CN111868058A - FGFR inhibitor, preparation method and pharmaceutical application thereof - Google Patents

Abstract

An FGFR inhibitor with a structure of a formula (I), a preparation method and a pharmaceutical application thereof are provided, and the definition of each substituent is described in the specification and the claims. The series of compounds can be widely applied to the preparation of medicines for treating tumors, cancers and bone marrowThe medicine for treating proliferative diseases, bone or cartilage cell disorder and hypophosphatemia is expected to be developed into a new generation of FGFR inhibitor medicine.

Description

FGFR inhibitor, preparation method and pharmaceutical application thereof Technical Field

The invention belongs to the field of drug synthesis, and particularly relates to an FGFR inhibitor, a preparation method thereof and pharmaceutical application thereof.

Technical Field

Fibroblast Growth Factor Receptors (FGFR) are tyrosine kinase receptors that bind to fibroblast growth factor ligands. There are currently 4 FGFR receptors that have been found to be capable of binding ligands and are closely related in a variety of physiological processes including tissue differentiation, angiogenesis, wound healing, and metabolic regulation. When the ligand binds, the receptor dimerizes and phosphorylates, stimulating activation of protein kinase activity, and recruits many intracellular proteins to bind. These protein interactions can help to activate a range of intracellular signaling pathways, including Ras-MAPK, AKT-PI3K, and phosphatase C, signaling pathways important to cell growth, proliferation, and survival.

Aberrant activation of this signaling pathway, such as overexpression of FGF ligands or activation mutations through FGFRs, can lead to tumor growth, progression and resistance to traditional cancer therapies. In human tumors, changes in genes that can bring about ligand-independent receptor activation, including gene amplification, chromosomal translocation, and somatic mutation, among others, have been described. While DNA sequencing of thousands of tumor samples in large batches has revealed that components in the FGFR signaling pathway are genes that are highly mutated in human cancers. For example, somatic mutations in FGFR1 have been found in gliomas and lung cancers, mutations in FGFR2 are found in gastric and endometrial cancers, mutations in FGFR3 are found in bladder cancer and multiple myeloma, and mutations in FGFG4 are found in primary rhabdomyosarcoma.

FGF/FGFR-associated tumor types include, but are not limited to, cancer (such as bladder cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer); hematological malignancies (such as multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, acute myelogenous leukemia, non-hodgkin's lymphoma, myeloproliferative tumors, and fahrenheit macroglobulinemia) and other tumors (such as glioblastoma, melanoma, and rhabdomyosarcoma). In addition to its role in tumors, FGFR activation has also been found to be associated with skeletal and chondrocyte pathologies, such as achondroplasia and craniosynostosis.

Although some FGFR inhibitors have already entered clinical and preclinical development, they usually have poor selectivity and inhibitory effect on other kinases such as c-kit and PDGFRa, which raises concerns that the therapeutic window is not large enough. Therefore, the development of inhibitors that target FGFR selectivity would be of great interest in the clinical treatment of diseases with elevated FGF or FGFR activity.

Disclosure of Invention

The invention aims to provide an FGFR inhibitor.

In a first aspect, the present invention provides a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof:

wherein X is selected from C (R)₇) Or N;

R₁selected from hydrogen, deuterium, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl or 5-to 10-membered heteroaryl, optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O)_rR₈、-C_0-8-O-R₉、-C_0-8-C(O)OR₉、-C_0-8-C(O)R₁₀、-C_0-8-O-C(O)R₁₀、-C_0-8-NR₁₁R₁₂、-C_0-8-C(＝NR₁₁)R₁₀、-C_0-8-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-8-C(O)NR₁₁R₁₂or-C_0-8-N(R₁₁)-C(O)R₁₀Optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C_{1- 10}Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O)_rR₈、-C_0-8-O-R₉、-C_0-8-C(O)OR₉、-C_0-8-C(O)R₁₀、-C_0-8-O-C(O)R₁₀、-C_0-8-NR₁₁R₁₂、-C_0-8-C(＝NR₁₁)R₁₀、-C_0-8-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_{0- 8}-C(O)NR₁₁R₁₂or-C_0-8-N(R₁₁)-C(O)R₁₀Substituted with the substituent(s);

R₂selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_{3- 10}Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₈、-C_0-8-O-R₉、-C_0-8-C(O)OR₉、-C_0-8-C(O)R₁₀、-C_0-8-O-C(O)R₁₀、-C_0-8-NR₁₁R₁₂、-C_0-8-C(＝NR₁₁)R₁₀、-C_0-8-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-8-C(O)NR₁₁R₁₂or-C_0-8-N(R₁₁)-C(O)R₁₀Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O)_rR₈、-C_0-8-O-R₉、-C_0-8-C(O)OR₉、-C_0-8-C(O)R₁₀、-C_0-8-O-C(O)R₁₀、-C_0-8-NR₁₁R₁₂、-C_0-8-C(＝NR₁₁)R₁₀、-C_0-8-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-8-C(O)NR₁₁R₁₂or-C_0-8-N(R₁₁)-C(O)R₁₀Optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_{1- 10}Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O)_rR₈、-C_0-8-O-R₉、-C_0-8-C(O)OR₉、-C_0-8-C(O)R₁₀、-C_0-8-O-C(O)R₁₀、-C_0-8-NR₁₁R₁₂、-C_0-8-C(＝NR₁₁)R₁₀、-C_{0- 8}-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-8-C(O)NR₁₁R₁₂or-C_0-8-N(R₁₁)-C(O)R₁₀Substituted with the substituent(s);

R₃、R₄each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, nitro, azido, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_2-10Alkenyl radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl or 5-10 membered heteroaryloxy, optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O)_rR₈、-C_0-8-O-R₉、-C_0-8-C(O)OR₉、-C_0-8-C(O)R₁₀、-C_0-8-O-C(O)R₁₀、-C_0-8-NR₁₁R₁₂、-C_0-8-C(＝NR₁₁)R₁₀、-C_0-8-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-8-C(O)NR₁₁R₁₂or-C_0-8-N(R₁₁)-C(O)R₁₀Substituted with the substituent(s);

R₅、R₆each is independentSelected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₈、-C_0-8-O-R₉、-C_0-8-C(O)OR₉、-C_0-8-C(O)R₁₀、-C_0-8-O-C(O)R₁₀、-C_0-8-NR₁₁R₁₂、-C_0-8-C(＝NR₁₁)R₁₀、-C_{0- 8}-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-8-C(O)NR₁₁R₁₂or-C_0-8-N(R₁₁)-C(O)R₁₀Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O)_rR₈、-C_0-8-O-R₉、-C_0-8-C(O)OR₉、-C_0-8-C(O)R₁₀、-C_0-8-O-C(O)R₁₀、-C_0-8-NR₁₁R₁₂、- C_0-8-C(＝NR₁₁)R₁₀、-C_0-8-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-8-C(O)NR₁₁R₁₂or-C_0-8-N(R₁₁)-C(O)R₁₀Substituted with the substituent(s);

R₇selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_{3- 10}Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₈、-C_0-8-O-R₉、-C_0-8-C(O)OR₉、-C_0-8-C(O)R₁₀、-C_0-8-O-C(O)R₁₀、-C_0-8-NR₁₁R₁₂、-C_0-8-C(＝NR₁₁)R₁₀、-C_0-8-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-8-C(O)NR₁₁R₁₂or-C_0-8-N(R₁₁)-C(O)R₁₀Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_{1- 10}Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O)_rR₈、-C_0-8-O-R₉、-C_0-8-C(O)OR₉、-C_0-8-C(O)R₁₀、-C_0-8-O-C(O)R₁₀、-C_0-8-NR₁₁R₁₂、-C_0-8-C(＝NR₁₁)R₁₀、-C_{0- 8}-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-8-C(O)NR₁₁R₁₂or-C_0-8-N(R₁₁)-C(O)R₁₀Substituted with the substituent(s);

each R₈Selected from hydrogen, deuterium, hydroxy, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_2-10Alkenyl radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or-NR₁₁R₁₂Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, hydroxy, carbonyl, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or-NR₁₁R₁₂Substituted with the substituent(s);

each R₉Selected from hydrogen, deuterium, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl or 5-10 membered heteroaryl, optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, carbonyl, cyano, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or-NR₁₁R₁₂Substituted with the substituent(s);

each R₁₀Selected from hydrogen, deuterium, hydroxy, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or-NR₁₁R₁₂Optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, cyano, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or-NR₁₁R₁₂Substituted with the substituent(s);

each R₁₁、R₁₂Each independently selected from hydrogen, deuterium, hydroxy, C_1-10Alkoxy radical, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_{2- 10}Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-to 10-membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, monoalkylamino, dialkylamino or C_1-10Alkanoyl optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-to 10-membered heteroaryl, 5-to 10-membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C_1-10Substituted by alkanoyl group;

or, R₁₁、R₁₂Together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclyl or 4-10 membered heteroaryl group, optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-to 10-membered heteroaryl, 5-to 10-membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C_1-10Substituted by alkanoyl group;

each r is independently 0, 1 or 2.

Preferably, in the compound of formula (I), the stereoisomer, the prodrug or the pharmaceutically acceptable salt thereof, X is selected from C (R)₇) Or N; r₇Selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-S(O)_rR₈、-C_0-4-O-R₉、-C_{0- 4}-C(O)OR₉、-C_0-4-C(O)R₁₀、-C_0-4-O-C(O)R₁₀、-C_0-4-NR₁₁R₁₂、-C_0-4-C(＝NR₁₁)R₁₀、-C_0-4-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-4-C(O)NR₁₁R₁₂or-C_0-4-N(R₁₁)-C(O)R₁₀The above radicalsOptionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo-substituted C_1-4Alkyl, deuterium substituted C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -C_0-4-S(O)_rR₈、-C_0-4-O-R₉、-C_0-4-C(O)OR₉、-C_0-4-C(O)R₁₀、-C_0-4-O-C(O)R₁₀、-C_0-4-NR₁₁R₁₂、-C_0-4-C(＝NR₁₁)R₁₀、-C_0-4-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-4-C(O)NR₁₁R₁₂or-C_0-4-N(R₁₁)-C(O)R₁₀Substituted with the substituent(s); r₈、R₉、R₁₀、R₁₁、R₁₂And r are as described above.

As a further preferred embodiment, said compound of formula (I), a stereoisomer, a prodrug thereof or a pharmaceutically acceptable salt thereof, wherein X is selected from C (R)₇) Or N; r₇Selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl, allyl, ethynyl, C_3-6Cycloalkyl, oxetanyl, azacyclopentyl, azacyclohexyl, phenyl, triazole, methanesulfonyl, isopropylsulfonyl, aminosulfonyl, methoxy, ethoxy, isopropoxy, methoxycarbonyl, ethoxycarbonyl, acetyl, acetoxy, acetoxymethyl, amino, dimethylamino, aminocarbonyl, dimethylaminocarbonyl, or acetylamino; the above groups are optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, cyano, methyl, ethyl, cyclopropyl, phenyl, methoxy, ethoxy, hydroxy or amino.

As a still further preferred embodiment, said compound of formula (I), a stereoisomer, a prodrug thereof or a pharmaceutically acceptable salt thereof, wherein X is selected from C (R)₇) Or N; r₇Selected from hydrogen, deuterium, fluorine, chlorine, cyano, nitro, azido, methyl, ethyl, isopropylAllyl, ethynyl, cyclopropyl, cyclopropylmethyl, oxetanyl, azacyclopentyl, azacyclohexyl, phenyl, triazole, methanesulfonyl, isopropylsulfonyl, aminosulfonyl, methoxy, ethoxy, isopropoxy, methoxyethyl, ethoxyethyl, hydroxymethyl, hydroxyethyl, cyanomethyl, trifluoromethyl, trithio-methyl, difluoromethyl, dideuteromethyl, methoxycarbonyl, ethoxycarbonyl, acetyl, acetoxy, acetoxymethyl, amino, dimethylamino, aminomethyl, aminocarbonyl, dimethylaminocarbonyl or acetamido.

