Pyrimidine derivative and application thereof in medicine

Abstract

The invention relates to a compound shown in a general formula (I) or a stereoisomer, a deuterated compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal of the compound, an intermediate and a preparation method of the compound, and application of the compound in preparation of drugs for treating diseases related to the activity or expression quantity of FGFR2 (Fibroblast Growth Factor Receptor 2). # imgabs0 #

Description

A pyrimidine derivative and its application in medicine Technical Field

[0001] The present invention relates to a compound of general formula (I) or its stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, as well as intermediates and preparation methods, and use of the compounds in preparing drugs for treating diseases related to FGFR2 activity or expression. Background Art

[0002] Biliary tract cancer (BTC) is a rare, heterogeneous disease encompassing various aggressive malignancies arising in the biliary tree. BTC includes intrahepatic cholangiocarcinoma (iCCA) and extrahepatic cholangiocarcinoma (eCCA). The 5-year overall survival rate for patients remains below 2%. Fibroblast growth factor receptors (FGFRs) are abnormally activated in approximately 15-20% of intrahepatic cholangiocarcinomas.

[0003] FGFR2, also known as CD332, is a protein encoded by a gene located on chromosome 10. The FGFR family includes four receptor subtypes: FGFR1, FGFR3, and FGFR4, as well as up to 22 fibroblast growth factor ligands (FGFs). They are part of the tyrosine kinase signaling pathway (FGFs / FGFRs signaling pathway) responsible for cell proliferation and differentiation. They are responsible for regulating basic developmental pathways in multiple organ systems and play an important role in many physiological and pathological processes, including angiogenesis, tissue homeostasis, wound repair, and tumor transformation by regulating cell proliferation, differentiation, survival, migration, and metabolism. Mutations have been found in various solid tumors, with urothelial carcinoma and intrahepatic cholangiocarcinoma being the most common. Fusion mutations in intrahepatic cholangiocarcinoma (ICC) account for 9% of total gene mutations. In addition, alternative splicing encodes b and c with different expression domains and ligand specificities.

[0004] Fusions, amplifications, and mutations are oncogenic drivers that occur in a variety of tumor types. Although the clinical efficacy observed with pan-FGFR inhibitors validates this driver status in fusion-positive intrahepatic cholangiocarcinoma (ICC), the emergence of FGFR1-mediated toxicities (hyperphosphatemia, tissue mineralization) and targeted resistance mutations limit the efficacy of pan-FGFR inhibitors. However, selective inhibitors can reduce toxicity and overcome acquired resistance to pan-FGFR inhibitors. Therefore, it is necessary to develop a compound that can inhibit with high selectivity for the treatment of related diseases caused by fusions, amplifications, and mutations.

[0005] Summary of the Invention

[0006] The present invention aims to provide a class of heterocyclic compounds or pharmaceutically acceptable salts thereof for use as FGFR2 inhibitors. The compounds of the present invention can effectively inhibit FGFR2 and can be used to treat diseases such as tumors.

[0007] The compound of the present invention has good selectivity and inhibitory activity against FGFR2 kinase, has good inhibitory activity against tumor cells, and exhibits excellent oral exposure and good bioavailability, good safety, and low CYP inhibition and hERG inhibition in pharmacokinetic tests.

[0008] The present invention provides a compound of general formula (I) or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

[0009] In some embodiments, the compound represented by general formula (I) is selected from the compounds represented by general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI), general formula (VII), and general formula (VIII).

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

[0011] W is selected from N or CH, a1 is selected from 0 or 1;

[0012] In some embodiments, the compound represented by general formula (I) is selected from the group consisting of general formula (Ib)

[0013] W is selected from N or CH, q1 is selected from 0, 1, 2, 3 or 4; in some embodiments, Selected from W is selected from N or CH, preferably

[0014] In some embodiments, Ring A, Ring B, and Ring C are each independently selected from phenyl, benzo 4-6 carbocyclic, 5- to 6-membered heteroaryl or 8- to 10-membered heteroaryl, wherein the ring A is optionally substituted by 1 to 4 R a substituted, said ring B is optionally substituted with 1 to 4 R b Substituted, the ring C is optionally substituted with 1 to 4 R c replace;

[0015] In some embodiments, ring B is selected from phenyl, naphthalene, benzo 4-6 Carbocyclic ring, benzo 4 to 6 membered heterocyclic ring, 5 to 6 membered heteroaryl, 8 to 10 membered heteroaryl ring, wherein the ring B is optionally substituted by 1 to 4 Rb replace;

[0016] In some embodiments, Ring B is selected from

[0017] In some embodiments, Ring B1 is selected from C 4-10 Carbocyclic ring, 4 to 10 membered heterocyclic ring, wherein the ring B1 is optionally substituted by 1 to 4 R b replace;

[0018] In some embodiments, Ring B1 is selected from Q3 is selected from C 4-10 Carbocyclic ring, 4 to 10 membered heterocyclic ring, wherein the ring B1 is optionally substituted by 1 to 4 R b substituted, said Q3 is optionally substituted with 1 to 4 R k replace;

[0019] In some embodiments, Ring B1 is selected from Q3 is selected from C 6-10 aryl, 5 to 10 membered heteroaryl, the ring B1 is optionally substituted by 1 to 4 R b substituted, said Q3 is optionally substituted with 1 to 4 R k replace;

[0020] In some embodiments, Ring B1 is selected from Q3 is selected from phenyl, pyridyl or pyrimidinyl, the ring B1 is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, methyl, ethyl, methoxy or ethoxy, and the Q3 is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, methyl, ethyl, methoxy or ethoxy;

[0021] In some embodiments, Ring B1 is selected from Q3 is selected from

[0022] In some embodiments, B2 is selected from C 4-6 Carbocyclic ring, B3 is selected from C 4-6 carbon ring;

[0023] In some embodiments, Q3 is selected from Ring B1 is selected from C 4-10 Carbocyclic ring, 4 to 10 membered heterocyclic ring, wherein the ring B1 is optionally substituted by 1 to 4 R b substituted, said Q3 is optionally substituted with 1 to 4 R k replace;

[0024] In some embodiments, Q3 is selected from Ring B1 is selected from phenyl, benzo4-6 Carbocyclic ring, benzo 4 to 6 membered heterocyclic ring, 5 to 6 membered heteroaryl, 8 to 10 membered heteroaryl, the ring B1 is optionally substituted by 1 to 4 R b substituted, said Q3 is optionally substituted with 1 to 4 R k replace;

[0025] In some embodiments, Q3 is selected from Ring B1 is selected from phenyl or pyridyl, and said ring B1 is optionally substituted by 1 to 4 R b substituted, said Q3 is optionally substituted with 1 to 4 R k Substitution; in some embodiments, Q3 is selected from Ring B1 is selected from

[0026] In some embodiments, ring A and ring B are each independently selected from phenyl, pyridine, and pyrimidine, and the ring A is optionally substituted with 1 to 4 R a substituted, said ring B is optionally substituted with 1 to 4 R b Substitution; In some embodiments, Ring C is selected from pyrrole, pyrimidine, 7H-pyrrolo[2,3-d]pyrimidine; In some embodiments, Ring A is selected from W is selected from N or CH;

[0027] Ring A is preferred In some embodiments, Selected from

[0028] In some embodiments, Ring B is selected from or Ring B1; In some embodiments, Ring B is selected from In some embodiments, Ring B is selected from In some embodiments, Selected from

[0029] In some embodiments, Ring C is selected from

[0030] In some embodiments, Ring C is selected from

[0031] In some embodiments, Selected from

[0032] In some embodiments, F1 or F2 is selected from N or CH;

[0033] In some embodiments, Q is selected from a bond, -O-、-N(R q3)-、-C(=O)N(R q3 )-、-N(R q3 )C(=O)、-C(=O)-、C 4-10 Carbocyclic ring, 4 to 10 membered heterocyclic ring, said carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0034] In some embodiments, Q is selected from -O-、-N(R q3 )-、-C(=O)N(R q3 )-、-N(R q3 )C(=O)、-C(=O)-、C 4-10 Carbocyclic ring, 4 to 10 membered heterocyclic ring, said carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0035] In some embodiments, Q is selected from Phenyl, naphthyl, benzo C 4-6 Carbocyclic ring, benzo 4 to 6 membered heterocyclic ring, -O-, -N(R q3 )-、-C(=O)N(R q3 )-、-N(R q3 )C(=O), -C(=O)-, the phenyl, naphthyl, benzo C 4-6 Carbocyclic ring, benzo 4 to 6 membered heterocyclic ring optionally 1 to 4 R k replace;

[0036] In some embodiments, Q is selected from -O-, -NH-, -N(CH3)-, -C(=O)NH-, -NHC(=O), -C(=O)-, the Optional 1 to 4 R k replace;

[0037] In some embodiments, Q is selected from -O-, -NH-, -N(CH3)-, -C(=O)NH-, -NHC(=O), -C(=O)-;

[0038] In some embodiments, Q is selected from Q1;

[0039] In some embodiments, Q1 is selected from -O-, -N(R q3 )-、-C(=O)N(R q3 )-、-N(R q3 )C(=O)、-C(=O)-、

[0040] In some embodiments, Q1 is selected from -O-, -NH-, -N(CH3)-, -C(=O)NH-, -NHC(=O), -C(=O)-,

[0041] In some embodiments, m is selected from 0 or 1;

[0042] In some embodiments, R q1 、R q2 、R q3 Each independently selected from H, C 1-6 Alkyl, said alkyl being optionally substituted by 1 to 4 R k replace;

[0043] In some embodiments, R q1 、R q2 、R q3 Each independently selected from H, C 1-4 Alkyl, said alkyl being optionally substituted by 1 to 4 R k replace;

[0044] In some embodiments, R q1 、R q2 、R q3 Each is independently selected from H, methyl, ethyl;

[0045] In some embodiments, D is selected from a bond, -NR n1 -、 The D is optionally replaced by 1 to 6 R d Substitution, the right side of D1 or D2 is directly connected to R1;

[0046] Q and D cannot be bonds at the same time;

[0047] In some embodiments, D is selected from -NR n1 -、 The D is optionally replaced by 1 to 4 R d Substitution, the right side of D1 or D2 is directly connected to R1;

[0048] In some embodiments, D is selected from -NR n1 -, Q is selected from

[0049] In some embodiments, D is selected from -NH-, -N(R n1 )-、 or optionally 1 to 4 R d One of the following groups substituted: Right side and R 1 Direct connection;

[0050] The bond between Q and D cannot form NN or NO;

[0051] In some embodiments, -D- in Formula (VI) is selected from

[0052] In some embodiments, in Formula (VII), D is selected from -NH-;

[0053] In some embodiments, D1 is selected from a 4- to 14-membered nitrogen-containing heterocyclic group;

[0054] In some embodiments, D1 is selected from 4 to 7 membered nitrogen-containing heteromonocycloalkyl, 4 to 7 membered nitrogen-containing heteromonocycloalkenyl, 5 to 14 membered nitrogen-containing heterospirocycloalkyl, 5 to 14 membered nitrogen-containing heterocycloalkyl, 5 to 14 membered nitrogen-containing heterobridged cycloalkyl;

[0055] In some embodiments, D1 is selected from

[0056] In some embodiments, D2 is selected from C 3-14 Carbocyclyl, 4- to 14-membered heterocyclyl;

[0057] In some embodiments, D2 is selected from phenyl, benzo 4-7 Carbocyclic group, benzo 4 to 7 membered heterocyclic group, 5 to 6 membered heteroaryl, C 3-7 Monocyclic alkyl, C 3-7 Monocyclic alkenyl, C 5-14 Spiroalkyl, C 5-14 Cycloalkyl, C 5-14 Bridged cycloalkyl, 4- to 7-membered nitrogen-containing heteromonocyclic group, 5- to 14-membered nitrogen-containing heterospirocyclic group, 5- to 14-membered nitrogen-containing heterocycloalkyl, 5- to 14-membered nitrogen-containing heterobridged ring group;

[0058] In some embodiments, D2 is selected from Phenyl, benzo C 4-6 Carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl;

[0059] In some embodiments, D3 is selected from C 7-14 Carbocyclic group;

[0060] In some embodiments, D3 is selected from benzo C 4-7 Carbocyclic group, C 7-14 Spiroalkyl, C 7-14 Cycloalkyl, C 7-14 bridged cycloalkyl;

[0061] In some embodiments, D3 is selected from

[0062] In some embodiments, D3 is selected from the group consisting of d One of the following groups substituted:

[0063] In some embodiments, n1, n3, and n5 are each independently selected from 0, 1, or 2;

[0064] In some embodiments, n2 and n4 are each independently selected from 0 or 1;

[0065] In some embodiments, n6 is selected from 0, 1, 2, or 3; in some embodiments, R n1 Selected from H, C 1-4 alkyl;

[0066] In some embodiments, R n1 Selected from H, methyl, ethyl;

[0067] In some embodiments, R a 、R b 、R c 、R d Each independently selected from H, deuterium, halogen, CN, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, -NH-5 to 6 membered heteroaryl-C 1-4 Alkyl, -NH-3 to 7 membered heterocyclic-C 3-6 Carbocycle, -NH-3 to 7-membered heterocycle, -4 to 6-membered heterocycle, -C 1-4 Alkylene-C 3-6 Carbocyclic ring, -C 1-4 Alkylene-3 to 7 membered heterocycle, -C(=O)NH2, -C(=O)NH-C 1-6 Alkyl, -C(=O)NH-C 3-6 Carbocycle, -NHC(=O)-C 1-6 Alkyl, -NHC(=O)-C 3-6 Carbon ring, C 3-6Carbocyclic ring, 3 to 7 membered heterocyclic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, heteroaryl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0068] In some embodiments, R a 、R b 、R d Each independently selected from deuterium, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 Carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, -C 1-2 Alkylene-C 3-6 Carbocyclic ring, -C 1-2 Alkylene-3 to 7 membered heterocycle, -C(=O)NH-C 1-6 Alkyl, -C(=O)NH-C 3-6 Carbon ring, C 3-6 Carbocyclic ring, 3 to 7 membered heterocyclic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0069] In some embodiments, R a 、R b 、R d Each independently selected from deuterium, F, Cl, Br, I, cyano, OH, NH2, NH(CH3), N(CH3)2, CF3, methyl, ethyl, propyl, isopropyl, butyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0070] In some embodiments, R a Each independently selected from deuterium, F, Cl, Br, cyano, CF3, methyl;

[0071] In some embodiments, R b Each independently selected from deuterium, F, Cl, Br, cyano, CF3, methyl;

[0072] In some embodiments, R d Each independently selected from deuterium, F, Cl, Br, I, cyano, OH, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy;

[0073] In some embodiments, Rc1 Selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl or 4 to 7 membered heterocycloalkyl, said alkyl, cycloalkyl or heterocycloalkyl being optionally substituted by 1 to 4 R k replace;

[0074] In some embodiments, R c1 Selected from H, C 1-4 Alkyl or C 3-6 Cycloalkyl, the alkyl or cycloalkyl group is optionally substituted by 1 to 4 R k replace;

[0075] In some embodiments, R c1 is selected from H, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein the methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl is optionally substituted by 1 to 4 R k replace;

[0076] In some embodiments, R c1 is selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl is optionally substituted by 1 to 4 R k replace;

[0077] In some embodiments, R c1 Selected from CD3, CF3, methyl, ethyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl,

[0078] In some embodiments, R c1 Selected from CD3, CF3, methyl, ethyl, propyl, isopropyl, cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl,

[0079] In some embodiments, R c2 Each independently selected from deuterium, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 Carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, -C 1-2 Alkylene-C 3-6 Carbocyclic ring, -C 1-2 Alkylene-3 to 7 membered heterocycle, -C(=O)NH-C 1-4 Alkyl, -C(=O)NH-C 3-6 Carbocycle, -NHC(=O)-C 1-4 Alkyl, -NHC(=O)-C 3-6 Carbon ring, C 3-6 Carbocyclic ring, 3 to 7 membered heterocyclic ring, the alkyl, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0080] In some embodiments, R c2 each independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, isopropyl, vinyl, propenyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -NH-pyrazole, -NH-imidazole, -NH-oxazole, -NH-thiazole, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -C(=O)NH-methyl, -C(=O)NH-ethyl, -C(=O)NH-cyclopropyl, -NHC(= O)-methyl, -NHC(=O)-ethyl, -NHC(=O)-cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, azetyl, oxetyl, oxetyl, piperazinyl, morpholinyl, pyrazole, imidazole, oxazole, thiazole, the methyl, ethyl, isopropyl, vinyl, propenyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, azetyl, oxetyl, oxetyl, oxetyl, piperazinyl, morpholinyl, pyrazole, imidazole, oxazole, thiazole are optionally replaced by 1 to 4 R k replace;

[0081] In some embodiments, R c2selected from deuterium, F, Cl, Br, OH, CN, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, isopropyl, vinyl, propenyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetyl, oxolyl, oxetyl, piperazinyl, morpholinyl, -NH-pyrazole, -NH-imidazole, -NH-oxazole, -NH-thiazole, -C(=O)NH-methyl, -C(=O)NH-ethyl, -C(=O)NH-cyclopropyl, -NHC(=O)-methyl, -NHC(=O)-ethyl alkyl, -NHC(=O)-cyclopropyl, wherein the methyl, ethyl, isopropyl, vinyl, propenyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazole, imidazole, oxazole, thiazole, azetidinyl, azetyl, azetyl, oxetyl, oxetyl, oxetyl, piperazinyl, morpholinyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;

[0082] In some embodiments, R c3 Each independently selected from H, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -C(=O)NH2, -C 1-2 Alkylene-C 3-6 Carbocyclic ring, -C 1-2 Alkylene-3 to 7 membered heterocyclic ring, -OC 3-6 Carbocyclic ring, -O-3 to 7 membered heterocyclic ring, C 3-6 Carbocyclic ring, 3 to 7 membered heterocyclic ring, the alkyl, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0083] In some embodiments, R c3 Each is independently selected from H, NH2, -C(=O)NH2, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl;

[0084] In some embodiments, R c3 Each is independently selected from H, NH2 or -C(=O)NH2;

[0085] In some embodiments, R c4 Selected from H, NH2, halogen, CN, OH, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -OC 3-6 Carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, -C 1-2 Alkylene-C 3-6 Carbocyclic ring, -C 1-2 Alkylene-3 to 7 membered heterocyclic ring, wherein the alkyl, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k Substituted; in some embodiments, R c4 is selected from H, NH2, F, Cl, Br, I, CN, methyl, ethyl, ethynyl, -NH-pyrazole, -NH-imidazole, -NH-oxazole, -NH-thiazole, wherein the methyl, ethyl, ethynyl, pyrazole, imidazole, oxazole, thiazole is optionally replaced by 1 to 4 R k replace;

[0086] In some embodiments, R c4 Selected from H, NH2, halogen, CN, C 1-4 Alkyl, C 2-4 Alkyl or -NH-5 to 6 membered heteroaromatic ring, wherein the alkyl, alkynyl or heteroaromatic ring is optionally substituted by 1 to 4 R k replace;

[0087] In some embodiments, R c4 Selected from H, NH2, F, CN, methyl,

[0088] In some embodiments, R c5 Selected from H, deuterium, halogen, CN, hydroxyl, NH2, -NHC1-4 alkyl, -NH-C 3-7 Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, -NH-5 to 6 membered heteroaryl-C 1-3 Alkylene-R c5a , -NH-5 to 6 membered heteroaryl-C 3-6 Carbocyclyl-R c5a , -NH-5 to 6 membered heteroaryl-4 to 6 membered heterocyclic group-R c5aThe alkyl, alkylene, alkoxy, cycloalkyl, carbocyclic, heterocyclic, or heteroaryl groups are optionally substituted by 1 to 4 R k replace;

[0089] In some embodiments, R c5 Selected from -NH-C 3-6 Carbocyclic ring, -NH-3 to 6 membered heterocyclic ring, -NH-5 to 6 membered heteroaryl-C 1-2 Alkylene-R c5a , -NH-5 to 6 membered heteroaryl-C 3-6 Carbocyclyl-R c5a , -NH-5 to 6 membered heteroaryl-4 to 6 membered heterocyclic group-R c5a The alkyl, alkylene, alkoxy, cycloalkyl, carbocyclic, heterocyclic, or heteroaryl groups are optionally substituted by 1 to 4 R k replace;

[0090] In some embodiments, R c5 Selected from -NH-C 3-6 Carbocycle, -NH-pyrazole, -NH-pyrrole, -NH-imidazole, -NH-triazole, -NH-5 to 6 membered heteroaryl-C 1-2 Alkylene-R c5a , -NH-5 to 6 membered heteroaryl-C 3-6 Carbocyclyl-R c5a , -NH-5 to 6 membered heteroaryl-4 to 6 membered heterocyclic group-R c5a , the 5- to 6-membered heteroaryl is selected from pyrazolyl, pyrrolyl, imidazolyl or triazolyl, and the alkylene, carbocyclic group, heterocyclic group, heteroaryl, pyrazolyl, pyrrolyl, imidazolyl or triazolyl is optionally substituted by 1 to 4 R k replace;

[0091] In some embodiments, R c5 Selected from

[0092] In some embodiments, R c6 Selected from H, halogen, OH, NH2, C 1-4 Alkyl, CN, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -C(=O)NH2, -C 1-2 Alkylene-C 3-6 Carbocyclic ring, -C 1-2 Alkylene-3 to 7 membered heterocyclic ring, -OC 3-6 Carbocyclic ring, -O-3 to 7 membered heterocyclic ring, C 3-6Carbocyclic or 3 to 7 membered heterocyclic rings, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic, heterocyclic rings are optionally substituted by 1 to 4 R k replace;

[0093] In some embodiments, R c6 Selected from H, halogen, OH, NH2, C 1-4 Alkyl, CN, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -C(=O)NH2, -C 1-2 Alkylene-C 3-6 Carbocyclic ring, -C 1-2 Alkylene-4 to 6 membered heterocyclic ring, -OC 3-6 Carbocyclic ring, -O-4 to 6 membered heterocyclic ring, C 3-6 Carbocyclic or 4 to 7 membered heterocycloalkane ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic, heterocyclic, heterocycloalkane ring is optionally substituted by 1 to 4 R k replace;

[0094] In some embodiments, R c6 is selected from H, F, Cl, Br, I, OH, NH2, CF3, methyl, ethyl, CN, ethynyl, -CH2-ethynyl, propynyl, methoxy, ethoxy, -C(=O)NH2, -CH2-cyclopropyl, -O-cyclopropyl, cyclopropyl, cyclobutyl or cyclopentyl, wherein the methyl, ethyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl or cyclopentyl is optionally substituted by 1 to 4 R k replace;

[0095] In some embodiments, when R c6 Selected from H, halogen, OH, NH2 or C 1-4 When alkyl, R c5 Selected from -NH-5 to 6 membered heteroaryl-C 1-3 Alkylene-R c5a , -NH-5 to 6 membered heteroaryl-C 3-6 Carbocyclyl-R c5a , -NH-5 to 6 membered heteroaryl-4 to 6 membered heterocyclic group-R c5a The alkyl, heteroaryl, alkylene, carbocyclic or heterocyclic group is optionally substituted by 1 to 3 R k replace;

[0096] In some embodiments, when R c6 Selected from H, halogen, OH, NH2 or C 1-4 When alkyl, R c5 Selected from -NH-5 to 6 membered heteroaryl-C1-2 Alkylene-R c5a , -NH-5 to 6 membered heteroaryl-C 3-6 Cycloalkyl-R c5a , -NH-5 to 6 membered heteroaryl-4 to 6 membered heterocycloalkyl-R c5a The alkyl, heteroaryl, alkylene, cycloalkyl or heterocycloalkyl group is optionally substituted by 1 to 3 R k replace;

[0097] In some embodiments, when R c6 When R is selected from H, F, Cl, Br, I, OH, NH2, CF3, methyl or ethyl, c5 Selected from -NH-5 to 6 membered heteroaryl-C 1-2 Alkylene-R c5a , -NH-5 to 6 membered heteroaryl-C 3-6 Cycloalkyl-R c5a , -NH-5 to 6 membered heteroaryl-4 to 6 membered heterocycloalkyl-R c5a , the 5- to 6-membered heteroaryl is selected from pyrazolyl, pyrrolyl, imidazolyl or triazolyl, and the heteroaryl, alkylene, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 3 R k replace;

