WO2022042613A1 - 1h-pyrazol-4-amide derivative, preparation method therefor, and use thereof - Google Patents

Abstract

Disclosed are a 1H-pyrazol-4-amide derivative having a structure as represented by formula (I), a preparation method therefor, a pharmaceutical composition containing same, the use thereof as an inhibitor for FGFR and a mutation thereof, the use thereof in the preparation of a drug for treating and/or preventing at least part of FGFR kinase mediated tumors or cancers and a drug for tumor patients having tolerance to FGFR inhibitors, and the use thereof in the preparation of a drug for tumor patients having mutations in V561, V565, N550, N540, V555, E566, K660, and/or V550 of an FGFR signaling pathway.

Description

A kind of 1H-pyrazole-4-amide derivative, its preparation method and application technical field

The invention belongs to the field of pharmaceutical synthesis, in particular to a 1H-pyrazole-4-amide derivative, a preparation method and application thereof.

Background technique

Fibroblast growth factor receptor (FGFR) is a tyrosine kinase receptor that binds to fibroblast growth factor ligands. Four FGFR receptors have been found to bind ligands. The fibroblast growth factor (FGF) signaling pathway is thought to play an important role in many processes, such as embryogenesis, tissue differentiation, wound healing, and metabolic regulation, and is also thought to be strongly associated with many tumor characteristics. When FGF binds to its receptor, the receptor dimerizes and phosphorylates, stimulates the activation of protein kinase activity, and helps activate a series of intracellular signaling pathways, including Ras-MAPK, AKT-PI3K, and phosphorylation Esterase C These signaling pathways are very important for cell growth, proliferation and survival.

Genetic changes in FGFR family members are often associated with tumor growth, metastasis, angiogenesis, and survival. There are many FGFR inhibitors in clinical trials that have shown clinical responses in patients with abnormal FGFR, and FGFR inhibitors have recently been approved for marketing. However, the rapid emergence of acquired resistance to FGFR inhibitors has been found in clinical trials, resulting in relatively short progression-free survival. Mutations affecting FGFR amino acids may confer resistance to or reduce the activity of FGFR inhibitors. The generation of secondary FGFR kinase domain mutations in response to FGFR inhibitors is an important mechanism for acquiring resistance to FGFR inhibition. Corresponding FGFR point mutations are also present in tumors. Gatekeeper mutations have been reported to be one of the main mechanisms of resistance to tyrosine kinases, and FGFR-resistant mutations have been reported in in vitro cell systems and clinical experiments. Gatekeeper mutations include FGFR3V555M, FGFR2V565F/V565I/V565L, and more. A recent study reported the gatekeeper mutation of FGFR2V565F in three of BGJ398-treated cholangiocarcinoma patients, and two of them had other mutations in other FGFR2 kinase regions. Therefore, in order to break through the acquired resistance to the first-generation FGFR inhibitor treatment in the clinic, there is an urgent need for a new generation of FGFR inhibitors that can have more durable activity in tumors with gene mutations in the FGFR signaling pathway. Such second-generation FGFR inhibitors need to be able to maintain the same activity against gatekeeper mutations that have weakened the activity of the first-generation inhibitors while maintaining the inhibitory activity against FGFR.

SUMMARY OF THE INVENTION

After extensive and in-depth research, the inventors of the present application have developed a 1H-pyrazole-4-amide derivative, its preparation method and application for the first time. The series of compounds of the present invention have good activity against mutated FGFR, especially against FGFR with gatekeeper mutation, especially against FGFR3V555M, FGFR2V565I, FGFR2V565F, FGFR2V565L and FGFR2N550K mutation with non-gatekeeper mutation, and are expected to develop a new generation of FGFR inhibitors.

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

in,

is a single or double bond;

X is C or N; Y is CR _6a , N, NR _6b , O or S;

Ring A is a 3-12-membered nitrogen-containing heterocyclic group, and the nitrogen atom is connected to a carbonyl group;

R ₁ is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl , 3-12-membered heterocyclyl, C _5-10 -membered aryl, 5-10-membered heteroaryl, -C _0-8 alkyl-SF ₅ , -C _0-8 alkyl-S(O) _r R ₈ , -C _0-8 alkyl-OR ₉ , -C _0-8 alkyl-C(O)OR ₉ , -C _0-8 alkyl-C(O)R ₁₀ , -C _0-8 alkyl- OC(O)R ₁₀ , -C _0-8 alkyl-NR ₁₁ R ₁₂ , -C _0-8 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-8 alkyl-N(R ₁₁ ) -C(=NR ₁₂ )R ₁₀ , -C _0-8 alkyl-C(O)NR ₁₁ R ₁₂ and -C _0-8 alkyl-N(R ₁₁ )-C(O)R ₁₀ , the above-mentioned groups The group is optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen C _1-10 alkyl, deuterium substituted C _1-10 alkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, =O, -C _0-8 alkyl-SF ₅ , -C _0-8 alkyl-S(O) _r R ₈ , -C _0-8 alkyl-OR ₉ , -C _0-8 alkyl-C(O) OR ₉ , -C _0-8 alkyl-C(O)R ₁₀ , -C _0-8 alkyl-OC(O)R ₁₀ , -C _0-8 alkyl-NR ₁₁ R ₁₂ , -C _{0- 8} alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-8 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-8 alkyl-C(O)NR ₁₁ R ₁₂ and -C _0-8 alkyl-N(R ₁₁ )-C(O)R ₁₀ substituents are substituted;

Each R2 is independently selected from _hydrogen , deuterium, halogen, cyano, nitro, azido, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, halo-substituted C _1-10 alkyl, deuterium substituted C _1-10 alkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, -C _{0 -8} alkyl-SF ₅ , -C _0-8 alkyl-S(O) _r R ₈ , -C _0-8 alkyl-OR ₉ , -C _0-8 alkyl-C(O)OR ₉ , -C _0-8 alkyl-C(O)R ₁₀ , -C _0-8 alkyl-OC(O)R ₁₀ , -C _0-8 alkyl-NR ₁₁ R ₁₂ , -C _0-8 alkyl -C(=NR ₁₁ )R ₁₀ , -C _0-8 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-8 alkyl-C(O)NR ₁₁ R ₁₂ and -C _0-8 alkyl-N(R ₁₁ )-C(O)R ₁₀ ;

Each _R is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, halo-substituted C _1-10 alkyl, deuterium substituted C _1-10 alkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, -C _{0 -8} alkyl-SF ₅ , -C _0-8 alkyl-S(O) _r R ₈ , -C _0-8 alkyl-OR ₉ , -C _0-8 alkyl-C(O)OR ₉ , -C _0-8 alkyl-C(O)R ₁₀ , -C _0-8 alkyl-OC(O)R ₁₀ , -C _0-8 alkyl-NR ₁₁ R ₁₂ , -C _0-8 alkyl -C(=NR ₁₁ )R ₁₀ , -C _0-8 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-8 alkyl-C(O)NR ₁₁ R ₁₂ and -C _0-8 alkyl-N(R ₁₁ )-C(O)R ₁₀ ;

R ₄ is selected from vinyl or ethynyl, and the aforementioned groups are independently optionally further selected from one or more groups selected from hydrogen, deuterium, halogen, cyano, C _1-10 alkyl, halogen-substituted C _1-10 alkyl, Deuterium substituted C _1-10 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, -C _0-8 alkyl-C(O)OR ₉ , -C _0-8 alkyl-C( O) R ₁₀ , -C _0-8 alkyl-C(O)-NR _7a R _7b and -C _0-8 alkyl-NR _7a R _7b are substituted by substituents;

R _5a and R _5b are each independently selected from hydrogen, deuterium, hydroxyl, C _1-10 alkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, -C _0-8 alkyl-C(O ) OR ₉ , -C _0-8 alkyl-C(O)R ₁₀ , -C _0-8 alkyl-C(=NR ₁₁ )R ₁₀ and -C _0-8 alkyl-C(O)NR ₁₁ R ₁₂ , alternatively, R _5a and R _5b together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclic group optionally further substituted by one or more groups selected from the group consisting of deuterium, halogen, cyano, nitro, Azido, C _1-10 alkyl, halogen substituted C _1-10 alkyl, deuterium substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 ring Alkyl, 3-12-membered heterocyclyl, C _5-10 -membered aryl, 5-10-membered heteroaryl, =O, -C _0-8 alkyl-SF ₅ , -C _0-8 alkyl-S ( O) _r R ₈ , -C _0-8 alkyl-OR ₉ , -C _0-8 alkyl-C(O)OR ₉ , -C _0-8 alkyl-C(O)R ₁₀ , -C _{0 -8} alkyl-OC(O)R ₁₀ , -C _0-8 alkyl-NR ₁₁ R ₁₂ , -C _0-8 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-8 alkyl- N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-8 alkyl-C(O)NR ₁₁ R ₁₂ and -C _0-8 alkyl-N(R ₁₁ )-C(O) Replaced by the substituent of R ₁₀ ;

R _6a is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen substituted C _1-10 alkane base, deuterium substituted C _1-10 alkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, -C _0-8 alkyl- SF ₅ , -C _0-8 alkyl-S(O) _r R ₈ , -C _0-8 alkyl-OR ₉ , -C _0-8 alkyl-C(O)OR ₉ , -C _0-8 Alkyl-C(O)R ₁₀ , -C _0-8 alkyl-OC(O)R ₁₀ , -C _0-8 alkyl-NR ₁₁ R ₁₂ , -C _0-8 alkyl-C(=NR ₁₁ ) R ₁₀ , -C _0-8 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-8 alkyl-C(O)NR ₁₁ R ₁₂ and -C _0-8 Alkyl-N(R ₁₁ )-C(O)R ₁₀ ;

R _6b is selected from hydrogen, deuterium, C _1-10 alkyl, C _2-10 alkenyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _5-10 aryl and 5-10 membered Heteroaryl, the above-mentioned groups are optionally further selected from one or more groups selected from deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 Alkynyl, halogen-substituted C _1-10 alkyl, deuterium-substituted C _1-10 alkyl, C _3-12 cycloalkyl, 3-12-membered heterocyclyl, C _5-10 -membered aryl, 5-10-membered heterocycle Aryl, =O, -C _0-8 alkyl-SF ₅ , -C _0-8 alkyl-S(O) _r R ₈ , -C _0-8 alkyl-OR ₉ , -C _0-8 alkane base-C(O)OR ₉ , -C _0-8 alkyl-C(O)R ₁₀ , -C _0-8 alkyl-OC(O)R ₁₀ , -C _0-8 alkyl-NR ₁₁ R ₁₂ , -C _0-8 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-8 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-8 alkyl- C(O)NR ₁₁ R ₁₂ and the substituents of -C _0-8 alkyl-N(R ₁₁ )-C(O)R ₁₀ ;

R _7a and R _7b are each independently selected from hydrogen, deuterium, hydroxy, C _1-10 alkyl, -C _0-8 alkyl-C(O)OR ₉ , -C _0-8 alkyl-C(O) R ₁₀ , -C _0-8 alkyl-C(=NR ₁₁ )R ₁₀ and -C _0-8 alkyl-C(O)NR ₁₁ R ₁₂ , or, alternatively, the nitrogen atom to which R _7a and R _7b are directly attached together form a 4-10 membered _heterocyclic group, the above-mentioned groups are optionally further substituted by one or more C _{1- 10} alkyl, deuterium substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _5-10 aryl base, 5-10-membered heteroaryl, =O, -C _0-8 alkyl-SF ₅ , -C _0-8 alkyl-S(O) _r R ₈ , -C _0-8 alkyl-OR ₉ , -C _0-8 alkyl-C(O)OR ₉ , -C _0-8 alkyl-C(O)R ₁₀ , -C _0-8 alkyl-OC(O)R ₁₀ , -C _{0- 8} alkyl-NR ₁₁ R ₁₂ , -C _0-8 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-8 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , - C _0-8 alkyl-C(O)NR ₁₁ R ₁₂ and the substituents of -C _0-8 alkyl-N(R ₁₁ )-C(O)R ₁₀ ;

Each R ₈ is independently selected from hydrogen, deuterium, hydroxyl, C _1-10 alkyl, C _2-10 alkenyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _5-10 Aryl, 5-10 membered heteroaryl and -NR ₁₁ R ₁₂ , the above-mentioned groups are independently optionally further selected by one or more groups selected from deuterium, halogen, hydroxyl, oxo, C _1-10 alkyl, C _{1 -10} alkoxy, C _3-12 cycloalkyl, C _3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C _5-10 aryl, C _{5- 10} -aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and substituents of -NR ₁₁ R ₁₂ ;

Each R ₉ is independently selected from hydrogen, deuterium, C _1-10 alkyl, C _2-10 alkenyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _5-10 aryl and 5-10-membered heteroaryl groups, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, oxo, cyano, C _1-10 alkyl, C _1-10 alkoxy , C _3-12 cycloalkyl, C _3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C _5-10 aryl, C _5-10 aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and substituents of -NR ₁₁ R ₁₂ ;

Each R ₁₀ is independently selected from hydrogen, deuterium, hydroxyl, C _1-10 alkyl, C _1-10 alkoxy, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 Cycloalkyl, C _3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C _5-10 aryl, C _5-10 aryloxy, 5-10-membered heterocycle Aryl, 5-10 membered heteroaryloxy and -NR ₁₁ R ₁₂ , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, cyano, C _1-10 alkyl, C _1-10 alkoxy, C _3-12 cycloalkyl, C _3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C _5-10 aryl, C _{5 -10} -aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and -NR ₁₁ R ₁₂ substituents;

Each of R ₁₁ and R ₁₂ is independently selected from hydrogen, deuterium, hydroxy, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, 3 -12-membered heterocyclyl, C _5-10 -membered aryl, 5-10-membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, amino Sulfonyl, dimethylaminosulfonyl, amino, mono-C _1-10 alkylamino, di-C _1-10 alkylamino and C _1-10 alkanoyl groups, independently optionally further selected by one or more From deuterium, halogen, hydroxyl, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen substituted C _1-10 alkyl, deuterium substituted C _1-10 alkyl, C _{1 -10} alkoxy, C _3-12 cycloalkyl, C _3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C _5-10 aryl, C _5- Substitution of ₁₀ -aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy, amino, mono-C _1-10 alkylamino, di-C _1-10 alkylamino and C _1-10 alkanoyl base substituted;

Alternatively, R ₁₁ and R ₁₂ together with the nitrogen atom to which they are directly attached form a 4-10-membered heterocyclic group or a 5-10-membered heteroaryl group, the 4-10-membered heterocyclic group or the 5-10-membered heteroaryl group being either is further selected by one or more selected from deuterium, halogen, hydroxyl, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen substituted C _1-10 alkyl, deuterium substituted C _1-10 alkyl, C _1-10 alkoxy, C _3-12 cycloalkyl, C _3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C _{5 -10} aryl, C _5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono-C _1-10 alkylamino, di-C _1-10 alkylamino and Substituents of C _1-10 alkanoyl groups are substituted;

m is 0, 1, 2 or 3;

n is 0, 1, 2, 3, or 4; and

Each r is independently 0, 1, or 2.

