CN115867547A

CN115867547A - 1H-pyrazole-4-amide derivative, and preparation method and application thereof

Info

Publication number: CN115867547A
Application number: CN202180047629.XA
Authority: CN
Inventors: 邓海兵; 时亚琼; 喻红平; 陈椎; 徐耀昌
Original assignee: Abbisko Therapeutics Co Ltd
Current assignee: Abbisko Therapeutics Co Ltd
Priority date: 2020-08-27
Filing date: 2021-08-25
Publication date: 2023-03-28
Also published as: WO2022042613A1

Abstract

1H-pyrazole-4-amide derivatives with a structure shown in a formula (I), a preparation method thereof, a pharmaceutical composition containing the derivatives, application of the derivatives as FGFR and mutation inhibitors thereof, application of the derivatives in preparing medicines for treating and/or preventing tumors or cancers at least partially mediated by FGFR kinase and tumor patients with FGFR inhibitors having tolerance, and application in preparing medicines for treating and/or preventing tumor patients with V561, V565, N550, N540, V555, E566, K660 and/or V550 of FGFR signaling pathways having mutation.

Description

1H-pyrazole-4-amide derivative, preparation method and application thereof

Technical Field

The invention belongs to the field of drug synthesis, and particularly relates to a 1H-pyrazole-4-amide derivative, and a preparation method and application thereof.

Background

Fibroblast Growth Factor Receptors (FGFR) are tyrosine kinase receptors that bind to fibroblast growth factor ligands. Currently, 4 FGFR receptors have been found to be able to bind ligands. Fibroblast Growth Factor (FGF) signaling pathways are thought to play important roles in many processes, such as embryogenesis, tissue differentiation, wound healing, metabolic regulation, and are also thought to be strongly associated with many tumor characteristics. When FGF binds to its receptor, the receptor dimerizes and phosphorylates, stimulating activation of protein kinase activity, and facilitates activation of a range of intracellular signaling pathways, including Ras-MAPK, AKT-PI3K, and phosphatase C, which are signaling pathways 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 that have shown clinical responses in clinical trials in patients with FGFR abnormalities, and FGFR inhibitors have recently been approved for marketing. However, in clinical trials it was found that there is a rapid emergence of acquired resistance to FGFR inhibitors, resulting in a relatively short progression-free survival. Mutations that affect FGFR amino acids may cause resistance to or reduce the activity of FGFR inhibitors. The generation of secondary FGFR kinase domain mutations under the action of FGFR inhibitors is an important mechanism for acquiring the resistance to FGFR inhibition. Corresponding FGFR point mutations are also present in tumors. The gate-keeping mutations are reported as one of the major mechanisms for resistance to tyrosine kinases, and FGFR-resistant mutations have been reported in both in vitro cell systems and clinical trials. The gate-keeping mutations include FGFR3V555M, FGFR2V565F/V565I/V565L, and the like. Recent studies reported that the gate-keeping mutation of FGFR2V565F was found in three of the patients with BGJ 398-treated cholangiocarcinoma, two of which had other mutations in other FGFR2 kinase regions. Therefore, to break through the acquired resistance to the first generation of FGFR inhibitor therapy in the clinic, there is an urgent clinical need for new generation FGFR inhibitors that have more durable activity in tumors with genetic mutations in the FGFR signaling pathway. While such second generation FGFR inhibitors need to maintain their inhibitory activity against FGFR, the same activity should be maintained for the gate-keeping mutations that diminish the activity of the first generation inhibitors.

Disclosure of Invention

The inventors of the present application have made extensive and intensive studies and have for the first time developed a 1H-pyrazole-4-amide derivative, a process for producing the same, and use thereof. The series of compounds have good activity on mutant FGFR, particularly on FGFR with gate-conserved mutation, particularly on FGFR3V555M, FGFR2V565I, FGFR2V565F, FGFR2V565L and FGFR2N550K with non-gate-conserved mutation, and are expected to develop a new-generation FGFR inhibitor.

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

wherein, the first and the second end of the pipe are connected with each other,

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 heterocyclyl, said nitrogen atom being attached to a carbonyl group;

R ₁ selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, 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-O-R ₉ 、-C _0-8 alkyl-C (O) OR ₉ 、-C _0-8 alkyl-C (O) R ₁₀ 、-C _0-8 alkyl-O-C (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 Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, halo-substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl radical, 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-O-R ₉ 、-C _0-8 alkyl-C (O) OR ₉ 、-C _0-8 alkyl-C (O) R ₁₀ 、-C _0-8 alkyl-O-C (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 Substituted with the substituent(s);

each R ₂ Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, halo-substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl radical, 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-O-R ₉ 、-C _0-8 alkyl-C (O) OR ₉ 、-C _0-8 alkyl-C (O) R ₁₀ 、-C _0-8 alkyl-O-C (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 ₃ Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, halo-substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl radical, 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-O-R ₉ 、-C _0-8 alkyl-C (O) OR ₉ 、-C _0-8 alkyl-C (O) R ₁₀ 、-C _0-8 alkyl-O-C (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 Selected from ethenyl or ethynyl, independently optionally further substituted by one or more groups selected from hydrogen, deuterium, halogen, cyano, C _1-10 Alkyl, halo-substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl radical, 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 Substituted with the substituent(s);

R _5a and R _5b Each independently selected from hydrogen, deuterium, hydroxy, C _1-10 Alkyl radical, 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 Or, R _5a And R _5b Together with the nitrogen atom to which they are directly attached form a 4-A 10 membered heterocyclic group optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl, halo-substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, 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-O-R ₉ 、-C _0-8 alkyl-C (O) OR ₉ 、-C _0-8 alkyl-C (O) R ₁₀ 、-C _0-8 alkyl-O-C (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 Substituted with the substituent(s);

R _6a selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, halo-substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl radical, 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-O-R ₉ 、-C _0-8 alkyl-C (O) OR ₉ 、-C _0-8 alkyl-C (O) R ₁₀ 、-C _0-8 alkyl-O-C (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 Selected from hydrogen, deuterium, C _1-10 Alkyl radical, C _2-10 Alkenyl radical, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _5-10 Aryl and 5-10 membered heteroaryl, optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, halo-substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl radical, 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-O-R ₉ 、-C _0-8 alkyl-C (O) OR ₉ 、-C _0-8 alkyl-C (O) R ₁₀ 、-C _0-8 alkyl-O-C (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 Substituted with the substituent(s);

R _7a and R _7b 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, R _7a And R _7b Together with the nitrogen atom to which they are directly attached form a 4-to 10-membered heterocyclic group, optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl, halo-substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, 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-O-R ₉ 、-C _0-8 alkyl-C (O) OR ₉ 、-C _0-8 alkyl-C (O) R ₁₀ 、-C _0-8 alkyl-O-C (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 Substituted with the substituent(s);

each R ₈ Each independently selected from hydrogen, deuterium, hydroxy, C _1-10 Alkyl radical, C _2-10 Alkenyl radical, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _5-10 Aryl, 5-10 membered heteroaryl and-NR ₁₁ R ₁₂ The above groups are independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, oxo, C _1-10 Alkyl radical, C _1-10 Alkoxy radical, C _3-12 Cycloalkyl radical, C _3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C _5-10 Aryl radical, C _5-10 Aryloxy, 5-to 10-membered heteroaryl, 5-to 10-memberedHeteroaryloxy and-NR ₁₁ R ₁₂ Substituted with the substituent(s);

each R ₉ Each independently selected from hydrogen, deuterium, C _1-10 Alkyl radical, C _2-10 Alkenyl radical, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _5-10 Aryl and 5-10 membered heteroaryl, independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, cyano, C _1-10 Alkyl radical, C _1-10 Alkoxy radical, C _3-12 Cycloalkyl radical, C _3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C _5-10 Aryl radical, C _5-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and-NR ₁₁ R ₁₂ Substituted with the substituent(s);

each R ₁₀ Each independently selected from hydrogen, deuterium, hydroxy, C _1-10 Alkyl radical, C _1-10 Alkoxy radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, C _3-12 Cycloalkyl radical, C _3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C _5-10 Aryl radical, C _5-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and-NR ₁₁ R ₁₂ The above groups are independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, cyano, C _1-10 Alkyl radical, C _1-10 Alkoxy radical, C _3-12 Cycloalkyl, C _3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C _5-10 Aryl radical, C _5-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and-NR ₁₁ R ₁₂ Substituted with a substituent of (a);

each R ₁₁ And R ₁₂ Each independently selected from hydrogen, deuterium, hydroxy, C _1-10 Alkyl radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _5-10 Aryl, 5-to 10-membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C _1-10 Alkylamino, di-C _1-10 Alkylamino and C _1-10 Alkanoyl, said groups being independently optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, C _1-10 Alkyl radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, halo-substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl radical, C _1-10 Alkoxy radical, C _3-12 Cycloalkyl radical, C _3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C _5-10 Aryl radical, C _5-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono C _1-10 Alkylamino, di-C _1-10 Alkylamino and C _1-10 Substituted by alkanoyl group;

or, R ₁₁ And R ₁₂ Together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclyl or 5-10 membered heteroaryl, said 4-10 membered heterocyclyl or 5-10 membered heteroaryl being optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, C _1-10 Alkyl radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, halo-substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl radical, C _1-10 Alkoxy radical, C _3-12 Cycloalkyl radical, C _3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C _5-10 Aryl radical, C _5-10 Aryloxy, 5-to 10-membered heteroaryl, 5-to 10-membered heteroaryloxy, amino, mono C _1-10 Alkylamino, di-C _1-10 Alkylamino and C _1-10 Substituted by alkanoyl group;

m is 0, 1,2 or 3;

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

Each r is independently 0, 1 or 2.

