Prodrug of indazole derivative, preparation method therefor and use thereof

Abstract

The present invention relates to a prodrug of an indazole derivative, a preparation method therefor and a use thereof. Specifically, the present invention relates to a prodrug compound represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, and a use thereof in treatment of diseases caused by FGFR mutations. Each group in general formula (I) is as defined in the description.

Description

A class of indazole derivative prodrugs, their preparation methods and uses Technical Field

[0001] This invention relates to a class of indazole derivative prodrugs, pharmaceutical compositions containing the prodrugs, synthetic methods for preparing the prodrugs and intermediates, and the use of the prodrugs and compositions in treating diseases caused by FGFR mutations, such as cancer. Background Technology

[0002] Fibroblast growth factor receptors (FGFRs) are a subfamily of tyrosine kinase receptors, comprising four isoforms: FGFR1, FGFR2, FGFR3, and FGFR4. Each FGFR consists of three distinct domains: an extracellular ligand-binding domain, a single-channel transmembrane domain, and an intracellular TK domain. Upon binding to fibroblast growth factor ligands (FGF), activated FGFRs phosphorylate several downstream signaling proteins, including PI3K-AKT, RAS-MAPK, and STAT. Therefore, FGFRs play crucial roles in numerous intracellular processes, including development, differentiation, survival, migration, and angiogenesis.

[0003] However, FGFR is susceptible to various somatic aberrations, resulting in common mutations such as overexpression, point mutations, and gene translocations, which can lead to carcinogenesis. FGFR overexpression caused by gene amplification, mutations in the FGFR EC region (extracellular domain) / TK region (kinase domain), and FGFR fusion can all cause FGFR signal dysregulation, thereby promoting the proliferation, survival, invasion, metastasis, and development of drug resistance of tumor cells, as well as the occurrence of tumor microenvironment (TME) angiogenesis and immune evasion [4]. FGFR aberrations account for about 7.1% of all solid tumor patients. The cancers most commonly affected by FGFR aberrations are urothelial carcinoma (32%), liver cancer (30%), cholangiocarcinoma (25%), breast cancer (18%), and gastric cancer (7%).

[0004] FGFR inhibitors inhibit tumor growth by blocking FGFR-mediated signaling pathways, making them a new option for targeted cancer therapy. Although many FGFR inhibitor compounds exhibit good biological activity and in vivo efficacy, in some cases it may be necessary to adjust their solubility or other properties to optimize their bioavailability. Summary of the Invention

[0005] This invention discloses novel prodrugs of a class of indazole derivatives, compositions containing the prodrugs, and their therapeutic uses, particularly as FGFR inhibitors. In some embodiments, the prodrugs are used to improve the solubility and oral bioavailability of the drug. In other embodiments, this invention relates to methods for preparing the prodrugs.

[0006] This invention provides a compound represented by general formula (I),

[0007] Or its pharmaceutically acceptable salts, hydrates, solvates, isotopic substitutes, or stereoisomers.

[0008] in,

[0009] X 1 N atom or CR 8 ;

[0010] X 2 N atom or CR 9 ;

[0011] X 3 N atom or CR 10 ;

[0012] X 4 N atom or CR 11 ;

[0013] X 5 N atom or CR 12 ;

[0014] Y is selected from O atom, S atom, -S(=O)-, -S(=O)2- and NR. 13 ;

[0015] Ring A is a 5-membered nitrogen-containing heteroaryl group, more preferably pyrazolyl or triazolyl;

[0016] R 0 For -LIN 1 -LIN 2 -LIN 3 -R 00 ,

[0017] Among them, LIN 1 Selected from chemical bonds, C 1-6 Alkylene and C 1-6 Ideonyl, LIN 2 Selected from chemical bonds, -O-, -S-, -C(=O)-, -OC(=O)-, -C(=O)-O-, -NR 13 -C(=O)-、-C(=O)-NR 13 -、 Among them, R a Selected from H atoms, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and metal cations; LIN 3 Selected from chemical bonds, C 1- 6-alkylene, C 1-6 imidene group, C 3-8Cycloalkylene and 3-8 membered heterocyclic alkylene groups; the C 1-6 Alkylene, C 1-6 imidene group, C 3-8 Cycloalkylene, 3-8 membered heterocyclic alkylene, C 1-6 Alkyl and C 1-6 Each haloalkyl group is independently selected from the D atom, C atom, or C atom. 1-6 Alkyl, C 1-6 Alkoxy, -OH, -COOH, -CN, halogen, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 The hydroxyalkyl group is substituted with one or more substituents;

[0018] R 00 Selected from H atoms, D atoms, C atoms 1-6 Alkyl, C 1-6 Alkyl group, -OH, -COOH, -NR 13 R 14 -CN, halogen, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(=O)-C 1-6 Alkyl group, -OC(=O)-C 1-6 Alkyl, -C(=O)-OC 1-6 Alkyl group, -NH-C(=O)-C 1-6 Alkyl group, -C(=O)-NH-C 1-6 Alkyl, C 6-10 Aryl, 5-8 quinone heteroaryl, C 3-8 cycloalkyl groups and 3-8 membered heterocyclic groups; the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-8 quinone heteroaryl, C 3-8 Cycloalkyl groups and 3-8 membered heterocyclic groups are each independently chosen to be bonded by the D atom, C atom, or C atom. 1-6 Alkyl, C 1-6 Alkyl group, -OH, -COOH, -NR 13 R 14 -CN, =O, halogen, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(=O)-C 1-6 Alkyl group, -OC(=O)-C 1-6 Alkyl, -C(=O)-OC 1-6Alkyl group, -NH-C(=O)-C 1-6 Alkyl group, -C(=O)-NH-C 1-6 Alkyl, C 3-8 It is substituted by one or more substituents of cycloalkyl and 3-8 membered heterocyclic groups;

[0019] R 1 and R 2 Each is independently selected from H atoms, -OH, and -SR. 15 -COOH, -NR 13 R 14 -NR 13 -C(=O)-NR 13 R 14 -NR 13 -C 1-6 Alkylene-C(=O)-NR 13 R 14 -NR 13 -C(=NR 13 )-NR 13 R 14 -C(=O)-NR 13 R 14 -C 1-6 Alkylene-NR 13 R 14 -OC 1-6 Alkylene-NR 13 R 14 -NR 13 -C 1-6 Alkylene-NR 13 R 14 -NR 13 -3-8 membered heterocyclic groups, -CN, halogens, C 1-6 Alkyl, C 1-6 Deuterated alkyl, -C 1-6 Alkylene-S(=O)2-C 1- 6-alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 6-10 Aryl, 5-10 heteroaryl, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently and optionally selected from C. 1-6 Alkyl, C 1-6Alkyl group, -OH, -COOH, -NR 13 R 14 -CN, halogen, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 The hydroxyalkyl group is substituted with one or more substituents;

[0020] R 3 Selected from H atoms, -OH, -SR 15 -COOH, -NR 13 R 14 -NR 13 -C(=O)-NR 13 R 14 -NR 13 -C(=NR 13 )-NR 13 R 14 -NR 13 -C 1-6 Alkylene-C(=O)-NR 13 R 14 -NR 13 -C(=NR 13 )-NR 13 R 14 -C(=O)-NR 13 R 14 -C 1-6 Alkylene-NR 13 R 14 -OC 1-6 Alkylene-NR 13 R 14 -NR 13 -C 1-6 Alkylene-NR 13 R 14 -NR 13 -3-8 membered heterocyclic groups, -CN, halogens, C 1-6 Alkyl, C 1-6 Deuterated alkyl, -C 1-6 Alkylene-S(=O)2-C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 cycloalkyl, C 5-15 Spirocycloalkyl, C 5-15Bridged cycloalkyl, 3-8 membered heterocyclic, 5-15 membered spiroheterocyclic and 5-15 membered bridged heterocyclic, wherein C 6- 10 Aryl, 5-10 heteroaryl, C 3-8 cycloalkyl, C 5-15 Spirocycloalkyl, C 5-15 Bridged cycloalkyl, 3-8 membered heterocyclic, 5-15 membered spirocyclic and 5-15 membered bridged heterocyclic are each independently selected from C. 1-6 Alkyl, C 1-6 Alkyl group, -OH, -COOH, -NR 13 R 14 -S(=O)2-C 1-6 Alkyl, -CN, Halogen, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 The hydroxyalkyl group is substituted with one or more substituents;

[0021] R 4 Selected from H atoms, -OH, -COOH, -NR 13 R 14 -NR 13 -C(=O)-NR 13 R 14 -C(=O)-NR 13 R 14 -C 1-6 Alkylene-NR 13 R 14 -CN, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups;

[0022] R 5 R 6 and R 7 Each is independently selected from H atoms, -OH, and -SR. 15 -COOH, -NR 13 R 14 -NR 13 -NR 13 R 14 -NR 13-C(=O)-NR 13 R 14 -NR 13 -C 1-6 Alkylene-C(=O)-NR 13 R 14 -NR 13 -C(=NR 13 )-NR 13 R 14 -C(=O)-NR 13 R 14 -C 1-6 Alkylene-NR 13 R 14 -OC 1-6 Alkylene-NR 13 R 14 -NR 13 -C 1- 6-alkylene-NR 13 R 14 -NR 13 -3-8 membered heterocyclic groups, -CN, halogens, C 1-6 Alkyl, C 1-6 Deuterated alkyl, -C 1- 6-alkylene-S(=O)2-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 6-10 Aryl, 5-10 heteroaryl, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently and optionally selected from C. 1-6 Alkyl, C 1-6 Alkyl group, -OH, -COOH, -NR 13 R 14 -CN, halogen, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 The hydroxyalkyl group is substituted with one or more substituents;

[0023] R 8 R 9 R 10 R 11 and R12 Each is independently selected from H atoms, -OH, and -SR. 15 -COOH, -NR 13 R 14 -NR 13 -C(=O)-NR 13 R 14 -NR 13 -C 1-6 Alkylene-C(=O)-NR 13 R 14 -NR 13 -C(=NR 13 )-NR 13 R 14 -C(=O)-NR 13 R 14 -C 1-6 Alkylene-NR 13 R 14 -OC 1-6 Alkylene-NR 13 R 14 -NR 13 -C 1-6 Alkylene-NR 13 R 14 -NR 13 -3-8 membered heterocyclic groups, -CN, halogens, C 1-6 Alkyl, C 1-6 Deuterated alkyl, -C 1-6 Alkylene-S(=O)2-C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 6-10 Aryl, 5-10 heteroaryl, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently and optionally selected from C. 1-6 Alkyl, C 1-6 Alkyl group, -OH, -COOH, -NR 13 R 14 -CN, halogen, C 1-6 Haloalkyl, C 1- 6-Hydroalkoxy and C 1-6 The hydroxyalkyl group is substituted with one or more substituents;

[0024] Each R 13 Independently selected from H atoms, -CN, -OH, -C(=O)H, -C(=O)-C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently and optionally selected from C. 1-6 Alkyl, C 1-6 Alkoxy, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 The hydroxyalkyl group is substituted with one or more substituents;

[0025] Each R 14 Independently selected from H atoms, -CN, -OH, -C(=O)H, -C(=O)-C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently and optionally selected from C. 1-6 Alkyl, C 1-6 Alkoxy, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 The hydroxyalkyl group is substituted with one or more substituents;

[0026] Or, R 13 R 14 Together with the N atom attached thereto, a 3-8 membered heterocyclic group is formed, wherein the 3-8 membered heterocyclic group is optionally selected from C. 1-6 Alkoxy, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Haloalkyl, C1-6 Halogenated alkoxy groups and C 1-6 The hydroxyalkyl group is substituted with one or more substituents;

[0027] Each R 15 Independently selected from H atoms, -CN, halogens, -OH, -C(=O)H, -C(=O)-C 1-6 Alkyl, C 1- 6-alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently and optionally selected from C. 1-6 Alkyl, C 1-6 Alkoxy, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 The hydroxyalkyl group is substituted with one or more substituents; and

[0028] m can be 0, 1, 2, or 3.

[0029] In some embodiments, the compound represented by general formula (I) is the compound represented by general formula (II).

[0030] in,

[0031] X 2 N atom or CR 9 ;

[0032] X 3 It is an N atom or CH;

[0033] X 4 It is an N atom or CH;

[0034] X 5 It is an N atom or CH;

[0035] X 6 For N atoms or CR 3c ;

[0036] R 3a R 3b and R 3c Each is independently selected from H atoms, -OH, and -SR. 15-COOH, -NR 13 R 14 -NR 13 -C(=O)-NR 13 R 14 -NR 13 -C(=NR 13 )-NR 13 R 14 -NR 13 -C 1-6 Alkylene-C(=O)-NR 13 R 14 -NR 13 -C(=NR 13 )-NR 13 R 14 -C(=O)-NR 13 R 14 -C 1-6 Alkylene-NR 13 R 14 -OC 1-6 Alkylene-NR 13 R 14 -NR 13 -C 1-6 Alkylene-NR 13 R 14 -NR 13 -3-8 membered heterocyclic groups, -CN, halogens, C 1-6 Alkyl, C 1-6 Deuterated alkyl, -C 1-6 Alkylene-S(=O)2-C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 cycloalkyl, C 5-15 Spirocycloalkyl, C 5-15 Bridged cycloalkyl, 3-8 membered heterocyclic, 5-15 membered spiroheterocyclic and 5-15 membered bridged heterocyclic, wherein C 6-10 Aryl, 5-10 heteroaryl, C 3-8 cycloalkyl, C 5-15 Spirocycloalkyl, C 5-15 Bridged cycloalkyl, 3-8 membered heterocyclic, 5-15 membered spirocyclic and 5-15 membered bridged heterocyclic are each independently selected from C. 1-6 Alkyl, C 1-6-alkoxy group, -OH, -COOH, -NR 13 R 14 -S(=O)2-C 1-6 Alkyl, -CN, Halogen, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 The hydroxyalkyl group is substituted with one or more substituents; and

[0037] R 0 R 1 R 2 R 4 R 5 R 6 R 7 R 8 R 9 R 13 R 14 and R 15 As defined in general formula (I).

[0038] In some embodiments, the compound represented by general formula (I) is a compound represented by general formula (II-1), (II-2), (II-3), (II-4), or (II-5).

[0039] Among them, R 0 R 1 R 2 R 4 R 5 R 6 R 7 R 8 R 9 R 3a R 3b and R 3c As defined in general formula (II).

[0040] In some embodiments, the compounds represented by general formula (I), (II), or (II-1) are compounds represented by general formula (III), or even compounds represented by general formula (IV).

[0041] in,

[0042] R 5 Selected from -NHR 13 -NH-C(=O)-NR 13 R 14 -NH-C 1-6 Alkylene-C(=O)-NR 13 R 14 -NH-C(=NH)-NHR13 -C 1-6 Alkylene-NR 13 R 14 -OC 1-6 Alkylene-NHR 14 -NH-C 1-6 Alkylene-NHR 13 -NH-3-8-membered heterocyclic group, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently and optionally substituted with one or more halogens; wherein each R 13 and R 14 Each is independently defined as in general formula (I); and

[0043] R 3 a is C 1-6 Alkyl or C 1-6 Deuterated alkyl groups.

[0044] In some embodiments, in the compounds represented by general formula (III) or (IV),

[0045] R 5 Selected from -NHR 13 and C 3-8 cycloalkyl, wherein the C 3-8 The cycloalkyl group may optionally be substituted with one or more halogens; wherein, R 13 As defined in general formula (I).

[0046] In some embodiments, in the compounds represented by general formula (III) or (IV),

[0047] R 5 Selected from -NH2, -NH(C 1-6 alkyl), -NH(C) 1-6 Halogenated alkyl), -NH(C) 1-6 (deuterated alkyl), C 3-8 cycloalkyl groups, C substituted with one or more halogens 3-8 cycloalkyl and -NH-C 3-8 Cycloalkyl.

[0048] In some embodiments, in the compounds represented by general formula (III) or (IV),

[0049] R 5 Selected from difluoromethyl, -NH2、

[0050] In some embodiments, R3a is a methyl group in the compounds represented by formula (III) or (IV).

[0051] In some embodiments, the compounds represented by general formulas (I), (II), or (II-2) are compounds represented by general formula (V), or even compounds represented by general formula (VI).

[0052] in,

[0053] R 9 Selected from H atoms, -OH, -COOH, -NR 13 R 14 -CN, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein R 13 and R 14 Each is defined independently by general formula (I); and

[0054] R 3a C 1-6 Alkyl or C 1-6 Deuterated alkyl groups;

[0055] In some embodiments, in the compounds represented by general formula (V) or (VI),

[0056] R 9 Selected from H atoms, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -CN, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 cycloalkyl and C 1-6 Halogenated alkyl groups.

[0057] In some embodiments, in the compounds represented by general formula (V) or (VI),

[0058] R 9 It is difluoromethyl.

[0059] In some embodiments, in compounds represented by general formula (V) or (VI), R 3a It is a methyl group.