[0098] In some embodiments, when R c6 When R is selected from H, F, Cl, Br, I, OH, NH2, CF3, methyl or ethyl, c5 Selected from

[0099] In some embodiments, when R c6 Selected from CN, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -C(=O)NH2, -C 1-2 Alkylene-C 3-6 Carbocyclic ring, -C 1-2 Alkylene-3 to 7 membered heterocyclic ring, -OC 3-6 Carbocyclic ring, -O-3 to 7 membered heterocyclic ring, C 3-6 When it is a carbocyclic ring or a 3- to 7-membered heterocyclic ring, R c5 Selected from H, deuterium, halogen, CN, hydroxyl, NH2, -NHC1-4 alkyl, -NH-C 3-7 Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6Cycloalkyl, the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl, carbocycle, heterocycle is optionally substituted by 1 to 4 R k replace;

[0100] In some embodiments, when R c6 Selected from CN, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -C(=O)NH2, -C 1-2 Alkylene-C 3-6 Carbocyclic ring, -C 1-2 Alkylene-4 to 6 membered heterocyclic ring, -OC 3-6 Carbocyclic ring, -O-4 to 6 membered heterocyclic ring, C 3-6 When the ring is a cycloalkyl group or a 4- to 7-membered heterocycloalkane ring, R c5 Selected from -NH-C 3-6 carbocyclic ring, -NH-5 to 6 membered heteroaromatic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, carbocyclic ring, heterocyclic ring, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R k replace;

[0101] In some embodiments, when R c6 When R is selected from CN, ethynyl, -CH2-ethynyl, propynyl, methoxy, ethoxy, -C(=O)NH2, -CH2-cyclopropyl, -O-cyclopropyl, cyclopropyl, cyclobutyl or cyclopentyl, c5 Selected from -NH-C 3-6 Carbocycle, -NH-pyrazole, -NH-pyrrole, -NH-imidazole, -NH-triazole, the CH2, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, pyrazolyl, pyrrolyl, imidazolyl or triazole group is optionally substituted by 1 to 4 R k replace;

[0102] In some embodiments, when R c6 When R is selected from CN, ethynyl, -CH2-ethynyl, propynyl, -C(=O)NH2, -CH2-cyclopropyl, -O-cyclopropyl, cyclopropyl, cyclobutyl or cyclopentyl, c5 Selected from

[0103] In some embodiments, R c7 Selected from H or R c2 ;

[0104] In some embodiments, R c5a Selected from CN, -OC 1-3 Alkyl, -SC 1-3Alkyl, C 3-6 Carbon ring, -OC 3-6 Carbocycle, 4- to 6-membered heterocycle, -O-4- to 6-membered heterocycle, -C(=O)C 3-6 Carbocycle, -C(=O)-4 to 6 membered heterocycle, wherein the alkyl, carbocycle or heterocycle is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent;

[0105] In some embodiments, R c5a is selected from CN or one of the following groups which are optionally substituted: -O-methyl, -O-ethyl, -S-methyl, -S-ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetyl, oxetyl, oxetyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, -O-azetidinyl, -O-azacyclopentyl, -O-azacyclohexyl, -C(=O)-cyclopropyl, -C(= -C(═O)-cyclobutyl, -C(═O)-cyclopentyl, -C(═O)-cyclohexyl, -C(═O)-azetidinyl, -C(═O)-azacyclopentyl, -C(═O)-azetidinyl, -C(═O)-azacyclohexyl, -C(═O)-oxetanyl, -C(═O)-oxolanyl, -C(═O)-oxhexyl, when substituted, by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, methyl, ethyl, methoxy or ethoxy;

[0106] In some embodiments, R c5a Selected from CN, -O-methyl, -O-ethyl, -S-methyl, -S-ethyl, cyclopropyl,

[0107] In some embodiments, p1 or p2 is selected from 0, 1, 2, or 3; in some embodiments, p1 or p2 is selected from 0, 1, or 2;

[0108] In some embodiments, R 1 Selected from halogen, CN,

[0109] In some embodiments, R 1 Selected from CN,

[0110] In some embodiments, R 1 Selected from

[0111] In some embodiments, -DR1 Selected from

[0112] In some embodiments, R 1a 、R 1b 、R 1c 、R 1d Each independently selected from H, deuterium, halogen, CN, -C(=O)R, -C(=O)OR, -C(=O)N(R)2, C(=O)N(R)OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Carbocyclic ring, 3 to 7 membered heterocyclic ring, said alkyl, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0113] In some embodiments, R 1a 、R 1b 、R 1c 、R 1d Each independently selected from H, deuterium, halogen, CN, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Carbocyclic ring, 3 to 7 membered heterocyclic ring, said alkyl, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0114] In some embodiments, R 1e is selected from halogen or -OS(=O)2R;

[0115] In some embodiments, R 1e Selected from halogen or -OS(=O)2C 1-4 Alkyl, the alkyl group is optionally substituted by 1 to 4 R k replace;

[0116] In some embodiments, R is selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Carbocyclic ring, 3 to 7 membered heterocyclic ring, said alkyl, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0117] In some embodiments, R 1e Selected from F, Cl, Br, I, -OS(=O)2CH3, -OS(=O)2CF3;

[0118] In some embodiments, R 1b With R1c 、R 1a With R 1b Direct connection to form C 3-6 Carbocyclic or 3- to 7-membered heterocyclic ring, the carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0119] In some embodiments, R n1 With R d Direct connection to form C 3-6 Carbocyclic or 3- to 7-membered heterocyclic ring, the carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0120] In some embodiments, R k Selected from deuterium, halogen, CN, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 Carbocycle, -NH-3 to 7-membered heterocycle, -C(=O)-C 3-6 Carbocycle, -C(=O)-3 to 7 membered heterocycle, -C 1-4 Alkylene-C 3-6 Carbocyclic ring, -C 1-4 Alkylene-3 to 7 membered heterocyclic ring, C 3-6 Carbocyclic ring, 3 to 7 membered heterocyclic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 groups selected from deuterium, halogen, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0121] In some embodiments, R k Selected from deuterium, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 Carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, -C 1-2 Alkylene-C 3-6 Carbocyclic ring, -C 1-2Alkylene-3 to 7 membered heterocyclic ring, C 3-6 Carbocyclic ring, 3 to 7 membered heterocyclic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 groups selected from deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0122] In some embodiments, R k is selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is optionally substituted by 1 to 4 halogens selected from halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0123] In some embodiments, Formula (Ia) Definition and general formula (VIII) Or general formula (VII) Same definition as in;

[0124] In some embodiments, Formula (VIII) middle

[0125] As a first embodiment of the present invention, the compound represented by the following general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0126] Ring A, Ring B, and Ring C are each independently selected from phenyl, benzo 4-6 carbocyclic, 5- to 6-membered heteroaryl or 8- to 10-membered heteroaryl, wherein the ring A is optionally substituted by 1 to 4 R a substituted, said ring B is optionally substituted with 1 to 4 R b Substituted, the ring C is optionally substituted with 1 to 4 R c replace;

[0127] Q is selected from the group consisting of a key, -O-、-N(R q3 )-、-C(=O)N(R q3 )-、-N(Rq3 )C(=O)、-C(=O)-、C 4-10 Carbocyclic ring, 4 to 10 membered heterocyclic ring, said carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0128] m is selected from 0 or 1;

[0129] R q1 、R q2 、R q3 Each independently selected from H, C 1-6 Alkyl, said alkyl being optionally substituted by 1 to 4 R k replace;

[0130] D is selected from a bond, -NR n1 -、 The D is optionally replaced by 1 to 6 R d Substitution, the right side of D1 or D2 is directly connected to R1;

[0131] Q and D cannot be bonds at the same time;

[0132] The bond between Q and D cannot form NN or NO;

[0133] D1 is selected from 4 to 14-membered nitrogen-containing heterocyclic groups;

[0134] D2 is selected from C 3-14 Carbocyclyl, 4- to 14-membered heterocyclyl;

[0135] D3 is selected from C 7-14 Carbocyclic group;

[0136] R n1 Selected from H, C 1-4 alkyl;

[0137] R a 、R b 、R c 、R d Each independently selected from H, deuterium, halogen, CN, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, -NH-5 to 6 membered heteroaryl-C 1-4 Alkyl, -NH-3 to 7 membered heterocyclic-C 3-6Carbocycle, -NH-3 to 7-membered heterocycle, -4 to 6-membered heterocycle, -C 1-4 Alkylene-C 3-6 Carbocyclic ring, -C 1-4 Alkylene-3 to 7 membered heterocycle, -C(=O)NH2, -C(=O)NH-C 1-6 Alkyl, -C(=O)NH-C 3-6 Carbocycle, -NHC(=O)-C 1-6 Alkyl, -NHC(=O)-C 3-6 Carbon ring, C 3-6 Carbocyclic ring, 3 to 7 membered heterocyclic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, heteroaryl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0138] R 1 Selected from halogen, CN,

[0139] R 1a 、R 1b 、R 1c 、R 1d Each independently selected from H, deuterium, halogen, CN, -C(=O)R, -C(=O)OR, -C(=O)N(R)2, C(=O)N(R)OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Carbocyclic ring, 3 to 7 membered heterocyclic ring, said alkyl, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0140] R 1e is selected from halogen or -OS(=O)2R;

[0141] R is selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Carbocyclic ring, 3 to 7 membered heterocyclic ring, said alkyl, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0142] Alternatively, R 1b With R 1c 、R 1a With R 1b Direct connection to form C 3-6 Carbocyclic or 3- to 7-membered heterocyclic ring, the carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0143] Alternatively, R n1With R d Direct connection to form C 3-6 Carbocyclic or 3- to 7-membered heterocyclic ring, the carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0144] R k Selected from deuterium, halogen, CN, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 Carbocycle, -NH-3 to 7-membered heterocycle, -C(=O)-C 3-6 Carbocycle, -C(=O)-3 to 7 membered heterocycle, -C 1-4 Alkylene-C 3-6 Carbocyclic ring, -C 1-4 Alkylene-3 to 7 membered heterocyclic ring, C 3-6 Carbocyclic ring, 3 to 7 membered heterocyclic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 groups selected from deuterium, halogen, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent.

[0145] As a second embodiment of the present invention, the compound represented by the above-mentioned general formula (I) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, the compound represented by the general formula (I) is selected from the compounds represented by the general formula (II), the general formula (III), the general formula (IV), the general formula (V), the general formula (VI), the general formula (VII) and the general formula (VIII),

[0146] Ring B is selected from phenyl, naphthalene, benzo 4-6 Carbocyclic ring, benzo 4 to 6 membered heterocyclic ring, 5 to 6 membered heteroaryl, 8 to 10 membered heteroaryl ring, wherein the ring B is optionally substituted by 1 to 4 R b replace;

[0147] Q3 is selected from C 4-10 Carbocyclic ring, 4 to 10 membered heterocyclic ring, said Q3 is optionally substituted by 1 to 4 R k replace;

[0148] Ring B1 is selected from Q3 is selected from C 4-10Carbocyclic ring, 4 to 10 membered heterocyclic ring, wherein the ring B1 is optionally substituted by 1 to 4 R b substituted, said Q3 is optionally substituted with 1 to 4 R k replace;

[0149] B2 is selected from C 4-6 Carbocyclic ring, B3 is selected from C 4-6 carbon ring;

[0150] Or Q3 is selected Ring B1 is selected from C 4-10 Carbocyclic ring, 4 to 10 membered heterocyclic ring, wherein the ring B1 is optionally substituted by 1 to 4 R b substituted, said Q3 is optionally substituted with 1 to 4 R k replace;

[0151] Ring C is selected from

[0152] F1 or F2 is selected from N or CH;

[0153] Q is selected from -O-、-N(R q3 )-、-C(=O)N(R q3 )-、-N(R q3 )C(=O)、-C(=O)-、C 4-10 Carbocyclic ring, 4 to 10 membered heterocyclic ring, said carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0154] Q1 is selected from -O-, -N(R q3 )-、-C(=O)N(R q3 )-、-N(R q3 )C(=O), -C(=O)-, optionally substituted with 1 to 4 R k Replaced

[0155] D is selected from -NR n1 -、 The D is optionally replaced by 1 to 4 R d Substitution, the right side of D1 or D2 is directly connected to R1;

[0156] D1 is selected from 4 to 7 membered nitrogen-containing heteromonocycloalkyl, 4 to 7 membered nitrogen-containing heteromonocycloalkenyl, 5 to 14 membered nitrogen-containing heterospirocycloalkyl, 5 to 14 membered nitrogen-containing heterocycloalkyl, 5 to 14 membered nitrogen-containing heterobridged cycloalkyl;

[0157] D2 is selected from phenyl, benzo 4-7 Carbocyclic group, benzo 4 to 7 membered heterocyclic group, 5 to 6 membered heteroaryl, C 3-7 Monocyclic alkyl, C 3-7 Monocyclic alkenyl, C 5-14Spiroalkyl, C 5-14 Cycloalkyl, C 5-14 Bridged cycloalkyl, 4- to 7-membered nitrogen-containing heteromonocyclic group, 5- to 14-membered nitrogen-containing heterospirocyclic group, 5- to 14-membered nitrogen-containing heterocycloalkyl, 5- to 14-membered nitrogen-containing heterobridged ring group;

[0158] D3 is selected from benzo C 4-7 Carbocyclic group, C 7-14 Spiroalkyl, C 7-14 Cycloalkyl, C 7-14 bridged cycloalkyl;

[0159] R c1 Selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl or 4 to 7 membered heterocycloalkyl, said alkyl, cycloalkyl or heterocycloalkyl being optionally substituted by 1 to 4 R k replace;

[0160] R c2 Each independently selected from deuterium, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 Carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, -C 1-2 Alkylene-C 3-6 Carbocyclic ring, -C 1-2 Alkylene-3 to 7 membered heterocycle, -C(=O)NH-C 1-4 Alkyl, -C(=O)NH-C 3-6 Carbocycle, -NHC(=O)-C 1-4 Alkyl, -NHC(=O)-C 3-6 Carbon ring, C 3-6 Carbocyclic ring, 3 to 7 membered heterocyclic ring, the alkyl, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0161] R c3 Each independently selected from H, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -C(=O)NH2, -C 1-2Alkylene-C 3-6 Carbocyclic ring, -C 1-2 Alkylene-3 to 7 membered heterocyclic ring, -OC 3-6 Carbocyclic ring, -O-3 to 7 membered heterocyclic ring, C 3-6 Carbocyclic ring, 3 to 7 membered heterocyclic ring, the alkyl, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0162] R c4 Selected from H, NH2, halogen, CN, OH, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -OC 3-6 Carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, -C 1-2 Alkylene-C 3-6 Carbocyclic ring, -C 1-2 Alkylene-3 to 7 membered heterocyclic ring, wherein the alkyl, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0163] R c5 Selected from H, deuterium, halogen, CN, hydroxyl, NH2, -NHC1-4 alkyl, -NH-C 3-7 Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, -NH-5 to 6 membered heteroaryl-C 1-3 Alkylene-R c5a , -NH-5 to 6 membered heteroaryl-C 3-6 Carbocyclyl-R c5a , -NH-5 to 6 membered heteroaryl-4 to 6 membered heterocyclic group-R c5a The alkyl, alkylene, alkoxy, cycloalkyl, carbocyclic, heterocyclic, or heteroaryl groups are optionally substituted by 1 to 4 R k replace;

[0164] R c6 Selected from H, halogen, OH, NH2, C 1-4 Alkyl, CN, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -C(=O)NH2, -C 1-2Alkylene-C 3-6 Carbocyclic ring, -C 1-2 Alkylene-3 to 7 membered heterocyclic ring, -OC 3-6 Carbocyclic ring, -O-3 to 7 membered heterocyclic ring, C 3-6 Carbocyclic or 3 to 7 membered heterocyclic rings, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl, carbocyclic ring, heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0165] When R c6 Selected from H, halogen, OH, NH2 or C 1-4 When alkyl, R c5 Selected from -NH-5 to 6 membered heteroaryl-C 1-3 Alkylene-R c5a , -NH-5 to 6 membered heteroaryl-C 3-6 Carbocyclyl-R c5a , -NH-5 to 6 membered heteroaryl-4 to 6 membered heterocyclic group-R c5a The alkyl, heteroaryl, alkylene, carbocyclic or heterocyclic group is optionally substituted by 1 to 3 R k replace;

[0166] R c5a Selected from CN, -OC 1-3 Alkyl, -SC 1-3 Alkyl, C 3-6 Carbon ring, -OC 3-6 Carbocycle, 4- to 6-membered heterocycle, -O-4- to 6-membered heterocycle, -C(=O)C 3-6 Carbocycle, -C(=O)-4 to 6 membered heterocycle, wherein the alkyl, carbocycle or heterocycle is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent;

[0167] When R c6 Selected from CN, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -C(=O)NH2, -C 1-2 Alkylene-C 3-6 Carbocyclic ring, -C 1-2 Alkylene-3 to 7 membered heterocyclic ring, -OC 3-6 Carbocyclic ring, -O-3 to 7 membered heterocyclic ring, C 3-6 When it is a carbocyclic ring or a 3- to 7-membered heterocyclic ring, R c5 Selected from H, deuterium, halogen, CN, hydroxyl, NH2, -NHC1-4 alkyl, -NH-C 3-7Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Cycloalkyl, the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl, carbocyclic, heterocyclic, optionally substituted by 1 to 4 R k replace;

[0168] R c7 Selected from H or R c2 ;

[0169] p1 or p2 is selected from 0, 1, 2 or 3;

[0170] The definitions of the respective groups are the same as those in the first embodiment.

[0171] As a third embodiment of the present invention, the compounds represented by the above-mentioned general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI), general formula (VII), general formula (VIII) or their stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0172] Q is selected from Phenyl, naphthyl, benzo C 4-6 Carbocyclic ring, benzo 4 to 6 membered heterocyclic ring, -O-, -N(R q3 )-、-C(=O)N(R q3 )-、-N(R q3 )C(=O), -C(=O)-, the phenyl, naphthyl, benzo C 4-6 Carbocyclic ring, benzo 4 to 6 membered heterocyclic ring optionally 1 to 4 R k replace;

[0173] R q1 、R q2 、R q3 Each independently selected from H, C 1-4 Alkyl, said alkyl being optionally substituted by 1 to 4 R k replace;

[0174] R a 、R b 、R d Each independently selected from deuterium, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 Carbocycle, -O-3 to 7 membered heterocycle, -NH-C3-6 Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, -C 1-2 Alkylene-C 3-6 Carbocyclic ring, -C 1-2 Alkylene-3 to 7 membered heterocycle, -C(=O)NH-C 1-6 Alkyl, -C(=O)NH-C 3-6 Carbon ring, C 3-6 Carbocyclic ring, 3 to 7 membered heterocyclic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0175] R c3 Each is independently selected from H, NH2, -C(=O)NH2, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl;

[0176] R c4 Selected from H, NH2, halogen, CN, C 1-4 Alkyl, C 2-4 Alkyl or -NH-5 to 6 membered heteroaromatic ring, wherein the alkyl, alkynyl or heteroaromatic ring is optionally substituted by 1 to 4 R k replace;

[0177] R c5 Selected from -NH-C 3-6 Carbocyclic ring, -NH-3 to 6 membered heterocyclic ring, -NH-5 to 6 membered heteroaryl-C 1-2 Alkylene-R c5a , -NH-5 to 6 membered heteroaryl-C 3-6 Carbocyclyl-R c5a , -NH-5 to 6 membered heteroaryl-4 to 6 membered heterocyclic group-R c5a The alkyl, alkylene, alkoxy, cycloalkyl, carbocyclic, heterocyclic, or heteroaryl groups are optionally substituted by 1 to 4 R k replace;

[0178] R c6 Selected from H, halogen, OH, NH2, C 1-4 Alkyl, CN, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -C(=O)NH2, -C 1-2 Alkylene-C 3-6 Carbocyclic ring, -C 1-2 Alkylene-4 to 6 membered heterocyclic ring, -OC 3-6 Carbocyclic ring, -O-4 to 6 membered heterocyclic ring, C 3-6A carbocyclic ring or a 4- to 7-membered heterocycloalkyl ring, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl, carbocyclic ring, heterocyclic ring, heterocycloalkyl ring is optionally substituted by 1 to 4 R k replace;

[0179] When R c6 Selected from H, halogen, OH, NH2 or C 1-4 When alkyl, R c5 Selected from -NH-5 to 6 membered heteroaryl-C 1-2 Alkylene-R c5a , -NH-5 to 6 membered heteroaryl-C 3-6 Cycloalkyl-R c5a , -NH-5 to 6 membered heteroaryl-4 to 6 membered heterocycloalkyl-R c5a The alkyl, heteroaryl, alkylene, cycloalkyl or heterocycloalkyl group is optionally substituted by 1 to 3 R k replace;

[0180] When R c6 Selected from CN, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -C(=O)NH2, -C 1-2 Alkylene-C 3-6 Carbocyclic ring, -C 1-2 Alkylene-4 to 6 membered heterocyclic ring, -OC 3-6 Carbocyclic ring, -O-4 to 6 membered heterocyclic ring, C 3-6 When the ring is a cycloalkyl group or a 4- to 7-membered heterocycloalkane ring, R c5 Selected from -NH-C 3-6 carbocyclic ring, -NH-5 to 6 membered heteroaromatic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, carbocyclic ring, heterocyclic ring, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R k replace;

[0181] R 1a 、R 1b 、R 1c 、R 1d Each independently selected from H, deuterium, halogen, CN, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Carbocyclic ring, 3 to 7 membered heterocyclic ring, said alkyl, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0182] Alternatively, R 1b With R 1c 、R 1a With R1b Direct connection to form C 3-6 Carbocyclic or 3- to 7-membered heterocyclic ring, the carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0183] R 1e Selected from halogen or -OS(=O)2C 1-4 Alkyl, the alkyl group is optionally substituted by 1 to 4 R k replace;

[0184] R k Selected from deuterium, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 Carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, -C 1-2 Alkylene-C 3-6 Carbocyclic ring, -C 1-2 Alkylene-3 to 7 membered heterocyclic ring, C 3-6 Carbocyclic ring, 3 to 7 membered heterocyclic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 groups selected from deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0185] The definitions of the remaining groups are the same as those of the second embodiment of the present invention.