AsPreferred embodiment, in said compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, R ₁ Selected from hydrogen, deuterium, halogen, cyano, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, 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-O-R ₉ 、-C _0-4 alkyl-C (O) OR ₉ 、-C _0-4 alkyl-C (O) R ₁₀ 、-C _0-4 alkyl-O-C (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 Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, halo-substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl radical, 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-O-R ₉ 、-C _0-4 alkyl-C (O) OR ₉ 、-C _0-4 alkyl-C (O) R ₁₀ 、-C _0-4 alkyl-O-C (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 Substituted with a substituent of (a);

each R ₂ Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, halo-substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl radical, 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-O-R ₉ 、-C _0-4 alkyl-C (O) OR ₉ 、-C _0-4 alkyl-C (O) R ₁₀ 、-C _0-4 alkyl-O-C (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 ₃ Each independently selected from hydrogen, deuterium, halogen, cyano, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, halo-substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl radical, 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-O-R ₉ 、-C _0-4 alkyl-C (O) OR ₉ 、-C _0-4 alkyl-C (O) R ₁₀ 、-C _0-4 alkyl-O-C (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 Each independently selected from hydrogen, deuterium, hydroxy, C _1-4 Alkyl radical, 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, or 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 deuterium, halogen, cyano, C _1-4 Alkyl, halo-substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl radical, C _2-4 Alkenyl radical, 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-O-R ₉ 、-C _0-4 alkyl-C (O) OR ₉ 、-C _0-4 alkyl-C (O) R ₁₀ 、-C _0-4 alkyl-O-C (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 Substituted with a substituent of (a);

R _6a selected from hydrogen, deuterium, halogen, cyano, nitro, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, halo-substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl radical, 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-O-R ₉ 、-C _0-4 alkyl-C (O) OR ₉ 、-C _0-4 alkyl-C (O) R ₁₀ 、-C _0-4 alkyl-O-C (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 Selected from hydrogen, deuterium, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _5-8 Aryl and 5-8 membered heteroaryl, optionally further substituted by one or more groups selected from deuterium, halogen, cyano, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, halo-substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl radical, 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-O-R ₉ 、-C _0-4 alkyl-C (O) OR ₉ 、-C _0-4 alkyl-C (O) R ₁₀ 、-C _0-4 alkyl-O-C (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 Substituted with the substituent(s);

R _7a and R _7b 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, R _7a And R _7b 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 deuterium, halogen, cyano, C _1-4 Alkyl, halo-substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl radical, C _2-4 Alkenyl radical, 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-O-R ₉ 、-C _0-4 alkyl-C (O) OR ₉ 、 -C _0-4 alkyl-C (O) R ₁₀ 、-C _0-4 alkyl-O-C (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 Substituted with the substituent(s);

wherein R is ₈ 、R ₉ 、R ₁₀ 、R ₁₁ 、R ₁₂ And r is as defined for compounds of formula (I).

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

wherein, in the compound of formula (IIa), Y ₁ Is NR _6b O or S; in the compounds of formula (IIb), Y ₂ Is CR _6a Or N;

each ring A is independently a 3-8 membered nitrogen containing heterocyclyl group, the nitrogen atom being attached to a carbonyl group;

each R ₁ Each independently selected from hydrogen, deuterium, halogen, cyano, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, -SF ₅ 、-S(O) _r R ₈ 、-O-R ₉ 、-C(O)OR ₉ 、-C(O)R ₁₀ 、-O-C(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 Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, halo-substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl radical, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _5-8 Aryl, 5-8 membered heteroaryl, = O, -SF ₅ 、-S(O) _r R ₈ 、-O-R ₉ 、-C(O)OR ₉ 、-C(O)R ₁₀ 、-O-C(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 Substituted with the substituent(s);

each R _2a And R _2b Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, halo-substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl radical, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, -SF ₅ 、-S(O) _r R ₈ 、-O-R ₉ 、-C(O)OR ₉ 、-C(O)R ₁₀ 、-O-C(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 Each independently being a vinyl group, said groups independently optionally being further substituted by one or more groups selected from hydrogen, deuterium, halogen, cyano, C _1-4 Alkyl, halo-substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl radical, 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 Substituent(s) ofSubstituted;

each R _5a And R _5b Each independently selected from hydrogen, deuterium, hydroxy, C _1-4 Alkyl radical, 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 Or, R _5a And R _5b 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, halo-substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, -SF ₅ 、-S(O) _r R ₈ 、-O-R ₉ 、-C(O)OR ₉ 、-C(O)R ₁₀ 、-O-C(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 Substituted with the substituent(s);

R _6a selected from hydrogen, deuterium, halogen, cyano, nitro, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, halo-substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl radical, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, -SF ₅ 、-S(O) _r R ₈ 、-O-R ₉ 、-C(O)OR ₉ 、-C(O)R ₁₀ 、-O-C(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 Selected from hydrogen, deuterium, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _3-6 Cycloalkyl and 3-6 membered heterocyclyl, optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, halo-substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl radical, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, = O, -SF ₅ 、-S(O) _r R ₈ 、-O-R ₉ 、-C(O)OR ₉ 、-C(O)R ₁₀ 、-O-C(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 Substituted with the substituent(s);

each R _7a And R _7b Each 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 Or, 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, halo-substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, -SF ₅ 、-S(O) _r R ₈ 、-O-R ₉ 、-C(O)OR ₉ 、-C(O)R ₁₀ 、-O-C(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 Substituted with the substituent(s);

wherein R is ₄ 、R ₈ 、R ₉ 、R ₁₀ 、R ₁₁ 、R ₁₂ And r is as defined for compounds of formula (I).

As a still further preferred embodiment, in the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, each ring a is independently:

as a still further preferred embodiment, the compound of formula (I) is a compound of formula (IIIa) or (IIIb):

wherein, in the compound of formula (IIIa), Y ₁ Is O or S;

each R ₁ Each independently selected from hydrogen, deuterium, halogen, cyano, C _1-2 Alkyl radical, C _3-4 Cycloalkyl, 3-4 membered heterocyclyl, -SF ₅ 、-O-R ₉ 、-C(O)OR ₉ 、-C(O)R ₁₀ 、-O-C(O)R ₁₀ and-NR ₁₁ R ₁₂ The above groups are optionally further substituted by one or more groups selected from deuterium, fluoro, chloro, bromo, cyano, C _1-2 Alkyl, halo-substituted C _1-2 Alkyl, deuterium substituted C _1-2 Alkyl radical, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, = O, -SF ₅ 、-O-R ₉ 、-C(O)OR ₉ 、-C(O)R ₁₀ 、-O-C(O)R ₁₀ and-NR ₁₁ R ₁₂ Substituted with the substituent(s);

each R _2a And R _2b Each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C _1-4 Alkyl, halo-substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl radical, C _3-6 Cycloalkyl, -SF ₅ 、-O-R ₉ 、-C(O)OR ₉ 、-C(O)R ₁₀ 、-O-C(O)R ₁₀ and-NR ₁₁ R ₁₂ ；

Wherein R is ₉ 、R ₁₀ 、R ₁₁ And R ₁₂ As defined for the compounds of formula (I).

As a further preferred embodiment, in the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, each R is ₈ Each independently selected from hydrogen, deuterium, hydroxy, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, 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 independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, oxo, C _1-4 Alkyl radical, C _1-4 Alkoxy radical, C _3-6 Cycloalkyl radical, C _3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C _5-8 Aryl radical, C _5-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR ₁₁ R ₁₂ Substituted with the substituent(s);

each R ₉ Each independently selected from hydrogen, deuterium, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _5-8 Aryl and 5-8 membered heteroaryl, independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, cyano, C _1-4 Alkyl radical, C _1-4 Alkoxy radical, C _3-6 Cycloalkyl radical, C _3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C _5-8 Aryl radical, C _5-8 Aryloxy radical5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR ₁₁ R ₁₂ Substituted with the substituent(s);

each R ₁₀ Each independently selected from hydrogen, deuterium, hydroxy, C _1-4 Alkyl radical, C _1-4 Alkoxy radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Cycloalkyl radical, C _3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy, C _5-8 Aryl radical, C _5-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR ₁₁ R ₁₂ The above groups are independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, cyano, C _1-4 Alkyl radical, C _1-4 Alkoxy radical, C _3-6 Cycloalkyl radical, C _3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy, C _5-8 Aryl radical, C _5-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR ₁₁ R ₁₂ Substituted with the substituent(s);

each R ₁₁ And R ₁₂ Each independently selected from hydrogen, deuterium, hydroxy, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, 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, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C _1-4 Alkylamino, di-C _1-4 Alkylamino and C _1-4 Alkanoyl, said groups being independently optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, halo-substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl radical, C _1-4 Alkoxy radical, C _3-6 Cycloalkyl radical, C _3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C _5-8 Aryl radicals、C _5-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono C _1-4 Alkylamino, di-C _1-4 Alkylamino and C _1-4 Substituted by alkanoyl group;

or, R ₁₁ And R ₁₂ Together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclyl or 5-10 membered heteroaryl, said 4-10 membered heterocyclyl or 5-10 membered heteroaryl being optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, halo-substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl radical, C _1-4 Alkoxy radical, C _3-6 Cycloalkyl radical, C _3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy, C _5-8 Aryl radical, C _5-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono C _1-4 Alkylamino, di-C _1-4 Alkylamino and C _1-4 Substituted by alkanoyl group.