As a preferred solution, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, R ₁ is selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, C _{2 -4} alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, -C _0-4 Alkyl-SF ₅ , -C _0-4 alkyl-S(O) _r R ₈ , -C _0-4 alkyl-OR ₉ , -C _0-4 alkyl-C(O)OR ₉ , -C _0-4 alkyl-C(O)R ₁₀ , -C _0-4 alkyl-OC(O)R ₁₀ , -C _0-4 alkyl-NR ₁₁ R ₁₂ , -C _0-4 alkyl-C (=NR ₁₁ )R ₁₀ , -C _0-4 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-4 alkyl-C(O)NR ₁₁ R ₁₂ and -C _0-4 alkyl-N(R ₁₁ )-C(O)R ₁₀ , the above-mentioned groups are optionally further selected from one or more groups selected from deuterium, halogen, cyano, C _1-4 alkyl, C _2-4 Alkenyl, C _2-4 alkynyl, halogen-substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 Aryl, 5-8 membered heteroaryl, =O, -C _0-4 alkyl-SF ₅ , -C _0-4 alkyl-S(O) _r R ₈ , -C _0-4 alkyl-OR ₉ , -C _0-4 alkyl-C(O)OR ₉ , -C _0-4 alkyl-C(O)R ₁₀ , -C _0-4 alkyl-OC(O)R ₁₀ , -C _{0 -4} alkyl-NR ₁₁ R ₁₂ , -C _0-4 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-4 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-4 alkyl-C(O)NR ₁₁ R ₁₂ and -C _0-4 alkyl-N(R ₁₁ )-C(O)R ₁₀ substituents;

Each R ₂ is independently selected from hydrogen, deuterium, halogen, cyano, nitro, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, -C _0-4 alkyl -SF ₅ , -C _0-4 alkyl-S(O) _r R ₈ , -C _0-4 alkyl-OR ₉ , -C _0-4 alkyl-C(O)OR ₉ , -C _{0- 4} alkyl-C(O)R ₁₀ , -C _0-4 alkyl-OC(O)R ₁₀ , -C _0-4 alkyl-NR ₁₁ R ₁₂ , -C _0-4 alkyl-C(= NR ₁₁ )R ₁₀ , -C _0-4 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-4 alkyl-C(O)NR ₁₁ R ₁₂ and -C _{0- 4} alkyl-N(R ₁₁ )-C(O)R ₁₀ ;

Each _R is independently selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halo-substituted C _1-4 alkyl, Deuterium substituted C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, -C _0-4 alkyl-SF ₅ , -C _0-4 alkyl-S(O) _r R ₈ , -C _0-4 alkyl-OR ₉ , -C _0-4 alkyl-C(O)OR ₉ , -C _0-4 alkyl -C(O)R ₁₀ , -C _0-4 alkyl-OC(O)R ₁₀ , -C _0-4 alkyl-NR ₁₁ R ₁₂ , -C _0-4 alkyl-C(=NR ₁₁ ) R ₁₀ , -C _0-4 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-4 alkyl-C(O)NR ₁₁ R ₁₂ and -C _0-4 alkyl -N(R ₁₁ )-C(O)R ₁₀ ;

R _5a and R _5b are each independently selected from hydrogen, deuterium, hydroxyl, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, -C _0-4 alkyl-C(O ) OR ₉ , -C _0-4 alkyl-C(O)R ₁₀ , -C _0-4 alkyl-C(=NR ₁₁ )R ₁₀ and -C _0-4 alkyl-C(O)NR ₁₁ R ₁₂ , or, alternatively, R _5a and R _5b together 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 the group consisting of deuterium, halogen, cyano, C _{1- 4} alkyl, halogen substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered Heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, =O, -C _0-4 alkyl-SF ₅ , -C _0-4 alkyl-S(O) _r R ₈ , - C _0-4 alkyl-OR ₉ , -C _0-4 alkyl-C(O)OR ₉ , -C _0-4 alkyl-C(O)R ₁₀ , -C _0-4 alkyl-OC ( O)R ₁₀ , -C _0-4 alkyl-NR ₁₁ R ₁₂ , -C _0-4 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-4 alkyl-N(R ₁₁ )-C (=NR ₁₂ ) R ₁₀ , -C _0-4 alkyl-C(O)NR ₁₁ R ₁₂ and -C _0-4 alkyl-N(R ₁₁ )-C(O)R ₁₀ substituents ;

R _6a is selected from hydrogen, deuterium, halogen, cyano, nitro, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, -C _0-4 alkyl-SF ₅ , - C _0-4 alkyl-S(O) _r R ₈ , -C _0-4 alkyl-OR ₉ , -C _0-4 alkyl-C(O)OR ₉ , -C _0-4 alkyl-C (O)R ₁₀ , -C _0-4 alkyl-OC(O)R ₁₀ , -C _0-4 alkyl-NR ₁₁ R ₁₂ , -C _0-4 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-4 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-4 alkyl-C(O)NR ₁₁ R ₁₂ and -C _0-4 alkyl-N (R ₁₁ )-C(O)R ₁₀ ;

R _6b is selected from hydrogen, deuterium, C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl and 5-8 membered Heteroaryl, the above-mentioned groups are optionally further substituted by one or more groups selected from deuterium, halogen, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, =O, - C _0-4 alkyl-SF ₅ , -C _0-4 alkyl-S(O) _r R ₈ , -C _0-4 alkyl-OR ₉ , -C _0-4 alkyl-C(O)OR ₉ , -C _0-4 alkyl-C(O)R ₁₀ , -C _0-4 alkyl-OC(O)R ₁₀ , -C _0-4 alkyl-NR ₁₁ R ₁₂ , -C _0-4 Alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-4 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-4 alkyl-C(O)NR ₁₁ R ₁₂ and -C _0-4 alkyl-N(R ₁₁ )-C(O)R ₁₀ substituent;

R _7a and R _7b are each independently selected from hydrogen, deuterium, hydroxy, C _1-4 alkyl, -C _0-4 alkyl-C(O)OR ₉ , -C _0-4 alkyl-C(O) R ₁₀ , -C _0-4 alkyl-C(=NR ₁₁ )R ₁₀ and -C _0-4 alkyl-C(O)NR ₁₁ R ₁₂ , or, alternatively, the nitrogen atom to which R _7a and R _7b are directly attached together form a 4-8 membered heterocyclic group, the above-mentioned groups are optionally further selected from one or more groups selected from deuterium, halogen, cyano, C _1-4 alkyl, halogen substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl, 5-8 membered heterocycle Aryl, =O, -C _0-4 alkyl-SF ₅ , -C _0-4 alkyl-S(O) _r R ₈ , -C _0-4 alkyl-OR ₉ , -C _0-4 alkane base-C(O)OR ₉ , -C _0-4 alkyl-C(O)R ₁₀ , -C _0-4 alkyl-OC(O)R ₁₀ , -C _0-4 alkyl-NR ₁₁ R ₁₂ , -C _0-4 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-4 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-4 alkyl- C(O)NR ₁₁ R ₁₂ and the substituents of -C _0-4 alkyl-N(R ₁₁ )-C(O)R ₁₀ ;

wherein R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and r are as defined in the compound of formula (I).

As a further preferred solution, the compound of formula (I) is the following compound of formula (IIa) or formula (IIb):

Wherein, in the compound of formula (IIa), Y ₁ is NR _6b , O or S; in the compound of formula (IIb), Y ₂ is CR _6a or N;

Each Ring A is independently a 3-8 membered nitrogen-containing heterocyclic group, and the nitrogen atom is attached to a carbonyl group;

Each R ₁ is independently selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3 -6-membered heterocyclyl, -SF ₅ , -S(O) _r R ₈ , -OR ₉ , -C(O)OR ₉ , -C(O)R ₁₀ , -OC(O)R ₁₀ , -NR ₁₁ R ₁₂ , -C(=NR ₁₁ )R ₁₀ , -N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C(O)NR ₁₁ R ₁₂ and -N(R ₁₁ )-C(O ) R ₁₀ , the above-mentioned groups are optionally further substituted by one or more groups selected from deuterium, halogen, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, =O, - SF ₅ , -S(O) _r R ₈ , -OR ₉ , -C(O)OR ₉ , -C(O)R ₁₀ , -OC(O)R ₁₀ , -NR ₁₁ R ₁₂ , -C(= Substituents substituted by NR ₁₁ )R ₁₀ , -N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C(O)NR ₁₁ R ₁₂ and -N(R ₁₁ )-C(O)R ₁₀ ;

Each of R _2a and R _2b is independently selected from hydrogen, deuterium, halogen, cyano, nitro, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, -SF ₅ , -S(O) _r R ₈ , -OR ₉ , -C (O)OR ₉ , -C(O)R ₁₀ , -OC(O)R ₁₀ , -NR ₁₁ R ₁₂ , -C(=NR ₁₁ )R ₁₀ , -N(R ₁₁ )-C(=NR ₁₂ ) R ₁₀ , -C(O)NR ₁₁ R ₁₂ and -N(R ₁₁ )-C(O)R ₁₀ ;

Each R ₄ is each independently vinyl, and the aforementioned groups are independently optionally further substituted with one or more C 1-4 alkyl groups selected from the group consisting of hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, halogen substituted C _1-4 alkyl , deuterium substituted C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, -C _0-4 alkyl-C(O)OR ₉ , -C _0-4 alkyl-C (O) R ₁₀ , -C _0-4 alkyl-C(O)-NR _7a R _7b and -C _0-4 alkyl-NR _7a R _7b substituents;

Each of R _5a and R _5b is independently selected from hydrogen, deuterium, hydroxy, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, -C(O)OR ₉ , - C(O)R ₁₀ , -C(=NR ₁₁ )R ₁₀ and -C(O)NR ₁₁ R ₁₂ , alternatively, R _5a and R _5b together with the nitrogen atom to which they are directly attached form a 4-6 membered heterocyclyl group , the above-mentioned groups are optionally further selected from one or more groups selected from deuterium, halogen, cyano, C _1-4 alkyl, halogen substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _2-4 Alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, -SF ₅ , -S(O) _r R ₈ , -OR ₉ , -C(O) OR ₉ , -C(O)R ₁₀ , -OC(O)R ₁₀ , -NR ₁₁ R ₁₂ , -C(=NR ₁₁ )R ₁₀ , -N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C(O)NR ₁₁ R ₁₂ and -N(R ₁₁ )-C(O) R ₁₀ substituents;

R _6a is selected from hydrogen, deuterium, halogen, cyano, nitro, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, -SF ₅ , -S(O) _r R ₈ , -OR ₉ , -C(O)OR ₉ , -C (O)R ₁₀ , -OC(O)R ₁₀ , -NR ₁₁ R ₁₂ , -C(=NR ₁₁ )R ₁₀ , -N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C(O ) NR ₁₁ R ₁₂ and -N(R ₁₁ )-C(O)R ₁₀ ;

R _6b is selected from the group consisting of hydrogen, deuterium, C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl and 3-6 membered heterocyclyl, the above-mentioned groups are optionally further modified by one or more selected from deuterium, halogen, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, =O, -SF ₅ , -S(O) _r R ₈ , -OR ₉ , -C(O)OR ₉ , -C(O)R ₁₀ , -OC(O)R ₁₀ , -NR ₁₁ R ₁₂ , -C(=NR ₁₁ )R ₁₀ , -N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C(O)NR ₁₁ R ₁₂ and the substituents of -N(R ₁₁ )-C(O)R ₁₀ are substituted;

Each of R _7a and R _7b is independently selected from hydrogen, deuterium, hydroxy, C _1-4 alkyl, -C(O)OR ₉ , -C(O)R ₁₀ , -C(=NR ₁₁ )R ₁₀ and -C(O)NR ₁₁ R ₁₂ , alternatively, R _7a and R _7b together with the nitrogen atom to which they are directly attached form a 4-6 membered heterocyclic group optionally further substituted by one or more groups selected from deuterium, Halogen, cyano, C _1-4 alkyl, halogen substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, -SF ₅ , -S(O) _r R ₈ , -OR ₉ , -C(O)OR ₉ , -C(O)R ₁₀ , -OC(O) R ₁₀ , -NR ₁₁ R ₁₂ , -C(=NR ₁₁ )R ₁₀ , -N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C(O)NR ₁₁ R ₁₂ and -N(R ₁₁ )-C(O) R ₁₀ is substituted by the substituent;

wherein R ₄ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and r are as defined in the compound of formula (I).

As a further preferred solution, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, each ring A is independently:

As a further preferred scheme, the compound of formula (I) is the compound of formula (IIIa) or formula (IIIb):

Wherein, in the compound of formula (IIIa), Y ₁ is O or S;

Each R ₁ is independently selected from hydrogen, deuterium, halogen, cyano, C _1-2 alkyl, C _3-4 cycloalkyl, 3-4 membered heterocyclyl, -SF ₅ , -OR ₉ , - C(O)OR ₉ , -C(O)R ₁₀ , -OC(O)R ₁₀ and -NR ₁₁ R ₁₂ , the above-mentioned groups are optionally further selected by one or more groups selected from deuterium, fluorine, chlorine, bromine, Cyano, C _1-2 alkyl, halogen-substituted C _1-2 alkyl, deuterium-substituted C _1-2 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, =O, -SF ₅ , -OR ₉ , -C(O)OR ₉ , -C(O)R ₁₀ , -OC(O)R ₁₀ and -NR ₁₁ R ₁₂ substituents;

Each of R _2a and R _2b is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, _C1-4 alkyl, halo-substituted _C1-4 alkyl, deuterium substituted _C1-4 alkyl, C _3-6 cycloalkyl, -SF ₅ , -OR ₉ , -C(O)OR ₉ , -C(O)R ₁₀ , -OC(O)R ₁₀ and -NR ₁₁ R ₁₂ ;

wherein R ₉ , R ₁₀ , R ₁₁ and R ₁₂ are as defined in the compound of formula (I).