[0186] As a fourth embodiment of the present invention, the compounds represented by the above-mentioned general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI), general formula (VII), general formula (VIII) or their stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0187] D1 is selected from

[0188] D2 is selected from Phenyl, benzo C 4-6 Carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl;

[0189] D3 is selected from

[0190] Q3 is selected from C 6-10 Aryl, 5 to 10 membered heteroaryl, said Q3 is optionally substituted by 1 to 4 R k replace;

[0191] Ring B1 is selected from Q3 is selected from C 6-10 aryl, 5 to 10 membered heteroaryl, the ring B1 is optionally substituted by 1 to 4 R b substituted, said Q3 is optionally substituted with 1 to 4 R k replace;

[0192] B2 is selected from C 4-6 Carbocyclic ring, B3 is selected from C 4-6 carbon ring;

[0193] Or Q3 is selected Ring B1 is selected from phenyl, benzo 4-6 Carbocyclic ring, benzo 4 to 6 membered heterocyclic ring, 5 to 6 membered heteroaryl, 8 to 10 membered heteroaryl, the ring B1 is optionally substituted by 1 to 4 R b substituted, said Q3 is optionally substituted with 1 to 4 R k replace;

[0194] n1, n3, n5 are each independently selected from 0, 1 or 2;

[0195] n2 and n4 are each independently selected from 0 or 1;

[0196] n6 is 0, 1, 2 or 3;

[0197] R q1 、R q2 、R q3 Each is independently selected from H, methyl, ethyl;

[0198] R n1 Selected from H, methyl, ethyl;

[0199] R a 、R b 、R d Each independently selected from deuterium, F, Cl, Br, I, cyano, OH, NH2, NH(CH3), N(CH3)2, CF3, methyl, ethyl, propyl, isopropyl, butyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0200] R c1is selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl is optionally substituted by 1 to 4 R k replace;

[0201] R c2 each independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, isopropyl, vinyl, propenyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -NH-pyrazole, -NH-imidazole, -NH-oxazole, -NH-thiazole, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -C(=O)NH-methyl, -C(=O)NH-ethyl, -C(=O)NH-cyclopropyl, -NHC(= O)-methyl, -NHC(=O)-ethyl, -NHC(=O)-cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, azetyl, oxetyl, oxetyl, piperazinyl, morpholinyl, pyrazole, imidazole, oxazole, thiazole, the methyl, ethyl, isopropyl, vinyl, propenyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, azetyl, oxetyl, oxetyl, oxetyl, piperazinyl, morpholinyl, pyrazole, imidazole, oxazole, thiazole are optionally replaced by 1 to 4 R k replace;

[0202] R c4 is selected from H, NH2, F, Cl, Br, I, CN, methyl, ethyl, ethynyl, -NH-pyrazole, -NH-imidazole, -NH-oxazole, -NH-thiazole, wherein the methyl, ethyl, ethynyl, pyrazole, imidazole, oxazole, thiazole is optionally replaced by 1 to 4 R k replace;

[0203] Ring B is selected from

[0204] R c5 Selected from -NH-C 3-6 Carbocycle, -NH-pyrazole, -NH-pyrrole, -NH-imidazole, -NH-triazole, -NH-5 to 6 membered heteroaryl-C 1-2 Alkylene-R c5a, -NH-5 to 6 membered heteroaryl-C 3-6 Carbocyclyl-R c5a , -NH-5 to 6 membered heteroaryl-4 to 6 membered heterocyclic group-R c5a , the 5- to 6-membered heteroaryl is selected from pyrazolyl, pyrrolyl, imidazolyl or triazolyl, and the alkylene, carbocyclic group, heterocyclic group, heteroaryl, pyrazolyl, pyrrolyl, imidazolyl or triazolyl is optionally substituted by 1 to 4 R k replace;

[0205] R c6 is selected from H, F, Cl, Br, I, OH, NH2, CF3, methyl, ethyl, CN, ethynyl, -CH2-ethynyl, propynyl, methoxy, ethoxy, -C(=O)NH2, -CH2-cyclopropyl, -O-cyclopropyl, cyclopropyl, cyclobutyl or cyclopentyl, wherein the methyl, ethyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl or cyclopentyl is optionally substituted by 1 to 4 R k replace;

[0206] When R c6 When R is selected from H, F, Cl, Br, I, OH, NH2, CF3, methyl or ethyl, c5 Selected from -NH-5 to 6 membered heteroaryl-C 1-2 Alkylene-R c5a , -NH-5 to 6 membered heteroaryl-C 3-6 Cycloalkyl-R c5a , -NH-5 to 6 membered heteroaryl-4 to 6 membered heterocycloalkyl-R c5a , the 5- to 6-membered heteroaryl is selected from pyrazolyl, pyrrolyl, imidazolyl or triazolyl, and the heteroaryl, alkylene, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 3 R k replace;

[0207] R c5ais selected from CN or one of the following groups which are optionally substituted: -O-methyl, -O-ethyl, -S-methyl, -S-ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetyl, oxetyl, oxetyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, -O-azetidinyl, -O-azacyclopentyl, -O-azacyclohexyl, -C(=O)-cyclopropyl, -C(= -C(═O)-cyclobutyl, -C(═O)-cyclopentyl, -C(═O)-cyclohexyl, -C(═O)-azetidinyl, -C(═O)-azacyclopentyl, -C(═O)-azetidinyl, -C(═O)-azacyclohexyl, -C(═O)-oxetanyl, -C(═O)-oxolanyl, -C(═O)-oxhexyl, when substituted, by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, methyl, ethyl, methoxy or ethoxy;

[0208] When R c6 When R is selected from CN, ethynyl, -CH2-ethynyl, propynyl, methoxy, ethoxy, -C(=O)NH2, -CH2-cyclopropyl, -O-cyclopropyl, cyclopropyl, cyclobutyl or cyclopentyl, c5 Selected from -NH-C 3-6 Carbocycle, -NH-pyrazole, -NH-pyrrole, -NH-imidazole, -NH-triazole, the CH2, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, pyrazolyl, pyrrolyl, imidazolyl or triazole group is optionally substituted by 1 to 4 R k replace;

[0209] R 1a 、R 1b 、R 1c 、R 1d Each independently selected from H, deuterium, F, Cl, Br, I, CN, methyl, ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein the methyl, ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is optionally substituted by 1 to 4 R k replace;

[0210] Alternatively, R 1b With R 1c 、R 1a With R 1b Direct connection to form C 3-6 Carbocyclic or 3- to 7-membered heterocyclic ring, the carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0211] Alternatively, R n1 With R d Direct connection to form C 3-6Carbocyclic or 3- to 7-membered heterocyclic ring, the carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0212] R 1e Selected from F, Cl, Br, I, -OS(=O)2CH3, -OS(=O)2CF3;

[0213] R k is selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is optionally substituted by 1 to 4 halogens selected from halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0214] The remaining groups are defined the same as in the second or third embodiment of the present invention.

[0215] As a fifth embodiment of the present invention, the compounds represented by the above-mentioned general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI), general formula (VII), general formula (VIII) or their stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0216] Q is selected from -O-, -NH-, -N(CH3)-, -C(=O)NH-, -NHC(=O), -C(=O)-, the Optional 1 to 4 R k replace;

[0217] Q1 is selected from -O-, -NH-, -N(CH3)-, -C(=O)NH-, -NHC(=O), -C(=O)-,

[0218] Selected from

[0219] Selected from

[0220] D is selected from -NH-, -N(R n1 )-、 or optionally 1 to 4 R d One of the following groups substituted: Right side and R 1 Direct connection;

[0221] D3 is optionally selected from 1 to 4 R d One of the following groups substituted:

[0222] R 1 Selected from CN,

[0223] p1 or p2 is selected from 0, 1 or 2;

[0224] The remaining groups are defined the same as in any one of the second, third or fourth embodiments of the present invention.

[0225] As a sixth embodiment of the present invention, the compounds represented by the aforementioned general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI), general formula (VII) or their stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0226] R a Each independently selected from deuterium, F, Cl, Br, cyano, CF3, methyl;

[0227] R b Each independently selected from deuterium, F, Cl, Br, cyano, CF3, methyl;

[0228] R d Each independently selected from deuterium, F, Cl, Br, I, cyano, OH, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy;

[0229] R c1 Selected from CD3, CF3, methyl, ethyl, propyl, isopropyl, cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl,

[0230] R c2selected from deuterium, F, Cl, Br, OH, CN, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, isopropyl, vinyl, propenyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetyl, oxolyl, oxetyl, piperazinyl, morpholinyl, -NH-pyrazole, -NH-imidazole, -NH-oxazole, -NH-thiazole, -C(=O)NH-methyl, -C(=O)NH-ethyl, -C(=O)NH-cyclopropyl, -NHC(=O)-methyl, -NHC(=O)-ethyl alkyl, -NHC(=O)-cyclopropyl, wherein the methyl, ethyl, isopropyl, vinyl, propenyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazole, imidazole, oxazole, thiazole, azetidinyl, azetyl, azetyl, oxetyl, oxetyl, oxetyl, piperazinyl, morpholinyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;

[0231] R c4 Selected from H, NH2, F, CN, methyl,

[0232] R c5 Selected from

[0233] When R c6 When R is selected from H, F, Cl, Br, I, OH, NH2, CF3, methyl or ethyl, c5 Selected from

[0234] R c5a Selected from CN, -O-methyl, -O-ethyl, -S-methyl, -S-ethyl, cyclopropyl,

[0235] When R c6 When R is selected from CN, ethynyl, -CH2-ethynyl, propynyl, -C(=O)NH2, -CH2-cyclopropyl, -O-cyclopropyl, cyclopropyl, cyclobutyl or cyclopentyl, c5 Selected from

[0236] Q3 is selected from phenyl, pyridyl or pyrimidinyl, said Q3 being optionally substituted with 1 to 4 substituents selected from F, Cl, Br, methyl, ethyl, methoxy or ethoxy;

[0237] Ring B1 is selected from Q3 is selected from phenyl, pyridyl or pyrimidinyl, the ring B1 is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, methyl, ethyl, methoxy or ethoxy, and the Q3 is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, methyl, ethyl, methoxy or ethoxy;

[0238] Or Q3 is selected Ring B1 is selected from phenyl or pyridyl, and said ring B1 is optionally substituted by 1 to 4 R b substituted, said Q3 is optionally substituted with 1 to 4 R k replace;

[0239] The remaining groups are defined the same as in any one of the second, third, fourth or fifth embodiments of the present invention.

[0240] As a seventh embodiment of the present invention, the compounds represented by the aforementioned general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI), general formula (VII), general formula (VIII) or their stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0241] Selected from

[0242] In the general formula (VI), -D- is selected from

[0243] Ring B1 is selected from Q3 is selected from

[0244] Or Q3 is selected Ring B1 is selected from

[0245] In the general formula (VII), D is selected from -NH-;

[0246] General formula (VIII) middle

[0247] The remaining groups are defined the same as in any one of the second, third, fourth, fifth or sixth embodiments of the present invention.

[0248] The present invention relates to the compound shown below or its stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures shown in Table E-1.

[0249] Table E-1

[0250] The present invention relates to a pharmaceutical composition comprising any of the above compounds or their stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and a pharmaceutically acceptable carrier.

[0251] The present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier.

[0252] In some embodiments, the pharmaceutical composition of the present invention may be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as the "preparation strength").

[0253] As used herein, an "effective amount" or "therapeutically effective amount" refers to administering a sufficient amount of a compound disclosed herein to alleviate, to some extent, one or more symptoms of the disease or condition being treated (e.g., a FGFR2 abnormality-related disease such as cancer). In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired changes in the biological system. For example, an "effective amount" for therapeutic use is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease symptoms.Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 mg, 6-600 mg, 10-600 mg, 20-600 mg, 25-600 mg, 30-600 mg, 40-600 mg, 50-600 mg, 60-600 mg, 70-600 mg, 75-600 mg, 80-600 mg, 90-600 mg, 100-600 mg, 200-600 mg, 1-500 mg, 2-500mg, 3-500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg , 80-500mg, 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg, 400-500mg, 5-400mg, 10-400mg, 20-400mg, 25-40 0mg, 30-400mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80-400mg, 90-400mg, 100-400mg, 125-400mg, 150-400mg, 200-400mg, 250- 400mg, 300-400mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300mg, 25-300mg, 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-300mg , 80-300mg, 90-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-200mg, 40-200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg, 80-1000mg, 80-800mg.

[0254] In some embodiments, the pharmaceutical composition includes but is not limited to 1-1000 mg, 20-800 mg, 40-800 mg, 40-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, 840 mg of a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

[0255] A method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, preferably 1-1500 mg. The disease is preferably a disease related to FGFR2 activity or expression (such as cancer).

[0256] A method for treating a disease in a mammal, comprising administering to a subject a compound of the present invention or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof at a daily dose of 1-1000 mg / day. The daily dose may be a single dose or divided doses. In some embodiments, the daily dose includes but is not limited to 10-1500 mg / day, 10-1000 mg / day, 10-800 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day. , 25-400 mg / day, 50-400 mg / day, 100-400 mg / day, 200-400 mg / day, in some embodiments, daily doses include but are not limited to 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 80 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 160 mg / day, 200 mg / day, 300 mg / day, 320 mg / day, 400 mg / day, 480 mg / day, 600 mg / day, 640 mg / day, 800 mg / day, 1000 mg / day.

[0257] The present invention relates to a kit, which may include a composition in single-dose or multi-dose form, wherein the kit contains a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and the amount of the compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is the same as the amount in the above-mentioned pharmaceutical composition.

[0258] The present invention relates to the use of any of the above-mentioned compounds or their stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals in the preparation of drugs for treating diseases related to FGFR2 activity or expression, preferably, the disease is selected from tumors.

[0259] The present invention relates to the use of the above-mentioned pharmaceutical composition in the preparation of a drug for treating a disease associated with FGFR2 activity or expression, preferably, the disease is selected from tumors.

[0260] The amount of the compound of the invention or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof is in each case calculated as the free base.

[0261] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0262] The carbon, hydrogen, oxygen, sulfur, nitrogen, F, Cl, Br, and I involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, or nitrogen involved in the groups and compounds of the present invention are optionally replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl, bromine include 79 Br and 81 Br.

[0263] "Halogen" refers to F, Cl, Br or I.

[0264] "Halogen-substituted" refers to substitution with F, Cl, Br or I, including but not limited to substitution with 1 to 10 substituents selected from F, Cl, Br or I, substitution with 1 to 6 substituents selected from F, Cl, Br or I, and substitution with 1 to 4 substituents selected from F, Cl, Br or I. "Halogen-substituted" is abbreviated as "halo".

[0265] "Alkyl" refers to a substituted or unsubstituted straight-chain or branched saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, and alkyl groups of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched chain isomers thereof; alkyl groups appearing herein have the same definition as this one. Alkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0266] "Alkylene" refers to substituted or unsubstituted straight-chain and branched divalent saturated hydrocarbon groups, including -(CH2) v -(v is an integer from 1 to 10), examples of alkylene include but are not limited to methylene, ethylene, propylene and butylene.

[0267] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon radical, typically having 3 to 10 carbon atoms, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Cycloalkyl groups as used herein are as defined above. Cycloalkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0268] "Heterocycloalkyl" refers to a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 10 atoms, 3 to 8 atoms, including 1 to 3 heteroatoms selected from N, O or S. The N and S optionally substituted in the ring of the heterocycloalkyl can be oxidized to various oxidation states. The heterocycloalkyl group can be connected to a heteroatom or a carbon atom, the heterocycloalkyl group can be connected to an aromatic ring or a non-aromatic ring, and the heterocycloalkyl group can be connected to a bridged ring or a spiro ring. Non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolane, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl. The heterocycloalkyl group can be monovalent, divalent, trivalent or tetravalent.

[0269] "Alkenyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbon groups having at least one, typically one, two or three carbon-carbon double bonds, with a backbone of 2 to 10, 2 to 6 or 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2- Methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, and 1,4-hexadiene; alkenyl groups appearing herein have the same definition as this one. Alkenyl groups may be monovalent, divalent, trivalent, or tetravalent.

[0270] "Alkynyl" refers to a substituted or unsubstituted linear or branched monovalent unsaturated hydrocarbon radical having at least one, typically one, two or three carbon-carbon triple bonds, including but not limited to 2 to 10 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms in the backbone chain. Examples of alkynyl radicals include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pent ... -methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, etc.; alkynyl can be monovalent, divalent, trivalent or tetravalent.

[0271] "Alkoxy" refers to a substituted or unsubstituted -O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyloxy, and cyclobutyloxy.

[0272] "Carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, which can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring, or a 10-15 membered tricyclic ring system, and the carbocyclyl can be attached to the aromatic or non-aromatic ring, which can be optionally a monocyclic ring, a bridged ring, or a spirocyclic ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, a benzene ring, a naphthalene ring, "Carbocyclyl" or "carbocycle" can be monovalent, divalent, trivalent, or tetravalent.

[0273] "Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, which can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring or a 10-15 membered tricyclic ring system, and contains one or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S. The N and S optionally substituted in the heterocyclyl ring can be oxidized to various oxidation states. The heterocyclic group can be connected to a heteroatom or a carbon atom, the heterocyclic group can be connected to an aromatic ring or a non-aromatic ring, and the heterocyclic group can be connected to a bridged ring or a spiro ring. Non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, py ... furanyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophenyl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptanyl, "Heterocyclyl" or "heterocycle" can be monovalent, divalent, trivalent or tetravalent.

[0274] "Spirocycle" or "spirocyclyl" refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called a spiro atom), and the number of ring atoms in the spirocycle system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and optionally may contain 0 to 5 atoms selected from N, O or S (=O) n Non-limiting examples include:

[0275] "Spirocycle" or "spirocyclyl" can be monovalent, divalent, trivalent or tetravalent.

[0276] "Parallel ring" or "parallel ring group" refers to a polycyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds and may be substituted or unsubstituted, and each ring in the parallel ring system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O) n or O, n is 0, 1 or 2). The number of ring atoms in the cyclic system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, and 5 to 10. Non-limiting examples include: "Bicyclic" or "bicyclic group" can be monovalent, divalent, trivalent or tetravalent.

[0277] "Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected, and may contain zero or more double bonds. Any ring in the bridged ring system may contain zero to five heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O) n or O, wherein n is 0, 1, 2). The number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include "Bridged ring" or "bridged ring group" may be monovalent, divalent, trivalent or tetravalent.

[0278] "Carbospirocycle," "spirocarbocyclyl," "spirocarbocyclyl," or "carbospirocyclyl" refers to a "spirocycle" wherein the ring system consists of only carbon atoms.

[0279] "Carbocyclyl," "carbocyclyl," "carbocyclyl," or "carbocyclyl" refers to a "carbocyclyl" ring system consisting of only carbon atoms.

[0280] "Carbobridged ring," "bridged carbocyclic group," "bridged carbocyclic group," or "carbon-bridged cyclic group" refers to a "bridged ring" in which the ring system consists of only carbon atoms.

[0281] "Heteromonocycle", "monocyclic heterocyclyl" or "heteromonocyclyl" refers to a "heterocyclyl" or "heterocycle" that is a monocyclic ring system.

[0282] "Heterocyclo", "heterocycloalkyl", "cycloheterocyclyl" or "heterocycloalkyl" refers to a cyclo ring containing a heteroatom.

[0283] "Heterospirocycle," "heterospirocyclyl," "spiroheterocyclyl," or "heterospirocyclyl" refers to a "spirocycle" containing a heteroatom.

[0284] "Heterobridged ring," "heterobridged cyclic group," "bridged heterocyclic group," or "heterobridged cyclic group" refers to a "bridged ring" containing a heteroatom.

[0285] "Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a single ring or a fused ring, wherein the number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring connected to the parent structure is the aryl ring, non-limiting examples of which include benzene ring, naphthalene ring, "Aryl" or "aromatic ring" can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the aryl ring.

[0286] "Heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, O or S(=O)n, n is 0, 1, 2), and the number of ring atoms in the heteroaromatic ring is but not limited to 5 to 15, 5 to 10 or 5 to 6. Non-limiting examples of heteroaryl include but are not limited to pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, etc. The heteroaryl ring can be fused to a saturated or unsaturated carbocyclic ring or heterocyclic ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include When heteroaryl appears in this document, its definition is consistent with this definition. Heteroaryl can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the attachment point is located on the heteroaryl ring.

[0287] "Substituted" or "substituted" refers to substitution by one or more (including but not limited to 2, 3, 4 or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, cycloalkyl, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH2), m -C(=O)-R a 、-O-(CH2) m -C(=O)-R a 、-(CH2) m -C(=O)-NR b R c 、-(CH2) m S(=O) n R a 、-(CH2) m -alkenyl-R a , OR d or -(CH2) m -alkynyl-R a (wherein m and n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR b R c etc., where R b With R c R is independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, b With R c Can form a five- or six-membered cycloalkyl or heterocyclic group, R a With R d Each is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring or paracyclic group.

[0288] “Containing 1 to 5 heteroatoms selected from O, S, and N” means containing 1, 2, 3, 4, or 5 heteroatoms selected from O, S, and N.

[0289] "Replaced by 0 to X substituents" means substituted by 0, 1, 2, 3, ..., X substituents, where X is selected from any integer between 1 and 10. For example, "replaced by 0 to 4 substituents" means substituted by 0, 1, 2, 3, or 4 substituents. For example, "replaced by 0 to 5 substituents" means substituted by 0, 1, 2, 3, 4, or 5 substituents. For example, "a heterobridged ring is optionally substituted by 0 to 4 substituents selected from H or F" means that the heterobridged ring is optionally substituted by 0, 1, 2, 3, or 4 substituents selected from H or F.

[0290] XY-membered rings (where X is selected from an integer less than Y and greater than or equal to 3, and Y is selected from any integer between 4 and 12) include rings with X+1, X+2, X+3, X+4, and so on. Rings include heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heteroparallel rings, heterospirocyclic rings, and heterobridged rings. For example, "4-7-membered heteromonocyclic ring" refers to a 4-, 5-, 6-, or 7-membered heteromonocyclic ring, and "5-10-membered heteroparallel ring" refers to a 5-, 6-, 7-, 8-, 9-, or 10-membered heteroparallel ring.

[0291] When a group has one or more bondable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are hydrogen atoms at the bondable sites, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of chemical bonds connected, and the group will become a group with the corresponding valence. For example Indicates that any linkable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Also included For example Indicates that the R group on the piperidinyl group can be located on C, can be located on N, and at least includes

[0292] When the listed linking groups do not specify their connection direction, their connection directions include connection from left to right and from right to left in the reading order, for example, when ALB, L is selected from -MW-, it includes AMWB and AWMB.

[0293] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not. For example, "alkyl optionally substituted with F" means that the alkyl group may but need not be substituted with F, and the description includes instances where the alkyl group is substituted with F and instances where the alkyl group is not substituted with F.

[0294] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, or the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0295] "Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, or stereoisomers, tautomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals thereof, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0296] "Carrier" refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

[0297] "Prescription strength" refers to the weight of the active ingredient per vial, tablet, or other unit of preparation. "Prodrug" refers to a compound of the present invention that can be metabolized in vivo to possess biological activity. Prodrugs of the present invention are prepared by modifying amino or carboxyl groups within a compound of the present invention. These modifications can be removed by conventional manipulation or in vivo to yield the parent compound. When the prodrug of the present invention is administered to a mammalian subject, it is cleaved to form free amino or carboxyl groups.

[0298] A "cocrystal" is a crystal formed by the active pharmaceutical ingredient (API) and cocrystal former (CCF) bound together by hydrogen bonds or other non-covalent bonds. Both the API and CCF are solid in their pure form at room temperature, and the components exist in a fixed stoichiometric ratio. A cocrystal is a multi-component crystal, encompassing both binary cocrystals formed between two neutral solids and multi-component cocrystals formed between a neutral solid and a salt or solvate.

[0299] "Animal" is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

[0300] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, optical isomers, enantiomers, and conformational isomers.

[0301] "Tautomers" refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions, such as keto-enol isomers and amide-imino alcohol isomers.

[0302] “IC 50 "It is the concentration of a drug or inhibitor required to inhibit a specified biological process (or a component of the process such as an enzyme, receptor, cell, etc.) by half. DETAILED DESCRIPTION

[0303] The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.

[0304] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0305] MS was determined using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0306] HPLC determination was performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM);

[0307] Thin layer chromatography silica gel plates used were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of the silica gel plates used for thin layer chromatography (TLC) were 0.15 mm to 0.20 mm, and the specifications used for thin layer chromatography separation and purification products were 0.4 mm to 0.5 mm.

[0308] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier;

[0309] In order to accomplish the purpose of the present invention, the compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources, including Shanghai Aladdin Biochemical Technology Co., Ltd., Shanghai McLean Biochemical Technology Co., Ltd., Sigma-Aldrich, Alfa Aesar (China) Chemical Co., Ltd., TCI (Shanghai) Chemical Industry Development Co., Ltd., Anage Chemical, Shanghai Titan Technology Co., Ltd., Kelon Chemical, Bailingwei Technology Co., Ltd., etc.

[0310] THF: tetrahydrofuran; DMF: N,N-dimethylformamide; DIPEA: N,N-diisopropylethylamine; HATU: CAS 148893-10-1; TCFH: CAS 94790-35-9

[0311] Example 1: Preparation of Compound 1

[0312] Step 1: Synthesis of 1j

[0313] 1i (2 g, 6.48 mmol) was added to 15 mL of methanol, followed by 15 mL of a 30% solution of sodium methoxide in methanol. The reaction was allowed to proceed at 80°C for 6 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was slurried with a mixture of ethyl acetate and petroleum ether and filtered to obtain the filter cake, yielding 1j (1.7 g, 86.29%).