[0060] In some embodiments, in compounds represented by general formulas (I), (II), (II-1), (II-2), (II-3), (II-4), (II-5), (III), (IV), (V), or (VI), R 0 Choose from any one of (i) to (v):

[0061] (i)-L 1 -OC(=O)-R 16 L 1 For chemical bonds, C 1-6 Alkylene or C 1-6 Ideonyl, R 16 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, 3-8 membered heterocyclic group, C 3-8 cycloalkyl, -NR 13 R 14 and -C 1-6 Alkylene-NR 13 R 14 The C 1-6 Alkylene, C 1-6 imidene group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently selected from the D atom, C ... 1-6 Alkyl, C 1-6 Alkyl group, -OH, -COOH, -NR 13 R 14 -CN, =O, halogen, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(=O)-C 1-6 Alkyl group, -OC(=O)-C 1-6 Alkyl, -C(=O)-OC 1-6 Alkyl group, -NH-C(=O)-C 1-6 Alkyl group, -C(=O)-NH-C 1-6 Alkyl, C 3-8 It is substituted by one or more substituents of cycloalkyl and 3-8 membered heterocyclic groups;

[0062] (ii)-C(=O)-R 17 , where R 17 Selected from C 1-6 Alkyl, 3-8 membered heterocyclic groups, C3-8 cycloalkyl, -NR 13 R 14 -C 1-6 Alkylene-NR 13 R 14 -NR 13 -C 1-6 Alkylene-NR 13 R 14 The C 1-6 Alkylene, C 1-6 Alkyl, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently selected from the D atom, C ... 1-6 Alkyl, C 1-6 Alkyl group, -OH, -COOH, -NR 13 R 14 -CN, =O, halogen, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(=O)-C 1-6 Alkyl group, -OC(=O)-C 1-6 Alkyl, -C(=O)-OC 1-6 Alkyl group, -NH-C(=O)-C 1-6 Alkyl group, -C(=O)-NH-C 1-6 Alkyl, C 3-8 It is substituted by one or more substituents of cycloalkyl and 3-8 membered heterocyclic groups;

[0063] (iii)-L 1 -C(=O)-OR 18 L 1 For chemical bonds, C 1-6 Alkylene or C 1-6 Ideonyl, R 18 Selected from -C 1-6 alkylene-3-8-membered heterocyclic group, -C 1-6 Alkylene-C 3-8 cycloalkyl, -C 1-6 Alkylene-NR 13 R 14 C 1-6 Alkyl, 3-8 membered heterocyclic groups, C 3-8 cycloalkyl, -C 1-6 Alkylene-OC(=O)-C 1-6 Alkyl, the C 1-6 Alkylene, C 1-6 imidene group, C 1-6 Alkyl, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently selected from the D atom, C ... 1-6Alkyl, C 1-6 Alkyl group, -OH, -COOH, -NR 13 R 14 -CN, =O, halogen, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(=O)-C 1-6 Alkyl group, -OC(=O)-C 1-6 Alkyl, -C(=O)-OC 1- 6-alkyl, -NH-C(=O)-C 1-6 Alkyl group, -C(=O)-NH-C 1-6 Alkyl, C 3-8 It is substituted by one or more substituents of cycloalkyl and 3-8 membered heterocyclic groups;

[0064] (iv)-C 1-6 alkylene-3-8-membered heterocyclic groups or -C 1-6 Alkylene-C 3-8 cycloalkyl, the C 1-6 Alkylene, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently selected from the D atom, C ... 1-6 Alkyl, C 1-6 Alkyl group, -OH, -COOH, -NR 13 R 14 -CN, =O, halogen, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1- 6-hydroxyalkyl, -C(=O)-C 1-6 Alkyl group, -OC(=O)-C 1-6 Alkyl group, -NH-C(=O)-C 1-6 Alkyl, C 3-8 Substituted with one or more substituents of cycloalkyl and 3-8 membered heterocyclic groups; and

[0065] (v) Among them, L 2 Selected from chemical bonds, C 1-6 Alkylene and -C 1-6 alkylene-O-, the C 1- 6-alkylene groups are optionally selected from the D atom, C atom, and C atom. 1-6 Alkyl, C 1-6 Alkyl group, -OH, -COOH, -NR 13 R 14 -CN, =O, halogen, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(=O)-C1-6 Alkyl group, -OC(=O)-C 1-6 Alkyl group, -NH-C(=O)-C 1-6 Alkyl, C 3-8 Replaced by one or more substituents of cycloalkyl and 3-8 membered heterocyclic groups, R a and R b Each is independently selected from H atoms and C atoms. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and metal cations.

[0066] In some embodiments, in compounds represented by general formulas (I), (II), (II-1), (II-2), (II-3), (II-4), (II-5), (III), (IV), (V), or (VI), R 0 Selected from:

[0067] (i)-C 1-6 Alkylene-OC(=O)-C 1-6 Alkyl, -C 1-6 Alkyl-substituted C 1-6 Alkylene-OC(=O)-C 1- 6-alkyl, -C 1-6 Alkylene-OC(=O)-3-8-membered heterocyclic group, -C 1-6 Alkylene-OC(=O)-3-8-membered heterocyclic-C(=O)-C 1-6 Alkyl, -C 1-6 Alkylene-OC(=O)-C 3-8 cycloalkyl, -C 1-6 Alkylene-OC(=O)-C 1-6 Alkylene-NH-C(=O)-C 1-6 Alkyl, -C 1-6 Alkylene-OC(=O)-C 1-6 Alkylene -COOH, -C 1-6 Alkylene-OC(=O)-NH(C) 1-6 Alkyl), -C 1-6 Alkylene-OC(=O)-OC 1-6 alkyl;

[0068] (ii)-C(=O)-C 1-6 Alkyl, -C(=O)-C 1-6 Haloalkyl, -C(=O)-C 1-6 Hydroxyalkyl, -C(=O)-C 3- 8-cycloalkyl, -C(=O)-C 1-6 Alkylene-NH-C(=O)-C 1-6 Alkyl, -C(=O)-C1-6 Alkylene-CN, -C(=O)-C 1-6 Alkylene groups - 3-8 membered heterocyclic groups containing nitrogen atoms, -C(=O)-C 1-6 Alkylene -COOH, -C(=O)-C 1-6 Alkylene-OC(=O)-C 1-6 Alkyl, -C(=O)-3-8 membered heterocyclic, -C(=O)-3-8 membered heterocyclic-3-8 membered heterocyclic, -C(=O)-NH-C 1-6 Alkylene-N(C) 1-6 Alkyl)2;

[0069] (iii)-C(=O)-OC 1-6 alkylene-3-8-membered heterocyclic group, wherein the 3-8-membered heterocyclic group is optionally selected from =O and C. 1- One or more substituents of the 6-alkyl group, -C(=O)-OC 1-6 Alkylene-N(C) 1-6 Alkyl)2、-C(=O)-OC 1- 6-alkylene-3-8 membered heterocyclic groups containing nitrogen atom, -C(=O)-OC 1-6 Alkyl, -C(=O)-OC 1-6 Hydroxyalkyl, -C(=O)-OC 1-6 Alkylene-OC(=O)-C 1-6 Alkyl, -C(=O)-O- with C 1-6 Alkyl-substituted C 1-6 Alkylene-OC(=O)-C 1-6 alkyl;

[0070] (iv)-C 1-6 alkylene-3-8-membered heterocyclic group, wherein the 3-8-membered heterocyclic group is optionally selected from =O and C. 1-6 Alkyl groups are substituted with one or more substituents; and

[0071] (v) Among them, L 2 Selected from chemical bonds, -C 1-6 alkylene-O- and --C 1-6 Alkyl-substituted C 1- 6-alkylene-O-,R a and R b Each is independently selected from H atoms and C atoms. 1-6 Alkyl and alkali metal cations.

[0072] In some embodiments, in compounds represented by general formulas (I), (II), (II-1), (II-2), (II-3), (II-4), (II-5), (III), (IV), (V), or (VI), R 0 Selected from -C 1-6 Alkylene-OC(=O)-C 1-6 Alkyl, -C 1-6 Alkylene-OC(=O)-C 1-6 Alkylene -COOH, -C(=O)-OC 1-6 Alkylene groups – 5-6 membered heterocyclic groups containing nitrogen atoms and -C(=O)-C 1-6 Alkylene-OC(=O)-C 1-6 alkyl.

[0073] In some embodiments, in compounds represented by general formulas (I), (II), (II-1), (II-2), (II-3), (II-4), (II-5), (III), (IV), (V), or (VI), R 0 Selected from:

[0074] In some embodiments, the compounds represented by general formulas (I), (II), (II-1) or (III) are compounds represented by general formulas (III-1), (III-2), (III-3) or (III-4).

[0075] Even compounds represented by general formulas (IV-1), (IV-2), (IV-3), or (IV-4),

[0076] in,

[0077] Each L 1 Each independently is C 1-6 Alkylene or C 1-6 Alkyl-substituted C 1-6 Alkylene;

[0078] R 16 Selected from C 1-6 Alkyl, 3-8 membered heterocyclic, -3-8 membered hypoheterocyclic -C(=O)-C 1-6 Alkyl, C 3-8 cycloalkyl, -C 1-6 Alkylene-NH-C(=O)-C 1-6 Alkyl, -C 1-6 Alkylene -COOH, -NH(C 1-6 alkyl) and C 1-6 Alkoxy;

[0079] R 17 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-8 cycloalkyl, -C 1-6 Alkylene-NH-C(=O)-C 1-6 Alkyl, -C 1-6 Alkylene-CN, -C 1-6 Alkylene - 3-8 membered heterocyclic groups containing nitrogen atom, -C 1-6 Alkylene -COOH, -C 1-6 Alkylene-OC(=O)-C 1-6 Alkyl, 3-8 membered heterocyclic, -3-8 membered heterocyclic, -3-8 membered heterocyclic, -NH-C 1-6 Alkylene-N(C) 1-6 Alkyl)2;

[0080] R 18 Selected from -C 1-6 alkylene-3-8-membered heterocyclic group, wherein the 3-8-membered heterocyclic group is optionally selected from =O and C. 1-6 Alkyl group with one or more substituents, -C 1-6 Alkylene-N(C) 1-6 Alkyl)2, -C 1-6 Alkylene - 3-8 membered heterocyclic groups containing nitrogen atoms, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-OC(=O)-C 1-6 Alkyl, -C 1-6 Alkyl-substituted C 1-6 Alkylene-OC(=O)-C 1-6 alkyl;

[0081] L 2 Selected from chemical bonds, -C 1-6 alkylene-O- and --C 1-6 Alkyl-substituted C 1-6 Alkylene-O-;

[0082] R a and R b Each is independently selected from H atoms and C atoms. 1-6 Alkyl and alkali metal cations; and

[0083] R 5 and R 3a As defined in general formula (III) or (IV).

[0084] In some embodiments, the compounds represented by general formulas (I), (II), (II-2) or (III) are compounds represented by general formulas (V-1), (V-2), (V-3) or (V-4).

[0085] Even compounds represented by general formulas (VI-1), (VI-2), (VI-3), or (VI-4),

[0086] in,

[0087] Each L 1 Each independently is C 1-6 Alkylene or C 1-6 Alkyl-substituted C 1-6 Alkylene;

[0088] R 16 Selected from C 1-6 Alkyl, 3-8 membered heterocyclic, -3-8 membered hypoheterocyclic -C(=O)-C 1-6 Alkyl, C 3-8 cycloalkyl, -C 1-6 Alkylene-NH-C(=O)-C 1-6 Alkyl, -C 1-6 Alkylene -COOH, -NH(C 1-6 alkyl) and C 1-6 Alkoxy;

[0089] R 17 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-8 cycloalkyl, -C 1-6 Alkylene-NH-C(=O)-C 1-6 Alkyl, -C 1-6 Alkylene-CN, -C 1-6 Alkylene - 3-8 membered heterocyclic groups containing nitrogen atom, -C 1-6 Alkylene -COOH, -C 1-6 Alkylene-OC(=O)-C 1-6 Alkyl, 3-8 membered heterocyclic, -3-8 membered heterocyclic, -3-8 membered heterocyclic, -NH-C 1-6 Alkylene-N(C) 1-6 Alkyl)2;

[0090] R 18 Selected from -C 1-6 alkylene-3-8-membered heterocyclic group, wherein the 3-8-membered heterocyclic group is optionally selected from =O and C. 1-6 Alkyl group with one or more substituents, -C 1-6Alkylene-N(C) 1-6 Alkyl)2, -C 1-6 Alkylene - 3-8 membered heterocyclic groups containing nitrogen atoms, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-OC(=O)-C 1-6 Alkyl, -C 1-6 Alkyl-substituted C 1-6 Alkylene-OC(=O)-C 1-6 alkyl;

[0091] L 2 Selected from chemical bonds, -C 1-6 alkylene-O- and --C 1-6 Alkyl-substituted C 1-6 Alkylene-O-;

[0092] R a and R b Each is independently selected from H atoms and C atoms. 1-6 Alkyl and alkali metal cations; and

[0093] R 9 and R 3a As defined in general formula (V) or (VI).

[0094] The compounds of typical general formulas (I), (II), (II-1), (II-2), (II-3), (II-4), (II-5), (III), (III-1), (III-2), (III-3), (III-4), (IV), (IV-1), (IV-2), (IV-3), (IV-4), (V), (V-1), (V-2), (V-3), (V-4), (VI), (VI-1), (VI-2), (VI-3), or (VI-4) of this invention include, but are not limited to, the following compounds:

[0095] The present invention also provides a method for preparing a compound of general formula (I), the method comprising:

[0096] The compound represented by the general formula (ID) and compound R 0 -LG 2 The reaction forms a compound of general formula (I);

[0097] in,

[0098] LG 2 The leaving group is preferably a halogen, methanesulfonyloxy, or p-toluenesulfonyloxy; and

[0099] X 1 To X 5 Y, ring A, R 0 To R 7 And m are as defined in general formula (I).

[0100] The present invention also provides a method for preparing a compound of general formula (I), the method comprising:

[0101] The compound represented by formula (IA) reacts with the compound represented by formula (IB) to form the compound represented by formula (IC), and the compound represented by formula (IC) is deprotected by the protecting group R. p To form a compound represented by general formula (ID), the compound represented by general formula (ID) and compound R 0 -LG 2 The reaction forms a compound of general formula (I);

[0102] Among them, R p It is tetrahydropyranyl, (trimethylsilyl)ethoxymethyl, p-methylbenzenesulfonyl, tert-butyl formate, benzyl or p-methoxybenzyl;

[0103] LG 1 The leaving group is preferably hydroxyl, halogen, methanesulfonyloxy, or p-toluenesulfonyloxy;

[0104] LG 2 The leaving group is preferably a halogen, methanesulfonyloxy, or p-toluenesulfonyloxy; and

[0105] X 1 To X 5 Y, ring A, R 0 To R 7 And m are as defined in general formula (I).

[0106] The present invention also provides a method for preparing a compound of general formula (II), the method comprising:

[0107] The compound represented by the general formula (IID) and compound R 0 -LG 2 The reaction forms a compound of general formula (II);

[0108] in,

[0109] LG 2 The leaving group is preferably a halogen, methanesulfonyloxy, or p-toluenesulfonyloxy; and

[0110] X 2 To X 6 R 1 R2 R 3a R 3b and R 4 To R 8 As defined in general formula (II).

[0111] The present invention also provides a method for preparing a compound of general formula (II), the method comprising:

[0112] The compound represented by formula (IIA) reacts with the compound represented by formula (IB) to form the compound represented by formula (IIB), wherein the compound represented by formula (IIB) is deprotected by the protecting group R. p To form a compound represented by general formula (IID), the compound represented by general formula (IID) and compound R 0 -LG 2 The reaction forms a compound of general formula (II);

[0113] Among them, R p It is tetrahydropyranyl, (trimethylsilyl)ethoxymethyl, p-methylbenzenesulfonyl, tert-butyl formate, benzyl or p-methoxybenzyl;

[0114] LG 1 The leaving group is preferably hydroxyl, halogen, methanesulfonyloxy, or p-toluenesulfonyloxy;

[0115] LG 2 The leaving group is preferably a halogen, methanesulfonyloxy, or p-toluenesulfonyloxy; and

[0116] X 2 To X 6 R 1 R 2 R 3a R 3b and R 4 To R 8 As defined in general formula (II).

[0117] The present invention also provides a method for preparing a compound of general formula (III), the method comprising:

[0118] The compound represented by general formula (IIID) and compound R 0 -LG 2 The reaction forms a compound of general formula (III);

[0119] in,

[0120] LG 2 The leaving group is preferably a halogen, methanesulfonyloxy, or p-toluenesulfonyloxy; and

[0121] R 5 and R 3a As defined in general formula (III).

[0122] The present invention also provides a method for preparing a compound of general formula (III), the method comprising:

[0123] The compound represented by formula (IIIA) reacts with the compound represented by formula (IIIB) to form the compound represented by formula (IIIC), and the compound represented by formula (IIIC) is deprotected by the protecting group R. p To form a compound represented by general formula (IIID), the compound represented by general formula (IIID) and compound R 0 -LG 2 The reaction forms a compound of general formula (III);

[0124] Among them, R p It is tetrahydropyranyl, (trimethylsilyl)ethoxymethyl, p-methylbenzenesulfonyl, tert-butyl formate, benzyl or p-methoxybenzyl;

[0125] LG 1 The leaving group is preferably hydroxyl, halogen, methanesulfonyloxy, or p-toluenesulfonyloxy;

[0126] LG 2 The leaving group is preferably a halogen, methanesulfonyloxy, or p-toluenesulfonyloxy; and

[0127] R 5 and R 3a As defined in general formula (III).

