Dihydropyrrolo[2,3-d]pyridazine-7-one derivatives, preparation methods and applications thereof

Abstract

A dihydropyrrolo[2,3-d]pyridazine-7-one derivative having a structure of formula (I), a preparation method thereof, a pharmaceutical composition containing the same, and its use as an inhibitor of FGFR and its mutations and its use in preparing drugs for treating and / or preventing tumors or cancers at least partially mediated by FGFR kinases and tumor patients with tolerance to FGFR inhibitors, especially for preparing drugs for treating and / or preventing tumor patients with mutations in V561, V565, N550, N540, V555, E566, K660 and / or V550 of the FGFR signaling pathway. The substituents in formula (I) are the same as those defined in the specification.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis, specifically relating to a dihydropyrrolo[2,3-d]pyridazine-7-one derivative, its preparation method and application. Background Technology

[0002] Fibroblast growth factor receptors (FGFRs) are tyrosine kinase receptors that bind to fibroblast growth factor ligands. Currently, four FGFR receptors have been identified that can bind to ligands. The fibroblast growth factor (FGF) signaling pathway is considered to play an important role in many processes, such as embryogenesis, tissue differentiation, wound healing, and metabolic regulation, and is also strongly associated with many tumor characteristics. When FGF binds to its receptor, the receptor undergoes dimerization and phosphorylation, stimulating the activation of protein kinase activity and facilitating the activation of a series of intracellular signaling pathways, including Ras-MAPK, AKT-PI3K, and phosphatase C—signaling pathways crucial for cell growth, proliferation, and survival.

[0003] Genetic alterations in FGFR family members are typically associated with tumor growth, metastasis, angiogenesis, and survival. Many FGFR inhibitors have demonstrated clinical responses in patients with FGFR abnormalities during clinical trials, and some have recently been approved for marketing. However, clinical trials have shown a rapid emergence of acquired resistance to FGFR inhibitors, resulting in relatively short progression-free survival. Mutations affecting FGFR amino acids may induce resistance to FGFR inhibitors or reduce their activity. The generation of secondary FGFR kinase domain mutations under the influence of FGFR inhibitors is an important mechanism for acquiring resistance to FGFR inhibition. Corresponding FGFR point mutations also exist in tumors. Gate mutations have been reported as one of the main mechanisms for developing resistance to tyrosine kinases, and resistant FGFR mutations have been reported in both in vitro cell systems and clinical trials. Gate mutations include FGFR3V555M, FGFR2V565F / V565I / V565L, etc. Recent studies have reported the presence of FGFR2V565F gatekeeper mutations in three patients with cholangiocarcinoma treated with BGJ398, with two of them also exhibiting other mutations in the FGFR2 kinase region. Therefore, to overcome acquired resistance to first-generation FGFR inhibitors in clinical practice, there is an urgent need for next-generation FGFR inhibitors that possess more durable activity in tumors with gene mutations in the FGFR signaling pathway. Such second-generation FGFR inhibitors need to maintain FGFR inhibitory activity while also maintaining similar activity against gatekeeper mutations where the activity of first-generation inhibitors has diminished. Summary of the Invention

[0004] Through extensive and in-depth research, the inventors of this application have, for the first time, developed a dihydropyrrolo[2,3-d]pyridazine-7-one derivative, its preparation method, and its applications. The compounds of this invention exhibit excellent activity against mutant FGFRs, particularly those with gate-guarding mutations, especially FGFR3 V555M, FGFR2 V565I, FGFR2 V565F, FGFR2 V565L, and the non-gate-guarding FGFR2 N550K mutation, and hold promise for the development of a new generation of FGFR inhibitors.

[0005] The first aspect of the present invention provides a compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof:

[0006]

[0007] in, Is it a single bond or a double bond?

[0008] X is C or N; Y is CR5, N, NR6, O or S; Z is CR5 or N;

[0009] Ring A is a 3-12 member nitrogen-containing heterocyclic group, wherein the nitrogen atom is connected to a carbonyl group;

[0010] R1 is selected from hydrogen, deuterium, halogen, cyano, nitro, azide, and C. 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 -C 0-8 Alkyl-OC(O)R 10 -C 0-8 Alkyl-NR 11 R 12 -C 0-8 Alkyl-C (=NR) 11 )R 10 -C 0-8 Alkyl-N(R) 11 )-C(=NR 12 )R 10 -C 0-8 Alkyl-C(O)NR 11 R 12and -C 0-8 Alkyl-N(R) 11 )-C(O)R 10 The above-mentioned groups may optionally be further divided by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 -C 0-8 Alkyl-OC(O)R 10 -C 0-8 Alkyl-NR 11 R 12 -C 0-8 Alkyl-C (=NR) 11 )R 10 -C 0-8 Alkyl-N(R) 11 )-C(=NR 12 )R 10 -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R) 11 )-C(O)R 10 The substituents are replaced;

[0011] Each R2 group is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, and C. 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 -C 0-8 Alkyl-OC(O)R 10 -C 0-8 Alkyl-NR 11 R 12 -C 0-8 Alkyl-C (=NR) 11 )R 10 -C 0-8 Alkyl-N(R) 11 )-C(=NR 12 )R 10 -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R) 11 )-C(O)R 10 ;

[0012] Each R3 group is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, and C. 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 -C 0-8 Alkyl-OC(O)R 10 -C 0-8 Alkyl-NR 11 R 12 -C 0-8 Alkyl-C (=NR) 11 )R 10 -C 0-8 Alkyl-N(R) 11 )-C(=NR 12 )R 10 -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8Alkyl-N(R) 11 )-C(O)R 10 ;

[0013] R4 is selected from vinyl or ethynyl groups, and the above groups are independently and optionally further selected from one or more groups selected from hydrogen, deuterium, halogen, cyano, C. 1-10 Alkyl, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, -C 0-8 Alkyl-C(O)OR9, -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 The substituents are replaced;

[0014] Each R5 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 -C 0-8 Alkyl-OC(O)R 10 -C 0-8 Alkyl-NR 11 R 12 -C 0-8 Alkyl-C (=NR) 11 )R 10 -C 0-8 Alkyl-N(R) 11 )-C(=NR 12 )R 10 -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R) 11)-C(O)R 10 ;

[0015] R6 is selected from hydrogen, deuterium, and C. 1-10 Alkyl, C 2-10 Alkenyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 5-10 aryl and 5-10 heteroaryl groups, wherein the above groups are optionally further divided by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 -C 0-8 Alkyl-OC(O)R 10 -C 0-8 Alkyl-NR 11 R 12 -C 0-8 Alkyl-C (=NR) 11 )R 10 -C 0-8 Alkyl-N(R) 11 )-C(=NR 12 )R 10 -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R) 11 )-C(O)R 10 The substituents are replaced;

[0016] R 7a and R 7b Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-10 Alkyl, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 -C 0-8 Alkyl-C (=NR) 11 )R 10 and -C0-8 Alkyl-C(O)NR 11 R 12 Or, R 7a and R 7b Together with the nitrogen atom directly attached thereto, a 4-10 membered heterocyclic group is formed, which may be further selected by one or more elements selected from deuterium, halogen, cyano, nitro, azide, C. 1-10 Alkyl, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 -C 0-8 Alkyl-OC(O)R 10 -C 0-8 Alkyl-NR 11 R 12 -C 0-8 Alkyl-C (=NR) 11 )R 10 -C 0-8 Alkyl-N(R) 11 )-C(=NR 12 )R 10 -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R) 11 )-C(O)R 10 The substituents are replaced;

[0017] Each R8 is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-10 Alkyl, C 2-10 Alkenyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 5-10 Aryl, 5-10 quinone heteroaryl and -NR 11 R 12 The aforementioned groups are independently and optionally further selected by one or more radicals selected from deuterium, halogen, hydroxyl, oxo, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 5-10 Aryl, C 5-10 aryloxy groups, 5-10 heteroaryl groups, 5-10 heteroaryloxy groups and -NR 11 R 12 The substituents are replaced;

[0018] Each R9 is independently selected from hydrogen, deuterium, and C. 1-10 Alkyl, C 2-10 Alkenyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 5-10 aryl and 5-10 heteroaryl groups, wherein the above groups are independently and optionally further selected by one or more radicals selected from deuterium, halogen, hydroxyl, oxo, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 5-10 Aryl, C 5-10 aryloxy groups, 5-10 heteroaryl groups, 5-10 heteroaryloxy groups and -NR 11 R 12 The substituents are replaced;

[0019] Each R 10 Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 5-10 Aryl, C 5-10 aryloxy groups, 5-10 heteroaryl groups, 5-10 heteroaryloxy groups and -NR 11 R 12 The aforementioned groups are independently and optionally further selected by one or more radicals selected from deuterium, halogen, hydroxyl, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 5-10 Aryl, C 5-10 aryloxy groups, 5-10 heteroaryl groups, 5-10 heteroaryloxy groups and -NR 11 R 12 The substituents are replaced;

[0020] Each R11 and R 12 Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropanesulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C 1-10 Alkylamino, diC 1-10 Alkylamino and C 1-10 Alkyl group, wherein the above groups are independently and optionally further selected by one or more radicals selected from deuterium, halogen, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 5-10 Aryl, C 5-10 Aryloxy, 5-10 heteroaryl, 5-10 heteroaryloxy, amino, mono-C 1-10 Alkylamino, diC 1-10 Alkylamino and C 1-10 The alkyl acyl group is replaced by a substituent;

[0021] Or, R 11 and R 12 Together with the nitrogen atom directly attached thereto, a 4-10 membered heterocyclic group or a 5-10 membered heteroaryl group is formed, wherein the 4-10 membered heterocyclic group or the 5-10 membered heteroaryl group is optionally further surrounded by one or more elements selected from deuterium, halogen, hydroxyl, C. 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 5-10 Aryl, C 5-10 Aryloxy, 5-10 heteroaryl, 5-10 heteroaryloxy, amino, mono-C 1-10 Alkylamino, diC 1-10 Alkylamino and C 1-10 The alkyl acyl group is replaced by a substituent;

[0022] m can be 0, 1, 2, or 3;

[0023] n is 0, 1, 2, 3, or 4; and

[0024] Each r is independently 0, 1, or 2.