As a still further preferred embodiment, in said compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, each R is ₁ Each independently selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, -SF ₅ Methoxy, ethoxy, carboxyl, acetyl, acetoxy, amino, methylamino and dimethylamino, optionally further substituted with one or more groups selected from deuterium, fluoro, chloro, bromo, cyano, methyl, ethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, = O, -SF ₅ Methoxy, ethoxy, carboxyl, acetyl, acetoxy, amino, methylamino, and dimethylamino;

each R _2a And R _2b Each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trifluoromethyl, and mixtures thereof,Trideuteromethyl, dideuterylmethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, -SF ₅ Methoxy, ethoxy, carboxyl, acetyl, acetoxy, amino, methylamino and dimethylamino.

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

in a second aspect, the present invention provides a process for the preparation of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the steps of:

alternatively, the first and second electrodes may be,

wherein, the ring A, X, Y, R ₁ 、R ₂ 、R ₃ 、R ₄ 、R _5a 、R _5b M and n are as defined for compounds of formula (I).

In a third aspect, 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 invention also relates to the use of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a patient suffering from a tumour which is resistant to FGFR inhibitors.

As a preferred approach, the tumor patient is a tumor patient having a mutation in FGFR V561, V565, N550, N540, V555, E566, K660 and/or V550;

as a further preferred approach, the tumor patient is preferred, said tumor patient being a tumor patient having FGFR2V565F, V565I, V565L, V565M, N550K, N550H, E566A, E566G, K M and/or K660Q mutations;

as a still further preferred embodiment, the tumor patient is a tumor patient having a mutation in FGFR3V555M/L and/or N540K.

The invention also relates to compounds of formula (I), stereoisomers thereof or pharmaceutically acceptable salts thereof, for use in the prevention or treatment of a disease state or condition mediated by a FGFR kinase.

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 a tumor or cancer mediated by a FGFR kinase.

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

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

The invention also relates to said myeloproliferative disease is selected from erythrocytosis, primary thrombocythemia or primary myelofibrosis; said skeletal or chondrocyte disorder is selected from dysplasia, achondroplasia, dwarfism, lethal Teratocarcinosis (TD), alpeller's syndrome, kluyverson's syndrome, jackson-Weiss syndrome, beare-Stevenson dermatofret syndrome, pfeiffer syndrome or cranial muscle atrophy syndrome; the hypophosphatemia is selected from X-linked hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets or oophormalacia induced by tumors.

The invention also relates to a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the selective FGFR2 and/or FGFR3 inhibitor for the treatment of diseases associated with aberrant expression, mutation or aberrant expression and activity of FGFR2 or FGFR3 receptors.

The present invention also relates to a method of treating a patient having a tumor that is resistant to 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 invention also relates to a method of treating a patient with a tumor having mutations in FGFR2V565F, V565I, V565L, V565M, N K, N H, E566A, E566 zxft 3432 660M and/or K660Q comprising administering to a patient in need thereof a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

Detailed Description

The inventors of the present application have made extensive and intensive studies and have for the first time developed a 1H-pyrazole-4-amide derivative, a method for preparing the same and use thereof. The series of compounds disclosed by the invention have good activity on mutant FGFR, particularly on FGFR with gate-keeping mutation, particularly on FGFR3V555M, FGFR2V565I, FGFR2V565F, FGFR2V565L and FGFR2N550K mutation.

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

<xnotran> "" , 1 10 1 6 1 4 , , , , , , , , , , 4984 zxft 4984- , 5272 zxft 5272- , 7945 zxft 7945- ,1- ,2- ,3- , ,1- -2- , 3272 zxft 3272- , 3424 zxft 3424- , 3535 zxft 3535- , 3584 zxft 3584- , 4284 zxft 4284- ,2- ,2- ,3- ,4- , 5325 zxft 5325- , ,2- ,3- ,4- ,5- , 5623 zxft 5623- , 6262 zxft 6262- , 3256 zxft 3256- , 3456 zxft 3456- ,2- ,3- , , 3838 zxft 3838- , 5749 zxft 5749- , 6595 zxft 6595- , 6898 zxft 6898- , 3428 zxft 3428- , 3476 zxft 3476- ,2- ,3- ,4- ,2- -2- ,2- -3- . </xnotran> "C _1-10 Alkyl "refers to straight and branched alkyl groups containing 1 to 10 carbon atoms," C _1-4 Alkyl "refers to straight and branched alkyl groups comprising 1 to 4 carbon atoms," C _1-2 Alkyl "refers to straight chain and branched alkyl groups comprising 1 to 2 carbon atoms," C _0-8 Alkyl "refers to straight and branched alkyl groups comprising from 0 to 8 carbon atoms," C _0-4 Alkyl "refers to straight and branched chain alkyl groups containing from 0 to 4 carbon atoms," C _0-2 Alkyl "refers to straight chain alkyl and branched chain containing alkyl groups comprising from 0 to 2 carbon atoms.

Alkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, halo-substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl radical, 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-O-R ₉ 、-C _0-8 alkyl-C (O) OR ₉ 、-C _0-8 alkyl-C (O) R ₁₀ 、-C _0-8 alkyl-O-C (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 Substituted with the substituent(s).

"cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, by which is meant a cyclic hydrocarbon which may contain one or more (preferably 1,2 or 3) double bonds, but none of the rings have a fully conjugated pi-electron system, and is classified as monocyclic cycloalkyl, polycyclic cycloalkyl, preferably cycloalkyl containing from 3 to 12 or from 3 to 8 or from 3 to 6 carbon atoms, e.g., "C _3-12 Cycloalkyl "refers to a cycloalkyl group comprising 3 to 12 carbon atoms," C _3-8 Cycloalkyl "refers to a cycloalkyl group comprising 3 to 8 carbon atoms," C _3-6 Cycloalkyl "refers to a cycloalkyl group comprising 3 to 6 carbon atoms," C _3-4 Cycloalkyl "refers to a cycloalkyl group including 3 to 4 carbon atoms, wherein:

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

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

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

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

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

Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, halo-substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl radical, 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-O-R ₉ 、-C _0-8 alkyl-C (O) OR ₉ 、-C _0-8 alkyl-C (O) R ₁₀ 、-C _0-8 alkyl-O-C (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 Substituted with the substituent(s).

"Heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which 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 pi-electron system, and heterocyclyl, 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 (wherein r is an integer 0, 1, 2) heteroatoms, but not the ring moiety of-O-O-, -O-S-or-S-S-, the remaining ring atoms being carbon, preferably a heterocyclyl comprising 3 to 12 or 3 to 8 or 3 to 6 ring atoms, e.g. "3-4 membered heterocyclyl" means a cyclic group comprising 3 to 4 ring atoms, "4-6 membered heterocyclyl" means a cyclic group comprising 4 to 6 ring atoms, "3-6 membered heterocyclyl" means a heterocyclic group comprisingA cyclic group containing 3 to 6 ring atoms, "3-8 membered heterocyclic group" means a cyclic group containing 3 to 8 ring atoms, "3-12 membered heterocyclic group" means a cyclic group containing 3 to 12 ring atoms, "4-8 membered heterocyclic group" means a cyclic group containing 4 to 8 ring atoms, and "4-10 membered heterocyclic group" means a cyclic 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 heterocyclic groups include spiro, fused, and bridged heterocyclic groups. "spiroheterocyclyl" refers to polycyclic heterocyclic groups having a single ring with one atom in common (referred to as a spiro atom), wherein one or more (preferably 1,2, 3, or 4) ring atoms are selected from nitrogen, oxygen, S (O) (= NH), or S (O) _r (wherein r is an integer of 0, 1, 2) and the remaining ring atoms are carbon. These may contain one or more double bonds (preferably 1,2 or 3), but none of the rings has a completely conjugated pi-electron system. Spiro heterocyclic groups are classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group, or a multi-spiro heterocyclic group according to the number of spiro atoms shared between rings. Spiroheterocyclyl groups include, but are not limited to:

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

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

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

the heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, halo-substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl radical, 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-O-R ₉ 、-C _0-8 alkyl-C (O) OR ₉ 、-C _0-8 alkyl-C (O) R ₁₀ 、-C _0-8 alkyl-O-C (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 Substituted with the substituent(s).

"aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group, a polycyclic (i.e., rings which carry adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably an all-carbon aryl group containing 5 to 10 or 5 to 8 carbons, e.g., "C _5-10 Aryl "means an all-carbon aryl group containing 5 to 10 carbons," C _5-8 Aryl "refers to all-carbon aryl groups containing 5 to 8 carbons, including but not limited to phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, including but not limited to:

"aryl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, halo-substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl radical, 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 radical-O-R ₉ 、-C _0-8 alkyl-C (O) OR ₉ 、-C _0-8 alkyl-C (O) R ₁₀ 、-C _0-8 alkyl-O-C (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 Substituted with the substituent(s).

"heteroaryl" refers to a heteroaromatic system containing one or more (preferably 1,2, 3, or 4) heteroatoms including nitrogen, oxygen, and S (O) r (where r is an integer 0, 1, 2), preferably a heteroaromatic system containing 5 to 10 or 5 to 8 or 5 to 6 ring atoms, e.g., "5-8 membered heteroaryl" refers to a heteroaromatic system containing 5 to 8 ring atoms, "5-10 membered heteroaryl" refers to a heteroaromatic system containing 5 to 10 ring atoms, including but not limited to furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, including, but not limited to:

"heteroaryl" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, halo-substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl radical, 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-O-R ₉ 、-C _0-8 alkyl-C (O) OR ₉ 、-C _0-8 alkyl-C (O) R ₁₀ 、-C _0-8 alkyl-O-C (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 Substituted with a substituent (b).

