Polycyclic HPK1 kinase inhibitor and application thereof in medicine

Abstract

The invention relates to a polycyclic HPK1 kinase inhibitor isoindoline-1-ketone derivative and application thereof in medicine, in particular to a compound shown in a general formula (I) or a general formula (II) or a stereoisomer, a tautomer, a racemate, a deuterated compound, a solvate, a prodrug, a metabolite, pharmaceutically acceptable salt or eutectic of the compound, an intermediate of the compound and a preparation method of the compound. The invention also discloses application of the compound in preparation of drugs for treating diseases related to HPK1 kinase activity or expression quantity. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a compound represented by general formula (I) or general formula (II), or its stereoisomer, tautomer, racemate, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and its intermediate and preparation method, as well as its application in the preparation of drugs for treating diseases related to HPK1 kinase activity or expression level. Background Art

[0002] Kinases catalyze the phosphorylation of proteins, lipids, sugars, nucleotides and other cellular metabolites, and play a key role in various aspects of eukaryotic cell physiology. In particular, protein kinases and lipid kinases are involved in controlling activated signal events, and the growth, differentiation and survival of cells in response to extracellular mediators or stimuli such as growth factors, cytokines or chemokines. Generally, protein kinases are divided into two categories, one preferentially phosphorylates tyrosine residues, and the other preferentially phosphorylates serine and / or threonine residues.

[0003] Hematopoietic progenitor kinase HPK1 (Hematopoietic Progenitor Kinase 1, also known as Mitogen-Activated Protein Kinase Kinase Kinase Kinase 1, MAP4K1) is a serine / threonine protein kinase and a member of the MAP4K family. It is a negative signal regulator of the T cell receptor (TCR). Activation of the TCR recruits and activates HPK1, which phosphorylates the Ser376 amino acid residue of the SLP76 protein, thereby destabilizing the TCR signal complex and ultimately inhibiting the activation and proliferation of T cells. Compared with wild-type mice, mice lacking HPK1 kinase showed better T cell proliferation activity and anti-tumor immunity under TCR stimulation. At the same time, mice lacking HPK1 kinase did not show lethal inflammatory responses. HPK1 has become an important therapeutic target, attracting extensive research and development interest. Therefore, it is necessary to develop novel HPK1 inhibitor drugs for the treatment of tumor diseases related to HPK1. Summary of the Invention

[0004] The object of the present invention is to provide a compound capable of inhibiting HPK1 kinase, or its stereoisomer, tautomer, racemate, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and its intermediate and preparation method, as well as its application in the preparation of drugs for treating diseases related to HPK1 activity or expression level.

[0005] The compounds of the present invention have good HPK1 inhibitory activity, good safety and pharmacokinetic activity.

[0006] The present invention provides a compound of general formula (I) or its stereoisomers, tautomers, racemates, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, wherein

[0007]

[0008] In some embodiments, general formula (I) is selected from general formula (Ia),

[0009]

[0010] In some embodiments, Y in the compound of general formula (I) 1 is selected from N, C or CH;

[0011] In some embodiments, Z in the compound of general formula (I) 1 is selected from N, C or CH;

[0012] In some embodiments, X in the compound of general formula (I) 1 is selected from N or CR x1 ;

[0013] In some embodiments, X in the compound of general formula (I) 2 is selected from N or CR x2 ;

[0014] In some embodiments, X in the compound of general formula (I) 1 is selected from N or CH;

[0015] In some embodiments, X in the compound of general formula (I) 2 is selected from N or CH;

[0016] In some embodiments, X in the compound of general formula (I) 1 is selected from N or CR x1 and X 2 is selected from CH;

[0017] In some embodiments, X in the compound of general formula (I) 1 is selected from N or CH, and X 2 is selected from CH;

[0018] In some embodiments, X in the compound of general formula (I) 1 is selected from CR x1 and X 2 is selected from CR x2 ;

[0019] In some embodiments, R x1 and R x2Each independently selected from H, deuterium, halogen, cyano, OH, NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6 alkyl, C 3-6 carbocyclic group, 4- to 7-membered heterocyclic group, and the alkyl, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 R k substituents;

[0020] In some embodiments, in the compound of formula (I), R x1 , R x2 Each independently selected from H, deuterium, halogen, cyano, OH, NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, C 3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, and the alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 4 R k substituents;

[0021] In some embodiments, in the compound of formula (I), R x1 , R x2 Each independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NH 2 , NHCH 3 , N(CH 3 ) 2 , methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, pyrrolidinyl, and the methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, pyrrolidinyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, methyl;

[0022] In some embodiments, in the compound of formula (I), R 1 is selected from C 5-14 carbocyclic group or 5- to 14-membered heterocyclic group, and the R 1 is optionally substituted with 1 to 6 R 1a substituents;

[0023] In some embodiments, R in the compound of formula (I) 1 is selected from phenyl, 5- to 6-membered heteroaryl, 8- to 10-membered bicyclic heteroaryl, 9- to 14-membered tricyclic heteroaryl, 8- to 10-membered fused heterocyclic group, 9- to 14-membered tricyclic heterocyclic group, benzo-C 4-6 carbocyclic group, benzo-4- to 6-membered heterocyclic group, and said R 1 is optionally substituted with 1 to 6 R 1a ;

[0024] In some embodiments, R in the compound of formula (I) 1 is selected from phenyl, 5- to 6-membered heteroaryl, 5-fused 5-membered heteroaryl, 5-fused 6-membered heteroaryl, 5-fused 5-membered partially saturated heterocyclic group, 5-fused 6-membered partially saturated heterocyclic group, 5-fused 7-membered partially saturated heterocyclic group, 9- to 14-membered tricyclic heteroaryl, 9- to 14-membered tricyclic heterocyclic group, and said heteroaryl or heterocyclic group contains 1 to 4 nitrogen atoms, and said R 1 is optionally substituted with 1 to 6 R 1a ;

[0025] In some embodiments, R in the compound of formula (I) 1 is selected from and said R 1 is optionally substituted with 1 to 6 R 1a ;

[0026] In some embodiments, R in the compound of formula (I) 1 is selected from and said R 1 is optionally substituted with 1 to 4 R 1a ;

[0027] In some embodiments, R in the compound of formula (I) 2 is selected from

[0028] In some embodiments, R in the compound of formula (I) 2 is selected from

[0029] In some embodiments, in the compound of formula (I), K 1 , K 2 , K 3 are each independently selected from N, CH or CR 2b ;

[0030] In some embodiments, in the compound of formula (I) is selected from Q is selected from a bond, CH 2 , NH or O;

[0031] In some embodiments, in the compound of formula (I) is selected from

[0032] In some embodiments, in the compound of formula (I) is selected from

[0033] In some embodiments, in the compound of formula (I) R is selected from

[0034] In some embodiments, in the compound of formula (I) R 2 is selected from

[0035] In some embodiments, in the compound of formula (I) R 2 is selected from

[0036] In some embodiments, in the compound of formula (I), ring D is selected from a 4- to 6-membered heterocyclic group, and the ring D is optionally substituted with 1 to 4 R d substituents;

[0037] In some embodiments, in the compound of formula (I), ring D is selected from a 4- to 6-membered heterocycloalkyl group, and the ring D is optionally substituted with 1 to 4 R d substituents;

[0038] In some embodiments, in the compound of formula (I) R 2a is directly connected to R D to form ring Y;

[0039] In some embodiments, in the compound of formula (I), ring Y is selected from a 9- to 13-membered heterocycle, and the heterocycle is optionally substituted with 1 to 4 R y substituents;

[0040] In some embodiments, in the compound of formula (I), ring Y is selected from a partially unsaturated 9- to 13-membered heterocycle, and the heterocycle is optionally substituted with 1 to 4 R y substituents;

[0041] In some embodiments, in the compound of formula (I), ring D, ring Y and K 1 , K 2 , K3 The number of ring atoms in the polycyclic formed together with the ring where it is located is greater than 16-membered;

[0042] In some embodiments, in the compound represented by general formula (I), R y are each independently selected from deuterium, halogen, ═O, CN, OH, C 1-6 alkyl, -OC 1-6 alkyl, C 0-4 alkylene-C 3-6 carbocyclic group, -C 0-4 alkylene-4- to 7-membered heterocyclic group, and the alkyl, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k substituents;

[0043] In some embodiments, in the compound represented by general formula (I), R y are each independently selected from deuterium, halogen, ═O, CN, OH, C 1-4 alkyl, -OC 1-4 alkyl, C 3-6 carbocyclic group, 4- to 7-membered heterocyclic group, C 1-2 alkylene-C 3-6 cycloalkyl group, -C 1-2 alkylene-4- to 7-membered heterocycloalkyl group, and the alkyl, alkylene, carbocyclic group, heterocyclic group, cycloalkyl group or heterocycloalkyl group is optionally substituted by 1 to 4 R k substituents;

[0044] In some embodiments, ring A in the compound represented by general formula (I) is selected from phenyl or 5- to 6-membered heteroaryl;

[0045] In some embodiments, ring B in the compound represented by general formula (I) is selected from 5- to 6-membered heterocyclic groups, and the ring B is optionally substituted by 1 to 2 R b substituents;

[0046] In some embodiments, ring B in the compound represented by general formula (I) is selected from 5- to 6-membered heterocyclic groups containing 1 to 2 nitrogen heteroatoms, and the ring B is optionally substituted by 1 to 2 R b substituents;

[0047] In some embodiments, in the compound represented by general formula (I), K 4 is selected from N or CH;

[0048] In some embodiments, in the compound represented by general formula (I), K 5 is selected from N or CH;

[0049] In some embodiments, in the compound represented by general formula (I), K 5 is selected from N;

[0050] In some embodiments, ring C in the compound of formula (I) is selected from C 6-10 a carbocyclic group or a 5- to 10-membered heterocyclic group;

[0051] In some embodiments, ring C in the compound of formula (I) is selected from phenyl, a 5- to 6-membered heteroaryl group, an 8- to 10-membered heteroaryl group, benzoC 4-6 a carbocyclic group, benzo-4- to 6-membered heteroaryl group;

[0052] In some embodiments, ring C in the compound of formula (I) is selected from phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, thienyl, pyrazolyl, pyrrolyl, imidazolyl;

[0053] In some embodiments, ring E in the compound of formula (I) is a 5- to 6-membered heterocyclic group containing 1 phosphorus atom, and the phosphorus atom is optionally oxidized to P(=O), P(=O) 2 ;

[0054] In some embodiments, ring E in the compound of formula (I) is selected from

[0055] In some embodiments, R 1a , R 2b , R a , R b , R c , R d , R e are each independently selected from deuterium, halogen, =O, CN, OH, NO 2 , COOH, CONH 2 , NH 2 , -C 0-4 alkylene-NHC 1-6 alkyl, -C 0-4 alkylene-N(C 1-6 alkyl) 2 , -C 0-4 alkylene-N(C 1-6 alkyl)-C 3-6 carbocyclic group, -C 0-4 alkylene-N(C 1-6 alkyl)-4- to 7-membered heterocyclic group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -O-C 3-6 carbocyclic group, -O-4- to 7-membered heterocyclic group, -NH-C 3-6 carbocyclic group, -NH-4- to 7-membered heterocyclic group, -C0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4 Alkylene-4- to 7-membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 R k substituents;

[0056] In some embodiments, in the compound of formula (I), R 1a , R 2b , R a , R b , R c , R d , R e are each independently selected from deuterium, halogen, =O, CN, OH, NO 2 , COOH, CONH 2 , NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , -C 1-2 alkylene-NHC 1-4 alkyl, -C 1-2 alkylene-N(C 1-4 alkyl) 2 , -C 1-2 alkylene-N(C 1-4 alkyl)-C 3-6 cycloalkyl, -C 1-2 alkylene-N(C 1-4 alkyl)-4- to 7-membered heterocycloalkyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -SC 1-4 alkyl, -O-C 3-6 cycloalkyl, -O-4- to 7-membered heterocycloalkyl, -NH-C 3-6 cycloalkyl, -NH-4- to 7-membered heterocycloalkyl, -C 1-2 alkylene-C 3-6 cycloalkyl, -C 1-2 alkylene-4- to 7-membered heterocycloalkyl, C 3-6 carbocyclic group, 4- to 7-membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group, heterocyclic group cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 4 R k substituents;

[0057] In some embodiments, in the compound of formula (I), R 1a , R 2b , R a , R b , R c2, R d , R e Each independently selected from deuterium, F, Cl, Br, I, =O, CN, OH, NO 2 , COOH, CONH 2 , NH 2 , NHCH 3 , N(CH 3 ) 2 , methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -azetidinyl, -CH 2 -oxetanyl, and the methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl are optionally substituted by 1 to 4 R k substituents;

[0058] In some embodiments, R c in the compound represented by the general formula (I) is selected from R c1 ;

[0059] In some embodiments, R c1 in the compound represented by the general formula (I) is selected from -CH 2 NHCH 3 , -CH 2 NHCH 2 CH 3 , -CH 2 N(CH 3 ) 2 , -CH 2 N(CH 2 CH 3 ) 2 , -CH 2 N(CH 3 )CH 2 CH 3 , -CH 2 N(CH 3 )-cyclopropyl, The CH 2 , methyl, ethyl, cyclopropyl, are optionally substituted by 1 to 4 R k substituents;

[0060] In some embodiments, R in the compound represented by the general formula (I) c1 is selected from -CH 2 NHCH 3 、-CH 2 NHCH 2 CH 3 、-CH 2 N(CH 3 ) 2 、-CH 2 N(CH 2 CH 3 ) 2 、-CH 2 N(CH 3 )CH 2 CH 3 、-CH 2 N(CH 3 )-cyclopropyl, the CH 2 described, methyl, ethyl, cyclopropyl, optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, methyl, ethyl, -CH 2 OH;

[0061] In some embodiments, R in the compound represented by the general formula (I) 1a are each independently selected from deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, methyl or ethyl;

[0062] In some embodiments, R in the compound represented by the general formula (I) a are each independently selected from deuterium, F, Cl, Br, I, CN, OH, methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, ethoxy, the methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, ethoxy optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, methyl, ethyl;

[0063] In some embodiments, R in the compound represented by the general formula (I) eEach independently selected from deuterium, F, Cl, Br, I, =O, CN, OH, methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, ethoxy, wherein the methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, ethoxy are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, methyl, ethyl;

[0064] In some embodiments, in the compound of formula (I), R 3 is selected from H, halogen, C 1-6 alkyl, and the alkyl is optionally substituted by 1 to 4 R k substituents;

[0065] In some embodiments, in the compound of formula (I), R 4 is selected from H, halogen, C 1-6 alkyl, and the alkyl is optionally substituted by 1 to 4 R k substituents;

[0066] In some embodiments, in the compound of formula (I), R 3 is selected from H, halogen, C 1-4 alkyl, and the alkyl is optionally substituted by 1 to 4 R k substituents;

[0067] In some embodiments, in the compound of formula (I), R 4 is selected from H, halogen, C 1-4 alkyl, and the alkyl is optionally substituted by 1 to 4 R k substituents;

[0068] In some embodiments, in the compound of formula (I), R 3 is selected from H or F;

[0069] In some embodiments, in the compound of formula (I), R 4 is selected from H or F;

[0070] In some embodiments, in the compound of formula (I), X 1 is selected from CH;

[0071] In some embodiments, in the compound of formula (I), X 2 is selected from CH;

[0072] In some embodiments, in the compound of formula (I), R 3 is selected from H;

[0073] In some embodiments, in the compound of formula (I), R 4 is selected from H;

[0074] In some embodiments, R in the compound of formula (I) k each independently selected from deuterium, halogen, ═O, CN, OH, SH, NO 2 , COOH, CONH 2 , NH 2 , SF 5 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -O-C 3-6 carbocyclic group, -O-4- to 7-membered heterocyclic group, -NH-C 3-6 carbocyclic group, -NH-4- to 7-membered heterocyclic group, -C 1-4 alkylene-C 3-6 carbocyclic group, -C 1-4 alkylene-4- to 7-membered heterocyclic group, C 3-6 carbocyclic group, 4- to 7-membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 substituents selected from deuterium, halogen, CN, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy;

[0075] In some embodiments, R in the compound of formula (I) k each independently selected from deuterium, halogen, ═O, CN, OH, SH, CONH 2 , NH 2 , SF 5 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -O-C 3-6 cycloalkyl, C 3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, -C 1-2 alkylene-C 3-6 cycloalkyl, -C 1-4 alkylene-4- to 7-membered heterocycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group, heterocyclic group cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 substituents selected from deuterium, halogen, CN, OH, NH 2 , C 1-4 alkyl, C 1-4substituted by a substituent of an alkoxy group;

[0076] In some embodiments, R in the compound represented by the general formula (I) k each independently selected from deuterium, F, Cl, Br, I, OH, ═O, CN, NH 2 , NHCH 3 , N(CH 3 ) 2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, ═O, CN, OH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy group;

[0077] In some embodiments, p1 in the compound represented by the general formula (I) is selected from 0, 1, 2 or 3;

[0078] In some embodiments, p2 in the compound represented by the general formula (I) is selected from 0, 1, 2 or 3;

[0079] In some embodiments, p3 in the compound represented by the general formula (I) is selected from 0, 1, 2, 3 or 4;

[0080] Optionally, when R in the compound represented by the general formula (I) 2 is selected from , R 1 is selected from R 1A ;

[0081] In some embodiments, R in the compound represented by the general formula (I) 1A is selected from phenyl or a 7- to 10-membered bicyclic heterocyclic group, and the R 1A is optionally substituted by 1 to 6 R 1a ;

[0082] In some embodiments, R in the compound represented by the general formula (I) 1A is selected from an 8- to 10-membered bicyclic heteroaryl or a partially saturated 8- to 10-membered bicyclic heterocyclic group, and the R 1A is optionally substituted by 1 to 6 R 1a ;

[0083] In some embodiments, R in the compound represented by the general formula (I) 1ASelected from 5-fused 5-membered heteroaryl, 5-fused 6-membered heteroaryl, 5-fused 5-membered partially saturated heterocyclic group, 5-fused 6-membered partially saturated heterocyclic group, 5-fused 7-membered partially saturated heterocyclic group, and the R 1A is optionally substituted with 1 to 6 R 1a substituents;

[0084] In some embodiments, in the compound of formula (I), R 1A is selected from and the R 1A is optionally substituted with 1 to 6 R 1a substituents;

[0085] In some embodiments, in the compound of formula (I), R 1A is selected from and the R 1A is optionally substituted with 1 to 4 R 1a substituents.

