Methionine adenosine transferase 2A inhibitor and medical application thereof

Abstract

The present invention relates to a compound, the compound is a compound represented by a formula (I), or an isomer, an isotope derivative, a polymorphic substance, a prodrug, a pharmaceutically acceptable salt or a solvate (I) thereof, and the definitions of A, B and C are the same as the definitions in the specification. Also provided are pharmaceutical compositions and compounds of formula (I) for use in methods of treating related diseases by inhibition of MAT2A, including some cancers in which a gene encoding a methylthioadenosine phosphorylase (MTAP) is deleted and / or not fully functioning.

Description

A methionine adenosyltransferase 2A inhibitor and its medical use Technical Field

[0001] The present invention belongs to the technical field of drug synthesis and relates to a methionine adenosyltransferase 2A inhibitor, a pharmaceutical composition containing the inhibitor and pharmaceutical uses thereof, in particular, use thereof in the preparation of anti-tumor drugs. Technical Background

[0002] Methionine adenosyltransferase (MAT), also known as S-adenosylmethionine synthetase, is a cellular enzyme that catalyzes the synthesis of S-adenosylmethionine (SAM or AdoMet) from methionine and ATP and is considered the rate-limiting step in the methionine cycle. SAM is the primary methyl donor for the synthesis of polyamines and glutathione during the methylation of nucleic acids, phospholipids, histones, biogenic amines, and proteins. Therefore, regulating SAM biosynthesis can affect cell growth, differentiation, and function. Studies have shown that tumor cell proliferation and metastasis are extremely dependent on methionine, and inhibiting the methionine cycle can significantly inhibit the proliferation and metastasis of stem cells.

[0003] In mammalian tissues, the MAT gene primarily exists in two distinct isoenzymes, encoded by MAT1 and MAT2. MAT1 is exclusively expressed in the liver, where it maintains the differentiation of hepatocytes and bile duct epithelial cells. MAT2 is ubiquitously expressed in both normal and cancer cells. MAT2 comprises two subunits, MAT2A and MAT2B, which serve as the catalytic and regulatory subunits, respectively. MAT2A is a key enzyme in the SAM biosynthesis pathway. Studies have shown that MAT2A expression is upregulated in various cancer cells, and knocking out the MAT2A gene can lead to cancer cell death. Therefore, MAT2A is an important anti-tumor target.

[0004] Studies have shown that MAT2A is a synthetic lethal target in cancers deficient in methylthioadenosine phosphorylase (MTAP). MTAP (methylthioadenosine phosphorylase) is an enzyme widely expressed in normal tissues that degrades MTA, a byproduct of polyamine synthesis, into adenine and 5-methylthioadenosine-1-phosphate (MTR-1p). Marjon et al. (Cell Reports 15(3)(2016)574-587) reported that MTAP-deficient cancer cell lines are particularly sensitive to inhibition of MAT2A. MTAP is located on chromosome 9P21, adjacent to the tumor suppressor gene CDKN2A. Nearly 15% of human cancers display MTAP gene deletions. MTAP deletions are found not only in tissue culture cells but also in primary leukemias, gliomas, melanomas, pancreatic cancer, non-small cell lung cancer (NSCLC), bladder cancer, astrocytomas, osteosarcomas, head and neck cancer, myxoid chondrosarcomas, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcomas, non-Hodgkin's lymphoma, and mesothelioma. MTAP is a key enzyme in the methionine recycling pathway and the only enzyme known to catalyze the degradation of MTA. Loss of MTAP is thought to lead to MTA accumulation in cancer cells. Increased MTA inhibits protein arginine methyltransferase 5 (PAT5), increasing the sensitivity of PRMT5 to further SAM depletion. Selective inhibition of MAT2A reduces the proliferative activity of MTAP-deficient cancer cells compared to cancer cells expressing normal MTAP. These results suggest that MAT2A inhibitors may provide a novel therapeutic approach for patients with tumors including those with MTAP deletions.

[0005] Summary of the Invention

[0006] The present invention provides a methionine adenosyltransferase 2A (MAT2A) inhibitor and a pharmaceutically acceptable salt thereof. Also disclosed herein are pharmaceutical compositions comprising such compounds and methods for treating diseases treatable by inhibiting MAT2A, such as cancer, including cancers characterized by reduced or absent methylthioadenosine phosphorylase (MTAP) activity.

[0007] The present invention adopts the following technical solution: In the first aspect of the present invention, a compound is provided, which is a compound represented by formula (I-1), or an isomer, isotopic derivative, polymorph, prodrug, pharmaceutically acceptable salt or solvate thereof:

[0008] wherein A1 and B1 are each independently selected from formula (II), (III), (IV), (V), (VI), (VII) and (VIII):

[0009] R1 is absent at each occurrence or is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, C 1-6 Alkyl, -SC 1-6 Alkyl, -S(O)-C 1-6 Alkyl, -S(O2)-C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and -NR 1a R 1b , where R 1a and R 1b are independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, C 3-12 Monocyclic, spirocyclic or bridged cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O, P and S 3-12 Monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 Aryl and C 5-10 Heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 3-12 Monocyclic, spirocyclic or bridged cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O, P and S 3-12 Monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 Aryl, and C 5-10 Heteroaryl is optionally substituted with 0, 1, 2, 3, 4, 5, or 6 substituents independently selected from halogen, deuterium, alkyl, deuterated alkyl, amino, hydroxy, alkylamino, aminoalkyl, cyano, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, and alkoxy; or R 1a and R 1b The nitrogen atom to which it is commonly attached forms a 3-10 membered heterocycloalkyl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkyl is optionally substituted by 0, 1, 2, 3 or 4 heteroatoms independently selected from halogen, deuterium, amino, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Alkyl, cyano, C 1-6 Substitution with aminoalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and hydroxy;

[0010] Each occurrence of Z is independently selected from C and N; when Z is selected from N, R1 is absent;

[0011] R2, R4 and R6 are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)C 1-6 Alkyl, C 1-6 Halogenated alkoxy, C 1-6 Haloalkylamino, hydroxy, C 2-6 alkoxy, 3-12 membered monocyclic cycloalkyl, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monoheterocycloalkyl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S, 5-12 membered spiroheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 4-12 membered bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, -SC 1-6 Alkyl, -SO-C 1-6 Alkyl, -SO2-C 1-6 Alkyl, 3-6 membered cycloalkyl-C 1-6 alkylene, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, 6-10 membered monocyclic aryl, 8-14 membered cycloaryl, 5-12 membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S, and 8-10 membered cycloheteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S; preferably, R2, R4 and R6 are each independently selected from hydrogen, halogen, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Haloalkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)C 1-6 Alkyl, C 1-6 Halogenated alkoxy, C 1-6 Haloalkylamino, 3-6 membered monocyclic cycloalkyl, 3-6 membered monoheterocyclic alkyl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S;

[0012] R5 is selected from hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl and C 1-6 Halogenated alkyl, optionally, the C 1-6 Alkyl, C3-10 Cycloalkyl, C 3-10 Heterocycloalkyl and C 1-6 haloalkyl is substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, aminoalkyl, alkylamino, and alkoxy;

[0013] G1 and G2 are each independently selected from O, S, and NR 2a ;

[0014] E0, E1, E2, E3, E4, E5, E6, E7, E8, E9, M1, M2, M3, M4, M5, M6 and E are independently selected from N and CR at each occurrence 2a , and E7, E8, and E9 are not CR at the same time 2a ;

[0015] R 2a Each occurrence is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, phenylmethylene, -CH2OCH2CH2Si(CH3)3, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl-S-, -S(O)-C 1-6 Alkyl, -SO2-C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -NR 2b R 2c 、-C(O)R 8c 、-C(O)NR 8a R 8b 、-C 1-6 Alkylene-C 3-6 Cycloalkyl, C 3-6 Cycloalkyl-NR 2b -, 3-6 membered heterocycloalkyl-NR containing 1-3 heteroatoms independently selected from N, O, P and S 2b-, 3-12 membered monocyclic heterocycloalkyl, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spiroheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 4-12 membered bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered halogenated heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered cycloalkyl-O-, 3-6 3-6 membered halogenated cycloalkyl, 3-6 membered halogenated cycloalkyl-O-, 3-6 membered halogenated heterocycloalkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered heterocycloalkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S, 6-12 membered monocyclic aryl, 8-12 membered cyclic aryl, 5-12 membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S, and 8-10 membered cyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S; preferably, R 2a Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl-S-, -S(O)-C 1-6 Alkyl, -SO2-C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)C 1-6 Alkyl, C 3-6 Cycloalkyl and -C 1-6 Alkylene-C 3-6 Cycloalkyl; preferably, R 2a Selected from hydrogen, halogen, cyano, hydroxy, amino, C 1-3 Alkyl, C 1-3 Haloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, and C 3-6 Cycloalkyl;

[0016] R 2b and R 2c Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, C 3-12 Cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O, P and S3-12 Heterocycloalkyl, C 6-10 Aryl and C 5-10 Heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 3-12 Cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O, P and S 3-12 Heterocycloalkyl, C 6-10 Aryl, and C 5-10 Heteroaryl is optionally substituted with 0, 1, 2, 3, 4, 5, or 6 substituents independently selected from halogen, deuterium, alkyl, deuterated alkyl, amino, hydroxy, alkylamino, aminoalkyl, cyano, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, and alkoxy; or R 2b and R 2c The nitrogen atom to which it is commonly attached forms a 3-10 membered heterocycloalkyl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkyl is optionally substituted by 0, 1, 2, 3 or 4 heteroatoms independently selected from halogen, deuterium, amino, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Alkyl, cyano, C 1-6 Substituted by aminoalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and hydroxy; preferably R 2b and R 2c are independently selected from hydrogen and C 1-6 alkyl;

[0017] R 8a and R 8b Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, C 3-12 Cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O, P and S 3-12 Heterocycloalkyl, C 6-10 Aryl and C 5-10 Heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 3-12 Cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O, P and S 3-12 Heterocycloalkyl, C 6-10 Aryl, and C 5-10Heteroaryl is optionally substituted with 0, 1, 2, 3, 4, 5, or 6 substituents independently selected from halogen, deuterium, alkyl, deuterated alkyl, amino, hydroxy, alkylamino, aminoalkyl, cyano, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, and alkoxy; or R 8a and R 8b The nitrogen atom to which it is commonly attached forms a 3-10 membered heterocycloalkyl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkyl is optionally substituted by 0, 1, 2, 3 or 4 heteroatoms independently selected from halogen, deuterium, amino, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Alkyl, cyano, C 1-6 Substituted by aminoalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and hydroxy; preferably R 8a and R 8b Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 haloalkyl and phenyl, the phenyl group is optionally substituted by 0-2 groups selected from C 1-4 Alkyl, -OR 8d and-X2-R 8d group substitution;

[0018] R 8c Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, C 3-12 Cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O, P and S 3-12 Heterocycloalkyl, C 6-10 Aryl and C 5-10 Heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 3-12 Cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O, P and S 3-12 Heterocycloalkyl, C 6-10 Aryl, and C 5-10 Heteroaryl is optionally substituted with 0, 1, 2, 3, 4, 5 or 6 substituents independently selected from halogen, deuterium, alkyl, deuterated alkyl, amino, hydroxy, alkylamino, aminoalkyl, cyano, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and alkoxy; preferably R 8c Selected from hydrogen, C 1-6 Alkyl, C 1-6Hydroxyalkyl, C 1-6 aminoalkyl and C 1-6 alkyl halide;

[0019] X2 is selected from C 1-6 Alkylene and C 2-6 alkenylene;

[0020] R 8d Selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0021] J1 and J2 are independently selected from a single bond, O, S, C(O), S(O), S(O2), C(R 1c R 1d ), C(=CR 1e R 1f ) and N(R3), preferably, J1 and J2 are not single bonds at the same time;

[0022] where R 1c 、R 1d 、R 1e and R 1f are independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl, C 3-12 Monocyclic, spirocyclic or bridged cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O, P and S 3-12 Monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 Aryl and C 5-10 Heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Monocyclic, spirocyclic or bridged cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O, P and S 3-12 Monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 Aryl, and C 5-10 Heteroaryl is optionally substituted by 0, 1, 2, 3, 4, 5 or 6 independently selected from halogen, deuterium, C 1-6 Alkyl, amino, hydroxyl, C 1-6 Alkylamino, C 1-6 aminoalkyl, cyano, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and C 1-6 Alkoxy is substituted by a substituent; or R 1c and R 1dThe carbon atoms to which they are connected together form a 3-10 membered cycloalkylene or a 3-10 membered heterocycloalkylene containing 1-3 heteroatoms independently selected from N, O, P and S, wherein the cycloalkylene or heterocycloalkylene is optionally substituted by 0, 1, 2, 3 or 4 atoms independently selected from halogen, deuterium, amino, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 The aminoalkyl group and the hydroxy group are substituted; or R 1e and R 1f The carbon atoms to which they are connected together form a 3-10 membered cycloalkylene or a 3-10 membered heterocycloalkylene containing 0, 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S, wherein the cycloalkylene or heterocycloalkylene is optionally substituted by 0, 1, 2, 3 or 4 heteroatoms independently selected from halogen, deuterium, amino, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Alkyl, cyano, C 1-6 aminoalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and hydroxyl; R3 is -X1-R8, X1 is selected from a single bond, -O-, -S-, C 1-6 Alkyleneoxy, C 2-6 Alkenylene and C 1-6 Alkylene; R8 is selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, -NR 8a R 8b 、-C(O)R 8c 、-C(O)NR 8a R 8b 、C 3-12 Cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O, P and S 3-12 Heterocycloalkyl, and 5-10 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S;

[0023] Linker C is the linker connecting A1 and B1, which is -L a -L b -L c -L d -L e -;

[0024] L a , L c , and L e Each occurrence is independently selected from -(L) n -;

[0025] n is selected from 1, 2, 3, 4, 5 and 6;

[0026] L is independently selected at each occurrence from a single bond, -O-, -S-, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 1-6 Haloalkylene, -N(R L6 )C(O)-、-N(R L6 )S(O)-、-N(R L6 )S(O2)-, -C(O)-, -OC(O)-, -NR L6 -, -S(O)-, -S(O2)-, -S(O2)NR L6 -、-CR L1 R L2 -, and C 1-6 Alkylene hydroxyl group, optionally, the C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, and C 1-6 Each haloalkylene group is independently substituted with 0, 1, 2, 3, 4, 5 or 6 substituents independently selected from halogen, deuterium, alkyl, deuterated alkyl, amino, hydroxy, alkylamino, aminoalkyl, cyano, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and alkoxy; preferably, each occurrence of L is independently selected from a single bond, -O-, -S-, C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylidene, -CR L1 R L2 -、-C(O)N(R L6 )-、-C(O)-、-OC(O)-、-NR L6 -, -S-, -S(O)-, and -S(O2)-, optionally, the C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, and C 1-6 each haloalkylene group is independently substituted with 0, 1, 2, 3, 4, 5, or 6 substituents independently selected from the group consisting of halogen, deuterium, alkyl, deuterated alkyl, amino, hydroxy, alkylamino, aminoalkyl, cyano, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, and alkoxy;

[0027] R L6 Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, C 3-12Cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O, P and S 3-12 Heterocycloalkyl, C 6-10 Aryl and C 5-10 Heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 3-12 Cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O, P and S 3-12 Heterocycloalkyl, C 6-10 Aryl, and C 5-10 The heteroaryl group is optionally substituted with 0, 1, 2, 3, 4, 5 or 6 substituents independently selected from halogen, deuterium, alkyl, deuterated alkyl, amino, hydroxy, alkylamino, aminoalkyl, cyano, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and alkoxy; preferably, R L6 Each occurrence is independently selected from hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl and C 1-6 Halogenated alkyl, optionally, the C 1-6 Alkyl, C 3-10 Cycloalkyl and C 1-6 haloalkyl is substituted with 0, 1, 2, 3, 4, 5, or 6 substituents independently selected from the group consisting of halogen, deuterium, alkyl, amino, hydroxy, aminoalkyl, alkylamino, and alkoxy;

[0028] R L1 and R L2 Each occurrence is independently selected from hydrogen, deuterium, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, -X L -OR L3 、-X L -NR L4 R L5 、C 1-6 Deuterated alkyl, C 3-12 Cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O, P and S 3-12 Heterocycloalkyl, C 6-10 Aryl and C 5-10 Heteroaryl, preferably R L1 and R L2 Each occurrence is independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -X L -OR L3 、-X L -NR L4 RL5 and C 3-10 Cycloalkyl; or R L1 and R L2 The carbon atoms to which they are commonly attached form a 3-10 membered cycloalkylene or a 3-10 membered heterocycloalkylene containing 1, 2 or 3 heteroatoms independently selected from N, O, P and S, wherein the cycloalkylene or heterocycloalkylene is optionally substituted by 0, 1, 2, 3 or 4 heteroatoms independently selected from halogen, deuterium, amino, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 The substituents of aminoalkyl and hydroxy are substituted; preferably, R L1 and R L2 and the carbon to which it is connected form a 3-10 membered cycloalkylene group;

[0029] X L Each occurrence is independently selected from C 1-6 Alkylene and C2-C6 alkenylene;

[0030] R L3 Selected from hydrogen, deuterium, C 1-6 Alkyl and C 1-6 alkyl halide;

[0031] R L4 and R L5 are independently selected from hydrogen, deuterium, C 1-6 Alkyl and C 1-6 alkyl halide;

[0032] L b , and L d Each occurrence is independently selected from a single bond, cycloalkylene, cycloalkenylene, heterocycloalkylene, arylene, heteroarylene, and fused heterocycloalkylene, said cycloalkylene, cycloalkenylene, heterocycloalkylene, arylene, heteroarylene, and fused heterocycloalkylene, which may be optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R9; preferably, L b , L d Each occurrence is independently selected from a single bond, phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1-4 heteroatoms independently selected from N, O, P and S, 3-7 membered heterocycloalkenylene, 5-6 membered heteroarylene and 4-12 membered fused heterocycloalkylene, said phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1-4 heteroatoms independently selected from N, O, P and S, 5-6 membered heteroarylene and 4-12 membered fused heterocycloalkylene optionally substituted with 0-6 R9; preferably and L a , L b , L c , L d , and L eNot all are single bonds;

[0033] Each occurrence of R9 is independently selected from halogen, deuterium, alkyl, haloalkyl, cyano, cycloalkyl, heterocycloalkyl, -S(O2)R 9a 、-NR 9b R 9c 、-X4-NR 9b R 9c 、-OR 9a AND-X4-OR 9a Preferably, R9 is independently selected from halogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, C 3-6 Cycloalkyl, C3-7 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S, -S(O2)R 9a 、-NR 9b R 9c 、-X4-NR 9b R 9c 、-OR 9a AND-X4-OR 9a Preferably, each occurrence of R9 is independently selected from F, Cl, Br, I, C 1-3 Alkyl, and C 1-3 alkyl halide;

[0034] R 9a 、R 9b and R 9c Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, C 3-12 Cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O, P and S 3-12 Heterocycloalkyl, C 6-10 Aryl and C 5-10 Heteroaryl; preferably, R 9a 、R 9b and R 9c Each occurrence is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0035] X4 selected from C 1-6 Alkylene and C 2-6 alkenylene;

[0036] When L b and L dWhen each independently represents a phenylene group, or a 5-membered heteroarylene group containing 1 or 2 heteroatoms selected from N and S, L a and L e At least one of them is not a single bond, or when L a and L e When both are single bonds, L c Selected from -S-, C 2-6 Alkylene, C 2-6 Alkyleneoxy, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 1-6 Haloalkylene, -N(R L6 )S(O)-、-N(R L6 )S(O2)-, -OC(O)-, -S(O)-, -S(O2)-, -S(O2)NR L6 -, - and C 1-6 Alkylene hydroxyl group, optionally, the C 2-6 Alkylene, C 2-6 Alkyleneoxy, C 2-6 Alkenylene, C 2-6 Alkynylidene, and C 1-6 each haloalkylene group is independently substituted with 0, 1, 2, 3, 4, 5, or 6 substituents independently selected from the group consisting of halogen, deuterium, alkyl, deuterated alkyl, amino, hydroxy, alkylamino, aminoalkyl, cyano, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, and alkoxy;

[0037] When Linker C is an aliphatic chain, Linker C is an optionally substituted -C8H 16 -, preferably optionally substituted -(CH2)8-, preferably -(CH2)8-;

[0038] When L b , L d When one of them is a phenylene group or a 6-membered heteroarylene group containing 3 N atoms and the other is a single bond, L a , and L e are not simultaneously single bonds; and

[0039] When A1 and B1 are both of formula (V), and L a , and L e When it is not a single bond, L a , and L e At least one is not -O-.

[0040] In some embodiments, wherein Linker C is selected from Formula (IX), (X), (XI), and (XII):

[0041] R 7a and R7b are independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -X3-OR 7c 、-X3-NR 7d R 7e and C 3-10 Cycloalkyl; X3 each occurrence is independently selected from C 1-6 Alkylene and C2-C6 alkenylene; R 7c Selected from hydrogen, deuterium, C 1-6 Alkyl and C 1-6 Haloalkyl; R 7d and R 7e are independently selected from hydrogen, deuterium, C 1-6 Alkyl and C 1-6 haloalkyl; or R 7a and R 7b and the carbon to which it is connected constitutes a 3-10 membered cycloalkyl group;

[0042] R 7a and R 7b Each occurrence is independently selected from hydrogen, deuterium, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, -X L -OR L3 、-X L -NR L4 R L5 、C 1-6 Deuterated alkyl, C 3-12 Cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O, P and S 3-12 Heterocycloalkyl, C 6-10 Aryl and C 5-10 Heteroaryl, preferably R L1 and R L2 Each occurrence is independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -X L -OR L3 、-X L -NR L4 R L5 and C 3-10 Cycloalkyl; or R 7a and R 7b The carbon atoms to which they are commonly attached form a 3-10 membered cycloalkylene or a 3-10 membered heterocycloalkylene containing 1, 2 or 3 heteroatoms independently selected from N, O, P and S, wherein the cycloalkylene or heterocycloalkylene is optionally substituted by 0, 1, 2, 3 or 4 heteroatoms independently selected from halogen, deuterium, amino, C1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 The substituents of aminoalkyl and hydroxy are substituted; preferably, R 7a and R 7b and the carbon to which it is connected form a 3-10 membered cycloalkylene group;

[0043] X L Each occurrence is independently selected from C 1-6 Alkylene and C2-C6 alkenylene;

[0044] R L3 Selected from hydrogen, deuterium, C 1-6 Alkyl and C 1-6 alkyl halide;

[0045] R L4 and R L5 are independently selected from hydrogen, deuterium, C 1-6 Alkyl and C 1-6 alkyl halide;

[0046] W is selected from the following groups:

[0047] Each occurrence of the Q ring and the R ring is independently selected from phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S, 3-7 membered heterocycloalkenylene, 5-6 membered heteroarylene and 4-12 membered fused heterocycloalkylene, said phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1-4 heteroatoms independently selected from N, O, P and S, 5-6 membered heteroarylene and 4-12 membered fused heterocycloalkylene, optionally substituted with 0-6 R9;

[0048] Each occurrence of R9 is independently selected from halogen, deuterium, alkyl, haloalkyl, cyano, cycloalkyl, heterocycloalkyl, -S(O2)R 9a 、-NR 9b R 9c 、-X4-NR 9b R 9c 、-OR 9a AND-X4-OR 9a Preferably, R9 is independently selected from halogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, C 3-6 Cycloalkyl, C3-7 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S, -S(O2)R 9a 、-NR 9b R 9c 、-X4-NR9b R 9c 、-OR 9a AND-X4-OR 9a Preferably, each occurrence of R9 is independently selected from F, Cl, Br, I, C 1-3 Alkyl, and C 1-3 Haloalkyl;

[0049] R 9a 、R 9b and R 9c Each occurrence is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0050] X4 selected from C 1-6 Alkylene and C 2-6 alkenylene;

[0051] Each occurrence of the T ring and the U ring is independently selected from phenylene, pyridinylene, pyrimidinylene and pyrazinylene, wherein the phenylene, pyridinylene, pyrimidinylene and pyrazinylene are optionally substituted by 0, 1, 2 or 3 groups independently selected from cyano, halogen, amino, alkylamino, aminoalkyl, hydroxy, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 Alkyl, C 3-6 Heterocycloalkyl, and C 3-6 The cycloalkyl group is substituted, preferably, by a substituent selected from F, Cl, Br, I, C 1-3 Alkyl, and C 1-3 Substitution with a haloalkyl substituent;

[0052] L1 is selected from the following groups:

[0053] L2 is selected from the following groups:

[0054] wherein Y1, Y2, Y3, Y4, Y5, Y6, and Y7 are each independently selected from -O-, -NH-, -NHC(O)-, -NHS(O)-, -NHS(O2)-, -CH2-, -C(O)-, -S(O)-, -S(O2)-, -C(O)NH-, -S(O2)NH-, -CH=CH-, -C≡C-, and a single bond;

[0055] a is selected from 0, 1, 2, 3, 4 and 5; b and c are independently selected from 0, 1, 2 and 3; d and e are independently selected from 0, 1 and 2;

[0056] L3 is selected from the following groups:

[0057] Y8, Y9, Y 10、Y 11 and Y 12 Each independently selected from -O-, -NH-, -NHC(O)-, -NHS(O)-, -NHS(O2)-, -CR Y1 R Y2 -, -C(O)-, -S(O)-, -S(O2)-, -C(O)NH-, -S(O2)NH-, -CH=CH-, -C≡C-, a single bond, a phenylene group, a 3-6 membered heterocycloalkylene group containing 1-4 heteroatoms independently selected from N, O, P and S, and a 5-6 membered heteroarylene group containing 1-4 heteroatoms independently selected from N, O, P and S;

[0058] R Y1 and R Y2 Each occurrence is independently selected from hydrogen and C 1-6 Alkyl, or R Y1 and R Y2 The C to which it is attached forms a 3-6 membered cycloalkylene or 3-6 membered heterocycloalkylene; and f, g, h, i and j are independently selected from 0, 1, 2 and 3. 3. The compound according to claim 1 or 2, wherein:

[0059] R1 is absent at each occurrence or is independently selected from hydrogen, deuterium, F, Cl, Br, I, cyano, hydroxy, amide, sulfonamide, C 1-3 Alkyl, -SC 1-3 Alkyl, -S(O)-C 1-3 Alkyl, -S(O2)-C 1-3 Alkyl, -OC 1-3 Alkyl, -OC 1-3 Halogenated alkyl, C 1-3 Deuterated alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl and -NR 1a R 1b , where R 1a and R 1b are independently selected from hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Deuterated alkyl, C 3-6 Monocyclic cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O, P and S 3-6 Monocyclic heterocycloalkyl, C 6-10 Aryl and C 5-10 Heteroaryl, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 3-6Monocyclic cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O, P and S 3-6 Monocyclic heterocycloalkyl, C 6-10 Aryl, and C 5-10 Heteroaryl is optionally substituted by 0, 1, 2, 3, 4, 5 or 6 atoms independently selected from F, Cl, Br, I, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, amino, hydroxyl, C 1-3 Alkylamino, C 1-3 aminoalkyl, cyano, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl and C 1-3 Alkoxy is substituted by a substituent; or R 1a and R 1b The nitrogen atom to which it is commonly attached forms a 3-6 membered heterocycloalkyl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkyl is optionally substituted by 0, 1, 2, 3 or 4 heteroatoms independently selected from F, Cl, Br, I, deuterium, amino, C 1-3 Alkoxy, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Alkyl, cyano, aminoalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl and hydroxyl groups are substituted; and / or

[0060] Each occurrence of Z is independently selected from C and N; and when Z is N, R1 is absent; and / or

[0061] R2, R4 and R6 are each independently selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C 2-3 Alkoxy, C 1-3 haloalkyl, 3-6 membered monocyclic cycloalkyl, 3-6 membered monocyclic heterocyclic alkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, and 3-12 membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S; preferably, R2, R4 and R6 are each independently selected from hydrogen, deuterium, chlorine, fluorine, Br, C 1-3 Alkyl, 3-6 membered monocyclic cycloalkyl, and 3-6 membered monoheterocyclic alkyl containing 1-3 heteroatoms independently selected from N, O, P and S; and / or

[0062] R5 is selected from hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl and C 1-4 haloalkyl; optionally, the C 1-4 Alkyl, C 3-6 Cycloalkyl and C1-4 Haloalkyl is substituted with 0-6 independently selected from halogen, deuterium, C 1-4 Alkyl, amino, hydroxyl, and C 1-4 Alkoxy is substituted by a substituent; preferably, R5 is selected from hydrogen, C 1-3 Alkyl and C 3-6 Cycloalkyl, optionally, the C 1-3 Alkyl, and C 3-6 Cycloalkyl is substituted by 0-6 independently selected from halogen, deuterium, C 1-6 Alkyl, amino and hydroxy substituents; More preferably, R5 is selected from H and C 1-3 Alkyl; and / or

[0063] Each occurrence of G1 and G2 is selected from O, S, and NR 2a and / or

[0064] R 2a Each occurrence is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, phenylmethylene, -CH2OCH2CH2Si(CH3)3, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkyl-S-, -S(O)-C 1-3 Alkyl, -SO2-C 1-3 Alkyl, -OC 1-3 Alkyl, -OC 1-3 Halogenated alkyl, -NR 2b R 2c 、-C 1-3 Alkylene-C 3-6 Cycloalkyl, C 3-6 Cycloalkyl-NR 2b -, 3-6 membered heterocycloalkyl-NR containing 1-3 heteroatoms independently selected from N, O, P and S 2b -, 3-6 membered monocyclic alkyl, 3-6 membered monocyclic heterocyclic alkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered halogenated heterocyclic alkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered cycloalkyl-O-, 3-6 membered halogenated cycloalkyl, 3-6 membered halogenated cycloalkyl-O-, 3-6 membered halogenated heterocyclic alkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered heterocyclic alkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S, 6-10 membered monocyclic aryl, 5-6 membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S, and 8-10 membered cyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S; preferably, R 2aSelected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, amino, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkyl-S-, -S(O)-C 1-3 Alkyl, -SO2-C 1-3 Alkyl, -OC 1-3 Alkyl, -OC 1-3 Haloalkyl, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)C 1-3 Alkyl, C 3-6 Cycloalkyl and -C 1-3 Alkylene-C 3-6 Cycloalkyl; preferably, R 2a Selected from hydrogen, F, Cl, Br, I, cyano, hydroxy, amino, C 1-3 Alkyl, C 1-3 Haloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, and C 3-6 Cycloalkyl; R 2b and R 2c are independently selected from hydrogen and C 1-6 Alkyl; and / or

[0065] J1 and J2 are independently selected from a single bond, -O-, -S-, -C(O)-, -S(O)-, -S(O2)-, -C(R 1c R 1d )-、-C(=CR 1e R 1f )- and -N(R3)-; preferably, J1 and J2 are not single bonds at the same time; wherein R 1c 、R 1d 、R 1e and R 1f are independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl, C 3-12 Monocyclic, spirocyclic or bridged cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O, P and S 3-12 Monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 Aryl and C 5-10 Heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Monocyclic, spirocyclic or bridged cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O, P and S 3-12 Monocyclic, spirocyclic or bridged heterocycloalkyl, C6-10 Aryl, and C 5-10 Heteroaryl is optionally substituted by 0, 1, 2, 3, 4, 5 or 6 independently selected from halogen, deuterium, C 1-6 Alkyl, amino, hydroxyl, C 1-6 Alkylamino, C 1-6 aminoalkyl, cyano, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and C 1-6 Alkoxy is substituted by a substituent; or R 1c and R 1d The carbon atoms to which they are connected together form a 3-10 membered cycloalkylene or a 3-10 membered heterocycloalkylene containing 1-3 heteroatoms independently selected from N, O, P and S, wherein the cycloalkylene or heterocycloalkylene is optionally substituted by 0, 1, 2, 3 or 4 atoms independently selected from halogen, deuterium, amino, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 The aminoalkyl group and the hydroxy group are substituted; or R 1e and R 1f The carbon atoms to which they are connected together form a 3-10 membered cycloalkylene or a 3-10 membered heterocycloalkylene containing 0, 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S, wherein the cycloalkylene or heterocycloalkylene is optionally substituted by 0, 1, 2, 3 or 4 heteroatoms independently selected from halogen, deuterium, amino, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Alkyl, cyano, C 1-6 Substituted with aminoalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and hydroxy; and / or

[0066] R3 is -X1-R8, X1 is selected from a single bond, -O-, -S-, C 1-3 Alkyleneoxy, C 2-3 Alkenylene and C 1-3 Alkylene; R8 is selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 6-10 Aryl, -NR 8a R 8b 、-C(O)R 8c 、-C(O)NR 8a R 8b 、C 3-6 Cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O, P and S 3-6 heterocycloalkyl, and 5-10 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S.

[0067] In some embodiments, the Q ring, R ring, L b and L d Each occurrence is independently selected from the following groups:

[0068] In some embodiments, the compound is selected from the following structures:

[0069] In some embodiments, the compound is selected from the following structures:

[0070] Wherein, A, B, Linker C, and formulas (II) to (XII) are as defined in any one of claims 1 to 8.

[0071] In some embodiments, Linker C is selected from the following structures:

[0072] 1. A compound, wherein the compound is a compound represented by formula (I), or an isomer, isotopic derivative, polymorph, prodrug, pharmaceutically acceptable salt or solvate thereof:

[0073] wherein Ring A and Ring B are independently selected from Formula (II), (III) and (IV):

[0074] Wherein Linker C is a linker connecting Ring A and Ring B, selected from Formula (V), (VI) and (VII):

[0075] Among them, R 1a 、R 1b 、R 1c and R 1d are independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 Monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 Aryl and C 5-10 Heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 Monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 Aryl, and C 5-10 Heteroaryl is optionally substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, alkylamino, aminoalkyl, and alkoxy; or R1a and R 1b and the nitrogen atom to which they are attached together form a 3-10 membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted with 0-3 substituents independently selected from halogen, deuterium, amino, alkoxy, alkylamino, aminoalkyl and hydroxy; or R 1c and R 1d and the nitrogen atom to which they are attached together form a 3-10 membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted with 0-3 substituents independently selected from halogen, deuterium, amino, alkoxy, aminoalkyl and hydroxy;

[0076] R2, R4 and R6 are independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Monoalkylamino, C 2-6 Dialkylamino, C 1-6 haloalkylamino, 3-12 membered monocyclic cycloalkyl, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monoheterocycloalkyl, 5-12 membered spiroheterocycloalkyl and 4-12 membered bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 1-6 Alkyl-S-, C 1-6 Alkyl-SO-, C 1-6 Alkyl-SO2-, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, 5-10 membered monocyclic aryl, 5-10 membered cycloheteroaryl, and 3-12 membered monocyclic heteroaryl and 7-10 membered cycloheteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S;

[0077] R5 is selected from hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl and C 1-6 Halogenated alkyl, optionally, the C 1-6 Alkyl, C 3-10 Cycloalkyl and C 1-6 haloalkyl is substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, aminoalkyl, alkylamino, and alkoxy;

[0078] Each occurrence of E, G, J and Z is independently selected from N and CR 2a ; where R 2a Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl-S-, C 1-6 Alkyl-SO-, C 1-6 Alkyl-SO2-, C1-6 Alkyl-O-, C 1-6 Haloalkyl-O-, -NR 2b R 2c 、C 3-6 Cycloalkylamino, 3-6 membered heterocycloalkylamino containing 1-3 heteroatoms independently selected from N, O, P and S, 3-12 membered monocyclic alkyl, 5-12 membered spirocycloalkyl and 4-12 membered bridged cycloalkyl, 3-12 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spirocycloheterocycloalkyl and 4-12 membered bridged heterocycloalkyl, 3-6 membered halogenated heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered cyclic alkyl-O-, 3-6 membered halogenated cycloalkyl, 3-6 membered halogenated cycloalkyl-O-, 3-6 membered halogenated heterocycloalkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered heterocycloalkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered monocyclic aryl, 5-12 membered paracyclic aryl, and 3-12 membered monocyclic heteroaryl and 7-10 membered paracyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S; R 2b and R 2c are independently selected from hydrogen and C 1-6 alkyl;

[0079] R3 is -X1-R8, X1 is selected from chemical bonds, C 2-6 Alkenylene and C 1-6 Alkylene; R8 is selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, -NR 8a R 8b 、-C(O)R 8c 、-C(O)NR 8a R 8b and a 5-10 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N, O, P and S; R 8a and R 8b Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 haloalkyl and phenyl, the phenyl group is optionally substituted by 0-2 groups selected from C 1-4 Alkyl, -OR 8d and-X2-R 8d Group substitution; R 8c Selected from hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl and C 1-6 Haloalkyl; X2 is selected from C1-6 Alkylene and C 2-6 Alkenylene; R 8d Selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0080] R 7a and R 7b are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -X3-OR 7c 、-X3-NR 7d R 7e and C 3-10 Cycloalkyl; X3 each occurrence is independently selected from C 1-6 Alkylene and C2-C6 alkenylene; R 7c Selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; R 7d and R 7e are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl; or R 7a and R 7b and the carbon to which it is connected form a 3-10 membered cycloalkyl group;

[0081] The W ring is selected from the following groups:

[0082] The Q ring is selected from 5-6 membered heterocycloalkylene and 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, said heterocycloalkylene and said heteroarylene are optionally substituted with 0-2 R9, each R9 being independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, C 3-6 Cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O and S 3-6 Heterocycloalkyl, -S(O2)R 9a 、-NR 9b R 9c 、-X4-NR 9b R 9c 、-OR 9a AND-X4-OR 9a ; R 9a 、R 9b and R 9c Each occurrence is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; X4 is selected from C 1-6 Alkylene and C 2-6 alkenylene;

[0083] The R ring is a 5-6 membered heterocycloalkylene or a 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkylene and heteroarylene are optionally substituted by 0-2 R 10 Replacement, R 10 Each occurrence is independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, C 3-6 Cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O and S 3-6 Heterocycloalkyl, -S(O2)R 10a 、-NR 10b R 10c 、-X5-NR 10b R 10c 、-OR 10a AND-X5-OR 10a ; R 10a 、R 10b and R 10c Each occurrence is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; X5 is selected from C 1-6 Alkylene and C 2-6 alkenylene;

[0084] The T ring and the U ring are independently selected from phenylene, pyridinyl, pyrimidinyl and pyrazinyl, wherein the phenylene, pyridinyl, pyrimidinyl and pyrazinyl are optionally substituted by 1-3 groups independently selected from halogen, amino, alkylamino, aminoalkyl, hydroxyl, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 Alkyl and C 3-6 Substitution of cycloalkyl groups;

[0085] L1 is selected from the following groups:

[0086] L2 is selected from the following groups:

[0087] wherein Y1, Y2, Y3, Y4, Y5, Y6, and Y7 are independently selected from -O-, -NH-, -NHC(O)-, -NHS(O)-, -NHS(O2)-, -CH2-, -C(O)-, -S(O)-, -S(O2)-, -C(O)NH-, -S(O2)NH-, -CH=CH-, -C≡C-, and a single bond, wherein the hydrogen atom is optionally replaced by 0-2 independently selected from deuterium, halogen, amino, alkylamino, aminoalkyl, hydroxy, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 Alkyl and C 3-6Substitution of cycloalkyl groups;

[0088] a is an integer from 0 to 5; b and c are each an integer from 0 to 3; d and e are each an integer from 0 to 2; and

[0089] L1 and L2 are optionally replaced by 1-5 R 11 Replacement, R 11 are independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from oxygen, sulfur and nitrogen, -S(O2)R 11a NR 11b R 11c 、-X6-NR 11b R 11c 、-OR 11a AND-X6-OR 11a ; R 11a 、R 11b and R 11c Each occurrence is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; X6 is selected from C 1-6 Alkylene and C 2-6 Alkenylene.

[0090] 2. The compound of claim 1, wherein:

[0091] R 1a and R 1b are independently selected from hydrogen, C 3-12 Monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 Monocyclic, spirocyclic or bridged heterocycloalkyl, and C 1-4 Alkyl, where C 1-4 Alkyl is optionally substituted with 0-6 substituents independently selected from halogen, deuterium, amino, hydroxy, aminoalkyl, and alkoxy; or R 1a and R 1b and the nitrogen atom to which they are commonly attached form a four-membered, five-membered or six-membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted with 0-3 substituents independently selected from halogen, amino and hydroxy; or

[0092] R2, R4 and R6 are independently selected from halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Monoalkylamino, C 1-3 Dialkylamino, C 1-3Halogenated alkylamino, cycloalkyl containing 3-12 membered monocyclic ring, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monoheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spiroheterocycloalkyl and 4-12 membered bridged heterocycloalkyl, C1-C6 alkyl-S-, C 1-6 Alkyl-SO-, C 1-6 Alkyl-SO2-, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, 5-10 membered monocyclic aryl, 5-10 membered cycloheteroaryl, and 3-12 membered monocyclic heteroaryl and 7-10 membered cycloheteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S; or

[0093] R5 is selected from hydrogen, C 1-3 Alkyl and C 1-3 haloalkyl; or

[0094] E, G, J and Z are independently selected from N and CR 2a ; where R 2a Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkyl-S-, C1-C3 alkyl-SO-, C 1-3 Alkyl-SO2-, C 1-3 Alkyl-O-, C 1-3 Haloalkyl-O-, -NR 2b R 2c 、C 3-6 Cycloalkylamino, 3-6 membered heterocycloalkylamino containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered halogenated cycloalkyl, 3-6 membered halogenated heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered cycloalkyl-O-, 3-6 membered halogenated cycloalkyl-O-, 3-6 membered heterocycloalkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S; R 2b and R 2c are independently selected from hydrogen and C1-C6 alkyl; or

[0095] R3 is -X1-R8, X1 is selected from a chemical bond, C2-C4 alkenylene and C1-C4 alkylene; R8 is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C6-C 10 Aryl, -NR 8a R 8b 、-C(O)R 8c 、-C(O)NR 8a R 8band a 5-10 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N, O, P and S; R 8a and R 8b Each occurrence is independently selected from hydrogen, deuterium, C1-C3 alkyl, C1-C3 haloalkyl and phenyl, said phenyl optionally substituted with 0-2 atoms selected from C 1-4 Alkyl, -OR 8d and-X2-R 8d Group substitution; R 8c Selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; X2 is selected from C 1-6 Alkylene and C 2-6 Alkenylene; R 8d Selected from hydrogen, C 1-4 Alkyl and C 1-4 haloalkyl; or

[0096] R 1c and R 1d are independently selected from hydrogen, C 3-12 Monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 Monocyclic, spirocyclic or bridged heterocycloalkyl, and C 1-4 Alkyl, where C 1-4 Alkyl is optionally substituted with 0-6 substituents independently selected from halogen, deuterium, amino, hydroxy, aminoalkyl, and alkoxy; or R 1c and R 1d and the nitrogen atom to which they are commonly attached form a four-membered, five-membered or six-membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted with 0-3 substituents independently selected from halogen, amino and hydroxy; or

[0097] R 7a and R 7b are independently selected from hydrogen, halogen, C 1-4 Alkyl and C 1-4 haloalkyl; or

[0098] The Q ring is optionally substituted with 1-2 R9, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, cyano, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms, the heteroatoms being independently selected from N, O and S, -S(O2)R 9a NR 9b R 9c AND-OR 9a ; Each R 9a 、R 9b and R 9c Each occurrence is independently selected from hydrogen, C 1-3 Alkyl and C 1-3 haloalkyl; or

[0099] The R ring is a 5-6 membered heterocycloalkylene or a 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkylene and heteroarylene are optionally substituted by 0-2 R 10 Replacement, R 10 Each occurrence is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, cyano, C3-C6 cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O and S 3-6 Heterocycloalkyl, -S(O2)R 10a 、-NR 10b R 10c AND-OR 10a ; R 10a 、R 10b and R 10c Each occurrence is independently selected from hydrogen, C1-C3 alkyl and C1-C3 haloalkyl; or

[0100] The T ring and the U ring are independently selected from phenylene and pyridinyl, wherein the phenylene and pyridinyl are optionally substituted by 1-3 groups independently selected from halogen, amino, alkylamino, aminoalkyl, hydroxyl, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 Alkyl and C 3-6 The cycloalkyl group is substituted with a substituent.

[0101] 3. The compound of claim 1, wherein:

[0102] R2 is selected from hydrogen, fluorine, chlorine, cyclopropyl, C 1-3 Alkyl and C 1-3 haloalkyl; or

[0103] R3 is hydrogen; or

[0104] R4 is selected from hydrogen, fluorine, chlorine, bromine and cyclopropyl; or

[0105] R6 is selected from hydrogen, fluorine, chlorine and cyclopropyl; or

[0106] R5 is selected from hydrogen and methyl; or

[0107] R 1c and R 1d are independently selected from hydrogen and C1-C3 alkyl; preferably, R 1c and R 1d are independently selected from hydrogen and methyl; or

[0108] The Q ring is selected from the following groups:

[0109] Wherein, the connection site on the left side of each Q ring group is independently connected to -CR in formula (V)7a R 7b - connected, the connection site on the right side of each Q ring group is independently connected to the R ring in formula (V); or

[0110] The R ring is selected from the following groups:

[0111] The right connecting site of each R ring group is independently connected to the Q ring in formula (V), and the left connecting site of each R ring group is independently connected to the A ring or the B ring in formula I.

[0112] 4. The compound according to any one of claims 1 to 3, wherein the compound is selected from the group consisting of compounds represented by formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F) and (I-G), or isomers, isotopic derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates thereof:

[0113] Among them, Q ring, R ring, T ring, U ring, W ring, R 1a 、R 1b 、R 1c 、R 1d 、R 7a 、R 7b , R2, R3, R4, R5 and R6 are defined as in claim 1 or 2 or 3.

[0114] 5. The compound according to any one of claims 1 to 3, wherein Ring A and Ring B are each independently selected from the group consisting of Formula (II-1), (IV-1) and (III-1):

[0115] Among them, R 1a 、R 1b 、R 1c 、R 1d , R2, R3, R4, R5 and R6 are defined as in claim 1 or 2 or 3.

[0116] 6. The compound according to any one of claims 1 to 3, wherein the compound is selected from the group consisting of compounds represented by formula (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-F-3), (I-F-4), (I-F-5), (I-F-6), (I-F-7) and (I-F-8), or isomers, isotopic derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates thereof:

[0117] where Q a The definition of the ring is consistent with the definition of the Q ring in claim 1, 2 or 3; Ra The definition of the ring is consistent with the definition of the R ring in claim 1, 2 or 3; R 1a 、R 1b 、R 1c 、R 1d 、R 7a 、R 7b , E, G, J, Z, L2, R2 and R6 are defined the same as in claim 1 or 2 or 3.