As a further preferred embodiment, R in said compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof₅、R₆Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-S(O)_rR₈、-C_0-4-O-R₉、-C_0-4-C(O)OR₉、-C_0-4-C(O)R₁₀、-C_0-4-O-C(O)R₁₀、-C_0-4-NR₁₁R₁₂、-C_0-4-C(＝NR₁₁)R₁₀、-C_0-4-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-4-C(O)NR₁₁R₁₂or-C_0-4-N(R₁₁)-C(O)R₁₀Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo-substituted C_1-4Alkyl, deuterium substituted C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -C_0-4-S(O)_rR₈、-C_0-4-O-R₉、-C_0-4-C(O)OR₉、-C_0-4-C(O)R₁₀、-C_0-4-O-C(O)R₁₀、-C_0-4-NR₁₁R₁₂、-C_0-4-C(＝NR₁₁)R₁₀、-C_0-4-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-4-C(O)NR₁₁R₁₂or-C_0-4-N(R₁₁)-C(O)R₁₀Substituted with the substituent(s); r₈、R₉、R₁₀、R₁₁、R₁₂And r are as described above.

As a still further preferred embodiment, R in said compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof₅、R₆Each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, nitro, azido, C_1-4Alkyl, allyl, ethynyl, C_3-6Cycloalkyl, oxetanyl, azacyclopentyl, azacyclohexyl, phenyl, triazole, methanesulfonyl, isopropylsulfonyl, aminosulfonyl, hydroxy, methoxy, ethoxy, isopropoxy, methoxycarbonyl, ethoxycarbonyl, acetyl, acetoxy, acetoxymethyl, amino, dimethylamino, aminocarbonyl, dimethylaminocarbonyl or acetamido; the above groups are optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, cyano, methyl, ethyl, cyclopropyl, phenyl, methoxy, ethoxy, hydroxy or amino.

As a further preferred embodiment, R in said compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof₃、R₄Each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, nitro, azido, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_2-4Alkenyl radical, C_3-8Cycloalkyl radical, C_3-8Cycloalkoxy, 3-to 8-membered heterocyclic group, 3-to 8-membered heterocyclic oxy group, C_5-8Aryl radical, C_5-8Aryloxy, 5-8 membered heteroaryl or 5-8 membered heteroaryloxy, optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo-substituted C_1-4Alkyl, deuterium substituted C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -C_0-4-S(O)_rR₈、-C_0-4-O-R₉、-C_0-4-C(O)OR₉、-C_0-4-C(O)R₁₀、-C_0-4-O-C(O)R₁₀、-C_0-4-NR₁₁R₁₂、-C_0-4-C(＝NR₁₁)R₁₀、-C_0-4-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-4-C(O)NR₁₁R₁₂or-C_0-4-N(R₁₁)-C(O)R₁₀Substituted with the substituent(s); r₈、R₉、R₁₀、R₁₁、R₁₂And r are as described above.

As a still further preferred embodiment, R in said compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof₃、R₄Each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, nitro, azido, C_1-4Alkyl radical, C_1-4Alkoxy, allyl, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy, phenyl, triazole or triazole; the above groups are optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, cyano, methyl, ethyl, cyclopropyl, phenyl, methoxy, ethoxy, hydroxy or amino.

As a further preferred embodiment, R in said compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof₂Selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_{3- 8}Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-S(O)_rR₈、-C_0-4-O-R₉、-C_0-4-C(O)OR₉、-C_0-4-C(O)R₁₀、-C_0-4-O-C(O)R₁₀、-C_0-4-NR₁₁R₁₂、-C_0-4-C(＝NR₁₁)R₁₀、-C_0-4-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-4-C(O)NR₁₁R₁₂or-C_0-4-N(R₁₁)-C(O)R₁₀Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -C_0-4-S(O)_rR₈、-C_0-4-O-R₉、-C_0-4-C(O)OR₉、-C_{0- 4}-C(O)R₁₀、-C_0-4-O-C(O)R₁₀、-C_0-4-NR₁₁R₁₂、-C_0-4-C(＝NR₁₁)R₁₀、-C_0-4-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-4-C(O)NR₁₁R₁₂or-C_0-4-N(R₁₁)-C(O)R₁₀Optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo-substituted C_{1- 4}Alkyl, deuterium substituted C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -C_0-4-S(O)_rR₈、-C_0-4-O-R₉、-C_0-4-C(O)OR₉、-C_0-4-C(O)R₁₀、-C_0-4-O-C(O)R₁₀、-C_0-4-NR₁₁R₁₂、-C_0-4-C(＝NR₁₁)R₁₀、-C_0-4-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-4-C(O)NR₁₁R₁₂or-C_0-4-N(R₁₁)-C(O)R₁₀Substituted with the substituent(s); r₈、R₉、R₁₀、R₁₁、R₁₂And r are as described above.

As a still further preferred embodiment, R in said compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof₂Selected from hydrogen, deuterium, halogen, C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-O-R₉、-C_0-4-NR₁₁R₁₂、-C_0-4-C(＝NR₁₁)R₁₀、-C_0-4-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-4-C(O)NR₁₁R₁₂or-C_0-4-N(R₁₁)-C(O)R₁₀Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -C_0-4-S(O)_rR₈、-C_0-4-O-R₉、-C_0-4-C(O)OR₉or-C_0-4-NR₁₁R₁₂Optionally further substituted by one or more substituents selected from deuterium, halogen, C_1-4Alkyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, cyclopropyl, ═ O, hydroxy, methoxy, ethoxy, isopropoxy, or carboxy; r₈、R₉、R₁₀、R₁₁、R₁₂And r are as described above.

As a further preferred embodiment, the compound of formula (I), its stereoisomer, prodrug or a pharmaceutically acceptable salt thereof has the following structure of formula (ii):

wherein R is₂Selected from hydrogen, deuterium, halogen, C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -C_0-4-O-R₉or-C_0-4-NR₁₁R₁₂Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -S (O)_rR₈、-O-R₉、-C(O)OR₉or-NR₁₁R₁₂Optionally further substituted by one or more substituents selected from deuterium, halogen, C_1-4Alkyl, halo-substituted C_1-4Alkyl, deuterium substituted C_1-4Alkyl radical, C_3-6Cycloalkyl, ═ O, hydroxy, methoxy, ethoxy, isopropoxy, or carboxy;

R₃、R₄each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, 3-6 membered heterocyclyl or 3-6 membered heterocyclyloxy; the above groups are optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, cyano, methyl, ethyl, cyclopropyl, methoxy, ethoxy, hydroxy or amino;

R₅、R₆each independently selected from hydrogen, deuterium, halogen, cyano, C_1-4Alkyl radical, C_3-6Cycloalkyl, hydroxy, methoxy, ethoxy or isopropoxy; the above groups are optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, cyano, methyl, ethyl, cyclopropyl, methoxy, ethoxy, hydroxy or amino;

R₁、R₈、R₉、R₁₁、R₁₂and r is as defined for the compound of formula (I).

As a still further preferred embodiment, R in said compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof₁Selected from hydrogen, deuterium, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl or 5-8 membered heteroaryl, optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -C_0-4-S(O)_rR₈、-C_0-4-O-R₉、-C_0-4-C(O)OR₉、-C_0-4-C(O)R₁₀、-C_0-4-O-C(O)R₁₀、-C_0-4-NR₁₁R₁₂、-C_0-4-C(＝NR₁₁)R₁₀、-C_0-4-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-4-C(O)NR₁₁R₁₂or-C_0-4-N(R₁₁)-C(O)R₁₀Optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo-substituted C_1-4Alkyl, deuterium substituted C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -C_0-4-S(O)_rR₈、-C_0-4-O-R₉、-C_0-4-C(O)OR₉、-C_0-4-C(O)R₁₀、-C_{0- 4}-O-C(O)R₁₀、-C_0-4-NR₁₁R₁₂、-C_0-4-C(＝NR₁₁)R₁₀、-C_0-4-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-4-C(O)NR₁₁R₁₂or-C_0-4-N(R₁₁)-C(O)R₁₀Substituted with the substituent(s); r₈、R₉、R₁₀、R₁₁、R₁₂And r are as described above.

As a still further preferred embodiment, R in said compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof₁Selected from hydrogen, deuterium, C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl or 5-8 membered heteroaryl, optionally further substituted by one or more groups selected from deuterium, halogen, cyano, C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -C_0-4-O-R₉、-C_0-4-C(O)OR₉or-C_0-4-NR₁₁R₁₂Optionally further substituted by one or more substituents selected from deuterium, halogen, C_1-4Alkyl, halo-substituted C_1-4Alkyl, deuterium substituted C_{1- 4}Alkyl radical, C_3-6Cycloalkyl, ═ O, hydroxy, methoxy, ethoxy, isopropoxy, or carboxy; r₉、R₁₀、R₁₁、R₁₂As previously described.

As a further preferred embodiment, the compound of formula (I), a stereoisomer, a prodrug thereof, or a pharmaceutically acceptable salt thereof, has the structure of formula (iii):

wherein R is₁Selected from hydrogen, deuterium, C_1-4Alkyl radical, C_3-8Cycloalkyl or 3-8 membered heterocyclyl, said groups optionally further substituted by one or more groups selected from deuterium, halogen, C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-8 membered heteroaryl, ═ O, -O-R₉、-C(O)OR₉or-NR₁₁R₁₂Optionally further substituted by one or more substituents selected from deuterium, halogen, C_1-4Alkyl, halo-substituted C_1-4Alkyl, deuterium substituted C_1-4Alkyl radical, C_3-6Cycloalkyl, ═ O, hydroxy, methoxy, ethoxy, isopropoxy, or carboxy;

R₂selected from hydrogen, deuterium, halogen, C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -O-R₉or-NR₁₁R₁₂Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -O-R₉、-C(O)OR₉or-NR₁₁R₁₂Optionally further substituted by one or more substituents selected from deuterium, halogen, C_1-4Alkyl, halo-substituted C_1-4Alkyl, deuterium substituted C_1-4Alkyl radical, C_3-6Cycloalkyl, ═ O, hydroxy, methoxy, ethoxy, isopropoxy, or carboxy;

R₉、R₁₁、R₁₂as defined for the compounds of formula (I).

As a still further preferred embodiment, R in said compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof₁Selected from hydrogen, deuterium, C_1-4Alkyl radical, C_3-6Cycloalkyl or 3-6 membered heterocyclyl, said groups optionally further substituted by one or more groups selected from deuterium, fluoro, chloro, methyl, ethyl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, ═ O, hydroxy, methoxy, ethoxy, carboxy, amino, dimethylamino, or diethylamino, optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, methyl, ethyl, difluoromethyl, trifluoromethyl, dideuteromethyl, trideuteromethyl, cyclopropyl, ═ O, hydroxy, methoxy, ethoxy, isopropoxy, or carboxy;

R₂selected from 3-8 membered heterocyclyl, 5-6 membered heteroaryl or-NR₁₁R₁₂Optionally further substituted with one or more groups selected from deuterium, fluoro, chloro, cyano, C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, ═ O, hydroxy, methoxy, ethoxy, isopropoxy, carboxy, amino, dimethylamino, or diethylamino, optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, methyl, ethyl, difluoromethyl, trifluoromethyl, dideuteromethyl, trideuteromethyl, cyclopropyl, ═ O, hydroxy, methoxy, ethoxy, isopropoxy, or carboxy;

R₁₁、R₁₂each independently selected from hydrogen, deuterium, C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-6Aryl or 5-6 membered heteroaryl, optionally further substituted by one or more groups selected from deuterium, fluoro, chloro, hydroxy, C_1-4Alkyl, halo-substituted C_{1- 4}Alkyl, deuterium substituted C_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, 3-to 8-membered heterocyclic group, 3-to 8-membered heterocyclic oxy group, C_5-6Aryl radical, C_5-6Aryloxy, 5-6 membered heteroaryl, 5-6 membered heteroaryloxy, amino, dimethylamino, diethylamino or C_1-4Substituted by alkanoyl group;

or, R₁₁、R₁₂Together with the nitrogen atom to which they are directly attached form a 4-8 membered heterocyclic group, optionally further substituted by one or more groups selected from deuterium, fluoro, chloro, hydroxy, C_1-4Alkyl, halo-substituted C_1-4Alkyl, deuterium substituted C_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, 3-to 8-membered heterocyclic group, 3-to 8-membered heterocyclic oxy group, C_5-6Aryl radical, C_5-6Aryloxy, 5-6 membered heteroaryl, 5-6 membered heteroaryloxy, amino, dimethylamino, diethylamino or C_1-4Substituted by alkanoyl group.