[0025] As a preferred embodiment, in the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof, R1 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-8 Aryl, 5-8 quinone heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O) r R8, -C 0-4 Alkyl-O-R9, -C 0-4 Alkyl-C(O)OR9, -C 0-4 Alkyl-C(O)R 10 -C 0-4 Alkyl-OC(O)R 10 -C 0-4 Alkyl-NR 11 R 12 -C 0-4 Alkyl-C (=NR) 11 )R 10 -C 0-4 Alkyl-N(R) 11 )-C(=NR 12 )R 10 -C 0-4 Alkyl-C(O)NR 11 R 12 and -C 0-4 Alkyl-N(R) 11 )-C(O)R 10 The above-mentioned groups may optionally be further divided by one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-8 Aryl, 5-8 heteroaryl, =O, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O) r R8, -C 0-4Alkyl-O-R9, -C 0-4 Alkyl-C(O)OR9, -C 0-4 Alkyl-C(O)R 10 -C 0-4 Alkyl-OC(O)R 10 -C 0-4 Alkyl-NR 11 R 12 -C 0-4 Alkyl-C (=NR) 11 )R 10 -C 0-4 Alkyl-N(R) 11 )-C(=NR 12 )R 10 -C 0-4 Alkyl-C(O)NR 11 R 12 and -C 0-4 Alkyl-N(R) 11 )-C(O)R 10 The substituents are replaced;

[0026] Each R2 group is independently selected from hydrogen, deuterium, halogen, cyano, nitro, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-8 Aryl, 5-8 quinone heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O) r R8, -C 0-4 Alkyl-O-R9, -C 0-4 Alkyl-C(O)OR9, -C 0-4 Alkyl-C(O)R 10 -C 0-4 Alkyl-OC(O)R 10 -C 0-4 Alkyl-NR 11 R 12 -C 0-4 Alkyl-C (=NR) 11 )R 10 -C 0-4 Alkyl-N(R) 11 )-C(=NR 12 )R 10 -C 0-4 Alkyl-C(O)NR 11 R 12 and -C0-4 Alkyl-N(R) 11 )-C(O)R 10 ;

[0027] Each R3 group is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-8 Aryl, 5-8 quinone heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O) r R8, -C 0-4 Alkyl-O-R9, -C 0-4 Alkyl-C(O)OR9, -C 0-4 Alkyl-C(O)R 10 -C 0-4 Alkyl-OC(O)R 10 -C 0-4 Alkyl-NR 11 R 12 -C 0-4 Alkyl-C (=NR) 11 )R 10 -C 0-4 Alkyl-N(R) 11 )-C(=NR 12 )R 10 -C 0-4 Alkyl-C(O)NR 11 R 12 and -C 0-4 Alkyl-N(R) 11 )-C(O)R 10 ;

[0028] Each R5 group is independently selected from hydrogen, deuterium, halogen, cyano, nitro, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-8 Aryl, 5-8 quinone heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O) r R8, -C 0-4 Alkyl-O-R9, -C 0-4Alkyl-C(O)OR9, -C 0-4 Alkyl-C(O)R 10 -C 0-4 Alkyl-OC(O)R 10 -C 0-4 Alkyl-NR 11 R 12 -C 0-4 Alkyl-C (=NR) 11 )R 10 -C 0-4 Alkyl-N(R) 11 )-C(=NR 12 )R 10 -C 0-4 Alkyl-C(O)NR 11 R 12 and -C 0-4 Alkyl-N(R) 11 )-C(O)R 10 ;

[0029] R6 is selected from hydrogen, deuterium, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-8 aryl and 5-8 heteroaryl groups, wherein the above groups are optionally further divided by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-8 Aryl, 5-8 heteroaryl, =O, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O) r R8, -C 0-4 Alkyl-O-R9, -C 0-4 Alkyl-C(O)OR9, -C 0-4 Alkyl-C(O)R 10 -C 0-4 Alkyl-OC(O)R 10 -C 0-4 Alkyl-NR 11 R 12 -C 0-4 Alkyl-C (=NR) 11 )R 10 -C 0-4 Alkyl-N(R) 11 )-C(=NR 12)R 10 -C 0-4 Alkyl-C(O)NR 11 R 12 and -C 0-4 Alkyl-N(R) 11 )-C(O)R 10 The substituents are replaced;

[0030] R 7a and R 7b Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-4 Alkyl, -C 0-4 Alkyl-C(O)OR9, -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 directly attached thereto, a 4-8 membered heterocyclic group is formed, which may be further optionally bonded by one or more elements selected from deuterium, halogen, cyano, C. 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-8 Aryl, 5-8 heteroaryl, =O, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O) r R8, -C 0-4 Alkyl-O-R9, -C 0-4 Alkyl-C(O)OR9, -C 0-4 Alkyl-C(O)R 10 -C 0-4 Alkyl-OC(O)R 10 -C 0-4 Alkyl-NR 11 R 12 -C 0-4 Alkyl-C (=NR) 11 )R 10 -C 0-4 Alkyl-N(R) 11 )-C(=NR 12 )R 10 -C 0-4 Alkyl-C(O)NR 11R 12 and -C 0-4 Alkyl-N(R) 11 )-C(O)R 10 The substituents are replaced;

[0031] Among them, R4, R8, R9, R 10 R 11 R 12 r is as defined in compound (I).

[0032] As a further preferred option, the compound of formula (I) is a compound of formula (IIa) or formula (IIb) as follows:

[0033]

[0034] In the compound of formula (IIa), Y1 is NR6, O or S; in the compound of formula (IIb), Y2 is CR5 or N.

[0035] Each Z is independently either CR5 or N;

[0036] Each ring A is independently a 3-8 member nitrogen-containing heterocyclic group, wherein the nitrogen atom is connected to a carbonyl group;

[0037] Each R1 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, -SF5, -S(O) r R8, -O-R9, -C(O)OR9, -C(O)R 10 -OC(O)R 10 -NR 11 R 12 -C(=NR) 11 )R 10 -N(R) 11 )-C(=NR 12 )R 10 -C(O)NR 11 R 12 and -N(R) 11 )-C(O)R 10 The above-mentioned groups may optionally be further divided by one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C5-8 Aryl, 5-8 heteroaryl, =O, -SF5, -S(O) r R8, -O-R9, -C(O)OR9, -C(O)R 10 -OC(O)R 10 -NR 11 R 12 -C(=NR) 11 )R 10 -N(R) 11 )-C(=NR 12 )R 10 -C(O)NR 11 R 12 and -N(R) 11 )-C(O)R 10 The substituents are replaced;

[0038] Each R 2a and R 2b Each is independently selected from hydrogen, deuterium, halogen, cyano, nitro, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, -SF5, -S(O) r R8, -O-R9, -C(O)OR9, -C(O)R 10 -OC(O)R 10 -NR 11 R 12 -C(=NR) 11 )R 10 -N(R) 11 )-C(=NR 12 )R 10 -C(O)NR 11 R 12 and -N(R) 11 )-C(O)R 10 ;

[0039] Each R4 is independently vinyl, and the aforementioned groups are optionally further selected by one or more groups selected from hydrogen, deuterium, halogen, cyano, C. 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic groups, -C 0-4 Alkyl-C(O)OR9, -C 0-4 Alkyl-C(O)R 10 -C0-4 Alkyl-C(O)-NR 7a R 7b and -C 0-4 Alkyl-NR 7a R 7b The substituents are replaced;

[0040] Each R5 group is independently selected from hydrogen, deuterium, halogen, cyano, nitro, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, -SF5, -S(O) r R8, -O-R9, -C(O)OR9, -C(O)R 10 -OC(O)R 10 -NR 11 R 12 -C(=NR) 11 )R 10 -N(R) 11 )-C(=NR 12 )R 10 -C(O)NR 11 R 12 and -N(R) 11 )-C(O)R 10 ;

[0041] R6 is selected from hydrogen, deuterium, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-8 aryl and 5-8 heteroaryl groups, wherein the above groups are optionally further divided by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-8 Aryl, 5-8 heteroaryl, =O, -SF5, -S(O) r R8, -O-R9, -C(O)OR9, -C(O)R 10 -OC(O)R 10 -NR 11 R 12 -C(=NR) 11 )R 10 -N(R)11 )-C(=NR 12 )R 10 -C(O)NR 11 R 12 and -N(R) 11 )-C(O)R 10 The substituents are replaced;

[0042] Each R 7a and R 7b Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-4 Alkyl, -C(O)OR9, -C(O)R 10 -C(=NR) 11 )R 10 and -C(O)NR 11 R 12 Or, R 7a and R 7b Each of these groups, together with the nitrogen atom directly attached to it, independently forms a 4-6 membered heterocyclic group, which may be further optionally bonded by one or more elements selected from deuterium, halogen, cyano, C. 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, -SF5, -S(O) r R8, -O-R9, -C(O)OR9, -C(O)R 10 -OC(O)R 10 -NR 11 R 12 -C(=NR) 11 )R 10 -N(R) 11 )-C(=NR 12 )R 10 -C(O)NR 11 R 12 and -N(R) 11 )-C(O)R 10 The substituents are replaced;

[0043] Among them, R8, R9, R 10 R 11 R 12 r is as defined in compound (I).

[0044] As a further preferred embodiment, in the compound of formula (I), its stereoisomers, or its pharmaceutically acceptable salts, each ring A is independently:

[0045] As a further preferred option, the compound of formula (I) is a compound of formula (IIIa) or formula (IIIb):

[0046]

[0047] In the compound of formula (IIIa), Y1 is O or S;

[0048] Each R1 is independently selected from hydrogen, deuterium, halogen, cyano, methyl, C 3-4 Cycloalkyl, 3-4 membered heterocyclic groups, -SF5, -O-R9, -C(O)OR9, -C(O)R 10 -OC(O)R 10 and -NR 11 R 12 The above groups may optionally be further divided by one or more radicals selected from deuterium, fluorine, chlorine, bromine, cyano, C 1-2 Alkyl, halogenated C 1-2 Alkyl, deuterated C 1-2 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, =O, -SF5, -O-R9, -C(O)OR9, -C(O)R 10 -OC(O)R 10 and -NR 11 R 12 The substituents are replaced;

[0049] Each R 2a and R 2b Each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, and C. 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 3-6 Cycloalkyl, -SF5, -O-R9, -C(O)OR9, -C(O)R 10 -OC(O)R 10 and -NR 11 R 12 ;

[0050] Among them, R9, R 10 R 11 and R 12 As defined in compound (I).