As a further preferred solution, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, each R ₈ is independently selected from hydrogen, deuterium, hydroxyl, C _1-4 alkyl , C _2-4 alkenyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl and -NR ₁₁ R ₁₂ , the above groups are independent optionally further selected by one or more selected from deuterium, halogen, hydroxyl, oxo, _C1-4 alkyl, _C1-4 alkoxy, _C3-6 cycloalkyl, _C3-6 cycloalkoxy base, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C _5-8 aryl, C _5-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR ₁₁ R ₁₂ substituents are substituted;

Each R ₉ is independently selected from hydrogen, deuterium, C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl and 5-8 membered heteroaryl groups, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, oxo, cyano, C _1-4 alkyl, C _1-4 alkoxy , C _3-6 cycloalkyl, C _3-6 cycloalkoxy, 3-6-membered heterocyclyl, 3-6-membered heterocyclyloxy, C _5-8 aryl, C _5-8 aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy and substituents of -NR ₁₁ R ₁₂ ;

Each R ₁₀ is independently selected from hydrogen, deuterium, hydroxyl, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 Cycloalkyl, C _3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C _5-8 aryl, C _5-8 aryloxy, 5-8 membered heterocycle Aryl, 5-8 membered heteroaryloxy and -NR ₁₁ R ₁₂ , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C _5-8 aryl, C _{5 -8} -aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy and -NR ₁₁ R ₁₂ substituents;

Each of R ₁₁ and R ₁₂ is independently selected from hydrogen, deuterium, hydroxyl, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3 -6-membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, amino Sulfonyl, dimethylaminosulfonyl, amino, mono-C _1-4 alkylamino, di-C _1-4 alkylamino and C _1-4 alkanoyl groups, independently optionally further selected by one or more From deuterium, halogen, hydroxyl, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _{1 -4} alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C _5-8 aryl, C _5- Substitution of ₈ -aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy, amino, mono-C _1-4 alkylamino, di-C _1-4 alkylamino and C _1-4 alkanoyl base substituted;

Alternatively, R ₁₁ and R ₁₂ together with the nitrogen atom to which they are directly attached form a 4-10-membered heterocyclic group or a 5-10-membered heteroaryl group, the 4-10-membered heterocyclic group or the 5-10-membered heteroaryl group being either is further selected from the group consisting of one or more deuterium, halogen, hydroxyl, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C _{5 -8} aryl, C _5-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono-C _1-4 alkylamino, di-C _1-4 alkylamino and Substituents of C _1-4 alkanoyl.

As a further preferred solution, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, each R ₁ is independently selected from hydrogen, deuterium, halogen, cyano, methyl , ethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidine, -SF ₅ , methoxy, ethoxy, carboxyl, acetyl, acetoxy, amino, methylamino and Dimethylamino, the above-mentioned groups are optionally further selected by one or more groups selected from the group consisting of deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, propyl, cyclobutyl, oxetanyl, azetidine, =O, _-SF5 , methoxy, ethoxy, carboxyl, acetyl, acetoxy, amino, methylamino and dimethyl Substituted by amino substituent;

Each R _2a and R _2b is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, Di-deuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidine, _-SF5 , methoxy, ethoxy, carboxyl, acetyl, acetoxy, amino, methylamino and dimethylamino.

As the most preferred solution, the compounds of formula (I), their stereoisomers or their pharmaceutically acceptable salts include but are not limited to the following compounds:

The second aspect of the present invention provides a preparation method of the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, comprising the following steps:

or,

wherein Rings A, X, Y, R ₁ , R ₂ , R ₃ , R ₄ , R _5a , R _5b , m and n are as defined in compounds of formula (I).

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

The present invention also relates to the use of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of tumor patients resistant to FGFR inhibitors.

As a preferred solution, the tumor patient is a tumor patient with mutations in FGFR V561, V565, N550, N540, V555, E566, K660 and/or V550;

As a further preferred solution, the tumor patient is preferred, and the tumor patient is a tumor patient with FGFR2 V565F, V565I, V565L, V565M, N550K, N550H, E566A, E566G, K660M and/or K660Q mutations;

As a further preferred solution, the tumor patient is a tumor patient with mutations in FGFR3 V555M/L and/or N540K.

The present invention also relates to compounds of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of disease states or disorders mediated by FGFR kinases.

The present invention also relates to a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of tumors or cancers mediated by FGFR kinases.

As a preferred solution, the tumor or cancer is selected from bladder cancer, breast cancer, cervical cancer, colorectal 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 myeloid leukemia, Hodgkin lymphoma, or non-Hodgkin lymphoma Lymphoma, Waldenstrom's macroglobulinemia, hair-like lymphoma, cellular lymphoma, Burkitt's lymphoma, glioblastoma, melanoma, or rhabdomyosarcoma.

The present invention also relates to the use of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of myeloproliferative diseases, skeletal or chondrocyte disorders, or hypophosphatemia.

The present invention also relates to said myeloproliferative disease selected from polycythemia, essential thrombocythemia or primary myelofibrosis; said bone or chondrocyte disorder selected from dysplasia, chondrodysplasia, dwarfism , Lethal Teratosis (TD), Appel's Syndrome, Crusson's Syndrome, Jackson-Weiss Syndrome, Beare-Stevenson's Syndrome, Pfeiffer's Syndrome or Muscular Dystrophy Syndrome; said The hypophosphatemia is selected from X-linked hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, or tumor-induced ovarian softening.

The present invention also relates to a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the foregoing, for use with a selective FGFR2 and/or FGFR3 inhibitor for the treatment of and FGFR2 or Use in diseases related to abnormal expression of FGFR3 receptor, abnormal expression and abnormal activity of mutation or corresponding ligand.

The present invention also relates to a method of treating a patient with a tumor resistant to an FGFR inhibitor, comprising administering to a patient in need thereof a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

The present invention also relates to a method of treating a patient with a tumor having a mutation in FGFR2 V565F, V565I, V565L, V565M, N550K, N550H, E566A, E566G, K660M and/or K660Q, comprising administering to a patient in need thereof a compound of formula (I), its stereotaxic Isomers or pharmaceutically acceptable salts thereof.

detailed description

The inventor of the present application has developed a 1H-pyrazole-4-amide derivative, its preparation method and application for the first time through extensive and in-depth research. The compounds of the present invention have good activity against mutated FGFRs, especially FGFRs with gatekeeper mutations, especially FGFR3V555M, FGFR2V565I, FGFR2V565F, FGFR2V565L and FGFR2N550K mutations.

DETAILED DESCRIPTION: Unless stated to the contrary or specifically stated, the following terms used in the specification and claims have the following meanings.

"Alkyl" refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon group, preferably a straight-chain alkyl group and a branched-chain alkyl group comprising 1 to 10 or 1 to 6 carbon atoms or 1 to 4 carbon atoms, Including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1, 2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methyl propylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3- Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2- Methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl base, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2, 5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethyl Hexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or various branched isomers thereof, etc. "C _1-10 alkyl" refers to straight-chain alkyl groups including 1 to 10 carbon atoms and branched alkyl groups, "C _1-4 alkyl" refers to straight-chain alkyl groups including 1 to 4 carbon atoms and A branched-chain alkyl group, "C _1-2 alkyl group" refers to a straight-chain alkyl group containing 1 to 2 carbon atoms and a branched chain alkyl group, "C _0-8 alkyl group" refers to a group containing 0 to 8 carbon atoms straight-chain and branched-chain alkyl groups, "C _0-4 alkyl" refers to straight-chain and branched-chain alkyl groups including 0 to 4 carbon atoms, "C _0-2 alkyl" refers to including Straight-chain and branched-chain alkyl groups of 0 to 2 carbon atoms.

Alkyl can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium, halogen, cyano group, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen substituted C _1-10 alkyl, deuterium substituted C _1-10 alkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, =O, -C _0-8 alkyl-SF ₅ , -C _0-8 Alkyl-S(O) _r R ₈ , -C _0-8 alkyl-OR ₉ , -C _0-8 alkyl-C(O)OR ₉ , -C _0-8 alkyl-C(O)R ₁₀ , -C _0-8 alkyl-OC(O)R ₁₀ , -C _0-8 alkyl-NR ₁₁ R ₁₂ , -C _0-8 alkyl-C(=NR ₁₁ )R ₁₀ , -C _{0 -8} alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-8 alkyl-C(O)NR ₁₁ R ₁₂ or -C _0-8 alkyl-N(R ₁₁ ) Substituents of -C(O)R ₁₀ are substituted.

"Cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the partially unsaturated cyclic hydrocarbon means that the cyclic hydrocarbon may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a completely conjugated π electron system, cycloalkyl is divided into monocyclic cycloalkyl, polycyclic cycloalkyl, preferably including 3 to 12 or 3 to 8 or 3 Cycloalkyl groups of up to 6 carbon atoms, for example, "C _3-12 cycloalkyl" refers to cycloalkyl groups including 3 to 12 carbon atoms, "C _3-8 cycloalkyl" refers to cycloalkyl groups including 3 to 8 carbon atoms atomic cycloalkyl, "C _3-6 cycloalkyl" refers to a cycloalkyl group including 3 to 6 carbon atoms, "C _3-4 cycloalkyl" refers to a cycloalkyl group including 3 to 4 carbon atoms, in:

Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, Cyclooctyl etc.

Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. "Spirocycloalkyl" refers to polycyclic groups in which a single carbon atom (called a spiro atom) is shared between the monocyclic rings, these may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings have Fully conjugated pi electron system. According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are divided into single spirocycloalkyl groups, double spirocycloalkyl groups or polyspirocycloalkyl groups, including but not limited to:

"Fused cycloalkyl" 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 rings may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings have a fully conjugated pi electron system. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, fused cycloalkyl groups include but are not limited to:

"Bridged cycloalkyl" refers to an all-carbon polycyclic group in which any two rings share two non-directly attached carbon atoms, these may contain one or more (preferably 1, 2 or 3) double bonds, but none The ring has a fully conjugated pi electron system. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, including but not limited to:

The cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl, including but not limited to indanyl, tetrahydronaphthyl , benzocycloheptyl, etc.

Cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen substituted C _1-10 alkyl, deuterium substituted C _1-10 alkyl , C _3-12 cycloalkyl, 3-12-membered heterocyclyl, C _5-10 aryl, 5-10-membered heteroaryl, =O, -C _0-8 alkyl-SF ₅ , -C _{0- 8} alkyl-S(O) _r R ₈ , -C _0-8 alkyl-OR ₉ , -C _0-8 alkyl-C(O)OR ₉ , -C _0-8 alkyl-C(O) R ₁₀ , -C _0-8 alkyl-OC(O)R ₁₀ , -C _0-8 alkyl-NR ₁₁ R ₁₂ , -C _0-8 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-8 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-8 alkyl-C(O)NR ₁₁ R ₁₂ or -C _0-8 alkyl-N(R ₁₁ )-C(O)R ₁₀ substituent.

"Heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the partially unsaturated cyclic hydrocarbon refers to a cyclic hydrocarbon that may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings have a fully conjugated pi-electron system, heterocyclyl wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen, S(O ) (=NH) or S(O) _r (where r is an integer 0, 1, 2) heteroatoms, excluding ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon, Heterocyclyl groups including 3 to 12 or 3 to 8 or 3 to 6 ring atoms are preferred, for example, "3-4 membered heterocyclyl" refers to a ring group containing 3 to 4 ring atoms, "4-6 "Membered heterocyclyl" refers to a ring group containing 4 to 6 ring atoms, "3-6 membered heterocyclyl" refers to a ring group containing 3 to 6 ring atoms, and "3-8 membered heterocyclyl" refers to a ring group containing 3 A ring group of up to 8 ring atoms, "3-12 membered heterocyclyl" refers to a ring group containing 3 to 12 ring atoms, and "4-8 membered heterocyclyl" refers to a ring group containing 4 to 8 ring atoms , "4-10 membered heterocyclyl" refers to a ring group containing 4 to 10 ring atoms.

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

Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls. "Spiroheterocyclyl" refers to a polycyclic heterocyclic group in which a single atom (called a spiro atom) is shared between the monocyclic rings, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen , S(O)(=NH) or S(O) _r (where r is an integer 0, 1, 2) heteroatoms and the remaining ring atoms are carbon. These may contain one or more double bonds (preferably 1, 2 or 3), but none of the rings have a fully conjugated pi-electron system. Spiroheterocyclyls are classified into mono-, bis-, or poly-spiroheterocyclyls according to the number of spiro atoms shared between the rings. Spiroheterocyclyl groups include, but are not limited to:

"Fused heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more (preferably 1, 2, 3 or 4) rings may be contains 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 Heteroatoms of nitrogen, oxygen, S(O)(=NH) or S(O) _r (where r is an integer 0, 1, 2) and the remaining ring atoms are carbon. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl groups, fused heterocyclic groups include but are not limited to:

"Bridged heterocyclyl" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, these may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings have a fully conjugated pi electron system in which one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen, S(O)(=NH) or S(O) _r (where r are heteroatoms of integers 0, 1, 2), and the remaining ring atoms are carbon. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, bridged heterocyclic groups include but are not limited to:

The heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclyl, including but not limited to:

Heterocyclyl can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen substituted C _1-10 alkyl, deuterium substituted C _1-10 alkyl , C _3-12 cycloalkyl, 3-12-membered heterocyclyl, C _5-10 aryl, 5-10-membered heteroaryl, =O, -C _0-8 alkyl-SF ₅ , -C _{0- 8} alkyl-S(O) _r R ₈ , -C _0-8 alkyl-OR ₉ , -C _0-8 alkyl-C(O)OR ₉ , -C _0-8 alkyl-C(O) R ₁₀ , -C _0-8 alkyl-OC(O)R ₁₀ , -C _0-8 alkyl-NR ₁₁ R ₁₂ , -C _0-8 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-8 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-8 alkyl-C(O)NR ₁₁ R ₁₂ or -C _0-8 alkyl-N(R ₁₁ )-C(O)R ₁₀ substituent.

"Aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic (ie, rings sharing adjacent pairs of carbon atoms) groups, polycyclic rings having a conjugated pi electron system (ie, with adjacent ring) groups for carbon atoms, preferably all-carbon aryl groups containing 5-10 or 5-8 carbons, for example, "C _5-10 aryl" refers to all-carbon aryl groups containing 5-10 carbons, "C _5-8 aryl" refers to a full carbon aryl group containing 5-8 carbons, including but not limited to phenyl and naphthyl. The aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, including but not limited to:

"Aryl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium, halogen, cyano group, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen substituted C _1-10 alkyl, deuterium substituted C _1-10 alkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, =O, -C _0-8 alkyl-SF ₅ , -C _0-8 Alkyl-S(O) _r R ₈ , -C _0-8 alkyl-OR ₉ , -C _0-8 alkyl-C(O)OR ₉ , -C _0-8 alkyl-C(O)R ₁₀ , -C _0-8 alkyl-OC(O)R ₁₀ , -C _0-8 alkyl-NR ₁₁ R ₁₂ , -C _0-8 alkyl-C(=NR ₁₁ )R ₁₀ , -C _{0 -8} alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-8 alkyl-C(O)NR ₁₁ R ₁₂ or -C _0-8 alkyl-N(R ₁₁ ) Substituents of -C(O)R ₁₀ are substituted.