As a still further preferred embodiment, R in said compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof₁Selected from hydrogen, deuterium, C_1-4Alkyl or 3-6 membered heterocyclyl, said groups optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, methyl, ethyl, cyclopropyl, 3-6 membered heterocyclyl, phenyl, amino, dimethylamino or diethylamino, said groups optionally further substituted with one or more substituents selected from deuterium, methyl, ethyl, difluoromethyl, trifluoromethyl, dideuteromethyl, trideuteromethyl or cyclopropyl;

R₂selected from diazoxide, triazolide or-NR₁₁R₁₂Optionally further substituted with one or more groups selected from deuterium, fluoro, chloro, cyano, C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, ═ O, hydroxy, methoxy, ethoxy, isopropoxy, or carboxy, said groups optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, methyl, ethyl, difluoromethyl, trifluoromethyl, dideuteromethyl, trideuteromethyl, or cyclopropyl;

R₁₁、R₁₂each independently selected from hydrogen, deuterium, C_1-4Alkyl radical, C_3-6Cycloalkyl or 3-6 membered heterocyclyl, said groups optionally further substituted by one or more groups selected from deuterium, fluoro, chloro, hydroxy, C_1-4Alkyl, difluoromethyl, trifluoromethyl, dideuteromethyl, trideuteromethyl, methoxy, ethoxy, isopropoxy, cyclopropyl, 3-8 membered heterocyclyl, phenyl, triazole, amino, dimethylamino, diethylamino or C_1-4Substituted by alkanoyl group;

R₁₁、R₁₂together with the nitrogen atom to which they are directly attached form a 4-8 membered heterocyclic group, optionally further substituted by one or more groups selected from deuterium, fluoro, chloro, hydroxy, C_1-4Alkyl, difluoromethyl, trifluoromethyl, dideuterylmethyl, trideuteromethyl, methoxy, ethoxy, isopropoxy, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, phenyl, diazo, triazolyl, amino, dimethylamino, diethylamino or C_1-4Substituted by alkanoyl group;

each of said heterocyclic groups independently optionally contains 1 or 2 heteroatoms selected from nitrogen atoms or oxygen atoms.

As a most preferred embodiment, the compound of formula (I), its stereoisomer, prodrug or a pharmaceutically acceptable salt thereof includes, but is not limited to, the following compounds:

in a second aspect, the present invention provides a process for the preparation of a compound of formula (I) as hereinbefore described, a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, which comprises the steps of:

alternatively, the first and second electrodes may be,

wherein, X, R₁、R₂、R₃、R₄、R₅、R₆As defined for the compounds of formula (I).

In a third aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described above, a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In a fourth aspect, the present invention provides a use of the compound of formula (I), its stereoisomer, prodrug or its pharmaceutically acceptable salt in the preparation of a medicament for treating tumor or cancer.

Preferably, the tumor or cancer is selected from bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, renal cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, thyroid cancer, skin cancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, acute myelocytic leukemia, hodgkin lymphoma or non-hodgkin lymphoma, fahrenheit macroglobulinemia, hairy lymphoma, cellular lymphoma, burkitt lymphoma, glioblastoma, melanoma or rhabdomyosarcoma.

In a fifth aspect, the present invention provides a use of a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating myeloproliferative diseases, bone or cartilage cell disorders, and hypophosphatemia.

Preferably, the myeloproliferative disease is selected from the group consisting of polycythemia, primary thrombocythemia, or primary myelofibrosis; said skeletal or chondrocyte disorder is selected from dysplasia, achondroplasia, dwarfism, lethal Teratocarcinosis (TD), Alpeller's syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Beare-Stevenson dermatoglyph syndrome, Pfeiffer syndrome or cranial muscle atrophy syndrome; the hypophosphatemia is selected from X-linked hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets or ovarian malacia induced by tumors.

In a sixth aspect, the present invention provides a compound of formula (I) as hereinbefore described, a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, for use as an FGFR inhibitor.

Detailed Description

The inventors of the present application have extensively and intensively studied and, for the first time, developed an FGFR inhibitor having the structure of formula (I), the preparation method and pharmaceutical use thereof, and the definition of each substituent is described in the specification and claims. The series of compounds can be widely applied to preparing medicines for treating tumors, cancers, myeloproliferative diseases, bone or cartilage cell disorder and hypophosphatemia, and are expected to be developed into a new generation of FGFR inhibitor medicines. On the basis of this, the present invention has been completed.

Detailed description: unless stated to the contrary, the following terms used in the specification and claims have the following meanings.

"alkyl" means a straight or branched chain saturated aliphatic hydrocarbon group, e.g., "C_1-10Alkyl "refers to straight chain alkyl groups and branched chain alkyl groups containing 1 to 10 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, 2-methylpentyl, 2-dimethylbutyl, and the like, N-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 23-dimethylpentyl group, 2, 4-dimethylpentyl group, 2-dimethylpentyl group, 3-dimethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, n-octyl group, 2, 3-dimethylhexyl group, 2, 4-dimethylhexyl group, 2, 5-dimethylhexyl group, 2-dimethylhexyl group, 3-dimethylhexyl group, 4-dimethylhexyl group, 2-ethylhexyl group, 3-ethylhexyl group, 4-ethylhexyl group, 2-methyl-2-ethylpentyl group, 2-methyl-3-ethylpentyl group, or various branched isomers thereof.

Alkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O)_rR₈、-C_0-8-O-R₉、-C_0-8-C(O)OR₉、-C_0-8-C(O)R₁₀、-C_0-8-O-C(O)R₁₀、-C_0-8-NR₁₁R₁₂、-C_0-8-C(＝NR₁₁)R₁₀、-C_0-8-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-8-C(O)NR₁₁R₁₂or-C_0-8-N(R₁₁)-C(O)R₁₀Substituted with the substituent(s).

"cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, e.g., "C_3-10Cycloalkyl "refers to cycloalkyl groups comprising 3 to 10 carbon atoms, divided into monocyclic cycloalkyl, polycyclic cycloalkyl groups, wherein:

monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.

Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. "spirocycloalkyl" refers to polycyclic groups which share a carbon atom (referred to as a spiro atom) between single rings, and these may contain one or more (preferably 1,2 or 3) double bonds, but none of the rings have a completely conjugated pi-electron system. Spirocycloalkyl groups are classified as mono-, di-or multi-spirocycloalkyl depending on the number of spiro atoms shared between rings, including but not limited to:

"fused cyclic alkyl" refers to an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more (preferably 1,2 or 3) double bonds, but none of the rings has a completely conjugated pi-electron system. And may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused ring alkyl groups depending on the number of constituent rings, including, but not limited to:

"bridged cycloalkyl" refers to all-carbon polycyclic groups in which any two rings share two carbon atoms not directly attached, and these may contain one or more (preferably 1,2 or 3) double bonds, but none of the rings have a completely conjugated pi-electron system. Depending on the number of constituent rings, bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl groups may be included, including but not limited to:

the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring to which the parent structure is attached is a cycloalkyl group, including but not limited to indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like.

Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably oneOr a plurality (preferably 1,2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O)_rR₈、-C_0-8-O-R₉、-C_0-8-C(O)OR₉、-C_0-8-C(O)R₁₀、-C_0-8-O-C(O)R₁₀、-C_0-8-NR₁₁R₁₂、-C_0-8-C(＝NR₁₁)R₁₀、-C_0-8-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-8-C(O)NR₁₁R₁₂or-C_0-8-N(R₁₁)-C(O)R₁₀Substituted with the substituent(s).

"Heterocyclyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent in which one or more (preferably 1,2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S (O)_r(wherein r is an integer 0, 1, 2) but does not include the ring moiety of-O-O-, -O-S-or-S-S-, the remaining ring atoms being carbon. For example, "5-10 membered heterocyclyl" refers to a cyclic group containing 5 to 10 ring atoms, and "3-10 membered heterocyclyl" refers to a cyclic group containing 3 to 10 ring atoms.

Monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.

Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups. "Spiroheterocyclyl" refers to polycyclic heterocyclic groups in which one atom (referred to as a spiro atom) is shared between monocyclic rings, and in which one or more (preferably 1,2, 3, or 4) ring atoms are selected from nitrogen, oxygen, or S (O)_r(wherein r is an integer of 0, 1, 2) and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Spiro heterocyclic groups are classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group, or a multi-spiro heterocyclic group according to the number of spiro atoms shared between rings. Spiroheterocyclic groups include, but are not limited toIn the following steps:

"fused heterocyclyl" means a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more (preferably 1,2, 3 or 4) rings may contain one or more (preferably 1,2 or 3) double bonds, but none of the rings has a fully conjugated pi-electron system, wherein one or more (preferably 1,2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S (O)_r(wherein r is an integer of 0, 1, 2) and the remaining ring atoms are carbon. They may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocycloalkyl depending on the number of rings comprising, but not limited to:

"bridged heterocyclyl" means polycyclic heterocyclic groups in which any two rings share two atoms not directly attached, which may contain one or more (preferably 1,2 or 3) double bonds, but none of the rings has a fully conjugated pi-electron system, wherein one or more (preferably 1,2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S (O)_r(wherein r is an integer of 0, 1, 2) and the remaining ring atoms are carbon. They may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups, depending on the number of constituent rings, including but not limited to:

the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterocyclyl, including but not limited to:

the heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O)_rR₈、-C_0-8-O-R₉、-C_0-8-C(O)OR₉、-C_0-8-C(O)R₁₀、-C_0-8-O-C(O)R₁₀、-C_0-8-NR₁₁R₁₂、-C_0-8-C(＝NR₁₁)R₁₀、-C_0-8-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-8-C(O)NR₁₁R₁₂or-C_0-8-N(R₁₁)-C(O)R₁₀Substituted with the substituent(s).

"aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group, a polycyclic (i.e., rings which carry adjacent pairs of carbon atoms) group having a conjugated pi-electron system, e.g., "C_5-10Aryl "refers to an all-carbon aryl group having 5 to 10 carbons, and" 5-10 membered aryl "refers to an all-carbon aryl group having 5 to 10 carbons, including but not limited to phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, including but not limited to:

aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O)_rR₈、-C_0-8-O-R₉、-C_0-8-C(O)OR₉、-C_0-8-C(O)R₁₀、-C_0-8-O-C(O)R₁₀、-C_0-8-NR₁₁R₁₂、-C_0-8-C(＝NR₁₁)R₁₀、-C_0-8-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-8-C(O)NR₁₁R₁₂or-C_0-8-N(R₁₁)-C(O)R₁₀Substituted with the substituent(s).

"heteroaryl" refers to a heteroaromatic system containing one or more (preferably 1,2, 3, or 4) heteroatoms including nitrogen, oxygen, and S (O) r (where r is an integer of 0, 1, 2), e.g., 5-8 membered heteroaryl refers to a heteroaromatic system containing 5-8 ring atoms, 5-10 membered heteroaryl refers to a heteroaromatic system containing 5-10 ring atoms, including but not limited to furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, including, but not limited to:

heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O)_rR₈、-C_0-8-O-R₉、-C_0-8-C(O)OR₉、-C_0-8-C(O)R₁₀、-C_0-8-O-C(O)R₁₀、-C_0-8-NR₁₁R₁₂、-C_0-8-C(＝NR₁₁)R₁₀、-C_0-8-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-8-C(O)NR₁₁R₁₂or-C_0-8-N(R₁₁)-C(O)R₁₀Substituted with the substituent(s).

"alkenyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, e.g., C_2-10Alkenyl means a straight or branched chain alkenyl group having 2 to 10 carbons. Including but not limited to ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like.

