A pyrrolopyridine derivative and its use in medicine

Abstract

A pyridopyrrole derivative and its pharmaceutical application, specifically relating to a compound of general formula (I0) or general formula (I0-1) or its stereoisomers, racemates, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, intermediates and preparation methods thereof, and its application in the preparation of medicaments for treating diseases related to FGFR2 activity or expression levels.

Description

A pyridopyrrole derivative and its application in medicine Technical Field

[0001] The present invention relates to a compound described by general formula (I0) or general formula (I0-1) or its stereoisomers, racemates, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, as well as intermediates and preparation methods, and use of the compounds in the preparation of drugs for treating diseases related to FGFR2 activity or expression. Background Art

[0002] Biliary tract cancer (BTC) is a rare, heterogeneous disease that includes a variety of aggressive malignancies arising in the biliary tree. BTC includes intrahepatic cholangiocarcinoma (iCCA) and extrahepatic cholangiocarcinoma (eCCA). The 5-year overall survival rate of patients has remained below 2%. Fibroblast growth factor receptors (FGFRs) are abnormally activated in approximately 15-20% of intrahepatic cholangiocarcinomas. In addition, next-generation sequencing of a large number of solid tumors has found abnormal signaling of fibroblast growth factor receptors (FGFRs) 1, 2, 3, and 4 in 7% of cancers, suggesting that this pathway is involved in tumorigenesis and serves as a potential point of therapeutic intervention (Clin. Cancer Res. 2016, 22(1): 259-267). FGFR signaling is initiated by the binding of extracellular FGF ligands, leading to receptor dimerization and cross-phosphorylation of the tyrosine kinase domain. After activation, the phosphorylated kinase domain continues to phosphorylate intracellular substrates such as PLCγ, Gab1, FRS2, and STAT1, subsequently activating downstream signaling pathways such as PI3K-Akt and Ras / Raf / Mek / Erk (J Med Chem. 2017, 60(15): 6516-6527). The recent approval of erdafitinib for the treatment of FGFR3-abnormal bladder cancer and pemigatinib for the treatment of FGFR2-abnormal cholangiocarcinoma has clinically validated FGFR as a high-quality target for drug development.

[0003] FGF receptor 2 (FGFR2) (Fibroblast Growth Factor Receptor 2): FGFR2, also known as CD332, is a protein encoded by the FGFR2 gene located on chromosome 10. The FGFR family includes four receptor subtypes: FGFR1, FGFR2, FGFR3, and FGFR4, as well as up to 22 fibroblast growth factor ligands (FGFs). They are part of the tyrosine kinase signaling pathway responsible for cell proliferation and differentiation (FGFs / FGFRs signaling pathway), regulating basic developmental pathways in multiple organ systems and playing 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. FGFR2 mutations have been found in a variety of solid tumors, with urothelial carcinoma and intrahepatic cholangiocarcinoma being the most common. Fusion mutations in intrahepatic cholangiocarcinoma (ICC) account for 9% of all gene mutations. In addition, FGFR2 encodes FGFR2b and FGFR2c with different expression domains and ligand specificities through alternative splicing.

[0004] FGFR2 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 the FGFR2 driver status in FGFR2 fusion-positive intrahepatic cholangiocarcinoma (ICC), the emergence of FGFR1-mediated toxicities (hyperphosphatemia, tissue mineralization) and targeted FGFR2 resistance mutations limit the efficacy of pan-FGFR inhibitors. Fortunately, FGFR2-selective inhibitors can reduce toxicity and overcome acquired resistance to pan-FGFR inhibitors. Therefore, it is necessary to develop a compound that can highly selectively inhibit FGFR2 for the treatment of diseases caused by FGFR2 fusions, amplifications, and mutations. Summary of the Invention

[0005] The present invention aims to provide a class of pyrimidopyrrole 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.

[0006] The compounds of the present invention have good FGFR2 kinase inhibitory activity and selectivity, have good inhibitory activity against SNU16 and KATO-III cell proliferation, but have no significant or poor inhibitory activity against Li-7 and / or RT112 / 84 cells, have good FGFR2 cell selectivity, have weak inhibitory activity against CYP3A4-M, have no significant inhibitory effect on the hERG potassium ion channel, exhibit good pharmacokinetic characteristics in animals (such as low clearance, good AUC and Cmax), and have good cell permeability.

[0007] The present invention provides a compound of general formula (I0) or general formula (I0-1) or a stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

[0008] In some embodiments, the ring C in the compound represented by formula (I0) is selected from

[0009] In some embodiments, the compound represented by general formula (I0) is selected from general formula (I) or general formula (II)

[0010] In some embodiments, X in the compound represented by formula (I0), formula (I) or formula (II) is selected from CH or N;

[0011] In some embodiments, ring D in the compound represented by formula (I0), formula (I) or formula (II) is selected from phenyl, naphthyl, 5- to 6-membered heteroaryl, and 5- to 12-membered heterocycle;

[0012] In some embodiments, ring D in the compound represented by formula (I0), formula (I) or formula (II) is selected from phenyl, naphthyl, 5- to 6-membered heteroaryl, 5- to 6-membered monocyclic heterocycle, and 7- to 12-membered spiroheterocycle;

[0013] In some embodiments, the ring D in the compound represented by formula (I0), formula (I) or formula (II) is selected from phenyl, naphthyl, pyridazinyl, pyrazinyl, pyridinyl, pyrimidinyl, In some embodiments, Selected from

[0014] In some embodiments, the ring B in the compound represented by formula (I0), formula (I) or formula (II) is selected from C 6-10 Aryl, benzo C 4-6 In some embodiments, the ring B in the compound represented by the general formula (I0), the general formula (I) or the general formula (II) is selected from phenyl, naphthyl, benzo C 4-6 carbocyclic ring, benzo 4- to 6-membered heterocyclic ring, 5- to 6-membered heteroaryl, 8- to 10-membered heteroaryl ring; in some embodiments, the ring B in the compound represented by the general formula (I0), the general formula (I) or the general formula (II) is selected from phenyl or naphthyl; in some embodiments, the ring B in the compound represented by the general formula (I0), the general formula (I) or the general formula (II) is selected from phenyl or naphthyl; Selected from

[0015] In some embodiments, R in the compound represented by formula (I0), formula (I) or formula (II) a 、R b 、R d Each independently 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 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;

[0016] In some embodiments, R in the compound represented by formula (I0), formula (I) or formula (II) 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 1-2Alkylene-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;

[0017] In some embodiments, in the compound represented by formula (I0), formula (I) or formula (II), 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,

[0018] In some embodiments, R in the compound represented by formula (I0), formula (I) or formula (II) d Selected from deuterium, F, Cl, Br, I, cyano, OH, NH2, NH(CH3), N(CH3)2, CF3, methyl, ethyl, propyl, isopropyl, butyl, ethynyl, methoxy, ethoxy;

[0019] In some embodiments, R in the compound represented by formula (I0), formula (I) or formula (II) 3 Selected from C 2-8 Alkyl, C 3-10 Carbocyclic group, 4 to 12 membered heterocyclic group, said alkyl, carbocyclic group or heterocyclic group is substituted by 5 to 10 halogens, said alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0020] In some embodiments, R in the compound represented by formula (I0), formula (I) or formula (II) 3 Selected from C 2-6 Alkyl, C 3-6 Cycloalkyl, 4- to 7-membered heterocycloalkyl, wherein the alkyl, cycloalkyl or heterocycloalkyl is substituted with 5 to 10 halogens;

[0021] In some embodiments, R in the compound represented by formula (I0), formula (I) or formula (II) 3 Selected from ethyl, propyl, isopropyl, butyl, pentyl, cyclopropyl, cyclobutyl, wherein the ethyl, propyl, isopropyl, butyl, pentyl, cyclopropyl, cyclobutyl is substituted with 5 to 8 substituents selected from F, Cl, Br, I;

[0022] In some embodiments, R in the compound represented by formula (I0), formula (I) or formula (II) 3 Selected from

[0023] In some embodiments, R in the compound represented by formula (I0), formula (I) or formula (II) 3 Selected from

[0024] In some embodiments, R in the compound represented by formula (I0), formula (I) or formula (II) c1 Selected from H, C 1-6 Alkyl, C 3-10 Carbocyclic group, 4 to 12 membered heterocyclic group, said alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0025] In some embodiments, R in the compound represented by formula (I0), formula (I) or formula (II) 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;

[0026] In some embodiments, R in the compound represented by formula (I0), formula (I) or formula (II) c1 Selected from C 1-4 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl being optionally substituted with 1 to 4 deuterium or halogen;

[0027] In some embodiments, R in the compound represented by formula (I0), formula (I) or formula (II) c1 is selected from methyl, ethyl, propyl, isopropyl, butyl, pentyl, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, propyl, isopropyl, butyl, pentyl, cyclopropyl, and cyclobutyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, and I;

[0028] In some embodiments, R in the compound represented by formula (I0), formula (I) or formula (II) c1 is selected from methyl, isopropyl or cyclopropyl, wherein the methyl, isopropyl or cyclopropyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I;

[0029] In some embodiments, R in the compound represented by formula (I0), formula (I) or formula (II) 1 Selected from halogen, CN, In some embodiments, R in the compound represented by formula (I0), formula (I) or formula (II) 1 Selected from CN, In some embodiments, R in the compound represented by formula (I0), formula (I) or formula (II) 1 Selected from CN, ethynyl;

[0030] In some embodiments, R in the compound represented by formula (I0), formula (I) or formula (II) 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, 3- to 7-membered heterocyclic, C 6-10 Aryl, 5 to 6 membered heteroaryl, the alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, C 6-10 Aryl or 5- to 6-membered heteroaryl is optionally substituted with 1 to 5 R k replace;

[0031] In some embodiments, R in the compound represented by formula (I0), formula (I) or formula (II) 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, 3- to 7-membered heterocyclic, C 6-10 Aryl, 5 to 6 membered heteroaryl, the alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, C 6-10 Aryl or 5- to 6-membered heteroaryl is optionally substituted with 1 to 5 R k replace;

[0032] In some embodiments, R in the compound represented by formula (I0), formula (I) or formula (II) 1a 、R 1b 、R 1c 、R 1dEach independently selected from H, deuterium, F, Cl, Br, I, CN, methyl, ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, phenyl, wherein the methyl, ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, phenyl is optionally substituted by 1 to 5 R k replace;

[0033] In some embodiments, R in the compound represented by formula (I0), formula (I) or formula (II) 1a 、R 1b 、R 1c Each independently selected from H, deuterium, F, Cl, Br, I, CN, methyl, ethyl, CF3, vinyl, ethynyl, phenyl;

[0034] In some embodiments, R in the compound represented by formula (I0), formula (I) or formula (II) 1e is selected from halogen or -OS(=O)2R;

[0035] In some embodiments, in the compound represented by formula (I0), formula (I) or formula (II), 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;

[0036] In some embodiments, R in the compound represented by formula (I0), formula (I) or formula (II) 1e Selected from halogen or -OS(=O)2C 1-4 Alkyl, the alkyl group is optionally substituted by 1 to 4 R k replace;

[0037] In some embodiments, R in the compound represented by formula (I0), formula (I) or formula (II) 2 Selected from H or C 1-4 alkyl;

[0038] In some embodiments, 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, said carbocyclic or heterocyclic ring being optionally substituted by 1 to 4 R k replace;

[0039] In some embodiments, R in the compound represented by formula (I0), formula (I) or formula (II)1a With R 2 、R 1b With R 2 directly connected to form a 4- to 7-membered heterocyclic ring, which is optionally substituted by 1 to 4 R k replace;

[0040] In some embodiments, the compound represented by formula (I0), formula (I) or formula (II) Selected from

[0041] In some embodiments, R in the compound represented by formula (I0), formula (I) or formula (II) k Each independently selected from deuterium, halogen, =O, 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;

[0042] In some embodiments, R in the compound represented by formula (I0), formula (I) or formula (II) k Each independently selected from deuterium, halogen, =O, 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, -C1-2 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;

[0043] In some embodiments, R in the compound represented by formula (I0), formula (I) or formula (II) k Each is independently selected from deuterium, F, Cl, Br, I, =O, 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, cyclo Pentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl are optionally substituted by 1 to 4 groups selected from halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0044] In some embodiments, p1 and p2 in the compound represented by formula (I0), formula (I) or formula (II) are each independently selected from 0, 1, 2, 3 or 4;

[0045] In some embodiments, p1 in the compound represented by formula (I0), formula (I) or formula (II) is 0 or 1;

[0046] In some embodiments, p3 in the compound represented by formula (I0), formula (I) or formula (II) is selected from 0, 1, 2, 3 or 4;

[0047] In some embodiments, p3 in the compound represented by formula (I0), formula (I) or formula (II) is selected from 0, 1 or 2;

[0048] In some embodiments, p4 in the compound represented by formula (I0), formula (I) or formula (II) is selected from 0 or 1;

[0049] In some embodiments, in the compound represented by formula (I), ring B is selected from phenyl or naphthyl, preferably phenyl, ring D is selected from phenyl or naphthyl, preferably phenyl, R c1 is selected from methyl, deuterated methyl or halomethyl, R c1 Preferably H, methyl, CD3, CHD2, CH2D, CF3, CHF2, CH2F, R a Each independently selected from methyl, deuterated methyl or halomethyl, R 3 Selected from R 3 Preferred Selected from ethynyl, R 1a 、R 1b 、R 1c Each independently selected from H, deuterium, F, Cl, Br, CN, methyl, ethyl, CF3, Preferably ethynyl, R b 、R d Each independently selected from deuterium, F, Cl, Br, I, cyano, OH, CF3, methyl, ethyl, propyl, isopropyl, butyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Preferably deuterium, F, Cl, Br, cyano, OH, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, p1 is 0 or 1, p2 or p3 are each independently selected from 0, 1, 2, 3 or 4;