"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 the integer 0 , 1, 2) heteroatoms, preferably heteroaromatic systems containing 5-10 or 5-8 or 5-6 ring atoms, for example, "5-8 membered heteroaryl" means containing 5-8 ring atoms Heteroaromatic systems of ring atoms, "5-10 membered heteroaryl" refers to heteroaromatic systems containing 5-10 ring atoms, including but not limited to furyl, thienyl, pyridyl, pyrrolyl, N-alkane pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl and the like. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, including but not limited to:

"Heteroaryl" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium, Halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen substituted C _1-10 alkyl, deuterium substituted C _1-10 Alkyl, C _3-12 cycloalkyl, 3-12-membered heterocyclyl, C _5-10 -membered aryl, 5-10-membered heteroaryl, =O, -C _0-8 alkyl-SF ₅ , -C _0-8 alkyl-S(O) _r R ₈ , -C _0-8 alkyl-OR ₉ , -C _0-8 alkyl-C(O)OR ₉ , -C _0-8 alkyl-C( O)R ₁₀ , -C _0-8 alkyl-OC(O)R ₁₀ , -C _0-8 alkyl-NR ₁₁ R ₁₂ , -C _0-8 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-8 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-8 alkyl-C(O)NR ₁₁ R ₁₂ or -C _0-8 alkyl-N( R ₁₁ )-C(O)R ₁₀ is substituted with the substituent.

"Alkenyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably a straight or branched chain alkenyl group containing 2-10 or 2-4 carbons For example, "C _2-10 alkenyl" refers to a straight-chain or branched alkenyl containing 2-10 carbons, and "C _2-4 alkenyl" refers to a straight-chain or branched alkenyl containing 2-4 carbons Branched alkenyl. Including but not limited to vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like.

"Alkenyl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen substituted C _1-10 alkyl, deuterium substituted C _1-10 alkyl , C _3-12 cycloalkyl, 3-12-membered heterocyclyl, C _5-10 aryl, 5-10-membered heteroaryl, =O, -C _0-8 alkyl-SF ₅ , -C _{0- 8} alkyl-S(O) _r R ₈ , -C _0-8 alkyl-OR ₉ , -C _0-8 alkyl-C(O)OR ₉ , -C _0-8 alkyl-C(O) R ₁₀ , -C _0-8 alkyl-OC(O)R ₁₀ , -C _0-8 alkyl-NR ₁₁ R ₁₂ , -C _0-8 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-8 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-8 alkyl-C(O)NR ₁₁ R ₁₂ or -C _0-8 alkyl-N(R ₁₁ )-C(O)R ₁₀ substituent.

"Alkynyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably a straight-chain or branched-chain alkynyl group containing 2-10 or 2-4 carbons, For example, "C _2-10 alkynyl" refers to a straight or branched chain alkynyl group containing 2-10 carbons, and "C _2-4 alkynyl" refers to a straight or branched chain containing 2-4 carbons alkynyl. Including, but not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.

"Alkynyl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen substituted C _1-10 alkyl, deuterium substituted C _1-10 alkyl , C _3-12 cycloalkyl, 3-12-membered heterocyclyl, C _5-10 aryl, 5-10-membered heteroaryl, =O, -C _0-8 alkyl-SF ₅ , -C _{0- 8} alkyl-S(O) _r R ₈ , -C _0-8 alkyl-OR ₉ , -C _0-8 alkyl-C(O)OR ₉ , -C _0-8 alkyl-C(O) R ₁₀ , -C _0-8 alkyl-OC(O)R ₁₀ , -C _0-8 alkyl-NR ₁₁ R ₁₂ , -C _0-8 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-8 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-8 alkyl-C(O)NR ₁₁ R ₁₂ or -C _0-8 alkyl-N(R ₁₁ )-C(O)R ₁₀ substituent.

"Alkoxy" refers to -O-alkyl, where alkyl is as defined above, eg, "C _1-10 alkoxy" refers to an alkyloxy group containing 1-10 carbons, C _1-4 alkoxy "Oxy" refers to an alkyloxy group containing 1-4 carbons including, but not limited to, methoxy, ethoxy, propoxy, butoxy, and the like.

"Alkoxy" may be optionally substituted or unsubstituted, and when substituted, the substituents, preferably one or more (preferably 1, 2, 3 or 4) of the following groups, are independently selected from deuterium , halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen substituted C _1-10 alkyl, deuterium substituted C _{1- 10} alkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, =O, -C _0-8 alkyl-SF ₅ , - C _0-8 alkyl-S(O) _r R ₈ , -C _0-8 alkyl-OR ₉ , -C _0-8 alkyl-C(O)OR ₉ , -C _0-8 alkyl-C (O)R ₁₀ , -C _0-8 alkyl-OC(O)R ₁₀ , -C _0-8 alkyl-NR ₁₁ R ₁₂ , -C _0-8 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-8 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-8 alkyl-C(O)NR ₁₁ R ₁₂ or -C _0-8 alkyl-N (R ₁₁ )-C(O)R ₁₀ is substituted with a substituent.

"Cycloalkoxy" refers to -O-cycloalkyl, where cycloalkyl is as defined above, for example, "C _3-12 cycloalkoxy" refers to a cycloalkyloxy group containing 3-12 carbons, "C _3-6 cycloalkoxy" refers to a cycloalkyloxy group containing 3-6 carbons, including but not limited to cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.

"Cycloalkoxy" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium , halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen substituted C _1-10 alkyl, deuterium substituted C _{1- 10} alkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, =O, -C _0-8 alkyl-SF ₅ , - C _0-8 alkyl-S(O) _r R ₈ , -C _0-8 alkyl-OR ₉ , -C _0-8 alkyl-C(O)OR ₉ , -C _0-8 alkyl-C (O)R ₁₀ , -C _0-8 alkyl-OC(O)R ₁₀ , -C _0-8 alkyl-NR ₁₁ R ₁₂ , -C _0-8 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-8 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-8 alkyl-C(O)NR ₁₁ R ₁₂ or -C _0-8 alkyl-N (R ₁₁ )-C(O)R ₁₀ is substituted with a substituent.

"Heterocyclyloxy" refers to -O-heterocyclyl, wherein heterocyclyl is as defined above, and heterocyclyloxy, including but not limited to azetidinyloxy, oxetanyloxy, nitrogen Heterocyclopentyloxy, nitrogen, oxhexyloxy, etc.

"Heterocyclyloxy" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium , halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen substituted C _1-10 alkyl, deuterium substituted C _{1- 10} alkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, =O, -C _0-8 alkyl-SF ₅ , - C _0-8 alkyl-S(O) _r R ₈ , -C _0-8 alkyl-OR ₉ , -C _0-8 alkyl-C(O)OR ₉ , -C _0-8 alkyl-C (O)R ₁₀ , -C _0-8 alkyl-OC(O)R ₁₀ , -C _0-8 alkyl-NR ₁₁ R ₁₂ , -C _0-8 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-8 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-8 alkyl-C(O)NR ₁₁ R ₁₂ or -C _0-8 alkyl-N (R ₁₁ )-C(O)R ₁₀ is substituted with a substituent.

"C _1-10 alkanoyl" refers to the monovalent atomic group left after C _1-10 alkanoic acid removes the hydroxyl group, usually also expressed as "C _0-9 -C(O)-", for example, "C ₁ -C (O)-" means acetyl; "C2 _- C(O)-" means propionyl; "C3 _- C(O)-" means butyryl or isobutyryl.

"-C _0-8 alkyl-S(O) _r R ₈ " means that the sulfur atom in -S(O) _r R ₈ is attached to the C _0-8 alkyl group, wherein the C _0-8 alkyl group is as defined above said.

"-C _0-8 alkyl-OR ₉ " means that the oxygen atom in -OR ₉ is attached to a C _0-8 alkyl group, wherein the C _0-8 alkyl group is as defined above.

"-C _0-8 alkyl-C(O)OR ₉ " means that the carbonyl group in -C(O)OR ₉ is attached to the C _0-8 alkyl group, wherein the C _0-8 alkyl group is as defined above.

"-C _0-8 alkyl-C(O)R ₁₀ " means that the carbonyl group in -C(O)R ₁₀ is attached to a C _0-8 alkyl group, wherein the C _0-8 alkyl group is as defined above.

"-C _0-8 -OC(O)R ₁₀ " means that the oxygen atom in -OC(O)R ₁₀ is attached to a C _0-8 alkyl group, wherein the C _0-8 alkyl group is as defined above.

"-C _0-8 -NR ₁₁ R ₁₂ " means that the nitrogen atom in -NR ₁₁ R ₁₂ is attached to a C _0-8 alkyl group, wherein the C _1-8 alkyl group is as defined above.

"-C _0-8 -C(=NR ₁₁ )R ₁₀ " means that the nitrogen atom in -C(=NR ₁₁ )R ₁₀ is attached to a C _0-8 alkyl group, wherein the C _0-8 alkyl group is as defined above said.

"-C _0-8 -N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ " means that the nitrogen atom in -N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ is attached to a C _0-8 alkyl group above, wherein Co- ₈ alkyl is as defined above.

"-C _0-8 -C(O)NR ₁₁ R ₁₂ " means that the carbonyl group in -C(O)NR ₁₁ R ₁₂ is attached to a C _0-8 alkyl group, wherein the C _0-8 alkyl group is as defined above described.

"-C _0-8 -N(R ₁₁ )-C(O)R ₁₀ " means that the nitrogen atom in -N(R ₁₁ )-C(O)R ₁₀ is attached to the C _0-8 alkyl group, wherein C _0-8 Alkyl is as defined above.

"Halo-substituted C _1-10 alkyl" refers to 1-10 carbon alkyl groups in which the hydrogen on the alkyl group is optionally substituted by fluorine, chlorine, bromine and iodine atoms, including but not limited to difluoromethyl, dichloro Methyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, etc.

"Halo-substituted C _1-10 alkoxy" refers to a 1-10 carbon alkoxy group in which 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.

"Deuterium-substituted _C1-10 alkyl" refers to a 1-10 carbon alkyl group in which the hydrogen on the alkyl group is optionally substituted with a deuterium atom. Including but not limited to deuteromethyl, di-deuteromethyl, tri-deuteromethyl and the like.

"Halogen" refers to fluorine, chlorine, bromine or iodine. "PE" refers to petroleum ether. "EtOAc" refers to ethyl acetate. "DCM" refers to dichloromethane.

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

"Substituted" means that one or more "hydrogen atoms" in a group are, independently of one another, substituted with the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, in accordance with valence bond theory in chemistry, and those skilled in the art can determine (either experimentally or theoretically) possible or impossible without undue effort replacement. For example, amino or hydroxyl groups with free hydrogen may be unstable when combined with carbon atoms with unsaturated bonds, such as alkenes.

"Stereoisomer", its English name is stereoisomer, refers to the isomers produced by the different arrangements of atoms in the molecule in space. It can be divided into cis-trans isomers and enantiomers. It can also be divided into two categories: enantiomers and diastereomers. Stereoisomers due to rotation of a single bond are called conformational stereo-isomers, and are sometimes called rotamers. Stereoisomers caused by bond length, bond angle, double bond in the molecule, ring, etc. are called configuration stereo-isomers, and configuration isomers are divided into two categories. Among them, the isomers caused by the double bond or the single bond of the ring carbon atom not being able to rotate freely are called geometric isomers, also known as cis-trans isomers, which are divided into Z, E two configurations. For example: cis-2-butene and trans-2-butene are a pair of geometric isomers, and the stereoisomers with different optical properties caused by the absence of anti-axial symmetry in the molecule are called optical isomers ( optical isomer), divided into R and S configurations. In the present invention, the "stereoisomer" may be understood to include one or more of the above-mentioned enantiomers, configurational isomers and conformational isomers unless otherwise specified.

"Pharmaceutically acceptable salts" in the present invention refer to pharmaceutically acceptable acid addition salts or base addition salts, including inorganic and organic acid salts, which can be prepared by methods known in the art.

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

The present invention will be further described in detail and completely below in conjunction with the examples, but the present invention is by no means limited, and the present invention is not limited to the contents of the examples.

The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts ([delta]) are given in parts per million (ppm). NMR was measured by Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated methanol (CD ₃ OD) and deuterated chloroform (CDCl ₃ ), and the internal standard was four Methylsilane (TMS).

An Agilent 6120 mass spectrometer was used for LC-MS determination. The determination of HPLC used Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150×4.6mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150×4.6mm chromatographic column).

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the specifications used for TLC are 0.15mm ~ 0.20mm, and the specifications used for TLC separation and purification products are 0.4mm ~ 0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

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

Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature is in degrees Celsius (°C).

1. Preparation of intermediates

Intermediate 1: Preparation of 2-cyclopropyl-7-ethynyl-6,8-difluoroimidazo[1,2-a]pyridine

The first step: Synthesis of 2-cyclopropyl-6,8-difluoro-7-iodoimidazo[1,2-a]pyridine

3,5-Difluoro-4-iodopyridin-2-amine (1.0 g, 4.0 mmol) was dissolved in DMF (10 mL), 2-bromo-1-cyclopropylethane-1-one (0.98 g) was added , 6.0 mmol). The mixture was stirred at 60°C for 16 hours. It was cooled to room temperature and then filtered to give 2-cyclopropyl-6,8-difluoro-7-iodoimidazo[1,2-a]pyridine (640 mg, yield: 50%). MS m/z (ESI): 321 [M+H] ⁺ .

The second step: Synthesis of 2-cyclopropyl-7-ethynyl-6,8-difluoroimidazo[1,2-a]pyridine

2-Cyclopropyl-6,8-difluoro-7-iodoimidazo[1,2-a]pyridine (320 mg, 1.0 mmol) was dissolved in DMF (5 mL) and tributyl(ethynyl)tin was added alkane (472 mg, 1.5 mmol) and tetrakistriphenylphosphine palladium (115.5 mg, 0.1 mmol). The mixture was stirred in the microwave at 130°C for 1 hour. It was cooled to room temperature, concentrated and separated by column chromatography to obtain 2-cyclopropyl-7-ethynyl-6,8-difluoroimidazo[1,2-a]pyridine (120 mg, yield: 55%). MS m/z (ESI): 219 [M+H] ⁺ .

Intermediate 2: Preparation of 2-cyclopropyl-7-ethynyl-6-fluoroimidazo[1,2-a]pyridine

The first step: Synthesis of 2-cyclopropyl-6-fluoro-7-iodoimidazo[1,2-a]pyridine

5-Fluoro-4-iodopyridin-2-amine (2.38 g, 10.0 mmol) was dissolved in DMF (20 mL) and 2-bromo-1-cyclopropylethan-1-one (2.44 g, 15.0 mmol) was added ). The mixture was stirred at 60°C for 16 hours. It was cooled to room temperature and filtered to obtain 2-cyclopropyl-6-fluoro-7-iodoimidazo[1,2-a]pyridine (2.20 mg, yield: 73%). MS m/z (ESI): 303 [M+H] ⁺ .

The second step: Synthesis of 2-cyclopropyl-7-ethynyl-6-fluoroimidazo[1,2-a]pyridine

2-Cyclopropyl-6-fluoro-7-iodoimidazo[1,2-a]pyridine (540 mg, 2.0 mmol) was dissolved in DMF (10 mL) and tributyl(ethynyl)stannane (1260 mg) was added , 4.0 mmol) and tetrakistriphenylphosphine palladium (116 mg, 0.1 mmol). The mixture was stirred at 60°C for 16 hours. It was cooled to room temperature, concentrated and separated by column chromatography to obtain 2-cyclopropyl-7-ethynyl-6-fluoroimidazo[1,2-a]pyridine (140 mg, yield: 40%). MS m/z (ESI): 175 [M+H] ⁺ .