"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 to 10 or 2 to 4 carbons, e.g., "C _2-10 Alkenyl "means a straight or branched chain alkenyl group having 2 to 10 carbons," C _2-4 Alkenyl "means a straight or branched chain alkenyl group containing 2 to 4 carbons. Including but not limited to ethenyl, 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) groups independently selected from deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, halo-substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl radical, 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-O-R ₉ 、-C _0-8 alkyl-C (O) OR ₉ 、-C _0-8 alkyl-C (O) R ₁₀ 、-C _0-8 alkyl-O-C (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 Substituted with the substituent(s).

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

"alkynyl" groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, halo-substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl radical, 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-O-R ₉ 、-C _0-8 alkyl-C (O) OR ₉ 、 -C _0-8 alkyl-C (O) R ₁₀ 、-C _0-8 alkyl-O-C (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 Substituted with the substituent(s).

"alkoxy" means an-O-alkyl group wherein the alkyl group is as defined above, e.g., "C _1-10 Alkoxy "means an alkyloxy group having 1 to 10 carbons, C _1-4 Alkoxy "means an alkyloxy group containing 1 to 4 carbons including but not limited to methoxy, ethoxy, propoxy, butoxy, and the like.

An "alkoxy" group may be optionally substituted or unsubstituted, and when substituted, the substituents, preferably one or more (preferably 1,2, 3 or 4) groups, are independently selected from deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, halo-substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl radical, 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-O-R ₉ 、-C _0-8 alkyl-C (O) OR ₉ 、-C _0-8 alkyl-C (O) R ₁₀ 、-C _0-8 alkyl-O-C (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 Substituted with the substituent(s).

"Cycloalkoxy" means an-O-cycloalkyl group in which the cycloalkyl group is as defined aboveFor example, "C _3-12 Cycloalkoxy "means a cycloalkyloxy group having 3 to 12 carbons," C _3-6 Cycloalkoxy "refers to cycloalkyloxy groups of 3-6 carbons, including but not limited to cyclopropyloxy, cyclobutyloxy, 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) groups independently selected from deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, halo-substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl radical, 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-O-R ₉ 、-C _0-8 alkyl-C (O) OR ₉ 、-C _0-8 alkyl-C (O) R ₁₀ 、-C _0-8 alkyl-O-C (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 Substituted with a substituent (b).

"heterocyclyloxy" refers to-O-heterocyclyl, wherein heterocyclyl is defined above, heterocyclyloxy including, but not limited to, azetidinyloxy, oxetanyloxy, cyclopentyloxy, nitrogen, oxacyclohexyloxy, and the like.

"heterocyclyloxy" may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitroAzido group, C _1-10 Alkyl radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, halo-substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl radical, 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-O-R ₉ 、-C _0-8 alkyl-C (O) OR ₉ 、-C _0-8 alkyl-C (O) R ₁₀ 、-C _0-8 alkyl-O-C (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 Substituted with a substituent (b).

“C _1-10 Alkanoyl "means C _1-10 The monovalent radical remaining after removal of the hydroxyl group from the alkyl acid, also commonly referred to as "C _0-9 -C (O) - ", e.g.," C ₁ -C (O) - "means acetyl; "C ₂ -C (O) - "refers to propionyl; "C ₃ -C (O) - "means butyryl or isobutyryl.

“-C _0-8 alkyl-S (O) _r R ₈ "finger-S (O) _r R ₈ With sulfur atoms bound to C _0-8 On the alkyl radical, wherein C _0-8 The alkyl group is as defined above.

“-C _0-8 alkyl-O-R ₉ "means-O-R ₉ In which the oxygen atom is bound to C _0-8 On the alkyl radical, wherein C _0-8 The alkyl group is as defined above.

“-C _0-8 alkyl-C (O))OR ₉ "refers to-C (O) OR ₉ Wherein the carbonyl group is bound to C _0-8 On the alkyl radical, wherein C _0-8 The alkyl group is as defined above.

“-C _0-8 alkyl-C (O) R ₁₀ "means-C (O) R ₁₀ Wherein the carbonyl group is bound to C _0-8 On the alkyl radical, wherein C _0-8 The alkyl group is as defined above.

“-C _0-8 -O-C(O)R ₁₀ "means-O-C (O) R ₁₀ In which the oxygen atom is bound to C _0-8 On the alkyl radical, wherein C _0-8 The alkyl group is as defined above.

“-C _0-8 -NR ₁₁ R ₁₂ "means-NR ₁₁ R ₁₂ In which the nitrogen atom is bound to C _0-8 On the alkyl radical, wherein C _1-8 The alkyl group is as defined above.

“-C _0-8 -C(＝NR ₁₁ )R ₁₀ "means-C (= NR) ₁₁ )R ₁₀ In which the nitrogen atom is bound to C _0-8 On the alkyl radical, wherein C _0-8 The alkyl group is as defined above.

“-C _0-8 -N(R ₁₁ )-C(＝NR ₁₂ )R ₁₀ "means-N (R) ₁₁ )-C(＝NR ₁₂ )R ₁₀ In which the nitrogen atom is bound to C _0-8 On the alkyl radical, wherein C _0-8 The alkyl group is as defined above.

“-C _0-8 -C(O)NR ₁₁ R ₁₂ "means-C (O) NR ₁₁ R ₁₂ Wherein the carbonyl group is bound to C _0-8 On the alkyl radical, wherein C _0-8 The alkyl group is as defined above.

“-C _0-8 -N(R ₁₁ )-C(O)R ₁₀ "means-N (R) ₁₁ )-C(O)R ₁₀ In which the nitrogen atom is bound to C _0-8 On the alkyl radical, wherein C _0-8 The alkyl group is as defined above.

"halogen substituted C _1-10 Alkyl "refers to a 1-10C alkyl group optionally substituted with fluorine, chlorine, bromine, iodine atoms for the hydrogen on the alkyl group, including but not limited to difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, and the like.

"halogen substituted C _1-10 Alkoxy "refers to a 1-10 carbon alkoxy group wherein the hydrogen on the alkyl group is optionally substituted with fluorine, chlorine, bromine, or iodine atoms. Including but not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, and the like.

"deuterium substituted C _1-10 Alkyl "refers to a 1-10 carbon alkyl group optionally substituted with deuterium atoms for the hydrogen on the alkyl group. Including but not limited to mono-deuteromethyl, dideuteromethyl, trideuteromethyl, and the like.

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

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

"stereoisomers", which are known under the name stereooisomers in the English language, refer to isomers resulting from the different arrangement of atoms in a molecule in space, and can be divided into cis-trans isomers, enantiomers, and enantiomers and diastereomers. Stereoisomers resulting from rotation of single bonds are called conformational isomers (conformational stereo-isomers) and sometimes rotamers (rotamers). Stereoisomers caused by bond length, bond angle, double bond in a molecule, ring and the like are called configurational isomers (configurational isomers), and the configurational isomers are divided into two types. Wherein the isomer caused by the non-free rotation of the double bond or the single bond of the ring-forming carbon atom becomes geometrical isomer (cis-trans isomer), also called cis-trans isomer, and is divided into two configurations Z, E. For example: cis-2-butene and trans-2-butene are a pair of geometric isomers, and stereoisomers with different optical rotation properties due to lack of trans-axial symmetry in the molecule are called optical isomers (optical isomers), and are classified into R, S configuration. In the present invention, the term "stereoisomer" is understood to include one or more of the above-mentioned enantiomers, configurational isomers and conformational isomers, unless otherwise specified.

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

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

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

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

The LC-MS was measured using an Agilent 6120 mass spectrometer. HPLC was carried out using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18X 4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18X 4.6mm column).

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

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

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

1. Preparation of intermediates

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

The first step is as follows: synthesis of 2-cyclopropyl-6,8-difluoro-7-iodoimidazo [1,2-a ] pyridine

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

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

2-cyclopropyl-6,8-difluoro-7-iodoimidazo [1,2-a]Pyridine (320mg, 1.0mmol) was dissolved in DMF (5 mL), and tributyl (ethynyl) stannane (472mg, 1.5mmol) and tetratriphenylphosphine palladium (115.5mg, 0.1mmol) were added. The mixture was stirred for 1 hour at 130 ℃ by microwave. Cooling to room temperature, concentrating, and separating 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 is as follows: synthesis of 2-cyclopropyl-6-fluoro-7-iodoimidazo [1,2-a ] pyridine

5-fluoro-4-iodopyridin-2-amine (2.38g, 10.0 mmol) was dissolved in DMF (20 mL) and 2-bromo-1-cyclopropylethane-1-one (2.44g, 15.0 mmol) was added. The mixture was stirred at 60 ℃ for 16 hours. Cooling to room temperature, filtering 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 (540mg, 2.0 mmol) was dissolved in DMF (10 mL), and tributyl (ethynyl) stannane (1260mg, 4.0 mmol) and tetratriphenylphosphine palladium (116mg, 0.10 mmol) were added. The mixture was stirred at 60 ℃ for 16 hours. Cooling to room temperature, concentrating, and separating by column chromatography to obtain 2-cyclopropyl-7-ethynyl-6-fluoroimidazo [1,2-a]Pyridine (140 mg, yield: 40%). MS m/z (ESI): 175[ deg. ] M + H] ⁺ 。

Intermediate 3 was prepared by selecting the corresponding starting materials in reference to the full or partial synthesis of intermediate 2:

intermediate 4: preparation of 2-cyclopropyl-5-ethynylbenzo [ d ] oxazole

The first step is as follows: synthesis of N- (5-bromo-2-hydroxyphenyl) cyclopropanecarboxamide