[0050] In some embodiments, Formula (I0-1) is selected from Formula (Ia),

[0051] In some embodiments, the ring B in the compound represented by the general formula (I0-1) is selected from C 6-10 Aryl, benzo C 4-6 Carbocyclic, 5- to 6-membered heteroaryl, 8- to 10-membered heteroaryl, partially saturated C 3-6 Carbocyclic group;

[0052] In some embodiments, the ring B in the compound represented by the general formula (I0-1) is selected from phenyl, naphthyl, C 3-6 Cycloalkyl, C 5-6 Cycloalkenyl, benzo C 4-6 Carbocyclic ring, benzo 4- to 6-membered heterocyclic ring, 5- to 6-membered heteroaryl, 8- to 10-membered heteroaryl ring;

[0053] In some embodiments, in the compound represented by general formula (I0-1), ring B is selected from phenyl, naphthyl, pyridyl, cyclopentyl, cyclohexyl, cyclopentenyl or cyclohexenyl;

[0054] In some embodiments, the compound represented by general formula (I0-1) Selected from

[0055] In some embodiments, in the compound represented by formula (I0-1), Q is selected from -C(=O)- or a bond;

[0056] In some embodiments, the ring D in the compound represented by formula (I0-1) or formula (Ia) is selected from C 6-10 Carbocyclic ring, 5- to 10-membered heterocyclic ring;

[0057] In some embodiments, the ring D in the compound represented by formula (I0-1) or formula (Ia) is selected from phenyl, benzo 4-6 Carbocycle, benzo 4- to 6-membered heterocycle, 5- to 6-membered heteroaryl, 5- to 6-membered partially saturated heterocyclic group;

[0058] In some embodiments, ring D in the compound represented by formula (I0-1) or formula (Ia) is selected from phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, azacyclopentenyl, azacyclohexyl or azacyclohexenyl;

[0059] In some embodiments, the ring D in the compound represented by formula (I0-1) or formula (Ia) is selected from D1, D2, D3, and D4 are each independently selected from N or CH, and at most 3 are selected from N;

[0060] In some embodiments, the compound represented by general formula (I0-1) Selected from or Selected from In some embodiments, the compound represented by general formula (I0-1) Selected from or Selected from In some embodiments, the compound represented by general formula (I0-1) Selected from or Selected from In some embodiments, the ring C in the compound represented by the general formula (I0-1) is selected from In some embodiments, the ring C in the compound represented by the general formula (I0-1) is selected from p3 is selected from 0, 1, 2, 3 or 4;

[0061] In some embodiments, C1, C2, C3, and C4 in the compound represented by the general formula (I0-1) are independently selected from N or CH, and at most two are selected from N, and the CH is optionally replaced by R c4 replace;

[0062] In some embodiments, R b 、R d 、R c4 Each independently 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 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;

[0063] In some embodiments, R b 、R d 、R c4 Each independently selected from H, 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, -OC3-6 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;

[0064] In some embodiments, R b 、R d Each is independently selected from H, deuterium, F, Cl, Br, I, cyano, OH, NH2, NH(CH3), N(CH3)2, CF3, CD3, methyl, ethyl, propyl, isopropyl, butyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;

[0065] In some embodiments, R in the compound represented by general formula (I0-1) c4 Each is independently selected from deuterium, F, Cl, Br, I, CN, methyl, ethyl, NH(CH3), N(CH3)2, methoxy, ethoxy, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrazolyl, wherein the methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrazolyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), N(CH3)2, CF3, CD3, methyl, ethyl, methoxy, ethoxy or cyclopropyl;

[0066] In some embodiments, R c1 Selected from H, OH, CN, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, -OC 1-6 Alkyl, said alkyl being optionally substituted by 1 to 4 R k replace;

[0067] In some embodiments, R c1 Selected from H, OH, CN, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C1-4 Alkyl, -OC 1-4 Alkyl, said alkyl being optionally substituted by 1 to 4 R k replace;

[0068] In some embodiments, R c2 Selected from H, halogen, CN, C 1-6 Alkyl, -OC 1-6 Alkyl, said alkyl being optionally substituted by 1 to 4 R k replace;

[0069] In some embodiments, R c2 Selected from H, halogen, CN, C 1-4 Alkyl, -OC 1-4 Alkyl, said alkyl being optionally substituted by 1 to 4 R k replace;

[0070] In some embodiments, R c3 Selected from NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, NHC 3-6 Carbocyclic ring, the alkyl group or carbocyclic ring is optionally substituted by 1 to 4 R k replace;

[0071] In some embodiments, R c3 Selected from NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, NHC 3-6 Cycloalkyl, said alkyl or cycloalkyl is optionally substituted by 1 to 4 R k replace;

[0072] In some embodiments, R c5 Selected from H, C 1-6 Alkyl, said alkyl being optionally substituted by 1 to 4 R k replace;

[0073] In some embodiments, R c5 is selected from H, methyl, ethyl, propyl or isopropyl, wherein the methyl, ethyl, propyl or isopropyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), N(CH3)2, CF3, CD3, methyl, ethyl, methoxy, ethoxy or cyclopropyl;

[0074] In some embodiments, R c6 Selected from H, deuterium, halogen, CN, C 1-6 Alkyl, -OC 1-6 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl is optionally substituted by 1 to 4 R k replace;

[0075] In some embodiments, R c6 Selected from H, deuterium, halogen, CN, C 1-4 Alkyl, -OC 1-4 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl is optionally substituted by 1 to 4 R k replace;

[0076] In some embodiments, R 1 Selected from halogen, CN, In some embodiments, R 1 Selected from CN,

[0077] 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;

[0078] 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 3-6Carbocyclic 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;

[0079] In some embodiments, 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, cyclohexyl, pyrrolidinyl, wherein the methyl, ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or pyrrolidinyl is optionally substituted by 1 to 4 R k replace;

[0080] In some embodiments, 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, cyclohexyl, or pyrrolidinyl, wherein the methyl, ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or pyrrolidinyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, ═O, NH2, NH(CH3), N(CH3)2, NH(CH2CH3), N(CH2CH3)2, CF3, CD3, methyl, ethyl, methoxy, ethoxy, cyclopropyl, azacyclohexyl, pyrrolidinyl, or morpholinyl;

[0081] In some embodiments, R 1e is selected from halogen or -OS(=O)2R;

[0082] 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;

[0083] In some embodiments, in the compound represented by formula (I0-1) or formula (Ia), R is selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3- 6-membered carbon ring, 3- to 7-membered heterocycle, wherein the alkyl, alkenyl, alkynyl, carbon ring or heterocycle is optionally substituted by 1 to 4 R kreplace;

[0084] In the compound represented by general formula (I0-1) or general formula (Ia), 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, said carbocyclic or heterocyclic ring being optionally substituted by 1 to 4 R k replace;

[0085] In some embodiments, R 2 Selected from H or C 1-6 alkyl;

[0086] In the compound represented by general formula (I0-1) or general formula (Ia), R 2 With R 1b 、R 2 With R 1a or R 2 With R d Directly connected to form a 4 to 7 membered heterocyclic group, the heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0087] In some embodiments, R 2 Selected from H or C 1-4 alkyl;

[0088] In the compound represented by general formula (I0-1) or general formula (Ia), R 2 With R 1b 、R 2 With R 1a or R 2 With R d Directly connected to form a 4 to 7 membered heterocyclic group, the heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0089] In some embodiments, R 2 Selected from H or methyl;

[0090] In the compound represented by general formula (I0-1) or general formula (Ia), R 2 With R 1b 、R 2 With R 1a or R 2 With R d directly connected to form a 5- to 7-membered heterocyclic ring, which is optionally substituted by 1 to 4 R k replace;

[0091] In some embodiments, R 3 、R 4 Each independently selected from C 1-6 Alkyl, C 3-6 Carbocyclic, 3 to 7 membered heterocyclic, 8 to 12 membered heterocyclic, said alkyl, carbocyclic or heterocyclic optionally substituted by 1 to 4 R k replace;

[0092] Or in the compound represented by general formula (I0-1) or general formula (Ia), R 3 、R 4 directly connected to form a 4- to 10-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0093] In some embodiments, R 3 、R 4 Each independently selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, 4 to 7 membered heterocycloalkyl, 8 to 12 membered heterocycloalkyl, wherein the alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R k replace;

[0094] Or in the compound represented by general formula (I0-1) or general formula (Ia), R 3 、R 4 Directly connected to form a partially saturated 4 to 10 membered heterocyclic group, the heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0095] In some embodiments, R 3 、R 4 Each independently selected from NH2, NHC 1-6 Alkyl, NH(C 3-6 carbon ring), N(C 3-6 Carbon ring) (C 1-6 alkyl), N(C 1-6 Alkyl) 2, wherein the alkyl group, carbocyclic ring is optionally substituted by 1 to 4 R k replace;

[0096] In some embodiments, R 3 、R 4 Each independently selected from NH2, NHC 1-4 Alkyl, NH(C 3-6 carbon ring), N(C 3-6 Carbon ring) (C 1-4alkyl), N(C 1-4 Alkyl) 2, wherein the alkyl group, carbocyclic ring is optionally substituted by 1 to 4 R k replace;

[0097] In some embodiments, R 3 、R 4 Each independently selected from optionally 1 to 4 R k substituted one of the following groups: NH(CH3), N(CH3)2, NH(CH2CH3), N(CH2CH3)2, N(cyclopropyl)(CH3), methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, oxolanyl, oxhexyl, azetidinyl, azetyl or azahexyl;

[0098] In some embodiments, R 3 、R 4 Each independently selected from optionally 1 to 4 R k Substituted one of the following groups: NH2, N(CH3)(CH2CH3), NH(cyclopropyl), NH(cyclobutyl), Azetidinylspirocyclobutyl, azetidinylspirocyclopropyl;

[0099] Or the compound represented by general formula (I0-1) or general formula (Ia) Selected from 1 to 4 R k One of the following groups substituted:

[0100] In some embodiments, the compound represented by formula (I0-1) or formula (Ia) is selected from one of the following optionally substituted groups: When substituted, it is substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, =O, NH2, NH(CH3), N(CH3)2, CHF2, CH2F, CHOCH3, CF3, CD3, methyl, ethyl, methoxy, ethoxy, -O-cyclopropyl or cyclopropyl;

[0101] In some embodiments, the compound represented by formula (I0-1) or formula (Ia) Selected from

[0102] In some embodiments, the compound represented by formula (I0-1) or formula (Ia) Selected from

[0103] Or the compound represented by general formula (I0-1) or general formula (Ia) Selected from

[0104] In some embodiments, the compound represented by formula (I0-1) or formula (Ia) Selected from In some embodiments, R 1 Selected from CN, In some embodiments, the compound represented by formula (I0-1) or formula (Ia) Selected from

[0105] In some embodiments, R 1a 、R 1b 、R 1c Each independently selected from H, deuterium, methyl or CF3;

[0106] In some embodiments, R k Each independently selected from deuterium, halogen, CN, =O, 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;

[0107] In some embodiments, R k Each independently selected from deuterium, halogen, CN, =O, 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;

[0108] In some embodiments, R k Each is independently selected from deuterium, F, Cl, Br, I, CN, =O, 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, cyclo Pentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl are optionally substituted by 1 to 4 groups selected from halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0109] In some embodiments, p1 and p2 in the compound represented by formula (I0-1) or formula (Ia) are each independently selected from 0, 1, 2, 3 or 4;

[0110] In some embodiments, p1 and p2 in the compound represented by formula (I0-1) or formula (Ia) are each independently selected from 0, 1, and 2;

[0111] In some embodiments, a in the compound represented by formula (I0-1) or formula (Ia) is selected from 0 or 1.

[0112] As a first embodiment of the present invention, the compound represented by the aforementioned general formula (I0) or general formula (I0-1) or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0113] When the compound is selected from the compounds represented by general formula (I0):

[0114] Ring C is selected from

[0115] X is selected from CH or N;

[0116] Ring D is selected from phenyl, naphthyl, 5- to 6-membered heteroaryl, and 5- to 12-membered heterocyclic ring;

[0117] Ring B is selected from C 6-10 Aryl, benzo C 4-6 Carbocyclic, 5- to 6-membered heteroaryl, or 8- to 10-membered cyclic heteroaryl;

[0118] R a 、R b 、R d Each independently 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 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)-C3-6 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;

[0119] R 3 Selected from C 2-8 Alkyl, C 3-10 Carbocyclic group, 4 to 12 membered heterocyclic group, said alkyl, carbocyclic group or heterocyclic group is substituted by 5 to 10 halogens, said alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0120] R c1 Selected from H, C 1-6 Alkyl, C 3-10 Carbocyclic group, 4 to 12 membered heterocyclic group, said alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0121] R 1 Selected from halogen, CN,

[0122] 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, 3- to 7-membered heterocyclic, C 6-10 Aryl, 5 to 6 membered heteroaryl, the alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl or heteroaryl group is optionally substituted by 1 to 5 R k replace;

[0123] R 1e is selected from halogen or -OS(=O)2R;

[0124] 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;

[0125] R 2 Selected from H or C 1-4 alkyl;

[0126] 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, said carbocyclic or heterocyclic ring being optionally substituted by 1 to 4 R k replace;

[0127] Alternatively, R 1a With R 2 、R 1b With R 2 directly connected to form a 4- to 7-membered heterocyclic ring, which is optionally substituted by 1 to 4 R k replace;

[0128] R k Each independently selected from deuterium, halogen, =O, 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;

[0129] p1 and p2 are each independently selected from 0, 1, 2, 3 or 4;

[0130] p3 is selected from 0, 1, 2, 3 or 4;

[0131] p4 is selected from 0 or 1;

[0132] When the compound is selected from the compounds represented by general formula (I0-1):

[0133] Ring B is selected from C 6-10 Aryl, benzo C 4-6 Carbocyclic, 5- to 6-membered heteroaryl, 8- to 10-membered heteroaryl, partially saturated C3-6 Carbocyclic group;

