Cyano-substituted bicyclic heterocyclic derivative and application thereof

Abstract

The invention relates to a substituted heterocyclic derivative and application thereof. Particularly, the invention relates to a compound as shown in a general formula (I), a preparation method thereof, a pharmaceutical composition thereof and application of the compound as shown in the general formula (I) or the pharmaceutical composition thereof in preparation of drugs for preventing and / or treating FGFR tyrosine kinase mediated diseases, and substituents in the general formula (I) are as defined in the specification. # imgabs0 #

Description

Technical Field

[0001] The present disclosure relates to novel compounds that act on FGFR tyrosine kinases, particularly FGFR1, FGFR2, FGFR3, and / or FGFR4, preparation processes, methods, and uses comprising such compounds. More specifically, the present invention relates to compounds that can be used to treat or prevent diseases treatable with FGFR inhibitors. Background Art

[0002] Mutations or abnormal expressions of protein tyrosine kinases (PTKs) are one of the main causes of cancer. Fibroblast growth factor receptors (FGFRs) are a subfamily of tyrosine kinase receptors, which have four subtypes, including FGFR1, FGFR2, FGFR3, and FGFR4. Fibroblast growth factors (FGFs) bind to their receptors (fibroblast growth factor receptors, FGFRs), activate the downstream signaling pathways they regulate, and play important roles in biological processes such as mitosis (embryogenesis, growth and development, etc.) and non-mitosis (neural regulation, metabolic regulation, etc.). Among the mitotic pathways, high expression, mutations, etc. of FGFR lead to abnormal activation of its signaling pathway. If the mitotic effect of the FGFR pathway is uncontrolled, tumors will follow.

[0003] FGFR3 is a tyrosine kinase receptor gene located on chromosome 4p16.3 and consists of 19 exons. The extracellular part can bind to fibroblast growth factors, triggering a cascade of downstream signals that ultimately affect cell growth, migration, angiogenesis, and differentiation. Mutations in fibroblast growth factor receptor 3 (FGFR3) mainly occur in low-grade non-invasive urothelial tumors. At the same time, FGFR3 is a negative regulator of bone growth. It inhibits the proliferation and differentiation of chondrocytes in the growth plates of patients, resulting in growth disorders of long bones. The CNP signaling pathway stimulates the proliferation and differentiation of chondrocytes in the growth plates, thereby promoting endochondral ossification of cartilage and long bone growth.

[0004] FGFR-targeted inhibitor drugs can inhibit the abnormal activation of the FGF / FGFR signaling pathway and have the potential to treat the above diseases. Therefore, FGFR inhibitor drugs have become one of the hotspots in drug research in recent years. Since 2019, inhibitors such as Erdafitinib, Pemigatinib, and Infigratinib have been successively launched. Although their development has been successful, because they belong to pan-FGFR inhibitors or FGFR1-3 inhibitors, there are still some treatment-related adverse events (TRAEs) in the above three approved FGFR inhibitors in clinical trials. For example, FGFR1-mediated hyperphosphatemia is a dose-limiting toxicity of pan-FGFR inhibitors; FGFR2-mediated skin / nail, ocular, and perioral toxicities lead to chronic intolerance of pan-FGFR inhibitors; therefore, the development of highly selective inhibitors targeting precise FGFR subtypes and second-generation FGFR inhibitors that overcome the resistance of existing FGFR inhibitors has become a major research direction at present. Summary of the Invention

[0005] The present invention provides a compound represented by general formula (I), its stereoisomer, or its pharmaceutically acceptable salt, which is an FGFR inhibitor and has good physicochemical properties, such as high solubility, physical and / or chemical stability, improved pharmacokinetic characteristics, high bioavailability, good safety, and low toxicity and side effects. It has the advantages of oral administration, fast absorption, high clearance rate, etc. In particular, it has high selectivity for FGFR3, superior to the inhibition of FGFR1 and FGFR2, and can reduce the toxicity and side effects caused by pan-FGFR.

[0006] The present invention relates to a compound represented by general formula (I), (II-1), (II-2), (III-1), (III-2), (IV-1), (IV-2), (V-1), (V-2), (VI-1), (VI-2), (VII-1), (VII-2), its stereoisomer, or its pharmaceutically acceptable salt:

[0007]

[0008]

[0009] Wherein:

[0010] Cy1 is C 3-11 cycloalkyl, 4-11 membered heteroalkyl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, optionally further substituted by 1-4 R c1 substituted; in some embodiments, Cy1 is selected from C 3-6A monocyclic cycloalkyl group, a 4- to 6-membered monocyclic saturated heterocycloalkyl group, a 4- to 6-membered monocyclic partially saturated heterocycloalkyl group, a 4- to 6-membered heterocycloalkyl group fused to a 3- to 6-membered cycloalkyl group, a 4- to 6-membered heterocycloalkyl group fused to a 4- to 6-membered heterocycloalkyl group, a 4- to 6-membered heterocycloalkyl group fused to a 5- to 6-membered heteroaryl group, a 5- to 6-membered heteroaryl group fused to a 5- to 6-membered heteroaryl group, a 5- to 8-membered bridged heterocycloalkyl group, a 6- to 8-membered spiro heterocycloalkyl group, optionally further substituted by 1 to 4 R c1 substituted; in some embodiments, Cy1 is selected from C 4-6 A monocyclic cycloalkyl group, a 4- to 6-membered saturated monocyclic heterocycloalkyl group containing 1 to 2 nitrogen atoms, a 4- to 6-membered partially unsaturated monocyclic heterocycloalkyl group containing 1 to 2 nitrogen atoms, a 5- to 8-membered saturated bridged heterocycloalkyl group containing 1 to 2 nitrogen atoms, a 4- to 6-membered heterocycloalkyl group fused to a 3- to 6-membered cycloalkyl group and containing 1 to 2 nitrogen atoms, a 6- to 8-membered saturated spiro heterocycloalkyl group containing 1 to 2 nitrogen atoms, a 4- to 6-membered heterocycloalkyl group fused to a 5- to 6-membered heteroaryl group, a 5- to 6-membered heteroaryl group fused to a 5- to 6-membered heteroaryl group, optionally further substituted by 1 to 4 R c1 substituted; in some embodiments, Cy1 is selected from optionally further substituted by 1 to 4 R c1 substituted;

[0011] In some embodiments, Cy1 is selected from optionally further substituted by 1 to 4 R c1 substituted;

[0012] In some embodiments, Cy1 is selected from optionally further substituted by 1 to 4 R c1 substituted;

[0013] In some embodiments, Cy1 is selected from C 4-6 A monocyclic cycloalkyl group, a 4- to 5-membered saturated monocyclic heterocycloalkyl group containing 1 to 2 nitrogen atoms, a 6-membered saturated monocyclic heterocycloalkyl group containing 2 nitrogen atoms, a 4- to 6-membered partially unsaturated monocyclic heterocycloalkyl group containing 1 to 2 nitrogen atoms, a 5- to 8-membered saturated bridged heterocycloalkyl group containing 1 to 2 nitrogen atoms, a 4- to 6-membered heterocycloalkyl group fused to a 3- to 6-membered cycloalkyl group and containing 1 to 2 nitrogen atoms, a 6- to 8-membered saturated spiro heterocycloalkyl group containing 1 to 2 nitrogen atoms, a 4- to 6-membered heterocycloalkyl group fused to a 5- to 6-membered heteroaryl group, a 5- to 6-membered heteroaryl group fused to a 5- to 6-membered heteroaryl group, optionally further substituted by 1 to 4 R c1 substituted; in some embodiments, Cy1 is selected from optionally further substituted by 1 to 4 R c1 substituted;