The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O)_rR₈、-C_0-8-O-R₉、-C_0-8-C(O)OR₉、-C_0-8-C(O)R₁₀、-C_0-8-O-C(O)R₁₀、-C_0-8-NR₁₁R₁₂、-C_0-8-C(＝NR₁₁)R₁₀、-C_0-8-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-8-C(O)NR₁₁R₁₂or-C_0-8-N(R₁₁)-C(O)R₁₀Substituted with the substituent(s).

"alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, e.g., C_2-10Alkynyl refers to straight or branched chain alkynyl groups containing 2-10 carbons. Including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-, 2-or 3-butynyl, and the like.

Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O)_rR₈、-C_0-8-O-R₉、-C_0-8-C(O)OR₉、-C_0-8-C(O)R₁₀、-C_0-8-O-C(O)R₁₀、-C_0-8-NR₁₁R₁₂、-C_0-8-C(＝NR₁₁)R₁₀、-C_0-8-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-8-C(O)NR₁₁R₁₂or-C_0-8-N(R₁₁)-C(O)R₁₀Substituted with the substituent(s).

"alkoxy" refers to-O- (alkyl) wherein alkyl is as defined above, e.g., "C_1-10Alkoxy "refers to an alkyloxy group having 1 to 10 carbons, including but not limited to methoxy, ethoxy, propoxy, butoxy, and the like.

Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents, preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10AlkynesAlkyl, halo substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O)_rR₈、-C_0-8-O-R₉、-C_0-8-C(O)OR₉、-C_0-8-C(O)R₁₀、-C_0-8-O-C(O)R₁₀、-C_0-8-NR₁₁R₁₂、-C_0-8-C(＝NR₁₁)R₁₀、-C_0-8-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-8-C(O)NR₁₁R₁₂or-C_0-8-N(R₁₁)-C(O)R₁₀Substituted with the substituent(s).

"Cycloalkoxy" means and-O- (unsubstituted cycloalkyl) wherein cycloalkyl is as defined above, e.g., "C_3-10Cycloalkoxy "refers to cycloalkyloxy groups containing 3-10 carbons, including but not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

Cycloalkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O)_rR₈、-C_0-8-O-R₉、-C_0-8-C(O)OR₉、-C_0-8-C(O)R₁₀、-C_0-8-O-C(O)R₁₀、-C_0-8-NR₁₁R₁₂、-C_0-8-C(＝NR₁₁)R₁₀、-C_0-8-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-8-C(O)NR₁₁R₁₂or-C_0-8-N(R₁₁)-C(O)R₁₀Substituted with the substituent(s).

"3-10 membered heterocyclyloxy" means and-O- (unsubstituted 3-10 membered heterocyclyl), wherein 3-10 membered heterocyclyl is as defined above, 3-10 membered heterocyclyloxy may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O)_rR₈、-C_0-8-O-R₉、-C_0-8-C(O)OR₉、-C_0-8-C(O)R₁₀、-C_0-8-O-C(O)R₁₀、-C_0-8-NR₁₁R₁₂、-C_0-8-C(＝NR₁₁)R₁₀、-C_0-8-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-8-C(O)NR₁₁R₁₂or-C_0-8-N(R₁₁)-C(O)R₁₀Substituted with the substituent(s).

“C_5-10Aryloxy means and-O- (unsubstituted C)_5-10Aryl) in which C_5-10Aryl is as defined above, C_5-10Aryloxy may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O)_rR₈、-C_0-8-O-R₉、-C_0-8-C(O)OR₉、-C_0-8-C(O)R₁₀、-C_0-8-O-C(O)R₁₀、-C_0-8-NR₁₁R₁₂、-C_0-8-C(＝NR₁₁)R₁₀、-C_0-8-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-8-C(O)NR₁₁R₁₂or-C_0-8-N(R₁₁)-C(O)R₁₀Substituted with the substituent(s).

"5-10 membered heteroaryloxy" means and-O- (unsubstituted 5-10 membered heteroaryl), wherein 5-10 membered heteroaryl is as defined above, and 5-10 membered heteroaryloxy may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O)_rR₈、-C_0-8-O-R₉、-C_0-8-C(O)OR₉、-C_0-8-C(O)R₁₀、-C_0-8-O-C(O)R₁₀、-C_0-8-NR₁₁R₁₂、-C_0-8-C(＝NR₁₁)R₁₀、-C_0-8-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-8-C(O)NR₁₁R₁₂or-C_0-8-N(R₁₁)-C(O)R₁₀Substituted with the substituent(s).

“C_1-8Alkanoyl "means C_1-8The monovalent radical remaining after removal of the hydroxyl group from the alkyl acid, also commonly referred to as "C_0-7-C (O) - ", e.g." C₁-c (o) — "means acetyl; "C₂-c (o) — "refers to propionyl; "C₃-C (O) -means butyryl or isobutyryl.

“-C_0-8-S(O)_rR₈"means-S (O)_rR₈With sulfur atoms bound to C_0-8On the alkyl radical, wherein C₀Alkyl means a bond, C_1-8The alkyl group is as defined above.

“-C_0-8-O-R₉"means-O-R₉In which the oxygen atom is bound to C_0-8On the alkyl radical, wherein C₀Alkyl means a bond, C_1-8The definition of alkyl is as described above.

“-C_0-8-C(O)OR₉"means-C (O) OR₉Wherein the carbonyl group is bound to C_0-8On the alkyl radical, wherein C₀Alkyl means a bond, C_1-8The alkyl group is as defined above.

“-C_0-8-C(O)R₁₀"means-C (O) R₁₀Wherein the carbonyl group is bound to C_0-8On the alkyl radical, wherein C₀Alkyl means a bond, C_1-8The alkyl group is as defined above.

“-C_0-8-O-C(O)R₁₀"means-O-C (O) R₁₀In which the oxygen atom is bound to C_0-8On the alkyl radical, wherein C₀Alkyl means a bond, C_{1- 8}The alkyl group is as defined above.

“-C_0-8-NR₁₁R₁₂"means-NR₁₁R₁₂In which the nitrogen atom is bound to C_0-8On the alkyl radical, wherein C₀Alkyl means a bond, C_1-8The alkyl group is as defined above.

“-C_0-8-C(＝NR₁₁)R₁₀"means-C (═ NR)₁₁)R₁₀Wherein the carbonyl group is bound to C_0-8On the alkyl radical, wherein C₀Alkyl means a bond, C_1-8The alkyl group is as defined above.

“-C_0-8-N(R₁₁)-C(＝NR₁₂)R₁₀"means-N (R)₁₁)-C(＝NR₁₂)R₁₀Wherein the carbonyl group is bound to C_0-8On the alkyl radical, wherein C₀Alkyl means a bond, C_1-8The alkyl group is as defined above.

“-C_0-8-C(O)NR₁₁R₁₂"means-C (O) NR₁₁R₁₂Wherein the carbonyl group is bound to C_0-8On the alkyl radical, wherein C₀Alkyl means a bond, C_1-8The alkyl group is as defined above.

“-C_0-8-N(R₁₂)-C(O)R₁₁"means-N (R)₁₂)-C(O)R₁₁In which the nitrogen atom is bound to C_0-8On the alkyl radical, wherein C₀Alkyl means a bond, C_1-8The alkyl group is as defined above.

"halogen substituted C_1-10Alkyl "refers to a 1-10 carbon alkyl group optionally substituted with fluorine, chlorine, bromine, iodine atoms for the hydrogen on the alkyl, including but not limited to difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, and the like.

"halogen substituted C_1-10Alkoxy "a 1-10 carbon alkoxy group wherein the hydrogen on the alkyl group is optionally substituted with fluorine, chlorine, bromine, or iodine atoms. Including but not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, and the like.

"halogen" means fluorine, chlorine, bromine or iodine.

"MeOH" refers to methanol. "DMF" refers to N, N-dimethylformamide. "DCE" refers to 1, 2-dichloroethane. "THF" refers to tetrahydrofuran. "PE" refers to petroleum ether. "EA/EtOAc" refers to ethyl acetate. "DCM" means dichloromethane. "LiOH" refers to lithium hydroxide. "NaOH" refers to sodium hydroxide. "NaNO₂"refers to sodium nitrite. "CuI" refers to cuprous iodide. "Na₂SO₄Refers to sodium sulfate. "" HOAc "refers to acetic acid. "NH₄Oac "refers to ammonium acetate. "Et₃N "refers to triethylamine. "NH₄Cl "refers to ammonium chloride. "TFA" refers to trifluoroacetic acid. "m-CPBA" refers to m-chloroperoxybenzoic acid. "Pd (PPh)₃)₄"refers to tetrakis (triphenylphosphine) palladium. "Pd (PPh)₃)₂Cl₂"" means "bis-triphenylphosphine palladium dichloride.

"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.

"substituted" means that one or more hydrogen atoms in a group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated bonds (e.g., olefins).

"pharmaceutically acceptable salts" as used herein refers to pharmaceutically acceptable acid addition salts, including inorganic and organic acid salts, which may be prepared by methods known in the art.

"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.

The present invention will be described more fully with reference to the following examples, but the present invention is not limited thereto, and the present invention is not limited to the examples.

The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass chromatography (LC-MS). NMR chemical shifts () are given in parts per million (ppm). NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d)₆) Deuterated methanol (CD)₃OD) and deuterated chloroform (CDCl)₃) Internal standard is Tetramethylsilane (TMS).

The LC-MS was measured using an Agilent 6120 mass spectrometer. HPLC was carried out using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150X 4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18150X 4.6mm column).

The thin layer chromatography silica gel plate adopts a tobacco yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification adopted by TLC is 0.15 mm-0.20 mm, and the specification adopted by the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.

The starting materials in the examples of the present invention are known and commercially available, or may be synthesized using or according to methods known in the art.

All reactions of the present invention are carried out under a dry nitrogen or argon atmosphere with continuous magnetic stirring, without specific indication, the solvent is a dry solvent, and the reaction temperature is given in degrees centigrade (deg.C).

Preparation of intermediate

1. Preparation of 8-chloro-6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d ] pyrimidine

The first step is as follows: synthesis of 2, 4-difluoro-3-iodo-1, 5-dimethoxybenzene

The compound 2, 6-difluoro-3, 5-dimethoxyaniline (27.0g, 143mmol) was added to 6.0M hydrochloric acid solution (240mL), NaNO was slowly added dropwise under cooling in an ice-water bath₂Aqueous solution (10.35g, 150mmol, 30mL water). The addition was completed in 25 minutes and the reaction was continued for 15 minutes to yield an orange suspension which was added to aqueous KI solution (94.9g, 570mmol, 150mL of water). The reaction was allowed to warm to room temperature and stirred for 30 minutes to precipitate a solid. Filtering and washing to obtain a crude product. The crude product was added to MeOH (60mL) and stirred at room temperature for 30 min. Filtration and drying were carried out to give 2, 4-difluoro-3-iodo-1, 5-dimethoxybenzene (29.3g, yield: 68%).¹H NMR(400MHz,DMSO-d₆)6.69(t,J＝8.0Hz,1H),3.88(s,6H)。

The second step is that: synthesis of (2, 6-difluoro-3, 5-dimethoxyphenylacetylene) yltrimethylsilane

2, 4-difluoro-3-iodo-1, 5-dimethoxybenzene (25.8g,86.0mmol), trimethylsilylacetylene (36.5mL, 258mmol), CuI (817mg, 4.3mmol), and triethylamine (35.8mL, 258mmol) were added to DMF (250 mL). Pumping gas, protecting with nitrogen, and adding Pd (PPh)₃)₂Cl₂(3.15g, 4.3 mmol). Heated to 50 ℃ and reacted for 2 hours. The reaction is completed, saturated NH is added₄The solution was quenched with aqueous Cl and extracted 3 times with dichloromethane. The organic phases were combined, Na₂SO₄And (5) drying. Filtration and concentration gave a crude product (27.0g) which was used directly in the next reaction.¹H NMR(400MHz,CDCl₃)6.61(t,J＝8.0Hz,1H),3.86(s,6H),0.28(s,9H)。