[0118] 2. A compound represented by formula (I), or an isomer, isotopic derivative, polymorph, prodrug, pharmaceutically acceptable salt, or solvate thereof:

[0119] wherein Ring A and Ring B are the same or different, and Ring A and Ring B are independently selected from Formula (II), (III) and (IV):

[0120] Wherein Linker C is a linker connecting Ring A and Ring B, selected from Formula (V), (VI), (VI-2) and (VII):

[0121] Among them, R 1a 、R 1b 、R 1c and R 1d are independently selected from hydrogen, deuterium, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyalkyl, C 1-6 Alkoxy, C 3-12 Monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 Monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 Aryl and C 5-10 Heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 Monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 Aryl, and C 5-10 Heteroaryl is optionally substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, alkylamino, aminoalkyl, and alkoxy; or R 1a and R 1b and the nitrogen atom to which they are attached together form a 3-10 membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted with 0-3 substituents independently selected from halogen, deuterium, amino, alkoxy, alkylamino, aminoalkyl and hydroxy; or R 1c and R 1dand the nitrogen atom to which they are attached together form a 3-10 membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted with 0-3 substituents independently selected from halogen, deuterium, amino, alkoxy, aminoalkyl and hydroxy;

[0122] R2, R4 and R6 are independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)C 1-6 Alkyl, C 1-6 Halogenated alkoxy, C 1-6 haloalkylamino, 3-12 membered monocyclic cycloalkyl, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monoheterocycloalkyl, 5-12 membered spiroheterocycloalkyl and 4-12 membered bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 1-6 Alkyl-S-, C 1-6 Alkyl-SO-, C 1-6 Alkyl-SO2-, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, 5-10 membered monocyclic aryl, 5-10 membered cycloheteroaryl, and 3-12 membered monocyclic heteroaryl and 7-10 membered cycloheteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S;

[0123] R5 is selected from hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl and C 1-6 Halogenated alkyl, optionally, the C 1-6 Alkyl, C 3-10 Cycloalkyl and C 1-6 haloalkyl is substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, aminoalkyl, alkylamino, and alkoxy;

[0124] Each occurrence of E, G, J and Z is independently selected from N and CR 2a ; where R 2a Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, --NHCO-C 1-6 Alkyl, -COHN2, -C 1-6 Alkyl-COHN2, sulfonamide, -NHCONH2, -NH-CS-NH2, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl-S-, C 1-6 Alkyl-SO-, C 1-6Alkyl-SO2-, C 1-6 Alkyl-O-, C 1-6 Haloalkyl-O-, -NR 2b R 2c 、C 1-6 Alkylamino, C 2-6 Dialkylamino, -CONH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)C 1-6 Alkyl, C 3-6 Cycloalkylamino, C 3-6 Cycloalkylalkoxy, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, 3-6 membered heterocycloalkylamino containing 1-3 heteroatoms independently selected from N, O, P and S, 3-12 membered monocyclic heterocycloalkyl, 5-12 membered spirocycloalkyl and 4-12 membered bridged cycloalkyl, 3-12 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spirocycloheterocycloalkyl and 4-12 membered bridged heterocycloalkyl, containing 1-3 heteroatoms independently selected from N, O, P and S R is a 3-6 membered halogenated heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from N, O, P and S, a 3-6 membered cycloalkyl-O-, a 3-6 membered halogenated cycloalkyl group, a 3-6 membered halogenated cycloalkyl-O-, a 3-6 membered halogenated heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from N, O, P and S, a 3-6 membered heterocycloalkyl-O- containing 1 to 3 heteroatoms independently selected from N, O, P and S, a 5-12 membered monocyclic aryl group, a 5-12 membered bicyclic aryl group, and a 3-12 membered monocyclic heteroaryl group and a 7-10 membered bicyclic heteroaryl group containing 1 to 3 heteroatoms independently selected from N, O, P and S; 2b and R 2c are independently selected from hydrogen and C 1-6 alkyl;

[0125] R3 is -X1-R8, X1 is selected from chemical bonds, -O-, -S-, alkoxy, C 2-6 Alkenylene and C 1-6 Alkylene; R8 is selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, -NR 8a R 8b 、-C(O)R 8c 、-C(O)NR 8a R 8b and a 5-10 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N, O, P and S; R 8a and R 8b Each occurrence is independently selected from hydrogen, deuterium, C 1-6Alkyl, C 1-6 haloalkyl and phenyl, the phenyl group is optionally substituted by 0-2 groups selected from C 1-4 Alkyl, halogen, hydroxy, cyano, amino, -OR 8d and-X2-R 8d Group substitution; R 8c Selected from hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl and C 1-6 Haloalkyl; X2 is selected from C 1-6 Alkylene and C 2-6 Alkenylene; R 8d Selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0126] R 7a and R 7b are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -X3-OR 7c 、-X3-NR 7d R 7e and C 3-10 Cycloalkyl; X3 each occurrence is independently selected from C 1-6 Alkylene and C2-C6 alkenylene; R 7c Selected from hydrogen, deuterium, C 1-6 Alkyl and C 1-6 Haloalkyl; R 7d and R 7e are independently selected from hydrogen, deuterium, C 1-6 Alkyl and C 1-6 haloalkyl; or R 7a and R 7b and the carbon to which it is connected form a 3-10 membered cycloalkyl group;

[0127] W is selected from the following groups:

[0128] The Q ring is selected from 5-6 membered heterocycloalkylene and 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, said heterocycloalkylene and said heteroarylene are optionally substituted with 0-2 R9, each R9 being independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, C 3-6 Cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O and S 3-6 Heterocycloalkyl, -S(O2)R 9a 、-NR 9b R 9c、-X4-NR 9b R 9c 、-OR 9a AND-X4-OR 9a ; R 9a 、R 9b and R 9c Each occurrence is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; X4 is selected from C 1-6 Alkylene and C 2-6 alkenylene;

[0129] The R ring is a 5-6 membered heterocycloalkylene or a 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkylene and heteroarylene are optionally substituted by 0-2 R 10 Replacement, R 10 Each occurrence is independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, C 3-6 Cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O and S 3-6 Heterocycloalkyl, -S(O2)R 10a 、-NR 10b R 10c、 -X5-NR 10b R 10c 、-OR 10a AND-X5-OR 10a ; R 10a 、R 10b and R 10c Each occurrence is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; X5 is selected from C 1-6 Alkylene and C 2-6 alkenylene;

[0130] The T ring and the U ring are independently selected from phenylene, pyridinyl, pyrimidinyl and pyrazinyl, wherein the phenylene, pyridinyl, pyrimidinyl and pyrazinyl are optionally substituted by 1-3 groups independently selected from halogen, amino, alkylamino, aminoalkyl, hydroxyl, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 Alkyl and C 3-6 Substitution of cycloalkyl groups;

[0131] L1 is selected from the following groups:

[0132] L2 is selected from the following groups:

[0133] wherein Y1, Y2, Y3, Y4, Y5, Y6, and Y7 are independently selected from -O-, -NH-, -NHC(O)-, -NHS(O)-, -NHS(O2)-, -CH2-, -C(O)-, -S(O)-, -S(O2)-, -C(O)NH-, -S(O2)NH-, -CH=CH-, -C≡C-, and a single bond, wherein the hydrogen atoms in L2 are independently selected from deuterium, halogen, amino, alkylamino, aminoalkyl, -CONH2, -NHCO-C 1-6 Alkyl, hydroxy, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 Alkyl and C 3-6 Any substituent of the cycloalkyl group;

[0134] a is an integer from 0 to 5; b and c are each an integer from 0 to 3; d and e are each an integer from 0 to 2; and

[0135] L1 and L2 are optionally replaced by 1-5 R 11 Replacement, R 11 are independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from oxygen, sulfur and nitrogen, -S(O2)R 11a NR 11b R 11c 、-X6-NR 11b R 11c 、-OR 11a AND-X6-OR 11a ; R 11a 、R 11b and R 11c Each occurrence is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; X6 is selected from C 1-6 Alkylene and C 2-6 Alkenylene.

[0136] 3. The compound of claim 2, wherein:

[0137] R 1a and R 1b are independently selected from hydrogen, C 3-12 Monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 Monocyclic, spirocyclic or bridged heterocycloalkyl, and C 1-4 Alkyl, where C 1-4 Alkyl is optionally substituted with 0-6 substituents independently selected from halogen, deuterium, amino, hydroxy, aminoalkyl, and alkoxy; or R 1a and R1b and the nitrogen atom to which they are commonly attached form a four-membered, five-membered or six-membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted with 0-3 substituents independently selected from halogen, amino and hydroxy; or

[0138] R2, R4 and R6 are independently selected from halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)C 1-3 Alkyl, C 1-3 Halogenated alkylamino, cycloalkyl containing 3-12 membered monocyclic ring, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monoheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spiroheterocycloalkyl and 4-12 membered bridged heterocycloalkyl, C1-C6 alkyl-S-, C 1-6 Alkyl-SO-, C 1-6 Alkyl-SO2-, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, 5-10 membered monocyclic aryl, 5-10 membered cycloheteroaryl, and 3-12 membered monocyclic heteroaryl and 7-10 membered cycloheteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S; or

[0139] R5 is selected from hydrogen, C 1-3 Alkyl and C 1-3 haloalkyl; or

[0140] E, G, J and Z are independently selected from N and CR 2a ; where R 2a Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, -NHCO-C 1-6 Alkyl, -CONH2, -C 1-6 Alkyl-CONH2, sulfonamide, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkyl-S-, C1-C3 alkyl-SO-, C 1-3 Alkyl-SO2-, C 1-3 Alkyl-O-, C 1-3 Haloalkyl-O-, -NR 2b R 2c 、C 3-6Cycloalkylamino, 3-6 membered heterocycloalkylamino containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered halogenated cycloalkyl, 3-6 membered halogenated heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered cycloalkyl-O-, 3-6 membered halogenated cycloalkyl-O-, 3-6 membered heterocycloalkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S; R 2b and R 2c are independently selected from hydrogen and C1-C6 alkyl; or

[0141] R3 is -X1-R8, X1 is selected from a chemical bond, C2-C4 alkenylene and C1-C4 alkylene; R8 is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C6-C 10 Aryl, -NR 8a R 8b 、-C(O)R 8c 、-C(O)NR 8a R 8b and a 5-10 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N, O, P and S; R 8a and R 8b Each occurrence is independently selected from hydrogen, deuterium, C1-C3 alkyl, C1-C3 haloalkyl and phenyl, said phenyl optionally substituted with 0-2 atoms selected from C 1-4 Alkyl, -OR 8d and-X2-R 8d Group substitution; R 8c Selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; X2 is selected from C 1-6 Alkylene and C 2-6 Alkenylene; R 8d Selected from hydrogen, C 1-4 Alkyl and C 1-4 haloalkyl; or

[0142] R 1c and R 1d are independently selected from hydrogen, C 3-12 Monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 Monocyclic, spirocyclic or bridged heterocycloalkyl, and C 1-4 Alkyl, where C 1-4 Alkyl is optionally substituted with 0-6 substituents independently selected from halogen, deuterium, amino, hydroxy, aminoalkyl, and alkoxy; or R 1c and R 1d and the nitrogen atom to which they are commonly attached form a four-membered, five-membered or six-membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted with 0-3 substituents independently selected from halogen, amino and hydroxy; or

[0143] R 7a and R 7b are independently selected from hydrogen, deuterium, halogen, C 1-4 Alkyl and C 1-4 haloalkyl; or

[0144] The Q ring is optionally substituted with 1-2 R9, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, cyano, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms, the heteroatoms being independently selected from N, O and S, -S(O2)R 9a NR 9b R 9c AND-OR 9a ; Each R 9a 、R 9b and R 9c Each occurrence is independently selected from hydrogen, deuterium, C 1-3 Alkyl and C 1-3 haloalkyl; or

[0145] The R ring is a 5-6 membered heterocycloalkylene or a 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkylene and heteroarylene are optionally substituted by 0-2 R 10 Replacement, R 10 Each occurrence is independently selected from halogen, C1-C3 alkyl, hydroxy, amino, C1-C3 haloalkyl, cyano, C3-C6 cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O and S 3-6 Heterocycloalkyl, -S(O2)R 10a 、-NR 10b R 10c AND-OR 10a ; R 10a 、R 10b and R 10c Each occurrence is independently selected from hydrogen, deuterium, C1-C3 alkyl and C1-C3 haloalkyl; or

[0146] The T ring and the U ring are independently selected from 5-6 membered heterocyclyl, phenylene and pyridylene containing 1, 2 or 3 N, O or S atoms, wherein the phenylene and pyridylene are optionally substituted by 1-3 groups independently selected from halogen, amino, alkylamino, aminoalkyl, cyano, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 Alkyl and C 3-6 The cycloalkyl group is substituted with a substituent.

[0147] 4. The compound of claim 3, wherein:

[0148] R2 is selected from hydrogen, fluorine, chlorine, cyclopropyl, C 1-3 Alkyl and C 1-3 haloalkyl; or

[0149] R3 is hydrogen; or

[0150] R4 is selected from hydrogen, fluorine, chlorine, bromine and cyclopropyl; or

[0151] R6 is selected from hydrogen, fluorine, chlorine and cyclopropyl; or

[0152] R5 is selected from hydrogen and methyl; or

[0153] R 1c and R 1d are independently selected from hydrogen and C1-C3 alkyl; preferably, R 1c and R 1d are independently selected from hydrogen and methyl; or

[0154] The Q ring is selected from the following groups:

[0155] Wherein, the connection site on the left side of each Q ring group is independently connected to -CR in formula (V) 7a R 7b - connected, the connection site on the right side of each Q ring group is independently connected to the R ring in formula (V); or

[0156] The R ring is selected from the following groups:

[0157] The right connecting site of each R ring group is independently connected to the Q ring in formula (V), and the left connecting site of each R ring group is independently connected to the A ring or the B ring in formula I.

[0158] 5. The compound according to any one of claims 1 to 4, wherein the compound is selected from the group consisting of compounds represented by formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F) and (I-G), or isomers, isotopic derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates thereof:

[0159] Among them, Q ring, R ring, T ring, U ring, L1, L2, W, R 1a 、R 1b 、R 1c 、R 1d 、R 7a 、R 7b , R2, R3, R4, R5 and R6 are defined as in claim 2, 3 or 4.

[0160] 6. The compound according to any one of claims 1 to 4, wherein Ring A and Ring B are the same or different, and Ring A and Ring B are each independently selected from Formula (II-1), (IV-1) and (III-1):

[0161] Among them, R 1a 、R 1b 、R 1c 、R 1d , R2, R3, R4, R5 and R6 are as defined in claim 1 or 2 or 3 or 4;

[0162] Preferably, the A ring and the B ring are identical.

[0163] 7. The compound according to any one of claims 1 to 4, wherein the compound is selected from the group consisting of compounds represented by formula (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-F-3), (I-F-4), (I-F-5), (I-F-6), (I-F-7) and (I-F-8), or isomers, isotopic derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates thereof:

[0164] where Q a The definition of the ring is consistent with the definition of the Q ring in claim 2, 3 or 4; R a The definition of the ring is consistent with the definition of the R ring in claim 2, 3 or 4; R 1a 、R 1b 、R 1c 、R 1d 、R 7a 、R 7b , E, G, J, Z, L2, R2 and R6 are defined the same as in claim 1 or 2 or 3 or 4.

[0165] In some embodiments, the compound is a compound represented by formula (I), or an isomer, isotopic derivative, polymorph, prodrug, pharmaceutically acceptable salt or solvate thereof:

[0166] wherein Ring A and Ring B are independently selected from Formula (II), (III) and (IV):

[0167] Wherein Linker C is a linker connecting Ring A and Ring B, selected from Formula (V), (VI) and (VII):

[0168] Among them, R 1a 、R 1b 、R 1c and R1d are independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 Monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 Aryl and C 5-10 Heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 Monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 Aryl, and C 5-10 Heteroaryl is optionally substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, alkylamino, aminoalkyl, and alkoxy; or R 1a and R 1b and the nitrogen atom to which they are attached together form a 3-10 membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted with 0-3 substituents independently selected from halogen, deuterium, amino, alkoxy, alkylamino, aminoalkyl and hydroxy; or R 1c and R 1d and the nitrogen atom to which they are attached together form a 3-10 membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted with 0-3 substituents independently selected from halogen, deuterium, amino, alkoxy, aminoalkyl and hydroxy;

[0169] R2, R4 and R6 are independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Monoalkylamino, C 2-6 Dialkylamino, C 1-6 haloalkylamino, 3-12 membered monocyclic cycloalkyl, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monoheterocycloalkyl, 5-12 membered spiroheterocycloalkyl and 4-12 membered bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 1-6 Alkyl-S-, C 1-6 Alkyl-SO-, C 1-6 Alkyl-SO2-, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, 5-10 membered monocyclic aryl, 5-10 membered cycloheteroaryl, and 3-12 membered monocyclic heteroaryl and 7-10 membered cycloheteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S;

[0170] R5 is selected from hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl and C1-6 Halogenated alkyl, optionally, the C 1-6 Alkyl, C 3-10 Cycloalkyl and C 1-6 haloalkyl is substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, aminoalkyl, alkylamino, and alkoxy;

[0171] Each occurrence of E, G, J and Z is independently selected from N and CR 2a ; where R 2a Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl-S-, C 1-6 Alkyl-SO-, C 1-6 Alkyl-SO2-, C 1-6 Alkyl-O-, C 1-6 Haloalkyl-O-, -NR 2b R 2c 、C 3-6 Cycloalkylamino, 3-6 membered heterocycloalkylamino containing 1-3 heteroatoms independently selected from N, O, P and S, 3-12 membered monocyclic alkyl, 5-12 membered spirocycloalkyl and 4-12 membered bridged cycloalkyl, 3-12 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spirocycloheterocycloalkyl and 4-12 membered bridged heterocycloalkyl, 3-6 membered halogenated heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered cyclic alkyl-O-, 3-6 membered halogenated cycloalkyl, 3-6 membered halogenated cycloalkyl-O-, 3-6 membered halogenated heterocycloalkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered heterocycloalkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered monocyclic aryl, 5-12 membered paracyclic aryl, and 3-12 membered monocyclic heteroaryl and 7-10 membered paracyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S; R 2b and R 2c are independently selected from hydrogen and C 1-6 alkyl;

[0172] R3 is -X1-R8, X1 is selected from chemical bonds, C 2-6 Alkenylene and C 1-6 Alkylene; R8 is selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, -NR 8a R 8b 、-C(O)R 8c、-C(O)NR 8a R 8b and a 5-10 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N, O, P and S; R 8a and R 8b Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 haloalkyl and phenyl, the phenyl group is optionally substituted by 0-2 groups selected from C 1-4 Alkyl, -OR 8d and-X2-R 8d Group substitution; R 8c Selected from hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl and C 1-6 Haloalkyl; X2 is selected from C 1-6 Alkylene and C 2-6 Alkenylene; R 8d Selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0173] R 7a and R 7b are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -X3-OR 7c 、-X3-NR 7d R 7e and C 3-10 Cycloalkyl; X3 each occurrence is independently selected from C 1-6 Alkylene and C2-C6 alkenylene; R 7c Selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; R 7d and R 7e are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl; or R 7a and R 7b and the carbon to which it is connected form a 3-10 membered cycloalkyl group;

[0174] The W ring is selected from the following groups:

[0175] The Q ring is selected from 5-6 membered heterocycloalkylene and 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, said heterocycloalkylene and said heteroarylene are optionally substituted with 0-2 R9, each R9 being independently selected from halogen, C 1-6 Alkyl, C 1-6Haloalkyl, cyano, C 3-6 Cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O and S 3-6 Heterocycloalkyl, -S(O2)R 9a 、-NR 9b R 9c 、-X4-NR 9b R 9c 、-OR 9a AND-X4-OR 9a ; R 9a 、R 9b and R 9c Each occurrence is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; X4 is selected from C 1-6 Alkylene and C 2-6 alkenylene;

[0176] The R ring is a 5-6 membered heterocycloalkylene or a 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkylene and heteroarylene are optionally substituted by 0-2 R 10 Replacement, R 10 Each occurrence is independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, C 3-6 Cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O and S 3-6 Heterocycloalkyl, -S(O2)R 10a 、-NR 10b R 10c 、-X5-NR 10b R 10c 、-OR 10a AND-X5-OR 10a ; R 10a 、R 10b and R 10c Each occurrence is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; X5 is selected from C 1-6 Alkylene and C 2-6 alkenylene;

[0177] The T ring and the U ring are independently selected from phenylene, pyridinyl, pyrimidinyl and pyrazinyl, wherein the phenylene, pyridinyl, pyrimidinyl and pyrazinyl are optionally substituted by 1-3 groups independently selected from halogen, amino, alkylamino, aminoalkyl, hydroxyl, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 Alkyl and C 3-6 Substitution of cycloalkyl groups;

[0178] L1 is selected from the following groups:

[0179] L2 is selected from the following groups:

[0180] wherein Y1, Y2, Y3, Y4, Y5, Y6, and Y7 are independently selected from -O-, -NH-, -NHC(O)-, -NHS(O)-, -NHS(O2)-, -CH2-, -C(O)-, -S(O)-, -S(O2)-, -C(O)NH-, -S(O2)NH-, -CH=CH-, -C≡C-, and a single bond, wherein the hydrogen atom is optionally replaced by 0-2 independently selected from deuterium, halogen, amino, alkylamino, aminoalkyl, hydroxy, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 Alkyl and C 3-6 Substitution of cycloalkyl groups;

[0181] a is an integer from 0 to 5; b and c are each an integer from 0 to 3; d and e are each an integer from 0 to 2; and

[0182] L1 and L2 are optionally replaced by 1-5 R 11 Replacement, R 11 are independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from oxygen, sulfur and nitrogen, -S(O2)R 11a NR 11b R 11c 、-X6-NR 11b R 11c 、-OR 11a AND-X6-OR 11a ; R 11a 、R 11b and R 11c Each occurrence is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; X6 is selected from C 1-6 Alkylene and C 2-6 Alkenylene.

[0183] wherein Ring A and Ring B are each independently selected from Formula (II), (III), (IV), (V), (VI), (VII) and (VIII):

[0184] Wherein Linker C is a linker connecting Ring A and Ring B, selected from Formula (IX), (X), (XI) and (XII):

[0185] wherein R1 is selected from the group consisting of absence, hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -S(O)-C 1-6 Alkyl, -S(O2)-C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl and -NR 1a R 1b , where R 1a and R 1b are independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, C 3-12 Monocyclic, spirocyclic or bridged cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O, P and S 3-12 Monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 Aryl and C 5-10 Heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 3-12 Monocyclic, spirocyclic or bridged cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O, P and S 3-12 Monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 Aryl, and C 5-10 Heteroaryl is optionally substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, alkylamino, aminoalkyl, and alkoxy; or R 1a and R 1b The nitrogen atom to which it is commonly attached forms a 3-10 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkyl is optionally substituted by 0-3 heteroatoms independently selected from halogen, deuterium, amino, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, cyano, C 1-6 Substitution of aminoalkyl and hydroxy substituents;

[0186] Z is selected from C and N; when Z is selected from N, R1 is absent;

[0187] R2, R4 and R6 are independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)C 1-6 Alkyl, C 1-6 Halogenated alkoxy, C 1-6 haloalkylamino, 3-12 membered monocyclic cycloalkyl, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monoheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spiroheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 4-12 membered bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, -SC 1-6 Alkyl, -SO-C 1-6 Alkyl, -SO2-C 1-6 Alkyl, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, 5-10 membered monocyclic aryl, 5-10 membered cycloheteroaryl, 3-12 membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S, and 7-10 membered cycloheteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S;

[0188] R5 is selected from hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl and C 1-6 Halogenated alkyl, optionally, the C 1-6 Alkyl, C 3-10 Cycloalkyl and C 1-6 haloalkyl is substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, aminoalkyl, alkylamino, and alkoxy;

[0189] G1 and G2 are selected from O, S, and NR 2a ;

[0190] E 0-9 、M 1-6 and E are independently selected from N and CR 2a ; where R 2a Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl-S-, -SO-C 1-6 Alkyl, -SO2-C 1-6 Alkyl, -OC1-6 Alkyl, -OC 1-6 Halogenated alkyl, -NR 2b R 2c 、-NHC 1-6 Alkyl, -N(C 1-6 Alkyl)C 1-6 Alkyl, -C(O)R 8c 、-C(O)NR 8a R 8b 、-C 1-6 Alkylene-C 1-6 Cycloalkyl, C 3-6 cycloalkylamino, 3-6 membered heterocycloalkylamino containing 1-3 heteroatoms independently selected from N, O, P and S, 3-12 membered monocycloalkyl, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monocycloheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spiroheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 4-12 membered bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered monocycloheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered halogenated heterocycloalkyl, 3-6 membered cycloalkyl-O-, 3-6 membered halogenated cycloalkyl, 3-6 membered halogenated cycloalkyl-O-, 3-6 membered halogenated heterocycloalkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered heterocycloalkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered monocyclic aryl, 5-12 membered cyclophenyl aryl, 3-12 membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S, 7-10 membered cyclophenyl heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S; R 2b and R 2c are independently selected from hydrogen and C 1-6 Alkyl; R 8a and R 8b Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 haloalkyl and phenyl, the phenyl group is optionally substituted by 0-2 groups selected from C 1-4 Alkyl, -OR 8d and-X2-R 8d Group substitution; R 8c Selected from hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl and C 1-6 Haloalkyl; X2 is selected from C 1-6 Alkylene and C 2-6 Alkenylene; R 8dSelected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0191] J1 and J2 are independently selected from a single bond, O, S, C(O), S(O), S(O2), C(R 1c R 1d ), C(=CR 1e R 1f ) and N(R3); wherein R 1c 、R 1d 、R 1e and R 1f are independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Monocyclic, spirocyclic or bridged cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O, P and S 3-12 Monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 Aryl and C 5-10 Heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Monocyclic, spirocyclic or bridged cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O, P and S 3-12 Monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 Aryl, and C 5-10 Heteroaryl is optionally substituted by 0-6 independently selected from halogen, deuterium, C 1-6 Alkyl, amino, hydroxyl, C 1-6 Alkylamino, C 1-6 aminoalkyl, and C 1-6 Alkoxy is substituted by a substituent; or R 1c and R 1d The carbon atoms to which they are connected together form a 3-10 membered cycloalkyl or a 3-10 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, wherein the cycloalkyl or heterocycloalkyl is optionally substituted by 0-3 heteroatoms independently selected from halogen, deuterium, amino, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 The aminoalkyl group and the hydroxy group are substituted; or R 1e and R 1f The carbon atoms to which they are connected together form a 3-10 membered cycloalkyl or a 3-10 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, wherein the cycloalkyl or heterocycloalkyl is optionally substituted by 0-3 heteroatoms independently selected from halogen, deuterium, amino, C 1-6 Alkoxy, C 1-6 Alkylamino, C1-6 Substitution of aminoalkyl and hydroxy substituents;

[0192] R3 is -X1-R8, X1 is selected from chemical bonds, -O-, -S-, alkoxy, C 2-6 Alkenylene and C 1-6 Alkylene; R8 is selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, -NR 8a R 8b 、-C(O)R 8c 、-C(O)NR 8a R 8b and a 5-10 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N, O, P and S; R 8a and R 8b Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 haloalkyl and phenyl, the phenyl group is optionally substituted by 0-2 groups selected from C 1-4 Alkyl, halogen, cyano, amino, -OR 8d and-X2-R 8d Group substitution; R 8c Selected from hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl and C 1-6 Haloalkyl; X2 is selected from C 1-6 Alkylene and C 2-6 Alkenylene; R 8d Selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0193] R 7a and R 7b are independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -X3-OR 7c 、-X3-NR 7d R 7e and C 3-10 Cycloalkyl; X3 each occurrence is independently selected from C 1-6 Alkylene and C2-C6 alkenylene; R 7c Selected from hydrogen, deuterium, C 1-6 Alkyl and C 1-6 Haloalkyl; R 7d and R 7e are independently selected from hydrogen, deuterium, C 1-6 Alkyl and C 1-6 haloalkyl; or R7a and R 7b and the carbon to which it is connected form a 3-10 membered cycloalkyl group;

[0194] W is selected from the following groups:

[0195] The Q ring is selected from phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1-4 heteroatoms independently selected from N, O, P and S, 3-7 membered heterocycloalkenylene, 5-6 membered heteroarylene and 4-12 membered fused heterocyclic ring, wherein the phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1-4 heteroatoms independently selected from N, O, P and S, 5-6 membered heteroarylene and 4-12 membered fused heterocyclic ring are optionally substituted with 0-6 R9, each occurrence of R9 is independently selected from halogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, C 3-6 Cycloalkyl, C3-7 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S, -S(O2)R 9a 、-NR 9b R 9c 、-X4-NR 9b R 9c 、-OR 9a AND-X4-OR 9a ; R 9a 、R 9b and R 9c Each occurrence is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; X4 is selected from C 1-6 Alkylene and C 2-6 alkenylene;

[0196] The R ring is selected from phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1-4 heteroatoms independently selected from N, O, P and S, 3-7 membered heterocycloalkenylene, 5-6 membered heteroarylene and 4-12 membered fused heterocyclic ring, wherein the phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1-4 heteroatoms independently selected from N, O, P and S, 3-7 membered heterocycloalkenylene, 5-6 membered heteroarylene and 4-12 membered fused heterocyclic ring are optionally substituted by 0-6 R 10 Replacement, R 10 Each occurrence is independently selected from halogen, deuterium, C 1-6 Alkyl, hydroxyl, amino, C 1-6 Haloalkyl, cyano, C 3-6Cycloalkyl, C3-7 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S, -S(O2)R 10a 、-NR 10b R 10c 、-X5-NR 10b R 10c 、-OR 10a AND-X5-OR 10a ; R 10a 、R 10b and R 10c Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl and C 1-6 Haloalkyl; X5 is selected from C 1-6 Alkylene and C 2-6 alkenylene;

[0197] The T ring and the U ring are independently selected from phenylene, pyridinyl, pyrimidinyl and pyrazinyl, wherein the phenylene, pyridinyl, pyrimidinyl and pyrazinyl are optionally substituted by 0-3 groups independently selected from halogen, amino, alkylamino, aminoalkyl, hydroxy, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 Alkyl and C 3-6 Substitution of cycloalkyl groups;

[0198] L1 is selected from the following groups:

[0199] L2 is selected from the following groups:

[0200] wherein Y1, Y2, Y3, Y4, Y5, Y6, and Y7 are independently selected from -O-, -NH-, -NHC(O)-, -NHS(O)-, -NHS(O2)-, -CH2-, -C(O)-, -S(O)-, -S(O2)-, -C(O)NH-, -S(O2)NH-, -CH=CH-, -C≡C-, and a single bond;

[0201] a is an integer from 0 to 5; b and c are each an integer from 0 to 3; d and e are each an integer from 0 to 2; and

[0202] L1 and L2 are optionally replaced by 0-5 R 11 Replacement, R 11 are independently selected from deuterium, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from oxygen, sulfur and nitrogen, -S(O2)R 11a NR 11b R 11c 、-X6-NR11b R 11c 、-OR 11a AND-X6-OR 11a ; R 11a 、R 11b and R 11c Each occurrence is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; X6 is selected from C 1-6 Alkylene and C 2-6 Alkenylene.

[0203] 11. The compound according to any one of claims 1 to 10, wherein the compound is selected from the following structures:

[0204] 12. A pharmaceutical composition, characterized in that it comprises a therapeutically effective dose of the compound according to any one of claims 1 to 11 and a pharmaceutically acceptable carrier or excipient.

[0205] 13. Use of the compound according to any one of claims 1 to 11 or the pharmaceutical composition according to claim 12 for preparing a medicament for treating a MAT2A-related disease; preferably, the MAT2A-related disease is cancer or tumor.

[0206] 14. A method for treating a MAT2A-related disease in a patient, the method comprising administering to the patient a therapeutically effective amount of one or more compounds according to any one of claims 1 to 11 or the pharmaceutical composition according to claim 12; preferably, the MAT2A-related disease is cancer or tumor.

[0207] 15. The compound according to any one of claims 1 to 11 or the pharmaceutical composition according to claim 12, for use in treating a MAT2A-related disease; preferably, the MAT2A-related disease is cancer or tumor. Specific implementation method:

[0208] The present invention will be further described below in conjunction with the examples, which are merely illustrative and are not intended to limit the scope of the present invention in any way. Various modifications made by those skilled in the art based on the teachings of the present invention should all be within the scope of protection required by the claims of this application.

[0209] definition:

[0210] Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this application and have the following meanings:

[0211] "Alkyl" refers to a straight-chain saturated monovalent hydrocarbon group having 1 to 6 carbon atoms or a branched-chain saturated monovalent hydrocarbon group having 3 to 6 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, butyl, pentyl, etc. Those skilled in the art will recognize that the term "alkyl" may include "alkylene" groups.

[0212] Unless otherwise specified, "alkylene" refers to a straight-chain saturated divalent hydrocarbon group having 1 to 6 carbon atoms or a branched-chain saturated divalent hydrocarbon group having 3 to 6 carbon atoms, such as methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.

[0213] The "alkenyl group" refers to a linear monovalent hydrocarbon group having 2 to 6 carbon atoms or a branched monovalent hydrocarbon group having 3 to 6 carbon atoms containing a double bond, for example, propenyl, butenyl, and the like.

[0214] The "alkynyl group" refers to a linear monovalent hydrocarbon group having 2 to 6 carbon atoms or a branched monovalent hydrocarbon group having 3 to 6 carbon atoms containing a triple bond, for example, ethynyl, propynyl, butynyl and the like.

[0215] "Alkoxy" refers to a -OR group where R is alkyl as defined above, for example, methoxy, ethoxy, propoxy or 2-propoxy, n-, iso- or tert-butoxy, and the like.

[0216] "Amino" refers to -NH2.

[0217] "Alkylamino" refers to an -NHR group where R is alkyl as defined above, for example, methylamino, ethylamino, propylamino, or 2-propylamino, and the like.

[0218] "Aryl" refers to a monovalent monocyclic or bicyclic aromatic hydrocarbon group having 3 to 12 ring atoms, for example, phenyl or naphthyl.

[0219] "Aralkyl" refers to an -(alkylene)-R group where R is aryl as defined above, eg, benzyl, phenethyl, and the like.

[0220] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0221] "Haloalkyl" refers to an alkyl group as defined above substituted by 1 to 5 halogen atoms, such as fluorine atoms or chlorine atoms, including groups substituted by different halogens, such as -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, etc. When the alkyl group is substituted only by fluorine, it may be referred to as a fluoroalkyl group in this application.

[0222] "Hydroxyalkyl" refers to a linear monovalent hydrocarbon radical having 1 to 6 carbon atoms or a branched monovalent hydrocarbon radical having 3 to 6 carbon atoms substituted with one or two hydroxy groups, provided that if two hydroxy groups are present, they are not simultaneously on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, and 2-(hydroxymethyl)-3-hydroxypropyl.

[0223] As used herein, "oxo," alone or in combination, refers to =(O).

[0224] As used herein, "pharmaceutically acceptable salts" are intended to include salts of the active compounds prepared with relatively nontoxic acids or bases, depending on the specific substituents found on the compounds described herein. When the compounds disclosed herein contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base (either neat or in a suitable inert solvent). Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, and the like, for example, arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid or phosphorous acid, and salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Also included are salts of amino acids such as arginine salts, and salts of organic acids such as glucuronic acid or galacturonic acid (see, for example, Berge, SM et al., "Pharmaceutically Acceptable Salts," Journal of Pharmaceutical Sciences, 1977, 66, pp. 1-19). Certain specific compounds of the present invention contain both basic and acidic functional groups, which allows the compounds to be converted into base addition salts or acid addition salts.

[0225] The neutral form of the compound can be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties (e.g., solubility in polar solvents), but for the purposes of the present invention, these salts are equivalent to the parent form of the compound.

[0226] The present invention also includes protected derivatives of compounds of the present invention. For example, when compounds of the present invention contain groups such as hydroxyl, carboxyl, thiol, or any group containing one or more nitrogen atoms, these groups may be protected by suitable protecting groups. A complete list of suitable protecting groups can be found in TW Greene, Protective Groups in Organic Synthesis, 5th Edition, John Wiley & Sons, Inc (2014), the disclosure of which is incorporated herein by reference in its entirety. Protected derivatives of compounds of the present invention can be prepared by methods well known in the art.

[0227] The present invention also includes prodrugs of the compounds, or pharmaceutically acceptable salts thereof. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide compounds of the present invention. An example of a prodrug, without limitation, is a compound administered as an ester ("prodrug") that is then metabolically hydrolyzed to a carboxylic acid, the active entity. In addition, prodrugs can be converted into compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, when a prodrug is placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent, it can be slowly converted into a compound of the present invention.

[0228] The compounds disclosed herein can exist in unsolvated forms as well as solvated forms, including hydrated forms. Generally, solvated forms are equivalent to unsolvated forms and are intended to be included within the scope of the present invention. Certain compounds of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-J), (I-K), (I-L), (I-M), (I-N), (I-O), (I-P), (I-Q), (I-R), (I-S), (I-T), (I-U), (I-V), (I-W), (I-X), (I-Y) and (I-Z) can exist in a variety of crystalline or amorphous forms. Generally, all physical forms, such as polymorphs, are equivalent for the intended uses of the present disclosure and are intended to fall within the scope of the present disclosure.

[0229] The compounds disclosed herein have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers, and individual isomers (e.g., individual enantiomers) are all intended to be included within the isomer scope of the compounds of the present invention. When stereochemical descriptions are shown, this refers to compounds in which one isomer is present and substantially free of the other isomer. "Substantially free" of the other isomer means that the ratio of the two isomers is at least 80 / 20, more preferably 90 / 10, or 95 / 5 or higher.

[0230] In some embodiments, one of the isomers will be present in an amount of at least 99%. The compounds disclosed herein may also contain unnatural amounts of isotopes on one or more atoms that make up such compounds. An unnatural amount of an isotope can be defined as the amount found in nature of the atom in question to 100%. It differs only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, for example, 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 32 P. 33 P. 35 S. 18 F. 36 Cl, 123 I and 125 I. Isotope-labeled compounds (e.g., 3 H and 14 C-labeled compounds) can be used in compound or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are useful because of their ease of preparation and detectability. In addition, heavier isotopes such as deuterium (i.e. 2 H) substitution may provide certain therapeutic advantages due to better metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, in the compounds disclosed herein, one or more hydrogen atoms are replaced by 2 H or 3 H, or one or more carbon atoms are replaced 13 C-or 14 C-enriched carbon substitution. Positron-emitting isotopes (e.g. 15 O. 13 N. 11 C and 15 F) can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy.

[0231] Isotopically labeled compounds can generally be prepared by following steps similar to those disclosed in the Examples of the present invention, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0232] "Pharmaceutically acceptable carrier or excipient" refers to a carrier or excipient that can be used to prepare a pharmaceutical composition and is generally safe, non-toxic, and not biologically or otherwise undesirable, and includes carriers or excipients that are acceptable for veterinary use as well as human pharmaceutical use. "Pharmaceutically acceptable carrier / excipient" as used in the specification and claims includes one or more such excipients.

[0233] As used herein, "disease" is intended to be generally synonymous with the terms "disorder," "condition," and "condition" (as in medical condition) and are used interchangeably because they all reflect an abnormal condition of the human or animal body or a part thereof that impairs the normal functioning, usually manifests as distinctive signs and symptoms, and results in a shortened lifespan or reduced quality of life in the human or animal.

[0234] "Patient" is generally synonymous with the term "subject" and, as used herein, includes all mammals (including humans). Examples of patients include humans, livestock (e.g., cows, goats, sheep, pigs, and rabbits), and companion animals (e.g., dogs, cats, rabbits, and horses). Preferably, the patient is a human.

[0235] As used herein, "in need of treatment" refers to a judgment made by a physician or other caregiver that a subject requires or will benefit from treatment. This judgment is based on a variety of factors within the physician's or caregiver's expertise.

[0236] "Administering," "administering," and the like, when used with respect to, for example, a patient, cell, tissue, organ, or biological fluid, refers to contacting a compound disclosed herein, a pharmaceutical composition comprising the same, or a diagnostic agent with a subject, cell, tissue, organ, or biological fluid. In the case of cells, administration includes contacting an agent with a cell (e.g., in vitro or ex vivo), as well as contacting an agent with a fluid, wherein the fluid is in contact with the cell.

[0237] As used herein, a "therapeutically effective amount" refers to an amount, for example, of a compound disclosed herein or an embodiment described herein, that is sufficient to affect the treatment of a disease when administered alone or as part of a pharmaceutical composition and in a single dose or as part of a series of doses to a patient treating a disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc. of the mammal to be treated. The therapeutically effective amount can be determined by measuring the relevant physiological effects and can be adjusted in conjunction with the dosing regimen and diagnostic analysis of the subject's condition. For example, measuring the serum level of a compound disclosed herein (or its metabolite) at a specific time after administration can indicate whether a therapeutically effective amount has been used.

[0238] "Treatment" or "treatment" of a disease includes:

[0239] (1) preventing a disease, that is, preventing the development of clinical symptoms of a disease in a mammal that may be exposed to or susceptible to the disease but does not yet experience or display symptoms of the disease;

[0240] (2) inhibit the disease, i.e., prevent or alleviate the development of the disease or its clinical symptoms; or

[0241] (3) Relieve the disease, that is, cause the disease or its clinical symptoms to disappear.

[0242] References to "inhibiting," "reducing," or any variation of these terms with respect to MAT2A include any measurable reduction or complete inhibition to achieve the desired result. For example, a reduction in MAT2A activity can be about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more, or any derivable range thereof, compared to its normal activity.

[0243] Abbreviations of substances used in the present invention and their corresponding full names DIEA N,N-diisopropylethylamine DCE dichloroethane DMF N,N-dimethylformamide TBTU O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate THF tetrahydrofuran NaHMDS sodium bis(trimethylsilyl)amide PE petroleum ether EA ethyl acetate DEAD diethyl azodicarboxylate SEMCl 2-(trimethylsilyl)ethoxymethyl chloride NBS N-bromosuccinimide TFA trifluoroacetic acid Boc tert-butyloxycarbonyl SFC supercritical fluid chromatography DMAP 4-dimethylaminopyridine DTT dithiothreitol L23 polyoxyethylene lauryl ether BGG, bovine serum gamma globulin HATU, 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate EDCI, 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide HOBT, 1-hydroxybenzotriazole DCC, N,N'-dicyclohexylcarbodiimide NMP, N-methylpyrrolidone PyBOP, 1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate DABCO, triethylenediamine SEM: (trimethylsilyl)ethoxymethyl

[0244] Example 1

[0245] Synthesis route

[0246] Step 1: Synthesis of compound 1-2

[0247] Dissolve 2-fluoro-4-chlorobenzamide (1.7 g, 10 mmol) in dichloroethane (30 mL). Slowly add oxalyl chloride (1.9 g, 15 mmol) dropwise at 0°C under nitrogen. After the addition is complete, heat and stir at 60°C until TLC indicates completion of the reaction. After the reaction mixture cools to room temperature, remove the solvent and excess oxalyl chloride on a rotary evaporator to obtain a solid mixture for later use.

[0248] The solid mixture obtained in the previous step was dissolved in dichloroethane (10 mL). Under nitrogen protection, this solution was slowly added dropwise to a dichloroethane solution (10 mL) of p-vinylaniline (1.3 g, 11 mmol) at 0°C. After the addition was complete, the mixture was allowed to react at room temperature for 1 hour until a large amount of white solid precipitated. The solid was filtered, and the filter cake was washed with dichloromethane and dried to obtain compound 1-2, 3.0 g, with a yield of 94%. LC-MS (ESI) m / z: 319 [M+H] + .

[0249] Step 2: Synthesis of Compound 1-3

[0250] Compound 1-2 (2.6 g, 8 mmol) was dissolved in DMF (50 mL), and NaHMDS (8 mL, 2 M in THF) was slowly added dropwise at 0°C under nitrogen. After the addition was complete, the mixture was heated and stirred at 100°C until TLC indicated the reaction was complete.

[0251] After the reaction mixture was cooled to room temperature, it was poured into ice water (20 mL), stirred, and extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with water (50 mL × 3), and dried over anhydrous sodium sulfate. The dried organic phase was evaporated to remove the solvent on a rotary evaporator, and the resulting residue was purified by column chromatography to obtain product 1-3, 1.9 g, with a yield of 78%. LC-MS (ESI) m / z: 299 [M+H] + .

[0252] Step 3: Synthesis of Compound 1-4

[0253] Dissolve compound 1-3 (0.3 g, 1 mmol) and N,N-diisopropylethylamine (0.3 g, 2 mmol) in anhydrous acetonitrile (10 mL). Add phosphorus oxychloride (0.3 g, 2 mmol) slowly dropwise at 0°C under nitrogen. After the addition is complete, heat and stir at 80°C until TLC indicates completion of the reaction. After the reaction mixture cools to room temperature, remove the solvent on a rotary evaporator to obtain a solid mixture for later use.

[0254] Step 4: Synthesis of Compound 1-5

[0255] A solution of dimethylamine (1 mL, 2 M in THF) was added dropwise to a solution of compound 1-4 in anhydrous tetrahydrofuran at 0°C and stirred at room temperature until TLC showed the reaction was complete.

[0256] The reaction mixture was poured into ice water (20 mL), stirred, and extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with water (50 mL x 3), and dried over anhydrous sodium sulfate. The dried organic phase was evaporated to remove the solvent on a rotary evaporator, and the resulting residue was purified by column chromatography to obtain product 1-5, 0.26 g, with a yield of 80%. LC-MS (ESI) m / z: 326 [M+H] + .

[0257] Step 5: Synthesis of compound 1-9

[0258] The synthesis of compound 1-9 refers to the synthesis of compound 1-5, except that p-vinylaniline in step 1 is replaced by p-bromoaniline.

[0259] Step 6: Synthesis of Compound 1

[0260] Compound 1-5 (0.16 g, 0.5 mmol), compound 1-9 (0.19 g, 0.5 mmol), pyridine (0.16 g, 2 mmol), zinc powder (0.03 g, 0.5 mmol) and (Ph3P)2Pd(II)Cl2 (0.04 g, 0.05 mmol) were dissolved in acetonitrile (10 mL) and heated with stirring at 80 ° C under nitrogen protection until TLC showed the reaction was complete.

[0261] The reaction mixture was poured into ice water (20 mL), stirred, and extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with water (50 mL x 3), and dried over anhydrous sodium sulfate. The dried organic phase was evaporated to remove the solvent on a rotary evaporator. The resulting residue was purified by column chromatography to obtain a crude product. After purification by HPLC, compound 1 was obtained, 71 mg, with a yield of 23%. LC-MS (ESI) m / z: 312.1 [M / 2+H]. + .

[0262] Example 2

[0263] Synthesis route

[0264] Step 1: Synthesis of compound 2

[0265] Compound 1 (62 mg, 0.1 mmol) was dissolved in methanol (10 mL). The atmosphere was replaced with nitrogen three times and stirred for 10 minutes. 10% palladium carbon (10 mg) was added and the atmosphere was replaced with hydrogen three times. The reaction was continued by stirring under a hydrogen atmosphere until TLC showed that the reaction was complete.

[0266] The reaction mixture was filtered through celite and poured into ice water (20 mL), stirred, and extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with water (50 mL x 3), and dried over anhydrous sodium sulfate. The dried organic phase was evaporated to remove the solvent on a rotary evaporator, and the resulting residue was purified by column chromatography to obtain the crude product. After purification by HPLC, compound 2 was obtained, 53 mg, in a 95% yield. LC-MS (ESI) m / z: 279.1 [M / 2+H]. + . 1 H NMR (600MHz, DMSO) δ8.01(d,J=8.2Hz,2H),7.51(d,J=8.1Hz,4H),7.46(t,J=7.9Hz,2H),7.2 2(d,J=8.1Hz,4H),7.15(t,J=7.7Hz,2H),6.45(d,J=8.5Hz,2H),3.31(s,12H),3.07(s,4H).

[0267] Example 3

[0268] Synthesis route

[0269] Step 1: Synthesis of compound 3-1

[0270] Dissolve m-iodoaniline (5.0 g, 22.8 mmol) in dichloromethane (15 mL), add di-tert-butyl dicarbonate (15.72 mL, 68.5 mmol) at room temperature, and stir overnight until TLC shows the reaction is complete.

[0271] The reaction mixture was poured into ice water (40 mL), stirred, and extracted with dichloromethane (40 mL x 3). The combined organic phases were washed with water (100 mL x 3), and dried over anhydrous sodium sulfate. The dried organic phase was evaporated to remove the solvent on a rotary evaporator, and the resulting residue was purified by column chromatography to obtain product 3-1, 7.0 g, with a yield of 96%. LC-MS (ESI) m / z: 220 [M+H-100] + .