[0014] Cy2 is present or absent; when Cy2 is present, Cy2 is a 3- to 8-membered heterocycloalkyl or a 5- to 10-membered heteroaryl, optionally further substituted by 1 to 5 R c2 substituents; in some embodiments, Cy2 is present or absent, and when Cy2 is present, Cy2 is selected from 5- to 6-membered heterocycloalkyl or 5- to 6-membered heteroaryl, optionally further substituted by 1 to 4 R c2 substituents; in some embodiments, Cy2 is absent or Cy2 is selected from 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, 5-membered heteroaryl or 6-membered heteroaryl, optionally further substituted by 1 to 4 R c2 substituents; in some embodiments, Cy2 is absent or Cy2 is selected from optionally further substituted by 1 to 4 R c2 substituents;

[0015] In some embodiments, Cy2 is absent or Cy2 is selected from 5-membered heteroaryl containing 1 to 2 nitrogen heteroatoms and containing 0 to 2 heteroatoms selected from O and S, 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S, and the heteroaryl is optionally further substituted by 1 to 2 R c2 substituents; in some embodiments, Cy2 is selected from the optionally further substituted by 1 to 2 R c2 substituents;

[0016] In some embodiments, Cy2 is absent or Cy2 is selected from optionally further substituted by 1 to 4 R c2 substituents;

[0017] In some embodiments, Cy2 is selected from the optionally further substituted by 1 to 2 R c2 substituents;

[0018] Cy3 is selected from C 3-14 cycloalkyl, 5- to 14-membered heterocycloalkyl, C 6-14 aryl or 5- to 14-membered heteroaryl, optionally further substituted by 1 to 4 R c3 substituents; in some embodiments, Cy3 is selected from C 4-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 4-6Cycloalkylphenyl, C 4-6 Cycloalkyl-fused 5- or 6-membered heteroaryl, 5- or 6-membered heterocycloalkylphenyl, 5- or 6-membered heterocycloalkyl-fused 5- or 6-membered heteroaryl, optionally further substituted by 1 to 4 R c3 In some embodiments, Cy3 is selected from cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, pyridyl, cyclopentyl-fused 5-membered heteroaryl, cyclopentyl-fused 6-membered heteroaryl, pyrrolidinylphenyl, pyrrolidinyl-fused 5-membered heteroaryl, pyrrolidinyl-fused 6-membered heteroaryl, optionally further substituted by 1 to 4 R c3 In some embodiments, Cy3 is selected from Optionally further substituted by 1 to 4 R c3 Substituted;

[0019] Each R c1 Independently is deuterium, halogen, hydroxy, cyano, amino, oxo, SF5, SCF3, -COOH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Alkylidene, C 1-6 Halogenated alkylidene, where the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino are optionally further substituted by 1 to 3 groups selected from halogen, oxo, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Alkylidene or C 1-3 Halogenated alkylidene; in some embodiments, R c1 Is selected from deuterium or C 1-6 Alkyl, in some embodiments, R c1 Is selected from deuterium or C 1-3 Alkyl, in some embodiments, R c1 Is selected from deuterium or methyl;

[0020] Each R c2 Independently is deuterium, halogen, hydroxy, cyano, amino, oxo, SF5, SCF3, -COOH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Alkyl subunit, C 1-6 Haloalkyl subunit, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl or C 3-8 Cycloalkylalkyl, the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally further substituted by 1-3 groups selected from halogen, oxo, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Alkyl subunit or C 1-3 In some embodiments, R c2 Selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl; in some embodiments, R c2 Selected from deuterium, halogen, oxo, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-4 Cycloalkyl, in some embodiments, R c2 is selected from deuterium, fluorine, chlorine, oxo, methyl, vinyl, ethynyl or cyclopropyl;

[0021] Each R c3 Each is independently deuterium, halogen, hydroxyl, cyano, amino, oxo, SF5, SCF3, -COOH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C1-6 Halogenated alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Alkylidene, C 1-6 Halogenated alkylidene, C 3-8 Cycloalkyl, 3 - 8 - membered hetero cycloalkyl, C 6-10 Aryl, 5 - 10 - membered heteroaryl or C 3-8 Cycloalkylalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted by 1 - 3 groups selected from halogen, oxo, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Alkylidene or C 1-3 Halogenated alkylidene; in some embodiments, R c3 Is selected from deuterium, halogen, hydroxy, cyano, amino, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Alkylidene, C 1-6 Halogenated alkylidene, C 3-8 Cycloalkyl, 3 - 8 - membered hetero cycloalkyl, C 6-10 Aryl, 5 - 10 - membered heteroaryl or C 3-8 Cycloalkylalkyl, in some embodiments, R c3 Is selected from deuterium, halogen, oxo, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkylidene, C 1-3 Halogenated alkylidene or C 3-4 Cycloalkylmethyl, in some embodiments, R c3 Is selected from deuterium, fluorine, chlorine, oxo, methyl, methylene, ethylene, 1 - methylethylene, fluoromethylene, difluoromethylene, vinyl, ethynyl or cyclopropylmethyl; [[ID=7^]]

[0022] [[ID=7^]]Or, any one R c1 And any one R c2 Linked with the ring atom to which it is attached to form a 5 - 8 - membered hetero cycloalkyl or 5 - 8 - membered heteroaryl, optionally further substituted by 1 - 3 groups selected from halogen, oxo, C1-3 alkyl, halo-C 1-3 alkyl, C 1-3 alkoxy, halo-C 1-3 alkoxy, C 1-3 alkylidene or C 1-3 substituted by a group of haloalkylidene; in some embodiments, any one of R c1 and any one of R c2 linked to the ring atom to which it is attached to form a 6- to 8-membered heterocycloalkyl or 6- to 8-membered heteroaryl, optionally further substituted by 1 to 3 groups selected from halogen, oxo, C 1-3 alkyl, halo-C 1-3 alkyl, C 1-3 alkoxy, halo-C 1-3 alkoxy, C 1-3 alkylidene or C 1-3 substituted by a group of haloalkylidene; in some embodiments, any one of R c1 and any one of R c2 linked to the ring atom to which it is attached to form a 6- or 7-membered heterocycloalkyl or 6-membered heteroaryl, optionally further substituted by 1, 2 or 3 groups selected from F, Cl, oxo, C 1-2 alkyl, halo-C 1-2 alkyl, methylene, ethylene, 1-methylethylene, fluoromethylene, difluoromethylene;

[0023] X1 is independently a bond, -CO-, C 1-3 alkylene, C 2-4 alkenylene or C 2-4 alkynylene, said alkylene optionally further substituted by 1 to 3 groups selected from halogen, C 2-4 alkenyl or C 2-4 alkynyl; in some embodiments, X1 is a bond, -CO-, C 1-3 alkylene, C 2-4 alkenylene or C 2-4 alkynylene, in some embodiments, X1 is a bond, -C≡C-; in some embodiments, X1 is a bond; in some embodiments, X1 is -C≡C-;