[0086] The present invention provides a compound of formula (II) or its stereoisomers, tautomers, racemates, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, wherein

[0087]

[0088] In certain embodiments, in the compound of formula (II), ring B is selected from which is connected to L on the left side, and the ring B is optionally substituted with 1 to 4 R b substituents;

[0089] In certain embodiments, in the compound of formula (II), ring B is selected from which is connected to L on the left side, and the ring B is optionally substituted with 1 to 4 R b substituents;

[0090] In certain embodiments, in the compound of formula (II), ring B is selected from which is connected to L on the left side, and the ring B is optionally substituted with 1 to 4 R b substituents;

[0091] In certain embodiments, in the compound of formula (II), X is selected from O or S;

[0092] In certain embodiments, in the compound of formula (II), Y is selected from CH 2 or Se;

[0093] In certain embodiments, ring B1 in the compound represented by formula (II) is selected from 5-membered heteroaryl;

[0094] In certain embodiments, each ring A in the compound represented by formula (II) is independently selected from C 6-12 -aryl, 5- to 12-membered heteroaryl, and said ring A is optionally substituted with 1 to 4 R a groups;

[0095] In certain embodiments, each ring A in the compound represented by formula (II) is independently selected from phenyl, naphthyl, 5- to 10-membered heteroaryl, and said ring A is optionally substituted with 1 to 4 R a groups;

[0096] In certain embodiments, each ring A in the compound represented by formula (II) is independently selected from phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thiophenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzopyrrolyl, benzopyrazolyl, benzimidazolyl, benzopyridyl, benzopyrimidinyl, benzopyridazinyl, benzopyrazinyl, benzofuranyl, benzothiophenyl, pyridinopyrrolyl, pyridinopyrazolyl, pyridinimidazolyl, pyridinopyrimidinyl, pyridinopyridazinyl, pyridinopyrazinyl, pyridinopyridyl, pyridinothiazolyl, pyrrolothiophenyl, pyrrolothiazolyl, pyrrolopyrrolyl, imidazolothiophenyl, and said ring A is optionally substituted with 1 to 4 R a groups;

[0097] In certain embodiments, each ring A in the compound represented by formula (II) is independently selected from phenyl, and said ring A is optionally substituted with 1 to 4 R a groups;

[0098] In certain embodiments, each ring C in the compound represented by formula (II) is independently selected from C 6-12 -aryl, 5- to 12-membered heteroaryl, and said ring C is optionally substituted with 1 to 4 R c groups;

[0099] In certain embodiments, each ring C in the compound represented by formula (II) is independently selected from phenyl, naphthyl, 5- to 10-membered heteroaryl, and said ring C is optionally substituted with 1 to 4 R c groups;

[0100] In certain embodiments, each ring C in the compounds of formula (II) is independently selected from phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzopyrrolyl, benzopyrazolyl, benzimidazolyl, benzopyridyl, benzopyrimidinyl, benzopyridazinyl, benzopyrazinyl, benzofuryl, benzothienyl, pyridopyrrolyl, pyridopyrazolyl, pyridopyrimidinyl, pyridopyridazinyl, pyridopyrazinyl, pyridopyridyl, pyridothiazolyl, pyrrolothienyl, pyrrolothiazolyl, pyrrolopyrrolyl, imidazolothienyl, and the ring C is optionally substituted with 1 to 4 R c substituted;

[0101] In certain embodiments, each ring C in the compounds of formula (II) is independently selected from phenyl, pyridyl, and the ring C is optionally substituted with 1 to 4 R c substituted;

[0102] In certain embodiments, each ring D in the compounds of formula (II) is independently selected from C 3-15 -membered cycloalkyl, 4- to 15-membered heterocycloalkyl, and the ring D is optionally substituted with 1 to 4 R d substituted;

[0103] In certain embodiments, each ring D in the compounds of formula (II) is independently selected from C 3-10 -membered cycloalkyl, 4- to 10-membered heterocycloalkyl, and the ring D is optionally substituted with 1 to 4 R d substituted;

[0104] In certain embodiments, each ring D in the compounds of formula (II) is independently selected from C 3-6 -membered cycloalkyl, 4- to 6-membered heterocycloalkyl, and the ring D is optionally substituted with 1 to 4 R d substituted;

[0105] In certain embodiments, each ring D in the compounds of formula (II) is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuryl, oxanyl, and the ring D is optionally substituted with 1 to 4 R d substituted;

[0106] In certain embodiments, in the compounds of formula (II) the ring D is optionally substituted with 1 to 4 R d substituted;

[0107] In certain embodiments, in the compounds of formula (II) selected from

[0108] In certain embodiments, in the compound of formula (II), L is selected from a bond, C 1-6 alkylene, O, S, NR L , NR L C═O, C═ONR L , and the alkylene is optionally substituted by 1 to 4 R k substituents;

[0109] In certain embodiments, in the compound of formula (II), L is selected from a bond, C 1-4 alkylene, O, S, NR L , NR L C═O, C═ONR L , and the alkylene is optionally substituted by 1 to 4 R k substituents;

[0110] In certain embodiments, in the compound of formula (II), L is selected from a bond, methyl, ethyl, O, S, NR L , NR L C═O, C═ONR L , and the alkylene is optionally substituted by 1 to 4 R k substituents;

[0111] In certain embodiments, in the compound of formula (II), L is selected from a bond, methyl, ethyl;

[0112] In certain embodiments, in the compound of formula (II), R L is selected from H, deuterium, C 1-6 alkyl, and the alkyl is optionally substituted by 1 to 4 R k substituents;

[0113] In certain embodiments, in the compound of formula (II), R L is selected from H, deuterium, C 1-4 alkyl, and the alkyl is optionally substituted by 1 to 4 R k substituents;

[0114] In certain embodiments, in the compound of formula (II), R L is selected from H, deuterium, methyl, ethyl, and the alkyl is optionally substituted by 1 to 4 R k substituents;

[0115] In certain embodiments, in the compound of formula (II), R b1 are each independently selected from H, deuterium, C 1-6 alkyl, -C 0-4 alkylene-C 3-6 carbocycle, -C 0-4An alkylene-3 to 7-membered heterocycle, wherein the alkyl, alkylene, carbocycle or heterocycle is optionally substituted by 1 to 4 Rs k substituted;

[0116] In certain embodiments, in the compound of formula (II), R b1 are each independently selected from H, deuterium, C 1-4 alkyl, -C 0-2 alkylene-C 3-6 carbocycle, -C 0-2 alkylene-3 to 7-membered heterocycle, wherein the alkyl, alkylene, carbocycle or heterocycle is optionally substituted by 1 to 4 Rs k substituted;

[0117] In certain embodiments, in the compound of formula (II), R b1 are each independently selected from H, deuterium, methyl, ethyl, cyclopropyl, and the methyl, ethyl, cyclopropyl are optionally substituted by 1 to 4 Rs k substituted;

[0118] In certain embodiments, in the compound of formula (II), R b2 is selected from deuterium, C 1-6 alkyl, -C 0-4 alkylene-C 3-6 carbocycle, -C 0-4 alkylene-3 to 7-membered heterocycle, wherein the alkyl, alkylene, carbocycle or heterocycle is optionally substituted by 1 to 4 deuteriums, halogens, CN, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy substituents;

[0119] In certain embodiments, in the compound of formula (II), R b2 is selected from deuterium, C 1-4 alkyl, -C 0-2 alkylene-C 3-6 carbocycle, -C 0-2 alkylene-3 to 7-membered heterocycle, wherein the alkyl, alkylene, carbocycle or heterocycle is optionally substituted by 1 to 4 deuteriums, halogens, CN, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy substituents;

[0120] In certain embodiments, in the compound of formula (II), R b2 is selected from deuterium, methyl, ethyl, cyclopropyl, and the methyl, ethyl, cyclopropyl are optionally substituted by 1 to 4 deuteriums, halogens, CN, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy substituents;

[0121] In certain embodiments, R in the compound represented by formula (II) b2 is selected from deuterium, methyl, ethyl, cyclopropyl, and the methyl, ethyl, and cyclopropyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH 2 , methyl, ethyl, methoxy, and ethoxy;

[0122] In certain embodiments, R in the compound represented by formula (II) b2 is selected from deuterium, methyl, ethyl, cyclopropyl, CHF 2 , CH 2 F, CF 3 ;

[0123] In certain embodiments, R in the compound represented by formula (II) b3 is selected from H, deuterium, C 1-6 alkyl, -C 0-4 alkylene-C 3-6 carbocycle, -C 0-4 alkylene-3- to 7-membered heterocycle, and the alkyl, alkylene, carbocycle, or heterocycle is optionally substituted with 1 to 4 R k ;

[0124] In certain embodiments, R in the compound represented by formula (II) b3 is selected from H, deuterium, C 1-4 alkyl, -C 0-2 alkylene-C 3-6 carbocycle, -C 0-2 alkylene-3- to 7-membered heterocycle, and the alkyl, alkylene, carbocycle, or heterocycle is optionally substituted with 1 to 4 R k ;

[0125] In certain embodiments, R in the compound represented by formula (II) b3 is selected from H, deuterium, methyl, ethyl, cyclopropyl, and the methyl, ethyl, and cyclopropyl are optionally substituted with 1 to 4 R k ;

[0126] In certain embodiments, R a , R b , R c , R d in the compound represented by formula (II) are each independently selected from H, deuterium, halogen, OH, =O, CN, NH 2 , NO 2 , COOH, CONH 2 , C(=O)NHCH 3 , S(=O) 2 CH 3 , C1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NHC 1-6 Alkyl, N(C 1-6 alkyl) 2 、-O-C 3-6 Carbocycle, -O-3- to 7-membered heterocycle, -NH-C 3-6 Carbocycle, -NH-3- to 7-membered heterocycle, -S-C 3-6 Carbocycle, -S-3- to 7-membered heterocycle, -C 0-4 Alkylene-C 3-6 Carbocycle, -C 0-4 Alkylene-3- to 7-membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R k substituted;

[0127] In certain embodiments, in the compound of formula (II), R a , R b , R c , R d are each independently selected from H, deuterium, halogen, OH, =O, CN, NH 2 , NO 2 , COOH, CONH 2 , C(=O)NHCH 3 , S(=O) 2 CH 3 , C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 alkyl) 2 , -O-C 3-62 Carbocycle, -O-3- to 7-membered heterocycle, -NH-C 3-6 Carbocycle, -NH-3- to 7-membered heterocycle, -S-C 3-6 Carbocycle, -S-3- to 7-membered heterocycle, -C 0-2 Alkylene-C 3-6 Carbocycle, -C 0-2 Alkylene-3- to 7-membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R k substituted;

[0128] In certain embodiments, in the compound of formula (II), R a , R b , Rc , R d are each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, CN, NH 2 , NHCH 3 , N(CH 3 ), 2 methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl are optionally substituted by 1 to 4 R k ;

[0129] In certain embodiments, in the compound represented by the general formula (II), R a , R b , R c , R d are each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, CN, NH 2 , NHCH 3 , N(CH 3 ), 2 , CF 3 , CHF 2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl,

[0130] In certain embodiments, in the compound represented by the general formula (II), R c are each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, methyl, ethyl, methoxy, ethoxy, cyclopropyl, NHCH 3 , N(CH 3 ), 2 ,

[0131] In certain embodiments, in the compound represented by the general formula (II), R k are each independently selected from deuterium, halogen, OH, ═O, CN, NH 2 , NO 2 , COOH, CONH 2 , C 1-6 alkyl, OC 1-6 alkyl, SC 1-6 alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl) 2 , -O-C 3-6 Carbocycle, -O-3- to 7-membered heterocycle, -NH-C 3-6 Carbocycle, -NH-3- to 7-membered heterocycle, -S-C 3-6 Carbocycle, -S-3- to 7-membered heterocycle, -C 0-4 Alkylene-C 3-6 Carbocycle, -C 0-4 Alkylene-3- to 7-membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =O, CN, OH, NH 2 , C 1-6 Alkyl, C 1-6 Alkoxy;

[0132] In certain embodiments, in the compounds of formula (II), R k Are each independently selected from deuterium, halogen, OH, =O, CN, NH 2 , NO 2 , COOH, CONH 2 , C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl) 2 , -O-C 3-6 Carbocycle, -O-3- to 7-membered heterocycle, -NH-C 3-6 Carbocycle, -NH-3- to 7-membered heterocycle, -S-C 3-6 Carbocycle, -S-3- to 7-membered heterocycle, -C 0-2 Alkylene-C 3-6 Carbocycle, -C 0-2 Alkylene-3- to 7-membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =O, CN, OH, NH 2 , C 1-6 Alkyl, C 1-6 Alkoxy;

[0133] In certain embodiments, in the compounds of formula (II), R k Are each independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH 2 , NHCH 3 , N(CH3 ) 2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, ═O, CN, OH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy;

[0134] Optionally, the compound is not of the following structure:

[0135] As the first embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, tautomer, racemate, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0136] X 1 is selected from N or CR x1 ;

[0137] X 2 is selected from N or CR x2 ;

[0138] R x1 , R x2 are each independently selected from H, deuterium, halogen, cyano, OH, NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6 alkyl, C 3-6 carbocyclic group, 4- to 7-membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k ;

[0139] R 1 is selected from C 5-14 carbocyclic group or 5- to 14-membered heterocyclic group, and the R 1 is optionally substituted by 1 to 6 R 1a ;

[0140] R 2 is selected from

[0141] K 1 、K 2 、K 3 Each is independently selected from N, CH or CR 2b ;

[0142] Ring D is selected from 4- to 6-membered heterocyclic groups, and said ring D is optionally substituted with 1 to 4 Rs d substituted;

[0143] R 2a and R D are directly connected to form ring Y, and ring Y is selected from 9- to 13-membered heterocycles, and said heterocycle is optionally substituted with 1 to 4 Rs y substituted;

[0144] Ring D, ring Y and K 1 、K 2 、K 3 The total number of ring atoms of the polycycle formed together with the rings where they are located is greater than 16;

[0145] R y Each is independently selected from deuterium, halogen, =O, CN, OH, C 1-6 alkyl, -OC 1-6 alkyl, C 0-4 alkylene-C 3-6 carbocyclic group, -C 0-4 alkylene-4- to 7-membered heterocyclic group, and said alkyl, alkylene, carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 Rs k substituted;

[0146] Ring A is selected from phenyl or 5- to 6-membered heteroaryl;

[0147] Ring B is selected from 5- to 6-membered heterocyclic groups, and said ring B is optionally substituted with 1 to 2 Rs b substituted;

[0148] K 4 is selected from N or CH;

[0149] K 5 is selected from N or CH;

[0150] Ring C is selected from C 6-10 carbocyclic group or 5- to 10-membered heterocyclic group;

[0151] Ring E is selected from 5- to 6-membered heterocyclic groups containing 1 phosphorus atom, and said phosphorus atom is optionally oxidized to P(=O), P(=O) 2 ;

[0152] R 1a 、R 2b 、R a 、Rb , R c , R d , R e are each independently selected from deuterium, halogen, =O, CN, OH, NO 2 , COOH, CONH 2 , NH 2 , -C 0-4 alkylene-NHC 1-6 alkyl, -C 0-4 alkylene-N(C 1-6 alkyl) 2 , -C 0-4 alkylene-N(C 1-6 alkyl)-C 3-6 carbocyclic group, -C 0-4 alkylene-N(C 1-6 alkyl)-4- to 7-membered heterocyclic group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -O-C 3-6 carbocyclic group, -O-4- to 7-membered heterocyclic group, -NH-C 3-6 carbocyclic group, -NH-4- to 7-membered heterocyclic group, -C 0-4 alkylene-C 3-6 carbocyclic group, -C 0-4 alkylene-4- to 7-membered heterocyclic group, and the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k ;

[0153] R 3 is selected from H, halogen, C 1-6 alkyl, and the alkyl is optionally substituted by 1 to 4 R k ;

[0154] R 4 is selected from H, halogen, C 1-6 alkyl, and the alkyl is optionally substituted by 1 to 4 R k ;

[0155] R k are each independently selected from deuterium, halogen, =O, CN, OH, SH, NO 2 , COOH, CONH 2 , NH 2 , SF 5 , NHC 1-6 , N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 2-6 alkenyl, C2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -O-C 3-6 Carbocyclic group, -O-4- to 7-membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-4- to 7-membered heterocyclic group, -C 1-4 Alkylene-C 3-6 Carbocyclic group, -C 1-4 Alkylene-4- to 7-membered heterocyclic group, C 3-6 Carbocyclic group, 4- to 7-membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 substituents selected from deuterium, halogen, CN, OH, NH 2 , C 1-6 Alkyl, C 1-6 alkoxy;

[0156] p1 is selected from 0, 1, 2 or 3;

[0157] p2 is selected from 0, 1, 2 or 3;

[0158] p3 is selected from 0, 1, 2, 3 or 4;

[0159] Provided that when R 2 is selected from , then R 1 is selected from R 1A ;

[0160] R 1A is selected from phenyl or a 7- to 10-membered bicyclic heterocyclic group, and the said R 1A is optionally substituted by 1 to 6 R 1a ;

[0161] As a second embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, tautomer, racemate, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0162] R x1 , R x2 are each independently selected from H, deuterium, halogen, cyano, OH, NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, C 3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R kSubstituted;

[0163] R 1 is selected from phenyl, 5- to 6-membered heteroaryl, 8- to 10-membered bicyclic heteroaryl, 9- to 14-membered tricyclic heteroaryl, 8- to 10-membered fused heterocyclic group, 9- to 14-membered tricyclic heterocyclic group, benzo-C 4-6 carbocyclic group, benzo-4- to 6-membered heterocyclic group, and said R 1 is optionally substituted by 1 to 6 R 1a Substituted;

[0164] Ring D is selected from 4- to 6-membered heterocycloalkyl, and said ring D is optionally substituted by 1 to 4 R d Substituted;

[0165] Ring B is selected from 5- to 6-membered heterocyclic groups containing 1 to 2 nitrogen heteroatoms, and said ring B is optionally substituted by 1 to 2 R b Substituted;

[0166] K 5 is selected from N;

[0167] Ring Y is selected from 9- to 13-membered partially unsaturated heterocycles, and said heterocycle is optionally substituted by 1 to 4 R y Substituted;

[0168] Ring C is selected from phenyl, 5- to 6-membered heteroaryl, 8- to 10-membered heteroaryl, benzo-C 4-6 carbocyclic group, benzo-4- to 6-membered heteroaryl;

[0169] R y are each independently selected from deuterium, halogen, =O, CN, OH, C 1-4 alkyl, -OC 1-4 alkyl, C 3-6 carbocyclic group, 4- to 7-membered heterocyclic group, C 1-2 alkylene-C 3-6 cycloalkyl, -C 1-2 alkylene-4- to 7-membered heterocycloalkyl, and said alkyl, alkylene, carbocyclic group, heterocyclic group cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R k Substituted;

[0170] R 1a , R 2b , R a , R b , R c , R d , R e are each independently selected from deuterium, halogen, =O, CN, OH, NO 2 , COOH, CONH 2 , NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2, -C 1-2 Alkylene-NHC 1-4 Alkyl, -C 1-2 Alkylene-N(C 1-4 Alkyl) 2 , -C 1-2 Alkylene-N(C 1-4 Alkyl)-C 3-6 Cycloalkyl, -C 1-2 Alkylene-N(C 1-4 Alkyl)-4- to 7-membered heterocycloalkyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -O-C 3-6 Cycloalkyl, -O-4- to 7-membered heterocycloalkyl, -NH-C 3-6 Cycloalkyl, -NH-4- to 7-membered heterocycloalkyl, -C 1-2 Alkylene-C 3-6 Cycloalkyl, -C 1-2 Alkylene-4- to 7-membered heterocycloalkyl, C 3-6 Carbocyclic group, 4- to 7-membered heterocyclic group, the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group, heterocyclic group, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R k substituents;

[0171] R 3 is selected from H, halogen, C 1-4 alkyl, the alkyl is optionally substituted by 1 to 4 R k substituents;

[0172] R 4 is selected from H, halogen, C 1-4 alkyl, the alkyl is optionally substituted by 1 to 4 R k substituents;

[0173] R k are each independently selected from deuterium, halogen, =O, CN, OH, SH, CONH 2 , NH 2 , SF 5 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -O-C 3-6 cycloalkyl, C 3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, -C 1-2 alkylene-C 3-6Cycloalkyl, -C 1-4 Alkylene-4- to 7-membered heterocycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group, heterocyclic group, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 substituents selected from deuterium, halogen, CN, OH, NH 2 , C 1-4 Alkyl, C 1-4 Alkoxy;

[0174] R 1A Is selected from an 8- to 10-membered bicyclic heteroaryl or a partially saturated 8- to 10-membered bicyclic heterocyclic group, and the R 1A Is optionally substituted by 1 to 6 R 1a Substituents;

[0175] The definitions of the remaining groups are the same as those in the first embodiment of the present invention.