[0128] The present invention also provides a method for preparing a compound of general formula (III), the method comprising:

[0129] The compound represented by general formula (IIID) reacts with formaldehyde to form the compound represented by general formula (IIIE);

[0130] (a) The compound represented by general formula (IIIE) and The reaction forms a compound of general formula (III), wherein R 0 for

[0131] (b) The compound represented by general formula (IIIE) and The reaction forms a compound of general formula (III), wherein R 0 for LG 3The leaving group is preferably halogen, methanesulfonyloxy, or p-toluenesulfonyloxy, R 13 and R 14 As defined in general formula (III).

[0132] The present invention also provides a method for preparing a compound of general formula (III), the method comprising:

[0133] The compound represented by general formula (IIID) and The reaction proceeds to form a compound of general formula (IIIF), which is dissolved in THF / H2O to form a compound of general formula (III), wherein R 0 for

[0134] The present invention also provides a method for preparing a compound of general formula (III), the method comprising:

[0135] The compound represented by general formula (IIID) and The reaction forms a compound of general formula (III), wherein R 0 for

[0136] The present invention also provides a method for preparing a compound of general formula (III), the method comprising:

[0137] The compound represented by general formula (IIID) and The reaction forms a compound of general formula (IIIG), which reacts with... The reaction forms a compound of general formula (III), wherein R 0 for

[0138] The present invention also provides a method for preparing a compound of general formula (III), the method comprising:

[0139] The compound represented by general formula (IIID) and The reaction yields a compound of general formula (IIIH), which reacts with potassium isobutyrate to form a compound of general formula (III), wherein R 0 for

[0140] The present invention also provides a method for preparing a compound of general formula (III), the method comprising:

[0141] The compound represented by general formula (IIID) and The reaction forms a compound of general formula (III), wherein R 0 for

[0142] The present invention also provides a method for preparing a compound of general formula (III), the method comprising:

[0143] The compound represented by general formula (IIID) and The reaction forms a compound of general formula (III), wherein R 0 for

[0144] The present invention also provides a method for preparing a compound of general formula (IV), the method comprising:

[0145] The compound represented by the general formula (IVD) and compound R 0 -LG 2 The reaction forms a compound represented by general formula (IV);

[0146] in,

[0147] LG 2 The leaving group is preferably a halogen, methanesulfonyloxy, or p-toluenesulfonyloxy; and

[0148] R 5 and R 3a As defined in general formula (IV).

[0149] The present invention also provides a method for preparing a compound of general formula (IV), the method comprising:

[0150] The compound represented by formula (IVA) reacts with the compound represented by formula (IVB) to form the compound represented by formula (IVC), and the compound represented by formula (IVC) is deprotected by the protecting group R. p To form compounds represented by general formula (IVD), the compounds represented by general formula (IVD) and compound R 0 -LG 2 The reaction forms a compound represented by general formula (IV);

[0151] Among them, R p It is tetrahydropyranyl, (trimethylsilyl)ethoxymethyl, p-methylbenzenesulfonyl, tert-butyl formate, benzyl or p-methoxybenzyl;

[0152] LG 1The leaving group is preferably hydroxyl, halogen, methanesulfonyloxy, or p-toluenesulfonyloxy;

[0153] LG 2 The leaving group is preferably a halogen, methanesulfonyloxy, or p-toluenesulfonyloxy; and

[0154] R 5 and R 3a As defined in general formula (IV).

[0155] The present invention also provides a method for preparing a compound of general formula (V), the method comprising:

[0156] The compound represented by the general formula (VA) and compound R 0 -LG 2 The reaction forms a compound represented by general formula (V);

[0157] in,

[0158] LG 2 The leaving group is preferably a halogen, methanesulfonyloxy, or p-toluenesulfonyloxy; and

[0159] R 9 and R 3a As defined in general formula (V).

[0160] The present invention also provides a method for preparing a compound of general formula (VI), the method comprising:

[0161] The compound represented by general formula (VIA) and compound R 0 -LG 2 The reaction forms a compound represented by general formula (VI);

[0162] in,

[0163] LG 2 The leaving group is preferably a halogen, methanesulfonyloxy, or p-toluenesulfonyloxy; and

[0164] R 9 and R 3a As defined in general formula (VI).

[0165] The present invention also provides a pharmaceutical composition comprising a compound of general formula (I), (II), (II-1), (II-2), (II-3), (II-4), (II-5), (III), (III-1), (III-2), (III-3), (III-4), (IV), (IV-1), (IV-2), (IV-3), (IV-4), (V), (V-1), (V-2), (V-3), (V-4), (VI), (VI-1), (VI-2), (VI-3) or (VI-4) and one or more pharmaceutically acceptable excipients.

[0166] This invention relates to the use of compounds or pharmaceutical compositions comprising the general formulas (I), (II), (II-1), (II-2), (II-3), (II-4), (II-5), (III), (III-1), (III-2), (III-3), (III-4), (IV), (IV-1), (IV-2), (IV-3), (IV-4), (V), (V-1), (V-2), (V-3), (V-4), (VI), (VI-1), (VI-2), (VI-3) or (VI-4) in the preparation of FGFR inhibitors.

[0167] The present invention also relates to the use of compounds or pharmaceutical compositions comprising the general formulas (I), (II), (II-1), (II-2), (II-3), (II-4), (II-5), (III), (III-1), (III-2), (III-3), (III-4), (IV), (IV-1), (IV-2), (IV-3), (IV-4), (V), (V-1), (V-2), (V-3), (V-4), (VI), (VI-1), (VI-2), (VI-3) or (VI-4) in the preparation of medicaments for the treatment and / or prevention of tumors.

[0168] The present invention also relates to compounds or pharmaceutical compositions comprising the general formulas (I), (II), (II-1), (II-2), (II-3), (II-4), (II-5), (III), (III-1), (III-2), (III-3), (III-4), (IV), (IV-1), (IV-2), (IV-3), (IV-4), (V), (V-1), (V-2), (V-3), (V-4), (VI), (VI-1), (VI-2), (VI-3) or (VI-4), which are used as pharmaceuticals.

[0169] The present invention also relates to compounds or pharmaceutical compositions comprising the general formulas (I), (II), (II-1), (II-2), (II-3), (II-4), (II-5), (III), (III-1), (III-2), (III-3), (III-4), (IV), (IV-1), (IV-2), (IV-3), (IV-4), (V), (V-1), (V-2), (V-3), (V-4), (VI), (VI-1), (VI-2), (VI-3) or (VI-4), which are used as FGFR inhibitors.

[0170] The present invention also relates to compounds or pharmaceutical compositions comprising the general formulas (I), (II), (II-1), (II-2), (II-3), (II-4), (II-5), (III), (III-1), (III-2), (III-3), (III-4), (IV), (IV-1), (IV-2), (IV-3), (IV-4), (V), (V-1), (V-2), (V-3), (V-4), (VI), (VI-1), (VI-2), (VI-3) or (VI-4), for the treatment and / or prevention of tumors.

[0171] The present invention also relates to a method for inhibiting FGFR, comprising administering to a desired patient a therapeutically effective amount of a compound or pharmaceutical composition comprising the formula (I), (II), (II-1), (II-2), (II-3), (II-4), (II-5), (III), (III-1), (III-2), (III-3), (III-4), (IV), (IV-1), (IV-2), (IV-3), (IV-4), (V), (V-1), (V-2), (V-3), (V-4), (VI), (VI-1), (VI-2), (VI-3), or (VI-4).

[0172] The present invention also relates to a method for treating and / or preventing tumors, comprising administering to a desired patient a therapeutically effective amount of a compound or pharmaceutical composition comprising the formula (I), (II), (II-1), (II-2), (II-3), (II-4), (II-5), (III), (III-1), (III-2), (III-3), (III-4), (IV), (IV-1), (IV-2), (IV-3), (IV-4), (V), (V-1), (V-2), (V-3), (V-4), (VI), (VI-1), (VI-2), (VI-3), or (VI-4).

[0173] In some implementations, the tumor is cancer; the cancer is preferably urothelial carcinoma.

[0174] The pharmaceutical compositions of the present invention can be in various conventional dosage forms, such as tablets, aqueous suspensions, oil suspensions, dispersible powders, dispersible granules, emulsions, hard capsules, soft capsules, sterile aqueous solutions for injection, sterile oil-in-water microemulsions for injection, or suppositories. All of the above dosage forms can be prepared by conventional methods.

[0175] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0176] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds. The treatment methods of this invention can be administered alone or in combination with other treatments or therapeutic agents.

[0177] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to: the activity of the specific compound used, the patient's age, the patient's weight, the patient's health status, the patient's behavior, the patient's diet, the timing of administration, the route of administration, the rate of excretion, and the combination of drugs; in addition, the optimal treatment mode, such as the treatment regimen, the daily dosage of the compound, or the pharmaceutically acceptable type of salt, can be validated based on conventional treatment protocols.

[0178] Terminology Definition

[0179] For terms not defined herein, they shall have the meanings commonly understood by those skilled in the art. For terms defined herein, they shall have the meanings set forth in the specification.

[0180] The term "substitution" or "substituent" refers to the replacement of one or more hydrogen atoms by a specified group. When the substitution position is not specified, substitution can occur at any position, but it is only permitted if a stable or chemically viable chemical is formed.

[0181] The terms “optional” or “optionally” refer to events or conditions that are subsequently described as possible but not necessary to occur, and the description includes both the occurrence of the event or condition and the non-occurrence of the event or condition.

[0182] When any variable (e.g., R) appears more than once in the structure of a compound, its definition is independent in each case. For example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most 2 Rs, and R has independent options in each case.

[0183] The term "alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20) carbon atoms, preferably C14. 1-10 Alkyl, more preferably C 1-6 Alkyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 2,2-dimethylpropyl, 2-methylbutyl, n-hexyl, 2,2-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-3-ethylhexyl, n-decyl, and 3,3-diethylhexyl.

[0184] The term "alkylene" refers to a divalent functional group formed by removing one hydrogen atom from an alkyl group. Alkyl groups are defined above, such as -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, and -CH(C). 1-5 Alkyl) or similar structures.

[0185] The term "alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group having 2 to 6 (e.g., 2, 3, 4, 5, and 6) carbon atoms and at least one carbon-carbon double bond, wherein the carbon-carbon double bond can be located at any position within the alkenyl group, preferably C. 2- 5. Alkenyl groups. Examples of alkenyl groups include, but are not limited to, -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, -CH=CH-CH2-CH3, -CH2-CH=CH-CH3, -CH=CH-CH=CH2, -CH=C(CH3)-CH3 and -CH2-C(CH3)=CH2.

[0186] The term "alkenyl" refers to a divalent functional group formed by removing one hydrogen atom from an alkenyl group. Alkenyl groups are defined as above, such as -CH=CH-, -C(CH3)=CH-, -C(CH3)-CH=CH-, or similar structures.

[0187] The term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon group having 2 to 6 (e.g., 2, 3, 4, 5, and 6) carbon atoms and at least one carbon-carbon triple bond, wherein the carbon-carbon triple bond can be located at any position within the alkynyl group, preferably C.2-5 Alkyne groups. Examples of alkynyl groups include, but are not limited to, -C≡CH, -C≡C-CH3, -CH2-C≡CH, -C≡C-CH2-CH3, -CH2-CH2-C≡CH, -CH(CH3)C≡CH, and -CH2-C≡C-CH3.

[0188] The term "cycloalkyl" includes two categories: conventional cycloalkyl and heterocyclic cycloalkyl.

[0189] Conventional cycloalkyl groups refer to aliphatic saturated or partially unsaturated monovalent cycloalkyl groups having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20) carbon atoms, preferably C4. 3-12 Conventional cycloalkyl, more preferably C10 3-10 Conventional cycloalkyl, more preferably C 3-8 Conventional cycloalkyl groups, with C4 being the most preferred. 3-6 Conventional cycloalkyl groups. Conventional cycloalkyl groups optionally contain one or more double or triple bonds.

[0190] Conventional cycloalkyl groups can be monocycloalkyl groups, examples of which include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptanetrienyl, and cyclooctyl. Conventional cycloalkyl groups can also be polycycloalkyl groups (e.g., bicycloalkyl and tricycloalkyl groups), including spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl groups.

[0191] The term "spirocycloalkyl" refers to a 5-20 quintone (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 quintone) spirocycloalkyl, preferably a 6-14 quintone spirocycloalkyl, and more preferably a 7-10 quintone spirocycloalkyl. The spirocycloalkyl can be monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl, preferably monospirocycloalkyl, and more preferably 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 monospirocycloalkyl. Examples of spirocycloalkyl include, but are not limited to:

[0192] The term "fused cycloalkyl" refers to a 5-20 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 membered) fused cycloalkyl, preferably a 6-14 membered fused cycloalkyl, more preferably a 7-10 membered fused cycloalkyl. The fused cycloalkyl can be bicyclic, tricyclic, tetracyclic, or pentacyclic or more, preferably bicyclic or tricyclic fused cycloalkyl, more preferably a 5-membered / 5-membered or 5-membered / 6-membered fused cycloalkyl. Examples of fused cycloalkyl include, but are not limited to:

[0193] The term "bridged cycloalkyl" refers to a 5-20 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 membered) bridged cycloalkyl, preferably a 6-14 membered bridged cycloalkyl, more preferably a 7-10 membered bridged cycloalkyl. The bridged cycloalkyl can be bicyclic, tricyclic, tetracyclic, or pentacyclic or more, preferably bicyclic, tricyclic, or tetracyclic bridged cycloalkyl, more preferably bicyclic or tricyclic bridged cycloalkyl. Examples of bridged cycloalkyl include, but are not limited to:

[0194] The term "heterocyclic cycloalkyl" includes monocyclic alkyl, spirocyclic alkyl, fused cycloalkyl, and bridged cycloalkyl groups fused to any one selected from conventional aryl, conventional heteroaryl, and conventional heterocyclic groups, with the linkage site located on the corresponding conventional cycloalkyl group (referring to monocyclic alkyl, spirocyclic alkyl, fused cycloalkyl, or bridged cycloalkyl). Examples of heterocyclic cycloalkyl groups include, but are not limited to:

[0195] The term "cycloalkylene" refers to a divalent functional group formed by removing one hydrogen atom from a cycloalkyl group, as defined above.

[0196] The term "heterocyclic group" includes two categories: conventional heterocyclic groups and heterostructure heterocyclic groups.

[0197] Conventional heterocyclic groups refer to aliphatic saturated or partially unsaturated monovalent cyclic hydrocarbon groups having 3-20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20) ring atoms, wherein one or more ring atoms are substituted by one or more elements selected from nitrogen, oxygen, S, S(=O), and S(=O)2, and the substitution does not form -OO-, -OS-, or -SS-; preferably 3-12 membered conventional heterocyclic groups, wherein 1-4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably 3-10 membered or 3-8 membered conventional heterocyclic groups, wherein 1-3 (e.g., 1, 2, and 3) are heteroatoms; most preferably 5-7 membered or 4-6 membered conventional heterocyclic groups, wherein 1-2 or 1-3 are heteroatoms.

[0198] Conventional heterocyclic groups can be monocyclic heterocyclic groups, examples of which include, but are not limited to, oxoheterobutyl, azaheterobutyl, 3-pyrrolinyl, pyrrolylalkyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazoyl, dihydrofuranyl, dihydropyrazoleyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and tetrahydropyranyl, preferably 1,2,5-oxadiazolyl, tetrahydropyranyl, or morpholinyl. Conventional heterocyclic groups can also be polycyclic heterocyclic groups, including spirocyclic heterocyclic groups, fused-ring heterocyclic groups, and bridged-ring heterocyclic groups.

[0199] The term "spiroheterocyclic group" refers to a 5-20 ternary (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 ternary) spiroheterocyclic group, preferably a 6-14 ternary spiroheterocyclic group, and more preferably a 7-10 ternary spiroheterocyclic group. The spiroheterocyclic group can be a monospirocyclic, bispirocyclic, or multispirocyclic group, preferably a monospirocyclic or bispirocyclic group, and more preferably a 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 monospirocyclic group. Examples of spiroheterocyclic groups include, but are not limited to:

[0200] The term "fused heterocyclic group" refers to a 5-20 member (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 member) fused heterocyclic group, preferably a 6-14 member fused heterocyclic group, and more preferably a 7-10 member fused heterocyclic group. The fused heterocyclic group can be bicyclic, tricyclic, tetracyclic, or more than five-ring fused heterocyclic groups, preferably bicyclic or tricyclic fused heterocyclic groups, and more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Examples of fused heterocyclic groups include, but are not limited to:

[0201] The term "bridged heterocyclic group" refers to a 5-14 quinary (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14 quinary) bridged heterocyclic group, preferably a 6-14 quinary bridged heterocyclic group, and more preferably a 7-10 quinary bridged heterocyclic group. The bridged heterocyclic group can be bicyclic, tricyclic, tetracyclic, or more quinary or higher, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Examples of bridged heterocyclic groups include, but are not limited to:

[0202] The term "heterogeneous heterocyclic group" includes monocyclic, spirocyclic, fused-ring, and bridged-ring heterocyclic groups fused to any one selected from conventional aryl, conventional heteroaryl, and conventional cycloalkyl groups, with the linkage site located on the corresponding conventional heterocyclic group (referring to monocyclic, spirocyclic, fused-ring, or bridged-ring heterocyclic groups). Examples of heterocyclic heterocyclic groups include, but are not limited to:

[0203] The term "hybridized group" refers to a divalent functional group formed by removing one hydrogen atom from a heterocyclic alkyl group, as defined above.