[0314] LCMS m / z(ESI):305.0[M+H] +

[0315] Step 2: 1k synthesis

[0316] To a sealed tube, 1j (400 mg, 1.32 mmol), 1d (CAS: 2549188-28-3) (565 mg, 1.71 mmol), Pd(dtbpf)Cl2 (CAS: 95408-45-0) (85 mg, 0.13 mmol), potassium phosphate (560 mg, 2.64 mmol), 10 mL of dioxane, and 2 mL of water were added and reacted at 90°C for 3 h. The mixture was cooled to room temperature, diluted with water, and extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain 1k (290 mg, 57.76% yield).

[0317] LCMS m / z(ESI):381.2[M+H] +

[0318] Step 3: Synthesis of 1l

[0319] 1k (230 mg, 0.60 mmol) was dissolved in 6 mL of dichloromethane, and trifluoroacetic acid (0.14 mL, 1.80 mmol) was added. NIS (CAS: 516-12-1) (203 mg, 0.90 mmol) was then added at 0°C and allowed to react for 1 h. The reaction was quenched with sodium thiosulfate solution, diluted with water, and extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain 1l (240 mg, 78.95% yield).

[0320] LCMS m / z(ESI):507.1[M+H] +

[0321] Step 4: Synthesis of compound 1

[0322] To a sealed tube, 1k (230 mg, 0.45 mmol), 1f (157 mg, 0.54 mmol), Pd(dppf)Cl2·CH2Cl2 (CAS: 95464-05-4) (41 mg, 0.05 mmol), potassium phosphate (191 mg, 0.90 mmol), 6 mL of dioxane, and 1 mL of water were added and reacted at 90°C for 3 h. The mixture was cooled to room temperature, diluted with water, and extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain compound 1 (50 mg, 20.58% yield).

[0323] LCMS m / z(ESI):540.3[M+H] +

[0324] Example 2: Preparation of Compound 2

[0325] Step 1: Synthesis of 2a

[0326] 1i (330 mg, 1.07 mmol) was added to a sealed tube and suspended in 5 mL of acetonitrile. 11 mL of a 2 M solution of dimethylamine in tetrahydrofuran was added and the reaction was allowed to proceed at 90°C for 2 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was slurried with a mixture of ethyl acetate and petroleum ether and filtered to obtain the filter cake 2a (330 mg, 97.34% yield).

[0327] LCMS m / z(ESI):318.0[M+H] +

[0328] Step 2: Synthesis of 2b

[0329] 2a (330 mg, 1.04 mmol), 1d (447 mg, 1.35 mmol), Pd(dtbpf)Cl2 (82 mg, 0.1 mmol), potassium phosphate (441 mg, 2.08 mmol), 5 mL of dioxane, and 1 mL of water were added to a sealed tube and reacted at 90°C for 3 h. The mixture was cooled to room temperature, diluted with water, and extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain 2b (202 mg, 49.39% yield).

[0330] LCMS m / z(ESI):394.2[M+H] +

[0331] Step 3: Synthesis of 2c

[0332] 2b (188 mg, 0.48 mmol) was dissolved in 6 mL of dichloromethane, and trifluoroacetic acid (0.11 mL, 1.43 mmol) was added. NIS (162 mg, 0.72 mmol) was added at 0°C and allowed to react for 1 h. The reaction was quenched with sodium thiosulfate solution, diluted with water, and extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was isolated by silica gel column chromatography to afford 2c (173 mg, 69.48% yield).

[0333] LCMS m / z(ESI):520.1[M+H] +

[0334] Step 4: Synthesis of compound 2

[0335] To a sealed tube, 2c (170 mg, 0.33 mmol), 1f (113 mg, 0.39 mmol), Pd(dppf)Cl2·DCM (25 mg, 0.03 mmol), potassium phosphate (140 mg, 0.66 mmol), 5 mL of dioxane, and 1 mL of water were added and reacted at 90°C for 3 h. The mixture was cooled to room temperature, diluted with water, and extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain compound 2 (35 mg, 19.23% yield).

[0336] LCMS m / z(ESI):553.3[M+H] +

[0337] Example 3: Preparation of Compound 3

[0338] Step 1: Preparation of 3b

[0339] Under nitrogen, 3a (0.5 g, 6 mmol) was dissolved in 5 mL of DMF. Triethylamine (1.7 mL, 12 mmol) and triethylamine (2.07 mL, 9 mmol) were added. The mixture was allowed to react at room temperature for 3 h. The mixture was diluted with 50 mL of ethyl acetate and washed with water (20 mL x 3) and then saturated brine (20 mL). The organic phase was dried and concentrated, and the residue was purified by column chromatography to afford 3b (0.77 g, 71% yield).

[0340] LCMS m / z=184.1[M+H] +

[0341] Step 2: Preparation of 3c

[0342] 3b (0.4 g, 2.2 mmol) was dissolved in 10 mL of DMF. Under nitrogen, bromomethylcyclopropane (0.32 mL, 3.3 mmol), potassium carbonate (912 mg, 6.6 mmol), and potassium iodide (365 mg, 2.2 mmol) were added sequentially. The reaction was allowed to react at 80°C overnight. The mixture was diluted with 50 mL of ethyl acetate and washed with water (20 mL x 3) and then with 20 mL of saturated brine. The organic phase was dried and concentrated, and the residue was purified by column chromatography to afford 3c (0.21 g, 40% yield).

[0343] LCMS m / z=238.2[M+H] +

[0344] Step 3: 3D preparation

[0345] Under nitrogen, 3c (0.21 g, 0.88 mmol) was dissolved in 5 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The system was then reacted at room temperature for 1 h and concentrated under reduced pressure. The residue was directly purified by reverse phase purification to afford 3d (98 mg, yield: 80%).

[0346] LCMS m / z=138.1[M+H] +

[0347] Step 4: Preparation of 3f

[0348] Under nitrogen protection, intermediate 3e (0.7 g, 3.07 mmol) was dissolved in 8 mL of 1,4-dioxane, and 3e-1 (884 mg, 3.07 mmol) and DIPEA (1.1 mL, 6.14 mmol) were added. The reaction was carried out at 80°C for 1 h. 30 mL of ethyl acetate was added to the reaction mixture, and the mixture was washed three times with water (20 mL × 3) and once with 20 mL of a saturated NaCl aqueous solution. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain 3f (1.2 g, yield: 98%).

[0349] LCMS m / z=389.1[M+H] +

[0350] Step 5: Preparation of 3g

[0351] Under nitrogen, intermediate 3f (0.25 g, 0.64 mmol) was dissolved in 15 mL of 1,4-dioxane and 1.5 mL of water. 1d (254 mg, 0.77 mmol), Pd(dppf)Cl2 (47 mg, 0.064 mmol), and potassium carbonate (354 mg, 2.56 mmol) were added. The system was then heated to 100°C for 1 h. 20 mL of ethyl acetate was added to the reaction mixture, and the mixture was washed with water (20 mL × 3) and once with 20 mL of a saturated NaCl aqueous solution. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain 3g (198 mg, yield: 58%).

[0352] LCMS m / z=513.2[M+H] +

[0353] Step 6: Preparation of 3h

[0354] Under nitrogen atmosphere, 3g (198 mg, 0.386 mmol), 3d (64 mg, 0.46 mmol), Pd2(dba)3 (36 mg, 0.0386 mmol), S-phos (CAS: 657408-07-6) (32 mg, 0.077 mmol), and cesium carbonate (252 mg, 0.77 mmol) were dissolved in 1,4-dioxane (6 mL) and reacted at 120°C for 16 h. The reaction was cooled to room temperature, 20 mL of ethyl acetate was added, and the mixture was washed with water (20 mL × 3) and 20 mL of a saturated NaCl solution once. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel chromatography to obtain 3h (166 mg, yield: 60%).

[0355] LCMS m / z=614.2[M+H] +

[0356] Step 7: Preparation of 3i

[0357] Under nitrogen protection, 3h (0.19 g, 0.27 mmol) was dissolved in 5 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The reaction was allowed to react at room temperature for 1 h. The solvent was removed by concentration under reduced pressure, and the residue was directly purified by reverse phase purification to give 3i (50 mg, yield: 36%).

[0358] LCMS m / z=514.2[M+H] +

[0359] Step 8: Preparation of compound 3

[0360] Under nitrogen, 3i (50 mg, 0.097 mmol) was dissolved in 2 mL of DMF, and acrylic acid (7 mg, 0.097 mmol), N-methylimidazole (16 mg, 0.194 mmol) and TCFH (41 mg, 0.146 mmol) were added sequentially. The reaction was carried out at room temperature for 1 h. 20 mL of ethyl acetate was added to the reaction mixture, and the mixture was washed with water (20 mL × 3) and once with 20 mL of a saturated aqueous solution of NaCl. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to give compound 3 (2.5 mg, yield: 4.5%).

[0361] LCMS m / z=568.2[M+H] +

[0362] 1 H NMR(400MHz,CD3OD)δ8.41(d,1H),8.00(s,1H),7.82(s,1H),7.58(s,1H),7.32(t,1H),7.23(dd,1H),7.21-7.17(m,1H),7.12(d,1H),6.32-6.16 (m,2H)5.70(dd,1H),4.39(s,2H),4.14(s,2H),4.07(s,4H),3.97(d,2H ),2.46(s,3H),1.31-1.27(m,1H),0.66-0.58(m,2H),0.45-0.36(m,2H).

[0363] Example 4: Synthesis of Compound 4

[0364] Step 1: Synthesis of 4B

[0365] 4A (10 g, 44.84 mmol), 2-chloro-4-methylpyrimidine (6.92 g, 53.81 mmol), and potassium carbonate (12.37 g, 89.68 mmol) were dissolved in 120 mL of DMF and reacted at 80°C for 10 h. The mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The product was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to afford 4B (7.5 g, 53.26%).

[0366] LC-Ms m / z(ESI):315.2[M+H] +

[0367] Step 2: Synthesis of 4C

[0368] 4B (6.0 g, 19.04 mmol), pinacol diboronate (7.25 g, 28.56 mmol), Pd(dppf)Cl2 (1.38 g, 1.9 mmol), and potassium acetate (3.73 g, 38.08 mmol) were dissolved in 120 mL of 1,4-dioxane, replaced with nitrogen, and reacted at 100°C for 3 h. The mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The product was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 4C (6.0 g, 87.05%).

[0369] LC-Ms m / z(ESI):363.1[M+H] +

[0370] Step 3: 4D synthesis

[0371] Under a nitrogen atmosphere, 4C (2.0 g, 5.52 mmol), 4C-1 (1.51 g, 5.52 mmol), Pd(dppf)Cl2 (400 mg, 0.55 mmol), and cesium carbonate (3.60 g, 11.04 mmol) were dissolved in 20 mL of 1,4-dioxane and 4 mL of water and reacted at 100°C for 3 h. The mixture was diluted with water and extracted with ethyl acetate (20 mL x 3). The product was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 4D (0.8 g, 37.90%).

[0372] LC-Ms m / z(ESI):383.6[M+H] +

[0373] Step 4: Synthesis of 4E

[0374] Under a nitrogen atmosphere, 4D (800 mg, 2.09 mmol) was dissolved in 10 mL of dichloromethane. Trifluoroacetic acid (477 mg, 4.18 mmol) and NIS (940 mg, 4.18 mmol) were added at 0°C, and the mixture was stirred at room temperature for 2 h. The mixture was quenched with saturated sodium bicarbonate and extracted with ethyl acetate (10 mL × 3). The mixture was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography to obtain 4E (0.5 g, 47.09%).

[0375] LC-Ms m / z(ESI):509.2[M+H] +

[0376] Step 5: Synthesis of compound 4

[0377] 4E (120 mg, 0.236 mmol), 1f (68 mg, 0.236 mmol), Pd(dppf)Cl2 (17.4 mg, 0.024 mmol), and cesium carbonate (154 mg, 0.472 mmol) were dissolved in 20 mL of 1,4-dioxane and 4 mL of water. The atmosphere was replaced with nitrogen and the reaction was carried out at 100°C for 3 h. The mixture was diluted with water and extracted with ethyl acetate (10 mL x 3). The mixture was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 4 (15 mg, 11.73%).

[0378] LC-Ms m / z(ESI):542.2[M+H] +

[0379] 1 H NMR(400MHz,CD3OD)δ8.39(d,1H),8.21(s,1H),7.91-7.77(s,3H),7.66-7.58(m,3H),7.42-7.35(m,1 H),7.34-7.26(m,3H),7.11(d,1H),5.77(s,1H),5.50(s,1H),3.74(s,3H),2.46(s,3H),2.00(s,3H).

[0380] Example 5: Synthesis of Compound 5

[0381] 4E (120 mg, 0.236 mmol), 5A (65 mg, 0.236 mmol), Pd(dppf)Cl2 (17.4 mg, 0.024 mmol), and cesium carbonate (154 mg, 0.472 mmol) were dissolved in 20 mL of 1,4-dioxane and 4 mL of water, purged with nitrogen, and reacted at 100°C for 3 h. The mixture was diluted with water and extracted with ethyl acetate (20 mL × 3). The mixture was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (elution conditions: dichloromethane / methanol (98:2-90:10) gradient elution). After concentration of the eluate, the residue was dissolved in 1 mL of acetonitrile, diluted with 1 mL of water, and lyophilized to obtain compound 5 (15 mg, 11.73%).

[0382] LC-Ms m / z(ESI):528.2[M+H] +

[0383] 1H NMR(400MHz,DMSO-d6)δ10.21(s,1H),8.46(d,1H),8.22(s,1H),7.92(d,1H),7.86(s,1H),7.82(d,1H),7.70-7.60(m,3 H),7.38-7.27(m,4H),7.16(d,1H),6.47-6.35(m,1H),6.29-6.19(m,1H),6.13-5.60(m,3H),3.65(s,3H),2.41(s,3H).

[0384] Example 6: Synthesis of Compound 6

[0385] Step 1: Synthesis of 6A

[0386] 3b (250 mg, 1.36 mmol) was dissolved in DMF (6 mL), and 2-bromoethyl methyl ether (280 mg, 2.04 mmol), potassium iodide (230 mg, 1.36 mmol), and potassium carbonate (560 mg, 4.08 mmol) were added. The reaction was allowed to react at 70°C for 16 h. The reaction mixture was cooled to room temperature, and 200 mL of ethyl acetate was added to the reaction mixture. The mixture was washed with water (200 mL × 3) and once with 200 mL of a saturated aqueous solution of NaCl. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel chromatography to obtain 6A (169 mg, 51.50% yield).

[0387] LC-Ms m / z(ESI):242.2[M+H] +

[0388] Step 2: Synthesis of 6B

[0389] Dissolve 6A (165 mg, 0.68 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (2 mL), and stir at room temperature for 2 h. Concentrate under reduced pressure to obtain crude product 6B (93 mg, yield 96.88%).

[0390] LC-Ms m / z(ESI):142.2[M+H] +

[0391] Step 3: Synthesis of 6C

[0392] Under a nitrogen atmosphere, 3 g (180 mg, 0.35 mmol), 6B (59 mg, 0.42 mmol), Pd2(dba)3 (32 mg, 0.035 mmol), S-phos (29 mg, 0.07 mmol), and cesium carbonate (230 mg, 0.70 mmol) were dissolved in 1,4-dioxane (10 mL) and reacted at 120°C for 2 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate (50 mL × 3), washed once with 200 mL of saturated aqueous NaCl solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain 6A (97 mg, 44.87% yield).

[0393] LC-Ms m / z(ESI):618.2[M+H] +

[0394] Step 4: 6D synthesis

[0395] Compound 6C (88 mg, 0.14 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was reacted at room temperature for 2 h. The mixture was concentrated under reduced pressure to obtain the trifluoroacetic acid salt of 6D (62 mg, yield 85.57%).

[0396] LC-Ms m / z(ESI):518.2[M+H] +

[0397] Step 5: Synthesis of compound 6

[0398] The crude trifluoroacetate of 6D (38 mg, 0.073 mmol) was dissolved in DMF (3 mL), and acrylic acid (5.3 mg, 0.073 mmol), TCFH (31 mg, 0.11 mmol), and N-methylimidazole (12 mg, 0.15 mmol) were added. The mixture was reacted at room temperature for 1 h. The mixture was diluted with water and extracted with ethyl acetate (10 mL × 3). The mixture was washed twice with 100 mL of a saturated NaCl solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography to obtain compound 6 (3 mg, 7.19% yield).

[0399] LC-Ms m / z(ESI):572.6[M+H] +

[0400] Example 7: Preparation of Compound 7

[0401] Step 1: Preparation of 7B

[0402] 7A (1.00 g, 2.84 mmol), triethylamine (0.86 g, 8.52 mmol), cuprous iodide (2.16 g, 11.36 mmol), anhydrous lithium chloride (0.96 g, 22.72 mmol), tert-butyl 3-ethynyl-1-azetidinecarboxylate (0.56 g, 3.12 mmol), and Pd(PPh3)2Cl2 (0.40 g, 0.56 mmol) were dissolved in DMF (20 mL) and reacted at 60°C under a nitrogen atmosphere for 3 h. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined and washed sequentially with water (20 mL × 2) and saturated aqueous NaCl solution (20 mL × 1). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain 7B (0.56 g, 39.76% yield).

[0403] LCMS m / z=440.1[M-55] +

[0404] Step 2: Preparation of 7C

[0405] 7B (0.56 g, 1.12 mmol), 1-methyl-1H-pyrazol-4-amine (0.22 g, 2.24 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (BINAP) (0.07 g, 0.11 mmol), cesium carbonate (0.72 g, 2.24 mmol), and palladium acetate (0.05 g, 0.22 mmol) were dissolved in 1,4-dioxane (20 mL) and reacted at 100°C under a nitrogen atmosphere for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was then purified by silica gel column chromatography to afford 7C (0.24 g, 38.50% yield).

[0406] LCMS m / z=557.70[M+H] +

[0407] Step 3: Preparation of 7D

[0408] 7C (0.10 g, 0.18 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was reacted at room temperature for 2 h. The reaction solvent was removed by concentration under reduced pressure to obtain the crude trifluoroacetate salt of 7D (0.08 g).

[0409] LCMS m / z=457.1[M+H] +

[0410] Step 4: Preparation of compound 7

[0411] The trifluoroacetate salt of 7D (0.06 g, 0.13 mmol) was dissolved in dichloromethane (4 mL). Triethylamine (0.05 g, 0.52 mmol) was added at 0°C under a nitrogen atmosphere. A solution of acryloyl chloride (0.011 g, 0.13 mmol) in dichloromethane (1 mL) was slowly added dropwise. The reaction was allowed to react at room temperature for 2 h. The reaction solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography to afford compound 7 (0.014 g, 21.09% yield).

[0412] LCMS m / z=511.2[M+H] +

[0413] 1 H NMR (400MHz, CDCl3) δ8.48(s,1H),8.40(d,1H),7.86(s,1H),7.51(s,1H),7.44-7.28(m,3H),7.12-7.00(m,1H),6.96(d,1H ),6.37-6.24(m,1H),6.17-6.05(m,1H),5.72-5.62(m,1H),4.50-4.07(m,4H),3.92(s,3H),3.70-3.57(m,1H),2.53(s,3H).

[0414] Example 8: Preparation of Compound 8

[0415] The trifluoroacetate salt of 7D (0.1 g, 0.22 mmol) was dissolved in dichloromethane (4 mL). Triethylamine (0.09 g, 0.88 mmol) was added at 0°C under a nitrogen atmosphere. A solution of methacryloyl chloride (0.023 g, 0.22 mmol) in dichloromethane (1 mL) was slowly added dropwise. The reaction was allowed to react at room temperature for 2 h. The reaction solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography to afford compound 8 (0.014 g, 12.13% yield).

[0416] LCMS m / z=525.50[M+H] +

[0417] 1H NMR (400MHz, CDCl3) δ8.48(s,1H),8.39(d,1H),7.86(s,1H),7.50(s,1H),7.42(dd,1H),7.37-7.28(m,2H),7.02-6.85(m ,2H),5.40-5.35(m,1H),5.29-5.25(m,1H),4.48-4.03(m,4H),3.92(s,3H),3.68-3.54(m,1H),2.52(s,3H),1.90(s,3H).

[0418] Example 9: Preparation of Compound 9

[0419] Referring to the synthetic route and preparation method of compound 7, compound 9 (25 mg) was obtained.

[0420] LCMS m / z=525.2[M+H] +

[0421] 1 H NMR(400MHz, CDCl3)δ8.46(d,1H),8.37(t,1H),7.86(d,1H),7.51(d,1H),7.4 3-7.31(m,2H),7.30-7.27(m,1H),7.12-7.01(m,1H),6.95(d,1H),6.41-6.31 (m,2H),5.71-5.62(m,1H),3.92(s,3H),3.88-3.79(m,1H),3.76-3.50(m,3H) ,3.33-3.17(m,1H),2.56-2.49(m,3H),2.31-2.17(m,1H),2.15-1.95(m,1H).

[0422] Example 10: Preparation of Compound 10

[0423] Referring to the synthetic route and preparation method of compound 7, compound 10 (25 mg) was obtained.

[0424] LCMS m / z=539.50[M+H] +

[0425] 1H NMR(400MHz, CDCl3)δ8.46(s,1H),8.38(d,1H),7.86(s,1H),7.50(s,1H),7.43-7.27(m,3H ),7.01-6.85(m,2H),5.29-5.22(m,1H),5.15-5.08(m,1H),3.92(s,3H),3.88-3.44(m,4H), 3.28-3.12(m,1H),2.52(s,3H),2.32-2.12(m,1H),2.07-1.97(m,1H),1.93(s,3H).

[0426] Example 11: Preparation of Compound 11

[0427] 9D (0.045 g, 0.096 mmol) was dissolved in DMF (4 mL), and 2-fluoroacrylic acid (0.011 g, 0.11 mmol), TCFH (0.04 g, 0.14 mmol), and N-methylimidazole (0.015 g, 0.19 mmol) were added. The mixture was allowed to react at room temperature for 16 h. Ethyl acetate (20 mL) was added to the reaction mixture, and the organic phase was washed sequentially with water (20 mL × 2) and a saturated aqueous NaCl solution (20 mL × 1). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on a silica gel column (dichloromethane:methanol = 25:1-8:1) to afford compound 11 (20 mg, 38.40% yield).

[0428] LCMS m / z=543.20[M+H] +

[0429] 1 H NMR(400MHz, CDCl3)δ8.46(s,1H),8.40-8.34(m,1H),7.89-7.83(m,1H),7.51(s,1H),7.42-7.27(m,3H),7.11-7.01(m,1H),6.95(d,1H),5. 52(dd,1H),5.16-5.06(m,1H),3.99-3.81(m,4H),3.78-3.53(s,3H), 3.30-3.14(m,1H),2.52(s,3H),2.28-2.15(m,1H),2.12-1.94(m,1H).

[0430] Example 12: Preparation of Compound 12

[0431] Step 1: Preparation of 12B

[0432] Under nitrogen, 12A (2 g, 8.99 mmol), pinacol diborate (2 g, 8.99 mmol), potassium acetate (1.76 g, 17.89 mmol), and Pd(dppf)Cl2.DCM (0.73 g, 0.89 mmol) were suspended in a mixture of 1,4-dioxane (8 mL) and water (1.5 mL) and reacted at 100°C for 3 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography to afford 12B (2.3 g, 95.05% yield).

[0433] LCMS m / z=270.2[M+H] +

[0434] Step 2: Preparation of 12C

[0435] Under a nitrogen atmosphere, 12B (1 g, 3.72 mmol) was dissolved in dichloromethane (15 mL). Pyridine (0.59 g, 7.48 mmol) was slowly added, and a dichloromethane solution (2 mL) of methacryloyl chloride (0.58 g, 5.54 mmol) was slowly added dropwise at 0°C. The mixture was allowed to react at room temperature for 2 h. Water (10 mL) was added, and the mixture was separated. The organic phase was washed with a saturated aqueous solution of NaCl (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to afford 12C (0.9 g, 71.74% yield).

