Polycyclic fused-ring BTK degradation agent and use thereof in medicine

Abstract

A polycyclic fused-ring BTK degradation agent and a use thereof in medicine. Specifically, the present invention relates to a compound of general formula (I) or a stereoisomer, tautomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, an intermediate thereof and a preparation method therefor, and a use in BTK-related diseases, such as tumors or autoimmune system diseases, preferably relapsed / refractory B-cell malignancies.

Description

A polycyclic BTK degrader and its application in medicine Technical Field

[0001] The present invention belongs to the field of medicinal chemistry and provides a polycyclic BTK degrader and its application in medicine. It specifically relates to a compound described by general formula (I) or its stereoisomers, tautomers, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and intermediates and preparation methods, as well as its use in BTK-related diseases such as tumors or autoimmune system diseases, preferably relapsed / refractory B-cell malignancies. Background Art

[0002] Bruton's tyrosine kinase (BTK), a member of the Tec family of non-receptor protein tyrosine kinases, is a key regulator of the B-cell antigen receptor (BCR) signaling pathway, distributed throughout the lymphatic, hematopoietic, and hematologic systems. BTK mutations can activate downstream signaling pathways involved in tumor cell proliferation, differentiation, and angiogenesis, leading to X-linked agammaglobulinemia, non-Hodgkin lymphoma (NHL), and numerous B-cell malignancies, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma, and diffuse large B-cell lymphoma. Because BTK is primarily expressed in B cells and myeloid cells, it is a well-targeted and safe target.

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

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

[0005] Summary of the Invention

[0006] 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 tumors or autoimmune diseases, preferably B-cell malignancies, more preferably relapsed / refractory B-cell malignancies.

[0007] The compound of the present invention has good pharmacokinetic properties and bioavailability, oral performance and good safety.

[0008] The present invention provides a compound or a stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein the compound is selected from the compound represented by general formula (I), BLK (I);

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

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

[0011] In certain embodiments, B is selected from

[0012] In certain embodiments, L is selected from Its left side is connected to B and its right side is connected to K;

[0013] In certain embodiments, K is selected from

[0014] In certain embodiments, X1, X2, and X3 are each independently selected from N or CR b3 ;

[0015] In certain embodiments, B1 is absent or selected from C 3-12 Carbocyclic group or 4-12 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R b1 replace;

[0016] In certain embodiments, B1 is absent or selected from C 3-7 Membered monocyclic carbocyclic group, C 5-12 Membered carbonyl ring, C 5-12 spirocarbocyclic group, C 5-12 4-7 membered bridged ring carbocyclic group, 4-7 membered monocyclic heterocyclic group, 4-12 membered cyclic heterocyclic group, 5-12 membered spirocyclic heterocyclic group, 5-12 membered bridged ring heterocyclic group, the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R b1 replace;

[0017] In certain embodiments, B1 is absent or selected from 4-6 membered heterocyclyl, cyclopropyl spiro 5 membered heterocyclyl, cyclobutyl spiro 5 membered heterocyclyl, 5- and 5-membered heterocyclyl, 6- and 5-membered heterocyclyl, wherein the heterocyclyl is optionally substituted by 1 to 4 R b1 replace;

[0018] In certain embodiments, B1 is selected from absent or optionally replaced by 1 to 2 R b1 Substituted groups:

[0019] In certain embodiments, B2 is selected from C 3-12 Carbocyclic group or 4-12 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R b2 replace;

[0020] In certain embodiments, B2 is selected from 4-7 membered monocyclic heterocyclic groups, 4-12 membered cyclic heterocyclic groups, 5-12 membered spirocyclic heterocyclic groups, 5-12 membered bridged heterocyclic groups, and the heterocyclic groups are optionally substituted by 1 to 4 R b2 replace;

[0021] In certain embodiments, B2 is selected from 4-6 membered monocyclic heterocyclic groups, 8-9 membered heterocyclic groups, 7-11 membered spirocyclic heterocyclic groups, 5-8 membered bridged heterocyclic groups, and the heterocyclic groups are optionally substituted by 1 to 4 R b2 replace;

[0022] In certain embodiments, B2 is selected from the group consisting of b2 Substituted groups: Its right side is connected to B;

[0023] In certain embodiments, B4 is selected from phenyl, 5-6 membered heteroaryl, 9-12 membered bicyclic cycloalkyl, Selected from aromatic or non-aromatic rings;

[0024] In certain embodiments, B4 is selected from phenyl, 5-6 membered heteroaryl, Benzo 5-membered heterocyclic group, benzo 6-membered heterocyclic group, benzo 5-membered carbocyclic group, benzo 6-membered carbocyclic group, benzo 7-membered carbocyclic group, benzo 8-membered carbocyclic group, pyrido 5-membered heterocyclic group, pyrido 6-membered heterocyclic group;

[0025] In certain embodiments, B4 is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, furanyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,

[0026] In certain embodiments, K1 is selected from phenyl, 5-6 membered heteroaryl, 9-12 membered bicyclic ring group, Selected from aromatic or non-aromatic rings;

[0027] In certain embodiments, K1 is selected from phenyl, 5-6 membered heteroaryl, Benzo 5-membered heterocyclic group, benzo 6-membered heterocyclic group;

[0028] In certain embodiments, K1 is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, furanyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,

[0029] In certain embodiments, Selected from

[0030] In certain embodiments, W is selected from 5-6 membered heterocyclyl;

[0031] In certain embodiments, Z2 is selected from CH or N;

[0032] In certain embodiments, Z3 is selected from CH or N;

[0033] In certain embodiments, L1 is selected from -Ak1-, -Ak1-Ak2-, -Cy1-, -Cy1-Cy2-, -Cy1-Ak1-, -Ak1-Cy1-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak1-, -Ak1-Cy1-Cy2-, -Cy1-Ak1-Cy2-Ak2-, -Ak1-Cy1-Ak2-Cy2-;

[0034] In certain embodiments, Ak1 and Ak2 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、CONR L , CO, C≡C, the alkylene, alkenylene, alkynylene are optionally substituted by 1 to 4 groups 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 substituted by a substituent of a 4- to 6-membered carbocyclic group or a 4- to 6-membered heterocyclic group;

[0035] In certain embodiments, Ak1 and Ak2 are each independently selected from C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, O, NR L NRL CO、CONR L , CO, wherein the alkylene, alkenylene, and alkynylene groups are optionally substituted by 1 to 4 groups 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 substituted by a substituent of a 4- to 6-membered carbocyclic group or a 4- to 6-membered heterocyclic group;

[0036] In certain embodiments, Ak1 and Ak2 are each independently selected from C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylidene, O, NR L NR L CO, CO, wherein the alkylene, alkenylene, alkynylene is optionally substituted by 1 to 4 groups 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 substituted by a substituent of a 4- to 6-membered carbocyclic group or a 4- to 6-membered heterocyclic group;

[0037] In certain embodiments, Ak1 and Ak2 are each independently selected from methylene, ethylene, vinylene, and ethynylene, wherein the methylene, ethylene, vinylene, and ethynylene are optionally substituted by 1 to 4 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;

[0038] In certain embodiments, 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 a monocyclic carbocyclyl, a 4-12-membered cyclic carbocyclyl, a 5-12-membered spirocyclic carbocyclyl, a 5-12-membered bridged carbocyclyl, a 5-12-membered heteroaryl or a 6-10-membered aryl, wherein the aryl, heteroaryl, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 atoms selected from deuterium, F, Cl, Br, I, OH, COOH, CONH2, CN, NH2, =O, C 1-6 Alkyl, halogen-substituted C1-6 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;

[0039] In certain embodiments, 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 a monocyclic carbocyclyl, a 4-10 membered cyclic carbocyclyl, a 5-11 membered spirocyclic carbocyclyl, a 5-10 membered bridged carbocyclyl, a 5-10 membered heteroaryl or a 6-10 membered aryl, wherein the aryl, heteroaryl, carbocyclyl or heterocyclyl is selected from 1 to 4 deuterium, F, Cl, Br, I, OH, COOH, CONH2, 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;

[0040] In certain embodiments, Cy1 and Cy2 are each independently selected from one of the following groups, which are substituted or unsubstituted: 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 and cyclohexyl, cyclopropyl spirocyclopropyl, cyclopropyl spirocyclobutyl, cyclopropyl spirocyclopentyl, cyclopropyl spirocyclohexyl, cyclobutyl spirocyclobutyl, cyclobutyl spirocyclopentyl, cyclobutyl spirocyclohexyl, cyclopentyl spirocyclopentyl, cyclopentyl spirocyclohexyl, cyclohexyl spirocyclohexyl, cyclopropyl and azetidinyl, cyclopropyl and pyrrolidinyl, cyclopropyl and piperidinyl, cyclobutyl and azetidinyl, cyclobutyl and pyrrolidinyl, cyclobutyl and piperidinyl, cyclopentyl and azetidinyl, Cyclopentylpyrrolidinyl, cyclopentylpiperidinyl, cyclohexylazetidinyl, cyclohexylpyrrolidinyl, cyclohexylpiperidinyl, azetidinylazetidinyl, azetidinylpyrrolidinyl, azetidinylpiperidinyl, pyrrolidinylazetidinyl, pyrrolidinylpyrrolidinyl, pyrrolidinylpiperidinyl, piperidinylazetidinyl, piperidinylpyrrolidinyl, piperidinylpiperidinyl, cyclobutylspiroazetidinyl, cyclobutylspiropyrrolidinyl , cyclobutyl spiropiperidinyl, cyclopentyl spiroazetidinyl, cyclopentyl spiropyrrolidinyl, cyclopentyl spiropiperidinyl, cyclohexyl spiroazetidinyl, cyclohexyl spiropyrrolidinyl, cyclohexyl spiropiperidinyl, azetidinyl spiroazetidinyl, azetidinyl spiropyrrolidinyl, azetidinyl spiropiperidinyl, pyrrolidinyl spiroazetidinyl, pyrrolidinyl spiropyrrolidinyl, pyrrolidinyl spiropiperidinyl, piperidinyl spiroazetidinyl, piperidinyl spiropyrrolidinyl, piperidinyl spiropiperidinyl, When substituted, it is optionally replaced by 1 to 4 atoms selected from deuterium, F, Cl, Br, I, OH, NH2, COOH, CONH2, CN, ═O, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted 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;

[0041] In certain embodiments, Cy1 and Cy2 are each independently selected from one of the following substituted or unsubstituted groups: When substituted, it is optionally replaced by 1 to 4 deuterium, F, Cl, Br, I, OH, ═O, NH 2 , CN, CONH 2 , COOH, C 1-4Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted 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;

[0042] In certain embodiments, R L or R N Each independently selected from H or C 1-6 alkyl;

[0043] In certain embodiments, R L or R N Each independently H or C 1-4 alkyl;

[0044] In certain embodiments, R L or R N Each independently selected from H, methyl or ethyl;

[0045] In certain embodiments, Q is selected from NR q CO、CONR q 、CO、NR q or key;

[0046] In certain embodiments, Q is selected from CONR q NR q CO、NR q or key;

[0047] In certain embodiments, Z1 is selected from N or CR k2 ;

[0048] In certain embodiments, R b1 、R b2 、R b3 、R b4 、R k1 、R k2 、R k3 、R q Each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, ═S, NH 2 , CN, COOH, CONH 2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 -membered carbocyclic group, 4-6 membered heterocyclic group, -OC 3-7 -O-4-6 membered carbocyclic group, -O-4-6 membered heterocyclic group, wherein the alkyl, alkoxy, heterocyclic group, and carbocyclic group are optionally substituted by 1 to 6 groups selected from deuterium, F, Cl, Br, I, OH, =O, NH2, CN, CONH2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C3-7 -membered carbocyclic group, 4-6 membered heterocyclic group, -OC 3-7 -O-4-6 membered heterocyclic group, fluorine-substituted C 3-7 membered carbocyclic group, C 2-6 Alkynyl, fluoro-substituted phenyl substituents;

[0049] In certain embodiments, R b1 、R b2 、R b3 、R b4 、R k1 、R k2 、R k3 、R q Each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, ═S, NH 2 , CN, COOH, CONH 2 , C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 -membered carbocyclic group, 4-6 membered heterocyclic group, -OC 3-6 -O-4-6 membered carbocyclic group, -O-4-6 membered heterocyclic group, wherein the alkyl, alkoxy, heterocyclic group, and carbocyclic group are optionally substituted by 1 to 6 groups 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, -OC 3-7 -O-4-6 membered heterocyclic group, fluorine-substituted C 3-7 membered carbocyclic group, C 2-6 Alkynyl, fluoro-substituted phenyl substituents;

[0050] In certain embodiments, R b1 、R b2 、R b3 、R b4 、R k1 、R k2 、R k3 、R qEach is independently selected from H, deuterium, F, Cl, Br, I, OH, =O, =S, NH2, CN, COOH, CONH2, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, oxetanyl, tetrahydrofuranyl, 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, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, oxetanyl, tetrahydrofuranyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, pyridyl are optionally substituted by 1 to 6 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, -OC 3-7 -O-4-6 membered heterocyclic group, fluorine-substituted C 3-7 membered carbocyclic group, C 2-6 Alkynyl, fluoro-substituted phenyl substituents;

[0051] In certain embodiments, R b1 Each is independently selected from H, deuterium, F, Cl, Br, I, OH, =O, =S, NH2, CN, COOH, CONH2, CF3, CD3, CHF2, CH2F, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, oxetanyl, tetrahydrofuranyl, oxetanyl, -CH2-cyclopropyl, -CH2CF3, fluoro-substituted phenyl,

[0052] In certain embodiments, R b1 is independently selected from CF3, CD3, CHF2, CH2F, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, oxetanyl, tetrahydrofuranyl, oxetanyl, -CH2-cyclopropyl, -CH2CF3, fluoro-substituted phenyl,

[0053] In certain embodiments, R b2 、R b3 、R b4 、Rk1 、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, CH2OH;

[0054] In certain embodiments, R b4 、R k1 Each is independently selected from H, deuterium, F, Cl, Br, I, OH, NH2, CN, COOH, CONH2, CF3, CHF2, CH2F, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, CH2OH;

[0055] In certain embodiments, R b4 、R k1 Each independently selected from H, deuterium, and F;

[0056] In certain embodiments, R k3 are each independently selected from H, deuterium, and methyl;

[0057] In certain embodiments, R q Each independently selected from H, deuterium, methyl

[0058] In certain embodiments, b4 is each independently selected from 0, 1, 2, 3, 4, 5, or 6;

[0059] In certain embodiments, b4 is selected from 0 or 1;

[0060] In certain embodiments, p1 or p2 are each independently selected from 0, 1, 2, 3, or 4;

[0061] In certain embodiments, L1 is selected from one of the fragments shown in Table L1-1;

[0062] Table L1-1

[0063] ;

[0064] In certain embodiments, L is selected from one of the fragments shown in Table A;

[0065] Table A

[0066] In certain embodiments, B is selected from one of the structural fragments shown in Table B-1;

[0067] Table B-1

[0068] In certain embodiments, K is selected from

[0069] In certain embodiments, K is selected from

[0070] Optionally,

[0071] K1 is selected from Or B4 is selected from

[0072] Optionally, the compound satisfies the following conditions:

[0073] K1 is selected from The remaining definitions in general formula (I) or general formula (II) are as described above;

[0074] Or B4 is selected from The remaining definitions in general formula (I) or general formula (II) are the same as above.

[0075] As a first embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0076] B is selected from

[0077] L is selected from Its left side is connected to B and its right side is connected to K;

[0078] K is selected from

[0079] B1 does not exist or is selected from C 3-12 Carbocyclic group or 4-12 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R b1 replace;

[0080] B2 is selected from C 3-12 Carbocyclic group or 4-12 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R b2 replace;

[0081] B4 is selected from phenyl, 5-6 membered heteroaryl, 9-12 membered bicyclic ring group,

[0082] K1 is selected from phenyl, 5-6 membered heteroaryl, 9-12 membered bicyclic ring group,

[0083] Selected from aromatic or non-aromatic rings;

[0084] W is selected from 5-6 membered heterocyclic group;

[0085] Z2 is selected from CH or N;

[0086] Z3 is selected from CH or N;

[0087] L1 is selected from the group consisting of -Ak1-, -Ak1-Ak2-, -Cy1-, -Cy1-Cy2-, -Cy1-Ak1-, -Ak1-Cy1-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak1-, -Ak1-Cy1-Cy2-, -Cy1-Ak1-Cy2-Ak2-, -Ak1-Cy1-Ak2-Cy2-;

[0088] Q is selected from NR q CO、CONR q 、CO、NR q or key;

[0089] X1, X2, X3 are each independently selected from N or CR b3 ;

[0090] Z1 is selected from N or CR k2 ;

[0091] Ak1 and Ak2 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、CONR L , CO, C≡C, the alkylene, alkenylene, alkynylene are optionally substituted by 1 to 4 groups 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 substituted by a substituent of a 4- to 6-membered carbocyclic group or a 4- to 6-membered heterocyclic group;

[0092] R L or R NEach independently selected from H or C 1-6 alkyl;

[0093] 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 a monocyclic carbocyclyl, a 4-12-membered cyclic carbocyclyl, a 5-12-membered spirocyclic carbocyclyl, a 5-12-membered bridged carbocyclyl, a 5-12-membered heteroaryl or a 6-10-membered aryl, wherein the aryl, heteroaryl, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 atoms selected from deuterium, F, Cl, Br, I, OH, COOH, CONH2, 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;

[0094] R b1 、R b2 、R b3 、R b4 、R k1 、R k2 、R k3 、R q Each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, ═S, NH 2 , CN, COOH, CONH 2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 -membered carbocyclic group, 4-6 membered heterocyclic group, -OC 3-7 The alkyl, alkoxy, heterocyclic group, and carbocyclic group are optionally substituted by 1 to 4 groups 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, -OC 3-7 -O-4-6 membered heterocyclic group, fluorine-substituted C 3-7 membered carbocyclic group, C 2-6 Alkynyl, fluoro-substituted phenyl substituents;

[0095] b4 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0096] p1 or p2 are each independently selected from 0, 1, 2, 3 or 4;

[0097] The condition is,

[0098] K1 is selected from Or B4 is selected from

[0099] As a second embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0100] B1 does not exist or is selected from C 3-7 Membered monocyclic carbocyclic group, C 5-12 Membered carbonyl ring, C 5-12 spirocarbocyclic group, C 5-12 4-7 membered bridged ring carbocyclic group, 4-7 membered monocyclic heterocyclic group, 4-12 membered cyclic heterocyclic group, 5-12 membered spirocyclic heterocyclic group, 5-12 membered bridged ring heterocyclic group, the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R b1 replace;

[0101] B2 is selected from 4-7 membered monocyclic heterocyclic group, 4-12 membered cyclic heterocyclic group, 5-12 membered spirocyclic heterocyclic group, 5-12 membered bridged heterocyclic group, and the heterocyclic group is optionally substituted by 1 to 4 R b2 replace;

[0102] B4 is selected from phenyl, 5-6 membered heteroaryl, Benzo 5-membered heterocyclic group, benzo 6-membered heterocyclic group, benzo 5-membered carbocyclic group, benzo 6-membered carbocyclic group, benzo 7-membered carbocyclic group, benzo 8-membered carbocyclic group, pyrido 5-membered heterocyclic group, pyrido 6-membered heterocyclic group;

[0103] K1 is selected from phenyl, 5-6 membered heteroaryl, Benzo 5-membered heterocyclic group, benzo 6-membered heterocyclic group;

[0104] Ak1 and Ak2 are each independently selected from C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, O, NR L NR L CO、CONR L , CO, wherein the alkylene, alkenylene, and alkynylene groups are optionally substituted by 1 to 4 groups 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 3-6substituted by a substituent of a 4- to 6-membered carbocyclic group or a 4- to 6-membered heterocyclic group;

[0105] R L or R N Each independently H or C 1-4 alkyl;

[0106] Cy1 and Cy2 are each independently selected from 3-6 membered monocyclic heterocyclic groups, 4-10 membered cyclic heterocyclic groups, 5-11 membered spirocyclic heterocyclic groups, 5-10 membered bridged heterocyclic groups, C 3-6 a monocyclic carbocyclyl, a 4-10 membered cyclic carbocyclyl, a 5-11 membered spirocyclic carbocyclyl, a 5-10 membered bridged carbocyclyl, a 5-10 membered heteroaryl or a 6-10 membered aryl, wherein the aryl, heteroaryl, carbocyclyl or heterocyclyl is selected from 1 to 4 deuterium, F, Cl, Br, I, OH, COOH, CONH2, 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;

[0107] R b1 、R b2 、R b3 、R b4 、R k1 、R k2 、R k3 、R q Each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, ═S, NH 2 , CN, COOH, CONH 2 , C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 -membered carbocyclic group, 4-6 membered heterocyclic group, -OC 3-6 -O-4-6 membered carbocyclic group, -O-4-6 membered heterocyclic group, wherein the alkyl, alkoxy, heterocyclic group, and carbocyclic group are optionally substituted by 1 to 6 groups 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, -OC 3-7 -O-4-6 membered heterocyclic group, fluorine-substituted C 3-7 membered carbocyclic group, C 2-6 Alkynyl, fluoro-substituted phenyl substituents;

[0108] The remaining definitions are the same as those of the first embodiment of the present invention.

[0109] As a third embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0110] B1 is absent or selected from 4-6 membered heterocyclic group, cyclopropyl spiro 5 membered heterocyclic group, cyclobutyl spiro 5 membered heterocyclic group, 5- and 5-membered heterocyclic group, 6- and 5-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 R b1 replace;

[0111] B2 is selected from 4-6 membered monocyclic heterocyclic group, 8-9 membered cyclic heterocyclic group, 7-11 membered spirocyclic heterocyclic group, 5-8 membered bridged heterocyclic group, and the heterocyclic group is optionally substituted by 1 to 4 R b2 replace;

[0112] Ak1 and Ak2 are each independently selected from C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylidene, O, NR L NR L CO, CO, wherein the alkylene, alkenylene, alkynylene is optionally substituted by 1 to 4 groups 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 substituted by a substituent of a 4- to 6-membered carbocyclic group or a 4- to 6-membered heterocyclic group;

[0113] R L or R N Each independently selected from H, methyl or ethyl;

[0114] 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, cyclopropyl-spirocyclopropyl, cyclopropyl-spirocyclobutyl, Cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylazetidinyl, cyclopropylpyrrolidinyl, cyclopropylpiperidinyl, cyclobutylazetidinyl, cyclobutylpyrrolidinyl, cyclobutylpiperidinyl, cyclopentylazetidinyl, cyclopentylpyrrolidinyl, cyclopentylpiperidinyl, cyclohexylazetidinyl, cyclohexylpyrrolidinyl, cyclohexylpiperidinyl, azetidinazetidinyl, azetidinpyrrolidinyl, azetidinpiperidinyl, pyrrolidinazetidinyl, Pyrrolidinyl and pyrrolidinyl, pyrrolidinyl and piperidinyl, piperidinyl and azetidinyl, piperidinyl and pyrrolidinyl, piperidinyl and piperidinyl, cyclobutyl spiroazetidinyl, cyclobutyl spiropyrrolidinyl, cyclobutyl spiropyridinyl, cyclopentyl spiroazetidinyl, cyclopentyl spiropyrrolidinyl, cyclopentyl spiropyridinyl, cyclohexyl spiroazetidinyl, cyclohexyl spiropyrrolidinyl, cyclohexyl spiropyridinyl, azetidinyl spiroazetidinyl, azetidinyl spiropyrrolidinyl, azetidinyl spiropyridinyl, pyrrolidinyl spiroazetidinyl, pyrrolidinyl spiropyridinyl, pyrrolidinyl spiropyridinyl, piperidinyl spiroazetidinyl, piperidinyl spiropyrrolidinyl, piperidinyl spiropyridinyl, When substituted, it is optionally replaced by 1 to 4 atoms selected from deuterium, F, Cl, Br, I, OH, NH2, COOH, CONH2, CN, ═O, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted 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;

[0115] The remaining definitions are the same as those of the first or second embodiment of the present invention.

[0116] As a fourth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0117] B1 is absent or optionally replaced by 1 to 2 Rb1 Substituted groups:

[0118] B2 is selected from 1 to 3 R b2 Substituted groups: Its right side is connected to B;

[0119] B4 is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, furyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,

[0120] b4 is selected from 0, 1, 2 or 3;

[0121] K1 is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, furyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,

[0122] Ak1 and Ak2 are each independently selected from methylene, ethylene, vinylene, and ethynylene, wherein the methylene, ethylene, vinylene, and ethynylene are optionally substituted by 1 to 4 groups 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;

[0123] Cy1 and Cy2 are each independently selected from one of the following substituted or unsubstituted groups: When substituted, it is optionally replaced by 1 to 4 deuterium, F, Cl, Br, I, OH, ═O, NH 2 , CN, CONH 2 , COOH, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted 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;

[0124] R b1 、R b2 、R b3 、R b4、R k1 、R k2 、R k3 、R q Each is independently selected from H, deuterium, F, Cl, Br, I, OH, =O, =S, NH2, CN, COOH, CONH2, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, oxetanyl, tetrahydrofuranyl, 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, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, oxetanyl, tetrahydrofuranyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, pyridyl are optionally substituted by 1 to 6 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, -OC 3-7 -O-4-6 membered heterocyclic group, fluorine-substituted C 3-7 membered carbocyclic group, C 2-6 Alkynyl, fluoro-substituted phenyl substituents;

[0125] The remaining definitions are the same as those of the first, second or third embodiment of the present invention.