[0204] The term "aryl" includes two categories: conventional aryl and heterostructure aryl.

[0205] Conventional aryl refers to 6-14 membered (e.g., 6, 7, 8, 9, 10, 11, 12, 13, and 14 membered) aromatic hydrocarbon groups, preferably C. 6-10 Conventional aryl groups, more preferably phenyl, naphthyl, phenanthryl or anthracene.

[0206] The term "heteroaryl" includes a conventional aryl group fused to any one selected from conventional heteroaryl, conventional heterocyclic, and conventional cycloalkyl groups, with the linkage site located on the conventional aryl group. Examples of heteroaryl groups include, but are not limited to:

[0207] The term "aryl" refers to a divalent functional group formed by removing one hydrogen atom from an aryl group, where the aryl group is as defined above.

[0208] The term "heteroaryl" includes two categories: conventional heteroaryl and heterostructure heteroaryl.

[0209] Conventional heteroaryl refers to a 5-14 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14 membered) aromatic hydrocarbon group in which 1-4 (e.g., 1, 2, 3, and 4) carbon atoms are replaced with heteroatoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Preferably, the number of ring atoms is 5-10, including 1-3 (e.g., 1, 2, and 3) heteroatoms. More preferably, the number of ring atoms is 5 or 6, including 1-2 heteroatoms. Examples of conventional heteroaryl groups include, but are not limited to, imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, pyrroleyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyridazinyl, pyrazinyl, quinolinyl, isoquinoline, naphridinyl, and imidazopyridinyl, preferably imidazolyl, thiazolyl, pyrazolyl, pyrimidinyl, or isothiazolyl, more preferably pyrazolyl or thiazolyl.

[0210] The term "hybrid heteroaryl" includes a conventional heteroaryl group fused to any one selected from conventional aryl, conventional cycloalkyl, and conventional heterocyclic groups, with the linkage site located on the conventional heteroaryl group. Examples of heteroaryl groups include, but are not limited to:

[0211] The term "hybrid aryl" refers to a divalent functional group formed by removing one hydrogen atom from a heteroaryl group, as defined above.

[0212] The term "alkoxy" includes -O-alkyl and -O-cycloalkyl, wherein "alkyl" and "cycloalkyl" are as defined above. Examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.

[0213] The term "halogenated alkyl" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above. Examples include trifluoromethyl, difluoromethyl, and trifluoroethyl.

[0214] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, where the alkoxy group is as defined above. Examples include trifluoromethoxy and difluoromethoxy.

[0215] The term “deuterated alkyl” refers to an alkyl group that is replaced by one or more deuterium atoms, wherein the alkyl group is as defined above.

[0216] The term “deuterated alkoxy” refers to an alkoxy group that is substituted by one or more deuterium atoms, as defined above.

[0217] The term "hydroxyalkyl" refers to the alkylene group -OH as described above.

[0218] The term "hydroxyl group" refers to -OH.

[0219] The term "halogen" refers to -F, -Cl, -Br, or -I.

[0220] The term "amino" refers to -NH2.

[0221] The term "cyano" refers to -CN.

[0222] The term "nitro" refers to -NO2.

[0223] The term "oxo group" refers to =O.

[0224] The term "carboxyl group" refers to -C(=O)OH.

[0225] The term "thiol" refers to -SH.

[0226] The term "ester group" refers to -C(=O)O-alkyl or -C(=O)O-cycloalkyl, where alkyl and cycloalkyl are as defined above.

[0227] The term "acyl" refers to -C(=O)R, where R is selected from alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups.

[0228] The term "metal cation" refers to a positively charged ion formed by the loss of electrons from a metal atom. Examples include monovalent ions such as sodium ions, potassium ions, and silver ions; divalent ions such as calcium ions, magnesium ions, ferrous ions, barium ions, zinc ions, copper ions, and mercury ions; and trivalent ions such as aluminum ions and iron ions.

[0229] The term "alkali metal cation" refers to the positive ion form of the first group of elements in the periodic table (lithium, sodium, potassium, rubidium, cesium, and francium).

[0230] symbol This refers to the connection site.

[0231] The term "stereoisomer" refers to isomers with the same structure but different spatial arrangements of atoms. These include cis and trans (or Z and E) isomers, (-)- and (+)- isomers, (R)- and (S)- enantiomers, diastereomers, (D)- and (L)- isomers, tautomers, blocked isomers, conformational isomers, and mixtures thereof (e.g., racemic mixtures, mixtures of diastereomers). Substituents in the compounds of this invention may contain additional asymmetric atoms. All such stereoisomers and mixtures thereof are included within the scope of this invention. Optically active (-)- and (+)- isomers, (R)- and (S)- enantiomers, and (D)- and (L)- isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. An isomer of a certain compound of the present invention can be prepared by asymmetric synthesis or with chiral auxiliaries, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), by forming a salt of the diastereomer with a suitable optically active acid or base, and then resolving the diastereomer using conventional methods known in the art to obtain the pure isomer. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by chromatography.

[0232] In the chemical structure of the compound described in this invention, the bond... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations. For all carbon-carbon double bonds, even if only one configuration is named, both the Z-type and E-type are included.

[0233] The compounds and intermediates of this invention may also exist in different tautomer forms, and all such forms are included within the scope of this invention. The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert via low energy barriers. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton transfer, such as keto-enol and imine-enamine, lactam-lactamimide isomerization.

[0234] The compounds of the present invention include all suitable isotopic substitutes thereof. The term "isotopic substitute" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be introduced into the compounds of the present invention include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, respectively. 2 H (deuterium, D) 3 H (tritium, T) 11 C 13 C 14 C15 N、 17 O、 18 O、 32 p、 33 p、 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl、 82 Br、 123 I, 124 I, 125 I, 129 I and 131 Grade I, with deuterium as the preferred grade.

[0235] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0236] When the term "about" is applied to parameters such as pH, concentration, and temperature, it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As those skilled in the art will understand, when a parameter is not critical, figures are usually given for illustrative purposes only, not as limitations. Detailed Implementation

[0237] The present disclosure is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0238] The compounds of this invention are prepared using convenient starting materials and common preparation steps. Typical or preferred reaction conditions are provided, such as reaction temperature, time, solvent, pressure, and molar ratio of reactants. However, unless otherwise specified, other reaction conditions may also be adopted. Optimal conditions may vary depending on the specific reactants or solvents used, but in general, the optimal reaction steps and conditions can be determined.

[0239] In addition, this invention may employ protecting groups to protect certain functional groups from unnecessary reactions. Suitable protecting groups for various functional groups and their protection or deprotection conditions are well known to those skilled in the art.

[0240] The separation and purification of compounds and intermediates are carried out using appropriate methods and procedures depending on specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin-layer chromatography, preparative high-performance liquid chromatography, or a combination of the above methods. Specific methods can be found in the examples described in this invention. Of course, other similar separation and purification methods can also be used. Conventional methods (including physical constants and spectroscopic data) can be used for characterization.

[0241] The purity analysis method is as follows: Kinetex EVO C18 (50×4.6mm, 5μm) was used. The chromatographic column was used with acetonitrile-water as the mobile phase for gradient elution at a flow rate of 1.5 mL / min and a detection wavelength of 220 nm.

[0242] MS measurements were performed using an LC (Agilent 1260 Infinity II) / MS (G6125B single quadrupole) mass spectrometer (manufacturer: Agilent) (Photodiode Array Detector).

[0243] The structure of the compound was determined by proton NMR spectroscopy using a WNMR-I-400MHz instrument.

[0244] Preparative liquid chromatography was performed using an Agilent 1260 Infinity II high-performance liquid chromatograph (manufacturer: Agilent). Column: Prep C18OBD™, 10μm, 19x250mm, mobile phase: water / acetonitrile = 100%-5% / 95%, gradient elution, with 0.1% formic acid added to the mobile phase by volume, flow rate: 20.0 mL / min

[0245] Thin-layer chromatography (TLC) uses Qingdao Ocean Chemical GF254 silica gel plates. The silica gel plates used for reaction monitoring in TLC are 0.20mm-0.25mm in size, while those used for separation and purification are 0.5mm in size.

[0246] Silica gel column chromatography uses Qingdao marine silica gel of 100-200 mesh, 200-300 mesh, and 300-400 mesh as carriers.

[0247] The known starting materials of this invention can be synthesized using or according to methods known in the art, or can be purchased from companies such as NetEase, Beijing Coupling, Sigma, Bailingwei, Yishiming, Shanghai Shuya, Shanghai Inokai, Anaiji Chemical, and Shanghai Bide.

[0248] Unless otherwise specified in the examples, all reactions were carried out under a nitrogen atmosphere.

[0249] A nitrogen atmosphere refers to a reaction flask connected to a nitrogen balloon with a volume of approximately 1L.

[0250] The reaction solvent, organic solvent, or inert solvent is defined as the solvent used in which it does not participate in the reaction under the described reaction conditions, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, dichloromethane (DCM), diethyl ether, methanol (MeOH), and N-methylpyrrolidone (NMP).

[0251] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0252] The chemical reactions described in this invention are generally carried out under normal pressure. The reaction time and conditions are, for example, at one atmosphere, between -78°C and 200°C, and are completed in approximately 1 to 24 hours. If the reaction is carried out overnight, the reaction time is generally 16 hours. Unless otherwise specified in the examples, the reaction temperature is room temperature, between 20°C and 30°C.

[0253] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be used in the methods of this invention.

[0254] Unless otherwise specified, all mixing ratios for different solvents are volume ratios.

[0255] Synthesis of key intermediate A1

[0256] Compound A1-1 (10 g, 74.55 mmol) was dissolved in DMF (100 mL) at room temperature. Imidazole (7.6 g, 111.82 mmol) and trimethylchlorosilane (13.4 g, 89.46 mmol) were added sequentially in an ice bath. After the addition was complete, the reaction mixture was stirred at room temperature for 5 h. LC-MS showed that the starting material reacted completely. The reaction mixture was quenched with water and then combined with EtOAc (200 mL x 3) and evaporated to dryness. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1) to give a yellow solid product A1-2 (16.74 g, purity 95%, yield 85.87%). LC-MS (ESI) m / z 249.13, (M+H) + .

[0257] Compound A1-2 (16.74 g, 67.39 mmol) was dissolved in DCM (150 mL) at room temperature, followed by the addition of NIS (18.2 g, 80.87 mmol). After the addition was complete, the reaction mixture was stirred at room temperature for 5 h. LCMS showed that the starting material reacted completely. The reaction mixture was quenched with water and then combined with DCM (100 mL x 3) and evaporated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to give a gray solid product A1-3 (23.8 g, purity 95%, yield 89.63%). LCMS (ESI) m / z 375.01, (M+H) + .

[0258] At room temperature, compounds A1-3 (23.8 g, 63.58 mmol) and A1-4 (29.1 g, 139.89 mmol) were dissolved in dioxane / H2O (250 mL, v / v = 3 / 1), followed by the addition of K2CO3 (35.1 g, 254.34 mmol). Pd(dppf)Cl2·DCM (2.6 g, 3.18 mmol) was added under nitrogen protection. The reaction mixture was stirred at 85 °C for 36 h. LC-MS showed complete reaction of the starting materials. The reaction mixture was quenched with water and filtered through diatomaceous earth. The filtrate was diluted with EtOAc (300 mL x 3), and the organic phases were combined and evaporated to dryness. The crude product was purified by silica gel column chromatography (eluent: DCM:EtOAc = 1:7) to give a brown oily product A1-5 (14 g, purity 95%, yield 63.67%). LCMS(ESI) m / z 329.17, (M+H) + .

[0259] Compound A1-5 (14 g, 42.62 mmol) was dissolved in THF (150 mL) under ice bath conditions, followed by the slow addition of NaH (2 g, 51.22 mmol) in portions. The reaction mixture was stirred at 0 °C for 1 h, followed by the addition of TsCl (9.73 g, 51.22 mmol) in portions. The reaction mixture was allowed to react at room temperature for 30 min. LCMS showed complete reaction of the starting material. The reaction mixture was quenched with saturated aqueous NH4Cl solution under ice bath conditions and extracted with EtOAc (50 mL x 3). The combined organic phases were evaporated to dryness. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to give a gray solid product A1-6 (14.5 g, purity 95%, yield 66.96%). LCMS (ESI) m / z 483.18, (M+H) + .

[0260] Compound A1-6 (14.5 g, 30.08 mmol) was dissolved in THF (150 mL) at room temperature, followed by the addition of TBAF aqueous solution (5.6 mL, 15.04 mmol). The reaction mixture was allowed to react at room temperature for 30 min. LCMS showed complete reaction of the starting material. After dilution with water, a large amount of white solid precipitated and was filtered. The filtrate was extracted with EtOAc (100 mL x 2). The organic phases were combined and evaporated to dryness. The crude product was purified by silica gel column chromatography (eluent: DCM:MeOH = 10:1) to give a white solid product A1 (9.2 g, purity 95%, yield 78.97%). LCMS (ESI) m / z 369.01, (M+H) + .

[0261] Synthesis of key intermediate A2:

[0262] Compound A2-1 (200 g, 1.123 mol) was dissolved in EtOH (2 L) at room temperature, and glyoxal aqueous solution (244 g, 1.68 mol) was added. The reaction mixture was stirred overnight at 80 °C. LCMS showed that the starting material reacted completely. After cooling to room temperature, the reaction mixture was filtered to give a yellow solid product A2-2 (188.4 g, purity 95%, yield 79.64%). LCMS (ESI) m / z 201.01, (M+H) + .

[0263] Compound A2-2 (197 g, 984.87 mmol) was dissolved in dioxane (2 L) at room temperature, and K2CO3 (272 g, 1.97 mol) and ethylboric acid (87 g, 1.18 mol) were added. Pd(dppf)Cl2·DCM (40 g, 49.24 mmol) was added under nitrogen protection. The reaction mixture was stirred at 95 °C for 48 h. LC-MS showed complete reaction of the starting material. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth. The filtrate was diluted with water and extracted with DCM (1000 mL x 3). The organic phases were combined and evaporated to dryness. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to give a yellow solid product A2-3 (115.3 g, purity 95%, yield 57.43%). LC-MS (ESI) m / z 194.01, (M+H) + .

[0264] Compound A2-3 (35 g, 180.75 mmol) was dissolved in CCl4 (400 mL) at room temperature, followed by the addition of NBS (35.4 g, 198.83 mmol) and AIBN (2.96 g, 18.07 mmol). The reaction mixture was stirred at 80 °C for 5 h. LCMS showed that the starting material reacted completely. After quenching with water, the reaction mixture was extracted with DCM (100 mL x 3), and the combined organic phases were evaporated to dryness. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1) to give a brown solid product A2-4 (46.1 g, purity 95%, yield 88.90%). LCMS (ESI) m / z 272.01 & 274.01, (M+H) + .

[0265] Compounds A2-4 (680 mg, 2.49 mmol) and A1 (920 mg, 2.49 mmol) were dissolved in DMF (10 mL) at room temperature, followed by the addition of K2CO3 (690 mg, 4.99 mmol). The reaction mixture was stirred at room temperature for 2 h. LCMS showed complete reaction of the starting materials. The reaction mixture was quenched with water and extracted with EtOAc (30 mL x 3). The organic phases were combined and evaporated to dryness. The crude product was slurried with MeOH (5 mL) and filtered to obtain a yellow solid intermediate A2 (1.2 g, 95% purity, 81.51% yield). LCMS (ESI) m / z 560.01, (M+H) + .

[0266] Example 1 (Mother Drug 1)

[0267] (R)-N-cyclopropyl-5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)pyrido[3,4-b]pyrazine-7-amine

[0268] At room temperature, compound A2 (11.2 g, 19.99 mmol) and cyclopropylamine (11.4 g, 199.99 mmol) were dissolved in tert-butanol (100 mL), and Cs₂CO₃ (13 g, 39.99 mmol) was added. Under nitrogen protection, palladium(II) methanesulfonate (2-dicyclohexylphosphine-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)methanesulfonate (1.84 g, 1.99 mmol) was added. The reaction mixture was heated to 55 °C and reacted overnight. The reaction mixture was quenched with water, extracted with DCM (200 mL x 3), and the organic phases were combined and evaporated to dryness. The crude product was purified by silica gel column chromatography (eluent: DCM:MeOH = 10:1) to give a brown solid compound (±)-1-1 (11.45 g, purity: 80%, yield: 78.8%). LCMS (ESI) m / z 581.01, (M+H) + .