[0024] X2 are each independently a bond, -CO-, C 1-3 alkylene, C 2-4 alkenylene or C 2-4 alkynylene, said alkylene optionally further substituted by 1 to 3 groups selected from halogen, C 2-4 alkenyl or C 2-4Substitution of the alkynyl group; in some embodiments, X2 is selected from a bond, -CO-, -CH(CH3)-, -CH═C(CH3)-, -C≡C-, -CH(CH═CH2)-, -CH(C≡CH)-; in some embodiments, X2 is selected from a bond, -CO-, -CH═C(CH3)-, -C≡C-, -CH(CH═CH2)-, -CH(C≡CH)-; in some embodiments, X2 is selected from a bond, -CO-, -C≡C-; in some embodiments, X2 is selected from -CH(CH3)-;

[0025] Y is a bond, -O-, -NR y - or -O-NR y -; in some embodiments, Y is selected from a bond, -O-, -NCH3-, -O-NCH3-; in some embodiments, Y is selected from a bond, -O-; in some embodiments, Y is selected from -O-; in some embodiments, Y is selected from a bond, -NCH3-, -O-NCH3-;

[0026] R y is hydrogen or C 1-3 alkyl; in some embodiments, R y is methyl;

[0027] R is cyano, -N(C 1-2 alkyl)-CN, -N(CN)2, amino, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio or C 1-6 alkylamino, and the amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio or alkylamino is optionally further substituted by 1 - 3 groups selected from halogen, hydroxy, cyano, amino, oxo, halo C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, C 1-3 alkylidene, C 1-3 haloalkylidene, C 3-6 cycloalkyl; in some embodiments, R is cyano, -N(C 1-2 alkyl)-CN, amino, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio or C 1-6 alkylamino, and the amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio or alkylamino is optionally further substituted by 1 - 3 groups selected from halogen, hydroxy, cyano, amino, oxo, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene, C 1-3 haloalkylidene, C 3-6 cycloalkyl; in some embodiments, R is selected from cyano, -N(C 1-2 alkyl)-CN, amino, -COOH, C 1-3 alkyl, C 2-4 alkenyl or C 2-4 alkynyl, and the amino, alkyl, alkenyl or alkynyl is optionally further substituted by 1 - 3 groups selected from halogen, hydroxy, cyano, amino, oxo, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene, C 1-3 haloalkylidene, C 3-6 cycloalkyl; in some embodiments, R is selected from cyano, -N(C 1-2 alkyl)-CN or C 2-4 alkynyl, and the alkynyl is optionally further substituted by 1 - 3 groups selected from hydroxy, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 3-4 cycloalkyl; in some embodiments, R is selected from cyano, -N(CH3)-CN, In some embodiments, R is selected from -N(CH3)-CN, In some embodiments, R is selected from cyano;

[0028] Provided that

[0029] (1) when Cy2 is absent and X1 is a bond, Cy1 is not a substituted or unsubstituted pyrazole, pyridine, pyrazine;

[0030] (2) [[ID=6\5]] is not

[0031] Unless otherwise specified, the heterocycloalkyl and heteroaryl contain 1, 2, 3, 4 or 5 heteroatoms selected from N, O, S, P, Si or oxidized groups of N, S, P.

[0032] Specifically, the first technical solution of the present invention relates to providing a compound represented by the general formula (I), its stereoisomers or its pharmaceutically acceptable salts,

[0033]

[0034] wherein:

[0035] Cy1 is selected from C 3-11 cycloalkyl, 4-11 membered hetero cycloalkyl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, optionally further substituted by 1-4 R c1 substituents;

[0036] Cy2 is present or absent; when Cy2 is present, Cy2 is 3-8 membered hetero cycloalkyl or 5-10 membered heteroaryl, optionally further substituted by 1-5 R c2 substituents;

[0037] Cy3 is selected from C 3-14 cycloalkyl, 5-14 membered hetero cycloalkyl, C 6-14 aryl or 5-14 membered heteroaryl, optionally further substituted by 1-4 R c3 substituents;

[0038] Each R c1 is independently deuterium, halogen, hydroxyl, cyano, amino, oxo, SF5, SCF3, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkylidene, C 1-6 haloalkylidene, and the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino are optionally further substituted by 1-3 groups selected from halogen, oxo, C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, C 1-3 alkylidene or C 1-3 haloalkylidene;

[0039] Each R c2 and R c3 are independently deuterium, halogen, hydroxyl, cyano, amino, oxo, SF5, SCF3, -COOH, C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Alkylidene, C 1-6 Halogenated alkylidene, C 3-8 Cycloalkyl, 3 - 8 - membered hetero cycloalkyl, C 6-10 Aryl, 5 - 10 - membered heteroaryl or C 3-8 Cycloalkylalkyl, the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted by 1 - 3 groups selected from halogen, oxo, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Alkylidene or C 1-3 Halogenated alkylidene;

[0040] Alternatively, any one R c1 and any one R c2 linked to the ring atom to which it is attached form a 5 - 8 - membered hetero cycloalkyl or 5 - 8 - membered heteroaryl, optionally further substituted by 1 - 3 groups selected from halogen, oxo, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Alkylidene or C 1-3 Halogenated alkylidene;

[0041] X1 and X2 are each independently a bond, -CO-, C 1-3 Alkylene, C 2-4 Alkenylene or C 2-4 Alkynylene, the alkylene is optionally further substituted by 1 - 3 groups selected from halogen, C 2-4 Alkenyl or C 2-4 Alkynyl;

[0042] Y is a bond, -O-, -NR y - or -O - NR y -;

[0043] R y is hydrogen or C 1-3 alkyl;

[0044] R is cyano, -N(C1-2 alkyl)-CN, -N(CN)2, amino, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio or C 1-6 alkylamino, and the amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio or alkylamino is optionally further substituted by 1 - 3 groups selected from halogen, hydroxy, cyano, amino, oxo, halo C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, C 1-3 alkylidene, C 1-3 haloalkylidene, C 3-6 substituted by cycloalkyl groups;

[0045] In some embodiments, R is cyano, -N(C 1-2 alkyl)-CN, amino, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio or C 1-6 alkylamino, and the amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio or alkylamino is optionally further substituted by 1 - 3 groups selected from halogen, hydroxy, cyano, amino, oxo, halo C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, C 1-3 alkylidene, C 1-3 haloalkylidene, C 3-6 substituted by cycloalkyl groups;

[0046] Provided that,

[0047] (1) When Cy2 is absent and X1 is a bond, Cy1 is not a substituted or unsubstituted pyrazole, pyridine, pyrazine;

[0048] (2) is not

[0049] Unless otherwise specified, the heterocycloalkyl and heteroaryl groups contain 1 to 5 heteroatoms selected from N, O, S, P, Si or the oxidized groups of N, S, P.