[0126] As a fifth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0127] L1 is selected from one of the structural fragments in Table L1-1;

[0128] Q is selected from CONR q NR q CO、NR q or key;

[0129] R b1Each is independently selected from H, deuterium, F, Cl, Br, I, OH, =O, =S, NH2, CN, COOH, CONH2, CF3, CD3, CHF2, CH2F, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, oxetanyl, tetrahydrofuranyl, oxetanyl, -CH2-cyclopropyl, -CH2CF3, fluoro-substituted phenyl,

[0130] 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, CH2OH;

[0131] R k3 are each independently selected from H, deuterium, and methyl;

[0132] R q are each independently selected from H, deuterium, and methyl;

[0133] The remaining definitions are the same as those of the first, second, third or fourth embodiment of the present invention.

[0134] As a sixth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0135] B is selected from one of the fragments shown in Table B-1;

[0136] L is selected from one of the fragments shown in Table A;

[0137] K is selected from

[0138] As a seventh embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, the compound represented by the general formula (I) is selected from the compound represented by the general formula (III),

[0139] X2 is selected from N or CH;

[0140] Q is selected from CONH, NHCO, NH or a bond;

[0141] Z1 is selected from N or CH, provided that Q and Z1 do not form a nitrogen-nitrogen bond;

[0142] L1, R b1 、R b4 、R k1 or b4 is the same as the corresponding definition in any one of the first, second, third and fourth embodiments of the present invention, preferably the same as the corresponding definition in the fourth embodiment.

[0143] As an eighth embodiment of the present invention, the compound represented by the aforementioned general formula (III) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0144] L1 is selected from

[0145] R b1 is independently selected from CF3, CD3, CHF2, CH2F, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, oxetanyl, tetrahydrofuranyl, oxetanyl, -CH2-cyclopropyl, -CH2CF3, fluoro-substituted phenyl,

[0146] R b4 、R k1 Each is independently selected from H, deuterium, F, Cl, Br, I, OH, NH2, CN, COOH, CONH2, CF3, CHF2, CH2F, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, CH2OH;

[0147] b4 is selected from 0 or 1;

[0148] The remaining definitions are the same as those in the seventh embodiment of the present invention.

[0149] The present invention relates to the following compound or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the following structures:

[0150] Table E-1

[0151] The present invention relates to a pharmaceutical composition comprising the above compound or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and a pharmaceutically acceptable carrier.

[0152] The present invention relates to the use of the above-mentioned compound or its stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals or the above-mentioned pharmaceutical compositions in preparing drugs for inhibiting or degrading BTK.

[0153] The present invention relates to the use of the above-mentioned compound or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals or the above-mentioned pharmaceutical compositions for preparing drugs for treating tumors or autoimmune diseases, preferably B-cell malignancies, more preferably relapsed / refractory B-cell malignancies.

[0154] The present invention relates to a pharmaceutical composition or pharmaceutical formulation comprising a therapeutically effective amount of a compound of the present invention, or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, and a pharmaceutically acceptable excipient. The pharmaceutical composition may be in the form of a unit dosage form (the amount of the active ingredient in the unit dosage form is also referred to as the "drug strength").

[0155] The present invention also provides a method for treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of the present invention, or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, cocrystal, or pharmaceutical composition thereof. In some embodiments, the mammal of the present invention comprises a human.

[0156] As used herein, an "effective amount" or "therapeutically effective amount" refers to administering a sufficient amount of a compound disclosed herein to alleviate, to some extent, one or more symptoms of the disease or condition being treated (e.g., cancer or autoimmune disease). In some embodiments, the result is a reduction and / or alleviation 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 the amount of a compound disclosed herein required to provide a clinically significant reduction in disease symptoms.Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1000 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 g, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg , 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg, 400-500mg, 5-400mg, 10-400mg, 20-400mg, 25-400mg, 30-400mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80-400mg, 90-400mg, 100-400mg, 125-400mg, 150-400mg, 200-400mg, 25 0-400mg, 300-400mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300mg, 25-300mg, 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 7 5-300mg, 80-300mg, 90-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200 mg, 25-200mg, 30-200mg, 40-200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg;.

[0157] In some embodiments, the pharmaceutical composition includes 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, 9 5 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg of a compound of the present invention or a stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

[0158] A method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, preferably 1-1500 mg. The disease is preferably a tumor or an autoimmune disease, more preferably a relapsed / refractory B-cell malignancy.

[0159] A method for treating a disease in a mammal, comprising administering to a subject a compound of the present invention or a stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof at a daily dose of 1-1500 mg / day, wherein the daily dose can be a single dose or divided doses. In some embodiments, the daily dose includes but is not limited to 10-1500 mg / day, 10-1000 mg / day, 10-800 mg / day, 25-800 mg / day, 50- 800 mg / day, 100-800 mg / day, 200-800 mg / day, 25-400 mg / day, 50-400 mg / day, 100-400 mg / day, 200-400 mg / day, in some embodiments, daily doses include but are not limited to 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 400 mg / day, 600 mg / day, 800 mg / day.

[0160] The present invention relates to a kit, which may include a composition in single-dose or multi-dose form, wherein the kit contains a compound of the present invention or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and the amount of the compound of the present invention or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is the same as the amount in the above-mentioned pharmaceutical composition.

[0161] The amount of the compound of the invention or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the present invention is in each case calculated as the free base.

[0162] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0163] The compounds of the present invention can be prepared by the following method:

[0164] General synthesis method 1:

[0165] The compound of the general formula (Z-1) and the compound of the general formula (Z-2) undergo nucleophilic substitution or coupling reaction to obtain the compound of the general formula (Z-3);

[0166] The compound of the general formula (Z-3) and the compound of the general formula (Z-4) undergo nucleophilic substitution or coupling reaction to obtain the compound of the general formula (Z-5);

[0167] The compound of the general formula (Z-5) is subjected to a hydrolysis reaction to obtain the compound of the general formula (Z-6);

[0168] The compound of the general formula (Z-6) is subjected to an oxidation reaction to obtain the compound of the general formula (Z-7);

[0169] The compound of the general formula (Z-7) and the compound of the general formula (Z-8) are reacted through reductive amination to obtain the compound of the general formula (Z-9), namely the compound of the general formula (I).

[0170] The definitions of the remaining groups are the same as those in the specification and claims.

[0171] Unless otherwise stated, the terms used in this specification and claims have the following meanings.

[0172] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C. 13C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl, bromine include 79 Br and 81 Br.

[0173] "Halogen" refers to F, Cl, Br or I.

[0174] "Halogen-substituted" refers to substitution with F, Cl, Br or I, including but not limited to substitution with 1 to 10 substituents selected from F, Cl, Br or I, substitution with 1 to 6 substituents selected from F, Cl, Br or I, and preferably substitution with 1 to 4 substituents selected from F, Cl, Br or I. "Halogen-substituted" is abbreviated as "halo".

[0175] "Alkyl" refers to a substituted or unsubstituted straight-chain or branched saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, and alkyl groups of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched chain isomers thereof; alkyl groups appearing herein have the same definition as this one. Alkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0176] "Alkylene" refers to substituted or unsubstituted straight-chain and branched divalent saturated hydrocarbon groups, including -(CH2) v -(v is an integer from 1 to 10), examples of alkylene include but are not limited to methylene, ethylene, propylene and butylene.

[0177] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon radical, typically having 3 to 10 carbon atoms, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Cycloalkyl groups as used herein are as defined above. Cycloalkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0178] "Heterocycloalkyl" refers to a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 10 atoms, 3 to 8 atoms, including 1 to 3 heteroatoms selected from N, O or S. The N and S optionally substituted in the heterocycloalkyl ring can be oxidized to various oxidation states. The heterocycloalkyl group can be attached to a heteroatom or a carbon atom, can be attached to an aromatic ring or a non-aromatic ring, can be connected to a bridged ring or a spirocycle, and non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl. The heterocycloalkyl group can be monovalent, divalent, trivalent or tetravalent.

[0179] "Alkenyl" refers to a substituted or unsubstituted straight-chain or branched unsaturated hydrocarbon group having at least one, typically one, two, or three, carbon-carbon double bonds, with a backbone of 2 to 10, 2 to 6, or 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, and the like. Alkenyl groups appearing herein are defined as such. Alkenyl groups may be monovalent, divalent, trivalent, or tetravalent.

[0180] "Alkynyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbon groups having at least one, typically one, two or three carbon-carbon triple bonds, with a backbone comprising 2 to 10 carbon atoms, including but not limited to 2 to 6 carbon atoms in the backbone and 2 to 4 carbon atoms in the backbone. Examples of alkynyl groups include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, and the like; alkynyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0181] "Propynyl" means 1-propynyl and 2-propynyl.

[0182] "Alkoxy" refers to a substituted or unsubstituted -O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyloxy, and cyclobutyloxy.

[0183] "Carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, which can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring, or a 10-15 membered tricyclic ring system. The carbocyclyl can be attached to the aromatic or non-aromatic ring, which can be optionally a monocyclic, bridged, or spirocyclic ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, a benzene ring, a naphthalene ring, "Carbocyclyl" or "carbocycle" can be monovalent, divalent, trivalent, or tetravalent.

[0184] "Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, which can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring or a 10-15 membered tricyclic ring system, and contains one or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S. The N and S optionally substituted in the heterocyclyl ring can be oxidized to various oxidation states. The heterocyclic group can be connected to a heteroatom or a carbon atom, the heterocyclic group can be connected to an aromatic ring or a non-aromatic ring, and the heterocyclic group can be connected to a bridged ring or a spiro ring. Non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, py ... furanyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophenyl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptanyl, "Heterocyclyl" or "heterocycle" can be monovalent, divalent, trivalent or tetravalent.

[0185] "Spirocycle" or "spirocyclyl" refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called a spiro atom), and the number of ring atoms in the spirocycle system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and optionally may contain 1 to 5 atoms selected from N, O or S (=O) n heteroatoms. "Spirocycle" or "spirocyclyl" can be monovalent, divalent, trivalent or tetravalent.

[0186] "Parallel ring" or "parallel ring group" refers to a polycyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds and may be substituted or unsubstituted, and each ring in the parallel ring system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O) n or O, n is 0, 1 or 2). The number of ring atoms in the cyclic system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, and 5 to 10. Non-limiting examples include: "Bicyclic" or "bicyclic group" can be monovalent, divalent, trivalent or tetravalent.

[0187] "Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing two atoms that are not directly connected to any two rings, and may contain zero or more double bonds. Any ring in the bridged ring system may contain zero to five atoms selected from heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O)n or O, where n is 0, 1, or 2). The number of ring atoms includes but is not limited to 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include "Bridged ring" or "bridged ring group" may be monovalent, divalent, trivalent or tetravalent.

[0188] "Carbospirocycle," "spirocarbocyclyl," "spirocarbocyclyl," or "carbospirocyclyl" refers to a "spirocycle" wherein the ring system consists of only carbon atoms.

[0189] "Carbocyclyl," "carbocyclyl," "carbocyclyl," or "carbocyclyl" refers to a "carbocyclyl" ring system consisting of only carbon atoms.

[0190] "Carbobridged ring," "bridged carbocyclic group," "bridged carbocyclic group," or "carbon-bridged cyclic group" refers to a "bridged ring" wherein the ring system consists of only carbon atoms.

[0191] "Heteromonocycle", "monocyclic heterocyclyl" or "heteromonocyclyl" refers to a monocyclic ring system of "heterocyclyl" or "heterocycle".

[0192] "Heterocyclo", "heterocycloalkyl", "cycloheterocyclyl" or "heterocycloalkyl" refers to a cyclo ring containing a heteroatom.

[0193] "Heterospirocycle," "heterospirocyclyl," "spiroheterocyclyl," or "heterospirocyclyl" refers to a "spirocycle" containing a heteroatom.

[0194] "Heterobridged ring," "heterobridged cyclic group," "bridged heterocyclic group," or "heterobridged cyclic group" refers to a "bridged ring" containing a heteroatom.

[0195] "Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a single ring or a fused ring, wherein the number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring connected to the parent structure is the aryl ring, non-limiting examples of which include benzene ring, naphthalene ring, "Aryl" or "aromatic ring" can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the aryl ring.

[0196] "Heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, O or S(=O)n, n is 0, 1, 2), and the number of ring atoms in the heteroaromatic ring is but not limited to 5 to 15, 5 to 10 or 5 to 6. Non-limiting examples of heteroaryl include but are not limited to pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, etc. The heteroaryl ring can be fused to a saturated or unsaturated carbocyclic ring or heterocyclic ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include When used herein, heteroaryl groups are defined as such. Heteroaryl groups may be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent, or tetravalent, the site of attachment is located on the heteroaryl ring.

[0197] "5-membered ring and 5-membered heteroaromatic ring" refers to a 5-membered fused heteroaromatic ring, at least one of the two fused rings contains one or more heteroatoms (including but not limited to O, S or N), and the entire group is aromatic. Non-limiting examples include pyrrolopyrrole ring, pyrazolopyrrole ring, pyrazolopyrazole ring, pyrrolofuran ring, pyrazolofuran ring, pyrrolothiophene ring, and pyrazolothiophene ring.

[0198] "5-membered and 6-membered heteroaromatic ring" refers to a 5-membered and 6-membered fused heteroaromatic ring, at least one of the two fused rings contains one or more heteroatoms (including but not limited to O, S or N), and the entire group is aromatic. Non-limiting examples include benzo 5-membered heteroaromatic group, 6-membered heteroaromatic ring and 5-membered heteroaromatic ring.

[0199] "Substituted" or "substituted" refers to substitution by one or more (including but not limited to 2, 3, 4 or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, cycloalkyl, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH2), m -C(=O)-R a 、-O-(CH2) m -C(=O)-R a 、-(CH2) m -C(=O)-NR b R c 、-(CH2) m S(=O) n R a 、-(CH2) m -alkenyl-R a , OR d or -(CH2) m -alkynyl-R a (wherein m and n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR b R c etc., where R b With R c R is independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, b With R c It can form a five- or six-membered cycloalkyl or heterocyclic group. a With R d Each is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring or paracyclic group.

[0200] “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.

[0201] "1 to X substituents selected from..." means substituted by 1, 2, 3, ....X substituents, where X is selected from any integer between 1 and 10. For example, "1 to 4 R k "Substituted" means replaced by 1, 2, 3 or 4 Rk Substitution. For example, "substituted with 1 to 5 substituents selected from..." means substituted with 1, 2, 3, 4, or 5 substituents selected from..." For example, "a heterobridged ring is optionally substituted with 1 to 4 substituents selected from D or F" means that the heterobridged ring is optionally substituted with 1, 2, 3, or 4 substituents selected from D or F.

[0202] An XY-membered ring (3≤X<Y, Y is any integer between 4 and 12) includes rings with X, X+1, X+2, X+3, X+4, ..., Y members. Rings include heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heterocyclic rings, heterospirocyclic rings, or heterobridged rings. For example, "4-7-membered heteromonocyclic ring" refers to a 4-, 5-, 6-, or 7-membered heteromonocyclic ring, and "5-10-membered heterocyclic ring" refers to a 5-, 6-, 7-, 8-, 9-, or 10-membered heterocyclic ring.

[0203] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not. For example, "alkyl optionally substituted with F" means that the alkyl group may but need not be substituted with F, and the description includes instances where the alkyl group is substituted with F and instances where the alkyl group is not substituted with F.

[0204] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, or the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0205] "Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, or stereoisomers, tautomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals thereof, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0206] "Carrier" refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

[0207] "Prodrugs" refer to compounds of the present invention that can be converted into biologically active compounds through in vivo metabolism. Prodrugs of the present invention are prepared by modifying amino or carboxyl groups in compounds of the present invention. These modifications can be removed by conventional manipulation or in vivo to yield the parent compound. When the prodrugs of the present invention are administered to a mammalian subject, the prodrugs are cleaved to form free amino or carboxyl groups.

[0208] A "cocrystal" is a crystal formed by the active pharmaceutical ingredient (API) and cocrystal former (CCF) bound together by hydrogen bonds or other non-covalent bonds. Both the API and CCF are solid in their pure form at room temperature, and the components exist in a fixed stoichiometric ratio. A cocrystal is a multi-component crystal, encompassing both binary cocrystals formed between two neutral solids and multi-component cocrystals formed between a neutral solid and a salt or solvate.

[0209] "Animal" is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

[0210] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers, and conformational isomers.

[0211] "Tautomers" refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions, such as keto-enol isomers and amide-imino alcohol isomers. DETAILED DESCRIPTION

[0212] The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.

[0213] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0214] MS was determined using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0215] HPLC determination was performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM);

[0216] Thin layer chromatography silica gel plate using Yantai Huanghai HSGF 254 or Qingdao GF 254 Silica gel plates, the specifications of silica gel plates used in thin layer chromatography (TLC) are 0.15mm-0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm;

[0217] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier;

[0218] Boc: tert-butyloxycarbonyl; Ts: p-toluenesulfonyl; Cbz: benzyloxycarbonyl; TMS: trimethylsilyl.

[0219] Synthesis of intermediate 1:

[0220] Step 1: Preparation of 1-B

[0221] 1-A (2.8 g, 13.58 mmol) (synthesis method, see Bioorganic & Medicinal Chemistry Letters, 2016, 26, 5877-5882) was dissolved in dichloromethane (50 mL), and Boc2O (5.93 g, 27.17 mmol) and DMAP (3.32 g, 27.18 mmol) were added. The reaction was allowed to react at room temperature for 16 h. The reaction system was washed with 0.5 mol / L hydrochloric acid (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether (v / v) = 0:1-1:9) to obtain the racemate of 1-B (3.4 g, yield: 82%).

[0222] The racemate of 1-B was subjected to chiral separation as follows:

[0223] 1. Instrument: SFC Prep 150AP; Chromatographic column: Daicel IC-H (19 mm × 250 mm).

[0224] 2. Dissolve the sample in methanol and filter with a 0.45 μm filter to prepare a sample solution.

[0225] 3. Preparative chromatographic conditions: a. Mobile phases consisted of a system of A and B: mobile phase A: CO2; mobile phase B: methanol / isopropanol (v / v) = 1:1; b. Isocratic elution, mobile phase B content was 20%; c. Flow rate was 40 mL / min.

[0226] Peak time: chiral isomer 1 (compound 1-B): 5.7 min, chiral isomer 2 (compound 2-A): 6.47 min.

[0227] According to the MicroED structure determination of compound 2-B, compound 1-B is R-configuration and compound 2-A is S-configuration.

[0228] LCMS m / z=307.3[M+1] + .

[0229] Step 2: Preparation of 1-C

[0230] 1-B (1.8 g, 5.88 mmol) was dissolved in acetonitrile (50 mL), and NBS (1.05 g, 5.90 mmol) was added. The reaction was allowed to react at room temperature for 1 h. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether (v / v) = 0:1-1:9) to obtain 1-C (1.6 g, yield: 71%).

[0231] LCMS m / z=385.3[M+1] + .

[0232] Step 3: Preparation of 1-D

[0233] 1-C (0.77 g, 2.0 mmol), 1-C′ (1.67 g, 4.0 mmol) (synthesis method, see WO2022235945), Pd(dppf)Cl2·DCM (0.16 g, 0.20 mmol), and cesium carbonate (1.30 g, 4.0 mmol) were added to a reaction flask. 1,4-dioxane (30 mL) and water (3 mL) were added, and the mixture was reacted at 100°C under a nitrogen atmosphere for 20 h. The reaction system was cooled to room temperature, and 50 mL of water and 50 mL of ethyl acetate were added. The aqueous phase was extracted with 50 mL of ethyl acetate, and the organic phase was washed with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-9:1) to obtain 1-D (0.70 g, yield: 59%).

[0234] Step 4: Preparation of 1-E

[0235] 1-D (0.70 g, 1.18 mmol) was dissolved in THF (20 mL), and 10% palladium on carbon (0.63 g) was added. The mixture was reacted at 45°C under a hydrogen balloon atmosphere for 20 h. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (MeOH:DCM (v / v) = 0:1-5:95) to obtain 1-E (0.25 g, yield: 51%).

[0236] LCMS m / z=418.1[M+1] + .

[0237] Step 5: Preparation of Intermediate 1

[0238] 1-E (250 mg, 0.6 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the mixture was allowed to react at room temperature for 3 h. The reaction system was concentrated under reduced pressure, 5 mL of dichloromethane and 1 mL of triethylamine were added, and the mixture was concentrated under reduced pressure to obtain crude intermediate 1 (190 mg).

[0239] LCMS m / z=318.3[M+1] + .

[0240] Synthesis of intermediate 2:

[0241] Step 1: Preparation of 2-B

[0242] 2-A (1.4 g, 4.57 mmol) was dissolved in acetonitrile (50 mL), and NBS (0.81 g, 4.55 mmol) was added. The reaction was allowed to react at room temperature for 1 h. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether (v / v) = 0:1-1:9) to obtain 2-B (1.6 g, yield: 92%).

[0243] LCMS m / z=385.3[M+1] + .

[0244] The compound 2-B was determined to be S-configuration by MicroED structure analysis.

[0245] Step 2: Preparation of 2-C

[0246] 2-B (1.6 g, 4.16 mmol), 2-B′ (3.46 g, 8.29 mmol), Pd(dppf)Cl2·DCM (0.34 g, 0.42 mmol), and cesium carbonate (2.70 g, 8.3 mmol) were added to a reaction flask. 1,4-dioxane (50 mL) and water (5 mL) were added, and the mixture was reacted at 100°C under a nitrogen atmosphere for 20 h. The reaction system was cooled to room temperature, and 50 mL of water and 50 mL of ethyl acetate were added. The aqueous phase was extracted with ethyl acetate (50 mL), and the organic phase was washed with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-9:1) to obtain 2-C (1.4 g, yield: 56%).

[0247] Step 3: Preparation of 2-D

[0248] 2-C (1.4 g, 2.35 mmol) was dissolved in THF (50 mL), and 10% palladium on carbon (1.25 g) was added. The mixture was reacted at 45°C under a hydrogen balloon atmosphere for 20 h. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (MeOH:DCM (v / v) = 0:1-5:95) to obtain 2-D (0.85 g, yield: 87%).

[0249] LCMS m / z=418.1[M+1] + .

[0250] Step 4: Preparation of Intermediate 2

[0251] 2-D (620 mg, 1.49 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (3 mL) was added, and the mixture was allowed to react at room temperature for 3 h. The reaction system was concentrated under reduced pressure, 5 mL of dichloromethane and 1 mL of triethylamine were added, and the mixture was concentrated under reduced pressure to obtain crude intermediate 2 (460 mg).

[0252] LCMS m / z=318.3[M+1] + .

[0253] Preparation of intermediate 3:

[0254] Step 1: Preparation of 3-A

[0255] Under a nitrogen atmosphere, 1-C (7.00 g, 18.17 mmol) and 70 mL of tetrahydrofuran were added to a reaction flask. A 2.5 mol / L n-butyllithium solution in n-hexane (14.50 mL, 36.25 mmol) was slowly added dropwise at -78°C. After stirring at -78°C for 1.5 h, the carbon dioxide was replaced three times. The reaction was then placed under a carbon dioxide balloon, maintaining the temperature below -40°C for 0.5 h. The reaction system was returned to room temperature, and 20 mL of ethyl acetate was added. The pH was adjusted to 2 with 1 mol / L hydrochloric acid, and the reaction was extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10:1-2:1) to afford 3-A (2.4 g, yield: 38%).

[0256] 1 H NMR(400MHz,DMSO-d6)δ7.42(d,1H),6.64(d,1H),4.00-3.82(m,3H),3.23-3.09(m,1H),3.08-2.90(m ,1H),2.90-2.77(m,1H),2.76-2.60(m,3H),2.05-1.90(m,1H),1.65-1.50(m,1H),1.49-1.35(m,9H).

[0257] Step 2: Preparation of Intermediate 3

[0258] To a reaction flask, 3-A (2.4 g, 6.85 mmol), HATU (3.13 g, 8.23 ​​mmol), diisopropylethylamine (2.66 g, 20.58 mmol), and 10 mL of DMF were added. After stirring at room temperature for 10 minutes, 3-amino-2,6-piperidinedione hydrochloride (1.35 g, 8.20 mmol) was added and allowed to react at room temperature for 30 minutes. The reaction mixture was poured into 100 mL of water and filtered. The filter cake was washed with 50 mL of water and dried under reduced pressure to obtain Intermediate 3 (2.0 g, yield: 63%).

[0259] LCMS m / z=461.2[M+1] +

[0260] Preparation of intermediate 4:

[0261] Intermediate 4 was obtained using compound 2-B as a raw material by referring to the synthetic method of intermediate 3.