[0272] Step 2: Synthesis of compound 3-2

[0273] Compound 3-1 (4.0 g, 12.5 mmol) and 1H-cyanoimidazole (1.4 g, 15.0 mmol) were dissolved in N,N-dimethylformamide (17 mL) and cesium carbonate (8.16 g, 25 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (0.45 mL, 10% wt), and cuprous iodide (0.40 g, 10% wt) were added sequentially. The mixture was heated to 100°C under a nitrogen atmosphere and reacted overnight. The reaction mixture was extracted with ethyl acetate and water, and the organic phases were combined and dried over anhydrous sodium sulfate. The dried organic phase was evaporated to remove the solvent on a rotary evaporator, and the resulting residue was purified by column chromatography to obtain compound 3-2, 1.97 g, in a 55% yield. LC-MS (ESI) m / z: 285 [M+H] + .

[0274] Step 3: Synthesis of compound 3-3

[0275] Compound 3-2 (1.5 g, 2.79 mmol) was dissolved in tetrahydrofuran (50 mL). 2.5 M LiAlH4 / THF (4.2 mL) was slowly added dropwise at 0°C. The mixture was gradually heated to 75°C and allowed to react for 20 min. The mixture was filtered through celite, washed with tetrahydrofuran, and the filtrate was concentrated to dryness to obtain crude compound 3-3 as a yellow oil, which was used directly in the next step. LC-MS (ESI) m / z: 189 [M+H] + .

[0276] Step 4: Synthesis of compound 3-4

[0277] 4-Chloro-2-fluorobenzamide (2.76 g, 16.0 mmol) was dissolved in 1,2-dichloroethane (30 mL). Oxalyl chloride (2.0 mL, 23.9 mmol) was slowly added dropwise at 0°C. The mixture was heated to 55°C for one hour, then raised to 80°C and allowed to react overnight. TLC monitoring indicated the near disappearance of the starting material, and the reaction solution was directly evaporated to dryness to yield the corresponding isocyanate intermediate. This intermediate was quickly dissolved in dichloroethane (DCE) (2 mL) and added dropwise to a mixture of compound 3-3 and DCE (5 mL) in an ice-water bath, gradually warming to room temperature. The reaction solution was dried over anhydrous sodium sulfate, and the dried organic phase was evaporated on a rotary evaporator to remove the solvent. The resulting residue was purified by column chromatography to yield compound 3-4 (1.1 g, 36%) as a white solid. LC-MS (ESI) m / z: 587 [M+H] + .

[0278] Step 5: Synthesis of compound 3-5

[0279] To a mixture of compound 3-4 (500 mg, 0.85 mmol) in tetrahydrofuran (15 mL) and N,N-dimethylformamide (0.5 mL) was slowly added dropwise 2M NaHMDS / THF (2.5 mL) at 0°C. The mixture was heated to 75°C and allowed to react for 1.5 days. TLC monitoring indicated that the starting material had essentially disappeared. The reaction solution was dried over anhydrous sodium sulfate, and the organic phase was evaporated on a rotary evaporator to remove the solvent. The resulting residue was purified by column chromatography to yield compound 3-5 (100 mg, 21%) as a white solid. LC-MS (ESI) m / z: 547 [M+H] + .

[0280] Step 6: Synthesis of compound 3

[0281] Compound 3-5 (100 mg, 0.18 mmol) was dispersed in acetonitrile (10 mL), and DIEA (0.3 mL, 1.8 mmol) and POCl3 (0.85 mL, 0.92 mmol) were added at 0°C. The temperature was raised to 80°C and refluxed overnight. TLC monitoring showed that the starting material had essentially disappeared. The reaction solution was spin-dried to dryness, and a solution of dimethylamine in tetrahydrofuran (3 mL) was quickly added and stirred at room temperature. TLC monitoring showed that the starting material had essentially disappeared. The reaction solution was dried over anhydrous sodium sulfate, and the dried organic phase was evaporated to remove the solvent on a rotary evaporator. The resulting residue was purified by column chromatography to obtain a crude product, which was then purified by HPLC to obtain compound 3, 57 mg, with a yield of 53%. LC-MS (ESI) m / z: 301.1 [M / 2+H]. + . 1 H NMR (400MHz, DMSO-d6) δ8.32(s,1H),8.05(d,J=8.8Hz,1H),7.96(d,J=8.8Hz,1H),7.81(d,J=8.2Hz,1H),7.68(dd,J=10.5,5.2H z, 3H), 7.27 (d, J = 7.8Hz, 1H), 7.19 (ddd, J = 15.2, 8.8, 2.0Hz, 2H), 6.43 (d, J = 2.0Hz, 1H), 5.20 (s, 2H), 3.31 (s, 6H), 3.24 (s, 6H).

[0282] Example 4

[0283] Synthesis route

[0284] Step 1: Synthesis of compound 4

[0285] Compound 3-5 (100 mg, 0.18 mmol) was dispersed in acetonitrile (10 mL), and DIEA (0.3 mL, 1.8 mmol) and POCl3 (0.85 mL, 0.92 mmol) were added at 0°C. The temperature was raised to 80°C and refluxed overnight. TLC monitoring showed that the starting material had essentially disappeared. The reaction solution was spin-dried to dryness, and a solution of methylamine in tetrahydrofuran (3 mL) was quickly added and stirred at room temperature. TLC monitoring showed that the starting material had essentially disappeared. The reaction solution was dried over anhydrous sodium sulfate, and the dried organic phase was evaporated to remove the solvent on a rotary evaporator. The resulting residue was purified by column chromatography to obtain a crude product, which was then purified by HPLC to obtain compound 4, 0.53 g, with a yield of 49%. LC-MS (ESI) m / z: 287.1 [M / 2+H]. + .

[0286] Example 5

[0287] Synthesis route

[0288] Step 1: Synthesis of compound 5

[0289] Compound 3 (30 mg, 0.05 mmol) was dissolved in methanol (10 mL). The atmosphere was replaced with nitrogen three times and stirred for 10 minutes. 10% palladium carbon (10 mg) was added and the atmosphere was replaced with hydrogen three times. The reaction was continued by stirring under a hydrogen atmosphere until TLC showed that the reaction was complete.

[0290] The reaction mixture was filtered through celite and poured into ice water (20 mL), stirred, and extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with water (50 mL x 3), and dried over anhydrous sodium sulfate. The dried organic phase was evaporated to remove the solvent on a rotary evaporator, and the resulting residue was purified by column chromatography to obtain the crude product. After preparative purification by HPLC, compound 5 was obtained, 23 mg, in an 88% yield. LC-MS (ESI) m / z: 267.1 [M / 2+H]. + .

[0291] Example 6

[0292] Synthesis route

[0293] Step 1: Synthesis of compound 6

[0294] Compound 4 (60 mg, 0.1 mmol) was dissolved in methanol (10 mL). The atmosphere was replaced with nitrogen three times and stirred for 10 minutes. 10% palladium carbon (20 mg) was added and the atmosphere was replaced with hydrogen three times. The reaction was continued by stirring under a hydrogen atmosphere until TLC showed that the reaction was complete.

[0295] The reaction mixture was filtered through celite and poured into ice water (20 mL), stirred, and extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with water (50 mL x 3), and dried over anhydrous sodium sulfate. The dried organic phase was evaporated to remove the solvent on a rotary evaporator, and the resulting residue was purified by column chromatography to obtain the crude product. After purification by HPLC, compound 6 was obtained, 38 mg, in a 73% yield. LC-MS (ESI) m / z: 253.1 [M / 2+H]. + .

[0296] Example 7

[0297] Synthesis route

[0298] Step 1: Synthesis of compound 7-1

[0299] Methyl m-hydroxybenzoate (1 g, 6.58 mmol) was dissolved in 20 mL of anhydrous acetonitrile at room temperature. Methyl 3-bromomethylbenzoate (1.5 g, 6.59 mmol) and cesium carbonate (4.3 g, 13.11 mmol) were added, and the mixture was heated to 80°C and stirred for 3 hours. TLC monitored the reaction completion, and extraction was repeated three times with 50 mL of water and 150 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated to afford compound 7-1, 1.97 g, in a 99% yield. LC-MS (ESI) m / z: 301 [M+H] + .

[0300] Step 2: Synthesis of compound 7-2

[0301] At room temperature, compound 7-1 (600 mg, 2 mmol) was dissolved in 10 mL of DMF. After cooling the system to 0°C, a 2.5 N solution of lithium aluminum hydride in THF (2.4 mL, 6 mmol) was slowly added dropwise. The mixture was then slowly warmed to room temperature and stirred for 30 minutes. TLC and LCMS monitored the reaction for completion. The reaction was quenched with water, and the aqueous phase was extracted three times with EA. The resulting mixture was concentrated and purified by flash chromatography (PE:EA = 2:1) to afford compound 7-2, 0.42 g, in an 86% yield. LC-MS (ESI) m / z: 245 [M+H] + .

[0302] Step 3: Synthesis of compound 7-3

[0303] At room temperature, compound 7-2 (420 mg, 1.71 mmol) was dissolved in 10 mL of DCM, and Dess-Martin periodinane (1.76 g, 4.15 mmol) was slowly added in portions. The mixture was stirred at room temperature for 16 hours. A gray suspension was obtained after the reaction. TLC and LCMS monitored the reaction for completion. Sodium bicarbonate solution was added to quench the reaction, and the organic phase was extracted three times with DCM. The combined organic phases were concentrated and separated by flash column chromatography (PE:EA, 0-70%, 10 minutes) to afford compound 7-3, 0.40 g, in a 97% yield. LC-MS (ESI) m / z: 241 [M+H] + .

[0304] Step 4: Synthesis of compound 7

[0305] At room temperature, compound 7-3 (90 mg, 0.373 mmol) was dissolved in 5 mL of anhydrous ethanol, p-toluenesulfonyl hydrazide (140 mg, 0.753 mmol) was added, and the mixture was stirred at room temperature for 1 hour. TLC monitored the compound for 3 hours and new spots were generated. 5-bromoisatin (170 mg, 0.756 mmol) and potassium carbonate (310 mg, 2.246 mmol) were then added, and the temperature was raised to 80 ° C. and stirred overnight. LCMS monitored the reaction to be complete, and the reaction solution was diluted with 30 mL of DCM and 10 mL of MeOH and filtered. The filtrate was slurried with EtOH and purified by HPLC to obtain compound 7, 52 mg, with a yield of 20%. LC-MS (ESI) m / z: 659.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.38(s,2H),9.57(s,2H),7.58(d,J=4.7Hz,2H),7.51–7.44(m,4H),7.34–7.27(m,3H),7. 15(dd,J=8.3,2.6Hz,1H),7.10(dd,J=4.4,2.2Hz,2H),7.03–7.00(m,1H),6.91(dt,J=7.5,1.2Hz,1H),5.22(s,2H).

[0306] Example 8

[0307] Synthesis route

[0308] Step 1: Synthesis of compound 8

[0309] The synthesis method of compound 8 refers to step 4 in Example 7, except that 5-bromo-7-aza-isatin is replaced by 5-bromo-7-aza-isatin. LC-MS (ESI) m / z: 661.0 [M+H] + .

[0310] Example 9

[0311] Synthesis route

[0312] Step 1: Synthesis of compound 9-1

[0313] Methyl isonicotinate (1.0 g, 7.3 mmol) was dissolved in 50 mL of methanol at room temperature, 0.2 mL of concentrated sulfuric acid was added, and the temperature was raised to 65°C. Ammonium persulfate (15 g, 65.79 mmol) was then dissolved in 25 mL of water and added dropwise to the reaction system. The mixture was refluxed at 70°C with stirring for 3 hours. TLC monitored the reaction completion, and the reaction was concentrated to remove the excess methanol. The reaction was then extracted three times with 50 mL of water and 150 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated to afford compound 9-1, a red solid (0.6 g, 52% yield). LC-MS (ESI) m / z: 168 [M+H]. + . Step 2: Synthesis of compound 9-2

[0314] Compound 9-1 (600 mg, 3.593 mmol) was dissolved in 20 mL of THF at room temperature. Methyl m-hydroxybenzoate (550 mg, 3.618 mmol) and triphenylphosphine (1.2 g, 4.563 mmol) were added. The temperature was lowered to 0°C, and DEAD (750 mg, 4.310 mmol) was slowly added dropwise. The mixture was then warmed to room temperature and stirred for 20 minutes. TLC monitored the reaction completion. The mixture was extracted three times with sodium bicarbonate solution and EA. After concentration, the mixture was separated and purified by flash chromatography (PE:EA, 0-50%, 15 min) to obtain compound 9-2 as a white solid (1.0 g, 93% yield). LC-MS (ESI) m / z: 302 [M+H] + .

[0315] Step 3: Synthesis of compound 9-3

[0316] At room temperature, compound 9-2 (1 g, 3.32 mmol) was dissolved in 20 mL of DMF. After cooling the system to 0°C, a 2.5 N solution of lithium aluminum hydride in THF (2.6 mL, 6.5 mmol) was slowly added dropwise. The mixture was then slowly warmed to room temperature and stirred for 30 minutes. TLC and LCMS confirmed the reaction was complete. The reaction was quenched with water, and the aqueous phase was extracted three times with EA. After concentration, the mixture was purified by flash chromatography (PE:EA = 2:1) to afford 550 mg of compound 9-3 as a yellow oil in a 68% yield. LC-MS (ESI) m / z: 246 [M+H] + .

[0317] Step 4: Synthesis of compound 9-4

[0318] At room temperature, compound 9-3 (550 mg, 2.236 mmol) was dissolved in 20 mL of DCM. Dess-Martin periodinane (2.27 g, 5.354 mmol) was slowly added in portions and stirred at room temperature for 16 hours. The reaction was completed, resulting in a dark green suspension. TLC and LCMS monitored the reaction for completion. Sodium bicarbonate solution was added to quench the reaction. The organic phase was extracted three times with DCM. The combined organic phases were concentrated and separated by flash column chromatography (PE:EA, 0-70%, 10 minutes) to afford compound 9-4 as a white solid (260 mg, 48% yield). LC-MS (ESI) m / z: 242 [M+H] + .

[0319] Step 5: Synthesis of compound 9

[0320] At room temperature, compound 9-4 (100 mg, 0.413 mmol) was dissolved in 5 mL of anhydrous ethanol, p-toluenesulfonyl hydrazide (160 mg, 0.860 mmol) was added, and the mixture was stirred at room temperature for 1 hour. TLC monitored the compound for 3 hours and new spots were generated. 5-bromoisatin (280 mg, 1.244 mmol) and potassium carbonate (340 mg, 2.464 mmol) were then added, and the temperature was raised to 80 ° C. and stirred overnight. LCMS monitored the reaction to be complete, and the reaction solution was diluted with 30 mL of DCM and 10 mL of MeOH and filtered. The filtrate was slurried with EtOH and purified by HPLC to obtain a white solid compound 9, 36 mg, with a yield of 13%. LC-MS (ESI) m / z: 660.0 [M+H] + .

[0321] Example 10

[0322] Synthesis route

[0323] Step 1: Synthesis of compound 10

[0324] The synthesis method of compound 10 refers to step 5 in Example 9, except that 5-bromo-7-aza-isatin is replaced by 5-bromo-isatin. LC-MS (ESI) m / z: 662.0 [M+H] + .

[0325] Example 11

[0326] Synthesis method

[0327] The synthesis method of compound 11 is similar to that of Example 3, except that 2-fluoro-4-chlorobenzamide in step 4 is replaced with 2-fluoro-4-trifluoromethylbenzamide. LC-MS (ESI) m / z: 335.1 [M / 2+H]+ .

[0328] Example 12

[0329] Synthesis route

[0330] Step 1: Synthesis of compound 12-1

[0331] 5-Bromoindigo carmine (3.0 g, 13.3 mmol) was dissolved in DMF (22 mL), potassium carbonate (3.7 g, 26.6 mmol) and SEMCl (3.3 g, 20.0 mmol) were added, and the mixture was stirred at room temperature overnight. TLC analysis indicated the near disappearance of the starting material. The reaction mixture was then dried, and the residue was purified by silica gel column chromatography (EA:PE = 1:19) to afford compound 12-1 (3.4 g, 72% yield) as a red solid. LC-MS (ESI) m / z: 356 [M+H] + .

[0332] Step 2: Synthesis of compound 12-2

[0333] m-Iodobenzaldehyde (2.22 g, 9.6 mmol) and p-methylbenzenesulfonylhydrazide (1.78 g, 9.6 mmol) were stirred in EtOH (15 mL) at room temperature for 1 hour. The starting material was essentially gone by TLC. Potassium carbonate (2.64 g, 1.84 mmol) and compound 12-1 (2.64 g, 9.6 mmol) were added sequentially. The mixture was heated to 80°C under a nitrogen atmosphere and allowed to react overnight. The starting material essentially disappeared by TLC. The reaction solution was spin-dried and the residue was purified by silica gel column chromatography (EA:PE = 1:24) to afford compound 12-2, 3.03 g, 56% yield, as a red oil. LC-MS (ESI) m / z: 572 [M+H] + .

[0334] Step 3: Synthesis of compound 12-3

[0335] Compound 12-2 (3.03 g, 5.3 mmol) was dissolved in tetrahydrofuran (25 mL), and potassium carbonate (732 mg, 5.3 mmol) and dimethyl sulfate (0.61 mL, 6.4 mmol) were added sequentially. The mixture was stirred at room temperature overnight. Extraction with EA / H2O was performed, and the organic phase was dried to afford compound 12-3 (3.40 g, 95% yield) as a red solid. LC-MS (ESI) m / z: 586 [M+H] + .

[0336] Step 4: Synthesis of compound 12-4

[0337] Compound 12-3 (1.5 g, 2.6 mmol) and 1H-cyanoimidazole (286 mg, 3.1 mmol) were dissolved in N,N-dimethylformamide (20 mL) and cesium carbonate (1.67 g, 5.1 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (0.17 mL, 10% wt), and cuprous iodide (150 mg, 10% wt) were added sequentially. The mixture was heated to 100°C under a nitrogen atmosphere and allowed to react overnight. The reaction mixture was extracted with ethyl acetate and water, and the organic phases were combined, concentrated, and purified by silica gel column chromatography (EA:PE = 1:2) to afford compound 12-4, 460 mg, in a 33% yield. LC-MS (ESI) m / z: 551 [M+H] + .

[0338] Step 5: Synthesis of compound 12-5

[0339] Compound 12-4 (198 mg, 0.36 mmol) was dispersed in 7N NH3 / MeOH (30 mL), and Raney nickel (200 mg) was added. The mixture was stirred at room temperature under a H2 atmosphere for 2 hours. TLC analysis showed almost no starting material. The reaction solution was purified by C-18 reverse-phase column chromatography to obtain compound 12-5 (180 mg, 91% yield) as a white solid. LC-MS (ESI) m / z: 555 [M+H] + .

[0340] Step 6: Synthesis of compound 12-6

[0341] 4-Chloro-2-fluorobenzamide (100 mg, 0.58 mmol) was dissolved in 1,2-dichloroethane (3 mL), and oxalyl chloride (0.07 mL, 0.87 mmol) was slowly added dropwise at 0 ° C. The mixture was heated to 55 ° C. and reacted for 1 hour. The reaction mixture was then heated to 80 ° C. and allowed to react overnight. TLC monitoring showed that the raw material had basically disappeared, and the reaction solution was directly spin-dried to obtain the corresponding isocyanate intermediate. It was dissolved in DCE (1 mL) as quickly as possible and added dropwise to a DCE (1 mL) mixture dispersed with compound 12-5 (180 mg, 0.32 mmol) under an ice-water bath, and gradually warmed to room temperature. The reaction solution was filtered to obtain compound 12-6, 40 mg, with a yield of 25%, as a white solid. LC-MS (ESI) m / z: 754 [M + H] + .

[0342] Step 7: Synthesis of compound 12-7

[0343] 2M NaHMDS / THF (120 μL) was slowly added dropwise to a mixture of compound 12-6 (50 mg, 66.4 μmol) in tetrahydrofuran (2 mL) at 0°C, heated to 80°C, and reacted for 4 hours. The reaction solution was spin-dried and purified by HPLC to obtain compound 12-7, 12 mg, with a yield of 22%, as a white solid. The above experiment was repeated to obtain compound 12-7 (30 mg). LC-MS (ESI) m / z: 734 [M+H] + .

[0344] Step 8: Synthesis of compound 12-8

[0345] Compound 12-7 (15 mg, 20.5 μmol) was dispersed in acetonitrile (3 mL). DIEA (0.3 mL) and POCl3 (0.1 mL) were added at 0°C, and the mixture was heated to 80°C and refluxed overnight. TLC analysis indicated the near disappearance of the starting material. The reaction mixture was then spin-dried to dryness, and a solution of dimethylamine in tetrahydrofuran (3 mL) was quickly added, followed by stirring at room temperature. Pre-TLC purification (MeOH:DCM = 1:10) afforded compound 12-8, 14 mg, in a 90% yield, as a yellow solid. LC-MS (ESI) m / z: 761 [M+H] + .

[0346] Step 9: Synthesis of compound 12

[0347] Compound 12-8 (14 mg) was dissolved in DCM (3 mL) and BBr3 was added dropwise at 0°C. The mixture was stirred for 10 minutes and then at room temperature for 3 hours. The reaction solution was dried and purified by HPLC to obtain compound 9 (5 mg, 44% yield). LC-MS (ESI) m / z: 309.0 [M / 2+H] + .

[0348] Example 13

[0349] Synthesis route

[0350] Synthesis method

[0351] Steps 1, 2, and 3 in the synthesis of compound 13 refer to steps 7, 8, and 9 in Example 12, respectively. LC-MS (ESI) m / z: 270.1 [M / 2+H] + Example 14

[0352] Synthesis method

[0353] The synthesis method of compound 14 is similar to that of Example 3, except that 2-fluoro-4-chlorobenzamide in step 4 is replaced with 2-fluoro-4-trifluoromethylbenzamide, and dimethylamine in the last step is replaced with azetidine. LC-MS (ESI) m / z: 347.1 [M / 2+H] + . 1 H NMR(600MHz,DMSO-d6)δ8.40-8.33(m,1H),8.05(d,J=8.4Hz, 1H),7.96(d,J=8.2Hz,1H),7.93(s,1H),7.83(dd,J=8.2,2.4Hz,1H),7.73-7.71(m,1H),7.71-7.68(m,2H),7.48(dd,1H),7.44(d,J= 8.5Hz,1H),7.30(dd,J=7.7,1.8Hz,1H),6.63(d,J=1.6Hz,1H),5.28(s,2H),5.02-4.54(m,4H),4.47-4.13(m,4H),2.46-2.38(m,4H).

[0354] Example 15

[0355] Synthesis method

[0356] The synthesis method of compound 15 is similar to that of Example 3, except that 2-fluoro-4-chlorobenzamide in step 4 is replaced with 2-fluoro-4-trifluoromethylbenzamide, and dimethylamine in the last step is replaced with 3-hydroxyazetidine hydrochloride. LC-MS (ESI) m / z: 363.1 [M / 2+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.31(s,1H),8.06(d,J=8.4Hz,1H),7.97(d,J=8.4Hz,1H),7.93(s ,1H),7.85-7.79(m,1H),7.74-7.65(m,3H),7.46(d,J=8.7Hz,1H),7.42(d,J=8.4Hz,1H), 7.28(d,1H),6.62(s,1H),5.98(d,J=5.9Hz,1H),5.90(d,J=5.9Hz,1H),5.27(s,2H),5.09 -4.75(m,2H),4.69-4.63(m,1H),4.62-4.58(m,1H),4.55-4.24(m,4H),4.26-3.73(m,2H).

[0357] Example 16

[0358] Synthesis method

[0359] The synthesis method of compound 16 is similar to that of Example 3, except that 2-fluoro-4-chlorobenzamide in step 4 is replaced with 2-fluoro-4-trifluoromethylbenzamide, and dimethylamine in the last step is replaced with pyrrolidine. LC-MS (ESI) m / z: 361.1 [M / 2+H] + . 1 H NMR (600MHz, DMSO-d6) δ8.37(d,J=8.5Hz,1H),8.33(s,1H),8.27(d,J=8.6Hz,1H),7.94(s,1H),7.82(d,J=8.3Hz,1H),7.74(s,1H),7.72-7.6 7(m,2H),7.48(d,J=8.6Hz,1H),7.43(d,J=8.5Hz,1H),7.29(d,J=7.8H z,1H),6.63(s,1H),5.27(s,2H),3.96-3.74(m,8H),2.03-1.88(m,8H).

[0360] Example 17

[0361] Synthesis method

[0362] The synthesis method of compound 17 is similar to that of Example 3, except that 2-fluoro-4-chlorobenzamide in step 4 is replaced with 2-fluoro-4-trifluoromethylbenzamide, and dimethylamine in the last step is replaced with cyclobutylamine. LC-MS (ESI) m / z: 361.1 [M / 2+H] + . 1 H NMR (600MHz, DMSO-d6) δ8.82(d,J=6.8Hz,1H),8.61(d,J=6.9Hz,1H),8.49(d,J=8.4Hz,1H),8.39(d, J=8.4Hz,1H),8.31(s,1H),7.88(s,1H),7.82(dd,J=8.3,2.3Hz,1H),7.74(d,J=2.3Hz,1H),7.71-7.6 6(m,2H),7.59(dd,J=8.5,1.7Hz,1H),7.52(d,J=8.4Hz,1H),7.30(dd,J=7.9,1.8Hz,1H),6.60(s,1H) ,5.26(s,2H),4.67(dd,J=23.8,8.0Hz,2H),2.36-2.26(m,4H),2.24-2.10(m,4H),1.81-1.68(m,4H).

[0363] Example 18

[0364] Synthesis method

[0365] The synthesis method of compound 18 is similar to that of Example 3, except that 2-fluoro-4-chlorobenzamide in step 4 is replaced with 2-fluoro-4-trifluoromethylbenzamide, and dimethylamine in the last step is replaced with (S)-pyrrolidin-3-ol. LC-MS (ESI) m / z: 377.1 [M / 2+H] + . 1 H NMR (600MHz, DMSO-d6) δ8.38(s,1H),8.32(d,J=1.4Hz,1H),8.28(d,J=8.6Hz,1H),7.95(s,1H),7 .83(ddd,J=8.2,2.4,0.9Hz,1H),7.75(s,1H),7.73-7.68(m,2H),7.48(dd,J=8.7,1.8Hz,1H),7. 43(dd,J=8.6,1.7Hz,1H),7.31(d,J=7.8Hz,1H),6.65-6.62(m,1H),5.19(s,2H),5.16(d,1H),5. 09(d,J=3.3Hz,1H),4.47-4.41(m,1H),4.41-4.36(m,1H),4.12-3.58(m,8H),2.05-1.89(m,4H).

[0366] Example 19

[0367] Synthesis method

[0368] The synthesis method of compound 19 is similar to that of Example 3, except that 2-fluoro-4-chlorobenzamide in step 4 is replaced with 2-fluoro-4-trifluoromethylbenzamide, and dimethylamine in the last step is replaced with methylethylamine. LC-MS (ESI) m / z: 349.1 [M / 2+H] + . 1H NMR (600MHz, DMSO-d6) δ8.33(d,J=1.5Hz,1H),8.19(d,J=8.6Hz,1H),8.08(d,J=8.5Hz,1H),7.97(s,1H), 7.83(ddd,J=8.3,2.4,1.0Hz,1H),7.75(t,J=2.1Hz,1H),7.73-7.67(m,2H),7.49(dd,J=8.6,1.8Hz,1H), 7.44(dd,J=8.5,1.7Hz,1H),7.34-7.30(m,1H),6.64(d,J=1.8Hz,1H),5.26(s,2H),3.74(q,J=6.8Hz,2H) ,3.66(q,J=7.0Hz,2H),3.34(s,3H),3.24(s,3H),1.33(t,J=7.6,6.0Hz,3H),1.28(t,J=7.0,1.5Hz,3H).

[0369] Example 20

[0370] Synthesis method

[0371] The synthesis method of compound 20 is similar to that of Example 3, except that 2-fluoro-4-chlorobenzamide in step 4 is replaced with 2-fluoro-4-trifluoromethylbenzamide, and dimethylamine in the last step is replaced with tetrahydrofuran-3-amine. LC-MS (ESI) m / z: 377.1 [M / 2+H] + . 1 H NMR (600MHz, DMSO-d6) δ8.69(d,J=6.3Hz,1H),8.56(d,J=8.5Hz,1H),8.51-8.43(m,2H),8. 33(s,1H),7.92(s,1H),7.83(dd,J=7.8,2.2Hz,1H),7.75(s,1H),7.73-7.66(m,2H),7.60(d ,J=8.6Hz,1H),7.53(d,J=8.4Hz,1H),7.32(d,J=7.9Hz,1H),6.61(s,1H),5.27(s,2H),4.8 2-4.67(m,2H),3.98-3.87(m,4H),3.79-3.71(m,3H),2.32-2.19(m,2H),2.04-1.95(m,3H).

[0372] Example 21

[0373] Synthesis method

[0374] The synthesis method of compound 21 is similar to that of Example 3, except that 2-fluoro-4-chlorobenzamide in step 4 is replaced with 2-fluoro-4-trifluoromethylbenzamide, and dimethylamine in the last step is replaced with (R)-pyrrolidin-3-ol. LC-MS (ESI) m / z: 377.1 [M / 2+H] + . 1 H NMR (600MHz, DMSO-d6) δ8.38(s,1H),8.32(d,J=1.4Hz,1H),8.28(d,J=8.6Hz,1H),7.95(s,1H),7 .83(ddd,J=8.2,2.4,0.9Hz,1H),7.75(s,1H),7.73-7.68(m,2H),7.48(dd,J=8.7,1.8Hz,1H),7. 43(dd,J=8.6,1.7Hz,1H),7.31(d,J=7.8Hz,1H),6.65-6.62(m,1H),5.19(s,2H),5.16(d,1H),5. 09(d,J=3.3Hz,1H),4.47-4.41(m,1H),4.41-4.36(m,1H),4.12-3.58(m,8H),2.05-1.89(m,4H).

[0375] Example 22

[0376] Synthesis method

[0377] The synthesis method of compound 22 is similar to that of Example 3, except that dimethylamine in the last step is replaced by methylethylamine. LC-MS (ESI) m / z: 315.1 [M / 2+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.33(d,J=1.3Hz,1H),7.98(d,J=8.8Hz,1H),7.88(d,J=8.8Hz,1H),7.82(dd, J=8.2,1.6Hz,1H),7.74-7.65(m,4H),7.28(d,J=8.6Hz,1H),7.20(ddd,J=14.5,8.8,2.0Hz,2H),6.42 (d,J=2.1Hz,1H),5.19(s,2H),3.70(q,J=7.1Hz,2H),3.63(q,J=7.1Hz,2H),3.30(s,3H),3.21(s,3H),1.32-1.26(m,6H).

[0378] Example 23

[0379] Synthesis route

[0380] Step 1: Synthesis of compound 23-1

[0381] 2-Chloro-3-cyanopyridine (1.0 g, 7 mmol), cyclopropylcarboxylic acid (3.1 g, 36 mmol), and silver nitrate (0.4 g, 2 mmol) were dissolved in 10% dilute sulfuric acid (10 mL) at room temperature and stirred at room temperature for 30 minutes. An aqueous ammonium persulfate solution (3.3 g, 14 mmol) was slowly added dropwise. The mixture was allowed to stand overnight at room temperature and the reaction was monitored for completion by TLC. The pH was adjusted to 8-9 with aqueous ammonia, filtered, and the filtrate was extracted three times with ethyl acetate. The organic phase was washed once with saturated sodium chloride solution, and the solvent was evaporated under reduced pressure to obtain compound 23-1, 1.1 g, in an 85% yield. LC-MS (ESI) m / z: 179 [M+H] + .

[0382] Step 2: Synthesis of compound 23-2

[0383] Compound 23-1 (1.1 g, 6 mmol) was dissolved in ethanol (10 mL). 80% hydrazine hydrate (5 mL) was added dropwise at room temperature. The mixture was heated to 80°C with a sealed tube and allowed to react overnight. TLC confirmed the reaction completion. The residue was purified by silica gel column chromatography to obtain compound 23-2, 0.8 g, in an 80% yield. LC-MS (ESI) m / z: 175 [M+H] + .

[0384] Step 3: Synthesis of compound 23-3

[0385] Methyl 3-hydroxybenzoate (100 mg, 0.66 mmol) was added to a mixture of methyl 3-(bromomethyl)benzoate (196 mg, 0.66 mmol) and potassium carbonate (272 mg, 19.8 mmol) in DMF (10 mL). The mixture was reacted at room temperature under nitrogen for 4 hours. TLC indicated complete reaction. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phases were combined, washed with water and saturated brine, and purified and concentrated by silica gel column chromatography to afford compound 23-3 (130 mg, 66% yield). LC-MS (ESI) m / z: 301 [M+H] + .

[0386] Step 4: Synthesis of compound 23-4

[0387] Compound 23-3 (130 mg, 0.43 mmol) was dissolved in methanol (2.5 mL) and aqueous sodium hydroxide solution (3 mL, 4 M) was added dropwise at 0°C. The mixture was allowed to react overnight at 50°C. TLC indicated complete reaction. The reaction mixture was cooled and the pH was adjusted to 3-4 with dilute hydrochloric acid at 0°C. The mixture was poured into ice water and extracted with ethyl acetate. The organic phase was concentrated to afford 78 mg of crude compound 23-4 in a 67% yield. LC-MS (ESI) m / z: 273 [M+H] + .

[0388] Step 5: Synthesis of compound 23

[0389] A solution of compound 23-4 (78 mg, 0.29 mmol) in DMF (0.5 mL) was added dropwise to a solution of TBTU (138 mg, 0.43 mmol) and triethylamine (73 mg, 0.72 mmol) in DMF (0.5 mL). Finally, a solution of compound 23-2 (100 mg, 0.57 mmol) in DMF (0.5 mL) was added dropwise. The mixture was allowed to react overnight at 50°C. TLC indicated complete reaction of the starting materials. After cooling, the reaction solution was extracted with 50 mL of water and 150 mL of ethyl acetate three times. The combined organic phases were concentrated and purified by HPLC to obtain compound 23 (25 mg, 12% yield). LC-MS (ESI) m / z: 585.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.11(dd,J=8.1,3.3Hz,2H),7.78(s,1H),7.68(t,J=6.7Hz,2H),7.52(t,J=7.7Hz,1H),7.41(t,J=7. 9Hz,1H),7.36(s,1H),7.32-7.21(m,4H),6.50(s,4H),5.24(s,2H),2.14-2.08(m,2H),0.93-0.83(m,4H),0.77-0.67(m,4H).

[0390] Example 24

[0391] Synthesis method

[0392] The synthesis method of compound 24 is similar to that of Example 3, except that dimethylamine in the last step is replaced by N-methyl-2-hydroxyethylamine. LC-MS (ESI) m / z: 331.1 [M / 2+H] + . 1H NMR (400MHz, DMSO-d6) δ8.33(d,J=1.3Hz,1H),8.20(d,J=8.8Hz,1H),8.11(d,J=8.8Hz,1H) ,7.82(d,J=9.8Hz,1H),7.72-7.70(m,1H),7.70-7.67(m,2H),7.30-7.26(m,1H),7.22(dd,J =8.8,2.0Hz,2H),7.18(dd,J=8.8,2.0Hz,1H),6.43(d,J=2.1Hz,1H),5.20(s,2H),5.05(t, 1H), 4.99 (t, J = 5.2Hz, 1H), 3.76-3.69 (m, 4H), 3.33 (s, 3H), 3.26 (s, 3H), 1.50-1.42 (m, 4H).

[0393] Example 25

[0394] Synthesis method

[0395] The synthesis method of compound 25 is similar to that of Example 3, except that dimethylamine in the last step is replaced by cyclopropylamine. LC-MS (ESI) m / z: 313.1 [M / 2+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.51(d,J=4.0Hz,1H),8.34-8.28(m,2H),8.17(d,J=8.7Hz,1H),8.09(d,J=8.8Hz,1H),7.82(d,J=8.3Hz,1H),7.74-7.61(m,3 H),7.27(dd,1H),7.23(dd,J=8.6,1.7Hz,1H),6.39(d,J=1.9Hz,1H),5.21( s,2H),3.11-2.98(m,2H),2.00(dd,J=14.3,6.8Hz,2H),0.83-0.63(m,6H).

[0396] Example 26

[0397] Synthesis method

[0398] The synthesis method of compound 26 is similar to that of Example 3, except that the dimethylamine in the last step is replaced by a methanolic ammonia solution. LC-MS (ESI) m / z: 273.0 [M / 2+H] + . 1H NMR (400MHz, DMSO-d6) δ8.32(d,J=1.2Hz,1H),8.16(d,J=8.7Hz,1H),8.08(d,J=8.6Hz,1H),7.81(d,J=9.7H z,1H),7.72(s,1H),7.69-7.61(m,4H),7.26-7.25(m,2H),6.39(d,J=1.9Hz,1H),5.77(s,4H),5.20(s,2H).

[0399] Example 27

[0400] Synthesis method

[0401] The synthesis method of compound 27 is similar to that of Example 3, except that 2-fluoro-4-chlorobenzamide in the first step is replaced with 2-fluoro-4-trifluoromethylbenzamide, and dimethylamine in the last step is replaced with a methanolic ammonia solution. LC-MS (ESI) m / z: 307.1 [M / 2+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.36(d,J=8.4Hz,1H),8.32(s,1H),8.27(d,J=8.4Hz,1H),7.91(s,1H),7.82(dd,J=8.5,2.3Hz,1H),7.75(t,J=2.1Hz ,1H),7.69(t,2H),7.56(d,J=8.6,1.7Hz,1H),7.50(d,J=8.5,1.6Hz,1H),7.30(d,J=7.8,1.9Hz,1H),6.90(s,4H),6.61(s,1H),5.26(s,2H).

[0402] Example 28

[0403] Synthesis method

[0404] The synthesis method of compound 28 is similar to that of Example 3, except that dimethylamine in the last step is replaced by 2,2,2-trifluoroethylamine. LC-MS (ESI) m / z: 355.1 [M / 2+H] + . 1H NMR(600MHz,DMSO-d6)δ9.09(t,J=6.0Hz,1H),8.89(t,J=6.1Hz,1H),8.32(d ,J=1.1Hz,1H),8.26(d,J=8.7Hz,1H),8.18(d,J=8.7Hz,1H),7.83(dd,1H),7. 76(s,1H),7.72(d,J=1.8Hz,1H),7.71-7.67(m,2H),7.36(dd,J=8.7,1.9Hz,1 H),7.33-7.30(m,2H),6.45(d,J=1.9Hz,1H),5.23(s,2H),4.50-4.32(m,4H).

[0405] Example 29

[0406] Synthesis method

[0407] The synthesis method of compound 29 is similar to that of Example 3, except that the dimethylamine in the last step is replaced by azetidine. LC-MS (ESI) m / z: 313.1 [M / 2+H] + .

[0408] Example 30

[0409] Synthesis route

[0410] Step 1: Synthesis of compound 30-1

[0411] m-Iodoaniline (500 mg, 2.3 mmol) and 5-cyanothiophene-2-boronic acid (524 mg, 3.4 mmol) were dissolved in THF (7.5 mL), and an aqueous solution (1.5 mL) of sodium carbonate (725 mg, 6.8 mmol) was added. 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (185 mg, 0.2 mmol) was added under a N2 atmosphere and heated to 65°C for overnight reaction. The mixture was extracted with EA / H2O, and the combined organic phases were concentrated and purified by silica gel column chromatography (EA:PE = 1:9). The experiment was repeated to obtain compound 30-1, 785 mg, with a yield of 57%, as a yellow solid. LC-MS (ESI) m / z: 201 [M+H] + .

[0412] Step 2: Synthesis of compound 30-2

[0413] Compound 30-1 (100 mg, 0.5 mmol) was dissolved in THF (2 mL) and 2.5 M LiAlH4 / THF (0.4 mL) was slowly added dropwise at 0°C with stirring at room temperature. The reaction was monitored by TLC and quenched with water. The mixture was extracted with EA, and the organic phases were combined, concentrated, and dried to afford compound 30-2, 86 mg, in an 85% yield, as a light yellow solid. LC-MS (ESI) m / z: 205 [M+H] + .

[0414] Step 3: Synthesis of compound 30-3

[0415] 4-Chloro-2-fluorobenzamide (100 mg, 0.58 mmol) was dissolved in 1,2-dichloroethane (3 mL), and oxalyl chloride (0.07 mL, 0.87 mmol) was slowly added dropwise at 0 ° C. The mixture was heated to 55 ° C. and reacted for 1 hour. The reaction mixture was then heated to 80 ° C. and allowed to react overnight. TLC monitoring showed that the raw material had basically disappeared, and the reaction solution was directly dried to obtain the corresponding isocyanate intermediate. The product was dissolved in DCE (1 mL) as quickly as possible and added dropwise to a mixed solution of DCE (1 mL) dispersed with compound 30-2 (86 mg, 0.42 mmol) under an ice-water bath, and gradually warmed to room temperature. The reaction solution was filtered to obtain compound 30-3, 210 mg, with a yield of 83%, as a light yellow solid. LC-MS (ESI) m / z: 603 [M + H] + .

[0416] Step 4: Synthesis of compound 30-4

[0417] To a solution of compound 30-3 (150 mg, 0.25 mmol) in DMF (5 mL) was slowly added dropwise 2M NaHMDS / THF (0.75 mL) at 0°C. The mixture was heated to 70°C and allowed to react for 4 hours. Excess water was added to quench the reaction. ACN was then added, and a large amount of white solid precipitated. The solid was filtered and dried. Compound 30-4 was obtained. The experiment was repeated to obtain 174 mg of compound 30-4 as a white solid in an 89% yield. LC-MS (ESI) m / z: 563 [M+H] + .

[0418] Step 5: Synthesis of compound 30

[0419] Compound 30-4 (111 mg, 0.2 mmol) was dispersed in acetonitrile (5 mL), and DIEA (0.34 mL) and POCl3 (0.1 mL) were added at 0°C. The mixture was heated to 70°C and refluxed overnight. TLC monitoring indicated that the starting material had essentially disappeared. The reaction solution was then spin-dried to dryness, and a tetrahydrofuran solution of dimethylamine (10 mL) was quickly added and stirred at room temperature. The reaction solution was spin-dried to dryness, slurried with methanol, and purified by HPLC to obtain compound 30, 44 mg, in a 36% yield. LC-MS (ESI) m / z: 309.1 [M / 2+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.04(d,J=8.8Hz,1H),7.98(d,J=8.8Hz,1H),7.72(d,J=8.0Hz,1H),7.67(d,J=1.9Hz,1H),7.57(dd,J=15.3,7. 5Hz,2H),7.45(d,J=3.7Hz,1H),7.27(d,J=3.7Hz,1H),7.24-7.16(m,3H),6.37(d,J=2.0Hz,1H),5.48(s,2H),3.30(s,6H),3.25(s,6H).

[0420] Example 31

[0421] Synthesis method

[0422] The synthesis method of compound 31 is similar to that of Example 30, except that dimethylamine in step 5 is replaced by methylethylamine. LC-MS (ESI) m / z: 323.1 [M / 2+H] + . 1 H NMR (600MHz, DMSO-d6) δ7.97(d,J=8.8Hz,1H),7.91(d,J=8.8Hz,1H),7.71(dt,J=7.8,1. 4Hz,1H),7.66(d,J=2.0Hz,1H),7.58(t,J=7.9Hz,1H),7.56(t,J=1.9Hz,1H),7.45(d,J=3 .7Hz,1H),7.27(d,J=3.7Hz,1H),7.23-7.19(m,3H),6.37(d,J=2.1Hz,1H),5.48(s,2H),3 .70(q,J=7.0Hz,2H),3.65(q,J=7.0Hz,2H),3.30(s,3H),3.23(s,3H),1.32-1.27(m,6H).

[0423] Example 32

[0424] Synthesis route

[0425] Step 1: Synthesis of compound 32-1

[0426] Hydrogen peroxide (10 mL) was added to a mixture of 2-fluoro-4-methylbenzonitrile (2.0 g, 14.81 mmol), water (15 mL), and sodium hydroxide solution (30%, 5 mL) at room temperature. Stirring was continued at 35°C overnight, and the reaction was monitored for completeness by TLC. Diluting with water (50 mL) resulted in the precipitation of a large amount of solid. Filtering the solid afforded compound 32-1, 1.4 g, as a white solid in a 61% yield. LC-MS (ESI) m / z: 154 [M+H] + .

[0427] Step 2: Synthesis of compound 32-2

[0428] 3-Iodoaniline (3.0 g, 13.70 mmol) and 1H-imidazole-4-carbonitrile (1.3 g, 13.70 mmol) were dissolved in N,N-dimethylformamide (30 mL) at room temperature. Cuprous iodide (260 mg, 1.37 mmol), trans-N,N-dimethyl-1,2-cyclohexanediamine (200 mg, 1.37 mmol), and cesium carbonate (13.4 g, 41.07 mmol) were added. The mixture was heated to 100°C and stirred under nitrogen for 18 hours. TLC confirmed the reaction was complete. 80 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was slurried with anhydrous ethanol (100 mL). The filtered solid was compound 32-2, 1.93 g, a pink solid, with a yield of 76%. LC-MS (ESI) m / z: 185 [M+H] + .

[0429] Step 3: Synthesis of compound 32-3

[0430] At room temperature, Raney nickel (1.8 g, 30.98 mmol) was added dropwise to a solution of compound 32-2 (1.9 g, 10.33 mmol) in ammonia-methanol (20 mL) and stirred overnight under a hydrogen atmosphere. TLC monitored the reaction for completion, and the Raney nickel was removed by filtration. The filtrate was purified by C18 column chromatography (water:acetonitrile, 5-95%, 20 min) to afford compound 32-3, 1.35 g, as a pink solid in a 69% yield. LC-MS (ESI) m / z: 189 [M+H] + .

[0431] Step 4: Synthesis of compound 32-4

[0432] Oxalyl chloride (2.0 g, 15.96 mmol) was added dropwise to a solution of compound 32-3 (1.2 g, 7.98 mmol) in dichloroethane (DCE) (10 mL) at 0°C. Under nitrogen protection, the reaction mixture was stirred at 70°C overnight. After removing excess oxalyl chloride by rotary evaporation under reduced pressure, the mixture was diluted with DCE (8 mL) and added dropwise to a solution of compound 2 (500 mg, 2.65 mmol) in DCE / DMF (1.5 mL / 0.5 mL). The reaction was stirred at room temperature for 3 hours. TLC monitored the complete reaction. Acetonitrile was added to slurry, and the solid after filtration was compound 32-4, 1.35 g, white solid, with a yield of 93%. LC-MS (ESI) m / z: 547 [M+H] + .

[0433] Step 5: Synthesis of compound 32-5

[0434] Sodium hydride (183 mg, 4.27 mmol) was added to a solution of compound 32-4 (500 mg, 0.85 mmol) in DMF (10 mL) at 0°C. Under nitrogen, the mixture was heated to 90°C and stirred for 3 hours. LC-MS analysis indicated that the starting material had essentially disappeared. The mixture was quenched with water and diluted hydrochloric acid (0.5 mol / L) was added dropwise until the pH was neutral. The solid was filtered and slurried with acetonitrile. The solid was filtered again to obtain compound 32-5, 396 mg, as a white solid in a 92% yield. LC-MS (ESI) m / z: 507 [M+H] + .

[0435] Step 6: Synthesis of compound 32

[0436] Phosphorus oxychloride (0.8 mL) was added to a solution of compound 5 (80 mg, 0.16 mmol) and N,N-diisopropylethylamine (0.8 mL) in acetonitrile (ACN) (4 mL) at 0°C. Under nitrogen protection, the reaction mixture was reacted at 90°C for 4 hours, and the excess phosphorus oxychloride was removed by rotary evaporation under reduced pressure. Methylethylamine (47 mg, 0.79 mmol) was dissolved in tetrahydrofuran (THF) (5 mL) and added dropwise to the reaction system after removal of phosphorus oxychloride. The mixture was stirred at room temperature for 30 minutes. LC-MS confirmed the complete reaction. After dissolution in dichloromethane / methanol, the product was purified by silica gel column chromatography (dichloromethane:methanol, 0-10%, 15 min) to obtain the crude product. After purification by HPLC, compound 32 was obtained, 4.25 mg, as a yellow solid, with a yield of 5%. LC-MS (ESI) m / z: 295.2 [M / 2+H] + . 1H NMR(600MHz,DMSO-d6)δ8.46(s,1H),8.32(d,1H),7.84(d,J=8.4Hz,1H),7.79(dd,J=9 .7Hz,1H),7.76(d,J=8.3Hz,1H),7.69–7.62(m,2H),7.38(s,1H),7.22(d,J=7.4Hz,1H) ,6.99(dd,J=14.6,8.4Hz,2H),6.29(s,1H),5.20(s,2H),3.69(q,J=6.8Hz,2H),3.62(q ,J=14.1,7.0Hz,2H),3.28(s,3H),3.18(s,3H),2.38(s,3H),2.21(s,3H),1.17(t,6H).