[0134] Q is selected from -C(=O)- or a bond;

[0135] Ring D is selected from C 6-10 Carbocyclic ring, 5- to 10-membered heterocyclic ring;

[0136] Ring C is selected from

[0137] C1, C2, C3, C4 are each independently selected from N or CH, and at most 2 are selected from N, and the CH is optionally replaced by R c4 replace;

[0138] R b 、R d 、R c4 Each independently 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 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;

[0139] R c1 Selected from H, OH, CN, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, -OC 1-6 Alkyl, said alkyl being optionally substituted by 1 to 4 R kreplace;

[0140] R c2 Selected from H, halogen, CN, C 1-6 Alkyl, -OC 1-6 Alkyl, said alkyl being optionally substituted by 1 to 4 R k replace;

[0141] R c3 Selected from NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, NHC 3-6 Carbocyclic ring, the alkyl group or carbocyclic ring is optionally substituted by 1 to 4 R k replace;

[0142] R c5 Selected from H, C 1-6 Alkyl, said alkyl being optionally substituted by 1 to 4 R k replace;

[0143] R c6 Selected from H, deuterium, halogen, CN, C 1-6 Alkyl, -OC 1-6 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl is optionally substituted by 1 to 4 R k replace;

[0144] R 1 Selected from halogen, CN,

[0145] 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;

[0146] R 1e is selected from halogen or -OS(=O)2R;

[0147] R is selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6Carbocyclic 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;

[0148] 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, said carbocyclic or heterocyclic ring being optionally substituted by 1 to 4 R k replace;

[0149] R 2 Selected from H or C 1-6 alkyl;

[0150] Alternatively, R 2 With R 1b 、R 2 With R 1a or R 2 With R d Directly connected to form a 4 to 7 membered heterocyclic group, the heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0151] R 3 、R 4 Each independently selected from C 1-6 Alkyl, C 3-6 Carbocyclic, 3 to 7 membered heterocyclic, 8 to 12 membered heterocyclic, said alkyl, carbocyclic or heterocyclic optionally substituted by 1 to 4 R k replace;

[0152] or R 3 、R 4 Each independently selected from NH2, NHC 1-6 Alkyl, NH(C 3-6 carbon ring), N(C 3-6 Carbon ring) (C 1-6 alkyl), N(C 1-6 Alkyl) 2, wherein the alkyl group, carbocyclic ring is optionally substituted by 1 to 4 R k replace;

[0153] or R 3 、R 4 directly connected to form a 4- to 10-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0154] R k Each independently selected from deuterium, halogen, CN, =O, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C2-6 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;

[0155] p1 and p2 are each independently selected from 0, 1, 2, 3 or 4;

[0156] a is selected from 0 or 1.

[0157] As a second embodiment of the present invention, the compound represented by the above-mentioned general formula (I0) or general formula (I0-1) or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, the compound represented by general formula (I0) is selected from general formula (I) or general formula (II)

[0158] The definitions of the remaining groups are the same as those in the first embodiment.

[0159] As a third embodiment of the present invention, the compound represented by the above-mentioned general formula (I0), general formula (I0-1), general formula (I) or general formula (II) or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0160] When the compound is selected from the compounds represented by general formula (I0), general formula (I) or general formula (II):

[0161] Ring B is selected from phenyl, naphthyl, benzo 4-6 Carbocyclic ring, benzo 4- to 6-membered heterocyclic ring, 5- to 6-membered heteroaryl, 8- to 10-membered heteroaryl ring;

[0162] Ring D is selected from phenyl, naphthyl, 5- to 6-membered heteroaryl, 5- to 6-membered monoheterocyclic ring, and 7- to 12-membered spiroheterocyclic ring;

[0163] R 3 Selected from C 2-6 Alkyl, C3-6 Cycloalkyl, 4- to 7-membered heterocycloalkyl, wherein the alkyl, cycloalkyl or heterocycloalkyl is substituted with 5 to 10 halogens;

[0164] R a 、R b 、R d Each independently selected from H, 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-membered carbon ring, 3- to 7-membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbon ring or heterocycle is optionally substituted by 1 to 4 R k replace;

[0165] 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;

[0166] 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, 3- to 7-membered heterocyclic, C 6-10 Aryl, 5 to 6 membered heteroaryl, the alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, C 6-10 Aryl or 5- to 6-membered heteroaryl is optionally substituted with 1 to 4 R k replace;

[0167] 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;

[0168] Alternatively, R 1a With R 2 、R 1b With R 2 directly connected to form a 4- to 7-membered heterocyclic ring, which is optionally substituted by 1 to 4 R k replace;

[0169] R k Each independently selected from deuterium, halogen, =O, 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;

[0170] When the compound is selected from the compounds represented by general formula (I0-1):

[0171] Ring B is selected from phenyl, naphthyl, C 3-6 Cycloalkyl, C 5-6 Cycloalkenyl, benzo C 4-6 Carbocyclic ring, benzo 4- to 6-membered heterocyclic ring, 5- to 6-membered heteroaryl, 8- to 10-membered heteroaryl ring;

[0172] Ring D is selected from phenyl, benzo 4-6 Carbocycle, benzo 4- to 6-membered heterocycle, 5- to 6-membered heteroaryl, 5- to 6-membered partially saturated heterocyclic group;

[0173] R b 、R d 、R c4 Each independently selected from H, 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, -OC1-4 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-membered carbon ring, 3- to 7-membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbon ring or heterocycle is optionally substituted by 1 to 4 R k replace;

[0174] R c1 Selected from H, OH, CN, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, -OC 1-4 Alkyl, said alkyl being optionally substituted by 1 to 4 R k replace;

[0175] R c2 Selected from H, halogen, CN, C 1-4 Alkyl, -OC 1-4 Alkyl, said alkyl being optionally substituted by 1 to 4 R k replace;

[0176] R c3 Selected from NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, NHC 3-6 Cycloalkyl, said alkyl or cycloalkyl is optionally substituted by 1 to 4 R k replace;

[0177] R c6 Selected from H, deuterium, halogen, CN, C 1-4 Alkyl, -OC 1-4 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl is optionally substituted by 1 to 4 R k replace;

[0178] 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 3-6Carbocyclic 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;

[0179] 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;

[0180] R 2 Selected from H or C 1-4 alkyl;

[0181] Alternatively, R 2 With R 1b 、R 2 With R 1a or R 2 With R d Directly connected to form a 4 to 7 membered heterocyclic group, the heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0182] R 3 、R 4 Each independently selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, 4 to 7 membered heterocycloalkyl, 8 to 12 membered heterocycloalkyl, wherein the alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R k replace;

[0183] or R 3 、R 4 Each independently selected from NH2, NHC 1-4 Alkyl, NH(C 3-6 carbon ring), N(C 3-6 Carbon ring) (C 1-4 alkyl), N(C 1-4 Alkyl) 2, wherein the alkyl group, carbocyclic ring is optionally substituted by 1 to 4 R k replace;

[0184] or R 3 、R 4 Directly connected to form a partially saturated 4 to 10 membered heterocyclic group, the heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0185] R k Each independently selected from deuterium, halogen, CN, =O, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC1-4 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;

[0186] The definitions of the remaining groups are the same as those in the first or second embodiment.

[0187] As a fourth embodiment of the present invention, the compound represented by the above-mentioned general formula (I0), general formula (I0-1), general formula (I) or general formula (II) or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0188] When the compound is selected from the compounds represented by general formula (I0), general formula (I) or general formula (II):

[0189] Ring B is selected from phenyl or naphthyl;

[0190] Ring D is selected from phenyl, naphthyl, pyridazinyl, pyrazinyl, pyridinyl, pyrimidinyl,

[0191] R c1 Selected from C 1-4 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl being optionally substituted with 1 to 4 deuterium or halogen;

[0192] R 1 Selected from CN,

[0193] Alternatively, R 1a With R 2 、R 1b With R 2 directly connected to form a 4- to 7-membered heterocyclic ring, which is optionally substituted by 1 to 4 R k replace;

[0194] R 3Selected from ethyl, propyl, isopropyl, butyl, pentyl, cyclopropyl, cyclobutyl, wherein the ethyl, propyl, isopropyl, butyl, pentyl, cyclopropyl, cyclobutyl is substituted with 5 to 8 substituents selected from F, Cl, Br, I;

[0195] When the compound is selected from the compounds represented by general formula (I0-1):

[0196] Ring B is selected from phenyl, naphthyl, pyridyl, cyclopentyl, cyclohexyl, cyclopentenyl or cyclohexenyl;

[0197] Ring D is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolidinyl, azacyclopentyl, azacyclohexyl or azacyclohexenyl;

[0198] Ring C is selected from

[0199] R 1 Selected from CN,

[0200] R 3 、R 4 Each independently selected from optionally 1 to 4 R k Substituted one of the following groups: NH2, NH(CH3), N(CH3)2, NH(CH2CH3), N(CH2CH3)2, N(cyclopropyl)(CH3), N(CH3)(CH2CH3), NH(cyclopropyl), NH(cyclobutyl), methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, oxolanyl, oxhexyl, azetidinyl, azerolyl, azetidinylspirobutyl, azerolspiropropyl, or azetidinyl;

[0201] or Selected from 1 to 4 R k One of the following groups substituted:

[0202] p3 is selected from 0, 1, 2, 3 or 4;

[0203] The remaining groups are defined the same as in the first, second or third embodiment of the present invention.

[0204] As a fifth embodiment of the present invention, the compound represented by the above-mentioned general formula (I0), general formula (I0-1), general formula (I) or general formula (II) or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0205] When the compound is selected from the compounds represented by general formula (I0), general formula (I) or general formula (II):

[0206] R 3 Selected from

[0207] Selected from

[0208] R c1 is selected from methyl, ethyl, propyl, isopropyl, butyl, pentyl, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, propyl, isopropyl, butyl, pentyl, cyclopropyl, and cyclobutyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, and I;

[0209] 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,

[0210] 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, cyclohexyl, pyrrolidinyl, phenyl, wherein the methyl, ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl or phenyl is optionally substituted by 1 to 4 R k replace;

[0211] Alternatively, R 1a With R 2 、R 1b With R 2 directly connected to form a 4- to 7-membered heterocyclic ring; the heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0212] R kEach is independently selected from deuterium, F, Cl, Br, I, =O, 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, cyclo Pentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl are optionally substituted by 1 to 4 groups selected from halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0213] p3 is selected from 0, 1, 2, 3 or 4;

[0214] When the compound is selected from the compounds represented by general formula (I0-1):

[0215] Selected from

[0216] Selected from or Selected from

[0217] R b 、R d Each is independently selected from H, deuterium, F, Cl, Br, I, cyano, OH, NH2, NH(CH3), N(CH3)2, CF3, CD3, methyl, ethyl, propyl, isopropyl, butyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;

[0218] R c4 Each is independently selected from deuterium, F, Cl, Br, I, CN, methyl, ethyl, NH(CH3), N(CH3)2, methoxy, ethoxy, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrazolyl, wherein the methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrazolyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), N(CH3)2, CF3, CD3, methyl, ethyl, methoxy, ethoxy or cyclopropyl;

[0219] R c5 is selected from H, methyl, ethyl, propyl or isopropyl, wherein the methyl, ethyl, propyl or isopropyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), N(CH3)2, CF3, CD3, methyl, ethyl, methoxy, ethoxy or cyclopropyl;

[0220] R c6 is selected from H, deuterium, halogen, F, Cl, Br, I, CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl or cyclobutyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl or cyclobutyl is optionally substituted by 1 to 4 R k replace;

[0221] 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, cyclohexyl, pyrrolidinyl, wherein the methyl, ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or pyrrolidinyl is optionally substituted by 1 to 4 R k replace;

[0222] R 2 Selected from H or methyl;

[0223] Alternatively, R 2 With R 1b 、R 2 With R 1a or R 2 With R d directly connected to form a 5- to 7-membered heterocyclic ring, which is optionally substituted by 1 to 4 R k replace;

[0224] is selected from one of the following optionally substituted groups: When substituted, it is substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, =O, NH2, NH(CH3), N(CH3)2, CF3, CD3, methyl, ethyl, methoxy, ethoxy or cyclopropyl;

[0225] R kEach is independently selected from deuterium, F, Cl, Br, I, CN, =O, 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, cyclo Pentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl are optionally substituted by 1 to 4 groups selected from halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0226] The remaining groups are defined the same as in any one of the first, second, third or fourth embodiments of the present invention.

[0227] As a sixth embodiment of the present invention, the compound represented by the above-mentioned general formula (I0), general formula (I0-1), general formula (I) or general formula (II) or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0228] When the compound is selected from the compounds represented by general formula (I0), general formula (I) or general formula (II):

[0229] R 1 Selected from CN, ethynyl; or

[0230] Selected from

[0231] R 1a 、R 1b 、R 1c Each independently selected from H, deuterium, F, Cl, Br, I, CN, methyl, ethyl, CF3, vinyl, ethynyl, phenyl;

[0232] Preferably, Selected from

[0233] p1 is 0 or 1;

[0234] R c1is selected from methyl, isopropyl or cyclopropyl, wherein the methyl, isopropyl or cyclopropyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I;

[0235] R3 is selected from

[0236] Selected from

[0237] R d Selected from deuterium, F, Cl, Br, I, cyano, OH, NH2, NH(CH3), N(CH3)2, CF3, methyl, ethyl, propyl, isopropyl, butyl, ethynyl, methoxy, ethoxy;

[0238] When the compound is selected from the compounds represented by general formula (I0-1):

[0239] Selected from

[0240] or Selected from

[0241] 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, cyclohexyl, or pyrrolidinyl, wherein the methyl, ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or pyrrolidinyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, ═O, NH2, NH(CH3), N(CH3)2, NH(CH2CH3), N(CH2CH3)2, CF3, CD3, methyl, ethyl, methoxy, ethoxy, cyclopropyl, azacyclohexyl, pyrrolidinyl, or morpholinyl;

[0242] The remaining groups are defined the same as in any one of the first, second, third, fourth or fifth embodiments of the present invention.