[0262] LCMS m / z=461.2[M+1] +

[0263] Preparation of intermediate 5:

[0264] Step 1: Preparation of 5-B

[0265] 5-A (2.2 g, 8.6 mmol) was added to a single-necked flask, followed by 1,4-dioxane (20 mL) and a 4 mol / L 1,4-dioxane hydrochloride solution (20 mL). The reaction was allowed to react at room temperature for 2 h. The reaction system was concentrated under reduced pressure, and p-nitrofluorobenzene (1.213 g, 8.6 mmol), N,N-dimethylformamide (30 mL), and potassium carbonate (4.7 g, 34.0 mmol) were added. The reaction was continued at 80°C for 16 h. The reaction system was cooled to room temperature and poured into 300 mL of water. The precipitated solid was filtered, and the filter cake was washed with 50 mL of water and dried under reduced pressure to obtain crude product 5-B (2 g).

[0266] LCMS m / z=277.1[M+1] +

[0267] Step 2: Preparation of Intermediate 5

[0268] The crude product 5-B (2 g) was dissolved in methanol (50 mL), 5% palladium on carbon (100 mg) was added, and the mixture was reacted at room temperature under a hydrogen balloon atmosphere for 4 h. The reaction system was filtered through celite, the filter cake was washed with 50 mL of dichloromethane, and the filtrate was concentrated under reduced pressure to obtain the crude intermediate 5 (1.7 g).

[0269] LCMS m / z=247.1[M+1] +

[0270] Preparation of intermediate 6:

[0271] Step 1: Preparation of 6-B

[0272] 6-A (6.29 g, 16.33 mmol) (synthesis method, see WO2023232133), 6A (4.14 g, 22.84 mmol), cesium carbonate (10.63 g, 32.63 mmol), palladium acetate (0.73 g, 3.25 mmol), and XantPhos (0.94 g, 1.62 mmol) were added to a 1,4-dioxane solution (100 mL) and reacted at 105°C under a nitrogen atmosphere for 16 hours. The reaction solution was cooled to room temperature, filtered through a pad of Celite, and the filter cake was washed with 50 mL of dichloromethane. The filtrate was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1:5) to obtain 6-B (6.94 g, yield: 88%).

[0273] LCMS m / z=486.2[M+1] +

[0274] Step 2: Preparation of 6-C

[0275] 6-B (6.94 g, 14.30 mmol) was added to methanol (200 mL), followed by 10% palladium on carbon (6.92 g) and ammonium acetate (6.79 g, 88.09 mmol). The mixture was reacted at room temperature under a hydrogen balloon for 12 h. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1:1) to obtain 6-C (4.15 g, 90% yield).

[0276] LCMS m / z=322.2[M+1] +

[0277] Step 3: Preparation of 6-D

[0278] 6-C (4.15 g, 12.92 mmol), 6B (3.88 g, 38.75 mmol), and N,N-diisopropylethylamine (5.01 g, 38.76 mmol) were added sequentially to ethanol (60 mL) and reacted at 100°C for 72 h. The reaction system was cooled to room temperature and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1:20) to obtain 6-D (3.91 g, yield: 72%).

[0279] LCMS m / z=422.3[M+1] +

[0280] Step 4: Preparation of 6-E

[0281] 6-D (0.50 g, 1.19 mmol) and N,N-diisopropylethylamine (0.46 g, 3.56 mmol) were added to tetrahydrofuran (20 mL). Triphosgene (0.39 g, 1.31 mmol) was slowly added and allowed to react at room temperature for 1 h. Aqueous ammonia (5 mL) was then added and the reaction continued at 50°C for 2 h. The reaction system was cooled to room temperature, and 100 mL of ethyl acetate was added. The organic phase was washed with water (50 mL × 3) and 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1:15) to obtain 6-E (0.46 g, yield: 83%).

[0282] LCMS m / z=465.3[M+1] +

[0283] Step 5: Preparation of Intermediate 6

[0284] 6-E (0.46 g, 0.99 mmol) was added to acetonitrile (10 mL), followed by a 40% benzyltrimethylammonium hydroxide methanol solution (1.2 mL). The reaction was allowed to react at 60°C for 2 h. The reaction system was cooled to room temperature and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1:15) to obtain intermediate 6 (0.21 g, yield: 51%).

[0285] Preparation of intermediate 7:

[0286] Intermediate 7 was obtained using compound 7-A (synthesis method see WO2023232133) as raw material and referring to the synthesis method of intermediate 6.

[0287] Preparation of intermediate 8:

[0288] Step 1: Preparation of 8-B

[0289] 8-A (10 g, 42.02 mmol) was dissolved in 80 mL of DMSO, and 8-A′ (7.41 g, 46.25 mmol) and DIPEA (16.29 g, 126.03 mmol) were added. The reaction was allowed to proceed at 50°C for 3 h. The reaction system was cooled to room temperature, and 300 mL of water and 400 mL of ethyl acetate were added. The organic phase was washed with 300 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 8-B (6.2 g).

[0290] Step 2: Preparation of 8-C

[0291] The crude product 8-B (6.2 g) was added to 150 mL of methanol and 30 mL of water, followed by the addition of iron powder (9.15 g, 163.4 mmol) and ammonium chloride (8.77 g, 163.96 mmol). The reaction was allowed to proceed at 70°C for 20 h. The reaction system was cooled to room temperature, filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. 300 mL of water and 400 mL of ethyl acetate were added to the residue. The organic phase was washed with 300 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (methanol:dichloromethane (v / v) = 0:1-1:9) to obtain 8-C (1.9 g, two-step yield: 13% based on compound 8-A).

[0292] Step 3: Preparation of 8-D

[0293] Dissolve 8-C (1.9 g, 5.46 mmol) and TEA (1.66 g, 16.40 mmol) in 20 mL of dichloromethane, add chloroacetyl chloride (0.99 g, 8.77 mmol) dropwise, and react at room temperature for 20 h. Add 50 mL of water to the reaction solution, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product 8-D (2.1 g).

[0294] Step 4: Preparation of 8-E

[0295] The crude product 8-D (0.95 g) was added to 15 mL of acetic acid and reacted at 50°C for 20 h. The reaction system was cooled to 0°C, the pH was adjusted to 8 with 25% aqueous ammonia, and extracted with 150 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (methanol:dichloromethane (v / v) = 0:1-1:9) to obtain 8-E (0.85 g, two-step yield based on compound 8-C: 85%).

[0296] Step 5: Preparation of 8-F

[0297] 8-E (7.3 g, 17.95 mmol) was dissolved in 80 mL of THF, and 20 mL of a 1 mol / L solution of potassium tert-butoxide in tetrahydrofuran was added. The mixture was allowed to react at room temperature for 19 h. 30 mL of water and 50 mL of ethyl acetate were added to the reaction system. The organic phase was washed with 300 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (methanol:dichloromethane (v / v) = 0:1-1:9) to obtain 8-F (3.6 g, yield: 54%).

[0298] Step 6: Preparation of 8-G

[0299] 8-F (2.0 g, 5.4 mmol), 2,6-bis(benzyloxypyridine-3-boronic acid pinacol ester (3.4 g, 8.15 mmol), Pd(dppf)Cl2·DCM (0.44 g, 0.54 mmol), and cesium carbonate (3.5 g, 10.74 mmol) were added sequentially to a reaction flask. 1,4-Dioxane (100 mL) and water (10 mL) were added, and the mixture was reacted at 100°C under a nitrogen atmosphere for 20 h. The reaction system was cooled to room temperature, and 300 mL of water and 300 mL of ethyl acetate were added. The organic phase was washed with 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-9:1) to obtain 8-G (2.6 g, yield: 83%).

[0300] LCMS m / z=581.4[M+1] + .

[0301] Step 7: Preparation of 8-H

[0302] 8-G (2.6 g, 4.48 mmol) was dissolved in THF (10 mL) and methanol (30 mL), and 10% palladium on carbon (2.5 g) was added. The mixture was reacted at 40°C under a hydrogen balloon atmosphere for 20 h. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 8-H (0.98 g).

[0303] LCMS m / z=403.3[M+1] + .

[0304] Step 8: Preparation of Intermediate 8

[0305] The crude product 8-H (100 mg) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, and the mixture was allowed to react at room temperature for 3 h. The reaction system was concentrated under reduced pressure, 5 mL of methanol was added, and 150 mg of solid sodium bicarbonate was added. After stirring for 10 min, the mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the crude intermediate 8 (80 mg).

[0306] Example 1: Preparation of Compound 1

[0307] Intermediate 3 (45 mg, 0.098 mmol) was added to a single-necked flask, followed by dichloromethane (10 mL) and a 4 mol / L hydrochloric acid solution in 1,4-dioxane (10 mL). The mixture was allowed to react at room temperature for 2 h. The reaction system was concentrated under reduced pressure, and dichloromethane (15 mL) and sodium bicarbonate (25 mg, 0.3 mmol) were added. After stirring at room temperature for 30 min, 1a (50 mg, 0.099 mmol) (synthesis method reference WO2023088406), anhydrous sodium sulfate (200 mg), and acetic acid (0.02 mL) were added. After reacting at room temperature for 16 h, sodium triacetoxyborohydride (42 mg, 0.198 mmol) was added and the mixture was allowed to react at room temperature for 2 h. Water (120 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phase was washed with saturated aqueous sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by prep-TLC (dichloromethane: methanol (v / v) = 93:7) to give compound 1 (36 mg, yield: 43%).

[0308] 1 H NMR (400MHz, CDCl3) δ10.63(s,1H),7.97(s,1H),7.66(d,1H),7.56-7.32(m,5H),7.05-6.80(m,2H),6.41(d,1H),5.22(s,1H),4.85-4.70(m, 1H),4.40-4.22(m,2H),3.86-3.74(m,1H),3.73-3.51(m,3H),3.44-3. 15(m,5H),3.15-2.60(m,16H),2.40-2.05(m,3H),2.04-1.55(m,12H).

[0309] LCMS m / z=851.4[M+1] +

[0310] Example 3: Preparation of Compound 3

[0311] 2-D (41 mg, 0.098 mmol) was added to a single-necked flask, followed by dichloromethane (10 mL) and a 4 mol / L hydrochloric acid solution in 1,4-dioxane (10 mL). The mixture was allowed to react at room temperature for 2 h. The reaction system was concentrated under reduced pressure, and dichloromethane (15 mL) and sodium bicarbonate (25 mg, 0.3 mmol) were added. After stirring at room temperature for 30 min, 1a (50 mg, 0.099 mmol) (synthesis method, see WO2023088406), anhydrous sodium sulfate (200 mg), and acetic acid (0.02 mL) were added. After reacting at room temperature for 16 h, sodium triacetoxyborohydride (42 mg, 0.198 mmol) was added and the reaction was continued at room temperature for 2 h. Water (120 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phase was washed with saturated aqueous sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by prep-TLC (dichloromethane: methanol (v / v) = 93:7) to give compound 3 (35 mg, yield: 44%).

[0312] 1 H NMR(400MHz, CDCl3)δ10.63(s,1H),7.96(s,1H),7.56-7.32(m,4H),7.00-6 .85(m,2H),6.71(d,1H),6.49(d,1H),5.16(s,1H),4.40-4.22(m,2H),3.88 -3.70(m,2H),3.70-3.53(m,3H),3.44-3.22(m,4H),3.18-3.00(m,2H),3.0 0-2.55(m,13H),2.35-2.07(m,5H),2.05-1.55(m,10H),1.48-1.28(m,2H).

[0313] LCMS m / z=808.6[M+1] +

[0314] Example 5: Preparation of Compound 5

[0315] Step 1: Preparation of 5b

[0316] 5a (1.1 g, 3.43 mmol) (synthesis method reference WO2023088406) was dissolved in 1,4-dioxane (30 mL). The crude intermediate 5 (1.27 g), cesium carbonate (3.35 g, 10.28 mmol), palladium acetate (76 mg, 0.34 mmol), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (321 mg, 0.52 mmol) were added. The reaction was incubated at 80°C under a nitrogen atmosphere for 6 h. The reaction system was cooled to room temperature and filtered. The filter cake was washed with 150 mL of dichloromethane. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 91:9) to obtain 5b (1.2 g, yield: 66%).

[0317] LCMS m / z=531.3[M+1] +

[0318] Step 2: Preparation of 5c

[0319] 5b (1.2 g, 2.26 mmol) was dissolved in 15 mL of DMSO, followed by the addition of cesium carbonate (735 mg, 2.23 mmol). 30% hydrogen peroxide (6 mL) was slowly added dropwise at 0°C, stirred at 0°C for 5 min, and then allowed to return to room temperature for 3 h. To the reaction system was added 50 mL of saturated sodium sulfite solution and 70 mL of ethyl acetate. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated sodium chloride solution (60 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was isolated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 91:9) to obtain 5c (0.92 g, yield: 74%).

[0320] LCMS m / z=549.3[M+1] +

[0321] Step 3: Preparation of 5d

[0322] 5c (820 mg, 1.50 mmol) was dissolved in a mixed solvent of dichloromethane (35 mL) and acetonitrile (5 mL), and To the mixture of 5-(4-nitropropionic acid)-5-nitropropionic acid (5-nitropropionic acid) and 5-nitropropionic acid (5-nitropropionic acid) was added 5-nitropropionic acid (5-nitropropionic acid) (260 mg, 2.22 mmol) and tetrapropylammonium perruthenate (26 mg, 0.074 mmol). The reaction was allowed to proceed at room temperature for 6 h. The reaction system was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 92:8) to afford 5d (260 mg, 32% yield).

[0323] LCMS m / z=547.3[M+1] +

[0324] Step 4: Preparation of compound 5

[0325] 1-E (41 mg, 0.098 mmol) was added to a single-necked flask, followed by dichloromethane (10 mL) and a 4 mol / L hydrochloric acid solution in 1,4-dioxane (10 mL). The mixture was allowed to react at room temperature for 2 h. The reaction system was concentrated under reduced pressure, and dichloromethane (15 mL) and sodium bicarbonate (25 mg, 0.3 mmol) were added. After stirring at room temperature for 30 min, 5d (54 mg, 0.099 mmol), anhydrous sodium sulfate (200 mg), and acetic acid (0.02 mL) were added. The mixture was allowed to react at room temperature for 16 h, and then sodium triacetoxyborohydride (42 mg, 0.198 mmol) was added and allowed to react at room temperature for 2 h. Water (120 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phase was washed with saturated aqueous sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by prep-TLC (dichloromethane: methanol (v / v) = 93:7) to give compound 5 (37 mg, yield: 45%).

[0326] 1 H NMR (400MHz, CDCl3) δ10.61(s,1H),7.95(s,1H),7.56-7.32(m,4H),6.98-6.85(m,2H), 6.71(d,1H),6.48(d,1H),5.14(s,1H),4.38-4.22(m,2H),3.87-3.70(m,2H),3.68-3.52(m,1H), 3.43-3.22(m,4H),3.20-3.05(m,4H),3.05-2.70(m,10H),2.70-2.43(m,5H),2.35-1.45(m,19H).

[0327] LCMS m / z=848.6[M+1] +

[0328] Example 7: Preparation of Compound 7

[0329] Intermediate 3 (45 mg, 0.098 mmol) was added to a single-necked flask, followed by dichloromethane (10 mL) and a 4 mol / L hydrochloric acid solution in 1,4-dioxane (10 mL). The mixture was allowed to react at room temperature for 2 h. The reaction system was concentrated under reduced pressure, and dichloromethane (15 mL) and sodium bicarbonate (25 mg, 0.3 mmol) were added. After stirring at room temperature for 30 min, 5d (54 mg, 0.099 mmol), anhydrous sodium sulfate (200 mg), and acetic acid (0.02 mL) were added. The mixture was allowed to react at room temperature for 16 h, and then sodium triacetoxyborohydride (42 mg, 0.198 mmol) was added and allowed to react at room temperature for 2 h. Water (120 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phase was washed with saturated aqueous sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by prep-TLC (dichloromethane: methanol (v / v) = 93:7) to give compound 7 (33 mg, yield: 38%).

[0330] 1 H NMR (400MHz, CDCl3) δ10.61(s,1H),7.91(s,1H),7.66(d,1H),7.53-7.30(m,5H),7.00-6.85(m,2H),6.40(d,1H) ,5.14(s,1H),4.84-4.70(m,1H),4.38-4.20(m,2H),3.88-3.60(m,2H),3.45-2.38(m,25H),2.30-1.45(m,17H).

[0331] LCMS m / z=891.5[M+1] +

[0332] The following compounds were obtained by referring to the synthesis methods of other examples:

[0333] Example 13: Preparation of Compound 13

[0334] Compound 13 was obtained using compound 13a (synthesis method reference WO2023088406) and intermediate 5 as raw materials, referring to the synthesis method of Example 5.

[0335] 1H NMR (400MHz, CDCl3) δ10.62(s,1H),7.97(s,1H),7.55-7.31(m,4H),7.00-6.82(m,2H),6.79-6.65(m,1H),6.48(d, 1H),5.16(s,1H),4.40-4.20(m,2H),3.90-3.52(m,3H),3.45-3.22(m,4H),3.18-2.40(m,18H),2.35-1.44(m,20H).

[0336] LCMS m / z=848.4[M+1] +

[0337] Example 17: Preparation of Compound 17

[0338] Step 1: Preparation of 17b

[0339] 17a (2 g, 6.23 mmol) (synthesis method, see WO2023088406) was dissolved in 1,4-dioxane (30 mL). (1-(4-aminophenyl)piperidin-4-yl)methanol (1.9 g, 9.21 mmol), cesium carbonate (6.1 g, 18.72 mmol), palladium acetate (140 mg, 0.624 mmol), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (578 mg, 0.93 mmol) were added. The atmosphere was purged with nitrogen three times and the reaction was carried out at 80°C for 6 h. The reaction system was cooled to room temperature and filtered. The filter cake was washed twice with 200 mL of dichloromethane. The filtrate was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 91:9) to obtain 17b (1.2 g, yield: 39%).

[0340] LCMS m / z=491.3[M+1] +

[0341] Step 2: Preparation of 17c

[0342] 17b (1.2 g, 2.45 mmol) was dissolved in DMSO (20 mL), and cesium carbonate (796 mg, 2.44 mmol) was added. 30% hydrogen peroxide (8 mL) was slowly added dropwise under an ice-water bath. After stirring for 5 min, the ice-water bath was removed and the reaction was allowed to react at room temperature for 3 h. To the reaction system was added 70 mL of saturated sodium sulfite solution and 70 mL of ethyl acetate. The aqueous phase was extracted with ethyl acetate (60 mL × 3). The organic phase was washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was isolated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 92:8) to obtain 17c (1 g, yield: 80%).

[0343] LCMS m / z=509.3[M+1] +

[0344] Step 3: Preparation of 17d

[0345] 17c (700 mg, 1.38 mmol) was dissolved in a mixed solvent of dichloromethane (35 mL) and acetonitrile (5 mL), and To the mixture of 500 mg molecular sieves (500 mg), N-methylmorpholine oxide (242 mg, 2.07 mmol) and tetrapropylammonium perruthenate (24 mg, 0.068 mmol) were added and the reaction was allowed to proceed at room temperature for 6 h. The reaction system was filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 92:8) to afford 17d (150 mg, yield: 21%).

[0346] LCMS m / z=507.3[M+1] +

[0347] Step 4: Preparation of 17e

[0348] 3-A (60 mg, 0.17 mmol) was added to a 50 mL single-necked flask, followed by dichloromethane (10 mL) and trifluoroacetic acid (3 mL). The reaction was allowed to react at room temperature for 2 h. The reaction system was concentrated under reduced pressure, and N,N-dimethylacetamide (6 mL) and 17d (86 mg, 0.17 mmol) were added. After reacting at room temperature for 16 h, sodium triacetylborohydride (60 mg, 0.28 mmol) was added and allowed to react at room temperature for 2 h. Water (60 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (60 mL × 3). The organic phase was washed with saturated brine (60 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 91:9) to obtain 17e (50 mg, yield: 40%).

[0349] LCMS m / z=741.5[M+1] +

[0350] Step 5: Preparation of compound 17

[0351] 17e (25 mg, 0.034 mmol) was added to a 50 mL single-necked flask, followed by N,N-dimethylformamide (6 mL), EDCI (10 mg, 0.052 mol), HOBt (8 mg, 0.0592 mmol), and N-methylimidazole (15 mg, 0.18 mmol). After stirring at room temperature for 30 min, (S)-3-aminopiperidine-2,6-dione hydrochloride (7 mg, 0.043 mmol) was added and the mixture was allowed to react at room temperature for 16 h. Water (70 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phase was washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified on a thick preparative plate (dichloromethane:methanol (v / v) = 92:8) to obtain compound 17 (20 mg, yield: 69%).

[0352] 1 H NMR (400MHz, CDCl3) δ10.70(s,1H),7.95(s,1H),7.66(d,1H),7.60-7.32(m,5H),7.14-6.85(m,2H),6.41(d,1H),5.17(s, 1H),4.84-4.70(m,1H),4.40-4.24(m,2H),3.88-3.56(m,4H),3.45-2.60(m,21H),2.50-2.12(m,3H),2.10-1.50(m,12H).

[0353] LCMS m / z=851.4[M+1] +

[0354] Example 18: Preparation of Compound 18

[0355] Compound 18 was prepared using compound 17e and (R)-3-aminopiperidine-2,6-dione hydrochloride as raw materials by referring to the synthetic method of Example 17.

[0356] 1 H NMR (400MHz, CDCl3) δ10.67(s,1H),7.97(s,1H),7.66(d,1H),7.58-7.30(m,5H),7.10-6.85(m,2H),6.41(d,1H),5.17(s, 1H),4.87-4.70(m,1H),4.41-4.20(m,2H),3.90-3.55(m,4H),3.45-2.55(m,21H),2.50-2.10(m,3H),2.09-1.50(m,12H).

[0357] LCMS m / z=851.4[M+1] +

[0358] Example 19: Preparation of Compound 19

[0359] Compound 19 was prepared using compound 17d and 4-A as raw materials according to the synthetic method of Example 17.

[0360] 1 H NMR (400MHz, CDCl3) δ10.69(s,1H),7.94(s,1H),7.67(d,1H),7.58-7.32(m,5H),7.13-6.80(m,2H),6.41(d,1H),5.17(s, 1H),4.84-4.72(m,1H),4.40-4.22(m,2H),3.88-3.57(m,4H),3.50-2.55(m,21H),2.50-2.10(m,3H),2.08-1.50(m,12H).

[0361] LCMS m / z=851.4[M+1] +

[0362] Example 20: Preparation of Compound 20

[0363] Compound 20 was prepared using compound 19a and (R)-3-aminopiperidine-2,6-dione hydrochloride as raw materials by referring to the synthetic method of Example 17.

[0364] 1 H NMR (400MHz, CDCl3) δ10.72(s,1H),7.94(s,1H),7.67(d,1H),7.61-7.32(m,5H),7.18-6.85(m,2H),6.42(d,1H),5.17(s, 1H),4.85-4.66(m,1H),4.43-4.21(m,2H),3.90-3.55(m,4H),3.45-3.25(m,5H),3.20-3.15(m,19H),2.10-1.55(m,12H).

[0365] LCMS m / z=851.4[M+1] +

[0366] Example 21: Preparation of Compound 21

[0367] Intermediate 6 (80 mg, 0.19 mmol) was added to a 50 mL single-necked flask, followed by dichloromethane (10 mL) and a 4 mol / L hydrochloric acid solution in 1,4-dioxane (10 mL). The mixture was allowed to react at room temperature for 2 h. The reaction system was concentrated under reduced pressure, and dichloromethane (20 mL) and sodium bicarbonate (48 mg, 0.59 mmol) were added. After stirring at room temperature for 30 min, 9a (96 mg, 0.19 mmol), anhydrous sodium sulfate (200 mg), and acetic acid (0.02 mL) were added. The mixture was stirred at room temperature for 16 h, and then sodium triacetoxyborohydride (81 mg, 0.38 mmol) was added and allowed to react at room temperature for 2 h. Water (120 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (70 mL × 3). The organic phase was washed with saturated brine (60 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified using a thick preparative plate (dichloromethane: methanol (v / v) = 93:7) to give compound 21 (70 mg, yield: 46%).

[0368] 1 H NMR (400MHz, CDCl3) δ10.64(s,1H),7.60-7.32(m,5H),7.10-6.75(m,3H),6.53(d,1H),5.16(s,1H),4.40-4.21(m,2H) ,3.89-3.51(m,6H),3.44-3.23(m,4H),3.19-2.55(m,14H),2.40-2.06(m,2H),2.05-1.55(m,12H),1.50-1.32(m,2H).

[0369] LCMS m / z=809.6[M+1] +

[0370] Example 23: Preparation of Compound 23

[0371] Step 1: Preparation of chiral isomers 1 and 2 of 23a

[0372] 23a (synthesis method see WO2021023105) was subjected to chiral resolution, and the preparation conditions were as follows:

[0373] 1. Instrument: Waters 150Prep-SFC E; Column: Chiralcel AD column.

[0374] 2. Dissolve the sample in acetonitrile and filter with a 0.45 μm filter to prepare a sample solution.

[0375] 3. Preparative chromatographic conditions: a. Mobile phases consisted of A and B: Mobile phase A: CO2; Mobile phase B: methanol; b. Isocratic elution, mobile phase B content was 10%; c. Flow rate was 120 mL / min.

[0376] Chiral analysis conditions are as follows:

[0377] 1. Instrument: SHIMADZU LC-30AD; Chromatographic column: Chiralcel AD column.

[0378] 2. Analytical chromatographic conditions: a. Mobile phases consisted of a system of A and B: Mobile phase A: CO2; Mobile phase B: methanol (containing 0.05% diethylamine); b. Isocratic elution, mobile phase B content was 5-40%; c. Flow rate was 3 mL / min.