[0269] Compound (±)-1-1 (11.45 g, 15.77 mmol) was dissolved in MeOH (100 mL) at room temperature, followed by the addition of methylamine methanol solution (30 mL) and K₂CO₃ (6.5 g, 47.32 mmol) sequentially. The reaction mixture was reacted at 70 °C for 2 h. The reaction mixture was diluted with water and extracted with DCM (300 mL x 3). The organic phases were combined and evaporated to dryness. The crude product was purified by silica gel column chromatography (eluent: DCM:MeOH = 10:1) to give an orange solid compound (±)-1 (5.465 g, purity: 100%, yield: 81.23%). LCMS (ESI) m / z 427.01, (M+H) + ; 1 H NMR (400MHz, DMSO) δ12.75(s,1H),8.95(d,J=1.8Hz,1H),8.71(d,J=1.8Hz,1H),7. 88(s,1H),7.70(d,J=1.6Hz,1H),7.55(s,1H),7.38(d,J=9.0Hz,1H),7.19(d,J=1.6 Hz,1H),7.05(dd,J=9.0,2.2Hz,1H),6.80(s,1H),6.75(q,J=6.4Hz,1H),3.92(s,3 H), 2.51–2.46 (m, 1H), 1.72 (d, J = 6.4Hz, 3H), 0.82–0.70 (m, 2H), 0.57–0.43 (m, 2H).

[0270] Compound (±)-1 (5.46 g) was resolved by a chiral column (column: AD-3, dimensions: 0.46 cm ID x 5 cm L, mobile phase: CO2:EtOH (0.05% DEA) = 70:30) to give a yellow solid product 1 (2.25 g, purity: 99.03%, enantiomeric excess percentage: 99.84%). LCMS (ESI) m / z 427.01, (M+H) + .1H NMR (400MHz, DMSO) δ12.75(s,1H),8.95(d,J=1.8Hz,1H),8.71(d,J=1.8Hz,1H ),7.88(s,1H),7.70(s,1H),7.55(s,1H),7.38(d,J=9.0Hz,1H),7.18(s,1H),7 .05(dd,J=9.0,2.2Hz,1H),6.80(s,1H),6.75(q,J=6.4Hz,1H),3.92(s,3H),2 .51–2.46(m,1H),1.72(d,J=6.4Hz,3H),0.84–0.70(m,2H),0.55–0.44(m,2H).

[0271] Example 2 (Mother Drug 2)

[0272] (R)-5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)-N-(2,2,2-trifluoroethyl)pyrido[3,4-b]pyrazine-7-amine

[0273] Compound (±)-2 (4.2 g) (prepared according to the synthesis of compound (±)-1) was resolved by a chiral column (column: IG-3, dimensions: 0.46 cm ID x 5 cm L, mobile phase: CO2:EtOH (0.05% DEA) = 70:30) to give a yellow solid product 2 (1.5 g, purity: 99.3%, enantiomeric excess percentage: 98.2%). LCMS (ESI) m / z 469.2, (M+H) + , 1 H NMR (400MHz, DMSO-d6) δ8.94(d,J=1.8Hz,1H),8.73(d,J=1.8Hz,1H),7.94(s,1H ),7.74(t,J=6.7Hz,1H),7.59(s,1H),7.48(d,J=7.1Hz,1H),7.43–7.36(m,1H), 7.36–7.26(m,1H),7.23(d,J=2.3Hz,1H),7.06(dd,J=9.0,2.2Hz,1H),6.92(s,1 H), 6.76 (q, J = 6.3Hz, 1H), 4.31–4.18 (m, 2H), 3.91 (s, 3H), 1.73 (d, J = 6.3Hz, 3H).

[0274] Example 3 (Mother Drug 3)

[0275] (R)-N-ethyl-5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)pyrido[3,4-b]pyrazine-7-amine

[0276] Compound (±)-3 (5.17 g) (prepared according to the synthesis of compound (±)-1) was resolved by a chiral column (column: AD-3, dimensions: 0.46 cm ID x 5 cm L, mobile phase: CO2:EtOH (0.05% DEA) = 70:30) to give a yellow solid product 3 (2.28 g, purity: 99%, enantiomeric excess percentage: 97.4%). LCMS (ESI) m / z 415.2, (M+H) + , 1H NMR (400MHz, DMSO) δ12.74(s,1H),8.89(d,J=1.6Hz,1H),8.65(d,J=1.6Hz,1 H),7.90(s,1H),7.56(s,1H),7.37(d,J=9.2Hz,1H),7.26(t,J=5.6Hz,1H),7 .20(s,1H),7.06(dd,J=9.2,2.0Hz,1H),6.73(q,J=6.4Hz,1H),6.54(s,1H), 3.92(s,3H),3.28–3.19(m,2H),1.73(d,J=6.4Hz,3H),1.17(t,J=7.2Hz,3H).

[0277] Example 4 (Mother Drug 4)

[0278] (R)-7-(difluoromethyl)-5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)pyrido[3,4-b]pyrazine

[0279] Compound (±)-4 (3.7 g) (prepared according to Example 236 of WO2024 / 40990A1) was subjected to chiral column chromatography (column: AD-3, dimensions: 0.46 cm ID x 5 cm L, mobile phase: CO2:EtOH (0.05% DEA) = 70:30) to give compound 4 (1.69 g, purity: 94.5%, enantiomeric excess percentage: 99.63%). LCMS (ESI) m / z 422.15, (M+H) + ; 1 H NMR (400MHz, DMSO-d6) δ12.77(s,1H),9.36(d,J=1.6Hz,1H),9.30(d,J=1.6Hz,1H),8.28(s,1H),8.07(s, 1H), 7.68 (s, 1H), 7.41–7.07 (m, 4H), 6.89 (q, J = 6.4Hz, 1H), 3.92 (d, J = 12.4Hz, 3H), 1.82 (d, J = 6.4Hz, 3H).

[0280] Example 5 (Mother Drug 5)

[0281] (R)-6-(difluoromethyl)-5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)quinoxaline

[0282] Compound (±)-5 (2.6 g) (prepared according to Example 232 of WO2024 / 40990A1) was subjected to a chiral column (column: AD-3, dimensions: 0.46 cm ID x 5 cm L, mobile phase: CO2:EtOH (0.05% DEA) = 70:30) to give compound 5 (1.18 g, purity: 100%, enantiomeric excess percentage: 99.5%). LCMS (ESI) m / z 421.15, (M+H)+; 1 H NMR (400MHz, DMSO-d6) δ12.80(s,1H),9.27(d,J=18.5Hz,2H),8.22(d,J=8.9Hz,1H),8.08(d,J=8.9Hz,1H),8.03(s,1H), 7.79(s,1H),7.40(d,J=6.3Hz,2H),7.25(q,J=6.6Hz,1H),7.10(dd,J=6.7,2.7Hz,2H),3.90(s,3H),1.85(d,J=6.6Hz,3H)

[0283] Example 6

[0284] (R)-(5-(1-(7-(cyclopropylamino)pyridino[3,4-b]pyrazin-5-yl)ethoxy)-3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl acetate

[0285] At 0°C, a DMF (1.5 mL) solution of compound 1 (50 mg, 0.12 mmol, 1.0 eq.) was slowly added to a DMF (0.5 mL) suspension of NaH (10 mg, 0.24 mmol, 2.0 eq.). The reaction mixture was stirred at 0°C for 15 minutes. Then, compound 6-1 (39 mg, 0.36 mmol, 3.0 eq.) was added dropwise. After the addition was complete, the mixture was heated to room temperature and stirred for 1 hour. The mixture was cooled to 0°C, and the reaction mixture was slowly poured into an aqueous solution of NH4Cl (10.0 mL). The mixture was extracted with ethyl acetate (10.0 mL x 2), and the organic phases were combined. The mixture was washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to give compound 6 (16.2 mg, yield 27.7%, purity 90.1%). LCMS(ESI) m / z 499.2(M+H)+;1H NMR(400MHz,DMSO)δ8.86(d,J=1.7Hz,1H),8.60(dd,J=5.3,1.8Hz,1H),7.93(s,1 H),7.60(d,J=1.9Hz,1H),7.56–7.50(m,2H),7.16(d,J=2.1Hz,1H),7.09(dd,J=9. 1,2.2Hz,1H),6.74–6.64(m,2H),6.19(q,J=11.4Hz,2H),3.85(s,3H),2.41-2.37 (m,1H),1.91(s,3H),1.64(d,J=6.4Hz,3H),0.71-0.65(m,2H),0.45-0.41(m,2H).

[0286] Example 7

[0287] (5-((R)-1-(7-(cyclopropylamino)pyrido[3,4-b]pyrazin-5-yl)ethoxy)-3-(1-methyl-1H-pyrazol-4-yl)-1H-indazole-1-yl)acetylproline methyl ester

[0288] At 0 °C, compound 7-1 (300 mg, 1.90 mmol) was dissolved in DCM (2 mL) and H₂O (2 mL), followed by the addition of NaHCO₃ (641 mg, 7.63 mmol) and tetrabutylammonium hydrogen sulfate (65 mg, 0.19 mmol). After 10 minutes, compound 7-2 (409 mg, 2.48 mmol) was added. The reaction mixture was stirred at room temperature for 20 h. LCMS showed no residue of the starting material. The mixture was extracted with ethyl acetate, and the combined organic phases were dried and then evaporated to dryness to obtain crude compound 7-3, which was directly used in the next step (76 mg, 80% purity). LCMS (ESI) m / z 206.2 [M+H]+

[0289] Compound 1 (40 mg, 0.09 mmol) and 7-3 (28.9 mg, 0.14 mmol) were dissolved in DMF (1 mL) at room temperature. NaI (28 mg, 0.18 mmol) and CS2CO3 (61 mg, 0.18 mmol) were added, and the reaction mixture was stirred at 50 °C for 16 h. After cooling to room temperature, the reaction mixture was filtered, and the crude product was purified by preparative liquid chromatography to obtain a yellow solid product 7 (10 mg, purity 95.57%, yield 13%). LCMS (ESI) m / z 596.2 [M+H]+ 1 H NMR (400MHz, DMSO) δ8.95(s,1H),8.70(s,1H),8.03(d,J=2.5Hz,1H),7.69(s,1H),7.61(t,J=8.9Hz ,2H),7.22(dd,J=26.3,9.8Hz,2H),6.82–6.74(m,2H),6.30(d,J=15.8Hz,1H),4.56(d,J=9.0Hz,1H ),4.21(dd,J=8.8,4.0Hz,1H),3.98(s,1H),3.94(s,3H),3.57–3.41(m,2H),2.03(s,1H),1.95(t,J =6.2Hz,3H),1.86–1.77(m,2H),1.73(d,J=6.3Hz,3H),1.71–1.57(m,2H),0.77(s,2H),0.51(s,2H).

[0290] Example 8

[0291] (R)-(5-(1-(7-(cyclopropylamino)pyridino[3,4-b]pyrazin-5-yl)ethoxy)-3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl neopentanoate

[0292] Compound 1 (30 mg, 0.07 mmol, 1.0 eq.) and compound 8-1 (21 mg, 0.07 mmol, 2.0 eq.) were dissolved in DMF (2 mL), and then Cs₂CO₃ (68 mg, 0.21 mmol, 3.0 eq.) was added. The mixture was stirred at 50 °C for 16 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was separated, dried, and evaporated to dryness to give a yellow solid. The solid was purified by preparative liquid chromatography to give a pale yellow solid, compound 8 (4.8 mg, 100% purity, 12.7% yield). LCMS (ESI) m / z 541.2, (M+H) + ; 1H NMR (400MHz, DMSO) δ8.95(d,J=1.2Hz,1H),8.70(d,J=1.2Hz,1H),8.02(s,1H),7.69(s,1H),7.61(t,J=4.4Hz,2H),7.25(s,1H),7.22–7.14(m,1H ),6.80(s,1H),6.76(t,J=6.4Hz,1H),6.29(s,2H),3.93(s,3H),2.30-2. 21(m,1H),1.73(d,J=6.4Hz,3H),1.06(s,9H),0.77(s,2H),0.51(s,2H).

[0293] The following compound was synthesized according to the route in Example 8.

[0294] Example 13

[0295] (R)-4-((5-(1-(7-(ethylamino)pyridino[3,4-b]pyrazin-5-yl)ethoxy)-3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-1-yl)methoxy)-4-oxobutyric acid

[0296] At room temperature, compound 3 (500 mg, 1.20 mmol) was dissolved in EtOH (4 mL). Then, formaldehyde (36%–38%, wt%, aqueous solution, 2 mL) was added dropwise to the reaction mixture over 1.0 min. The original suspension turned into a clear, dark brown solution. The reaction solution was stirred at 70 °C for 48 h. The reaction mixture was diluted with ethyl acetate (100.0 mL), washed with water (2 x 50.0 mL) and brine (50.0 mL), dried over Na₂SO₄, filtered, and concentrated to a brown solid, compound 13-1 (0.18 g). The crude product was used directly in the next step of the reaction without purification.

[0297] Compound 13-1 (60 mg, 0.14 mmol, 1.0 eq.) and compound 13-2 (45 mg, 0.45 mmol, 4 eq.) were dissolved in DMSO (2 mL), and DMAP (6.8 mg, 0.05 mol, 0.5 eq.) was added. The mixture was stirred at 25 °C for 18 hours. LCMS showed that the reaction was complete. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was separated, dried, and evaporated to dryness. The residue was purified by preparative liquid chromatography to give a pale yellow solid, compound 13 (25 mg, purity 97.98%, yield 32.9%). LCMS (ESI) m / z 543.2, (MH) - ; 1H NMR (400MHz, DMSO) δ12.24(s,1H),8.87(dd,J=4.4,1.6Hz,1H),8.61(dd,J=10.0,1.6Hz,1H),8.27 (s,1H),8.16(d,J=9.2Hz,1H),7.76(d,J=0.4Hz,1H),7.41(d,J=2.4Hz,1H),7.29(dd,J=9.2,2.4H z,1H),7.22(t,J=5.6Hz,1H),6.79(q,J=6.4Hz,1H),6.53(d,J=6.4Hz,1H),3.94(d,J=8.4Hz,3H), 3.22(dd,J=10.0,5.2Hz,2H), 2.66(t,J=6.4Hz,2H), 1.74(t,J=6.0Hz,3H), 1.13(t,J=7.2Hz,3H).

[0298] Example 14

[0299] (5-((R)-1-(7-(cyclopropylamino)pyrido[3,4-b]pyrazin-5-yl)ethoxy)-3-(1-methyl-1H-pyrazol-4-yl)-1H-indazole-1-yl)tert-butyl phosphonate

[0300] At room temperature, compound 14-2 (120 mg, 0.51 mmol) was dissolved in CCl4 and 20% NaOH (20 mL, v / v = 1 / 1), and compound 14-1 (1 g, 5.15 mmol) was slowly added. The reaction mixture was reacted at room temperature for 3 h, then diluted with water and extracted with DCM (50 mL x 3). The combined organic phases were dried over Na2SO4 and then evaporated to dryness to obtain a yellow oily crude compound 14-3 (1.27 g), which was used directly in the next step.

[0301] Compound 1 (100 mg, 0.234 mmol) was dissolved in THF (5 mL) under ice bath conditions, and NaH (23 mg, 0.586 mmol) was slowly added. After stirring the reaction mixture at room temperature for half an hour, compound 14-3 (160 mg, crude product) was added dropwise. The reaction mixture was stirred at room temperature for another hour, and LC-MS showed complete reaction of the starting material. The reaction mixture was quenched with water, and the pH was adjusted to weakly alkaline with a saturated aqueous solution of Na₂CO₃. The aqueous phase was extracted with DCM (40 mL x 3). The organic phases were combined and evaporated to dryness. The crude product was purified by preparative liquid chromatography to give a yellow solid compound 14-4 (142 mg, 90% purity, 88.8% yield). LC-MS (ESI) m / z 619.2 (M+H)+.

[0302] Compound 14-4 (60 mg, 0.097 mmol) was dissolved in THF / H₂O (5 mL, v / v = 1 / 1) at room temperature and heated to 50 °C. The reaction mixture was stirred at 50 °C for 1 h. The reaction mixture was purified by preparative liquid chromatography to give a yellow solid product 14 (14.6 mg, purity 90.5%, yield 26.8%). LCMS (ESI) m / z 563.2, (M+H)+; 1 H NMR (400MHz, DMSO) δ8.95(d,J=1.2Hz,1H),8.71(d,J=1.2Hz,1H),8.01(d,J=9.0Hz, 1H),7.89(d,J=5.6Hz,1H),7.69(s,1H),7.58(s,1H),7.11(s,1H),7.01(d,J=8.8Hz ,1H),6.81(s,1H),6.74(q,J=6.2Hz,1H),3.92(s,3H),2.51–2.47(m,1H),1.71(d,J =6.4Hz, 3H), 1.40 (d, J = 5.6Hz, 1H), 1.13 (s, 9H), 0.77 (s, 2H), 0.52 (d, J = 3.4Hz, 2H).