[0051] As a further preferred embodiment, in the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof, each R8 is independently selected from hydrogen, deuterium, hydroxyl, C... 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C5-8 Aryl, 5-8 quinone heteroaryl and -NR 11 R 12 The aforementioned groups are independently and optionally further selected by one or more radicals selected from deuterium, halogen, hydroxyl, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 5-8 Aryl, C 5-8 aryloxy, 5-8 heteroaryl, 5-8 heteroaryloxy and -NR 11 R 12 The substituents are replaced;

[0052] Each R9 is independently selected from hydrogen, deuterium, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-8 aryl and 5-8 heteroaryl groups, wherein the above groups are independently and optionally further selected by one or more radicals selected from deuterium, halogen, hydroxyl, oxo, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 5-8 Aryl, C 5-8 aryloxy, 5-8 heteroaryl, 5-8 heteroaryloxy and -NR 11 R 12 The substituents are replaced;

[0053] Each R 10 Selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 5-8 Aryl, C 5-8 aryloxy, 5-8 heteroaryl, 5-8 heteroaryloxy and -NR 11 R 12 The aforementioned groups are independently and optionally further selected by one or more radicals selected from deuterium, halogen, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 5-8 Aryl, C5-8 aryloxy, 5-8 heteroaryl, 5-8 heteroaryloxy and -NR 11 R 12 The substituents are replaced;

[0054] Each R 11 and R 12 Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-8 Aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropanesulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C 1-4 Alkylamino, diC 1-4 Alkylamino and C 1-4 Alkyl group, wherein the above groups are independently and optionally further selected by one or more radicals selected from deuterium, halogen, hydroxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 5-8 Aryl, C 5-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group, amino group, mono-C group 1-4 Alkylamino, diC 1-4 Alkylamino and C 1-4 The alkyl acyl group is replaced by a substituent;

[0055] Or, R 11 and R 12 Together with the nitrogen atom directly attached thereto, a 4-10 membered heterocyclic group or a 5-10 membered heteroaryl group is formed, wherein the 4-10 membered heterocyclic group or the 5-10 membered heteroaryl group is optionally further surrounded by one or more elements selected from deuterium, halogen, hydroxyl, C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 5-8 Aryl, C 5-8Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group, amino group, mono-C group 1-4 Alkylamino, diC 1-4 Alkylamino and C 1-4 The alkyl group is replaced by a substituent.

[0056] As a further preferred embodiment, in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, each R1 is independently selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, cyclopropyl, cyclobutyl, oxetyl, aziroxy, -SF5, methoxy, ethoxy, carboxyl, acetyl, acetoxy, amino, methylamino and dimethylamino, wherein the above groups are optionally further substituted by one or more substituents selected from deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, difluoromethyl, trideuterylmethyl, dideuterylmethyl, cyclopropyl, cyclobutyl, oxetyl, aziroxy, =O, -SF5, methoxy, ethoxy, carboxyl, acetyl, acetoxy, amino, methylamino and dimethylamino;

[0057] Each R 2a and R 2b Each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideutermethyl, dideutermethyl, cyclopropyl, cyclobutyl, oxetyl, azirtobutyl, -SF5, methoxy, ethoxy, carboxyl, acetyl, acetoxy, amino, methylamino, and dimethylamino.

[0058] As the most preferred embodiment, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof include, but are not limited to, the following compounds:

[0059]

[0060]

[0061] A second aspect of the present invention provides a method for preparing a compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0062]

[0063] or,

[0064]

[0065] Among them, rings A, X, Y, Z, R1, R2, R3, R4, m and n are as defined in the compound of formula (I).

[0066] A third aspect of the present invention provides a pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0067] The present invention also relates to the use of compounds of formula (I), their stereoisomers or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating cancer patients resistant to FGFR inhibitors.

[0068] As a preferred embodiment, the tumor patient is a tumor patient with mutations in FGFR V561, V565, N550, N540, V555, E566, K660 and / or V550.

[0069] As a further preferred option, the tumor patient is preferably a tumor patient with FGFR2V565F, V565I, V565L, V565M, N550K, N550H, E566A, E566G, K660M and / or K660Q mutations.

[0070] As a further preferred embodiment, the tumor patient is a tumor patient with mutations in FGFR3 V555M / L and / or N540K.

[0071] The present invention also relates to compounds of formula (I), their stereoisomers or pharmaceutically acceptable salts thereof, for the prevention or treatment of disease states or conditions mediated by FGFR kinases.

[0072] The present invention also relates to compounds of formula (I), their stereoisomers or pharmaceutically acceptable salts thereof, for the prevention or treatment of tumors or cancers mediated by FGFR kinases.

[0073] As a preferred embodiment, the tumor or cancer is selected from bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, thyroid cancer, skin cancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, acute myeloid leukemia, Hodgkin lymphoma or non-Hodgkin lymphoma, Waldenström macroglobulinemia, trichomeomatous lymphoma, cell lymphoma, Burkitt lymphoma, glioblastoma, melanoma or rhabdomyosarcoma.

[0074] The present invention also relates to the use of compounds of formula (I), their stereoisomers or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment of myeloproliferative disorders, bone or chondrocyte disorders or hypophosphatemia.

[0075] The present invention also relates to the following: the myeloproliferative disorders are selected from polycythemia vera, essential thrombocythemia, or primary myelofibrosis; the bone or chondrocyte disorders are selected from dysplasia, achondroplasia, dwarfism, lethal teratoma (TD), Appel syndrome, Krusen syndrome, Jackson-Weiss syndrome, Beare-Stevenson skin crease syndrome, Pfeiffer syndrome, or craniomyopathy; the hypophosphatemia is selected from X-linked hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, or tumor-induced ovarian softening.

[0076] The present invention also relates to the use of compounds of formula (I), their stereoisomers or pharmaceutically acceptable salts thereof, or the aforementioned pharmaceutical compositions, for the use of selective FGFR 2 and / or FGFR 3 inhibitors to treat diseases associated with abnormal expression, mutation or corresponding ligand abnormal expression and activity of FGFR2 or FGFR3 receptors.

[0077] The present invention also relates to a method for treating cancer patients who are resistant to FGFR inhibitors, comprising administering a compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof to the patient in need.

[0078] The present invention also relates to a method of treating tumor patients with mutations in FGFR2 V565F, V565I, V565L, V565M, N550K, N550H, E566A, E566G, K660M and / or K660Q, comprising administering to the desired patient a compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof. Detailed Implementation

[0079] Through extensive and in-depth research, the inventors of this application have, for the first time, developed a dihydropyrrolo[2,3-d]pyridazine-7-one derivative, its preparation method, and its applications. The compounds of this invention exhibit excellent activity against mutated FGFRs, particularly those with gate-guarding mutations, especially FGFR3 V555M, FGFR2 V565I, FGFR2 V565F, FGFR2 V565L, and FGFR2 N550K mutations.

[0080] Detailed explanation: Unless otherwise stated or specifically stated, the terms used in the specification and claims shall have the following meanings.

[0081] "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group, preferably including straight-chain alkyl groups with 1 to 10, 1 to 6, or 1 to 4 carbon atoms, and branched alkyl groups, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, and 2-methylpentyl. 3-Methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or their various branched isomers, etc. "C 1-10 "Alkyl" refers to straight-chain alkyl groups comprising 1 to 10 carbon atoms and branched alkyl groups. 1-4 "Alkyl" refers to straight-chain alkyl groups comprising 1 to 4 carbon atoms and branched alkyl groups. 0-8 "Alkyl" refers to straight-chain alkyl groups comprising 0 to 8 carbon atoms and branched alkyl groups. 0-4 "Alkyl" refers to straight-chain alkyl groups containing 0 to 4 carbon atoms and branched alkyl groups.

[0082] The alkyl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C... 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R10 -C 0-8 Alkyl-OC(O)R 10 -C 0-8 Alkyl-NR 11 R 12 -C 0-8 Alkyl-C (=NR) 11 )R 10 -C 0-8 Alkyl-N(R) 11 )-C(=NR 12 )R 10 -C 0-8 Alkyl-C(O)NR 11 R 12 or -C 0-8 Alkyl-N(R) 11 )-C(O)R 10 The substituents are replaced by the substituents.

[0083] "Cycloalkyl" or "carbocyclic" refers to a substituent in a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon. A partially unsaturated cyclic hydrocarbon is one that may contain one or more (preferably 1, 2, or 3) double bonds, but none of the rings has a fully conjugated π-electron system. Cycloalkyl groups are classified as monocyclic or polycyclic, and preferably include 3 to 12, 3 to 8, or 3 to 6 carbon atoms. For example, "C..." 3-12 "Cycloalkyl" refers to a cycloalkyl group consisting of 3 to 12 carbon atoms, "C 3-8 "Cycloalkyl" refers to a cycloalkyl group consisting of 3 to 8 carbon atoms, "C 3-6 "Cycloalkyl" refers to a cycloalkyl group consisting of 3 to 6 carbon atoms, "C 3-4 "Cycloalkyl" refers to a cycloalkyl group comprising 3 to 4 carbon atoms, wherein:

[0084] Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptanetrienyl, and cyclooctyl.

[0085] Polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups. "Spirocycloalkyl" refers to a polycyclic group in which a single carbon atom (called a spiro atom) is shared between the rings. These groups may contain one or more (preferably 1, 2, or 3) double bonds, but none of the rings has a fully conjugated π-electron system. Based on the number of shared spiro atoms between the rings, spirocycloalkyl groups are classified into monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups. Spirocycloalkyl groups include, but are not limited to:

[0086]

[0087] "Fused cyclic alkyl" refers to a polycyclic aromatic hydrocarbon group in which each ring shares an adjacent pair of carbon atoms with the other rings in the system. One or more rings may contain one or more (preferably 1, 2, or 3) double bonds, but no ring has a fully conjugated π-electron system. Based on the number of constituent rings, fused cyclic alkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic. Fused cyclic alkyl groups include, but are not limited to:

[0088]

[0089] "Bridged cycloalkyl" refers to a polycyclic aromatic hydrocarbon group in which any two rings share two non-directly bonded carbon atoms. These groups may contain one or more (preferably 1, 2, or 3) double bonds, but none of the rings has a fully conjugated π-electron system. Based on the number of constituent rings, bridged cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic. Bridged cycloalkyl groups include, but are not limited to:

[0090]

[0091] The cycloalkyl ring can be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl ring, including but not limited to indanyl, tetrahydronaphthyl, benzocycloheptyl, etc.

[0092] The cycloalkyl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C64, halogen, cyano, nitro, azido, and C64. 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 -C 0-8 Alkyl-OC(O)R 10 -C 0-8 Alkyl-NR 11 R 12 -C 0-8 Alkyl-C (=NR) 11 )R 10 -C 0-8 Alkyl-N(R)11 )-C(=NR 12 )R 10 -C 0-8 Alkyl-C(O)NR 11 R 12 or -C 0-8 Alkyl-N(R) 11 )-C(O)R 10 The substituents are replaced by the substituents.