[0436] LCMS m / z=338.2[M+H] +

[0437] Step 3: Preparation of compound 12

[0438] Under nitrogen, 12D (0.06 g, 0.13 mmol), 12C (0.044 g, 0.13 mmol), potassium acetate (0.036 g, 0.26 mmol), and Pd(dppf)Cl2.DCM (0.011 g, 0.013 mmol) were dissolved in 1,4-dioxane (4 mL) and water (0.5 mL) and reacted at 100°C for 3 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography to afford compound 12 (21 mg, 28.87% yield).

[0439] LCMS m / z=560.1[M+H] +

[0440] 1H NMR(400MHz, CDCl3)δ8.40(s,1H),8.35-8.29(d,2H),7.83-7.66(m,4H),7.52(dd,1H),7.33(dd,1H),7.21-7.14(m, 1H),7.12-7.03(m,2H),6.91(d,1H),5.86(s,1H),5.52(s,1H),5.15(s,2H),3.76(s,3H),2.47(s,3H),2.11(s,3H).

[0441] Example 13: Preparation of Compound 13

[0442] Step 1: Preparation of 13A

[0443] Under a nitrogen atmosphere, 12A (1 g, 4.50 mmol) was dissolved in dichloromethane (10 mL). Triethylamine (0.59 g, 5.85 mmol) was slowly added, and a dichloromethane solution (2 mL) of acryloyl chloride (0.43 g, 4.70 mmol) was slowly added dropwise at 0°C. The reaction was continued for 2 h. The mixture was quenched with water and extracted three times with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to afford 13A (1.2 g, 96.57% yield).

[0444] LCMS m / z=276.0[M+H] +

[0445] Step 2: Preparation of 13B

[0446] 13A (200 mg, 0.72 mmol) was added to a sealed tube and dissolved in dioxane (10 mL). Then, pinacol diborate (370 mg, 1.44 mmol), potassium acetate (280 mg, 2.88 mmol), and Pd(dppf)Cl2.DCM (0.73 g, 0.89 mmol) were added. The reaction was incubated at 90°C under nitrogen for 16 h. The mixture was cooled to room temperature, diluted with water, and extracted three times with EA. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by column chromatography to obtain 13B (200 mg, 85.95% yield).

[0447] LCMS m / z=324.50[M+H] +

[0448] Step 3: Preparation of compound 13

[0449] 12D (70 mg, 0.15 mmol), 13B (68 mg, 0.21 mmol), potassium carbonate (41 mg, 0.30 mmol), and Pd(dppf)Cl2.DCM (12 mg, 0.015 mmol) were added to a sealed tube and dissolved in 1,4-dioxane (4 mL) and water (1 mL). The atmosphere was replaced with nitrogen. The reaction was incubated at 100°C for 5 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the crude product, which was then purified by reverse-phase column chromatography and lyophilized to afford compound 13 (36 mg, 43.99% yield).

[0450] LCMS m / z=546.1[M+H] +

[0451] 1 H NMR (400MHz, DMSO-d6) δ10.40(s,1H),8.44(d,1H),8.42(s,1H),8.23(s,1H),7.92-7.84(m,3H),7.68(dd,1H),7.43(dd,1H),7.30( t,1H),7.21(dd,1H),7.15(d,1H),7.13(d,1H),6.50(dd,1H),6.31(dd,1H),6.00(brs,2H),5.80(dd,1H),3.65(s,3H),2.38(s,3H).

[0452] Example 14: Preparation of Compound 14

[0453] Step 1: Preparation of 14A

[0454] Under a nitrogen atmosphere, 2-fluoroacrylic acid (430 mg, 4.78 mmol) was dissolved in dichloromethane (12 mL). TCFH (1.89 g, 6.75 mmol) and N-methylimidazole (0.74 g, 9.00 mmol) were added. After 30 minutes of nitrogen replacement, 12A (1 g, 4.50 mmol) was added and the reaction continued for 2 hours. The mixture was quenched with water and extracted three times with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was isolated by column chromatography to afford 14A (580 mg, 43.82% yield).

[0455] LCMS m / z=294.1[M+H] +

[0456] Step 2: Preparation of 14B

[0457] 14A (200 mg, 0.68 mmol) was added to a sealed tube and dissolved in dioxane (10 mL). Then, pinacol diborate (350 mg, 1.36 mmol), potassium acetate (270 mg, 2.72 mmol), and Pd(dppf)Cl2.DCM (0.56 g, 0.068 mmol) were added. The atmosphere was replaced with nitrogen for protection. The reaction was carried out at 90°C for 16 h. The mixture was cooled to room temperature, diluted with water, and extracted three times with EA. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by column chromatography to obtain 14B (195 mg, 84.05% yield).

[0458] LCMS m / z=342.40[M+H] +

[0459] Step 3: Preparation of compound 14

[0460] 12D (70 mg, 0.15 mmol), 14B (72 mg, 0.21 mmol), potassium carbonate (41 mg, 0.30 mmol), and Pd(dppf)Cl2.DCM (12 mg, 0.015 mmol) were added to a sealed tube and dissolved in 1,4-dioxane (4 mL) and water (1 mL). The atmosphere was replaced with nitrogen. The reaction was incubated at 100°C for 5 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the crude product, which was then purified by reverse-phase column chromatography and lyophilized to afford compound 14 (37 mg, 43.77% yield).

[0461] LCMS m / z=546.1[M+H] +

[0462] 1 H NMR (400MHz, DMSO-d6) δ10.53(s,1H),8.44(d,1H),8.40(s,1H),8.24(s,1H),7.94-7.86(m,3H),7.82(dd,1H),7.45(dd,1H),7. 30(t,1H),7.21(dd,1H),7.15(d,1H),7.14-7.10(m,1H),6.01(brs,2H),5.77(dd,1H),5.47(dd,1H),3.66(s,3H),2.38(s,3H).

[0463] Example 15: Synthesis of Compound 15

[0464] Step 1: Preparation of 15b

[0465] Under nitrogen, 15a (5.0 g, 21.12 mmol) was dissolved in 50 mL of dichloromethane at 0°C. Triethylamine (4.28 g, 42.27 mmol) was added, and acryloyl chloride (1.91 g, 21.12 mmol) was added dropwise. The reaction was allowed to react at room temperature for 1 h. The reaction was quenched by the addition of 50 mL of water, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to give 15b (3.0 g, yield: 48.80%).

[0466] LCMS m / z=292.1[M+H] +

[0467] Step 2: Preparation of 15c

[0468] 15b (1.0 g, 3.44 mmol), pinacol diboronate (1.75 g, 6.88 mmol), Pd(dppf)Cl2 (0.28 g, 0.34 mmol), and potassium acetate (1.01 g, 10.32 mmol) were dissolved in 20 mL of 1,4-dioxane, purged with nitrogen, and reacted at 100°C for 1 h. The mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The product was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to afford 15c (0.15 g, 19.98%).

[0469] LC-Ms m / z(ESI):292.1[M+H] +

[0470] Step 3: Preparation of compound 15

[0471] 4E (120 mg, 0.236 mmol), 15c (70 mg, 0.236 mmol), Pd(dppf)Cl2 (17.4 mg, 0.024 mmol), and cesium carbonate (154 mg, 0.472 mmol) were dissolved in 5 mL of 1,4-dioxane and 1 mL of water. The atmosphere was replaced with nitrogen and the reaction was carried out at 100°C for 3 h. The mixture was diluted with water and extracted with ethyl acetate (20 mL x 3). The product was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 15 (10 mg, 7.64%).

[0472] LC-Ms m / z(ESI):546.2[M+H] +

[0473] 1H NMR(400MHz, CDCl3)δ8.39(s,1H),8.35(d,1H),7.85-7.69(m,4H),7.64-7.59(m,1H),7.42(s,1H),7.38-7.30(m,2H) ,7.07-6.99(m,2H),6.92(d,1H),6.45(d,1H),6.22(dd,1H),5.81(d,1H),5.07(br.s,2H),3.70(s,3H),2.52(s,3H).

[0474] Example 16: Synthesis of Compound 16

[0475] Step 1: Synthesis of 16b

[0476] 16a (0.9 g, 3.72 mmol), 2-chloro-4-methylpyrimidine (0.96 g, 7.43 mmol), and potassium carbonate (1.54 g, 11.14 mmol) were dissolved in 20 mL of DMF and reacted at 80°C for 10 h. The mixture was diluted with water and extracted with ethyl acetate (20 mL × 3). The product was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 16b (0.6 g, 48.41%).

[0477] LC-Ms m / z(ESI):333.1[M+H] +

[0478] Step 2: Synthesis of 16c

[0479] 16b (0.6 g, 1.80 mmol), pinacol diboronate (0.91 g, 3.60 mmol), Pd(dppf)Cl2 (0.15 g, 0.18 mmol), and potassium acetate (0.53 g, 5.4 mmol) were dissolved in 20 mL of 1,4-dioxane, purged with nitrogen, and reacted at 100°C for 3 h. The mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The product was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to afford 16c (0.55 g, 80.36%).

[0480] LC-Ms m / z(ESI):381.2[M+H] +

[0481] Step 3: Synthesis of 16d

[0482] Under a nitrogen atmosphere, 16c (0.56 g, 1.47 mmol), 4C-1 (0.60 g, 2.21 mmol), Pd(dppf)Cl2 (0.12 g, 0.15 mmol), and cesium carbonate (0.61 g, 4.41 mmol) were dissolved in 20 mL of 1,4-dioxane and 4 mL of water and reacted at 100°C for 3 h. The mixture was diluted with water and extracted with ethyl acetate (20 mL × 3). The product was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to afford 16d (0.3 g, 50.97%).

[0483] LC-Ms m / z(ESI):401.2[M+H] +

[0484] Step 4: Synthesis of 16e

[0485] Under nitrogen atmosphere, 16d (0.3 g, 0.75 mmol) was dissolved in 10 mL of dichloromethane, and trifluoroacetic acid (0.17 mg, 1.50 mmol) and NIS (CAS 516-12-1) (0.34 g, 1.50 mmol) were added at 0°C. The mixture was stirred at room temperature for 2 h, quenched with saturated sodium bicarbonate, extracted with ethyl acetate (10 mL×3), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give 16e (0.24 g, 60.80%).

[0486] LC-Ms m / z(ESI):527.1[M+H] +

[0487] Step 5: Synthesis of compound 16

[0488] 16e (120 mg, 0.24 mmol), 5A (70 mg, 0.24 mmol), Pd(dppf)Cl2 (17.4 mg, 0.024 mmol), and cesium carbonate (154 mg, 0.472 mmol) were dissolved in 20 mL of 1,4-dioxane and 4 mL of water. The atmosphere was replaced with nitrogen and the reaction was carried out at 100°C for 3 h. The mixture was diluted with water and extracted with ethyl acetate (10 mL x 3). The mixture was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 16 (10 mg, 7.64%).

[0489] LC-Ms m / z(ESI):546.2[M+H] +

[0490] Example 17: Preparation of Compound 17:

[0491] Referring to the synthetic route and preparation method of compound 3, compound 17 (8 mg) was obtained.

[0492] LCMS m / z=582.3[M+H] +

[0493] 1 H NMR(400MHz,CD3OD)δ8.41(d,1H),8.00(s,1H),7.82(s,1H),7.59(s,1H),7 .32(t,1H),7.23(dd,1H),7.19(dd,1H),7.13(d,1H),5.43-5.39(m,1H),5.3 5-5.32(m,1H),4.39(s,2H),4.12(s,2H),4.06(s,4H),3.97(d,2H),2.46(s ,3H),1.86(s,3H),1.31-1.27(m,1H),0.66-0.59(m,2H),0.43-0.38(m,2H).

[0494] Example 18: Preparation of Compound 18:

[0495] Under nitrogen, 3i (120 mg, 0.23 mmol) was dissolved in 5 mL of DMF, and 2-fluoroacrylic acid (25 mg, 0.28 mmol), N-methylimidazole (38 mg, 0.46 mmol) and TCFH (97 mg, 0.35 mmol) were added sequentially. The reaction was carried out at room temperature for 1 h. 20 mL of ethyl acetate was added to the reaction mixture, and the mixture was washed with water (20 mL × 3) and once with 20 mL of a saturated NaCl aqueous solution. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to give compound 18 (31 mg, yield: 23.02%).

[0496] LCMS m / z=586.2[M+H] +

[0497] Example 19: Preparation of Compound 19:

[0498] Step 1: Preparation of 19B

[0499] 19A (1 g, 5.81 mmol) was dissolved in 10 mL of DMF, and triethylamine (0.97 mL, 6.97 mmol) was added. The atmosphere was replaced with nitrogen, and acryloyl chloride (0.53 mL, 6.39 mmol) was slowly added dropwise under ice-cooling. The reaction was allowed to proceed at room temperature for 1 h. The mixture was quenched with water and extracted three times with ethyl acetate. The organic phases were combined and washed twice with saturated brine. The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography to obtain the product 19B (1 g, yield: 76.06%).

[0500] LCMS m / z=171.2[M+H-56] +

[0501] Step 2: Preparation of 19C

[0502] 19B (600 mg, 2.65 mmol) was dissolved in 10 mL of DCM. 2 mL of trifluoroacetic acid was added dropwise under ice-cooling. The reaction was continued for 3 h. Saturated sodium bicarbonate solution was added to adjust the pH to 7. The product was extracted three times with a DCM / MeOH (10 / 1) mixture. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain product 19C (280 mg, yield: 83.70%).

[0503] LCMS m / z=127.1[M+H] +

[0504] Step 3: Preparation of 19E

[0505] In an autoclave, 19D (300 mg, 0.63 mmol) was dissolved in 6 mL of methanol. Triethylamine (0.19 mL, 1.39 mmol) and Pd(dppf)Cl2 (103 mg, 0.13 mmol) were added. The atmosphere was replaced with CO and the mixture was reacted at 60°C for 24 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography to afford product 19E (230 mg, yield: 89.49%).

[0506] LCMS m / z=409.40[M+H] +

[0507] Step 4: Preparation of 19F

[0508] 19E (230 mg, 0.56 mmol) was dissolved in 6 mL of ethanol and 2 mL of water, and lithium hydroxide monohydrate (24 mg, 5.63 mmol) was added. The reaction was stirred at room temperature for 3 h and concentrated under reduced pressure. The residue was separated and purified by reverse phase column chromatography and lyophilized to obtain 19F (100 mg, yield: 45.05%).

[0509] LCMS m / z=395.40[M+H]+

[0510] Step 5: Preparation of Compound 19

[0511] 19F (60 mg, 0.15 mmol) was dissolved in 3 mL of DMF, and TCFH (TCFH) (64 mg, 0.23 mmol) and N-methylimidazole (25 mg, 0.30 mmol) were added. The atmosphere was replaced with nitrogen for protection, and the reaction was carried out at room temperature for 30 minutes. 19C (29 mg, 0.23 mmol) was added, and the reaction was continued for 2 hours. The reaction was quenched with water and extracted three times with ethyl acetate. The organic phases were combined and washed twice with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by reverse phase column chromatography and lyophilized to obtain compound 19 (4 mg, yield: 5.23%).

[0512] LCMS m / z=503.70[M+H] +

[0513] 1 H NMR(400MHz,CD3OD)δ8.45(d,1H),8.38(s,1H),7.52(t,1H),7.45-7.34(m,2H),7.19(d,1H),6.25-6 .09(m,1H),5.73-5.64(m,1H),4.50-4.33(m,2H),4.05-3.83(m,5H),3.52-3.41(m,1H),2.52(s,3H).

[0514] Example 20: Preparation of Compound 20:

[0515] Referring to the synthetic route and preparation method of compound 19, compound 20 (3 mg) was obtained.

[0516] LCMS m / z=517.3[M+H] +

[0517] 1 H NMR(400MHz,CD3OD)δ8.45(d,1H),8.36(s,1H),7.52(t,1H),7.44-7.33(m,2H),7.19(d,1H),5.67(s,1H),5.41(s,1H ),4.48-4.30(m,2H),4.12-4.02(m,1H),3.93(s,3H),3.88-3.78(m,1H),3.57-3.45(m,1H),2.52(s,3H),1.89(s,3H).

[0518] Example 21: Synthesis of Compound 21

[0519] Step 1: Preparation of 21b

[0520] 3a (10 g, 120.29 mmol) was dissolved in 50 mL of DMF, and triethylamine (24.35 g, 240.58 mmol) and N-[2-(trimethylsilyl)ethoxycarbonyloxy]succinimide (40.55 g, 156.38 mmol) were added sequentially. The reaction mixture was allowed to react at room temperature for 16 h. 50 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 2). The ethyl acetate layers were combined and washed with water (80 mL x 2) and once with 100 mL of saturated aqueous NaCl. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on a silica gel column (dichloromethane:methanol = 50:1) to obtain 21b (19 g, yield: 69.48%).

[0521] LCMS m / z=228.1[M+H] +

[0522] Step 2: Preparation of 21d

[0523] 21b (5 g, 21.99 mmol) was dissolved in 20 mL of DMF, and intermediate 21c (6.53 g, 32.98 mmol) and potassium carbonate (6.08 g, 43.98 mmol) were added sequentially. The reaction was carried out at 80°C for 16 h. The mixture was cooled to room temperature, and 40 mL of water was added. The mixture was extracted with ethyl acetate (40 mL × 2). The ethyl acetate layers were combined and washed sequentially with water (50 mL × 2) and saturated aqueous NaCl solution (50 mL once). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on a silica gel column (dichloromethane:methanol = 50:1) to afford 21d (3.6 g, yield: 55.04%).

[0524] LCMS m / z=298.1[M+H] +

[0525] Step 3: Preparation of 21e

[0526] Dissolve 21d (3.6 g, 12.10 mmol) in 30 mL of tetrahydrofuran, add tetrabutylammonium fluoride (4.75 g, 18.17 mmol), and react at room temperature for 16 h. The reaction solvent was removed by concentration under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane:methanol = 50:1) to obtain 21e (1.4 g, yield: 75.53%).

[0527] LCMS m / z=154.1[M+H] +

[0528] Step 4: Preparation of 21f

[0529] 3g (0.18g, 0.35mmol) was dissolved in 6mL of ultra-dry 1,4-dioxane. 21e (0.08g, 0.52mmol), Pd2(dba)3 (0.032g, 0.035mmol), cesium carbonate (0.23g, 0.70mmol), and S-phos (0.029g, 0.07mmol) were added sequentially. The reaction was allowed to proceed at 100°C for 1h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to afford 21f (0.09g, yield: 40.84%).

[0530] LCMS m / z=630.3[M+H] +

[0531] Step 5: Preparation of 21g

[0532] Dissolve 21f (0.05 g, 0.079 mmol) in 5 mL of dichloromethane, add 1 mL of trifluoroacetic acid at room temperature, and react for 3 h. Concentrate under reduced pressure to remove the solvent, leaving a residue of 21 g, which is used directly in the next step.

[0533] LCMS m / z=530.4[M+H] +

[0534] Step 6: Preparation of Compound 21

[0535] Dissolve 21 g of the crude product in 5 mL of dichloromethane. Under a nitrogen atmosphere, slowly add triethylamine (0.15 g, 1.44 mmol) and 1 mL of a dichloromethane solution of acryloyl chloride (7.2 mg, 0.081 mmol) dropwise at 0°C. Allow to react at room temperature for 1 h. Add 10 mL of water to the reaction mixture, and extract twice with dichloromethane (10 mL x 2). Combine the dichloromethane layers, dry the dichloromethane over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is then chromatographed on a silica gel column (dichloromethane:methanol = 50:1) to obtain compound 21 (14 mg, two-step yield: 30.43%).

[0536] LCMS m / z=584.40[M+H] +

[0537] 1H NMR(400MHz,CD3OD)δ8.41(d,1H),8.13(s,1H),7.83(s,1H),7.61(s,1H),7.32(t,1H),7.2 6-7.18(m,2H),7.13(d,1H),6.32-6.24(m,1H),6.23-6.17(m,1H),5.70(dd,1H),5.16-5.09 (m,1H),4.66-4.58(m,1H),4.40-4.37(m,3H),4.34(dd,2H),4.14(s,2H),4.07(s,4H),2.76-2.66(m,1H),2.46(s,3H),2.44-2.39(m,1H).

[0538] Example 22: Synthesis of Compound 22

[0539] Step 1: Preparation of 21g

[0540] Dissolve 21f (0.05 g, 0.079 mmol) in 5 mL of dichloromethane, add 1 mL of trifluoroacetic acid, and react at room temperature for 3 h. Concentrate under reduced pressure to remove the solvent, leaving a residue of 21 g, which is used directly in the next reaction.

[0541] LCMS m / z=530.4[M+H] +

[0542] Step 2: Preparation of compound 22

[0543] Under nitrogen protection, 21 g of the crude product was dissolved in 5 mL of DMF, and 2-fluoroacrylic acid (10.72 mg, 0.12 mmol), N-methylimidazole (20 mg, 0.24 mmol) and TCFH (33 mg, 0.12 mmol) were added in sequence. The reaction was carried out at room temperature for 1 h. 20 mL of ethyl acetate was added to the reaction mixture, and the mixture was washed with water (20 mL × 3) and saturated NaCl aqueous solution (20 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain compound 22 (15 mg, two-step yield: 31.25%).

[0544] LCMS m / z=602.2[M+H] +

[0545] 1H NMR(400MHz,CD3OD)δ8.41(d,1H),8.13(s,1H),7.82(s,1H),7.61(s,1H),7.32(t,1H),7.26-7.17(m,2H),7.13(d,1H),5.49(dd,1H),5.20-5.11(m 2H),4.67-4.59(m,1H),4.53(d,2H),4.42-4.38(m,1H),4.37-4.29(m,2H),4 .17(s,2H),4.07(s,4H),2.77-2.66(m,1H),2.46(s,3H),2.45-2.37(m,1H).

[0546] Example 23: Synthesis of Compound 23

[0547] Step 1: Preparation of 23b

[0548] 23a (2 g, 7.29 mmol) was dissolved in 15 mL of 1,4-dioxane and 1 mL of water. 1d (3.13 g, 9.48 mmol), potassium carbonate (2.02 g, 14.58 mmol), and Pd(dppf)Cl2·DCM (0.6 g, 0.73 mmol) were added sequentially. The reaction was stirred at 100°C for 3 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to afford 23b (1.17 g, yield: 39.06%).

[0549] LCMS m / z=351.1[M+H] +

[0550] Step 2: Preparation of 23c

[0551] 23b (1.1 g, 3.13 mmol) was dissolved in 12 mL of 1,4-dioxane and 1 mL of water. 4-(BOC-amino)-2-fluorophenylboronic acid pinacol ester (1.06 g, 3.13 mmol), potassium carbonate (0.87 g, 6.29 mmol), and Pd(dppf)Cl2·DCM (0.51 g, 0.62 mmol) were added sequentially. The reaction was allowed to proceed at 100°C for 2 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate = 2:1) to afford 23c (0.7 g, yield: 42.52%).

[0552] LCMS m / z=526.1[M+H] +

[0553] Step 3: Preparation of 23d

[0554] 23c (0.46 g, 0.87 mmol) was dissolved in 10 mL of ultra-dry 1,4-dioxane, and 6B (0.18 g, 1.28 mmol), Pd2(dba)3 (0.08 g, 0.087 mmol), cesium carbonate (0.57 g, 1.75 mmol), and S-phos (0.036 g, 0.087 mmol) were added sequentially. The reaction was allowed to proceed at 100°C under a nitrogen atmosphere for 1 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to afford 23d (0.12 g, yield: 21.87%).

[0555] LCMS m / z=631.1[M+H] +

[0556] Step 4: Preparation of 23e

[0557] 23d (0.075 g, 0.12 mmol) was dissolved in 4 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 1 h, and the solvent was removed by concentration under reduced pressure. The residue was 23e (61 mg, yield: 95.82%).