2-amino-4-bromophenol (2.0g, 10.6mmol) was dissolved in DCM (30 mL), and triethylamine (1.29g, 12.8mmol) and cyclopropylcarbonyl chloride (1.11g, 10.6mmol) were added in this order at 0 ℃. The mixture was stirred at 0 ℃ for 1 hour, diluted with aqueous sodium bicarbonate and extracted with DCM, the organic phase was washed with brine, dried over anhydrous sodium sulfate, concentrated and isolated by column chromatography to give N- (5-bromo-2-hydroxyphenyl) cyclopropanecarboxamide (1.34 g)The yield is as follows: 49%). MS m/z (ESI) 256/258[ m ] +H] ⁺ 。

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

N- (5-bromo-2-hydroxyphenyl) cyclopropanecarboxamide (1.04g, 4.06mmol) was dissolved in acetonitrile (30 mL), and triphenylphosphine (4.26g, 16.2mmol) and carbon tetrachloride (1.25g, 8.1mmol) were added in this order at room temperature. Stirring the mixture at 60 deg.C for 1 hr, diluting with water, extracting with ethyl acetate, washing the organic phase with saturated brine, drying over anhydrous sodium sulfate, concentrating, and separating by column chromatography to obtain 5-bromo-2-cyclopropylbenzo [ d]Oxazole (548 mg, yield: 55%). MS m/z (ESI) 238/240[ 2/M ] +H] ⁺ 。

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

Reacting 5-bromo-2-cyclopropylbenzo [ d ]]Oxazole (200mg, 0.84mmol) was placed in DMF (3 mL) and triethylamine (1 mL), cuprous iodide (1695g, 0.084mmol), trimethylsilylacetylene (825mg, 8.4mmol), tetrakistriphenylphosphine palladium (49mg, 0.042mmol) were added sequentially at room temperature. The mixture was stirred at 80 ℃ for 16 hours, diluted with water and extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and subjected to column chromatography to give 2-cyclopropyl-5- ((trimethylsilyl) ethynyl) benzo [ d]Oxazole (204 mg, yield: 95%). MS m/z (ESI) 256[ 2 ], [ M ] +H] ⁺ 。

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

2-cyclopropyl-5- ((trimethylsilyl) ethynyl) benzo [ d]Oxazole (204mg, 0.8 mmol) was dissolved in methanol (8 mL), potassium carbonate (1.1g, 8 mmol) was added at room temperature, 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, dried over anhydrous sodium sulfate, concentrated and subjected to column chromatography to give 2-cyclopropyl-5-ethynylbenzo [ d]Oxazole (112 mg, yield: 76%). MS m/z (ESI) 184[ 2 ], [ M ] +H] ⁺ 。

Intermediates 5 to 8 were prepared by selecting the corresponding starting materials in reference to the full or partial synthesis of intermediate 4:

intermediate 9: preparation of 2-cyclopropyl-5-ethynyl-6-fluorobenzo [ d ] thiazole

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

5-bromo-2,4-difluoroaniline (1.04g, 5.0mmol) was dissolved in dichloromethane (20 mL), cyclopropylchloride (572mg, 5.5 mmol) was added, the mixture was stirred at room temperature overnight, directly dried by spin-drying and then subjected to column chromatography to give N- (5-bromo-2,4-difluorophenyl) cyclopropylamide (1.0 g, yield: 72%). MS m/z (ESI) 276/278[ m ] +H] ⁺ 。

The second step is that: synthesis of N- (5-bromo-2,4-difluorophenyl) cyclopropylmethionine amide

N- (5-bromo-2,4-difluorophenyl) cyclopropanecarboxamide (1.0g, 3.6 mmol), lawson's reagent (750mg, 1.85mmol) was dissolved in acetonitrile (25 mL), heated to 85 ℃ and stirred overnight. The N- (5-bromo-2,4-difluorophenyl) cyclopropylmethionine amide solution was used directly after the reaction was complete for 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 (1.7g, 18mmol) was added to the cooled solution of N- (5-bromo-2,4-difluorophenyl) cyclopropylmethionine and the mixture was heated to 50 ℃ and stirred for 16 hours. Concentrating, and separating by column chromatography to obtain 5-bromo-2-cyclopropyl-6-fluorobenzo [ d]Thiazole (0.82 g, yield: 83%). MS m/z (ESI) 2712/274[ m ] +H] ⁺ 。

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

Reacting 5-bromo-2-cyclopropyl-6-fluorobenzo [ d]Thiazole (0.82g, 3.0 mmol) was dissolved in DMF (15 mL), tributyl (ethynyl) stannane (1.9g, 6.0 mmol) and tetratriphenylphosphine palladium (173mg, 0.15mmol) were added and stirred in a microwave reactor at 130 ℃ for 0.5 h. Concentrating, and separating by column chromatography to obtain 2-cyclopropyl-5-ethynyl-6-fluorobenzo [ d]Thiazole (0.16 g, yield: 25%). MS m/z (ESI): 218[ m ] +H] ⁺ 。

Intermediates 10-14 were prepared by selecting the corresponding starting materials in reference to the full or partial synthesis of intermediate 9:

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

The first step is as follows: synthesis of N- (2,4-difluorophenyl) cyclopropanecarboxamide

2,4-difluoroaniline (10g, 77.45mmol) was dissolved in dichloromethane (100 mL), triethylamine (15.64g, 154.9mmol) was added, and cyclopropylcarbonyl chloride (8.1g, 77.45mmol) was added dropwise under ice bath and stirred at room temperature overnight. The reaction mixture was washed with an appropriate amount of a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution, respectively, dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel column chromatography to give N- (2,4-difluorophenyl) cyclopropanecarboxamide (10.1 g, yield: 66%). MS m/z (ESI): 196[ 2 ], [ M ] +H] ⁺ 。

The second step is that: synthesis of N- (2,4-difluorophenyl) cyclopropylmethionine amide

N- (2,4-difluorophenyl) cyclopropanecarboxamide (5g, 25.36mmol) was dissolved in xylene (80 mL), lawson's reagent (7.18g, 17.75mmol) was added, heated to 120 ℃ and stirred overnight. After concentration, the extract was subjected to direct silica gel column chromatography to give N- (2,4-difluorophenyl) cyclopropylmethionine amide (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) cyclopropylmethionine amide (1g, 4.69mmol) was dissolved in sodium hydroxide solution (1.69g, 42.2mmol,5mL ethanol and 10mL water) and the resulting solution was added dropwise to K preheated to 90 deg.C ₃ Fe(CN) ₆ Stirring in water solution (6.18g, 18.78mmol,10mL water) for 2 hr, stopping heating, cooling, adjusting to weak acidity with concentrated hydrochloric acid, extracting with ethyl acetate, washing the obtained extract with saturated saline, concentrating, and separating with silica gel column chromatography to obtain 2-cyclopropyl-4,6-difluorobenzo [ d ] c]Thiazole (500 mg, yield: 51%). MS m/z (ESI): 212[ m ] +H] ⁺ 。

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

2-cyclopropyl-4,6-difluorobenzo [ d]Thiazole (980mg, 4.64mmol) was dissolved in tetrahydrofuran (15 mL) and cooled to-70 ℃, LDA (2.55mL, 5.10mmol, 2M) was added thereto, after maintaining the temperature for 2 hours, DMF (1.01g, 13.92mmol) was added thereto, after maintaining the temperature for 2 hours, LCMS was added to monitor completion of the reaction, an appropriate amount of ammonium chloride aqueous solution was added to quench the reaction and warm to room temperature, the reaction solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated, and subjected to silica gel column chromatography to give 2-cyclopropyl-4,6-difluorobenzo [ d ] benzo]Thiazole-5-carbaldehyde (675 mg, yield: 65%). MS m/z (ESI): 240[ m ] +H] ⁺ 。

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

2-cyclopropyl-4,6-difluorobenzo[d]Thiazole-5-carbaldehyde (122mg, 0.51mmol) was dissolved in methanol (10 mL), and potassium carbonate (211mg, 1.53mmol) and (1-diazo-2-oxo-propanol) -phosphonic acid dimethyl ester (159mg, 0.76mmol) were added in that order and stirred at room temperature overnight. Directly concentrating, separating with 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 was prepared by selecting the corresponding starting materials in reference to the overall or partial synthesis of intermediate 15:

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

The first step is as follows: synthesis of 2-amino-4-bromo-5-fluorophenol

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

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

2-amino-4-bromo-5-fluorophenol (3.2 g,15.5 mmol) was placed in ethanol (50 mL), and potassium ethylsulfonate (2.48g, 15.5 mmol) was added at room temperature. The mixture was stirred at 80 ℃ for 17 hours. Directly concentrating the reaction solution, and separating 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[ 2 ], [ M ] +H] ⁺ 。

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

5-bromo-6-fluorobenzo [ d ] oxazole-2 (3H) -thione (1.76g, 7.1 mmol) was dissolved in dichloromethane (15 mL) and N, N-dimethylformamide (0.5 mL) and thionyl chloride (5.0 mL,68.9 mmol) were added sequentially at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was diluted with methylene chloride (100 mL), washed with a saturated sodium bicarbonate solution (50 mL) and brine (50 mL), and dried over anhydrous sodium sulfate. Suction filtration, concentration of the filtrate, and column chromatography separation gave 5-bromo-2-chloro-6-fluorobenzo [ d ] oxazole (1.30 g, yield: 73%).