[0379] Peak time: chiral isomer 1: 0.60 min, chiral isomer 2: 0.78 min.

[0380] Chiral isomer 1 and chiral isomer 2 of compound 23a are respectively one of the isomers of structure 23a-1 or 23a-2.

[0381] Step 2: Preparation of 23b trifluoroacetate

[0382] The chiral isomer 1 of 23a (6.3 g, 25.07 mmol) was dissolved in 80 mL of dichloromethane, and 20 mL of trifluoroacetic acid was slowly added, and the mixture was reacted at 25° C. for 2 h. The reaction solution was concentrated under reduced pressure to obtain the crude trifluoroacetate salt of 23b (5.6 g).

[0383] Compound 23b is one of the isomers of structure 23b-1 or 23b-2.

[0384] Step 3: Preparation of 23c

[0385] The trifluoroacetate salt (5.6 g) of the crude product 23b was dissolved in 100 mL of DMF, and potassium carbonate (13.8 g, 100 mmol) and p-nitrofluorobenzene (4.2 g, 29.8 mmol) were added. The mixture was reacted at 80°C for 16 h. The reaction solution was cooled to room temperature, 500 mL of purified water was added, and the mixture was extracted twice with 300 mL of dichloromethane. The organic phases were combined, washed with 600 mL of purified water, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:1) to obtain 23c (4.5 g, yield: 55%).

[0386] LCMS m / z=273.1[M+1] +

[0387] Compound 23c is an isomer of structure 23c-1 or 23c-2.

[0388] Step 4: Preparation of 23d

[0389] 23c (4.5 g, 16.54 mmol) was dissolved in 100 mL of ethanol, and iron powder (4.5 g, 80.36 mmol) and 20 mL of saturated ammonium chloride solution were added. The reaction mixture was refluxed for 3 h. The reaction system was cooled to room temperature, 300 mL of dichloromethane was added, and the mixture was filtered. The filtrate was concentrated under reduced pressure to afford crude product 23d (3.9 g).

[0390] Compound 23d is an isomer of structure 23d-1 or 23d-2.

[0391] Step 5: Preparation of 23e

[0392] The crude product 23d (3.9 g) was dissolved in 100 mL of 1,4-dioxane, and 17a (5.2 g, 16.21 mmol), palladium acetate (0.36 g, 1.6 mmol), BINAP (2.0 g, 3.2 mmol), and cesium carbonate (13 g, 39.9 mmol) were added. The reaction was refluxed for 12 h. The reaction system was cooled to room temperature, 300 mL of dichloromethane was added, and the mixture was filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 15:1) to afford 23e (4.6 g, 54% yield).

[0393] LCMS m / z=527.5[M+1] +

[0394] Compound 23e is an isomer of structure 23e-1 or 23e-2.

[0395] Step 6: Preparation of 23f

[0396] 23e (4.6 g, 8.7 mmol) was dissolved in 180 mL of methanol, and 10 mL of DMSO and cesium carbonate (3.3 g, 10.13 mmol) were added. 50 mL of 30% aqueous hydrogen peroxide was slowly added, and the mixture was allowed to react at 25°C for 3 h. The reaction solution was concentrated under reduced pressure, and 300 mL of purified water was added to precipitate a yellow solid. The solid was filtered, and the filter cake was dried under reduced pressure to afford crude product 23f (3.8 g).

[0397] LCMS m / z=545.5[M+1] +

[0398] Compound 23f is an isomer of structure 23f-1 or 23f-2.

[0399] Step 7: Preparation of 23g

[0400] The crude product 23f (0.33 g) was dissolved in 20 mL of dichloromethane, and triethylamine (0.12 g, 1.19 mmol) and methanesulfonic anhydride (0.14 g, 0.8 mmol) were added. The mixture was allowed to react at 25°C for 3 h. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 15:1) to obtain 23g (0.36 g, two-step yield: 77% based on compound 23e).

[0401] Compound 23g is one of the isomers of structure 23g-1 or 23g-2.

[0402] Step 8: Preparation of compound 23

[0403] Intermediate 7 (0.21 g, 0.50 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (5 mL) was added, and the mixture was allowed to react at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, 10 mL of dichloromethane and 1 mL of isopropanol were added, the pH was adjusted to 9 with saturated sodium bicarbonate aqueous solution, and the mixture was extracted three times with 100 mL of a mixed solvent of dichloromethane / isopropanol (v / v) = 10:1. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product (0.158 g). 23 g (0.125 g, 0.2 mmol) was dissolved in a mixed solvent of 10 mL of acetonitrile and 5 mL of tetrahydrofuran, potassium carbonate (0.07 g, 0.51 mmol) and the above crude product (0.064 g) were added, and the mixture was refluxed for 8 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to obtain compound 23 (22 mg, yield: 13%).

[0404] 1 H NMR (400MHz, CDCl3) δ10.48(s,1H),7.56-7.34(m,4H),7.28-7.24(m,1H),6.87(d,1H),6.60-6.43(m,3H),5.35(s,1H ),4.38-4.20(m,2H),4.10-3.50(m,9H),3.42-2.72(m,18H),2.72-2.57(m,3H),2.25-2.07(m,1H),2.05-1.58(m,7H).

[0405] LCMS m / z=845.4[M+1] +

[0406] Compound 23 is one of the isomers of compound 23-A or 23-B.

[0407] Example 24: Preparation of Compound 24

[0408] Compound 24 was obtained using chiral isomer 2 of compound 23a as starting material by referring to the synthetic method of Example 23.

[0409] 1 H NMR(400MHz, CDCl3)δ10.48(s,1H),7.50-7.32(m,4H),7.27-7.23(m,1H),6.89(d,1H),6.60-6.43(m,3H),5 .39(s,1H),4.38-4.20(m,2H),4.10-3.50(m,9H),3.42-2.50(m,21H),2.25-2.07(m,1H),2.05-1.58(m,7H).

[0410] LCMS m / z=845.4[M+1] +

[0411] Compound 24 is one of the isomers of compound 23-A or 23-B.

[0412] Example 25: Preparation of Compound 25

[0413] Compound 25 was obtained using compound 23g and intermediate 6 as raw materials by referring to the synthetic method of Example 23.

[0414] 1 H NMR (400MHz, CDCl3) δ10.48(s,1H),7.54-7.30(m,4H),7.29-7.23(m,1H),6.95-6.82(m,1H),6.60-6.43(m,3H) ,5.35(s,1H),4.38-4.22(m,2H),4.10-3.50(m,9H),3.42-2.50(m,21H),2.25-2.07(m,1H),2.05-1.55(m,7H).

[0415] LCMS m / z=845.3[M+1] +

[0416] Compound 25 is one of the isomers of compound 25-A or 25-B.

[0417] Example 26: Preparation of Compound 26

[0418] Compound 26 was obtained using compound 24f and intermediate 6 as raw materials, referring to the synthetic method of Example 23.

[0419] 1 H NMR (400MHz, CDCl3) δ10.49(s,1H),7.55-7.30(m,4H),7.29-7.23(m,1H),6.95-6.82(m,1H),6.60-6.43(m,3H) ,5.37(s,1H),4.38-4.20(m,2H),4.10-3.50(m,9H),3.45-2.50(m,21H),2.25-2.07(m,1H),2.05-1.55(m,7H).

[0420] LCMS m / z=423.3[M / 2+1] +

[0421] Compound 26 is one of the isomers of compound 25-A or 25-B.

[0422] Example 27: Preparation of Compound 27

[0423] 23g (0.125g, 0.2mmol) was dissolved in a mixed solvent of 10mL of acetonitrile and 5mL of tetrahydrofuran. Potassium carbonate (0.07g, 0.51mmol) and 27a (0.064g, 0.2mmol) (synthesis method, see WO2023232133) were added and refluxed for 8h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to obtain compound 27 (47mg, yield: 28%).

[0424] 1 H NMR (400MHz, CDCl3) δ10.55(s,1H),8.02(d,1H),7.55-7.28(m,4H),6.80-6.66(m,1H),6.58-6.42( m,3H),5.17(s,1H),4.40-4.20(m,2H),3.90-3.52(m,6H),3.45-2.50(m,20H),2.45-1.40(m,13H).

[0425] LCMS m / z=844.4[M+1] +

[0426] Compound 27 is one of the isomers of compound 27-A or 27-B.

[0427] Example 28: Preparation of Compound 28

[0428] Compound 28 was prepared using compounds 27a and 24f as raw materials according to the synthetic method of Example 27.

[0429] 1 H NMR (400MHz, CDCl3) δ10.56(s,1H),8.06-7.96(m,1H),7.56-7.30(m,4H),6.80-6.66(m,1H),6.58-6. 42(m,3H),5.17(s,1H),4.40-4.20(m,2H),3.90-3.52(m,6H),3.45-2.50(m,20H),2.35-1.40(m,13H).

[0430] Compound 28 is one of the isomers of compound 27-A or 27-B.

[0431] Example 29: Preparation of Compound 29

[0432] Compound 29 was obtained using compounds 23g and 29a (synthesis method see WO2023232133) as raw materials and referring to the synthesis method of Example 27.

[0433] 1 H NMR (400MHz, CDCl3) δ10.54(s,1H),8.04-7.91(m,1H),7.55-7.30(m,4H),6.80-6.66(m,1H),6.58-6. 42(m,3H),5.15(s,1H),4.40-4.20(m,2H),3.90-3.52(m,6H),3.45-2.45(m,20H),2.37-1.40(m,13H).

[0434] Compound 29 is one of the isomers of compound 29-A or 29-B.

[0435] Example 30: Preparation of Compound 30

[0436] Compound 30 was obtained using compounds 24f and 29a as raw materials according to the synthetic method of Example 27.

[0437] 1H NMR (400MHz, CDCl3) δ10.55(s,1H),8.06-7.88(m,1H),7.62-7.30(m,4H),6.80-6.66(m,1H),6.58-6. 42(m,3H),5.15(s,1H),4.40-4.16(m,2H),3.90-3.52(m,6H),3.45-2.40(m,20H),2.35-1.40(m,13H).

[0438] Compound 30 is one of the isomers of compound 29-A or 29-B.

[0439] Example 31: Preparation of Compound 31

[0440] Step 1: Preparation of 31b trifluoroacetate

[0441] 31a (10 g, 41.79 mmol) was dissolved in 100 mL of dichloromethane, and 30 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 5 h. The reaction system was concentrated under reduced pressure to obtain the crude trifluoroacetate salt of 31b (12 g).

[0442] Step 2: Preparation of 31c

[0443] 4-Nitrofluorobenzene (5.36 g, 37.99 mmol) and the trifluoroacetate salt of the crude product 31b (12 g) were dissolved in 100 mL of DMF. Potassium carbonate (15.75 g, 113.97 mmol) was added and the mixture was reacted at 80°C for 18 h. The reaction system was cooled to room temperature and slowly poured into 1000 mL of water. The precipitated solid was filtered, and the filter cake was washed with water (20 mL x 3) and dried under reduced pressure to obtain crude product 31c (9.5 g).

[0444] LCMS m / z=261.1[M+1] +

[0445] Step 3: Preparation of 31d

[0446] The crude product 31c (3.0 g) was dissolved in 50 mL of methanol, and trimethyl orthoformate (4.89 g, 46.08 mmol) and p-toluenesulfonic acid (0.2 g, 1.16 mmol) were added. The mixture was reacted at 40°C for 16 h. The reaction system was concentrated under reduced pressure to obtain the crude product 31d (3.8 g).

[0447] Step 4: Preparation of 31e

[0448] The crude product 31d (3.5 g) was dissolved in 60 mL of methanol, and 1.0 g of 10% palladium on carbon was added. The mixture was reacted at room temperature under a hydrogen balloon for 5 h. The reaction mixture was filtered through Celite, the filter cake was washed with 50 mL of DCM, and the filtrate was concentrated under reduced pressure to afford the crude product 31e (3.0 g).

[0449] Step 5: Preparation of 31f

[0450] 17a (1.5 g, 4.68 mmol) was dissolved in 1,4-dioxane (60 mL), and the crude product 31e (1.45 g), cesium carbonate (4.87 g, 14.95 mmol), palladium acetate (170 mg, 0.76 mmol), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (310 mg, 0.50 mmol) were added. The atmosphere was purged with nitrogen three times, and the reaction was carried out at 100°C for 16 h. The reaction system was cooled to room temperature and filtered. The filter cake was washed twice with 200 mL of dichloromethane. The filtrate was concentrated under reduced pressure, and the crude product was isolated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1) to obtain 31f (1.8 g, yield: 69%).

[0451] LCMS m / z=561.3[M+1] +

[0452] Step 6: Preparation of 31g

[0453] 31f (1.0 g, 3.21 mmol) was dissolved in DMSO (5 mL), and cesium carbonate (580 mg, 1.78 mmol) was added. 30% hydrogen peroxide (5 mL) was slowly added dropwise under an ice-water bath. After stirring for 5 min, the ice-water bath was removed and the reaction was allowed to react at room temperature for 5 h. 50 mL of saturated aqueous sodium sulfite solution was added to the reaction system, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was slurried with a mixed solvent of 50 mL of methyl tert-butyl ether and 5 mL of dichloromethane, filtered, and the filter cake was dried under reduced pressure to obtain a crude product 31 g (0.88 g).

[0454] LCMS m / z=579.3[M+1] +

[0455] Step 7: Preparation for 31h

[0456] The crude product 31g (0.25g) was dissolved in 10mL of DCM, 2mL of trifluoroacetic acid was added, and the mixture was reacted at room temperature for 5h. The reaction system was concentrated under reduced pressure to obtain the crude product 31h (0.3g).

[0457] LCMS m / z=533.3[M+1] +

[0458] Step 8: Preparation of compound 31

[0459] 31A (90 mg, 0.22 mmol) (synthesis method, see WO2023232133) was added to a 50 mL single-necked flask, followed by dichloromethane (5 mL) and trifluoroacetic acid (2 mL), and the reaction was allowed to proceed at room temperature for 5 h. The reaction system was concentrated under reduced pressure, and 10 mL of tetrahydrofuran, the crude product 31h (150 mg), and sodium bicarbonate (100 mg, 1.19 mmol) were added. After stirring at room temperature for 30 min, acetic acid (36 mg, 0.60 mmol) was added. After stirring at room temperature for 2 h, sodium triacetoxyborohydride (85 mg, 0.40 mmol) was added and the reaction was allowed to proceed at room temperature for 16 h. Water (30 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phase was washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 12:1) to give compound 31 (50 mg, yield: 27%).

[0460] 1 H NMR (400MHz, CDCl3) δ10.62(s,1H),8.10(s,1H),7.53-7.35(m,4H),6.95-6.87(m,2H),6.71(d,1H),6.49(d,1H) ,5.21(s,1H),4.38-4.21(m,2H),3.88-3.56(m,3H),3.43-3.22(m,4H),3.20-2.57(m,18H),2.34-1.55(m,18H).

[0461] LCMS m / z=834.7[M+1] +

[0462] Example 32: Preparation of Compound 32

[0463] Compound 32 was obtained using compounds 31h and 32a (synthesis method see WO2023232133) as raw materials and referring to the synthesis method of Example 31.

[0464] 1H NMR (400MHz, CDCl3) δ10.62(s,1H),8.01(s,1H),7.53-7.35(m,4H),6.96-6.86(m,2H),6.71(d,1H),6.49(d,1H) ,5.17(s,1H),4.38-4.22(m,2H),3.88-3.55(m,3H),3.48-3.22(m,4H),3.18-2.55(m,18H),2.34-1.55(m,18H).

[0465] LCMS m / z=834.6[M+1] +

[0466] Example 33: Preparation of Compound 33

[0467] Step 1: Preparation of 33a

[0468] 3-A (150 mg, 0.43 mmol) was added to a 50 mL single-necked flask, followed by dichloromethane (5 mL) and trifluoroacetic acid (2 mL). The reaction was allowed to react at room temperature for 5 h. The reaction system was concentrated under reduced pressure, and 10 mL of tetrahydrofuran, the crude product 31h (300 mg), and sodium bicarbonate (210 mg, 2.5 mmol) were added. After stirring at room temperature for 30 min, acetic acid (74 mg, 1.23 mmol) was added. After stirring at 30°C for 2 h, sodium triacetoxyborohydride (170 mg, 0.80 mmol) was added and the reaction was allowed to react at room temperature for 16 h. Water (30 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (50 mL x 3). The organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 12:1) to obtain 33a (200 mg, yield: 61%).

[0469] LCMS m / z=767.6[M+1] +

[0470] Step 2: Preparation of compound 33

[0471] 33a (200 mg, 0.26 mmol) was added to a 50 mL single-necked bottle, along with N,N-dimethylformamide (5 mL), EDCI (100 mg, 0.52 mmol), HOBt (70 mg, 0.52 mmol), and N-methylimidazole (130 mg, 1.58 mmol). After stirring at room temperature for 30 min, (S)-3-aminopiperidine-2,6-dione hydrochloride (86 mg, 0.52 mmol) was added and the mixture was allowed to react at room temperature for 16 h. Water (70 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phase was washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was then subjected to pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, preparative column model: SunFire@Prep C18, 5 μm, i.d. × length = 19 mm × 250 mm). Preparation: A DMSO solution of the crude product was filtered through a 0.45 μm filter to prepare a sample solution. The mobile phase was water (containing 10 mmol / L ammonium bicarbonate) / acetonitrile. Gradient elution was performed using acetonitrile from 10% to 50% (elution time 15 min). Freeze-dried to afford compound 33 (120 mg, 53% yield).

[0472] 1 H NMR(400MHz,DMSO-d6)δ10.96(s,1H),10.82(s,1H),7.94(t,1H),7.72-7.66(m, 1H),7.60(s,1H),7.45-7.30(m,3H),7.29-7.21(m,1H),6.94-6.80(m,2H),6.67( d,1H),4.79-4.65(m,1H),4.45-4.18(m,2H),3.93-3.80(m,1H),3.68-3.52(m,1H ),3.40-3.20(m,5H),3.15-2.60(m,16H),2.58-2.45(m,1H),2.20-1.50(m,18H).

[0473] LCMS m / z=877.4[M+1] +

[0474] Example 34: Preparation of Compound 34

[0475] Compound 34 was obtained using compound 31h and 4-A as raw materials by referring to the synthetic method of Example 33.

[0476] 1H NMR(400MHz,DMSO-d6)δ10.96(s,1H),10.82(s,1H),7.93(t,1H),7.69(s,1H) ,7.60(s,1H),7.46-7.31(m,3H),7.26(s,1H),6.94-6.80(m,2H),6.68(d,1H) ,4.78-4.65(m,1H),4.43-4.16(m,2H),3.95-3.80(m,1H),3.68-3.54(m,1H), 3.42-3.18(m,5H),3.17-2.61(m,16H),2.58-2.50(m,1H),2.20-1.45(m,18H).

[0477] LCMS m / z=877.9[M+1] +

[0478] Example 35: Preparation of Compound 35 Trifluoroacetate

[0479] Compound 35 trifluoroacetate was prepared from compound 35a by lyophilization in acidic solution [water (containing 0.1% TFA) / acetonitrile] according to the synthesis methods of Examples 31 and 33.

[0480] 1 H NMR(400MHz,DMSO-d6)δ11.07(s,1H),10.83(s,1H),8.04(t,1H),7.72(s,1H) ,7.63(s,1H),7.54-7.37(m,3H),7.28(s,1H),7.05-6.93(m,2H),6.87(d,1H) ,4.80-4.65(m,1H),4.43-4.17(m,3H),3.86-3.54(m,5H),3.50-2.86(m,11H) ,2.85-2.63(m,8H),2.60-2.47(m,1H),2.30-1.93(m,5H),1.90-1.45(m,7H).

[0481] LCMS m / z=837.8[M+1] +

[0482] Example 36: Preparation of Compound 36 Trifluoroacetate

[0483] Compound 36 trifluoroacetate was obtained using compound 35h and 4-A as raw materials according to the synthetic method of Example 35.

[0484] 1H NMR(400MHz,DMSO-d6)δ11.04(s,1H),10.83(s,1H),8.04(t,1H),7.72(s,1H) ,7.62(s,1H),7.54-7.37(m,3H),7.27(s,1H),7.02-6.91(m,2H),6.87(d,1H) ,4.80-4.65(m,1H),4.43-4.17(m,3H),3.86-3.54(m,5H),3.50-2.85(m,11H) ,2.85-2.63(m,8H),2.60-2.47(m,1H),2.30-1.93(m,5H),1.90-1.45(m,7H).

[0485] LCMS m / z=837.6[M+1] +

[0486] Example 37: Preparation of Compound 37

[0487] Step 1: Preparation of 37a

[0488] 3-A (0.175 g, 0.5 mmol) was dissolved in 10 mL of dichloromethane, and TCFH (0.28 g, 1.0 mmol) and NMI (0.24 g, 2.92 mmol) were added. The mixture was allowed to react at room temperature for 2 h. Then, 2 mL of anhydrous methanol was added to the reaction system and the reaction was continued at room temperature for 16 h. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 3:1) to obtain 37a (0.17 g, yield: 93%).

[0489] Step 2: Preparation of 37b trifluoroacetate

[0490] 37a (0.17 g, 0.47 mmol) was dissolved in 6 mL of dichloromethane, and 2 mL of trifluoroacetic acid was slowly added, and the mixture was reacted at 25° C. for 2 h. The reaction solution was concentrated under reduced pressure to obtain the crude trifluoroacetate salt of 37b (0.12 g).

[0491] Step 3: Preparation of 37c

[0492] 24f (0.25 g, 0.4 mmol) was dissolved in a mixture of 20 mL of acetonitrile and 5 mL of tetrahydrofuran. Potassium carbonate (0.14 g, 1.01 mmol) and the trifluoroacetate salt of the crude product 37b (0.12 g) were added, and the mixture was refluxed for 8 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to afford 37c (0.2 g, 63% yield).

[0493] LCMS m / z=791.5[M+1] +

[0494] Compound 37c is one of the isomers of structure 37c-1 or 37c-2.

[0495] Step 4: Preparation of 37d

[0496] 37c (0.2 g, 0.25 mmol) was dissolved in a mixture of 10 mL of tetrahydrofuran and 3 mL of methanol. 3 mL of purified water and lithium hydroxide monohydrate (0.63 g, 15 mmol) were added, and the mixture was allowed to react at 25°C for 12 h. The reaction solution was adjusted to pH 7 with 1 mol / L hydrochloric acid and concentrated under reduced pressure to afford crude product 37d (0.15 g).

[0497] LCMS m / z=777.3[M+1] +

[0498] Compound 37d is one of the isomers of structure 37d-1 or 37d-2.

[0499] Step 5: Preparation of compound 37

[0500] The crude product 37d (0.15 g) was dissolved in 10 mL of DMF, and EDCI (0.1 g, 0.52 mmol), NMI (0.24 g, 2.92 mmol), HOBt (0.07 g, 0.52 mmol), and 37A (66.6 mg, 0.52 mmol) were added. The reaction was allowed to react at room temperature for 12 h. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to obtain compound 37 (62 mg, yield: 13%).

[0501] 1 H NMR (400MHz, CDCl3) δ10.56(s,1H),7.97-7.84(m,1H),7.75-7.31(m,6H),6.60-6.30(m,3H),5.30-5.03( m,1H),4.87-4.70(m,1H),4.48-4.15(m,2H),3.90-3.57(m,4H),3.50-2.45(m,21H),2.25-1.40(m,13H).

[0502] Compound 37 is one of the isomers of compound 37-A or 37-B.

[0503] Example 38: Preparation of Compound 38

[0504] Compound 38 was obtained using compound 4-A as raw material by referring to the synthetic method of Example 37.

[0505] 1 H NMR (400MHz, CDCl3) δ10.56(s,1H),8.05-7.92(m,1H),7.75-7.31(m,6H),6.60-6.30(m,3H),5.12(s,1H),4.87 -4.70(m,1H),4.37-4.20(m,2H),3.90-3.57(m,5H),3.43-3.23(m,4H),3.20-2.43(m,16H),2.40-1.55(m,13H).

[0506] Compound 38 is one of the isomers of compound 38-A or 38-B.

[0507] Example 39: Preparation of Compound 39

[0508] Compound 39 was obtained using compound 23g as raw material by referring to the synthetic method of Example 37.

[0509] 1 H NMR (400MHz, CDCl3) δ10.55(s,1H),8.05-7.90(m,1H),7.75-7.31(m,6H),6.60-6.30(m,3H),5.30-5.05(m,1H),4. 85-4.70(m,1H),4.52-4.22(m,2H),3.90-3.55(m,4H),3.45-3.21(m,5H),3.21-2.43(m,16H),2.40-1.55(m,13H).

[0510] Compound 39 is one of the isomers of compound 37-A or 37-B.

[0511] Example 40: Preparation of Compound 40

[0512] Compound 40 was obtained using compounds 23g and 38b as raw materials according to the synthetic method of Example 37.

[0513] 1H NMR (400MHz, CDCl3) δ10.57(s,1H),7.93(s,1H),7.75-7.31(m,6H),6.60-6.30(m,3H),5.15(s,1H),4.87-4. 68(m,1H),4.37-4.20(m,2H),3.90-3.55(m,6H),3.45-3.23(m,5H),3.21-2.57(m,16H),2.30-1.55(m,11H).