[0093] "Heterocyclic group" or "heterocycle" refers to a substituent for a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon. A partially unsaturated cyclic hydrocarbon is one that may contain one or more (preferably 1, 2, or 3) double bonds, but none of the rings has a fully conjugated π-electron system. In a heterocyclic group, one or more (preferably 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, S(O) (=NH), or S(O). r (where r is an integer 0, 1, or 2) heteroatoms, but excluding the ring portions of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon, preferably including heterocyclic groups of 3 to 12, 3 to 8, or 3 to 6 ring atoms. For example, "3-8 membered heterocyclic group" refers to a cyclic group containing 3 to 8 ring atoms, "3-6 membered heterocyclic group" refers to a cyclic group containing 3 to 6 ring atoms, "3-4 membered heterocyclic group" refers to a cyclic group containing 3 to 4 ring atoms, "4-6 membered heterocyclic group" refers to a cyclic group containing 4 to 6 ring atoms, "4-10 membered heterocyclic group" refers to a cyclic group containing 4 to 10 ring atoms, "4-8 membered heterocyclic group" refers to a cyclic group containing 4 to 8 ring atoms, and "3-12 membered heterocyclic group" refers to a cyclic group containing 3 to 12 ring atoms.

[0094] Monocyclic heterocyclic groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl.

[0095] Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups. A "spiroheterocyclic group" refers to a polycyclic heterocyclic group in which one or more (preferably 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, S(O) (=NH), or S(O). r (Where r is an integer 0, 1, or 2) heteroatoms, with the remaining ring atoms being carbon. These may contain one or more double bonds (preferably 1, 2, or 3), but none of the rings has a fully conjugated π-electron system. Spiroheterocyclic groups are classified into monospirocyclic, bispirocyclic, or polyspirocyclic groups based on the number of shared spiroatoms between rings. Spiroheterocyclic groups include, but are not limited to:

[0096]

[0097] "Fused heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system. One or more (preferably 1, 2, 3, or 4) rings may contain one or more (preferably 1, 2, or 3) double bonds, but no ring has a fully conjugated π-electron system. The one or more (preferably 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, S(O) (=NH), or S(O). r (where r is an integer 0, 1, or 2) heteroatoms, with the remaining ring atoms being carbon. Based on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic alkyl groups. Fused heterocyclic groups include, but are not limited to:

[0098]

[0099] "Bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected. These groups may contain one or more (preferably 1, 2, or 3) double bonds, but none of the rings has a fully conjugated π-electron system. The one or more (preferably 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, S(O) (=NH), or S(O). r Bridged heterocyclic groups consist of heteroatoms (where r is an integer of 0, 1, or 2) and the remaining ring atoms are carbon. Based on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups. Bridged heterocyclic groups include, but are not limited to:

[0100]

[0101] The heterocyclic ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, including but not limited to:

[0102]

[0103] The heterocyclic group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8Alkyl-C(O)R 10 -C 0-8 Alkyl-OC(O)R 10 -C 0-8 Alkyl-NR 11 R 12 -C 0-8 Alkyl-C (=NR) 11 )R 10 -C 0-8 Alkyl-N(R) 11 )-C(=NR 12 )R 10 -C 0-8 Alkyl-C(O)NR 11 R 12 or -C 0-8 Alkyl-N(R) 11 )-C(O)R 10 The substituents are replaced by the substituents.

[0104] "Aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group, a polycyclic (i.e., a ring with adjacent carbon atom pairs) group with a conjugated π-electron system, preferably an all-carbon aryl group containing 5-10 or 5-8 carbons, for example, "C 5-10 "Aryl" refers to a fully carbon-based aryl group containing 5-10 carbons. 5-8 "Aryl" refers to a full-carbon aryl group containing 5-8 carbons, including but not limited to phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, including but not limited to:

[0105]

[0106] The "aryl" group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8Alkyl-C(O)R 10 -C 0-8 Alkyl-OC(O)R 10 -C 0-8 Alkyl-NR 11 R 12 -C 0-8 Alkyl-C (=NR) 11 )R 10 -C 0-8 Alkyl-N(R) 11 )-C(=NR 12 )R 10 -C 0-8 Alkyl-C(O)NR 11 R 12 or -C 0-8 Alkyl-N(R) 11 )-C(O)R 10 The substituents are replaced by the substituents.

[0107] "Heteroaryl" refers to a heteroaryl 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, or 2) heteroatoms, preferably heteroaromatic systems containing 5-10, 5-8, or 5-6 ring atoms. For example, "5-8-membered heteroaryl" refers to a heteroaromatic system containing 5-8 ring atoms, and "5-10-membered heteroaryl" refers to a heteroaromatic system containing 5-10 ring atoms, including but not limited to furanyl, thiophene, pyridinyl, pyrrolithyl, N-alkylpyrrolithyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring can be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, including but not limited to:

[0108]

[0109] The "heteroaryl" group can be optionally substituted or unsubstituted. 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, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 -C 0-8 Alkyl-OC(O)R 10 -C 0-8 Alkyl-NR 11 R 12 -C 0-8 Alkyl-C (=NR) 11 )R 10 -C 0-8 Alkyl-N(R) 11 )-C(=NR 12 )R 10 -C 0-8 Alkyl-C(O)NR 11 R 12 or -C 0-8 Alkyl-N(R) 11 )-C(O)R 10 The substituents are replaced by the substituents.

[0110] "Alkenyl" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably containing... 2-10 Straight-chain or branched alkenyl groups with one or two to four carbons, for example, "C 2-10 "Alkenyl" refers to a chain containing 2-10 A straight-chain or branched alkenyl group of one carbon atom, "C 2-4 "Alkenyl" refers to straight-chain or branched alkenyl groups containing 2-4 carbons. These include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl groups.

[0111] The "alkenyl" group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10-C 0-8 Alkyl-OC(O)R 10 -C 0-8 Alkyl-NR 11 R 12 -C 0-8 Alkyl-C (=NR) 11 )R 10 -C 0-8 Alkyl-N(R) 11 )-C(=NR 12 )R 10 -C 0-8 Alkyl-C(O)NR 11 R 12 or -C 0-8 Alkyl-N(R) 11 )-C(O)R 10 The substituents are replaced by the substituents.

[0112] "Alkyne group" 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-chain or branched alkynyl group containing 2-10 or 2-4 carbon atoms, for example, "C 2-10 "Alkyne group" refers to a straight-chain or branched alkynyl group containing 2-10 carbons. 2-4 "Alynyl" refers to a straight-chain or branched alkynyl group containing 2-4 carbon atoms. It includes, but is not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, etc.

[0113] The "alkynyl group" can be substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 -C 0-8 Alkyl-OC(O)R 10 -C 0-8 Alkyl-NR 11 R 12-C 0-8 Alkyl-C (=NR) 11 )R 10 -C 0-8 Alkyl-N(R) 11 )-C(=NR 12 )R 10 -C 0-8 Alkyl-C(O)NR 11 R 12 or -C 0-8 Alkyl-N(R) 11 )-C(O)R 10 The substituents are replaced by the substituents.

[0114] "Alkoxy" refers to -O-alkyl, where alkyl is defined as described above, for example, "C 1-10 "Alkoxy" refers to an alkyloxy group containing 1-10 carbon atoms, C 1-4 "Alkoxy" refers to alkyloxy groups containing 1-4 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, butoxy, etc.

[0115] The "alkoxy group" can be optionally substituted or unsubstituted. When substituted, the substituent, preferably one or more (preferably 1, 2, 3, or 4) groups, is independently selected from deuterium, halogen, cyano, nitro, azido, C... 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 -C 0-8 Alkyl-OC(O)R 10 -C 0-8 Alkyl-NR 11 R 12 -C 0-8 Alkyl-C (=NR) 11 )R 10 -C 0-8 Alkyl-N(R) 11 )-C(=NR 12 )R 10 -C 0-8Alkyl-C(O)NR 11 R 12 or -C 0-8 Alkyl-N(R) 11 )-C(O)R 10 The substituents are replaced by the substituents.

[0116] "Cycloalkoxy" refers to -O-cycloalkyl, where cycloalkyl is defined as described above, for example, "C 3-12 "Cycloalkoxy" refers to a cycloalkyloxy group containing 3-12 carbons, "C 3-6 "Cycloalkoxy" refers to cycloalkyloxy groups containing 3-6 carbons, including but not limited to cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, etc.

[0117] The "cycloalkoxy" group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C64, halogen, cycloalkoxy ... 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 -C 0-8 Alkyl-OC(O)R 10 -C 0-8 Alkyl-NR 11 R 12 -C 0-8 Alkyl-C (=NR) 11 )R 10 -C 0-8 Alkyl-N(R) 11 )-C(=NR 12 )R 10 -C 0-8 Alkyl-C(O)NR 11 R 12 or -C 0-8 Alkyl-N(R) 11 )-C(O)R 10 The substituents are replaced by the substituents.

[0118] "Heterocyclic group" refers to -O-heterocyclic group, where the definition of heterocyclic group is as described above. Heterocyclic group oxygen groups include, but are not limited to, azirrocyclobutyroxy, oxocyclobutyroxy, azirrocyclopentyloxy, nitrogen, oxocyclohexyloxy, etc.

[0119] The "heterocyclic group" can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 5-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 -C 0-8 Alkyl-OC(O)R 10 -C 0-8 Alkyl-NR 11 R 12 -C 0-8 Alkyl-C (=NR) 11 )R 10 -C 0-8 Alkyl-N(R) 11 )-C(=NR 12 )R 10 -C 0-8 Alkyl-C(O)NR 11 R 12 or -C 0-8 Alkyl-N(R) 11 )-C(O)R 10 The substituents are replaced by the substituents.

[0120] “C 1-10 "alkylyl" refers to C 1-10 The monovalent group remaining after removing the hydroxyl group from an alkyl acid is usually also represented as "C". 0-9 "-C(O)-", for example, "C1-C(O)-" refers to acetyl; "C2-C(O)-" refers to propionyl; "C3-C(O)-" refers to butyryl or isobutyryl.

[0121] -C 0-8Alkyl-S(O) r "R8" refers to -S(O) r The sulfur atom in R8 is bonded to C. 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.

[0122] -C 0-8 "alkyl-O-R9" refers to the oxygen atom in -O-R9 being attached to the C-axis. 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.