[0243] As a seventh embodiment of the present invention, the compound represented by the above general formula (I0-1) or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0244] Selected from or Selected from

[0245] R 1 Selected from CN,

[0246] or Selected from

[0247] R 1a 、R 1b 、R 1c Each independently selected from H, deuterium, methyl or CF3;

[0248] The remaining groups are defined the same as in any one of the first, second, third, fourth, fifth or sixth embodiments of the present invention.

[0249] As an eighth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0250] Ring B is selected from phenyl or naphthyl, preferably phenyl, Ring D is selected from phenyl or naphthyl, preferably phenyl, R c1 is selected from methyl, deuterated methyl or halomethyl, R c1 Preferably H, methyl, CD3, CHD2, CH2D, CF3, CHF2, CH2F, R a Each independently selected from methyl, deuterated methyl or halomethyl, R 3 Selected from R 3 Preferred Selected from ethynyl, R 1a 、R 1b 、R 1c Each independently selected from H, deuterium, F, Cl, Br, CN, methyl, ethyl, CF3, Preferably ethynyl, R b 、R d Each independently selected from deuterium, F, Cl, Br, I, cyano, OH, CF3, methyl, ethyl, propyl, isopropyl, butyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Preferred are deuterium, F, Cl, Br, cyano, OH, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, p1 is 0 or 1, and p2 or p3 are each independently selected from 0, 1, 2, 3 or 4.

[0251] As a ninth embodiment of the present invention, the compound represented by the above general formula (I0-1) or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, the general formula (I0-1) is selected from the general formula (Ia)

[0252] Ring D is selected from phenyl or 5- to 6-membered heteroaryl, Preferred R2 is selected from H, R 1a 、R 1b 、R 1c Each independently selected from H, deuterium, F, Cl, Br, CN, methyl, ethyl, CF3, Preferred R b 、R d Each independently selected from deuterium, F, Cl, Br, I, cyano, OH, CF3, methyl, ethyl, propyl, isopropyl, butyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Deuterium, F, Cl, Br, cyano, OH, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, is selected from one of the following optionally substituted groups: When substituted, it is substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, =O, NH2, NH(CH3), N(CH3)2, CF3, CD3, methyl, ethyl, methoxy, ethoxy or cyclopropyl; p1 or p2 are each independently selected from 0, 1, 2, 3 or 4.

[0253] The present invention relates to the compounds shown below, or stereoisomers, racemates, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals thereof, wherein the compound is selected from one of the structures shown in Table E-1 or Table E-2;

[0254] Table E-1

[0255] Table E-2

[0256] The present invention relates to a pharmaceutical composition comprising any of the above compounds or their stereoisomers, racemates, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and a pharmaceutically acceptable carrier.

[0257] 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, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier.

[0258] 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").

[0259] 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.

[0260] 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, 1 25 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, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

[0261] 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, racemate, 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 a tumor or cancer).

[0262] A method for treating a disease in a mammal, comprising administering to a subject a compound of the present invention or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof at a daily dose of 1-1000 mg / day, wherein the daily dose can be a single dose or divided doses. In some embodiments, the daily dose includes but is not limited to 10-1500 mg / day, 10-1000 mg / day, 10-800 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, / 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.

[0263] 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, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and the amount of the compound of the present invention or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is the same as the amount in the above-mentioned pharmaceutical composition.

[0264] The present invention relates to the use of any of the above-mentioned compounds or their stereoisomers, racemates, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals for the preparation of drugs for treating diseases related to FGFR2 activity or expression. Preferably, the disease is selected from tumors or cancers, preferably solid tumors, bile duct cancer or intrahepatic bile duct cancer.

[0265] The present invention relates to the use of the above-mentioned pharmaceutical composition in the preparation of a drug for treating a disease related to FGFR2 activity or expression. Preferably, the disease is selected from tumors or cancers, preferably solid tumors, bile duct cancer or intrahepatic bile duct cancer.

[0266] The amount of the compound of the invention or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is in each case calculated as the free base.

[0267] The compounds of the present invention can be prepared by the following method:

[0268] General synthesis method 1 of general formula (I):

[0269] The compound of the general formula (M-1) and the compound of the general formula (M-2) undergo a substitution reaction to obtain the compound of the general formula (M-3);

[0270] Compound (M-3) and compound (M-4) undergo coupling reaction to obtain compound (M-5);

[0271] The general formula compound (M-5) is reacted with NIS to obtain the general formula compound (M-6);

[0272] Compound (M-6) and compound (M-7) are reacted by coupling reaction to obtain compound (I);

[0273] R m1 Selected from halogen, trifluoromethanesulfonyl, methylsulfonyl and other easy leaving groups;

[0274] R m2 and R m3 each selected from borate esters, boric acid, borate salts;

[0275] The definitions of the remaining groups are consistent with those in the description of the present invention.

[0276] General synthesis method of formula (II-A):

[0277] Compound (M-8) and compound (M-9) of the general formula are reacted by coupling reaction to obtain compound (M-10);

[0278] The compound of the general formula (M-10) is subjected to a halogenation reaction to obtain the compound of the general formula (M-11);

[0279] The compound of the general formula (M-11) and the compound of the general formula (M-4) are reacted by coupling reaction to obtain the compound of the general formula (M-12);

[0280] The compound of the general formula (M-12) is subjected to removal of the amino protecting group to obtain the compound of the general formula (M-13);

[0281] The compound of the general formula (M-13) and the compound of the general formula (M-14) are reacted by condensation or substitution to obtain the compound of the general formula (II-A);

[0282] R m2 and R m3 For borate ester, boric acid, borate;

[0283] R m4 is an amino protecting group such as Boc or Cbz;

[0284] R m5 is a group such as Cl, bromine or iodine;

[0285] R m6 is a hydroxyl, Cl, bromine or iodine group;

[0286] The definitions of the remaining groups are consistent with those in the description of the present invention.

[0287] General formula Z synthesis method 1:

[0288] Compound Z-1 and compound Z-2 undergo coupling reaction to obtain compound Z-3;

[0289] Compound Z-3 and compound Z-4 undergo condensation or substitution reaction to obtain compound Z;

[0290] R m1 Each is independently selected from substituents such as Cl, bromine, iodine, boric acid, boric ester or borate;

[0291] R m2 A substituent selected from Cl, Br, OH, etc.;

[0292] The definitions of the remaining groups are the same as those in the specification.

[0293] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0294] 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.

[0295] "Halogen" refers to F, Cl, Br or I.

[0296] "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".

[0297] "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.

[0298] "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.

[0299] "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.

[0300] "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.

[0301] "Alkenyl" refers to a substituted or unsubstituted straight-chain or branched unsaturated hydrocarbon group having at least one, typically one, two, or three, carbon-carbon double bonds, with a backbone of 2 to 10, 2 to 6, or 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, and 2-methyl-3-butenyl. Alkenyl groups appearing herein have the same definition as herein. Alkenyl groups may be monovalent, divalent, trivalent, or tetravalent.

[0302] "Alkynyl" refers to a substituted or unsubstituted straight 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, or 2 to 4 carbon atoms in the backbone. 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-pentynyl, 1-methyl-1-butynyl, and the like. Alkynyl radicals can be monovalent, divalent, trivalent, or tetravalent.

[0303] "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.

[0304] "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.

[0305] "Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, which may 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 selectively substituted in the heterocyclyl ring may be oxidized to various oxidation states. The heterocyclyl may be attached to a heteroatom or a carbon atom, the heterocyclyl may be attached to an aromatic ring or a non-aromatic ring, the heterocyclyl may be attached to a bridged ring or a spirocycle, non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolane, 1,4-dioxolane, 1,3-dioxahexanyl, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, Pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithiazyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophenyl, benzofuranyl, benzopyrrolyl, benzimidazolyl. "Heterocyclyl" or "heterocycle" can be monovalent, divalent, trivalent or tetravalent.

[0306] "Spirocycle" or "spirocyclyl" refers to a polycyclic group in which the substituted or unsubstituted rings share an 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:

[0307] "Spirocycle" or "spirocyclyl" can be monovalent, divalent, trivalent or tetravalent.

[0308] "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.

[0309] "Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected, which may contain zero or more double bonds, and any ring in the 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.

[0310] "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.

[0311] "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 divalent, trivalent or tetravalent, the attachment point is located on the heteroaryl ring.

[0312] "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 dEach is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring or paracyclic group.

[0313] “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.

[0314] "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.

[0315] 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.

[0316] "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.

[0317] "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.

[0318] "Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, or stereoisomers, racemates, 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.

[0319] "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.

[0320] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0321] "Animal" is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

[0322] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, optical isomers, enantiomers, diastereomers and conformational isomers.

[0323] "Tautomers" refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions, such as keto-enol isomers and amide-imino alcohol isomers. DETAILED DESCRIPTION

[0324] 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.

[0325] 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).

[0326] MS was determined using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0327] HPLC determination was performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM);

[0328] 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.

[0329] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier;

[0330] 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.

[0331] THF: tetrahydrofuran; DMF: N,N-dimethylformamide; DIPEA: N,N-diisopropylethylamine; HATU: CAS 148893-10-1; NIS: N-iodosuccinimide; TCFH: tetramethylchlorouronium hexafluorophosphate; DME: ethylene glycol dimethyl ether;

[0332] PdCl2(dtbpf)CAS:95408-45-0;

[0333] XantPhos CAS:161265-03-8;

[0334] Pd(dppf)Cl2.DCM CAS 95464-05-4.

[0335] The trifluoroacetate salt of the compound is prepared from its free base by dissolving the trifluoroacetate salt in DCM, adjusting the pH to >8 with 1N sodium bicarbonate solution, separating the organic phase, and extracting the aqueous phase three times with DCM. The combined organic phases are dried over anhydrous sodium sulfate, concentrated, and the residue is dissolved in acetonitrile / water and lyophilized to obtain the free base form of the compound.

[0336] Example 1: Preparation of Compound 1

[0337] Step 1: Preparation of 1C

[0338] 1A (30 g, 96.76 mmol) was dissolved in 500 mL of ether, cooled to 0°C, and vinyl ethyl ether 1B (6.98 g, 96.76 mmol) and pyridine (7.65 g, 96.76 mmol) were slowly added dropwise. The mixture was stirred at room temperature for 12 h. 150 mL of 1N dilute hydrochloric acid was added, and the organic phase was separated, washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1C (20 g, 94.76%).

[0339] Step 2: 1D preparation

[0340] Dissolve urea (6.06 g, 100.86 mmol) in 500 mL of methanol under nitrogen. Slowly add 1C (20 g, 91.69 mmol) to the reaction mixture in an ice bath and stir for 15 min. Add 150 mL of concentrated hydrochloric acid and react at 60°C overnight. Cool to room temperature and stir at 0°C for 1 h. Filter the precipitated white solid, wash twice with water and then twice with petroleum ether, then concentrate under reduced pressure to remove residual water and solvent to yield 1D (4 g, 20.38%).

[0341] Step 3: Preparation of 1E

[0342] Under nitrogen, 1D (4 g, 18.68 mmol) was dissolved in 30 mL of phosphorus oxychloride solution and reacted at 70°C for 2 h. The reaction solution was slowly added to ice water, and the pH was adjusted to neutral by adding aqueous sodium bicarbonate. The solution was extracted with ethyl acetate (30 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a silica gel column to obtain 1E (2 g, 46.03%).

[0343] Step 4: Preparation of 1G

[0344] Under nitrogen, 1E (2 g, 8.60 mmol) and 1F (0.82 g, 4.30 mmol) were dissolved in 50 mL of DMF, and cesium carbonate (8.41 g, 25.80 mmol) was added. The mixture was reacted at 100°C overnight. The reaction solution was cooled to room temperature, and water (20 mL) was added. The mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined and washed sequentially with water (20 mL × 2) and a saturated aqueous solution of NaCl (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 column chromatography to obtain 1G (0.8 g, 24.03% yield).

[0345] LCMS m / z(ESI):386.9[M+H] +

[0346] Step 5: Preparation of 1H

[0347] Under nitrogen, 1G (0.8 g, 2.07 mmol), bis(pinacolato) borate (0.79 g, 3.10 mmol), potassium acetate (0.61 g, 6.21 mmol), and Pd(dppf)Cl2.DCM (0.34 g, 0.41 mmol) were dissolved in 20 mL of 1,4-dioxane and reacted at 90°C for 3 h. The reaction solution was cooled to room temperature, 50 mL of acetonitrile was added, and the mixture was stirred at room temperature for 30 min. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 1H (0.5 g, yield: 55.73%).

[0348] LCMS m / z(ESI):435.2[M+H] +

[0349] Step 6: Preparation of 1J

[0350] Under nitrogen, 1H (0.5 g, 1.15 mmol), 1I (0.38 g, 1.38 mmol), potassium fluoride (0.201 g, 3.45 mmol), and PdCl2(dtbpf) (0.15 g, 0.23 mmol) were dissolved in a mixture of DMF and water (10 mL:1 mL) and reacted at 50°C for 2 h. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL × 2). The organic phases were combined and washed sequentially with water (20 mL × 2) and a saturated aqueous solution of NaCl (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 column chromatography to afford 1J (0.38 g, 72.62% yield).

[0351] LCMS m / z(ESI):455.3[M+H] +

[0352] Step 7: Preparation of 1K

[0353] 1J (0.38 g, 0.84 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (0.34 g, 2.94 mmol) and N-iodosuccinimide (0.47 g, 2.10 mmol) were added sequentially. The mixture was allowed to react at room temperature for 16 h. The reaction solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography to afford compound 1K (0.32 g, 65.94% yield).