[0303] Example 15

[0304] (R)-(5-(1-(7-(cyclopropylamino)pyridino[3,4-b]pyrazin-5-yl)ethoxy)-3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-1-yl)sodium tert-butyl phosphonate

[0305] Compound 14-4 (60 mg, 0.097 mmol) was dissolved in THF / H₂O (3 mL, v / v = 1 / 1) at room temperature, followed by the addition of sodium acetate (15.9 mg, 0.194 mmol) and heating to 50 °C. The reaction mixture was stirred at 50 °C for 1 h. The reaction mixture was purified by preparative liquid chromatography to give a yellow solid product 15 (12.3 mg, purity 97.3%, yield 21.7%). LCMS (ESI) m / z 563.2, (M+H)+; 1H NMR (400MHz, DMSO) δ8.95(d,J=1.6Hz,1H),8.71(d,J=1.6Hz,1H),8.02(d,J=9.0 Hz,1H),7.88(s,1H),7.69(d,J=1.2Hz,1H),7.57(s,1H),7.10(s,1H),7.00(dd, J=9.2,2.0Hz,1H),6.81(s,1H),6.74(q,J=6.4Hz,1H),3.92(s,3H),2.51–2.47( m,1H),1.71(d,J=6.4Hz,3H),1.12(s,9H),0.83–0.70(m,2H),0.58–0.45(m,2H).

[0306] Example 16

[0307] 2-Morpholinoethyl(R)-5-(1-(7-(cyclopropylamino)pyrido[3,4-b]pyrazin-5-yl)ethoxy)-3-(1-methyl-1H-pyrazol-4-yl)-1H-indazole-1-carboxylate

[0308] At room temperature, compound 16-1 (0.262 g, 2.0 mmol) and triethylamine (0.405 g, 4.0 mmol) were added to tetrahydrofuran (2.0 mL). The resulting mixture was cooled in an ice-water bath, and then a tetrahydrofuran (2.0 mL) solution of compound 16-2 (0.423 g, 2.1 mmol) was slowly added dropwise. The reaction mixture was stirred at 0 °C for 10 min, then at room temperature for 14 h. The reaction mixture was diluted with dichloromethane (15.0 mL), washed successively with saturated NaHCO3 aqueous solution (10.0 mL) and water (10.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product, a yellow oily compound 16-3 (0.561 g, crude yield: 79%, purity: 83.10%), was given. LCMS (ESI) m / z 297.2, (M+H)+.

[0309] Compound 1 (50 mg, 0.12 mmol) and compound 16-3 (45 mg, 0.15 mmol) were dissolved in MeCN (1 mL) at room temperature, and Cs₂CO₃ (78 mg, 0.24 mmol) was added. The reaction solution was reacted at 50 °C for 2 h. The reaction solution was purified by preparative liquid chromatography to give a yellow solid product 16 (27.5 mg, purity 96.67%, yield 38.8%). LCMS (ESI) m / z 584.10, (M+H)+; 1H NMR (400MHz, DMSO) δ8.92(d,J=1.8Hz,1H),8.66(d,J=1.8Hz,1H),8.22(s,1H),8.06(d,J=9.2Hz,1 H),7.71(s,1H),7.65(d,J=2.0Hz,1H),7.38(d,J=2.4Hz,1H),7.27(dd,J=9.2,2.4Hz,1H),6.84–6 .75(m,2H),4.51(t,J=5.6Hz,2H),3.94(s,3H),3.59–3.48(m,4H),2.71(t,J=5.8Hz,2H),2.47(d, J=4.8Hz,4H),1.73(d,J=6.4Hz,3H),1.24(d,J=7.0Hz,1H),0.80–0.68(m,2H),0.54–0.42(m,2H).

[0310] The following compound was synthesized according to the route in Example 16.

[0311] Example 26

[0312] 2-(dimethylamino)ethyl(R)-5-(1-(7-(cyclopropylamino)pyrido[3,4-b]pyrazin-5-yl)ethoxy)-3-(1-methyl-1H-pyrazol-4-yl)-1H-indazole-1-carboxylate

[0313] Compound 1 (60 mg, 0.14 mmol) and 26-1 (33 mg, 0.42 mmol) were dissolved in THF (2 mL) and DMF (0.6 mL) at room temperature. Pyridine (56 mg, 0.28 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 2 h. 26-3 (12 mg, 0.13 mmol) was dissolved in DMF (1 mL) and added to the above reaction mixture, followed by TEA (13.6 mg, 0.13 mmol) and DMAP (6.8 mg, 0.06 mmol). The reaction mixture was stirred at 50°C for 16 h. After cooling to room temperature, the reaction mixture was filtered. The crude product was purified by preparative liquid chromatography to obtain a yellow solid product 26 (12.1 mg, purity 98.9%, yield 21.9%). LCMS (ESI) m / z 542.3 [M+H] + ; 1H NMR (400MHz, DMSO) δ8.94(d,J=1.5Hz,1H),8.68(d,J=1.6Hz,1H),8.23(s,1H),8.02( d,J=9.1Hz,1H),7.72(s,1H),7.66(s,1H),7.39(d,J=1.9Hz,1H),7.29(dd,J=9.1,2.2 Hz,1H),6.84–6.76(m,2H),4.50(t,J=5.7Hz,2H),3.96(s,3H),2.66(t,J=5.7Hz,2H) ,2.49(s,1H),2.22(s,6H),1.74(d,J=6.3Hz,3H),0.77(d,J=3.6Hz,2H),0.50(s,2H).

[0314] The following compound was synthesized according to the route in Example 26.

[0315] Example 30

[0316] (isobutyryloxy)methyl(R)-5-(1-(7-(cyclopropylamino)pyridino[3,4-b]pyrazin-5-yl)ethoxy)-3-(1-methyl-1H-pyrazol-4-yl)-1H-indazole-1-carboxylate

[0317] Triethylamine (37 mg, 0.36 mmol, 3.0 eq.) was slowly added to THF (1.0 mL) containing compound 1 (50 mg, 0.12 mmol, 1.0 eq) and compound 30-1 (11 mg, 0.15 mmol, 1.2 eq). The mixture was stirred at 0 °C for 3 hours. The reaction solution was poured into an aqueous NaCl solution (10.0 mL) and extracted with EtOAc (10.0 mL x 2). The organic phases were combined, washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow solid compound 30-2 (60 mg, 98.2% yield).

[0318] Compound 30-2 (60 mg, 0.12 mmol, 1.0 eq), potassium isobutyrate (44 mg, 0.35 mmol, 3.0 eq), and (n-Bu)4NI (64 mg, 0.17 mmol, 1.5 eq) were sequentially added to a DMF (1.0 mL) solution and stirred at room temperature for 2 hours. The reaction mixture was poured into a NaCl aqueous solution (10.0 mL), extracted with EtOAc (10.0 mL x 2), and the organic phases were combined, washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography to give a yellow solid 30 (2.5 mg, yield 3.7%, purity 100%). LCMS: (ESI) m / z 571.3, (M+H)+; 1 H NMR (400MHz, DMSO-d6) δ8.94(d,J=1.8Hz,1H),8.68(d,J=1.8Hz,1H),8.29(s,1H),7.98(d, J=9.1Hz,1H),7.76(s,1H),7.66(s,1H),7.43(d,J=2.4Hz,1H),7.33(dd,J=9.2,2.4Hz,1H) ,6.82(d,J=8.3Hz,2H),6.04(s,2H),3.96(s,3H),2.65(p,J=7.2Hz,1H),2.50(m,1H),1.75 (d, J=6.4Hz, 3H), 1.11 (d, J=7.0Hz, 6H), 0.77 (dq, J=6.5, 3.4Hz, 2H), 0.50 (p, J=3.8Hz, 2H).

[0319] Example 31

[0320] (R)-N-(2-(5-(1-(7-(cyclopropylamino)pyridino[3,4-b]pyrazin-5-yl)ethoxy)-3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-1-yl)-2-oxoethyl)acetamide

[0321] At room temperature, BOP (100 mg, 0.23 mmol, 2.5 eq.) was slowly added to a DMF (1 mL) solution of compound 1 (40 mg, 0.09 mmol, 1.0 eq.), compound 31-1 (14 mg, 0.12 mmol, 1.3 eq.), and DIPEA (35 mg, 0.27 mmol, 3.0 eq.). The reaction mixture was stirred at room temperature for 16 hours. A saturated sodium bicarbonate aqueous solution (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 2). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to give compound 31 (44.5 mg, yield 90.3%, purity 97.2%). LCMS (ESI) m / z = 526.3 (M+H). + ; 1 H NMR (400MHz, DMSO) δ8.92(d,J=1.7Hz,1H),8.66(d,J=1.7Hz,1H),8.36(t,J=5.8Hz,1H), 8.27(s,1H),8.14(d,J=9.1Hz,1H),7.78(s,1H),7.63(s,1H),7.42(d,J=2.1Hz,1H),7.30 (dd,J=9.1,2.2Hz,1H),6.85–6.76(m,2H),4.65(dd,J=5.7,2.2Hz,2H),3.95(s,3H),2.4 8-2.45(m,1H),1.93(s,3H),1.73(d,J=6.3Hz,3H),0.78–0.72(m,2H),0.52–0.46(m,2H).

[0322] The following compound was synthesized according to the route in Example 31.

[0323] Example 35

[0324] (R)-1-(5-(1-(7-(cyclopropylamino)pyridino[3,4-b]pyrazin-5-yl)ethoxy)-3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-1-yl)-3,3,3-trifluoroprop-1-one

[0325] Compound 1 (0.085 g, 0.20 mmol) and N,N-diisopropylethylamine (0.078 g, 0.60 mmol) were added to a mixed solvent of anhydrous acetonitrile (0.50 mL) and N,N-dimethylformamide (0.50 mL), followed by the addition of 3,3,3-trifluoropropionyl chloride (0.038 g, 0.26 mmol). The resulting mixture was stirred at room temperature for 4 hours, and LC-MS showed product formation. The reaction mixture was diluted with acetonitrile (1.0 mL), filtered, and purified by preparative liquid chromatography to give a yellow solid 35 (0.015 g, yield: 14%, purity: 97.16%). LC-MS (ESI) m / z 537.2, (M+H) + ; 1 H NMR (400MHz, DMSO) δ8.92(d,J=1.6Hz,1H),8.66(d,J=1.6Hz,1H),8.31(s,1H),8.17( d,J=9.2Hz,1H),7.81(s,1H),7.64(d,J=2.0Hz,1H),7.44(d,J=2.4Hz,1H),7.33(dd,J =9.2,2.4Hz,1H),6.82(q,J=6.4Hz,1H),6.80(s,1H),4.45(q,J=10.8Hz,2H),3.96(s ,3H),2.48–2.45(m,1H),1.74(d,J=6.4Hz,3H),0.78–0.73(m,2H),0.51–0.45(m,2H).

[0326] Example 36

[0327] (R)-4-(5-(1-(7-(cyclopropylamino)pyridino[3,4-b]pyrazin-5-yl)ethoxy)-3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-1-yl)-4-oxobutyric acid

[0328] Compound 1 (30 mg, 0.07 mmol, 1.0 eq.) and compound 36-1 (21 mg, 0.2 mmol, 3.0 eq.) were dissolved in dioxane (2 mL) and stirred at 80 °C for 16 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was separated, dried, and evaporated to dryness to obtain a yellow solid. The solid was purified by preparative liquid chromatography to obtain a pale yellow solid, compound 36 (6 mg, 100% purity, 16% yield). LCMS (ESI) m / z 527.2, (M+H) + ; 1H NMR (400MHz, DMSO) δ8.94(d,J=1.6Hz,1H),8.68(d,J=1.6Hz,1H),8.26(s,1H),8.22–8.15(m,1H),7.76(s,1H),7.68(s,1H),7.40(d,J=2.0Hz,1H), 7.30(dd,J=9.2,2.2Hz,1H),6.86–6.78(m,2H),3.97(s,3H),2.68(t,J=6. 4Hz, 2H), 1.80–1.71 (m, 3H), 0.77 (d, J = 3.6Hz, 2H), 0.51 (d, J = 2.4Hz, 2H).

[0329] Example 37

[0330] (R)-N-(2-(dimethylamino)ethyl)-5-(1-(7-(cyclopropylamino)pyridino[3,4-b]pyrazin-5-yl)ethoxy)-3-(1-methyl-1H-pyrazol-4-yl)-1H-indazole-1-carboxamide

[0331] At room temperature, compound 26-1 (20 mg, 0.1 mmol, 1.2 eq.) was slowly added to a mixed solution of compound 1 (35 mg, 0.08 mmol, 1.0 eq.) and pyridine (10 mg, 0.12 mmol, 1.5 eq.) in DMF (0.3 mL) and THF (1 mL). The reaction mixture was stirred at room temperature for 2 hours. Compound 37-1 (22 mg, 0.25 mmol, 3.0 eq.) was then slowly added to the above reaction mixture. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by preparative liquid chromatography to obtain 37 (26.1 mg, yield 58.3%, purity 100%). LCMS (ESI) m / z = 541.3 (M+H)+; 1H NMR (400MHz, DMSO) δ8.93(d,J=1.8Hz,1H),8.67(d,J=1.8Hz,1H),8.11(t,J=4.5Hz,2H),7. 98(t,J=5.8Hz,1H),7.72(s,1H),7.67(d,J=2.0Hz,1H),7.31(d,J=2.2Hz,1H),7.23(dd,J=9 .1,2.3Hz,1H),6.84–6.73(m,2H),3.95(s,3H),3.41–3.36(m,2H),2.49-2.45(m,1H),2.42 (t,J=6.6Hz,2H),2.18(s,6H),1.72(d,J=6.4Hz,3H),0.80–0.71(m,2H),0.53–0.43(m,2H).

[0332] The following compound was synthesized according to the route in Example 37.

[0333] Example 40

[0334] (R)-(5-(1-(7-(cyclopropylamino)pyridino[3,4-b]pyrazin-5-yl)ethoxy)-3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-1-yl)methylcarbamate

[0335] At 0°C, 40% formaldehyde aqueous solution (440 mg, 5.8 mmol, 10.0 eq.) was added to compound 1 (250 mg, 0.59 mmol, 1.0 eq.) and Et3N (178 mg, 1.7 mmol, 3.0 eq.) in MeCN (1.0 mL), and stirred at room temperature for 16 hours. The reaction solution was poured into NaCl aqueous solution (30.0 mL), extracted with EtOAc (30.0 mL x 2), the organic phases were combined, washed with saturated brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude yellow solid compound 40-1 (315 mg), which was directly used in the next reaction.

[0336] Compound 40-2 (43 mg, 0.46 mmol, 3.0 eq) was added to a THF / DMF (1.0 / 0.3 mL) mixture of compound 40-1 (70 mg, 0.15 mmol, 1.0 eq) and Et3N (77 mg, 0.77 mmol, 5.0 eq) and stirred at room temperature for 16 hours. The reaction mixture was poured into a NaCl aqueous solution (10.0 mL), extracted with EtOAc (10.0 mL x 2), and the organic phases were combined, washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: ethyl acetate / petroleum ether = 1 / 0) to give a yellow solid compound 40 (41.8 mg, yield 53.1%, purity 100%). LCMS: (ESI) m / z 514.3, (M+H)+; 1 H NMR (400MHz, DMSO-d6) δ8.95(d,J=1.8Hz,1H),8.70(d,J=1.8Hz,1H),7.99(s,1H),7.73–7.62(m,2H),7.59(s,1H),7.27–7.12(m,3H),6.83–6.71(m ,2H),6.20(d,J=2.1Hz,2H),3.93(s,3H),2.54(s,3H),2.48(m,1H),1.73( d, J=6.3Hz, 3H), 0.77 (dt, J=7.3, 4.0Hz, 2H), 0.51 (dq, J=5.4, 3.2Hz, 2H).

[0337] Test Example 1

[0338] Kinetic solubility test experiment

[0339] 1) Preparation of buffer solutions: Prepare PBS buffer solutions with pH 1.65, pH 6.4, and pH 7.4.

[0340] Dissolve / dilute the compound powder / solution with an appropriate volume of DMSO to obtain a working solution with a concentration of 30 mM.

[0341] 2) Solubility determination

[0342] Add 485 μL of buffer solutions with pH values ​​of 1.65, 6.4, and 7.4 to their respective centrifuge tubes. Add 15 μL of the 30 mM working solution of the test compound to each centrifuge tube containing a different pH buffer. Vortex to mix the solutions. Prepare duplicate samples for each pH of each compound. Transfer the solubility sample plate to a temperature-controlled metal mixer and vortex at 25°C and 1200 RPM for 2 hours. After vortexing, centrifuge all samples at 18000 rpm for 10 minutes at 25°C. Transfer the supernatant to an EP tube and centrifuge again under the same conditions for 10 minutes. After centrifugation, add 5 μL of the supernatant to a 96-well plate containing 5 μL of DMSO and 490 μL of acetonitrile-water (v:v = 1:1) mixture to a final volume of 500 μL. Mix well and centrifuge at 4000 rpm for 10 minutes at 25°C.