[0123] -C 0-8 "alkyl-C(O)OR9" refers to the carbonyl group in -C(O)OR9 being attached to the C10 group. 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.

[0124] -C 0-8 Alkyl-C(O)R 10 "Referring to -C(O)R" 10 The carbonyl group in the C group is linked to the C group. 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.

[0125] -C 0-8 -OC(O)R 10 "Refers to -OC(O)R 10 The oxygen atom in C is attached to C 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.

[0126] -C 0-8 -NR 11 R 12 "Referring to -NR" 11 R 12 The nitrogen atom in C is attached to C 0-8 On alkyl groups, where C 1-8 The definition of alkyl is as described above.

[0127] -C 0-8 -C(=NR 11 )R 10 "Refers to -C(=NR)" 11 )R 10 The nitrogen atom in C is attached to C 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.

[0128] -C 0-8 -N(R 11 )-C(=NR 12 )R10 "Referring to -N(R)" 11 )-C(=NR 12 )R 10 The nitrogen atom in C is attached to C 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.

[0129] -C 0-8 -C(O)NR 11 R 12 "Refers to -C(O)NR" 11 R 12 The carbonyl group in the C group is linked to the C group. 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.

[0130] -C 0-8 -N(R 11 )-C(O)R 10 "Referring to -N(R)" 11 )-C(O)R 10 The nitrogen atom in C is attached to C 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.

[0131] "Hydrogen replaces C" 1-10 "Alkyl" refers to 1-10 carbon alkyl groups on an alkyl group in which the hydrogen atoms are optionally replaced by fluorine, chlorine, bromine, or iodine atoms, including but not limited to difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, etc.

[0132] "Hydrogen replaces C" 1-10 "Alkoxy" refers to 1-10 carbon alkoxy groups on an alkyl group, where the hydrogen atom is optionally replaced by a fluorine, chlorine, bromine, or iodine atom. These include, but are not limited to, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, and tribromomethoxy.

[0133] "Deuterium replaces C" 1-10 "Alkyl" refers to a 1-10 carbon alkyl group on an alkyl group in which the hydrogen atom is optionally replaced by a deuterium atom. This includes, but is not limited to, monodeuterylmethyl, dideuterylmethyl, trideuterylmethyl, etc.

[0134] "Halogen" refers to fluorine, chlorine, bromine, or iodine. "PE" refers to petroleum ether. "EtOAc" refers to ethyl acetate. "DCM" refers to dichloromethane.

[0135] "Optional" or "optionally" means that the event or environment described below may but does not have to occur. This description includes the possibility that the event or environment may or may not occur, that is, it includes both substituted and unsubstituted cases. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present. This description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0136] "Substituted" means that one or more "hydrogen atoms" in a group are independently replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, conforming to the valence bond theory in chemistry, and that a person skilled in the art can determine (through experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated bond (such as an alkene).

[0137] Stereoisomers, also known as cis-trans isomers, are isomers formed by different spatial arrangements of atoms in a molecule. They can be classified into two main categories: cis-trans isomers and enantiomers, or enantiomers and diastereomers. Stereoisomers resulting from the rotation of single bonds are called conformational stereo-isomers, sometimes also called rotamers. Stereoisomers resulting from bond length, bond angle, the presence of double bonds, or rings within the molecule are called configurational stereo-isomers. Configurational stereo-isomers are further divided into two categories. Those resulting from the inability of single bonds in double bonds or cyclic carbon atoms to rotate freely are called geometrical isomers, also known as cis-trans isomers, and have two configurations: Z and E. For example, cis-2-butene and trans-2-butene are a pair of geometric isomers. Stereoisomers with different optical properties due to the lack of antiaxial symmetry in their molecules are called optical isomers, which are classified into R and S configurations. In this invention, unless otherwise specified, "stereoisomer" can be understood to include one or more of the enantiomers, configuration isomers, and conformational isomers described above.

[0138] In this invention, "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable acid addition salt or base addition salt, including inorganic acid salts and organic acid salts, which can be prepared by methods known in the art.

[0139] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0140] The present invention will be further described in detail and completely below with reference to the embodiments, but this is by no means a limitation of the present invention, nor is the present invention limited to the contents of the embodiments.

[0141] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as solvents, and tetramethylsilane (TMS) as the internal standard.

[0142] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 6120 mass spectrometer. HPLC was performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high-performance liquid chromatograph (Gimini C18 150×4.6 mm column).

[0143] Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The TLC plate size is 0.15mm to 0.20mm, while the thin-layer chromatography separation and purification product size is 0.4mm to 0.5mm. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0144] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using or in accordance with methods known in the art.

[0145] Unless otherwise specified, all reactions in this invention are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, using a dry solvent, and the reaction temperature is expressed in degrees Celsius (°C).

[0146] I. Preparation of intermediates

[0147] Preparation of Intermediate 1: 2-Cyclopropyl-7-ethynyl-6,8-difluoroimidazo[1,2-a]pyridine

[0148]

[0149] Step 1: Synthesis of 2-cyclopropyl-6,8-difluoro-7-iodomizo[1,2-a]pyridine

[0150]

[0151] 3,5-Difluoro-4-iodopyridin-2-amine (1.0 g, 4.0 mmol) was dissolved in DMF (10 mL), and 2-bromo-1-cyclopropylethane-1-one (0.98 g, 6.0 mmol) was added. The mixture was stirred at 60 °C for 16 hours. After cooling to room temperature, it was filtered to give 2-cyclopropyl-6,8-difluoro-7-iodoimidazole[1,2-a]pyridine (640 mg, yield: 50%). MS m / z (ESI): 321 [M+H] + .

[0152] Step 2: Synthesis of 2-cyclopropyl-7-ethynyl-6,8-difluoroimidazo[1,2-a]pyridine

[0153]

[0154] 2-Cyclopropyl-6,8-difluoro-7-iodoimidazole[1,2-a]pyridine (320 mg, 1.0 mmol) was dissolved in DMF (5 mL), and tributyl(ethynyl)stanane (472 mg, 1.5 mmol) and tetrakis(triphenylphosphine)palladium (115.5 mg, 0.1 mmol) were added. The mixture was stirred in a microwave at 130 °C for 1 hour. After cooling to room temperature, the mixture was concentrated and separated by column chromatography to obtain 2-cyclopropyl-7-ethynyl-6,8-difluoroimidazole[1,2-a]pyridine (120 mg, yield: 55%). MS m / z (ESI): 219 [M+H] + .

[0155] Preparation of Intermediate 2: 2-Cyclopropyl-7-ethynyl-6-fluoroimidazolo[1,2-a]pyridine

[0156]

[0157] Step 1: Synthesis of 2-cyclopropyl-6-fluoro-7-iodoimidazole[1,2-a]pyridine

[0158]

[0159] 5-Fluoro-4-iodopyridin-2-amine (2.38 g, 10.0 mmol) was dissolved in DMF (20 mL), and 2-bromo-1-cyclopropylethane-1-one (2.44 g, 15.0 mmol) was added. The mixture was stirred at 60 °C for 16 hours. After cooling to room temperature, it was filtered to give 2-cyclopropyl-6-fluoro-7-iodoimidazole[1,2-a]pyridine (2.20 mg, yield: 73%). MS m / z (ESI): 303 [M+H] + .

[0160] Step 2: Synthesis of 2-cyclopropyl-7-ethynyl-6-fluoroimidazole[1,2-a]pyridine

[0161]

[0162] 2-Cyclopropyl-6-fluoro-7-iodoimidazole[1,2-a]pyridine (540 mg, 2.0 mmol) was dissolved in DMF (10 mL), and tributyl(ethynyl)stanane (1260 mg, 4.0 mmol) and tetrakis(triphenylphosphine)palladium (116 mg, 0.1 mmol) were added. The mixture was stirred at 60 °C for 16 hours. After cooling to room temperature, the mixture was concentrated and separated by column chromatography to obtain 2-cyclopropyl-7-ethynyl-6-fluoroimidazole[1,2-a]pyridine (140 mg, yield: 40%). MS m / z (ESI): 175 [M+H] + .

[0163] Preparation of intermediate 3: 2-Cyclopropyl-5-ethynylbenzo[d]oxazole

[0164]

[0165] Step 1: Synthesis of N-(5-bromo-2-hydroxyphenyl)cyclopropaneformamide

[0166]

[0167] 2-Amino-4-bromophenol (2.0 g, 10.6 mmol) was dissolved in DCM (30 mL), and triethylamine (1.29 g, 12.8 mmol) and cyclopropylformyl chloride (1.11 g, 10.6 mmol) were added sequentially at 0 °C. The mixture was stirred at 0 °C for 1 hour, diluted with aqueous sodium bicarbonate solution, and extracted with DCM. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, column chromatography was used to obtain N-(5-bromo-2-hydroxyphenyl)cyclopropylformamide (1.34 g, yield: 49%). MS m / z (ESI): 256 / 258 [M+H] + .

[0168] Step 2: Synthesis of 5-bromo-2-cyclopropylbenzo[d]oxazole

[0169]

[0170] N-(5-bromo-2-hydroxyphenyl)cyclopropylformamide (1.04 g, 4.06 mmol) was dissolved in acetonitrile (30 mL), and triphenylphosphine (4.26 g, 16.2 mmol) and carbon tetrachloride (1.25 g, 8.1 mmol) were added sequentially at room temperature. The mixture was stirred at 60 °C for 1 hour, diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, column chromatography was used to obtain 5-bromo-2-cyclopropylbenzo[d]oxazole (548 mg, yield: 55%). MS m / z (ESI): 238 / 240 [M+H] + .

[0171] Step 3: Synthesis of 2-cyclopropyl-5-((trimethylsilyl)ethynyl)benzo[d]oxazole

[0172]

[0173] 5-Bromo-2-cyclopropylbenzo[d]oxazole (200 mg, 0.84 mmol) was placed in DMF (3 mL), and triethylamine (1 mL), cuprous iodide (16 mg, 0.084 mmol), trimethylsilylacetylene (825 mg, 8.4 mmol), and tetratetraphenylphosphine palladium (49 mg, 0.042 mmol) were added sequentially at room temperature. The mixture was stirred at 80 °C for 16 hours, diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain 2-cyclopropyl-5-((trimethylsilyl)acetylene)benzo[d]oxazole (204 mg, yield: 95%). MS m / z (ESI): 256 [M+H] + .

