phenyl, wherein the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, phenyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, pyridinyl is optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, =O, NH2, CN, CONH2, COOH, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-7 The group may be substituted by a substituent of a 4- to 6-membered carbocyclic group or a 4- to 6-membered heterocyclic group.

5. The compound according to claim 4 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: L1 or L3 is selected from a bond; L2 is selected from -C(=O)CH2-, methylene or ethylene; Cy1 and Cy2 are each independently selected from one of the following substituted or unsubstituted groups: When substituted, it may be optionally substituted with 1 to 4 R Cy replaced by; R Cy Each is independently selected from deuterium, F, Cl, Br, I, OH, NH2, CN, CF3, CHF2, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, methoxymethyl; R b1 , R b2 , R b3 , R b4 , R k1 , R k2 Each is independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, CF3, CHF2, CH2F, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl; R bL Each is independently selected from H, deuterium, and methyl.

6. The compound according to claim 5 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: Selected from B4 is selected from phenyl or pyridyl; Selected from one of the fragments shown in Table A; Selected from 7. The compound according to claim 1 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 E-1, 8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition contains 1 to 1500 mg of a compound according to any one of claims 1 to 7 or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

9. Use of the compound according to any one of claims 1 to 7 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or the pharmaceutical composition according to claim 8 in the preparation of drugs related to the inhibition or degradation of BTK.

10. Use of the compound according to any one of claims 1 to 7 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating tumors or autoimmune diseases.

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