[0514] Compound 40 is one of the isomers of compound 38-A or 38-B.

[0515] Example 41: Preparation of Compound 41 Trifluoroacetate

[0516] 41a (90 mg, 0.22 mmol) (synthesis method, see WO2023232133) was added to a 50 mL single-necked flask, followed by dichloromethane (5 mL) and trifluoroacetic acid (2 mL), and the reaction was allowed to proceed at room temperature for 5 h. The reaction system was concentrated under reduced pressure, and 5 mL of DMA, 35h (120 mg, 0.24 mmol), and sodium bicarbonate (100 mg, 1.19 mmol) were added. After stirring at room temperature for 30 min, acetic acid (36 mg, 0.60 mmol) was added, and the reaction was continued at 30°C for 2 h. Then, sodium triacetoxyborohydride (85 mg, 0.40 mmol) was added and the reaction was allowed to proceed at room temperature for 16 h. Water (30 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phase was washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was subjected to Pre-HPLC (Instrument and Preparative Column: Waters 2767 Preparative Liquid Phase, Preparative Column Model: SunFire@Prep C18, 5 μm, ID × Length = 19 mm × 250 mm). Preparation Method: A DMSO solution of the crude product was filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile was gradient eluted from 10% to 50% (elution time: 15 min). The product was lyophilized to obtain the trifluoroacetate salt of compound 41 (12 mg).

[0517] 1H NMR (400MHz, DMSO-d6) δ10.97(s,1H),10.76(s,1H),7.69(s,1H),7.60(s,1H),7. 47-7.35(m,2H),7.25(s,1H),6.94-6.84(m,2H),6.79(d,1H),6.62(d,1H),4.44-4 .18(m,2H),3.88-3.55(m,5H),3.50-3.10(m,4H),3.10-2.85(m,5H),2.80-2.55(m ,9H),2.55-2.45(m,1H),2.41-2.22(m,2H),2.20-1.70(m,9H),1.68-1.44(m,4H).

[0518] Example 42: Preparation of Compound 42

[0519] Compound 42 was prepared by freeze-drying using compound 42a (synthesis method see WO2023232133) as the raw material, referring to the synthesis method of Example 41, using a neutral preparation [mobile phase system: water (containing 5 mmol / L ammonium acetate) / acetonitrile].

[0520] 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),10.76(s,1H),7.69(s,1H),7.60(s,1H),7. 47-7.35(m,2H),7.25(s,1H),6.94-6.84(m,2H),6.79(d,1H),6.62(d,1H),4.44-4 .18(m,2H),3.88-3.55(m,5H),3.50-3.10(m,4H),3.10-2.85(m,5H),2.80-2.55(m ,9H),2.55-2.45(m,1H),2.41-2.22(m,2H),2.20-1.70(m,9H),1.68-1.44(m,4H).

[0521] Example 43: Preparation of Compound 43

[0522] Step 1: Preparation of 43b

[0523] 43A (2.34 g, 10.00 mmol) and 43a (3.01 g, 12.01 mmol) (synthesis method, see WO2023083194) were dissolved in 20 mL of DCM, and DIPEA (1.68 g, 13.0 mmol) was slowly added dropwise. The reaction was allowed to react at room temperature for 10 min. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:1) to afford 43b (4.4 g, yield: 98%).

[0524] LCMS m / z=448.4[M+1] +

[0525] Step 2: Preparation of 43c

[0526] 43b (4.4 g, 9.83 mmol) was added to 30 mL of methanol, and 80 mL of a 7 mol / L methanolic ammonia solution was slowly added dropwise. The mixture was allowed to react at room temperature for 3 h. The reaction system was filtered, and the filter cake was collected and washed with 30 mL of petroleum ether and dried under reduced pressure to obtain crude product 43c (3.8 g).

[0527] LCMS m / z=419.1[M+1] +

[0528] Step 3: Preparation of 43d

[0529] The crude product 43c (1.0 g) was dissolved in 20 mL of NMP, and m-chloroperbenzoic acid (1.45 g, 8.4 mmol) was added, and the reaction was allowed to react at room temperature for 16 h. DIPEA (1.15 g, 8.90 mmol) and 43B (525 mg, 2.86 mmol) (synthesis method, see WO2023088406) were added to the reaction system, and the reaction was allowed to proceed at 80°C for 4 h. The reaction system was cooled to room temperature, 60 mL of water was added, and the mixture was extracted with ethyl acetate (80 mL × 2). The organic phases were combined, washed with water (100 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (DCM:MeOH (v / v) = 15:1) to obtain 43d (0.6 g, yield: 38%).

[0530] LCMS m / z=554.7[M+1] +

[0531] Step 4: Preparation of 43e trifluoroacetate

[0532] 43d (0.3 g, 0.54 mmol) was dissolved in 10 mL of DCM, and 2 mL of trifluoroacetic acid was added, and the mixture was allowed to react at room temperature for 3 h. The reaction system was concentrated under reduced pressure to afford the crude trifluoroacetic acid salt of 43e (0.35 g).

[0533] LCMS m / z=508.8[M+1] +

[0534] Step 5: Preparation of compound 43

[0535] 43C (120 mg, 0.29 mmol) (synthesis method, see WO2023232133) was added to a 50 mL single-necked flask, followed by dichloromethane (5 mL) and trifluoroacetic acid (2 mL), and the reaction was allowed to proceed at room temperature for 5 h. The reaction system was concentrated under reduced pressure, and 5 mL of DMA, the above-mentioned crude product 43e trifluoroacetate (175 mg), and sodium bicarbonate (87 mg, 1.04 mmol) were added. After stirring at room temperature for 30 min, acetic acid (47 mg, 0.78 mmol) was added, and the reaction was continued at 30°C for 2 h. Then, sodium triacetoxyborohydride (170 mg, 0.80 mmol) was added and the reaction was continued at room temperature for 16 h. Water (30 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phase was washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was subjected to Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid phase, preparative column model: SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter membrane to prepare a sample solution. The mobile phase system was water (containing 10 mmol / L ammonium bicarbonate) / acetonitrile. Gradient elution method: Acetonitrile was gradient eluted from 10% to 50% (elution time 15 min). The product was lyophilized to obtain compound 43 (55 mg, yield: 23%).

[0536] 1 H NMR(400MHz,DMSO-d6)δ11.07(s,1H),10.76(s,1H),8.28(s,1H),7.66(s, 1H),7.57-7.42(m,2H),7.00-6.87(m,2H),6.79(d,1H),6.62(d,1H),5.00 -4.17(m,2H),3.88-3.52(m,5H),3.41-3.18(m,5H),3.17-2.80(m,5H),2. 80-2.54(m,9H),2.54-2.42(m,1H),2.25-1.40(m,14H),1.32-1.12(m,2H).

[0537] LCMS m / z=809.4[M+1] +

[0538] Example 44: Preparation of Compound 44

[0539] Compound 44 was obtained using compound 44a (synthesis method see WO2023232133) as raw material and referring to the synthesis method of Example 43.

[0540] 1 H NMR(400MHz,DMSO-d6)δ11.07(s,1H),10.76(s,1H),8.28(s,1H),7.67(s,1H),7.55 -7.44(m,2H),7.00-6.87(m,2H),6.79(d,1H),6.62(d,1H),5.00-4.20(m,2H),3.88 -3.52(m,5H),3.42-3.18(m,5H),3.16-2.83(m,5H),2.78-2.54(m,9H),2.54-2.43( m,1H),2.25-1.99(m,4H),1.99-1.65(m,8H),1.65-1.43(m,2H),1.33-1.12(m,2H).

[0541] LCMS m / z=809.3[M+1] +

[0542] Example 45: Preparation of Compound 45 Trifluoroacetate

[0543] Intermediate 7 (200 mg, 0.48 mmol) was added to a 50 mL single-necked flask, followed by dichloromethane (10 mL) and a 4 mol / L hydrochloric acid solution in 1,4-dioxane (10 mL). The mixture was allowed to react at room temperature for 2 h. The reaction system was concentrated under reduced pressure, and the trifluoroacetate salt of the crude product 43e (175 mg), sodium bicarbonate (87 mg, 1.04 mmol), and DMA (5 mL) were added. After stirring at room temperature for 30 min, acetic acid (47 mg, 0.78 mmol) was added. The reaction was continued at 30°C for 2 h, followed by the addition of sodium triacetoxyborohydride (170 mg, 0.80 mmol), and the reaction was continued at room temperature for 16 h. Water (30 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (50 mL x 3). The organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was then subjected to Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid chromatography, preparative column model: SunFire@Prep C18, 5 μm, inner diameter x length = 19 mm x 250 mm). Preparation method: A DMSO solution of the crude product was filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile was gradient eluted from 10% to 50% (elution time 15 min). The trifluoroacetate salt of compound 45 (35 mg) was lyophilized.

[0544] 1 H NMR(400MHz,DMSO-d6)δ11.31(s,1H),10.37(s,1H),8.33(s,1H),7.81(s,1H),7.64-7.54(m,2H),7.15-6.97(m,3 H),6.90(d,1H),4.90-4.25(m,2H),4.20-4.05(m,1H),3.78-3.55(m,7H),3.48-2.60(m,21H),2.18-1.30(m,11H).

[0545] LCMS m / z=810.4[M+1] +

[0546] Example 46: Preparation of Compound 46 Trifluoroacetate

[0547] Compound 46 trifluoroacetate was obtained from intermediate 6 by referring to the synthesis method of Example 45.

[0548] 1 H NMR(400MHz,DMSO-d6)δ11.31(s,1H),10.37(s,1H),8.34(s,1H),7.81(s,1H),7.64-7.54(m,2H),7.15-6.97(m,3 H),6.91(d,1H),4.90-4.30(m,2H),4.20-4.05(m,1H),3.78-3.55(m,7H),3.48-2.60(m,21H),2.18-1.30(m,11H).

[0549] LCMS m / z=810.4[M+1] +

[0550] Example 47: Preparation of Compound 47

[0551] Step 1: Preparation of 47a

[0552] 3-A (110 mg, 0.31 mmol) was added to a 50 mL single-necked flask, followed by dichloromethane (5 mL) and trifluoroacetic acid (2 mL). The reaction was allowed to react at room temperature for 5 h. The reaction system was concentrated under reduced pressure, and 5 mL of DMA, the trifluoroacetate salt of the crude product 43e (180 mg), and sodium bicarbonate (91 mg, 1.08 mmol) were added. After stirring at room temperature for 30 min, acetic acid (64 mg, 1.07 mmol) was added. After reacting at 30°C for 2 h, sodium triacetoxyborohydride (115 mg, 0.54 mmol) was added and the reaction was allowed to react at room temperature for 16 h. Water (30 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phase was washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 12:1) to obtain 47a (150 mg, yield: 65%).

[0553] LCMS m / z=742.4[M+1] +

[0554] Step 2: Preparation of compound 47

[0555] 47a (150 mg, 0.20 mmol) was added to a 50 mL single-necked flask, along with N,N-dimethylformamide (5 mL), EDCI (77 mg, 0.40 mol), HOBt (54 mg, 0.40 mmol), and N-methylimidazole (99 mg, 1.20 mmol). After stirring at room temperature for 30 min, (S)-3-aminopiperidine-2,6-dione hydrochloride (66 mg, 0.4 mmol) was added and the mixture was allowed to react at room temperature for 16 h. Water (70 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phase was washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was then subjected to pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, preparative column model: SunFire@Prep C18, 5 μm, i.d. × length = 19 mm × 250 mm). Preparation: A DMSO solution of the crude product was filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase: water (containing 10 mmol / L ammonium bicarbonate) / acetonitrile. Gradient elution: 10% to 50% acetonitrile (elution time 15 min). Lyophilization afforded compound 47 (62 mg, 36% yield).

[0556] 1H NMR(400MHz,DMSO-d6)δ11.08(s,1H),10.82(s,1H),8.29(s,1H),7.95(t,1H),7.6 7(s,1H),7.56-7.45(m,2H),7.36(d,1H),7.04-6.86(m,2H),6.68(d,1H),5.00-4. 25(m,3H),3.94-3.78(m,1H),3.73-3.55(m,3H),3.40-3.20(m,5H),3.18-2.60(m, 14H),2.59-2.45(m,1H),2.30-1.88(m,6H),1.88-1.40(m,8H),1.32-1.14(m,2H).

[0557] LCMS m / z=852.4[M+1] +

[0558] Example 48: Preparation of Compound 48

[0559] Compound 48 was obtained using compound 4-A as the raw material by referring to the synthetic method of Example 47.

[0560] 1 H NMR(400MHz,DMSO-d6)δ11.07(s,1H),10.82(s,1H),8.28(s,1H),7.95(t,1H),7.6 7(s,1H),7.56-7.45(m,2H),7.36(d,1H),7.04-6.86(m,2H),6.68(d,1H),5.00-4. 25(m,3H),3.94-3.78(m,1H),3.73-3.55(m,3H),3.40-3.20(m,5H),3.18-2.60(m, 14H),2.59-2.45(m,1H),2.30-1.88(m,6H),1.88-1.40(m,8H),1.32-1.14(m,2H).

[0561] LCMS m / z=852.3[M+1] +

[0562] Example 49: Preparation of Compound 49

[0563] Step 1: Preparation of 49a

[0564] 4-A (64 mg, 0.18 mmol) was added to a 50 mL single-necked flask, followed by dichloromethane (12 mL) and trifluoroacetic acid (4 mL). The mixture was allowed to react at room temperature for 2 h, then concentrated under reduced pressure. N,N-dimethylacetamide (10 mL) and 13d (100 mg, 0.18 mmol) were added, and the reaction was continued at room temperature for 16 h. Then, sodium triacetoxyborohydride (76 mg, 0.36 mmol) was added and allowed to react at room temperature for 2 h. Water (60 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (70 mL × 3). The organic phase was washed with saturated brine (80 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 91:9) to obtain 49a (48 mg, yield: 34%).

[0565] LCMS m / z=781.5[M+1] +

[0566] Step 2: Preparation of compound 49

[0567] 49a (48 mg, 0.061 mmol) was added to a 50 mL single-necked bottle, and N,N-dimethylformamide (6 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (17.8 mg, 0.093 mmol), 1-hydroxybenzotriazole (12 mg, 0.089 mmol), and N-methylimidazole (26 mg, 0.32 mmol) were added. After stirring at room temperature for 30 min, (S)-3-aminopiperidine-2,6-dione hydrochloride (20 mg, 0.12 mmol) was added and the reaction was allowed to react at room temperature for 16 h. Water (80 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (60 mL × 3). The organic phase was washed with saturated brine (60 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by thick silica gel plate (dichloromethane:methanol (v / v) = 93:7) to give compound 49 (30 mg, yield: 55%).

[0568] 1 H NMR (400MHz, CDCl3) δ10.63(s,1H),7.93(s,1H),7.67(d,1H),7.54-7.32(m,5H),6.98-6.85(m,2H),6.40(d,1H),5.14(s, 1H),4.85-4.72(m,1H),4.40-4.20(m,2H),3.85-3.65(m,2H),3.43-3.23(m,5H),3.18-2.55(m,20H),2.50-1.45(m,17H).

[0569] LCMS m / z=891.5[M+1]+

[0570] Example 50: Preparation of Compound 50

[0571] Compound 50 was obtained using compound 3-A as a raw material by referring to the synthetic method of Example 49.

[0572] 1 H NMR (400MHz, CDCl3) δ10.61(s,1H),7.98(s,1H),7.65(d,1H),7.54-7.31(m,5H),6.97-6.80(m,2H),6.40(d,1H),5.16(s,1H),4.84 -4.70(m,1H),4.38-4.22(m,2H),3.86-3.74(m,1H),3.72-3.60(m,1H),3.44-3.17(m,5H),3.16-2.41(m,20H),2.33-1.45(m,17H).

[0573] LCMS m / z=891.5[M+1] +

[0574] Example 51: Preparation of Compound 51

[0575] Step 1: Preparation of 51-B

[0576] 51-A (21.0 g, 77.97 mmol) (synthesis method, see WO2020081450) was dissolved in 150 mL of tetrahydrofuran. 60% NaH (6.24 g) was added at 0°C. After stirring at 0°C for 30 minutes, deuterated iodomethane (12.43 g, 85.75 mmol) was added and the mixture was allowed to react at room temperature for 16 hours. 200 mL of water was added to the reaction solution, and the mixture was extracted three times with 200 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-1:1) to obtain 51-B (22.0 g, yield: 99%).

[0577] LCMS m / z=287.3[M+1] +

[0578] Step 2: Preparation of 51B hydrochloride

[0579] Dissolve 51-B (5.0 g, 17.46 mmol) in 10 mL of dichloromethane, add 4 mol / L hydrochloric acid in 1,4-dioxane (30 mL), and react at room temperature for 3 h. Concentrate the reaction system under reduced pressure to obtain the crude hydrochloride salt of 51B (4.0 g).

[0580] Step 3: Preparation of 51b

[0581] 51a (2.15 g, 9.20 mmol) and 51A (2.94 g, 11.04 mmol) (synthesis method, see CN116143757) were dissolved in 20 mL of DCM. DIPEA (1.55 g, 11.99 mmol) was slowly added dropwise and allowed to react at room temperature for 10 min. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:1) to afford 51b (4.0 g, 94% yield).

[0582] LCMS m / z=464.2[M+1] +

[0583] Step 4: Preparation of 51c

[0584] 51b (4.0 g, 8.64 mmol) was added to 30 mL of methanol, and 80 mL of 7 mol / L methanolic ammonia solution was slowly added dropwise. The reaction was allowed to react at room temperature for 3 h. The reaction system was filtered, and the filter cake was collected, washed with 30 mL of petroleum ether, and dried under reduced pressure to obtain crude product 51c (3.7 g).

[0585] Step 5: Preparation of 51d

[0586] To a reaction flask, crude product 51c (2.0 g), m-CPBA (4.38 g), and 20 mL of NMP were added. After stirring at room temperature for 16 h, DIPEA (2.79 g, 21.59 mmol) and the hydrochloride salt of crude product 51b (1.54 g) were added sequentially, and the mixture was reacted at 80°C for 16 h. The reaction system was cooled to room temperature, 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL x 4). The organic phases were combined, washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 1:0 to 0:1) to afford 51d (0.97 g, 36% yield over two steps based on compound 51b).

[0587] LCMS m / z=573.4[M+1] +

[0588] Step 6: Preparation of 51e

[0589] 51d (0.97 g, 1.69 mmol) was dissolved in 5 mL of tetrahydrofuran, and 3 mol / L hydrochloric acid (7 mL) was added. The reaction was allowed to react at 80°C for 3 h. The reaction system was cooled to room temperature, and saturated aqueous sodium bicarbonate was added to adjust the pH to 9. The reaction system was extracted with dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 51e (1.52 g).

[0590] LCMS m / z=529.3[M+1] +

[0591] Step 7: Preparation of compound 51

[0592] To a reaction flask, crude product 51e (0.25 g), crude intermediate 2 (0.15 g), 0.2 mL of glacial acetic acid, and 5 mL of DMAc were added. The mixture was allowed to react at room temperature for 1 h. Then, sodium triacetoxyborohydride (0.25 g, 1.18 mmol) was added and allowed to react at room temperature for 16 h. The reaction system was subjected to pre-HPLC (apparatus and preparative column: SHIMADZ LC-20AP preparative HPLC, C18 preparative column). Preparation method: A DMSO solution of the crude product was filtered through a 0.45 μm filter to prepare a sample solution. The mobile phase system consisted of water (containing 10 mmol / L ammonium bicarbonate) / acetonitrile. Gradient elution was performed: 33% to 63% acetonitrile (elution time 15 min). The product was then lyophilized to afford compound 51 (30.0 mg, two-step yield: 13% based on compound 51d).

[0593] 1 H NMR (400MHz, CDCl3) δ10.88(s,1H),8.38(s,1H),7.73(s,1H),7.54(d,1H),7.21(s,1H),6.95(t,1H),6.70(d,1H),6.48(d,1H),5.73(s,1H ),5.25-4.20(m,2H),3.85-3.67(m,2H),3.67-3.52(m,1H),3.52-3.24(m,6H),3.24-2.50(m,12H),2.35-2.07(m,5H),2.05-1.55(m,10H), 1.55-1.30(m,2H).

[0594] LCMS m / z=830.3[M+1] +

[0595] Example 52: Preparation of Compound 52

[0596] Compound 52 was obtained using compound 51e and intermediate 1 as raw materials by referring to the synthetic method of Example 51.

[0597] 1 H NMR(400MHz,DMSO-d6)δ11.26(s,1H),10.75(s,1H),8.32(s,1H),7.77-7.22(m,3H) ,7.03(t,1H),6.79(d,1H),6.62(d,1H),5.10-4.05(m,2H),3.88-3.76(m,1H),3.76 -3.66(m,1H),3.66-3.52(m,1H),3.40-3.20(m,6H),3.19-2.83(m,5H),2.82-2.54( m,6H),2.54-2.44(m,1H),2.28-2.00(m,4H),2.00-1.44(m,11H),1.38-1.18(m,2H).

[0598] LCMS m / z=830.3[M+1] +

[0599] Example 53: Preparation of Compound 53

[0600] Compound 53 was prepared from compound 51e and intermediate 7 by neutral preparation [water (containing 10 mmol / L ammonium bicarbonate) / acetonitrile] according to the synthesis method of Example 45.

[0601] 1 H NMR(400MHz,DMSO-d6)δ11.26(s,1H),10.33(s,1H),8.32(s,1H),7.72(s,1H),7.6 5-7.20(m,2H),7.03(t,1H),6.92(d,1H),6.72(d,1H),5.10-4.20(m,2H),3.80-3. 68(m,1H),3.67-3.50(m,3H),3.40-3.20(m,6H),3.20-2.82(m,5H),2.82-2.50(m, 7H),2.27-2.14(m,2H),2.12-1.97(m,1H),1.96-1.43(m,10H),1.38-1.16(m,2H).

[0602] LCMS m / z=831.4[M+1] +

[0603] Example 54: Preparation of Compound 54

[0604] Compound 54 was prepared from compound 51e and intermediate 6 by neutral preparation [water (containing 10 mmol / L ammonium bicarbonate) / acetonitrile] according to the synthesis method of Example 45.

[0605] 1 H NMR(400MHz,DMSO-d6)δ11.26(s,1H),10.32(s,1H),8.32(s,1H),7.71(s,1H),7.65-7.23(m,2H),7.03(t,1H),6.93(d,1H),6.71(d,1H),5 .10-4.20(m,2H),3.80-3.69(m,1H),3.67-3.54(m,3H),3.40-3.20(m ,6H),3.20-2.85(m,5H),2.82-2.50(m,7H),2.30-2.15(m,2H),2.14- 1.98(m,1H),1.96-1.45(m,10H),1.40-1.18(m,2H).

[0606] LCMS m / z=831.4[M+1] +

[0607] Example 55: Preparation of Compound 55

[0608] Step 1: Preparation of 55A trifluoroacetate

[0609] 3-A (0.329 g, 0.94 mmol) was added to a reaction flask, dissolved in 10 mL of dichloromethane, and trifluoroacetic acid (3 mL) was added. The reaction was allowed to react at room temperature for 2 h. The reaction system was concentrated under reduced pressure to obtain the crude trifluoroacetate salt of 55A (1.5 g).

[0610] Step 2: Preparation of 55a

[0611] To a reaction flask, crude product 51e (0.52 g), the trifluoroacetate salt of crude product 55A (0.30 g), 0.2 mL of glacial acetic acid, and 5 mL of DMAc were added. The mixture was allowed to react at room temperature for 1 h. Then, sodium triacetoxyborohydride (0.5 g, 2.36 mmol) was added and the reaction was continued at room temperature for 16 h. 20 mL of water was added to the reaction mixture to precipitate a solid, which was filtered and purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0:1-1:9) to afford 55a (0.14 g, 98% yield over two steps based on compound 3-A).

[0612] LCMS m / z=763.5[M+1] +

[0613] Step 3: Preparation of Compound 55

[0614] To a reaction flask, 55a (0.14 g, 0.18 mmol), (S)-3-aminopiperidine-2,6-dione hydrochloride (0.059 g, 0.36 mmol), EDCI (0.069 g, 0.36 mmol), HOBt (0.049 g, 0.36 mmol), N-methylmorpholine (0.055 g, 0.54 mmol), and 4 mL of DMF were added and allowed to react at room temperature for 16 h. The reaction mixture was then added with 20 mL of water and extracted with dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was then subjected to pre-HPLC (apparatus and preparative column: SHIMADZ LC-20AP preparative HPLC, C18 column). Preparation method: The crude product solution in DMSO was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was water (containing 10 mmol / L ammonium bicarbonate) / acetonitrile. Gradient elution method: acetonitrile was gradient eluted from 33% to 63% (elution time 15 min), and lyophilized to obtain compound 55 (52.0 mg, yield: 33%).

[0615] 1 H NMR(400MHz,DMSO-d6)δ11.26(s,1H),10.81(s,1H),8.38-8.27(m,1H),7. 93(t,1H),7.71(s,1H),7.64-7.25(m,3H),7.03(t,1H),6.67(d,1H),5.00- 4.20(m,3H),3.93-3.76(m,1H),3.70-3.52(m,1H),3.40-3.20(m,6H),3.1 9-2.57(m,12H),2.57-2.47(m,1H),2.28-1.46(m,14H),1.40-1.20(m,2H).