[0558] LCMS m / z=531.3[M+H] +

[0559] Step 5: Preparation of compound 23

[0560] 23e (61 mg, 0.11 mmol) was dissolved in 4 mL of dichloromethane. Under a nitrogen atmosphere, triethylamine (44 mg, 0.44 mmol) was added. 0.5 mL of a dichloromethane solution of acryloyl chloride (10 mg, 0.14 mmol) was slowly added dropwise at 0°C. The reaction was allowed to react at room temperature for 1 h. 10 mL of water was added to the reaction, and the mixture was extracted with dichloromethane (10 mL × 2). The organic phases were combined and washed once with 10 mL of a saturated aqueous solution of NaCl. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography on a silica gel column (dichloromethane: methanol = 15:1) to give compound 23 (6 mg, yield: 9.33%).

[0561] LCMS m / z=585.2[M+H] +

[0562] 1H NMR(400MHz,CD3OD)δ8.49(s,1H),8.38(d,1H),8.05(s,1H),7.64(s,1H),7.60-7.49(m,2H),7.44(dd,1H),7.17(t,1H) ,7.09(d,1H),7.06-6.97(m,2H),6.42-6.37(m,2H),5.79(dd,1H),4.25(t,2H),3.72(t,2H),3.31(s,3H),2.44(s,3H).

[0563] Example 24: Synthesis of Compound 24

[0564] Step 1: Preparation of 24b

[0565] 24a (1.5 g, 8.94 mmol) was dissolved in 10 mL of dichloromethane and 4 mL of acetonitrile, and NIS (3.02 g, 13.42 mmol) was added. The reaction mixture was incubated at 50°C for 3 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to afford 24b (1.43 g, yield: 54.37%).

[0566] LCMS m / z=295.0[M+H] +

[0567] Step 2: Preparation of 24c

[0568] 24b (0.5 g, 1.70 mmol) was dissolved in 8 mL of acetonitrile, and DIPEA (0.66 g, 5.10 mmol) and phosphorus oxychloride (1.31 g, 8.55 mmol) were added sequentially. The reaction was incubated at 85°C for 2 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to afford 24c (0.4 g, yield: 75.18%).

[0569] LCMS m / z=313.1[M+H] +

[0570] Step 3: Preparation of 24d

[0571] 24c (0.4 g, 1.28 mmol) was dissolved in 8 mL of 1,4-dioxane and 1 mL of water. Intermediate 1d (0.42 g, 1.28 mmol), cesium carbonate (0.83 g, 2.55 mmol), and PdCl2(dppf) in DCM (CAS: 95464-05-4) (0.10 g, 0.12 mmol) were added sequentially. The mixture was reacted at 100°C under a nitrogen atmosphere for 3 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate = 1:1) to obtain the target compound 24d (0.3 g, yield: 62.70%).

[0572] LCMS m / z=389.1[M+H] +

[0573] Step 4: Preparation of 24e

[0574] 24d (0.053 g, 0.14 mmol) was dissolved in 2 mL of 1,4-dioxane, and 1f (0.048 g, 0.17 mmol), potassium carbonate (0.039 g, 0.28 mmol), and PdCl2(dppf) in DCM (0.011 g, 0.013 mmol) were added sequentially. The reaction was stirred at 100°C under a nitrogen atmosphere for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to afford 24e (0.048 g, yield: 66.77%).

[0575] LCMS m / z=514.2[M+H] +

[0576] Step 5: Preparation of 24f

[0577] 24e (0.048 g, 0.093 mmol) was dissolved in a mixture of 2 mL of ethanol and 0.2 mL of water. Lithium hydroxide (0.039 g, 0.93 mmol) was added and allowed to react at room temperature for 2 h. The reaction solvent was removed by concentration under reduced pressure, and the pH was adjusted to 4 with 1N HCl. The mixture was extracted twice with dichloromethane (5 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford 24f (0.014 g, yield: 33.33%).

[0578] LCMS m / z=486.1[M+H] +

[0579] Step 6: Preparation of Compound 24

[0580] 24f (0.014 g, 0.029 mmol) was dissolved in 1.5 mL of DMF, and DIPEA (0.011 g, 0.085 mmol), HATU (0.022 g, 0.058 mmol), and ammonium chloride (0.015 g, 0.28 mmol) were added sequentially. The mixture was allowed to react at room temperature for 16 h. 10 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 2). The organic phase was washed twice with water (10 mL × 2) and once with 10 mL of saturated aqueous NaCl solution. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on a silica gel column (dichloromethane:methanol = 30:1-10:1) to obtain compound 24 (7 mg, yield: 49.82%).

[0581] LCMS m / z=485.0[M+H] +

[0582] 1 H NMR(400MHz, CDCl3)δ9.26(s,1H),8.40(d,1H),7.52(d,2H),7.36(d,2H),7.22(t,1H) ,7.03-6.94(m,2H),6.92(d,1H),5.78(s,1H),5.48(d,1H),2.49(s,3H),2.05(s,3H).

[0583] Example 25: Synthesis of Compound 25

[0584] Step 1: Synthesis of 25A

[0585] 3f (670 mg, 1.72 mmol) dissolved in dioxane (10 mL) and water (2 mL) was added to a sealed tube. 4C (720 mg, 1.89 mmol), Pd(dppf)Cl2.DCM (140 mg, 0.17 mmol), and potassium carbonate (480 mg, 3.47 mmol) were added, and the atmosphere was replaced with nitrogen. The reaction was carried out at 100°C for 5 h. The reaction mixture was cooled to room temperature, diluted with 100 mL of water, and extracted with ethyl acetate (100 mL x 3). The organic phases were combined and washed once with 200 mL of saturated NaCl aqueous solution. The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain 25A (603 mg, 62.27% yield).

[0586] LC-Ms m / z(ESI):545.60[M+H] +

[0587] Step 2: Synthesis of 25B

[0588] 25A (600 mg, 1.10 mmol), 6B (230 mg, 1.65 mmol), Pd2(dba)3 (100 mg, 0.11 mmol), S-phos (90 mg, 0.22 mmol), and cesium carbonate (720 mg, 2.2 mmol) were added to a sealed tube and dissolved in 1,4-dioxane (12 mL). The atmosphere was replaced with nitrogen and the reaction was carried out at 110°C for 2 h. The reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate (50 mL × 3), and washed once with 200 mL of saturated NaCl aqueous solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain 25B (210 mg, 29.38% yield).

[0589] LC-Ms m / z(ESI):650.70[M+H] +

[0590] Step 3: Synthesis of 25C

[0591] 6C (117 mg, 0.18 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and the mixture was allowed to react at room temperature for 2 h. The mixture was concentrated under reduced pressure, and the residue was purified by reverse phase column chromatography and lyophilized to obtain 25C (62 mg, 62.67% yield).

[0592] LC-Ms m / z(ESI):550.3[M+H] +

[0593] Step 4: Synthesis of compound 25

[0594] 25C (16 mg, 0.029 mmol) was dissolved in DCM (3 mL), and triethylamine (5.9 mg, 0.058 mmol) was added. Acryloyl chloride (2.6 mg, 0.029 mmol) in 1 mL of dichloromethane was slowly added under ice-cooling and allowed to react for 1 h. The mixture was diluted with water and extracted with ethyl acetate (10 mL × 3). The mixture was washed twice with 100 mL of saturated NaCl aqueous solution. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain compound 25 (5 mg, yield: 28.56%).

[0595] LC-Ms m / z(ESI):604.2[M+H] +

[0596] 1H NMR(400MHz,CD3OD)δ8.41(d,1H),8.02(s,1H),7.97(d,1H),7.90(d,1H),7.88(s,1H), 7.85(s,1H),7.66(d,1H),7.61(s,1H),7.51(dd,1H),7.35(dd,1H),7.12(d,1H),6.28-6.12(m,2H),5. 67(dd,1H),4.54(s,2H),4.28(t,2H),4.08(s,2H),4.01(s,4H),3.75(t,2H),3.34(s,3H),2.47(s,3H).

[0597] Example 26: Synthesis of Compound 26

[0598] Referring to the synthetic route and preparation method of compound 6, compound 26 (3 mg) was obtained.

[0599] LC-Ms m / z(ESI):586.3[M+H] +

[0600] 1 H NMR(400MHz,CD3OD)δ8.41(d,1H),7.99(s,1H),7.82(s,1H),7.59(s,1H),7.32(t,1H),7.27-7.17(m,2H),7.13(d,1H), 5.49(dd,1H),5.16(dd,1H),4.54(d,2H),4.27(t,2H),4.18(s,2H),4.07(s,4H),3.74(t,2H),3.33(s,3H),2.46(s,3H).

[0601] Example 27: Synthesis of Compound 27

[0602] Referring to the synthetic route and preparation method of compound 6, compound 27 (4 mg) was obtained.

[0603] LC-Ms m / z(ESI):590.2[M+H] +

[0604] 1H NMR(400MHz,DMSO-d6)δ9.16(s,1H),8.49(d,1H),7.89(s,2H),7.52(s,1H),7.38(t,1H),7.31(dd,1H),7.20(d,1H),7.17(dd,1H),5. 39-5.35(m,1H),5.30-5.26(m,1H),4.33(s,2H),4.21(t,2H),4.09-3.88(m,6H),3.66(t,2H),3.24(s,3H),2.43(s,3H),1.77(s,3H).

[0605] Example 28: Synthesis of Compound 28

[0606] Step 1: Synthesis of 28B:

[0607] Under nitrogen, 28A (1.0 g, 5.74 mmol), intermediate 28 (2.0 g, 6.31 mmol), PdCl(dppf) (CAS: 72287-26-4) (420.0 mg, 0.57 mmol), and potassium carbonate (2.4 g, 17.22 mmol) were dissolved in 1,4-dioxane (10 mL) and water (2 mL) in that order and reacted at 80°C overnight. After cooling to room temperature, the solvent was removed under reduced pressure, 80 mL of water was added, and the mixture was extracted with ethyl acetate (80 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 5:1) to obtain 28B (1.20 g, 63.20% yield).

[0608] Ms m / z(ESI):331.1[M+H] +

[0609] Step 2: Synthesis of 28C

[0610] 28B (500.0 mg, 1.51 mmol) was dissolved in 1,4-dioxane (5 mL), and 1-methyl-1H-pyrazol-4-amine (175.98 mg, 1.81 mmol), Pd(dba) (138.27 mg, 0.15 mmol), Sphos (123.98 mg, 0.30 mmol), and cesium carbonate (983.98 g, 3.02 mmol) were added sequentially. The reaction was continued at 100°C overnight. After cooling to room temperature, the solvent was removed under reduced pressure, 30 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was then purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain 28C (400.0 mg, yield: 67.68%).

[0611] Ms m / z(ESI):390.3[MH] +

[0612] Step 3: Synthesis of 28D

[0613] 28C (200.0 mg, 0.51 mmol) was dissolved in dichloromethane (5 mL), and NIS (229.48 mg, 1.02 mmol) and trifluoroacetic acid (116.30 mg, 1.02 mmol) were added sequentially. The mixture was reacted at room temperature for 30 min, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH=20:1) to obtain 28D (200.0 mg, yield: 75.81%).

[0614] Ms m / z(ESI):518.5[M+H] +

[0615] Step 4: Synthesis of 28E

[0616] 28D (400.0 mg, 0.88 mmol) was dissolved in DMF (10 mL), followed by the addition of 1d (319.59 mg, 0.97 mmol), RuPhos Pd G3 (CAS: 1445085-77-7) (74.0 mg, 0.088 mmol), and potassium phosphate (560.0 mg, 2.64 mmol). The mixture was reacted at 80°C overnight under a nitrogen atmosphere. After cooling to room temperature, the solvent was removed under reduced pressure, 30 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (DCM:MeOH = 20:1) to afford 28E (200.0 mg, 42.64% yield).

[0617] Ms m / z(ESI):594.3[M+H] +

[0618] Step 5: Synthesis of 28F

[0619] 28E (200.0 mg, 0.38 mmol) was dissolved in DCM (3 mL), and a hydrochloric acid-1,4-dioxane solution (2 mL) was added. The mixture was reacted at room temperature for 1 h, and triethylamine was added to adjust the pH to about 7-8. The solvent was removed to obtain a crude solid product of 28F (0.1 g).

[0620] Ms m / z(ESI):494.6[M+H] +

[0621] Step 6: Synthesis of compound 28

[0622] Under nitrogen protection, the crude product of 28F (100.0 mg, 0.201 mmol) was dissolved in DCM (4 mL), and triethylamine (30.36 mg, 0.30 mmol) was added. A 1 mL solution of acryloyl chloride (20.0 mg, 0.22 mmol) in dichloromethane was slowly added dropwise. The mixture was reacted at room temperature for 30 min. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (DCM:MeOH=20:1) to obtain compound 28 (15.0 mg, yield: 11.34%).

[0623] Ms m / z(ESI):548.3[M+H] +

[0624] 1 H NMR(400MHz, CDCl3)δ8.41(d,1H),8.25(s,1H),8.06(d,2H),7.76(d,2H),7.46(t,1H),7.38(s,2 H),7.00(d,1H),6.88(s,1H),6.50(d,1H),6.28(dd,1H),5.86(d,1H),3.90(s,3H),2.55(s,3H).

[0625] Example 29: Synthesis of Compound 29

[0626] Compound 29 (40 mg) was obtained by the synthesis of reference compound 4

[0627] LC-Ms m / z(ESI):564.6[M+H] +

[0628] 1 H NMR(400MHz, CDCl3)δ8.38(s,1H),8.36(d,1H),7.95(d,1H),7.86-7.70(m,4H),7.62(d,1H),7.3 5(dd,1H),7.10-7.04(m,2H),6.93(d,1H),5.85(dd,1H),5.29(dd,1H),3.72(s,3H),2.53(s,3H).

[0629] Example 30: Synthesis of Compound 30

[0630] Compound 30 (50 mg) was obtained by the synthesis of reference compound 16

[0631] LC-Ms m / z(ESI):582.6[M+H] +

[0632] 1 H NMR(400MHz, CDCl3)δ8.36(s,1H),8.35(d,1H),8.03(d,1H),7.97(d,1H),7.82-7.74(m,2H),7.61(d,1H),7.44-7 .36(m,2H),7.13-7.05(m,2H),6.94(d,1H),5.85(dd,1H),5.51(brs,2H),5.29(dd,1H),3.72(s,3H),2.52(s,3H).

[0633] Example 31: Synthesis of Compound 31

[0634] Step 1: Synthesis of 31B:

[0635] To a sealed tube, 23b (967 mg, 2.75 mmol), 31A (synthesis reference WO2022206939) (570 mg, 2.61 mmol), and DIPEA (710 mg, 5.5 mmol) were dissolved in ethanol (12 mL) and replaced with nitrogen. The reaction was allowed to proceed overnight at 80°C. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 31B (780 mg, 53.41% yield).

[0636] Ms m / z(ESI):531.50[M+H] +

[0637] Step 2: Synthesis of 31C:

[0638] 31B (470 mg, 0.89 mmol), 6B (160 mg, 1.16 mmol), Pd2(dba)3 (81 mg, 0.089 mmol), S-phos (73 mg, 0.18 mmol), and cesium carbonate (580 mg, 1.78 mmol) were added to a sealed tube and dissolved in 1,4-dioxane (10 mL). The atmosphere was replaced with nitrogen and the reaction was carried out at 110°C for 2 h. The mixture was cooled to room temperature, diluted with water, and extracted three times with EA. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 31C (211 mg, 37.39% yield).

[0639] Ms m / z(ESI):636.80[M+H] +

[0640] Step 3: Synthesis of 31D

[0641] 31C (200 mg, 0.31 mmol) was dissolved in tetrahydrofuran (4 mL), trifluoroacetic acid (1.5 mL) was added, and the mixture was stirred at 70°C for 6 h. The mixture was concentrated under reduced pressure to obtain 31D (170 mg, crude product).

[0642] LC-Ms m / z(ESI):532.9[M+H] +

[0643] Step 4: Synthesis of compound 31

[0644] The crude product 31D (170 mg, crude) was dissolved in DCM (3 mL), and triethylamine (65 mg, 0.64 mmol) was added. A 1 mL solution of acryloyl chloride (26 mg, 0.29 mmol) in dichloromethane was slowly added under ice-cooling and allowed to react for 1 h. The mixture was diluted with water and extracted three times with ethyl acetate (10 mL × 3). The mixture was washed twice with 100 mL of saturated NaCl solution. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 31 (27 mg, two-step yield: 14.87%).

[0645] LC-Ms m / z(ESI):586.50[M+H] +

[0646] 1 H NMR(400MHz,CD3OD)δ8.41(d,1H),7.99(s,1H),7.83(s,1H),7.60(s,1H),7.33( t,1H),7.27-7.18(m,2H),7.12(d,1H),6.39-6.16(m,2H),5.78-5.64(m,1H),4.6 4-4.39(m,1H),4.38-4.30(m,1H),4.30-4.23(m,2H),4.17-3.97(m,4H),3.91-3. 82(m,1H),3.77-3.71(m,2H),3.36-3.32(m,3H),2.46(s,3H),1.50-1.41(m,3H).

[0647] Example 32: Synthesis of Compound 32

[0648] The synthesis of compound 32A refers to the synthesis of intermediate 3 in Example 28 in patent WO2020 / 231990

[0649] Step 1: Synthesis of 32B:

[0650] To a sealed tube, 4E (720 mg, 1.42 mmol), 32A (510 mg, 1.85 mmol), Pd(dppf)Cl2.DCM (120 mg, 0.14 mmol), and sodium carbonate (300 mg, 2.84 mmol) were added and dissolved in ethylene glycol dimethyl ether (8 mL) and water (1 mL). The atmosphere was replaced with nitrogen and the reaction was carried out at 90°C for 1.5 h. The mixture was cooled to room temperature, diluted with water, and extracted three times with EA. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 32B (200 mg, 22.98% yield).

[0651] Ms m / z(ESI):613.2[M+H] +

[0652] Step 2: Synthesis of compound 32:

[0653] 32B (108 mg, 0.18 mmol) was added to a single-necked flask and dissolved in 12 mL of tetrahydrofuran. Tetrabutylammonium fluoride trihydrate (110 mg, 0.36 mmol) was added, and the atmosphere was replaced with nitrogen. The reaction was allowed to react at room temperature for 1 h. The mixture was diluted with water and extracted three times with EA. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 32 (50 mg, 55.72% yield).

[0654] Ms m / z(ESI):499.1[M+H] +

[0655] 1 H NMR(400MHz,CD3OD)δ8.73(s,1H),8.43(s,1H),8.39(d,1H),7.91(d,2H),7.86(s,1H),7.67 (d,1H),7.40-7.33(m,2H),7.11(d,1H),3.87(s,1H),3.74(s,3H),2.45(s,3H),2.22(s,3H).

[0656] Example 33: Synthesis of Compound 33

[0657] Compound 33 (50 mg) was obtained by the synthesis of reference compound 16

[0658] LC-Ms m / z(ESI):564.1[M+H] +

[0659] 1H NMR(400MHz, CDCl3)δ8.40(s,1H),8.34(d,1H),8.01(d,1H),7.82-7.75(m,2H),7.60(d,1H),7.50(s,1H),7.45-7.35(m ,2H),7.10-7.00(m,2H),6.94(d,1H),6.45(dd,1H),6.23(dd,1H),5.81(dd,1H),5.02(s,2H),3.71(s,3H),2.52(s,3H).

[0660] Example 34: Synthesis of Compound 34

[0661] Step 1: Synthesis of 34B

[0662] 34A (3.6 g, 16.91 mmol), cyclopropylboronic acid (2.91 g, 33.82 mmol), 2,2'-bipyridine (2.64 g, 16.91 mmol), copper acetate (3.07 g, 16.91 mmol), and sodium carbonate (3.58 g, 33.82 mmol) were dissolved in 35 mL of 1,2-dichloroethane and reacted at 70°C for 16 h. The mixture was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate. The filtrate was diluted with water and extracted with ethyl acetate (40 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 34B (560 mg, 13.08%).

[0663] LC-Ms m / z(ESI):253.1[M+H] +

[0664] Step 2: Synthesis of 34C

[0665] 34B (560 mg, 2.21 mmol), 4C (1.44 g, 3.98 mmol), Pd(dppf)Cl2 (140 mg, 0.22 mmol), and potassium carbonate (610 mg, 4.42 mmol) were dissolved in 10 mL of 1,4-dioxane and 3 mL of water. The atmosphere was replaced with nitrogen and the reaction was carried out at 100°C for 2 h. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate (20 mL x 3). The product was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 34C (0.9 g, 99.70%).

[0666] LC-Ms m / z(ESI):409.2[M+H] +

[0667] Step 3: 34D synthesis

[0668] Under a nitrogen atmosphere, 34C (1.04 g, 2.55 mmol) was dissolved in 40 mL of dichloromethane. Trifluoroacetic acid (0.38 mL, 5.1 mmol) and NIS (1.15 g, 5.1 mmol) were added at 0°C, and the mixture was stirred at room temperature for 2 h. The mixture was diluted with water and quenched with saturated sodium bicarbonate. The mixture was extracted with dichloromethane (20 mL × 3), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give 34D (0.67 g, 49.17%).

[0669] LC-Ms m / z(ESI):535.0[M+H] +

[0670] Step 4: Synthesis of compound 34

[0671] 34D (135 mg, 0.25 mmol), intermediate 5A (100 mg, 0.38 mmol), Pd(dppf)Cl2 (20 mg, 0.025 mmol), and potassium carbonate (69 mg, 0.5 mmol) were dissolved in 4 mL of 1,4-dioxane and 1 mL of water. The atmosphere was purged with nitrogen and the reaction was carried out at 100°C for 3 h. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate (10 mL x 3). The mixture was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography and then by reverse-phase column chromatography and lyophilized to obtain compound 34 (45 mg, 32.51%).

[0672] LC-Ms m / z(ESI):554.3[M+H] +

[0673] 1 H NMR (400MHz, CD3OD) δ8.39(d,1H),8.22(s,1H),7.90-7.80(m,3H),7.64(d,1H),7.60(d,2H),7.40-7.30(m,4H),7. 11(d,1H),6.45-6.29(m,2H),5.75(dd,1H),3.49-3.41(m,1H),2.46(s,3H),1.04-0.92(m,2H),0.78-0.65(m,2H).

[0674] Example 35: Synthesis of Compound 35

[0675] Step 1: Synthesis of 35B

[0676] 35A (1.2 g, 5.45 mmol) was dissolved in 25 mL of dichloromethane. Triethylamine (1.13 mL, 8.15 mmol) was added at 0°C, and the atmosphere was replaced with nitrogen. Acryloyl chloride (0.54 g, 6.0 mmol) was slowly added dropwise. The reaction was continued in an ice bath for 1 h. The mixture was diluted with water and extracted with dichloromethane (40 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 35B (1 g, 95.58%).

[0677] LC-Ms m / z(ESI):193.2[M+H] +

[0678] Step 2: Synthesis of compound 35

[0679] 34D (120 mg, 0.22 mmol), 35B (76 mg, 0.4 mmol), Pd(dppf)Cl2 (18 mg, 0.022 mmol), and potassium carbonate (61 mg, 0.44 mmol) were dissolved in 4 mL of 1,4-dioxane and 1 mL of water, purged with nitrogen, and reacted at 100°C for 3 h. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate (10 mL × 3). The mixture was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography and then by reverse-phase column chromatography, and lyophilized to obtain 35 (38 mg, 31.14%).

[0680] LC-Ms m / z(ESI):555.3[M+H] +

[0681] 1 H NMR(400MHz,CD3OD)δ8.42(d,1H),8.26(s,1H),8.25-8.18(m,2H),7.94-7.86(m,4H),7.68(d,1H),7.44-7.33(m,2H) ,7.13(d,1H),6.55-6.36(m,2H),5.81(dd,1H),3.55-3.46(m,1H),2.48(s,3H),1.10-1.01(m,2H),0.82-0.73(m,2H).