[0437] Example 33

[0438] Synthesis method

[0439] The synthesis method of compound 33 is similar to that of Example 32, except that methylethylamine in step 6 is replaced with diethylamine. LC-MS (ESI) m / z: 309.2 [M / 2+H] + . 1 H NMR (600MHz, DMSO-d6) δ8.76(s,1H),8.39(d,1H),7.84(d,J=8.4Hz,1H),7.79(dd,J=9.7Hz,1H),7.76(d,J=8.3Hz,1H),7.69–7.62(m,2H),7.38(s, 1H),7.28(d,J=7.4Hz,1H),6.53(dd,2H),6.41(s,1H),5.20(s,2H),3.71 (q,4H),3.56(q,4H),3.25(s,3H),3.16(s,3H),1.38(t,6H),1.24(t,6H).

[0440] Example 34

[0441] Synthesis route

[0442] Step 1: Synthesis of compound 34-1

[0443] A solution of methyl 4-bromobutyrate (1.8 g, 9.8 mmol) in DMF (3 mL) was added dropwise to a mixture of m-hydroxybenzaldehyde (1.0 g, 8.2 mmol) and potassium carbonate (2.3 g, 16.4 mmol) in DMF (10 mL). The mixture was allowed to react overnight at 50°C under nitrogen. TLC monitored the reaction for completion. After the reaction solution cooled, 50 mL of water and 150 mL of ethyl acetate were added for extraction three times. The organic phases were combined and purified by C-18 reverse-phase column chromatography (ACN:H2O = 39%). The resulting mixture was concentrated to afford 900 mg of compound 34-1 in a 50% yield. LC-MS (ESI) m / z: 223 [M+H] + .

[0444] Step 2: Synthesis of compound 34-2

[0445] At room temperature, compound 34-1 (900 mg, 4 mmol) was dissolved in 5 mL of anhydrous ethanol, and p-toluenesulfonyl hydrazide (755 mg, 4 mmol) was added, and the mixture was stirred at room temperature overnight. TLC monitoring showed that the reaction of compound 34-1 was complete and new spots were generated. 5-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)isatin (1.4 g, 4 mmol) and potassium carbonate (1.11 g, 4 mmol) were then added, and the temperature was raised to 80°C and stirred for 45 minutes. LCMS monitoring showed that the reaction was complete. After the reaction solution was cooled, 50 mL of water and 150 mL of ethyl acetate were added for extraction, and the extraction was repeated three times. The organic phases were combined, purified and concentrated by silica gel column chromatography, and then slurried with methanol to obtain compound 34-2, 630 mg, with a yield of 28%. LC-MS (ESI) m / z: 562 [M+H] + .

[0446] Step 3: Synthesis of compound 34-3

[0447] Compound 34-2 (630 mg, 1.12 mmol) was dissolved in 6 mL of methanol, and sodium hydroxide (90 mg, 2.25 mmol) and 1 mL of water were added. The mixture was heated to 50°C and stirred overnight. After cooling, the pH was adjusted to neutral with dilute hydrochloric acid at 0°C. The reaction solution was diluted with 30 mL of DCM and 10 mL of MeOH, filtered, and the filtrate was slurried with methanol to obtain compound 34-3 (188 mg, 30% yield). LC-MS (ESI) m / z: 548 [M+H] + .

[0448] Step 4: Synthesis of compound 34-4

[0449] A solution of compound 34-3 (188 mg, 0.34 mmol) in DMF (0.3 mL) was added dropwise to a solution of TBTU (166 mg, 0.52 mmol) and triethylamine (87 mg, 0.82 mmol) in DMF (0.3 mL). Finally, a solution of compound 23-2 in DMF (0.3 mL) was added dropwise. The mixture was allowed to react overnight at 50°C. TLC indicated complete reaction of the starting materials. After cooling, the reaction solution was extracted with 50 mL of water and 150 mL of ethyl acetate three times. The combined organic phases were concentrated and purified by HPLC to obtain compound 34-4, 70 mg, in a 29% yield. LC-MS (ESI) m / z: 704 [M+H] + .

[0450] Step 5: Synthesis of compound 34

[0451] Compound 34-4 (70 mg, 0.1 mmol) was dissolved in a mixture of trifluoroacetic acid and dichloromethane (6 mL, v:v = 1:5) and stirred at room temperature for 4 hours. TLC indicated completion of the reaction. The reaction solution was concentrated, purified by silica gel column chromatography, and then purified by HPLC to afford compound 34, 3.5 mg, in a 6% yield. LC-MS (ESI) m / z: 574.1 [M+H] + .

[0452] Example 35

[0453] Synthesis method

[0454] The synthesis method of compound 35 is similar to that of Example 32, except that dimethylamine is used in place of methylethylamine in step 6. LC-MS (ESI) m / z: 281.1 [M / 2+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.32(s,1H),7.91(d,J=8.3Hz,1H),7.83(d,J=8.4Hz,1H),7.79(dd,J=7.9Hz,1H),7.68-7.61(m,2H),7 .36(s,1H),7.21(d,J=6.2Hz,2H),6.98(t,2H),6.28(s,1H),5.20(s,2H),3.29(s,6H),3.22(s,6H),2.37(s,3H),2.21(s,3H).

[0455] Example 36

[0456] Synthesis method

[0457] The synthesis method of compound 36 is similar to that of Example 32, except that methylethylamine in step 6 is replaced with tert-butylamine. LC-MS (ESI) m / z: 309.2 [M / 2+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.71(s,1H),8.45(s,1H),8.32(s,1H),8.16(d,J=8.4Hz,1H),8.08(d,J=8.1Hz,1H),7.79(d,J=8.2Hz,1H),7.72(s,1H),7 .65(t,J=8.0Hz,2H),7.34(d,J=14.6Hz,2H),6.97(t,J=9.3Hz,2H),6.21 (s,1H),5.18(s,2H),2.36(s,3H),2.19(s,3H),1.53(s,9H),1.50(s,9H).

[0458] Example 37

[0459] Synthesis method

[0460] The synthesis method of compound 37 is similar to that of Example 32, except that 2-fluoro-4-methylbenzamide in step 4 is replaced with 2,4-difluorobenzamide. LC-MS (ESI) m / z: 299.1 [M / 2+H] + . 1 H NMR(400MHz, DMSO-d6)δ8.30(d,J=1.5Hz,1H),8.05(q,J=9.1,6.0Hz,1H),7.95(q,J=9.1, 6.2Hz,1H),7.80(dd,J=7.9,2.3Hz,1H),7.72-7.63(m,3H),7.42(dd,J=11.6,2.6Hz,1H), 7.26(d,J=7.5,1.8Hz,1H),7.06-6.96(m,2H),6.20(dd,J=10.7,2.6Hz,1H),5.18(s,2H), 3.70(q,J=7.0Hz,2H),3.63(q,J=7.0Hz,2H),3.30(s,3H),3.21(s,3H),1.34-1.29(m,6H).

[0461] Example 38

[0462] Synthesis method

[0463] The synthesis method of compound 38 is similar to that of Example 32, except that 2-fluoro-4-methylbenzamide in step 4 is replaced by 2,4-difluorobenzamide, and methylethylamine in step 6 is replaced by dimethylamine. LC-MS (ESI) m / z: 285.1 [M / 2+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.30(d,J=1.4Hz,1H),8.11(dd,J=9.1,6.0Hz,1H),8.02(dd,J=9.1,6.2Hz,1H),7.81(dd,1H),7.71-7.64(m,3H),7.4 1(dd,J=11.7,2.6Hz,1H),7.26(d,J=8.0,1.4Hz,1H),7.06-6.96(m,2H),6.20(dd,J=10.8,2.6Hz,1H),5.19(s,2H),3.30(s,6H),3.23(s,6H).

[0464] Example 39

[0465] Synthesis method

[0466] The synthesis method of compound 39 is similar to that of Example 32, except that 2-fluoro-4-methylbenzamide in step 4 is replaced with 2-fluoro-4-cyclopropylbenzamide. LC-MS (ESI) m / z: 321.2 [M / 2+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.33 (s, 1H), 7.80 (t, J = 8.6Hz, 2H), 7.75-7.63 (m, 4H), 7.27 (s, 1H), 7. 22(d,J=7.7Hz,1H),6.83(d,J=8.5Hz,1H),6.75(d,J=8.6Hz,1H),6.24(d,J=1.7Hz,1H),5.20(s ,2H),3.67(q,J=7.0Hz,2H),3.61(q,J=7.0Hz,2H),3.26(s,3H),3.18(s,3H),2.57(d,J=9.7Hz ,3H),2.54(d,J=5.7Hz,3H),1.81(tt,J=8.4,4.9Hz,1H),1.49-1.42(m,1H),1.10-0.98(m,8H).

[0467] Example 40

[0468] Synthesis method

[0469] The synthesis method of compound 40 is similar to that of Example 32, except that 2-fluoro-4-methylbenzamide in step 4 is replaced with 2-fluoro-4-cyclopropylbenzamide, and methylethylamine in step 6 is replaced with dimethylamine. LC-MS (ESI) m / z: 307.1 [M / 2+H] + .

[0470] Example 41

[0471] Synthesis route

[0472] Step 1: Synthesis of compound 41-1

[0473] m-Nitrophenyl borate (2.12 g, 12.8 mmol) and 4-bromothiophene-2-carbonitrile (2.0 g, 10.6 mmol) were dissolved in a mixture of dioxane (30 mL) and DMF (4 mL). A 13 mL solution of sodium carbonate (3.38 g, 31.8 mmol) was added. 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (500 mg, 0.05 mmol) was added under a nitrogen atmosphere. The mixture was heated to 100°C and allowed to react overnight. TLC indicated the reaction was complete. The reaction solution was extracted with EA / H2O, and the organic phases were combined, concentrated, and purified by silica gel column chromatography to afford compound 41-1, 3.4 g, 81% yield, as a white solid. LC-MS (ESI) m / z: 231 [M+H] + .

[0474] Step 2: Synthesis of compound 41-2

[0475] Compound 41-1 (500 mg, 2.2 mmol) was dispersed in THF (5 mL), and Raney nickel (200 mg) was added. The mixture was stirred at room temperature overnight under a H2 atmosphere. TLC and LC-MS analysis showed that there was almost no starting material. The reaction solution was filtered through celite, washed with THF, and purified by C-18 reverse column chromatography to obtain compound 41-2, 200 mg, in a 45% yield, as a white solid. LC-MS (ESI) m / z: 205 [M+H] + .1H NMR (400MHz, DMSO-d6) δ7.44(d,J=1.5Hz,1H),7.21(d,J=1.6Hz,1H),7.03(t,J=7.8Hz,1H),6.83(t,J=2. 0Hz,1H),6.78(dt,J=7.7,1.3Hz,1H),6.50-6.46(m,1H),5.08(s,2H),3.90(d,J=1.1Hz,2H),2.03(s,2H).

[0476] Step 3: Synthesis of compound 41-3

[0477] 4-Chloro-2-fluorobenzamide (200 mg, 1.16 mmol) was dissolved in 1,2-dichloroethane (3 mL), and oxalyl chloride (0.3 mL, 1.74 mmol) was slowly added dropwise at 0 ° C. The mixture was heated to 55 ° C. and reacted for 1 hour. The reaction mixture was then heated to 80 ° C. and allowed to react overnight. TLC monitored the disappearance of the raw material, and the reaction solution was directly spin-dried to obtain the corresponding isocyanate intermediate. It was dissolved in DCE (1 mL) as quickly as possible and added dropwise to a DCE (1 mL) mixture dispersed with compound 41-2 (100 mg, 0.05 mmol) under an ice-water bath, and gradually warmed to room temperature. The reaction solution was filtered to obtain compound 41-3, 244 mg, with a yield of 83%, as a white solid. LC-MS (ESI) m / z: 603 [M + H] + .

[0478] Step 4: Synthesis of compound 41-4

[0479] To a solution of compound 41-3 (224 mg, 0.37 mmol) in DMF (7 mL) was slowly added dropwise 2M NaHMDS / THF (1.1 mL) at 0°C. The mixture was heated to 75°C and allowed to react for 4 hours. The reaction was quenched by the addition of excess water, followed by the addition of ACN. A large amount of white solid precipitated, which was filtered and dried. The experiment was repeated to obtain compound 41-4 (200 mg, 88% yield) as a white solid. LC-MS (ESI) m / z: 563 [M+H] + .

[0480] Step 5: Synthesis of compound 41

[0481] Compound 41-4 (100 mg, 0.18 mmol) was dispersed in acetonitrile (5 mL). DIEA (0.3 mL) and POCl3 (0.1 mL) were added at 0°C, and the mixture was heated to 80°C and refluxed overnight. TLC analysis indicated the near disappearance of the starting material. The reaction solution was then dried and a solution of dimethylamine in tetrahydrofuran (3 mL) was quickly added, followed by stirring at room temperature. The reaction solution was then dried and purified by HPLC to yield compound 41 (12.34 mg, 11%) as a light yellow solid. LC-MS (ESI) m / z: 309.1 [M / 2+H] + . 1H NMR(400MHz, DMSO-d6)δ8.06(d,J=8.8Hz,1H),7.98(d,J=8.8Hz,1H),7.87-7.78(m,2H),7.74(s,1H) ,7.69-7.58(m,3H),7.26-7.16(m,3H),6.40(d,J=2.1Hz,1H),5.47(s,2H),3.31(s,6H),3.25(s,6H).

[0482] Example 42

[0483] Synthesis method

[0484] The synthesis method of compound 42 is similar to that of Example 41, except that dimethylamine in step 5 is replaced by methylethylamine. LC-MS (ESI) m / z: 323.1 [M / 2+H] + . 1 H NMR (600MHz, DMSO-d6) δ7.99(d,J=8.8Hz,1H),7.91(d,J=8.8Hz,1H),7.85(d,J=1.5 Hz,1H),7.82(d,J=7.9Hz,1H),7.75(s,1H),7.66(d,J=2.0Hz,1H),7.63(t,2H),7.2 5-7.19(m,3H),6.40(d,J=2.1Hz,1H),5.46(s,2H),3.71(q,J=7.0Hz,2H),3.65(q,J =7.0Hz,2H),3.31(s,3H),3.23(s,3H),1.32(t,J=7.0Hz,3H),1.27(t,J=7.0Hz,3H).

[0485] Example 43

[0486] Synthesis method

[0487] The synthesis method of compound 43 is similar to that of Example 41, except that dimethylamine in step 5 is replaced by methylamine. LC-MS (ESI) m / z: 295.0 [M / 2+H] + . 1H NMR(600MHz,DMSO-d6)δ8.67(q,J=4.5Hz,1H),8.56(q,J=4.5Hz,1H),8.12(d,J=8.7Hz,1H), 8.07(d,J=8.7Hz,1H),7.84(d,J=1.5Hz,1H),7.82-7.80(m,1H),7.72(s,1H),7.64-7.61(m, 2H),7.28(td,J=8.3,2.0Hz,2H),7.22(dd,J=7.7,2.1Hz,1H),6.37(d,J=2.1Hz,1H),5.48(s ,2H),2.98(d,J=4.5Hz,3H),2.94(d,J=4.5Hz,3H),2.03-1.96(m,1H),0.86(t,J=6.9Hz,1H).

[0488] Example 44

[0489] Synthesis route

[0490] Step 1: Synthesis of compound 44-1

[0491] At room temperature, 5-bromo-3-amino-2-methylpyridine (2 g, 10.70 mmol), diboronic acid pinacol ester (10.8 g, 42.52 mmol), Pd(dppf)Cl2 (860 mg, 1.176 mmol), and potassium acetate (3 g, 32.26 mmol) were dissolved in 60 mL of dioxane. The atmosphere was purged with nitrogen three times, then the temperature was raised to 100°C in an oil bath for 5 hours. LCMS monitored the reaction for completion. After cooling, 5-bromothiophene-2-carbonitrile (2 g, 10.64 mmol), sodium carbonate (3.4 g, 32.08 mmol), tetrakistriphenylphosphine palladium (1.22 g, 1.055 mmol), and 12 mL of water were added, and the temperature was then raised to 80°C with stirring for 16 hours. LC-MS showed the reaction was complete. The mixture was extracted three times with water and EA. The combined organic phases were concentrated and separated by flash chromatography (DCM:MeOH, 0-10%, 20 min) to afford compound 44-1, 1.5 g, 65% yield, as a green solid. LC-MS (ESI) m / z: 216 [M+H] + .

[0492] Step 2: Synthesis of compound 44-2

[0493] At room temperature, compound 44-1 (1.5 g, 6.944 mmol) was dissolved in 20 mL of 7N ammonia methanol solution. 2 mL of water-sealed Raney nickel was added, and the supernatant was removed after precipitation. The product was washed twice with methanol. After settling, the supernatant was removed. The precipitate was diluted with methanol and added to the reaction system. The hydrogen atmosphere was replaced three times, and the reaction was maintained at room temperature for 4 hours. LC-MS monitored the reaction for completion. The reaction solution was diluted with 50 mL of DCM and 10 mL of methanol, then filtered through Celite. The filtrate was concentrated and purified by flash chromatography (DCM:MeOH, 0-10%, 20 min) to obtain compound 44-2, 160 mg, 10% yield, as a yellow semi-oil. LC-MS (ESI) m / z: 220 [M+H] + .

[0494] Step 3: Synthesis of compound 44-3

[0495] At room temperature, 2-fluoro-4-chlorobenzamide (250 mg, 1.445 mmol) was dissolved in 5 mL of DCE. After cooling to 0°C, oxalyl chloride (280 mg, 2.204 mmol) was slowly added dropwise. The temperature was slowly raised to room temperature and then to 70°C, and stirred for 16 hours. The excess oxalyl chloride was then removed by concentration, dissolved in 1 mL of DCE, and added dropwise to a solution of compound 44-2 (160 mg, 0.727 mmol) in DCE (5 mL). The reaction was maintained at room temperature for 3 hours. A large amount of white solid precipitated. Compound 44-3 was obtained by filtration, 230 mg, 51% yield, as a yellowish-brown solid. LC-MS (ESI) m / z: 618 [M+H] + .

[0496] Step 4: Synthesis of compound 44-4

[0497] At room temperature, compound 44-3 (230 mg, 0.372 mmol) was dissolved in 4 mL of DMF, cooled to 0°C, and sodium hydride (60 mg, 1.5 mmol) was added portionwise. The mixture was stirred at room temperature for 10 minutes, then heated to 90°C and stirred for 16 hours. LC-MS monitored the reaction completion, and water was added to quench the reaction. The pH was then adjusted to approximately 6 with 1 M hydrochloric acid. A large amount of solid precipitated, which was filtered and the filter cake was re-slurried with DCM / MeOH to afford compound 44-4, 150 mg, 70% yield, as a white solid. LC-MS (ESI) m / z: 578 [M+H] + .

[0498] Step 5: Synthesis of compound 44

[0499] At room temperature, compound 44-4 (50 mg, 0.0865 mmol) was dissolved in 3 mL of anhydrous acetonitrile, cooled to 0°C, and DIEA (100 mg, 0.775 mmol) and phosphorus oxychloride (130 mg, 0.850 mmol) were added. The mixture was slowly warmed to room temperature and then heated to 80°C with stirring for 6 hours. The reaction solution was concentrated to remove the bulk of the phosphorus oxychloride, followed by addition of dimethylamine in THF (2 mL, 2.5 N) and stirring at room temperature for 30 minutes. LC-MS monitored the reaction for completion. After concentration, the crude product was separated by flash chromatography (DCM:MeOH, 0-10% over 20 min). This was then purified by HPLC to afford compound 44, 11.2 mg (20% yield) as a pale yellow solid. LC-MS (ESI) m / z: 316.6 [M / 2+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.82(d,J=2.3Hz,1H),8.09(d,J=8.8Hz,1H),8.00-7.95(m,2H),7.67(d,J=2.0Hz,1H),7.52(d,J=3.7Hz,1H),7.32(d,J= 3.7Hz,1H),7.24(dd,J=8.8,2.1Hz,1H),7.20(dd,J=8.8,2.0Hz,1H),6.38(d,J=2.1Hz,1H),5.49(s,2H),3.33(s,6H),3.25(s,6H),2.14(s,3H).

[0500] Example 45

[0501] Synthesis method

[0502] The synthesis method of compound 45 is similar to that of Example 44, except that dimethylamine in step 5 is replaced by methylamine. LC-MS (ESI) m / z: 302.6 [M / 2+H] + . 1H NMR (400MHz, DMSO-d6) δ8.81(d,J=2.2Hz,1H),8.14(d,J=8.7Hz,1H),8.06(d,J=8.7 Hz,1H),7.97(d,J=2.2Hz,1H),7.65(d,J=1.9Hz,1H),7.51(d,J=3.7Hz,1H),7.32(dd ,J=8.5,2.0Hz,1H),7.28(dd,J=8.8,2.4Hz,1H),7.23(s,1H),6.69(s,2H),6.35(d,J =2.0Hz,1H),5.50(s,2H),2.99(d,J=4.4Hz,3H),2.93(d,J=4.3Hz,3H),2.14(s,3H).

[0503] Example 46

[0504] Synthesis route

[0505] Step 1: Synthesis of compound 46-1

[0506] At room temperature, a solution of methyl 4-bromobutyrate (1.3 g, 7.5 mmol) in DMF (3 mL) was added dropwise to a mixture of m-nitrophenol (1.0 g, 7.1 mmol) and potassium carbonate (2.0 g, 14.2 mmol) in DMF:H₂O (14 mL:2.3 mL). The mixture was allowed to react at 50°C overnight under nitrogen. After cooling, the reaction mixture was extracted with 50 mL of water and 150 mL of ethyl acetate three times. The organic phases were combined and purified by C-18 reverse-phase column chromatography (ACN:H₂O = 45%). The resulting mixture was concentrated to afford compound 46-1, 1.0 g, in a 60% yield. LC-MS (ESI) m / z: 240 [M+H] + .

[0507] Step 2: Synthesis of compound 46-2

[0508] Iron powder (1.2 g, 21 mmol) and ammonium chloride (2.2 g, 42 mmol) were dissolved in water. The mixture was heated and stirred at 100°C under nitrogen for half an hour, followed by the addition of compound 46-1 (1.0 g, 4.2 mmol). The mixture was heated and stirred at 100°C overnight, and the reaction was monitored for completion by TLC. After the reaction solution cooled, it was filtered, and the filtrate was extracted with 50 mL of water and 150 mL of dichloromethane three times. The organic phases were combined and purified by silica gel column chromatography to yield compound 46-2, 470 mg, in a 53% yield. LC-MS (ESI) m / z: 210 [M+H] + .

[0509] Step 3: Synthesis of compound 46-3

[0510] At room temperature, 2-fluoro-4-chlorobenzamide (434 mg, 2.5 mmol) was dissolved in 10 mL of DCE. After cooling to 0°C, oxalyl chloride (470 mg, 3.7 mmol) was slowly added dropwise. The temperature was slowly raised to room temperature and then to 70°C, with stirring for 16 hours. Excess oxalyl chloride was removed by concentration, dissolved in 2 mL of DCE, and added dropwise to a solution of compound 46-2 (470 mg, 2.24 mmol) in DCE. The reaction was maintained at room temperature for 3 hours. A large amount of white solid precipitated. Compound 46-3 was obtained by filtration, yielding 800 mg of a white solid in 78% yield. LC-MS (ESI) m / z: 409 [M+H] + .

[0511] Step 4: Synthesis of compound 46-4

[0512] Compound 46-3 (800 mg, 2.0 mmol) was dissolved in DMF (8 mL) at room temperature, cooled to 0°C, and NaHMDS (2 mol / L, 2.2 mL) was added dropwise. The mixture was stirred at room temperature for 10 minutes, then heated to 65°C and stirred for 2 hours. LC-MS monitored the reaction completion, and water was added to quench the reaction. The reaction solution was extracted with 50 mL of water and 150 mL of dichloromethane three times. The organic phases were combined to obtain compound 46-4, 500 mg, in a 65% yield. LC-MS (ESI) m / z: 389 [M+H] + .

[0513] Step 5: Synthesis of compound 46-5

[0514] Compound 46-4 (500 mg, 1.29 mmol) was dissolved in anhydrous acetonitrile (8 mL) at room temperature and cooled to 0°C. DIEA (666 mg, 0.9 mL) and phosphorus oxychloride (493 mg, 0.3 mL) were added, and the mixture was slowly warmed to room temperature and then heated to 80°C with stirring for 6 hours. The reaction solution was concentrated to remove the bulk of the phosphorus oxychloride, and then a solution of methylethylamine in THF (10 mL, 2.5 N) was added and stirred at room temperature for 30 minutes. LC-MS monitored the reaction for completion. After concentration, the product was separated by column chromatography (DCM:MeOH, 0-10%, 20 min) to afford compound 46-5, 350 mg, in a 63% yield. LC-MS (ESI) m / z: 430 [M+H] + .

[0515] Step 6: Synthesis of compound 46-6

[0516] Compound 46-5 (350 mg, 0.81 mmol) was dissolved in methanol (5 mL), and sodium hydroxide (65 mg, 1.6 mmol) and water (1 mL) were added. The mixture was stirred overnight. The reaction was complete as monitored by LC-MS. The pH was adjusted to neutral with dilute hydrochloric acid at 0°C. The reaction solution was diluted with 30 mL of DCM and 10 mL of MeOH, filtered, and the filtrate was slurried with methanol to obtain compound 46-6, 50 mg, in a 15% yield. LC-MS (ESI) m / z: 416 [M+H] + .

[0517] Step 7: Synthesis of compound 46

[0518] A solution of compound 46-6 (50 mg, 0.12 mmol) in DMF (0.3 mL) was added dropwise to a solution of TBTU (48 mg, 0.15 mmol) and triethylamine (30 mg, 0.3 mmol) in DMF (0.3 mL). Finally, a solution of compound 23-2 (21 mg, 0.12 mmol) in DMF (0.3 mL) was added dropwise. The mixture was allowed to react overnight at 50°C. TLC indicated complete reaction of the starting materials. After cooling, the reaction solution was extracted with 10 mL of water and 20 mL of ethyl acetate three times. The combined organic phases were concentrated and purified by HPLC to obtain compound 46 (20 mg, 29% yield). LC-MS (ESI) m / z: 572.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.09(d,J=8.1Hz,1H),7.96(d,J=8.8Hz,1H),7.48(t,J=8.1Hz,1H),7.25( d,J=8.1Hz,1H),7.20(dd,J=8.8,2.0Hz,1H),7.09(dd,J=8.4,1.9Hz,1H),6.90(s,1H),6.86(d,J=7 .7Hz,1H),6.40(s,2H),6.38(d,J=2.0Hz,1H),4.15-4.07(m,2H),3.70(q,J=7.0Hz,2H),3.29(s,3 H),2.26-2.14(m,2H),2.13-2.06(m,2H),2.04-1.94(m,1H),1.36-1.26(m,3H),1.06-0.94(m,4H).

[0519] Example 47

[0520] Synthesis route

[0521] Step 1: Synthesis of compound 47-1

[0522] At room temperature, 5-bromo-3-aminopyridine (2.0 g, 11.56 mmol), diboronic acid pinacol ester (10.8 g, 42.52 mmol), Pd(dppf)Cl2 (860 mg, 1.176 mmol), and potassium acetate (3 g, 32.26 mmol) were dissolved in 60 mL of dioxane. The atmosphere was replaced with nitrogen three times and then heated to 100 °C in an oil bath for 5 hours. The reaction was monitored by LC-MS for completion. The dioxane was concentrated to remove the residue, and the reaction solution was dispersed with PE and filtered. The filter cake was dispersed with a DCM / MeOH mixed solution and filtered again. The filtrate was concentrated, and 5-bromothiophene-2-carbonitrile (1.0 g, 5.32 mmol), sodium carbonate (3.4 g, 32.08 mmol), tetrakistriphenylphosphine palladium (1.22 g, 1.055 mmol), 30 mL of THF, and 6 mL of water were added. The mixture was then heated to 60 °C and stirred for 5 hours. LC-MS monitoring revealed the disappearance of 5-bromothiophene-2-carbonitrile. The mixture was extracted three times with water and EA. The organic phases were combined, concentrated, and separated by flash chromatography (DCM:MeOH, 0-10%, 20 min) to afford compound 47-1, 650 mg, 60% yield, as a gray-green solid. LC-MS (ESI) m / z: 202 [M+H] + .

[0523] Step 2: Synthesis of compound 47-2

[0524] At room temperature, compound 47-1 (650 mg, 6.944 mmol) was dissolved in a 7N methanolic ammonia solution (20 mL). 2 mL of water-sealed Raney nickel was added, and the supernatant was removed after precipitation. The product was washed twice with methanol. After settling, the supernatant was removed. The precipitate was diluted with methanol and added to the reaction system. The hydrogen atmosphere was replaced three times, and the reaction was maintained at room temperature for 4 hours. LC-MS monitored the reaction for completion. The reaction solution was diluted with 50 mL of DCM and 10 mL of methanol, then filtered through Celite. The filtrate was concentrated and purified by flash chromatography (DCM:MeOH, 0-10%, 20 min) to obtain compound 47-2, 240 mg, 36% yield, as a pale yellow solid. LC-MS (ESI) m / z: 206 [M+H] + .

[0525] Step 3: Synthesis of compound 47-3

[0526] At room temperature, 2-fluoro-4-chlorobenzamide (400 mg, 2.312 mmol) was dissolved in 5 mL of DCE. After cooling to 0°C, oxalyl chloride (450 mg, 3.543 mmol) was slowly added dropwise. The temperature was slowly raised to room temperature and then to 70°C, and stirred for 16 hours. The excess oxalyl chloride was then removed by concentration, dissolved in 1 mL of DCE, and added dropwise to a solution of compound 47-2 (240 mg, 1.165 mmol) in DCE (5 mL). The reaction was maintained at room temperature for 3 hours. A large amount of white solid precipitated. Compound 47-3 was obtained by filtration, 430 mg, 61% yield, as a yellow-brown solid. LC-MS (ESI) m / z: 604 [M+H] + .

[0527] Step 4: Synthesis of compound 47-4

[0528] At room temperature, compound 47-3 (430 mg, 0.712 mmol) was dissolved in 7 mL of DMF, cooled to 0°C, and sodium hydride (120 mg, 3.0 mmol) was added portionwise. The mixture was stirred at room temperature for 10 minutes, then heated to 90°C and stirred for 16 hours. LC-MS monitored the reaction completion, and water was added to quench the reaction. The pH was then adjusted to approximately 6 with 1 M hydrochloric acid. A large amount of solid precipitated, which was filtered and the filter cake was re-slurried with DCM / MeOH to afford compound 47-4, 360 mg, 90% yield, as a yellow solid. LC-MS (ESI) m / z: 564 [M+H] + .

[0529] Step 5: Synthesis of compound 47

[0530] At room temperature, compound 47-4 (100 mg, 0.177 mmol) was dissolved in 3 mL of anhydrous acetonitrile, cooled to 0°C, and DIEA (100 mg, 0.775 mmol) and phosphorus oxychloride (130 mg, 0.850 mmol) were added. The mixture was slowly warmed to room temperature and then heated to 80°C with stirring for 6 hours. The reaction solution was concentrated to remove the bulk of the phosphorus oxychloride, followed by addition of dimethylamine in THF (2 mL, 2.5 N) and stirring at room temperature for 30 minutes. LC-MS monitored the reaction for completion. After concentration, the product was separated by flash chromatography (DCM:MeOH, 0-10% over 20 min) to afford 130 mg of crude product. This was then purified by HPLC to afford compound 47, 9 mg (16% yield), as a pale yellow solid. LC-MS (ESI) m / z: 309.6 [M / 2+H] + . 1H NMR (400MHz, DMSO-d6) δ8.94(d,J=2.2Hz,1H),8.42(d,J=2.2Hz,1H),8.09-8.03(m,2H),7.98(d,J=8.8Hz,1H),7.67(d,J=2.0Hz,1H),7.59 (d,J=3.7Hz,1H),7.34(d,J=3.8Hz,1H),7.21(ddd,J=10.2,8.7,2.0Hz,2H),6.47(d,J=2.1Hz,1H),5.51(s,2H),3.31(s,6H),3.25(s,6H).

[0531] Example 48

[0532] Synthesis method

[0533] The synthesis method of compound 48 is similar to that of Example 47, except that dimethylamine in step 5 is replaced by methylethylamine. LC-MS (ESI) m / z: 323.6 [M / 2+H] + . 1 H NMR (600MHz, DMSO-d6) δ8.94(d,J=2.2Hz,1H),8.42(d,J=2.2Hz,1H),8.07(t,J=2.2Hz,1H),7. 99(d,J=8.8Hz,1H),7.91(d,J=8.7Hz,1H),7.67(d,J=2.0Hz,1H),7.59(d,J=3.7Hz,1H),7.34( d,J=3.7Hz,1H),7.26-7.18(m,2H),6.47(d,J=2.1Hz,1H),5.50(s,2H),3.72(q,J=7.0Hz,2H), 3.65(q,J=7.0Hz,2H),3.31(s,3H),3.23(s,3H),1.31(t,J=7.0Hz,3H),1.27(t,J=7.0Hz,3H).

[0534] Example 49

[0535] Synthesis method

[0536] The synthesis method of compound 49 is similar to that of Example 47, except that dimethylamine in step 5 is replaced by methylamine. LC-MS (ESI) m / z: 295.5 [M / 2+H] + . 1H NMR (600MHz, DMSO-d6) δ8.93(d,J=2.1Hz,1H),8.71(q,J=4.8Hz,1H),8.56(q,J=4.7Hz,1H),8.41(d,J=2.2Hz,1H),8.12(d,J=8.7Hz,1H),8.09-8.04(m ,2H),7.65(d,J=1.9Hz,1H),7.58(d,J=3.7Hz,1H),7.35-7.26(m,3H),6.45 (d,J=1.9Hz,1H),5.52(s,2H),2.98(d,J=4.5Hz,3H),2.94(d,J=4.4Hz,3H).

[0537] Example 50

[0538] Synthesis route

[0539] Step 1: Synthesis of compound 50-1

[0540] 3-Thiophenecarbonitrile (1.0 g, 9.2 mmol) was dissolved in acetic acid:chloroform (15 mL, 1 v / 2 v), and NBS (2.52 g, 13.8 mmol) was added portionwise. The mixture was allowed to react at 70°C overnight. TLC indicated the reaction was complete. The reaction solution was quenched with water and extracted three times with DCM. The organic phases were combined, concentrated, and purified by silica gel column chromatography (EA:PE = 1:19) to afford compound 50-1, 520 mg, 30% yield, as a brown oil. LC-MS (ESI) m / z: 188 [M+H] + .

[0541] Step 2: Synthesis of compound 50-2

[0542] m-Nitrophenylboronic acid (500 mg, 4.5 mmol) and compound 50-1 (470 mg, 2.5 mmol) were dissolved in a mixture of dioxane (5 mL) and DMF (1 mL). A 2 mL solution of sodium carbonate (795 mg, 7.5 mmol) was added. 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride complex (100 mg, 0.125 mmol) was added under a nitrogen atmosphere. The mixture was heated to 100°C and allowed to react overnight. TLC indicated the reaction was complete. The reaction solution was purified by silica gel column chromatography (EA:PE = 2:25) to obtain crude compound 50-2 (565 mg, 93% yield) as a pale yellow solid, which was used directly in the next step. LC-MS (ESI) m / z: 231 [M+H] + .

[0543] Step 3: Synthesis of compound 50-3

[0544] Compound 50-2 (295 mg, 1.3 mmol) was dispersed in THF (5 mL), and Raney nickel (200 mg) was added. The mixture was stirred at room temperature under a H2 atmosphere for 5 hours. LC-MS and TLC analysis revealed almost no residual starting material. The reaction solution was filtered through celite, washed with THF, and purified by C-18 reverse-phase column chromatography to obtain compound 50-3 (100 mg, 39% yield) as a yellow solid. LC-MS (ESI) m / z: 205 [M+H] + .

[0545] Step 4: Synthesis of compound 50-4

[0546] 4-Chloro-2-fluorobenzamide (200 mg, 1.2 mmol) was dissolved in 1,2-dichloroethane (5 mL), and oxalyl chloride (0.15 mL, 1.7 mmol) was slowly added dropwise at 0 ° C, heated to 55 ° C, reacted for 1 hour, and then heated to 80 ° C and reacted overnight. TLC monitoring showed that the raw material had basically disappeared, and the reaction solution was directly spin-dried to obtain the corresponding isocyanate intermediate. It was dissolved in DCE (1 mL) as soon as possible and added dropwise to a mixture of DCE (1.5 mL) and DMF (1 mL) containing compound 50-3 (100 mg, 0.5 mmol) under an ice-water bath, and gradually warmed to room temperature. The reaction solution was filtered and dried to obtain compound 50-4, 140 mg, 47%, which was a white solid. LC-MS (ESI) m / z: 603 [M + H] + .

[0547] Step 5: Synthesis of compound 50-5

[0548] To a solution of compound 50-4 (120 mg, 0.2 mmol) in DMF (2 mL) was slowly added NaH (50 mg, 60%) at 0°C, heated to 80°C, and allowed to react for 2 hours. TLC analysis indicated the near disappearance of the starting material. The reaction was quenched by addition of excess water and the pH of the reaction mixture was adjusted to neutral with dilute hydrochloric acid. A large amount of white solid precipitated, which was filtered and dried. The crude product, compound 50-5, was obtained as a white solid (125 mg, 99% yield) and used directly in the next step. LC-MS (ESI) m / z: 563 [M+H] + .

[0549] Step 6: Synthesis of compound 50

[0550] Compound 50-5 (50 mg, 0.09 mmol) was dispersed in acetonitrile (4 mL), and DIEA (0.15 mL) and POCl3 (0.05 mL) were added at 0°C, respectively. The temperature was raised to 80°C and refluxed for 4 hours. TLC monitoring showed that the starting material had essentially disappeared. The reaction solution was spin-dried to dryness, and a solution of dimethylamine in tetrahydrofuran (2 mL) was quickly added and stirred at room temperature. The reaction solution was spin-dried to dryness and purified by pre-TLC (MeOH:DCM = 1:9), followed by HPLC purification to obtain compound 50, 12 mg, with a yield of 25%, as a white solid. LC-MS (ESI) m / z: 309.1 [M / 2+H] + . 1 H NMR (600MHz, DMSO-d6) δ8.05(d,J=8.8Hz,1H),7.98(d,J=8.8Hz,1H),7.73(dt,J=8.0,1.3Hz,1H),7.61(t,J=7.8Hz,1H),7.57(t,J=1.9Hz,1H),7.48 (dd,J=12.9,1.7Hz,2H),7.40(d,J=1.3Hz,1H),7.26-7.23(m,1H),7.22-7 .16(m,2H),6.40(d,J=2.1Hz,1H),5.28(s,2H),3.31(s,6H),3.25(s,6H).

[0551] Example 51

[0552] Synthesis method

[0553] The synthesis method of compound 51 is similar to that of Example 50, except that dimethylamine in step 5 is replaced by methylethylamine. LC-MS (ESI) m / z: 323.1 [M / 2+H] + . 1H NMR(600MHz,DMSO-d6)δ7.98(d,J=8.8Hz,1H),7.91(d,J=8.8Hz,1H),7.74-7.71(m,1H),7.61(t ,J=7.8Hz,1H),7.58(d,J=2.0Hz,1H),7.50(d,J=1.4Hz,1H),7.46(d,J=2.0Hz,1H),7.39(s,1H) ,7.26-7.23(m,1H),7.23-7.17(m,2H),6.40(d,J=2.1Hz,1H),5.27(s,2H),3.71(q,J=7.0Hz,2H ),3.65(q,J=7.0Hz,2H),3.30(s,3H),3.23(s,3H),1.32(t,J=7.0Hz,3H),1.28(t,J=7.0Hz,3H).

[0554] Example 52

[0555] Synthesis method

[0556] The synthesis method of compound 52 is similar to that of Example 44, except that 5-bromothiophene-2-carbonitrile in step 2 is replaced with 4-bromothiophene-2-carbonitrile. LC-MS (ESI) m / z: 316.6 [M / 2+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.95(d,J=2.1Hz,1H),8.11(d,J=8.8Hz,1H),8.03(d,J=2.2Hz,1H),7.98(d,J=8.8Hz,1H),7.79(d,J=1.6Hz,1H),7.64(d, J=2.0Hz,1H),7.25(dd,J=8.8,2.1Hz,1H),7.19(dd,J=8.8,2.0Hz,1H),6 .41(d,J=2.1Hz,1H),5.47(s,2H),3.34(s,6H),3.25(s,6H),2.16(s,3H).

[0557] Example 53

[0558] Synthesis method

[0559] The synthesis method of compound 53 refers to Example 44, except that 5-bromothiophene-2-carbonitrile in step 2 is replaced with 4-bromothiophene-2-carbonitrile, and the tetrahydrofuran solution of dimethylamine in step 5 is replaced with a methanol solution of ammonia. LC-MS (ESI) m / z: 288.5 [M / 2+H] + .1 H NMR(400MHz, DMSO-d6)δ8.94(d,J=2.2Hz,1H),8.30(s,1H),8.20(d,J=8.7H z,2H),8.10(d,J=8.5Hz,2H),8.05(d,J=2.1Hz,1H),8.02-7.98(m,1H),7.9 3(s,1H),7.78(s,1H),7.61(d,J=1.9Hz,1H),7.31(dd,J=8.6,2.0Hz,1H),7 .26(dd,J=8.6,1.8Hz,1H),6.38(d,J=2.0Hz,1H),5.47(s,2H),2.16(s,3H).

[0560] Example 54

[0561] Synthesis method

[0562] The synthesis method of compound 54 is similar to that of Example 30, except that 2-fluoro-4-chlorobenzamide in step 3 is replaced with 2-fluoro-4-trifluoromethylbenzamide. LC-MS (ESI) m / z: 343.1 [M / 2+H] + .1H NMR (400MHz, DMSO-d6) δ8.24(d,J=8.5Hz,1H),8.17(d,J=8.4Hz,1H),7.87(s,1H),7.72(dt,J=8.0,1.3Hz,1H),7.60-7.56(m,2H),7 .47-7.45(m,1H),7.45(d,J=3.5Hz,2H),7.26(dd,J=4.7,2.9Hz,2H),6.62(d,J=1.8Hz,1H),5.57(s,2H),3.33(s,6H),3.28(s,6H).

[0563] Example 55

[0564] Synthesis route

[0565] Step 1: Synthesis of compound 55-1

[0566] Pyrrole-3-carboxaldehyde (2.0 g, 21.0 mmol) was dissolved in THF (20 mL), and NBS (3.94 g, 22.0 mmol) was added in batches at -2°C and stirred for 2 hours. The reaction was monitored by TLC, and 0.1 eq of NBS was added, and the reaction was continued for 1 hour. Sodium thiosulfate solution was added to the reaction solution to quench the reaction, and the mixture was extracted three times with EA. The organic phases were combined and concentrated, and purified by silica gel column chromatography (EA:PE=13:50) to obtain a crude compound. The solid was slurried with ethyl acetate to obtain compound 55-2, 2.4 g, 65%, which was a pink solid. LC-MS (ESI) m / z: 174 [M+H] + .

[0567] Step 2: Synthesis of compound 55-2

[0568] At 0°C, (aminooxy)sulfonic acid (6.2 g, 54.8 mmol) was dissolved in water (20 mL), and compound 55-1 (2.4 g, 13.7 mmol) was added portionwise and stirred at room temperature. After TLC detection showed no starting material, the pH was adjusted to 7-8 with aqueous sodium bicarbonate solution. Dichloromethane was added to the reaction solution for extraction, and the organic phases were combined, concentrated, and purified by silica gel column chromatography (EA:PE = 9:50) to obtain compound 55-2, 1.3 g, 57%, as a white solid. LC-MS (ESI) m / z: 171 [M+H] + .

[0569] Step 3: Synthesis of compound 55-3

[0570] Compound 55-2 (1.3 g, 7.7 mmol) was dissolved in DMF (10 mL), potassium carbonate (2.13 g, 15.4 mmol) and SEMCl (2.1 mL, 2.8 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction solution was purified by silica gel column chromatography (EA:PE = 1:19) to obtain compound 55-3, 2.79 g, 91%, as a pink solid. LC-MS (ESI) m / z: 301 [M+H] + .

[0571] Step 4: Synthesis of compound 55-4

[0572] m-Nitrophenyl borate (1.86 g, 11.1 mmol) and compound 55-3 (2.79 g, 9.3 mmol) were dissolved in a mixture of dioxane (25 mL) and DMF (4 mL). A solution of sodium carbonate (2.96 g, 27.9 mmol) in water (7 mL) was added. 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (380 mg, 0.46 mmol) was added under a nitrogen atmosphere. The mixture was heated to 50°C and allowed to react overnight. The reaction solution was purified by silica gel column chromatography (EA:PE = 1:9) to give compound 55-4, 2.4 g, 74%, as a light yellow solid. LC-MS (ESI) m / z: 344 [M+H] + .

[0573] Step 5: Synthesis of compound 55-5

[0574] Compound 55-4 (1.7 g, 4.9 mmol) was dispersed in NH3 / MeOH (70 mL), and Raney nickel (2.0 g) was added. The mixture was stirred at room temperature under a H2 atmosphere for 5 hours. LC-MS and TLC showed that there was almost no starting material. The reaction solution was filtered through celite, washed with THF, and then purified by C-18 reverse phase column chromatography to obtain compound 55-5, 1.0 g, 64%, as a light yellow solid. LC-MS (ESI) m / z: 318 [M+H] + .

[0575] Step 6: Synthesis of compound 55-6

[0576] 4-Chloro-2-fluorobenzamide (300mg, 1.7mmol) was dissolved in 1,2-dichloroethane (5mL), and oxalyl chloride (0.22mL, 2.6mmol) was slowly added dropwise at 0°C, heated to 55°C, reacted for 1 hour, and then heated to 80°C and reacted overnight. TLC monitoring showed that the raw material had basically disappeared, and the reaction solution was directly spin-dried to obtain the corresponding isocyanate intermediate. It was dissolved in DCE (1mL) as quickly as possible and added dropwise to a DCE (1mL) mixture dispersed with compound 55-5 (200mg, 0.6mmol) under an ice-water bath, and gradually warmed to room temperature. The reaction solution was filtered to give compound 55-6, 380mg, 84%, which was a white solid. LC-MS (ESI) m / z: 716[M+H] + .

[0577] Step 7: Synthesis of compound 55-7

[0578] To a solution of compound 55-6 (360 mg, 0.5 mmol) in DMF (3 mL) was slowly added dropwise 2M NaHMDS / THF (1.5 mL) at 0°C. The mixture was heated to 90°C and allowed to react for 2 hours. The reaction was quenched by adding excess water and the pH of the reaction mixture was adjusted to neutral with dilute hydrochloric acid. A large amount of white solid precipitated. The solid was filtered and dried to afford compound 55-7, 270 mg, 79%, as a white solid. LC-MS (ESI) m / z: 676 [M+H] + .