[0176] As the third embodiment of the present invention, the compound represented by the foregoing general formula (I) or its stereoisomer, tautomer, racemate, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0177] X 1 Is selected from N or CH;

[0178] X 2 Is selected from N or CH;

[0179] R 1 Is selected from phenyl, 5- to 6-membered heteroaryl, 5-fused-5-membered heteroaryl, 5-fused-6-membered heteroaryl, 5-fused-5-membered partially saturated heterocyclic group, 5-fused-6-membered partially saturated heterocyclic group, 5-fused-7-membered partially saturated heterocyclic group, 9- to 14-membered tricyclic heteroaryl, 9- to 14-membered tricyclic heterocyclic group, the heteroaryl or heterocyclic group contains 1 to 4 nitrogen atoms, and the R 1 Is optionally substituted by 1 to 6 R 1a Substituents;

[0180] Is selected from

[0181] Q is selected from a bond, CH 2 , NH or O;

[0182] Is selected from

[0183] Ring C is selected from phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, thienyl, pyrazolyl, pyrrolyl, imidazolyl;

[0184] Ring E is selected from

[0185] R 1A selected from 5-fused 5-membered heteroaryl, 5-fused 6-membered heteroaryl, 5-fused 5-membered partially saturated heterocyclic group, 5-fused 6-membered partially saturated heterocyclic group, 5-fused 7-membered partially saturated heterocyclic group, and said R 1A is optionally substituted by 1 to 6 R 1a substituents;

[0186] The definitions of the remaining groups are consistent with any one of the first and second embodiments of the present invention.

[0187] As the fourth embodiment of the present invention, the compound represented by the foregoing general formula (I) or its stereoisomer, tautomer, racemate, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0188] R 1 is selected from said R 1 is optionally substituted by 1 to 6 R 1a substituents;

[0189] R 1A is selected from said R 1A is optionally substituted by 1 to 6 R 1a substituents;

[0190] is selected from

[0191] R c1 is selected from -CH 2 NHCH 3 -CH 2 NHCH 2 CH 3 -CH 2 N(CH 3 ) 2 -CH 2 N(CH 2 CH 3 ) 2 -CH 2 N(CH 3 )CH 2 CH 3 -CH 2 N(CH 3 )-cyclopropyl, said CH 2 methyl, ethyl, cyclopropyl, is optionally substituted by 1 to 4 R kSubstituted;

[0192] R 3 is selected from H or F;

[0193] R 4 is selected from H or F;

[0194] R 1a 、R 2b 、R a 、R b 、R c2 、R d 、R e each independently is selected from deuterium, F, Cl, Br, I, =O, CN, OH, NO 2 、COOH、CONH 2 、NH 2 、NHCH 3 、N(CH 3 ) 2 、methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -azetidinyl, -CH 2 -oxetanyl, and the methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl are optionally substituted by 1 to 4 R k Substituted;

[0195] R k each independently is selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH 2 、NHCH 3 、N(CH 3 ) 2 、methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl are optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH 2 、C 1-4 alkyl, C 1-4substituted by substituents of alkoxy groups;

[0196] The definitions of the remaining groups are consistent with any one of the first, second, and third embodiments of the present invention.

[0197] As the fifth embodiment of the present invention, the compound represented by the foregoing general formula (I) or its stereoisomer, tautomer, racemate, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0198] R 1 is selected from said R 1 is optionally substituted by 1 to 4 R 1a substituents;

[0199] R 1A is selected from said R 1A is optionally substituted by 1 to 4 R 1a substituents;

[0200] R 1a are each independently selected from deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, methyl or ethyl;

[0201]

[0202] or R 2 is selected from

[0203] R c1 is selected from -CH 2 NHCH 3 、-CH 2 NHCH 2 CH 3 、-CH 2 N(CH 3 ) 2 、-CH 2 N(CH 2 CH 3 ) 2 、-CH 2 N(CH 3 )CH 2 CH 3 、-CH2 N(CH 3 )-cyclopropyl, The CH 2 , methyl, ethyl, cyclopropyl, optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, methyl, ethyl, -CH 2 OH;

[0204] R a each independently selected from deuterium, F, Cl, Br, I, CN, OH, methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, ethoxy, and the methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, ethoxy are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, methyl, ethyl;

[0205] R e each independently selected from deuterium, F, Cl, Br, I, =O, CN, OH, methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, ethoxy, and the methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, ethoxy are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, methyl, ethyl;

[0206] X 1 is selected from CH;

[0207] X 2 is selected from CH;

[0208] R 3 is selected from H;

[0209] R 4 is selected from H;

[0210] The definitions of the remaining groups are the same as any one of the first, second, third, or fourth embodiments of the present invention.

[0211] As the sixth embodiment of the present invention, the compound represented by the foregoing general formula (II) or its stereoisomer, racemate, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0212] Ring B is selected from which is connected to L on the left side, and the ring B is optionally substituted with 1 to 4 R b substituents;

[0213] Ring B1 is selected from 5-membered heteroaryl;

[0214] X is selected from O or S;

[0215] Y is selected from CH2 or Se;

[0216] Ring A is independently selected from C 6-12 aryl having 6 to 12 ring atoms, heteroaryl having 5 to 12 ring atoms, and said Ring A is optionally substituted with 1 to 4 R a substituents;

[0217] Ring C is independently selected from C 6-12 aryl having 6 to 12 ring atoms, heteroaryl having 5 to 12 ring atoms, and said Ring C is optionally substituted with 1 to 4 R c substituents;

[0218] Ring D is independently selected from C 3-15 cycloalkyl having 3 to 15 ring atoms, heterocycloalkyl having 4 to 15 ring atoms, and said Ring D is optionally substituted with 1 to 4 R d substituents;

[0219] L is selected from a bond, C 1-6 alkylene, O, S, NR L , NR L C=O, C=ONR L , and said alkylene is optionally substituted with 1 to 4 R k substituents;

[0220] R L is selected from H, deuterium, C 1-6 alkyl, and said alkyl is optionally substituted with 1 to 4 R k substituents;

[0221] R b1 is independently selected from H, deuterium, C 1-6 alkyl, -C 0-4 alkylene-C 3-6 carbocyclic ring, -C 0-4 alkylene-3- to 7-membered heterocyclic ring, and said alkyl, alkylene, carbocyclic ring or heterocyclic ring is optionally substituted with 1 to 4 R k substituents;

[0222] R b2 is selected from deuterium, C 1-6 alkyl, -C 0-4 alkylene-C 3-6 carbocyclic ring, -C 0-4 alkylene-3- to 7-membered heterocyclic ring, and said alkyl, alkylene, carbocyclic ring or heterocyclic ring is optionally substituted with 1 to 4 deuterium, halogen, CN, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy substituents;

[0223] R b3 is selected from H, deuterium, C 1-6 alkyl, -C 0-4 alkylene-C 3-6 carbocyclic ring, -C0-4 An alkylene-3- to 7-membered heterocycle, wherein the alkyl, alkylene, carbocycle or heterocycle is optionally substituted by 1 to 4 Rs k ;

[0224] R a , R b , R c , R d are each independently selected from H, deuterium, halogen, OH, =O, CN, NH 2 , NO 2 , COOH, CONH 2 , C(=O)NHCH 3 , S(=O) 2 CH 3 , C 1-6 alkyl, OC 1-6 alkyl, SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , -O-C 3-6 carbocycle, -O-3- to 7-membered heterocycle, -NH-C 3-6 carbocycle, -NH-3- to 7-membered heterocycle, -S-C 3-6 carbocycle, -S-3- to 7-membered heterocycle, -C 0-4 alkylene-C 3-6 carbocycle, -C 0-4 alkylene-3- to 7-membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 Rs k ;

[0225] R k are each independently selected from deuterium, halogen, OH, =O, CN, NH 2 , NO 2 , COOH, CONH 2 , C 1-6 alkyl, OC 1-6 alkyl, SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , -O-C 3-6 carbocycle, -O-3- to 7-membered heterocycle, -NH-C 3-6 carbocycle, -NH-3- to 7-membered heterocycle, -S-C 3-6 carbocycle, -S-3- to 7-membered heterocycle, -C 0-4 alkylene-C 3-6Carbocyclic ring, -C 0-4 Alkylene-3- to 7-membered heterocyclic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =O, CN, OH, NH 2 , C 1-6 Alkyl, C 1-6 Alkoxy;

[0226] Provided that the compound is not of the following structure:

[0227] As the seventh embodiment of the present invention, the compound represented by the foregoing general formula (II)), or its stereoisomer, racemate, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0228] Ring B is selected from which is connected to L on the left side, and the ring B is optionally substituted with 1 to 4 R b substituents;

[0229] Ring A is independently selected from phenyl, naphthyl, 5- to 10-membered heteroaryl, and the ring A is optionally substituted with 1 to 4 R a substituents;

[0230] Ring C is independently selected from phenyl, naphthyl, 5- to 10-membered heteroaryl, and the ring C is optionally substituted with 1 to 4 R c substituents;

[0231] Ring D is independently selected from C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, and the ring D is optionally substituted with 1 to 4 R d substituents;

[0232] L is selected from a bond, C 1-4 alkylene, O, S, NR L , NR L C=O, C=ONR L , and the alkylene is optionally substituted with 1 to 4 R k substituents;

[0233] R L is selected from H, deuterium, C 1-4 alkyl, and the alkyl is optionally substituted with 1 to 4 R k substituents;

[0234] R b1 are independently selected from H, deuterium, C 1-4 alkyl, -C 0-2 alkylene-C 3-6 carbocyclic ring, -C 0-2An alkylene-3 to 7-membered heterocycle, wherein the alkyl, alkylene, carbocycle or heterocycle is optionally substituted by 1 to 4 R k ;

[0235] R b2 is selected from deuterium, C 1-4 alkyl, -C 0-2 alkylene-C 3-6 carbocycle, -C 0-2 alkylene-3 to 7-membered heterocycle, wherein the alkyl, alkylene, carbocycle or heterocycle is optionally substituted by 1 to 4 deuterium, halogen, CN, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy substituents;

[0236] R b3 is selected from H, deuterium, C 1-4 alkyl, -C 0-2 alkylene-C 3-6 carbocycle, -C 0-2 alkylene-3 to 7-membered heterocycle, wherein the alkyl, alkylene, carbocycle or heterocycle is optionally substituted by 1 to 4 R k ;

[0237] R a , R b , R c , R d are each independently selected from H, deuterium, halogen, OH, =O, CN, NH 2 , NO 2 , COOH, CONH 2 , C(=O)NHCH 3 , S(=O) 2 CH 3 , C 1-4 alkyl, OC 1-4 alkyl, SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , -O-C 3-62 carbocycle, -O-3 to 7-membered heterocycle, -NH-C 3-6 carbocycle, -NH-3 to 7-membered heterocycle, -S-C 3-6 carbocycle, -S-3 to 7-membered heterocycle, -C 0-2 alkylene-C 3-6 carbocycle, -C 0-2 alkylene-3 to 7-membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R k ;

[0238] R k Each independently selected from deuterium, halogen, OH, =O, CN, NH 2 , NO 2 , COOH, CONH 2 , C 1-4 alkyl, OC 1-4 alkyl, SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , -O-C 3-6 carbocycle, -O-3- to 7-membered heterocycle, -NH-C 3-6 carbocycle, -NH-3- to 7-membered heterocycle, -S-C 3-6 carbocycle, -S-3- to 7-membered heterocycle, -C 0-2 alkylene-C 3-6 carbocycle, -C 0-2 alkylene-3- to 7-membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 substituents selected from deuterium, halogen, =O, CN, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy;

[0239] The remaining definitions are the same as those in the sixth embodiment of the present invention.

[0240] As the eighth embodiment of the present invention, the compound represented by the foregoing general formula (II) or its stereoisomer, racemate, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0241] Ring A is each independently selected from phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzopyrrolyl, benzopyrazolyl, benzimidazolyl, benzopyridyl, benzopyrimidinyl, benzopyridazinyl, benzopyrazinyl, benzofuryl, benzothienyl, pyridopyrrolyl, pyridopyrazolyl, pyridopyrimidinyl, pyridopyridazinyl, pyridopyrazinyl, pyridopyridyl, pyridothiazolyl, pyrrolothienyl, pyrrolothiazolyl, pyrrolopyrrolyl, imidazolothienyl, and the ring A is optionally substituted by 1 to 4 R a substituents;

[0242] Each ring C is independently selected from phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzopyrrolyl, benzopyrazolyl, benzimidazolyl, benzopyridyl, benzopyrimidinyl, benzopyridazinyl, benzopyrazinyl, benzofuryl, benzothienyl, pyridopyrrolyl, pyridopyrazolyl, pyridopyrimidinyl, pyridopyridazinyl, pyridopyrazinyl, pyridopyridyl, pyridothiazolyl, pyrrolothienyl, pyrrolothiazolyl, pyrrolopyrrolyl, imidazolothienyl, and the ring C is optionally substituted with 1 to 4 R c substituted;

[0243] Each ring D is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuryl, oxacyclohexyl, and the ring D is optionally substituted with 1 to 4 R d substituted;

[0244] L is selected from a bond, methyl, ethyl, O, S, NR L , NR L C═O, C═ONR L , and the alkylene is optionally substituted with 1 to 4 R k substituted;

[0245] R L is selected from H, deuterium, methyl, ethyl, and the alkyl is optionally substituted with 1 to 4 R k substituted;

[0246] Each R b1 is independently selected from H, deuterium, methyl, ethyl, cyclopropyl, and the methyl, ethyl, cyclopropyl are optionally substituted with 1 to 4 R k substituted;

[0247] R b2 is selected from deuterium, methyl, ethyl, cyclopropyl, and the methyl, ethyl, cyclopropyl are optionally substituted with 1 to 4 deuterium, halogen, CN, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy substituents;

[0248] Each R b3 is independently selected from H, deuterium, methyl, ethyl, cyclopropyl, and the methyl, ethyl, cyclopropyl are optionally substituted with 1 to 4 R k substituted;

[0249] Each R a , R b , R c , R d is independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, CN, NH2 , NHCH 3 , N(CH 3 ) 2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl are optionally substituted by 1 to 4 R k ;

[0250] R k are each independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH 2 , NHCH 3 , N(CH 3 ) 2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy;

[0251] The remaining definitions are the same as in the sixth or seventh embodiment of the present invention.

[0252] As the ninth embodiment of the present invention, the compound represented by the foregoing general formula (II) or its stereoisomer, racemate, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0253] Ring B is selected from which is connected to L on the left side, and the ring B is optionally substituted by 1 to 4 R b ;

[0254] Ring A is each independently selected from phenyl, and the ring A is optionally substituted by 1 to 4 R a ;

[0255] Ring C is each independently selected from phenyl, pyridyl, and the ring C is optionally substituted by 1 to 4 Rc Substituted;

[0256] Ring D is independently selected from said Ring D is optionally substituted by 1 to 4 Rs d Substituted;

[0257] L is selected from a bond, methyl, ethyl;

[0258] R a , R b , R c , R d are independently selected from H, deuterium, F, Cl, Br, I, OH, =O, CN, NH 2 , NHCH 3 , N(CH 3 ) 2 , CF 3 , CHF 2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl,

[0259] The remaining definitions are the same as those in the sixth, seventh or eighth embodiment of the present invention.

[0260] The present invention relates to a compound as shown below or its stereoisomers, tautomers, racemates, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, wherein the compound is selected from one of the structures shown in Table E or Table E-1.

[0261] Table E

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268] Table E-1

[0269]

[0270]

[0271] The present invention relates to a pharmaceutical composition comprising any of the above-mentioned compounds or their stereoisomers, tautomers, racemates, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and a pharmaceutically acceptable carrier.

[0272] The present invention relates to the use of any of the above-mentioned compounds or their stereoisomers, tautomers, racemates, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, or the pharmaceutical composition, in the preparation of a medicament for treating a disease related to the HPK1 kinase activity or expression level. Preferably, the disease is selected from tumors.

[0273] The present invention relates to a pharmaceutical composition or pharmaceutical preparation, which comprises a therapeutically effective amount of the compound or its stereoisomers, tautomers, racemates, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals according to the present invention, and a pharmaceutical excipient. The pharmaceutical composition can be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as the "preparation specification").