[0682] Example 36: Synthesis of Compound 36

[0683] Step 1: Synthesis of 36A

[0684] 35A (1.3 g, 5.89 mmol) and 2-fluoroacrylic acid (0.8 g, 8.88 mmol) were dissolved in 25 mL of dichloromethane, followed by the addition of HATU (3.36 g, 8.83 mmol) and DIPEA (1.52 g, 11.78 mmol). The atmosphere was replaced with nitrogen and allowed to react at room temperature for 16 h. The mixture was diluted with water and extracted with dichloromethane (40 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to yield 36A (0.8 g, 64.69%).

[0685] LC-Ms m / z(ESI):211.1[M+H] +

[0686] Step 2: Synthesis of compound 36

[0687] Compound 36 (50 mg) was obtained by the synthesis of reference compound 35

[0688] LC-Ms m / z(ESI):573.3[M+H] +

[0689] 1 H NMR (400MHz, CD3OD) δ8.42(d,1H),8.29(d,1H),8.26(s,1H),8.17(d,1H),7.98-7.87(m,4H),7.68(d,1H),7.45-7.32( m,2H),7.13(d,1H),5.78(dd,1H),5.35(dd,1H),3.54-3.46(m,1H),2.48(s,3H),1.10-1.01(m,2H),0.82-0.73(m,2H).

[0690] Example 37: Synthesis of Compound 37

[0691] Compound 37 (50 mg) was obtained by the synthesis of reference compound 35

[0692] LC-Ms m / z(ESI):529.2[M+H] +

[0693] 1H NMR(400MHz,CD3OD)δ8.41(s,1H),8.40(d,1H),8.31-8.20(m,2H),7.94-7.84(m,4H),7.68(d,1 H),7.42-7.35(m,2H),7.12(d,1H),6.54-6.37(m,2H),5.81(dd,1H),3.87(s,3H),2.46(s,3H).

[0694] Example 38: Synthesis of Compound 38

[0695] Compound 38 (30 mg) was obtained by the synthesis of reference compound 36

[0696] LC-Ms m / z(ESI):547.2[M+H] +

[0697] 1 H NMR (400MHz, CD3OD) δ8.42(s,1H),8.40(d,1H),8.27(d,1H),8.22(d,1H),7.95-7.86(m,4H),7.67(s, 1H),7.40(dd,1H),7.36(dd,1H),7.12(d,1H),5.76(dd,1H),5.35(dd,1H),3.87(s,3H),2.46(s,3H).

[0698] Example 39: Synthesis of Compound 39

[0699] Step 1: Synthesis of 39A

[0700] 35A (1 g, 4.56 mmol) was dissolved in 25 mL of dichloromethane. Triethylamine (1.14 mL, 8.21 mmol) was added at 0°C, and the atmosphere was replaced with nitrogen. Methacryloyl chloride (0.51 g, 4.83 mmol) was slowly added dropwise. The reaction was continued in an ice bath for 1 h. The mixture was diluted with water and extracted with dichloromethane (40 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to yield 39A (0.45 g, 47.90%).

[0701] LC-Ms m / z(ESI):193.2[M+H] +

[0702] Step 2: Synthesis of compound 39

[0703] Compound 39 (30 mg) was obtained by the synthesis of reference compound 35

[0704] LC-Ms m / z(ESI):543.3[M+H] +

[0705] 1 H NMR(400MHz,CD3OD)δ8.42(d,1H),8.25(s,1H),8.24-8.16(m,2H),7.94-7.83(m,4H),7.67(d,1H),7.4 2(dd,1H),7.35(dd,1H),7.13(d,1H),5.87(s,1H),5.58(d,1H),3.79(s,3H),2.48(s,3H),2.03(s,3H).

[0706] With reference to the synthetic method of the above examples, the following compounds were prepared:

[0707] Biological test cases

[0708] FGFR1 kinase inhibitory activity assay

[0709] Test compounds were diluted in DMSO to 2.5x the assay concentration. 4 μL of compound was transferred to a 384-well plate (784075, Greiner) using an electronic pipette. FGFR1 kinase solution (working concentration: 0.3 nM) was prepared in kinase reaction buffer (5× buffer, 5 mM MgCl2, 1 mM DTT, 1% Tween 20). 2 μL of the kinase solution was transferred to the 384-well plate. The reaction was centrifuged at 1000 rpm for 1 minute and incubated at 25°C for 10 minutes. A mixture of substrate (TK-sub working concentration: 1 μM) and ATP (working concentration: 50 μM) was prepared in kinase reaction buffer. 4 μL of the substrate and ATP mixture was added to the plate to initiate the reaction. The reaction was centrifuged at 1000 rpm for 1 minute. The plate was sealed with a film sealer and incubated at 25°C for 60 minutes. XL665 and antibody detection reagents were prepared in assay buffer. Add 5 μL of kinase detection reagent to each well of the 384 reaction plate, centrifuge at 1000 rpm for 60 seconds, and incubate at 25°C for 60 minutes. Read the fluorescence signal at 620 nm (Cryptate) and 665 nm (XL665) using a microplate reader.

[0710] FGFR2 kinase inhibitory activity assay

[0711] Compounds were diluted in DMSO to 200× the assay concentration. Using an Echo 665, 25 nL of compound was transferred to a 384-well plate (784075, Greiner). Kinase solution (working concentration: 0.3 nM) was prepared in kinase reaction buffer (5X Buffer, 5 mM MgCl2, 1 mM DTT). 2.5 μL of the kinase solution was transferred to the 384-well plate. The reaction was centrifuged at 1000 rpm for 1 minute and incubated at 25°C for 10 minutes. A mixture of substrate (TK-sub working concentration: 1 μM) and ATP (working concentration: 50 μM) was prepared in kinase reaction buffer. 2.5 μL of the substrate and ATP mixture was added to the plate to initiate the reaction. The reaction was centrifuged at 1000 rpm for 1 minute. The plate was sealed with a film sealer and incubated at 25°C for 50 minutes. The XL665 and antibody detection reagents were prepared in assay buffer. Add 5 μL of kinase detection reagent to each well of the 384-well reaction plate, centrifuge at 1000 rpm for 60 seconds, and incubate at 25°C for 1 hour. Read the fluorescence signal at 620 nm (Cryptate) and 665 nm (XL665) using a microplate reader.

[0712] Table 1 Inhibitory activity of compounds against FGFR1 and FGFR2 kinases

[0713] FGFR3 kinase inhibitory activity assay

[0714] Compounds were diluted in DMSO to 200× the assay concentration. Using an Echo 665, 25 nL of compound was transferred to a 384-well plate (784075, Greiner). Kinase solution (working concentration: 0.6 nM) was prepared in kinase reaction buffer (5X Buffer, 5 mM MgCl2, 1 mM DTT). 2.5 μL of the kinase solution was transferred to the 384-well plate. The reaction was centrifuged at 1000 rpm for 1 minute and incubated at 25°C for 10 minutes. A mixture of substrate (TK-sub working concentration: 1 μM) and ATP (working concentration: 50 μM) was prepared in kinase reaction buffer. 2.5 μL of the substrate and ATP mixture was added to the plate to initiate the reaction. The reaction was centrifuged at 1000 rpm for 1 minute. The plate was sealed with a film sealer and incubated at 25°C for 50 minutes. The XL665 and antibody detection reagents were prepared in assay buffer. Add 5 μL of kinase detection reagent to each well of the 384-well reaction plate, centrifuge at 1000 rpm for 60 seconds, and incubate at 25°C for 1 hour. Read the fluorescence signal at 620 nm (Cryptate) and 665 nm (XL665) using a microplate reader.

[0715] FGFR2 N549H kinase inhibitory activity assay

[0716] Compounds were diluted in DMSO to 200× the assay concentration. Using an Echo 665, 25 nL of compound was transferred to a 384-well plate (784075, Greiner). Kinase solution (working concentration: 0.3 nM) was prepared in kinase reaction buffer (5X Buffer, 5 mM MgCl2, 1 mM DTT). 2.5 μL of the kinase solution was transferred to the 384-well plate. The reaction was centrifuged at 1000 rpm for 1 minute and incubated at 25°C for 10 minutes. A mixture of substrate (TK-sub working concentration: 1 μM) and ATP (working concentration: 5 μM) was prepared in kinase reaction buffer. 2.5 μL of the substrate and ATP mixture was added to the plate to initiate the reaction. The reaction was centrifuged at 1000 rpm for 1 minute. The plate was sealed with a film sealer and incubated at 25°C for 50 minutes. The XL665 and antibody detection reagents were prepared in assay buffer. Add 5 μL of kinase detection reagent to each well of the 384-well reaction plate, centrifuge at 1000 rpm for 60 seconds, and incubate at 25°C for 1 hour. Read the fluorescence signal at 620 nm (Cryptate) and 665 nm (XL665) using a microplate reader.

[0717] FGFR2 V564F kinase inhibitory activity assay

[0718] Compounds were diluted in DMSO to 200× the assay concentration. Using an Echo 665, 25 nL of compound was transferred to a 384-well plate (784075, Greiner). Kinase solution (working concentration: 0.3 nM) was prepared in kinase reaction buffer (5X buffer, 5 mM MgCl2, 1 mM DTT). 2.5 μL of the kinase solution was transferred to the 384-well plate. The reaction was centrifuged at 1000 rpm for 1 minute and incubated at 25°C for 10 minutes. A mixture of substrate (TK-sub working concentration: 1 μM) and ATP (working concentration: 10 μM) was prepared in kinase reaction buffer. 2.5 μL of the substrate and ATP mixture was added to the plate to initiate the reaction. The reaction was centrifuged at 1000 rpm for 1 minute. The plate was sealed with a film sealer and incubated at 25°C for 50 minutes. The XL665 and antibody detection reagents were prepared in assay buffer. Add 5 μL of kinase detection reagent to each well of the 384-well reaction plate, centrifuge at 1000 rpm for 60 seconds, and incubate at 25°C for 1 hour. Read the fluorescence signal at 620 nm (Cryptate) and 665 nm (XL665) using a microplate reader.

[0719] Conclusion: The compounds of the present invention, such as the example compounds, specifically compounds 1 to 46, have good FGFR2 kinase inhibitory activity and have good selectivity for FGFR2 kinase compared to FGFR1.

[0720] SNU16 cell proliferation inhibition

[0721] SNU16 cells (ATCC, CRL-5974) were cultured in DMEM complete medium (+10% FBS) in a CO2 incubator at 37°C for 48 h. The cells were trypsinized and counted, and then the density was adjusted to 4.44 × 10 4 Cells / mL. 90 μL (4000 cells) of cells were inoculated into each well of a 96-well plate with a transparent bottom, and transferred to a CO2 incubator and cultured overnight at 37°C. After the cells were incubated overnight, 10 μL of the diluted compound (final concentration 1 μM, 3-fold dilution, 11 concentrations) was added to each well using a spray gun. The positive control was a serum-free medium containing DMSO. After mixing well, the plate was placed in a CO2 incubator at 37°C for 5 days. After the incubation, the cells were removed. The kit detection solution (Vazyme, DD1101-03) was returned to room temperature, 100 μL of CellCounting-Lite2.0 detection solution was added to each well, the plate was sealed with a film, and the plate was placed on an oscillator for 15 minutes (the whole process should be kept away from light). The fluorescence signal value LUM of each well was detected using the Luminescence module of the microplate reader (BMG LRBTECH). Calculate the inhibition rate of the compound. Use Graphpad software to fit the log (inhibitor) vs. response--Variable slope (four parameters) equation to calculate the IC of the sample. 50 The vertical axis is the percentage of inhibition rate, and the horizontal axis is the logarithm of the sample concentration (Log 10 ).

[0722] Table 2 Inhibitory activity of compounds on SNU16 cell proliferation

[0723] Conclusion: The compounds of the present invention, especially the compounds of the examples, specifically compounds 1 to 46, have good inhibitory activity against the proliferation of SNU16 cells.

[0724] KATO III cell proliferation inhibition

[0725] KATO III cells (ATCC, HTB-103) were cultured in IMDM complete medium (+10% FBS) in a CO2 incubator at 37°C for 48 h. The cells were trypsinized and counted, and then the density was adjusted to 1.67 × 10 4Cells / mL. 90 μL (1500 cells) of cells were inoculated into each well of a 96-well plate with a transparent bottom, and transferred to a CO2 incubator and cultured overnight at 37°C. After the cells were incubated overnight, 10 μL of the diluted compound (final concentration 1 μM, 3-fold dilution, 10 concentrations) was added to each well using a spray gun. The positive control was a serum-free medium containing DMSO. After mixing well, the plate was placed in a CO2 incubator at 37°C for 96 hours. After the incubation, the cells were removed. The kit detection solution (Vazyme, DD1101-03) was returned to room temperature, 100 μL of CellCounting-Lite2.0 detection solution was added to each well, the plate was sealed with a film, and the plate was placed on an oscillator for 15 minutes (the whole process should be kept away from light). The fluorescence signal value LUM of each well was detected using the Luminescence module of the microplate reader (BMG LRBTECH). Calculate the inhibition rate of the compound. Use Graphpad software to fit the log (inhibitor) vs. response--Variable slope (four parameters) equation to calculate the IC of the sample. 50 The vertical axis is the percentage of inhibition rate, and the horizontal axis is the logarithm of the sample concentration (Log 10 ).

[0726] Table 3 Inhibitory activity of compounds on KATO III cell proliferation

[0727] Conclusion: The compounds of the present invention, such as Example Compounds 1 to 46, have good inhibitory activity against KATO III cell proliferation, as shown in Table 3.

[0728] Li7 cell proliferation inhibition

[0729] Li7 cells (Mingzhou Bio, MZ-0519) were cultured in RPMI-1640 complete medium (+10% FBS) in a CO2 incubator at 37°C for 48 h. Cells were trypsinized and counted, and then the density was adjusted to 1.67 × 10 4 Cells / mL. 90 μL (3000 cells) of cells were seeded into each well of a 96-well plate with a transparent bottom, and transferred to a CO2 incubator and cultured overnight at 37°C. After the cells were incubated overnight, 10 μL of the diluted compound (starting at a final concentration of 10 μM, 3-fold dilution, 10 concentrations) was added to each well using a spray gun. The test compound was a serum-free medium containing DMSO. After mixing well, the plate was placed in a CO2 incubator at 37°C for 96 hours. After the incubation, the cells were removed. The kit detection solution (Vazyme, DD1101-03) was returned to room temperature, 100 μL of CellCounting-Lite2.0 detection solution was added to each well, the plate was sealed with a film, and the plate was placed on an oscillator for 15 minutes (the whole process should be kept away from light). The fluorescence signal value LUM of each well was detected using the Luminescence module of the microplate reader (BMG LRBTECH). Calculate the inhibition rate of the compound. Use Graphpad software to fit the log (inhibitor) vs. response--Variable slope (four parameters) equation to calculate the IC of the sample. 50 The vertical axis is the percentage of inhibition rate, and the horizontal axis is the logarithm of the sample concentration (Log 10 ).

[0730] Conclusion: Compared with Li-7 cells, the compounds of the present invention, such as Example Compounds 1 to 46, have selective inhibitory effects on SUN-16 cells and KATO III cells.

[0731] 4.CYP450 enzyme inhibition test

[0732] The purpose of this study was to evaluate the effects of test substances on the activities of five cytochrome P450 (CYP) isoforms (CYP1A2, CYP2C9, CYP2D6, and CYP3A4) in human liver microsomes using an in vitro assay system. Specific probe substrates for each CYP450 isoform were incubated with human liver microsomes and varying concentrations of the test substances. The reactions were initiated by the addition of reduced nicotinamide adenine dinucleotide phosphate (NADPH). Following the reaction, samples were processed and metabolites generated from the specific substrates were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS). Changes in CYP enzyme activity were measured, and IC50 values ​​were calculated to evaluate the inhibitory potential of the test substances against each CYP isoform, CYP1A2, CYP2C9, CYP2D6, and CYP3A4-M (using midazolam as a substrate).

[0733] Conclusion: The compounds of the present invention, such as Example Compounds 1 to 46, have no significant inhibitory effect on any subtype of CYP enzymes.

[0734] 5. Pharmacokinetic Testing in Mice

[0735] Experimental animals: Male BALB / c mice, 20-25 g, 6 mice per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0736] Experimental Design: On the day of the experiment, six BALB / c mice were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0737] Table 4. Dosing Information

[0738] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.5% MC

[0739] DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; 0.5% MC: 0.5% methylcellulose aqueous solution

[0740] Before and after drug administration, 0.06 mL of blood was collected via the orbital cavity under isoflurane anesthesia. The blood was placed in an EDTAK2 centrifuge tube and centrifuged at 5000 rpm at 4°C for 10 minutes to collect plasma. Blood was collected from both the intravenous and oral gavage groups at 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0741] Table 5: Pharmacokinetic results of test compounds in mice

[0742] Conclusion: The compounds of the present invention, such as Example Compounds 1 to 46, have good pharmacokinetic properties. Specifically, Compound 15 has good oral absorption and lower clearance in mice.

[0743] The control compound 1 is

[0744] 6. Pharmacokinetic Test in Rat

[0745] Experimental animals: Male SD rats, about 220 g, 6 to 8 weeks old, 6 rats per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0746] Experimental Design: On the day of the experiment, 6 SD rats / compound were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0747] Table 6. Dosing Information

[0748] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.5% MC

[0749] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline; 0.5% MC: 0.5% aqueous solution of methylcellulose. MC:

[0750] Before and after drug administration, 0.10 mL of blood was collected via the orbital cavity under isoflurane anesthesia. The blood was placed in an EDTAK2 centrifuge tube and centrifuged at 5000 rpm at 4°C for 10 minutes to collect plasma. Blood was collected from both the intravenous and oral gavage groups at 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0751] Table 7: Pharmacokinetic results of test compounds in rats

[0752] Conclusion: The compounds of the present invention, such as Example Compounds 1 to 46, have good pharmacokinetic properties. Specifically, Compound 5 has better oral absorption and / or lower clearance in rats.

[0753] 7. Beagle Dog Pharmacokinetic Test

[0754] Experimental animals: Male beagle dogs, weighing about 8-11 kg, 5-6 per compound, purchased from Beijing Masi Biotechnology Co., Ltd.

[0755] Test method: On the test day, 5-6 beagle dogs were randomly divided into groups according to body weight. The dogs were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0756] Table 8: Dosing Information

[0757] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.5% MC: (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; 0.5% MC: 0.5% methylcellulose aqueous solution.

[0758] Before and after administration, 1 ml of blood was collected from the jugular vein or limb vein and placed in an EDTAK2 centrifuge tube. The blood was centrifuged at 5000 rpm at 4°C for 10 min, and plasma was collected. For both the intravenous and oral gavage groups in groups G1 and G2, blood was collected at the following time points: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, 48, and 72 h. For both the intravenous and oral gavage groups in groups G3 and G4, blood was collected at the following time points: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, and 24 h. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0759] Conclusion: The compounds of the present invention, such as Example Compounds 1 to 46, have good oral absorption properties in beagle dogs.

[0760] 8. Monkey Pharmacokinetic Test

[0761] Experimental animals: Male cynomolgus monkeys, 3-5 kg, 3-6 years old, 4-6 per compound, purchased from Suzhou Xishan Biotechnology Co., Ltd.

[0762] Test method: On the day of the test, 4-6 monkeys / compound were randomly divided into groups according to body weight. The monkeys were fasted but not watered for 14-18 hours before administration and fed 4 hours after administration.

[0763] Table 9: Dosing Information

[0764] Note: Intravenous administration vehicle: 5% DMA + 5% Solutol + 90% Saline; Oral administration vehicle: 0.5% MC (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; 0.5% MC: 0.5% methylcellulose aqueous solution).

[0765] *Dosage is based on the free base.

[0766] Before and after dosing, 1.0 mL of blood was collected from a limb vein and placed in an EDTAK2 centrifuge tube. The samples were centrifuged at 5000 rpm at 4°C for 10 minutes, and plasma was collected. Blood was collected from both the intravenous and oral administration groups at the following time points: 0, 5 minutes, 15 minutes, 30 minutes, and 1, 2, 4, 6, 8, 10, 12, and 24 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0767] Conclusion: The compounds of the present invention, such as Example Compounds 1 to 46, have good oral absorption properties in monkeys.

[0768] 9. hERG potassium channel effect test

[0769] Experimental platform: electrophysiology manual patch clamp system

[0770] Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channel

[0771] Experimental Methods: hERG potassium channel currents were recorded using the whole-cell patch-clamp technique at room temperature in CHO (Chinese Hamster Ovary) cells stably expressing the hERG potassium channel. Glass microelectrodes were pulled from glass electrode blanks (BF150-86-10, Sutter) using a puller. After perfusion with electrode solution, the tip resistance was approximately 2-5 MΩ. The microelectrodes were connected to the patch-clamp amplifier by inserting them into the amplifier headstage. Clamping voltage and data recording were controlled and recorded by a computer using pClamp 10 software with a sampling frequency of 10 kHz and a filter frequency of 2 kHz. After whole-cell recordings were obtained, cells were clamped at -80 mV. To elicit hERG potassium currents (I hERG ), a 2-second depolarization step from -80 mV to +20 mV was applied, followed by repolarization to -50 mV, which was maintained for 1 second before returning to -80 mV. This voltage stimulus was applied every 10 seconds, and drug administration was initiated after confirming the stability of the hERG potassium current (at least 1 minute). Compounds were administered for at least 1 minute at each tested concentration, and at least two cells were tested at each concentration (n≥2).

[0772] Data processing: Data analysis was performed using pClamp 10, GraphPad Prism 5, and Excel. The degree of inhibition of hERG potassium current (peak hERG tail current induced at -50 mV) by different compound concentrations was calculated using the following formula: Inhibition% = [1-(I / Io)] × 100%

[0773] Wherein, Inhibition% represents the inhibition percentage of the compound on hERG potassium current, and I and Io represent the amplitude of hERG potassium current before and after drug addition, respectively.

[0774] The IC50 of the compound was calculated using GraphPad Prism 5 software by fitting the following equation: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X)×HillSlope))

[0775] Where X is the Log value of the test sample concentration, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0776] Conclusion: The compounds of the present invention, such as Example Compounds 1 to 46, have no significant hERG inhibitory activity.

[0777] 10. Steady-state blood phosphorus detection in mice given oral administration of compounds

[0778] On D0, the animals were weighed before grouping. About 250 μL of whole blood was collected from each animal. After centrifugation, at least 60 μL of serum was extracted. The basal blood phosphorus value was determined using an automatic biochemical analyzer (Cobas; Cat: C311). Grouping was performed based on the measured value. No medication was administered on the day of grouping.

[0779] The first day after grouping was recorded as D1. The compound was initially administered twice a day. Concomitant PK was measured 0.5, 1, 4, 7, and 24 h after administration on D1, and the second administration was performed 6 h after the first administration. The animal body weight was recorded and the administration record was filled in on Days 1, 2, 3, 4, and 5. On D5, blood phosphorus was measured 4 h after the first administration of the day, and concomitant PK was measured 0.5, 1, 4, 7, and 24 h after administration.

[0780] Conclusion: The compounds of the present invention, such as compound 1 to compound 46, do not significantly cause an increase in blood phosphorus in mice.