[0616] LCMS m / z=873.4[M+1] +

[0617] Example 56: Preparation of Compound 56

[0618] Compound 56 was obtained using compound 51e and 4-A as raw materials by referring to the synthetic method of Example 55.

[0619] 1H NMR(400MHz,DMSO-d6)δ11.26(s,1H),10.81(s,1H),8.38-8.27(m,1H),7. 93(t,1H),7.71(s,1H),7.64-7.25(m,3H),7.04(t,1H),6.68(d,1H),5.05- 4.20(m,3H),3.95-3.76(m,1H),3.70-3.52(m,1H),3.40-3.20(m,6H),3.1 9-2.57(m,12H),2.57-2.47(m,1H),2.28-1.46(m,14H),1.40-1.20(m,2H).

[0620] LCMS m / z=873.4[M+1] +

[0621] Example 57: Preparation of Compound 57

[0622] Step 1: Preparation of 57a

[0623] To a reaction flask, 43c (2.0 g, 4.78 mmol), m-CPBA (4.85 g), and 20 mL of NMP were added. After stirring at room temperature for 16 h, DIPEA (1.85 g, 14.31 mmol) and the hydrochloride salt of the crude product 51B (1.60 g) were added sequentially, and the reaction was continued at 80°C for 16 h. The reaction system was cooled to room temperature, 100 mL of water was added, and extraction was performed with ethyl acetate (100 mL x 4). The organic phases were combined, washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 1:0 to 0:1) to obtain 57a ​​(0.75 g, yield: 28%).

[0624] LCMS m / z=557.4[M+1] +

[0625] Step 2: Preparation of 57b trifluoroacetate

[0626] 57a (0.75 g, 1.35 mmol) was dissolved in 5 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The mixture was allowed to react at room temperature for 3 h. The reaction system was concentrated under reduced pressure to obtain the crude trifluoroacetic acid salt of 57b (1.52 g).

[0627] Step 3: Preparation of Compound 57

[0628] To a reaction flask, the trifluoroacetate salt of crude product 57b (0.25 g), crude intermediate 2 (0.15 g), 0.2 mL of glacial acetic acid, and 5 mL of DMAc were added. The mixture was allowed to react at room temperature for 1 h. Then, sodium triacetoxyborohydride (0.25 g, 1.18 mmol) was added and the reaction was continued at room temperature for 16 h. The reaction system was subjected to pre-HPLC (apparatus and preparative column: SHIMADZ LC-20AP preparative HPLC, C18 preparative column). Preparation method: A DMSO solution of the crude product was filtered through a 0.45 μm filter to prepare a sample solution. The mobile phase system was water (containing 10 mmol / L ammonium bicarbonate) / acetonitrile. Gradient elution was performed: 35% to 65% acetonitrile (elution time 15 min). The product was then lyophilized to obtain compound 57 (25.0 mg, two-step yield: 14% based on compound 57a).

[0629] 1 H NMR (400MHz, CDCl3) δ10.73(s,1H),8.43(s,1H),7.73(s,1H),7.58-7.46(m,2 H),7.00-6.90(m,2H),6.71(d,1H),6.49(d,1H),5.68(s,1H),5.20-4.25(m,2H ),3.88-3.72(m,2H),3.72-3.63(m,2H),3.63-3.54(m,1H),3.46-3.24(m,4H), 3.24-2.55(m,12H),2.37-2.10(m,5H),2.10-1.55(m,10H),1.48-1.27(m,2H).

[0630] LCMS m / z=406.8[M / 2+1] +

[0631] Example 58: Preparation of Compound 58

[0632] Compound 58 was prepared using the trifluoroacetate salt of compound 57b and intermediate 1 as raw materials, following the synthetic method of Example 57.

[0633] 1H NMR(400MHz,DMSO-d6)δ11.08(s,1H),10.76(s,1H),8.28(s,1H),7.67(s,1H), 7.55-7.42(m,2H),7.00-6.87(m,2H),6.79(d,1H),6.61(d,1H),5.10-4.20(m, 2H),3.88-3.76(m,1H),3.76-3.52(m,4H),3.40-3.17(m,5H),3.15-2.82(m,5H ),2.82-2.54(m,6H),2.54-2.42(m,1H),2.25-1.40(m,14H),1.30-1.14(m,2H).

[0634] LCMS m / z=406.8[M / 2+1] +

[0635] Example 59: Preparation of Compound 59

[0636] Compound 59 was prepared from the trifluoroacetic acid salt of compound 57b and intermediate 7 by neutral preparation [water (containing 10 mmol / L ammonium bicarbonate) / acetonitrile] according to the synthesis method of Example 45.

[0637] 1 H NMR(400MHz,DMSO-d6)δ11.07(s,1H),10.33(s,1H),8.28(s,1H),7.67(s,1 H),7.56-7.42(m,2H),6.99-6.87(m,3H),6.72(d,1H),5.00-4.20(m,2H),3. 82-3.52(m,6H),3.40-3.18(m,4H),3.15-2.82(m,5H),2.82-2.55(m,7H),2 .27-2.13(m,2H),2.12-1.97(m,1H),1.97-1.41(m,10H),1.33-1.10(m,2H).

[0638] LCMS m / z=813.4[M+1] +

[0639] Example 60: Preparation of Compound 60

[0640] Compound 60 was prepared from the trifluoroacetate salt of compound 57b and intermediate 6 by neutral preparation [water (containing 10 mmol / L ammonium bicarbonate) / acetonitrile] according to the synthesis method of Example 45.

[0641] 1 H NMR (400MHz, DMSO-d6) δ11.07(s,1H),10.32(s,1H),8.28(s,1H),7.66(s,1H),7.54-7.46(m,2H),7.00-6.86(m,3H),6.72(d,1H),5.05-4.15( m,2H),3.82-3.71(m,1H),3.71-3.53(m,5H),3.39-3.18(m,4H),3.15- 2.83(m,5H),2.81-2.54(m,7H),2.27-1.43(m,13H),1.33-1.13(m,2H).

[0642] LCMS m / z=813.4[M+1] +

[0643] Example 61: Preparation of Compound 61

[0644] Step 1: Preparation of 61a

[0645] To a reaction flask, the trifluoroacetate salt of crude product 57b (0.52 g), the trifluoroacetate salt of crude product 55A (0.30 g), 0.2 mL of glacial acetic acid, and 5 mL of DMAc were added. The mixture was allowed to react at room temperature for 1 h. Then, sodium triacetoxyborohydride (0.5 g, 2.36 mmol) was added and the reaction was continued at room temperature for 16 h. 20 mL of water was added to the reaction mixture to precipitate a solid, which was filtered and purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0:1-1:9) to afford 61a (0.13 g, 93% yield for two steps based on compound 3-A).

[0646] LCMS m / z=745.5[M+1] +

[0647] Step 2: Preparation of compound 61

[0648] To a reaction flask, 61a (0.13 g, 0.175 mmol), (S)-3-aminopiperidine-2,6-dione hydrochloride (0.059 g, 0.36 mmol), EDCI (0.069 g, 0.36 mmol), HOBt (0.049 g, 0.36 mmol), N-methylmorpholine (0.055 g, 0.54 mmol), and 4 mL of DMF were added and allowed to react at room temperature for 16 h. The reaction mixture was added with 20 mL of water and extracted three times with 50 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was then subjected to pre-HPLC (apparatus and preparative column: SHIMADZ LC-20AP preparative HPLC, C18 column). Preparation method: The crude product solution in DMSO was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was water (containing 10 mmol / L ammonium bicarbonate) / acetonitrile. Gradient elution method: acetonitrile was gradient eluted from 30% to 60% (elution time 15 min), and lyophilized to obtain compound 61 (46.0 mg, yield: 15%).

[0649] 1 H NMR(400MHz,DMSO-d6)δ11.07(s,1H),10.80(s,1H),8.27(s,1H),7.93(t,1H) ,7.66(s,1H),7.55-7.43(m,2H),7.36(d,1H),7.00-6.88(m,2H),6.67(d,1H) ,5.10-4.20(m,3H),3.93-3.77(m,1H),3.73-3.52(m,3H),3.40-3.18(m,4H), 3.18-2.58(m,11H),2.57-2.47(m,1H),2.25-1.44(m,15H),1.32-1.13(m,2H).

[0650] LCMS m / z=428.3[M / 2+1] +

[0651] Example 62: Preparation of Compound 62

[0652] Compound 62 was obtained using compounds 57b and 56A as raw materials according to the synthetic method of Example 61.

[0653] 1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),10.82(s,1H),8.28(s,1H),7.94(t,1H),7.67(s, 1H),7.55-7.45(m,2H),7.36(d,1H),7.00-6.87(m,2H),6.68(d,1H),5.10-4.20(m,3H),3.95-3.78(m,1H),3.74 -3.50(m,3H),3.43-3.18(m,4H),3.17-2.57(m,11H),2.57-2.46(m,1H),2.28-1.42(m,15H),1.32-1.14(m,2H).

[0654] LCMS m / z=428.3[M / 2+1] +

[0655] Example 63: Preparation of Compound 63 Trifluoroacetate

[0656] Step 1: Preparation of 63b

[0657] The crude hydrochloride of 51B (3.85 g) was dissolved in 20 mL of DMF, and DIPEA (6.68 g, 51.68 mmol) was added. After stirring at room temperature for 10 min, 63a (3.00 g, 17.24 mmol) was added and stirred at room temperature for 16 h. The reaction mixture was added with 100 mL of water and extracted with ethyl acetate (80 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:1 to 0:1) to afford 63b (4.60 g, 83% yield).

[0658] LCMS m / z=324.2[M+1] +

[0659] Step 2: Preparation of 63c

[0660] 63b (2.10 g, 6.50 mmol) and 63A (1.95 g, 7.79 mmol) (synthesis method, see WO2023083194) were dissolved in 40 mL of 1,4-dioxane, and Pd(OAc)2 (150 mg, 0.67 mmol), BINAP (604 mg, 0.97 mmol) and cesium carbonate (6.34 g, 19.46 mmol) were added respectively. The nitrogen atmosphere was replaced three times and the reaction was carried out at 100°C for 16 h. The reaction system was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. 100 mL of dichloromethane and 100 mL of water were added to the residue, and the layers were separated. The aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 1:0-9:1) to give 63c (2.80 g, yield: 80%).

[0661] LCMS m / z=538.3[M+1] +

[0662] Step 3: Preparation of 63d

[0663] Compound 63c (2.80 g, 5.21 mmol) was dissolved in 5 mL of DMSO, and cesium carbonate (1.70 g, 5.22 mmol) was added. 30% hydrogen peroxide solution (8 mL) was slowly added dropwise and allowed to react at room temperature for 4 h. The reaction mixture was then added with 10 mL of water and filtered. The filter cake was collected, washed with 20 mL of water, and dried under reduced pressure to afford crude product 63d (2.50 g).

[0664] LCMS m / z=556.4[M+1] +

[0665] Step 4: Preparation of 63e trifluoroacetate

[0666] The crude product 63d (1.0 g) was dissolved in 5 mL of dichloromethane, and 3 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 3 h. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetic acid salt of the crude product 63e (1.5 g).

[0667] LCMS m / z=510.3[M+1] +

[0668] Step 5: Preparation of trifluoroacetate salt of compound 63

[0669] The trifluoroacetate salt of crude product 63e (150 mg) and crude intermediate 2 (76 mg) were dissolved in 5 mL of DMAc. 0.2 mL of glacial acetic acid was added and the mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (130 mg, 0.61 mmol) was then added portionwise and allowed to react at room temperature for 16 hours. The reaction solution was subjected to pre-HPLC (instrument and preparative column: SHIMADZU LC-20AP preparative HPLC, SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was water (containing 0.1% TFA) / acetonitrile. Gradient elution was performed: 15% to 35% acetonitrile (elution time 16 minutes). The mixture was then lyophilized to obtain compound 63 trifluoroacetate salt (5.0 mg).

[0670] LCMS m / z=811.7[M+1] +

[0671] After the fifth step reaction, the reaction solution was neutralized [mobile phase system: water (containing 5 mmol / L ammonium acetate) / acetonitrile] and freeze-dried to obtain compound 63.

[0672] 1 H NMR (400MHz, CDCl3) δ10.64(s,1H),8.09(s,1H),7.56-7.33(m,4H),7.00-6.85(m,2H),6.71(d,1H),6.49(d,1H),5.22(s,1H),4.39-4.23(m, 2H),3.88-3.70(m,2H),3.70-3.52(m,3H),3.47-3.21(m,4H),3.20-2. 55(m,12H),2.40-2.08(m,5H),2.03-1.55(m,10H),1.52-1.28(m,2H).

[0673] LCMS m / z=406.3[M / 2+1] +

[0674] Example 64: Preparation of Compound 64

[0675] Compound 64 was prepared from the trifluoroacetate salt of compound 63e and intermediate 1 by referring to the synthesis method of Example 63, and then freeze-dried from neutral solution [water (10 mmol / L ammonium bicarbonate) / acetonitrile].

[0676] 1H NMR (400MHz, CDCl3) δ10.64(s,1H),7.95(s,1H),7.56-7.31(m,4H),7.03-6.85(m,2H),6.72(d,1H),6.49(d,1H),5.15(s,1H),4.39-4.22(m, 2H),3.88-3.70(m,2H),3.70-3.50(m,3H),3.43-3.21(m,4H),3.20-2. 55(m,12H),2.40-2.08(m,5H),2.03-1.50(m,10H),1.50-1.28(m,2H).

[0677] LCMS m / z=811.8[M+1] +

[0678] Example 65: Preparation of Compound 65

[0679] Compound 65 was obtained using trifluoroacetate of compound 63e and intermediate 6 as raw materials, referring to the synthetic method of Example 21.

[0680] 1 H NMR(400MHz,DMSO-d6)δ10.96(s,1H),10.33(s,1H),7.70(s,1H),7.65-7.57(m, 1H),7.48-7.35(m,2H),7.26(s,1H),7.00-6.82(m,3H),6.72(d,1H),4.47-4.15( m,2H),3.82-3.71(m,1H),3.70-3.53(m,5H),3.50-3.15(m,4H),3.10-2.83(m,5 H),2.82-2.54(m,8H),2.27-2.15(m,2H),2.12-1.39(m,11H),1.33-1.12(m,2H).

[0681] LCMS m / z=812.6[M+1] +

[0682] Example 66: Preparation of Compound 66

[0683] Step 1: Preparation of 66a

[0684] 63b (1.8 g, 5.56 mmol) was dissolved in 30 mL of 1,4-dioxane, and (1-(4-aminophenyl)piperidin-4-yl)methanol (1.15 g, 5.57 mmol), cesium carbonate (5.43 g, 16.67 mmol), palladium acetate (127.7 mg, 0.57 mmol), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (523.1 mg, 0.84 mmol) were added. The atmosphere was purged with nitrogen three times, and the reaction was carried out at 100°C for 16 h. The reaction system was cooled to room temperature and filtered. The filter cake was washed with dichloromethane (110 mL x 2), and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 92:8) to obtain 66a (2.1 g, yield: 77%).

[0685] LCMS m / z=494.3[M+1] +

[0686] Step 2: Preparation of 66b

[0687] 66a (2.10 g, 4.26 mmol) was dissolved in 20 mL of DMSO, and cesium carbonate (1.38 g, 4.24 mmol) was added. 30% hydrogen peroxide (15 mL) was slowly added dropwise under an ice-water bath. After stirring for 5 min, the ice-water bath was removed and the reaction was allowed to react at room temperature for 3 h. To the reaction system was added 80 mL of saturated sodium sulfite solution and 200 mL of ethyl acetate. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (80 mL × 3). The combined organic phases were washed with saturated brine (90 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 9:1) to afford 66b (2.0 g, yield: 92%).

[0688] LCMS m / z=512.3[M+1] +

[0689] Step 3: Preparation of 66c

[0690] 66b (1.5 g, 2.93 mmol) was dissolved in 20 mL of dichloromethane, and N,N-diisopropylethylamine (1.14 g, 8.82 mmol) was added. A solution of pyridine sulfur trioxide (1.40 g, 8.80 mmol) in DMSO (10 mL) was slowly added dropwise at 0°C. The mixture was allowed to warm to room temperature and the reaction was continued for 2 h. 300 mL of water and 100 mL of ethyl acetate were added to the reaction system, and the aqueous phase was extracted with ethyl acetate (60 mL x 2). The organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was isolated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 9:1) to obtain 66c (1.05 g, yield: 70%).

[0691] LCMS m / z=510.3[M+1] +

[0692] Step 4: Preparation of compound 66

[0693] Intermediate 7 (164 mg, 0.39 mmol) was dissolved in 10 mL of dichloromethane, and 3 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 2 h. The reaction system was concentrated under reduced pressure, and 15 mL of dichloromethane and sodium bicarbonate (98 mg, 1.17 mmol) were added. After stirring at room temperature for 30 min, 66c (200 mg, 0.39 mmol), anhydrous sodium sulfate (300 mg) and 0.03 mL of acetic acid were added respectively. After reacting at room temperature for 16 h, sodium triacetoxyborohydride (165 mg, 0.78 mmol) was added and the mixture was reacted at room temperature for 2 h. 120 mL of water was added to the reaction system, and the mixture was extracted with dichloromethane (80 mL × 3). The organic phases were combined, washed with saturated brine (70 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was separated and purified by silica gel thin layer chromatography (dichloromethane: methanol (v / v) = 9:1) to give compound 66 (160 mg, yield: 51%).

[0694] 1 H NMR (400MHz, CDCl3) δ10.65(s,1H),7.60-7.30(m,5H),7.10-6.80(m,3H),6.53(d,1H),5.17(s,1H),4.40-4. 20(m,2H),3.90-3.52(m,6H),3.45-3.23(m,4H),3.23-2.57(m,11H),2.45-2.08(m,2H),2.05-1.30(m,14H).

[0695] LCMS m / z=812.4[M+1] +

[0696] Example 67: Preparation of Compound 67

[0697] Step 1: Preparation of 67a

[0698] 4-A (170 mg, 0.49 mmol) was dissolved in 10 mL of dichloromethane, and 3 mL of trifluoroacetic acid was added. The mixture was allowed to react at room temperature for 2 h. The reaction system was concentrated under reduced pressure, and 15 mL of dichloromethane and sodium bicarbonate (123 mg, 1.46 mmol) were added. After stirring at room temperature for 30 min, 66c (250 mg, 0.49 mmol), anhydrous sodium sulfate (300 mg), and 0.1 mL of glacial acetic acid were added. The mixture was allowed to react at room temperature for 16 h, and then sodium triacetoxyborohydride (208 mg, 0.98 mmol) was added. The reaction mixture was allowed to react at room temperature for 2 h. 130 mL of water was added to the reaction system, and the mixture was extracted with dichloromethane (80 mL x 3). The organic phases were combined, washed with saturated brine (70 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel thin-layer chromatography (dichloromethane:methanol (v / v) = 9:1) to obtain 67a (130 mg, yield: 36%).

[0699] LCMS m / z=744.4[M+1] +

[0700] Step 2: Preparation of compound 67

[0701] 67a (210 mg, 0.28 mmol) was dissolved in 10 mL of DMF, and EDCI (81 mg, 0.42 mmol), HOBt (57 mg, 0.42 mmol), and N-methylmorpholine (142 mg, 1.40 mmol) were added. After stirring at room temperature for 30 min, (S)-3-aminopiperidine-2,6-dione hydrochloride (92 mg, 0.56 mmol) was added and the mixture was allowed to react at room temperature for 16 h. 100 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (60 mL × 3). The organic phases were combined, washed with saturated brine (70 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 9:1) to obtain compound 67 (52.0 mg, yield: 22%).

[0702] 1 H NMR (400MHz, CDCl3) δ10.66(s,1H),8.08(s,1H),7.66(d,1H),7.57-7.32(m,5H),7.15-6.85(m,2H),6.41(d,1H),5.21(s, 1H),4.87-4.70(m,1H),4.40-4.20(m,2H),3.88-3.51(m,4H),3.44-2.60(m,18H),2.45-2.10(m,3H),2.05-1.35(m,12H).

[0703] LCMS m / z=854.0[M+1] +

[0704] Example 68: Preparation of Compound 68

[0705] Compound 68 was obtained using compound 3-A as raw material by referring to the synthetic method of Example 67.

[0706] 1 H NMR (400MHz, CDCl3) δ10.75(s,1H),7.92(s,1H),7.67(d,1H),7.62-7.32(m,5H),7.18- 6.90(m,2H),6.42(d,1H),5.19(s,1H),4.84-4.70(m,1H),4.40-4.24(m,2H), 3.88-3.51(m,4H),3.44-2.60(m,18H),2.58-2.24(m,3H),2.10-1.35(m,12H).

[0707] LCMS m / z=854.7[M+1] +

[0708] The following compounds were obtained by referring to the synthesis methods of other examples:

[0709] Example 75: Preparation of Compound 75

[0710] To the crude product 8-H (100 mg) were added dichloromethane (12 mL) and trifluoroacetic acid (3 mL), and the mixture was allowed to react at room temperature for 2 h. The reaction system was concentrated under reduced pressure, and dichloromethane (15 mL) and sodium bicarbonate (73 mg, 0.87 mmol) were added. After stirring at room temperature for 30 min, 9a (147 mg, 0.29 mmol), anhydrous sodium sulfate (300 mg), and acetic acid (0.06 mL) were added. After reacting at room temperature for 16 h, sodium triacetoxyborohydride (123 mg, 0.58 mmol) was added and the mixture was allowed to react at room temperature for 2 h. Water (120 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (80 mL × 3). The organic phase was washed with saturated brine (70 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was subjected to Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid phase, preparative column model: SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter to prepare a sample solution. The mobile phase system was water (containing 10 mmol / L ammonium bicarbonate) / acetonitrile. Gradient elution method: Acetonitrile was gradient eluted from 10% to 50% (elution time 15 min). The product was lyophilized to obtain compound 75 (52 mg, yield: 23%).

[0711] 1 H NMR(400MHz,DMSO-d6)δ10.96(s,1H),10.82(s,1H),7.68(s,1H),7.60(s,1H),7.51-7.3 4(m,4H),7.25(s,1H),6.92-6.83(m,2H),4.46-4.18(m,2H),4.15-4.04(m,3H),3.80(s, 2H),3.68-3.52(m,3H),3.40-3.18(m,4H),3.08-2.87(m,4H),2.85-2.40(m,9H),2.38-2 .18(m,1H),2.09-1.97(m,1H),1.90-1.67(m,6H),1.65-1.45(m,1H),1.38-1.16(m,2H).

[0712] LCMS m / z=793.3[M+1] +

[0713] Example 76: Preparation of Compound 76

[0714] Step 1: Preparation of 76-B

[0715] Dissolve 76-A (10.0 g, 62.66 mmol) and 4-hydroxymethylpiperidine (7.6 g, 66.0 mmol) in 200 mL of DMF. Slowly add potassium carbonate (13.03 g, 94.28 mmol) under ice-cooling. React at room temperature for 16 h. Pour the reaction mixture into 500 mL of water, filter, and dry the filter cake under reduced pressure to obtain crude product 76-B (15.0 g).

[0716] Step 2: Preparation of 76-C

[0717] The crude product 76-B (5.0 g) was dissolved in 100 mL of methanol, 10% palladium carbon (3.0 g) was added, and the mixture was reacted at room temperature for 12 h under a hydrogen balloon atmosphere. The reaction solution was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to obtain the crude product 76-C (4.3 g).

[0718] LCMS m / z=225.1[M+1] +

[0719] Step 3: Preparation of 76b

[0720] 76a (4.0 g, 17.12 mmol) and the crude product 76-C (4.3 g) were dissolved in 20 mL of DCM. DIPEA (2.88 g, 22.28 mmol) was slowly added dropwise and stirred at room temperature for 30 min. The reaction mixture was filtered and the filter cake was dried under reduced pressure to afford crude product 76b (5.69 g).

[0721] LCMS m / z=422.1[M+1] +

[0722] Step 4: Preparation of 76c

[0723] The crude product 76b (3.8 g) was added to 20 mL of methanol, and 90 mL of a 7 mol / L methanolic ammonia solution was slowly added dropwise. The reaction was allowed to react at room temperature for 3 h. The reaction system was filtered, and the filter cake was collected and washed with 50 mL of petroleum ether and dried under reduced pressure to obtain crude product 76c (3.1 g).

[0724] LCMS m / z=393.0[M+1] +

[0725] Step 5: Preparation of 76d

[0726] To a reaction flask, crude product 76c (3.11 g), m-CPBA (8.04 g), and 10 mL of NMP were added. The mixture was allowed to react at room temperature for 16 h. DIPEA (5.12 g, 39.61 mmol) and 76-D (2.18 g, 11.90 mmol) (synthesis method, see WO2023088406) were then added sequentially to the reaction system and allowed to react at 80°C for 16 h. The reaction solution was cooled to room temperature, 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL x 4). The organic phase was washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 1:0 to 0:1) to afford 76d (1.2 g, yield: 19%).