[0354] LCMS m / z=581.2[M+H] +

[0355] Step 8: Preparation of Compound 1

[0356] 1K (0.1 g, 0.17 mmol), 1L (0.06 g, 0.22 mmol), PdCl2(dtbpf) (0.022 g, 0.034 mmol), and cesium fluoride (0.077 g, 0.51 mmol) were dissolved in a mixed solvent of DMF (5 mL) and water (1 mL) and reacted at 50°C for 2 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL × 2). The organic phases were combined and washed sequentially with water (20 mL × 2) and a saturated aqueous solution of NaCl (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 chromatographed on a silica gel column to obtain the crude product, which was then purified preparatively to obtain the trifluoroacetic acid salt of compound 1 (5 mg, 4.84% yield).

[0357] Preparation Conditions: 1. Apparatus: Waters 2767 Preparative HPLC; Chromatographic Column: Sunfire C18 (19 mm × 250 mm), 5 μm. 2. Dissolve the sample in DMF and filter through a 0.45 μm filter to prepare the sample solution. 3. a. Mobile Phase A, B Composition: Mobile Phase A: Water (containing 1 / 1000th of TFA v / v); Mobile Phase B: Acetonitrile. b. Gradient elution, with Mobile Phase B increasing from 10 to 55. c. Flow rate: 15 ml / min. d. Elution time: 18 min. e. Retention time: Rt = 18.13 min.

[0358] 1 H NMR(400MHz,DMSO-d6)δ10.28(s,1H),9.08(d,1H),8.44(s,1H),7.89(d,1H),7.74(d,2H),7.45(t,1 H),7.33(d,2H),7.28(dd,1H),7.12(dd,1H),6.44(dd,1H),6.27(dd,1H),5.78(dd,1H),3.66(s,3H).

[0359] LCMS m / z(ESI):600.1[M+H] +

[0360] According to the synthesis method of Example 1, the following compounds can be obtained:

[0361] Example 6: Preparation of Compound 6

[0362] Step 1: Preparation of 6C

[0363] Compound 6A (895 mg, 1.92 mmol) (synthesized by replacing 1F with 6-bromo-2-naphthol), 6B (600 mg, 1.48 mmol) (synthesized by patent WO 2023046117), tetrakis(triphenylphosphine)palladium (171 mg, 0.148 mmol), and potassium carbonate (408 mg, 2.96 mmol) were dissolved in 1,4-dioxane (15 mL) and water (3 mL) and reacted at 100°C for 2 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL × 2). The organic phases were combined and washed sequentially with water (20 mL × 2) and a saturated aqueous solution of NaCl (20 mL × 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 6C (600 mg, 60.84% ​​yield).

[0364] LCMS m / z=665.2[M+H] +

[0365] Step 2: Preparation of 6D

[0366] 6C (600 mg, 0.90 mmol) was dissolved in 2N HCl in ethyl acetate (10 mL) and reacted at room temperature for 1 h. The reaction solvent was removed by concentration under reduced pressure to obtain 6D (450 mg, yield 88.29%).

[0367] LCMS m / z=565.2[M+H] +

[0368] Step 3: Preparation of compound 6

[0369] 6D (150 mg, 0.27 mmol) was dissolved in 5 mL of dichloromethane, cooled to 0°C, and triethylamine (118 mg, 0.56 mmol) was added. Acryloyl chloride 6E (26 mg, 0.29 mmol) was then added dropwise. The mixture was allowed to react at room temperature for 1 h. The reaction solvent was removed by concentration under reduced pressure, and the residue was purified by column chromatography to afford compound 6 (30 mg, yield: 18.25%).

[0370] LCMS m / z=619.0[M+H] +

[0371] 1 H NMR(400MHz,CD3OD)δ8.93(d,1H),8.10(s,1H),8.07(d,1H),8.02(d,2H),7.83(d,1H) ,7.67(d,1H),7.57–7.51(m,3H),7.49–7.44(m,3H),6.44–6.30(m,2H),5.75(dd,1H).

[0372] Example 7: Preparation of Compound 7

[0373] Referring to the preparation method of compound 6, 6E was replaced by 7A to prepare compound 7 (10 mg, yield 5.94%)

[0374] LCMS m / z=633.0[M+H] +

[0375] 1 H NMR(400MHz,CD3OD)δ8.93(d,1H),8.11(s,1H),8.07(d,1H),8.02(d,2H),7.83(d,1H),7 .67(d,1H),7.57–7.50(m,3H),7.49–7.44(m,3H),5.76(s,1H),5.49(s,1H),1.99(s,3H).

[0376] Example 8: Preparation of Compound 8

[0377] 6D (150 mg, 0.27 mmol) was dissolved in 5 mL of dichloromethane. 2-Fluoroacrylic acid 8A (25 mg, 0.28 mmol), N-methylimidazole (48 mg, 0.58 mmol), and TCFH (162 mg, 0.58 mmol) were added at 0°C and allowed to react at room temperature for 1 h. The reaction solvent was removed by concentration under reduced pressure, and the residue was purified by column chromatography to obtain compound 8 (20 mg, yield: 11.82%).

[0378] LCMS m / z=637.0[M+H] +

[0379] 1 H NMR(400MHz,CD3OD)δ8.93(d,1H),8.11(s,1H),8.07(d,1H),8.03(d,2H),7.84(d,1 H),7.67(d,1H),7.60–7.52(m,3H),7.51–7.44(m,3H),5.68(dd,1H),5.27(dd,1H).

[0380] Example 12: Preparation of Compound 12

[0381] Step 1: Preparation of 12B

[0382] 1K (0.325 g, 0.56 mmol), 12A (0.31 g, 1.12 mmol), Pd(dppf)Cl2.DCM (46 mg, 0.056 mmol), and sodium carbonate (120 mg, 1.12 mmol) were added to a sealed tube in sequence and dissolved in a mixture of DME (5 mL) and water (1 mL). The atmosphere was replaced with nitrogen and the reaction was carried out at 90°C for 2 h. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with water (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford compound 12B (300 mg, 78.22% yield).

[0383] LCMS m / z(ESI):685.3[M+H] +

[0384] Step 2: Preparation of compound 12

[0385] 12B (300 mg, 0.44 mmol) and cesium fluoride (200 mg, 1.32 mmol) were added to a single-necked flask and dissolved in DMF (4 mL). The mixture was reacted at room temperature for 3 h. Water (20 mL) was added for dilution 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 a saturated aqueous solution of NaCl (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 HPLC to obtain the trifluoroacetate salt of compound 12 (30 mg, yield: 12.00%).

[0386] Preparation method: Instrument name: SHIMADZU LC-20AP; Chromatographic column: C18; Mobile phase: A: 0.1% trifluoroacetic acid in water; B: acetonitrile; Elution conditions: Gradient elution of B in A from 20% to 40% concentration over 15 minutes; Flow rate: 30 mL / min; Column temperature: Room temperature; Detection wavelengths: 210 & 254 nm;

[0387] 1 H NMR (400MHz, CDCl3) δ10.68(s,1H),8.83(d,1H),8.58(s,1H),8.33(s,1H),7.49(d,1H ),7.37(t,1H),7.07–6.97(m,2H),5.76(s,1H),3.70(s,3H),3.27(s,1H),2.31(s,3H).

[0388] LCMS m / z(ESI):571.0[M+H] +

[0389] Example 13: Preparation of Compound 13

[0390] Compound 13 (30 mg) was obtained by referring to the preparation method of Example 12.

[0391] 1 H NMR (400MHz, CDCl3) δ11.09(s,1H),8.84(d,1H),8.52(s,1H),8.30(s,1H),7.48(d,1H),7. 45(s,1H),7.32(t,1H),7.02(dd,2H),5.73(s,1H),3.66(s,3H),3.29(s,1H),2.03(s,3H).

[0392] LCMS m / z(ESI):570.2[M+H] +

[0393] Example 14: Preparation of Compound 14

[0394] Step 1: Preparation of 14B

[0395] 14A (5 g, 21.50 mmol) was dissolved in acetonitrile (50 mL), and 1-fluorocyclopropanecarboxylic acid (4.48 g, 43.0 mmol) was added. The mixture was heated to 80°C under nitrogen, and 4 mL of silver nitrate aqueous solution (14.61 g, 86 mmol) was added. 6 mL of ammonium persulfate aqueous solution (24.53 g, 107.5 mmol) was slowly added dropwise over approximately 1 hour. The mixture was allowed to react at 80°C for 3 hours. After completion of the reaction, the reaction solution was cooled to room temperature, poured into 50 mL of water, and 5 mL of aqueous ammonia was added. The mixture was then extracted with ethyl acetate (50 mL x 2). The organic phases were combined, washed sequentially with water (50 mL) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 14B (2.2 g, 35.21% yield).

[0396] Step 2: Preparation of compound 14

[0397] The preparation of compound 14 from step 2 to step 6 can refer to the synthetic route of compound 1 from step 4 to step 8, and compound 14 (100 mg, 31.5%) was obtained by HPLC preparation and purification.

[0398] Preparation method: Instrument: SHIMADZU LC-20AP; Preparative column: C18 reversed-phase column; Mobile phase: A: 10 mmol NH4HCO3 aqueous solution; B: acetonitrile; Elution conditions: Gradient elution from 42% to 72% of B in A; Flow rate: 75 mL / min; Column temperature: room temperature; Detection wavelengths: 210 & 254 nm;

[0399] 1 H NMR (400MHz, DMSO-d6) δ10.39(s,1H),8.21(s,1H),7.87–7.76(m,1H),7.76(s,2H),7.39(t,1H),7.32(d,2H),7.20(dd ,1H),7.10(dd,1H),6.16–5.85(m,1H),5.72(dd,1H),5.44(dd,1H),3.61(s,3H),1.78–1.64(m,2H),1.34–1.21(m,2H).

[0400] LCMS m / z(ESI):676.3[M+H] +

[0401] Example 15: Preparation of Compound 15

[0402] Referring to the synthesis method of compound 14, 3A was used instead of 2A, and compound 15 (50 mg) was obtained by HPLC preparation and purification.

[0403] Preparation method: Instrument: SHIMADZU LC-20AP; Preparative column: C18 reversed-phase column; Mobile phase: A: 10 mmol NH4HCO3 aqueous solution; B: acetonitrile; Elution conditions: Gradient elution from 42% to 72% of B in A; Flow rate: 75 mL / min; Column temperature: room temperature; Detection wavelengths: 210 & 254 nm;

[0404] 1 H NMR(400MHz,DMSO-d6)δ9.90(s,1H),8.20(s,1H),7.85(s,1H),7.75(d,2H),7.60–7.45(m,1H),7.39(t,1H),7.28(d,2H),7.20(d d,1H),7.10(d,1H),6.10–5.87(s,1H),5.78(s,1H),5.53(s,1H),3.61(s,3H),1.95(s,3H),1.79–1.64(m,2H),1.34–1.20(m,2H).

[0405] LCMS m / z(ESI):672.2[M+H] +

[0406] Example 18: Preparation of Compound 18

[0407] Step 1: Preparation of 18C

[0408] 18A (600 mg, 1.48 mmol) (synthesis reference patent WO 2023046117), 18B (616 mg, 1.92 mmol) (synthesis reference patent WO 2024008128), tetrakis(triphenylphosphine)palladium (171 mg, 0.148 mmol), and potassium carbonate (408 mg, 2.96 mmol) were dissolved in a mixture of 1,4-dioxane (15 mL) and water (3 mL) and reacted at 100°C for 2 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL × 2). The organic phases were combined and washed sequentially with water (20 mL × 2) and a saturated aqueous solution of NaCl (20 mL × 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 18C (400 mg, 51.89% yield).

[0409] LCMS m / z=520.2[M+H] +

[0410] Step 2: Preparation of 18D

[0411] 18C (400 mg, 0.77 mmol) was dissolved in 2N HCl in ethyl acetate (10 mL) and reacted at room temperature for 1 h. The reaction solvent was removed by concentration under reduced pressure to obtain 18D (300 mg, yield 92.89%).

[0412] LCMS m / z=420.2[M+H] +

[0413] Step 3: Preparation of compound 18

[0414] 18D (120 mg, 0.29 mmol) was dissolved in 5 mL of dichloromethane, cooled to 0°C, and triethylamine (59 mg, 0.28 mmol) was added dropwise. 6E (26 mg, 0.29 mmol) was then added dropwise and allowed to react at room temperature for 1 h. The reaction solvent was removed by concentration under reduced pressure, and the residue was purified by column chromatography to afford compound 18 (30 mg, yield: 22.14%).

[0415] LCMS m / z=474.2[M+H] +

[0416] 1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),8.29(brs,1H),8.11(s,1H),7.61(d,2H),7.43(d,2H),7.24(d,2H),7.03(d,2H), 6.48–6.38(m,1H),6.25(dd,1H),5.75(dd,1H),5.36(brs,1H),3.49–3.39(m,2H),3.34–3.25(m,2H),2.30–2.10(m,4H).

[0417] According to the synthesis method of Example 18, the following compounds can be obtained:

[0418] Example 21: Preparation of Compound 21

[0419] Step 1: Preparation of 21C

[0420] 21A (600 mg, 2.80 mmol) (synthesis reference WO 2023046117), 21B (1.42 g, 4.20 mmol), X-Phos-Pd-G2 (220 mg, 0.28 mmol), and potassium phosphate (1.23 g, 5.60 mmol) were dissolved in 1,4-dioxane (15 mL) and water (3 mL) and reacted at 100°C for 2 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL x 2). The organic phases were combined and washed sequentially with water (20 mL x 2) and a saturated aqueous solution of NaCl (20 mL x 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 21C (600 mg, 62.20% yield).