[0274] The present invention also provides a method for treating a disease in a mammal, which comprises administering to the mammal a therapeutically effective amount of the compound or its stereoisomers, tautomers, racemates, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, or the pharmaceutical composition according to the present invention. In some embodiments, the mammal in the present invention includes humans.

[0275] As used herein, "effective amount" or "therapeutically effective amount" means an amount of a compound disclosed herein that, to some extent, will alleviate one or more symptoms of a disease or disorder being treated (e.g., a tumor). 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 an amount of a compound disclosed herein that is required to provide a clinically significant reduction in the symptoms of the disease.Examples of a therapeutically effective amount include, but are not limited to, 1 - 1500 mg, 1 - 600 mg, 2 - 600 mg, 3 - 600 mg, 4 - 600 mg, 5 - 600 mg, 6 - 600 mg, 10 - 600 mg, 20 - 600 mg, 25 - 600 mg, 30 - 600 mg, 40 - 600 mg, 50 - 600 mg, 60 - 600 mg, 70 - 600 mg, 75 - 600 mg, 80 - 600 mg, 90 - 600 mg, 100 - 600 mg, 200 - 600 mg, 1 - 500 mg, 2 - 500 mg, 3 - 500 mg, 4 - 500 mg, 5 - 500 mg, 6 - 500 mg, 10 - 500 mg, 20 - 500 mg, 25 - 500 mg, 30 - 500 mg, 40 - 500 mg, 50 - 500 mg, 60 - 500 mg, 70 - 500 mg, 75 - 500 mg, 80 - 500 mg, 90 - 500 mg, 100 - 500 mg, 125 - 500 mg, 150 - 500 mg, 200 - 500 mg, 250 - 500 mg, 300 - 500 mg, 400 - 500 mg, 5 - 400 mg, 10 - 400 mg, 20 - 400 mg, 25 - 400 mg, 30 - 400 mg, 40 - 400 mg, 50 - 400 mg, 60 - 400 mg, 70 - 400 mg, 75 - 400 mg, 80 - 400 mg, 90 - 400 mg, 100 - 400 mg, 125 - 400 mg, 150 - 400 mg, 200 - 400 mg, 250 - 400 mg, 300 - 400 mg, 1 - 300 mg, 2 - 300 mg, 5 - 300 mg, 10 - 300 mg, 20 - 300 mg, 25 - 300 mg, 30 - 300 mg, 40 - 300 mg, 50 - 300 mg, 60 - 300 mg, 70 - 300 mg, 75 - 300 mg, 80 - 300 mg, 90 - 300 mg, 100 - 300 mg, 125 - 300 mg, 150 - 300 mg, 200 - 300 mg, 250 - 300 mg, 1 - 200 mg, 2 - 200 mg, 5 - 200 mg, 10 - 200 mg, 20 - 200 mg, 25 - 200 mg, 30 - 200 mg, 40 - 200 mg, 50 - 200 mg, 60 - 200 mg, 70 - 200 mg, 75 - 200 mg, 80 - 200 mg, 90 - 200 mg, 100 - 200 mg, 125 - 200 mg, 150 - 200 mg;.

[0276] In some embodiments, the pharmaceutical composition comprises, but is not limited to, 1 - 1500 mg, 1 - 600 mg, 20 - 400 mg, 25 - 200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg of the compound of the present invention or its stereoisomers, tautomers, racemates, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals.

[0277] A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of the compound of the present invention or its stereoisomers, tautomers, racemates, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, the therapeutically effective amount being preferably 1 - 1500 mg, and the disease being preferably cancer.

[0278] A method for treating a disease in a mammal, the method comprising administering to a subject the drug, the compound of the present invention or its stereoisomers, tautomers, racemates, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, at a daily dose of 1 - 1500 mg / day, the daily dose may be a single dose or divided doses. In some embodiments, the daily dose comprises, but is not limited to, 10 - 1500 mg /

[0279] day, 10 - 800 mg / day, 25 - 800 mg / day, 50 - 800 mg / day, 100 - 800 mg / day, 200 - 800 mg / day, 25 - 400 mg / day, 50 - 400 mg / day, 100 - 400 mg / day, 200 - 400 mg / day. In some embodiments, the daily dose comprises, but is not limited to, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 400 mg / day, 600 mg / day, 800 mg / day, 1500 mg / day, 2000 mg / day.

[0280] The present invention relates to a kit, which may include a composition in single-dose or multi-dose form. The kit contains the compound of the present invention or its stereoisomers, tautomers, racemates, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and the amount of the compound of the present invention or its stereoisomers, tautomers, racemates, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals is the same as that in the above-mentioned pharmaceutical composition.

[0281] In the present invention, the amount of the compound of the present invention or its stereoisomers, tautomers, racemates, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals is converted in the form of free base in each case.

[0282] Unless otherwise specified, the terms used in the specification and claims have the following meanings.

[0283] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention all include their isotope situations, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, where the isotopes of carbon include 12 C, 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called superheavy hydrogen), and the isotopes of oxygen include 16 O, 17 O and 18 O, the isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, the isotopes of nitrogen include 14 N and 15 N, the isotopes of fluorine include 17 F and 19 F, the isotopes of chlorine include 35 Cl and 37 Cl, the isotopes of bromine include 79 Br and 81 Br.

[0284] "CN" refers to a cyano group.

[0285] "Halogen" refers to F, Cl, Br or I.

[0286] "Halogen-substituted" means substitution with F, Cl, Br, or I, including but not limited to substitution with 1 to 10 substituents selected from F, Cl, Br, or I, substitution with 1 to 6 substituents selected from F, Cl, Br, or I, and substitution with 1 to 4 substituents selected from F, Cl, Br, or I. "Halogen-substituted" is abbreviated as "halogenated".

[0287] "Alkyl" means a substituted or unsubstituted straight-chain or branched-chain saturated aliphatic hydrocarbon group, including but not limited to alkyl groups having 1 to 20 carbon atoms, alkyl groups having 1 to 8 carbon atoms, alkyl groups having 1 to 6 carbon atoms, and alkyl groups having 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and their various branched isomers; the alkyl group can be monovalent, divalent, trivalent, or tetravalent.

[0288] "Alkylene" means a substituted or unsubstituted straight-chain and branched-chain divalent saturated hydrocarbon group, including - (CH 2 ) v - (where v is an integer from 1 to 10). Examples of alkylene groups include but are not limited to methylene, ethylene, propylene, and butylene.

[0289] "Cycloalkyl" means a substituted or unsubstituted saturated carbocyclic hydrocarbon group, usually having 3 to 12 carbon atoms. The cycloalkyl group can be monocyclic, fused-ring, bridged-ring, and spiro-ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl-fused-cyclobutyl, cyclobutyl-spiro-cyclobutyl, adamantane, etc. The cycloalkyl group can be monovalent, divalent, trivalent, or tetravalent.

[0290] "Heterocycloalkyl" means a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 12 atoms, 3 to 8 atoms, containing 1 to 3 heteroatoms selected from N, O, or S. The C, N, and S on the ring of the heterocycloalkyl group can be oxidized to various oxidation states. The heterocycloalkyl group can be monocyclic, fused-ring, bridged-ring, and spiro-ring. The heterocycloalkyl group can be attached to a heteroatom or a carbon atom. Non-limiting examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl, dioxanyl, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl. The heterocycloalkyl group can be monovalent, divalent, trivalent, or tetravalent.

[0291] "Alkenyl" refers to a substituted or unsubstituted straight-chain or branched-chain unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon double bonds, and the main chain includes but is not limited to 2 to 10, 2 to 6 or 2 to 4 carbon atoms. Examples of alkenyl include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, etc.; alkenyl can be monovalent, divalent, trivalent or tetravalent.

[0292] "Alkynyl" refers to a substituted or unsubstituted straight-chain or branched-chain unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, and the main chain includes 2 to 10 carbon atoms, including but not limited to having 2 to 6 carbon atoms in the main chain and having 2 to 4 carbon atoms in the main chain. Examples of alkynyl include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, etc.; alkynyl can be monovalent, divalent, trivalent or tetravalent.

[0293] "Alkoxy" refers to a substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropoxy and cyclobutoxy.

[0294] "Carbocyclic group" or "carbocycle" refers to a substituted or unsubstituted aromatic ring or non-aromatic ring. The aromatic ring or non-aromatic ring can be a 3- to 8-membered monocyclic, 4- to 12-membered bicyclic, 10- to 15-membered tricyclic, 12- to 18-membered tetracyclic system. The carbocyclic group can be attached to an aromatic ring or a non-aromatic ring, and the ring is optionally a monocyclic, fused ring, bridged ring or spiro ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring, "Carbocyclic group" or "carbocycle" can be monovalent, divalent, trivalent or tetravalent.

[0295] "Heterocyclic group" or "heterocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, or a 10- to 15-membered tricyclic ring, or a 12- to 18-membered tetracyclic system, and contains one or more (including but not limited to 2, 3, 4, or 5) heteroatoms selected from N, O, S, or Se. The optionally substituted C, N, and S in the ring of the heterocyclic group can be oxidized to various oxidation states. The heterocyclic group can be attached to a heteroatom or a carbon atom, and can be attached to an aromatic ring or a non-aromatic ring. The heterocyclic group is optionally a monocyclic, bridged, fused, or spiro ring. Non-limiting examples include epoxyethyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithienyl, dihydrofuryl, dihydropyranyl, dithiolanyl, tetrahydrofuryl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuryl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl, benzofuryl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecanyl, azadamantyl, oxaspiro[3.3]heptanyl, "Heterocyclic group" or "heterocycle" can be monovalent, divalent, trivalent, or tetravalent.

[0296] "Spiro ring" or "spiro group" refers to a polycyclic group in which a substituted or unsubstituted monocyclic ring shares one atom (called the spiro atom). The number of ring atoms in the spiro system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, and one or more of the rings can contain zero or more (including but not limited to 1, 2, 3, or 4) double bonds, and optionally can contain 0 to 5 heteroatoms selected from N, O, S(=O) n or Se(=O) n (n is 0, 1, or 2).

[0297] "Spiro ring" or "spiro group" can be monovalent, divalent, trivalent, or tetravalent.

[0298] "Fused ring" or "fused ring group" refers to a polycyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, where one or more rings may contain zero or more (including but not limited to 1, 2, 3, or 4) double bonds, and may be substituted or unsubstituted. Each ring in the fused ring system may contain from 0 to 5 heteroatoms or heteroatom-containing groups (including but not limited to selected from N, S(=O) n , Se(=O) n or O, and n is 0, 1, or 2). The number of ring atoms in the fused ring system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include: "Fused ring" or "fused ring group" can be monovalent, divalent, trivalent, or tetravalent.

[0299] "Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two non-directly connected atoms, which may contain zero or more double bonds. Any ring in the bridged ring system may contain from 0 to 5 heteroatoms or heteroatom-containing groups (including but not limited to N, S(=O)n, Se(=O) n or O, where n is 0, 1, 2). The number of ring atoms includes but is not limited to 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include cubane, adamantane, "Bridged ring" or "bridged ring group" can be monovalent, divalent, trivalent, or tetravalent.

[0300] "Carbospirocycle", "spirocarbocyclic group", "spirocarbon group" or "carbospiro group" refers to a "spirocycle" whose ring system consists only of carbon atoms.

[0301] "Carbofused ring", "fused carbocyclic group", "carbofused group" or "carbofused ring group" refers to a "fused ring" whose ring system consists only of carbon atoms.

[0302] "Carbobridged ring", "bridged carbocyclic group", "carbobridged group" or "carbobridged ring group" refers to a "bridged ring" whose ring system consists only of carbon atoms.

[0303] "Heteromonocycle", "monocyclic heterocyclic group" or "heteromonocyclic group" refers to a "heterocyclic group" or "heterocycle" of a monocyclic system,

[0304] "Heterofused ring", "heterofused ring group", "fused heterocyclic group" or "heterofused heterocyclic group" refers to a "fused ring" containing heteroatoms.

[0305] "Heterospirocycle", "heterospirocyclic group", "spiroheterocyclic group" or "heterospiroheterocyclic group" refers to a "spirocycle" containing heteroatoms.

[0306] "Spiroheterocycle", "spiroheterocyclic group", "bridged heterocyclic group" or "bridged heterocycle" means a "bridged ring" containing a heteroatom.

[0307] "Aryl" or "aromatic ring" means a substituted or unsubstituted aromatic hydrocarbon group having a monocyclic or fused ring, and the number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12 or 6 to 10 carbon atoms. The aryl ring may be fused to a saturated or unsaturated carbocyclic ring, and the ring connected to the parent structure is the aryl ring. Non-limiting examples include benzene ring, naphthalene ring, "Aryl" or "aromatic ring" can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the connection site is on the aryl ring.

[0308] "Heteroaryl" or "heteroaromatic ring" means a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or groups containing heteroatoms (including, but not limited to, N, O, S(=O)n, Se(=O) n , where n is 0, 1, 2), and the number of ring atoms in the heteroaromatic ring includes, but is not limited to, 5 to 15, 5 to 10 or 5 to 6. The atoms C, N, S, Se on the ring are optionally oxidized (i.e., C(=O), NO, S(=O)n, Se(=O)n, where n is 1, 2). Non-limiting examples of heteroaryl include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazolyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, pyridone, etc. The heteroaryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, and the ring connected to the parent structure is the aryl ring. Non-limiting examples include The heteroaryl appearing in this article has the same definition as this definition. Heteroaryl can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the connection site is on the aromatic ring.

[0309] "Substituted" or "substitution" means being substituted by one or more (including, but not limited to, 2, 3, 4 or 5) substituents, and the substituents include, but are not limited to, H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, mercaptan, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic group, bridged ring group, spiro ring group, fused ring group, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH 2 ) m -C(=O)-R a 、-O-(CH 2 ) m -C(=O)-R a 、-(CH 2 ) m -C(=O)-NRb R c ,-(CH 2 ) m S(=O) n R a ,-(CH 2 ) m -alkenyl-R a 、OR d or-(CH 2 ) m -alkynyl-R a (where m, n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR b R c and other groups, where R b and R c are independently selected from the group consisting of H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl. Optionally, R b and R c can form a five- or six-membered cycloalkyl or heterocyclic group, R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic group, carbonyl, ester group, bridged ring group, spiro ring group or fused ring group.

[0310] "Substituted by 1 to X substituents selected from..." means substituted by 1, 2, 3... X substituents selected from..., and X is any integer between 1 and 10. For example, "substituted by 1 to 4 R k " means substituted by 1, 2, 3 or 4 R k ". For example, "substituted by 1 to 5 substituents selected from..." means substituted by 1, 2, 3, 4 or 5 substituents selected from.... For example, "the heterobridged ring is optionally substituted by 1 to 4 substituents selected from H or F" means the heterobridged ring is optionally substituted by 1, 2, 3 or 4 substituents selected from H or F.

[0311] A ring of X - Y members (X, Y are integers, and 3 ≤ X < Y, X < Y ≤ 20, X and Y are any integers between 4 and 20) includes rings of X, X + 1, X + 2, X + 3, X + 4... Y members. The ring includes heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, hetero-fused rings, heterospiro rings or heterobridged rings. For example, "4 - 7 membered heteromonocyclic ring" means a 4-membered, 5-membered, 6-membered or 7-membered heteromonocyclic ring, and "5 - 10 membered hetero-fused ring" means a 5-membered, 6-membered, 7-membered, 8-membered, 9-membered or 10-membered hetero-fused ring.

[0312] C x-y The carbocyclic ring (including aryl, cycloalkyl, monocyclic carbocyclic ring, spirocarbocyclic ring, fused carbocyclic ring or bridged carbocyclic ring) includes C x 、C x+1 、Cx+2 , C x+3 , C x+4 …C y membered ring of C 3-6 "cycloalkyl" means C 3 , C 4 , C 5 or C 6 cycloalkyl;

[0313] When a group has one or more connectable sites, any one or more of these sites of the group can be connected to other groups by chemical bonds. When the connection mode of the chemical bond is non - specific and there are hydrogen atoms at the connectable sites, then when connecting the chemical bonds, the number of H atoms at this site will correspondingly decrease according to the number of connected chemical bonds to form a group with the corresponding valence. For example indicates that any connectable site on this piperidyl group can be connected to other groups by 1 chemical bond, including at least these 4 connection modes. Even if H atoms are drawn on - N - it also includes For example indicates that the R group on this piperidyl group can be located on C or on N, including at least

[0314] When the listed connecting groups do not specify their connection directions, their connection directions include the directions of the reading orders from left to right and from right to left for connection. For example, for A - L - B, when L is selected from - M - W -, it includes A - M - W - B and A - W - M - B.

[0315] "optionally" or "optionally" means that the subsequent described event or circumstance can but does not have to occur, and this description includes the occasions where the event or circumstance occurs or does not occur. For example: "optionally fluorine - substituted alkyl" means that the alkyl can but does not have to be fluorine - substituted, and the description includes the case where the alkyl is fluorine - substituted and the case where the alkyl is not fluorine - substituted.

[0316] "pharmaceutically acceptable salt" or "its pharmaceutically acceptable salt" means that the compound of the present invention retains the biological effectiveness and characteristics of the free acid or free base, and the salt obtained by reacting the free acid with a non - toxic inorganic base or organic base, and the free base with a non - toxic inorganic acid or organic acid.

[0317] "Pharmaceutical composition" refers to a mixture formed by one or more compounds described in the present invention, or their stereoisomers, racemates, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals and other chemical components. Among them, "other chemical components" refer to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0318] "Dosage form specification" refers to the weight of the active ingredient contained in each vial, tablet or other unit dosage form.

[0319] "Carrier" refers to a material that does not cause obvious irritation to organisms and does not eliminate the biological activity and characteristics of the administered compound.

[0320] "Prodrug" refers to a compound of the present invention that can be metabolically converted in vivo into a bioactive compound. The prodrugs of the present invention are prepared by modifying the amino or carboxyl groups in the compounds of the present invention, and this modification can be removed by conventional operations or in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian individual, the prodrug is cleaved to form free amino or carboxyl groups.

[0321] "Cocrystal" refers to a crystal formed by the combination of an active pharmaceutical ingredient (API) and a cocrystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, where both the pure states of the API and the CCF are solids at room temperature, and there is a fixed stoichiometric ratio between the components. Cocrystals are multi-component crystals, including binary cocrystals formed between two neutral solids, as well as multi-component cocrystals formed between a neutral solid and a salt or solvate.

[0322] "Animal" refers to including mammals, such as humans, companion animals, zoo animals and livestock, preferably humans, horses or dogs.