[0050] The second technical solution of the present invention relates to a compound represented by the general formula (I), its stereoisomer or its pharmaceutically acceptable salt, which is characterized in that it satisfies one or more of the following conditions:

[0051] (1) Cy1 is selected from C 3-6 monocyclic cycloalkyl, 4- to 6-membered monocyclic saturated heterocycloalkyl, 4- to 6-membered monocyclic partially saturated heterocycloalkyl, 4- to 6-membered heterocycloalkyl fused to a 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl fused to a 4- to 6-membered heterocycloalkyl, 4- to 6-membered heterocycloalkyl fused to a 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl fused to a 5- to 6-membered heteroaryl, 5- to 8-membered bridged heterocycloalkyl, 6- to 8-membered spiroheterocycloalkyl, optionally further substituted by 1 to 4 R c1 substituted; in some embodiments, Cy1 is selected from C 4-6 monocyclic cycloalkyl, 4- to 6-membered saturated monocyclic heterocycloalkyl containing 1 to 2 nitrogen atoms, 4- to 6-membered partially unsaturated monocyclic heterocycloalkyl containing 1 to 2 nitrogen atoms, 5- to 8-membered saturated bridged heterocycloalkyl containing 1 to 2 nitrogen atoms, 4- to 6-membered heterocycloalkyl fused to a 3- to 6-membered cycloalkyl containing 1 to 2 nitrogen atoms, 6- to 8-membered saturated spiroheterocycloalkyl containing 1 to 2 nitrogen atoms, 4- to 6-membered heterocycloalkyl fused to a 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl fused to a 5- to 6-membered heteroaryl, optionally further substituted by 1 to 4 R c1 substituted; in some embodiments, Cy1 is selected from optionally further substituted by 1 to 4 R c1 substituted; in some embodiments, Cy1 is selected from optionally further substituted by 1 to 4 R c1 substituted;

[0052] (2) Cy2 is present or absent. When Cy2 is present, Cy2 is selected from 5- to 6-membered heterocycloalkyl or 5- to 6-membered heteroaryl, optionally further substituted by 1 to 4 R c2 substituted; in some embodiments, Cy2 is absent or Cy2 is selected from 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, 5-membered heteroaryl or 6-membered heteroaryl, optionally further substituted by 1 to 4 R c2 substituted; in some embodiments, Cy2 is absent or Cy2 is selected from optionally further substituted by 1 to 4 R c2 substituted; in some embodiments, Cy2 is absent or Cy2 is selected from Optionally further substituted by 1 to 4 Rs c2 ;

[0053] (3) X1 is a bond, -CO-, C 1-3 alkylene, C 2-4 alkenylene or C 2-4 alkynylene, and in some embodiments, X1 is a bond, -C≡C-;

[0054] (4) R is selected from cyano, -N(C 1-2 alkyl)-CN, -N(CN)2, amino, -COOH, C 1-3 alkyl, C 2-4 alkenyl or C 2-4 alkynyl, and the amino, alkyl, alkenyl or alkynyl is optionally further substituted by 1 to 3 groups selected from halogen, hydroxy, cyano, amino, oxo, halo-C 1-3 alkyl, C 1-3 alkoxy, halo-C 1-3 alkoxy, C 1-3 alkylidene, C 1-3 haloalkylidene, C 3-6 cycloalkyl;

[0055] In some embodiments, R is selected from cyano, -N(C 1-2 alkyl)-CN, amino, -COOH, C 1-3 alkyl, C 2-4 alkenyl or C 2-4 alkynyl, and the amino, alkyl, alkenyl or alkynyl is optionally further substituted by 1 to 3 groups selected from halogen, hydroxy, cyano, amino, oxo, halo-C 1-3 alkyl, C 1-3 alkoxy, halo-C 1-3 alkoxy, C 1-3 alkylidene, C 1-3 haloalkylidene, C 3-6 cycloalkyl; in some embodiments, R is selected from cyano, -N(C 1-2 alkyl)-CN or C 2-4 alkynyl, and the alkynyl is optionally further substituted by 1 to 3 groups selected from hydroxy, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 3-4 cycloalkyl; in some embodiments, R is selected from cyano;

[0056] (5) Cy3 is selected from C 4-6 cycloalkyl, 4- to 6-membered heteroalkyl, 5- to 6-membered heteroaryl, C 4-6 cycloalkylphenyl, C 4-6Cycloalkyl-fused 5- or 6-membered heteroaryl, 5- or 6-membered heterocycloalkyl-fused phenyl, 5- or 6-membered heterocycloalkyl-fused 5- or 6-membered heteroaryl, optionally further substituted by 1 to 4 Rs c3 substituted; in some embodiments, Cy3 is selected from cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, pyridyl, cyclopentyl-fused 5-membered heteroaryl, cyclopentyl-fused 6-membered heteroaryl, pyrrolidinyl-fused phenyl, pyrrolidinyl-fused 5-membered heteroaryl, pyrrolidinyl-fused 6-membered heteroaryl, optionally further substituted by 1 to 4 Rs c3 substituted; in some embodiments, Cy3 is selected from optionally further substituted by 1 to 4 Rs c3 substituted;

[0057] (6) X2 is selected from a bond, -CO-, -CH(CH3)-, -CH=C(CH3)-, -C≡C-, -CH(CH=CH2)-, -CH(C≡CH)-;

[0058] (7) Y is selected from a bond, -O-, -NCH3-, -O-NCH3-;

[0059] (8) R c1 is selected from deuterium or C 1-6 alkyl; in some embodiments, R c1 is selected from deuterium or C 1-3 alkyl; in some embodiments, R c1 is selected from deuterium or methyl;

[0060] (9) R c2 is selected from deuterium, halogen, hydroxy, cyano, amino, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl; in some embodiments, R c2 is selected from deuterium, halogen, oxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 3-4 cycloalkyl; in some embodiments, R c2 is selected from deuterium, fluorine, chlorine, oxo, methyl, vinyl, ethynyl or cyclopropyl;

[0061] (10)R c3 Selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkylidene, C 1-6 haloalkylidene, C 3-8 cycloalkyl, 3-8 membered hetero cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or C 3-8 cycloalkylalkyl; in some embodiments, R c3 Selected from deuterium, halogen, oxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkylidene, C 1-3 haloalkylidene or C 3-4 cycloalkylmethyl; in some embodiments, R c3 Selected from deuterium, fluorine, chlorine, oxo, methyl, methylene, ethylidene, 1-methylethylidene, fluoromethylene, difluoromethylene, vinyl, ethynyl or cyclopropylmethyl.

[0062] The third technical solution of the present invention relates to a compound represented by the general formula (I), its stereoisomers or its pharmaceutically acceptable salts, characterized in that it satisfies one or more of the following conditions:

[0063] (1) Cy1 is selected from C 4-6 monocyclic cycloalkyl, 4-5 membered saturated monocyclic heterocycloalkyl containing 1-2 nitrogen atoms, 6 membered saturated monocyclic heterocycloalkyl containing 2 nitrogen atoms, 4-6 membered partially unsaturated monocyclic heterocycloalkyl containing 1-2 nitrogen atoms, 5-8 membered saturated bridged heterocycloalkyl containing 1-2 nitrogen atoms, 4-6 membered heterocycloalkyl fused to 3-6 membered cycloalkyl, 6-8 membered saturated spiro heterocycloalkyl containing 1-2 nitrogen atoms, 4-6 membered heterocycloalkyl fused to 5-6 membered heteroaryl, 5-6 membered heteroaryl fused to 5-6 membered heteroaryl, optionally further substituted by 1-4 R c1 substituted; in some embodiments, Cy1 is selected from optionally further substituted by 1-4 R c1 substituted; in some embodiments, Cy1 is selected from Optionally further substituted by 1 - 4 R c1 ;

[0064] (2) Cy2 is absent or Cy2 is selected from 5 - membered heteroaryl containing 1 - 2 nitrogen heteroatoms and 0 - 2 heteroatoms selected from O and S, 6 - membered heteroaryl containing 1 - 3 heteroatoms selected from N, O, and S, and the heteroaryl is optionally further substituted by 1 - 2 R c2 ; In some embodiments, Cy2 is selected from

[0065] the optionally further substituted by 1 - 2 R c2 ; In some embodiments, Cy2 is selected from the optionally further substituted by 1 - 2 R c2 ;