Intermediate 3 is prepared by selecting corresponding raw materials with reference to all or part of the synthesis methods of intermediate 2:

Intermediate 4: Preparation of 2-cyclopropyl-5-ethynylbenzo[d]oxazole

The first step: the synthesis of N-(5-bromo-2-hydroxyphenyl) cyclopropanecarboxamide

2-Amino-4-bromophenol (2.0 g, 10.6 mmol) was dissolved in DCM (30 mL), triethylamine (1.29 g, 12.8 mmol), cyclopropylcarbonyl chloride (1.11 g, 10.6 mmol) were added successively at 0 °C mmol). The mixture was stirred at 0°C for 1 hour, diluted with aqueous sodium bicarbonate solution and extracted with DCM. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, column chromatography was performed to obtain N-(5-bromo-2- Hydroxyphenyl)cyclopropanecarboxamide (1.34 g, yield: 49%). MS m/z (ESI): 256/258 [M+H] ⁺ .

The second step: the synthesis of 5-bromo-2-cyclopropylbenzo[d]oxazole

N-(5-Bromo-2-hydroxyphenyl)cyclopropanecarboxamide (1.04 g, 4.06 mmol) was dissolved in acetonitrile (30 mL), and triphenylphosphine (4.26 g, 16.2 mmol) was added successively at room temperature. Carbon chloride (1.25 g, 8.1 mmol). The mixture was stirred at 60°C for 1 hour, diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and separated by column chromatography to obtain 5-bromo-2-cyclopropylbenzoic acid. [d] Oxazole (548 mg, yield: 55%). MS m/z (ESI): 238/240 [M+H] ⁺ .

The third step: Synthesis of 2-cyclopropyl-5-((trimethylsilyl)ethynyl)benzo[d]oxazole

5-Bromo-2-cyclopropylbenzo[d]oxazole (200 mg, 0.84 mmol) was placed in DMF (3 mL), triethylamine (1 mL) was added successively at room temperature, cuprous iodide (16 mg, 0.084 mmol), trimethylsilylacetylene (825 mg, 8.4 mmol), tetrakistriphenylphosphine palladium (49 mg, 0.042 mmol). The mixture was stirred at 80° C. for 16 hours, diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was separated by column chromatography to obtain 2-cyclopropyl-5-((tri) Methylsilyl)ethynyl)benzo[d]oxazole (204 mg, yield: 95%). MS m/z (ESI): 256 [M+H] ⁺ .

The fourth step: the synthesis of 2-cyclopropyl-5-ethynylbenzo[d]oxazole

2-Cyclopropyl-5-((trimethylsilyl)ethynyl)benzo[d]oxazole (204 mg, 0.8 mmol) was dissolved in methanol (8 mL), potassium carbonate (1.1 g, 8 mmol). The mixture was stirred at room temperature for 1 hour, diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, column chromatography was performed to obtain 2-cyclopropyl-5-acetylene Benzo[d]oxazole (112 mg, yield: 76%). MS m/z (ESI): 184 [M+H] ⁺ .

Intermediates 5-8 are prepared by selecting corresponding raw materials with reference to all or part of the synthesis methods of intermediate 4:

Intermediate 9: Preparation of 2-cyclopropyl-5-ethynyl-6-fluorobenzo[d]thiazole

The first step: the synthesis of N-(5-bromo-2,4-difluorophenyl) cyclopropanecarboxamide

Dissolve 5-bromo-2,4-difluoroaniline (1.04 g, 5.0 mmol) in dichloromethane (20 mL), add cyclopropionyl chloride (572 mg, 5.5 mmol), stir at room temperature overnight, and spin to dry directly. Chromatography gave N-(5-bromo-2,4-difluorophenyl)cyclopropanecarboxamide (1.0 g, yield: 72%). MS m/z (ESI): 276/278 [M+H] ⁺ .

The second step: the synthesis of N-(5-bromo-2,4-difluorophenyl) cyclopropylmethylthioamide

N-(5-Bromo-2,4-difluorophenyl)cyclopropanecarboxamide (1.0 g, 3.6 mmol), Lawson's reagent (750 mg, 1.85 mmol), dissolved in acetonitrile (25 mL), heated to 85°C , and stirred overnight. After the reaction, the N-(5-bromo-2,4-difluorophenyl)cyclopropylmethylthioamide solution was directly used in the next experiment. MS m/z (ESI): 292/294 [M+H] ⁺ .

The third step: Synthesis of 5-bromo-2-cyclopropyl-6-fluorobenzo[d]thiazole

Sodium tert-butoxide (1.7 g, 18 mmol) was added to the cooled N-(5-bromo-2,4-difluorophenyl)cyclopropylmethylthioamide solution, heated to 50°C and stirred for 16 hours. After concentration, column chromatography gave 5-bromo-2-cyclopropyl-6-fluorobenzo[d]thiazole (0.82 g, yield: 83%). MS m/z (ESI): 2712/274 [M+H] ⁺ .

The fourth step: the synthesis of 2-cyclopropyl-5-ethynyl-6-fluorobenzo[d]thiazole

5-Bromo-2-cyclopropyl-6-fluorobenzo[d]thiazole (0.82 g, 3.0 mmol) was dissolved in DMF (15 mL) and tributyl(ethynyl)stannane (1.9 g, 6.0 mmol) was added ) and tetrakistriphenylphosphine palladium (173 mg, 0.15 mmol) and stirred in a microwave reactor at 130° C. for 0.5 h. After concentration, column chromatography gave 2-cyclopropyl-5-ethynyl-6-fluorobenzo[d]thiazole (0.16 g, yield: 25%). MS m/z (ESI): 218 [M+H] ⁺ .

Intermediates 10-14 are prepared by selecting corresponding raw materials with reference to all or part of the synthetic methods of intermediate 9:

Intermediate 15: Preparation of 2-cyclopropyl-5-ethynyl-4,6-difluorobenzo[d]thiazole

The first step: the synthesis of N-(2,4-difluorophenyl) cyclopropanecarboxamide

2,4-Difluoroaniline (10 g, 77.45 mmol) was dissolved in dichloromethane (100 mL), triethylamine (15.64 g, 154.9 mmol) was added, and cyclopropylcarbonyl chloride (8.1 g, 77.45 mmol) and stirred overnight at room temperature. The reaction solution was washed with an appropriate amount of saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography to obtain N-(2,4-difluorophenyl)cyclopropanecarboxamide (10.1 g, Yield: 66%). MS m/z (ESI): 196 [M+H] ⁺ .

Step 2: Synthesis of N-(2,4-difluorophenyl)cyclopropylmethylthioamide

Dissolve N-(2,4-difluorophenyl)cyclopropanecarboxamide (5 g, 25.36 mmol) in xylene (80 mL), add Lawson's reagent (7.18 g, 17.75 mmol), heat to 120 °C and stir overnight . After concentration, it was directly separated by silica gel column chromatography to obtain N-(2,4-difluorophenyl)cyclopropylmethylthioamide (4.1 g, yield: 75%). MS m/z (ESI): 212 [M+H] ⁺ .

The third step: synthesis of 2-cyclopropyl-4,6-difluorobenzo[d]thiazole

N-(2,4-difluorophenyl)cyclopropylmethylthioamide (1 g, 4.69 mmol) was dissolved in sodium hydroxide solution (1.69 g, 42.2 mmol, 5 mL of ethanol and 10 mL of water), and the resulting solution was added dropwise to a pre- Heating to a K ₃ Fe(CN) ₆ aqueous solution (6.18 g, 18.78 mmol, 10 mL water) at 90° C., stirring for 2 hours, then stopping the heating immediately, adjusting to weak acidity with concentrated hydrochloric acid after cooling, and extracting with ethyl acetate, the obtained The extract was washed with saturated brine, concentrated and separated by silica gel column chromatography to obtain 2-cyclopropyl-4,6-difluorobenzo[d]thiazole (500 mg, yield: 51%). MS m/z (ESI): 212 [M+H] ⁺ .

The fourth step: the synthesis of 2-cyclopropyl-4,6-difluorobenzo[d]thiazole-5-carbaldehyde

2-Cyclopropyl-4,6-difluorobenzo[d]thiazole (980 mg, 4.64 mmol) was dissolved in tetrahydrofuran (15 mL) and cooled to -70°C, LDA (2.55 mL, 5.10 mmol, 2M) was added dropwise, After maintaining the temperature for 2 hours, DMF (1.01 g, 13.92 mmol) was added. After maintaining the temperature for 2 hours, LCMS was used to monitor the completion of the reaction. An appropriate amount of ammonium chloride aqueous solution was added to quench the reaction and the temperature was raised to room temperature. The reaction solution was extracted with ethyl acetate, and anhydrous After drying over sodium sulfate, the mixture was filtered and concentrated, and then separated by silica gel column chromatography to obtain 2-cyclopropyl-4,6-difluorobenzo[d]thiazole-5-carbaldehyde (675 mg, yield: 65%). MS m/z (ESI): 240 [M+H] ⁺ .

The fifth step: the synthesis of 2-cyclopropyl-5-ethynyl-4,6-difluorobenzo[d]thiazole

2-Cyclopropyl-4,6-difluorobenzo[d]thiazole-5-carbaldehyde (122 mg, 0.51 mmol) was dissolved in methanol (10 mL), followed by potassium carbonate (211 mg, 1.53 mmol) and (1-plex) Nitrogen-2-oxo-propanol)-phosphonic acid dimethyl ester (159 mg, 0.76 mmol) and stirred at room temperature overnight. After direct concentration, it was separated by silica gel column chromatography to obtain 2-cyclopropyl-5-ethynyl-4,6-difluorobenzo[d]thiazole (73 mg, yield: 61%). MS m/z (ESI): 236 [M+H] ⁺ .

Intermediate 16 is prepared by selecting corresponding raw materials with reference to all or part of the synthetic methods of intermediate 15:

Intermediate 17: Preparation of 5-ethynyl-6-fluoro-N-methylbenzo[d]oxazol-2-amine

The first step: the synthesis of 2-amino-4-bromo-5-fluorophenol

4-Bromo-5-fluoro-2-nitrophenol (5.00 g, 21.2 mmol) was dissolved in tetrahydrofuran/water (60 mL/30 mL), and ammonium chloride (5.66 g, 105.9 mmol) and zinc powder were added in sequence at room temperature (6.89 g, 105.9 mmol). The mixture was stirred at room temperature for 1 hour. The reaction solution was filtered, washed with ethyl acetate (50 mL), and extracted by liquid separation. After the organic phase was concentrated, column chromatography was performed to obtain 2-amino-4-bromo-5-fluorophenol (3.2 g, yield: 73%). MS m/z (ESI): 206/208 [M+H] ⁺ .

The second step: the synthesis of 5-bromo-6-fluorobenzo[d]oxazole-2(3H)-thione

2-Amino-4-bromo-5-fluorophenol (3.2 g, 15.5 mmol) was taken up in ethanol (50 mL) and potassium ethylsulfonate (2.48 g, 15.5 mmol) was added at room temperature. The mixture was stirred at 80°C for 17 hours. The reaction solution was directly concentrated and separated by column chromatography to obtain 5-bromo-6-fluorobenzo[d]oxazole-2(3H)-thione (1.80 g, yield: 47%). MS m/z (ESI): 248/250 [M+H] ⁺ .

The third step: Synthesis of 5-bromo-2-chloro-6-fluorobenzo[d]oxazole

5-Bromo-6-fluorobenzo[d]oxazole-2(3H)-thione (1.76 g, 7.1 mmol) was dissolved in dichloromethane (15 mL), and N,N-dimethylmethane was added sequentially at room temperature formamide (0.5 mL) and thionyl chloride (5.0 mL, 68.9 mmol). The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was diluted with dichloromethane (100 mL), washed successively with saturated sodium bicarbonate solution (50 mL) and brine (50 mL), and dried over anhydrous sodium sulfate. After suction filtration, the filtrate was concentrated and separated by column chromatography to obtain 5-bromo-2-chloro-6-fluorobenzo[d]oxazole (1.30 g, yield: 73%).

The fourth step: the synthesis of 5-bromo-6-fluoro-N-methylbenzo[d]oxazol-2-amine

5-Bromo-2-chloro-6-fluorobenzo[d]oxazole (250 mg, 1.0 mmol) was placed in acetonitrile (5 mL), and methylamine aqueous solution (1.0 mL, mass fraction 25-30%) was added at room temperature . The mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with brine, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, concentrated to give 5-bromo-6-fluoro-N-methylbenzo[d]oxazol-2-amine (245 mg, Yield: 100%). MS m/z (ESI): 245/247 [M+H] ⁺ .

The fifth step: the synthesis of 6-fluoro-N-methyl-5-((trimethylsilyl)ethynyl)benzo[d]oxazol-2-amine

5-Bromo-6-fluoro-N-methylbenzo[d]oxazol-2-amine (190 mg, 0.78 mmol) was placed in 1,4-dioxane/N,N-dimethylformamide (10 mL/1 mL), tributyl(trimethylsilylethynyl)tin (600 mg, 1.55 mmol) and tetrakistriphenylphosphine palladium (90 mg, 0.08 mmol) were added at room temperature. The mixture was reacted in the microwave at 120°C for 6 hours. The reaction solution was directly concentrated and separated by column chromatography to obtain 6-fluoro-N-methyl-5-((trimethylsilyl)ethynyl)benzo[d]oxazol-2-amine (158 mg, yield: 78%). MS m/z (ESI): 263 [M+H] ⁺ .

Step 6: Synthesis of 5-ethynyl-6-fluoro-N-methylbenzo[d]oxazol-2-amine

6-Fluoro-N-methyl-5-((trimethylsilyl)ethynyl)benzo[d]oxazol-2-amine (158 mg, 0.60 mmol) was placed in methanol (10 mL) at room temperature Potassium carbonate (248 mg, 1.80 mmol) was added at the bottom. The mixture was stirred at room temperature for 1 hour. The reaction solution was directly concentrated and separated by column chromatography to obtain 5-ethynyl-6-fluoro-N-methylbenzo[d]oxazol-2-amine (95 mg, yield: 83%). MS m/z (ESI): 191 [M+H] ⁺ .

Intermediates 18-20 are prepared by selecting corresponding raw materials with reference to all or part of the synthesis methods of intermediate 17:

Intermediate 21: Preparation of 2-(azetidin-1-yl)-5-ethynyl-4,6-difluorobenzo[d]oxazole

The first step: synthesis of 2-amino-3,5-difluorophenol

Dissolve 3,5-difluoro-2-nitrophenol (10 g, 57.11 mmol) in methanol (100 mL), add palladium on carbon (1 g), stir at room temperature overnight, filter, and spin dry the filtrate to obtain 2-amino-3 ,5-difluorophenol (8.5 g, yield: 100%). MS m/z (ESI): 146 [M+H] ⁺ .