The third step: synthesis of 3-ethynyl-2, 4-difluoro-1, 5-dimethoxybenzene

(2, 6-difluoro-3, 5-dimethoxyphenylacetylene) yltrimethylsilane (27.0g, crude) was added THF/MeOH (200/200mL), followed by aqueous NaOH (8.6mL, 8.6mmol, 1.0N). Stir at room temperature for 15 minutes. The reaction is completed, saturated NH is added₄The solution was quenched with aqueous Cl and extracted 3 times with dichloromethane. The organic phases were combined and anhydrous Na₂SO₄And (5) drying. Filtered, concentrated, and the crude product slurried with MeOH (50mL) and stirred at room temperature for 30 min. Filtration gave 3-ethynyl-2, 4-difluoro-1, 5-dimethoxybenzene (15.0g, 2-step yield: 88%).¹H NMR(400MHz,CDCl₃)6.66(t,J＝8.0Hz,1H),3.88(s,6H),3.52(s,1H)。

The fourth step: synthesis of methyl 5- ((2, 6-difluoro-3, 5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylate

3-ethynyl-2, 4-difluoro-1, 5-dimethoxybenzene (10.0g, 50.5mmol) and methyl 5-bromo-2-methylsulfanyl-pyrimidine-4-carboxylate (13.0g, 49.5mmol) were dissolved in DMF (100mL) and CuI (479mg, 2.52mmol), Pd (PPh) and added₃)₄(2.91g, 2.52mmol) and Et₃N (35.0mL, 252.5mmol), nitrogen blanket. The reaction was heated to 100 ℃ for 1.5 hours. The reaction is completed, cooled to room temperature, and saturated NH is added₄The solution was quenched with aqueous Cl and extracted 3 times with dichloromethane. The organic phases were combined and anhydrous Na₂SO₄Drying, filtering and concentrating. The crude product was separated by silica gel column chromatography (PE: EA: DCM ═ 10:2:1) to give methyl 5- ((2, 6-difluoro-3, 5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylate (15.4g, yield: 82%).¹H NMR(400MHz,CDCl₃)8.82(s,1H),6.69(t,J＝8.0Hz,1H),4.03(s,3H),3.90(s,6H),2.63(s,3H).

The fifth step: synthesis of 5- ((2, 6-difluoro-3, 5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylic acid

Methyl 5- ((2, 6-difluoro-3, 5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylate (30.0g, 78.9mmol) was dissolved in THF (300mL) and LiOH/H added₂O (236.8mL, 236.8mmol, 1M). The reaction was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated to remove THF, and acidified with dilute hydrochloric acid to a pH of about 3 to precipitate a solid. Filtration, washing with water, and drying gave 5- ((2, 6-difluoro-3, 5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylic acid (28.5g, yield: 99%).¹H NMR(400MHz,DMSO-d₆)8.98(s,1H),7.15(t,J＝8.0Hz,1H),3.90(s,6H),2.59(s,3H)。

And a sixth step: synthesis of 6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) -8H-pyrano [3,4-d ] pyrimidin-8-one

5- ((2, 6-difluoro-3, 5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylic acid (2.5g, 6.83mmol) was dissolved in DCE (50mL) and TFA (0.5mL) and copper acetate (62mg, 0.34mmol) were added. The mixture was heated to reflux and reacted overnight. The reaction is complete and the reaction is complete,concentrate, add MeOH (50mL) and slurry, stir at room temperature for 30 min. Filtration, washing of the solid with MeOH (10mL), and drying to give 6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) -8H-pyrano [3,4-d]Pyrimidin-8-one (2.0g, yield: 80%).¹H NMR(400MHz,DMSO-d₆)9.23(s,1H),7.22(t,J＝8.4Hz,1H),7.17(s,1H),3.93(s,6H),2.63(s,3H).

The seventh step: synthesis of 6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d ] pyrimidin-8 (7H) -one

6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) -8H-pyrano [3,4-d]Pyrimidin-8-one (4.5g, 12.3mmol) was dissolved in HOAc (45mL) and NH was added₄OAc (9.4g, 123mmol), and the reaction was stirred at 120 ℃ overnight. Cooling at room temperature, adding appropriate amount of water (30mL), stirring, vacuum filtering, washing the filter cake with water (20mL), and drying to obtain 6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d]Pyrimidin-8 (7H) -one (4.22g, yield: 94%).¹H NMR(400MHz,DMSO-d₆)12.28(s,1H),9.24(s,1H),7.17(t,J＝8.4Hz,1H),6.76(s,1H),3.92(s,6H),2.63(s,3H).

Eighth step: synthesis of 8-chloro-6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d ] pyrimidine

6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d]Pyrimidin-8 (7H) -one (1g,2.74mmol) was dissolved in DCE (80mL), heated to 90 ℃, then phenylphosphonyl dichloride (3.0mL, 21.92mmol) was added, heated with stirring for 16H, cooled, pH adjusted to neutral with sodium bicarbonate while on ice, extracted with DCM, and chromatographed on silica gel (DCM/EtOAc ═ 0-10%)) to give 8-chloro-6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d ] as a reaction product]Pyrimidine (930mg, 88% yield).¹H NMR(400MHz,CDCl₃)9.25(s,1H),7.78(t,J＝1.2Hz,1H),6.75(t,J＝8.0Hz,1H),3.93(s,6H),2.77(s,3H)。MS m/z(ESI):384[M+H]⁺。

2. Preparation of 8-chloro-6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylsulfonyl) pyrido [3,4-d ] pyrimidine

8-chloro-6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d]Pyrimidine (930mg, 2.42mmol) was dissolved in DCM (50mL), and m-CPBA (1.23g, 6.05mmol) was added and stirred at room temperature for 2 h. The reaction was complete, quenched with sodium thiosulfate, extracted with DCM and isolated by silica gel column chromatography (DCM/EtOAc 0-35%) to give 8-chloro-6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylsulfonyl) pyrido [3,4-d]Pyrimidine (800mg, 79% yield).¹H NMR(400MHz,CDCl₃)9.76(s,1H),8.03(t,J＝1.2Hz,1H),6.80(t,J＝8.0Hz,1H),3.95(s,6H),3.58(s,3H)。MS m/z(ESI):416[M+H]⁺。

Preparation of the example Compounds

Example preparation of 11- (2- ((4- (diethylamino) butyl) amino) -6- (2, 6-difluoro-3, 5-dimethoxyphenyl) pyrido [3,4-d ] pyrimidin-8-yl) -3-methylazetidin-3-ol

The first step is as follows: synthesis of 1- (6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d ] pyrimidin-8-yl) -3-methylazetidin-3-ol

In the presence of 8-chloro-6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d]Pyrimidine (300mg,0.782mmol) and 3-methyl-3-acridinium alkoxide (290mg,2.345mmol) in acetonitrile (6)mL) was added N, N-diisopropylethylamine (0.605mg,4.692 mmol). The reaction solution was placed in a sealed tube and stirred at 95 ℃ for 18 hours. After cooling, the mixture was diluted with ethyl acetate (50mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography [ eluent (dichloromethane: ethyl acetate 0-40%)]To obtain 1- (6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d]Pyrimidin-8-yl) -3-methylazetidin-3-ol (328mg, yield: 96%). MS M/z (ESI) 435.4[ M + H]⁺

The second step is that: synthesis of 1- (6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylsulfonyl) pyrido [3,4-d ] pyrimidin-8-yl) -3-methylazetidin-3-ol

In the presence of 1- (6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d]To a solution of pyrimidin-8-yl) -3-methylazetidin-3-ol (328mg,0.755mmol) in dichloromethane (8mL) was added m-chloroperoxybenzoic acid (390mg,2.265mmol) in one portion. The reaction solution was stirred at room temperature for 20 hours. Washing the reaction solution with a saturated sodium sulfite solution and a sodium bicarbonate solution in sequence, washing with a saturated sodium chloride solution, drying with anhydrous sodium sulfate, concentrating, and performing column chromatography separation [ eluent (dichloromethane: ethyl acetate: 0-80%)]To obtain 1- (6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylsulfonyl) pyrido [3,4-d]Pyrimidin-8-yl) -3-methylazetidin-3-ol (151mg, yield: 42%). MS M/z (ESI) 467.4[ M + H]⁺。

The third step: synthesis of 1- (2- ((4- (diethylamino) butyl) amino) -6- (2, 6-difluoro-3, 5-dimethoxyphenyl) pyrido [3,4-d ] pyrimidin-8-yl) -3-methylazetidin-3-ol

1- (6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylsulfonyl) pyrido [3,4-d]Pyrimidin-8-yl) -3-methylazetidin-3-ol (14mg,0.03mmol) and N¹,N¹-Diethylbutane-1, 4-diamine (13mg,0.09mmol) was dissolved in acetonitrile (0.5 mL). The reaction solution was placed in a sealed tube and stirred at 80 ℃ for 3 hours. Directly concentrating the reaction solution, and separating by reverse phase column chromatography (mobile phase (acetonitrile: water (0.1% formic acid) ═ 5-35%)]And freeze-drying the aqueous phase to obtain 1- (2- ((4- (diethylamino) butyl) amino) -6- (2, 6-difluoro-3, 5-dimethoxyphenyl) pyrido [3,4-d]Pyrimidin-8-yl) -3-methylazetidin-3-ol (9mg, yield 53%). MS M/z (ESI) 531.6[ M + H]⁺。

¹H NMR(400MHz,CDCl₃)8.82(s,1H),8.53(s,1H,HCO₂H),6.87(s,1H),6.66(t,J＝7.9Hz,1H),5.67(s,1H),4.43(s,4H),3.91(s,6H),3.52(s,2H),3.10–3.00(m,6H),2.12–1.64(m,4H),1.57(s,3H),1.25(t,J＝7.3Hz,6H).

Example 2N¹- (8- (azetidin-1-yl) -6- (2, 6-difluoro-3, 5-dimethoxyphenyl) pyrido [3,4-d]Preparation of pyrimidin-2-yl) -N4, N4-diethylbutane-1, 4-diamine

The first step is as follows: synthesis of 8- (azetidin-1-yl) -6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d ] pyrimidine

In the presence of 8-chloro-6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d]To a solution of pyrimidine (600mg,1.407mmol) and azetidine hydrochloride (395mg,4.221mmol) in acetonitrile (12mL) was added N, N-diisopropylethylamine (1.09g,8.442 mmol). The reaction solution was placed in a sealed tube and stirred at 95 ℃ for 16 hours. After cooling, the mixture was diluted with ethyl acetate (50mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography [ eluent (dichloromethane: ethyl acetate 0-15%)]To give 8- (azetidin-1-yl) -6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d]Pyrimidine (483mg, yield: 84.9%). MS M/z (ESI) 405.4[ M + H ]]⁺.

The second step is that: synthesis of 8- (azetidin-1-yl) -6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylsulfonyl) pyrido [3,4-d ] pyrimidine

In the presence of 8- (azetidin-1-yl) -6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d]To a solution of pyrimidine (483mg,1.194mmol) in dichloromethane (10mL) was added m-chloroperoxybenzoic acid (515mg,2.986mmol) in one portion. The reaction solution was stirred at room temperature for 24 hours. The reaction solution was washed with a saturated sodium sulfite solution and a sodium bicarbonate solution in this order, finally washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated and then subjected to column chromatography [ eluent (dichloromethane: methanol 0 to 5%)]To give 8- (azetidin-1-yl) -6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylsulfonyl) pyrido [3,4-d]Pyrimidine (214mg, yield: 41%). MS M/z (ESI) 437.4[ M + H ]]⁺.

The third step: n is a radical of¹- (8- (azetidin-1-yl) -6- (2, 6-difluoro-3, 5-dimethoxyphenyl) pyrido [3,4-d]Synthesis of pyrimidin-2-yl) -N4, N4-diethylbutane-1, 4-diamine

In the presence of 8- (azetidin-1-yl) -6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylsulfonyl) pyrido [3,4-d]Pyrimidine (40mg,0.091mmol) and N¹,N¹To a solution of diethylbutane-1, 4-diamine (39.6mg,0.275mmol) in acetonitrile (2mL) was added N, N-diisopropylethylamine (35.5mg,0.275 mmol). The reaction solution was placed in a sealed tube and stirred at 110 ℃ for 18 hours. After cooling, the mixture was diluted with ethyl acetate (20mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and concentrated with C₁₈Reversed phase column separation [ mobile phase (acetonitrile: water (0.1% formic acid) ═ 10-30% ]]And freeze-drying to obtain N¹- (8- (azetidine)-1-yl) -6- (2, 6-difluoro-3, 5-dimethoxyphenyl) pyrido [3,4-d]Pyrimidin-2-yl) -N4, N4-diethylbutane-1, 4-diamine (25mg, yield: 54%). MS M/z (ESI) 501.6[ M + H ]]⁺.