[0066] (3) R is selected from -N(C 1-2 alkyl)-CN, -N(CN)2, amino, -COOH, C 1-3 alkyl, C 2-4 alkenyl or C 2-4 alkynyl, and the amino, alkyl, alkenyl or alkynyl is optionally further substituted by 1 - 3 groups selected from halogen, hydroxy, cyano, amino, oxo, C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, C 1-3 alkylidene, C 1-3 haloalkylidene, C 3-6 cycloalkyl; In some embodiments, R is selected from -N(C 1-2 alkyl)-CN, amino, -COOH, C 1-3 alkyl, C 2-4 alkenyl or C 2-4 alkynyl, and the amino, alkyl, alkenyl or alkynyl is optionally further substituted by 1 - 3 groups selected from halogen, hydroxy, cyano, amino, oxo, C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, C 1-3 alkylidene, C 1-3 haloalkylidene, C3-6 In some embodiments, R is selected from -N(C 1-2 Alkyl)-CN or C 2-4 Alkynyl, said alkynyl optionally further substituted by 1-3 groups selected from hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-4 radical substitution of cycloalkyl groups;

[0067] (4) Cy3 is selected from C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 5 membered heteroaryl, C 4-6 Cycloalkylphenyl, C 4-6 Cycloalkyl and 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl and phenyl, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl, the Cy3 is optionally further replaced by 1-3 R c3 In some embodiments, Cy3 is preferably selected from cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, pyridinyl, cyclopentyl and 5-membered heteroaryl, cyclopentyl and 6-membered heteroaryl, azacyclopentyl and phenyl, azacyclopentyl and 5-membered heteroaryl, azacyclopentyl and 6-membered heteroaryl, optionally further substituted by 1-4 R c3 Substitution; In some embodiments, Cy3 is selected from Optionally further 1-4 R c3 replace;

[0068] (5) Any R c1 and any R c2 The ring atoms to which it is connected are linked to form a 5-8 membered heterocycloalkyl or a 5-8 membered heteroaryl, optionally further substituted by 1-2 groups selected from halogen, oxo, C 1-2 Alkyl, halogenated C 1-2 Alkyl, C 1-2 Alkoxy, halogenated C 1-2 Alkoxy, C 1-2 Alkyl subunit or C 1-2 The radical of the haloalkylene group is substituted.

[0069] The fourth technical solution of the present invention relates to providing a compound represented by general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that general formula (I) is further represented by general formula (II-1), (II-2), (III-1), (III-2), (IV-1), (IV-2), (V-1), (V-2), (VI-1), (VI-2), (VII-1), (VII-2):

[0070]

[0071] Wherein,

[0072] R c21 is selected from C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl; in some embodiments, R c21 is selected from C 3-4 cycloalkyl, 3-4 membered heterocycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl; in some embodiments, R c21 is selected from cyclopropyl, cyclobutyl, oxetanyl, vinyl, ethynyl;

[0073] C y11 is selected from C 4-6 monocyclic cycloalkyl, 4-5 membered saturated monocyclic heterocycloalkyl, 6 membered saturated monocyclic heterocycloalkyl containing 2 nitrogen atoms, 4-6 membered partially unsaturated monocyclic heterocycloalkyl containing 1-2 nitrogen atoms, 5-8 membered saturated bridged heterocycloalkyl containing 1-2 nitrogen atoms, 4-6 membered heterocycloalkyl fused to 3-6 membered cycloalkyl, 6-8 membered saturated spiroheterocycloalkyl containing 1-2 nitrogen atoms, 4-6 membered heterocycloalkyl fused to 5-6 membered heteroaryl, 5-6 membered heteroaryl fused to 5-6 membered heteroaryl, optionally further substituted by 1-4 R c1 substituents; in some embodiments, C y11 is selected from 4-, 5- or 6-cycloalkyl, 4-, 5- or 6-membered heterocycloalkyl containing 1-2 selected from N, O, S, 6 membered saturated monocyclic heterocycloalkyl containing 2 nitrogen atoms, 4-, 5-, 6-membered partially unsaturated monocyclic heterocycloalkyl containing 1-2 nitrogen atoms, 5-, 6-, 7-, 8-membered saturated bridged heterocycloalkyl containing 1-2 nitrogen atoms, 4-, 5-, 6-membered heterocycloalkyl fused to 3-, 4-, 5-, 6-membered cycloalkyl, 6-, 7-, 8-membered saturated spiroheterocycloalkyl containing 1-2 nitrogen atoms, 4-, 5-, 6-membered monocyclic heterocycloalkyl fused to 5-, 6-membered heteroaryl, 5-6 membered heteroaryl fused to 5-6 membered heteroaryl, optionally further substituted by 1-4 R c1 substituents; in some embodiments, C y11 is selected from

[0074] optionally further substituted by 1-4 R c1 substituents; in some embodiments, C y11 is selected from

[0075] optionally further substituted by 1-4 R c1 substituents;

[0076] C y12 is selected from 4- to 6-membered heterocycloalkyl-fused 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl-fused 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl-fused 5- to 6-membered heteroaryl containing 1 to 2 nitrogen atoms, and is optionally further substituted by 1 to 2 R c1 ; in some embodiments, C y12 is selected from

[0077] and is optionally further substituted by 1 to 2 R c1 ;

[0078] C y21 is selected from 5-membered heteroaryl containing 1 to 2 nitrogen heteroatoms and 0 to 2 heteroatoms selected from O and S, 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S, and the heteroaryl is optionally further substituted by 1 to 2 R c2 ; in some embodiments, C y21 is selected from

[0079] and is optionally further substituted by 1 to 2 R c2 ;

[0080] The definitions of other groups are the same as those in any of the previous technical solutions.

[0081] In the specific fifth embodiment, the compounds, their stereoisomers or their pharmaceutically acceptable salts represented by the general formulas (I), (II-1), (II-2), (III-1), (III-2), (IV-1), (IV-2), (V-1), (V-2), (VI-1), (VI-2), (VII-1), (VII-2) are selected from the compounds shown in Table 1 and Table 2 below:

[0082] Table 1

[0083]

[0084] Table 2

[0085]

[0086]

[0087] In the specific sixth embodiment, the present invention further provides a pharmaceutical composition, which comprises a therapeutically effective dose of the compounds, their stereoisomers or their pharmaceutically acceptable salts described in the first to fifth embodiments above, and one or more pharmaceutically acceptable carriers or excipients.

[0088] Specific seventh embodiment, the pharmaceutical composition as described above, which comprises 1 - 1500 mg of the compound, its stereoisomer or its pharmaceutically acceptable salt as described in the first to fifth embodiments above, and one or more pharmaceutically acceptable carriers or excipients.

[0089] Specific eighth embodiment, the present invention also provides the use of the compound, its stereoisomer or its pharmaceutically acceptable salt as described in the first to fifth embodiments above, or the pharmaceutical composition as described in the sixth to seventh embodiments above in the preparation of a medicament, preferably the medicament is for preventing and / or treating FGFR3-mediated diseases.

[0090] Specific ninth embodiment, the FGFR3-mediated diseases are selected from systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, lethal dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome or cancer, wherein the cancer is selected from breast cancer, invasive ductal breast cancer, invasive lobular breast cancer, lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small cell lung cancer, urothelial carcinoma, bladder cancer, urothelial bladder cancer, non-muscle invasive bladder cancer, muscle invasive bladder cancer, upper urinary tract cancer, urothelial upper urinary tract cancer, urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma, cutaneous melanoma, head and neck cancer, oral cancer, thyroid cancer, kidney cancer, renal pelvis cancer, glioblastoma, endometrial cancer, cervical cancer, ovarian cancer and testicular cancer.