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

Reacting 5-bromo-2-chloro-6-fluorobenzo [ d]Oxazole (250mg, 1.0 mmol) was placed in acetonitrile (5 mL), and an aqueous methylamine solution (1.0 mL, 25-30% by mass) was added at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction solution is diluted by adding salt solution,extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, and concentrating to obtain 5-bromo-6-fluoro-N-methylbenzo [ d]Oxazol-2-amine (245 mg, yield: 100%). MS m/z (ESI) 245/247M + H] ⁺ 。

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

Reacting 5-bromo-6-fluoro-N-methylbenzo [ d]Oxazol-2-amine (190mg, 0.78mmol) was placed in 1,4-dioxane/N, N-dimethylformamide (10 mL/1 mL) and tributyl (trimethylsilylethynyl) tin (600mg, 1.55mmol) and tetratriphenylphosphine palladium (90mg, 0.08mmol) were added at room temperature. The mixture was reacted at 120 ℃ for 6 hours by microwave. Directly concentrating the reaction solution, and performing column chromatography separation 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] ⁺ 。

And a sixth step: synthesis of 5-ethynyl-6-fluoro-N-methylbenzo [ d ] oxazol-2-amine

Reacting 6-fluoro-N-methyl-5- ((trimethylsilyl) ethynyl) benzo [ d]Oxazol-2-amine (158mg, 0.60mmol) was placed in methanol (10 mL) and potassium carbonate (248mg, 1.80mmol) was added at room temperature. The mixture was stirred at room temperature for 1 hour. Directly concentrating the reaction solution, and separating 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 were prepared by selecting the corresponding starting materials in reference to the full or partial synthesis of intermediate 17:

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

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

3,5-difluoro-2-nitrophenol (10g, 57.11mmol) was dissolved in methanol (100 mL), palladium on carbon (1 g) was added, and the mixture was stirred at room temperature overnight, filtered, and the filtrate was spin-dried to give 2-amino-3,5-difluorophenol (8.5 g, yield: 100%). MS m/z (ESI): 146[ M ] +H] ⁺ 。

The second step: synthesis of 4,6-difluorobenzo [ d ] oxazole-2-thiol

2-amino-3,5-difluorophenol (8.5g, 58.62mmol) was dissolved in ethanol (100 mL), potassium O-ethyldithioate (1.13g, 70.34mmol) was added, and the mixture was heated to 95 ℃ overnight. The mixture was cooled, filtered, and concentrated to give 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-benzeneBenzoxazole-2-thiol (4 g, 21.37mmol) was dissolved in dichloromethane (50 mL), oxalyl chloride (10.85g, 85.48mmol) and N, N-dimethylformamide (0.16g, 2.14mmol) were added, stirred at room temperature for 2 hours, and spin-dried to give 2-chloro-4,6-difluorobenzo [ d ] s]The crude oxazole (4.05 g, yield: 100%) was used directly in the next reaction. MS m/z (ESI): 190[ m ] +H] ⁺ 。

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

Reacting 2-chloro-4,6-difluorobenzo [ d]Dissolving crude oxazole (4.05g, 21.36mmol) in tetrahydrofuran (50 mL), adding N, N-diisopropylethylamine (5.51g, 42.72mmol) and azetidine hydrochloride (2.40g, 25.63mmol), stirring at room temperature for 2 hours, drying the reaction mixture, adding ethyl acetate, washing twice with saturated aqueous ammonium chloride solution, washing twice with saturated saline solution, drying with sodium sulfate, filtering, concentrating the filtrate, and separating 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[ 2 ], [ M ] +H] ⁺ 。

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

Reacting 2- (azetidin-1-yl) -4,6-difluorobenzo [ d]Dissolving oxazole (3 g, 14.28mmol) in tetrahydrofuran (100 ml), cooling to-70 deg.C, adding lithium diisopropylamide solution in tetrahydrofuran (10.7 mL,21.41mmol, 2M) dropwise, stirring at low temperature for 1 hr, adding N, N-dimethylformamide (11.04mL, 142.73mmol) at one time, stirring at low temperature for 2 hr, adding saturated aqueous ammonium chloride solution to quench reaction, heating to room temperature, extracting with ethyl acetate twice, combining ethyl acetate phases, washing with saturated saline twice, drying with sodium sulfate, and concentratingDrying, filtering to obtain filtrate, concentrating, and separating with silica gel column chromatography to obtain 2- (azetidin-1-yl) -4,6-difluorobenzo [ d]Oxazole-5-carbaldehyde (0.8 g, yield: 24%). MS m/z (ESI): 239[ m ] +H] ⁺ 。

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

Reacting 2- (azetidin-1-yl) -4,6-difluorobenzo [ d]Dissolving oxazole-5-formaldehyde (0.8g, 3.40mmol) in methanol (10 mL) and tetrahydrofuran (10 mL), adding potassium carbonate (1.17g, 8.5mmol) and (1-diazo-2-oxopropyl) dimethyl phosphonate (1.31g, 6.801mmol), stirring at room temperature for two hours, concentrating, adding a proper amount of saturated ammonium chloride aqueous solution to quench reaction, heating to room temperature, extracting with ethyl acetate twice, combining, washing with saturated saline twice, drying with sodium sulfate, filtering to obtain a filtrate, concentrating, and separating by silica gel column chromatography to obtain 2- (azetidin-1-yl) -5-ethynyl-4,6-difluorobenzo [ d ] d]Oxazole (0.75 g, yield: 94%). MS m/z (ESI): 235[ m ] +H] ⁺ 。

Intermediate 22 was prepared by selecting the corresponding starting materials in reference to the full or partial synthesis of intermediate 21:

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

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

3-amino-1H-pyrazole-4-carbonitrile (25.0 g, 231mmol) was dissolved in DMF (200 mL), N-bromosuccinimide (42.0 g,236 mmol) was added in portions in ice bath, after the addition, the temperature was slowly raised to room temperature, and stirring was continued for 2 hours. After the reaction, water was added, extracted with ethyl acetate, and 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) 187/189M + H] ⁺ 。

The second step is that: synthesis of tert-butyl (S) -3- (5-amino-3-bromo-4-cyano-1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid ester

3-amino-5-bromo-1H-pyrazole-4-carbonitrile (14.7g, 78.6 mmol), tert-butyl (R) -3- (tosyloxo) pyrrolidine-1-carboxylate (32.2g, 94.3 mmol) were dissolved in DMF (200 mL), and cesium carbonate (51.2g, 157.2mmol) was added. The reaction was stirred at 90 ℃ for 18 hours, cooled to room temperature after completion of the reaction, added with 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 isolated by column chromatography to give tert-butyl (S) -3- (5-amino-3-bromo-4-cyano-1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid ester (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-carboxylic acid ester

Tert-butyl (S) -3- (5-amino-3-bromo-4-cyano-1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acidThe acid ester (1.85g, 5.19mmol) is dissolved in DMSO (30 mL), an aqueous solution (10 mL) of sodium hydroxide (208mg, 5.19mmol) is added, a hydrogen peroxide solution (30 wt%,16.4 mL) is slowly added under ice-bath cooling, after the addition is finished, the temperature is raised to room temperature, stirring is continued for 2 hours, after the reaction is finished, saturated saline water is added, and extraction is carried out with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was isolated by column chromatography to give tert-butyl (S) -3- (5-amino-3-bromo-4-carbamoyl-1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid ester (1.24 g, yield: 63.8%). MS m/z (ESI) 374/376[ m ] +H] ⁺ 。

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

Tert-butyl (S) -3- (5-amino-3-bromo-4-carbamoyl-1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid ester (1.24g, 3.31mmol) was dissolved in dichloromethane (15 mL), an ethanol solution of hydrochloric acid (10M, 3.3mL, 33mmol) 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 was used in the next reaction without isolation to give (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: synthesis of (S) -1- (1-acryloylpyrrolidin-3-yl) -5-amino-3-bromo-1H-pyrazole-4-carboxamide

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

2. Preparation of specific examples

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

(S) -1- (1-acryloylpyrrolidin-3-yl) -5-amino-3-bromo-1H-pyrazole-4-carboxamide (200mg, 0.61mmol), 2-cyclopropyl-5-ethynyl-6-fluorobenzo [ d]Thiazole (170mg, 0.79mmol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (35.2mg, 0.03mmol) and cuprous iodide (11.4mg, 0.06mmol) were dissolved in N, N-dimethylformamide (5 mL), and triethylamine (1 mL) was added and stirred at microwave 130 ℃ for 2 hours. Concentrating, and separating by column chromatography to obtain (S) -1- (1-acryloyl pyrrolidine-3-yl) -5-amino-3- ((2-cyclopropyl-6-fluorobenzo [ d)]Thiazol-5-yl) ethynyl) -1H-pyrazole-4-carboxamide (130 mg, yield: 45.8%). MS m/z (ESI) 465[ 2 ], [ M ] +H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.12(dd,J＝9.6,7.6Hz,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).

Examples 2 to 22 were prepared by selecting the corresponding starting materials with reference to all or part of the synthesis of example 1:

the nuclear magnetic data of the compound prepared in the above example are as follows:

biological test evaluation

1. BaF3-Tel-FGFR2WT and various mutant FGFR2 cell proliferation assays

The compounds of the embodiment of the invention adopt cell strains which stably express TEL-FGFR2WT intracellular kinase domain fusion proteins or intracellular domain fusion proteins containing FGFR2V564I, V564F, V564L, N549K and K659M mutations in Baf cells by a transfection method to determine the proliferation effect of Baf3-Tel-FGFR2WT and various mutant FGFR2 cells. The specific test process is as follows:

1) Seeding 90 μ L of cell suspension in 96-well plates in growth medium (DMEM containing 1% Glutamax, 10% FBS and 1% Pen/Strep) for a total of 2000-4000 cells per well, then at 37 ℃ and 5% CO ₂ The mixture was incubated overnight.

2) 10 μ L of growth medium containing a 10-fold stock solution of test compound was added to the cell culture (9 dose points, 3x serial dilutions, starting at 1 μ M, final 0.3% dmso).

3) CO at 37 ℃ and 5% ₂ The cells were incubated for 48 hours.

4) A50. Mu.L volume 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) RLU (relative light units) is measured on a microplate reader with a luminescence detection module. RLU values were normalized to% survival and concentration-response curves were plotted using Prism to calculate IC ₅₀ (unit: nM), the results are shown in the table below.