[0579] Step 8: Synthesis of compound 55-8

[0580] Compound 55-7 (100 mg, 0.15 mmol) was dispersed in acetonitrile (4 mL), and DIEA (0.26 mL) and POCl3 (0.1 mL) were added at 0°C, respectively. The temperature was raised to 80°C and refluxed for 4 hours. TLC monitoring showed that the starting material had essentially disappeared. The reaction solution was spin-dried and a tetrahydrofuran solution of dimethylamine (4 mL) was quickly added and stirred at room temperature. The reaction solution was purified by pre-TLC (MeOH:DCM=1:15) and then purified by C-18 reverse phase column chromatography to obtain compound 55-8, 50 mg, 46%, as a white solid. LC-MS (ESI) m / z: 365 [M / 2+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.03(d,J=8.8Hz,1H),7.95(d,J=8.9Hz,1H),7.60(d,J=6.4Hz, 2H),7.56(d,J=2.1Hz,1H),7.43(d,J=2.3Hz,1H),7.21(d,J=2.1Hz,1H),7.19-7.13(m, 2H),7.07(d,J=1.9Hz,1H),6.42(d,J=2.1Hz,1H),6.35(d,J=1.9Hz,1H),5.19(s,2H),5 .14(s,2H),3.42(s,3H),3.30(s,6H),3.23(s,6H),0.70(t,J=7.8Hz,2H),0.23(s,9H).

[0581] Step 9: Synthesis of compound 55

[0582] Compound 55-8 (15 mg, 0.02 mmol) was dissolved in DCM (7 mL), TFA (0.5 mL) was added, and the mixture was stirred at room temperature overnight. The reaction solution was spin-dried and purified by HPLC to obtain compound 55 (2.5 mg, 21% yield) as a pink solid. LC-MS (ESI) m / z: 300.6 [M / 2+H]+ .

[0583] Example 56

[0584] Synthesis method

[0585] The synthesis method of compound 56 refers to Example 44, except that 5-bromothiophene-2-carbonitrile in step 1 is replaced with 4-bromothiophene-2-carbonitrile, and dimethylamine in step 5 is replaced with methylethylamine. LC-MS (ESI) m / z: 330.6 [M / 2+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.94(d,J=2.2Hz,1H),8.07-7.99(m,2H),7.97-7.8 7(m,2H),7.80(d,J=1.6Hz,1H),7.64(d,J=2.1Hz,1H),7.26(dd,J=8.8,2.1 Hz,1H),7.20(dd,J=8.7,2.0Hz,1H),6.40(d,J=2.2Hz,1H),5.46(s,2H),3. 82-3.62(m,4H),3.33(s,3H),3.23(s,3H),2.15(s,3H),1.32-1.23(m,6H).

[0586] Example 57

[0587] Synthesis route

[0588] Step 1: Synthesis of compound 57-1

[0589] At room temperature, 5-bromo-3-aminopyridine (2.0 g, 11.56 mmol), diboronic acid pinacol ester (10.8 g, 42.52 mmol), Pd(dppf)Cl2 (860 mg, 1.176 mmol), and potassium acetate (3.0 g, 32.26 mmol) were dissolved in 60 mL of dioxane. The atmosphere was replaced with nitrogen three times and then heated to 100 ° C. in an oil bath for 5 hours. The reaction was monitored by LC-MS to be complete. The dioxane was concentrated to remove the reaction solution, and PE was added to disperse the reaction solution and then filtered. The filter cake was dispersed with a DCM / MeOH mixed solution and filtered again. The filtrate was concentrated, and 4-bromothiophene-2-carbonitrile (2.0 g, 10.64 mmol), sodium carbonate (3.4 g, 32.08 mmol), tetrakistriphenylphosphine palladium (1.22 g, 1.055 mmol), 30 mL of THF and 6 mL of water were added, and then the temperature was raised to 60 ° C. and stirred for 5 hours. LC-MS monitoring revealed the disappearance of 4-bromothiophene-2-carbonitrile. The product was extracted three times with water and EA. The combined organic phases were concentrated and separated by flash chromatography (DCM:MeOH, 0-10%, 20 min) to afford compound 57-1, 2.0 g, 86% yield, as a green solid. LC-MS (ESI) m / z: 202 [M+H] + .

[0590] Step 2: Synthesis of compound 57-2

[0591] At room temperature, compound 57-1 (2.0 g, 9.90 mmol) was dissolved in a 7N methanolic ammonia solution (20 mL). 2 mL of water-sealed Raney nickel was added, and the supernatant was removed after precipitation. The product was washed twice with methanol. After settling, the supernatant was removed. The precipitate was diluted with methanol and added to the reaction system. The hydrogen atmosphere was replaced three times, and the reaction was maintained at room temperature for 4 hours. LC-MS monitored the reaction for completion. The reaction solution was diluted with 50 mL of DCM and 10 mL of methanol, then filtered through Celite. The filtrate was concentrated and purified by flash chromatography (DCM:MeOH, 0-10%, 20 min) to obtain compound 57-2, 700 mg, 34% yield, as a yellow solid. LC-MS (ESI) m / z: 206 [M+H] + .

[0592] Step 3: Synthesis of compound 57-3

[0593] At room temperature, 2-fluoro-4-chlorobenzamide (1.2 g, 6.936 mmol) was dissolved in 20 mL of DCE. After cooling to 0°C, oxalyl chloride (1.3 g, 10.24 mmol) was slowly added dropwise. The temperature was slowly raised to room temperature and then to 70°C, with stirring for 16 hours. The excess oxalyl chloride was then removed by concentration, dissolved in 3 mL of DCE, and added dropwise to a solution of compound 57-2 (700 mg, 3.4 mmol) in DCE / DMF (20 mL, 5:1). The reaction was maintained at room temperature for 30 minutes. A large amount of solid precipitated. Compound 57-3 was obtained by filtration, yielding 1.5 g of a light yellow solid in a 73% yield. LC-MS (ESI) m / z: 604 [M+H] + .

[0594] Step 4: Synthesis of compound 57-4

[0595] At room temperature, compound 57-3 (1.5 g, 2.5 mmol) was dissolved in 30 mL of DMF, cooled to 0°C, and sodium hydride (400 mg, 10 mmol) was added portionwise. The mixture was stirred at room temperature for 10 minutes, then heated to 90°C and stirred for 16 hours. LC-MS monitored the reaction completion, and water was added to quench the reaction. The pH was then adjusted to approximately 6 with 1 M hydrochloric acid. A large amount of solid precipitated, which was filtered and the filter cake was re-slurried with DCM / MeOH to afford compound 57-4, 1.0 g, 71% yield, as a red solid. LC-MS (ESI) m / z: 564 [M+H] + .

[0596] Step 5: Synthesis of compound 57

[0597] At room temperature, compound 57-4 (100 mg, 0.18 mmol) was dissolved in 3 mL of anhydrous acetonitrile, cooled to 0°C, and DIEA (100 mg, 0.78 mmol) and phosphorus oxychloride (130 mg, 0.85 mmol) were added. The mixture was slowly warmed to room temperature and then heated to 80°C with stirring for 6 hours. The reaction solution was concentrated to remove the bulk of the phosphorus oxychloride, followed by addition of a solution of dimethylamine in THF (2 mL, 2.5 N) and stirring at room temperature for 30 minutes. LC-MS monitored the reaction for completion. After concentration, the crude product was separated by flash chromatography (DCM:MeOH, 0-10% over 20 min). This was then purified by HPLC to afford compound 57, 19 mg (35% yield), as a white solid. LC-MS (ESI) m / z: 309.6 [M / 2+H] + .

[0598] 1H NMR (400MHz, DMSO-d6) δ9.06(d,J=2.1Hz,1H),8.44(d,J=2.2Hz,1H),8.14(t,J=2.2Hz,1H),8.07(d,J=8.8Hz,1H),8.03-7.95(m,2H),7.82 (d,J=1.6Hz,1H),7.64(d,J=2.1Hz,1H),7.22(ddd,J=17.5,8.8,2.0Hz,2H),6.50(d,J=2.1Hz,1H),5.48(s,2H),3.33(s,6H),3.25(s,6H).

[0599] Example 58

[0600] Synthesis method

[0601] The synthesis method of compound 58 is similar to that of Example 57, except that dimethylamine in step 5 is replaced by methylethylamine. LC-MS (ESI) m / z: 323.6 [M / 2+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.06(d,J=2.1Hz,1H),8.45(d,J=2.2Hz,1H),8.15(t,J=2.2Hz,1H),8.05-7.98(m,2 H),7.91(d,J=8.8Hz,1H),7.83(d,J=1.6Hz,1H),7.64(d,J=2.0Hz,1H),7.22(ddd,J=17.6,8.8,2.0Hz,2H), 6.49(d,J=2.1Hz,1H),5.47(s,2H),3.72(q,J=7.0Hz,2H),3.65(q,J=7.1Hz,2H),3.32(s,3H),3.23(s,3H),1.34-1.24(m,6H).

[0602] Example 59

[0603] Synthesis method

[0604] The synthesis method of compound 59 is similar to that of Example 57, except that dimethylamine in step 5 is replaced with dimethyl-D6-amine hydrochloride. LC-MS (ESI) m / z: 315.6 [M / 2+H] + . 1H NMR (400MHz, DMSO-d6) δ9.07(d,J=2.0Hz,1H),8.45(d,J=2.2Hz,1H),8.17(d,J=2.3Hz,1H),8.07(d,J=8.7Hz,1H),8.02(d,J=1.5Hz,1H),7 .99(d,J=8.8Hz,1H),7.82(d,J=1.5Hz,1H),7.64(d,J=2.0Hz,1H),7.22(ddd,J=16.2,8.7,2.0Hz,2H),6.51(d,J=2.1Hz,1H),5.48(s,2H).

[0605] Example 60

[0606] Synthesis route

[0607] Step 1: Synthesis of compound 60-1

[0608] Ethyl 2-bromothiophene-5-carboxylate (1.5 g, 6.38 mmol), 3-nitrophenylboronic acid (1.3 g, 7.66 mmol), and sodium carbonate (2.0 g, 19.15 mmol) were dissolved in tetrahydrofuran (12 mL) at room temperature. Tetrakistriphenylphosphine palladium (750 mg, 0.64 mmol) and water (3 mL) were added. The mixture was heated to 70°C and stirred for 18 hours under nitrogen. TLC monitored the reaction completion. 30 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate, 0-50%, 15 min) to obtain compound 60-1, 1.1 g, 62% yield, as a light yellow solid. LC-MS (ESI) m / z: 279 [M+H] + .

[0609] Step 2: Synthesis of compound 60-2

[0610] Compound 60-1 (1.1 g, 3.96 mmol) was dissolved in an amine-methanol solution (75 mL) at room temperature and stirred for 4 hours. TLC monitored the reaction until complete. After vacuum rotary evaporation, the solid obtained was compound 60-2, 984 mg, with a yield of 99%, as a pale yellow solid. Compound 60-2 was used directly in the next reaction without purification. LC-MS (ESI) m / z: 250 [M+H] + .

[0611] Step 3: Synthesis of compound 60-3

[0612] At room temperature, compound 60-2 (500 mg, 2.01 mmol) was dissolved in tetrahydrofuran (5 mL), cooled to 0°C, and a solution of lithium aluminum tetrahydride in tetrahydrofuran (2.5 mL) was added dropwise. Under nitrogen protection, the temperature was raised to 70°C and stirred for 2 hours. TLC monitored the complete reaction. The reaction system was quenched with water (10 mL), extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol, 0-10%, 15 min). After concentration, compound 60-3 was obtained, 146 mg, 35% yield, as a light yellow solid. LC-MS (ESI) m / z: 206 [M+H] + .

[0613] Step 4: Synthesis of compound 60-4

[0614] Oxalyl chloride (555 mg, 4.37 mmol) was added dropwise to a solution of 4-chloro-2-fluorobenzamide (380 mg, 2.18 mmol) in dichloroethane (DCE) (5 mL) at 0°C. Under nitrogen protection, the reaction mixture was stirred at 70°C overnight. After removing excess oxalyl chloride by rotary evaporation under reduced pressure, the mixture was diluted with DCE (2 mL) and added dropwise to a solution of compound 60-3 (146 mg, 0.71 mmol) in DCE (3 mL). The reaction was stirred at room temperature for 3 hours. TLC monitored the complete reaction. Acetonitrile was added to the reaction system to slurry, and the solid after filtration was compound 60-4, 248 mg, 58% yield, as a white solid. LC-MS (ESI) m / z: 604 [M+H] + .

[0615] Step 5: Synthesis of compound 60-5

[0616] Sodium hydride (87 mg, 2.05 mmol) was added to a solution of compound 60-4 (248 mg, 0.41 mmol) in DMF (5 mL) at 0°C. The mixture was heated to 90°C and stirred for 3 hours under nitrogen. LC-MS analysis indicated that the starting material had essentially disappeared. The reaction system was quenched with water and diluted hydrochloric acid (0.5 mol / L) was added dropwise until the pH was neutral. After filtration, the solid was slurried with acetonitrile and filtered again to obtain compound 60-5, 70 mg, 30% yield, as a white solid. LC-MS (ESI) m / z: 564 [M+H] + .

[0617] Step 6: Synthesis of compound 60

[0618] Phosphorus oxychloride (0.8 mL) was added to a solution of compound 5 (70 mg, 0.12 mmol) and N,N-diisopropylethylamine (0.8 mL) in acetonitrile / ACN (4 mL) at 0°C. Under nitrogen protection, the reaction mixture was reacted at 90°C for 4 hours, and the excess phosphorus oxychloride was removed by rotary evaporation under reduced pressure. A solution of dimethylamine in tetrahydrofuran (4 mL) was added dropwise to the reaction system after removal of phosphorus oxychloride, and stirred at room temperature for 30 minutes. LC-MS confirmed the complete reaction. After dissolution in dichloromethane / methanol, the product was purified by silica gel column chromatography (dichloromethane:methanol, 0-10%, 15 min) to obtain the crude product, which was then purified by HPLC to obtain compound 60, 21.03 mg, 28.40% yield, as a light yellow solid. LC-MS (ESI) m / z: 309.6 [M / 2+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.13(s,1H),8.06-7.95(m,3H),7.82(t,J=1.9Hz,1H),7.78(d,J=2.1Hz,1H),7.68(t,J=7.9Hz,1H),7. 41(dd,J=7.8,2.1,1.1Hz,1H),7.20(ddd,J=8.8,3.6,2.0Hz,2H),6.37(d,J=2.1Hz,1H),5.53(s,2H),3.31(s,6H),3.24(s,6H).

[0619] Example 61

[0620] Synthesis method

[0621] The synthesis method of compound 61 is similar to that of Example 57, except that dimethylamine in step 5 is replaced by methylamine. LC-MS (ESI) m / z: 295.5 [M / 2+H] + . 1 H NMR(600MHz,DMSO-d6)δ9.06(d,J=2.1Hz,1H),8.83-8.77(m,1H),8.73-8.62(m,1H ),8.44(d,J=2.2Hz,1H),8.18-8.13(m,2H),8.09(d,J=8.7Hz,1H),8.01(d,J=1.6H z,1H),7.80(s,1H),7.62(d,J=2.0Hz,1H),7.31(ddd,J=19.5,8.6,1.9Hz,2H),6.4 8(d,J=2.0Hz,1H),5.55-5.42(m,2H),3.00(d,J=4.4Hz,3H),2.95(d,J=4.3Hz,3H).

[0622] Example 62

[0623] Synthesis route

[0624] Step 1: Synthesis of compound 62-1

[0625] At room temperature, 2-amino-6-bromopyridine (1 g, 5.8 mmol), 1-H-4-cyanoimidazole (540 mg, 5.8 mmol), cuprous iodide (110 mg, 0.6 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (90 mg, 0.6 mmol), and cesium carbonate (5.6 g, 17.2 mmol) were dissolved in 20 mL of anhydrous DMF. The atmosphere was purged with nitrogen three times, and the mixture was heated to 100°C in an oil bath for 16 hours. LC-MS monitored the reaction completion. The mixture was extracted three times with water and EA. The combined organic phases were washed twice with saturated brine, concentrated, and slurried with ethanol to obtain compound 62-1, 500 mg, with a yield of 47%, as a yellow solid. LC-MS (ESI) m / z: 186 [M+H] + .

[0626] Step 2: Synthesis of compound 62-2

[0627] At room temperature, compound 62-1 (500 mg, 2.7 mmol) was dissolved in a 7N methanolic ammonia solution (10 mL). 2 mL of water-sealed Raney nickel was added, precipitated, and the supernatant removed. The mixture was washed twice with methanol, allowed to settle, and the supernatant removed. The precipitate was diluted with methanol and added to the reaction system. The hydrogen atmosphere was replaced three times, and the reaction was maintained at room temperature for 4 hours. LC-MS monitored the reaction for completion. The reaction solution was diluted with 50 mL of DCM and 10 mL of methanol, then filtered through celite. The filtrate was concentrated and purified by reverse-phase chromatography (water / acetonitrile, 40%) to obtain compound 62-2, 500 mg, in a 97% yield. LC-MS (ESI) m / z: 190 [M+H] + .

[0628] Step 3: Synthesis of compound 62-3

[0629] At room temperature, 2-fluoro-4-trifluoromethylbenzamide (920 mg, 5.3 mmol) was dissolved in 10 mL of DCE. After cooling to 0°C, oxalyl chloride (1 g, 7.9 mmol) was slowly added dropwise. The temperature was slowly raised to room temperature and then to 70°C, and stirred for 16 hours. The excess oxalyl chloride was then removed by concentration, dissolved in 2 mL of DCE, and added dropwise to a solution of compound 62-2 (500 mg, 2.6 mmol) in DCE / DMF (20 mL, 5:1). The reaction was maintained at room temperature for 1 hour. A large amount of white solid precipitated. Compound 62-3 was obtained by filtration, 957 mg, 62% yield, as a white solid. LC-MS (ESI) m / z: 588 [M+H] + .

[0630] Step 4: Synthesis of compound 62-4

[0631] At room temperature, compound 62-3 (957 mg, 1.6 mmol) was dissolved in 10 mL of DMF, cooled to 0°C, and sodium hydride (260 mg, 6.5 mmol) was added portionwise. The mixture was stirred at room temperature for 10 minutes, then heated to 90°C and stirred for 16 hours. LC-MS monitored the reaction completion, and water was added to quench the reaction. The pH was then adjusted to approximately 6 with 1 M hydrochloric acid. A large amount of solid precipitated, which was filtered and the filter cake was re-slurried with DCM / MeOH to afford compound 62-4, 700 mg, 79% yield, as a yellow solid. LC-MS (ESI) m / z: 548 [M+H] + .

[0632] Step 5: Synthesis of compound 62

[0633] At room temperature, compound 62-4 (100 mg, 0.18 mmol) was dissolved in 5 mL of anhydrous acetonitrile, cooled to 0°C, and DIEA (0.5 mL) and phosphorus oxychloride (0.5 mL) were added. The mixture was slowly warmed to room temperature and then heated to 80°C with stirring for 6 hours. The reaction solution was concentrated to remove the bulk of the phosphorus oxychloride, followed by addition of a solution of dimethylamine in THF (3 mL, 2.5 N) and stirring at room temperature for 30 minutes. LCMS monitored the reaction for completion. After concentration, the crude product was separated by flash chromatography (DCM:MeOH, 0-10%, 20 min). This was then purified by HPLC to afford compound 62, 19 mg, 17% yield, as a white solid. LC-MS (ESI) m / z: 301.6 [M / 2+H] + . 1H NMR (600MHz, DMSO-d6) δ8.55(s,1H),8.24(t,J=7.9Hz,1H),8.06(d,J=8.8Hz,1H),7.96(dd,J=14.2,8.5Hz,2H),7.77(s,1H),7.67(d,J=2.0Hz,1 H),7.46(d,J=7.6Hz,1H),7.23(dd,J=8.8,2.1Hz,1H),7.17(dd,J=8.7,2.0Hz,1H),6.55(d,J=2.1Hz,1H),5.21(s,2H),3.33(s,6H),3.23(s,6H).

[0634] Example 63

[0635] Synthesis method

[0636] The synthesis method of compound 63 is similar to that of Example 62, except that dimethylamine in step 5 is replaced by methylethylamine. LC-MS (ESI) m / z: 315.6 [M / 2+H] + . 1 H NMR(400MHz, DMSO-d6)δ8.51(d,J=1.4Hz,1H),8.23(t,J=7.9Hz,1H),7.98(dd,J=11.0,8.5Hz,2H), 7.87(d,J=8.8Hz,1H),7.75(d,J=1.4Hz,1H),7.67(d,J=2.1Hz,1H),7.45(d,J=7.6Hz,1H),7.24(dd, J=8.8,2.1Hz,1H),7.17(dd,J=8.7,2.0Hz,1H),6.54(d,J=2.1Hz,1H),5.19(s,2H),3.72(q,J=7.0Hz ,2H),3.63(q,J=7.0Hz,2H),3.32(s,3H),3.21(s,3H),1.31(t,J=7.0Hz,3H),1.27(t,J=7.0Hz,3H).

[0637] Example 64

[0638] Synthesis method

[0639] The synthesis method of compound 64 is similar to that of Example 46, except that methylethylamine in step 5 is replaced by methylamine. LC-MS (ESI) m / z: 272.6 [M / 2+H] +.1H NMR(400MHz, DMSO-d6)δ8.62(d,J=4.5Hz,1H),8.12-8.05(m,2H),7.48(t,J=8.1 Hz,1H),7.30-7.23(m,2H),7.09(dd,J=8.3,2.0Hz,1H),6.90(s,1H),6.85(d,J=7 .7Hz,1H),6.42(s,2H),6.35(d,J=1.9Hz,1H),4.10(t,J=6.2Hz,2H),2.97(d,J=4 .4Hz,3H),2.26-2.15(m,2H),2.14-2.05(m,2H),1.23(s,1H),1.05-0.97(m,4H).

[0640] Example 65

[0641] Synthesis method

[0642] The synthesis method of compound 65 is similar to that of Example 62, except that dimethylamine in step 5 is replaced by methylamine. LC-MS (ESI) m / z: 287.6 [M / 2+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.96-8.89(m,1H),8.61-8.56(m,1H),8.48(s,1H),8.20(dt,J =15.4,8.3Hz,2H),8.06(d,J=8.7Hz,1H),7.96(d,J=8.2Hz,1H),7.73(s,1H),7.61(d,J =1.9Hz,1H),7.43(d,J=7.6Hz,1H),7.31(dd,J=8.6,2.0Hz,1H),7.23(dd,J=8.6,1.9Hz ,1H),6.51(d,J=1.9Hz,1H),5.20(s,2H),2.98(d,J=4.3Hz,3H),2.92(d,J=4.4Hz,3H).

[0643] Example 66

[0644] Synthesis route

[0645] Step 1: Synthesis of compound 66-1

[0646] To a mixture of methyl 5-bromo-4-methyl-2-thiophenecarboxylate (1.0 g, 4.3 mmol) and (5-aminopyridin-3-yl)boronic acid (0.75 g, 5.1 mmol) in dioxane (10 mL) and N,N-dimethylformamide (2 mL) was added an aqueous solution (2 mL) containing sodium carbonate (1.35 g, 12.9 mmol). After nitrogen displacement, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (0.30 g, 0.43 mmol) was added. Under a nitrogen atmosphere, the temperature was raised to 70°C and the reaction was allowed to proceed for 5 hours. After completion of the reaction, the mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated and extracted three times with ethyl acetate and water. The organic phases were combined. The residue was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (EA:PE=22:25) to obtain compound 66-1, 0.66 g, as a yellow oil, with a yield of 95%. LC-MS (ESI) m / z: 249 [M+H] + .

[0647] Step 2: Synthesis of compound 66-2

[0648] Aqueous ammonia (20 mL) was added to compound 66-1 (0.44 g, 1.8 mmol) and stirred at room temperature for 24 hours. After completion of the reaction, the mixture was filtered and dried to obtain compound 66-2 (0.27 mg) as a white solid in a 65% yield. LC-MS (ESI) m / z: 234 [M+H] + .

[0649] Step 3: Synthesis of compound 66-3

[0650] To a solution of compound 66-2 (0.25 g, 1.1 mmol) in tetrahydrofuran (3 mL) at 0°C was added LiAlH4 (1.7 mL, 2.5 M in THF) dropwise. The temperature was raised to 80°C and stirred overnight. After completion of the reaction, as determined by LC-MS, the reaction mixture was quenched with ice water and filtered through celite. The filter cake was washed with a mixture of methanol and dichloromethane (MeOH:DCM = 1:10). The filtrate was concentrated and purified by reverse-phase column chromatography to afford compound 66-3, 0.10 g, as a light yellow solid in a 44% yield. LC-MS (ESI) m / z: 220 [M+H] + .

[0651] Step 4: Synthesis of compound 66-4

[0652] Compound 2-fluoro-4-chlorobenzamide (180 mg, 1.0 mmol) was dissolved in 1,2-dichloroethane (5 mL) and oxalyl chloride (0.2 mL, 1.6 mmol) was slowly added dropwise at 0 ° C under nitrogen protection. After the addition was complete, the mixture was heated to 55 ° C and stirred for 1 hour, then heated to 80 ° C and stirred overnight. TLC showed that the reaction was complete. After the reaction mixture was cooled to room temperature, the solvent and excess oxalyl chloride were evaporated on a rotary evaporator to obtain a white solid mixture. The obtained solid mixture was dissolved in dichloroethane (1 mL) and the solution was slowly added dropwise to compound 3 in dichloroethane (1 mL) at 0 ° C under nitrogen protection. After the addition was complete, the reaction was allowed to react at room temperature for 2 hours until a large amount of white solid precipitated. It was filtered and dried to obtain compound 66-4, 0.11 g, with a yield of 36%, as a white solid. LC-MS (ESI) m / z: 618 [M+H] + .

[0653] Step 5: Synthesis of compound 66-5

[0654] Compound 66-4 (70 mg, 0.11 mmol) was dissolved in DMF (2.5 mL). NaH (27 mg, 60% paraffin) was added at 0°C under nitrogen protection. The mixture was heated to 70°C and allowed to react for 3 hours. After the reaction was completed, the mixture was cooled to room temperature and quenched with excess water. The pH of the reaction mixture was adjusted to neutral with dilute hydrochloric acid. A large amount of white solid precipitated. The solid was filtered and dried to obtain compound 66-5, 50 mg, in a 77% yield, as a white solid. LC-MS (ESI) m / z: 578 [M+H] + .

[0655] Step 6: Synthesis of compound 66

[0656] Compound 66-5 (30 mg, 0.052 mmol) was dispersed in acetonitrile (2 mL). DIEA (0.1 mL) and POCl3 (0.05 mL) were added dropwise at 0°C under a nitrogen atmosphere. The mixture was heated to 80°C and refluxed for 4 hours. After TLC indicated the reaction was complete, the reaction solution was cooled to room temperature and the solvent was removed on a rotary evaporator to obtain a solid mixture. A solution of dimethylamine in tetrahydrofuran (2.5 mL, 2 M in THF) was quickly added to the solid mixture at room temperature and stirred at room temperature. After the reaction was completed, the solvent was removed on a rotary evaporator to obtain an oil. The oil was dissolved in a mixture of methanol and dichloromethane and purified by pre-TLC (MeOH:DCM = 1:10) and then by high-performance liquid chromatography to obtain compound 66, 4.1 mg, 13% yield, as a white solid. LC-MS (ESI) m / z: 316.6 [M / 2+H] + . 1H NMR (400MHz, DMSO-d6) δ8.74(d,J=2.1Hz,1H),8.48(d,J=2.3Hz,1H),8.05(d,J=8.8Hz,1H),7.99(d,J=8.8Hz,1H),7.90(t,J=2.2Hz,1 H),7.67(d,J=2.0Hz,1H),7.25-7.19(m,2H),7.15(s,1H),6.51(d,J=2.1Hz,1H),5.46(s,2H),3.31(s,6H),3.25(s,6H),2.27(s,3H).

[0657] Example 67

[0658] Synthesis method

[0659] The synthesis method of compound 67 is similar to that of Example 62, except that 2-amino-6-bromopyridine in step 1 is replaced with 2-bromo-4-aminopyridine. LC-MS (ESI) m / z: 301.6 [M / 2+H] + . 1 H NMR (600MHz, DMSO-d6) δ8.67(d,J=5.3Hz,1H),8.53(s,1H),8.06(d,J=8.7Hz,1H),7.97(d,J=8.7Hz,1H),7.93(s,1H),7.81(s,1H),7.63(d,J=2.1Hz ,1H),7.38(d,J=5.3Hz,1H),7.25(dd,J=8.8,2.1Hz,1H),7.18(dd,J=8.7, 2.0Hz,1H),6.66(d,J=2.1Hz,1H),5.22(s,2H),3.32(s,6H),3.24(s,6H).

[0660] Example 68

[0661] Synthesis route

[0662] Step 1: Synthesis of compound 68-1

[0663] 5-Bromo-3-aminopyridine (5.0 g, 28.90 mmol), bis(pinacol boronate) (29.4 g, 115.61 mmol), and potassium acetate (8.1 g, 86.71 mmol) were dissolved in 50 mL of 1,4-dioxane at room temperature. [1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (1.2 g, 1.45 mmol) was added. The mixture was heated to 100°C and stirred overnight under nitrogen. TLC monitored the reaction completion. Petroleum ether (80 mL x 3) was added and the remaining bis(pinacol boronate) was removed by filtration. The residue was dissolved in 100 mL of a 10:1 solution of dichloromethane / methanol and filtered to remove the remaining potassium acetate. The filtrate was concentrated and slurried with 100 mL of ethyl acetate. Filtration yielded compound 68-1, 4.6 g, as a gray solid, which was used directly in subsequent reactions without further purification. LC-MS (ESI) m / z: 139 [M+H] + .

[0664] Step 2: Synthesis of compound 68-2

[0665] Methyl 2-bromothiazole-4-carboxylate (4.0 g, 18.02 mmol) was dissolved in 50 mL of amine-methanol solution at room temperature and stirred at room temperature for 4 hours. TLC monitored the reaction for completion. The resulting solid, concentrated by rotary evaporation under reduced pressure, was compound 68-2, a yellow solid (3.6 g, 97% yield). Compound 68-2 was used directly in the next reaction without purification. LC-MS (ESI) m / z: 207 [M+H] + .

[0666] Step 3: Synthesis of compound 68-3

[0667] At room temperature, compound 68-2 (1.0 mg, 4.86 mmol) was dissolved in 10 mL of dichloromethane. Triethylamine (1.8 mL) was added, and the temperature was lowered to 0°C. Trifluoroacetic anhydride (0.8 mL) was added dropwise, and the mixture was stirred at room temperature for 2 hours. TLC monitored the complete reaction. The reaction system was quenched with saturated sodium bicarbonate solution (4 mL), extracted with dichloromethane (20 mL × 3), and the organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate, 0-50%, 15 min) and concentrated to obtain compound 68-3, 846 mg, 92% yield, as a light yellow solid. LC-MS (ESI) m / z: 189 [M+H] + .

[0668] Step 4: Synthesis of compound 68-4

[0669] Compound 68-3 (500 mg, 2.66 mmol), compound 68-1 (1.1 g, 7.98 mmol), and sodium carbonate (845 mg, 7.98 mmol) were dissolved in 5 mL of tetrahydrofuran at room temperature. Water (1.25 mL) and tetrakistriphenylphosphine palladium (307 mg, 0.27 mmol) were added. The mixture was heated to 70°C and stirred overnight under nitrogen. TLC monitored the reaction for completion. After adding water (10 mL), the mixture was extracted with ethyl acetate (20 mL × 3) and the organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol, 0-10%, 15 min). After concentration, compound 68-4 (487 mg, 91% yield) was obtained as a light yellow solid. LC-MS (ESI) m / z: 203 [M+H] + .

[0670] Step 5: Synthesis of compound 68-5

[0671] Compound 68-4 (487 mg, 2.41 mmol) was dissolved in 10 mL of amine-methanol solution at room temperature, and Raney nickel was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. TLC monitored the reaction for completion, and the Raney nickel was removed by filtration. The crude product was chromatographed on a C18 column (acetonitrile:water, 5-95%, 15 min) and concentrated by rotary evaporation under reduced pressure to obtain compound 68-5, a light yellow oil (140 mg, 28% yield). LC-MS (ESI) m / z: 207 [M+H] + .

[0672] Step 6: Synthesis of compound 68-6

[0673] Oxalyl chloride (460 mg, 4.06 mmol) was added dropwise to a solution of 4-chloro-2-fluorobenzamide (320 mg, 2.03 mmol) in dichloroethane (DCE) (5 mL) at 0°C. Under nitrogen protection, the reaction mixture was stirred at 70°C overnight. After removing excess oxalyl chloride by rotary evaporation under reduced pressure, the mixture was diluted with DCE (2 mL) and added dropwise to a solution of compound 68-5 (140 mg, 0.67 mmol) in DCE (3 mL). The reaction was stirred at room temperature for 3 hours. TLC monitored the complete reaction. Acetonitrile was added to the reaction system to slurry, and the solid after filtration was compound 68-6, 299 mg, 74% yield, as a white solid. LC-MS (ESI) m / z: 604 [M+H] + .

[0674] Step 7: Synthesis of compound 68-7

[0675] Sodium hydride (102 mg, 2.48 mmol) was added to a solution of compound 68-6 (299 mg, 0.50 mmol) in DMF (5 mL) at 0°C. The mixture was heated to 90°C and stirred for 3 hours under nitrogen. LC-MS analysis showed that the starting material had essentially disappeared. The reaction system was quenched with water and diluted hydrochloric acid (0.5 mol / L) was added dropwise to a neutral pH. After filtration, the solid was slurried with acetonitrile and filtered again to obtain compound 68-7, 246 mg, 87% yield, as a white solid. LC-MS (ESI) m / z: 564 [M+H] + .

[0676] Step 8: Synthesis of compound 68

[0677] Phosphorus oxychloride (0.8 mL) was added to a solution of compound 68-7 (60 mg, 0.11 mmol) and N,N-diisopropylethylamine (0.8 mL) in acetonitrile / ACN (4 mL) at 0°C. Under nitrogen protection, the reaction mixture was reacted at 90°C for 4 hours, and the excess phosphorus oxychloride was removed by rotary evaporation under reduced pressure. A solution of dimethylamine in tetrahydrofuran (4 mL) was added dropwise to the reaction system after removal of phosphorus oxychloride, and stirred at room temperature for 30 minutes. LC-MS confirmed the complete reaction. After dissolution in dichloromethane / methanol, the product was purified by silica gel column chromatography (dichloromethane:methanol, 0-10%, 15 min) to obtain the crude product, which was then purified by HPLC to obtain compound 68, 20.57 mg, 30% yield, as a light yellow solid. LC-MS (ESI) m / z: 310.1 [M / 2+H] + . 1 H NMR (600MHz, DMSO-d6) δ9.21(d,J=2.0Hz,1H),8.64(d,J=2.2Hz,1H),8.32(t,J=2.2Hz,1H),8.08(d,J=8.8Hz,1H),7.98(d,J=8.9Hz,1H),7.68(d, J=2.0Hz,1H),7.59(s,1H),7.25(dd,J=8.8,2.1Hz,1H),7.18(dd,J=8.8, 2.0Hz,1H),6.59(d,J=2.1Hz,1H),5.45(s,2H),3.37(s,6H),3.26(s,6H).

[0678] Example 69

[0679] Synthesis method

[0680] The synthesis method of compound 69 refers to Example 68, except that dimethylamine in step 8 is replaced by methylethylamine. LC-MS (ESI) m / z: 324.1 [M / 2+H] +. 1 H NMR(600MHz,DMSO-d6)δ9.21(d,J=2.0Hz,1H),8.65(d,J=2.3Hz,1H),8.32(t,J=2.2Hz,1H),8.0 1(d,J=8.8Hz,1H),7.91(d,J=8.8Hz,1H),7.69(d,J=2.0Hz,1H),7.58(s,1H),7.26(dd,J=8.8,2 .1Hz,1H),7.18(dd,J=8.8,2.0Hz,1H),6.59(d,J=2.1Hz,1H),5.44(s,2H),3.74(q,J=7.0Hz,2H ),3.65(q,J=7.0Hz,2H),3.37(s,3H),3.24(s,3H),1.33(t,J=7.0Hz,3H),1.27(t,J=7.0Hz,3H).

[0681] Example 70

[0682] Synthesis method

[0683] The synthesis method of compound 70 is similar to that of Example 68, except that dimethylamine in step 8 is replaced by methylamine. LC-MS (ESI) m / z: 296.0 [M / 2+H] + . 1 H NMR (600MHz, DMSO-d6) δ9.21(d,J=2.0Hz,1H),8.77(q,J=4.8Hz,1H),8.63(d,J=2.2Hz,1 H),8.56(q,J=4.6Hz,1H),8.32(t,J=2.1Hz,1H),8.15(d,J=8.7Hz,1H),8.08(d,J=8.7Hz, 1H),7.62(d,J=1.9Hz,1H),7.54(s,1H),7.33(dd,J=8.7,1.9Hz,1H),7.26(dd,J=8.6,1.8 Hz,1H),6.57(d,J=1.9Hz,1H),5.47(s,2H),3.00(d,J=4.4Hz,3H),2.95(d,J=4.4Hz,3H).

[0684] Example 71

[0685] Synthesis method

[0686] The synthesis method of compound 71 is similar to that of Example 46, except that methylethylamine in step 5 is replaced by dimethylamine. LC-MS (ESI) m / z: 279.6 [M / 2+H]+ . 1 H NMR(600MHz,DMSO-d6)δ8.10(d,J=8.1Hz,1H),8.03(d,J=8.8Hz,1H),7.53-7.47(m,1H),7 .26(d,J=8.1Hz,1H),7.19(dd,J=8.8,2.0Hz,1H),7.11-7.07(m,1H),6.90(t,J=1.9Hz,1H) ,6.86(d,J=7.7Hz,1H),6.42(s,2H),6.38(dd,J=8.3,1.9Hz,1H),4.11(t,J=6.2Hz,2H),3. 30(s,6H),2.21(qd,J=7.9,4.0Hz,1H),2.16-2.10(m,2H),2.08(s,2H),1.06-0.96(m,4H).

[0687] Example 72

[0688] Synthesis route

[0689] Step 1: Synthesis of compound 72-1

[0690] 5-Bromo-3-aminopyridine (5.0 g, 28.90 mmol), bis(pinacol boronate) (29.4 g, 115.61 mmol), and potassium acetate (8.1 g, 86.71 mmol) were dissolved in 50 mL of 1,4-dioxane at room temperature. [1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (1.2 g, 1.45 mmol) was added. The mixture was heated to 100°C and stirred overnight under nitrogen. TLC monitored the reaction completion. Petroleum ether (80 mL x 3) was added and the remaining bis(pinacol boronate) was removed by filtration. The residue was dissolved in 100 mL of a 10:1 solution of dichloromethane / methanol and filtered to remove the remaining potassium acetate. The filtrate was concentrated and slurried with 100 mL of ethyl acetate. Filtration afforded compound 72-1, a 4.6 g gray solid, which was used directly in subsequent reactions without further purification. LC-MS (ESI) m / z: 139 [M+H] + .

[0691] Step 2: Synthesis of compound 72-2

[0692] Ethyl 2-bromothiazole-5-carboxylate (5.0 g, 21.18 mmol) was dissolved in 50 mL of amine-methanol solution at room temperature and stirred for 4 h. The reaction was monitored for completeness by TLC. After concentration under reduced pressure, compound 72-2 (4.5 g, yellow solid) was obtained, which was used directly in the next step without purification. The yield was 100%. LC-MS (ESI) m / z: 207 [M+H] + .

[0693] Step 3: Synthesis of compound 72-3

[0694] At room temperature, compound 72-2 (4.5 g, 21.74 mmol) was dissolved in 50 mL of dichloromethane. 11.3 mL of triethylamine was added, the temperature was lowered to 0°C, and 5.0 mL of trifluoroacetic anhydride was added dropwise. The mixture was stirred at room temperature for 2 h. TLC monitored the reaction for completion. The reaction system was quenched with 40 mL of saturated sodium bicarbonate solution, extracted with dichloromethane (80 mL x 3), and the organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate, 0-50%, 15 min) to obtain compound 3 (4.1 g, light yellow solid) in a 99% yield. LC-MS (ESI) m / z: 189 [M+H] + .

[0695] Step 4: Synthesis of compound 72-4

[0696] At room temperature, compound 72-3 (4.1 g, 21.69 mmol), compound 72-1 (3.3 g, 23.86 mmol), and sodium carbonate (6.9 g, 65.07 mmol) were dissolved in 50 mL of tetrahydrofuran. Water (12.5 mL) and tetrakistriphenylphosphine palladium (1.2 g, 1.08 mmol) were added thereto. The temperature was raised to 70°C and stirred overnight under nitrogen. TLC monitored the complete reaction. After adding 60 mL of water, the mixture was extracted with ethyl acetate (100 mL x 3) and the organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol, 0-10%, 15 min) to give compound 72-4 (2.1 g, red solid) with a yield of 48%. LC-MS (ESI) m / z: 203 [M+H] + .

[0697] Step 5: Synthesis of compound 72-5

[0698] Compound 72-4 (2.1 g, 10.34 mmol) was dissolved in 20 mL of amine-methanol solution at room temperature, and Raney nickel was added. The mixture was stirred at room temperature for 4 h under a hydrogen atmosphere. TLC monitored the reaction for completion. The Raney nickel was removed by filtration, and the crude product was purified by C18 column chromatography (acetonitrile:water, 5-95%, 15 min) to afford compound 72-5 (1.8 g, light yellow oil) in an 84% yield. LC-MS (ESI) m / z: 207 [M+H] + .

[0699] Step 6: Synthesis of compound 72-6

[0700] Oxalyl chloride (5.9 g, 52.14 mmol) was added dropwise to a solution of 4-chloro-2-fluorobenzamide (4.1 g, 26.07 mmol) in dichloroethane (DCE) (50 mL) at 0°C. Under nitrogen protection, the reaction mixture was stirred at 70°C overnight. After removing excess oxalyl chloride under reduced pressure, the mixture was diluted with DCE (20 mL) and added dropwise to a solution of compound 72-5 (1.8 g, 8.69 mmol) in DCE (20 mL). The reaction was stirred at room temperature for 3 h. TLC monitored the complete reaction. Acetonitrile was added to the reaction system to slurry, and the mixture was filtered to obtain compound 72-6 (2.7 g, red solid) with a yield of 51%. LC-MS (ESI) m / z: 605 [M+H] + .

[0701] Step 7: Synthesis of compound 72-7

[0702] Sodium hydride (0.9 g, 22.30 mmol) was added to a solution of compound 72-6 (2.7 g, 4.46 mmol) in DMF (30 mL) at 0°C. Under nitrogen, the mixture was heated to 90°C and stirred for 3 h. LC-MS analysis indicated that the starting material had essentially disappeared. The reaction system was quenched with water and diluted hydrochloric acid (0.5 mol / L) was added dropwise to a neutral pH. After filtration, the solid was slurried with acetonitrile and filtered again to obtain compound 72-7 (2.1 g, light red solid) in an 83% yield. LC-MS (ESI) m / z: 565 [M+H] + .

[0703] Step 8: Synthesis of Compound 72

[0704] Phosphorus oxychloride (0.8 mL) was added to a solution of compound 72-7 (60 mg, 0.11 mmol) and N,N-diisopropylethylamine (0.8 mL) in acetonitrile (ACN) (4 mL) at 0°C. Under nitrogen, the reaction mixture was incubated at 90°C for 4 h, and the excess phosphorus oxychloride was removed under reduced pressure. A solution of deuterated dimethylamine in tetrahydrofuran (4 mL) was added dropwise to the reaction system after removal of phosphorus oxychloride, and the mixture was stirred at room temperature for 30 min. LC-MS confirmed the reaction was complete. The product was dissolved in dichloromethane / methanol and purified by silica gel column chromatography (dichloromethane:methanol, 0-10%, 15 min) to obtain the crude product. After purification by HPLC, compound 72 (3.61 mg, white solid) was obtained in a 10.42% yield. LC-MS (ESI) m / z: 316.1 [M / 2+H] + . 1 H NMR (600MHz, DMSO-d6) δ9.17(d,J=2.0Hz,1H),8.61(dd,J=9.7,2.2Hz,1H),8.32(dd,J=11.9,2.1Hz,1H),8.21(t,J=9.0,7.2Hz,2H ),8.00(d,J=8.4Hz,1H),7.98(d,J=8.7,1.8Hz,1H),7.79(d,J=2.1Hz,1H),7.36–7.31(m,1H),6.53(t,J=2.5Hz,1H),5.56(s,2H).

[0705] Example 73

[0706] Synthesis method

[0707] The synthesis method of compound 73 is similar to that of Example 62, except that 2-amino-6-bromopyridine in step 1 is replaced with 4-amino-6-bromopyrimidine. LC-MS (ESI) m / z: 302.1 [M / 2+H] + . 1 H NMR (600MHz, DMSO-d6) δ9.18(d,J=1.1Hz,1H),8.71(d,J=1.4Hz,1H),8.15(d,J=1.1Hz,1H),8.07(d,J=8.8Hz,1H),7.97(d,J=8.8Hz,1H),7.89(d,J=1. 3Hz, 1H), 7.57 (d, J = 2.1Hz, 1H), 7.27 (dd, J = 8.8, 2.0Hz, 1H), 7.19 (dd, J = 8. 8,2.0Hz,1H),6.96(d,J=2.0Hz,1H),5.25(s,2H),3.32(s,6H),3.25(s,6H).

[0708] Example 74

[0709] Synthesis method

[0710] The synthesis method of compound 74 is similar to that of Example 47, except that dimethylamine in step 5 is replaced by azetidine. LC-MS (ESI) m / z: 321.6 [M / 2+H] + . 1 H NMR (600MHz, DMSO-d6) δ8.93(d,J=2.2Hz,1H),8.39(d,J=2.2Hz,1H),8.04(t,J=2.2Hz,1H),7.84(d,J=8.7Hz,1H),7.77(d,J=8.8Hz,1H),7.66(d,J =2.0Hz,1H),7.58(d,J=3.7Hz,1H),7.31(d,J=3.7Hz,1H),7.24-7.18(m,3 H),5.52(s,2H),5.37-5.29(m,2H),4.95-4.01(m,8H),3.26-3.20(m,2H).

[0711] Example 75

[0712] Synthesis method

[0713] NaH (5.5 mg, 0.23 mmol) was slowly added portionwise to a solution of compound 71 (30 mg, 0.05 mmol) in DMF (0.5 mL) at 0°C. After stirring at room temperature for half an hour under nitrogen, iodomethane (23 mg, 0.16 mmol) was added dropwise to the reaction solution. Stirring at room temperature for one hour was continued, and the reaction was complete as determined by TLC. Post-treatment: The reaction solution was quenched by dropwise addition to ice water, extracted three times with 50 mL of ethyl acetate, and the organic phase was washed once with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by HPLC to obtain compound 75 (8 mg, 27% yield). LC-MS (ESI) m / z: 293.6 [M / 2+H]. + . 1H NMR(600MHz,DMSO-d6)δ8.03(d,J=8.8Hz,2H),7.48-7.40(m,1H),7.20(dd, J=8.8,2.1Hz,1H),7.15(d,J=6.5Hz,1H),6.94(s,1H),6.83(d,J=7.4Hz,1H) ,6.75(s,1H),6.40-6.35(m,1H),3.92(s,2H),3.34(s,6H),3.30(s,6H),2. 23(dd,J=12.4,6.2Hz,2H),1.91(s,1H),1.24(s,2H),1.04(d,J=6.4Hz,4H).

[0714] Example 76

[0715] Synthesis method

[0716] The synthesis method of compound 76 is similar to that of Example 47, except that dimethylamine in step 5 is replaced with deuterated dimethylamine. LC-MS (ESI) m / z: 315.6 [M / 2+H] + . 1 H NMR (600MHz, DMSO-d6) δ8.94(d,J=2.2Hz,1H),8.42(d,J=2.2Hz,1H),8.07-8.02(m,2H),7.97(d,J=8.7Hz,1H),7.67(d,J=2.0 Hz,1H),7.58(d,J=3.7Hz,1H),7.33(d,J=3.7Hz,1H),7.21(ddd,J=10.2,8.7,2.0Hz,2H),6.47(d,J=2.1Hz,1H),5.51(s,2H).