[0174] Step 4: Synthesis of 2-cyclopropyl-5-ethynylbenzo[d]oxazole

[0175]

[0176] 2-Cyclopropyl-5-((trimethylsilyl)ethynyl)benzo[d]oxazole (204 mg, 0.8 mmol) was dissolved in methanol (8 mL), and potassium carbonate (1.1 g, 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 separated by column chromatography to give 2-cyclopropyl-5-ethynylbenzo[d]oxazole (112 mg, yield: 76%). MS m / z (ESI): 184 [M+H] + .

[0177] Intermediates 4-7 are prepared using appropriate raw materials, following all or part of the synthesis method for intermediate 3.

[0178]

[0179] Preparation of Intermediate 8: 2-Cyclopropyl-5-ethynyl-6-fluorobenzo[d]thiazole

[0180]

[0181] Step 1: Synthesis of N-(5-bromo-2,4-difluorophenyl)cyclopropaneformamide

[0182]

[0183] 5-Bromo-2,4-difluoroaniline (1.04 g, 5.0 mmol) was dissolved in dichloromethane (20 mL), and cyclopropionyl chloride (572 mg, 5.5 mmol) was added. The mixture was stirred overnight at room temperature, and the solution was directly evaporated to dryness before column chromatography to obtain N-(5-bromo-2,4-difluorophenyl)cyclopropionamide (1.0 g, yield: 72%). MS m / z (ESI): 276 / 278 [M+H] + .

[0184] Step 2: Synthesis of N-(5-bromo-2,4-difluorophenyl)cyclopropyl methylthioamide

[0185]

[0186] N-(5-bromo-2,4-difluorophenyl)cyclopropylformamide (1.0 g, 3.6 mmol) and Lawson's reagent (750 mg, 1.85 mmol) were dissolved in acetonitrile (25 mL), heated to 85 °C, and stirred overnight. After the reaction was complete, this N-(5-bromo-2,4-difluorophenyl)cyclopropylformamide solution was used directly in the next experiment. MS m / z (ESI): 292 / 294 [M+H] + .

[0187] Step 3: Synthesis of 5-bromo-2-cyclopropyl-6-fluorobenzo[d]thiazole

[0188]

[0189] Sodium tert-butoxide (1.7 g, 18 mmol) was added to a cooled solution of N-(5-bromo-2,4-difluorophenyl)cyclopropylmethylthioamide, and the mixture was heated to 50 °C and stirred for 16 hours. After concentration, column chromatography was used to separate the solution to 5-bromo-2-cyclopropyl-6-fluorobenzo[d]thiazole (0.82 g, yield: 83%). MS m / z (ESI): 2712 / 274 [M+H]+ .

[0190] Step 4: Synthesis of 2-cyclopropyl-5-ethynyl-6-fluorobenzo[d]thiazole

[0191]

[0192] 5-Bromo-2-cyclopropyl-6-fluorobenzo[d]thiazole (0.82 g, 3.0 mmol) was dissolved in DMF (15 mL), and tributyl(ethynyl)stanane (1.9 g, 6.0 mmol) and tetrakis(triphenylphosphine)palladium (173 mg, 0.15 mmol) were added. The mixture was stirred at 130 °C for 0.5 h in a microwave reactor. After concentration, column chromatography was used to obtain 2-cyclopropyl-5-ethynyl-6-fluorobenzo[d]thiazole (0.16 g, yield: 25%). MS m / z (ESI): 218 [M+H] + .

[0193] Intermediates 9-10 are prepared by selecting appropriate raw materials according to all or part of the synthesis method of intermediate 8:

[0194]

[0195] Preparation of Intermediate 11: 2-Cyclopropyl-5-ethynyl-4,6-difluorobenzo[d]thiazole

[0196]

[0197] Step 1: Synthesis of N-(2,4-difluorophenyl)cyclopropaneformamide

[0198]

[0199] 2,4-Difluoroaniline (10 g, 77.45 mmol) was dissolved in dichloromethane (100 mL), and triethylamine (15.64 g, 154.9 mmol) was added. Cyclopropylformyl chloride (8.1 g, 77.45 mmol) was added dropwise under ice bath conditions, and the mixture was stirred overnight at room temperature. The reaction solution was washed with appropriate amounts of saturated ammonium chloride aqueous solution and saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography to obtain N-(2,4-difluorophenyl)cyclopropylformamide (10.1 g, yield: 66%). MS m / z (ESI): 196 [M+H] + .

[0200] Step 2: Synthesis of N-(2,4-difluorophenyl)cyclopropyl methylthioamide

[0201]

[0202] N-(2,4-difluorophenyl)cyclopropylformamide (5 g, 25.36 mmol) was dissolved in xylene (80 mL), and Lawson's reagent (7.18 g, 17.75 mmol) was added. The mixture was heated to 120 °C and stirred overnight. After concentration, N-(2,4-difluorophenyl)cyclopropylmethylthioamide (4.1 g, yield: 75%) was obtained by direct silica gel column chromatography. MS m / z (ESI): 212 [M+H] + .

[0203] Step 3: Synthesis of 2-cyclopropyl-4,6-difluorobenzo[d]thiazole

[0204]

[0205] N-(2,4-difluorophenyl)cyclopropylmethylthioamide (1 g, 4.69 mmol) was dissolved in sodium hydroxide solution (1.69 g, 42.21 mmol, 5 mL ethanol, and 10 mL water). The resulting solution was added dropwise to a K3Fe(CN)6 aqueous solution preheated to 90 °C (6.18 g, 18.78 mmol, and 10 mL water). After stirring for 2 hours, heating was immediately stopped. After cooling, the solution was adjusted to weakly acidic with concentrated hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, concentrated, and separated by silica gel column chromatography to obtain 2-cyclopropyl-4,6-difluorobenzo[d]thiazole (500 mg, yield: 51%). MS m / z (ESI): 212 [M+H] + .

[0206] Step 4: Synthesis of 2-cyclopropyl-4,6-difluorobenzo[d]thiazole-5-carboxaldehyde

[0207]

[0208] 2-Cyclopropyl-4,6-difluorobenzo[d]thiazole (980 mg, 4.64 mmol) was dissolved in tetrahydrofuran (15 mL) and cooled to -70 °C. LDA (2.55 mL, 5.104 mmol, 2 M) was added dropwise, and the mixture was kept at this temperature for 2 hours. DMF (1.01 g, 13.92 mmol) was then added, and the mixture was kept at this temperature for another 2 hours. The reaction was quenched with an appropriate amount of ammonium chloride aqueous solution and brought to room temperature. The reaction mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. Silica gel column chromatography was used to separate the solution to 2-cyclopropyl-4,6-difluorobenzo[d]thiazole-5-carboxaldehyde (675 mg, yield: 65%). MS m / z (ESI): 240 [M+H] + .

[0209] Step 5: Synthesis of 2-cyclopropyl-5-ethynyl-4,6-difluorobenzo[d]thiazole

[0210]

[0211] 2-Cyclopropyl-4,6-difluorobenzo[d]thiazol-5-carboxaldehyde (122 mg, 0.51 mmol) was dissolved in methanol (10 mL), followed by the addition of potassium carbonate (211 mg, 1.53 mmol) and dimethyl (1-diazo-2-oxo-propanol)-phosphonate (159 mg, 0.76 mmol). The mixture was stirred overnight at room temperature. Direct concentration followed by silica gel column chromatography yielded 2-cyclopropyl-5-ethynyl-4,6-difluorobenzo[d]thiazolium (73 mg, yield: 61%). MS m / z (ESI): 236 [M+H] + .

[0212] Intermediate 12 is prepared by selecting appropriate raw materials according to all or part of the synthesis method of intermediate 11:

[0213]

[0214] Preparation of Intermediate 13: 5-ethynyl-6-fluoro-N-methylbenzo[d]oxazol-2-amine

[0215]

[0216] Step 1: Synthesis of 2-amino-4-bromo-5-fluorophenol

[0217]

[0218] 4-Bromo-5-fluoro-2-nitrophenol (5.00 g, 21.2 mmol) was dissolved in tetrahydrofuran / water (60 mL / 30 mL), and ammonium chloride (5.66 g, 105.9 mmol) and zinc powder (6.89 g, 105.9 mmol) were added sequentially at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction solution was filtered, washed with ethyl acetate (50 mL), extracted separately, concentrated the organic phase, and separated by column chromatography to obtain 2-amino-4-bromo-5-fluorophenol (3.2 g, yield: 73%). MS m / z (ESI): 206 / 208 [M+H] + .

[0219] Step 2: Synthesis of 5-bromo-6-fluorobenzo[d]oxazol-2(3H)-thione

[0220]

[0221] 2-Amino-4-bromo-5-fluorophenol (3.2 g, 15.5 mmol) was placed in ethanol (50 mL), and potassium ethylsulfonate (2.48 g, 15.5 mmol) was added at room temperature. The mixture was stirred at 80 °C for 17 hours. The reaction solution was directly concentrated and separated by column chromatography to give 5-bromo-6-fluorobenzo[d]oxazol-2(3H)-thione (1.80 g, yield: 47%). MS m / z (ESI): 248 / 250 [M+H] + Step 3: Synthesis of 5-bromo-2-chloro-6-fluorobenzo[d]oxazole

[0222]

[0223] 1.76 g (7.1 mmol) of 5-bromo-6-fluorobenzo[d]oxazole-2(3H)-thione was dissolved in 15 mL of dichloromethane. 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 100 mL of dichloromethane, washed sequentially with 50 mL of saturated sodium bicarbonate solution and 50 mL of brine, and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and separated by column chromatography to obtain 1.30 g (73% yield) of 5-bromo-2-chloro-6-fluorobenzo[d]oxazole.

[0224] Step 4: Synthesis of 5-bromo-6-fluoro-N-methylbenzo[d]oxazol-2-amine

[0225]

[0226] 5-Bromo-2-chloro-6-fluorobenzo[d]oxazole (250 mg, 1.0 mmol) was placed in acetonitrile (5 mL), and an aqueous solution of methylamine (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 was diluted with brine (50 mL), extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give 5-bromo-6-fluoro-N-methylbenzo[d]oxazole-2-amine (245 mg, yield: 100%). MS m / z (ESI): 245 / 247 [M+H] + .