[0421] LCMS m / z=345.1[M+H] +

[0422] Step 2: Preparation of 21D

[0423] 21C (600 mg, 1.74 mmol) was dissolved in acetonitrile (15 mL), and N-bromosuccinimide (310 mg, 1.74 mmol) was added. The mixture was reacted at 25°C for 10 minutes. Water (20 mL) was added to quench the reaction, and the mixture was filtered. The filter cake was washed twice with water (5 mL x 2) to obtain 21D (600 mg, 81.51% yield).

[0424] LCMS m / z=423.0[M+H] +

[0425] Step 3: Preparation of 21E

[0426] 21D (600 mg, 1.42 mmol), 18B (616 mg, 1.92 mmol), tetrakis(triphenylphosphine)palladium (171 mg, 0.148 mmol), and potassium carbonate (408 mg, 2.96 mmol) were dissolved in a mixture of 1,4-dioxane (15 mL) and water (3 mL) and reacted at 100°C for 2 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL × 2). The organic phases were combined and washed sequentially with water (20 mL × 2) and a saturated aqueous solution of NaCl (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 column chromatography to afford 21E (400 mg, 52.39% yield).

[0427] LCMS m / z=538.2[M+H] +

[0428] Step 4: Preparation of 21F

[0429] 21E (400 mg, 0.74 mmol) was dissolved in 2N HCl in ethyl acetate (10 mL) and reacted at room temperature for 1 h. The reaction solvent was removed by concentration under reduced pressure to obtain the hydrochloride salt of 21F (300 mg).

[0430] LCMS m / z=438.2[M+H] +

[0431] Step 5: Preparation of compound 21

[0432] 21F (120 mg, 0.27 mmol) was dissolved in 5 mL of dichloromethane, cooled to 0°C, and triethylamine (59 mg, 0.28 mmol) was added. 6E (24 mg, 0.27 mmol) was then added dropwise. The mixture was allowed to react at room temperature for 1 h. The reaction solvent was removed by concentration under reduced pressure, and the residue was purified by preparative HPLC to afford compound 21 (25 mg, yield: 18.54%).

[0433] Preparation method: Instrument name: SHIMADZU LC-20AP; Chromatographic column: C18; Mobile phase: A: 10 mmol / L NH4HCO3 aqueous solution; B: acetonitrile; Elution conditions: Gradient elution of B in A solution from 18% to 38% over 15 minutes; Flow rate: 30 mL / min; Column temperature: Room temperature; Detection wavelengths: 210 & 254 nm;

[0434] LCMS m / z=492.1[M+H] +

[0435] 1 H NMR(400MHz,CD3OD)δ8.08(s,1H),7.62(dd,1H),7.40–7.29(m,2H),7.24–7.17(m,2H),7.12–7.05(m,2H),6 .43–6.36(m,2H),5.79(dd,1H),3.50–3.38(m,2H),3.30–3.21(m,2H),2.41–2.30(m,2H),2.29–2.17(m,2H).

[0436] Example 24: Synthesis of Compound 24

[0437] Step 1: Synthesis of 24C

[0438] 24A (1.9 g, 4.96 mmol), Pd(dppf)Cl2.DCM (0.41 g, 0.50 mmol), 24B (1.17 g, 4.96 mmol), cuprous iodide (0.19 g, 0.99 mmol), and triethylamine (1.51 g, 14.88 mmol) were dissolved in 40 mL of 1,4-dioxane and reacted at 50°C under a nitrogen atmosphere for 3 h. The mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography to afford 24C (2.0 g, 82.21%).

[0439] LCMS m / z=490.2[M+H] +

[0440] Step 2: Synthesis of 24E

[0441] 24C (2.0 g, 4.08 mmol), Pd2(dba)3 (0.37 g, 0.41 mmol), 24D (0.86 g, 4.08 mmol), XantPhos (0.47 g, 0.82 mmol), and cesium carbonate (2.66 g, 8.16 mmol) were dissolved in 30 mL of 1,4-dioxane / water (4:1) and reacted at 100°C under a nitrogen atmosphere for 12 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 24E (1.4 g, 55.38%).

[0442] LCMS m / z=620.2[M+H] +

[0443] Step 3: Synthesis of 24F

[0444] Compound 24E (1.4 g, 2.26 mmol) was dissolved in 30 mL of acetonitrile, and NBS (360 mg, 2.03 mmol) was slowly added at 0°C. The mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 24F (1.4 g, 88.7%).

[0445] LCMS m / z=698.3[M+H] +

[0446] Step 4: Synthesis of 24G

[0447] 24F (1.4 g, 2.00 mmol), Pd(dppf)Cl2.DCM (0.16 g, 0.20 mmol), trimethylboroxine (1.26 g, 10 mmol), and cesium carbonate (1.95 g, 6 mmol) were dissolved in 40 mL of 1,4-dioxane and 5 mL of water and reacted at 110°C under a nitrogen atmosphere for 4 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound 24G (1.4 g, 88.7%).

[0448] LCMS m / z=634.2[M+H] +

[0449] Step 5: 24H synthesis

[0450] 24G (0.3 g, 0.47 mmol) was dissolved in 1 mL of 1,4-dioxane and 3 mL of aqueous ammonia, stirred at 180°C in a microwave oven for 4 h, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 24H (0.16 g, 75.01%).

[0451] LCMS m / z=451.1[M+H] +

[0452] Step 6: Synthesis of compound 24

[0453] 24H (0.13 g, 0.29 mmol) and 24I (20.9 mg, 0.29 mmol) were dissolved in 10 mL of dichloromethane, and N-methylimidazole (95 mg, 1.16 mmol) was slowly added. The mixture was stirred at room temperature for 10 minutes, and TCFH (0.16 g, 0.58 mmol) was slowly added. The mixture was reacted at room temperature for 12 hours. After concentration under reduced pressure, compound 24 (10 mg, 6.87%) was obtained by silica gel column chromatography.

[0454] LCMS m / z=505.2[M+H] +

[0455] The following compounds can be prepared by referring to the synthesis method of Example 24:

[0456] Example 33: Synthesis of Compound 33

[0457] Step 1: Preparation of 33B

[0458] 33A (1.4 g, 4.2 mmol) was dissolved in acetonitrile (30 mL). N-chlorosuccinimide (0.62 g, 4.6 mmol) and a solution of tetrabutylammonium fluoride in THF (4.6 mL, 4.6 mmol, 1 M) were added at 0°C. The mixture was allowed to react at room temperature for 30 minutes. The mixture was concentrated under reduced pressure, dissolved in acetonitrile (20 mL), and 3-(S)-fluoropyrrolidine (0.82 g, 9.2 mmol) was added. The reaction was allowed to react at room temperature for 2 hours. The reaction solution was concentrated and dried, and purified by column chromatography (PE / EtOAc = 0-20%) to obtain 33B (1.0 g, 56.70% yield).

[0459] Step 2: Preparation of 33C

[0460] 33B (1.0 g, 2.37 mmol), pinacol diboronate (721 mg, 2.84 mmol), Pd(dppf)Cl2.DCM (173 mg, 0.237 mmol), and potassium acetate (697 mg, 7.11 mmol) were dissolved in 1,4-dioxane (15 mL) and reacted at 100°C for 12 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL × 2). The organic phases were combined and washed sequentially with water (20 mL × 2) and a saturated aqueous solution of NaCl (20 mL × 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 33C (400 mg, 40.0% yield).

[0461] LCMS m / z=423.1[M+H] +

[0462] The remaining steps of the synthesis of compound 33 refer to the synthesis method of compound 32.

[0463] Compound 33 was prepared by chiral SFC to give isomers 33-1 (33 mg, retention time by chiral SFC analysis: 2.124 min) and 33-2 (32 mg, retention time by chiral SFC analysis: 2.366 min). One of the isomers 33-1 or 33-2 is 33-A, and the other is 33-B.

[0464] (SFC separation conditions: Instrument: Waters 150Prep-SFC; Column: Chiral IK column; Mobile phase: A: CO2; B: 0.1% ammonia in ethanol; Elution: Isocratic elution of 35% B in A; Flow rate: 120 mL / min; Pressure: 100 bar; Column temperature: Room temperature; Detection wavelength: 220 nm. Chiral SFC analysis method: Instrument: SHIMADZU LC-30AD SFC; Column: Chiral IK column; Mobile phase: A: CO2; B: 0.05% diethylamine in ethanol; Mobile phase: Gradient elution from 5% to 40% B in A; Flow rate: 3 mL / min; Pressure: 100 bar; Column temperature: 35°C; Detection wavelength: 220 nm)

[0465] Compound 33-1: LCMS m / z=607.2 [M+H] +

[0466] 1 H NMR(400MHz,CD3OD)δ8.10(s,1H),7.53–7.47(m,2H),7.22–7.17(m,3H),7.13–7.08(m,2H),5.71( dd,1H),5.38–5.20(m,2H),3.92–3.71(m,2H),3.66–3.50(m,2H),2.35–2.12(m,2H),2.08(s,3H).

[0467] Compound 33-2: LCMS m / z=607.2 [M+H] +

[0468] 1 H NMR(400MHz,CD3OD)δ8.10(s,1H),7.53–7.47(m,2H),7.22–7.17(m,3H),7.12–7.08(m,2 H),5.71(dd,1H),5.37–5.20(m,2H),3.78–3.59(m,4H),2.36–2.11(m,2H),2.08(s,3H).

[0469] Example 34: Synthesis of Compound 34

[0470] Compound 34 was prepared by referring to the synthesis method of compound 33. Chiral SFC analysis of compound 34 afforded isomers 34-1 (21 mg, retention time by chiral SFC analysis: 2.271 min) and 34-2 (26 mg, retention time by chiral SFC analysis: 2.543 min). One of isomers 34-1 or 34-2 was 34-A, and the other was 34-B.

[0471] (SFC separation conditions: Instrument: Waters 150Prep-SFC; Column: Chiral IK column; Mobile phase: A: CO2; B: 0.1% ammonia in ethanol; Elution: Isocratic elution of 35% B in A; Flow rate: 120 mL / min; Pressure: 100 bar; Column temperature: Room temperature; Detection wavelength: 220 nm. Chiral SFC analysis method: Instrument: SHIMADZU LC-30AD SFC; Column: Chiral IK column; Mobile phase: A: CO2; B: 0.05% diethylamine in ethanol; Mobile phase: Gradient elution from 5% to 40% B in A; Flow rate: 3 mL / min; Pressure: 100 bar; Column temperature: 35°C; Detection wavelength: 220 nm)

[0472] Compound 34-1: LCMS m / z=589.2 [M+H] +

[0473] 1 H NMR(400MHz,CD3OD)δ8.10(s,1H),7.55–7.47(m,2H),7.22–7.16(m,3H),7.11–7.05(m ,2H),5.71(dd,1H),5.29(dd,1H),3.59–3.37(m,4H),2.08(s,3H),2.00–1.90(m,4H).

[0474] Compound 34-2: LCMS m / z=589.2 [M+H] +

[0475] 1 H NMR(400MHz,CD3OD)δ8.10(s,1H),7.54–7.47(m,2H),7.22–7.16(m,3H),7.11–7.04(m ,2H),5.71(dd,1H),5.29(dd,1H),3.60–3.37(m,4H),2.08(s,3H),1.99–1.90(m,4H).

[0476] Example 35: Synthesis of Compound 35

[0477] Compound 35 was prepared by referring to the synthesis method of compound 33. Chiral SFC analysis of compound 35 afforded isomers 35-1 (18 mg, retention time by chiral SFC analysis: 2.117 min) and 35-2 (22 mg, retention time by chiral SFC analysis: 2.341 min). One of isomers 35-1 or 35-2 was designated 35-A, and the other was designated 35-B.

[0478] (SFC separation conditions: Instrument: Waters 150Prep-SFC; Column: Chiral IK column; Mobile phase: A: CO2; B: 0.1% ammonia in ethanol; Elution: Isocratic elution of 35% B in A; Flow rate: 120 mL / min; Pressure: 100 bar; Column temperature: Room temperature; Detection wavelength: 220 nm. Chiral SFC analysis method: Instrument: SHIMADZU LC-30AD SFC; Column: Chiral IK column; Mobile phase: A: CO2; B: 0.05% diethylamine in ethanol; Mobile phase: Gradient elution from 5% to 40% B in A; Flow rate: 3 mL / min; Pressure: 100 bar; Column temperature: 35°C; Detection wavelength: 220 nm)

[0479] Compound 35-1: LCMS m / z=607.1 [M+H] +

[0480] 1 H NMR(400MHz,CD3OD)δ8.10(s,1H),7.55–7.46(m,2H),7.23–7.16(m,3H),7.13–7. 07(m,2H),5.71(dd,1H),5.37–5.19(m,2H),3.77–3.59(m,4H),2.35–2.01(m,5H).

[0481] Compound 35-2: LCMS m / z=607.1 [M+H] +

[0482] 1 H NMR(400MHz,CD3OD)δ8.10(s,1H),7.54–7.46(m,2H),7.23–7.15(m,3H),7.13–7.06(m,2H),5.70( dd,1H),5.37–5.19(m,2H),3.90–3.71(m,2H),3.66–3.50(m,2H),2.37–2.11(m,2H),2.08(s,3H).

[0483] Biological test cases

[0484] FGFR1 kinase inhibitory activity assay

[0485] 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.

[0486] FGFR2 kinase inhibitory activity assay

[0487] 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.

[0488] FGFR3 kinase inhibitory activity assay

[0489] 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.

[0490] FGFR2 N549H kinase inhibitory activity assay

[0491] 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.

[0492] FGFR2 V564F kinase inhibitory activity assay

[0493] 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.

[0494] Table 1 FGFR2 kinase inhibitory activity of compounds

[0495] Conclusion: The compounds of the present invention, such as the example compounds, have good FGFR2 kinase inhibitory activity, poor FGFR1 kinase inhibitory activity, and good FGFR2 kinase selectivity.

[0496] KATO III cell proliferation inhibition

[0497] 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 4 Cells / 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 ).