[0717] Example 77

[0718] Synthesis method

[0719] The synthesis method of compound 77 is similar to that of Example 47, except that dimethylamine in step 5 is replaced by pyrrolidine. LC-MS (ESI) m / z: 335.6 [M / 2+H] + . 1H NMR(600MHz,DMSO-d6)δ8.93(d,J=2.2Hz,1H),8.40(d,J=2.2Hz,1H),8.17(d ,J=8.8Hz,1H),8.11(d,J=8.8Hz,1H),8.05(t,J=2.3Hz,1H),7.65(d,J=2.1Hz ,1H),7.59(d,J=3.7Hz,1H),7.32(d,J=3.7Hz,1H),7.21(td,J=8.7,2.1Hz,2 H), 6.46 (d, J = 2.1Hz, 1H), 5.52 (s, 2H), 3.90-3.72 (m, 7H), 2.03-1.86 (m, 9H).

[0720] Example 78

[0721] Synthesis method

[0722] The synthesis method of compound 78 is similar to that of Example 72, except that deuterated dimethylamine in step 8 is replaced with methylethylamine. LC-MS (ESI) m / z: 324.1 [M / 2+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.17(d,J=2.1Hz,1H),8.60(d,J=2.2Hz,1H),8.31(t,J =2.2Hz,1H),8.22(s,1H),7.99(d,J=8.8Hz,1H),7.91(d,J=8.8Hz,1H),7.78(d, J=2.0Hz,1H),7.25-7.20(m,2H),6.52(d,J=2.1Hz,1H),5.55(s,2H),3.72(q,J= 7.0Hz,2H),3.65(q,J=7.0Hz,2H),3.32(s,3H),3.23(s,3H),1.35-1.27(m,6H).

[0723] Example 79

[0724] Synthesis route

[0725] Step 1: Synthesis of compound 79-1

[0726] Methyl 2-bromothiazole-5-carboxylate (5.0 g, 21.18 mmol) was dissolved in 50 mL of amine-methanol solution at room temperature and stirred for 4 h. The reaction was monitored for completeness by TLC. After concentration under reduced pressure, compound 79-1 (4.5 g, yellow solid) was obtained, which was used directly in the next reaction without purification in a 100% yield. LC-MS (ESI) m / z: 207 [M+H] + .

[0727] Step 2: Synthesis of compound 79-2

[0728] At room temperature, compound 79-1 (4.5 g, 21.74 mmol) was dissolved in 50 mL of dichloromethane. 11.3 mL of triethylamine was added, the temperature was lowered to 0°C, and 5.0 mL of trifluoroacetic anhydride was added dropwise. The mixture was stirred at room temperature for 2 h. TLC monitored the reaction for completion. The reaction system was quenched with 40 mL of saturated sodium bicarbonate solution, extracted with dichloromethane (80 mL x 3), and the organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate, 0-50%, 15 min) to obtain compound 79-2 (4.1 g, light yellow solid) in a 99% yield. LC-MS (ESI) m / z: 189 [M+H] + .

[0729] Step 3: Synthesis of compound 79-3

[0730] At room temperature, compound 79-2 (2.0 g, 10.58 mmol) was dissolved in 20 mL of N,N-dimethylformamide, and 3-tert-butyloxycarbonylaminopiperidine (2.3 g, 11.64 mmol) and potassium carbonate (4.4 g, 31.74 mmol) were added. The mixture was stirred at room temperature for 16 h. TLC monitored the reaction for completion. Water was added to the reaction system, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol, 0-10%, 15 min) to afford compound 79-3 (2.9 g, white solid) in an 89% yield. LC-MS (ESI) m / z: 309 [M+H] + .

[0731] Step 4: Synthesis of compound 79-4

[0732] Compound 79-3 (2.9 g, 9.42 mmol) was dissolved in 20 mL of 1,4-dioxane at room temperature. 20 mL of a hydrochloric acid-dioxane solution was added and stirred at room temperature for 30 min. TLC confirmed the reaction was complete. After concentration, the hydrochloride salt of compound 79-4 (2.2 g, white solid) was obtained in a 96% yield. LC-MS (ESI) m / z: 209 [M+H] + Step 5: Synthesis of compound 79-5

[0733] The hydrochloride salt of compound 79-4 (2.2 g, 9.02 mmol) was dissolved in 25 mL of amine-methanol solution at room temperature. Raney nickel was added and stirred at room temperature for 4 h under a hydrogen atmosphere. TLC confirmed the reaction was complete. The Raney nickel was removed by filtration. The crude product was purified by C18 column chromatography (acetonitrile:water, 5-95%, 15 min) to afford compound 79-5 (1.7 g, white solid) in an 88% yield. LC-MS (ESI) m / z: 213 [M+H] +

[0734] Step 6: Synthesis of compound 79-6

[0735] Oxalyl chloride (6.1 g, 47.88 mmol) was added dropwise to a solution of 4-chloro-2-fluorobenzamide (4.1 g, 23.94 mmol) in dichloroethane (DCE) (50 mL) at 0°C. Under nitrogen protection, the reaction mixture was stirred at 70°C overnight. After removing excess oxalyl chloride by rotary evaporation under reduced pressure, the mixture was diluted with DCE (20 mL) and added dropwise to a solution of compound 79-5 (1.7 g, 7.98 mmol) in DCE (30 mL). The reaction was stirred at room temperature for 3 h. TLC monitored the complete reaction. Acetonitrile was added to the reaction system, and the mixture was slurried and filtered to obtain compound 6 (2.5 g, white solid) with a yield of 51%. LC-MS (ESI) m / z: 611 [M+H] + .

[0736] Step 7: Synthesis of compound 79-7

[0737] Sodium hydride (0.8 g, 20.46 mmol) was added to a solution of compound 79-6 (2.5 g, 4.09 mmol) in DMF (25 mL) at 0°C. Under nitrogen, the mixture was heated to 90°C and stirred for 3 h. LC-MS analysis indicated that the starting material had essentially disappeared. The reaction system was quenched with water and diluted hydrochloric acid (0.5 mol / L) was added dropwise to a neutral pH. After filtration, the solid was slurried with acetonitrile and filtered again to obtain compound 79-7 (1.7 g, white solid) in a 70% yield. LC-MS (ESI) m / z: 591 [M+H] + .

[0738] Step 8: Synthesis of Compound 79

[0739] Phosphorus oxychloride (0.8 mL) was added to a solution of compound 79-7 (60 mg, 0.10 mmol) and N,N-diisopropylethylamine (0.8 mL) in acetonitrile (ACN) (4 mL) at 0°C. Under nitrogen, the reaction mixture was incubated at 90°C for 4 h, and the excess phosphorus oxychloride was removed by rotary evaporation. A 4 mL solution of N-ethylmethylamine in tetrahydrofuran was added dropwise to the reaction system, and the mixture was stirred at room temperature for 30 min. LC-MS confirmed the reaction was complete. The product was dissolved in dichloromethane / methanol and purified by silica gel column chromatography (dichloromethane:methanol, 0-10%, 15 min) to obtain the crude product. After preparative purification by HPLC, compound 79 (2.76 mg, white solid) was obtained in an 8.5% yield. LC-MS (ESI) m / z: 327 [M / 2+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.90(d,J=8.8Hz,1H),7.82(dd,J=5.4,3.4Hz,2H), 7.78(d,J=2.0Hz,1H),7.42(s,1H),7.22-7.18(m,2H),5.29(s,2H),3.95-3 .84(m,1H),3.61(q,J=23.2,7.0Hz,4H),3.39(s,3H),3.32(s,3H),3.22(s, 3H),3.19(s,3H),2.03-1.95(m,4H),1.77-1.71(m,2H),1.50-1.41(m,2H).

[0740] Example 80

[0741] Synthesis method

[0742] The synthesis method of compound 80 is similar to that of Example 79, except that dimethylamine is used in place of methylethylamine in step 8. LC-MS (ESI) m / z: 313.1 [M / 2+H] + . 1H NMR (600MHz, DMSO-d6) δ7.98(d,J=8.8Hz,1H),7.89(d,J=8.7Hz,1H),7.81(d,J=2.0Hz, 1H),7.77(d,J=2.0Hz,1H),7.42(s,1H),7.20(ddd,J=8.6,6.5,1.9Hz,2H),5.33-5.25(m ,2H),4.16(t,1H),3.96(dd,J=12.3,4.0Hz,1H),3.93-3.86(m,1H),3.72(d,J=12.9Hz, 1H),3.24(s,6H),3.21(s,6H),3.15-3.07(m,1H),2.80-2.71(m,1H),1.81-1.70(m,3H).

[0743] Example 81

[0744] Synthesis route

[0745] Step 1: Synthesis of compound 81-1

[0746] Potassium hydroxide (1.1 g, 19.6 mmol) was added to a solution of 3-nitrobenzyl bromide (4 g, 18.5 mmol) in 1,3-propylene glycol (40 mL) and the mixture was reacted at 80°C for three hours under nitrogen. After the reaction solution was cooled, 300 mL of water and 500 mL of dichloromethane were added for extraction three times. The organic phase was dried over anhydrous sodium sulfate and concentrated. The mixture was purified by silica gel column chromatography (EA:PE = 20%) to obtain compound 81-1 (2.4 g, LC-MS (ESI) m / z: 212 [M+H] + , yield 62%). Step 2: Synthesis of compound 81-2

[0747] Compound 81-1 (2.4 g, 11.3 mmol), triisopropylsilyl chloride (4.4 g, 22.8 mmol) and imidazole (2.3 g, 33.8 mmol) were dissolved in dichloromethane (30 ml) and stirred at room temperature overnight under nitrogen atmosphere. The reaction was complete after monitoring by TLC. The reaction solution was extracted with 200 mL of water and 250 mL of dichloromethane three times. The organic phases were combined, purified and concentrated by silica gel column chromatography to obtain compound 82-2 (4 g, LC-MS (ESI) m / z: 368 [M+H] + , yield 96%). Step 3: Synthesis of compound 81-3

[0748] Iron powder and ammonium chloride were dissolved in water under nitrogen atmosphere and heated at 100°C with stirring for half an hour. Compound 81-2 (1 g, 2.72 mmol) was then added and heated at 100°C with stirring overnight. The reaction was monitored by TLC to be complete. The reaction solution was cooled and filtered. The filtrate was extracted with 100 mL of water and 200 mL of dichloromethane, and the extraction was repeated three times. The organic phases were combined and concentrated to obtain compound 82-3 (700 mg, LC-MS (ESI) m / z: 338 [M+H] + , yield 76%).

[0749] Step 4: Synthesis of compound 81-4

[0750] At room temperature, 2-fluoro-4-chlorobenzamide (434 mg, 2.5 mmol) was dissolved in 10 mL of DCE, cooled to 0 ° C, and oxalyl chloride (470 mg, 3.7 mmol) was slowly added dropwise. The temperature was slowly raised to room temperature and then raised to 70 ° C and stirred for 16 hours. The excess oxalyl chloride was removed by concentration, dissolved in 2 mL of DCE, and added dropwise to a DCE solution of compound 81-3 (700 mg, 2.07 mmol), and the reaction was maintained at room temperature for 3 hours. A large amount of white solid precipitated. Filtration gave the title compound 81-4 (650 mg, LC-MS (ESI) m / z: 537 [M + H] + , yield 60%).

[0751] Step 5: Synthesis of compound 81-5

[0752] At room temperature, compound 81-4 (650 mg, 1.2 mmol) was dissolved in 8 mL of DMF, cooled to 0°C, and NaHMDS (2 mol / L, 0.6 mL) was added dropwise. After stirring at room temperature for 10 minutes, the temperature was raised to 65°C and stirred for 2 hours. LC-MS monitored the reaction completion, and water was added to quench the reaction. The reaction solution was extracted with 50 mL of water and 150 mL of dichloromethane, and the extraction was repeated three times. The organic phases were combined, purified and concentrated by silica gel column chromatography to obtain compound 81-5 (570 mg, LC-MS (ESI) m / z: 517 [M+H] + , yield 92%).

[0753] Step 6: Synthesis of compound 81-6

[0754] At room temperature, compound 81-5 (570 mg, 1.1 mmol) was dissolved in 10 mL of anhydrous acetonitrile, cooled to 0°C, and DIEA (712 mg, 0.96 mL) and phosphorus oxychloride (493 mg, 0.3 mL) were added. The mixture was slowly heated to room temperature and then heated to 80°C with stirring for 6 hours. The reaction solution was concentrated to remove a large amount of phosphorus oxychloride, and then a tetrahydrofuran solution of dimethylamine (5 mL, 2M in THF) was added and stirred at room temperature for 30 minutes. LC-MS monitored the reaction to be complete. After concentration, the mixture was separated by column chromatography (EA, 100%, 6 min) to give compound 81-6 (488 mg, LC-MS (ESI) m / z: 544 [M+H] + , yield 81%).

[0755] Step 7: Synthesis of compound 81-7

[0756] Compound 81-6 (488 mg, 0.89 mmol) was dissolved in 10 mL of methanol. Tetrabutylammonium fluoride (1.7 ml, 1.78 mmol) was added dropwise to the reaction solution at 0°C and stirred at room temperature for half an hour. The reaction was complete after LC-MS monitoring. 80 mL of brine and 100 mL of dichloromethane were added for extraction, and the extraction was repeated three times. The organic phase was concentrated to obtain compound 81-7 (207 mg, LC-MS (ESI) m / z: 388 [M+H] + , yield 61%).

[0757] Step 8: Synthesis of compound 81-8

[0758] Compound 81-7 (200 mg, 0.51 mmol) was dissolved in a mixed solution of 10 mL acetone and 1 mL acetic acid. Jones reagent (0.4 mL, 1.02 mmol) was added dropwise to the reaction solution at 0°C and stirred at room temperature for eight hours. The reaction was complete after LC-MS monitoring. Extraction was performed with 40 mL water and 50 mL ethyl acetate, and the mixture was repeated three times. The organic phase was concentrated and purified by HPLC to obtain 30 mg of compound 81-8 (66 mg, LC-MS (ESI) m / z: 402 [M+H] + , yield 32%).

[0759] Step 9: Synthesis of Compound 81

[0760] A solution of compound 81-8 (20 mg, 0.05 mmol) in DMF (0.3 mL) was added dropwise to a solution of TBTU (48 mg, 0.15 mmol) and triethylamine (20 mg, 0.19 mmol) in DMF (0.3 mL). Finally, a solution of compound 23-2 (9.5 mg, 0.05 mmol) in DMF (0.3 mL) was added dropwise. The mixture was reacted at 50°C for half an hour. TLC showed that the reaction of the raw materials was complete. After the reaction solution was cooled, 10 mL of water and 20 mL of ethyl acetate were added for extraction three times. The organic phase was washed once with brine, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The mixture was purified by HPLC to give 11.5 mg of compound 81 (LC-MS (ESI) m / z: 279.6 [M / 2+H] + , yield 5.4%).

[0761] Example 82

[0762] Synthesis method

[0763] The synthesis method of compound 82 is similar to that of Example 72, except that deuterated dimethylamine in step 8 is replaced with dimethylamine. LC-MS (ESI) m / z: 310.1 [M / 2+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.17(d,J=2.1Hz,1H),8.60(d,J=2.3Hz,1H),8.31(t,J=2.2Hz,1H),8.21(s,1H),8.05(d,J=8.8Hz,1H) ,7.98(d,J=8.7Hz,1H),7.79(d,J=2.0Hz,1H),7.24-7.19(m,2H),6.53(d,J=2.1Hz,1H),5.56(s,2H),3.32(s,6H),3.25(s,6H).

[0764] Example 83

[0765] Synthesis method

[0766] The synthesis method of compound 83 was similar to that of Example 72, except that deuterated dimethylamine in step 8 was replaced with azetidine. LC-MS (ESI) m / z: 322.1 [M / 2+H] + . 1H NMR (400MHz, DMSO-d6) δ9.16(d,J=2.1Hz,1H),8.57(d,J=2.3Hz,1H),8.29(t,J=2.2Hz,1H),8.18(s,1H),7.84(d,J=8.7Hz,1H) ,7.77(dd,J=5.3,3.4Hz,2H),7.22(dt,J=8.7,2.3Hz,2H),6.51(d,J=2.0Hz,1H),5.56(s,2H),3.53(t,8H),2.45-2.36(m,4H).

[0767] Example 84

[0768] Synthesis method

[0769] The synthesis method of compound 84 was similar to that of Example 47, except that the hydrogen in step 2 was replaced by deuterium. LC-MS (ESI) m / z: 310.4 [M / 2+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.94(d,J=2.2Hz,1H),8.42(d,J=2.2Hz,1H),8.08-8.03(m,2H),7.98(d,J=8.8Hz,1H),7.67(s,1H),7. 58(d,J=3.7Hz,1H),7.33(d,J=3.8Hz,1H),7.21(ddd,J=10.2,8.9,2.1Hz,2H),6.48(d,J=2.1Hz,1H),3.32(s,6H),3.25(s,6H).

[0770] Example 85

[0771] Synthesis route

[0772] Step 1: Synthesis of compound 85

[0773] Phosphorus oxychloride (1.0 mL) was added to a solution of compound 72-7 (80 mg, 0.14 mmol) and N,N-diisopropylethylamine (1.0 mL) in acetonitrile (5 mL) of ACN at 0°C. Under nitrogen, the reaction mixture was incubated at 90°C for 4 h, and the excess phosphorus oxychloride was removed by rotary evaporation under reduced pressure. 4 mL of water was added dropwise to the reaction system, and the mixture was stirred at room temperature for 30 min. LC-MS confirmed the complete reaction. The product was dissolved in dichloromethane / methanol and purified by silica gel column chromatography (dichloromethane:methanol, 0-10%, 15 min) to obtain the crude product. After purification by HPLC, compound 85 (3.05 mg, white solid) was obtained in a 3.86% yield. LC-MS (ESI) m / z: 565.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.91(s,2H),9.25(d,J=2.1Hz,1H),8.74(d,J=2.3Hz,1H),8.49(t,J=2.2Hz,1H),8.21(s,1H),8 .02(dd,J=18.2,8.4Hz,2H),7.83(d,J=1.8Hz,1H),7.34(dq,J=8.5,3.4,1.8Hz,2H),6.57(d,J=1.9Hz,1H),5.59(s,2H).

[0774] Example 86

[0775] Synthesis method

[0776] The synthesis method of compound 86 was similar to that of Example 47, except that the hydrogen in step 2 was replaced by deuterium, and the dimethylamine in step 5 was replaced by methylethylamine. LC-MS (ESI) m / z: 324.6 [M / 2+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.94(d,J=2.1Hz,1H),8.42(d,J=2.2Hz,1H),8.07(d,J=2.0 Hz,1H),7.99(d,J=8.8Hz,1H),7.91(d,J=8.8Hz,1H),7.67(s,1H),7.59(d,J=3.7Hz, 1H),7.34(d,J=4.4Hz,1H),7.22(td,J=9.9,9.4,2.1Hz,2H),6.47(d,J=2.1Hz,1H),3 .68(dq,J=25.6,7.0Hz,4H),3.31(s,3H),3.23(s,3H),1.30(dd,J=15.1,8.0Hz,6H).

[0777] Example 87

[0778] Synthesis method

[0779] The synthesis method of compound 87 was similar to that of Example 47, except that the hydrogen in step 2 was replaced by deuterium, and the dimethylamine in step 5 was replaced by methylisopropylamine. LC-MS (ESI) m / z: 338.6 [M / 2+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.94(d,J=2.1Hz,1H),8.43(d,J=2.2Hz,1H),8.07(d,J=2.2Hz,1H ),7.97(d,J=8.8Hz,1H),7.90(d,J=8.7Hz,1H),7.67(t,J=1.7Hz,1H),7.59(d,J=3.7Hz,1H ),7.36-7.31(m,1H),7.21(ddd,J=10.9,8.7,2.1Hz,2H),6.47(d,J=2.1Hz,1H),4.77(dp,J =28.9,6.6Hz,2H),3.15(s,3H),3.07(s,3H),1.29(d,J=6.6Hz,6H),1.24(d,J=6.6Hz,6H).

[0780] Example 88

[0781] Synthesis method

[0782] The synthesis method of compound 88 was similar to that of Example 47, except that the hydrogen in step 2 was replaced by deuterium, and the dimethylamine in step 5 was replaced by ethylamine. LC-MS (ESI) m / z: 310.6 [M / 2+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.93(d,J=2.2Hz,1H),8.66(t,J=5.5Hz,1H),8.48(t,J=5.4 Hz,1H),8.42(d,J=2.2Hz,1H),8.18(d,J=8.7Hz,1H),8.12(d,J=8.7Hz,1H),8.07(d ,J=2.0Hz,1H),7.64(s,1H),7.58(d,J=3.7Hz,1H),7.30(dd,J=8.4,2.4Hz,2H),6.4 4(d,J=2.0Hz,1H),3.58-3.45(m,4H),1.24(d,J=4.1Hz,3H),1.21(d,J=7.1Hz,3H).

[0783] Example 89

[0784] Synthesis route

[0785] Step 1: Synthesis of compound 89

[0786] Compound 76 (5 mg, 0.00794 mmol) was dissolved in a mixture of 0.4 mL of dichloromethane and 0.1 mL of methanol at room temperature. 30 μL of 4N hydrochloric acid in dioxane was added and stirred at room temperature for 20 minutes. The mixture was then concentrated under reduced pressure and lyophilized to yield 4 mg of compound 89 as a white solid. LC-MS (ESI) m / z: 315.6 [M / 2+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.02(d,J=2.2Hz,1H),8.53(d,J=2.2Hz,1H),8.20(d,J=2.2Hz,1H),8.08(dd,J=12.8,8.8Hz,2H),7.75 (d,J=2.0Hz,1H),7.64(d,J=3.7Hz,1H),7.37(d,J=3.7Hz,1H),7.27(dt,J=9.0,2.4Hz,2H),6.59(d,J=2.0Hz,1H),5.55(s,2H).

[0787] Example 90

[0788] Synthesis method

[0789] The synthesis method of compound 90 is similar to that of Example 47, except that the dimethylamine in step 5 is replaced by a methanolic ammonia solution. LC-MS (ESI) m / z: 281.5 [M / 2+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.93(d,J=2.2Hz,1H),8.46-8.39(m,2H),8.16(d,J=8.7Hz,2H),8.1-8.07(m,3 H),7.64(d,J=1.9Hz,1H),7.58(d,J=3.7Hz,1H),7.32-7.24(m,4H),6.45(d,J=1.9Hz,1H),5.51(s,2H).

[0790] Example 91

[0791] Synthesis method

[0792] The synthesis method of compound 91 is similar to that of Example 47, except that dimethylamine in step 5 is replaced with N,O-dimethylhydroxylamine. LC-MS (ESI) m / z: 325.6 [M / 2+H] + . 1 H NMR (600MHz, DMSO-d6) δ8.97(d,J=2.1Hz,1H),8.51(d,J=9.0Hz,1H),8.47-8.44(m,2H),8.09(t,J=2.2Hz,1H),7.73(d,J=2.0Hz,1H),7.60(d,J=3 .8Hz,1H),7.35(d,J=3.8Hz,1H),7.32-7.25(m,2H),6.51(d,J=2.1Hz,1H ),5.59-5.54(m,2H),3.84(s,3H),3.78(s,3H),3.50(s,3H),3.44(s,3H).

[0793] Example 92

[0794] Synthesis method

[0795] The synthesis method of compound 92 was similar to that of Example 79, except that methylethylamine in step 8 was replaced with azetidine. LC-MS (ESI) m / z: 325.1 [M / 2+H] + . 1 H NMR(600MHz,DMSO-d6)δ7.80-7.70(m,4H),7.38(s,1H),7.19(dt,J=8.7,6.8,1 .9Hz,2H),5.31(s,2H),4.45(d,J=270.0Hz,8H),3.99-3.82(m,2H),3.71(d,J= 13.3Hz,1H),3.09(td,J=13.0,12.4,4.3Hz,1H),2.77(dd,J=11.6,4.7Hz,1H), 2.43-2.33(m,4H),2.17(m,1H),2.05-1.96(m,1H),1.76(q,J=10.7,7.7Hz,2H).

[0796] Example 93

[0797] Synthesis method

[0798] The synthesis method of compound 93 is similar to that of Example 47, except that dimethylamine in step 5 is replaced with azetidine-3-carbonitrile hydrochloride. LC-MS (ESI) m / z: 346.6 [M / 2+H] + .1 H NMR (600MHz, DMSO-d6) δ8.95(d,J=2.1Hz,1H),8.40(d,J=2.2Hz,1H),8.04(t,J=2.2Hz,1H),7.80(d,J=8.7Hz,1H),7.76-7.69(m,2H),7.58(d ,J=3.7Hz,1H),7.32(d,J=3.8Hz,1H),7.23(td,J=12.0,8.7,2.0Hz,2H),6.51(d,J=2.0Hz,1H),5.54(s,2H),4.73(m,8H),4.07-3.92(m,2H).

[0799] Example 94

[0800] Synthesis method

[0801] The synthesis method of compound 94 was similar to that of Example 47, except that the hydrogen in step 2 was replaced by deuterium, and the dimethylamine in step 5 was replaced by azetidine. LC-MS (ESI) m / z: 322.6 [M / 2+H] + . 1 H NMR (600MHz, DMSO-d6) δ8.93(d,J=2.1Hz,1H),8.39(d,J=2.2Hz,1H),8.04(t,J=1 .7Hz,1H),7.84(d,J=8.7Hz,1H),7.77(d,J=8.7Hz,1H),7.66(q,J=1.6Hz,1H),7.5 8(d,J=3.7Hz,1H),7.31(dd,J=3.8,1.6Hz,1H),7.21(ddd,J=12.1,8.7,2.0Hz,2H ),6.46(d,J=2.1Hz,1H),4.53(d,J=311.1Hz,8H),2.46-2.43(m,2H),2.40(m,2H).

[0802] Example 95

[0803] Synthesis method

[0804] The synthesis method of compound 95 is similar to that of Example 47, except that the dimethylamine in step 5 is replaced with 3-methyl-3-azetidinol hydrochloride. LC-MS (ESI) m / z: 351.6 [M / 2+H] + . 1H NMR (600MHz, DMSO-d6) δ8.94(d,J=2.2Hz,1H),8.39(d,J=2.2Hz,1H),8.04(t,J=2.2Hz,1 H),7.85(d,J=8.8Hz,1H),7.79(d,J=8.7Hz,1H),7.67(d,J=2.0Hz,1H),7.58(d,J=3.7Hz ,1H),7.31(d,J=3.7Hz,1H),7.20(td,J=10.1,8.7,2.0Hz,2H),6.47(d,J=2.1Hz,1H),5. 87(s,1H),5.81(s,1H),5.52(s,2H),4.36(m,J=255.2Hz,8H),1.48(s,3H),1.44(s,3H).

[0805] Example 96

[0806] Synthesis method

[0807] The synthesis method of compound 96 is similar to that of Example 79, except that methylethylamine in step 8 is replaced by water. LC-MS (ESI) m / z: 571.1 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ11.82(s,1H),11.58(s,1H),7.99(t,J=8.4Hz,2H),7.8 2(d,2H),7.41(s,1H),7.32(ddd,J=12.5,8.4,1.7Hz,2H),5.33(s,2H),3.98(d ,J=12.4Hz,1H),3.86(t,J=11.7Hz,1H),3.81(d,J=13.1Hz,1H),3.05(t,J=12. 6Hz,1H),2.04-1.99(m,2H),1.85-1.81(m,1H),1.77(q,1H),1.48-1.44(m,1H).

[0808] Example 97

[0809] Synthesis method

[0810] The synthesis method of compound 97 is similar to that of Example 68, except that dimethylamine in step 8 is replaced with methylethylisopropylamine. LC-MS (ESI) m / z: 338.1 [M / 2+H] + . 1H NMR (400MHz, DMSO-d6) δ9.19(d,J=4.4Hz,1H),8.65(d,J=2.1Hz,1H),8.31(t,J=2.0Hz,1H ),7.99(d,J=8.8Hz,1H),7.89(d,J=8.8Hz,1H),7.69(d,1H),7.57(s,1H),7.25(dd,J=8.8, 1.9Hz,1H),7.17(dd,J=8.7Hz,1H),6.58(d,J=1.9Hz,1H),5.43(s,2H),4.87-4.78(m,1H), 4.77-4.67(m,1H),3.17(s,3H),3.07(s,3H),1.30(d,J=6.6Hz,6H),1.23(d,J=6.6Hz,6H).

[0811] Example 98

[0812] Synthesis method

[0813] The synthesis method of compound 98 is similar to that of Example 47, except that the dimethylamine in step 5 is replaced with 3-methyl-azetidine hydrochloride. LC-MS (ESI) m / z: 335.6 [M / 2+H] + . 1 H NMR (400MHz, DMSO-d6)8.93(d,J=2.2Hz,1H),8.39(d,J=2.2Hz,1H),8.04(t,J=2.2Hz,1H) ,7.84(d,J=8.8Hz,1H),7.77(d,J=8.7Hz,1H),7.65(d,J=2.0Hz,1H),7.58(d,J=3.7Hz,1H ),7.30(d,J=3.6Hz,1H),7.20(td,J=8.3,2.0Hz,2H),6.46(d,J=2.0Hz,1H),5.51(s,2H), 4.35(m,J=208.4Hz,8H),2.95-2.80(m,2H),1.30(d,J=6.9Hz,3H),1.26(d,J=6.9Hz,3H).

[0814] Example 99

[0815] Synthesis method

[0816] The synthesis method of compound 99 refers to Example 47, except that the dimethylamine in step 5 is replaced by 3,3-difluoroazetidine hydrochloride. LC-MS (ESI) m / z: 357.5 [M / 2+H] + .1 H NMR(400MHz, DMSO-d6)8.96(d,J=2.1Hz,1H),8.41(d,J=2.2Hz,1H),8.06(t,J=2.2Hz,1H),7.83(d,J=8.7Hz,1H),7.77(d,J=8.5Hz,2 H),7.59(d,J=3.7Hz,1H),7.33(d,J=3.7Hz,1H),7.25(td,J=8.5,2.0Hz,2H),6.53(d,J=2.0Hz,1H),5.56(s,2H),5.11-4.76(m,8H).

[0817] Example 100

[0818] Synthesis method

[0819] The synthesis method of compound 100 was similar to that of Example 68, except that dimethylamine in step 8 was replaced with azetidine. LC-MS (ESI) m / z: 322.1 [M / 2+H] + . 1 H NMR (600MHz, DMSO-d6) δ9.20(d,J=1.9Hz,1H),8.61(d,J=2.2Hz,1H),8.28(t,J=2.0Hz,1H),7.86(d,J=8.8Hz,1H),7.78(d,J=8.7Hz,1H),7.65(d,J =1.7Hz,1H),7.56(s,1H),7.25(dd,J=8.7,1.9Hz,1H),7.18(dd,J=8.7,1 .8Hz,1H),6.58(d,J=1.9Hz,1H),5.46(s,2H),2.50-2.37(m,8H),1.24(s, 2H),0.89-0.77(m,2H).

[0820] Example 101

[0821] Synthesis route

[0822] Step 1: Synthesis of compound 101-1

[0823] 2,4,7-Trichloroquinazoline (5.0 g, 21.44 mmol) was dissolved in 50 mL of tetrahydrofuran (THF) at room temperature. 15 mL (31.12 mmol) of a 2 M solution of N-ethylmethylamine in THF was added, and the mixture was stirred at room temperature for 16 h. The reaction was monitored for completion by TLC. The product was concentrated by rotary evaporation under reduced pressure to afford compound 101-1 (3.7 g, white solid), which was used directly in the next step without purification in a 68% yield. LC-MS (ESI) m / z: 256 [M+H] + .

[0824] Step 2: Synthesis of compound 101-2

[0825] At room temperature, compound 101-1 (3.7 g, 14.45 mmol) was dissolved in 50 mL of glacial acetic acid, heated to 100°C, and stirred for 16 h. TLC monitored the reaction for completion. The reaction system was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (80 mL x 3). The organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol, 0-20%, 15 min) to obtain compound 101-2 (3.1 g, light yellow solid) in a 90% yield. LC-MS (ESI) m / z: 238.0 [M+H] + .

[0826] Step 3: Synthesis of compound 101-3

[0827] At room temperature, compound 101-2 (1.0 g, 4.20 mmol) was dissolved in 10 mL of N,N-dimethylformamide, and 2-bromo-5-bromomethylthiazole (1.3 g, 5.04 mmol) and potassium carbonate (1.8 g, 12.61 mmol) were added thereto. The mixture was stirred at room temperature for 16 h. TLC monitored the reaction for completion. Water was added to the reaction system, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate, 0-100%, 20 min) to obtain compound 101-3 (970 mg, white solid) in a 56% yield. LC-MS (ESI) m / z: 413 [M+H] + .

[0828] Step 4: Synthesis of compound 101-4

[0829] Oxalyl chloride (5.5 g, 43.01 mmol) was added dropwise to a solution of 4-chloro-2-fluorobenzamide (3.7 g, 21.51 mmol) in dichloroethane (DCE) (50 mL) at 0°C. Under nitrogen protection, the reaction mixture was stirred at 70°C overnight. After removing excess oxalyl chloride under reduced pressure, the mixture was diluted with DCE (20 mL) and added dropwise to a solution of 1-Boc-3-aminopyrrolidine (2.0 g, 10.75 mmol) in DCE (30 mL). The reaction was stirred at room temperature for 3 hours. TLC monitored the complete reaction. Acetonitrile was added to the reaction system, and the mixture was slurried and filtered to obtain compound 101-4 (3.7 g, white solid) with a yield of 89%. LC-MS (ESI) m / z: 386 [M+H] + .

[0830] Step 5: Synthesis of compound 101-5

[0831] Sodium hydride (960 mg, 24.03 mmol) was added to a solution of compound 4 (3.7 g, 9.61 mmol) in DMF (40 mL) at 0°C. Under nitrogen, the mixture was heated to 90°C and stirred for 3 h. LC-MS analysis indicated that the starting material had essentially disappeared. The reaction system was quenched with water and diluted hydrochloric acid (0.5 mol / L) was added dropwise to a neutral pH. After filtration, the solid was slurried with acetonitrile and filtered again to obtain compound 101-5 (2.7 g, white solid) in a 77% yield. LC-MS (ESI) m / z: 366 [M+H] + .

[0832] Step 6: Synthesis of compound 101-6

[0833] Compound 101-5 (2.7 g, 7.40 mmol) was dissolved in 30 mL of acetonitrile at room temperature, and 1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (5.8 g, 11.10 mmol) and a tetrahydrofuran solution of dimethylamine (9 mL, 18.49 mmol) were added thereto. 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (3.9 g, 25.89 mmol) was then added dropwise. The reaction mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC for complete reaction. The crude product was purified by silica gel column chromatography (dichloromethane:methanol, 0-10%, 15 min) to give compound 101-6 (2.1 g, white solid) in a yield of 72%. LC-MS (ESI) m / z: 393 [M+H] + .

[0834] Step 7: Synthesis of Compound 101-7

[0835] Compound 101-6 (2.1 g, 5.36 mmol) was dissolved in 20 mL of 1,4-dioxane at room temperature. 20 mL of a hydrochloric acid-dioxane solution was added and stirred at room temperature for 30 min. TLC confirmed the reaction completion. After concentration, the hydrochloride salt of compound 101-7 (1.7 g, white solid) was obtained in a 97% yield. LC-MS (ESI) m / z: 292 [M+H] + Step 8: Synthesis of Compound 101

[0836] Compound 101-7 (50 mg, 0.15 mmol) was dissolved in 1 mL of N,N-dimethylformamide at room temperature, and compound 101-3 (62 mg, 0.15 mmol) and cesium carbonate (148 mg, 0.45 mmol) were added. The reaction mixture was stirred at 120°C for 16 h. LC-MS confirmed the reaction was complete. The crude product was purified by silica gel column chromatography (dichloromethane:methanol, 0-10%, 15 min). After preparative HPLC purification, compound 101 (1.27 mg, white solid) was obtained in a 1.36% yield. LC-MS (ESI) m / z: 313.1 [M / 2+H] + . 1 HNMR(400MHz,DMSO-d6)δ7.90(dd,J=8.8,4.8Hz,2H),7.72(dd,J=12.4,2.0Hz,2H),7.38(s,1H),7.20(d,2H),5.29(s,2H),3.75-3.69(m,1H ),3.66(q,2H),3.64-3.61(m,1H),3.41(q,1H),3.22(s,9H),2.71-2.5 5(m,2H),2.30-2.21(m,1H),1.51-1.39(m,1H),1.29(t,J=7.3Hz,3H).

[0837] Example 102

[0838] Synthesis route

[0839] Step 1: Synthesis of compound 102-1

[0840] Oxalyl chloride (5.5 g, 43.01 mmol) was added dropwise to a solution of 4-chloro-2-fluorobenzamide (3.7 g, 21.51 mmol) in dichloroethane (DCE) (50 mL) at 0°C. Under nitrogen, the reaction mixture was stirred at 70°C overnight. After removing excess oxalyl chloride under reduced pressure, the mixture was diluted with DCE (20 mL) and added dropwise to a solution of 1-tert-butyloxycarbonyl-3-aminopiperidine (2.0 g, 9.98 mmol) in DCE (30 mL). The reaction was stirred at room temperature for 3 h. TLC monitored the reaction for completeness. Acetonitrile was added to the reaction system, and the mixture was slurried and filtered to obtain compound 102-1 (3.9 g, white solid) with a yield of 98%. LC-MS (ESI) m / z: 400 [M+H] + .

[0841] Step 2: Synthesis of compound 102-2

[0842] Sodium hydride (980 mg, 24.43 mmol) was added to a solution of compound 102-1 (3.9 g, 9.77 mmol) in DMF (40 mL) at 0°C. Under nitrogen, the mixture was heated to 90°C and stirred for 3 h. LC-MS analysis indicated that the starting material had essentially disappeared. The reaction system was quenched with water and diluted hydrochloric acid (0.5 mol / L) was added dropwise to a neutral pH. After filtration, the solid was slurried with acetonitrile and filtered again to obtain compound 102-2 (2.2 g, white solid) in a 59% yield. LC-MS (ESI) m / z: 380 [M+H] + .

[0843] Step 3: Synthesis of compound 102-3

[0844] Compound 102-2 (2.2 g, 5.80 mmol) was dissolved in 30 mL of acetonitrile at room temperature, and 1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (4.5 g, 8.71 mmol) and a tetrahydrofuran solution of dimethylamine (8 mL, 14.51 mmol) were added, followed by dropwise addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (3.1 g, 20.31 mmol). The reaction mixture was stirred at room temperature for 30 min, and the reaction was monitored for completeness by TLC. The crude product was purified by silica gel column chromatography (dichloromethane:methanol, 0-10%, 15 min) to afford compound 102-3 (2.0 g, white solid) in 85% yield. LC-MS (ESI) m / z: 407 [M+H] + .

[0845] Step 4: Synthesis of compound 102-4

[0846] Compound 102-3 (2.0 g, 4.92 mmol) was dissolved in 20 mL of 1,4-dioxane at room temperature. 20 mL of a hydrochloric acid-dioxane solution was added and stirred at room temperature for 30 min. TLC confirmed the reaction completion and the product was concentrated to afford the hydrochloride salt of compound 102-4 (1.5 g, white solid) in an 89% yield. LC-MS (ESI) m / z: 307 [M+H] + Step 5: Synthesis of compound 102

[0847] Compound 102-4 (15 mg, 0.05 mmol) was dissolved in 1 mL of N,N-dimethylformamide at room temperature, and compound 101-3 (20 mg, 0.05 mmol) and cesium carbonate (50 mg, 0.15 mmol) were added. The reaction mixture was stirred at 120°C for 16 h. LC-MS confirmed the reaction was complete. The crude product was purified by silica gel column chromatography (dichloromethane:methanol, 0-10%, 15 min). After preparative HPLC purification, compound 102 (1.22 mg, white solid) was obtained in a 3.8% yield. LC-MS (ESI) m / z: 319.1 [M / 2+H] + . 1 HNMR (400MHz, DMSO-d6) δ7.90 (dd, J=8.8, 4.4Hz, 2H), 7.79 (dd, J=17.2, 2.0Hz, 2H), 7. 41(s,1H),7.20(td,J=8.9,7.1,1.9Hz,2H),5.29(d,J=3.8Hz,2H),4.22-4.13(m,1H),4 .00-3.93(m,2H),3.89(t,1H),3.72(d,J=13.3Hz,1H),3.64(q,J=7.0Hz,2H),3.34(t,3 H),3.22(s,3H),3.21(s,6H),3.16-3.05(m,1H),2.81-2.70(m,1H),2.04-1.99(m,2H).

[0848] Example 103

[0849] Synthesis method

[0850] The synthesis method of compound 103 was similar to that of Example 68, except that the dimethylamine in step 8 was replaced with 3-methylazetidine hydrochloride. LC-MS (ESI) m / z: 336.1 [M / 2+H] + . 1H NMR (400MHz, DMSO-d6) δ9.19(d,J=2.0Hz,1H),8.61(d,J=2.3Hz,1H),8.28(d,J=2. 4Hz,1H),7.86(d,J=8.8Hz,1H),7.78(d,J=8.7Hz,1H),7.65(d,J=2.0Hz,1H),7.56 (s,1H),7.24(dd,J=8.7,2.0Hz,1H),7.18(dd,J=8.7,1.9Hz,1H),6.57(d,J=2.0Hz ,1H),5.46(s,2H),5.10-3.75(m,8H),1.31(d,J=6.9Hz,3H),1.27(d,J=6.9Hz,3H).

[0851] Example 104

[0852] Synthesis method

[0853] The synthesis method of compound 104 was similar to that of Example 68, except that dimethylamine in step 8 was replaced with 3,3-difluoroazetidine hydrochloride. LC-MS (ESI) m / z: 358.0 [M / 2+H] + . 1 H NMR (600MHz, DMSO-d6) δ9.22(d,J=2.0Hz,1H),8.63(d,J=2.3Hz,1H),8.31(t,J=2.3Hz,1H),7.85(d,J=8.8Hz,1H),7.80-7.7 2(m,2H),7.62(s,1H),7.28(dd,J=8.7,2.0Hz,1H),7.22(dd,J=8.6,1.9Hz,1H),6.66(s,1H),5.51(s,2H),5.18-4.78(m,8H).

[0854] Example 105

[0855] Synthesis method

[0856] The synthesis method of compound 105 was similar to that of Example 68, except that dimethylamine in step 8 was replaced with azetidine-3-carbonitrile hydrochloride. LC-MS (ESI) m / z: 347.1 [M / 2+H] + . 1H NMR(600MHz,DMSO-d6)δ9.20(d,J=2.0Hz,1H),8.62(d,J=2.3Hz,1H),8.29(t,J =2.3Hz,1H),7.82(d,J=8.8Hz,1H),7.75-7.69(m,2H),7.59(s,1H),7.26(dd,J =8.7,2.0Hz,1H),7.20(dd,J=8.7,2.0Hz,1H),6.62(d,J=2.0Hz,1H),5.48(s,2 H),5.12-4.32(m,8H),4.04(tt,J=8.9,6.1Hz,1H),3.98(tt,J=9.1,6.1Hz,1H).

[0857] Example 106

[0858] Synthesis method

[0859] The synthesis method of compound 106 is similar to that of Example 101, except that dimethylamine is used in place of methylethylamine in step 1. LC-MS (ESI) m / z: 306.1 [M / 2+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.97(d,J=9.0Hz,1H),7.91(d,1H),7.72(dd,J=13.6,2.0Hz,2H),7.38(s,1H),7.20(d,J=8.6Hz,2H),5.30(s,2H),4.07 -3.96(m,1H),3.75-3.69(m,1H),3.68-3.63(m,1H),3.24(s,6H),3.22( s,6H),2.64-2.57(m,1H),2.27(q,J=8.1,4.1Hz,1H),2.04-1.99(m,2H).

[0860] Example 107

[0861] Synthesis method

[0862] The synthesis method of compound 107 was similar to that of Example 68, except that dimethylamine in step 8 was replaced with N,O-dimethylhydroxylamine. LC-MS (ESI) m / z: 326.1 [M / 2+H] + . 1H NMR(600MHz,DMSO-d6)δ9.23(d,J=2.1Hz,1H),8.66(d,J=2.2Hz,1H),8.54(d ,J=9.0Hz,1H),8.46(d,J=9.0Hz,1H),8.36(d,J=2.3Hz,1H),7.72(d,J=2.1H z,1H),7.61(s,1H),7.31(dd,J=9.0,2.2Hz,1H),7.26(dd,J=9.0,2.0Hz,1H) ,6.63(d,J=2.3Hz,1H),5.51(s,2H),3.86(s,3H),3.79(s,3H).3.52(s,6H).

[0863] Example 108

[0864] Synthesis method

[0865] The synthesis method of compound 108 was similar to that of Example 68, except that the dimethylamine in step 8 was replaced with 3-methyl-3-azetidinol hydrochloride. LC-MS (ESI) m / z: 352.1 [M / 2+H] + . 1 H NMR (600MHz, DMSO-d6) δ9.20(d,J=2.0Hz,1H),8.62(d,J=2.3Hz,1H),8.29(d,J=2.4 Hz,1H),7.87(d,J=8.8Hz,1H),7.79(d,J=8.7Hz,1H),7.66(d,J=2.0Hz,1H),7.57(s, 1H),7.23(dd,J=8.6,2.0Hz,1H),7.17(dd,J=8.8,1.9Hz,1H),6.58(d,J=2.0Hz,1H), 5.88(s,1H),5.81(s,1H),5.46(s,2H),4.88-3.95(m,8H),1.49(s,3H),1.45(s,3H).

[0866] Examples 109 & 110

[0867] Compound 79 was resolved by SFC to give single-configuration compounds 109 (79-P1) and 110 (79-P2).

[0868] Examples 111 & 112

[0869] Compound 80 was resolved by SFC to give single-configuration compounds 111 and 112.

[0870] Examples 113 & 114

[0871] Synthesis route

[0872] Step 1: Synthesis of compound 113-1

[0873] At room temperature, piperazine (930 mg, 10.8 mmol) was dissolved in 20 mL of anhydrous acetonitrile. 1-Bromo-2-butanol (5 g, 32.7 mmol) and potassium carbonate (6.4 g, 46.4 mmol) were added, and the mixture was heated to 80°C and allowed to react overnight. TLC was performed using an iodine-based colorimeter to monitor the reaction completion. After cooling to room temperature, the potassium carbonate was removed by filtration. The filtrate was concentrated and purified by column chromatography to yield 1.4 g of compound 113-1 as a white solid in a 64% yield. LC-MS (ESI) m / z: 231 [M+H]. + .

[0874] Step 2: Synthesis of compound 113-2

[0875] At room temperature, compound 113-1 (1.4 g, 6.93 mmol) was dissolved in 20 mL of dry dichloromethane and cooled to 0°C. Carbon tetrabromide (6.4 g, 19.3 mmol) was added portionwise, followed by triphenylphosphine (3.4 g, 13.0 mmol). The mixture was slowly warmed to room temperature and stirred for 2 hours. TLC was performed using an iodine developer to monitor the reaction completion. The system was separated by flash column chromatography (PE:EA, 0-100%, 15 min) to afford 700 mg of compound 113-2 as a yellow oil in a 31% yield. LC-MS (ESI) m / z: 355 [M+H] + .

[0876] Step 3: Synthesis of compounds 113 & 114

[0877] 7-Chloro-4-(dimethylamino)quinazolin-2(1H)-one (100 mg, 0.446 mmol) was dissolved in 2 mL of dry DMF at room temperature. Potassium carbonate (250 mg, 1.812 mmol) was added, and the mixture was heated to 100°C and stirred for 20 minutes. Compound 113-2 (150 mg, 0.459 mmol) was then added, and the mixture was stirred at 100°C for 20 minutes. The reaction was monitored for completion by LC-MS, and the system was separated by flash column chromatography (EA:MeOH, 0-30% over 15 minutes) to yield 50 mg of the crude product. Compounds 113 and 114 were then purified by HPLC.