[0343] 3) Preparation of Standards (STD)

[0344] Add 3 μL of the analyte compound at a concentration of 30 mM to 97 μL of DMSO to a final volume of 100 μL and a final concentration of 900 μM. Vortex to mix the solution. Add 5 μL of this solution to the corresponding well containing 490 μL of acetonitrile-water (v:v = 1:1) mixture. Then add 5 μL of buffer solution with pH 1.65, 6.4, or 7.4 to the corresponding well to a final volume of 500 μL and a final STD concentration of 9 μM. Mix well and centrifuge at 4000 rpm for 10 min at 25 °C.

[0345] 4) Sample Analysis

[0346] Transfer 50 μL of the supernatant from centrifugation to a new 96-well plate, add 150 μL of internal standard and 200 μL of 50% acetonitrile (the dilution factor can be adjusted according to the solubility value and LC-MS / MS response signal). After mixing and centrifuging the 96-well plate, place the sample plate into the plate autosampler. Evaluate the sample by LC-MS / MS analysis.

[0347] 5) Data Analysis

[0348] Establish a quantitative method to analyze and quantify the filtrate using standards of known concentrations. The solubility value of the test compound is calculated using the following formula:

[0349] Where [Sample] represents the sample concentration; AREA Sample CF is the peak area of ​​the sample; Sample The calculation factor for the sample is the STD concentration; AREA STD This represents the area of ​​the STD peak.

[0350] Table 1. Kinetic solubility of compounds in pH 7.4 buffer solution

[0351] Conclusion: Compared with the corresponding parent drug, the prodrug showed significantly improved kinetic solubility in pH 7.4 buffer.

[0352] Test Example 2

[0353] In vivo pharmacokinetic studies in mice

[0354] Laboratory animals: CD-1 mice (male, 30-35g) were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0355] Experimental Procedure: Male CD-1 mice (30-35g) were intravenously injected with the test compound (2 mg / kg) and administered the test compound (100 mg / kg) via gavage. Plasma samples were collected from mice at 5 min, 15 min, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after intravenous injection. Plasma samples were also collected from mice administered via gavage at the same times. Compound concentrations were determined by LC-MS / MS. Pharmacokinetic parameters included plasma clearance (Cl), elimination half-life (T1 / 2), peak time (Tmax), peak concentration (Cmax), area under the curve (AUC), apparent volume of distribution (Vss), and bioavailability (F).

[0356] Assay Method: Dilute the stock solution of the analyte with 50% acetonitrile to obtain the required series of working solution concentrations. Add 1 μL of working solution (10, 20, 50, 100, 500, 1000, 5000, 10000, 50000 ng / mL) to 9 μL of blank CD1 mouse plasma to achieve a total volume of 10 μL for calibration standards ranging from 1 to 5000 ng / mL (1, 2, 5, 10, 50, 100, 500, 1000, 5000 ng / mL). Four quality control (QC) samples (2 ng / mL, 5 ng / mL, 200 ng / mL, 4000 ng / mL) are prepared on the day of analysis in the same manner as the calibration standards. Add 10 μL of standard, 10 μL of QC sample, and 10 μL of unknown sample to 200 μL of IS mixture containing acetonitrile to precipitate the protein. Then vortex the samples for 10 min. After centrifugation at 4℃ and 4000rpm for 15min, the supernatant was diluted with ultrapure water at a ratio of 1:1 (V / V), and then 10μL of the diluted supernatant was injected into the LC / MS / MS system for quantitative analysis.

[0357] Table 2 Pharmacokinetic parameters of the compounds

[0358] IV: Intravenous injection; PO: Oral administration; Cl: Apparent clearance; T 1 / 2Half-life; AUC last Area under the curve (AUC) from the start of administration to the last point (24 hours). inf The area under the drug-time curve (MRT) is the time from the start of drug administration to the theoretical extrapolation infinity. last Mean residence time from the start of administration to the last point (24 hours); Vss: apparent volume of distribution; T max Peak time; C max Peak concentration; F: Bioavailability

[0359] The prodrugs from Examples 16, 17, 32, 34, and 41 were not detected in animal plasma. The pharmacokinetic parameters are the values ​​of the corresponding parent drugs that were detected, and F represents the relative bioavailability of the corresponding parent drug.

[0360] Conclusion: Compared with the corresponding parent drug itself, the prodrug released in mice significantly increased the oral exposure of the parent drug and significantly improved the relative bioavailability.

[0361] Test Example 3

[0362] In vitro FGFR3 kinase activity inhibition assay

[0363] via Invitrogen LanthaScreen TM The assay measures FGFR3 kinase activity using fluorescently labeled peptides and terbium-labeled antibodies, directly measuring the amount of substrate phosphorylation via time-resolved fluorescence energy transfer (TR FRET).

[0364] ① Dilution of the test compound: The initial concentration was 1 μM, prepared by three-fold serial dilution in a buffer consisting of 50 mM HEPES, 10 mM MgCl2, 0.01% Triton X 100, 0.01% BSA, 4 mM DTT pH 7.5 and 1% DMSO;

[0365] ② Prepare a 2× solution of 0.01 nM recombinant human GST fusion protein FGFR3 cytoplasmic domain [436-806 (terminal) amino acids] (Carna: 08-135), mix it with the test compound, and incubate at 23°C for 10 minutes;

[0366] ③ Prepare a 2× solution by mixing 28 nM Fluorescein-Poly GT peptide substrate (Life Technologies: PV3611) and 28 μM ATP, and incubate with the test compound and enzyme from ② at 23°C for 30 minutes.

[0367] ④ Add 10 μL of 2 nM Tb PY20 antibody (Life Technologies: PV3552) and 10 mM EDTA to quench the kinase reaction and incubate at 22°C for 60 minutes.

[0368] ⑤ The reaction was measured using a PerkinElmer EnVision multi-mode plate reader via TR FRET dual-wavelength detection.

[0369] 1. Copy the RFU value from the Envision program.

[0370] 2. Calculate the ratio of RFU 520nm / RFU 495nm.

[0371] 3. Convert the ratio value to a percentage suppression value.

[0372] % Inhibition = (max - data) / (max - min) × 100

[0373] “min” represents the ratio of enzyme-free control, “max” represents the ratio of DMSO control, and “data” represents the ratio of different concentrations of pore compounds.

[0374] The final result is displayed in Excel, with the curve fitted using XLFit Excel plugin version 5.5.0.5, IC. 50 Calculation formula: Y = Bottom + (Top - Bottom) / (1 + (IC) 50 / X)^HillSlope.

[0375] "Top" refers to the maximum response, "Bottom" refers to the minimum response, and "HillSlope" refers to the slope of the curve.

[0376] Table 3 Results of FGFR3 kinase activity inhibition by compounds

[0377] Conclusion: The parent drug of the prodrug of this invention exhibits excellent inhibitory activity against FGFR3 kinase.

[0378] Test Example 4

[0379] Experiment on the inhibitory activity of the compound on the proliferation of RT-112 (bladder cancer cells) cells

[0380] This experiment uses The Luminescent Cell Viability Assay (Promega: G7573) kit is a homogenization method for detecting cell viability by quantifying ATP to determine the viability of cultured cells.

[0381] ①RT112 cells were cultured at 37℃ and 5% CO2 in MEM complete medium (Gibco: 51200038) (10% FBS (Gibco: 10091-148) + 1% Pen Strep (Gibco: 15140122) + 1% NEAA (Gibco: 11140050)).

[0382] ② Harvest cells in the logarithmic growth phase and count them using a platelet counter. Assess cell viability using the trypan blue rejection assay to ensure it is above 90%.

[0383] ③ Adjust the cell density using MEM complete medium, and then seed 90 μL of the medium into 96-well cell culture plates, for a total of 3000 cells.

[0384] ④ Incubate the cells in the 96-well plate at 37°C and 5% CO2 for 24 hours.

[0385] ⑤ After 24 hours, prepare a 10-fold drug solution with an initial maximum drug concentration of 10 μM. Dilute the drug 10 times and 4 times. Then transfer 10 μL of each serially diluted compound to the corresponding well of the 96-well cell plate. Set up two replicates for each drug concentration.

[0386] ⑥ The cells in the 96-well plate with the added drug were cultured at 37°C and 5% CO2 for 72 hours, and then CTG analysis was performed.

[0387] ⑦ Melt the CTG reagent and equilibrate the cell plate to room temperature for 30 minutes.

[0388] ⑧ Add 50 μL of CTG solution to each well.

[0389] ⑨ Vibrate on a fixed-track shaking table for 5 minutes to cause cell lysis.

[0390] ⑩ Place the cell plate at room temperature for 20 minutes to stabilize the cold light signal. Read the cold light value and collect the data.

[0391] The data was analyzed using the XLFit Excel plugin version 5.5.0.5. A nonlinear S-curve regression was used to fit the data to derive the dose-response curve, and the IC was calculated from this curve. 50 value.

[0392] Y=Bottom+(Top-Bottom) / (1+(IC 50 / X)^HillSlope

[0393] "Top" refers to the maximum response, "Bottom" refers to the minimum response, and "HillSlope" refers to the slope of the curve.

[0394] Cell inhibition rate (%) = (Max-Lum of test drug) / (Max-Min) × 100%.

[0395] “Max” represents the average value of the cell + DMSO control, and “Min” represents the average value of the culture medium control + DMSO.

[0396] Table 4 shows the results of the compounds' inhibitory effect on the proliferation activity of RT-112 (bladder cancer cells).

[0397] Conclusion: The parent drug of the prodrug of this invention exhibits good inhibitory activity against the proliferation of RT-112 (bladder cancer cells).

Claims

1. A compound represented by general formula (I), Or its pharmaceutically acceptable salts, hydrates, solvates, isotopic substitutes, or stereoisomers. in, X 1 N atom or CR 8 ; X 2 N atom or CR 9 ; X 3 N atom or CR 10 ; X 4 N atom or CR 11 ; X 5 N atom or CR 12 ; Y is selected from O atom, S atom, -S(=O)-, -S(=O)2- and NR. 13 ; Ring A is a 5-membered nitrogen-containing heteroaryl group, more preferably pyrazolyl or triazolyl; R 0 For -LIN 1 -LIN 2 -LIN 3 -R 00 , Among them, LIN 1 Selected from chemical bonds, C 1-6 Alkylene and C 1-6 Ideonyl, LIN 2 Selected from chemical bonds, -O-, -S-, -C(=O)-, -OC(=O)-, -C(=O)-O-, -NR 13 -C(=O)-、-C(=O)-NR 13 -、 Among them, R a Selected from H atoms, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and metal cations; LIN 3 Selected from chemical bonds, C 1- 6-alkylene, C 1-6 imidene group, C 3-8 Cycloalkylene and 3-8 membered heterocyclic alkylene groups; the C 1-6 Alkylene, C 1-6 imidene group, C 3-8 Cycloalkylene, 3-8 membered heterocyclic alkylene, C 1-6 Alkyl and C 1-6 Each haloalkyl group is independently selected from the D atom, C atom, or C atom. 1-6 Alkyl, C 1-6 Alkoxy, -OH, -COOH, -CN, halogen, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 The hydroxyalkyl group is substituted with one or more substituents; R 00 Selected from H atoms, D atoms, C atoms 1-6 Alkyl, C 1-6 Alkyl group, -OH, -COOH, -NR 13 R 14 -CN, halogen, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(=O)-C 1-6 Alkyl group, -OC(=O)-C 1- 6-alkyl, -C(=O)-OC 1-6 Alkyl group, -NH-C(=O)-C 1-6 Alkyl group, -C(=O)-NH-C 1-6 Alkyl, C 6-10 Aryl, 5-8 quinone heteroaryl, C 3-8 cycloalkyl groups and 3-8 membered heterocyclic groups; the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-8 quinone heteroaryl, C 3-8 Cycloalkyl groups and 3-8 membered heterocyclic groups are each independently chosen to be bonded by the D atom, C atom, or C atom. 1-6 Alkyl, C 1-6 Alkyl group, -OH, -COOH, -NR 13 R 14 -CN, =O, halogen, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(=O)-C 1-6 Alkyl group, -OC(=O)-C 1- 6-alkyl, -C(=O)-OC 1-6 Alkyl group, -NH-C(=O)-C 1-6 Alkyl group, -C(=O)-NH-C 1-6 Alkyl, C 3-8 It is substituted by one or more substituents of cycloalkyl and 3-8 membered heterocyclic groups; R 1 and R 2 Each is independently selected from H atoms, -OH, and -SR. 15 -COOH, -NR 13 R 14 -NR 13 -C(=O)-NR 13 R 14 -NR 13 -C 1-6 Alkylene-C(=O)-NR 13 R 14 -NR 13 -C(=NR 13 )-NR 13 R 14 -C(=O)-NR 13 R 14 -C 1-6 Alkylene-NR 13 R 14 -OC 1-6 Alkylene-NR 13 R 14 -NR 13 -C 1-6 Alkylene-NR 13 R 14 -NR 13 -3-8 membered heterocyclic groups, -CN, halogens, C 1-6 Alkyl, C 1-6 Deuterated alkyl, -C 1-6 Alkylene-S(=O)2-C 1- 6-alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 6-10 Aryl, 5-10 heteroaryl, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently and optionally selected from C. 1-6 Alkyl, C 1-6 Alkyl group, -OH, -COOH, -NR 13 R 14 -CN, halogen, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 The hydroxyalkyl group is substituted with one or more substituents; R 3 Selected from H atoms, -OH, -SR 15 -COOH, -NR 13 R 14 -NR 13 -C(=O)-NR 13 R 14 -NR 13 -C(=NR 13 )-NR 13 R 14 -NR 13 -C 1-6 Alkylene-C(=O)-NR 13 R 14 -NR 13 -C(=NR 13 )-NR 13 R 14 -C(=O)-NR 13 R 14 -C 1-6 Alkylene-NR 13 R 14 -OC 1-6 Alkylene-NR 13 R 14 -NR 13 -C 1-6 Alkylene-NR 13 R 14 -NR 13 -3-8 membered heterocyclic groups, -CN, halogens, C 1-6 Alkyl, C 1-6 Deuterated alkyl, -C 1-6 Alkylene-S(=O)2-C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 cycloalkyl, C 5-15 Spirocycloalkyl, C 5-15 Bridged cycloalkyl, 3-8 membered heterocyclic, 5-15 membered spiroheterocyclic and 5-15 membered bridged heterocyclic, wherein C 6- 10 Aryl, 5-10 heteroaryl, C 3-8 cycloalkyl, C 5-15 Spirocycloalkyl, C 5-15 Bridged cycloalkyl, 3-8 membered heterocyclic, 5-15 membered spirocyclic and 5-15 membered bridged heterocyclic are each independently selected from C. 1-6 Alkyl, C 1-6 Alkyl group, -OH, -COOH, -NR 13 R 14 -S(=O)2-C 1-6 Alkyl, -CN, Halogen, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 The hydroxyalkyl group is substituted with one or more substituents; R 4 Selected from H atoms, -OH, -COOH, -NR 13 R 14 -NR 13 -C(=O)-NR 13 R 14 -C(=O)-NR 13 R 14 -C 1-6 Alkylene-NR 13 R 14 -CN, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups; R 5 R 6 and R 7 Each is independently selected from H atoms, -OH, and -SR. 15 -COOH, -NR 13 R 14 -NR 13 -NR 13 R 14 -NR 13 -C(=O)-NR 13 R 14 -NR 13 -C 1-6 Alkylene-C(=O)-NR 13 R 14 -NR 13 -C(=NR 13 )-NR 13 R 14 -C(=O)-NR 13 R 14 -C 1-6 Alkylene-NR 13 R 14 -OC 1-6 Alkylene-NR 13 R 14 -NR 13 -C 1- 6-alkylene-NR 13 R 14 -NR 13 -3-8 membered heterocyclic groups, -CN, halogens, C 1-6 Alkyl, C 1-6 Deuterated alkyl, -C 1- 6-alkylene-S(=O)2-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 6-10 Aryl, 5-10 heteroaryl, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently and optionally selected from C. 1-6 Alkyl, C 1-6 Alkyl group, -OH, -COOH, -NR 13 R 14 -CN, halogen, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 The hydroxyalkyl group is substituted with one or more substituents; R 8 R 9 R 10 R 11 and R 12 Each is independently selected from H atoms, -OH, and -SR. 15 -COOH, -NR 13 R 14 -NR 13 -C(=O)-NR 13 R 14 -NR 13 -C 1-6 Alkylene-C(=O)-NR 13 R 14 -NR 13 -C(=NR 13 )-NR 13 R 14 -C(=O)-NR 13 R 14 -C 1-6 Alkylene-NR 13 R 14 -OC 1-6 Alkylene-NR 13 R 14 -NR 13 -C 1-6 Alkylene-NR 13 R 14 -NR 13 -3-8 membered heterocyclic groups, -CN, halogens, C 1-6 Alkyl, C 1-6 Deuterated alkyl, -C 1-6 Alkylene-S(=O)2-C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 6-10 Aryl, 5-10 heteroaryl, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently and optionally selected from C. 1-6 Alkyl, C 1-6 Alkyl group, -OH, -COOH, -NR 13 R 14 -CN, halogen, C 1-6 Haloalkyl, C 1- 6-Hydroalkoxy and C 1-6 The hydroxyalkyl group is substituted with one or more substituents; Each R 13 Independently selected from H atoms, -CN, -OH, -C(=O)H, -C(=O)-C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently and optionally selected from C. 1-6 Alkyl, C 1-6 Alkoxy, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 The hydroxyalkyl group is substituted with one or more substituents; Each R 14 Independently selected from H atoms, -CN, -OH, -C(=O)H, -C(=O)-C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently and optionally selected from C. 1-6 Alkyl, C 1-6 Alkoxy, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 The hydroxyalkyl group is substituted with one or more substituents; Or, R 13 R 14 Together with the N atom attached thereto, a 3-8 membered heterocyclic group is formed, wherein the 3-8 membered heterocyclic group is optionally selected from C. 1-6 Alkoxy, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 The hydroxyalkyl group is substituted with one or more substituents; Each R 15 Independently selected from H atoms, -CN, halogens, -OH, -C(=O)H, -C(=O)-C 1-6 Alkyl, C 1- 6-alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently and optionally selected from C. 1-6 Alkyl, C 1-6 Alkoxy, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 The hydroxyalkyl group is substituted with one or more substituents; and m can be 0, 1, 2, or 3.