[0727] LCMS m / z=528.7[M+1] +

[0728] Step 6: Preparation of 76e

[0729] 76d (0.7 g, 1.33 mmol) was dissolved in 2 mL of DMSO, and triethylamine (0.67 g, 6.62 mmol) was added. Sulfur trioxide (1.05 g, 6.60 mmol) was then added with stirring at room temperature. The mixture was allowed to react at room temperature for 10 min. 20 mL of water was added to the reaction system, and the mixture was extracted with 50 mL of ethyl acetate. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 1:0 to 0:1) to afford 76e (0.59 g, 84% yield).

[0730] LCMS m / z=526.3[M+1] +

[0731] Step 7: Preparation of Compound 76

[0732] To a reaction flask, 76e (0.15 g, 0.29 mmol), the crude intermediate 2 (0.12 g), 0.5 mL of glacial acetic acid, and 5 mL of DMAc were added. The mixture was allowed to react at room temperature for 1 h. Then, sodium triacetoxyborohydride (0.18 g, 0.85 mmol) was added and the reaction was continued at room temperature for 16 h. The reaction solution was subjected to pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, SunFire@Prep C18, 5 μm, i.d. x length = 19 mm x 250 mm). Preparation method: A DMSO solution of the crude product was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was water (containing 10 mmol / L ammonium bicarbonate) / acetonitrile. Gradient elution was performed: 10% acetonitrile to 50% (elution time 15 min). The product was then lyophilized to afford compound 76 (72 mg, yield: 30%).

[0733] 1 H NMR (400MHz, CDCl3) δ10.88(s,1H),8.19(s,1H),7.71(s,1H),7.55(d,1H) ,7.22(s,1H),6.96(t,1H),6.71(d,1H),6.49(d,1H),5.59(s,1H),5.20-4 .20(m,2H),3.86-3.70(m,2H),3.66-3.52(m,1H),3.52-3.26(m,6H),3.26 -2.55(m,15H),2.40-2.07(m,5H),2.05-1.55(m,10H),1.54-1.35(m,2H).

[0734] LCMS m / z=827.4[M+1] +

[0735] Example 80: Preparation of Compound 80

[0736] Compound 80 was obtained using compound 76e and 3-A as raw materials according to the synthetic method of Example 17.

[0737] 1 H NMR(400MHz,DMSO-d6)δ11.26(s,1H),10.82(s,1H),8.33(s,1H),7.94(t ,1H),7.72(s,1H),7.64-7.28(m,3H),7.04(t,1H),6.68(d,1H),5.00-4. 20(m,3H),3.92-3.77(m,1H),3.68-3.52(m,1H),3.40-3.20(m,6H),3.19 -2.57(m,15H),2.57-2.45(m,1H),2.29-1.44(m,14H),1.37-1.20(m,2H).

[0738] LCMS m / z=870.4[M+1] +

[0739] Example 81: Preparation of Compound 81

[0740] Compound 81 was obtained using compound 76e and 4-A as raw materials according to the synthetic method of Example 17.

[0741] 1H NMR(400MHz,DMSO-d6)δ11.26(s,1H),10.82(s,1H),8.33(s,1H),7.94(t ,1H),7.72(s,1H),7.64-7.28(m,3H),7.03(t,1H),6.68(d,1H),5.00-4. 20(m,3H),3.92-3.77(m,1H),3.68-3.52(m,1H),3.40-3.20(m,6H),3.19 -2.57(m,15H),2.57-2.45(m,1H),2.29-1.44(m,14H),1.37-1.20(m,2H).

[0742] LCMS m / z=870.4[M+1] +

[0743] Example 82: Preparation of Compound 82

[0744] Step 1: Preparation of 82b

[0745] 82a (5 g, 18.56 mmol) (synthesis method, see WO2020081450) was added to a 250 mL three-necked flask, followed by dry tetrahydrofuran (80 mL). The mixture was cooled to 0°C in an ice-water bath under nitrogen. 60% sodium hydride (1.48 g) was added, stirred at this temperature for 10 min, and then allowed to return to room temperature for 1 h. The reaction system was cooled to 0°C, and 1-iodo-2-methoxyethane (5.2 g, 27.96 mmol) was slowly added. The mixture was allowed to return to room temperature for 16 h. 100 mL of ice water was added to the reaction system, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phase was washed with saturated brine (80 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:1) to obtain 82b (3.8 g, yield: 63%).

[0746] Compound 82 was obtained using compound 82b and 2-D as raw materials by referring to the synthetic methods of Examples 43 and 51.

[0747] 1H NMR (400MHz, CDCl3) δ10.73(s,1H),7.91(s,1H),7.73-7.64(m,1H),7.59-7.4 7(m,2H),7.04-6.87(m,2H),6.78-6.66(m,1H),6.49(d,1H),5.40-5.28(m,1H ),5.10-4.20(m,2H),3.90-3.58(m,5H),3.58-3.48(m,2H),3.48-3.30(m,9H) ,3.27-2.55(m,13H),2.38-2.07(m,5H),2.05-1.60(m,9H),1.50-1.22(m,2H).

[0748] LCMS m / z=427.5[M / 2+1] +

[0749] Example 83: Preparation of Compound 83

[0750] Compound 83 was prepared using compounds 76c and 82c as raw materials according to the synthetic method of Example 76.

[0751] 1 H NMR (400MHz, CDCl3) δ10.88(s,1H),7.93(s,1H),7.74-7.65(m,1H),7.62-7.50( m,1H),7.30-7.14(m,1H),6.95(t,1H),6.80-6.65(m,1H),6.49(d,1H),5.39(s, 1H),5.20-4.20(m,2H),3.90-3.70(m,2H),3.70-3.49(m,3H),3.49-3.30(m,10H ),3.28-2.55(m,13H),2.45-2.10(m,5H),2.05-1.60(m,10H),1.58-1.34(m,2H).

[0752] LCMS m / z=436.4[M / 2+1] +

[0753] Example 84: Preparation of Compound 84

[0754] Compound 84 was obtained using compounds 82c, 84a, 84A and 2-D as raw materials, referring to the synthetic methods of Examples 63 and 66.

[0755] 1H NMR (400MHz, CDCl3) δ10.67(s,1H),7.94(s,1H),7.56-7.32(m,4H),7.05-6.83(m,2H),6.72(d,1H),6.49(d,1H),5.15(s,1H),4.40-4.23(m, 2H),3.88-3.72(m,2H),3.70-3.50(m,5H),3.48-3.27(m,8H),3.20-2. 55(m,13H),2.42-2.08(m,5H),2.05-1.60(m,10H),1.57-1.30(m,2H).

[0756] LCMS m / z=426.8[M / 2+1] +

[0757] Example 85: Preparation of Compound 85

[0758] Step 1: Preparation of 85a

[0759] 82a (3 g, 11.14 mmol) (synthesis method, see WO2020081450) was dissolved in 50 mL of DMF. 60% sodium hydride (0.89 g) was added at 0°C. After stirring at 0°C for 30 min, bromomethylcyclopropane (3.01 g, 22.3 mmol) was added and allowed to react at room temperature for 16 h. 200 mL of water was added to the reaction solution, and the mixture was extracted three times with 100 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-1:1) to obtain 85a (2.5 g, yield: 69%).

[0760] LCMS m / z=324.1[M+1] +

[0761] Step 2: Preparation of 85b trifluoroacetate

[0762] 85a (2.0 g, 6.19 mmol) was dissolved in 10 mL of dichloromethane, and 4 mL of trifluoroacetic acid was added. The mixture was allowed to react at room temperature for 3 h. The reaction system was concentrated under reduced pressure to obtain the crude trifluoroacetate salt of 85b (4.0 g).

[0763] LCMS m / z=224.2[M+1] +

[0764] Compound 85 was prepared using the trifluoroacetic acid salts of compounds 85c and 85b as starting materials by referring to the synthetic methods of Examples 31, 33 and 63.

[0765] 1H NMR(400MHz,DMSO-d6)δ11.00(s,1H),10.81(s,1H),7.93(t,1H),7.68(s,1H),7.60(s,1H),7.46- 7.32(m,3H),7.28-7.21(m,1H),6.92-6.82(m,2H),6.67(d,1H),4.79-4.65(m,1H),4.48-4.32(m,1 H),4.32-4.17(m,1H),3.94-3.79(m,1H),3.70-3.54(m,1H),3.45-3.20(m,5H),3.18-2.60(m,16H ),2.58-2.44(m,1H),2.20-1.50(m,17H),0.98-0.80(m,1H),0.55-0.40(m,2H),0.25-0.12(m,2H).

[0766] LCMS m / z=459.5[M / 2+1] +

[0767] Example 86: Preparation of Compound 86

[0768] Compound 86 was prepared using the trifluoroacetic acid salts of compounds 76c and 85b and 4-A as raw materials, following the synthetic methods of Examples 76 and 17.

[0769] 1 H NMR(400MHz,DMSO-d6)δ11.26(s,1H),10.81(s,1H),8.32(s,1H),7.93(t,1H),7.71(s, 1H),7.63-7.24(m,3H),7.04(t,1H),6.68(d,1H),5.05-4.20(m,3H),3.93-3.77(m,1H) ,3.70-3.52(m,1H),3.47-3.19(m,8H),3.19-2.58(m,12H),2.58-2.45(m,1H),2.30-1. 45(m,14H),1.38-1.20(m,2H),0.95-0.77(m,1H),0.55-0.40(m,2H),0.25-0.12(m,2H).

[0770] LCMS m / z=455.7[M / 2+1] +

[0771] Example 87: Preparation of Compound 87

[0772] Compound 87 was obtained using compound 85d and 2-D as raw materials according to the synthetic method of Example 66.

[0773] 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),10.76(s,1H),7.69(s,1H),7.60(s,1H),7.47-7.37(m, 2H),7.31-7.21(m,1H),6.92-6.84(m,2H),6.79(d,1H),6.62(d,1H),4.50-4.15(m,2H),3.88 -3.50(m,5H),3.45-3.25(m,4H),3.14-2.83(m,7H),2.82-2.55(m,6H),2.55-2.42(m,1H),2. 27-1.45(m,15H),1.34-1.15(m,2H),0.95-0.80(m,1H),0.54-0.42(m,2H),0.24-0.12(m,2H).

[0774] LCMS m / z=424.8[M / 2+1] +

[0775] Example 88: Preparation of Compound 88

[0776] Step 1: Preparation of 88a

[0777] 82a (5 g, 18.56 mmol) (synthesis method, see WO2020081450) was dissolved in 50 mL of DMF, and cyclopropylboronic acid (5.74 g, 66.82 mmol), pyridine (7.05 g, 89.13 mmol), and copper acetate (6.07 g, 33.42 mmol) were added. The reaction was allowed to react open-air at 45°C for 72 h. 200 mL of water was added to the reaction solution, and the mixture was extracted three times with 100 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-1:1) to afford 88a (2.0 g, yield: 35%).

[0778] Step 2: Preparation of 88b trifluoroacetate

[0779] 88a (2.0 g, 6.46 mmol) was dissolved in 10 mL of dichloromethane, and 4 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 3 h. The reaction system was concentrated under reduced pressure to obtain the crude trifluoroacetate salt of 88b (4.0 g).

[0780] LCMS m / z=210.2[M+1] +

[0781] Compound 88 was prepared from the trifluoroacetate salt of compound 88b by referring to the synthesis method of Example 63 and freeze-dried from neutral solution (water (containing 10 mmol / L ammonium bicarbonate) / acetonitrile).

[0782] Example 89: Preparation of Compound 89

[0783] Compound 89 was prepared using the trifluoroacetate salts of compounds 43c and 88b and 2-D as raw materials, following the synthetic method of Example 43.

[0784] 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),10.75(s,1H),8.27(s,1H),7.66(s,1H),7. 55-7.45(m,2H),7.00-6.87(m,2H),6.84-6.74(m,1H),6.68-6.56(m,1H),5.15-3. 95(m,2H),3.88-3.54(m,5H),3.35-3.14(m,5H),3.10-2.83(m,5H),2.80-2.55(m, 6H),2.50-2.30(m,2H),2.26-1.40(m,14H),1.30-1.12(m,2H),0.70-0.50(m,4H).

[0785] LCMS m / z=418.3[M / 2+1] +

[0786] Example 90: Preparation of Compound 90

[0787] Compound 90 was prepared using the trifluoroacetic acid salts of compounds 76c and 88b and 4-A as raw materials, following the synthetic methods of Examples 76 and 17.

[0788] 1H NMR(400MHz,DMSO-d6)δ11.28(s,1H),10.81(s,1H),8.32(s,1H),7.93(t,1H),7.75-7.6 7(m,1H),7.64-7.45(m,1H),7.42-7.30(m,2H),7.04(t,1H),6.68(d,1H),5.00-4.10(m,3 H),3.94-3.77(m,1H),3.70-3.52(m,1H),3.40-3.18(m,6H),3.17-2.57(m,12H),2.54-2 .32(m,2H),2.27-2.17(m,2H),2.15-1.45(m,12H),1.38-1.17(m,2H),0.70-0.47(m,4H).

[0789] LCMS m / z=448.8[M / 2+1] +

[0790] Example 91: Preparation of Compound 91

[0791] Compound 91 was prepared using the trifluoroacetate salts of compounds 91a and 88b as starting materials by referring to the synthetic methods of Examples 31, 33 and 63.

[0792] 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),10.81(s,1H),7.93(t,1H),7.69(s,1H),7.6 0(s,1H),7.46-7.32(m,3H),7.25(s,1H),6.94-6.82(m,2H),6.67(d,1H),4.80-4. 65(m,1H),4.44-4.18(m,2H),3.94-3.80(m,1H),3.70-3.52(m,1H),3.38-3.18(m, 5H),3.16-2.60(m,13H),2.58-2.35(m,2H),2.20-1.45(m,18H),0.68-0.54(m,4H).

[0793] LCMS m / z=452.4[M / 2+1] +

[0794] Example 92: Preparation of Compound 92

[0795] Compound 92 was prepared using compounds 84b and 31e as raw materials by referring to the synthetic methods of Examples 31 and 33.

[0796] 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),10.82(s,1H),7.94(t,1H),7.69(s,1H),7.6 0(s,1H),7.46-7.31(m,3H),7.26(s,1H),6.92-6.82(m,2H),6.68(d,1H),4.80-4.6 5(m,1H),4.44-4.18(m,2H),3.94-3.80(m,1H),3.70-3.52(m,1H),3.50-3.42(m,2 H),3.38-3.20(m,10H),3.16-2.60(m,13H),2.58-2.41(m,1H),2.20-1.45(m,18H).

[0797] LCMS m / z=461.4[M / 2+1] +

[0798] Example 93: Preparation of Compound 93 Trifluoroacetate

[0799] Compound 93 trifluoroacetate was prepared from the trifluoroacetate of compounds 43c and 85b and 2-D by lyophilization in acidic preparation [water (containing 0.1% TFA) / acetonitrile] according to the synthesis method of Example 43.

[0800] 1 H NMR(400MHz,DMSO-d6)δ11.24(s,1H),10.79(s,1H),8.32(s,1H),7.74(s,1H),7.6 3-7.51(m,2H),7.10-6.72(m,4H),5.00-4.30(m,2H),4.20-4.00(m,1H),3.95-3.7 7(m,1H),3.77-3.55(m,4H),3.47-3.25(m,6H),3.23-2.57(m,14H),2.57-2.45(m, 1H),2.24-1.22(m,13H),0.98-0.80(m,1H),0.58-0.40(m,2H),0.28-0.10(m,2H).

[0801] LCMS m / z=425.3[M / 2+1] +

[0802] Example 94: Preparation of Compound 94

[0803] Compound 94 was prepared using the trifluoroacetate salts of compounds 76c and 85b as starting materials according to the synthetic method of Example 76.

[0804] 1 H NMR(400MHz,DMSO-d6)δ11.25(s,1H),10.75(s,1H),8.31(s,1H),7.71(s,1H),7.6 3-7.20(m,2H),7.04(t,1H),6.79(d,1H),6.62(d,1H),5.20-4.10(m,2H),3.88-3. 55(m,3H),3.45-3.22(m,6H),3.20-2.55(m,13H),2.54-2.40(m,1H),2.28-1.45(m ,15H),1.37-1.20(m,2H),0.95-0.80(m,1H),0.52-0.42(m,2H),0.22-0.12(m,2H).

[0805] LCMS m / z=434.3[M / 2+1] +

[0806] Example 95: Preparation of Compound 95

[0807] Compound 95 was prepared using compounds 63b, 76-C and 2-D as raw materials according to the synthetic method of Example 66.

[0808] 1 H NMR(400MHz,DMSO-d6)δ11.22(s,1H),10.75(s,1H),7.75(s,1H),7.67(s,1H), 7.49(dd,1H),7.33(s,1H),7.26-7.18(m,1H),6.97(t,1H),6.79(d,1H),6.62(d ,1H),4.38-4.20(m,2H),3.88-3.52(m,3H),3.40-3.20(m,6H),3.15-2.82(m,5H ),2.80-2.55(m,6H),2.55-2.45(m,1H),2.30-1.46(m,15H),1.38-1.20(m,2H).

[0809] LCMS m / z=829.4[M+1] +

[0810] Example 96: Preparation of Compound 96

[0811] Compound 96 was prepared using compounds 17a, 76-C and 2-D as raw materials according to the synthetic method of Example 66.

[0812] 1 H NMR(400MHz,DMSO-d6)δ11.22(s,1H),10.75(s,1H),7.75(s,1H),7.67(s,1H), 7.49(dd,1H),7.33(s,1H),7.26-7.18(m,1H),6.97(t,1H),6.79(d,1H),6.62(d ,1H),4.38-4.20(m,2H),3.88-3.52(m,3H),3.40-3.20(m,6H),3.15-2.82(m,5H ),2.80-2.55(m,9H),2.55-2.45(m,1H),2.30-1.46(m,15H),1.38-1.20(m,2H).

[0813] LCMS m / z=826.4[M+1] +

[0814] Biological test cases

[0815] 1. Cell proliferation inhibition experiment

[0816] When SU-DHL-4 cells grew to 5×10 6 Mino cells were grown to 2×10 6 When the number of cells / mL is 20,000, the cells are plated. Use a pipette to mix the cells in the culture dish / bottle and transfer them to a 15mL (50mL) sterile centrifuge tube. Centrifuge at 1500rpm for 3 minutes. After centrifugation, remove the cells and discard the supernatant. Add 5mL of culture medium to the centrifuge tube to resuspend the cells and count them. According to the counting results, dilute the SU-DHL-4 cells to 20,000 cells / 90μL and the Mino cells to 5,000 cells / 90μL. Use a spray gun to plate the cells, 90μL per well. While plating, pay attention to mix the cells in the sample tank evenly and mark the cell information on the 96-well plate.

[0817] SU-DHL-4 cells: P13I and test compound stock solutions at 10 mM, starting at 10,000 nM, were diluted three-fold over nine stages. Compound concentrations: 10,000, 3333.33, 1111.11, 370.37, 123.46, 41.15, 13.72, 4.57, and 1.52 nM. Dilution schedule: In well 1, add 5 μL of compound stock solution to 495 μL of culture medium. In wells 2-9, add 80 μL of culture medium containing 1% DMSO to wells 2-9, plus 40 μL of the dilution from the previous well.

[0818] Mino cells: P13I and test compound stock solutions at 10 mM, starting at 10,000 nM, were diluted 5-fold over six gradients. Dosing concentrations: 10,000, 2,000, 400, 80, 16, and 3.2 nM. Dilution schedule: In well 1, add 5 μL of compound stock solution + 495 μL of culture medium. In wells 2-6, add 80 μL of culture medium containing 1% DMSO + 20 μL of the dilution from the previous well.

[0819] Add 10 μL / well of compound to the 96-well plate with cells. Set up three replicates for each concentration, with the last column serving as the DMSO vehicle control group. Continue culturing at 37°C, 5% CO2 for 72 hours.

[0820] After 72 hours, 100 μL of detection reagent (Cell Viability Assay, Promega, G7573) was added to each well, mixed for 2 minutes, incubated at room temperature for 10 minutes, and the chemiluminescence readings were measured using a microplate reader.

[0821] Cell proliferation inhibition assay (IC 50 ):Use origin9.2 software to calculate the IC of the compound to inhibit cell proliferation 50 value.

[0822] Conclusion: The compounds of the present invention, such as the compounds in the examples, have a good inhibitory effect on the proliferation of Mino cells (mantle cell lymphoma cells).

[0823] 2. TMD-8 cell proliferation inhibitory activity test:

[0824] TMD-8 is a human lymphoma cell line that expresses BTK protein and is used to evaluate the efficacy of compounds. TMD-8 cell culture medium is RPMI-1640 + 10% FBS + 1% double antibody, and cultured at 37 ° C, 5% CO2 incubator. Cells were plated in 96-well culture plates (Biosharp, BS-MP-96W), 3000 cells / well. After plating, different concentrations of compounds were added to a final volume of 100 μL / well and cultured in a 37 ° C, 5% CO2 incubator for 72 hours. After the culture is completed, 50 μL of detection solution ( Promega, G7573), mixed for 2 minutes, incubated at room temperature for 10 minutes, and the chemiluminescence readings were detected by microplate reader (Molecular Devices, SpectraMax Paradigm). The inhibition rate of the compound on cell proliferation was calculated according to formula (1), where RLU compound Read the compound wells, RLU control Read the value for the DMSO control well, RLU blankThe data were analyzed using Graphpad Prism 8.0 software, and a four-parameter equation was fitted to generate concentration-response curves and calculate the IC of the compounds for inhibiting cell proliferation. 50 Inh% = 100% - (RLU compound -RLU blank ) / (RLU control -RLU blank )*100% Formula (1)

[0825] Table 1 IC for inhibition of TMD-8 cell proliferation 50 value

[0826] Conclusion: The compounds of the present invention, such as the compounds in the examples, have a good inhibitory effect on the proliferation of TMD-8 cells.

[0827] 3. Detection of BTK degradation in Mino cells

[0828] Mino is a human mantle cell lymphoma cell line purchased from ATCC. Culture conditions: RPMI-1640 + 15% FBS + 1% double-antibody, cultured at 37°C in a 5% CO2 incubator. Cells were plated in 6-well plates, 5×10 5 / well. After plating, different concentrations of compounds were added and cultured in a 37°C, 5% CO2 incubator for 6 hours. After the culture was completed, the cells were collected and lysed on ice for 15 minutes with RIPA lysis buffer (beyotime, Cat. P0013B). After centrifugation at 12000 rpm and 4°C for 10 minutes, the supernatant protein sample was collected and quantified using a BCA kit (Beyotime, Cat. P0009). The protein was diluted to 0.2 mg / mL and the expression of BTK (CST, Cat. 8547S) and the internal reference β-actin (CST, Cat. 3700S) was detected using an automatic protein blot quantitative analyzer (Proteinsimple). The relative peak area of ​​BTK was calculated using the "Compass for SW" software when the internal reference area was 10000. The degradation rate of BTK at different drug concentrations was calculated according to formula (2), where BTK treat is the relative peak area of ​​the drug-treated group, BTK solvent The data processed according to formula (2) were used to calculate DC using GraphPad Prism 8.3.0 software using a four-parameter nonlinear regression model. 50 value. BTK Deg.%=100%-(BTK treat / BTK solvent ×100%) Formula 2

[0829] Table 2 DCs of BTK degradation in Mino cells 50 value

[0830] Conclusion: The compounds of the present invention, such as the compounds in the examples, have a good degradation effect on BTK in Mino cells.

[0831] 4. Detection of BTK degradation in REC-1 BTK L528W mutant cells

[0832] REC-1 is a human lymphoma cell line. A BTK L528W knock-in mutant cell line was constructed in REC-1 cells using the gene editing technology CRISPR / Cas9. Culture conditions: RPMI-1640 + 10% FBS + 1% double-antibody, cultured at 37°C in a 5% CO2 incubator. Cells were plated in 6-well plates, 5×10 5 / well. After plating, different concentrations of compounds were added and cultured in a 37°C, 5% CO2 incubator for 6 hours. After the culture was completed, the cells were collected and lysed on ice for 15 minutes with RIPA lysis buffer (beyotime, Cat.P0013B). After centrifugation at 12000 rpm and 4°C for 10 minutes, the supernatant protein samples were collected and quantified using a BCA kit (Beyotime, Cat.P0009). The protein was diluted to 0.2 mg / mL and the expression of BTK (CST, Cat.8547S) and the internal reference β-Actin (CST, Cat.3700S) was detected using an automatic protein blot quantitative analyzer (Proteinsimple). The relative peak area of ​​BTK was calculated using the "Compass for SW" software when the internal reference area was 10000. The degradation rate of BTK at different drug concentrations was calculated according to formula (3), where BTK treat is the relative peak area of ​​the drug-treated group, BTK solvent The data processed according to formula (3) were used to calculate DC using GraphPad Prism 8.3.0 software using a four-parameter nonlinear regression model. 50 value. BTK Deg.%=100%-(BTK treat / BTK solvent ×100%) Formula 3

[0833] Table 3 DCs of BTK degradation in REC-1BTK L528W cells 50 value

[0834] Table 4 BTK degradation rate at 5 nM concentration in REC-1 BTK L528W cells

[0835] Conclusion: The compounds of the present invention, such as the compounds in the examples, have a good degradation effect on BTK in REC-1 BTK L528W cells.