[0498] SNU16 cell proliferation inhibition:

[0499] 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 ).

[0500] Li7 cell proliferation inhibition:

[0501] 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 inoculated into each well of a 96-well plate with a transparent bottom, and then 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 was completed, 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 ).

[0502] Inhibition of RT112 / 84 cell proliferation (FGFR3-TACC3 fusion)

[0503] RT112 / 84 cells (Cobioer, CBP60316) were cultured in DMEM 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 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 10 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 ).

[0504] Table 2: Cell proliferation inhibitory activity of the tested compounds

[0505] Conclusion: The compounds of the present invention, such as the example compounds, have good inhibitory activity against SNU-16 and KATO-III cells, but have no obvious or poor inhibitory activity against Li-7 and / or RT112 / 84 cells, and have good cell selectivity for FGFR2.

[0506] CYP450 enzyme inhibition testing

[0507] The purpose of this study was to evaluate the effects of test substances on the activities of five isoenzymes of cytochrome P450 (CYP) in human liver microsomes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) using an in vitro test system. Specific probe substrates for the CYP450 isoenzymes were incubated with human liver microsomes and varying concentrations of the test substances. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction. After the reaction, the samples were processed and the metabolites produced by the specific substrates were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS). Changes in CYP enzyme activity were measured, and the IC values ​​were calculated. 50 The inhibitory potential of the test substance on each CYP enzyme subtype CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4-M (with midazolam as substrate) was evaluated.

[0508] Experimental results: Under the test conditions, when the incubation concentrations were 0.03, 0.1, 0.3, 1, 3, 10, and 30 μM, the IC values ​​of each test compound for CYP enzyme inhibition were 50 .

[0509] Table 3 IC inhibitory activity of the test compounds on CYP3A4-M 50

[0510] Conclusion: The compounds of the present invention, such as the example compounds, have no significant inhibitory effect on CYP enzymes. As shown in Table 3, there is no significant inhibitory effect on CYP 3A4-M, and the potential risk of drug interactions is low. In addition, compounds 18 and 20 have no significant inhibitory activity on the five subtypes of CYP enzymes, including 1A2, 2C9, 2C19, 2D6, and 3A4-M. IC 50 >30μM.

[0511] hERG potassium channel function test

[0512] Experimental platform: electrophysiology manual patch clamp system

[0513] Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channel

[0514] Experimental methods: CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents using the whole-cell patch clamp technique at room temperature. Glass microelectrodes were pulled from glass electrode blanks (BF150-86-10, Sutter) using a puller. The tip resistance after perfusing the electrode liquid was about 2-5 MΩ. The glass microelectrode was inserted into the amplifier probe to connect to the patch clamp amplifier. The clamping voltage and data recording were controlled and recorded by a computer using pClamp 10 software, with a sampling frequency of 10 kHz and a filter frequency of 2 kHz. After obtaining the whole-cell recording, the cell was clamped at -80 mV to induce the hERG potassium current (I hERG ) was administered with a 2-second depolarization step from -80 mV to +20 mV, followed by repolarization to -50 mV for 1 second before returning to -80 mV. This voltage stimulus was administered every 10 seconds, and administration began after confirming that the hERG potassium current was stable (for at least 1 minute). Compounds were administered for at least 1 minute at each test concentration, and at least two cells (n ≥ 2) were tested for each concentration.

[0515] Data processing: Data analysis was performed using pClamp 10, GraphPad Prism 5, and Excel software. 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%

[0516] Wherein, Inhibition% represents the inhibition percentage of the compound on hERG potassium current, and I and Io represent the amplitudes of hERG potassium current before and after drug addition, respectively.

[0517] Compound IC 50 Calculated using GraphPad Prism 5 software by fitting the following equation: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC50-X)*HillSlope))

[0518] 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.

[0519] Table 4: IC values ​​of compounds for inhibition of hERG potassium channel current 50

[0520] Conclusion: The compounds of the present invention, such as the examples, have no significant hERG inhibitory activity.

[0521] Mouse pharmacokinetic test

[0522] Experimental animals: Male C57 mice, 20-25 g, 6 mice per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0523] Experimental Design: On the day of the experiment, six C57 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.

[0524] Table 5 Dosage information Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.5% MC

[0525] DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline; 0.5% MC: 0.5% aqueous solution of methylcellulose.

[0526] 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.

[0527] Table 5-1 Pharmacokinetic results of test compounds in mice

[0528] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic properties in mice (such as lower clearance, better AUC).

[0529] Rat pharmacokinetic test

[0530] 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.

[0531] 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.

[0532] Table 7 Dosage information Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.5% MC

[0533] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline; 0.5% MC: 0.5% aqueous solution of methylcellulose.

[0534] 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.

[0535] Table 7-1 Pharmacokinetic results of test compounds in rats

[0536] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic properties in rats. Specifically, compound 11 has a low clearance rate in rats.

[0537] Beagle dog pharmacokinetic testing

[0538] Experimental animals: Male beagle dogs, weighing about 8-11 kg, 6 per compound, purchased from Beijing Masi Biotechnology Co., Ltd.

[0539] Test method: On the day of the test, 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.

[0540] Table 8 Dosage information Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.5% MC or Oral administration solvent: 5% DMSO + 5% Solutol HS15 + 90% (20% SBE-β-CD)

[0541] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline; 0.5% MC: 0.5% aqueous solution of methylcellulose.

[0542] Before and after administration, 1 ml of blood was collected from the jugular vein or limb vein into 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.

[0543] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic properties in dogs.

[0544] Monkey pharmacokinetic testing

[0545] Test animals: Male cynomolgus monkeys, 3-5 kg, 3-6 years old, 4 per compound, purchased from Suzhou Xishan Biotechnology Co., Ltd.

[0546] Test method: On the day of the test, 4 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.

[0547] Table 9 Dosage information Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.5% MC

[0548] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline; 0.5% MC: 0.5% aqueous solution of methylcellulose.

[0549] *Dosage is based on the free base.

[0550] 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.

[0551] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic properties in monkeys.

[0552] Caco2 permeability test

[0553] The experiment used Caco-2 cell monolayers in 96-well Transwell plates, incubated in triplicate. Transport buffer (HBSS, 10 mM HEPES, pH 7.4 ± 0.05) containing the compound of the invention (2 μM) or the control compounds digoxin (10 μM), nadolol (2 μM), and metoprolol (2 μM) was added to the apical or basolateral wells of the cell monolayer. Transport buffer containing DMSO was added to the corresponding receiving wells. After incubation at 37 ± 1°C for 2 hours, the cell plate was removed and appropriate samples were taken from the apical and basolateral wells to a new 96-well plate. Proteins were then precipitated by adding acetonitrile containing an internal standard. Samples were analyzed using LC-MS / MS to determine the concentrations of the compound of the invention and the control compound. The concentration data were used to calculate the apparent permeability coefficients for transport from the apical to basolateral side of the cell monolayer and from the basolateral to apical side, thereby calculating the efflux rate. The integrity of the cell monolayer after 2 hours of incubation was assessed by leakage of Lucifer Yellow.

[0554] Table 10: Caco2 test results of the compounds of the present invention

[0555] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good permeability.

Claims

1. A compound or its stereoisomer, racemate, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from the compounds represented by general formula (I0) or general formula (I0-1), where, When the compound is selected from the compounds represented by the general formula (I0): Ring C is selected from X is selected from CH or N; Ring D is selected from phenyl, naphthyl, 5- to 6-membered heteroaryl, 5- to 12-membered heterocycle; Ring B is selected from C 6-10 aryl, benzo C 4-6 carbocyclic ring, 5- to 6-membered heteroaryl or 8- to 10-membered fused heteroaryl; R a 、R b 、R d are each independently 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, -O-C 3-6 carbocycle, -O-3- to 7-membered heterocycle, -NH-C 3-6 carbocycle, -NH-3- to 7-membered heterocycle, -NH-5- to 6-membered heteroaryl-C 1-4 alkyl, -NH-3- to 7-membered heterocycle-C 3-6 carbocycle, -NH-3- to 7-membered heterocycle-4- to 6-membered heterocycle, -C 1- 4-alkylene-C 3-6 carbocycle, -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 carbocycle, C 3-6 carbocycle, 3- to 7-membered heterocycle, and the alkyl, alkylene, alkenyl, alkynyl, heteroaryl, carbocycle or heterocycle is optionally substituted by 1 to 4 R k substituents; R 3 selected from C 2-8 alkyl, C 3-10 carbocyclic group, 4- to 12-membered heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group is substituted by 5 to 10 halogens, and the alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k substituted; R c1 selected from H, C 1-6 alkyl, C 3-10 carbocyclic group, 4- to 12-membered heterocyclic group, and the alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k substituted; R 1 selected from halogen, CN, R 1a 、R 1b 、R 1c 、R 1d are 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 carbocycle, 3- to 7-membered heterocycle, C 6-10 aryl, 5- to 6-membered heteroaryl, and the alkyl, alkenyl, alkynyl, carbocycle, heterocycle, aryl or heteroaryl is optionally substituted by 1 to 5 R k substituents; R 1e 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 carbocycle, 3- to 7-membered heterocycle, and the alkyl, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R k substituents; R 2 selected from H or C 1-4 alkyl; Alternatively, R 1b is directly connected to R 1c , R 1a is directly connected to R 1b to form a C 3-6 carbocyclic ring or a 3- to 7-membered heterocyclic ring, which carbocyclic ring or heterocyclic ring is optionally substituted with 1 to 4 R k substituents; Alternatively, R 1a is directly linked to R 2 , R 1b is directly linked to R 2 to form a 4- to 7-membered heterocycle which is optionally substituted by 1 to 4 R k groups; R k Each independently selected from deuterium, halogen, =O, 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, -O-C 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 carbocycle, -C 1-4 alkylene-3- to 7-membered heterocycle, C 3-6 carbocycle, 3- to 7-membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, CN, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy; p1 and p2 are each independently selected from 0, 1, 2, 3 or 4; p3 is selected from 0, 1, 2, 3 or 4; p4 is selected from 0 or 1; When the compound is selected from the compounds represented by the general formula (I0-1): Ring B is selected from C 6-10 aryl, benzo C 4-6 carbocycle, 5- to 6-membered heteroaryl, 8- to 10-membered fused heteroaryl, partially saturated C 3-6 carbocyclic group; Q is selected from -C(=O)- or a bond; Ring D is selected from C 6-10 carbocyclic ring, 5- to 10-membered heterocyclic group; Ring C is selected from C1, C2, C3, C4 are each independently selected from N or CH, and at most two of them are selected from N, and the CH is optionally substituted by R c4 substituted; R b 、R d 、R c4 are each independently 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, -O-C 3-6 carbocycle, -O-3- to 7-membered heterocycle, -NH-C 3-6 carbocycle, -NH-3- to 7-membered heterocycle, -NH-5- to 6-membered heteroaryl-C 1-4 alkyl, -NH-3- to 7-membered heterocycle-C 3-6 carbocycle, -NH-3- to 7-membered heterocycle-4- to 6-membered heterocycle, -C 1- 4-alkylene-C 3-6 carbocycle, -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 carbocycle, C 3-6 carbocycle, 3- to 7-membered heterocycle, and the alkyl, alkylene, alkenyl, alkynyl, heteroaryl, carbocycle or heterocycle is optionally substituted by 1 to 4 R k substituents; R c1 Selected from H, OH, CN, NH2, NHC 1-6 alkyl, N(C 1-6 alkyl)2, C 1-6 alkyl, -OC 1-6 alkyl, wherein the alkyl is optionally substituted by 1 to 4 R k substituents; R c2 selected from H, halogen, CN, C 1-6 alkyl, -OC 1-6 alkyl, wherein the alkyl is optionally substituted by 1 to 4 R k substituted; R c3 Selected from NH2, NHC 1-6 alkyl, N(C 1-6 alkyl)2, NHC 3-6 carbocycle, wherein the alkyl or carbocycle is optionally substituted by 1 to 4 R k substituents; R c5 Selected from H, C 1-6 alkyl group, said alkyl group being optionally substituted by 1 to 4 R k substituted; R c6 selected from H, deuterium, halogen, CN, C 1-6 alkyl, -OC 1-6 alkyl or C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally substituted by 1 to 4 R k substituents; 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 carbocycle, 3- to 7-membered heterocycle, and the alkyl, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 R k substituents; R 1e 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 carbocycle, 3- to 7-membered heterocycle, and the alkyl, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R k substituted; Alternatively, R 1b is directly connected to R 1c , R 1a is directly connected to R 1b to form a C 3-6 carbocyclic ring or a 3- to 7-membered heterocyclic ring, which carbocyclic ring or heterocyclic ring is optionally substituted with 1 to 4 R k substituents; R 2 selected from H or C 1-6 alkyl; Alternatively, R 2 is directly linked to R 1b , R 2 is directly linked to R 1a or R 2 is directly linked to R d to form a 4- to 7-membered heterocyclic group, which heterocyclic group is optionally substituted by 1 to 4 R k substituents; R 3 and R 4 are each independently selected from C 1-6 alkyl, C 3-6 carbocyclic ring, 3- to 7-membered heterocyclic ring, 8- to 12-membered heterocyclic group, wherein the alkyl, carbocyclic ring or heterocyclic ring is optionally substituted with 1 to 4 R k substituents; or R 3 、R 4 are each independently selected from NH2, NHC 1-6 alkyl, NH(C 3-6 carbocyclic ring), N(C 3-6 carbocyclic ring)(C 1-6 alkyl), N(C 1-6 alkyl)2, and the alkyl and carbocyclic ring are optionally substituted with 1 to 4 R k substituents; or R 3 、R 4 are directly linked to form a 4- to 10-membered heterocyclic group, and the heterocyclic group is optionally substituted by 1 to 4 R k substituents; R k Each independently selected from deuterium, halogen, CN, =O, 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, -O-C 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 carbocycle, -C 1-4 alkylene-3- to 7-membered heterocycle, C 3-6 carbocycle, 3- to 7-membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 substituents selected from deuterium, halogen, CN, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy; p1 and p2 are each independently selected from 0, 1, 2, 3 or 4; a is selected from 0 or 1.