[0091] Specific tenth embodiment, the present invention also provides a method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of the compound, its stereoisomer or its pharmaceutically acceptable salt as described in the first to fifth embodiments above, or the pharmaceutical composition as described in the sixth to seventh embodiments above, wherein the therapeutically effective amount is preferably 1 - 1500 mg, and the disease is selected from systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, lethal dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome or cancer, wherein the cancer is selected from breast cancer, invasive ductal breast cancer, invasive lobular breast cancer, lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small cell lung cancer, urothelial carcinoma, bladder cancer, urothelial bladder cancer, non-muscle invasive bladder cancer, muscle invasive bladder cancer, upper urinary tract cancer, urothelial upper urinary tract cancer, urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma, cutaneous melanoma, head and neck cancer, oral cancer, thyroid cancer, kidney cancer, renal pelvis cancer, glioblastoma, endometrial cancer, cervical cancer, ovarian cancer and testicular cancer.

[0092] As used herein, the term "effective amount" or "therapeutically effective amount" means an amount of a compound disclosed herein that, when administered, will, to some extent, alleviate one or more symptoms of the disease or disorder being treated. In some embodiments, the result is a reduction and / or amelioration of the signs, symptoms, or causes of the disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a peptide compound, conjugate, or a pharmaceutically acceptable salt thereof disclosed herein that is required to provide a clinically significant reduction in the symptoms of the disease. Examples of therapeutically effective amounts include, but are not limited to, 1 - 1500 mg, 1 - 1400 mg, 1 - 1300 mg, 1 - 1200 mg, 1 - 1000 mg, 1 - 900 mg, 1 - 800 mg, 1 - 700 mg, 1 - 600 mg, 1 - 500 mg, 1 - 400 mg, 1 - 300 mg, 1 - 250 mg, 1 - 200 mg, 1 - 150 mg, 1 - 125 mg, 1 - 100 mg, 1 - 80 mg, 1 - 60 mg, 1 - 50 mg, 1 - 40 mg, 1 - 25 mg, 1 - 20 mg, 5 - 1500 mg, 5 - 1000 mg, 5 - 900 mg, 5 - 800 mg, 5 - 700 mg, 5 - 600 mg, 5 - 500 mg, 5 - 400 mg, 5 - 300 mg, 5 - 250 mg, 5 - 200 mg, 5 - 150 mg, 5 - 125 mg, 5 - 100 mg, 5 - 90 mg, 5 - 70 mg, 5 - 80 mg, 5 - 60 mg, 5 - 50 mg, 5 - 40 mg, 5 - 30 mg, 5 - 25 mg, 5 - 20 mg, 10 - 1500 mg, 10 - 1000 mg, 10 - 900 mg, 10 - 800 mg, 10 - 700 mg, 10 - 600 mg, 10 - 500 mg, 10 - 450 mg, 10 - 400 mg, 10 - 300 mg, 10 - 250 mg, 10 - 200 mg, 10 - 150 mg, 10 - 125 mg, 10 - 100 mg, 10 - 90 mg, 10 - 80 mg, 10 - 70 mg, 10 - 60 mg, 10 - 50 mg, 10 - 40 mg, 10 - 30 mg, 10 - 20 mg; 20 - 1500 mg, 20 - 1000 mg, 20 - 900 mg, 20 - 800 mg, 20 - 700 mg, 20 - 600 mg, 20 - 500 mg, 20 - 400 mg, 20 - 350 mg, 20 - 300 mg, 20 - 250 mg, 20 - 200 mg, 20 - 150 mg, 20 - 125 mg, 20 - 100 mg, 20 - 90 mg, 20 - 80 mg, 20 - 70 mg, 20 - 60 mg, 20 - 50 mg, 20 - 40 mg, 20 - 30 mg;50 - 1500 mg, 50 - 1000 mg, 50 - 900 mg, 50 - 800 mg, 50 - 700 mg, 50 - 600 mg, 50 - 500 mg, 50 - 400 mg, 50 - 300 mg, 50 - 250 mg, 50 - 200 mg, 50 - 150 mg, 50 - 125 mg, 50 - 100 mg; 100 - 1500 mg, 100 - 1000 mg, 100 - 900 mg, 100 - 800 mg, 100 - 700 mg, 100 - 600 mg, 100 - 500 mg, 100 - 400 mg, 100 - 300 mg, 100 - 250 mg, 100 - 200 mg;

[0093] In some embodiments, the pharmaceutical composition or formulation of the present invention contains the compound, its stereoisomer or its pharmaceutically acceptable salt shown in any one of the above-mentioned therapeutically effective amounts.

[0094] The present invention further relates to a pharmaceutical composition or formulation, which comprises a therapeutically effective amount of the compound, its stereoisomer or its pharmaceutically acceptable salt shown in any one of the above-mentioned, and one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical composition can be in the form of a unit dosage form (the amount of the active ingredient in the unit dosage form is also referred to as the "formulation specification"). In some embodiments, the pharmaceutical composition includes, but is not limited to, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg of the compound, its stereoisomer or its pharmaceutically acceptable salt shown in any one of the above-mentioned.

[0095] The present invention further relates to a method for treating a disease in a mammal, the method comprising administering to a subject a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as shown in any one of the above of the present invention, and one or more pharmaceutically acceptable carriers or excipients, in a daily dose of 1 - 1500 mg / day, which daily dose may be a single dose or divided doses. In some embodiments, the daily dose includes, but is not limited to, 10 - 1500 mg / day, 20 - 1500 mg / day, 25 - 1500 mg / day, 50 - 1500 mg / day, 75 - 1500 mg / day, 100 - 1500 mg / day, 200 - 1500 mg / day, 10 - 1000 mg / day, 20 - 1000 mg / day, 25 - 1000 mg / day, 50 - 1000 mg / day, 75 - 1000 mg / day, 100 - 1000 mg / day, 200 - 1000 mg / day, 25 - 800 mg / day, 50 - 800 mg / day, 100 - 800 mg / day, 200 - 800 mg / day, 25 - 400 mg / day, 50 - 400 mg / day, 100 - 400 mg / day, 200 - 400 mg / day. In some embodiments, the daily dose includes, but is not limited to, 1 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 75 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 300 mg / day, 400 mg / day, 600 mg / day, 800 mg / day, 1000 mg / day, 1200 mg / day, 1400 mg / day, 1500 mg / day.

[0096] The present invention relates to a kit, which may comprise a composition in single - dose or multi - dose form, and the kit contains a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as shown in any one of the above of the present invention, and the amount of the compound, stereoisomer or pharmaceutically acceptable salt of the present invention is the same as that in the above pharmaceutical composition.

[0097] In the present invention, the amount of the compound, stereoisomer or pharmaceutically acceptable salt of the present invention is converted in the form of the free base in each case.

[0098] "Formulation specification" refers to the weight of the active ingredient contained in each vial, tablet or other unit formulation.

[0099] Synthesis route

[0100] Those skilled in the art can prepare the compounds of the present invention by combining known organic synthesis techniques, and the starting materials thereof are commercially available chemicals and / or compounds described in chemical literature. "Commercially available chemicals" are obtained from regular commercial sources, and the suppliers include: Titan Technology, Energy Chemical, Shanghai Dermachem, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Nanjing Pharmaron, WuXi AppTec, and J&K Scientific, etc.