Step 2: Synthesis of 4,6-difluorobenzo[d]oxazole-2-thiol

2-Amino-3,5-difluorophenol (8.5 g, 58.62 mmol) was dissolved in ethanol (100 mL), potassium O-ethyldisulfate (1.13 g, 70.34 mmol) was added, and the mixture was heated to 95°C overnight. After cooling and filtration, the filtrate was concentrated and separated by silica gel column chromatography to obtain 4,6-difluoro-1,3-benzoxazole-2-thiol (11 g, yield: 95.31%). MS m/z (ESI): 188 [M+H] ⁺ .

The third step: synthesis of 2-chloro-4,6-difluorobenzo[d]oxazole

4,6-Difluoro-1,3-benzoxazole-2-thiol (4 g, 21.37 mmol) was dissolved in dichloromethane (50 mL), oxalyl chloride (10.85 g, 85.48 mmol) and N, N-dimethylformamide (0.16 g, 2.14 mmol), stirred at room temperature for 2 hours, and spin-dried to obtain a crude product of 2-chloro-4,6-difluorobenzo[d]oxazole (4.05 g, yield: 100%), which was directly used in the next reaction. MS m/z (ESI): 190 [M+H] ⁺ .

The fourth step: the synthesis of 2-(azetidin-1-yl)-4,6-difluorobenzo[d]oxazole

The crude product of 2-chloro-4,6-difluorobenzo[d]oxazole (4.05 g, 21.36 mmol) was dissolved in tetrahydrofuran (50 mL), and N,N-diisopropylethylamine (5.51 g, 42.72 mmol) and azetidine hydrochloride (2.40 g, 25.63 mmol), stirred at room temperature for 2 hours, the reaction solution was spin-dried, ethyl acetate was added, washed twice with saturated aqueous ammonium chloride, and twice with saturated brine. After three times, sodium sulfate was added to dry and filtered. The filtrate was concentrated and separated by silica gel column chromatography to obtain 2-(azetidin-1-yl)-4,6-difluorobenzo[d]oxazole (3.2 g, yield : 72%). MS m/z (ESI): 211 [M+H] ⁺ .

The fifth step: the synthesis of 2-(azetidine-1-yl)-4,6-difluorobenzo[d]oxazole-5-carbaldehyde

2-(azetidin-1-yl)-4,6-difluorobenzo[d]oxazole (3g, 14.28mmol) was dissolved in tetrahydrofuran (100ml), cooled to -70°C, and diisopropyl was added dropwise A solution of lithium amide in tetrahydrofuran (10.7 mL, 21.41 mmol, 2 M) was stirred at low temperature for 1 hour, then N,N-dimethylformamide (11.04 mL, 142.73 mmol) was added at one time, stirred at low temperature for 2 hours, and added An appropriate amount of saturated aqueous ammonium chloride solution was used to quench the reaction. After warming to room temperature, extraction with ethyl acetate was performed twice. The ethyl acetate phases were combined, washed twice with saturated brine, dried over sodium sulfate, and filtered to obtain a filtrate. After concentration, silica gel column chromatography was performed. 2-(azetidin-1-yl)-4,6-difluorobenzo[d]oxazole-5-carbaldehyde was isolated (0.8 g, yield: 24%). MS m/z (ESI): 239 [M+H] ⁺ .

The sixth step: the synthesis of 2-(azetidin-1-yl)-5-ethynyl-4,6-difluorobenzo[d]oxazole

2-(azetidin-1-yl)-4,6-difluorobenzo[d]oxazole-5-carbaldehyde (0.8 g, 3.40 mmol) was dissolved in methanol (10 mL) and tetrahydrofuran (10 mL), added Potassium carbonate (1.17g, 8.5mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (1.31g, 6.801mmol) were stirred at room temperature for two hours, concentrated, and an appropriate amount of saturated chloride was added. Aqueous ammonium solution was used to quench the reaction. After warming to room temperature, it was extracted twice with ethyl acetate. After the combination, it was washed twice with saturated brine. After drying over sodium sulfate, the filtrate was filtered to obtain the filtrate. -1-yl)-5-ethynyl-4,6-difluorobenzo[d]oxazole (0.75 g, yield: 94%). MS m/z (ESI): 235 [M+H] ⁺ .

Intermediate 22 is prepared by selecting corresponding raw materials with reference to all or part of the synthesis methods of intermediate 21:

Intermediate 23: Preparation of (S)-1-(1-acryloylpyrrolidin-3-yl)-5-amino-3-bromo-1H-pyrazole-4-carboxamide

The first step: the synthesis of 3-amino-5-bromo-1H-pyrazole-4-carbonitrile

3-Amino-1H-pyrazole-4-carbonitrile (25.0 g, 231 mmol) was dissolved in DMF (200 mL), and N-bromosuccinimide (42.0 g, 236 mmol) was added in portions under ice bath , after the addition was completed, it was slowly raised to room temperature, and stirring was continued for 2 hours. After the completion of the reaction, water was added, extracted with ethyl acetate, the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was separated by column chromatography to give 3-amino-5-bromo-1H-pyrazole-4-carbonitrile (14.7 g, yield: 34%). MS m/z (ESI): 187/189 [M+H] ⁺ .

The second step: synthesis of tert-butyl (S)-3-(5-amino-3-bromo-4-cyano-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate

3-Amino-5-bromo-1H-pyrazole-4-carbonitrile (14.7 g, 78.6 mmol), tert-butyl(R)-3-(toluenesulfonyloxo)pyrrolidine-1-carboxylic acid The ester (32.2 g, 94.3 mmol) was dissolved in DMF (200 mL) and cesium carbonate (51.2 g, 157.2 mmol) was added. The reaction was stirred at 90°C for 18 hours, cooled to room temperature after completion of the reaction, added water and extracted with ethyl acetate. The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was separated by column chromatography to give tert-butyl (S)-3-(5-amino-3-bromo-4-cyano-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (7.5 g, yield: 26.8%). MS m/z (ESI): 300/302 [M+H] ⁺ .

The third step: synthesis of tert-butyl (S)-3-(5-amino-3-bromo-4-carbamoyl-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate

tert-Butyl (S)-3-(5-amino-3-bromo-4-cyano-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (1.85 g, 5.19 mmol) was dissolved in In DMSO (30 mL), sodium hydroxide (208 mg, 5.19 mmol) aqueous solution (10 mL) was added, and hydrogen peroxide solution (30 wt %, 16.4 mL) was slowly added under ice-cooling. After the addition, it was raised to room temperature and stirred for 2 hours. After the completion of the reaction, saturated brine was added, followed by extraction with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was separated by column chromatography to obtain tert-butyl (S)-3-(5-amino-3-bromo-4-carbamoyl-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate ( 1.24 g, yield: 63.8%). MS m/z (ESI): 374/376 [M+H] ⁺ .

The fourth step: the synthesis of (S)-5-amino-3-bromo-1-(pyrrolidin-3-yl)-1H-pyrazole-4-carboxamide hydrochloride

Dissolve tert-butyl (S)-3-(5-amino-3-bromo-4-carbamoyl-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (1.24 g, 3.31 mmol) In dichloromethane (15 mL), ethanolic hydrochloric acid solution (10 M, 3.3 mL, 33 mmol) was added at room temperature, and after the addition was completed, stirring was continued for 30 minutes until the reaction was completed, and the reaction system was directly concentrated. The crude product can be directly used in the next step without separation to obtain (S)-5-amino-3-bromo-1-(pyrrolidin-3-yl)-1H-pyrazole-4-carboxamide hydrochloride (1.03 g, yield: 100%). MS m/z (ESI): 274/276 [M+H] ⁺ .

The fifth step: the synthesis of (S)-1-(1-acryloylpyrrolidin-3-yl)-5-amino-3-bromo-1H-pyrazole-4-carboxamide

Combine (S)-5-amino-3-bromo-1-(pyrrolidin-3-yl)-1H-pyrazole-4-carboxamide hydrochloride (1.03 g, 3.31 mmol) and sodium bicarbonate (836 mg, 9.95 mmol) was dissolved in THF/water (10/2 mL), acryloyl chloride (300 mg, 3.31 mmol) was slowly added dropwise under an ice bath, and the ice bath was removed after the dropwise addition and continued stirring for 30 minutes. After the completion of the reaction, saturated brine was added, followed by extraction with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the target product (S)-1-(1-acryloylpyrrolidin-3-yl)-5-amino-3-bromo-1H-pyrazole-4 - Formamide (930 mg, yield: 85.5%). MS m/z (ESI): 328/330 [M+H] ⁺ .

Two, the preparation of specific embodiment

Example 1: (S)-1-(1-Acryloylpyrrolidin-3-yl)-5-amino-3-((2-cyclopropyl-6-fluorobenzo[d]thiazol-5-yl ) ethynyl)-1H-pyrazole-4-carboxamide preparation

(S)-1-(1-Acryloylpyrrolidin-3-yl)-5-amino-3-bromo-1H-pyrazole-4-carboxamide (200 mg, 0.61 mmol), 2-cyclopropyl- 5-Ethynyl-6-fluorobenzo[d]thiazole (170 mg, 0.79 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (35.2 mg, 0.03 mmol) , cuprous iodide (11.4 mg, 0.06 mmol) was dissolved in N,N-dimethylformamide (5 mL), triethylamine (1 mL) was added, and the mixture was stirred in a microwave at 130° C. for 2 hours. After concentration, (S)-1-(1-acryloylpyrrolidin-3-yl)-5-amino-3-((2-cyclopropyl-6-fluorobenzo[d]) was obtained by column chromatography Thiazol-5-yl)ethynyl)-1H-pyrazole-4-carboxamide (130 mg, yield: 45.8%). MS m/z (ESI): 465 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.12 (dd, J=9.6, 7.6 Hz, 2H), 7.35 (brs, 1H), 6.76-6.51 (m, 3H), 6.22-6.13 (m, 1H), 5.80-5.61(m, 1H), 5.09-4.90(m, 1H), 4.08-3.76(m, 2H), 3.76-3.47(m, 2H), 2.63-2.53(m, 1H), 2.47- 2.10(m,2H),1.38-1.05(m,4H).

Embodiment 2～22 selects corresponding raw material to prepare with reference to all or part of the synthetic method of embodiment 1:

The NMR data of the compounds prepared in the above-described examples are as follows:

Biological Test Evaluation

1. Proliferation assay of BaF3-Tel-FGFR2WT and various mutant FGFR2 cells

The compounds of the examples of the present invention are used to stably express the TEL-FGFR2WT intracellular kinase domain fusion protein by transfection in Baf cells, or the intracellular domain fusion protein containing FGFR2 V564I, V564F, V564L, N549K, K659M mutations. Cell lines were used to measure the proliferation effect of Baf3-Tel-FGFR2WT and various mutant FGFR2 cells. The specific test process is as follows:

1) Seed 90 μL of cell suspension in growth medium (DMEM containing 1% Glutamax, 10% FBS, and 1% Pen/Strep in total 2000-4000 cells per well) in a 96-well plate, then incubate at 37°C and 5% CO ₂ overnight.

2) Add 10 [mu]L of growth medium containing a 10x stock solution of the test compound to the cell culture (9 dose points, 3x serial dilutions, starting at 1 [mu]M, final 0.3% DMSO).

3) Incubate for 48 hours at 37°C and 5% _CO2 .

4) A volume of 50 μL of CellTiter Glo (CTG) reagent was added to a 96-well plate containing cells and the plate was incubated at room temperature for 10 minutes.

5) Measure RLU (relative light units) on a microplate reader with a luminescence detection module. RLU values were normalized to % survival and concentration-response curves were drawn using Prism to calculate _IC50 (unit: nM) and the results of the experiments are shown in the table below.

2. Proliferation assay of BaF3-Tel-FGFR3WT and FGFR3V555M cells

The compounds of the examples of the present invention were used to stably express TEL-FGFR3WT intracellular kinase domain fusion protein by transfection in Baf cells, or a cell line containing FGFR3V555M mutant intracellular domain fusion protein to determine BaF3-Tel- Proliferation effect of FGFR3WT and R3V555M cells. The specific test process is as follows:

1) Seed 90 μL of cell suspension in growth medium (DMEM containing 1% Glutamax, 10% FBS, and 1% Pen/Strep in total 2000-4000 cells per well) in a 96-well plate, then incubate at 37°C and 5% CO ₂ overnight.

2) Add 10 [mu]L of growth medium containing 10x stock solutions of test compounds to cell cultures (9 dose points, 3x serial dilutions, starting at 1 [mu]M, final 0.3% DMSO).

3) Incubate for 48 hours at 37°C and 5% _CO2 .

4) A volume of 50 μL of CellTiter Glo (CTG) reagent was added to a 96-well plate containing cells and the plate was incubated at room temperature for 10 minutes.

5) Measure RLU (relative light units) on a microplate reader with a luminescence detection module. RLU values were normalized to % survival and concentration-response curves were drawn using Prism to calculate _IC50 (unit: nM) and the results of the experiments are shown in the table below.

Judging from the biological activity data of the compounds in the specific examples, the series of compounds of the present invention have strong inhibitory effects on both the wild-type FGFR and the mutant FGFR at the cellular level, and the inhibitory effect in the mutation is not weakened.