[0227] Step 5: Synthesis of 6-fluoro-N-methyl-5-((trimethylsilyl)ethynyl)benzo[d]oxazol-2-amine

[0228]

[0229] 5-Bromo-6-fluoro-N-methylbenzo[d]oxazol-2-amine (190 mg, 0.78 mmol) was placed in 1,4-dioxane / N,N-dimethylformamide (10 mL / 1 mL), and tributyl(trimethylsilylethynyl)tin (600 mg, 1.55 mmol) and tetrakis(triphenylphosphine)palladium (90 mg, 0.08 mmol) were added at room temperature. The mixture was reacted in a microwave oven at 120 °C for 6 hours. The reaction solution was directly concentrated and separated by column chromatography to give 6-fluoro-N-methyl-5-((trimethylsilyl)ethynyl)benzo[d]oxazol-2-amine (158 mg, yield: 78%). MS m / z (ESI): 263 [M+H] + .

[0230] Step 6: Synthesis of 5-ethynyl-6-fluoro-N-methylbenzo[d]oxazol-2-amine

[0231]

[0232] 158 mg (0.60 mmol) of 6-fluoro-N-methyl-5-((trimethylsilyl)ethynyl)benzo[d]oxazol-2-amine was placed in 10 mL of methanol, and 248 mg (1.80 mmol) of potassium carbonate was added at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction solution was directly concentrated and separated by column chromatography to obtain 95 mg (83%) of 5-ethynyl-6-fluoro-N-methylbenzo[d]oxazol-2-amine. MS m / z (ESI): 191 [M+H] + .

[0233] Intermediates 14-16 are prepared by selecting appropriate raw materials according to all or part of the synthesis method of intermediate 13:

[0234]

[0235] Preparation of Intermediate 17: 2-(acetidin-1-yl)-5-ethynyl-4,6-difluorobenzo[d]oxazole

[0236]

[0237] Step 1: Synthesis of 2-amino-3,5-difluorophenol

[0238]

[0239] 3,5-Difluoro-2-nitrophenol (10 g, 57.11 mmol) was dissolved in methanol (100 mL), palladium on carbon (1 g) was added, the mixture was stirred overnight at room temperature, filtered, and the filtrate was evaporated to dryness to give 2-amino-3,5-difluorophenol (8.5 g, yield: 100%), MS m / z (ESI): 146 [M+H]+ .

[0240] Step 2: Synthesis of 4,6-difluorobenzo[d]oxazol-2-thiol

[0241]

[0242] 2-Amino-3,5-difluorophenol (8.5 g, 58.62 mmol) was dissolved in ethanol (100 mL), and potassium O-ethyl disulfate (113 g, 70.34 mmol) was added. The mixture was heated to 95 °C overnight. After cooling and filtration, the filtrate was concentrated and separated by silica gel column chromatography to obtain 4,6-difluoro-1,3-benzoxazole-2-thiol (11 g, yield: 95.31%). MS m / z (ESI): 188 [M+H] + .

[0243] Step 3: Synthesis of 2-chloro-4,6-difluorobenzo[d]oxazole

[0244]

[0245] 4,6-Difluoro-1,3-benzoxazole-2-thiol (4 g, 21.37 mmol) was dissolved in dichloromethane (50 mL), and oxalyl chloride (10.85 g, 85.48 mmol) and N,N-dimethylformamide (0.16 g, 2.14 mmol) were added. The mixture was stirred at room temperature for 2 hours, and then evaporated to dryness to obtain crude 2-chloro-4,6-difluorobenzo[d]oxazole (4.05 g, yield: 100%), which was used directly in the next reaction. MS m / z (ESI): 190 [M+H] + .

[0246] Step 4: Synthesis of 2-(acetidin-1-yl)-4,6-difluorobenzo[d]oxazole

[0247]

[0248] Crude 2-chloro-4,6-difluorobenzo[d]oxazole (4.05 g, 21.36 mmol) was dissolved in tetrahydrofuran (50 mL), and N,N-diisopropylethylamine (5.51 g, 42.72 mmol) and cyclobutane hydrochloride (2.40 g, 25.63 mmol) were added. The mixture was stirred at room temperature for 2 hours, and the reaction solution was evaporated to dryness. Ethyl acetate was added, and the solution was washed twice with saturated ammonium chloride aqueous solution and twice with saturated brine. Sodium sulfate was added, and the solution was dried and filtered. The filtrate was concentrated and separated by silica gel column chromatography to obtain 2-(acetidin-1-yl)-4,6-difluorobenzo[d]oxazole (3.2 g, yield: 72%). MS m / z (ESI): 211 [M+H] + .

[0249] Step 5: Synthesis of 2-(acetidin-1-yl)-4,6-difluorobenzo[d]oxazol-5-carboxaldehyde

[0250]

[0251] 2-(acetidin-1-yl)-4,6-difluorobenzo[d]oxazole (3 g, 14.28 mmol) was dissolved in tetrahydrofuran (100 mL), cooled to -70 °C, and a tetrahydrofuran solution of lithium diisopropylamino in 10.7 mL (21.41 mmol, 2 M) was added dropwise. The mixture was stirred at low temperature for 1 hour, and then N,N-dimethylformamide (11.04 mL, 142.73 mmol) was added in one go. The mixture was stirred at low temperature for 2 hours, and the reaction was quenched with an appropriate amount of saturated ammonium chloride aqueous solution. After warming to room temperature, the mixture was extracted twice with ethyl acetate. The ethyl acetate phases were combined, washed twice with saturated brine, dried over sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated and separated by silica gel column chromatography to obtain 2-(acetidin-1-yl)-4,6-difluorobenzo[d]oxazole-5-carboxaldehyde (0.8 g, yield: 24%). MS m / z (ESI): 239 [M+H] + .

[0252] Step 6: Synthesis of 2-(acetidin-1-yl)-5-ethynyl-4,6-difluorobenzo[d]oxazole

[0253]

[0254] 2-(acadirin-1-yl)-4,6-difluorobenzo[d]oxazol-5-carboxaldehyde (0.8 g, 3.40 mmol) was dissolved in methanol (10 mL) and tetrahydrofuran (10 mL). Potassium carbonate (1.17 g, 8.5 mmol) and dimethyl (1.31 g, 6.80 mmol) phosphonate were added. The mixture was stirred at room temperature for two hours, concentrated, and the reaction was quenched with a suitable amount of saturated ammonium chloride aqueous solution. After warming to room temperature, the mixture was extracted twice with ethyl acetate, and the extracts were combined and washed twice with saturated brine. The solution was dried over sodium sulfate and filtered to obtain the filtrate. The filtrate was concentrated and separated by silica gel column chromatography to obtain 2-(acadirin-1-yl)-5-ethynyl-4,6-difluorobenzo[d]oxazol (0.75 g, yield: 94%). MS m / z (ESI): 235 [M+H] + .

[0255] Intermediate 18 is prepared by selecting appropriate raw materials according to all or part of the synthesis method of intermediate 17:

[0256]

[0257] Preparation of Intermediate 19: (S)-1-(1-Acryloylpyrrolidone-3-yl)-4-amino-3-iodo-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one

[0258]

[0259] Step 1: Synthesis of diethyl(2E,4E,6E)-3,6-dicyano-2,7-dihydroxyoctyl-2,4,6-trienedioate

[0260]

[0261] Sodium ethoxide (21%, 100 mL, 270.0 mmol) was dissolved in ethanol (80 mL). Diethyl oxalate (40 mL, 270.0 mmol) was added at 0 °C and stirred for 30 minutes, followed by (E)-hexane-3-enedionitrile (9.56 g, 90.0 mmol). The mixture was stirred at room temperature for 16 hours. After cooling to 0 °C, the solid was filtered, dissolved in 240 mL of water, and the pH was adjusted to approximately 4 with dilute hydrochloric acid, resulting in the precipitation of a large amount of solid. Filtration yielded diethyl(2E,4E,6E)-3,6-dicyano-2,7-dihydroxyoctyl-2,4,6-trienediate (10.0 g, yield: 36%). MS m / z (ESI): 307 [M+H] + .

[0262] Step 2: Synthesis of ethyl 3-cyano-1H-pyrrole-2-carboxylic acid ester

[0263]

[0264] Diethyl(2E,4E,6E)-3,6-dicyano-2,7-dihydroxyoctyl-2,4,6-trienidate (3.0 g, 10.0 mmol) was dissolved in ethyl acetate (50 mL), heated to 60 °C, and an ammonia / dioxane solution (50 mL, 20.0 mmol) was added and stirred for 16 hours. After cooling to room temperature, the solution was concentrated and separated by column chromatography to give ethyl 3-cyano-1H-pyrrole-2-carboxylic acid ester (380 mg, yield: 23%). MS m / z (ESI): 165 [M+H] + .

[0265] Step 3: Synthesis of ethyl(S)-1-(1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-cyano-1H-pyrrole-2-carboxylic acid ester

[0266]

[0267] Ethyl 3-cyano-1H-pyrrole-2-carboxylic acid ester (380.0 mg, 2.3 mmol), tert-butyl(R)-3-((methanesulfonyl)oxy)pyrrolidin-1-carboxylic acid ester (676 mg, 2.5 mmol), and cesium carbonate (1.6 g, 5.0 mmol) were dissolved in N,N-dimethylformamide (10 mL) and heated to 80 °C with stirring for 16 hours. The mixture was then cooled to room temperature, evaporated to dryness, and separated by column chromatography to give ethyl(S)-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-cyano-1H-pyrrole-2-carboxylic acid ester (650 mg, yield: 85%). MS m / z (ESI): 334 [M+H] + .

[0268] Step 4: Synthesis of ethyl(S)-1-(1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-cyano-4-iodo-1H-pyrrole-2-carboxylic acid ester

[0269]

[0270] Ethyl (S)-1-(1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-cyano-1H-pyrrole-2-carboxylic acid ester (100 mg, 0.3 mmol) and N-iodosuccinimide (675 mg, 0.9 mmol) were dissolved in a 1:1 mixture of N,N-dimethylformamide and acetic acid (4 mL) and stirred at room temperature for 16 hours. The solution was evaporated to dryness and separated by column chromatography to obtain ethyl (S)-1-(1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-cyano-4-iodo-1H-pyrpyrrole-2-carboxylic acid ester (100 mg, yield: 72%). MS m / z (ESI): 460 [M+H] + .

[0271] Step 5: Synthesis of tert-butyl(S)-3-(4-amino-3-iodo-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)pyrrolidine-1-carboxylic acid ester

[0272]

[0273] Ethyl (S)-1-(1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-cyano-4-iodo-1H-pyrrole-2-carboxylic acid ester (100 mg, 0.2 mmol) was dissolved in ethanol (5 mL) and 1 mL of hydrazine hydrate was added. The mixture was stirred at 70 °C for 16 hours. The solution was evaporated to dryness to give tert-butyl (S)-3-(4-amino-3-iodo-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)pyrrolidine-1-carboxylic acid ester (100 mg, yield: 100%). MS m / z (ESI): 446 [M+H] + .