¹H NMR(400MHz,CDCl₃)8.84(s,1H),8.61(s,1H,HCOOH),6.88(s,1H),6.66(t,J＝7.9Hz,1H),5.81(br s,1H),4.60-4.30(m,4H),3.91(s,6H),3.53(t,J＝6.4Hz,2H),2.98(q,J＝7.3Hz,4H),2.90(t,J＝8.0Hz,2H),2.40(p,J＝7.5Hz,2H),1.87–1.75(m,2H),1.76–1.67(m,2H),1.23(t,J＝7.2Hz,6H).

Examples 3-21 were prepared according to the synthetic method of example 1 or 2:

example 22N⁸- (cyclopropylmethyl) -6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -N²- (2- (4-methylpiperazin-1-yl) ethyl) pyrido [3,4-d]Preparation of pyrimidine-2, 8-diamines

The first step is as follows: synthesis of 8-chloro-6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -N- (2- (4-methylpiperazin-1-yl) ethyl) pyrido [3,4-d ] pyrimidin-2-amine

In the presence of 8-chloro-6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylsulfonyl) pyrido [3,4-d]To a solution of pyrimidine (400mg,0.962mmol) and 4-methyl-1-piperazineethylamine (344mg,2.405mmol) in dichloromethane (10mL) was added N, N-diisopropylethylamine (372mg,2.886 mmol). The reaction solution was stirred under reflux at 50 ℃ for 2 hours. After cooling, the reaction mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 8-chloro-6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -N- (2- (4-methylpiperazin-1-yl) ethyl) pyrido [3,4-d]Pyrimidin-2-amine. MS M/z (ESI) 479.6[ M + H ]]⁺.

The second step is that: n is a radical of⁸- (cyclopropylmethyl) -6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -N²- (2- (4-methylpiperazin-1-yl) ethyl) pyrido [3,4-d]Synthesis of pyrimidine-2, 8-diamines

In the presence of 8-chloro-6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -N- (2- (4-methylpiperazin-1-yl) ethyl) pyrido [3,4-d]To a solution of pyrimidin-2-amine (40mg,0.084mmol) and cyclopropylmethylamine (30mg,0.418mmol) in tert-butanol (2mL) was added N, N-diisopropylethylamine (32.5mg,0.275 mmol). The reaction solution was placed in a sealed tube and stirred at 115 ℃ for 18 hours. After concentration, the mixture was diluted with ethyl acetate (20mL), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated, followed by separation on a preparative plate [ developing solvent (dichloromethane: methanol (5% ammonia) ═ 10: 1)]To obtain N⁸- (cyclopropylmethyl) -6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -N²- (2- (4-methylpiperazin-1-yl) ethyl) pyrido [3,4-d]Pyrimidine-2, 8-diamine (17.7mg, yield: 51%). MS M/z (ESI) 514.6[ M + H]⁺.

¹H NMR(400MHz,CDCl₃)8.86(s,1H),6.88(s,1H),6.66(t,J＝7.9Hz,1H),6.56–6.50(m,1H),5.88(s,1H),3.91(s,6H),3.64(dd,J＝11.1,5.2Hz,2H),3.44(dd,J＝7.0,5.5Hz,2H),3.04–2.50(m,10H),2.42(s,3H),0.88(t,J＝6.9Hz,1H),0.58–0.49(m,2H),0.35–0.26(m,2H).

Example 23 was prepared according to the synthetic method of example 22:

example 246 preparation of- (2, 6-difluoro-3, 5-dimethoxyphenyl) -8- (1-methyl-1H-pyrazol-4-yl) -N- (2- (4-methylpiperazin-1-yl) ethyl) pyrido [3,4-d ] pyrimidin-2-amine

The first step is as follows: synthesis of 6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -8- (1-methyl-1H-pyrazol-4-yl) -2- (methylthio) pyrido [3,4-d ] pyrimidine

8-chloro-6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d]Pyrimidine (200mg,0.52mmol), (1-methyl-1H-pyrazol-4-yl) boronic acid (131mg,1.04mmol), potassium phosphate (221mg,1.04mmol), XPhos-Pd-G2(41mg,0.052mmol) were dissolved in tetrahydrofuran (10mL) and water (3mL), replaced with nitrogen three times, and the reaction was left to stir at 45 ℃ overnight. Cooled, diluted with ethyl acetate (100mL), washed once with water (20mL × 2) and saturated brine (20mL × 2), dried over sodium sulfate, filtered, concentrated and separated by column chromatography on silica gel (eluent: PE/EA ═ 3/1) to give 6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -8- (1-methyl-1H-pyrazol-4-yl) -2- (methylthio) pyrido [3,4-d]Pyrimidine (230mg, 100% yield). MS M/z (ESI) 430.4[ M + H ]]⁺.

The second step is that: synthesis of 6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -8- (1-methyl-1H-pyrazol-4-yl) -2- (methylsulfonyl) pyrido [3,4-d ] pyrimidine

6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -8- (1-methyl-1H-pyrazol-4-yl) -2- (methylthio) pyrido [3,4-d]Pyrimidine (230mg, 0.54mmol) was dissolved in methylene chloride (10m L), and m-chloroperoxybenzoic acid (282mg,1.38mmol) was added thereto, followed by stirring at room temperature overnight. Adding sodium thiosulfate for quenching, adjusting saturated sodium bicarbonate to be alkaline, extracting by dichloromethane, washing by saturated sodium bicarbonate and common salt water once, and concentrating to obtain 6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -8- (1-methyl-1H-pyrazol-4-yl) -2- (methylsulfonyl) pyrido [3,4-d]Crude pyrimidine (300mg), was used directly in the next step. MS M/z (ESI) 462.4[ M + H ]]⁺。

The third step: synthesis of 6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -8- (1-methyl-1H-pyrazol-4-yl) -N- (2- (4-methylpiperazin-1-yl) ethyl) pyrido [3,4-d ] pyrimidin-2-amine

6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -8- (1-methyl-1H-pyrazol-4-yl) -2- (methylsulfonyl) pyrido [3,4-d]Crude pyrimidine (100mg,0.18mmol),2- (4-methylpiperazin-1-yl) ethan-1-amine (51mg,0.36mmol), DIPEA (70mg,0.54mmol) were dissolved in 20mL acetonitrile, reacted using a lock tube, and stirred at 110 ℃ overnight. Directly concentrating, separating by reverse phase column chromatography (eluent: 30% water/acetonitrile, adding 5% formic acid), and lyophilizing the water phase to obtain 6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -8- (1-methyl-1H-pyrazol-4-yl) -N- (2- (4-methylpiperazin-1-yl) ethyl) pyrido [3,4-d]Pyrimidin-2-amine (70mg, yield 72%). MS M/z (ESI) 525.6[ M + H ]]⁺.

¹H NMR(400MHz,Methanol-d₄)9.19(s,1H),8.60(s,2H),8.48(s,2H,HCOOH),7.65(s,1H),6.99(t,J＝8.1Hz,1H),4.01(s,3H),3.95(s,6H),3.78(t,J＝6.4Hz,2H),3.27–3.08(m,8H),2.91–2.86(m,2H),2.80(s,3H).

Biological test evaluation

FGFR 1-3 in vitro biochemical kinase analysis

The invention adopts Caliper Assay to determine the characteristics of the compounds on the inhibitory activity of FGFR1, FGFR2 and FGFR 3. The specific experimental process is as follows:

1. the kinase reaction carried out by the present invention was carried out in a 384-well plate by incubating the reaction system with a certain concentration of kinase (Carna), a certain concentration of ATP and 1. mu.M of peptide FAM-P22(GL Biochem, Cat. No.112393)) at 28 ℃ for a certain period of time in a reaction system of 50mM HEPES, pH7.5, 0.0015% Brij-35 and a basic kinase buffer; for FGFR1, the enzyme concentration was 0.25nM, the ATP concentration was 382 μ M, and the reaction time was 20 minutes; for FGFR2, the enzyme concentration was 2.5nM, the ATP concentration was 1 μ M, and the reaction time was 40 minutes; for FGFR3, the enzyme concentration was 8nM, ATP concentration was 4.7. mu.M, and the reaction time was 30 minutes

2. The reaction was stopped by adding a stop solution (100mM HEPES, pH7.5, 0.2% Caliper coating reagent, 50mM EDTA and 0.015% Brij 35);

3. transferring the hole plate with the stopped kinase reaction to a Caliper to read data;

4. the phosphorylated and unphosphorylated peptides were separated using Caliper microfluidic migration shift technology and the analyte was transferred by constant buffer flow through the chip and the migration of the substrate peptide was monitored by its labeled fluorescent signal. Kinase activity was calculated using the amount of phosphopeptide formed.

5. Determination of IC by analysis of percent inhibition by non-Linear regression at different Compound concentrations₅₀The value is obtained. The enzymatic activities of the compounds of the specific examples are shown in Table 1.

Second, Cell Titer Glo (CTG) experiment)

The inhibition of cell proliferation by compounds dependent on the FGFR signaling pathway was evaluated by a survival assay, measured using CTG reagent (Promega, # G7573). Cell lines representing different tumor types, such as H1581 lung cancer cell (with FGFR1 gene amplification) or Snu-16 stomach cancer cell (with FGFR2 gene amplification) from Nanjing Kebai, were selected and the specific experimental procedures were as follows:

1. 90ul of cells were seeded into tissue culture medium-treated 96-well plates (Costar #3904), incubated overnight at 37 ℃ in a 5% carbon dioxide incubator, followed by the addition of 10. mu.L of medium containing 10-fold dilutions of the compound at its final concentration.

2. Dose-effect effects were evaluated by serial dilutions of test compounds, starting at concentrations of 10 μ M or less.

3. Cells were incubated at 37 ℃ with 5% CO₂After 3 days of incubation, 50 μ L of CTG was added and readings were taken using envision (pelkin elmer) to quantify cellular ATP levels the percent inhibition of cell proliferation/survival by the compounds was assessed by comparing cellular ATP levels after the action of different concentrations of inhibitor to cellular ATP levels of DMSO control

4. Four parameter curve fitting in Graphpad Prism was used to determine the concentration of compound that resulted in half maximal growth Inhibition (IC)₅₀). Specific examples the compounds were shown in table 1 for their cellular activity.

TABLE 1 results of enzymology and cellular Activity assays

From the enzymatic activity data of the compounds of the specific embodiments, the compounds of the series have strong inhibition effects on the kinase activities of FGFR1, FGFR2 and FGFR 3. From the data of the cell activities of the compounds of the specific examples, the compounds of the invention have strong inhibition effect on the proliferation activity of H1581 lung cancer cells and/or Snu16 gastric cancer cells highly expressed by FGFR1, FGFR2 and FGFR 3.