2. The compound according to claim 1, or its stereoisomer, racemate, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, the compound represented by the general formula (I0) is selected from the general formula (I) or the general formula (II) 3. The compound or its stereoisomer, racemate, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal according to claim 1 or 2, In the compounds represented by general formula (I0), general formula (I) or general formula (II): Ring B is selected from phenyl, naphthyl, benzo C 4-6 carbocyclic ring, benzo 4- to 6-membered heterocyclic ring, 5- to 6-membered heteroaryl, 8- to 10-membered fused heterocyclic aryl; Ring D is selected from phenyl, naphthyl, 5- to 6-membered heteroaryl, 5- to 6-membered monocyclic heterocycle, 7- to 12-membered spiro heterocycle; R 3 selected from C 2-6 alkyl, C 3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, wherein the alkyl, cycloalkyl or heterocycloalkyl is substituted with 5 to 10 halogens; R a 、R b 、R d are each independently selected from deuterium, a 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, -O-C 3-6 carbocycle, -O-3- to 7-membered heterocycle, -NH-C 3-6 carbocycle, -NH-3- to 7-membered heterocycle, -C 1-2 alkylene-C 3-6 carbocycle, -C 1-2 alkylene-3- to 7-membered heterocycle, -C(=O)NH-C 1-6 alkyl, -C(=O)NH-C 3-6 carbocycle, C 3-6 carbocycle, 3- to 7-membered heterocycle, and the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 R k substituents; R c1 selected from H, C 1-4 alkyl or C 3-6 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by 1 to 4 R k substituents; R 1a 、R 1b 、R 1c 、R 1d are each independently selected from H, deuterium, halogen, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocycle, 3- to 7-membered heterocycle, C 6-10 aryl, 5- to 6-membered heteroaryl, and the alkyl, alkenyl, alkynyl, carbocycle, heterocycle, C 6-10 aryl or 5- to 6-membered heteroaryl is optionally substituted with 1 to 5 R k substituents; R 1e selected from halogen or -OS(=O)2C 1-4 alkyl, said alkyl being optionally substituted with 1 to 4 R k substituents; Alternatively, R 1a is directly connected to R 2 , R 1b is directly connected to R 2 to form a 4- to 7-membered heterocycle, which heterocycle is optionally substituted by 1 to 4 R k groups; R k Each independently selected from deuterium, halogen, =O, 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, -O-C 3-6 carbocycle, -O-3- to 7-membered heterocycle, -NH-C 3-6 carbocycle, -NH-3- to 7-membered heterocycle, -C 1-2 alkylene-C 3-6 carbocycle, -C 1-2 alkylene-3- to 7-membered heterocycle, C 3-6 carbocycle, 3- to 7-membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 substituents selected from deuterium, halogen, CN, OH, NH2, C 1-4 alkyl, C 1-4 alkoxy; In the compounds represented by general formula (I0-1): Ring B is selected from phenyl, naphthyl, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, benzoC 4-6 carbocyclic ring, benzo 4- to 6-membered heterocyclic ring, 5- to 6-membered heteroaryl, 8- to 10-membered fused heterocyclic aryl; Ring D is selected from phenyl, benzo C 4-6 carbocyclic ring, benzo 4- to 6-membered heterocyclic ring, 5- to 6-membered heteroaryl group, 5- to 6-membered partially saturated heterocyclic group; R b 、R d 、R c4 are each independently selected from H, 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, -O-C 3-6 carbocycle, -O-3- to 7-membered heterocycle, -NH-C 3-6 carbocycle, -NH-3- to 7-membered heterocycle, -C 1-2 alkylene-C 3-6 carbocycle, -C 1-2 alkylene-3- to 7-membered heterocycle, -C(=O)NH-C 1-6 alkyl, -C(=O)NH-C 3-6 carbocycle, C 3- 6-carbon ring, 3- to 7-membered heterocycle, and the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R k substituents; R c1 Selected from H, OH, CN, NH2, NHC 1-4 alkyl, N(C 1-4 alkyl)2, C 1-4 alkyl, -OC 1-4 alkyl, wherein the alkyl is optionally substituted by 1 to 4 R k substituents; R c2 Selected from H, halogen, CN, C 1-4 alkyl, -OC 1-4 alkyl, wherein the alkyl is optionally substituted by 1 to 4 R k substituents; R c3 selected from NH2, NHC 1-4 alkyl, N(C 1-4 alkyl)2, NHC 3-6 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by 1 to 4 R k substituents; R c6 selected from H, deuterium, halogen, CN, C 1-4 alkyl, -OC 1-4 alkyl or C 3-6 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by 1 to 4 R k substituents; R 1a 、R 1b 、R 1c 、R 1d are each independently selected from H, deuterium, halogen, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocycle, 3- to 7-membered heterocycle, and the alkyl, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R k substituents; R 1e selected from halogen or -OS(=O)2C 1-4 alkyl, said alkyl being optionally substituted by 1 to 4 R k substituents; R 2 Selected from H or C 1-4 alkyl; Alternatively, R 2 is directly linked to R 1b , R 2 is directly linked to R 1a or R 2 is directly linked to R d to form a 4- to 7-membered heterocyclic group, which heterocyclic group is optionally substituted by 1 to 4 R k substituents; R 3 、R 4 Each independently selected from C 1-4 alkyl, C 3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, 8- to 12-membered heterocycloalkyl, wherein the alkyl, cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 4 R k substituents; or R 3 、R 4 each independently selected from NH2, NHC 1-4 alkyl, NH(C 3-6 carbocyclic ring), N(C 3-6 carbocyclic ring)(C 1-4 alkyl), N(C 1-4 alkyl)2, and the alkyl and carbocyclic ring are optionally substituted by 1 to 4 R k substituents; or R 3 、R 4 are directly connected to form a partially saturated 4- to 10-membered heterocyclic group, and the heterocyclic group is optionally substituted with 1 to 4 R k substituents; R k Each independently selected from deuterium, halogen, CN, =O, 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, -O-C 3-6 carbocycle, -O-3- to 7-membered heterocycle, -NH-C 3-6 carbocycle, -NH-3- to 7-membered heterocycle, -C 1-2 alkylene-C 3-6 carbocycle, -C 1-2 alkylene-3- to 7-membered heterocycle, C 3-6 carbocycle, 3- to 7-membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 substituents selected from deuterium, halogen, CN, OH, NH2, C 1-4 alkyl, C 1-4 alkoxy.

4. The compound or its stereoisomer, racemate, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal according to claim 3, In the compounds represented by general formula (I0), general formula (I) or general formula (II): Ring B is selected from phenyl or naphthyl; Ring D is selected from phenyl, naphthyl, pyridazinyl, pyrazinyl, pyridyl, pyrimidinyl, R c1 selected from C 1-4 alkyl or C 3-6 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with 1 to 4 deuteriums or halogens; R 1 selected from CN, Alternatively, R 1a is directly connected to R 2 , R 1b is directly connected to R 2 to form a 4- to 7-membered heterocycle, which heterocycle is optionally substituted with 1 to 4 R k substituents; R 3 selected from ethyl, propyl, isopropyl, butyl, pentyl, cyclopropyl, cyclobutyl, wherein the ethyl, propyl, isopropyl, butyl, pentyl, cyclopropyl, cyclobutyl are substituted with 5 to 8 substituents selected from F, Cl, Br, I; In the compounds represented by general formula (I0-1): Ring B is selected from phenyl, naphthyl, pyridyl, cyclopentyl, cyclohexyl, cyclopentenyl or cyclohexenyl; Ring D is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolidinyl, azetylenyl, azacyclohexyl or azacyclohexenyl; Ring C is selected from R 1 selected from CN, R 3 and R 4 each independently selected from one of the following groups optionally substituted with 1 to 4 R k groups: NH2, NH(CH3), N(CH3)2, NH(CH2CH3), N(CH2CH3)2, N(cyclopropyl)(CH3), N(CH3)(CH2CH3), NH(cyclopropyl), NH(cyclobutyl), Methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, oxolanyl, oxanyl, azetidinyl, pyrrolidinyl, azetidinyl spirocyclobutyl, pyrrolidinyl spirocyclopropyl or azacyclohexyl; Or Selected from among the following groups optionally substituted by 1 to 4 Rs k one of the following: p3 is selected from 0, 1, 2, 3 or 4.

5. The compound or its stereoisomer, racemate, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal according to claim 4, wherein, In the compounds represented by general formula (I0), general formula (I) or general formula (II): R 3 selected from Selected from R c1 selected from methyl, ethyl, propyl, isopropyl, butyl, pentyl, cyclopropyl, cyclobutyl, wherein the methyl, ethyl, propyl, isopropyl, butyl, pentyl, cyclopropyl, cyclobutyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I; 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 1a 、R 1b 、R 1c 、R 1d are each independently selected from H, deuterium, F, Cl, Br, I, CN, methyl, ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, phenyl, and the methyl, ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, phenyl are optionally substituted by 1 to 5 R k substituents; Alternatively, R 1a is directly connected to R 2 , R 1b is directly connected to R 2 to form a 4- to 7-membered heterocycle; the heterocycle is optionally substituted with 1 to 4 R k substituents; R k Each independently selected from deuterium, F, Cl, Br, I, =O, 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, oxetanyl, tetrahydrofuranyl, oxanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, oxanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl are optionally substituted by 1 to 4 substituents selected from halogen, CN, OH, NH2, C 1-4 alkyl, C 1-4 alkoxy; p3 is selected from 0, 1, 2, 3 or 4; In the compounds represented by general formula (I0-1): Selected from Selected from Or Selected from R b 、R d each independently selected from H, deuterium, F, Cl, Br, I, cyano, OH, NH2, NH(CH3), N(CH3)2, CF3, CD3, methyl, ethyl, propyl, isopropyl, butyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; R c4 Each independently selected from deuterium, F, Cl, Br, I, CN, methyl, ethyl, NH(CH3), N(CH3)2, methoxy, ethoxy, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrazolyl, and the methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrazolyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), N(CH3)2, CF3, CD3, methyl, ethyl, methoxy, ethoxy or cyclopropyl; R c5 selected from H, methyl, ethyl, propyl or isopropyl, wherein the methyl, ethyl, propyl or isopropyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), N(CH3)2, CF3, CD3, methyl, ethyl, methoxy, ethoxy or cyclopropyl; R c6 selected from H, deuterium, halogen, F, Cl, Br, I, CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl or cyclobutyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl or cyclobutyl is optionally substituted with 1 to 4 R k substituents; R 1a 、R 1b 、R 1c 、R 1d are each independently selected from H, deuterium, F, Cl, Br, I, CN, methyl, ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, and the methyl, ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or pyrrolidinyl is optionally substituted with 1 to 4 R k substituents; R 2 selected from H or methyl; Alternatively, R 2 and R 1b , R 2 and R 1a or R 2 and R d are directly linked to form a 5- to 7-membered heterocycle, which heterocycle is optionally substituted by 1 to 4 R k substituents; Selected from one of the following optionally substituted groups: When substituted, it is substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, =O, NH2, NH(CH3), N(CH3)2, CHF2, CH2F, CF3, CD3, methyl, ethyl, CH2OCH3, methoxy, ethoxy, -O-cyclopropyl or cyclopropyl; R k Each independently selected from deuterium, F, Cl, Br, I, CN, =O, 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, oxetanyl, tetrahydrofuranyl, oxanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, oxanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl are optionally substituted with 1 to 4 substituents selected from halogen, CN, OH, NH2, C 1-4 alkyl, C 1-4 alkoxy.

6. The compound or its stereoisomer, racemate, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal according to claim 5, wherein, In the compounds represented by general formula (I0), general formula (I) or general formula (II): R 1 selected from CN, Ethynyl; or Selected from R 1a 、R 1b 、R 1c are each independently selected from H, deuterium, F, Cl, Br, I, CN, methyl, ethyl, CF3, vinyl, ethynyl, phenyl; Preferably, Selected from p1 is 0 or 1; R c1 selected from methyl, isopropyl or cyclopropyl, wherein the methyl, isopropyl or cyclopropyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I; R 3 selected from Selected from R d Selected from deuterium, F, Cl, Br, I, cyano, OH, NH2, NH(CH3), N(CH3)2, CF3, methyl, ethyl, propyl, isopropyl, butyl, ethynyl, methoxy, ethoxy; In the compounds represented by general formula (I0-1): Selected from Or Selected from R 1a 、R 1b 、R 1c 、R 1d are each independently selected from H, deuterium, F, Cl, Br, I, CN, methyl, ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, and the methyl, ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or pyrrolidinyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, ═O, NH2, NH(CH3), N(CH3)2, NH(CH2CH3), N(CH2CH3)2, CF3, CD3, methyl, ethyl, methoxy, ethoxy, cyclopropyl, azacyclohexyl, pyrrolidinyl, morpholinyl.

7. The compound according to claim 5, or its stereoisomer, racemate, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: In the compound represented by general formula (I0-1): Selected from Or Selected from R 1 selected from CN, Or Selected from R 1a 、R 1b 、R 1c are each independently selected from H, deuterium, methyl or CF3.

8. The compound according to claim 1, or its stereoisomer, racemate, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures shown in Table E-1 or Table E-2.

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

10. Use of the compound according to any one of claims 1-8, or its stereoisomer, racemate, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, in the preparation of a drug for treating a disease related to FGFR2 activity or expression level.

11. The application according to claim 10, wherein The disease is selected from tumors or cancers, preferably solid tumors, cholangiocarcinoma or intrahepatic cholangiocarcinoma.

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