[0323] "Stereoisomer" refers to an isomer produced by the different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereoisomers and conformational isomers.

[0324] "Tautomer" refers to a functional group isomer produced by the rapid movement of a certain atom in a molecule between two positions, such as keto-enol tautomerism and amide-imidol tautomerism, etc.

[0325] The first synthesis method of the compound shown in general formula (I):

[0326]

[0327] R D1-1 、R D1-2 are selected from halogen, OTf, OTs, OMs, preferably from Cl, Br, I, OTf;

[0328] PGD1-1 Selected from amino protecting groups;

[0329] R 2 Selected from

[0330] The definitions of the remaining groups are the same as those in the specification;

[0331] The compound of general formula (D1-1) or the compound of general formula (D1-2) and the general formula (D1-3) are subjected to a coupling reaction or a nucleophilic substitution reaction to obtain the compound of general formula (D1-4);

[0332] The compound of general formula (D1-4) is subjected to a coupling reaction to obtain the compound of general formula (D1-5);

[0333] The compound of general formula (D1-5) is subjected to a coupling reaction to obtain the compound of general formula (D1-6);

[0334] The compound of general formula (D1-6) is deprotected to obtain the compound of general formula (I-A).

[0335] The second method for synthesizing the compound represented by the general formula (I):

[0336]

[0337] Selected from

[0338] R D2-1 Selected from halogen or OTf, preferably Br, I, OTf;

[0339] PG D2-1 Selected from amino protecting groups;

[0340] R D1-1 、R D1-2 Selected from halogen, OTf, OTs, OMs, preferably Cl, Br, I, OTf;

[0341] PG D1-1 Selected from amino protecting groups;

[0342] The definitions of the remaining groups are the same as those in the specification;

[0343] The compound of general formula (D2-1) or the compound of general formula (D2-2) and the general formula (D2-3) are subjected to a coupling reaction or a nucleophilic substitution reaction to obtain the compound of general formula (D2-4);

[0344] The compound of general formula (D2-4) is deprotected to obtain the compound of general formula (D2-5);

[0345] The compound of general formula (D2-5) and the compound of general formula (D1-3) are subjected to a coupling reaction or a nucleophilic substitution reaction to obtain the compound of general formula (D2-6);

[0346] The compound of general formula (D2-6) is subjected to a coupling reaction to obtain the compound of general formula (D2-7);

[0347] The compound of general formula (D2-7) is subjected to a coupling reaction to obtain the compound of general formula (D2-8);

[0348] The compound of general formula (D2-8) is deprotected from the amino group to obtain the compound of general formula (I-B).

[0349] Synthesis method 1 of the compound shown in general formula (II):

[0350]

[0351] R X1 、R X2 are selected from halogen or OTf, OTs, OMs, preferably Cl, Br, I, OTf;

[0352] The definitions of the remaining groups are consistent with those in the specification;

[0353] The compound of general formula (D1-1) and the compound of general formula (D1-1b) are subjected to an aldol condensation reaction to obtain the compound of general formula (D1-2);

[0354] The compound of general formula (D1-2) and the compound of general formula (D1-2b) are subjected to a coupling reaction or a substitution reaction to obtain the compound of general formula (D1-3);

[0355] The compound of general formula (D1-3) and the compound of general formula (D1-3b) are subjected to a coupling reaction to obtain the compound of general formula (I-A);

[0356] Synthesis method 2 of the compound shown in general formula (II):

[0357]

[0358] R X2 、R X4 are selected from halogen or OTf, OTs, OMs, preferably Cl, Br, I, OTf;

[0359] R X3 is selected from Cl, Br, I;

[0360] The definitions of the remaining groups are consistent with those in the specification;

[0361] The compound of general formula (D2-1) and ammonia are subjected to a substitution and condensation reaction to obtain the compound of general formula (D2-2);

[0362] The compound of general formula (D2-2) is obtained by a reduction reaction to give the compound of general formula (D2-3);

[0363] The compound of general formula (D2-3) is obtained by a Sandmeyer reaction to give the compound of general formula (D2-4);

[0364] The compound of general formula (D2-4) and the compound of general formula (D2-4b) are subjected to a substitution or coupling reaction to give the compound of general formula (D2-5); the compound of general formula (D2-5) and the compound of general formula (D2-5b) are subjected to a coupling reaction to give the compound of general formula (D2-6);

[0365] The compound of general formula (D2-6) is subjected to a coupling reaction to give the compound of general formula (D2-7);

[0366] The compound of general formula (D2-7) and the compound of general formula (D2-7b) are subjected to a coupling reaction to give the compound of general formula (I-B);

[0367] Synthetic method three of the compound represented by general formula (II):

[0368]

[0369] R X2 、R X4 are selected from halogen or OTf, OTs, OMs, preferably Cl, Br, I, OTf;

[0370] R X3 is selected from Cl, Br, I;

[0371] The definitions of the remaining groups are the same as those in the specification;

[0372] The compound of general formula (D3-0) and the compound of general formula (D3-0b) are subjected to a substitution or coupling reaction to give the compound of general formula (D3-1);

[0373] The compound of general formula (D3-1) and the compound of general formula (D3-1b) are subjected to a coupling reaction to give the compound of general formula (D3-2);

[0374] The compound of general formula (D3-2) is subjected to a coupling reaction to give the compound of general formula (D3-3);

[0375] The compound of general formula (D3-3) and the compound of general formula (D3-3b) are subjected to a coupling reaction to give the compound of general formula (D3-4);

[0376] The compound of general formula (D3-4) reacts with Lawesson's reagent to give the compound of general formula (I-C);

[0377] Synthetic method four of the compound represented by general formula (II):

[0378]

[0379] Ring B is selected from

[0380] R X1 、R X2 、R X4 selected from halogen or OTf, OTs, OMs, preferably Cl, Br, I, OTf;

[0381] The definitions of the remaining groups are consistent with those in the specification;

[0382] The compound of general formula (D4-1) or the compound of general formula (D4-2) reacts with hydrazine hydrate to obtain the compound of general formula (D4-3) or the compound of general formula (D4-4) respectively;

[0383] The compound of general formula (D4-3) or the compound of general formula (D4-4) reacts with the compound (D4-4b) through a substitution or coupling reaction to obtain the compound of general formula (D4-5);

[0384] The compound of general formula (D4-5) reacts with the compound (D4-5b) through a substitution reaction or a coupling reaction to obtain the compound of general formula (D4-6);

[0385] The compound of general formula (D4-6) undergoes a coupling reaction to obtain the compound of general formula (D4-7);

[0386] The compound of general formula (D4-7) reacts with the compound (D4-7b) through a coupling reaction to obtain the compound of general formula (I-D);

[0387] Synthesis method five of the compound shown in general formula (II):

[0388]

[0389] R X4 、R X5 selected from halogen or OTf, OTs, OMs, preferably Cl, Br, I, OTf;

[0390] The definitions of the remaining groups are consistent with those in the specification;

[0391] The compound of general formula (D5-1) reacts with R b1 -R X4 compound through a substitution or coupling reaction to obtain the compound of general formula (D5-2);

[0392] The compound of general formula (D5-2) undergoes a nucleophilic addition reaction to obtain the compound of general formula (D5-3);

[0393] The compound of general formula (D5-3) reacts with to obtain the compound of general formula (D5-4);

[0394] The compound of general formula (D5-4) is converted to the compound of general formula (I-E) through a coupling reaction. Detailed Description of the Invention

[0395] The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to this.

[0396] The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in units of 10 -6 (ppm). The NMR measurements are performed using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic resonance spectrometers, and the solvents for the measurements are deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard is tetramethylsilane (TMS);

[0397] The MS measurements are performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0398] The HPLC measurements are performed using an Agilent 1260 or Shimadzu LC–20AT high-performance liquid chromatograph (Xtimate C18 (4.6×50 mm, 3 μm));

[0399] The thin-layer chromatography silica gel plates used are Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of the silica gel plates used in thin-layer chromatography (TLC) are 0.15 mm - 0.20 mm, and the specifications of the silica gel plates used for thin-layer chromatography separation and purification of products are 0.4 mm - 0.5 mm;

[0400] Column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200 - 300 as the carrier;

[0401] The starting materials of the present invention can be synthesized by adopting or according to the methods known in the art, or can be purchased from companies such as Titan Technology, Energy Chemical, Shanghai Dermochem, Chengdu Kelong Chemical Industry, Shaoyuan Chemical Technology, and J&K Scientific.

[0402] XantPhos: CAS 161265-03-8; PD 2 (DBA) 3 : CAS 51364-51-3; XPHOS-Pd-G2: CAS 1310584-14-5; NBS: N-bromosuccinimide.

[0403] Example 1: Preparation of Compound 1

[0404]

[0405] Step 1: Preparation of Compound 1B

[0406] Dissolve Compound 1A (2 g, 9.7 mmol, CAS: 256929-98-3) and 2-chloro-5-fluoropyridine-6-carbaldehyde (CAS: 884494-77-3, 3.1 g, 19.4 mmol) in DMF (20 mL), add sodium bicarbonate (4.07 g, 48.5 mmol). After adding, heat to 100 °C under nitrogen protection and stir for 2 h. Add water (50 mL) and extract with ethyl acetate (50 mL × 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure. The concentrated residue is purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate (v / v) = 10 / 1) to obtain Compound 1B (2.8 g, yield: 84%).

[0407] Step 2: Preparation of Compound 1C

[0408] Dissolve Compound 1B (2.8 g, 8.1 mmol) and a tetrahydrofuran solution of dimethylamine (8.1 mL, 2.0 mol / l in THF) in dichloromethane (50 mL). Dropwise add glacial acetic acid (0.97 g, 16.2 mmol) at room temperature. After stirring at room temperature for 0.5 h, add sodium triacetoxyborohydride (3.43 g, 16.2 mmol). After adding, stir at room temperature for 16 h. Adjust to alkaline with 1N aqueous sodium hydroxide solution, extract with dichloromethane 3 times, combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (dichloromethane / methanol (V / V) = 15 / 1) to obtain Compound 1C (2.5 g, yield: 82%).

[0409] Step 3: Preparation of Compound 1D

[0410] Dissolve Compound 1C (2.5 g, 6.67 mmol) and cyclopropanecarboxamide (1.14 g, 13.34 mmol) in 1,4-dioxane solution (70 mL), add tris(dibenzylideneacetone)dipalladium (0.69 g, 0.67 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.77 g, 1.33 mmol) and cesium carbonate (5.43 g, 13.68 mmol). After adding, heat to 100 °C under nitrogen protection and stir for 6 h. Add water (50 mL) and extract with ethyl acetate (50 mL × 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure. The concentrated residue is separated and purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (v / v) = 20 / 1) to obtain Compound 1D (1.5 g, yield: 53%).

[0411] Step 4: Preparation of Compound 1E

[0412] Dissolve Compound 1D (1.5 g, 3.54 mmol) in methanol solution (20 mL) and aqueous solution (5 mL), and add sodium hydroxide (2.12 g, 53.1 mmol). Heat to 80 °C and stir for 12 h. Concentrate under reduced pressure, add water (30 mL), extract with ethyl acetate (30 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The concentrated residue is separated and purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (v / v) = 5 / 1) to obtain Compound 1E (0.75 g, yield: 60%).

[0413] LCMS m / z = 356.3 [M+H] +

[0414] Step 5: Preparation of Compound 1F

[0415] Dissolve Compound 1E (0.75 g, 2.11 mmol) and tert-butyl 7-bromo-4-chloro-1-oxoisoindoline-2-carboxylate (CAS: 2628351-94-8, 0.88 g, 2.53 mmol) in 1,4-dioxane solution (60 mL), add tris(dibenzylideneacetone)dipalladium(0) (0.22 g, 0.21 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.24 g, 0.42 mmol), and cesium carbonate (1.72 g, 5.27 mmol). After addition, heat to 90 °C under nitrogen protection and stir for 3 h. Add water (40 mL), extract with ethyl acetate (40 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The concentrated residue is separated and purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (v / v) = 10 / 1) to obtain Compound 1F (1 g, yield: 76%).

[0416] Step 6: Preparation of 1G

[0417] Compound 1F (0.4 g, 0.64 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.05 g, 0.064 mmol), 7-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (CAS: 2628351-34-6, 0.2 g, 0.77 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.12 g, 0.13 mmol) and potassium phosphate (0.41 g, 1.92 mmol) were added to a mixed solvent of dioxane (60 mL) and water (20 mL). Under a nitrogen atmosphere, the reaction was carried out at 100 °C for 2 h. After adding water (30 mL), the mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography to obtain 1G (0.3 g, yield: 65%).

[0418] LCMS m / z = 721.7 [M+H] +

[0419] Step 7: Preparation of Compound 1

[0420] 1G (0.3 g, 0.42 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added dropwise at room temperature. The mixture was stirred at room temperature for 1 h. The reaction solution was directly concentrated under reduced pressure to remove trifluoroacetic acid. The crude product was purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; chromatographic column: XBridge@Prep C18 (30 mm×150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)). The preparation was lyophilized to obtain the trifluoroacetate salt of Compound 1 (0.1 g).

[0421] LCMS m / z = 621.3 [M+H] +

[0422] 1 H NMR (400 MHz, CDCl 3 / CD 3OD (v / v) = 1 / 1) δ 8.59 (d, 1H), 8.53–8.43 (m, 1H), 7.95 (s, 1H), 7.81–7.71 (m, 2H), 7.68 (dd, 1H), 7.30–7.22 (m, 1H), 7.16 (d, 1H), 7.00–6.89 (m, 1H), 6.58 (dd, 1H), 6.47–6.37 (m, 1H), 4.62 (s, 2H), 4.40 (s, 2H), 3.91–3.78 (m, 1H), 3.31–3.23 (m, 1H), 3.14–3.01 (m, 9H), 3.00–2.93 (m, 1H), 2.92–2.69 (m, 3H), 2.03 - 1.94 (m, 1H), 1.91–1.77 (m, 1H).

[0423] Example 2: Preparation of Compound 2

[0424]

[0425] First step: Synthesis of 2A

[0426] Compound 2A-0 (CAS: 256930-03-7, 2 g, 9.70 mmol), 2-chloro-5-fluoropyridine-6-carbaldehyde (3.10 g, 19.4 mmol), sodium bicarbonate (3.26 g, 38.8 mmol) and DMF (30 mL) were added to a reaction flask. The mixture was stirred at 95 °C in an oil bath for 5 hours, cooled to room temperature, ethyl acetate and water were added, and the mixture was stirred and separated into layers. The organic layer was washed once with saturated sodium chloride aqueous solution and then concentrated to dryness under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: PE-EA = 100-0 to 75-25) to obtain Compound 2A (2.6 g, yield: 78%).

[0427] LCMS m / z = 346.0 [M + H] +

[0428] Second step: Synthesis of 2B

[0429] 2A (2.4 g, 6.94 mmol), tetrahydrofuran solution of dimethylamine (2 M, 1.2 eq) and glacial acetic acid (0.83 g, 13.88 mmol) were added to a reaction flask. The mixture was stirred at room temperature for 1 hour, and sodium triacetoxyborohydride (4.41 g, 20.82 mmol) was added. The mixture was stirred overnight at room temperature. Dichloromethane was added to the reaction solution, and then the mixture was washed successively with water and saturated sodium bicarbonate aqueous solution. The organic layer was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: DCM-CH 3 OH = 100-0 to 90-10) to obtain Compound 2B (2.0 g, yield: 77%).

[0430] LCMS m / z = 375.1 [M+H] +

[0431] Step 3: Synthesis of 2C

[0432] Add 2B (2.0 g, 5.34 mmol), cyclopropylcarboxamide (0.91 g, 10.68 mmol), Pd 2 (dba) 3 (CAS: 60748-47-2; 0.49 g, 0.53 mmol), X-PHOS (CAS: 564483-18-7, 1.53 g, 3.20 mmol), potassium carbonate (2.21 g, 16.02 mmol) and 1,4-dioxane (30 mL) into the reaction flask. After purging with nitrogen three times, heat the mixture in an oil bath at 100 °C overnight under nitrogen protection. Cool to room temperature, add an appropriate amount of silica gel and concentrate under reduced pressure. Purify the residue by silica gel column chromatography (eluent: DCM-CH 3 OH = 100-0 to 90-10) to obtain compound 2C (1.6 g, yield: 71%).

[0433] Step 4: Synthesis of 2D

[0434] Add 2C (1.6 g, 3.78 mmol), sodium hydroxide (1.51 g, 37.8 mmol), methanol (20 mL), water (5 mL) into the reaction flask. Heat the mixture in an oil bath at 70 °C for four days. Cool to room temperature, concentrate under reduced pressure to remove most of the solvent, add water and dichloromethane for extraction and stirring to separate layers. Add an appropriate amount of silica gel to the organic layer and concentrate under reduced pressure. Purify the residue by silica gel column chromatography (eluent: DCM-CH 3 OH = 100-0 to 80-20) to obtain compound 2D (0.9 g, yield: 67%).