Claims

1. A compound or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, the compound being selected from the compounds represented by general formula (I), wherein Ring A, Ring B, and Ring C are each independently selected from phenyl, benzo 4-6 carbocyclic, 5- to 6-membered heteroaryl or 8- to 10-membered heteroaryl, wherein the ring A is optionally substituted by 1 to 4 R a substituted, said ring B is optionally substituted with 1 to 4 R b Substituted, the ring C is optionally substituted with 1 to 4 R c replace; Q is selected from the group consisting of a key, -O-、-N(R q3 )-、-C(=O)N(R q3 )-、-N(R q3 )C(=O)、-C(=O)-、C 4-10 Carbocyclic ring, 4 to 10 membered heterocyclic ring, said carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace; m is selected from 0 or 1; R q1 、R q2 、R q3 Each independently selected from H, C 1-6 Alkyl, said alkyl being optionally substituted by 1 to 4 R k replace; D is selected from a bond, -NR n1 -、 The D is optionally replaced by 1 to 6 R d Substitution, the right side of D1 or D2 is directly connected to R1; Q and D cannot be bonds at the same time; The bond between Q and D cannot form NN or NO; D1 is selected from 4 to 14-membered nitrogen-containing heterocyclic groups; D2 is selected from C 3-14 Carbocyclyl, 4- to 14-membered heterocyclyl; D3 is selected from C 7-14 Carbocyclic group; R n1 Selected from H, C 1-4 alkyl; R a 、R b 、R c 、R d Each independently selected from H, deuterium, halogen, CN, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, -NH-5 to 6 membered heteroaryl-C 1-4 Alkyl, -NH-3 to 7 membered heterocyclic-C 3-6 Carbocycle, -NH-3 to 7-membered heterocycle, -4 to 6-membered heterocycle, -C 1-4 Alkylene-C 3-6 Carbocyclic ring, -C 1-4 Alkylene-3 to 7 membered heterocycle, -C(=O)NH2, -C(=O)NH-C 1-6 Alkyl, -C(=O)NH-C 3-6 Carbocycle, -NHC(=O)-C 1-6 Alkyl, -NHC(=O)-C 3-6 Carbon ring, C 3-6 Carbocyclic ring, 3 to 7 membered heterocyclic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, heteroaryl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace; R 1 Selected from halogen, CN, R 1a 、R 1b 、R 1c 、R 1d Each independently selected from H, deuterium, halogen, CN, -C(=O)R, -C(=O)OR, -C(=O)N(R)2, C(=O)N(R)OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Carbocyclic ring, 3 to 7 membered heterocyclic ring, said alkyl, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace; R 1e is selected from halogen or -OS(=O)2R; R is selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Carbocyclic ring, 3 to 7 membered heterocyclic ring, said alkyl, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace; Alternatively, R 1b With R 1c 、R 1a With R 1b Direct connection to form C 3-6 Carbocyclic or 3- to 7-membered heterocyclic ring, the carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 R k replace; Alternatively, R n1 With R d Direct connection to form C 3-6 Carbocyclic or 3- to 7-membered heterocyclic ring, the carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 R k replace; R k Selected from deuterium, halogen, CN, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 Carbocycle, -NH-3 to 7-membered heterocycle, -C(=O)-C 3-6 Carbocycle, -C(=O)-3 to 7 membered heterocycle, -C 1-4 Alkylene-C 3-6 Carbocyclic ring, -C 1-4 Alkylene-3 to 7 membered heterocyclic ring, C 3-6 Carbocyclic ring, 3 to 7 membered heterocyclic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 groups selected from deuterium, halogen, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent.

2. The compound according to claim 1 or its stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound represented by general formula (I) is selected from the group consisting of compounds represented by general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI), general formula (VII) and general formula (VIII), Ring B is selected from phenyl, naphthalene, benzo 4-6 Carbocyclic ring, benzo 4 to 6 membered heterocyclic ring, 5 to 6 membered heteroaryl, 8 to 10 membered heteroaryl ring, wherein the ring B is optionally substituted by 1 to 4 R b replace; Q3 is selected from C 4-10 Carbocyclic ring, 4 to 10 membered heterocyclic ring, said Q3 is optionally substituted by 1 to 4 R k replace; Ring B1 is selected from Q3 is selected from C 4-10 Carbocyclic ring, 4 to 10 membered heterocyclic ring, wherein the ring B1 is optionally substituted by 1 to 4 R b substituted, said Q3 is optionally substituted with 1 to 4 R k replace; B2 is selected from C 4-6 Carbocyclic ring, B3 is selected from C 4-6 carbon ring; Or Q3 is selected Ring B1 is selected from C 4-10 Carbocyclic ring, 4 to 10 membered heterocyclic ring, wherein the ring B1 is optionally substituted by 1 to 4 R b substituted, said Q3 is optionally substituted with 1 to 4 R k replace; Ring C is selected from F1 or F2 is selected from N or CH; Q is selected from -O-、-N(R q3 )-、-C(=O)N(R q3 )-、-N(R q3 )C(=O)、-C(=O)-、C 4-10 Carbocyclic ring, 4 to 10 membered heterocyclic ring, said carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace; Q1 is selected from -O-, -N(R q3 )-、-C(=O)N(R q3 )-、-N(R q3 )C(=O), -C(=O)-, optionally substituted with 1 to 4 R k Replaced D is selected from -NR n1 -、 The D is optionally replaced by 1 to 4 R d Substitution, the right side of D1 or D2 is directly connected to R1; D1 is selected from 4 to 7 membered nitrogen-containing heteromonocycloalkyl, 4 to 7 membered nitrogen-containing heteromonocycloalkenyl, 5 to 14 membered nitrogen-containing heterospirocycloalkyl, 5 to 14 membered nitrogen-containing heterocycloalkyl, 5 to 14 membered nitrogen-containing heterobridged cycloalkyl; D2 is selected from phenyl, benzo 4-7 Carbocyclic group, benzo 4 to 7 membered heterocyclic group, 5 to 6 membered heteroaryl, C 3-7 Monocyclic alkyl, C 3-7 Monocyclic alkenyl, C 5-14 Spiroalkyl, C 5-14 Cycloalkyl, C 5-14 Bridged cycloalkyl, 4- to 7-membered nitrogen-containing heteromonocyclic group, 5- to 14-membered nitrogen-containing heterospirocyclic group, 5- to 14-membered nitrogen-containing heterocycloalkyl, 5- to 14-membered nitrogen-containing heterobridged ring group; D3 is selected from benzo C 4-7 Carbocyclic group, C 7-14 Spiroalkyl, C 7-14 Cycloalkyl, C 7-14 bridged cycloalkyl; R c1 Selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl or 4 to 7 membered heterocycloalkyl, said alkyl, cycloalkyl or heterocycloalkyl being optionally substituted by 1 to 4 R k replace; R c2 Each independently selected from deuterium, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 Carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, -C 1-2 Alkylene-C 3-6 Carbocyclic ring, -C 1-2 Alkylene-3 to 7 membered heterocycle, -C(=O)NH-C 1-4 Alkyl, -C(=O)NH-C 3-6 Carbocycle, -NHC(=O)-C 1-4 Alkyl, -NHC(=O)-C 3-6 Carbon ring, C 3-6 Carbocyclic ring, 3 to 7 membered heterocyclic ring, the alkyl, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace; R c3 Each independently selected from H, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -C(=O)NH2, -C 1-2 Alkylene-C 3-6 Carbocyclic ring, -C 1-2 Alkylene-3 to 7 membered heterocyclic ring, -OC 3-6 Carbocyclic ring, -O-3 to 7 membered heterocyclic ring, C 3-6 Carbocyclic ring, 3 to 7 membered heterocyclic ring, the alkyl, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace; R c4 Selected from H, NH2, halogen, CN, OH, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -OC 3-6 Carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, -C 1-2 Alkylene-C 3-6 Carbocyclic ring, -C 1-2 Alkylene-3 to 7 membered heterocyclic ring, wherein the alkyl, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace; R c5 Selected from H, deuterium, halogen, CN, hydroxyl, NH2, -NHC 1-4 Alkyl, -NH-C 3-7 Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, -NH-5 to 6 membered heteroaryl-C 1-3 Alkylene-R c5a , -NH-5 to 6 membered heteroaryl-C 3-6 Carbocyclyl-R c5a , -NH-5 to 6 membered heteroaryl-4 to 6 membered heterocyclic group-R c5a The alkyl, alkylene, alkoxy, cycloalkyl, carbocyclic, heterocyclic, heteroaryl groups are optionally substituted by 1 to 4 R k replace; R c6 Selected from H, halogen, OH, NH2, C 1-4 Alkyl, CN, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -C(=O)NH2, -C 1-2 Alkylene-C 3-6 Carbocyclic ring, -C 1-2 Alkylene-3 to 7 membered heterocyclic ring, -OC 3-6 Carbocyclic ring, -O-3 to 7 membered heterocyclic ring, C 3-6 Carbocyclic or 3 to 7 membered heterocyclic rings, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic ring, heterocyclic ring is optionally substituted by 1 to 4 R k replace; When R c6 Selected from H, halogen, OH, NH2 or C 1-4 When alkyl, R c5 Selected from -NH-5 to 6 membered heteroaryl-C 1-3 Alkylene-R c5a , -NH-5 to 6 membered heteroaryl-C 3-6 Carbocyclyl-R c5a , -NH-5 to 6 membered heteroaryl-4 to 6 membered heterocyclic group-R c5a The alkyl, heteroaryl, alkylene, carbocyclic or heterocyclic group is optionally substituted by 1 to 3 R k replace; R c5a Selected from CN, -OC 1-3 Alkyl, -SC 1-3 Alkyl, C 3-6 Carbon ring, -OC 3-6 Carbocycle, 4- to 6-membered heterocycle, -O-4- to 6-membered heterocycle, -C(=O)C 3-6 Carbocycle, -C(=O)-4 to 6 membered heterocycle, wherein the alkyl, carbocycle or heterocycle is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent; When R c6 Selected from CN, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -C(=O)NH2, -C 1-2 Alkylene-C 3-6 Carbocyclic ring, -C 1-2 Alkylene-3 to 7 membered heterocyclic ring, -OC 3-6 Carbocyclic ring, -O-3 to 7 membered heterocyclic ring, C 3-6 When it is a carbocyclic ring or a 3- to 7-membered heterocyclic ring, R c5 Selected from H, deuterium, halogen, CN, hydroxyl, NH2, -NHC 1-4 Alkyl, -NH-C 3-7 carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, C1-4 alkyl, C1-4 alkoxy or C3-6 cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl, carbocyclic ring, heterocyclic ring are optionally substituted by 1 to 4 R k replace; R c7 Selected from H or R c2 ; p1 or p2 is selected from 0, 1, 2 or 3.

3. The compound according to claim 2, or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, Q is selected from Phenyl, naphthyl, benzo C 4-6 Carbocyclic ring, benzo 4 to 6 membered heterocyclic ring, -O-, -N(R q3 )-、-C(=O)N(R q3 )-、-N(R q3 )C(=O), -C(=O)-, the phenyl, naphthyl, benzo C 4-6 Carbocyclic ring, benzene and a 4- to 6-membered heterocyclic ring optionally substituted with 1 to 4 R k replace; R q1 、R q2 、R q3 Each independently selected from H, C 1-4 Alkyl, said alkyl being optionally substituted by 1 to 4 R k replace; R a 、R b 、R d Each independently selected from deuterium, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 Carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, -C 1-2 Alkylene-C 3-6 Carbocyclic ring, -C 1-2 Alkylene-3 to 7 membered heterocycle, -C(=O)NH-C 1-6 Alkyl, -C(=O)NH-C 3-6 Carbon ring, C 3-6 Carbocyclic ring, 3 to 7 membered heterocyclic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace; R c3 Each is independently selected from H, NH2, -C(=O)NH2, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl; R c4 Selected from H, NH2, halogen, CN, C 1-4 Alkyl, C 2-4 Alkyl or -NH-5 to 6 membered heteroaromatic ring, wherein the alkyl, alkynyl or heteroaromatic ring is optionally substituted by 1 to 4 R k replace; R c5 Selected from -NH-C 3-6 Carbocyclic ring, -NH-3 to 6 membered heterocyclic ring, -NH-5 to 6 membered heteroaryl-C 1-2 Alkylene-R c5a , -NH-5 to 6 membered heteroaryl-C 3-6 Carbocyclyl-R c5a , -NH-5 to 6 membered heteroaryl-4 to 6 membered heterocyclic group-R c5a The alkyl, alkylene, alkoxy, cycloalkyl, carbocyclic, heterocyclic, heteroaryl groups are optionally substituted by 1 to 4 R k replace; R c6 Selected from H, halogen, OH, NH2, C 1-4 Alkyl, CN, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -C(=O)NH2, -C 1-2 Alkylene-C 3-6 Carbocyclic ring, -C 1-2 Alkylene-4 to 6 membered heterocyclic ring, -OC 3-6 Carbocyclic ring, -O-4 to 6 membered heterocyclic ring, C 3-6 Carbocyclic or 4 to 7 membered heterocycloalkane ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic, heterocyclic, heterocycloalkane ring is optionally substituted by 1 to 4 R k replace; When R c6 Selected from H, halogen, OH, NH2 or C 1-4 When alkyl, R c5 Selected from -NH-5 to 6 membered heteroaryl-C 1-2 Alkylene-R c5a , -NH-5 to 6 membered heteroaryl-C 3-6 Cycloalkyl-R c5a , -NH-5 to 6 membered heteroaryl-4 to 6 membered heterocycloalkyl-R c5a The alkyl, heteroaryl, alkylene, cycloalkyl or heterocycloalkyl group is optionally substituted by 1 to 3 R k replace; When R c6 Selected from CN, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -C(=O)NH2, -C 1-2 Alkylene-C 3-6 Carbocyclic ring, -C 1-2 Alkylene-4 to 6 membered heterocyclic ring, -OC 3-6 Carbocyclic ring, -O-4 to 6 membered heterocyclic ring, C 3-6 When the ring is a cycloalkyl group or a 4- to 7-membered heterocycloalkane ring, R c5 Selected from -NH-C 3-6 carbocyclic ring, -NH-5 to 6 membered heteroaromatic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, carbocyclic ring, heterocyclic ring, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R k replace; R 1a 、R 1b 、R 1c 、R 1d Each independently selected from H, deuterium, halogen, CN, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Carbocyclic ring, 3 to 7 membered heterocyclic ring, said alkyl, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace; Alternatively, R 1b With R 1c 、R 1a With R 1b Direct connection to form C 3-6 Carbocyclic or 3- to 7-membered heterocyclic ring, the carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 R k replace; R 1e Selected from halogen or -OS(=O)2C 1-4 Alkyl, the alkyl group is optionally substituted by 1 to 4 R k replace; R k Selected from deuterium, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 Carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, -C 1-2 Alkylene-C 3-6 Carbocyclic ring, -C 1-2 Alkylene-3 to 7 membered heterocyclic ring, C 3-6 Carbocyclic ring, 3 to 7 membered heterocyclic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 groups selected from deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent.

4. The compound according to claim 3, or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein: D1 is selected from D2 is selected from Phenyl, benzo C 4-6 Carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl; D3 is selected from Q3 is selected from C 6-10 Aryl, 5 to 10 membered heteroaryl, said Q3 is optionally substituted by 1 to 4 R k replace; Ring B1 is selected from Q3 is selected from C 6-10 aryl, 5 to 10 membered heteroaryl, the ring B1 is optionally substituted by 1 to 4 R b substituted, said Q3 is optionally substituted with 1 to 4 R k replace; B2 is selected from C 4-6 Carbocyclic ring, B3 is selected from C 4-6 carbon ring; Or Q3 is selected Ring B1 is selected from phenyl, benzo 4-6 Carbocyclic ring, benzo 4 to 6 membered heterocyclic ring, 5 to 6 membered heteroaryl, 8 to 10 membered heteroaryl, the ring B1 is optionally substituted by 1 to 4 R b substituted, said Q3 is optionally substituted with 1 to 4 R k replace; n1, n3, n5 are each independently selected from 0, 1 or 2; n2 and n4 are each independently selected from 0 or 1; n6 is 0, 1, 2 or 3; R q1 、R q2 、R q3 Each is independently selected from H, methyl, ethyl; R n1 Selected from H, methyl, ethyl; R a 、R b 、R d Each independently selected from deuterium, F, Cl, Br, I, cyano, OH, NH2, NH(CH3), N(CH3)2, CF3, methyl, ethyl, propyl, isopropyl, butyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; R c1 is selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl is optionally substituted by 1 to 4 R k replace; R c2 Each independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, isopropyl, vinyl, propenyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -NH-pyrazole, -NH-imidazole, -NH-oxazole, -NH-thiazole, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -C(=O)NH-methyl, -C(=O)NH-ethyl, -C(=O)NH-cyclopropyl, -NHC(=O)-methyl, -NHC(=O)-ethyl, -NHC(=O)-cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxet ... R, methyl, ethyl, isopropyl, vinyl, propenyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetyl, oxetyl, oxetyl, piperazinyl, morpholinyl, pyrazole, imidazole, oxazole, thiazole, 1 to 4 R k replace; R c4 is selected from H, NH2, F, Cl, Br, I, CN, methyl, ethyl, ethynyl, -NH-pyrazole, -NH-imidazole, -NH-oxazole, -NH-thiazole, wherein the methyl, ethyl, ethynyl, pyrazole, imidazole, oxazole, thiazole is optionally replaced by 1 to 4 R k replace; Ring B is selected from R c5 Selected from -NH-C 3-6 Carbocycle, -NH-pyrazole, -NH-pyrrole, -NH-imidazole, -NH-triazole, -NH-5 to 6 membered heteroaryl-C 1-2 Alkylene-R c5a , -NH-5 to 6 membered heteroaryl-C 3-6 Carbocyclyl-R c5a , -NH-5 to 6 membered heteroaryl-4 to 6 membered heterocyclic group-R c5a , the 5- to 6-membered heteroaryl is selected from pyrazolyl, pyrrolyl, imidazolyl or triazolyl, and the alkylene, carbocyclic group, heterocyclic group, heteroaryl, pyrazolyl, pyrrolyl, imidazolyl or triazolyl is optionally substituted by 1 to 4 R k replace; R c6 is selected from H, F, Cl, Br, I, OH, NH2, CF3, methyl, ethyl, CN, ethynyl, -CH2-ethynyl, propynyl, methoxy, ethoxy, -C(=O)NH2, -CH2-cyclopropyl, -O-cyclopropyl, cyclopropyl, cyclobutyl or cyclopentyl, wherein the methyl, ethyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl or cyclopentyl is optionally substituted by 1 to 4 R k replace; When R c6 When R is selected from H, F, Cl, Br, I, OH, NH2, CF3, methyl or ethyl, c5 Selected from -NH-5 to 6 membered heteroaryl-C 1-2 Alkylene-R c5a , -NH-5 to 6 membered heteroaryl-C 3-6 Cycloalkyl-R c5a , -NH-5 to 6 membered heteroaryl-4 to 6 membered heterocycloalkyl-R c5a , the 5- to 6-membered heteroaryl is selected from pyrazolyl, pyrrolyl, imidazolyl or triazolyl, and the heteroaryl, alkylene, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 3 R k replace; R c5a is selected from CN or one of the following groups which are optionally substituted: -O-methyl, -O-ethyl, -S-methyl, -S-ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetyl, oxetyl, oxetyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, -O-azetidinyl, -O-azacyclopentyl, -O-azacyclohexyl, -C(=O)-cyclopropyl, -C(= -C(═O)-cyclobutyl, -C(═O)-cyclopentyl, -C(═O)-cyclohexyl, -C(═O)-azetidinyl, -C(═O)-azacyclopentyl, -C(═O)-azetidinyl, -C(═O)-azacyclohexyl, -C(═O)-oxetanyl, -C(═O)-oxolanyl, -C(═O)-oxhexyl, when substituted, by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, methyl, ethyl, methoxy or ethoxy; When R c6 When R is selected from CN, ethynyl, -CH2-ethynyl, propynyl, methoxy, ethoxy, -C(=O)NH2, -CH2-cyclopropyl, -O-cyclopropyl, cyclopropyl, cyclobutyl or cyclopentyl, c5 Selected from -NH-C 3-6 Carbocycle, -NH-pyrazole, -NH-pyrrole, -NH-imidazole, -NH-triazole, the CH2, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, pyrazolyl, pyrrolyl, imidazolyl or triazole group is optionally substituted by 1 to 4 R k replace; R 1a 、R 1b 、R 1c 、R 1d Each independently selected from H, deuterium, F, Cl, Br, I, CN, methyl, ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, the methyl, ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl optionally substituted with 1 to 4 R k replace; Alternatively, R 1b With R 1c 、R 1a With R 1b Direct connection to form C 3-6 Carbocyclic or 3- to 7-membered heterocyclic ring, the carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 R k replace; Alternatively, R n1 With R d Direct connection to form C 3-6 Carbocyclic or 3- to 7-membered heterocyclic ring, the carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 R k replace; R 1e Selected from F, Cl, Br, I, -OS(=O)2CH3, -OS(=O)2CF3; R k is selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is optionally substituted by 1 to 4 halogens selected from halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent.

5. The compound according to claim 4 or its stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein Q is selected from -O-, -NH-, -N(CH3)-, -C(=O)NH-, -NHC(=O), -C(=O)-, the Optional 1 to 4 R k replace; Q1 is selected from -O-, -NH-, -N(CH3)-, -C(=O)NH-, -NHC(=O), -C(=O)-, Selected from Selected from D is selected from -NH-, -N(R n1 )-、 or optionally 1 to 4 R d One of the following groups substituted: Right side and R 1 Direct connection; D3 is optionally selected from 1 to 4 R d One of the following groups substituted: R 1 Selected from CN, p1 or p2 is selected from 0, 1 or 2.

6. The compound according to claim 5, or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, R a Each independently selected from deuterium, F, Cl, Br, cyano, CF3, methyl; R b Each independently selected from deuterium, F, Cl, Br, cyano, CF3, methyl; R d Each independently selected from deuterium, F, Cl, Br, I, cyano, OH, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy; R c1 Selected from CD3, CF3, methyl, ethyl, propyl, isopropyl, cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, R c2 selected from deuterium, F, Cl, Br, OH, CN, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, isopropyl, vinyl, propenyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetyl, oxolyl, oxetyl, piperazinyl, morpholinyl, -NH-pyrazole, -NH-imidazole, -NH-oxazole, -NH-thiazole, -C(=O)NH-methyl, -C(=O)NH-ethyl, -C(=O)NH-cyclopropyl, -NHC(=O)-methyl, -NHC(=O)-ethyl alkyl, -NHC(=O)-cyclopropyl, wherein the methyl, ethyl, isopropyl, vinyl, propenyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazole, imidazole, oxazole, thiazole, azetidinyl, azetyl, azetyl, oxetyl, oxetyl, oxetyl, piperazinyl, morpholinyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; R c4 Selected from H, NH2, F, CN, methyl, R c5 Selected from When R c6 When R is selected from H, F, Cl, Br, I, OH, NH2, CF3, methyl or ethyl, c5 Selected from R c5a Selected from CN, -O-methyl, -O-ethyl, -S-methyl, -S-ethyl, cyclopropyl, When R c6 When R is selected from CN, ethynyl, -CH2-ethynyl, propynyl, -C(=O)NH2, -CH2-cyclopropyl, -O-cyclopropyl, cyclopropyl, cyclobutyl or cyclopentyl, c5 Selected from Q3 is selected from phenyl, pyridyl or pyrimidinyl, said Q3 being optionally substituted with 1 to 4 substituents selected from F, Cl, Br, methyl, ethyl, methoxy or ethoxy; Ring B1 is selected from Q3 is selected from phenyl, pyridyl or pyrimidinyl, the ring B1 is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, methyl, ethyl, methoxy or ethoxy, and the Q3 is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, methyl, ethyl, methoxy or ethoxy; Or Q3 is selected Ring B1 is selected from phenyl or pyridyl, and said ring B1 is optionally substituted by 1 to 4 R b substituted, said Q3 is optionally substituted with 1 to 4 R k replace.

7. The compound according to claim 6, or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, Selected from In the general formula (VI), -D- is selected from Ring B1 is selected from Q3 is selected from Or Q3 is selected Ring B1 is selected from In the general formula (VII), D is selected from -NH-; General formula (VIII) middle 8. The compound according to claim 1, or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein the compound is selected from one of the structures shown in Table E-1.

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition comprises 1 to 1500 mg of the compound according to any one of claims 1 to 8 or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

10. Use of the compound according to any one of claims 1 to 8, or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, in the preparation of a medicament for treating a disease associated with FGFR2 activity or expression. The use according to claim 10 , wherein the disease is selected from tumors.

12. A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 8, or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, preferably 1-1500 mg, wherein the disease is preferably a disease related to FGFR2 activity or expression.

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