2. Determination of cell proliferation of BaF3-Tel-FGFR3WT and FGFR3V555M

The compounds of the embodiment of the invention are used for stably expressing TEL-FGFR3WT intracellular kinase domain fusion protein or intracellular domain fusion protein containing FGFR3V555M mutation in Baf cells by a transfection method to measure the proliferation effect of BaF3-Tel-FGFR3WT and R3V555M cells. The specific test process is as follows:

3) CO at 37 ℃ and 5% ₂ The cells were incubated for 48 hours.

From the bioactivity data of the compounds of the specific examples, the compounds of the series of the invention have strong inhibition effects on wild-type FGFR and mutant FGFR at cellular level, and the inhibition effect in mutation is not weakened.

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

Claims

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

wherein, the first and the second end of the pipe are connected with each other,
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 heterocyclyl, said nitrogen atom being attached to a carbonyl group;

R ₁ selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, 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-O-R ₉ 、-C _0-8 alkyl-C (O) OR ₉ 、-C _0-8 alkyl-C (O) R ₁₀ 、-C _0-8 alkyl-O-C (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 Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, halo-substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl radical, 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-O-R ₉ 、-C _0-8 alkyl-C (O) OR ₉ 、-C _0-8 alkyl-C (O) R ₁₀ 、-C _0-8 alkyl-O-C (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 Substituted with the substituent(s);

each R ₂ Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, halo-substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl radical, 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-O-R ₉ 、-C _0-8 alkyl-C (O) OR ₉ 、-C _0-8 alkyl-C (O) R ₁₀ 、-C _0-8 alkyl-O-C (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 ₃ Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, halo-substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl radical, 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-O-R ₉ 、-C _0-8 alkyl-C (O) OR ₉ 、-C _0-8 alkyl-C (O) R ₁₀ 、-C _0-8 alkyl-O-C (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 Selected from ethenyl or ethynyl, independently optionally further substituted by one or more groups selected from hydrogen, deuterium, halogen, cyano, C _1-10 Alkyl, halo-substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl radical, 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 Substituted with the substituent(s);

R _5a and R _5b Each independently selected from hydrogen, deuterium, hydroxy, C _1-10 Alkyl radical, 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 Or, R _5a And R _5b Together with the nitrogen atom to which they are directly attached form a 4-to 10-membered heterocyclic group, optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl, halo-substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, 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-O-R ₉ 、-C _0-8 alkyl-C (O) OR ₉ 、-C _0-8 alkyl-C (O) R ₁₀ 、-C _0-8 alkyl-O-C (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 Substituted with the substituent(s);

R _6a selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, halo-substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl radical, 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-O-R ₉ 、-C _0-8 alkyl-C (O) OR ₉ 、-C _0-8 alkyl-C (O) R ₁₀ 、-C _0-8 alkyl-O-C (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 Selected from hydrogen, deuterium, C _1-10 Alkyl radical, C _2-10 Alkenyl radical, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _5-10 Aryl and 5-to 10-membered heteroaryl, optionally further substituted by oneOr more selected from deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, halo-substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl radical, 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-O-R ₉ 、-C _0-8 alkyl-C (O) OR ₉ 、-C _0-8 alkyl-C (O) R ₁₀ 、-C _0-8 alkyl-O-C (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 Substituted with a substituent of (a);

R _7a and R _7b 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, R _7a And R _7b Together with the nitrogen atom to which they are directly attached form a 4-to 10-membered heterocyclic group, optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl, halo-substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, 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-O-R ₉ 、-C _0-8 alkyl-C (O) OR ₉ 、-C _0-8 alkyl-C (O) R ₁₀ 、-C _0-8 alkyl-O-C (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 Substituted with the substituent(s);

each R ₈ Each independently selected from hydrogen, deuterium, hydroxy, C _1-10 Alkyl radical, C _2-10 Alkenyl radical, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _5-10 Aryl, 5-10 membered heteroaryl and-NR ₁₁ R ₁₂ The above groups are independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, oxo, C _1-10 Alkyl radical, C _1-10 Alkoxy radical, C _3-12 Cycloalkyl radical, C _3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C _5-10 Aryl radical, C _5-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and-NR ₁₁ R ₁₂ Substituted with a substituent of (a);

each R ₉ Each independently selected from hydrogen, deuterium, C _1-10 Alkyl radical, C _2-10 Alkenyl radical, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _5-10 Aryl and 5-to 10-membered heteroaryl, each of which is independentlyOptionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, oxo, cyano, C _1-10 Alkyl radical, C _1-10 Alkoxy radical, C _3-12 Cycloalkyl radical, C _3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C _5-10 Aryl radical, C _5-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and-NR ₁₁ R ₁₂ Substituted with the substituent(s);

each R ₁₀ Each independently selected from hydrogen, deuterium, hydroxy, C _1-10 Alkyl radical, C _1-10 Alkoxy radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, C _3-12 Cycloalkyl radical, C _3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C _5-10 Aryl radical, C _5-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, and-NR ₁₁ R ₁₂ The above groups are independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, cyano, C _1-10 Alkyl radical, C _1-10 Alkoxy radical, C _3-12 Cycloalkyl radical, C _3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C _5-10 Aryl radical, C _5-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and-NR ₁₁ R ₁₂ Substituted with a substituent of (a);

each R ₁₁ And R ₁₂ Each independently selected from hydrogen, deuterium, hydroxy, C _1-10 Alkyl radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _5-10 Aryl, 5-to 10-membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C _1-10 Alkylamino, di-C _1-10 Alkylamino and C _1-10 Alkanoyl radicalIndependently, the above groups are optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, C _1-10 Alkyl radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, halo-substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl radical, C _1-10 Alkoxy radical, C _3-12 Cycloalkyl radical, C _3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C _5-10 Aryl radical, C _5-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono C _1-10 Alkylamino, di-C _1-10 Alkylamino and C _1-10 Substituted by a substituent of alkanoyl;

or, R ₁₁ And R ₁₂ Together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclyl or 5-10 membered heteroaryl, said 4-10 membered heterocyclyl or 5-10 membered heteroaryl being optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, C _1-10 Alkyl radical, C _2-10 Alkenyl radical, C _2-10 Alkynyl, halo-substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl radical, C _1-10 Alkoxy radical, C _3-12 Cycloalkyl radical, C _3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C _5-10 Aryl radical, C _5-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono C _1-10 Alkylamino, di-C _1-10 Alkylamino and C _1-10 Substituted by alkanoyl group;

m is 0, 1,2 or 3;

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

Each r is independently 0, 1 or 2.
The compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R is ₁ Selected from hydrogen, deuterium, halogen, cyano, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, 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-O-R ₉ 、-C _0-4 alkyl-C (O) OR ₉ 、-C _0-4 alkyl-C (O) R ₁₀ 、-C _0-4 alkyl-O-C (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 groups are optionally further substituted by one or more groups selected from deuterium, halogen, cyano, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, halo-substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl radical, 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-O-R ₉ 、-C _0-4 alkyl-C (O) OR ₉ 、-C _0-4 alkyl-C (O) R ₁₀ 、-C _0-4 alkyl-O-C (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 radical-C(O)NR ₁₁ R ₁₂ and-C _0-4 alkyl-N (R) ₁₁ )-C(O)R ₁₀ Substituted with the substituent(s);

each R ₂ Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, halo-substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl radical, 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-O-R ₉ 、-C _0-4 alkyl-C (O) OR ₉ 、-C _0-4 alkyl-C (O) R ₁₀ 、-C _0-4 alkyl-O-C (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 ₃ Each independently selected from hydrogen, deuterium, halogen, cyano, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, halo-substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl radical, 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-O-R ₉ 、-C _0-4 alkyl-C (O) OR ₉ 、-C _0-4 alkyl-C (O) R ₁₀ 、-C _0-4 alkyl-O-C (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 Each independently selected from hydrogen, deuterium, hydroxy, C _1-4 Alkyl radical, 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, 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 deuterium, halogen, cyano, C _1-4 Alkyl, halo-substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl radical, C _2-4 Alkenyl radical, 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-O-R ₉ 、-C _0-4 alkyl-C (O) OR ₉ 、-C _0-4 alkyl-C (O) R ₁₀ 、-C _0-4 alkyl-O-C (O) R ₁₀ 、-C _0-4 alkyl-NR ₁₁ R ₁₂ 、-C _0-4 alkyl-C (= 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 Substituted with the substituent(s);

R _6a selected from hydrogen, deuterium, halogen, cyano, nitro, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, halo-substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl radical, 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-O-R ₉ 、-C _0-4 alkyl-C (O) OR ₉ 、-C _0-4 alkyl-C (O) R ₁₀ 、-C _0-4 alkyl-O-C (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 Selected from hydrogen, deuterium, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _5-8 Aryl and 5-8 membered heteroaryl, optionally further substituted by one or more groups selected from deuterium, halogen, cyano, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, halo-substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl radical, 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-O-R ₉ 、-C _0-4 alkyl-C (O) OR ₉ 、-C _0-4 alkyl-C (O) R ₁₀ 、-C _0-4 alkyl-O-C (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 Substituted with the substituent(s);