2. The compound according to claim 1, wherein it is a compound represented by general formula (II), in, X 2 N atom or CR 9 ; X 3 It is an N atom or CH; X 4 It is an N atom or CH; X 5 It is an N atom or CH; X 6 N atom or CR 3c ; R 3a R 3b and R 3c Each is independently selected from H atoms, -OH, and -SR. 15 -COOH, -NR 13 R 14 -NR 13 -C(=O)-NR 13 R 14 -NR 13 -C(=NR 13 )-NR 13 R 14 -NR 13 -C 1-6 Alkylene-C(=O)-NR 13 R 14 -NR 13 -C(=NR 13 )-NR 13 R 14 -C(=O)-NR 13 R 14 -C 1-6 Alkylene-NR 13 R 14 -OC 1-6 Alkylene-NR 13 R 14 -NR 13 -C 1-6 Alkylene-NR 13 R 14 -NR 13 -3-8 membered heterocyclic groups, -CN, halogens, C 1-6 Alkyl, C 1-6 Deuterated alkyl, -C 1-6 Alkylene-S(=O)2-C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 cycloalkyl, C 5-15 Spirocycloalkyl, C 5-15 Bridged cycloalkyl, 3-8 membered heterocyclic, 5-15 membered spiroheterocyclic and 5-15 membered bridged heterocyclic, wherein C 6-10 Aryl, 5-10 heteroaryl, C 3-8 cycloalkyl, C 5-15 Spirocycloalkyl, C 5-15 Bridged cycloalkyl, 3-8 membered heterocyclic, 5-15 membered spirocyclic and 5-15 membered bridged heterocyclic are each independently selected from C. 1-6 Alkyl, C 1- 6-alkoxy group, -OH, -COOH, -NR 13 R 14 -S(=O)2-C 1-6 Alkyl, -CN, Halogen, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 The hydroxyalkyl group is substituted with one or more substituents; and R 0 R 1 R 2 R 4 R 5 R 6 R 7 R 8 R 9 R 13 R 14 and R 15 As defined in claim 1.

3. The compound according to claim 1 or 2, wherein it is a compound represented by general formula (II-1), (II-2), (II-3), (II-4) or (II-5). in, R 0 R 1 R 2 R 4 R 5 R 6 R 7 R 8 R 9 R 3a R 3b and R 3c As defined in claim 2.

4. The compound according to any one of claims 1-3, wherein it is a compound represented by general formula (III) or (V), or even a compound represented by general formula (IV) or (VI), in, R 5 Selected from -NHR 13 -NH-C(=O)-NR 13 R 14 -NH-C 1-6 Alkylene-C(=O)-NR 13 R 14 -NH-C(=NH)-NHR 13 -C 1-6 Alkylene-NR 13 R 14 -OC 1-6 Alkylene-NHR 14 -NH-C 1-6 Alkylene-NHR 13 -NH-3-8-membered heterocyclic group, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently and optionally substituted with one or more halogens; wherein each R 13 and R 14 Each is independent of the definition in claim 1; Preferably, R 5 Selected from -NHR 13 and C 3-8 cycloalkyl, wherein the C 3-8 The cycloalkyl group may optionally be substituted with one or more halogens; wherein, R 13 As defined in claim 1; More preferably, R 5 Selected from -NH2, -NH(C 1-6 alkyl), -NH(C) 1-6 Halogenated alkyl), -NH(C) 1-6 (deuterated alkyl), C 3-8 cycloalkyl groups, C substituted with one or more halogens 3-8 cycloalkyl and -NH-C 3-8 cycloalkyl; R 3a C 1-6 Alkyl or C 1-6 Deuterated alkyl groups; Even more preferably, R 5 Selected from difluoromethyl, -NH2, R 9 Selected from H atoms, -OH, -COOH, -NR 13 R 14 -CN, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein R 13 and R 14 Each is independent of the definition in claim 1; Preferably, R 9 Selected from H atoms, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -CN, halogen, C 1- 6-alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 cycloalkyl and C 1-6 Halogenated alkyl groups; More preferably, R 9 It is difluoromethyl; and R 3a C 1-6 Alkyl or C 1-6 Deuterated alkyl; preferably, R 3a It is a methyl group.

5. The compound according to any one of claims 1-4, wherein R 0 Choose from any one of (i) to (v): (i)-L 1 -OC(=O)-R 16 L 1 For chemical bonds, C 1-6 Alkylene or C 1-6 Ideonyl, R 16 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, 3-8 membered heterocyclic group, C 3-8 cycloalkyl, -NR 13 R 14 and -C 1-6 Alkylene-NR 13 R 14 The C 1-6 Alkylene, C 1-6 imidene group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently selected from the D atom, C ... 1-6 Alkyl, C 1-6 Alkyl group, -OH, -COOH, -NR 13 R 14 -CN, =O, halogen, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(=O)-C 1-6 Alkyl group, -OC(=O)-C 1-6 Alkyl, -C(=O)-OC 1-6 Alkyl group, -NH-C(=O)-C 1-6 Alkyl group, -C(=O)-NH-C 1-6 Alkyl, C 3-8 It is substituted by one or more substituents of cycloalkyl and 3-8 membered heterocyclic groups; (ii)-C(=O)-R 17 , where R 17 Selected from C 1-6 Alkyl, 3-8 membered heterocyclic groups, C 3-8 cycloalkyl, -NR 13 R 14 -C 1-6 Alkylene-NR 13 R 14 -NR 13 -C 1-6 Alkylene-NR 13 R 14 The C 1-6 Alkylene, C 1-6 Alkyl, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently selected from the D atom, C ... 1-6 Alkyl, C 1-6 Alkyl group, -OH, -COOH, -NR 13 R 14 -CN, =O, halogen, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(=O)-C 1-6 Alkyl group, -OC(=O)-C 1-6 Alkyl, -C(=O)-OC 1-6 Alkyl group, -NH-C(=O)-C 1-6 Alkyl group, -C(=O)-NH-C 1-6 Alkyl, C 3-8 It is substituted by one or more substituents of cycloalkyl and 3-8 membered heterocyclic groups; (iii)-L 1 -C(=O)-OR 18 L 1 For chemical bonds, C 1-6 Alkylene or C 1-6 Ideonyl, R 18 Selected from -C 1-6 Alkyl-3-8-membered heterocyclic group, -C 1-6 Alkylene-C 3-8 cycloalkyl, -C 1-6 Alkylene-NR 13 R 14 C 1-6 Alkyl, 3-8 membered heterocyclic groups, C 3-8 cycloalkyl, -C 1-6 Alkylene-OC(=O)-C 1-6 Alkyl, the C 1-6 Alkylene, C 1-6 imidene group, C 1-6 Alkyl, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently selected from the D atom, C ... 1-6 Alkyl, C 1-6 Alkyl group, -OH, -COOH, -NR 13 R 14 -CN, =O, halogen, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(=O)-C 1-6 Alkyl group, -OC(=O)-C 1-6 Alkyl, -C(=O)-OC 1- 6-alkyl, -NH-C(=O)-C 1-6 Alkyl group, -C(=O)-NH-C 1-6 Alkyl, C 3-8 It is substituted by one or more substituents of cycloalkyl and 3-8 membered heterocyclic groups; (iv)-C 1-6 alkylene-3-8-membered heterocyclic groups or -C 1-6 Alkylene-C 3-8 cycloalkyl, the C 1-6 Alkylene, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently selected from the D atom, C ... 1-6 Alkyl, C 1-6 Alkyl group, -OH, -COOH, -NR 13 R 14 -CN, =O, halogen, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1- 6-hydroxyalkyl, -C(=O)-C 1-6 Alkyl group, -OC(=O)-C 1-6 Alkyl group, -NH-C(=O)-C 1-6 Alkyl, C 3-8 Substituted with one or more substituents of cycloalkyl and 3-8 membered heterocyclic groups; and (v) in, L 2 Selected from chemical bonds, C 1-6 Alkylene and -C 1-6 alkylene-O-, the C 1- 6-alkylene groups are optionally selected from the D atom, C atom, and C atom. 1-6 Alkyl, C 1-6 Alkyl group, -OH, -COOH, -NR 13 R 14 -CN, =O, halogen, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(=O)-C 1-6 Alkyl group, -OC(=O)-C 1-6 Alkyl group, -NH-C(=O)-C 1-6 Alkyl, C 3-8 Replaced by one or more substituents of cycloalkyl and 3-8 membered heterocyclic groups, R a and R b Each is independently selected from H atoms and C atoms. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and metal cations.

6. The compound according to any one of claims 1-5, wherein, R 0 Selected from: (i)-C 1-6 Alkylene-OC(=O)-C 1-6 Alkyl, -C 1-6 Alkyl-substituted C 1-6 Alkylene-OC(=O)-C 1- 6-alkyl, -C 1-6 Alkylene-OC(=O)-3-8-membered heterocyclic group, -C 1-6 Alkylene-OC(=O)-3-8-membered heterocyclic-C(=O)-C 1-6 Alkyl, -C 1-6 Alkylene-OC(=O)-C 3-8 cycloalkyl, -C 1-6 Alkylene-OC(=O)-C 1-6 Alkylene-NH-C(=O)-C 1-6 Alkyl, -C 1-6 Alkylene-OC(=O)-C 1-6 Alkylene -COOH, -C 1-6 Alkylene-OC(=O)-NH(C) 1-6 Alkyl), -C 1-6 Alkylene-OC(=O)-OC 1-6 alkyl; (ii)-C(=O)-C 1-6 Alkyl, -C(=O)-C 1-6 Haloalkyl, -C(=O)-C 1-6 Hydroxyalkyl, -C(=O)-C 3- 8-cycloalkyl, -C(=O)-C 1-6 Alkylene-NH-C(=O)-C 1-6 Alkyl, -C(=O)-C 1-6 Alkylene-CN, -C(=O)-C 1-6 Alkylene groups - 3-8 membered heterocyclic groups containing nitrogen atoms, -C(=O)-C 1-6 Alkylene -COOH, -C(=O)-C 1-6 Alkylene-OC(=O)-C 1-6 Alkyl, -C(=O)-3-8 membered heterocyclic, -C(=O)-3-8 membered heterocyclic-3-8 membered heterocyclic, -C(=O)-NH-C 1-6 Alkylene-N(C) 1-6 Alkyl)2; (iii)-C(=O)-OC 1-6 alkylene-3-8-membered heterocyclic group, wherein the 3-8-membered heterocyclic group is optionally selected from =O and C. 1- One or more substituents of the 6-alkyl group, -C(=O)-OC 1-6 Alkylene-N(C) 1-6 Alkyl)2、-C(=O)-OC 1- 6-alkylene-3-8 membered heterocyclic groups containing nitrogen atom, -C(=O)-OC 1-6 Alkyl, -C(=O)-OC 1-6 Hydroxyalkyl, -C(=O)-OC 1-6 Alkylene-OC(=O)-C 1-6 Alkyl, -C(=O)-O- with C 1-6 Alkyl-substituted C 1-6 Alkylene-OC(=O)-C 1-6 alkyl; (iv)-C 1-6 alkylene-3-8-membered heterocyclic group, wherein the 3-8-membered heterocyclic group is optionally selected from =O and C. 1-6 Alkyl groups are substituted with one or more substituents; and (v) Among them, L 2 Selected from chemical bonds, -C 1-6 alkylene-O- and --C 1-6 Alkyl-substituted C 1- 6-alkylene-O-,R a and R b Each is independently selected from H atoms and C atoms. 1-6 Alkyl and alkali metal cations.

7. The compound according to any one of claims 1-6, wherein, R 0 Selected from -C 1-6 Alkylene-OC(=O)-C 1-6 Alkyl, -C 1-6 Alkylene-OC(=O)-C 1-6 Alkylene -COOH, -C(=O)-OC 1-6 Alkylene groups – 5-6 membered heterocyclic groups containing nitrogen atoms and -C(=O)-C 1-6 Alkylene-OC(=O)-C 1-6 alkyl.

8. The compound according to any one of claims 1-6, wherein, R 0 Selected from:

9. The compound according to any one of claims 1-4, wherein it is a compound represented by the general formula (III-1), (III-2), (III-3), (III-4), (V-1), (V-2), (V-3), or (V-4). Even compounds represented by the general formulas (IV-1), (IV-2), (IV-3), (IV-4), (VI-1), (VI-2), (VI-3), or (VI-4), in, Each L 1 Each independently is C 1-6 Alkylene or C 1-6 Alkyl-substituted C 1-6 Alkylene; R 16 Selected from C 1-6 Alkyl, 3-8 membered heterocyclic, -3-8 membered hypoheterocyclic -C(=O)-C 1-6 Alkyl, C 3-8 cycloalkyl, -C 1-6 Alkylene-NH-C(=O)-C 1-6 Alkyl, -C 1-6 Alkylene -COOH, -NH(C 1-6 alkyl) and C 1-6 Alkoxy; R 17 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-8 cycloalkyl, -C 1-6 Alkylene-NH-C(=O)-C 1-6 Alkyl, -C 1-6 Alkylene-CN, -C 1-6 Alkylene - 3-8 membered heterocyclic groups containing nitrogen atom, -C 1-6 Alkylene -COOH, -C 1-6 Alkylene-OC(=O)-C 1-6 Alkyl, 3-8 membered heterocyclic, -3-8 membered heterocyclic, -3-8 membered heterocyclic, -NH-C 1-6 Alkylene-N(C) 1-6 Alkyl)2; R 18 Selected from -C 1-6 alkylene-3-8-membered heterocyclic group, wherein the 3-8-membered heterocyclic group is optionally selected from =O and C. 1-6 Alkyl group with one or more substituents, -C 1-6 Alkylene-N(C) 1-6 Alkyl)2, -C 1-6 Alkylene - 3-8 membered heterocyclic groups containing nitrogen atoms, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-OC(=O)-C 1-6 Alkyl, -C 1-6 Alkyl-substituted C 1-6 Alkylene-OC(=O)-C 1-6 alkyl; L 2 Selected from chemical bonds, -C 1-6 alkylene-O- and --C 1-6 Alkyl-substituted C 1-6 Alkylene-O-; R a and R b Each is independently selected from H atoms and C atoms. 1-6 Alkyl and alkali metal cations; and R 5 R 9 and R 3a As defined in claim 4.

10. The compound according to any one of claims 1-9, wherein the compound is selected from:

11. A method for preparing the compound of general formula (I) according to claim 1, the method comprising: The compound represented by the general formula (ID) and compound R 0 -LG 2 The reaction forms a compound of general formula (I); in, LG 2 The leaving group is preferably a halogen, methanesulfonyloxy, or p-toluenesulfonyloxy; and X 1 To X 5 Y, ring A, R 0 To R 7 and m as defined in claim 1.

12. A pharmaceutical composition comprising a compound according to any one of claims 1-10, or a pharmaceutically acceptable salt, hydrate, solvate, isotope substitute, or stereoisomer thereof, and one or more pharmaceutically acceptable excipients.

13. Use of the compound according to any one of claims 1-10, or a pharmaceutically acceptable salt, hydrate, solvate, isotope substitute, or stereoisomer thereof, or the pharmaceutical composition according to claim 12, in the preparation of an FGFR inhibitor.

14. The use of the compound according to any one of claims 1-10, or a pharmaceutically acceptable salt, hydrate, solvate, isotope substitute, or stereoisomer thereof, or the pharmaceutical composition according to claim 12, in the preparation of a medicament for treating and / or preventing tumors; particularly, the tumor is cancer; the cancer is preferably selected from cholangiocarcinoma, liver cancer, breast cancer, prostate cancer, lung cancer, thyroid cancer, gastric cancer, ovarian cancer, colorectal cancer, endometrial cancer, urothelial carcinoma, testicular cancer, cervical cancer, leukemia, skin cancer, esophageal cancer, head and neck cancer, kidney cancer, pancreatic cancer, bone cancer, lymphoma, melanoma, glioma; more preferably selected from cholangiocarcinoma, liver cancer, breast cancer, prostate cancer, lung cancer, thyroid cancer, gastric cancer, ovarian cancer, colorectal cancer, endometrial cancer, and urothelial carcinoma.

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