[0101] Through the indexes of known chemical substances prepared by the Chemical Abstracts Service of the American Chemical Society, specific and similar reactants can be selectively identified, and these indexes are available in most public libraries, university libraries and online. Chemicals that are known but not commercially available in the catalog are optionally prepared by custom chemical synthesis factories, and many standard chemical supply factories (such as those listed above) provide custom synthesis services.

[0102] Terms

[0103] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present invention pertains. In case of conflict, the definitions provided in this application shall prevail. When trade names appear herein, they are intended to refer to their corresponding products or their active ingredients. All patents, published patent applications and publications cited herein are incorporated herein by reference.

[0104] The term "alkyl" refers to a saturated straight-chain or branched aliphatic 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 or 20) carbon atoms, i.e., "C 1-20 alkyl". The alkyl preferably has an alkyl group having 1 to 12 carbon atoms (i.e., C 1-12 alkyl), more preferably an alkyl group having 1 to 8 carbon atoms (i.e., C 1-8 alkyl), further preferably an alkyl group having 1 to 6 carbon atoms (i.e., C 1-6 alkyl), and most preferably an alkyl group having 1 to 3 carbon atoms (i.e., C 1-3(alkyl). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and their various branched isomers, etc. The alkyl group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any available attachment point. When the alkyl group is substituted by a substituent, the substituent is not further substituted.

[0105] The term "alkylene" refers to divalent straight-chain and branched-chain saturated alkyl groups. Examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), etc.

[0106] The term "alkenyl" refers to a straight-chain or branched-chain hydrocarbon group containing at least one carbon-carbon double bond (C═C), usually containing 2 to 18 carbon atoms, such as 2 to 8 carbon atoms, further such as 2 to 6 carbon atoms, still further such as 2 to 4 carbon atoms. Examples include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, and 1,4-hexadiene, etc.; the alkenyl can be substituted or unsubstituted. When substituted, the substituent can be substituted at any available attachment point. When the alkenyl is substituted by a substituent, the substituent is not further substituted.

[0107] The term "alkynyl" refers to a straight-chain or branched-chain hydrocarbon group containing at least one carbon-carbon triple bond (C≡C), usually containing 2 to 18 carbon atoms, further containing 2 to 8 carbon atoms, further containing 2 to 6 carbon atoms, still further containing 2 to 4 carbon atoms. Examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, and 4-decynyl, etc.; the alkynyl can be substituted or unsubstituted. When substituted, the substituent can be substituted at any available attachment point. When the alkynyl is substituted by a substituent, the substituent is not further substituted.

[0108] The term "heterocyclic" or "heterocyclic group" refers to a substituted or unsubstituted, saturated or unsaturated aromatic or non-aromatic ring, which, unless otherwise specified, contains 1 to 3 heteroatoms selected from N, O or S, including monocyclic heterocycles, bicyclic bridged heterocycles, bicyclic fused heterocycles and bicyclic spiro heterocycles, etc. Unless otherwise specified, it is a 3- to 12-membered heterocycle, more preferably a 4- to 12-membered heterocycle, more preferably a 4- to 10-membered heterocycle, and further preferably a 4- to 7-membered heterocycle. Its definition includes heterocyclic alkyl and heteroaryl. The N and S in the heterocyclic group ring can be oxidized to various oxidation states. The heterocyclic group can be attached to a heteroatom or a carbon atom. Non-limiting examples include epoxyethyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazolyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithienyl, dihydrofuryl, dihydropyranyl, dithiolanyl, tetrahydrofuryl, tetrahydropyrrolyl, tetrahydroimidazolyl, oxazolyl, dihydrooxazolyl, tetrahydrooxazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuryl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecanyl, azadamantyl and oxaspiro[3.3]heptanyl, etc.

[0109] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic hydrocarbon substituent (i.e., monocyclic cycloalkyl) or polycyclic hydrocarbon substituent (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms, i.e., C 3-20 cycloalkyl. The cycloalkyl preferably has a cycloalkyl of 3 to 12 carbon atoms (i.e., C 3-12 cycloalkyl), more preferably a cycloalkyl of 3 to 8 carbon atoms (i.e., C 3-8 cycloalkyl), further preferably a cycloalkyl of 3 to 6 carbon atoms (i.e., C 3-6 cycloalkyl), and most preferably a cycloalkyl of 3 to 5 carbon atoms (i.e., C 3-5 cycloalkyl). Non-limiting examples of the monocyclic cycloalkyl include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl and cyclooctyl, etc. Non-limiting examples of the polycyclic cycloalkyl include: spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl.

[0110] The term "spiroalkyl" refers to a polycyclic group in which a single carbon atom (referred to as the spiro atom) is shared between monocyclic rings, which may contain one or more double bonds, but none of the rings has a fully conjugated π - electron system, and which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., C 5-20 spiroalkyl). The spiroalkyl preferably has 6 to 14 ring atoms (i.e., C 6-14 spiroalkyl), more preferably has 7 to 10 ring atoms (i.e., C 7-10 spiroalkyl). The spiroalkyl is classified into monospiroalkyl, dispiroalkyl, or polyspiroalkyl according to the number of spiro atoms shared between rings, preferably monospiroalkyl or dispiroalkyl, more preferably 3 - membered / 4 - membered, 3 - membered / 5 - membered, 3 - membered / 6 - membered, 4 - membered / 4 - membered, 4 - membered / 5 - membered, 4 - membered / 6 - membered, 5 - membered / 3 - membered, 5 - membered / 4 - membered, 5 - membered / 5 - membered, 5 - membered / 6 - membered, 5 - membered / 7 - membered, 6 - membered / 3 - membered, 6 - membered / 4 - membered, 6 - membered / 5 - membered, 6 - membered / 6 - membered, 6 - membered / 7 - membered, 7 - membered / 5 - membered, or 7 - membered / 6 - membered monospiroalkyl.

[0111] The term "fused - ring alkyl" refers to a fully carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., C 5-20 fused - ring alkyl). It may contain one or more double bonds, but none of the rings has a fully conjugated π - electron system. The fused - ring alkyl preferably has 6 to 14 ring atoms (i.e., C 6-14 fused - ring alkyl), more preferably has 7 to 10 ring atoms (i.e., C 7-10 fused - ring alkyl). It is classified into bicyclic, tricyclic, tetracyclic, or polycyclic fused - ring alkyl according to the number of constituent rings, preferably bicyclic fused - ring alkyl or tricyclic fused - ring alkyl, more preferably 3 - membered / 4 - membered, 3 - membered / 5 - membered, 3 - membered / 6 - membered, 4 - membered / 4 - membered, 4 - membered / 5 - membered, 4 - membered / 6 - membered, 5 - membered / 3 - membered, 5 - membered / 4 - membered, 5 - membered / 5 - membered, 5 - membered / 6 - membered, 5 - membered / 7 - membered, 6 - membered / 3 - membered, 6 - membered / 4 - membered, 6 - membered / 5 - membered, 6 - membered / 6 - membered, 6 - membered / 7 - membered, 7 - membered / 5 - membered, or 7 - membered / 6 - membered bicyclic fused - ring alkyl.