[0836] 5. Pharmacokinetic Test in Rat

[0837] Experimental purpose: This study administered the test substance to SD rats by single-dose intravenous and oral gavage, determined the concentration of the test substance in rat plasma, and evaluated the pharmacokinetic characteristics of the test substance in rats.

[0838] Experimental animals: Male SD rats, 200-220 g, 6-8 weeks old, 6 rats / compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0839] Experimental method: On the day of the experiment, 6 SD rats were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0840] Table 5 Dosing information for rat pharmacokinetic test

[0841] *Dosage is based on the free base.

[0842] Sampling: Before and after drug administration, 0.06-0.15 mL of blood was collected from the eye socket under isoflurane anesthesia and placed in an EDTAK2 centrifuge tube. The tube was centrifuged at 5000 rpm and 4°C for 10 min to collect plasma.

[0843] The time points for plasma collection in the PO group were: 0, 5 min, 15 min, 30 min, 1, 2, 4, 7, 24, and 48 h.

[0844] The time points for plasma collection in group IV were: 0, 5 min, 15 min, 30 min, 1, 2, 4, 7, and 24 h.

[0845] All samples were stored at -60°C before analysis and quantitative analysis was performed using LC-MS / MS.

[0846] Table 6 Pharmacokinetic parameters of the compounds of the present invention in rat plasma

[0847] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption in rats.

[0848] 4. Caco2 permeability test

[0849] The experiment used Caco-2 cell monolayers in 96-well Transwell plates, incubated in triplicate. Transport buffer (HBSS, 10 mM HEPES, pH 7.4 ± 0.05) containing the compound of the invention (2 μM) or the control compounds digoxin (10 μM), nadolol (2 μM), and metoprolol (2 μM) was added to the apical or basolateral wells of the cell monolayer. Transport buffer containing DMSO was added to the corresponding receiving wells. After incubation at 37 ± 1°C for 2 hours, the cell plate was removed and appropriate samples were taken from the apical and basolateral wells to a new 96-well plate. Proteins were then precipitated by adding acetonitrile containing an internal standard. Samples were analyzed using LC-MS / MS to determine the concentrations of the compound of the invention and the control compound. The concentration data were used to calculate the apparent permeability coefficients for transport from the apical to basolateral side of the cell monolayer and from the basolateral to apical side, thereby calculating the efflux rate. The integrity of the cell monolayer after 2 hours of incubation was assessed by leakage of Lucifer Yellow.

[0850] Table 7 Caco2 test results of the compounds of the present invention

[0851] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good Caco2 permeability.

[0852] 5. Pharmacokinetic Testing in Mice

[0853] Experimental purpose: This study administered the test substance to ICR mice by single-dose intravenous and oral gavage, measured the concentration of the test substance in mouse plasma, and evaluated the pharmacokinetic characteristics of the test substance in mice.

[0854] Experimental animals: Male ICR mice, 6 per compound, were purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0855] Experimental method: On the day of the experiment, 6 SD mice were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0856] Table 8 Dosing information for mouse pharmacokinetic test

[0857] *Dosage is based on the free base.

[0858] Sampling: Before and after drug administration, 0.06 mL of blood was collected from the eye socket under isoflurane anesthesia and placed in an EDTAK2 centrifuge tube. The tube was centrifuged at 5000 rpm and 4°C for 10 min to collect plasma.

[0859] The time points for plasma collection in the PO group were: 0, 5 min, 15 min, 30 min, 1, 2, 4, 7, 24, and 48 h.

[0860] The time points for plasma collection in group IV were: 0, 5 min, 15 min, 30 min, 1, 2, 4, 7, 24, and 48 h.

[0861] All samples were stored at -60°C before analysis and quantitative analysis was performed using LC-MS / MS.

[0862] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption in mice.

[0863] 6. Pharmacokinetic Testing in Beagle Dogs

[0864] Experimental animals: Male beagle dogs, weighing about 8-10 kg, 6 per compound, purchased from Beijing Masi Biotechnology Co., Ltd.

[0865] Experimental method: On the day of the experiment, 6 beagle dogs were randomly divided into groups according to body weight. They were fasted but not watered for 14-18 hours before administration and fed 4 hours after administration.

[0866] Table 9. Dosing information for beagle dog pharmacokinetic study

[0867] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% NS;

[0868] Oral (gavage) administration solvent: 5% DMSO + 5% Solutol + 10% PEG400 + 80% (20% SBE-CD);

[0869] *Dosage is based on the free base.

[0870] Before and after dosing, 1 ml of blood was collected from the jugular vein or limb vein into an EDTAK2 centrifuge tube. The samples were centrifuged at 5000 rpm at 4°C for 10 minutes, and plasma was collected. Blood was collected at the following time points for both the intravenous and oral administration groups: 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, 10, 12, 24, and 48 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0871] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption in dogs.

[0872] 7. Monkey Pharmacokinetic Test

[0873] Test animals: Male cynomolgus monkeys, 3-5 kg, 3-6 years old, 4 per compound, purchased from Suzhou Xishan Biotechnology Co., Ltd.

[0874] Experimental method: On the day of the experiment, four monkeys were randomly divided into groups according to body weight. They were fasted but not watered for 14-18 hours before administration and fed 4 hours after administration.

[0875] Table 10. Dosing information for monkey pharmacokinetic studies

[0876] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% NS;

[0877] Oral (gavage) administration solvent: 5% DMSO + 5% Solutol + 10% PEG400 + 80% (20% SBE-CD);

[0878] *Dosage is based on the free base.

[0879] Before and after dosing, 1.0 mL of blood was collected from the jugular vein and placed in an EDTAK2 centrifuge tube. The samples were centrifuged at 5000 rpm at 4°C for 10 minutes, and plasma was collected. Blood was collected at the following time points for both the intravenous and oral administration groups: 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, 10, 12, 24, and 48 hours. All samples were stored at -60°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0880] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption in monkeys.

[0881] 8. hERG potassium channel effect test

[0882] Experimental platform: electrophysiology manual patch clamp system

[0883] Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channel

[0884] Experimental methods: CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents using the whole-cell patch clamp technique at room temperature. Glass microelectrodes were pulled from glass electrode blanks (BF150-86-10, Sutter) using a puller. The tip resistance after perfusing the electrode liquid was about 2-5 MΩ. The glass microelectrode was inserted into the amplifier probe to connect to the patch clamp amplifier. The clamping voltage and data recording were controlled and recorded by a computer using pClamp 10 software, with a sampling frequency of 10 kHz and a filter frequency of 2 kHz. After obtaining the whole-cell recording, the cell was clamped at -80 mV to induce the hERG potassium current (I hERG ) was administered with a 2-second depolarization step from -80 mV to +20 mV, followed by repolarization to -50 mV for 1 second before returning to -80 mV. This voltage stimulus was administered every 10 seconds, and administration began after confirming that the hERG potassium current was stable (for at least 1 minute). Compounds were administered for at least 1 minute at each test concentration, and at least two cells (n ≥ 2) were tested for each concentration.

[0885] Data processing: Data analysis was performed using pClamp 10, GraphPad Prism 5, and Excel. The degree of inhibition of hERG potassium current (peak hERG tail current induced at -50 mV) by different compound concentrations was calculated using the following formula: Inhibition% = [1-(I / Io)] × 100%

[0886] Wherein, Inhibition% represents the inhibition percentage of the compound on hERG potassium current, and I and Io represent the amplitudes of hERG potassium current before and after drug addition, respectively.

[0887] Compound IC 50 The results were calculated using GraphPad Prism 5 software by fitting the following equation: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X)*HillSlope))

[0888] Where X is the Log value of the test sample concentration, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0889] Conclusion: The compounds of the present invention, such as the compounds in the examples, have no significant inhibitory effect on hERG potassium channel current.

[0890] 9. Liver microsome stability test

[0891] In this study, liver microsomes from five species, including humans, dogs, rats, and mice, were used as in vitro models to evaluate the metabolic stability of the test substances.

[0892] At 37°C, 1 μM of the test substance was incubated with microsomal proteins and coenzyme NADPH. The reaction was terminated by adding ice-cold acetonitrile containing an internal standard after a certain time (5, 10, 20, 30, 60 min). The concentration of the test substance in the sample was detected by LC-MS / MS. The T value was calculated based on the ln value of the drug residual rate in the incubation system and the incubation time. 1 / 2 , and further calculated the liver microsomal intrinsic clearance CL int(mic) and hepatic intrinsic clearance CL int(Liver) .

[0893] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good liver microsomal stability.

[0894] 10.CYP450 enzyme inhibition test

[0895] The purpose of this study was to evaluate the effects of test substances on the activities of five isoenzymes of cytochrome P450 (CYP) in human liver microsomes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) using an in vitro test system. Specific probe substrates for the CYP450 isoenzymes were incubated with human liver microsomes and varying concentrations of the test substances. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction. After the reaction, the samples were processed and the metabolites produced by the specific substrates were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS). Changes in CYP enzyme activity were measured, and the IC values ​​were calculated. 50 The inhibitory potential of the test substance on each CYP enzyme isoform was evaluated.

[0896] Conclusion: The compounds of the present invention, such as the compounds in the examples, have no significant inhibitory effect on the five isoenzymes of human liver microsomal cytochrome P450.

[0897] 11. REC-1 cell proliferation inhibition experiment

[0898] REC-1 is a human lymphoma cell line cultured in RPMI-1640 (ATCC, Cat. 30-2001) + 10% FBS (HyClone, Cat. SV3028.02) + 1% bispecific antibody (Gibco, Cat. 15140-122) at 37°C in a 5% CO2 incubator. Cells were harvested and plated in 96-well plates at a density of 3,000 cells / 180 μL / well. 20 μL of compound at various concentrations or 0.1% DMSO were then added. A blank control group was also established, containing only 200 μL of culture medium. The cells were cultured at 37°C in a 5% CO2 incubator for 5 days. After the incubation, 50 μL of CellCounting-Lite 2.0 Reagent (Vazyme, Cat. DD1101-03) was added directly to each well and mixed for 10 minutes. Then, the fluorescence signal RLU was read and recorded using a PHERAstar FSX multifunctional microplate reader (BMG LRBTECH). The cell proliferation inhibition rate of different concentrations of compounds was calculated according to formula (4). DMSO is the average signal value of the DMSO group, RLU blank is the average signal value of the blank control group, RLU compound The data processed according to formula (4) were used to fit the curve using GraphPad Prism software using four parameters to calculate the concentration IC of the compound when the inhibition rate was 50%. 50 Inhibition% = (1-(RLU compound -RLU blank ) / (RLU DMSO-RLU blank ))×100% Formula (4)

[0899] Conclusion: The compounds of the present invention, such as the compounds in the examples, have a significant inhibitory effect on the proliferation of REC-1 cells.

[0900] 12. REC-1 BTK L528W mutant cell proliferation inhibition experiment

[0901] REC-1 is a human lymphoma cell line. A BTK L528W knock-in mutant cell line was constructed in REC-1 cells using the gene-editing technology CRISPR / Cas9. Culture conditions: RPMI-1640 (ATCC, Cat. 30-2001) + 10% FBS (HyClone, Cat. SV3028.02) + 1% bispecific antibody (Gibco, Cat. 15240-062), incubated at 37°C in a 5% CO2 incubator. Cells were harvested and plated in 96-well plates at a density of 3000 cells / 180 μL / well. 20 μL of compound at various concentrations or 0.1% DMSO were then added. A blank control group containing only 200 μL of culture medium was also established and cultured at 37°C in a 5% CO2 incubator for 5 days. After the incubation period, 50 μL of CellCounting-Lite 2.0 Reagent (Vazyme, Cat. DD1101-03) was added directly to each well and mixed for 10 minutes. The fluorescence signal RLU was then read and recorded using a PHERAstar FSX multifunctional microplate reader (BMG LRBTECH). The cell proliferation inhibition rate of the compound at different concentrations was calculated according to formula (5). DMSO is the average signal value of the DMSO group, RLU blank is the average signal value of the blank control group, RLU compound The data processed according to formula (5) were used to fit the curve using GraphPad Prism software using four parameters to calculate the concentration IC of the compound when the inhibition rate was 50%. 50 Inhibition% = (1-(RLU compound -RLU blank ) / (RLU DMSO -RLU blank ))×100% Formula (5)

[0902] Conclusion: The compounds of the present invention, such as the compounds in the examples, have a significant inhibitory effect on the proliferation of REC-1BTK L528W mutant cells.

[0903] 13.OCI-LY10 cell proliferation inhibition experiment

[0904] OCI-LY10 is a human diffuse large B-cell lymphoma cell line cultured in IMDM (Gibco, Cat. 12440053) + 10% FBS (Avantor, Cat. 76294-180) + 1% bispecific antibody (Gibco, Cat. 15140-122) at 37°C in a 5% CO2 incubator. Cells were harvested and plated in 384-well plates at a density of 5000 cells / 40 μL / well. 40 nL of DMSO or various concentrations of compound were then added. A blank control group was also maintained with 40 μL of culture medium alone and cultured for 3 days at 37°C in a 5% CO2 incubator. After the incubation, 20 μL of CellCounting-Lite 2.0 Reagent (Vazyme, Cat. DD1101-03) was added directly to each well, mixed for 2 minutes, and then incubated at room temperature for 30 minutes. The fluorescence signal RLU was then read and recorded using a PHERAstar FSX multifunctional microplate reader (BMG LRBTECH). The cell proliferation inhibition rate of different concentrations of compounds was calculated according to formula (6). DMSO is the average signal value of the DMSO group, RLU blank is the average signal value of the blank control group, RLU compound The data processed according to formula (6) were used to fit the curve using XLfit software with four parameters to calculate the concentration IC of the compound when the inhibition rate was 50%. 50 Inhibition% = (RLU DMSO -RLU compound ) / (RLU DMSO -RLU blank )×100% Formula (6)

[0905] Conclusion: The compounds of the present invention, such as the compounds in the examples, have a significant inhibitory effect on the proliferation of OCI-LY10 cells.

[0906] 14. OCI-LY10 BTK L528W mutant cell proliferation inhibition experiment

[0907] OCI-LY10 is a human diffuse large B-cell lymphoma cell line. A BTK L528W knock-in mutant cell line was constructed in OCI-LY10 cells using the gene-editing technology CRISPR / Cas9. Culture conditions: IMDM (Gibco, Cat. 12440053) + 10% FBS (Avantor, Cat. 76294-180) + 1% bispecific antibody (Gibco, Cat. 15140-122), incubated at 37°C in a 5% CO2 incubator. Cells were harvested and plated in 384-well plates at a density of 5000 cells / 40 μL / well. 40 nL of DMSO or various concentrations of compound were then added. A blank control group was also established, containing only 40 μL of culture medium. The cells were cultured at 37°C in a 5% CO2 incubator for 3 days. After the incubation, 20 μL of CellCounting-Lite 2.0 Reagent (Vazyme, Cat. DD1101-03) was added directly to each well, mixed for 2 minutes, and then incubated at room temperature for 30 minutes. The fluorescence signal RLU was then read and recorded using a PHERAstar FSX multifunctional microplate reader (BMG LRBTECH). The cell proliferation inhibition rate of different concentrations of compounds was calculated according to formula (7). DMSO is the average signal value of the DMSO group, RLU blank is the average signal value of the blank control group, RLU compound The data processed according to formula (7) were used to fit the curve using XLfit software with four parameters to calculate the concentration IC of the compound when the inhibition rate was 50%. 50 Inhibition% = (RLU DMSO -RLU compound ) / (RLU DMSO -RLU blank )×100% Formula (7)

[0908] Conclusion: The compounds of the present invention, such as the compounds in the examples, have a significant inhibitory effect on the proliferation of OCI-LY10 BTK L528W mutant cells.

[0909] 15. Human CD34+ hematopoietic stem cell proliferation inhibition experiment

[0910] Human CD34+ hematopoietic stem cells (TPCS, Cat. hmPB34-P-2CW) were obtained from human PBMCs by immunomagnetic separation and expressed CD34. Culture conditions were: DPBS (Gibco, Cat. 14190-144) + StemSpan SFEMII (STEMCELL, Cat. 9655) + 1X StemSpan CD34+ Expansion Supplement (STEMCELL, Cat. 2691). 40 nL of DMSO, the positive control talazoparib, or the test compound were added to a 384-well plate (Corning, Cat. 3764). The cell suspension was then added at a density of 400 cells / 40 μL / well, resulting in a final concentration of 0.1% DMSO, 3 μM talazoparib, or various concentrations of the test compound. The cells were centrifuged at 1000 rpm for 1 minute at room temperature and then incubated at 37°C in a 5% CO2 incubator for 7 days. After the incubation, 20 μL of CellTiter-Glo Reagent (Promega, Cat. G7573) was added directly to each well, centrifuged at 1000 rpm for 1 minute at room temperature, and then incubated in the dark for 20 minutes. After the incubation, the chemiluminescent signal CFU was read and recorded using the Envision multi-mode microplate reader (PerkinElmer, Cat. 2104). The cell proliferation inhibition rate of different concentrations of compounds was calculated according to formula (8), CFU high control is the average signal value of the DMSO group, CFU low control is the average signal value of Talazoparib group, CFU compound The data processed according to formula (8) were fitted with XLfit or GraphPad Prism software using four parameters to calculate the concentration IC of the compound when the inhibition rate was 50%. 50 value. Inhibiton%=(CFU high control -CFU compound ) / (CFU high control -CFU low control )×100% (Formula 8)

[0911] Conclusion: The compounds of the present invention, such as the compounds in the examples, have no significant inhibitory effect on the proliferation of CD34+ hematopoietic stem cells.

[0912] The structure of reference compound 1 is as follows:

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: BLK(I); B is selected from L is selected from Its left side is connected to B and its right side is connected to K; K is selected from B1 does not exist or is selected from C 3-12 A carbocyclic group or a 4-12 membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 R b1 replace; B2 is selected from C 3-12 A carbocyclic group or a 4-12 membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 R b2 replace; B4 is selected from phenyl, 5-6 membered heteroaryl, 9-12 membered bicyclic ring radical, K1 is selected from phenyl, 5-6 membered heteroaryl, 9-12 membered bicyclic ring group, Selected from aromatic or non-aromatic rings; W is selected from a 5-6 membered heterocyclic group; Z2 is selected from CH or N; Z3 is selected from CH or N; L1 is selected from the group consisting of -Ak1-, -Ak1-Ak2-, -Cy1-, -Cy1-Cy2-, -Cy1-Ak1-, -Ak1-Cy1-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak1-, -Ak1-Cy1-Cy2-, -Cy1-Ak1-Cy2-Ak2-, -Ak1-Cy1-Ak2-Cy2-; Q is selected from NR q CO、CONR q 、CO、NR q or key; X1, X2, X3 are each independently selected from N or CR b3 ; Z1 is selected from N or CR k2 ; Ak1, Ak2 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、CONR L , CO, C≡C, the alkylene, alkenylene, alkynylene are 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 or R N Each independently selected 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 , 4-12-membered monocyclic carbocyclic group, 4-12-membered cyclic carbocyclic group, 5-12-membered spirocyclic carbocyclic group, 5-12-membered bridged carbocyclic group, 5-12-membered heteroaryl group or 6-10-membered aryl group, wherein the aryl, heteroaryl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, COOH, CONH2, 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 b1 , R b2 , R b3 , R b4 , R k1 , R k2 , R k3 , R q Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, =S, 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, alkoxy, heterocyclic group, and carbocyclic group are optionally substituted by 1 to 6 deuterium, F, Cl, Br, I, OH, =O, NH2, CN, CONH2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 4-6 membered carbocyclic group, 4-6 membered heterocyclic group, -OC 3-7 -O-4-6 membered heterocyclic group, fluorine-substituted C 3-7 Member carbocyclic group, C 2-6 Alkynyl, substituted by a substituent of fluorine-substituted phenyl; b4 are each independently selected from 0, 1, 2, 3, 4, 5 or 6; p1 or p2 are each independently selected from 0, 1, 2, 3 or 4; The condition is, K1 is selected from Or B4 is selected from 2. The compound according to claim 1 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: B1 does not exist or is selected from C 3-7 1-membered monocyclic carbocyclic group, C 5-12 1-membered carbonyl ring, C 5-12 spirocyclic carbocyclic group, C 5-12 4-7 membered monocyclic heterocyclic group, 4-12 membered cyclic heterocyclic group, 5-12 membered spirocyclic heterocyclic group, 5-12 membered bridged heterocyclic group, the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R b1 replace; B2 is selected from 4-7 membered monocyclic heterocyclic group, 4-12 membered cyclic heterocyclic group, 5-12 membered spirocyclic heterocyclic group, 5-12 membered bridged heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 R b2 replace; B4 is selected from phenyl, 5-6 membered heteroaryl, benzo 5-membered heterocyclic group, benzo 6-membered heterocyclic group, benzo 5-membered carbocyclic group, benzo 6-membered carbocyclic group, benzo 7-membered carbocyclic group, benzo 8-membered carbocyclic group, pyrido 5-membered heterocyclic group, pyrido 6-membered heterocyclic group; K1 is selected from phenyl, 5-6 membered heteroaryl, Benzo 5-membered heterocyclic group, benzo 6-membered heterocyclic group; Ak1 and Ak2 are each independently selected from C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, O, NR L NR L CO、CONR L , CO, 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 or R N Each independently 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, heteroaryl, carbocyclic group or heterocyclic group is selected from 1 to 4 deuterium, F, Cl, Br, I, OH, COOH, CONH2, 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 b1 , R b2 , R b3 , R b4 , R k1 , R k2 , R k3 , R q Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, =S, 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, alkoxy, heterocyclic group, and carbocyclic group are optionally substituted by 1 to 6 deuterium, F, Cl, Br, I, OH, =O, NH2, CN, CONH2, COOH, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-7 4-6 membered carbocyclic group, 4-6 membered heterocyclic group, -OC 3-7 -O-4-6 membered heterocyclic group, fluorine-substituted C 3-7 Member carbocyclic group, C 2-6 The phenyl group may be substituted by a substituent of an alkynyl group or a fluorine-substituted phenyl group.

3. The compound according to claim 2 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: B1 is absent or selected from 4-6 membered heterocyclic group, cyclopropyl spiro 5 membered heterocyclic group, cyclobutyl spiro 5 membered heterocyclic group, 5- and 5-membered heterocyclic group, 6- and 5-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 R b1 replace; B2 is selected from 4-6 membered monocyclic heterocyclic group, 8-9 membered cyclic heterocyclic group, 7-11 membered spirocyclic heterocyclic group, 5-8 membered bridged heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 R b2 replace; Ak1 and Ak2 are each independently selected from C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylidene, O, NR L NR L CO, CO, 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 Membered carbocyclic group, 4-6 membered substituted by a substituent of a heterocyclic group; R L or R N Each independently 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 replaced by 1 to 4 moieties selected from deuterium, F, Cl, Br, I, OH, NH2, COOH, CONH2, CN, =O, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted 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, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: B1 is absent or optionally replaced by 1 to 2 R b1 Substituted with the following groups: B2 is selected from 1 to 3 R b2 Substituted with the following groups: Its right side is connected to Company B catch; B4 is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, furanyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, b4 is selected from 0, 1, 2 or 3; K1 is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, furanyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, Ak1 and Ak2 are each independently selected from methylene, ethylene, vinylene, and ethynylene, wherein the methylene, ethylene, vinylene, and ethynylene are optionally substituted by 1 to 4 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 replaced by 1 to 4 deuterium, F, Cl, Br, I, OH, =O, NH2, CN, CONH2, COOH, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted 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 k3 , R q Each is independently selected from H, deuterium, F, Cl, Br, I, OH, =O, =S, NH2, CN, COOH, CONH2, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, oxetanyl, tetrahydrofuranyl, oxacyclohexyl, 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, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, oxetanyl, tetrahydrofuranyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, pyridyl are optionally substituted by 1 to 6 deuterium, F, Cl, Br, I, OH, =O, NH2, CN, CONH2, COOH, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-7 4-6 membered carbocyclic group, 4-6 membered heterocyclic group, -OC 3-7 -O-4-6 membered heterocyclic group, fluorine-substituted C 3-7 Member carbocyclic group, C 2-6 The phenyl group may be substituted by a substituent of an alkynyl group or a fluorine-substituted phenyl group.

5. The compound according to claim 4 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: L1 is selected from one of the structural fragments in Table L1-1; Q is selected from CONR q NR q CO、NR q or key; R b1 Each is independently selected from H, deuterium, F, Cl, Br, I, OH, =O, =S, NH2, CN, COOH, CONH2, CF3, CD3, CHF2, CH2F, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, oxetanyl, tetrahydrofuranyl, oxetanyl, -CH2-cyclopropyl, -CH2CF3, fluoro-substituted phenyl, 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, CH2OH; R k3 Each is independently selected from H, deuterium, and methyl; R q Each is independently selected from H, deuterium, and methyl.

6. The compound according to claim 5 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: B is selected from one of the fragments shown in Table B-1; L is selected from one of the fragments shown in Table A; K is selected from 7. The compound according to claim 1, or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein the compound is selected from one of the structures in Table 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 stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals or the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating tumors or autoimmune diseases, preferably relapsed / refractory B-cell malignancies.

11. A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 7 or a stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, or a pharmaceutical composition according to claim 8, the therapeutically effective amount preferably being 1-1500 mg, the disease preferably being a tumor or an autoimmune disease, more preferably being a relapsed / refractory B-cell malignancy.

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