[0435] Step 5: Synthesis of 2E

[0436] Add 2D (0.45 g, 1.27 mmol), tert-butyl 7-bromo-4-chloro-1-oxoisoindoline-2-carboxylate (CAS: 2628351-94-8, 0.44 g, 1.27 mmol), Pd 2 (dba) 3 (0.12 g, 0.13 mmol), XantPhos (0.15 g, 0.25 mmol), potassium carbonate (0.53 g, 3.81 mmol) and 1,4-dioxane (10 mL) into the reaction flask. After purging with nitrogen three times, heat the mixture in an oil bath at 95 °C overnight under nitrogen protection. Cool to room temperature, add an appropriate amount of silica gel and concentrate under reduced pressure. Purify the residue by silica gel column chromatography (eluent: DCM-CH 3Compound 2E (0.48 g, yield: 61%) was obtained by separation and purification from OH = 100 - 0 to 90 - 10

[0437] LCMS m / z = 621.3 [M+H] +

[0438] Step 6: Synthesis of 2F

[0439] 2E (0.21 g, 0.34 mmol), 7-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (CAS: 2628351-34-6, 0.13 g, 0.51 mmol), XPHOS-Pd-G2 (0.027 g, 0.034 mmol), X-PHOS (0.032 g, 0.068 mmol), potassium phosphate (0.22 g, 1.02 mmol), dioxane (10 mL) and water (3 mL) were added to a reaction flask. After purging with nitrogen three times, the mixture was stirred at 90 °C under nitrogen protection for 18 hours. After cooling to room temperature, ethyl acetate and saturated sodium chloride aqueous solution were added, and the mixture was stirred and separated. The organic layer was concentrated under reduced pressure after adding an appropriate amount of silica gel, and the residue was purified by silica gel column chromatography (eluent: DCM-CH 3 Compound 2F (0.17 g, yield: 70%) was obtained by separation and purification from OH = 100 - 0 to 90 - 10

[0440] LCMS m / z = 721.4 [M+H] +

[0441] Step 7: Synthesis of Compound 2

[0442] 2F (0.17 g, 0.24 mmol) and dichloromethane (5 mL) were added to a reaction flask. Trifluoroacetic acid (2 mL) was added dropwise with stirring, and the mixture was stirred at room temperature for 2 hours. After concentration to dryness under reduced pressure, dichloromethane and saturated sodium bicarbonate aqueous solution were added, and the mixture was stirred and separated. The organic layer was concentrated under reduced pressure after adding an appropriate amount of silica gel, and the residue was purified by silica gel column chromatography (eluent: DCM-CH 3 Compound 2 (80 mg, yield: 55%) was obtained by separation and purification from OH = 100 - 0 to 80 - 20

[0443] LCMS m / z = 621.4 [M+H] +

[0444] 1 H NMR (400 MHz, CDCl 3 / CD 3OD (v / v) = 1 / 1) δ 8.70 (d, 1H), 8.20 (dd, 1H), 7.68–7.57 (m, 3H), 7.30 (dd, 1H), 7.01 (d, 1H), 6.94 (t, 1H), 6.90–6.84 (m, 1H), 6.57 (dd, 1H), 6.45 - 6.35 (m, 1H), 4.36 (s, 2H), 4.10 (s, 2H), 3.86–3.76 (m, 1H), 3.30 - 3.21 (m, 1H), 3.17–3.09 (m, 1H), 3.09–2.98 (m, 3H), 2.92–2.81 (m, 1H), 2.78–2.69 (m, 2H), 2.67 (s, 6H), 2.02 - 1.93 (m, 1H), 1.90–1.75 (m, 1H).

[0445] Example 3: Preparation of Compound 3

[0446]

[0447] First step: Preparation of 3B

[0448] Dissolve Compound 3A (1.9 g, 16.79 mmol, CAS: 148860 - 48 - 4) in DMF (20 mL), add 6 - bromo - 3 - fluoro - 2 - pyridinecarboxaldehyde (6.85 g, 33.58 mmol) and sodium bicarbonate (14.11 g, 167.90 mmol). After addition, warm the mixture to 100 °C and stir for 1 hour. After the reaction mixture is cooled, add 60 mL of water and 600 mL of ethyl acetate, stir and separate the layers. The organic phase is washed twice with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue is purified by flash column chromatography (mobile phase: petroleum ether / ethyl acetate (v / v) = 6 / 1) to obtain Compound 3B (3.6 g, yield: 72%).

[0449] Second step: Preparation of 3C

[0450] Dissolve 3B (3.6 g, 12.12 mmol) in 100 mL of dichloroethane, add allylamine (1.38 g, 24.24 mmol), acetic acid (1.46 g, 24.24 mmol), anhydrous sodium sulfate (2 g), stir at room temperature for 1 hour, then slowly add sodium triacetoxyborohydride (5.14 g, 24.24 mmol), and continue to stir for 2 hours. Add 50 mL of saturated aqueous sodium bicarbonate solution to the reaction mixture, separate the layers. The organic phase is washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue is purified by flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 10 / 1) to obtain Compound 3C (2.6 g, yield: 63%).

[0451] LCMS m / z = 338.1 [M + H]+

[0452] Step 3: Preparation of 3D

[0453] Dissolve 3C (2.6 g, 7.69 mmol) in 100 mL of dichloroethane, add formaldehyde (0.69 g, 23.07 mmol), acetic acid (0.92, 15.38 mmol), and anhydrous sodium sulfate (2 g). After stirring at room temperature for 1 hour, slowly add sodium triacetoxyborohydride (3.26 g, 15.38 mmol), and continue stirring for 2 hours. Add 50 mL of saturated sodium bicarbonate aqueous solution to the reaction solution, separate the layers, wash the organic phase once with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and subject the residue to flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 10 / 1) to obtain compound 3D (2.13 g, yield: 79%).

[0454] LCMS m / z = 352.1 [M+H] +

[0455] Step 4: Preparation of 3E

[0456] Dissolve compound 3D (780 mg, 2.2 mmol) in toluene (150 mL). After bubbling the reaction solution with nitrogen for 15 min, add HOVEYDA-GRUBBS catalyst (CAS: 301224-40-8, 0.42 g, 0.7 mmol). After addition, heat to 100 °C and stir for 2 hours. After the reaction solution is cooled, add 60 mL of water and 600 mL of ethyl acetate, stir and separate the layers. Wash the organic phase twice with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and subject the residue to flash column chromatography (mobile phase: petroleum ether / ethyl acetate (v / v) = 6 / 1) to obtain compound 3E (100 mg, yield: 14%).

[0457] LCMS m / z = 324.1 [M+H] +

[0458] Step 5: Preparation of 3F

[0459] 3E (0.1 g, 0.31 mmol) was dissolved in 1,4-dioxane (40 mL), and cyclopropanecarboxamide (0.079 g, 0.93 mmol), cesium carbonate (0.3 g, 0.93 mmol), tris(dibenzylideneacetone)dipalladium (0.028 g, 0.031 mmol), and XantPhos (0.036 g, 0.062 mmol) were added. After purging with nitrogen three times, the temperature was raised to 100 °C and the reaction was carried out overnight. The reaction solution was diluted with 100 mL of ethyl acetate and filtered through diatomaceous earth. The filter cake was washed three times with ethyl acetate. After combining the filtrates, they were washed once with water and once with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 10 / 1) to obtain compound 3F (0.07 g, yield: 69%).

[0460] LCMS m / z = 329.2 [M+H] +

[0461] Step 6: Preparation of 3G

[0462] 3F (70 mg, 0.21 mmol) was dissolved in methanol (3 mL), and water (0.7 mL) and sodium hydroxide (84 mg, 2.1 mmol) were added. Under nitrogen protection, the temperature was raised to 80 °C and the reaction was carried out overnight. Methanol was removed by concentration. 5 mL of dichloromethane and 2 mL of water were added, and the mixture was stirred and separated into layers. The aqueous layer was extracted twice with dichloromethane. The combined organic phases were washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3G (55 mg).

[0463] LCMS m / z = 261.3 [M+H] +

[0464] Step 7: Preparation of 3H

[0465] Compound 3G (55 mg, 0.21 mmol) and tert-butyl 7-bromo-4-chloro-1-oxoisoindoline-2-carboxylate (CAS: 2628351-94-8, 0.073 g, 0.21 mmol) were dissolved in 1,4-dioxane solution (20 mL), and tris(dibenzylideneacetone)dipalladium(0) (0.019 g, 0.021 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.024 g, 0.042 mmol), and cesium carbonate (0.21 g, 0.63 mmol) were added. After addition, the temperature was raised to 95 °C under nitrogen protection and stirred for 5 h. The reaction solution was diluted with 50 mL of ethyl acetate, filtered through diatomaceous earth, and the filter cake was washed 3 times with ethyl acetate. After combining the filtrates, they were washed once with water and once with saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 10 / 1) to obtain compound 3H (0.08 g, yield: 72%).

[0466] LCMS m / z = 526.0 [M+H] +

[0467] Step 8: Preparation of 3I

[0468] Compound 3H (80 mg, 0.15 mmol), 7-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (47 mg, 0.18 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (14 mg, 0.030 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (12 mg, 0.015 mmol), and potassium phosphate (96 mg, 0.45 mmol) were added to a mixed solvent of dioxane (30 mL) and water (5 mL). After purging with nitrogen three times, the reaction was carried out at 90 °C overnight. After adding water (30 mL), it was extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography to obtain 3I (53 mg, yield: 56%).

[0469] LCMS m / z = 626.2 [M+H] +

[0470] Step 9: Preparation of Compound 3

[0471] Dissolve 3I (0.026 g, 0.12 mmol) in dichloromethane (1 mL), add trifluoroacetic acid (0.3 mL) dropwise at room temperature, and stir at room temperature for 1 h. The reaction solution was directly concentrated under reduced pressure to remove trifluoroacetic acid. The crude product was purified by preparative HPLC (instrument: Waters 2767 preparative liquid phase; chromatographic column: XBridge@Prep C18 (30 mm × 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)), and the preparation solution was freeze-dried to obtain the trifluoroacetate salt of compound 3 (12 mg).

[0472] LCMS m / z = 526.2 [M+H] +

[0473] Example 4: Preparation of Compound 4

[0474]

[0475] First step: Preparation of 4A

[0476] Add 2A-0 (1.3 g, 6.30 mmol), 5-fluoro-2-nitropyridine (0.90 g, 6.3 mmol), sodium bicarbonate (1.59 g, 18.9 mmol), DMF (20 mL), heat the reaction at 95 °C in an oil bath for 3 hours, cool to room temperature, add water (60 mL), stir to crystallize for 1 hour, filter, wash the filter cake with water, concentrate and dry under reduced pressure to obtain 4A (2 g, yield: 96.64%).

[0477] Second step: Preparation of 4B

[0478] Add 4A (2 g, 6.09 mmol), iron powder (1.70 g, 30.45 mmol), ammonium chloride (1.63 g, 30.45 mmol), ethanol (20 mL) and water (5 mL), heat the reaction at 90 °C in an oil bath for 1 hour, spread an appropriate amount of diatomaceous earth, filter, wash the filtrate with ethyl acetate, add ethyl acetate and water to the filtrate, stir to separate layers, add an appropriate amount of silica gel to the organic layer to make sand, and purify by column chromatography. Eluent: DCM-CH 3 OH = 100 - 0 to 90 - 10, to obtain 4B (0.85 g, yield: 46.77%).

[0479] Third step: Preparation of 4C

[0480] Add 4B (0.22 g, 0.74 mmol), tert-butyl 7-bromo-4-chloro-1-oxoisoindoline-2-carboxylate (CAS: 2628351-94-8, 0.28 g, 81 mmol), PD 2 (DBA) 3(0.068 g, 0.074 mmol), XantPhos (0.086 g, 0.15 mmol), potassium carbonate (0.31 g, 2.22 mmol) and 1,4-dioxane (10 mL). After purging with nitrogen three times, the mixture was heated under nitrogen protection in an oil bath at 90 °C overnight. After cooling to room temperature, an appropriate amount of silica gel was added and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE-EA = 100 - 0 to 75 - 25) to obtain compound 4C (0.37 g, yield: 88.96%)

[0481] LCMS m / z = 564.6 [M+H] +

[0482] Step 4: Preparation of 4D

[0483] Add 4C (0.2 g, 0.35 mmol), 7-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (CAS: 2628351-34-6, 0.52 mmol, Purity 100%), XPHOS-Pd-G2 (0.028 g, 0.035 mmol), XPHOS (0.033 g, 0.070 mmol), potassium phosphate (0.22 g, 1.05 mmol), 1,4-dioxane (20 mL), water (5 mL). After purging with nitrogen three times, the mixture was stirred and reacted in an oil bath at 95 °C under nitrogen protection for 3 hours. After cooling to room temperature, ethyl acetate and water were added, and the mixture was stirred and separated. The organic layer was added with an appropriate amount of silica gel to make sand, and purified by column chromatography. The eluent was DCM-CH 3 OH = 100 - 0 to 90 - 10, to obtain 4D (0.23 g, yield: 97.73%)

[0484] LCMS m / z = 664.3 [M+H] +

[0485] Step 5: Preparation of compound 4

[0486] Add 4D (0.23 g, 0.35 mmol), dichloromethane (5 mL), and trifluoroacetic acid (3 mL) was added dropwise with stirring. The mixture was stirred at room temperature for 2 hours. The reaction solution was directly concentrated under reduced pressure to remove trifluoroacetic acid. The crude product was purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; chromatographic column: XBridge@Prep C18 (30 mm × 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)). The preparation solution was lyophilized to obtain the trifluoroacetate salt of compound 4 (90 mg)

[0487] LCMS m / z = 564.3 [M+H] +

[0488] Example 5: Preparation of Compound 5

[0489]

[0490] First Step: Preparation of Compound 5A

[0491] The hydrochloride of Compound 1A (1.95 g, 8.06 mmol) and 5-fluoro-2-nitropyridine (CAS: 779345-37-8, 1.15 g, 8.06 mmol) were dissolved in DMF (20 mL), and sodium bicarbonate (1.35 g, 16.12 mmol) was added. After addition, the temperature was raised to 100 °C under nitrogen protection and stirred for 2 h. After adding water (50 mL), it was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate (v / v) = 10 / 1) to obtain Compound 5A (1.7 g, yield: 60%).

[0492] LCMS m / z = 329.1 [M+H] +

[0493] Second Step: Preparation of Compound 5B

[0494] Compound 5A (1.60 g, 4.87 mmol) was dissolved in THF (20 mL) and water (5 mL), and ammonium chloride (1.6 g, 29.9 mmol) and iron powder (1.6 g, 28.65 mmol) were added. After addition, it was stirred at room temperature for 2 h. The reaction solution was filtered through diatomaceous earth. After adding water (50 mL) to the filtrate, it was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (v / v) = 18 / 1) to obtain Compound 5B (1.7 g).

[0495] LCMS m / z = 299.3 [M+H] +

[0496] Third Step: Synthesis of 5C

[0497] 5B (0.40 g, 1.34 mmol), tert-butyl 7-bromo-4-chloro-1-oxoisoindoline-2-carboxylate (CAS: 2628351-94-8, 0.56 g, 1.61 mmol), and Pd 2 (dba) 3(0.25 g, 0.27 mmol), XantPhos (0.16 g, 0.27 mmol), potassium carbonate (0.56 g, 4.02 mmol) and 1,4-dioxane (10 mL). After purging with nitrogen three times, the reaction mixture was heated under nitrogen protection in an oil bath at 95 °C for 5 hours. After cooling to room temperature, an appropriate amount of silica gel was added and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: DCM-CH 3 OH = 100 - 0 to 90 - 10) to obtain compound 5C (0.4 g, yield: 53%)

[0498] LCMS m / z = 564.0 [M+H] +

[0499] Step 4: Synthesis of 5D

[0500] To a reaction flask was added 5C (250 mg, 0.44 mmol), 7-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (CAS: 2628351-34-6, 138 mg, 0.53 mmol), XPHOS-Pd-G2 (35 mg, 0.044 mmol), XPHOS (21 mg, 0.044 mmol), potassium phosphate (280 mg, 1.32 mmol), dioxane (10 mL) and water (3 mL). After purging with nitrogen three times, the reaction mixture was stirred under nitrogen protection in an oil bath at 90 °C for 3 hours. After cooling to room temperature, ethyl acetate and saturated aqueous sodium chloride were added, and the mixture was stirred and separated. The organic layer was concentrated under reduced pressure after adding an appropriate amount of silica gel. The residue was purified by silica gel column chromatography (eluent: DCM-CH 3 OH = 100 - 0 to 90 - 10) to obtain compound 5D (152 mg, yield: 52%).

[0501] LCMS m / z = 664.1 [M+H] +

[0502] Step 7: Synthesis of compound 5

[0503] To a reaction flask was added 5D (152 mg, 0.23 mmol) and dichloromethane (5 mL). Trifluoroacetic acid (2 mL) was added dropwise with stirring at room temperature, and the reaction mixture was stirred for 2 hours. After concentration to dryness under reduced pressure, dichloromethane and saturated aqueous sodium bicarbonate were added, and the mixture was stirred and separated. The organic layer was concentrated under reduced pressure after adding an appropriate amount of silica gel. The residue was purified by silica gel column chromatography (eluent: DCM-CH 3 OH = 100 - 0 to 90 - 10) to obtain 100 mg of crude product. The obtained crude product was purified by preparative liquid chromatography to obtain the trifluoroacetate salt of compound 5 (50 mg)

[0504] LCMS m / z = 564.2 [M+H] +

[0505] Example 6: Preparation of Compound 6

[0506]

[0507] First Step: Synthesis of 6A

[0508] Add 2A (2.0 g, 5.78 mmol), 3,3-difluorotrimethyleneimine hydrochloride (0.75 g, 5.78 mmol) and glacial acetic acid (0.35 g, 5.78 mmol) into a reaction flask, stir at room temperature for 2 hours, add sodium triacetoxyborohydride (3.68 g, 17.34 mmol), and stir at room temperature overnight. After adding dichloromethane to the reaction solution, wash it successively with water and saturated sodium bicarbonate aqueous solution. The organic layer is concentrated under reduced pressure, and the residue is separated and purified by silica gel column chromatography (eluent: DCM-CH 3 OH = 100 - 0 to 90 - 10) to obtain Compound 6A (1.0 g, yield: 41%).

[0509] LCMS m / z = 423.2 [M+H] +

[0510] Second Step: Synthesis of 6B

[0511] Add 6A (1.0 g, 2.36 mmol), cyclopropanecarboxamide (0.2 g, 2.36 mmol), PD 2 (DBA) 3 (0.43 g, 0.47 mmol), X-PHOS (0.27 g, 0.47 mmol), cesium carbonate (1.54 g, 4.72 mmol) and 1,4-dioxane (30 mL) into a reaction flask. After purging with nitrogen three times, heat it in an oil bath at 100 °C overnight under nitrogen protection. Cool to room temperature, add an appropriate amount of silica gel to make sand, and then concentrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (eluent: DCM-CH 3 OH = 100 - 0 to 90 - 10) to obtain Compound 6B (0.94 g, yield: 84%).

[0512] LCMS m / z = 472.1 [M+H] +

[0513] Third Step: Synthesis of 6C

[0514] 6B (0.47 g, 1.0 mmol), sodium hydroxide (0.80 g, 20.0 mmol), methanol (20 mL), and water (5 mL) were added to a reaction flask. The mixture was heated under an oil bath at 80 °C for 2 days, cooled to room temperature, and concentrated under reduced pressure to remove most of the solvent. Water and dichloromethane were added for extraction and stirring to separate the layers. The organic layer was concentrated under reduced pressure after adding an appropriate amount of silica gel. The residue was purified by silica gel column chromatography (eluent: DCM-CH 3 OH = 100 - 0 to 80 - 20) to obtain compound 6C (0.4 g).