All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (17)

1. A compound of formula (I), a stereoisomer, a prodrug thereof, or a pharmaceutically acceptable salt thereof:

   

   wherein the content of the first and second substances,

   x is selected from C (R)₇) Or N;

   R₁selected from hydrogen, deuterium, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl or 5-to 10-membered heteroaryl, optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O)_rR₈、-C_0-8-O-R₉、-C_0-8-C(O)OR₉、-C_0-8-C(O)R₁₀、-C_0-8-O-C(O)R₁₀、-C_0-8-NR₁₁R₁₂、-C_0-8-C(＝NR₁₁)R₁₀、-C_0-8-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-8-C(O)NR₁₁R₁₂or-C_0-8-N(R₁₁)-C(O)R₁₀Optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C_{1- 10}Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O)_rR₈、-C_0-8-O-R₉、-C_0-8-C(O)OR₉、-C_0-8-C(O)R₁₀、-C_0-8-O-C(O)R₁₀、-C_0-8-NR₁₁R₁₂、-C_0-8-C(＝NR₁₁)R₁₀、-C_0-8-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_{0- 8}-C(O)NR₁₁R₁₂or-C_0-8-N(R₁₁)-C(O)R₁₀Substituted with the substituent(s);

   R₂selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_{3- 10}Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₈、-C_0-8-O-R₉、-C_0-8-C(O)OR₉、-C_0-8-C(O)R₁₀、-C_0-8-O-C(O)R₁₀、-C_0-8-NR₁₁R₁₂、-C_0-8-C(＝NR₁₁)R₁₀、-C_0-8-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-8-C(O)NR₁₁R₁₂or-C_0-8-N(R₁₁)-C(O)R₁₀Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O)_rR₈、-C_0-8-O-R₉、-C_0-8-C(O)OR₉、-C_0-8-C(O)R₁₀、-C_0-8-O-C(O)R₁₀、-C_0-8-NR₁₁R₁₂、-C_0-8-C(＝NR₁₁)R₁₀、-C_0-8-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-8-C(O)NR₁₁R₁₂or-C_0-8-N(R₁₁)-C(O)R₁₀Optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl radicalHalogen substituted C_1-10Alkyl, deuterium substituted C_{1- 10}Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O)_rR₈、-C_0-8-O-R₉、-C_0-8-C(O)OR₉、-C_0-8-C(O)R₁₀、-C_0-8-O-C(O)R₁₀、-C_0-8-NR₁₁R₁₂、-C_0-8-C(＝NR₁₁)R₁₀、-C_{0- 8}-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-8-C(O)NR₁₁R₁₂or-C_0-8-N(R₁₁)-C(O)R₁₀Substituted with the substituent(s);

   R₃、R₄each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, nitro, azido, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_2-10Alkenyl radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl or 5-10 membered heteroaryloxy, optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O)_rR₈、-C_0-8-O-R₉、-C_0-8-C(O)OR₉、-C_0-8-C(O)R₁₀、-C_0-8-O-C(O)R₁₀、-C_0-8-NR₁₁R₁₂、-C_0-8-C(＝NR₁₁)R₁₀、-C_0-8-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-8-C(O)NR₁₁R₁₂or-C_0-8-N(R₁₁)-C(O)R₁₀Substituted with the substituent(s);

   R₅、R₆are independently selected fromFrom hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₈、-C_0-8-O-R₉、-C_0-8-C(O)OR₉、-C_0-8-C(O)R₁₀、-C_0-8-O-C(O)R₁₀、-C_0-8-NR₁₁R₁₂、-C_0-8-C(＝NR₁₁)R₁₀、-C_{0- 8}-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-8-C(O)NR₁₁R₁₂or-C_0-8-N(R₁₁)-C(O)R₁₀Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O)_rR₈、-C_0-8-O-R₉、-C_0-8-C(O)OR₉、-C_0-8-C(O)R₁₀、-C_0-8-O-C(O)R₁₀、-C_0-8-NR₁₁R₁₂、-C_0-8-C(＝NR₁₁)R₁₀、-C_0-8-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-8-C(O)NR₁₁R₁₂or-C_0-8-N(R₁₁)-C(O)R₁₀Substituted with the substituent(s);

   R₇selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_{3- 10}Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O)_rR₈、-C_0-8-O-R₉、-C_0-8-C(O)OR₉、-C_0-8-C(O)R₁₀、-C_0-8-O-C(O)R₁₀、-C_0-8-NR₁₁R₁₂、-C_0-8-C(＝NR₁₁)R₁₀、-C_0-8-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-8-C(O)NR₁₁R₁₂or-C_0-8-N(R₁₁)-C(O)R₁₀Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_{1- 10}Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O)_rR₈、-C_0-8-O-R₉、-C_0-8-C(O)OR₉、-C_0-8-C(O)R₁₀、-C_0-8-O-C(O)R₁₀、-C_0-8-NR₁₁R₁₂、-C_0-8-C(＝NR₁₁)R₁₀、-C_{0- 8}-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-8-C(O)NR₁₁R₁₂or-C_0-8-N(R₁₁)-C(O)R₁₀Substituted with the substituent(s);

   each R₈Selected from hydrogen, deuterium, hydroxy, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_2-10Alkenyl radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or-NR₁₁R₁₂Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, hydroxy, carbonyl, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or-NR₁₁R₁₂Substituted with the substituent(s);

   each R₉Selected from hydrogen, deuterium, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl or 5-10 membered heteroaryl, optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, carbonyl, cyano, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or-NR₁₁R₁₂Substituted with the substituent(s);

   each R₁₀Selected from hydrogen, deuterium, hydroxy, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or-NR₁₁R₁₂Optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, cyano, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or-NR₁₁R₁₂Substituted with the substituent(s);

   each R₁₁、R₁₂Each independently selected from hydrogen, deuterium, hydroxy, C_1-10Alkoxy radical, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_{2- 10}Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-to 10-membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, monoalkylamino, dialkylamino or C_1-10Alkanoyl optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substitutionC_1-10Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-to 10-membered heteroaryl, 5-to 10-membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C_1-10Substituted by alkanoyl group;

   or, R₁₁、R₁₂Together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclyl or 4-10 membered heteroaryl group, optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-to 10-membered heteroaryl, 5-to 10-membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C_1-10Substituted by alkanoyl group;

   each r is independently 0, 1 or 2.
2. The compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof according to claim 1, wherein X is selected from C (R)₇) Or N;

   R₇selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-S(O)_rR₈、-C_0-4-O-R₉、-C_0-4-C(O)OR₉、-C_0-4-C(O)R₁₀、-C_0-4-O-C(O)R₁₀、-C_0-4-NR₁₁R₁₂、-C_0-4-C(＝NR₁₁)R₁₀、-C_0-4-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-4-C(O)NR₁₁R₁₂or-C_0-4-N(R₁₁)-C(O)R₁₀Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo-substituted C_1-4Alkyl, deuterium substituted C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -C_0-4-S(O)_rR₈、-C_0-4-O-R₉、-C_0-4-C(O)OR₉、-C_0-4-C(O)R₁₀、-C_0-4-O-C(O)R₁₀、-C_0-4-NR₁₁R₁₂、-C_0-4-C(＝NR₁₁)R₁₀、-C_0-4-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-4-C(O)NR₁₁R₁₂or-C_0-4-N(R₁₁)-C(O)R₁₀Substituted with the substituent(s);

   R₈、R₉、R₁₀、R₁₁、R₁₂r is as defined in claim 1;

   preferably, R₇Selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl, allyl, ethynyl, C_{3- 6}Cycloalkyl, oxetanyl, azacyclopentyl, azacyclohexyl, phenyl, triazole, methanesulfonyl, isopropylsulfonyl, aminosulfonyl, methoxy, ethoxy, isopropoxy, methoxycarbonyl, ethoxycarbonyl, acetyl, acetoxy, acetoxymethyl, amino, dimethylamino, aminocarbonyl, dimethylaminocarbonyl, or acetylamino; the above groups are optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, cyano, methyl, ethyl, cyclopropyl, phenyl, methoxy, ethoxy, hydroxy or amino;

   more preferably, R₇Selected from hydrogen, deuterium, fluorine, chlorine, cyano, nitro, azido, methyl, ethyl, isopropyl, allyl, ethynyl, cyclopropyl, cyclopropylmethyl, oxetanyl, aziridinyl, azacyclohexyl, phenyl, triazole, methanesulfonylA group, isopropylsulfonyl, aminosulfonyl, methoxy, ethoxy, isopropoxy, methoxyethyl, ethoxyethyl, hydroxymethyl, hydroxyethyl, cyanomethyl, trifluoromethyl, trideuteromethyl, difluoromethyl, dideuteromethyl, methoxycarbonyl, ethoxycarbonyl, acetyl, acetoxy, acetoxymethyl, amino, dimethylamino, aminomethyl, aminocarbonyl, dimethylaminocarbonyl or acetylamino.
3. The compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof according to claim 1,

   R₅、R₆each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_{2- 4}Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-S(O)_rR₈、-C_0-4-O-R₉、-C_0-4-C(O)OR₉、-C_0-4-C(O)R₁₀、-C_0-4-O-C(O)R₁₀、-C_0-4-NR₁₁R₁₂、-C_0-4-C(＝NR₁₁)R₁₀、-C_0-4-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-4-C(O)NR₁₁R₁₂or-C_0-4-N(R₁₁)-C(O)R₁₀Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo-substituted C_1-4Alkyl, deuterium substituted C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -C_0-4-S(O)_rR₈、-C_0-4-O-R₉、-C_0-4-C(O)OR₉、-C_0-4-C(O)R₁₀、-C_0-4-O-C(O)R₁₀、-C_0-4-NR₁₁R₁₂、-C_0-4-C(＝NR₁₁)R₁₀、-C_0-4-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-4-C(O)NR₁₁R₁₂or-C_0-4-N(R₁₁)-C(O)R₁₀Substituted with the substituent(s); r₈、R₉、R₁₀、R₁₁、R₁₂R is as defined in claim 1;

   preferably, R₅、R₆Each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, nitro, azido, C_1-4Alkyl, allyl, ethynyl, C_3-6Cycloalkyl, oxetanyl, azacyclopentyl, azacyclohexyl, phenyl, triazole, methanesulfonyl, isopropylsulfonyl, aminosulfonyl, hydroxy, methoxy, ethoxy, isopropoxy, methoxycarbonyl, ethoxycarbonyl, acetyl, acetoxy, acetoxymethyl, amino, dimethylamino, aminocarbonyl, dimethylaminocarbonyl or acetamido; the above groups are optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, cyano, methyl, ethyl, cyclopropyl, phenyl, methoxy, ethoxy, hydroxy or amino.
4. The compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof according to claim 1,

   R₃、R₄each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, nitro, azido, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_2-4Alkenyl radical, C_3-8Cycloalkyl radical, C_3-8Cycloalkoxy, 3-to 8-membered heterocyclic group, 3-to 8-membered heterocyclic oxy group, C_5-8Aryl radical, C_{5- 8}Aryloxy, 5-8 membered heteroaryl or 5-8 membered heteroaryloxy, optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo-substituted C_1-4Alkyl, deuterium substituted C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -C_0-4-S(O)_rR₈、-C_0-4-O-R₉、-C_0-4-C(O)OR₉、-C_0-4-C(O)R₁₀、-C_0-4-O-C(O)R₁₀、-C_0-4-NR₁₁R₁₂、-C_0-4-C(＝NR₁₁)R₁₀、-C_0-4-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-4-C(O)NR₁₁R₁₂or-C_0-4-N(R₁₁)-C(O)R₁₀Substituted with the substituent(s); r₈、R₉、R₁₀、R₁₁、R₁₂R is as defined in claim 1;

   preferably, R₃、R₄Each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, nitro, azido, C_1-4Alkyl radical, C_1-4Alkoxy, allyl, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy, phenyl, triazole or triazole; the above groups are optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, cyano, methyl, ethyl, cyclopropyl, phenyl, methoxy, ethoxy, hydroxy or amino.
5. The compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof according to claim 1,