All documents mentioned herein are incorporated by reference in this application as if each document were individually incorporated by reference. In addition, it should be understood that after reading the above disclosure of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (14)

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

   

   in,

   

   is a single or double bond;

   X is C or N; Y is CR _6a , N, NR _6b , O or S;

   Ring A is a 3-12-membered nitrogen-containing heterocyclic group, and the nitrogen atom is connected to a carbonyl group;

   R ₁ is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl , 3-12-membered heterocyclyl, C _5-10 -membered aryl, 5-10-membered heteroaryl, -C _0-8 alkyl-SF ₅ , -C _0-8 alkyl-S(O) _r R ₈ , -C _0-8 alkyl-OR ₉ , -C _0-8 alkyl-C(O)OR ₉ , -C _0-8 alkyl-C(O)R ₁₀ , -C _0-8 alkyl- OC(O)R ₁₀ , -C _0-8 alkyl-NR ₁₁ R ₁₂ , -C _0-8 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-8 alkyl-N(R ₁₁ ) -C(=NR ₁₂ )R ₁₀ , -C _0-8 alkyl-C(O)NR ₁₁ R ₁₂ and -C _0-8 alkyl-N(R ₁₁ )-C(O)R ₁₀ , the above-mentioned groups The group is optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen C _1-10 alkyl, deuterium substituted C _1-10 alkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, =O, -C _0-8 alkyl-SF ₅ , -C _0-8 alkyl-S(O) _r R ₈ , -C _0-8 alkyl-OR ₉ , -C _0-8 alkyl-C(O) OR ₉ , -C _0-8 alkyl-C(O)R ₁₀ , -C _0-8 alkyl-OC(O)R ₁₀ , -C _0-8 alkyl-NR ₁₁ R ₁₂ , -C _{0- 8} alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-8 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-8 alkyl-C(O)NR ₁₁ R ₁₂ and -C _0-8 alkyl-N(R ₁₁ )-C(O)R ₁₀ substituents are substituted;

   Each R2 is independently selected from _hydrogen , deuterium, halogen, cyano, nitro, azido, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, halo-substituted C _1-10 alkyl, deuterium substituted C _1-10 alkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, -C _{0 -8} alkyl-SF ₅ , -C _0-8 alkyl-S(O) _r R ₈ , -C _0-8 alkyl-OR ₉ , -C _0-8 alkyl-C(O)OR ₉ , -C _0-8 alkyl-C(O)R ₁₀ , -C _0-8 alkyl-OC(O)R ₁₀ , -C _0-8 alkyl-NR ₁₁ R ₁₂ , -C _0-8 alkyl -C(=NR ₁₁ )R ₁₀ , -C _0-8 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-8 alkyl-C(O)NR ₁₁ R ₁₂ and -C _0-8 alkyl-N(R ₁₁ )-C(O)R ₁₀ ;

   Each _R is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, halo-substituted C _1-10 alkyl, deuterium substituted C _1-10 alkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, -C _{0 -8} alkyl-SF ₅ , -C _0-8 alkyl-S(O) _r R ₈ , -C _0-8 alkyl-OR ₉ , -C _0-8 alkyl-C(O)OR ₉ , -C _0-8 alkyl-C(O)R ₁₀ , -C _0-8 alkyl-OC(O)R ₁₀ , -C _0-8 alkyl-NR ₁₁ R ₁₂ , -C _0-8 alkyl -C(=NR ₁₁ )R ₁₀ , -C _0-8 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-8 alkyl-C(O)NR ₁₁ R ₁₂ and -C _0-8 alkyl-N(R ₁₁ )-C(O)R ₁₀ ;

   R ₄ is selected from vinyl or ethynyl, and the above groups are independently optionally further substituted by one or more selected from hydrogen, deuterium, halogen, cyano, C _1-10 alkyl, halogen-substituted C _1-10 alkyl, Deuterium substituted C _1-10 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, -C _0-8 alkyl-C(O)OR ₉ , -C _0-8 alkyl-C( O) R ₁₀ , -C _0-8 alkyl-C(O)-NR _7a R _7b and -C _0-8 alkyl-NR _7a R _7b are substituted by substituents;

   R _5a and R _5b are each independently selected from hydrogen, deuterium, hydroxyl, C _1-10 alkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, -C _0-8 alkyl-C(O ) OR ₉ , -C _0-8 alkyl-C(O)R ₁₀ , -C _0-8 alkyl-C(=NR ₁₁ )R ₁₀ and -C _0-8 alkyl-C(O)NR ₁₁ R ₁₂ , alternatively, R _5a and R _5b together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclic group optionally further substituted by one or more groups selected from the group consisting of deuterium, halogen, cyano, nitro, Azido, C _1-10 alkyl, halogen substituted C _1-10 alkyl, deuterium substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 ring Alkyl, 3-12-membered heterocyclyl, C _5-10 -membered aryl, 5-10-membered heteroaryl, =O, -C _0-8 alkyl-SF ₅ , -C _0-8 alkyl-S ( O) _r R ₈ , -C _0-8 alkyl-OR ₉ , -C _0-8 alkyl-C(O)OR ₉ , -C _0-8 alkyl-C(O)R ₁₀ , -C _{0 -8} alkyl-OC(O)R ₁₀ , -C _0-8 alkyl-NR ₁₁ R ₁₂ , -C _0-8 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-8 alkyl- N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-8 alkyl-C(O)NR ₁₁ R ₁₂ and -C _0-8 alkyl-N(R ₁₁ )-C(O) Replaced by the substituent of R ₁₀ ;

   R _6a is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen substituted C _1-10 alkane base, deuterium substituted C _1-10 alkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, -C _0-8 alkyl- SF ₅ , -C _0-8 alkyl-S(O) _r R ₈ , -C _0-8 alkyl-OR ₉ , -C _0-8 alkyl-C(O)OR ₉ , -C _0-8 Alkyl-C(O)R ₁₀ , -C _0-8 alkyl-OC(O)R ₁₀ , -C _0-8 alkyl-NR ₁₁ R ₁₂ , -C _0-8 alkyl-C(=NR ₁₁ ) R ₁₀ , -C _0-8 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-8 alkyl-C(O)NR ₁₁ R ₁₂ and -C _0-8 Alkyl-N(R ₁₁ )-C(O)R ₁₀ ;

   R _6b is selected from hydrogen, deuterium, C _1-10 alkyl, C _2-10 alkenyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _5-10 aryl and 5-10 membered Heteroaryl, the above-mentioned groups are optionally further selected from one or more groups selected from deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 Alkynyl, halogen-substituted C _1-10 alkyl, deuterium-substituted C _1-10 alkyl, C _3-12 cycloalkyl, 3-12-membered heterocyclyl, C _5-10 -membered aryl, 5-10-membered heterocycle Aryl, =O, -C _0-8 alkyl-SF ₅ , -C _0-8 alkyl-S(O) _r R ₈ , -C _0-8 alkyl-OR ₉ , -C _0-8 alkane base-C(O)OR ₉ , -C _0-8 alkyl-C(O)R ₁₀ , -C _0-8 alkyl-OC(O)R ₁₀ , -C _0-8 alkyl-NR ₁₁ R ₁₂ , -C _0-8 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-8 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-8 alkyl- C(O)NR ₁₁ R ₁₂ and the substituents of -C _0-8 alkyl-N(R ₁₁ )-C(O)R ₁₀ ;

   R _7a and R _7b are each independently selected from hydrogen, deuterium, hydroxy, C _1-10 alkyl, -C _0-8 alkyl-C(O)OR ₉ , -C _0-8 alkyl-C(O) R ₁₀ , -C _0-8 alkyl-C(=NR ₁₁ )R ₁₀ and -C _0-8 alkyl-C(O)NR ₁₁ R ₁₂ , or, alternatively, the nitrogen atom to which R _7a and R _7b are directly attached together form a 4-10 membered _heterocyclic group, the above-mentioned groups are optionally further substituted by one or more C _{1- 10} alkyl, deuterium substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _5-10 aryl base, 5-10-membered heteroaryl, =O, -C _0-8 alkyl-SF ₅ , -C _0-8 alkyl-S(O) _r R ₈ , -C _0-8 alkyl-OR ₉ , -C _0-8 alkyl-C(O)OR ₉ , -C _0-8 alkyl-C(O)R ₁₀ , -C _0-8 alkyl-OC(O)R ₁₀ , -C _{0- 8} alkyl-NR ₁₁ R ₁₂ , -C _0-8 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-8 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , - C _0-8 alkyl-C(O)NR ₁₁ R ₁₂ and the substituents of -C _0-8 alkyl-N(R ₁₁ )-C(O)R ₁₀ ;

   Each R ₈ is independently selected from hydrogen, deuterium, hydroxyl, C _1-10 alkyl, C _2-10 alkenyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _5-10 Aryl, 5-10 membered heteroaryl and -NR ₁₁ R ₁₂ , the above-mentioned groups are independently optionally further selected by one or more groups selected from deuterium, halogen, hydroxyl, oxo, C _1-10 alkyl, C _{1 -10} alkoxy, C _3-12 cycloalkyl, C _3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C _5-10 aryl, C _{5- 10} -aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and substituents of -NR ₁₁ R ₁₂ ;

   Each R ₉ is independently selected from hydrogen, deuterium, C _1-10 alkyl, C _2-10 alkenyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _5-10 aryl and 5-10-membered heteroaryl groups, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, oxo, cyano, C _1-10 alkyl, C _1-10 alkoxy , C _3-12 cycloalkyl, C _3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C _5-10 aryl, C _5-10 aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and substituents of -NR ₁₁ R ₁₂ ;

   Each R ₁₀ is independently selected from hydrogen, deuterium, hydroxyl, C _1-10 alkyl, C _1-10 alkoxy, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 Cycloalkyl, C _3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C _5-10 aryl, C _5-10 aryloxy, 5-10-membered heterocycle Aryl, 5-10 membered heteroaryloxy and -NR ₁₁ R ₁₂ , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, cyano, C _1-10 alkyl, C _1-10 alkoxy, C _3-12 cycloalkyl, C _3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C _5-10 aryl, C _{5 -10} -aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and -NR ₁₁ R ₁₂ substituents;

   Each of R ₁₁ and R ₁₂ is independently selected from hydrogen, deuterium, hydroxy, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, 3 -12-membered heterocyclyl, C _5-10 -membered aryl, 5-10-membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, amino Sulfonyl, dimethylaminosulfonyl, amino, mono-C _1-10 alkylamino, di-C _1-10 alkylamino and C _1-10 alkanoyl groups, independently optionally further selected by one or more From deuterium, halogen, hydroxyl, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen substituted C _1-10 alkyl, deuterium substituted C _1-10 alkyl, C _{1 -10} alkoxy, C _3-12 cycloalkyl, C _3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C _5-10 aryl, C _5- Substitution of ₁₀ -aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy, amino, mono-C _1-10 alkylamino, di-C _1-10 alkylamino and C _1-10 alkanoyl base substituted;

   Alternatively, R ₁₁ and R ₁₂ together with the nitrogen atom to which they are directly attached form a 4-10-membered heterocyclic group or a 5-10-membered heteroaryl group, the 4-10-membered heterocyclic group or the 5-10-membered heteroaryl group being either is further selected by one or more selected from deuterium, halogen, hydroxyl, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen substituted C _1-10 alkyl, deuterium substituted C _1-10 alkyl, C _1-10 alkoxy, C _3-12 cycloalkyl, C _3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C _{5 -10} aryl, C _5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono-C _1-10 alkylamino, di-C _1-10 alkylamino and Substituents of C _1-10 alkanoyl groups are substituted;

   m is 0, 1, 2 or 3;

   n is 0, 1, 2, 3, or 4; and

   Each r is independently 0, 1, or 2.
2. The compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ₁ is selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, -C _{0 -4} alkyl-SF ₅ , -C _0-4 alkyl-S(O) _r R ₈ , -C _0-4 alkyl-OR ₉ , -C _0-4 alkyl-C(O)OR ₉ , -C _0-4 alkyl-C(O)R ₁₀ , -C _0-4 alkyl-OC(O)R ₁₀ , -C _0-4 alkyl-NR ₁₁ R ₁₂ , -C _0-4 alkyl -C(=NR ₁₁ )R ₁₀ , -C _0-4 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-4 alkyl-C(O)NR ₁₁ R ₁₂ and -C _0-4 alkyl-N(R ₁₁ )-C(O)R ₁₀ , the above-mentioned groups are optionally further selected by one or more groups selected from deuterium, halogen, cyano, C _1-4 alkyl, C _{2 -4} alkenyl, C _2-4 alkynyl, halogen substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _{5 -8} -aryl, 5-8-membered heteroaryl, =O, -C _0-4 alkyl-SF ₅ , -C _0-4 alkyl-S(O) _r R ₈ , -C _0-4 alkyl -OR ₉ , -C _0-4 alkyl-C(O)OR ₉ , -C _0-4 alkyl-C(O)R ₁₀ , -C _0-4 alkyl-OC(O)R ₁₀ , - C _0-4 alkyl-NR ₁₁ R ₁₂ , -C _0-4 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-4 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , substituted by the substituents of -C _0-4 alkyl-C(O)NR ₁₁ R ₁₂ and -C _0-4 alkyl-N(R ₁₁ )-C(O)R ₁₀ ;

   Each R ₂ is independently selected from hydrogen, deuterium, halogen, cyano, nitro, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, -C _0-4 alkyl -SF ₅ , -C _0-4 alkyl-S(O) _r R ₈ , -C _0-4 alkyl-OR ₉ , -C _0-4 alkyl-C(O)OR ₉ , -C _{0- 4} alkyl-C(O)R ₁₀ , -C _0-4 alkyl-OC(O)R ₁₀ , -C _0-4 alkyl-NR ₁₁ R ₁₂ , -C _0-4 alkyl-C(= NR ₁₁ )R ₁₀ , -C _0-4 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-4 alkyl-C(O)NR ₁₁ R ₁₂ and -C _{0- 4} alkyl-N(R ₁₁ )-C(O)R ₁₀ ;

   Each _R is independently selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halo-substituted C _1-4 alkyl, Deuterium substituted C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, -C _0-4 alkyl-SF ₅ , -C _0-4 alkyl-S(O) _r R ₈ , -C _0-4 alkyl-OR ₉ , -C _0-4 alkyl-C(O)OR ₉ , -C _0-4 alkyl -C(O)R ₁₀ , -C _0-4 alkyl-OC(O)R ₁₀ , -C _0-4 alkyl-NR ₁₁ R ₁₂ , -C _0-4 alkyl-C(=NR ₁₁ ) R ₁₀ , -C _0-4 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-4 alkyl-C(O)NR ₁₁ R ₁₂ and -C _0-4 alkyl -N(R ₁₁ )-C(O)R ₁₀ ;

   R _5a and R _5b are each independently selected from hydrogen, deuterium, hydroxyl, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, -C _0-4 alkyl-C(O ) OR ₉ , -C _0-4 alkyl-C(O)R ₁₀ , -C _0-4 alkyl-C(=NR ₁₁ )R ₁₀ and -C _0-4 alkyl-C(O)NR ₁₁ R ₁₂ , or, alternatively, R _5a and R _5b together 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 the group consisting of deuterium, halogen, cyano, C _{1- 4} alkyl, halogen substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered Heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, =O, -C _0-4 alkyl-SF ₅ , -C _0-4 alkyl-S(O) _r R ₈ , - C _0-4 alkyl-OR ₉ , -C _0-4 alkyl-C(O)OR ₉ , -C _0-4 alkyl-C(O)R ₁₀ , -C _0-4 alkyl-OC ( O)R ₁₀ , -C _0-4 alkyl-NR ₁₁ R ₁₂ , -C _0-4 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-4 alkyl-N(R ₁₁ )-C (=NR ₁₂ ) R ₁₀ , -C _0-4 alkyl-C(O)NR ₁₁ R ₁₂ and substituents of -C _0-4 alkyl-N(R ₁₁ )-C(O)R ₁₀ ;

   R _6a is selected from hydrogen, deuterium, halogen, cyano, nitro, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, -C _0-4 alkyl-SF ₅ , - C _0-4 alkyl-S(O) _r R ₈ , -C _0-4 alkyl-OR ₉ , -C _0-4 alkyl-C(O)OR ₉ , -C _0-4 alkyl-C (O)R ₁₀ , -C _0-4 alkyl-OC(O)R ₁₀ , -C _0-4 alkyl-NR ₁₁ R ₁₂ , -C _0-4 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-4 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-4 alkyl-C(O)NR ₁₁ R ₁₂ and -C _0-4 alkyl-N (R ₁₁ )-C(O)R ₁₀ ;