[0878] Compound 113: 12 mg, white solid, yield 8%, LC-MS (ESI) m / z: 214.4 [M / 3+H]+ . 1 H NMR(600MHz,DMSO-d6)δ8.15-8.10(m,1H),7.93-7.86(m,1H),7.59-7.47(m,2H),7.29-7.17(m,2H),4.12-3.97(m,2H),3.20(s,3H),3.30-3.2 4(m,9H),3.23-3.20(m,2H),3.19-3.17(m,2H),3.00-2.94(m,1H),2.9 3-2.88(m,1H),2.62-2.60(m,2H),2.42-2.36(m,4H),0.93-0.88(m,6H)

[0879] Compound 114: 9 mg, white solid, yield 6%, LC-MS (ESI) m / z: 214.4 [M / 3+H] + . 1 H NMR (600MHz, DMSO-d6)7.94(dd,J=8.7,3.5Hz,2H),7.55(d,J=10.6Hz,2H),7.17(d,J=8.9Hz,2H),4.12-3.94(m,5H),3.49(q,2H),3.30(q,2H ),3.22(d,J=3.2Hz,12H),2.62-2.60(m,2H),2.43-2.41(m,1H),2.39- 2.38(m,1H),2.34-2.32(m,2H),2.30-2.28(m,2H),0.88-0.86(m,6H).

[0880] Example 115

[0881] Synthesis method

[0882] The synthesis method of compound 115 was similar to that of Example 68, except that dimethylamine in step 8 was replaced with 4-methylpiperazine. LC-MS (ESI) m / z: 365.1 [M / 2+H] + . 1H NMR(600MHz,DMSO-d6)δ9.24(d,J=2.1Hz,1H),8.66(d,J=2.3Hz,1H),8.37–8.31( m,1H),7.96(d,J=8.7Hz,1H),7.88(d,J=8.7Hz,1H),7.80(d,J=1.9Hz,1H),7.63(s ,1H),7.31(dd,J=8.7,2.0Hz,1H),7.26(dd,J=8.7,1.9Hz,1H),6.71(d,J=2.0Hz,1 H),5.50(s,2H),4.55-4.18(m,5H),3.58(s,3H),3.56(s,3H),2.89-2.76(m,11H).

[0883] Example 116

[0884] Synthesis method

[0885] The synthesis method of compound 116 was similar to that of Example 102, except that dimethylamine in step 3 was replaced with azetidine, and 101-3 in step 5 was replaced with 1-((2-bromothiazol-5-yl)methyl)-7-chloro-4-(dimethylamino)quinazolin-2(1H)-one. LC-MS (ESI) m / z: 319.1 [M / 2+H] + . 1 H NMR(600MHz,DMSO-d6)δ7.97(d,J=8.8Hz,1H),7.77(dd,J=5.7,2.0Hz,2H),7.73(d,J=8 .6Hz,1H),7.41(s,1H),7.19(td,2H),5.29(d,J=6.4Hz,2H),4.71-4.08(m,4H),3.95-3. 87(m,2H),3.72(d,J=13.3Hz,1H),3.24(s,6H),3.09(td,J=13.0,4.3Hz,1H),2.77(q,J= 15.6Hz,1H),2.37(q,2H),2.04-1.95(m,1H),1.80-1.72(m,2H),1.70(d,J=12.0Hz,1H).

[0886] Example 117

[0887] Synthesis method

[0888] The synthesis method of compound 117 was similar to that of Example 102, except that dimethylamine in step 3 was replaced with azetidine. LC-MS (ESI) m / z: 326.1 [M / 2+H]+ . 1 H NMR (600MHz, DMSO-d6) δ7.84(d,J=8.8Hz,1H),7.72(dd,J=5.7,2.0Hz,2H),7.65(d,J=8.6Hz ,1H),7.41(s,1H),7.16(td,2H),5.27(d,J=6.4Hz,2H),4.74-4.18(m,4H),3.99-3.79(m,2H ),3.72(q,2H),3.62(m,1H),3.29(s,3H),3.13(t,3H),3.09(td,J=13.0,4.3Hz,1H),2.77(q ,J=15.6Hz,1H),2.27(q,2H),2.19-1.95(m,1H),1.82-1.74(m,2H),1.66(d,J=12.0Hz,1H).

[0889] Example 118

[0890] Synthesis method

[0891] The synthesis method of compound 118 is similar to that of Example 101, except that methylethylamine in step 1 is replaced with dimethylamine, and dimethylamine in step 6 is replaced with azetidine. LC-MS (ESI) m / z: 312.1 [M / 2+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.97(d,J=8.8Hz,1H),7.79-7.70(m,3H),7.38(s,1H) ,7.20(dd,J=8.7,1.9Hz,2H),5.30(s,2H),4.49(s,2H),3.72(dd,J=9.6,7.0Hz ,2H),3.69-3.66(m,1H),3.68-3.64(m,1H),3.61(t,J=9.5Hz,2H),3.24(s,6H) ,2.54(m,1H),2.44(m,1H),2.38(q,J=7.5Hz,2H),2.24(td,J=8.1,3.8Hz,1H).

[0892] Example 119

[0893] Synthesis route

[0894] Step 1: Synthesis of compound 119-1

[0895] 2-Bromothiazole-4-carboxaldehyde (1 g, 5.21 mmol) was dissolved in 10 mL of THF at room temperature and cooled to 0°C. Methylmagnesium bromide (3N) was slowly added dropwise under nitrogen, and the reaction mixture was allowed to warm to room temperature for 1 hour. LCMS confirmed the reaction was complete, and saturated ammonium chloride solution was added dropwise under an ice bath to quench the reaction. The product was extracted three times with EA. The combined organic phases were concentrated and separated by flash chromatography (PE:EA, 0-50%, 10 min) to afford 737 mg of compound 119-1, in a 68% yield. LC-MS (ESI) m / z: 208 [M+H] + .

[0896] Step 2: Synthesis of compound 119-2

[0897] Compound 119-1 (737 mg, 3.54 mmol) was dissolved in 10 mL of dry DCM at room temperature, cooled to 0°C, and phosphorus tribromide (1.5 g, 5.54 mmol) was slowly added dropwise under nitrogen. The mixture was then allowed to warm to room temperature for 1 hour. LC-MS confirmed the reaction was complete. The reaction was quenched by adding sodium bicarbonate solution dropwise under an ice bath, and extracted three times with DCM. The combined organic phases were concentrated and separated by flash chromatography (PE:EA, 0-50%, 10 min) to afford 780 mg of compound 119-2, in an 82% yield. LC-MS (ESI) m / z: 270 [M+H] + .

[0898] Step 3: Synthesis of compound 119-3

[0899] At room temperature, compound 119-2 (300 mg, 1.102 mmol) and 7-chloro-4-(dimethylamino)quinazolin-2(1H)-one (250 mg, 1.12 mmol) were dissolved in 5 mL of dry DMF. Potassium carbonate (460 mg, 3.33 mmol) was added, and the mixture was heated to 100°C and stirred overnight. LC-MS monitored the reaction completion. The mixture was extracted three times with water and EA, washed with saturated brine, and the combined organic phases were concentrated and separated by flash chromatography (DCM:MeOH, 0-10%, 10 min) to afford 35 mg of compound 119-3, in an 8% yield. LC-MS (ESI) m / z: 413 [M+H] + .

[0900] Step 4: Synthesis of compound 119

[0901] Compound 119-3 (35 mg, 0.0847 mmol) and 7-chloro-4-(dimethylamino)-1-(pyrrolidin-3-yl)quinazolin-2(1H)-one (101-7, 30 mg, 0.103 mmol) were dissolved in 2 mL of dry DMF at room temperature. Cesium carbonate (83 mg, 0.255 mmol) was added, and the mixture was heated to 120°C and stirred overnight. LC-MS monitored the reaction for completion. The mixture was extracted three times with water and EA, washed with saturated brine, and the combined organic phases were concentrated and separated by flash chromatography (DCM:MeOH, 0-10%, 10 min) to afford 30 mg of a pale yellow crude product. This was then purified by HPLC to afford 3.9 mg of compound 119, a 6% yield. LC-MS (ESI) m / z: 313.1 [M / 2+H] + . 1 H NMR (600MHz, DMSO-d6) δ7.91 (dd, J=8.7, 4.9Hz, 2H), 7.74 (dd, J=7.2, 2.0Hz, 1H ),7.67(dd,J=10.6,2.0Hz,1H),7.21(dt,J=9.0,2.4Hz,1H),7.13(ddd,J=8.7, 5.2,2.0Hz,1H),6.64(d,J=1.8Hz,1H),6.17-6.09(m,1H),5.34-5.29(m,1H),3 .77-3.60(m,4H),3.23-3.21(m,12H),2.70-2.63(m,2H),1.73(d,J=7.2Hz,3H).

[0902] Example 120

[0903] Synthesis method

[0904] The synthesis method of compound 120 is similar to that of Example 119, except that 101-7 in step 4 is replaced with 7-chloro-4-amino-1-(pyrrolidin-3-yl)quinazolin-2(1H)-one. LC-MS (ESI) m / z: 299.1 [M / 2+H] + . 1H NMR (400MHz, DMSO-d6) δ7.99(d,J=8.4Hz,1H),7.91(d,J=8.7Hz,1H),7.78(d,J=3.9Hz,1H),7.63(s,1H),7.30(d,J=8.4Hz,1H),7.13(dt,J=8.9,2 .7Hz,1H),6.65(d,J=6.1Hz,1H),6.18-6.07(m,1H),5.60-5.48(m,1H),3 .80-3.63(m,4H),3.22(s,6H),2.68-2.56(m,2H),1.72(d,J=7.1Hz,3H).

[0905] Examples 121 & 122

[0906] Synthesis method

[0907] The synthesis method of compounds 121 and 122 refers to Examples 113 and 114, except that 1-bromo-2-butanol in step 1 is replaced by 2-iodoethanol.

[0908] Compound 121: LC-MS (ESI) m / z: 195.7 [M / 3+H] + . 1 H NMR(600MHz,DMSO-d6)δ8.12(d,J=9.0Hz,1H),7.94(d,J=8.8Hz,1H),7.52(d, J=2.0Hz,1H),7.50(s,1H),7.26(dd,J=9.0,2.0Hz,1H),7.18(d,J=8.7Hz,1H), 4.37(dd,J=24.0,18.4Hz,2H),4.11(dd,J=25.5,19.1Hz,2H),3.41-3.47(m,4H ),3.31(s,6H),3.22(s,6H),2.69(dd,J=17.6,12.0Hz,2H),2.34-2.42(m,6H).

[0909] Compound 122: LC-MS (ESI) m / z: 195.7 [M / 3+H] + . 1 H NMR(600MHz,DMSO-d6)δ7.95(t,J=6.7Hz,2H),7.51(d,J=1.7Hz,2H),7.19(d d,J=8.8,1.7Hz,2H),4.14(t,J=6.6Hz,4H),3.22(s,12H),2.51-2.47(m,4H).

[0910] Example 123

[0911] Synthesis route

[0912] Step 1: Synthesis of compound 123-1

[0913] 2,4,7-Trichloroquinazoline (5.0 g, 21.44 mmol) was dissolved in 50 mL of tetrahydrofuran (THF) at room temperature. A 2 M solution of dimethylamine in THF (17 mL, 31.12 mmol) was added and stirred at room temperature for 16 h. TLC monitored the reaction for completion. The product was concentrated by rotary evaporation under reduced pressure to afford compound 123-1 (3.8 g, white solid), which was used directly in the next step without purification in a 74% yield. LC-MS (ESI) m / z: 242 [M+H] + .

[0914] Step 2: Synthesis of compound 123-2

[0915] Compound 123-1 (3.8 g, 15.77 mmol) was dissolved in 50 mL of glacial acetic acid at room temperature, heated to 100°C, and stirred for 16 h. TLC monitored the reaction for completion. The reaction system was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (80 mL x 3). The organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol, 0-20%, 15 min) to afford compound 123-2 (3.3 g, light yellow solid) in a 93% yield. LC-MS (ESI) m / z: 224 [M+H] + .

[0916] Step 3: Synthesis of compound 123-3

[0917] At room temperature, compound 123-2 (1.0 g, 4.48 mmol) was dissolved in 10 mL of N,N-dimethylformamide, and 1-Boc-3-bromomethylpyrrolidine (1.4 g, 5.38 mmol) and potassium carbonate (1.9 g, 13.44 mmol) were added. The mixture was stirred at room temperature for 16 h. TLC monitored the reaction for completion. Water was added to the reaction system, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate, 0-100%, 20 min) to obtain compound 123-3 (340 mg, white solid) in a 19% yield. LC-MS (ESI) m / z: 407 [M+H] + .

[0918] Step 4: Synthesis of compound 123-4

[0919] Compound 123-3 (340 mg, 0.84 mmol) was dissolved in 4 mL of 1,4-dioxane at room temperature. 4 mL of a hydrochloric acid-dioxane solution was added and stirred at room temperature for 30 min. TLC confirmed the reaction was complete. After concentration, the hydrochloride salt of compound 123-4 (251 mg, white solid) was obtained in a 98% yield. LC-MS (ESI) m / z: 307 [M+H] + Step 5: Synthesis of compound 123-5

[0920] Oxalyl chloride (14.7 g, 115.61 mmol) was added dropwise to a solution of 4-chloro-2-fluorobenzamide (10.0 g, 57.80 mmol) in dichloroethane (DCE) (100 mL) at 0°C. Under nitrogen protection, the reaction mixture was stirred at 70°C overnight. After removing excess oxalyl chloride under reduced pressure, the mixture was diluted with DCE (50 mL) and then added dropwise to a solution of 2-amino-6-bromopyridine (5.0 g, 28.90 mmol) in DCE (50 mL). The reaction was stirred at room temperature for 3 hours. TLC monitored the complete reaction. Acetonitrile was added to the reaction system, and the mixture was slurried and filtered to obtain compound 123-5 (10.3 g, white solid) with a yield of 93%. LC-MS (ESI) m / z: 370 [M+H] + .

[0921] Step 6: Synthesis of compound 123-6

[0922] A solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (36.5 mL, 69.41 mmol) was added to a solution of compound 123-5 (10.3 g, 27.76 mmol) in tetrahydrofuran (100 mL) at 0°C. Under nitrogen, the mixture was heated to 70°C and stirred for 3 h. LC-MS analysis confirmed the reaction was complete. The system was quenched with water and diluted hydrochloric acid (0.5 mol / L) was added dropwise to a neutral pH. After filtration, the solid was slurried with acetonitrile and filtered again to obtain compound 123-6 (9.2 g, white solid) in a 95% yield. LC-MS (ESI) m / z: 352 [M+H] + .

[0923] Step 7: Synthesis of compound 123-7

[0924] Compound 123-6 (200 mg, 0.57 mmol) was dissolved in 5 mL of acetonitrile at room temperature, and 1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (444 mg, 0.85 mmol) and a tetrahydrofuran solution of dimethylamine (0.7 mg, 1.42 mmol) were added, followed by dropwise addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (303 mg, 1.99 mmol). The reaction mixture was stirred at room temperature for 30 min, and the reaction was monitored for completeness by TLC. The crude product was purified by silica gel column chromatography (dichloromethane:methanol, 0-10%, 15 min) to afford compound 123-7 (127 mg, white solid) in a 92% yield. LC-MS (ESI) m / z: 379 [M+H] + .

[0925] Step 8: Synthesis of compound 123

[0926] Compound 123-7 (50 mg, 0.13 mmol) was dissolved in 1 mL of N,N-dimethylformamide at room temperature, and compound 123-4 (45 mg, 0.13 mmol) and cesium carbonate (128 mg, 0.39 mmol) were added. The reaction mixture was stirred at 120°C for 16 h. LC-MS confirmed the reaction was complete. The crude product was purified by silica gel column chromatography (dichloromethane:methanol, 0-10%, 15 min). After preparative HPLC purification, compound 123 (9.86 mg, white solid) was obtained in a 9.6% yield. LC-MS (ESI) m / z: 303.1 [M / 2+H] + . 1 HN MR(400MHz, DMSO-d6)δ8.03(d,J=8.8Hz,1H),7.97(d,J=8.7Hz,1H),7.72(t,J=7. 8Hz,1H),7.60(d,J=2.0Hz,1H),7.20(dt,2H),6.54(dd,J=7.9,3.5Hz,2H),6.45(d ,J=2.1Hz,1H),5.41(d,2H),4.22(dq,J=41.1,14.4,7.4Hz,1H),3.69(m,1H),3.51 (d,J=3.8Hz,2H),3.30(s,6H),3.23(s,6H),2.04-1.96(m,1H),1.86-1.79(m,1H).

[0927] Example 124

[0928] Synthesis route

[0929] Step 1: Synthesis of compound 124-1

[0930] At room temperature, compound 123-2 (1.0 g, 4.48 mmol) was dissolved in 10 mL of N,N-dimethylformamide, and 1-Boc-3-bromomethylpyrrolidine (1.4 g, 5.38 mmol) and potassium carbonate (1.9 g, 13.44 mmol) were added, and the mixture was stirred at room temperature for 16 h. TLC monitored the reaction for completion. Water was added to the reaction system, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate, 0-100%, 20 min) to obtain compound 124-1 (631 mg, white solid) in a 35% yield. LC-MS (ESI) m / z: 407 [M+H] + .

[0931] Step 2: Synthesis of compound 124-2

[0932] Compound 124-1 (631 mg, 1.56 mmol) was dissolved in 7 mL of 1,4-dioxane at room temperature. 7 mL of a hydrochloric acid-dioxane solution was added and stirred at room temperature for 30 min. TLC confirmed the reaction was complete. After concentration, the hydrochloride salt of compound 124-2 (526 mg, white solid) was obtained in a 97% yield. LC-MS (ESI) m / z: 307 [M+H] + Step 3: Synthesis of compound 124

[0933] Compound 124-2 (50 mg, 0.13 mmol) was dissolved in 1 mL of N,N-dimethylformamide at room temperature, and compound 123-7 (45 mg, 0.13 mmol) and cesium carbonate (128 mg, 0.39 mmol) were added. The reaction mixture was stirred at 120°C for 16 h. LC-MS confirmed the reaction was complete. The crude product was purified by silica gel column chromatography (dichloromethane:methanol, 0-10%, 15 min). After preparative HPLC purification, compound 124 (4.09 mg, white solid) was obtained in a 5.2% yield. LC-MS (ESI) m / z: 303.1 [M / 2+H] + . 1HN MR(400MHz, DMSO-d6)δ8.03(d,J=8.8Hz,1H),7.97(d,J=8.7Hz,1H),7.72(t,J=7. 8Hz,1H),7.60(d,J=2.0Hz,1H),7.20(dt,2H),6.54(dd,J=7.9,3.5Hz,2H),6.45(d ,J=2.1Hz,1H),5.41(d,2H),4.22(dq,J=41.1,14.4,7.4Hz,1H),3.69(m,1H),3.51 (d,J=3.8Hz,2H),3.30(s,6H),3.23(s,6H),2.04-1.96(m,1H),1.86-1.79(m,1H).

[0934] Examples 125 & 126

[0935] Synthesis method

[0936] The synthesis of compounds 125 and 126 was similar to that of Examples 113 and 114, except that 1-bromo-2-butanol in step 1 was replaced with 2-bromo-1-propanol, and 7-chloro-4-(dimethylamino)quinazolin-2(1H)-one (123-2) in step 3 was replaced with 101-2. LC-MS (ESI) m / z: 214.4 [M / 3+H] + .

[0937] Examples 127 & 128

[0938] Synthesis method

[0939] The synthesis method of compounds 127 and 128 refers to Examples 113 and 114, except that 1-bromo-2-butanol in step 1 is replaced by 2-iodoethanol, and 7-chloro-4-(dimethylamino)quinazolin-2(1H)-one (123-2) in step 3 is replaced by 7-chloro-4-aminoquinazolin-2(1H)-one.

[0940] Compound 127: LC-MS (ESI) m / z: 177.1 [M / 3+H] + . 1H NMR (400MHz, DMSO-d6) δ8.15(d,J=8.7Hz,1H),8.06(d,J=8.6Hz,1H),8.01-7.81(m,4H),7.51-.45(m,2H),7.32(dd,J=8.7,2.2Hz,1H ),7.23(dd,J=8.6,1.9Hz,1H),4.37(t,J=5.8Hz,2H),4.14(t,J=6.7Hz,2H),2.68-2.61(m,4H),2.35-2.31(m,4H),2.09-1.92(m,4H).

[0941] Compound 128: LC-MS (ESI) m / z: 177.1 [M / 3+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.06(d,J=8.6Hz,2H),7.99-7.91(m,2H),7.89-7.82(m,2H),7.48-7.46(m,2H), 7.24(dd,J=8.6,1.9Hz,2H),4.16-4.10(m,4H),2.71-2.63(m,4H),2.47-2.46(m,4H),2.05-1.94(m,4H).

[0942] Example 129

[0943] Synthesis method

[0944] The synthesis method of compound 129 was similar to that of Example 113, except that 1-bromo-2-butanol in step 1 was replaced with 2-iodoethanol, and 7-chloro-4-(dimethylamino)quinazolin-2(1H)-one (123-2) in step 3 was replaced with 7-chloro-4-(methylamino)quinazolin-2(1H)-one. LC-MS (ESI) m / z: 186.4 [M / 3+H] + . 1 H NMR (600MHz, DMSO-d6) δ8.44(s,2H),8.21(d,J=8.9Hz,1H),7.97(d,J=8.8Hz,1H),7.55(s,1H),7.37(s,1H),7.26(dd,J=9.0,2.3H z,1H),7.14(dd,J=8.9,2.0Hz,1H),5.41(d,J=16.2Hz,4H),5.17(d,J=11.0Hz,4H),3.74–3.59(m,8H),3.32,(s,3H),3.26(s,3H).

[0945] Examples 130 & 131

[0946] Synthesis method

[0947] The synthesis methods of compounds 130 and 131 refer to Examples 113 and 114.

[0948] Compound 130: LC-MS (ESI) m / z: 205.1 [M / 3+H] + . 1 H NMR (600MHz, DMSO-d6) δ8.16(d,J=8.9Hz,1H),7.98(d,J=8.8Hz,1H),7.53(s,1H),7.37(s,1H),7.29(dd,J=9.0,2.3Hz,1H) ,7.20(dd,J=8.9,2.0Hz,1H),5.11(d,J=16.2Hz,2H),5.03(d,J=11.0Hz,2H),3.74-3.59(m,8H),3.32,(s,6H),3.26(s,6H).

[0949] Compound 131: LC-MS (ESI) m / z: 205.1 [M / 3+H] + . 1 H NMR (600MHz, DMSO-d6) δ7.99(d,J=8.8Hz,2H),7.39(d,J=2.0Hz,2H),7.20(dd,J=8.7,2 .0Hz,2H),5.04(d,J=21.0Hz,4H),3.78(s,2H),3.64(d,4H),3.49(s,2H),3.26(s,12H).

[0950] Examples 132 & 133

[0951] Synthesis method

[0952] The synthesis of compounds 132 and 133 was carried out by referring to Examples 113 and 114, except that 1-bromo-2-butanol in step 1 was replaced by 2-methyl-2-bromoethanol.

[0953] Compound 132: LC-MS (ESI) m / z: 200.4 [M / 3+H] + . 1H NMR(600MHz,DMSO-d6)δδ8.12(t,J=8.9Hz,1H),7.92(dd,J=8.8,3.2Hz,1H),7.58 -7.47(m,2H),7.26(t,J=9.4,7.2Hz,1H),7.14(t,J=8.4Hz,1H),4.44-4.35(m,1H) ,4.15-4.09(m,1H),4.08-3.95(m,2H),3.23-3.22(m,1H),3.21(s,6H),3.19-3.17 (m,1H),2.98-2.87(m,4H),2.39-2.29(m,4H),1.27(d,J=6.4Hz,3H),0.92(d,3H).

[0954] Compound 133: LC-MS (ESI) m / z: 200.4 [M / 3+H] + . 1 H NMR(600MHz,DMSO-d6)δ7.94(d,2H),7.55(d,J=8.0Hz,2H),7.17(d,2H),4.14-3.94(m,4H),3. 22(s,12H),3.20(d,J=4.8Hz,2H),2.96-2.81(m,4H),2.31-2.24(m,4H),0.90(d,J=6.8Hz,6H).

[0955] Examples 134 & 135

[0956] Synthesis method

[0957] The synthesis method of compounds 134 and 135 refers to Examples 113 and 114, except that 1-bromo-2-butanol in step 1 is replaced by 2-iodoethanol, and 7-chloro-4-(dimethylamino)quinazolin-2(1H)-one (123-2) in step 3 is replaced by 4-(acridin-1-yl)-7-chloroquinazolin-2(1H)-one.

[0958] Compound 134: LC-MS (ESI) m / z: 203.7 [M / 3+H] + . 1 H NMR (600MHz, DMSO-d6) δ7.88(d,J=8.8Hz,1H),7.77(d,J=8.7Hz,1H),7.64-7.47(m,2H),7.29(d, J=8.8Hz,1H),7.21(d,J=8.6Hz,1H),4.85-4.04(m,12H),3.29-2.52(m,10H),2.50-2.27(m,6H).

[0959] Compound 135: LC-MS (ESI) m / z: 203.7 [M / 3+H] + . 1 H NMR (600MHz, DMSO-d6) δ7.75(d,J=8.7Hz,2H),7.50(d,2H),7.19(d,J=8.7Hz,2H),4.68-4.32(m,8H),4.19-4.09(m, 4H),2.47-2.42(m,10H),2.40-2.36(m,6H).

[0960] Example 136

[0961] Synthesis method

[0962] The synthesis method of compound 136 refers to Example 102. LC-MS (ESI) m / z: 320.1 [M / 2+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.90 (dd, J=8.8, 4.4Hz, 2H), 7.79 (dd, J=17.2, 2.0Hz, 2H), 7.4 1(s,1H),7.20(td,J=8.9,7.1,1.9Hz,2H),5.29(d,J=3.8Hz,2H),4.22-4.13(m,1H),4. 00-3.93(m,2H),3.89(t,1H),3.72(d,J=13.3Hz,1H),3.64(q,J=7.0Hz,2H),3.34(t,3 H),3.22(s,3H),3.21(s,6H),3.16-3.05(m,1H),2.81-2.70(m,1H),2.04-1.99(m,2H).

[0963] Examples 137 & 138

[0964] Compound 136 was separated by SFC to obtain single-configuration compounds 137 (136-P1) and 138 (136-P1).

[0965] Example 139

[0966] Synthesis method

[0967] The synthesis method of compound 139 is similar to that of Example 123, except that 2-amino-6-bromopyridine in step 5 is replaced with 5-bromo-3-aminopyridine. LC-MS (ESI) m / z: 303.1 [M / 2+H]+ . 1 H NMR (400MHz, DMSO-d6) δ8.07-7.94(m,3H),7.72(d,J=1.9Hz,1H),7.59(d,J=2.0Hz,1H) ,7.21(dq,J=8.8,4.5,2.0Hz,2H),6.84(s,1H),6.46(d,J=2.1Hz,1H),4.21(dq,J=44.5, 14.3,7.5Hz,2H),3.49(q,J=7.0Hz,1H),3.31(s,6H),3.24(s,6H),3.21-3.14(m,1H),2. 80(q,J=7.0Hz,1H),2.13-2.03(m,1H),2.00(dt,J=12.4,6.7Hz,2H),1.90-1.81(m,1H).

[0968] Example 140

[0969] Synthesis method

[0970] The synthesis method of compound 140 refers to Example 124, except that 123-7 in step 3 is replaced with 1-(5-bromopyridin-3-yl)-7-chloro-4-(dimethylamino)quinazolin-2(1H)-one. LC-MS (ESI) m / z: 303.1 [M / 2+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.13(d,J=9.1Hz,1H),8.07(d,J=2.7Hz,1H),8.04(d,J=8.8Hz,1H ),7.73(d,J=1.9Hz,1H),7.54(d,J=2.3Hz,1H),7.31-7.18(m,2H),6.93(t,J=2.3Hz,1H),6 .45(d,J=2.1Hz,1H),4.42-4.29(m,2H),3.57-3.49(m,1H),3.50-3.41(m,1H),3.32(s,6H) ,3.31(s,6H),3.25-3.17(m,1H),2.91-2.80(m,1H),2.26-2.15(m,1H),2.05-1.86(m,2H).

[0971] Examples 141 & 142

[0972] Synthesis method

[0973] The synthesis method of compounds 141 and 142 refers to Examples 113 and 114, except that 1-bromo-2-butanol in step 1 is replaced by 2-iodoethanol, and 7-chloro-4-(dimethylamino)quinazolin-2(1H)-one (123-2) in step 3 is replaced by 101-2.

[0974] Compound 141: LC-MS (ESI) m / z: 205.1 [M / 3+H] + . 1 H NMR (600MHz, DMSO-d6) δ7.88(dd,J=8.8,2.7Hz,2H),7.61(d,J=1.9Hz,2H),7.19(dd,J=8.7,1.9Hz,2H),4.84(t,J=5.8Hz,2H),4.44(s,2H),4.1 0(t,J=6.2Hz,3H),3.65-3.58(m,8H),3.49(dd,J=10.2,5.1Hz,2H),3.41(dd,J=10.0,5.0Hz,2H),3.39(s,4H),3.20(s,3H),1.29-1.24(m,6H).

[0975] Compound 142: LC-MS (ESI) m / z: 205.1 [M / 3+H] + . 1 H NMR (600MHz, DMSO-d6) δ8.07(d,J=9.0Hz,2H),7.53(t,J=4.3Hz,2H),7.28(dd,...

Claims

1. A compound, wherein the compound is a compound represented by formula (I-1), or an isomer, isotope derivative, polymorph, prodrug, pharmaceutically acceptable salt or solvate thereof: wherein A1 and B1 are each independently selected from formula (II), (III), (IV), (V), (VI), (VII) and (VIII): R1 is absent at each occurrence or is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, C 1-6 Alkyl, -SC 1-6 Alkyl, -S(O)-C 1-6 Alkyl, -S(O2)-C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, C 1-6 deuterated alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and -NR 1a R 1b , where R 1a and R 1b are independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 3-12 A monocyclic, spirocyclic or bridged cycloalkyl group, a C 3-12 Monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 Aryl and C 5-10 Heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-12 A monocyclic, spirocyclic or bridged cycloalkyl group, a C 3-12 Monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 Aryl, and C 5-10 heteroaryl is optionally substituted with 0, 1, 2, 3, 4, 5 or 6 substituents independently selected from halogen, deuterium, alkyl, deuterated alkyl, amino, hydroxy, alkylamino, aminoalkyl, cyano, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and alkoxy; or R 1a and R 1b The nitrogen atom to which it is commonly attached forms a 3-10 membered heterocycloalkyl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkyl is optionally substituted by 0, 1, 2, 3 or 4 heteroatoms independently selected from halogen, deuterium, amino, C1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Alkyl, cyano, C 1-6 Substitution with aminoalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and hydroxy; Each occurrence of Z is independently selected from C and N; when Z is selected from N, R1 is absent; R2, R4 and R6 are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)C 1-6 Alkyl, C 1-6 Haloalkoxy, C 1-6 Haloalkylamino, hydroxy, C 2-6 alkyl, -SC; alkyl, -S-(4-membered)-1, -S-(4-membered)-1, -S-(4-membered)-2, -S-(4-membered)-3, -S-(4-membered)-4, -S-(4-membered)-5, -S-(4-membered)-6, -S-(4-membered)-7, -S-(4-membered)-8, -S-(4-membered)-9, -S-(4-membered)-10, -S-(4-membered)-11, -S-(4-membered)-12, -S-(4-membered)-24, -S-(4-membered)-3, -S-(4-membered)-4, -S-(4-membered)-6, -S-(4-membered)-7, -S-(4-membered)-8, -S-(4-membered)-12, -S-(4-membered)-11, -S-(4-membered)-24, -S-(4-membered)-3, -S-(4-membered)-12, -S-(4-membered)- 1-6 Alkyl, -SO-C 1-6 Alkyl, -SO2-C 1-6 Alkyl, 3-6 membered cycloalkyl-C 1-6 alkylene, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, 6-10 membered monocyclic aryl, 8-14 membered cycloaryl, 5-12 membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S, and 8-10 membered cycloheteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S; preferably, R2, R4 and R6 are each independently selected from hydrogen, halogen, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Haloalkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)C 1-6 Alkyl, C 1-6 Haloalkoxy, C 1-6 Haloalkylamino, 3-6 membered monocyclic cycloalkyl, 3-6 membered monoheterocyclic alkyl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S; R5 is selected from hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl and C 1-6 haloalkyl, optionally, the C 1-6 Alkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl and C 1-6 The haloalkyl group is composed of 0-6 atoms independently selected from halogen, deuterium, alkane substituted with substituents of alkyl, amino, hydroxy, aminoalkyl, alkylamino, and alkoxy; G1 and G2 are each independently selected from O, S, and NR 2a ; E0, E1, E2, E3, E4, E5, E6, E7, E8, E9, M1, M2, M3, M4, M5, M6 and E are independently selected from N and CR at each occurrence 2a , and E7, E8, and E9 are not CR at the same time 2a ; R 2a Each occurrence is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, phenylmethylene, -CH2OCH2CH2Si(CH3)3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl-S-, -S(O)-C 1-6 Alkyl, -SO2-C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -NR 2b R 2c 、-C(O)R 8c 、-C(O)NR 8a R 8b , -C 1-6 Alkylene-C 3-6 Cycloalkyl, C 3-6 Cycloalkyl-NR 2b -, a 3-6 membered heterocycloalkyl-NR containing 1-3 heteroatoms independently selected from N, O, P and S 2b-, 3-12 membered monocyclic heterocycloalkyl, 5-12 membered spirocyclic heterocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spirocyclic heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 4-12 membered bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered halogenated heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered cycloalkyl-O-, 3-6 3-6 membered halogenated cycloalkyl-O-, 3-6 membered halogenated heterocycloalkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered heterocycloalkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S, 6-12 membered monocyclic aryl, 8-12 membered cycloheteroaryl, 5-12 membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S, and 8-10 membered cycloheteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S; preferably, R 2a is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl-S-, -S(O)-C 1-6 Alkyl, -SO2-C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)C 1-6 Alkyl, C 3-6 Cycloalkyl and -C 1-6 Alkylene-C 3-6 Cycloalkyl; preferably, R 2a Selected from hydrogen, halogen, cyano, hydroxyl, amino, C 1-3 Alkyl, C 1-3 Haloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, and C 3-6 Cycloalkyl; R 2b and R 2c Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 3-12 Cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O, P and S 3-12 Heterocycloalkyl, C6-10 Aryl and C 5-10 Heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-12 Cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O, P and S 3-12 Heterocycloalkyl, C 6-10 Aryl, and C 5-10 heteroaryl is optionally substituted with 0, 1, 2, 3, 4, 5 or 6 substituents independently selected from halogen, deuterium, alkyl, deuterated alkyl, amino, hydroxy, alkylamino, aminoalkyl, cyano, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and alkoxy; or R 2b and R 2c The nitrogen atom to which it is commonly attached forms a 3-10 membered heterocycloalkyl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkyl is optionally substituted by 0, 1, 2, 3 or 4 heteroatoms independently selected from halogen, deuterium, amino, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Alkyl, cyano, C 1-6 The substituents are aminoalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and hydroxy; preferably R 2b and R 2c are independently selected from hydrogen and C 1-6 alkyl; R 8a and R 8b Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 3-12 Cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O, P and S 3-12 Heterocycloalkyl, C 6-10 Aryl and C 5-10 Heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-12 Cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O, P and S 3-12 Heterocycloalkyl, C 6-10 Aryl, and C 5-10heteroaryl is optionally substituted with 0, 1, 2, 3, 4, 5 or 6 substituents independently selected from halogen, deuterium, alkyl, deuterated alkyl, amino, hydroxy, alkylamino, aminoalkyl, cyano, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and alkoxy; or R 8a and R 8b The nitrogen atom to which it is commonly attached forms a 3-10 membered heterocycloalkyl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkyl is optionally substituted by 0, 1, 2, 3 or 4 heteroatoms independently selected from halogen, deuterium, amino, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Deuterium Alkyl, C 1-6 Alkyl, cyano, C 1-6 The substituents are aminoalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and hydroxy; preferably R 8a and R 8b Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 haloalkyl and phenyl, the phenyl group is optionally substituted by 0-2 groups selected from C 1-4 Alkyl, -OR 8d and-X2-R 8d group substitution; R 8c Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 3-12 Cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O, P and S 3-12 Heterocycloalkyl, C 6-10 Aryl and C 5-10 Heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-12 Cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O, P and S 3-12 Heterocycloalkyl, C 6-10 Aryl, and C 5-10 The heteroaryl group is optionally substituted with 0, 1, 2, 3, 4, 5 or 6 substituents independently selected from halogen, deuterium, alkyl, deuterated alkyl, amino, hydroxy, alkylamino, aminoalkyl, cyano, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and alkoxy; preferably R 8c Selected from hydrogen, C 1-6 Alkyl, C 1-6Hydroxyalkyl, C 1-6 Aminoalkyl and C 1-6 Haloalkyl; X2 Selected from C 1-6 Alkylene and C 2-6 alkenylene; R 8d Selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; J1 and J2 are independently selected from a single bond, O, S, C(O), S(O), S(O2), C(R 1c R 1d ), C(=CR 1e R 1f ) and N(R3), preferably, J1 and J2 are not single bonds at the same time; Where R 1c , R 1d , R 1e and R 1f are independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl, C 3-12 A monocyclic, spirocyclic or bridged cycloalkyl group, a C 3-12 Monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 Aryl and C 5-10 Heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 A monocyclic, spirocyclic or bridged cycloalkyl group, a C 3-12 Monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 Aryl, and C 5-10 Heteroaryl is optionally substituted by 0, 1, 2, 3, 4, 5 or 6 independently selected from halogen, deuterium, C 1-6 Alkyl, amino, hydroxyl, C 1-6 Alkylamino, C 1-6 aminoalkyl, cyano, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and C 1-6 The alkoxy substituent is substituted; or R 1c and R 1d The carbon atoms to which they are connected together form a 3-10 membered cycloalkylene or a 3-10 membered heterocycloalkylene containing 1-3 heteroatoms independently selected from N, O, P and S, wherein the cycloalkylene or heterocycloalkylene is optionally substituted by 0, 1, 2, 3 or 4 atoms independently selected from halogen, deuterium, amino, C 1-6 Alkoxy, C1-6 Alkylamino, C 1-6 The aminoalkyl group and the hydroxy group are substituted; or R 1e and R 1f The carbon atoms to which they are connected together form a 3-10 membered cycloalkylene or a 3-10 membered heterocycloalkylene containing 0, 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S, wherein the cycloalkylene or heterocycloalkylene is optionally substituted by 0, 1, 2, 3 or 4 heteroatoms independently selected from halogen, deuterium, amino, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Alkyl, cyano, C 1-6 The substituents are aminoalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and hydroxy; R3 is -X1-R8, X1 is selected from a single bond, -O-, -S-, C 1-6 Alkyleneoxy, C 2-6 Alkenylene and C 1-6 Alkylene; R8 is selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 Aryl, -NR 8a R 8b 、-C(O)R 8c 、-C(O)NR 8a R 8b , C 3-12 Cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O, P and S 3-12 Heterocycloalkyl, and 5-10 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S; Linker C is the linker connecting A1 and B1, which is -L a -L b -L c -L d -L e -; L a , L c , and L e Each occurrence is independently selected from -(L) n -; n is selected from 1, 2, 3, 4, 5 and 6; L at each occurrence is independently selected from a single bond, -O-, -S-, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 1-6 Haloalkylene, -N(R L6 )C(O)-、-N(RL6 )S(O)-、-N(R L6 )S(O2)-, -C(O)-, -OC(O)-, -NR L6 -, -S(O)-, -S(O2)-, -S(O2)NR L6 -、-CR L1 R L2 -, and C 1-6 Alkylene hydroxyl group, optionally, the C 1-6 Alkane Base, C 2-6 Alkenylene, C 2-6 Alkyne, and C 1-6 The haloalkylene group is each independently substituted with 0, 1, 2, 3, 4, 5 or 6 substituents independently selected from halogen, deuterium, alkyl, deuterated alkyl, amino, hydroxy, alkylamino, aminoalkyl, cyano, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and alkoxy; preferably, each occurrence of L is independently selected from a single bond, -O-, -S-, C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylidene, -CR L1 R L2 -、-C(O)N(R L6 )-、-C(O)-、-OC(O)-、-NR L6 -, -S-, -S(O)-, and -S(O2)-, optionally, the C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkyne, and C 1-6 each haloalkylene group is independently substituted with 0, 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of halogen, deuterium, alkyl, deuterated alkyl, amino, hydroxy, alkylamino, aminoalkyl, cyano, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and alkoxy; R L6 Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 3-12 Cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O, P and S 3-12 Heterocycloalkyl, C 6-10 Aryl and C 5-10 Heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-12Cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O, P and S 3-12 Heterocycloalkyl, C 6-10 Aryl, and C 5-10 The heteroaryl group is optionally substituted with 0, 1, 2, 3, 4, 5 or 6 substituents independently selected from halogen, deuterium, alkyl, deuterated alkyl, amino, hydroxy, alkylamino, aminoalkyl, cyano, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and alkoxy; preferably, R L6 Each occurrence is independently selected from hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl and C 1-6 haloalkyl, optionally, the C 1-6 Alkyl, C 3-10 Cycloalkyl and C 1-6 haloalkyl is substituted with 0, 1, 2, 3, 4, 5 or 6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, aminoalkyl, alkylamino, and alkoxy; R L1 and R L2 Each occurrence is independently selected from hydrogen, deuterium, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, -X L -OR L3 , -X L -NR L4 R L5 , C 1-6 Deuterated alkyl, C 3-12 Cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O, P and S 3-12 Heterocycloalkyl, C 6-10 Aryl and C 5-10 Heteroaryl, preferably R L1 and R L2 Each occurrence is independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -X L -OR L3 , -X L -NR L4 R L5 and C 3-10 Cycloalkyl; or R L1 and R L2 The carbon atom commonly connected thereto forms a 3-10 membered cycloalkylene or a 3-10 membered heterocycloalkylene containing 1, 2 or 3 heteroatoms independently selected from N, O, P and S, wherein the cycloalkylene or heterocycloalkylene is optionally substituted by 0, 1, 2, 3 or 4 heteroatoms independently selected from halogen, deuterium, amino, C1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 The aminoalkyl and hydroxy groups are substituted; preferably, R L1 and R L2 The carbon to which it is connected forms a 3-10-membered cycloalkylene group; X L Each occurrence is independently selected from C 1-6 Alkylene and C2-C6 alkenylene; R L3 Selected from hydrogen, deuterium, C 1-6 Alkyl and C 1-6 Haloalkyl; R L4 and R L5 are independently selected from hydrogen, deuterium, C 1-6 Alkyl and C 1-6 Haloalkyl; L b , and L d Each occurrence is independently selected from a single bond, cycloalkylene, cycloalkenylene, heterocycloalkylene, arylene, heteroarylene, and fused heterocycloalkylene, wherein the cycloalkylene, cycloalkenylene, heterocycloalkylene, arylene, heteroarylene, and fused heterocycloalkylene may be optionally substituted with 0, 1, 2, 3, 4, 5 or 6 R9; preferably, L b , L d Each occurrence is independently selected from a single bond, phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1-4 heteroatoms independently selected from N, O, P and S, 3-7 membered heterocycloalkenylene, 5-6 membered heteroarylene and 4-12 membered fused heterocycloalkylene, said phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1-4 heteroatoms independently selected from N, O, P and S, 5-6 membered heteroarylene and 4-12 membered fused heterocycloalkylene optionally substituted with 0-6 R9; preferably, L a , L b , L c , L d , and L e Not all are single bonds at the same time; R9 at each occurrence is independently selected from halogen, deuterium, alkyl, haloalkyl, cyano, cycloalkyl, heterocycloalkyl, -S(O2)R 9a 、-NR 9b R 9c 、-X4-NR 9b R 9c 、-OR 9a AND-X4-OR 9a Preferably, each occurrence of R9 is independently selected from halogen, deuterium, C 1-6Alkyl, C 1-6 Haloalkyl, cyano, C 3-6 Cycloalkyl, containing 1-3 independently selected C of heteroatoms N, O and S 3-7 Heterocycloalkyl, -S(O2)R 9a 、-NR 9b R 9c 、-X4-NR 9b R 9c 、-OR 9a AND-X4-OR 9a Preferably, each occurrence of R9 is independently selected from F, Cl, Br, I, C 1-3 Alkyl, and C 1-3 Haloalkyl; R 9a , R 9b and R 9c Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 3-12 Cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O, P and S 3-12 Heterocycloalkyl, C 6-10 Aryl and C 5-10 Heteroaryl; preferably, R 9a , R 9b and R 9c Each occurrence is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; X4 Selected from C 1-6 Alkylene and C 2-6 alkenylene; When L b and L d When each independently represents a phenylene group or a 5-membered heteroarylene group containing 1 or 2 heteroatoms selected from N and S, L a and L e At least one of them is not a single bond, or when L a and L e When both are single bonds, L c Selected from -S-, C 2-6 Alkylene, C 2-6 Alkyleneoxy, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 1-6 Haloalkylene, -N(R L6 )S(O)-、-N(R L6)S(O2)-, -OC(O)-, -S(O)-, -S(O2)-, -S(O2)NR L6 -, - and C 1-6 Alkylene hydroxyl group, optionally, the C 2-6 Alkylene, C 2-6 Alkyleneoxy, C 2-6 Alkenylene, C 2-6 Alkyne, and C 1-6 each haloalkylene group is independently substituted with 0, 1, 2, 3, 4, 5 or 6 substituents independently selected from halogen, deuterium, alkyl, deuterated alkyl, amino, hydroxy, alkylamino, aminoalkyl, cyano, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and alkoxy; When Linker C is an aliphatic chain, Linker C is an optionally substituted -C8H 16 -, preferably optionally substituted -(CH2)8-, preferably -(CH2)8-; When L b , L d When one of them is a phenylene group or a 6-membered heteroarylene group containing 3 N atoms and the other is a single bond, L a , and L e are not simultaneously single bonds; and When A1 and B1 are both of formula (V), and L a , and L e When it is not a single bond, L a , and L e At least one is not -O-.