[0515] LCMS m / z = 404.2 [M + H] +

[0516] Step 4: Synthesis of 6D

[0517] 6C (0.20 g, 0.5 mmol), tert-butyl 7-bromo-4-chloro-1-oxoisoindoline-2-carboxylate (CAS: 2628351-94-8, 0.21 g, 0.60 mmol), PD 2 (DBA) 3 (0.09 g, 0.10 mmol), XantPhos (0.055 g, 0.10 mmol), potassium carbonate (0.21 g, 1.50 mmol), and 1,4-dioxane (10 mL) were added to a reaction flask. After purging with nitrogen three times, the mixture was heated under an oil bath at 95 °C for 5 hours under nitrogen protection. It was cooled to room temperature, an appropriate amount of silica gel was added, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: DCM-CH 3 OH = 100 - 0 to 90 - 10) to obtain compound 6D (287 mg, yield: 85%).

[0518] Step 5: Synthesis of 6E

[0519] 6D (287 mg, 0.43 mmol), 7-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (CAS: 2628351-34-6, 135 mg, 0.52 mmol), XPHOS-Pd-G2 (34 mg, 0.043 mmol), XPHOS (21 mg, 0.043 mmol), potassium phosphate (274 mg, 1.29 mmol), dioxane (10 mL), and water (3 mL) were added to a reaction flask. After purging with nitrogen three times, the mixture was stirred and reacted under an oil bath at 90 °C for 18 hours under nitrogen protection. It was cooled to room temperature, ethyl acetate and saturated aqueous sodium chloride solution were added, and stirred to separate the layers. The organic layer was concentrated under reduced pressure after adding an appropriate amount of silica gel. The residue was purified by silica gel column chromatography (eluent: DCM-CH 3Compound 6E (268 mg, yield: 81%) was obtained by separation and purification from OH = 100 - 0 to 90 - 10).

[0520] Step 6: Synthesis of Compound 6

[0521] 6E (268 mg, 0.27 mmol) was added to a reaction flask, followed by dichloromethane (5 mL). Trifluoroacetic acid (2 mL) was added with stirring, and the mixture was stirred at room temperature for 2 hours. It was concentrated under reduced pressure to dryness, then dichloromethane and saturated aqueous sodium bicarbonate were added. After stirring and separating the layers, the organic layer was concentrated under reduced pressure after adding an appropriate amount of silica gel. The residue was purified by silica gel column chromatography (eluent: DCM - CH 3 OH = 100 - 0 to 80 - 20) to separate and purify the crude product. The obtained crude product was separated and purified by preparative liquid chromatography (instrument: waters 2767 preparative liquid chromatography; chromatographic column: XBridge@Prep C18 (30 mm × 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)). The preparative solution was lyophilized to obtain the trifluoroacetate salt of Compound 6 (60 mg)

[0522] LCMS m / z = 669.3 [M + H] +

[0523] Example 7: Preparation of Compound 7

[0524]

[0525] Step 1: Preparation of 7A

[0526] Methyl 2,4 - dimethyl - 3 - aminobenzoate (5 g, 27.90 mmol) was dissolved in acetonitrile (50 mL). NBS (4.97 g, 27.9 mmol) was added under ice bath, and the mixture was stirred at room temperature for 2 h after natural warming. 100 mL of ethyl acetate and 100 mL of water were added for extraction, and the organic layer was washed twice with saturated brine (50 mL). It was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was directly used for the next step.

[0527] 1 H NMR (400 MHz, DMSO - d 6 ) δ 7.09 (s, 1H), 4.95 (br.s, 2H), 3.82 (s, 3H), 2.09 (s, 3H), 1.99 (s, 3H).

[0528] Step 2: Preparation of 7B

[0529] Compound 7A (7.5 g, 29.06 mmol) was placed in a 250 mL single-necked flask, 20 mL of water was added, and 10 mL of concentrated hydrochloric acid was added under an ice bath. A large amount of solid precipitated. Then, 20 mL of water and 5 mL of concentrated hydrochloric acid were added continuously. After addition, sodium nitrite (2.41 g, 34.87 mmol) was slowly added under an ice bath. After addition, the mixture was continuously stirred under an ice bath until the reaction solution became clear, and then 10 mL of an aqueous solution of sodium tetrafluoroborate (4.79 g, 43.59 mmol) was added, resulting in a large amount of solid precipitation. The mixture was allowed to warm to room temperature naturally and stirred for another 30 min. It was filtered, and the filter cake was washed successively with 10 mL of water and 20 mL of petroleum ether, and then dried under reduced pressure at room temperature for 30 min. This filter cake was placed in a 100 mL single-necked flask, chloroform (50 mL) was added, and potassium acetate (4.28 g, 43.59 mmol) and 16-crown-6 (0.77 g, 2.91 mmol) were added successively under stirring at room temperature, and the mixture was stirred for another 1 h. 50 mL of dichloromethane and 50 mL of water were added and stirred to separate the layers. The organic layer was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10 - 1 / 1) and then by SFC purification (instrument: SFC Prep 150AP; chromatographic column: IG (19 mm × 250 mm); mobile phase A: CO 2 ; mobile phase B: methanol / acetonitrile = 1 / 1; isocratic elution, the content of mobile phase B was 30%; flow rate 45 ml / min) to obtain compound 7B (3.1 g, yield: 40%).

[0530] 1 1H NMR (400 MHz, DMSO-d 6 ) δ 13.58 (s, 1H), 8.11 (s, 1H), 7.98 (s, 1H), 3.91 (s, 3H), 2.49 (s, 3H).

[0531] Step 3: Preparation of 7C

[0532] Compound 7B (1 g, 3.72 mmol) was dissolved in THF (20 mL), and triethylamine (1.13 g, 11.16 mmol) and 4-dimethylaminopyridine (0.45 g, 3.72 mmol) were added successively. After addition, benzenesulfonyl chloride (0.99 g, 5.58 mmol) was slowly added dropwise at room temperature, and the mixture was stirred overnight at room temperature. 30 mL of ethyl acetate and 30 mL of water were added for extraction. The organic layer was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 1 - 1 / 1) to obtain 7C (1.6 g).

[0533] Step 4: Preparation of 7D

[0534] Dissolve compound 7C (1.6 g, 3.91 mmol) in carbon tetrachloride (20 mL). Sequentially add NBS (1.39 g, 7.82 mmol) and azobisisobutyronitrile (0.064 g, 0.39 mmol). Replace the gas with nitrogen three times, heat to 80 °C and stir overnight. Add 20 mL of dichloromethane and 20 mL of water for extraction. Dry the organic layer with anhydrous sodium sulfate, concentrate under reduced pressure to obtain the crude product of 7D, which is directly used for the next step.

[0535] LCMS m / z = 486.9 [M+H] +

[0536] Step 5: Preparation of 7E

[0537] Add 20 mL of 7N ammonia-methanol solution to a 50 mL single-necked flask. Slowly add 5 mL of the dichloromethane solution of the crude product of 7D at room temperature. After addition, stir at room temperature for 1 h. A large amount of solid precipitates. Filter, wash the filter cake with a small amount of dichloromethane, and dry the filter cake under reduced pressure. Combine the filtrates, concentrate under reduced pressure, purify the residue by column chromatography (dichloromethane / methanol = 100 / 0 - 10 / 1), concentrate the preparation solution under reduced pressure, and combine the filter cakes to obtain 7E (0.8 g).

[0538] LCMS m / z = 252.1 [M+H] +

[0539] Step 6: Preparation of 7F

[0540] Dissolve compound 7E (0.8 g, 3.17 mmol) in THF (15 mL). Sequentially add 4-dimethylaminopyridine (0.39 g, 3.17 mmol), triethylamine (0.96 g, 9.51 mmol) and Boc anhydride (2.08 g, 9.51 mmol), and stir at room temperature for 2 h. Add methanol (15 mL) and potassium carbonate (2.63 g, 19.02 mmol), heat to 50 °C and stir for 2 h. Add 50 mL of dichloromethane and 50 mL of water for extraction. Wash the organic layer once with saturated brine, concentrate under reduced pressure, and purify the residue by column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10 - 1 / 1) to obtain 7F (0.6 g, yield: 53%).

[0541] LCMS m / z = 296.0 [M-55] +

[0542] 1 H NMR (400 MHz, DMSO-d 6 ) δ13.85 (s, 1H), 8.24 (s, 1H), 8.13 (s, 1H), 4.97 (s, 2H), 1.55 (s, 9H).

[0543] Step 7: Preparation of 7G-1 and 7G-2

[0544] Compound 7F (0.25 g, 0.71 mmol), 4-fluorophenylboronic acid (0.20 g, 1.42 mmol) and copper(II) acetate monohydrate (0.14 g, 0.71 mmol) were mixed and dissolved in 1,2-dichloroethane (15 mL). Pyridine (0.17 g, 2.13 mmol) was added, and the mixture was purged with oxygen three times. The temperature was raised to 70 °C and stirred for 2 h. After filtration, the filter cake was washed with 20 mL of dichloromethane. The filtrates were combined and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10 - 1 / 3) to obtain a mixture of 7G-1 and 7G-2, which was further prepared by SFC (instrument: SFC Prep 150AP; column: TORUS2-PIC (19 mm × 250 mm); mobile phase A: CO 2 ; mobile phase B: methanol / dichloromethane = 3 / 2; isocratic elution, 25% content of mobile phase B; flow rate 42 ml / min) to obtain 7G-1 and 7G-2.

[0545] 7G-1 (0.09 g, yield: 28%)

[0546] 1 H NMR (400 MHz, CDCl 3 ) δ 8.24 (s, 1H), 8.09 (s, 1H), 7.54–7.47 (m, 2H), 7.32–7.26 (m, 3H), 4.49 (s, 2H), 1.58 (s, 9H).

[0547] 7G-2 (0.11 g, yield: 35%)

[0548] 1 H NMR (400 MHz, CDCl 3 ) δ 8.43 (s, 1H), 7.99 (s, 1H), 7.94–7.85 (m, 2H), 7.31 - 7.23 (m, 3H), 5.05 (s, 2H), 1.63 (s, 9H).

[0549] Step 8: Preparation of 7H

[0550] Compound 7G-1 (0.090 g, 0.21 mmol), 6-[(dimethylamino)methyl]-5-(oxoalkan-3-yl)pyridin-2-amine (CAS: 2628347-73-7, synthesis reference WO2022187856) (0.056 g, 0.25 mmol), XantPhos (R2, 0.024 g, 0.042 mmol), Pd 2 (DBA) 3(R3, 0.019 g, 0.021 mmol) and potassium carbonate (0.087 g, 0.63 mmol) were mixed and dissolved in 1,4 - Dioxane (10 mL). The mixture was purged with nitrogen three times and then heated to 100 °C and stirred for 2 h. After cooling to room temperature, 30 mL of dichloromethane and 30 mL of water were added for extraction. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (V / V) = 100 / 0 - 100 / 7) to obtain 7H (80 mg, yield: 67%).

[0551] LCMS m / z = 587.4 [M + H] +

[0552] Step 9: Preparation of Compound 7

[0553] Compound 7H (0.080 g, 0.14 mmol) was dissolved in DCM (2 mL). Trifluoroacetic acid (2 mL) was added at room temperature. After addition, the mixture was stirred at room temperature for 1 h. It was concentrated under reduced pressure, and the residue was purified by preparative HPLC (preparation conditions: 0.1% TFA water / acetonitrile = 10% - 70%) to obtain the trifluoroacetate salt of Compound 7 (50 mg).

[0554] LCMS m / z = 487.0 [M + H] +

[0555] 1 H NMR (400 MHz, DMSO - d 6 ) δ 10.17 (s, 1H), 8.96 (s, 1H), 8.71 (s, 1H), 8.41 (s, 1H), 7.79–7.68 (m, 3H), 7.51–7.37 (m, 2H), 7.09 (d, 1H), 4.62 (d, 2H), 4.33 (s, 2H), 4.05–3.95 (m, 2H), 3.83 (dd, 1H), 3.62–3.49 (m, 2H), 3.11–2.93 (m, 6H), 2.40–2.27 (m, 1H), 1.98–1.81 (m, 1H).

[0556] Example 8: Preparation of Compound 8

[0557]

[0558] Step 1: Preparation of 8A

[0559] Compound 7G-2 (0.11 g, 0.26 mmol), 6-[(dimethylamino)methyl]-5-(oxoalkan-3-yl)pyridin-2-amine (Cas: 2628347-73-7, synthesis reference WO2022187856) (0.069 g, 0.31 mmol), XantPhos (0.030 g, 0.052 mmol), Pd 2 (DBA) 3 (0.024 g, 0.026 mmol) and potassium carbonate (0.11 g, 0.78 mmol) were mixed and dissolved in 1,4-Dioxane (10 mL). The mixture was purged with nitrogen three times, heated to 100 °C and stirred for 2 h. After cooling to room temperature, 30 mL of dichloromethane and 30 mL of water were added for extraction. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (V / V) = 100 / 0 - 100 / 7) to obtain 8A (0.12 g, yield: 80%).

[0560] LCMS m / z = 587.4 [M+H] +

[0561] Step 2: Preparation of Compound 8

[0562] Compound 8A (0.12 g, 0.20 mmol) was dissolved in DCM (2 mL). Trifluoroacetic acid (2 mL) was added at room temperature. After addition, the mixture was stirred at room temperature for 1 h. It was concentrated under reduced pressure, and the residue was purified by preparative HPLC (preparation conditions: 0.1% TFA water / acetonitrile = 10% - 70%) to obtain the trifluoroacetate salt of Compound 8 (57 mg).

[0563] LCMS m / z = 487.0 [M+H] +

[0564] Biological Test Example

[0565] Test Example 1: Detection of SLP76 Phosphorylation Level in Jurkat Cells

[0566] Jurkat cells from ATCC were placed in RPMI-1640 complete medium (supplemented with 10% FBS and 1% double antibody) and cultured at 37 °C and 5% CO 2 conditions. Cells in the logarithmic growth phase were collected, and the cell density was adjusted to 5×10 5 cells / well with the medium and added to a 6-well cell culture plate at a volume of 1 mL / well. The test compound was formulated to a final concentration three times as high. In the dosing wells, 500 μL of the compound at different concentrations was added, and in the control wells, the medium containing 0.3% DMSO was added. Incubate at 37 °C and 5% CO 2Incubate for 4 hours under the conditions. Add 500 μL of CD3 antibody (BD, Cat#555329; final concentration 1 μg / mL), and incubate at 37 °C and 5% CO 2 for 10 minutes. After incubation, collect the cells in a 1.5 mL centrifuge tube and wash twice with pre-cooled PBS. After preparing the protease inhibitor mixture, phosphatase inhibitor and lysis buffer at a ratio of 1:1:100, add 10 μL of lysis buffer to each sample to resuspend the cells, place on ice for 15 minutes, and shake repeatedly during this period until the cells are completely lysed. Then centrifuge at 12,000 rpm at 4 °C for 15 minutes, collect the supernatant, and measure the protein content by the BCA method. Dilute the protein samples to be measured to 2 mg / mL and 0.8 mg / mL, and use an automated protein expression quantitative analyzer (ProteinSimple) to detect the phosphorylated SLP76 (p-SLP76) and the total protein level of SLP76 (the antibodies are all from CST). Use the software (Compass for SW) of the automated protein expression quantitative analyzer to process the raw data, calculate the peak area A, and calculate according to A [p-SLP76] / A [SLP76] the expression level R of p-SLP76 relative to the total protein of SLP76, and calculate the inhibition rate of p-SLP76 according to [1 - (R 给药孔 -R 阴性对照 ) / (R 阳性对照 -R 阴性对照 )]×100%, where R 阴性对照 is the control well with only the medium containing 0.3% DMSO added, and R 阳性对照 is the control well with CD3 antibody added. Use the four-parameter non-linear fitting model in Graphpad 8.3.0 software to calculate the IC 50 value.

[0567] Conclusion: Compounds of the present application, such as the example compounds, have a good inhibitory effect on the phosphorylation of SLP76 in Jurkat cells.

[0568] Test Example 2: HPK1 kinase detection experiment (1 mM ATP)

[0569] The kinase HPK1 (Carna, Cat. No 07-410) was formulated into a 2× kinase solution using 1× kinase buffer. The substrate Fluorescein-PKC (Invitrogen, Cat. No. PV3506) and ATP (working concentration: 1 mM) (Sigma, Cat. No. 2383-5G) were formulated into a 2× substrate solution using 1× kinase buffer. The detection reagent was diluted to twice the final concentration using antibody diluent. 100 nL of compounds at different concentrations, 5 μL of kinase solution were added to each well of a 384-well plate and incubated at room temperature for 10 minutes. After incubation, 5 μL of substrate solution was added to each well and reacted at room temperature for 90 minutes. After the reaction ended, 10 μL of detection reagent was added to each well to terminate the reaction and incubated at room temperature for 60 minutes. Fluorescence readings at an excitation wavelength of 320 nm and emission wavelengths of 520 nm and 495 nm were detected using an Envision instrument. The IC 50 value was calculated using the XLFit excel add-in version 5.4.0.8 software. The formula for the inhibition rate is shown in Equation 2-1, where max is the Ratio of the DMSO control, min is the Ratio of the negative control without enzyme, and sample is the Ratio of the compound.

[0570] Ratio = RFU 520nm / RFU 495nm

[0571] Inhibition% = (max - sample) / (max - min) × 100% (Equation 2-1)

[0572] Table 2-1 Inhibitory activities of the test compounds against HPK1 kinase

[0573] Compound number <![CDATA[IC 50 (nM)]]> Trifluoroacetate salt of Compound 1 A Compound 2 A

[0574] Note: In Table 2-1, A < 30 nM, 30 nM ≤ B < 100 nM, 100 nM ≤ C

[0575] Conclusion: The compounds of the present invention, such as the example compounds, have good inhibitory effects on HPK1 kinase.