[0274] Step 6: Synthesis of (S)-4-amino-3-iodo-1-(pyrrolidine-3-yl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one

[0275]

[0276] 100 mg (0.2 mmol) of tert-butyl(S)-3-(4-amino-3-iodo-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl)pyrrolidine-1-carboxylic acid ester was dissolved in 5 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 2 hours. The system was evaporated to dryness to give ethyl(S)-4-amino-3-iodo-1-(pyrrolo-3-yl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (70 mg, yield: 97%). MS m / z (ESI): 346 [M+H] + .

[0277] Step 7: Synthesis of (S)-1-(1-Acryloylpyrrolidone-3-yl)-4-amino-3-iodo-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one

[0278]

[0279] Ethyl(S)-4-amino-3-iodo-1-(pyrrolidone-3-yl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (70 mg, 0.2 mmol) was dissolved in N,N-dimethylformamide (5 mL), followed by acrylic acid (22 mg, 0.3 mmol), then O-(7-azabenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (115 mg, 0.3 mmol), and finally diisopropylethylamine (129 mg, 1.0 mmol). The mixture was stirred at room temperature for 2 hours. The solution was evaporated to dryness and separated by column chromatography to obtain (S)-1-(1-acryloylpyrrolidone-3-yl)-4-amino-3-iodo-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (40.0 mg, yield: 50%). MSm / z (ESI): 400 [M+H] + .

[0280] II. Preparation of Specific Embodiments

[0281] Example 1: Preparation of (S)-1-(1-Acryloylpyrrolidone-3-yl)-4-amino-3-((2-cyclopropyl-6,8-difluoroimidazo[1,2-a]pyridin-7-yl)ethynyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one

[0282]

[0283] (S)-1-(1-acryloylpyrrolidone-3-yl)-4-amino-3-iodo-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (40 mg, 0.1 mmol), 2-cyclopropyl-7-ethynyl-6,8-difluoroimidazo[1,2-a]pyridine (30 mg, 0.13 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (4.0 mg, 0.01 mmol), and cuprous iodide (1.9 mg, 0.01 mmol) were dissolved in N,N-dimethylformamide (2.5 mL), and triethylamine (0.5 mL) was added. The mixture was stirred at 60 °C for 1 hour. The solution was evaporated to dryness and separated by column chromatography to obtain (S)-1-(1-acryloylpyrrolidone-3-yl)-4-amino-3-((2-cyclopropyl-6,8-difluoroimidazo[1,2-a]pyridin-7-yl)ethynyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (5.0 mg, yield: 10.2%). MS m / z (ESI): 490 [M+H] + .

[0284] 1 H NMR (400MHz, DMSO-d6): δ11.57 (d, J=3.6Hz, 1H), 8.72 (d, J=4.6Hz, 1H), 8.09 (d, J =21.0Hz, 1H), 7.92 (d, J = 3.2Hz, 1H), 6.75-6.45 (m, 1H), 6.24-6.12 (m, 1H), 6.11-5 .92(m, 1H), 5.76-5.64(m, 1H), 5.57(brs, 2H), 4.15-3.91(m, 1H), 3.90-3.49(m, 3 H), 2.47-2.27(m, 2H), 2.18-2.01(m, 1H), 1.04-0.96(m, 2H), 0.91(d, J=6.7Hz, 2H)

[0285] Examples 2-18 were prepared using appropriate raw materials, following all or part of the synthesis method described in Example 1:

[0286]

[0287]

[0288]

[0289]

[0290]

[0291] The NMR data of the compounds prepared in the above examples are as follows:

[0292]

[0293]

[0294] Biological testing evaluation

[0295] I. Proliferation assay of BaF3-Tel-FGFR2 WT and various mutant FGFR2 cells

[0296] In this invention, the compounds were used to determine the proliferation effects of Baf3-Tel-FGFR2 WT and various mutant FGFR2 cells by transfection with a cell line that stably expressed the TEL-FGFR2 WT intracellular kinase domain fusion protein or a cell line containing intracellular domain fusion proteins with FGFR2 V564I, V564F, V564L, N549K, and K659M mutations. The specific experimental procedure is as follows:

[0297] 1) Seed 90 μL of cell suspension in growth medium (DMEM containing 1% Glutamax, 10% FBS and 1% Pen / Strep, totaling 2000-4000 cells per well) in 96-well plates and incubate overnight at 37°C and 5% CO2.

[0298] 2) Add 10 μL of growth medium containing a 10-fold stock solution of the test compound to the cell culture (9 dose points, 3x serial dilutions, starting from 1 μM and ending with 0.3% DMSO).

[0299] 3) Incubate at 37℃ and 5% CO2 for 48 hours.

[0300] 4) Add 50 μL of CellTiter Glo (CTG) reagent to a 96-well plate containing cells and incubate the plate at room temperature for 10 minutes.

[0301] 5) Measure the RLU (Relative Light Unit) on a microplate reader with a light emission detection module. Normalize the RLU values ​​to survival percentage and plot concentration-response curves using Prism to calculate IC. 50 (Unit: nM), the experimental results are shown in the table below.

[0302]

[0303]

[0304] II. Cell proliferation assays of BaF3-Tel-FGFR3 WT, FGFR3V555M, and FGFR3N540K cells

[0305] In this invention, the compounds were used to determine cell proliferation effects by transfecting Baf cells with a stable expression of the TEL-FGFR3WT intracellular kinase domain fusion protein, or cell lines containing intracellular domain fusion proteins with FGFR3V555M or FGFR3N540K mutations. The specific experimental procedure is as follows:

[0306] 1) Seed 90 μL of cell suspension in growth medium (DMEM containing 1% Glutamax, 10% FBS and 1% Pen / Strep, totaling 2000-4000 cells per well) in 96-well plates and incubate overnight at 37°C and 5% CO2.

[0307] 2) Add 10 μL of growth medium containing a 10-fold stock solution of the test compound to the cell culture (9 dose points, 3x serial dilutions, starting from 1 μM and ending with 0.3% DMSO).

[0308] 3) Incubate at 37℃ and 5% CO2 for 48 hours.

[0309] 4) Add 50 μL of CellTiter Glo (CTG) reagent to a 96-well plate containing cells and incubate the plate at room temperature for 10 minutes.

[0310] 5) Measure the RLU (Relative Light Unit) on a microplate reader with a light emission detection module. Normalize the RLU values ​​to survival percentage and plot concentration-response curves using Prism to calculate IC. 50 (Unit: nM), the experimental results are shown in the table below.

[0311]

[0312]

[0313] Based on the bioactivity data of the compounds in the specific embodiments, the series of compounds of the present invention have a strong inhibitory effect on both wild-type FGFR and mutant FGFR at the cellular level, and the inhibitory effect in mutant FGFR is not weakened.

[0314] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the above disclosure of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: The compound of formula (I) has the structure of formula (IIIa) or formula (IIIb): in, In the compound of formula (IIIa), Y1 is O or S; Each R1 is independently selected from hydrogen, deuterium, halogen, cyano, methyl, cyclopropyl, cyclobutyl, 3-4 membered heterocyclyl, -SF5, methoxy, ethoxy, carboxyl, acetyl, acetoxy, amino, methylamino and dimethylamino, and the above groups are optionally further substituted with one or more substituents selected from deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, difluoromethyl, trideuteriummethyl, dideuteriummethyl, cyclopropyl, cyclobutyl, 3-6 membered heterocyclyl, =O, -SF5, methoxy, ethoxy, carboxyl, acetyl, acetoxy, amino, methylamino and dimethylamino; Each R 2a and R 2b Each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteriomethyl, dideuteriomethyl, cyclopropyl, cyclobutyl, -SF5, methoxy, ethoxy, carboxyl, acetyl, acetoxy, amino, methylamino and dimethylamino.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: Selected from the following compounds:

3. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, comprising the following steps: or, in, Ring A, X, Y, Z, R1, R2, R3, R4, m and n are as defined in claim 1.

4. A pharmaceutical composition comprising: A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2; and A pharmaceutically acceptable carrier.

5. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2 in the preparation of a medicament for treating a tumor patient resistant to an FGFR inhibitor, wherein the tumor patient is a tumor patient having FGFR2 V564F, V564L, V564I, N549K and / or K659M mutations; or the tumor patient is a tumor patient having FGFR3 V555M, V555L and / or N540K mutations.

6. Use of a compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a tumor mediated by FGFR2 and / or FGFR3 kinase, wherein the tumor is selected from bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, thyroid cancer, skin cancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, B-cell lymphoma, Hodgkin's lymphoma or non-Hodgkin's lymphoma, hair-like lymphoma, glioblastoma, melanoma or rhabdomyosarcoma.

7. Use of a compound of formula (I) according to claim 1 or 2 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating leukemia mediated by FGFR2 and / or FGFR3 kinase, wherein the leukemia is adult T-cell leukemia, acute myeloid leukemia or Waldenstrom's macroglobulinemia.

8. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2 in the preparation of a medicament for preventing or treating non-Hodgkin's lymphoma mediated by FGFR2 and / or FGFR3 kinase, wherein the non-Hodgkin's lymphoma is Burkitt's lymphoma.

9. Use of a compound of formula (I) according to claim 1 or 2 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating myeloproliferative diseases, bone or cartilage cell disorders, or hypophosphatemia mediated by FGFR2 and / or FGFR3 kinases; wherein, The myeloproliferative disease is selected from polycythemia vera, essential thrombocythemia or primary myelofibrosis; The bone or cartilage cell disorder is selected from dysplasia, dwarfism, lethal teratogenicity (TD), Appel's syndrome, Crouzon's syndrome, Jackson-Weiss syndrome, Beare-Stevenson skin fold syndrome, Pfeiffer syndrome or cranial muscular dystrophy syndrome; The hypophosphatemia is selected from X-linked hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets or tumor-induced ovarian softening.

10. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2 in the preparation of a medicament for treating FGFR2 and / or FGFR3 kinase-mediated chondrodysplasia.

11. Use of a compound of formula (I) according to claim 1 or 2 or a pharmaceutically acceptable salt thereof in the preparation of a selective FGFR2 and / or FGFR3 inhibitor, wherein the inhibitor is used to treat diseases associated with abnormal expression or mutation of FGFR2 or FGFR3 receptors or abnormal expression and activity of the corresponding ligands.

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