2. The compound according to claim 1, wherein Linker C is selected from the group consisting of formula (IX), (X), (XI) and (XII): R 7a and R 7b are independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -X3-OR 7c 、-X3-NR 7d R 7e and C 3-10 Cycloalkyl; X3 each occurrence is independently selected from C 1-6 Alkylene and C2-C6 alkenylene; R 7c Selected from hydrogen, deuterium, C 1-6 Alkyl and C 1-6 Haloalkyl; R 7d and R 7e are independently selected from hydrogen, deuterium, C 1-6 Alkyl and C 1-6 haloalkyl; or R 7a and R7b and the carbon to which it is connected constitutes a 3-10 membered cycloalkyl group; R 7a and R 7b Each occurrence is independently selected from hydrogen, deuterium, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, -X L -OR L3 , -X L -NR L4 R L5 , C 1-6 Deuterated alkyl, C 3-12 Cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O, P and S 3-12 Heterocycloalkyl, C 6-10 Aryl and C 5-10 Heteroaryl, preferably R L1 and R L2 Each occurrence is independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -X L -OR L3 , -X L -NR L4 R L5 and C 3-10 Cycloalkyl; or R 7a and R 7b The carbon atom connected to it forms a 3-10 membered cycloalkylene or a 3-10 membered heterocycloalkylene containing 1, 2 or 3 heteroatoms independently selected from N, O, P and S. wherein the cycloalkylene or heterocycloalkylene is optionally substituted by 0, 1, 2, 3 or 4 independently selected from halogen, deuterium, amino, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 The aminoalkyl and hydroxy groups are substituted; preferably, R 7a and R 7b The carbon to which it is connected forms a 3-10-membered cycloalkylene group; X L Each occurrence is independently selected from C 1-6 Alkylene and C2-C6 alkenylene; R L3 Selected from hydrogen, deuterium, C 1-6 Alkyl and C 1-6 Haloalkyl; R L4 and R L5 are independently selected from hydrogen, deuterium, C 1-6 Alkyl and C1-6 Haloalkyl; W is selected from the following groups: Q ring and R ring are each independently selected at each occurrence from phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S, 3-7 membered heterocycloalkenylene, 5-6 membered heteroarylene and 4-12 membered fused heterocycloalkylene, said phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1-4 heteroatoms independently selected from N, O, P and S, 5-6 membered heteroarylene and 4-12 membered fused heterocycloalkylene optionally substituted with 0-6 R9; R9 at each occurrence is independently selected from halogen, deuterium, alkyl, haloalkyl, cyano, cycloalkyl, heterocycloalkyl, -S(O2)R 9a 、-NR 9b R 9c 、-X4-NR 9b R 9c 、-OR 9a AND-X4-OR 9a Preferably, each occurrence of R9 is independently selected from halogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, C 3-6 Cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O and S 3-7 Heterocycloalkyl, -S(O2)R 9a 、-NR 9b R 9c 、-X4-NR 9b R 9c 、-OR 9a AND-X4-OR 9a Preferably, each occurrence of R9 is independently selected from F, Cl, Br, I, C 1-3 Alkyl, and C 1-3 Haloalkyl; R 9a , R 9b and R 9c Each occurrence is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; X4 Selected from C 1-6 Alkylene and C 2-6 alkenylene; Each occurrence of the T ring and the U ring is independently selected from phenylene, pyridinylene, pyrimidinylene and pyrazinylene, wherein the phenylene, pyridinylene, pyrimidinylene and pyrazinylene are optionally substituted by 0, 1, 2 or 3 groups independently selected from cyano, halogen, amino, alkylamino, aminoalkyl, hydroxyl, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 Alkyl, C 3-6 Heterocycloalkyl, and C 3-6 The cycloalkyl group is substituted with a substituent, preferably, optionally selected from F, Cl, Br, I, C 1-3 Alkyl, and C 1-3 Substitution with a haloalkyl substituent; L1 is selected from the following groups: L2 is selected from the following groups: wherein Y1, Y2, Y3, Y4, Y5, Y6, and Y7 are independently selected from -O-, -NH-, -NHC(O)-, -NHS(O)-, -NHS(O2)-, -CH2-, -C(O)-, -S(O)-, -S(O2)-, -C(O)NH-, -S(O2)NH-, -CH=CH-, -C≡C-, and a single bond at each occurrence; a is selected from 0, 1, 2, 3, 4 and 5; b and c are independently selected from 0, 1, 2 and 3; d and e are independently selected from 0, 1, and 2; L3 is selected from the following groups: Y8, Y9, Y 10 , Y 11 and Y 12 are independently selected from -O-, -NH-, -NHC(O)-, -NHS(O)-, -NHS(O2)-, -CR Y1 R Y2 -, -C(O)-, -S(O)-, -S(O2)-, -C(O)NH-, -S(O2)NH-, -CH=CH-, -C≡C-, a single bond, a phenylene group, a 3-6 membered heterocycloalkylene group containing 1-4 heteroatoms independently selected from N, O, P and S, and a 5-6 membered heteroarylene group containing 1-4 heteroatoms independently selected from N, O, P and S; R Y1 and R Y2 Each occurrence is independently selected from hydrogen and C 1-6 Alkyl, or R Y1 and R Y2 The C to which it is connected forms a 3-6 membered cycloalkylene group or a 3-6 membered heterocycloalkylene group; and f, g, h, i and j are independently selected from 0, 1, 2 and 3.

3. The compound of claim 1 or 2, wherein: R1 is absent at each occurrence or is independently selected from hydrogen, deuterium, F, Cl, Br, I, cyano, hydroxyl, amide, sulfonamide, C 1-3 Alkyl, -SC 1-3 Alkyl, -S(O)-C 1-3 Alkyl, -S(O2)-C 1-3 Alkyl, -OC 1-3 Alkyl, -OC 1-3 Haloalkyl, C 1-3 Deuterated alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl and -NR 1a R 1b , where R 1a and R 1b are independently selected from hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Deuterated alkyl, C 3-6 Monocyclic cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O, P and S 3-6 Monocyclic heterocycloalkyl, C 6-10 Aryl and C 5-10 Heteroaryl, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 3-6 Monocyclic cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O, P and S 3-6 Monocyclic heterocycloalkyl, C 6-10 Aryl, and C 5-10 The heteroaryl group is optionally substituted with 0, 1, 2, 3, 4, 5 or 6 atoms independently selected from F, Cl, Br, I, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, amino, hydroxyl, C 1-3 Alkylamino, C 1-3 aminoalkyl, cyano, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl and C 1-3 The alkoxy substituent is substituted; or R 1a and R 1b The nitrogen atom to which it is commonly attached forms a 3-6 membered heterocycloalkyl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkyl is optionally substituted by 0, 1, 2, 3 or 4 heteroatoms independently selected from F, Cl, Br, I, deuterium, amino, C 1-3 Alkoxy, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Alkyl, cyano, aminoalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl and hydroxy are substituted; and / or Z is independently selected from C and N at each occurrence; and when Z is N, R1 is absent; and / or R2, R4 and R6 are each independently selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C 2-3 Alkoxy, C 1-3 haloalkyl, 3-6 membered monocyclic cycloalkyl, 3-6 membered monocyclic heterocyclic alkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered cycloalkyl-O-, 3-6 membered heterocyclic alkyl-O-, and 3-12 membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S; preferably, R2, R4 and R6 are each independently selected from hydrogen, deuterium, chlorine, fluorine, Br, C 1-3 Alkyl, 3-6 membered monocyclic cycloalkyl, and 3-6 membered monoheterocyclic alkyl containing 1-3 heteroatoms independently selected from N, O, P and S; and / or R5 is selected from hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl and C 1-4 haloalkyl; optionally, the C 1-4 Alkyl, C 3-6 Cycloalkyl and C 1-4 The haloalkyl group is substituted with 0-6 atoms independently selected from halogen, deuterium, C 1-4 Alkyl, amino, hydroxyl, and C 1-4 Preferably, R5 is selected from hydrogen, C 1-3 Alkyl and C 3-6 Cycloalkyl, optionally, the C 1-3 Alkyl, and C 3-6 Cycloalkyl is substituted with 0-6 atoms independently selected from halogen, deuterium, C 1-6 Alkyl, amino and hydroxyl groups are substituted; more preferably, R5 is selected from H and C 1-3 Alkyl; and / or Each occurrence of G1 and G2 is selected from O, S, and NR 2a ; and / or R 2a Each occurrence is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, phenylmethylene, -CH2OCH2CH2Si(CH3)3, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkyl-S-, -S(O)-C 1-3 Alkyl, -SO2-C 1-3 Alkyl, -OC 1-3 Alkyl, -OC 1-3 Haloalkyl, -NR 2b R 2c , -C 1-3 Alkylene-C 3-6 Cycloalkyl, C 3-6 Cycloalkyl-NR 2b -, a 3-6 membered heterocycloalkyl-NR containing 1-3 heteroatoms independently selected from N, O, P and S 2b -, 3-6 membered monocyclic alkyl, 3-6 membered monocyclic heterocyclic alkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered halogenated heterocyclic alkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered cycloalkyl-O-, 3-6 membered halogenated cycloalkyl, 3-6 membered halogenated cycloalkyl-O-, 3-6 membered halogenated heterocyclic alkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered heterocyclic alkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S, 6-10 membered monocyclic aryl, 5-6 membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S, and 8-10 membered cyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S; preferably, R 2a is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, amino, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkyl-S-, -S(O)-C 1-3 Alkyl, -SO2-C 1-3 Alkyl, -OC 1-3 Alkyl, -OC 1-3 Haloalkyl, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)C 1-3 Alkyl, C 3-6 Cycloalkyl and -C 1-3 Alkylene-C 3-6 Cycloalkyl; preferably, R 2a Selected from hydrogen, F, Cl, Br, I, cyano, hydroxyl, amino, C 1-3 Alkyl, C 1-3 Haloalkyl, -C 1-3 Alkylene-C 3-6 Cycloalkyl, and C 3-6 Cycloalkyl; R 2b and R 2c are independently selected from hydrogen and C 1-6 Alkyl; and / or J1 and J2 are independently selected from a single bond, -O-, -S-, -C(O)-, -S(O)-, -S(O2)-, -C(R 1c R 1d )-、-C(=CR 1e R 1f )- and -N(R3)-; preferably, J1 and J2 are not single bonds at the same time; wherein R 1c , R 1d , R 1e and R 1f are independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl, C 3-12 A monocyclic, spirocyclic or bridged cycloalkyl group, a C 3-12 Monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 Aryl and C 5-10 Heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 A monocyclic, spirocyclic or bridged cycloalkyl group, a C 3-12 Monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 Aryl, and C 5-10 Heteroaryl is optionally substituted by 0, 1, 2, 3, 4, 5 or 6 independently selected from halogen, deuterium, C 1-6 Alkyl, amino, hydroxyl, C 1-6 Alkylamino, C 1-6 aminoalkyl, cyano, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and C 1-6 The alkoxy substituent is substituted; or R 1c and R 1d The carbon atoms to which they are connected together form a 3-10 membered cycloalkylene or a 3-10 membered heterocycloalkylene containing 1-3 heteroatoms independently selected from N, O, P and S, wherein the cycloalkylene or heterocycloalkylene is optionally substituted by 0, 1, 2, 3 or 4 atoms independently selected from halogen, deuterium, amino, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 The aminoalkyl group and the hydroxy group are substituted; or R 1e and R 1f The carbon atoms to which they are connected together form a 3-10 membered cycloalkylene or a 3-10 membered heterocycloalkylene containing 0, 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S, wherein the cycloalkylene or heterocycloalkylene is optionally substituted by 0, 1, 2, 3 or 4 heteroatoms independently selected from halogen, deuterium, amino, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Alkyl, cyano, C 1-6 Substitution with aminoalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and hydroxy; and / or R3 is -X1-R8, X1 is selected from a single bond, -O-, -S-, C 1-3 Alkyleneoxy, C 2-3 Alkenylene and C 1-3 Alkylene; R8 is selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 6-10 Aryl, -NR 8a R 8b 、-C(O)R 8c 、-C(O)NR 8a R 8b , C 3-6 Cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O, P and S 3-6 heterocycloalkyl, and 5-10 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S.

3. The compound according to any one of claims 1 to 2, wherein the Q ring, the R ring, the L ring b and L d Each occurrence is independently selected from the following groups:

4. The compound according to any one of claims 1 to 3, wherein the compound is selected from the following structures: Preferably: the compound is selected from the following structures: in, A, B, Linker C, and formulas (II) to (XII) are defined as in any one of claims 1 to 3.

5. The compound according to any one of claims 1 to 4, wherein Linker C is selected from the following structures:

6. A compound, wherein the compound is a compound represented by formula (I), or an isomer, isotopic derivative, polymorph, prodrug, pharmaceutically acceptable salt or solvate thereof: Wherein ring A and ring B are independently selected from formula (II), (III) and (IV): Wherein Linker C is a linker connecting Ring A and Ring B, selected from Formula (V), (VI) and (VII): in, R 1a , R 1b , R 1c and R 1d are independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 Monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 Aryl and C 5-10 Heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 Monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 Aryl, and C 5-10 Heteroaryl is optionally substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, alkylamino, aminoalkyl, and alkoxy; or R 1a and R 1b and the nitrogen atom to which they are commonly attached form a 3-10 membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted with 0-3 substituents independently selected from halogen, deuterium, amino, alkoxy, alkylamino, aminoalkyl and hydroxy; or R 1c and R 1d Connect with The nitrogen atom of the cycloalkyl group forms a 3-10 membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted with 0-3 substituents independently selected from halogen, deuterium, amino, alkoxy, aminoalkyl and hydroxy; R2, R4 and R6 are independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Monoalkylamino, C 2-6 Dialkylamino, C 1-6 haloalkylamino, 3-12 membered monocyclic cycloalkyl, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monoheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spiroheterocycloalkyl and 4-12 membered bridged heterocycloalkyl, C 1-6 Alkyl-S-, C 1-6 Alkyl-SO-, C 1-6 Alkyl-SO2-, 3-6-membered cycloalkyl-O-, 3-6-membered heterocycloalkyl-O-, 5-10-membered monocyclic aryl, 5-10-membered cycloheteroaryl, and 3-12-membered monocyclic heteroaryl and 7-10-membered cycloheteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S; R5 is selected from hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl and C 1-6 haloalkyl, optionally, the C 1-6 Alkyl, C 3-10 Cycloalkyl and C 1-6 haloalkyl is substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, aminoalkyl, alkylamino, and alkoxy; Each occurrence of E, G, J and Z is independently selected from N and CR 2a ; where R 2a is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl-S-, C 1-6 Alkyl-SO-, C 1-6 Alkyl-SO2-, C 1-6 Alkyl-O-, C 1-6 Haloalkyl-O-, -NR 2b R 2c , C 3-6 Cycloalkylamino, 3-6 membered heterocycloalkylamino containing 1-3 heteroatoms independently selected from N, O, P and S, 3-12 membered monocyclic alkyl, 5-12 membered spirocycloalkyl and 4-12 membered bridged cycloalkyl, 3-12 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spirocycloheterocycloalkyl and 4-12 membered bridged heterocycloalkyl, 3-6 membered halogenated heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered cyclic alkyl-O-, 3-6 membered halogenated cycloalkyl, 3-6 membered halogenated cycloalkyl-O-, 3-6 membered halogenated heterocycloalkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered heterocycloalkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered monocyclic aryl, 5-12 membered paracyclic aryl, and 3-12 membered monocyclic heteroaryl and 7-10 membered paracyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S; R 2b and R 2c are independently selected from hydrogen and C 1-6 alkyl; R3 is -X1-R8, X1 is selected from a chemical bond, C 2-6 Alkenylene and C 1-6 Alkylene; R8 is selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 Aryl, -NR 8a R 8b 、-C(O)R 8c 、-C(O)NR 8a R 8b and a 5-10 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N, O, P and S; R 8a and R 8b Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 haloalkyl and phenyl, the phenyl group is optionally substituted by 0-2 groups selected from C 1-4 Alkyl, -OR 8d and-X2-R 8d Group substitution; R 8c Selected from hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl and C 1-6 Haloalkyl; X2 is selected Since C 1-6 Alkylene and C 2-6 Alkenylene; R 8d Selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; R 7a and R 7b are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -X3-OR 7c 、-X3-NR 7d R 7e and C 3-10 Cycloalkyl; X3 each occurrence is independently selected from C 1-6 Alkylene and C2-C6 alkenylene; R 7c Selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; R 7d and R 7e are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl; or R 7a and R 7b The carbon to which it is connected forms a 3-10 membered cycloalkyl group; The W ring is selected from the following groups: The Q ring is selected from 5-6 membered heterocycloalkylene and 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, and the heterocycloalkylene and heteroarylene are optionally substituted by 0-2 R9, each R9 being independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, C 3-6 Cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O and S 3-6 Heterocycloalkyl, -S(O2)R 9a 、-NR 9b R 9c 、-X4-NR 9b R 9c 、-OR 9a AND-X4-OR 9a ; R 9a , R 9b and R 9c Each occurrence is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; X4 is selected from C 1-6 Alkylene and C 2-6 alkenylene; The R ring is a 5-6 membered heterocycloalkylene or a 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkylene and heteroarylene are optionally substituted by 0-2 R 10 Replacement, R 10 Each occurrence is independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, C 3-6 Cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O and S 3-6 Heterocycloalkyl, -S(O2)R 10a 、-NR 10b R 10c 、-X5-NR 10b R 10c 、-OR 10a AND-X5-OR 10a ; R 10a , R 10b and R 10c Each occurrence is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; X5 is selected from C 1-6 Alkylene and C 2-6 alkenylene; The T ring and the U ring are independently selected from phenylene, pyridinylene, pyrimidinylene and pyrazinylene, wherein the phenylene, pyridinylene, pyrimidinylene and pyrazinylene are optionally substituted by 1-3 groups independently selected from halogen, amino, alkylamino, aminoalkyl, hydroxyl, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 Alkyl and C 3-6 Substitution of cycloalkyl groups; L1 is selected from the following groups: L2 is selected from the following groups: wherein Y1, Y2, Y3, Y4, Y5, Y6, and Y7 are independently selected from -O-, -NH-, -NHC(O)-, -NHS(O)-, -NHS(O2)-, -CH2-, -C(O)-, -S(O)-, -S(O2)-, -C(O)NH-, -S(O2)NH-, -CH=CH-, -C≡C-, and a single bond, wherein the hydrogen atom is optionally replaced by 0-2 independently selected from deuterium, halogen, amino, alkylamino, aminoalkyl, hydroxyl, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 Alkyl and C 3-6 Substitution of cycloalkyl groups; a is an integer from 0 to 5; b and c are each an integer from 0 to 3; d and e are each an integer from 0 to 2; and L1 and L2 are optionally replaced by 1-5 R 11 Replacement, R 11 are independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from oxygen, sulfur and nitrogen, -S(O2)R 11a NR 11b R 11c 、-X6-NR 11b R 11c 、-OR 11a AND-X6-OR 11a ; R 11a , R 11b and R 11c Each occurrence is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; X6 is selected from C 1-6 Alkylene and C 2-6 Alkenylene.

7. The compound of claim 6, wherein: R 1a and R 1b are independently selected from hydrogen, C 3-12 Monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 Monocyclic, spirocyclic or bridged heterocycloalkyl, and C 1-4 Alkyl, where C 1-4 Alkyl is optionally substituted with 0-6 substituents independently selected from halogen, deuterium, amino, hydroxy, aminoalkyl and alkoxy; or R 1a and R 1b and the nitrogen atom to which they are commonly connected form a four-membered, five-membered or six-membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by 0-3 substituents independently selected from halogen, amino and hydroxy; or R2, R4 and R6 are independently selected from halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Monoalkylamino, C 1-3 Dialkylamino, C 1-3 haloalkylamino, 3-12 membered monocyclic cycloalkyl, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monocyclic heterocyclic alkyl, 5-12 membered spirocycloheterocyclic alkyl and 4-12 membered bridged heterocyclic alkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C1-C6 alkyl-S-, C 1-6 Alkyl-SO-, C 1-6 Alkyl-SO2-, 3-6-membered cycloalkyl-O-, 3-6-membered heterocycloalkyl-O-, 5-10-membered monocyclic aryl, 5-10-membered cycloheteroaryl, and 3-12-membered monocyclic heteroaryl and 7-10-membered cycloheteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S; or R5 is selected from hydrogen, C 1-3 Alkyl and C 1-3 haloalkyl; or E, G, J and Z are independently selected from N and CR 2a ; where R 2a is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkyl-S-, C1-C3 alkyl-SO-, C 1-3 Alkyl-SO2-, C 1-3 Alkyl-O-, C 1-3 Haloalkyl-O-, -NR 2b R 2c , C 3-6 Cycloalkylamino, 3-6 membered heterocycloalkylamino containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered halogenated cycloalkyl, 3-6 membered halogenated heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered cycloalkyl-O-, 3-6 membered halogenated cycloalkyl-O-, 3-6 membered heterocycloalkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S; R 2b and R 2c are independently selected from hydrogen and C1-C6 alkyl; or R3 is -X1-R8, X1 is selected from a chemical bond, C2-C4 alkenylene and C1-C4 alkylene; R8 is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C6-C 10 Aryl, -NR 8a R 8b 、-C(O)R 8c 、-C(O)NR 8a R 8b and a 5-10 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N, O, P and S; R 8a and R 8b Each occurrence is independently selected from hydrogen, deuterium, C1-C3 alkyl, C1-C3 haloalkyl and phenyl, the phenyl being optionally substituted with 0-2 selected from C 1-4 Alkyl, -OR 8d and-X2-R 8d Group substitution; R 8c Selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; X2 is selected from C 1-6 Alkylene and C 2-6 Alkenylene; R 8d Selected from hydrogen, C 1-4 Alkyl and C 1-4 haloalkyl; or R 1c and R 1d are independently selected from hydrogen, C 3-12 Monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 Monocyclic, spirocyclic or bridged heterocycloalkyl, and C 1-4 Alkyl, where C 1-4 Alkyl is optionally substituted with 0-6 substituents independently selected from halogen, deuterium, amino, hydroxy, aminoalkyl and alkoxy; or R 1c and R 1d and the nitrogen atom to which they are commonly connected form a four-membered, five-membered or six-membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by 0-3 substituents independently selected from halogen, amino and hydroxy; or R 7a and R 7b are independently selected from hydrogen, halogen, C 1-4 Alkyl and C 1-4 haloalkyl; or The Q ring is optionally substituted by 1-2 R9, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, cyano, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the heteroatoms are independently selected from N, O and S, -S(O2)R 9a NR 9b R 9c AND-OR 9a ; Each R 9a , R 9b and R 9c Each occurrence is independently selected from hydrogen, C 1-3 Alkyl and C 1-3 haloalkyl; or The R ring is a 5-6 membered heterocycloalkylene or a 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkylene and heteroarylene are optionally substituted by 0-2 R 10 Replacement, R 10 Each occurrence is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, cyano, C3-C6 cycloalkyl, C3-6 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S, -S(O2)R 10a 、-NR 10b R 10c AND-OR 10a ; R 10a , R 10b and R 10c Each occurrence is independently selected from hydrogen, C1-C3 alkyl and C1-C3 haloalkyl; or The T ring and the U ring are independently selected from phenylene and pyridinyl, wherein the phenylene and pyridinyl are optionally substituted by 1-3 groups independently selected from halogen, amino, alkylamino, aminoalkyl, hydroxyl, hydroxyalkyl, aminoacyl, aminosulfonyl, Acyl, C 1-6 Alkyl and C 3-6 The cycloalkyl group is substituted with a substituent.

8. A compound according to any one of claims 6 to 7, wherein: R2 is selected from hydrogen, fluorine, chlorine, cyclopropyl, C 1-3 Alkyl and C 1-3 haloalkyl; or R3 is hydrogen; or R4 is selected from hydrogen, fluorine, chlorine, bromine and cyclopropyl; or R6 is selected from hydrogen, fluorine, chlorine and cyclopropyl; or R5 is selected from hydrogen and methyl; or R 1c and R 1d are independently selected from hydrogen and C1-C3 alkyl; preferably, R 1c and R 1d are independently selected from hydrogen and methyl; or The Q ring is selected from the following groups: Wherein, the connection site on the left side of each Q ring group is independently connected to -CR in formula (V) 7a R 7b - connected, the connection sites on the right side of each Q ring group are independently connected to the R ring in formula (V); or The R ring is selected from the following groups: The right connecting site of each R ring group is independently connected to the Q ring in formula (V), and the left connecting site of each R ring group is independently connected to the A ring or the B ring in formula I.

9. The compound according to any one of claims 6 to 8, wherein the compound is selected from the compounds represented by formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F) and (I-G), or their isomers, isotopic derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates: in, Q ring, R ring, T ring, U ring, W ring, R 1a , R 1b , R 1c , R 1d , R 7a , R 7b , R2, R3, R4, R5 and R6 are defined as in claim 1 or 2 or 3.

10. The compound according to any one of claims 6 to 9, wherein Ring A and Ring B are each independently selected from formula (II-1), (IV-1) and (III-1): Among them, R 1a , R 1b , R 1c , R 1d , R2, R3, R4, R5 and R6 are defined as in claim 1, 2 or 3.

11. A compound according to any one of claims 6 to 10, wherein the compound is selected from the group consisting of compounds represented by formula (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-F-3), (I-F-4), (I-F-5), (I-F-6), (I-F-7) and (I-F-8), or isomers, isotopic derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates thereof: Where Q a The definition of the ring is consistent with the definition of the Q ring in claim 1, 2 or 3; R a The definition of the ring is consistent with the definition of the R ring in claim 1, 2 or 3; R 1a , R 1b , R 1c , R 1d , R 7a , R 7b , E, G, J, Z, L2, R2 and R6 are defined as in claim 1, 2 or 3.

12. A compound, wherein the compound is a compound represented by formula (I), or an isomer, isotopic derivative, polymorph, prodrug, pharmaceutically acceptable salt or solvate thereof: Wherein ring A and ring B are the same or different, and ring A and ring B are independently selected from formula (II), (III) and (IV): Wherein Linker C is a linker connecting Ring A and Ring B, selected from Formula (V), (VI), (VI-2) and (VII): in, R 1a , R 1b , R 1c and R 1d are independently selected from hydrogen, deuterium, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyalkyl, C 1-6 Alkoxy, C 3-12 Monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 Monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 Aryl and C 5-10 Heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 Monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 Aryl, and C 5-10 Heteroaryl is optionally substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, alkylamino, aminoalkyl, and alkoxy; or R 1a and R 1b and the nitrogen atom to which they are commonly attached form a 3-10 membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted with 0-3 substituents independently selected from halogen, deuterium, amino, alkoxy, alkylamino, aminoalkyl and hydroxy; or R 1c and R 1d and the nitrogen atom to which they are commonly attached form a 3-10 membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted with 0-3 substituents independently selected from halogen, deuterium, amino, alkoxy, aminoalkyl and hydroxy; R2, R4 and R6 are independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)C 1-6 Alkyl, C 1-6 Haloalkoxy, C 1-6 haloalkylamino, 3-12 membered monocyclic cycloalkyl, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monoheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spiroheterocycloalkyl and 4-12 membered bridged cycloalkyl Heterocycloalkyl, C 1-6 Alkyl-S-, C 1-6 Alkyl-SO-, C 1-6 Alkyl-SO2-, 3-6-membered cycloalkyl-O-, 3-6-membered heterocycloalkyl-O-, 5-10-membered monocyclic aryl, 5-10-membered cycloheteroaryl, and 3-12-membered monocyclic heteroaryl and 7-10-membered cycloheteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S; R5 is selected from hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl and C 1-6 haloalkyl, optionally, the C 1-6 Alkyl, C 3-10 Cycloalkyl and C 1-6 haloalkyl is substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, aminoalkyl, alkylamino, and alkoxy; Each occurrence of E, G, J and Z is independently selected from N and CR 2a ; where R 2a Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, --NHCO-C 1-6 Alkyl, -COHN2, -C 1-6 Alkyl-COHN2, sulfonamide, -NHCONH2, -NH-CS-NH2, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl-S-, C 1-6 Alkyl-SO-, C 1-6 Alkyl-SO2-, C 1-6 Alkyl-O-, C 1-6 Haloalkyl-O-, -NR 2b R 2c , C 1-6 Alkylamino, C 2-6 Dialkylamino, -CONH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)C 1-6 Alkyl, C 3-6 Cycloalkylamino, C 3-6 Cycloalkylalkoxy, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, 3-6 membered heterocycloalkylamino containing 1-3 heteroatoms independently selected from N, O, P and S, 3-12 membered monocyclic alkyl, 5-12 membered spirocycloalkyl and 4-12 membered bridged cycloalkyl, 3-12 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spirocycloheterocycloalkyl and 4-12 membered bridged heterocycloalkyl, containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered halogenated heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered cycloalkyl-O-, 3-6 membered halogenated cycloalkyl, 3-6 membered halogenated cycloalkyl-O-, 3-6 membered halogenated heterocycloalkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered heterocycloalkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered monocyclic aryl, 5-12 membered paracyclic aryl, 3-12 membered monocyclic heteroaryl and 7-10 membered paracyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S; R 2b and R 2c are independently selected from hydrogen and C 1-6 alkyl; R3 is -X1-R8, X1 is selected from a chemical bond, -O-, -S-, alkoxy, C 2-6 Alkenylene and C 1-6 Alkylene; R8 is selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 Aryl, -NR 8a R 8b 、-C(O)R 8c 、-C(O)NR 8a R 8b and a 5-10 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N, O, P and S; R 8a and R 8b Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 haloalkyl and phenyl, the phenyl group is optionally substituted by 0-2 groups selected from C 1-4 Alkyl, halogen, hydroxyl, cyano, amino, -OR 8d and-X2-R 8d Group substitution; R 8c Selected from hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl and C 1-6 Haloalkyl; X2 is selected from C 1-6 Alkylene and C 2-6 Alkenylene; R 8d Selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; R 7a and R 7b are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -X3-OR 7c 、-X3-NR 7d R 7e and C 3-10 Cycloalkyl; X3 each occurrence is independently selected from C 1-6 Alkylene and C2-C6 alkenylene; R 7c Selected from hydrogen, deuterium, C 1-6 Alkyl and C 1-6 Haloalkyl; R 7d and R 7e are independently selected from hydrogen, deuterium, C 1-6 Alkyl and C 1-6 haloalkyl; or R 7a and R 7b The carbon to which it is connected forms a 3-10 membered cycloalkyl group; W is selected from the following groups: The Q ring is selected from 5-6 membered heterocycloalkylene and 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, and the heterocycloalkylene and heteroarylene are optionally substituted by 0-2 R9, each R9 being independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, C 3-6 Cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O and S 3-6 Heterocycloalkyl, -S(O2)R 9a 、-NR 9b R 9c 、-X4-NR 9b R 9c 、-OR 9a AND-X4-OR 9a ; R 9a , R 9b and R 9c Each occurrence is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; X4 is selected from C 1-6 Alkylene and C 2-6 alkenylene; The R ring is a 5-6 membered heterocycloalkylene or a 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkylene and heteroarylene are optionally substituted by 0-2 R 10 Replacement, R 10 Each occurrence is independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, C 3-6 Cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O and S 3-6 Heterocycloalkyl, -S(O2)R 10a 、-NR 10b R 10c 、-X5-NR 10b R 10c 、-OR 10a AND-X5-OR 10a ; R 10a , R 10b and R 10c Each occurrence is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; X5 is selected from C 1-6 Alkylene and C 2-6 alkenylene; The T ring and the U ring are independently selected from phenylene, pyridinylene, pyrimidinylene and pyrazinylene, wherein the phenylene, pyridinylene, pyrimidinylene and pyrazinylene are optionally substituted by 1-3 groups independently selected from halogen, amino, alkylamino, aminoalkyl, hydroxyl, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 Alkyl and C 3-6 Substitution of cycloalkyl groups; L1 is selected from the following groups: L2 is selected from the following groups: wherein Y1, Y2, Y3, Y4, Y5, Y6, and Y7 are independently selected from -O-, -NH-, -NHC(O)-, -NHS(O)-, -NHS(O2)-, -CH2-, -C(O)-, -S(O)-, -S(O2)-, -C(O)NH-, -S(O2)NH-, -CH=CH-, -C≡C-, and a single bond, wherein the hydrogen atoms in L2 are independently selected from deuterium, halogen, amino, alkylamino, aminoalkyl, -CONH2, -NHCO-C 1-6 Alkyl, hydroxyl, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 Alkyl and C 3-6 Any substituent of the cycloalkyl group; a is an integer from 0 to 5; b and c are each an integer from 0 to 3; d and e are each an integer from 0 to 2; and L1 and L2 are optionally replaced by 1-5 R 11 Replacement, R 11 are independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from oxygen, sulfur and nitrogen, -S(O2)R 11a NR 11b R 11c 、-X6-NR 11b R 11c 、-OR 11a AND-X6-OR 11a ; R 11a , R 11b and R 11c Each occurrence is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; X6 is selected from C 1-6 Alkylene and C 2-6 Alkenylene.

3. The compound of claim 2, wherein: R 1a and R 1b are independently selected from hydrogen, C 3-12 Monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 Monocyclic, spirocyclic or bridged heterocycloalkyl, and C 1-4 Alkyl, where C 1-4 Alkyl is optionally substituted with 0-6 substituents independently selected from halogen, deuterium, amino, hydroxy, aminoalkyl and alkoxy; or R 1a and R 1b and the nitrogen atom to which they are commonly connected form a four-membered, five-membered or six-membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by 0-3 substituents independently selected from halogen, amino and hydroxy; or R2, R4 and R6 are independently selected from halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)C 1-3 Alkyl, C 1-3 haloalkylamino, 3-12 membered monocyclic cycloalkyl, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monocyclic heterocyclic alkyl, 5-12 membered spirocycloheterocyclic alkyl and 4-12 membered bridged heterocyclic alkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C1-C6 alkyl-S-, C 1-6 Alkyl-SO-, C 1-6 Alkyl-SO2-, 3-6-membered cycloalkyl-O-, 3-6-membered heterocycloalkyl-O-, 5-10-membered monocyclic aryl, 5-10-membered cycloheteroaryl, and 3-12-membered monocyclic heteroaryl and 7-10-membered cycloheteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S; or R5 is selected from hydrogen, C 1-3 Alkyl and C 1-3 haloalkyl; or E, G, J and Z are independently selected from N and CR 2a ; where R 2a is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, -NHCO-C 1-6 Alkyl, -CONH2, -C 1-6 Alkyl-CONH2, sulfonamide, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkyl-S-, C1-C3 alkyl-SO-, C 1-3 Alkyl-SO2-, C 1-3 Alkyl-O-, C 1-3 Haloalkyl-O-, -NR 2b R 2c , C 3-6 Cycloalkylamino, 3-6 membered heterocycloalkylamino containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered halogenated cycloalkyl, 3-6 membered halogenated heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered cycloalkyl-O-, 3-6 membered halogenated cycloalkyl-O-, 3-6 membered heterocycloalkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S; R 2b and R 2c are independently selected from hydrogen and C1-C6 alkyl; or R3 is -X1-R8, X1 is selected from a chemical bond, C2-C4 alkenylene and C1-C4 alkylene; R8 is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C6-C 10 Aryl, -NR 8a R 8b 、-C(O)R 8c 、-C(O)NR 8a R 8b and a 5-10 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N, O, P and S; R 8a and R 8b Each occurrence is independently selected from hydrogen, deuterium, C1-C3 alkyl, C1-C3 haloalkyl and phenyl, the phenyl being optionally substituted with 0-2 selected from C 1-4 Alkyl, -OR 8d and-X2-R 8d Group substitution; R 8c Selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; X2 is selected from C 1-6 Alkylene and C 2-6 Alkenylene; R 8d Selected from hydrogen, C 1-4 Alkyl and C 1-4 haloalkyl; or R 1c and R 1d are independently selected from hydrogen, C 3-12 Monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 Monocyclic, spirocyclic or bridged heterocycloalkyl, and C 1-4 Alkyl, where C 1-4 Alkyl is optionally substituted with 0-6 substituents independently selected from halogen, deuterium, amino, hydroxy, aminoalkyl and alkoxy; or R 1c and R 1d and the nitrogen atom to which they are commonly connected form a four-membered, five-membered or six-membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by 0-3 substituents independently selected from halogen, amino and hydroxy; or R 7a and R 7b are independently selected from hydrogen, deuterium, halogen, C 1-4 Alkyl and C 1-4 haloalkyl; or The Q ring is optionally substituted by 1-2 R9, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, cyano, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the heteroatoms are independently selected from N, O and S, -S(O2)R 9a NR 9b R 9c AND-OR 9a ; Each R 9a , R 9b and R 9c Each occurrence is independently selected from hydrogen, deuterium, C 1-3 Alkyl and C 1-3 haloalkyl; or The R ring is a 5-6 membered heterocycloalkylene or a 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkylene and heteroarylene are optionally substituted by 0-2 R 10 Replacement, R 10 Each occurrence is independently selected from halogen, C1-C3 alkyl, hydroxy, amino, C1-C3 haloalkyl, cyano, C3-C6 cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O and S 3-6 Heterocycloalkyl, -S(O2)R 10a 、-NR 10b R 10c AND-OR 10a ; R 10a , R 10b and R 10c is independently selected at each occurrence from hydrogen, deuterium, C1-C3 alkyl and C1-C3 haloalkyl; or The T ring and the U ring are independently selected from 5-6 membered heterocyclic groups containing 1, 2, 3 N, O, S atoms, phenylene groups, wherein the phenylene and pyridinyl groups are optionally substituted by 1 to 3 groups independently selected from halogen, amino, alkylamino, aminoalkyl, cyano, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 Alkyl and C 3-6 The cycloalkyl group is substituted with a substituent.

13. The compound of claim 12, wherein: R2 is selected from hydrogen, fluorine, chlorine, cyclopropyl, C 1-3 Alkyl and C 1-3 haloalkyl; or R3 is hydrogen; or R4 is selected from hydrogen, fluorine, chlorine, bromine and cyclopropyl; or R6 is selected from hydrogen, fluorine, chlorine and cyclopropyl; or R5 is selected from hydrogen and methyl; or R 1c and R 1d are independently selected from hydrogen and C1-C3 alkyl; preferably, R 1c and R 1d are each independently selected from hydrogen and methyl; or The Q ring is selected from the following groups: Wherein, the connection site on the left side of each Q ring group is independently connected to -CR in formula (V) 7a R 7b - connected, the connection sites on the right side of each Q ring group are independently connected to the R ring in formula (V); or The R ring is selected from the following groups: The right connecting site of each R ring group is independently connected to the Q ring in formula (V), and the left connecting site of each R ring group is independently connected to the A ring or the B ring in formula I.

14. The compound according to any one of claims 12 to 13, wherein the compound is selected from the compounds represented by formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F) and (I-G), or their isomers, isotopic derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates: in, Q ring, R ring, T ring, U ring, L1, L2, W, R 1a , R 1b , R 1c , R 1d , R 7a , R 7b , R2, R3, R4, R5 and R6 are as defined in claim 12, 13 or 14.

15. The compound according to any one of claims 12 to 14, wherein Ring A and Ring B are the same or different, and the ring A and ring B are each independently selected from formula (II-1), (IV-1) and (III-1): Among them, R 1a , R 1b , R 1c , R 1d , R2, R3, R4, R5 and R6 are defined as in claim 12 or 13 or 14; preferably, the A ring and the B ring are the same.

16. A compound according to any one of claims 12 to 15, wherein the compound is selected from the group consisting of compounds represented by formula (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-F-3), (I-F-4), (I-F-5), (I-F-6), (I-F-7) and (I-F-8), or isomers, isotopic derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates thereof:

17. A compound selected from the following structures: Wherein Ring A and Ring B are independently selected from Formula (II), (III), (IV), (V), (VI), (VII) and (VIII): Wherein Linker C is a linker connecting Ring A and Ring B, selected from Formula (IX), (X), (XI) and (XII): in, R1 is selected from the group consisting of absent, hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -S(O)-C 1-6 Alkyl, -S(O2)-C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, C 1-6 Deuterated alkyl and -NR 1a R 1b , where R 1a and R 1b are independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 3-12 A monocyclic, spirocyclic or bridged cycloalkyl group, a C 3-12 Monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 Aryl and C 5-10 Heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-12 A monocyclic, spirocyclic or bridged cycloalkyl group, a C 3-12 Monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 Aryl, and C 5-10 The heteroaryl group is optionally substituted by 0-6 atoms independently selected from halogen, deuterium, alkane substituted with a substituent selected from the group consisting of alkyl, amino, hydroxy, alkylamino, aminoalkyl, and alkoxy; or R 1a and R 1b The nitrogen atom to which it is commonly connected forms a 3-10 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkyl is optionally substituted by 0-3 heteroatoms independently selected from halogen, deuterium, amino, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, cyano, C 1-6 Substitution of aminoalkyl and hydroxy groups; Z is selected from C and N; when Z is selected from N, R1 is absent; R2, R4 and R6 are independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)C 1-6 Alkyl, C 1-6 Haloalkoxy, C 1-6 haloalkylamino, 3-12 membered monocyclic cycloalkyl, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monoheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spiroheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 4-12 membered bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, -SC 1-6 Alkyl, -SO-C 1-6 Alkyl, -SO2-C 1-6 Alkyl, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, 5-10 membered monocyclic aryl, 5-10 membered cyclohexyl, 3-12 membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S, and 7-10 membered cyclohexyl containing 1-3 heteroatoms independently selected from N, O, P and S; R5 is selected from hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl and C 1-6 haloalkyl, optionally, the C 1-6 Alkyl, C 3-10 Cycloalkyl and C 1-6 haloalkyl is substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, aminoalkyl, alkylamino, and alkoxy; G1 and G2 are selected from O, S, and NR 2a ; E 0-9 、M 1-6 and E are independently selected from N and CR 2a ; where R 2a is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl-S-, -SO-C 1-6 Alkyl, -SO2-C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -NR 2b R 2c 、-NHC 1-6 Alkyl, -N(C 1-6 Alkyl)C 1-6 Alkyl, -C(O)R 8c 、-C(O)NR 8a R 8b , -C 1-6 Alkylene-C 1-6 Cycloalkyl, C 3-6 Cycloalkylamino, 3-6 membered heterocycloalkylamino containing 1-3 heteroatoms independently selected from N, O, P and S, 3-12 membered monocyclic alkyl, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spiroheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 4-12 membered bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered halogenated heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered cycloalkyl-O-, 3-6 membered halogenated cycloalkyl, 3-6 membered halogenated cycloalkyl-O-, containing 1-3 heteroatoms independently selected from N, O, P and S heteroatoms, 3-6 membered halogenated heterocycloalkyl-O-, 3-6 membered heterocycloalkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered monocyclic aryl, 5-12 membered cycloheteroaryl, 3-12 membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S, 7-10 membered cycloheteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S; R 2b and R 2c are independently selected from hydrogen and C 1-6 Alkyl; R 8a and R 8b Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 haloalkyl and phenyl, the phenyl group is optionally substituted by 0-2 groups selected from C 1-4 Alkyl, -OR 8d and-X2-R 8d Group substitution; R 8c Selected from hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl and C 1-6 Haloalkyl; X2 is selected from C 1-6 Alkylene and C 2-6 Alkenylene; R 8d Selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; J1 and J2 are independently selected from a single bond, O, S, C(O), S(O), S(O2), C(R 1c R 1d ), C(=CR 1e R 1f ) and N(R3); where R 1c , R 1d , R 1e and R 1f are independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 A monocyclic, spirocyclic or bridged cycloalkyl group, a C 3-12 Monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 Aryl and C 5-10 Heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 A monocyclic, spirocyclic or bridged cycloalkyl group, a C 3-12 Monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 Aryl, and C 5-10 Heteroaryl is optionally substituted by 0-6 independently selected from halogen, deuterium, C 1-6 Alkyl, amino, hydroxyl, C 1-6 Alkylamino, C 1-6 Aminoalkyl, and C 1-6 The alkoxy substituent is substituted; or R 1c and R 1d The carbon atoms connected to them form a 3-10 membered cycloalkyl or a 3-10 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, wherein the cycloalkyl or heterocycloalkyl is optionally substituted by 0-3 heteroatoms independently selected from halogen, deuterium, amino, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 The aminoalkyl and hydroxy groups are substituted; or R 1e and R 1f The carbon atoms connected to them form a 3-10 membered cycloalkyl or a 3-10 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, wherein the cycloalkyl or heterocycloalkyl is optionally substituted by 0-3 heteroatoms independently selected from halogen, deuterium, amino, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Substitution of aminoalkyl and hydroxy groups; R3 is -X1-R8, X1 is selected from a chemical bond, -O-, -S-, alkoxy, C 2-6 Alkenylene and C 1-6 Alkylene; R8 is selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 Aryl, -NR 8a R 8b 、-C(O)R 8c 、-C(O)NR 8a R 8b and a 5-10 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N, O, P and S; R 8a and R 8b Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 haloalkyl and phenyl, the phenyl group is optionally substituted by 0-2 groups selected from C 1-4 Alkyl, halogen, cyano, amino, -OR 8d and-X2-R 8d Group substitution; R 8c Selected from hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl and C 1-6 Haloalkyl; X2 is selected from C 1-6 Alkylene and C 2-6 Alkenylene; R 8d Selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; R 7a and R 7b are independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -X3-OR 7c 、-X3-NR 7d R 7e and C 3-10 Cycloalkyl; X3 each occurrence is independently selected from C 1-6 Alkylene and C2-C6 alkenylene; R 7c Selected from hydrogen, deuterium, C 1-6 Alkyl and C 1-6 Haloalkyl; R 7d and R 7e are independently selected from hydrogen, deuterium, C 1-6 Alkyl and C 1-6 haloalkyl; or R 7a and R 7b The carbon to which it is connected forms a 3-10 membered cycloalkyl group; W is selected from the following groups: The Q ring is selected from phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1-4 heteroatoms independently selected from N, O, P and S, 3-7 membered heterocycloalkenylene, 5-6 membered heteroarylene and 4-12 membered fused heterocyclic ring, wherein the phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1-4 heteroatoms independently selected from N, O, P and S, 5-6 membered heteroarylene and 4-12 membered fused heterocyclic ring are optionally substituted with 0-6 R9, each occurrence of R9 is independently selected from halogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, C 3-6 Cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O and S 3-7 Heterocycloalkyl, -S(O2)R 9a 、-NR 9b R 9c 、-X4-NR 9b R 9c 、-OR 9a AND-X4-OR 9a ; R 9a , R 9b and R 9c Each occurrence is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; X4 is selected from C 1-6 Alkylene and C 2-6 alkenylene; The R ring is selected from phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1-4 heteroatoms independently selected from N, O, P and S, 3-7 membered heterocycloalkenylene, 5-6 membered heteroarylene and 4-12 membered fused heterocyclic ring, wherein the phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1-4 heteroatoms independently selected from N, O, P and S, 3-7 membered heterocycloalkenylene, 5-6 membered heteroarylene and 4-12 membered fused heterocyclic ring are optionally substituted by 0-6 R 10 Replacement, R 10 Each occurrence is independently selected from halogen, deuterium, C 1-6 Alkyl, hydroxyl, amino, C 1-6 Haloalkyl, cyano, C 3-6 Cycloalkyl, C containing 1-3 heteroatoms independently selected from N, O and S 3-7 Heterocycloalkyl, -S(O2)R 10a 、-NR 10b R 10c 、-X5-NR 10b R 10c 、-OR 10a AND-X5-OR 10a ; R 10a , R 10b and R 10c Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl and C 1-6 Haloalkyl; X5 is selected from C 1-6 Alkylene and C 2-6 alkenylene; The T ring and the U ring are independently selected from phenylene, pyridinylene, pyrimidinylene and pyrazinylene, wherein the phenylene, pyridinylene, pyrimidinylene and pyrazinylene are optionally substituted by 0-3 independently selected from halogen, amino, alkylamino, aminoalkyl, hydroxyl, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 Alkyl and C 3-6 Substitution of cycloalkyl groups; L1 is selected from the following groups: L2 is selected from the following groups: wherein Y1, Y2, Y3, Y4, Y5, Y6, and Y7 are independently selected from -O-, -NH-, -NHC(O)-, -NHS(O)-, -NHS(O2)-, -CH2-, -C(O)-, -S(O)-, -S(O2)-, -C(O)NH-, -S(O2)NH-, -CH=CH-, -C≡C-, and a single bond; a is an integer from 0 to 5; b and c are each an integer from 0 to 3; d and e are each an integer from 0 to 2; and L1 and L2 are optionally replaced by 0-5 R 11 Replacement, R 11 are independently selected from deuterium, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from oxygen, sulfur and nitrogen, -S(O2)R 11a NR 11b R 11c 、-X6-NR 11b R 11c 、-OR 11a AND-X6-OR 11a ; R 11a , R 11b and R 11c Each occurrence is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; X6 is selected from C 1-6 Alkylene and C 2-6 Alkenylene.

18. The compound of any one of claims 1 to 17, wherein the compound is selected from the following structures:

19. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises a therapeutically effective dose of the compound according to any one of claims 1 to 18 and a pharmaceutically acceptable carrier or excipient.

20. Use of the compound according to any one of claims 1 to 18 or the pharmaceutical composition according to claim 19 for preparing a medicament for treating a MAT2A-related disease; preferably, the MAT2A-related disease is cancer or tumor.

21. A method for treating a MAT2A-related disease in a patient, the method comprising administering to the patient a therapeutically effective amount of one or more compounds of any one of claims 1-18 or the pharmaceutical composition of claim 19; preferably, the MAT2A-related disease is cancer or tumor.

22. The compound of any one of claims 1-18 or the pharmaceutical composition of claim 19, for use in treating a MAT2A-related disease; preferably, the MAT2A-related disease is cancer or tumor.

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