   R₂selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-S(O)_rR₈、-C_0-4-O-R₉、-C_0-4-C(O)OR₉、-C_0-4-C(O)R₁₀、-C_0-4-O-C(O)R₁₀、-C_0-4-NR₁₁R₁₂、-C_0-4-C(＝NR₁₁)R₁₀、-C_0-4-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-4-C(O)NR₁₁R₁₂or-C_0-4-N(R₁₁)-C(O)R₁₀Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -C_0-4-S(O)_rR₈、-C_0-4-O-R₉、-C_0-4-C(O)OR₉、-C_0-4-C(O)R₁₀、-C_0-4-O-C(O)R₁₀、-C_0-4-NR₁₁R₁₂、-C_0-4-C(＝NR₁₁)R₁₀、-C_0-4-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-4-C(O)NR₁₁R₁₂or-C_0-4-N(R₁₁)-C(O)R₁₀Optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo-substituted C_1-4Alkyl, deuterium substituted C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -C_0-4-S(O)_rR₈、-C_0-4-O-R₉、-C_0-4-C(O)OR₉、-C_0-4-C(O)R₁₀、-C_0-4-O-C(O)R₁₀、-C_0-4-NR₁₁R₁₂、-C_0-4-C(＝NR₁₁)R₁₀、-C_0-4-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-4-C(O)NR₁₁R₁₂or-C_0-4-N(R₁₁)-C(O)R₁₀Is substituted by a substituent of (A), R₈、R₉、R₁₀、R₁₁、R₁₂R is as defined in claim 1;

   preferably, R₂Selected from hydrogen, deuterium, halogen, C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-O-R₉、-C_0-4-NR₁₁R₁₂、-C_0-4-C(＝NR₁₁)R₁₀、-C_0-4-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-4-C(O)NR₁₁R₁₂or-C_0-4-N(R₁₁)-C(O)R₁₀Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -C_0-4-S(O)_rR₈、-C_0-4-O-R₉、-C_0-4-C(O)OR₉or-C_0-4-NR₁₁R₁₂Optionally further substituted by one or more substituents selected from deuterium, halogen, C_1-4Alkyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, cyclopropyl, ═ O, hydroxy, methoxy, ethoxy, isopropoxy, or carboxy;

   R₈、R₉、R₁₀、R₁₁、R₁₂r is as defined in claim 1.
6. The compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof according to claim 1, wherein said compound of formula (I) has the following structure (ii):

   

   wherein the content of the first and second substances,

   R₂selected from hydrogen, deuterium, halogen, C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -C_{0- 4}-O-R₉or-C_0-4-NR₁₁R₁₂Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -S (O)_rR₈、-O-R₉、-C(O)OR₉or-NR₁₁R₁₂Optionally further substituted by one or more substituents selected from deuterium, halogen, C_1-4Alkyl, halo-substituted C_1-4Alkyl, deuterium substituted C_1-4Alkyl radical, C_3-6Cycloalkyl, ═ O, hydroxy, methoxy, ethoxy, isopropoxy, or carboxy;

   R₃、R₄each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, 3-6 membered heterocyclyl or 3-6 membered heterocyclyloxy; the above groups are optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, cyano, methyl, ethyl, cyclopropyl, methoxy, ethoxy, hydroxy or amino;

   R₅、R₆each independently selected from hydrogen, deuterium, halogen, cyano, C_1-4Alkyl radical, C_3-6Cycloalkyl, hydroxy, methoxy, ethoxy or isopropoxy; the above groups are optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, cyano, methyl, ethyl, cyclopropyl, methoxy, ethoxy, hydroxy or amino;

   R₁、R₈、R₉、R₁₁、R₁₂r is as defined in claim 1.
7. The compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof according to claim 6,

   R₁selected from hydrogen, deuterium, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl or 5-8 membered heteroaryl, optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -C_0-4-S(O)_rR₈、-C_0-4-O-R₉、-C_0-4-C(O)OR₉、-C_0-4-C(O)R₁₀、-C_0-4-O-C(O)R₁₀、-C_0-4-NR₁₁R₁₂、-C_0-4-C(＝NR₁₁)R₁₀、-C_0-4-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-4-C(O)NR₁₁R₁₂or-C_0-4-N(R₁₁)-C(O)R₁₀Optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo-substituted C_1-4Alkyl, deuterium substituted C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -C_0-4-S(O)_rR₈、-C_0-4-O-R₉、-C_0-4-C(O)OR₉、-C_0-4-C(O)R₁₀、-C_{0- 4}-O-C(O)R₁₀、-C_0-4-NR₁₁R₁₂、-C_0-4-C(＝NR₁₁)R₁₀、-C_0-4-N(R₁₁)-C(＝NR₁₂)R₁₀、-C_0-4-C(O)NR₁₁R₁₂or-C_0-4-N(R₁₁)-C(O)R₁₀Is substituted by a substituent of (A), R₈、R₉、R₁₀、R₁₁、R₁₂R is as defined in claim 6;

   preferably, R₁Selected from hydrogen, deuterium, C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl or 5-8 membered heteroaryl, optionally further substituted by one or more groups selected from deuterium, halogen, cyano, C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -C_0-4-O-R₉、-C_0-4-C(O)OR₉or-C_0-4-NR₁₁R₁₂Optionally further substituted by one or more substituents selected from deuterium, halogen, C_1-4Alkyl, halo-substituted C_1-4Alkyl, deuterium substituted C_1-4Alkyl radical、C_3-6Cycloalkyl, ═ O, hydroxy, methoxy, ethoxy, isopropoxy, or carboxyl, R₉、R₁₀、R₁₁、R₁₂As claimed in claim 6.
8. The compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof according to claim 6, wherein said compound of formula (I) has the structure of formula (iii):

   

   wherein the content of the first and second substances,

   R₁selected from hydrogen, deuterium, C_1-4Alkyl radical, C_3-8Cycloalkyl or 3-8 membered heterocyclyl, said groups optionally further substituted by one or more groups selected from deuterium, halogen, C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-8 membered heteroaryl, ═ O, -O-R₉、-C(O)OR₉or-NR₁₁R₁₂Optionally further substituted by one or more substituents selected from deuterium, halogen, C_1-4Alkyl, halo-substituted C_1-4Alkyl, deuterium substituted C_1-4Alkyl radical, C_3-6Cycloalkyl, ═ O, hydroxy, methoxy, ethoxy, isopropoxy, or carboxy;

   R₂selected from hydrogen, deuterium, halogen, C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -O-R₉or-NR₁₁R₁₂Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -O-R₉、-C(O)OR₉or-NR₁₁R₁₂Optionally further substituted by one or more substituents selected from deuterium, halogen, C_1-4Alkyl, halo-substituted C_1-4Alkyl, deuterium substituted C_1-4Alkyl radical、C_3-6Cycloalkyl, ═ O, hydroxy, methoxy, ethoxy, isopropoxy, or carboxy;

   R₉、R₁₁、R₁₂as claimed in claim 6.
9. The compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof according to claim 8,

   R₁selected from hydrogen, deuterium, C_1-4Alkyl radical, C_3-6Cycloalkyl or 3-6 membered heterocyclyl, said groups optionally further substituted by one or more groups selected from deuterium, fluoro, chloro, methyl, ethyl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, ═ O, hydroxy, methoxy, ethoxy, carboxy, amino, dimethylamino, or diethylamino, optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, methyl, ethyl, difluoromethyl, trifluoromethyl, dideuteromethyl, trideuteromethyl, cyclopropyl, ═ O, hydroxy, methoxy, ethoxy, isopropoxy, or carboxy;

   R₂selected from 3-8 membered heterocyclyl, 5-6 membered heteroaryl or-NR₁₁R₁₂Optionally further substituted with one or more groups selected from deuterium, fluoro, chloro, cyano, C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, ═ O, hydroxy, methoxy, ethoxy, isopropoxy, carboxy, amino, dimethylamino, or diethylamino, optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, methyl, ethyl, difluoromethyl, trifluoromethyl, dideuteromethyl, trideuteromethyl, cyclopropyl, ═ O, hydroxy, methoxy, ethoxy, isopropoxy, or carboxy;

   R₁₁、R₁₂each independently selected from hydrogen, deuterium, C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-6Aryl or 5-6 membered heteroaryl, optionally further substituted by one or more groups selected from deuterium, fluoro, chloro, hydroxy, C_1-4Alkyl, halo substitutedC_{1- 4}Alkyl, deuterium substituted C_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, 3-to 8-membered heterocyclic group, 3-to 8-membered heterocyclic oxy group, C_5-6Aryl radical, C_5-6Aryloxy, 5-6 membered heteroaryl, 5-6 membered heteroaryloxy, amino, dimethylamino, diethylamino or C_1-4Substituted by alkanoyl group;

   or, R₁₁、R₁₂Together with the nitrogen atom to which they are directly attached form a 4-8 membered heterocyclic group, optionally further substituted by one or more groups selected from deuterium, fluoro, chloro, hydroxy, C_1-4Alkyl, halo-substituted C_1-4Alkyl, deuterium substituted C_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, 3-to 8-membered heterocyclic group, 3-to 8-membered heterocyclic oxy group, C_5-6Aryl radical, C_5-6Aryloxy, 5-6 membered heteroaryl, 5-6 membered heteroaryloxy, amino, dimethylamino, diethylamino or C_1-4Substituted by alkanoyl group.
10. The compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof according to claim 8,

    R₁selected from hydrogen, deuterium, C_1-4Alkyl or 3-6 membered heterocyclyl, said groups optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, methyl, ethyl, cyclopropyl, 3-6 membered heterocyclyl, phenyl, amino, dimethylamino or diethylamino, said groups optionally further substituted with one or more substituents selected from deuterium, methyl, ethyl, difluoromethyl, trifluoromethyl, dideuteromethyl, trideuteromethyl or cyclopropyl;

    R₂selected from diazoxide, triazolide or-NR₁₁R₁₂Optionally further substituted with one or more groups selected from deuterium, fluoro, chloro, cyano, C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, ═ O, hydroxy, methoxy, ethoxy, isopropoxy, or carboxy, said groups optionally being further substituted by one or more substituentsSubstituted with a plurality of substituents selected from deuterium, fluoro, chloro, methyl, ethyl, difluoromethyl, trifluoromethyl, dideuteromethyl, trideuteromethyl or cyclopropyl;

    R₁₁、R₁₂each independently selected from hydrogen, deuterium, C_1-4Alkyl radical, C_3-6Cycloalkyl or 3-6 membered heterocyclyl, said groups optionally further substituted by one or more groups selected from deuterium, fluoro, chloro, hydroxy, C_1-4Alkyl, difluoromethyl, trifluoromethyl, dideuteromethyl, trideuteromethyl, methoxy, ethoxy, isopropoxy, cyclopropyl, 3-8 membered heterocyclyl, phenyl, triazole, amino, dimethylamino, diethylamino or C_1-4Substituted by alkanoyl group;

    R₁₁、R₁₂together with the nitrogen atom to which they are directly attached form a 4-8 membered heterocyclic group, optionally further substituted by one or more groups selected from deuterium, fluoro, chloro, hydroxy, C_1-4Alkyl, difluoromethyl, trifluoromethyl, dideuterylmethyl, trideuteromethyl, methoxy, ethoxy, isopropoxy, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, phenyl, triazole, amino, dimethylamino, diethylamino or C_1-4Substituted by alkanoyl group;

    each of said heterocyclic groups independently optionally contains 1 or 2 heteroatoms selected from nitrogen atoms or oxygen atoms.
11. A compound of formula (I), a stereoisomer, a prodrug thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, which is selected from the group consisting of:

    

    
12. a process for the preparation of a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof as claimed in claim 1, comprising the steps of:

    

    alternatively, the first and second electrodes may be,

    

    wherein, X, R₁、R₂、R₃、R₄、R₅、R₆As claimed in claim 1.
13. A pharmaceutical composition which comprises a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 11, and a pharmaceutically acceptable carrier.
14. The use of a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 11 in the manufacture of a medicament for the treatment of a tumour or cancer; preferably, the tumor or cancer is selected from bladder cancer, breast cancer, cervical cancer, large intestine cancer, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, thyroid cancer, skin cancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, acute myelogenous leukemia, hodgkin lymphoma or non-hodgkin lymphoma, fahrenheit macroglobulinemia, hairy lymphoma, cellular lymphoma, burkitt lymphoma, glioblastoma, melanoma or rhabdomyosarcoma.
15. The use of a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 11 in the manufacture of a medicament for the treatment of myeloproliferative disorders, bone or chondrocyte disorders, hypophosphatemia.
16. The use according to claim 15, wherein the myeloproliferative disorder is selected from the group consisting of polycythemia, essential thrombocythemia, or essential myelofibrosis; said skeletal or chondrocyte disorder is selected from dysplasia, achondroplasia, dwarfism, lethal Teratocarcinosis (TD), Alpeller's syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Beare-Stevenson dermatoglyph syndrome, Pfeiffer syndrome or cranial muscle atrophy syndrome; the hypophosphatemia is selected from X-linked hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets or ovarian malacia induced by tumors.
17. A compound of formula (I), a stereoisomer, a prodrug thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 for use as an FGFR inhibitor.