R _7a and R _7b 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, R _7a And R _7b 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 deuterium, halogen, cyano, C _1-4 Alkyl, halo-substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl radical, C _2-4 Alkenyl radical, 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-O-R ₉ 、-C _0-4 alkyl-C (O) OR ₉ 、-C _0-4 alkyl-C (O) R ₁₀ 、-C _0-4 alkyl-O-C (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 Substituted with the substituent(s);

wherein R is ₄ 、R ₈ 、R ₉ 、R ₁₀ 、R ₁₁ 、R ₁₂ And r is as defined in claim 1.
The compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, according to claim 1, wherein said compound of formula (I) has the structure of formula (iia) or formula (iib):

wherein, in the compound of formula (IIa), Y ₁ Is NR _6b O or S; in the compounds of formula (IIb), Y ₂ Is CR _6a Or N;

each ring A is independently a 3-8 membered nitrogen containing heterocyclyl group, the nitrogen atom being attached to a carbonyl group;

each R ₁ Each independently selected from hydrogen, deuterium, halogen, cyano, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, -SF ₅ 、-S(O) _r R ₈ 、-O-R ₉ 、-C(O)OR ₉ 、-C(O)R ₁₀ 、-O-C(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 Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, halo-substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl radical, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _5-8 Aryl, 5-8 membered heteroaryl, = O, -SF ₅ 、-S(O) _r R ₈ 、-O-R ₉ 、-C(O)OR ₉ 、-C(O)R ₁₀ 、-O-C(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 Substituted with a substituent of (a);

each R _2a And R _2b Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, halo-substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl radical, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, -SF ₅ 、-S(O) _r R ₈ 、-O-R ₉ 、-C(O)OR ₉ 、-C(O)R ₁₀ 、-O-C(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 Each independently being a vinyl group, said groups independently optionally being further substituted by one or more groups selected from hydrogen, deuterium, halogen, cyano, C _1-4 Alkyl, halo-substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl radical, 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 Substituted with the substituent(s);

each R _5a And R _5b Each independently selected from hydrogen, deuterium, hydroxy, C _1-4 Alkyl radical, 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 Or, R _5a And R _5b 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, halo-substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, -SF ₅ 、-S(O) _r R ₈ 、-O-R ₉ 、-C(O)OR ₉ 、-C(O)R ₁₀ 、-O-C(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 Substituted with the substituent(s);

R _6a selected from hydrogen, deuterium, halogen, cyano, nitro, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, halo-substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl radical, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, -SF ₅ 、-S(O) _r R ₈ 、-O-R ₉ 、-C(O)OR ₉ 、-C(O)R ₁₀ 、-O-C(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 Selected from hydrogen, deuterium, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _3-6 Cycloalkyl and 3-6 membered heterocyclyl, said groups optionally further substituted by one or more groups selected from deuterium, halogen, cyano, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, halo-substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl radical, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, = O, -SF ₅ 、-S(O) _r R ₈ 、-O-R ₉ 、-C(O)OR ₉ 、-C(O)R ₁₀ 、-O-C(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 Substituted with a substituent of (a);

each R _7a And R _7b Each 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 Or, 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, halo-substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, -SF ₅ 、-S(O) _r R ₈ 、-O-R ₉ 、-C(O)OR ₉ 、-C(O)R ₁₀ 、-O-C(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 Substituted with the substituent(s);

wherein R is ₈ 、R ₉ 、R ₁₀ 、R ₁₁ 、R ₁₂ And r is as defined in claim 1.
A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 3, wherein each ring a is, independently:
the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein the compound of formula (I) has the structure of formula (iiia) or formula (iiib):

wherein, in the compound of formula (IIIa), Y ₁ Is O or S;

each R ₁ Each independently selected from hydrogen, deuterium, halogen, cyano, C _1-2 Alkyl radical, C _3-4 Cycloalkyl, 3-4 membered heterocyclyl, -SF ₅ 、-O-R ₉ 、-C(O)OR ₉ 、-C(O)R ₁₀ 、-O-C(O)R ₁₀ and-NR ₁₁ R ₁₂ The above groups are optionally further substituted by one or more groups selected from deuterium, fluoro, chloro, bromo, cyano, C _1-2 Alkyl, halo-substituted C _1-2 Alkyl, deuterium substituted C _1-2 Alkyl radical, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, = O, -SF ₅ 、-O-R ₉ 、-C(O)OR ₉ 、-C(O)R ₁₀ 、-O-C(O)R ₁₀ and-NR ₁₁ R ₁₂ Substituted with the substituent(s);

each R _2a And R _2b Each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C _1-4 Alkyl, halo-substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl radical, C _3-6 Cycloalkyl, -SF ₅ 、-O-R ₉ 、-C(O)OR ₉ 、-C(O)R ₁₀ 、-O-C(O)R ₁₀ and-NR ₁₁ R ₁₂ ；

Wherein R is ₉ 、R ₁₀ 、R ₁₁ And R ₁₂ As claimed in claim 1.
The compound of claim 1 of the formula (A)I) A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein each R is ₈ Each independently selected from hydrogen, deuterium, hydroxy, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, 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 independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, oxo, C _1-4 Alkyl radical, C _1-4 Alkoxy radical, C _3-6 Cycloalkyl radical, C _3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C _5-8 Aryl radical, C _5-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR ₁₁ R ₁₂ Substituted with the substituent(s);

each R ₉ Each independently selected from hydrogen, deuterium, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _5-8 Aryl and 5-8 membered heteroaryl, independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, cyano, C _1-4 Alkyl radical, C _1-4 Alkoxy radical, C _3-6 Cycloalkyl radical, C _3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy, C _5-8 Aryl radical, C _5-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR ₁₁ R ₁₂ Substituted with the substituent(s);

each R ₁₀ Each independently selected from hydrogen, deuterium, hydroxy, C _1-4 Alkyl radical, C _1-4 Alkoxy radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Cycloalkyl radical, C _3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C _5-8 Aryl radical, C _5-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR ₁₁ R ₁₂ The above groups are independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, cyano, C _1-4 Alkyl radical, C _1-4 Alkoxy radical, C _3-6 Cycloalkyl radical, C _3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy, C _5-8 Aryl radical, C _5-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR ₁₁ R ₁₂ Substituted with the substituent(s);

each R ₁₁ And R ₁₂ Each independently selected from hydrogen, deuterium, hydroxy, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, 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, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C _1-4 Alkylamino, di-C _1-4 Alkylamino and C _1-4 Alkanoyl, said groups being independently optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, halo-substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl radical, C _1-4 Alkoxy radical, C _3-6 Cycloalkyl radical, C _3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C _5-8 Aryl radical, C _5-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono C _1-4 Alkylamino, di-C _1-4 Alkylamino and C _1-4 Substituted by alkanoyl group;

or, R ₁₁ And R ₁₂ Together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclyl or 5-10 membered heteroaryl, said 4-10 membered heterocyclyl or 5-10 membered heteroaryl being optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, C _1-4 Alkyl radical、C _2-4 Alkenyl radical, C _2-4 Alkynyl, halo-substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl radical, C _1-4 Alkoxy radical, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C _5-8 Aryl radical, C _5-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono C _1-4 Alkylamino, di-C _1-4 Alkylamino and C _1-4 Substituted by alkanoyl group.
The compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof, according to claim 6, wherein each R is ₁ Each independently selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, -SF ₅ Methoxy, ethoxy, carboxyl, acetyl, acetoxy, amino, methylamino and dimethylamino, optionally further substituted with one or more groups selected from deuterium, fluoro, chloro, bromo, cyano, methyl, ethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, = O, -SF ₅ Methoxy, ethoxy, carboxyl, acetyl, acetoxy, amino, methylamino, and dimethylamino;

each R _2a And R _2b Each independently selected from hydrogen, deuterium, fluoro, chloro, bromo, cyano, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, -SF ₅ Methoxy, ethoxy, carboxyl, acetyl, acetoxy, amino, methylamino and dimethylamino.
A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, which is selected from the following compounds:
a process for the preparation of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 8, comprising the steps of:

alternatively, the first and second electrodes may be,

wherein, the ring A, X, Y, R ₁ 、R ₂ 、R ₃ 、R ₄ 、R _5a 、R _5b M and n are as defined in claim 1.
A pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 8, and a pharmaceutically acceptable carrier.
Use of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 8 in the manufacture of a medicament for the treatment of a patient with a neoplasm resistant to FGFR inhibitors, said patient having a mutation in FGFR V561, V565, N550, N540, V555, E566, K660 and/or V550;

preferably, the tumor patient is one having FGFR2V565F, V565I, V565L, V565M, N550K, N550H, E566A, E566G, K M and/or K660Q mutations;

preferably, the tumor patient is a tumor patient having FGFR3V555M, V L and/or N540K mutation.
A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 8 for use in the prevention or treatment of a tumour or cancer mediated by FGFR kinase, which is selected from bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, renal cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, thyroid cancer, skin cancer, leukaemia, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukaemia, B-cell lymphoma, acute myeloid leukaemia, hodgkin lymphoma or non-hodgkin lymphoma, fahrenheit macroglobulinemia, hairy lymphoma, cellular lymphoma, burkitt lymphoma, glioblastoma, melanoma or rhabdomyosarcoma.
The use of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, in the manufacture of a medicament for the treatment of a myeloproliferative disease, a bone or chondrocyte disorder, or hypophosphatemia; the myeloproliferative disease is selected from erythrocytosis, primary thrombocythemia or primary myelofibrosis; said skeletal or chondrocyte disorder is selected from dysplasia, achondroplasia, dwarfism, lethal Teratocarcinosis (TD), alpeler's syndrome, kluyverson syndrome, jackson-Weiss syndrome, beare-Stevenson dermatoglyph syndrome, pfeiffer syndrome or cranial muscle atrophy syndrome; the hypophosphatemia is selected from X-linked hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets or ovarian malacia induced by tumors.
A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8 for use in a selective FGFR2 and/or FGFR3 inhibitor for the treatment of a disease associated with aberrant expression, mutation or aberrant expression and activity of the respective ligand of the FGFR2 or FGFR3 receptor.