   R _6b is selected from hydrogen, deuterium, C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl and 5-8 membered Heteroaryl, the above-mentioned groups are optionally further substituted by one or more groups selected from deuterium, halogen, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, =O, - C _0-4 alkyl-SF ₅ , -C _0-4 alkyl-S(O) _r R ₈ , -C _0-4 alkyl-OR ₉ , -C _0-4 alkyl-C(O)OR ₉ , -C _0-4 alkyl-C(O)R ₁₀ , -C _0-4 alkyl-OC(O)R ₁₀ , -C _0-4 alkyl-NR ₁₁ R ₁₂ , -C _0-4 Alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-4 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-4 alkyl-C(O)NR ₁₁ R ₁₂ and -C _0-4 alkyl-N(R ₁₁ )-C(O)R ₁₀ substituent;

   R _7a and R _7b are each independently selected from hydrogen, deuterium, hydroxy, C _1-4 alkyl, -C _0-4 alkyl-C(O)OR ₉ , -C _0-4 alkyl-C(O) R ₁₀ , -C _0-4 alkyl-C(=NR ₁₁ )R ₁₀ and -C _0-4 alkyl-C(O)NR ₁₁ R ₁₂ , or, alternatively, the nitrogen atom to which R _7a and R _7b are directly attached Together to form a 4-8 membered heterocyclic group, the above-mentioned groups are optionally further selected from one or more groups selected from deuterium, halogen, cyano, C _1-4 alkyl, halogen substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl, 5-8 membered heterocycle Aryl, =O, -C _0-4 alkyl-SF ₅ , -C _0-4 alkyl-S(O) _r R ₈ , -C _0-4 alkyl-OR ₉ , -C _0-4 alkane base-C(O)OR ₉ , -C _0-4 alkyl-C(O)R ₁₀ , -C _0-4 alkyl-OC(O)R ₁₀ , -C _0-4 alkyl-NR ₁₁ R ₁₂ , -C _0-4 alkyl-C(=NR ₁₁ )R ₁₀ , -C _0-4 alkyl-N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C _0-4 alkyl- C(O)NR ₁₁ R ₁₂ and the substituents of -C _0-4 alkyl-N(R ₁₁ )-C(O)R ₁₀ ;

   wherein R ₄ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and r are as defined in claim 1 .
3. The compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) has the structure of the compound of formula (IIa) or (IIb) :

   

   Wherein, in the compound of formula (IIa), Y ₁ is NR _6b , O or S; in the compound of formula (IIb), Y ₂ is CR _6a or N;

   Each Ring A is independently a 3-8 membered nitrogen-containing heterocyclic group, and the nitrogen atom is attached to a carbonyl group;

   Each R ₁ is independently selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3 -6-membered heterocyclyl, -SF ₅ , -S(O) _r R ₈ , -OR ₉ , -C(O)OR ₉ , -C(O)R ₁₀ , -OC(O)R ₁₀ , -NR ₁₁ R ₁₂ , -C(=NR ₁₁ )R ₁₀ , -N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C(O)NR ₁₁ R ₁₂ and -N(R ₁₁ )-C(O ) R ₁₀ , the above-mentioned groups are optionally further substituted by one or more groups selected from deuterium, halogen, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, =O, - SF ₅ , -S(O) _r R ₈ , -OR ₉ , -C(O)OR ₉ , -C(O)R ₁₀ , -OC(O)R ₁₀ , -NR ₁₁ R ₁₂ , -C(= Substituents substituted by NR ₁₁ )R ₁₀ , -N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C(O)NR ₁₁ R ₁₂ and -N(R ₁₁ )-C(O)R ₁₀ ;

   Each of R _2a and R _2b is independently selected from hydrogen, deuterium, halogen, cyano, nitro, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, -SF ₅ , -S(O) _r R ₈ , -OR ₉ , -C (O)OR ₉ , -C(O)R ₁₀ , -OC(O)R ₁₀ , -NR ₁₁ R ₁₂ , -C(=NR ₁₁ )R ₁₀ , -N(R ₁₁ )-C(=NR ₁₂ ) R ₁₀ , -C(O)NR ₁₁ R ₁₂ and -N(R ₁₁ )-C(O)R ₁₀ ;

   Each R ₄ is each independently vinyl, and the aforementioned groups are independently optionally further substituted with one or more C 1-4 alkyl groups selected from the group consisting of hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, halogen substituted C _1-4 alkyl , deuterium substituted C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, -C _0-4 alkyl-C(O)OR ₉ , -C _0-4 alkyl-C (O) R ₁₀ , -C _0-4 alkyl-C(O)-NR _7a R _7b and -C _0-4 alkyl-NR _7a R _7b substituents;

   Each R _5a and R _5b is independently selected from hydrogen, deuterium, hydroxy, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, -C(O)OR ₉ , - C(O)R ₁₀ , -C(=NR ₁₁ )R ₁₀ and -C(O)NR ₁₁ R ₁₂ , alternatively, R _5a and R _5b together with the nitrogen atom to which they are directly attached form a 4-6 membered heterocyclyl group , the above-mentioned groups are optionally further selected from one or more groups selected from deuterium, halogen, cyano, C _1-4 alkyl, halogen substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _2-4 Alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, -SF ₅ , -S(O) _r R ₈ , -OR ₉ , -C(O) OR ₉ , -C(O)R ₁₀ , -OC(O)R ₁₀ , -NR ₁₁ R ₁₂ , -C(=NR ₁₁ )R ₁₀ , -N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C(O)NR ₁₁ R ₁₂ and -N(R ₁₁ )-C(O) R ₁₀ substituents;

   R _6a is selected from hydrogen, deuterium, halogen, cyano, nitro, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, -SF ₅ , -S(O) _r R ₈ , -OR ₉ , -C(O)OR ₉ , -C (O)R ₁₀ , -OC(O)R ₁₀ , -NR ₁₁ R ₁₂ , -C(=NR ₁₁ )R ₁₀ , -N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C(O ) NR ₁₁ R ₁₂ and -N(R ₁₁ )-C(O)R ₁₀ ;

   R _6b is selected from the group consisting of hydrogen, deuterium, C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl and 3-6 membered heterocyclyl, the above-mentioned groups are optionally further modified by one or more selected from deuterium, halogen, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, =O, -SF ₅ , -S(O) _r R ₈ , -OR ₉ , -C(O)OR ₉ , -C(O)R ₁₀ , -OC(O)R ₁₀ , -NR ₁₁ R ₁₂ , -C(=NR ₁₁ )R ₁₀ , -N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C(O)NR ₁₁ R ₁₂ and the substituents of -N(R ₁₁ )-C(O)R ₁₀ are substituted;

   Each of R _7a and R _7b is independently selected from hydrogen, deuterium, hydroxy, C _1-4 alkyl, -C(O)OR ₉ , -C(O)R ₁₀ , -C(=NR ₁₁ )R ₁₀ and -C(O)NR ₁₁ R ₁₂ , alternatively, R _7a and R _7b together with the nitrogen atom to which they are directly attached form a 4-6 membered heterocyclic group optionally further substituted by one or more groups selected from deuterium, Halogen, cyano, C _1-4 alkyl, halogen substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, -SF ₅ , -S(O) _r R ₈ , -OR ₉ , -C(O)OR ₉ , -C(O)R ₁₀ , -OC(O) R ₁₀ , -NR ₁₁ R ₁₂ , -C(=NR ₁₁ )R ₁₀ , -N(R ₁₁ )-C(=NR ₁₂ )R ₁₀ , -C(O)NR ₁₁ R ₁₂ and -N(R ₁₁ )-C(O) R ₁₀ is substituted by the substituent;

   wherein R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and r are as defined in claim 1 .
4. The compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof according to claim 3, wherein each ring A is independently:

   
5. The compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1, wherein said compound of formula (I) has the structure of compound of formula (IIIa) or (IIIb) :

   

   Wherein, in the compound of formula (IIIa), Y ₁ is O or S;

   Each R ₁ is independently selected from hydrogen, deuterium, halogen, cyano, C _1-2 alkyl, C _3-4 cycloalkyl, 3-4 membered heterocyclyl, -SF ₅ , -OR ₉ , - C(O)OR ₉ , -C(O)R ₁₀ , -OC(O)R ₁₀ and -NR ₁₁ R ₁₂ , the above-mentioned groups are optionally further selected by one or more groups selected from deuterium, fluorine, chlorine, bromine, Cyano, C _1-2 alkyl, halogen-substituted C _1-2 alkyl, deuterium-substituted C _1-2 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, =O, -SF ₅ , -OR ₉ , -C(O)OR ₉ , -C(O)R ₁₀ , -OC(O)R ₁₀ and -NR ₁₁ R ₁₂ substituents;

   Each of R _2a and R _2b is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, _C1-4 alkyl, halo-substituted _C1-4 alkyl, deuterium substituted _C1-4 alkyl, C _3-6 cycloalkyl, -SF ₅ , -OR ₉ , -C(O)OR ₉ , -C(O)R ₁₀ , -OC(O)R ₁₀ and -NR ₁₁ R ₁₂ ;

   wherein, R ₉ , R ₁₀ , R ₁₁ and R ₁₂ are as described in claim 1 .
6. The compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, wherein each R ₈ is independently selected from hydrogen, deuterium, hydroxyl, C _1-4 alkane group, C _2-4 alkenyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl and -NR ₁₁ R ₁₂ , the above-mentioned groups independently optionally further selected by one or more selected from the group consisting of deuterium, halogen, hydroxyl, oxo, _C1-4 alkyl, _C1-4 alkoxy, _C3-6 cycloalkyl, _C3-6 cycloalkane Oxy group, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C _5-8 aryl, C _5-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy substituted with the substituent of -NR ₁₁ R ₁₂ ;

   Each R ₉ is independently selected from hydrogen, deuterium, C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl and 5-8 membered heteroaryl groups, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, oxo, cyano, C _1-4 alkyl, C _1-4 alkoxy , C _3-6 cycloalkyl, C _3-6 cycloalkoxy, 3-6-membered heterocyclyl, 3-6-membered heterocyclyloxy, C _5-8 aryl, C _5-8 aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy and substituents of -NR ₁₁ R ₁₂ ;

   Each R ₁₀ is independently selected from hydrogen, deuterium, hydroxyl, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 Cycloalkyl, C _3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C _5-8 aryl, C _5-8 aryloxy, 5-8 membered heterocycle Aryl, 5-8 membered heteroaryloxy and -NR ₁₁ R ₁₂ , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C _5-8 aryl, C _{5 -8} -aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy and -NR ₁₁ R ₁₂ substituents;

   Each of R ₁₁ and R ₁₂ is independently selected from hydrogen, deuterium, hydroxyl, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3 -6-membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, amino Sulfonyl, dimethylaminosulfonyl, amino, mono-C _1-4 alkylamino, di-C _1-4 alkylamino and C _1-4 alkanoyl groups, independently optionally further selected by one or more From deuterium, halogen, hydroxyl, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _{1 -4} alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C _5-8 aryl, C _5- Substitution of ₈ -aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy, amino, mono-C _1-4 alkylamino, di-C _1-4 alkylamino and C _1-4 alkanoyl base substituted;

   Alternatively, R ₁₁ and R ₁₂ together with the nitrogen atom to which they are directly attached form a 4-10-membered heterocyclic group or a 5-10-membered heteroaryl group, the 4-10-membered heterocyclic group or the 5-10-membered heteroaryl group being either is further selected from the group consisting of one or more deuterium, halogen, hydroxyl, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C _{5 -8} aryl, C _5-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono-C _1-4 alkylamino, di-C _1-4 alkylamino and Substituents of C _1-4 alkanoyl.
7. The compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 6, wherein each R ₁ is independently selected from hydrogen, deuterium, halogen, cyano, methyl , ethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidine, _-SF5 , methoxy, ethoxy, carboxyl, acetyl, acetoxy, amino, methylamino and Dimethylamino, the above-mentioned groups are optionally further selected by one or more groups selected from the group consisting of deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, propyl, cyclobutyl, oxetanyl, azetidine, =O, _-SF5 , methoxy, ethoxy, carboxyl, acetyl, acetoxy, amino, methylamino and dimethyl Substituted by amino substituent;

   Each R _2a and R _2b is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, Di-deuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidine, _-SF5 , methoxy, ethoxy, carboxyl, acetyl, acetoxy, amino, methylamino and dimethylamino.
8. The compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-7, characterized in that, it is selected from the following compounds:

   

   

   
9. The preparation method of the compound of formula (I) according to any one of claims 1-8, its stereoisomer or its pharmaceutically acceptable salt, comprising the steps:

   

   or,

   

   wherein Rings A, X, Y, R ₁ , R ₂ , R ₃ , R ₄ , R _5a , R _5b , m and n are as defined in claim 1 .
10. A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1-8, a stereoisomer thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
11. The application of the compound of formula (I) described in any one of claims 1-8, its stereoisomer or its pharmaceutically acceptable salt in the preparation of a medicine for the treatment of a tumor patient that is resistant to an FGFR inhibitor , the tumor patient is a tumor patient with a mutation in FGFR V561, V565, N550, N540, V555, E566, K660 and/or V550;

    Preferably, the tumor patient is a tumor patient with FGFR2 V565F, V565I, V565L, V565M, N550K, N550H, E566A, E566G, K660M and/or K660Q mutations;

    Preferably, the tumor patient is a tumor patient with FGFR3 V555M, V555L and/or N540K mutations.
12. The compound of formula (I) described in any one of claim 1-8, its stereoisomer or its pharmaceutically acceptable salt, it is used for preventing or treating tumor or cancer mediated by FGFR kinase, described tumor Or cancer is selected from bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, stomach 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 myeloid leukemia, Hodgkin's lymphoma or non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia disease, hair-like lymphoma, cellular lymphoma, Burkitt lymphoma, glioblastoma, melanoma, or rhabdomyosarcoma.
13. A compound of formula (I) according to any one of claims 1-7, a stereoisomer thereof or a pharmaceutically acceptable salt thereof in preparation for the treatment of myeloproliferative diseases, skeletal or chondrocyte disorders, or hypophosphatemia the application in the medicine; the myeloproliferative disease is selected from polycythemia, essential thrombocythemia or primary myelofibrosis; the bone or chondrocyte disorder is selected from dysplasia, chondrodysplasia, Dwarfism, fatal teratogenicity (TD), Appel's syndrome, Crusson's syndrome, Jackson-Weiss syndrome, Beare-Stevenson dermatoglyphic syndrome, Pfeiffer syndrome, or cranial muscular dystrophy syndrome; The hypophosphatemia is selected from X-linked hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets or tumor-induced ovarian softening.
14. A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-8, for use as a selective FGFR2 and/or FGFR3 inhibitor for the treatment of and FGFR2 Or the use of FGFR3 receptor abnormal expression, mutation or abnormal expression and activity of corresponding ligand related diseases.