Claims

1. A compound or its stereoisomer, tautomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, the compound being selected from the compounds represented by general formula (I) or general formula (II), wherein When the compound is selected from the compounds represented by general formula (I): X1 is selected from N or CR x1 ; X2 is selected from N or CR x2 ; R x1 , R x2 are each independently selected from H, deuterium, halogen, cyano, OH, NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, C 3-6 carbocyclic group, 4 to 7 membered heterocyclic group, the alkyl, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace; R 1 Selected from C 5-14 A carbocyclic group or a 5- to 14-membered heterocyclic group, wherein R 1 Optional 1 to 6 R 1a replace; R 2 Selected from K1, K2, K3 are each independently selected from N, CH or CR 2b ; Ring D is selected from a 4- to 6-membered heterocyclic group, wherein the ring D is optionally substituted by 1 to 4 R d replace; R 2a With R D directly connected to form ring Y, ring Y is selected from 9 to 13 membered heterocyclic rings, the heterocyclic rings are optionally substituted by 1 to 4 R y replace; The number of ring atoms in the polycyclic ring formed by ring D, ring Y, and the rings where K1, K2, and K3 are located is greater than 16; R y Each independently selected from deuterium, halogen, =O, CN, OH, C 1-6 Alkyl, -OC 1-6 Alkyl, C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4 Alkylene-4 to 7 membered heterocyclic group, wherein the alkyl, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace; Ring A is selected from phenyl or 5- to 6-membered heteroaryl; Ring B is selected from a 5- to 6-membered heterocyclic group, and the ring B is optionally substituted by 1 to 2 R b replace; K4 is selected from N or CH; K5 is selected from N or CH; Ring C is selected from C 6-10 Carbocyclic group or 5- to 10-membered heterocyclic group; Ring E is selected from a 5- to 6-membered heterocyclic group containing 1 phosphorus atom, wherein the phosphorus atom is optionally oxidized to P(=O), P(=O)2; R 1a , R 2b , R a , R b , R c , R d , R e Each independently selected from deuterium, halogen, =O, CN, OH, NO2, COOH, CONH2, NH2, -C 0-4 Alkylene-NHC 1-6 Alkyl, -C 0-4 Alkylene-N(C 1-6 Alkyl)2, -C 0-4 Alkylene-N(C 1-6 Alkyl)-C 3-6 Carbocyclic group, -C 0-4 Alkylene-N(C 1-6 alkyl)-4 to 7 membered heterocyclic group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 carbocyclyl, -O-4 to 7 membered heterocyclyl, -NH-C 3-6 carbocyclic group, -NH-4 to 7 membered heterocyclic group, -C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4 Alkylene-4 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace; R 3 Selected from H, halogen, C 1-6 Alkyl, the alkyl group is optionally substituted by 1 to 4 R k replace; R 4 Selected from H, halogen, C 1-6 Alkyl, the alkyl group is optionally substituted by 1 to 4 R k replace; R k Each independently selected from deuterium, halogen, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 carbocyclyl, -O-4 to 7 membered heterocyclyl, -NH-C 3-6 carbocyclic group, -NH-4 to 7 membered heterocyclic group, -C 1-4 Alkylene-C 3-6 Carbocyclic group, -C 1-4 Alkylene-4 to 7 membered heterocyclic group, C 3-6 carbocyclic group, 4 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from deuterium, halogen, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent; p1 is selected from 0, 1, 2 or 3; p2 is selected from 0, 1, 2 or 3; p3 is selected from 0, 1, 2, 3 or 4; The condition is that when R 2 Selected from When R 1 Selected from R 1A ; R 1A is selected from phenyl or 7 to 10-membered bicyclic heterocyclic group, wherein R 1A Optional 1 to 6 R 1a replace; When the compound is selected from the compounds represented by general formula (II): Ring B is selected from Its left side is connected to L, and the ring B is optionally substituted by 1 to 4 R b replace; Ring B1 is selected from 5-membered heteroaryl groups; X is selected from O or S; Y is selected from CH2 or Se; Ring A is independently selected from C 6-12 5-12 membered aryl, 5-12 membered heteroaryl, the ring A is optionally substituted by 1 to 4 R a replace; Ring C is independently selected from C 6-12 5-12 membered aryl, 5-12 membered heteroaryl, the ring C is optionally substituted by 1 to 4 R c replace; Ring D is each independently selected from C 3-15 4-15 membered cycloalkyl, 4-15 membered heterocycloalkyl, the ring D is optionally substituted by 1 to 4 R d replace; L is selected from a bond, C 1-6 Alkylene, O, S, NR L NR L C=O、C=ONR L , the alkylene group is optionally substituted by 1 to 4 R k replace; R L Selected from H, deuterium, C 1-6 Alkyl, the alkyl group is optionally substituted by 1 to 4 R k replaced by; R b1 are each independently selected from H, deuterium, C 1-6 Alkyl, -C 0-4 Alkylene-C 3-6 Carbon ring, -C 0-4 Alkylene-3 to 7 membered heterocyclic ring, wherein the alkyl, alkylene, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replaced by; R b2 Selected from deuterium, C 1-6 Alkyl, -C 0-4 Alkylene-C 3-6 Carbon ring, -C 0-4 Alkylene-3 to 7 membered heterocycle, wherein the alkyl, alkylene, carbocycle or heterocycle is optionally substituted by 1 to 4 deuterium, halogen, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent; R b3 Selected from H, deuterium, C 1-6 Alkyl, -C 0-4 Alkylene-C 3-6 Carbon ring, -C 0-4 Alkylene-3 to 7 membered heterocyclic ring, wherein the alkyl, alkylene, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replaced by; R a , R b , R c , R d Each is independently selected from H, deuterium, halogen, OH, =O, CN, NH2, NO2, COOH, CONH2, C(=O)NHCH3, S(=O)2CH3, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, -OC 3-6 Carbocyclic ring, -O-3 to 7 membered heterocyclic ring, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7-membered heterocyclic ring, -SC 3-6 Carbocyclic ring, -S-3 to 7 membered heterocyclic ring, -C 0-4 Alkylene-C 3-6 Carbon ring, -C 0-4 Alkylene-3 to 7 membered heterocyclic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replaced by; R k Each independently selected from deuterium, halogen, OH, =O, CN, NH2, NO2, COOH, CONH2, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, -OC 3-6 Carbocyclic ring, -O-3 to 7 membered heterocyclic ring, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7-membered heterocyclic ring, -SC 3-6 Carbocyclic ring, -S-3 to 7 membered heterocyclic ring, -C 0-4 Alkylene-C 3-6 Carbon ring, -C 0-4 Alkylene-3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent; The condition is, The compound is not of the following structure:

2. The compound according to claim 1 or its stereoisomer, tautomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, In the compound represented by general formula (I): R x1 , R x2 are each independently selected from H, deuterium, halogen, cyano, OH, NH2, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, C 3-6 Cycloalkyl, 4 to 7 membered heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R k replace; R 1 is selected from phenyl, 5- to 6-membered heteroaryl, 8- to 10-membered bicyclic heteroaryl, 9- to 14-membered tricyclic heteroaryl, 8- to 10-membered cycloheterocyclyl, 9- to 14-membered tricyclic heterocyclyl, benzoC 4-6 Carbocyclic group, benzo 4 to 6 membered heterocyclic group, said R 1 Optional 1 to 6 R 1a replace; Ring D is selected from 4 to 6 membered heterocycloalkyl, said ring D being optionally substituted with 1 to 4 R d replace; Ring B is selected from a 5- to 6-membered heterocyclic group containing 1 to 2 nitrogen heteroatoms, and the ring B is optionally substituted by 1 to 2 R b replace; K5 is selected from N; Ring Y is selected from an unsaturated 9- to 13-membered heterocyclic ring, which is optionally substituted by 1 to 4 R y replace; Ring C is selected from phenyl, 5- to 6-membered heteroaryl, 8- to 10-membered heteroaryl, benzo 4-6 Carbocyclyl, benzo 4- to 6-membered heteroaryl; R y Each independently selected from deuterium, halogen, =O, CN, OH, C 1-4 Alkyl, -OC 1-4 Alkyl, C 3-6 Carbocyclic group, 4 to 7 membered heterocyclic group, C 1-2 Alkylene-C 3-6 Cycloalkyl, -C 1-2 Alkylene-4 to 7 membered heterocycloalkyl, wherein the alkyl, alkylene, carbocyclyl, heterocyclylcycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R k replace; R 1a , R 2b , R a , R b , R c , R d , R e Each independently selected from deuterium, halogen, =O, CN, OH, NO2, COOH, CONH2, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -C 1-2 Alkylene-NHC 1-4 Alkyl, -C 1-2 Alkylene-N(C 1-4 Alkyl)2, -C 1-2 Alkylene-N(C 1-4 Alkyl)-C 3-6 Cycloalkyl, -C 1-2 Alkylene-N(C 1-4 alkyl)-4 to 7 membered heterocycloalkyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 Cycloalkyl, -O-4 to 7 membered heterocycloalkyl, -NH-C 3-6 Cycloalkyl, -NH-4 to 7 membered heterocycloalkyl, -C 1-2 Alkylene-C 3-6 Cycloalkyl, -C 1-2 Alkylene-4 to 7 membered heterocycloalkyl, C 3-6 The alkyl, alkylene, alkenyl, alkynyl, carbocyclyl, heterocyclylcycloalkyl or heterocycloalkyl group is optionally substituted by 1 to 4 R k replace; R 3 Selected from H, halogen, C 1-4 Alkyl, the alkyl group is optionally substituted by 1 to 4 R k replace; R 4 Selected from H, halogen, C 1-4 Alkyl, the alkyl group is optionally substituted by 1 to 4 R k replace; R k Each independently selected from deuterium, halogen, =O, CN, OH, SH, CONH2, NH2, SF5, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, 4- to 7-membered heterocycloalkyl, -C 1-2 Alkylene-C 3-6 Cycloalkyl, -C 1-4 Alkylene-4 to 7 membered heterocycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl, heterocyclylcycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; R 1A is selected from 8- to 10-membered bicyclic heteroaryl or partially saturated 8- to 10-membered bicyclic heterocyclic group, wherein R 1A Optional 1 to 6 R 1a replace; In the compound represented by general formula (II): Ring B is selected from Its left side is connected to L, and the ring B is optionally substituted by 1 to 4 R b replace; Ring A is independently selected from phenyl, naphthyl, 5-10 membered heteroaryl, and the ring A is optionally substituted by 1 to 4 R a replace; Ring C is independently selected from phenyl, naphthyl, 5-10 membered heteroaryl, and the ring C is optionally substituted by 1 to 4 R c replace; Ring D is independently selected from C 3-10 4-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, the ring D is optionally substituted by 1 to 4 R d replace; L is selected from a bond, C 1-4 Alkylene, O, S, NR L NR L C=O、C=ONR L , the alkylene group is optionally substituted by 1 to 4 R k replace; R L Selected from H, deuterium, C 1-4 Alkyl, the alkyl group is optionally substituted by 1 to 4 R k replaced by; R b1 are each independently selected from H, deuterium, C 1-4 Alkyl, -C 0-2 Alkylene-C 3-6 Carbon ring, -C 0-2 Alkylene-3 to 7 membered heterocyclic ring, wherein the alkyl, alkylene, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replaced by; R b2 Selected from deuterium, C 1-4 Alkyl, -C 0-2 Alkylene-C 3-6 Carbon ring, -C 0-2 Alkylene-3 to 7 membered heterocycle, wherein the alkyl, alkylene, carbocycle or heterocycle is optionally substituted by 1 to 4 deuterium, halogen, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent; R b3 Selected from H, deuterium, C 1-4 Alkyl, -C 0-2 Alkylene-C 3-6 Carbon ring, -C 0-2 Alkylene-3 to 7 membered heterocyclic ring, wherein the alkyl, alkylene, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replaced by; R a , R b , R c , R d Each is independently selected from H, deuterium, halogen, OH, =O, CN, NH2, NO2, COOH, CONH2, C(=O)NHCH3, S(=O)2CH3, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -OC 3-62 Carbocyclic ring, -O-3 to 7 membered heterocyclic ring, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7-membered heterocyclic ring, -SC 3-6 Carbocyclic ring, -S-3 to 7 membered heterocyclic ring, -C 0-2 Alkylene-C 3-6 Carbon ring, -C 0-2 Alkylene-3 to 7 membered heterocyclic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replaced by; R k Each independently selected from deuterium, halogen, OH, =O, CN, NH2, NO2, COOH, CONH2, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -OC 3-6 Carbocyclic ring, -O-3 to 7 membered heterocyclic ring, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7-membered heterocyclic ring, -SC 3-6 Carbocyclic ring, -S-3 to 7 membered heterocyclic ring, -C 0-2 Alkylene-C 3-6 Carbon ring, -C 0-2 Alkylene-3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 The alkoxy group is substituted with an alkoxy substituent.

3. The compound according to claim 2, or a stereoisomer, tautomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, In the compound represented by general formula (I): X1 is selected from N or CH; X2 is selected from N or CH; R 1 is selected from phenyl, 5- to 6-membered heteroaryl, 5- and 5-membered heteroaryl, 5- and 6-membered heteroaryl, 5- and 5-membered partially saturated heterocyclic group, 5- and 6-membered partially saturated heterocyclic group, 5- and 7-membered partially saturated heterocyclic group, 9- to 14-membered tricyclic heteroaryl, 9- to 14-membered tricyclic heterocyclic group, wherein the heteroaryl or heterocyclic group contains 1 to 4 nitrogen atoms, and R 1 Optional 1 to 6 R 1a replace; Selected from Q is selected from a bond, CH2, NH or O; Selected from Ring C is selected from phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, thienyl, pyrazolyl, pyrrolyl, imidazolyl; Ring E is selected from R 1A is selected from 5- and 5-membered heteroaryl, 5- and 6-membered heteroaryl, 5- and 5-membered partially saturated heterocyclic group, 5- and 6-membered partially saturated heterocyclic group, and 5- and 7-membered partially saturated heterocyclic group, wherein R 1A Optional 1 to 6 R 1a replace; In the compound represented by general formula (II): Ring A is each independently selected from phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzopyrrolyl, benzopyrazolyl, benzimidazolyl, benzopyridinyl, benzopyrimidinyl, benzopyridazinyl, benzopyrazinyl, benzofuranyl, benzothienyl, pyridopyrrolyl, pyridopyrazolyl, pyridoimidazolyl, pyridopyrimidinyl, pyridopyrazinyl, pyridopyridinyl, pyridothiazolyl, pyrrolothienyl, pyrrolothiazolyl, pyrrolopyrrolyl, imidazothienyl, and the ring A is optionally substituted by 1 to 4 R a replace; Ring C is each independently selected from phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzopyrrolyl, benzopyrazolyl, benzimidazolyl, benzopyridinyl, benzopyrimidinyl, benzopyridazinyl, benzopyrazinyl, benzofuranyl, benzothienyl, pyridopyrrolyl, pyridopyrazolyl, pyridoimidazolyl, pyridopyrimidinyl, pyridopyrazinyl, pyridopyridinyl, pyridothiazolyl, pyrrolothienyl, pyrrolothiazolyl, pyrrolopyrrolyl, imidazothienyl, and the ring C is optionally substituted by 1 to 4 R c replace; Ring D is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, oxetanyl, and said ring D is optionally substituted by 1 to 4 R d replace; L is selected from a bond, methyl, ethyl, O, S, NR L NR L C=O、C=ONR L , the alkylene group is optionally substituted by 1 to 4 R k replace; R L is selected from H, deuterium, methyl, ethyl, the alkyl group is optionally substituted by 1 to 4 R k replaced by; R b1 Each is independently selected from H, deuterium, methyl, ethyl, cyclopropyl, wherein the methyl, ethyl, cyclopropyl is optionally substituted by 1 to 4 R k replaced by; R b2 is selected from deuterium, methyl, ethyl, cyclopropyl, wherein the methyl, ethyl, cyclopropyl is optionally substituted with 1 to 4 deuterium, halogen, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent; R b3 is selected from H, deuterium, methyl, ethyl, cyclopropyl, wherein the methyl, ethyl, cyclopropyl is optionally substituted by 1 to 4 R k replaced by; R a , R b , R c , R d Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, CN, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl is optionally replaced by 1 to 4 R k replaced by; R k each independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, =O, CN, OH, NH2, C 1-4 Alkyl, C 1-4 The alkoxy group is substituted with an alkoxy substituent.

4. The compound according to claim 3 or its stereoisomer, tautomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein In the compound represented by general formula (I): R 1 Selected from The R 1 Optional 1 to 6 R 1a replace; R 1A Selected from The R 1A Optional 1 to 6 R 1a replace; Selected from R c1 Selected from -CH2NHCH3, -CH2NHCH2CH3, -CH2N(CH3)2, -CH2N(CH2CH3)2, -CH2N(CH3)CH2CH3, -CH2N(CH3)-cyclopropyl, The CH2, methyl, ethyl, cyclopropyl, Optional 1 to 4 R k replace; R 3 Selected from H or F; R 4 Selected from H or F; R 1a , R 2b , R a , R b , R c2 , R d , R e each independently selected from deuterium, F, Cl, Br, I, =O, CN, OH, NO2, COOH, CONH2, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-azetidinyl, -CH2-oxetanyl, wherein the methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl is optionally substituted by 1 to 4 R k replace; R k each independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, =O, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; In the compound represented by general formula (II): Ring B is selected from Its left side is connected to L, and the ring B is optionally substituted by 1 to 4 R b replace; Ring A is independently selected from phenyl, The ring A is optionally substituted with 1 to 4 R a replace; Ring C is independently selected from phenyl, pyridyl, and the ring C is optionally substituted by 1 to 4 R c replace; Ring D is each independently selected from The ring D is optionally substituted with 1 to 4 R d replace; L is selected from a bond, a methyl group, an ethyl group; R a , R b , R c , R d Each is independently selected from H, deuterium, F, Cl, Br, I, OH, =O, CN, NH2, NHCH3, N(CH3)2, CF3, CHF2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, 5. The compound according to claim 4 or its stereoisomer, tautomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein In the compound represented by general formula (I): R 1 Selected from The R 1 Optional 1 to 4 R 1a replace; R 1A Selected from The R 1A Optional 1 to 4 R 1a replace; R 1a Each independently selected from deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, methyl or ethyl; R 2 Selected from R c1 Selected from -CH2NHCH3, -CH2NHCH2CH3, -CH2N(CH3)2, -CH2N(CH2CH3)2, -CH2N(CH3)CH2CH3, -CH2N(CH3)-cyclopropyl, The CH2, methyl, ethyl, cyclopropyl, Optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, methyl, ethyl, -CH2OH; R a Each independently selected from deuterium, F, Cl, Br, I, CN, OH, methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, ethoxy, wherein the methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, ethoxy is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, methyl, ethyl; R e Each independently selected from deuterium, F, Cl, Br, I, =O, CN, OH, methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, ethoxy, wherein the methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, ethoxy is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, methyl, ethyl; X1 is selected from CH; X2 is selected from CH; R 3 Selected from H; R 4 Selected from H.

6. The compound according to claim 1 or its stereoisomer, tautomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from the structures shown in Table E or Table E-1.

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 or a stereoisomer, tautomer, racemate, 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 6 or a stereoisomer, tautomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

8. Use of the compound according to any one of claims 1 to 6 or its stereoisomer, tautomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, or the pharmaceutical composition according to claim 7 in the preparation of a medicament for treating a disease associated with HPK1 kinase activity or expression.

9. The use according to claim 8, characterized in that: The disease is selected from tumors.

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