[0112] The term "bridged - ring alkyl" refers to a fully carbon polycyclic group in which any two rings share two non - directly - connected carbon atoms, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., C 5-20Bicycloalkyl). It contains one or more double bonds, but none of the rings has a fully conjugated π - electron system. The bicycloalkyl preferably has a bicycloalkyl with 6 to 14 ring atoms (i.e., C 6-14 Bicycloalkyl), more preferably a bicycloalkyl with 7 to 10 ring atoms (i.e., C 7-10 Bicycloalkyl). According to the number of constituent rings, it is divided into bicyclic, tricyclic, tetracyclic or polycyclic bicycloalkyl, preferably bicyclic bicycloalkyl or tricyclic bicycloalkyl.

[0113] The cycloalkyl includes polycyclic cycloalkyl that can be fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring connected to the parent structure is cycloalkyl, for example, including C 5-6 Cycloalkyl - biphenyl, C 5-6 Cycloalkyl - 5 - or 6 - membered heteroaryl, C 5-6 Cycloalkyl - 5 - or 6 - membered heterocycloalkyl, etc. Preferably, cyclopentyl - 5 - membered heterocycloalkyl, cyclopentyl - 6 - membered heterocycloalkyl, cyclopentyl - 5 - membered heteroaryl, cyclopentyl - 6 - membered heteroaryl, cyclohexyl - 5 - membered heterocycloalkyl, cyclohexyl - 6 - membered heterocycloalkyl, cyclohexyl - 5 - membered heteroaryl, cyclohexyl - 6 - membered heteroaryl, etc. The cycloalkyl can be optionally substituted or unsubstituted. When substituted, the substituent can be substituted at any available attachment point. When the cycloalkyl is substituted by a substituent, the substituent is not further substituted.

[0114] The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic heterocyclic hydrocarbon substituent (i.e., monocyclic heterocycloalkyl) or polycyclic heterocyclic hydrocarbon substituent (i.e., polycyclic heterocycloalkyl), which has 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 3 - 20 - membered heterocycloalkyl), where one or more (e.g., 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen, P(O) m and S(O) n(wherein m and n are integers from 0 to 2) heteroatoms, but excluding the ring portion of -O-O-, -O-S- or -S-S-, and the remaining ring atoms are carbon. The heterocycloalkyl group preferably has 3 to 12 ring atoms (i.e., 3- to 12-membered heterocycloalkyl), containing 1 to 4 heteroatoms selected from N, O, and S atoms, more preferably having 3 to 8 ring atoms (i.e., 3- to 8-membered heterocycloalkyl), containing 1 to 4, 1 to 3, or 1 to 2 heteroatoms selected from N, O, and S atoms, further preferably having 3 to 6 ring atoms (i.e., 3- to 6-membered heterocycloalkyl), containing 1 to 4, 1 to 3, or 1 to 2 heteroatoms selected from N, O, and S atoms, and most preferably having 5 to 6 ring atoms (i.e., 5- to 6-membered heterocycloalkyl), containing 1 to 4, 1 to 3, or 1 to 2 heteroatoms selected from N, O, and S atoms. Non-limiting examples of the monocyclic heterocycloalkyl group include: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, piperidinyl, piperazinyl, morpholinyl, 1,3-dioxolanyl, 2,2-difluoro-1,3-dioxolanyl, cyclopentanone, 2,2-difluorocyclopentanone, azepanyl, oxolanyl or azolanyl, etc. Non-limiting examples of the polycyclic heterocycloalkyl group include: spiroheterocycloalkyl, fused heterocycloalkyl, and bridged heterocycloalkyl.

[0115] The term "spiroheterocycloalkyl" refers to a polycyclic heterocycloalkyl group in which a single atom (referred to as a spiro atom) is shared between monocyclic rings, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5- to 20-membered spiroheterocycloalkyl), where one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, P(O) m and S(O) nheteroatoms where m and n are integers from 0 to 2, but excluding the ring moieties of -O-O-, -O-S- or -S-S-, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. The spiroheterocycloalkyl group preferably has a spiroheterocycloalkyl group with 6 to 14 ring atoms (i.e., 6- to 14-membered spiroheterocycloalkyl group), more preferably a spiroheterocycloalkyl group with 7 to 10 ring atoms (i.e., 7- to 10-membered spiroheterocycloalkyl group). The spiroheterocycloalkyl group is classified into monospiroheterocycloalkyl group, bisspiroheterocycloalkyl group or polyspiroheterocycloalkyl group according to the number of spiro atoms shared between rings, preferably monospiroheterocycloalkyl group or bisspiroheterocycloalkyl group, more preferably 3 / 4, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 3, 5 / 4, 5 / 5, 5 / 6, 5 / 7, 6 / 3, 6 / 4, 6 / 5, 6 / 6, 6 / 7, 7 / 5 or 7 / 6 monospiroheterocycloalkyl groups. Non-limiting examples thereof include: etc.

[0116] The term "fused heterocycloalkyl" or "condensed heterocycloalkyl" refers to a polycyclic heterocycloalkyl group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5- to 20-membered fused heterocycloalkyl), wherein one or more (e.g., 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen, P(O) m and S(O) n heteroatoms where m and n are integers from 0 to 2, but excluding the ring moieties of -O-O-, -O-S- or -S-S-, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. The fused heterocycloalkyl group preferably has a fused heterocycloalkyl group with 6 to 14 ring atoms (i.e., 6- to 14-membered fused heterocycloalkyl group), more preferably a fused heterocycloalkyl group with 7 to 10 ring atoms (i.e., 7- to 10-membered fused heterocycloalkyl group). It is classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl groups according to the number of constituent rings, preferably bicyclic fused heterocycloalkyl groups or tricyclic fused heterocycloalkyl groups, more preferably 3 / 4, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 3, 5 / 4, 5 / 5, 5 / 6, 5 / 7, 6 / 3, 6 / 4, 6 / 5, 6 / 6, 6 / 7, 7 / 5 or 7 / 6 bicyclic fused heterocycloalkyl groups. Non-limiting examples thereof include: etc.

[0117] The term "bridged heterocycloalkyl" refers to a polycyclic heterocycloalkyl group in which any two rings share two non-directly connected atoms, having 5 to 20 (such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5- to 20-membered bridged heterocycloalkyl), wherein one or more (such as 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen, P(O) m and S(O) n (wherein m, n are integers from 0 to 2) of heteroatoms, but excluding the ring moiety of -O-O-, -O-S- or -S-S-, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. The bridged heterocycloalkyl preferably has 6 to 14 ring atoms (i.e., 6- to 14-membered bridged heterocycloalkyl), more preferably has 7 to 10 ring atoms (i.e., 7- to 10-membered bridged heterocycloalkyl). According to the number of constituent rings, it is divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocycloalkyl, preferably bicyclic bridged heterocycloalkyl or tricyclic bridged heterocycloalkyl. Non-limiting examples thereof include: etc.

[0118] The heterocycloalkyl described includes polycyclic heterocycloalkyl that can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is heterocycloalkyl, for example, including 5- or 6-membered heterocycloalkyl-fused phenyl, 5- or 6-membered heterocycloalkyl-fused 5- or 6-membered heteroaryl, 5- or 6-membered heterocycloalkyl-fused C 5-6 cycloalkyl etc., preferably 5-membered heterocycloalkyl-fused 5-membered heterocycloalkyl, 5-membered heterocycloalkyl-fused 6-membered heterocycloalkyl, 5-membered heterocycloalkyl-fused 5-membered heteroaryl, 5-membered heterocycloalkyl-fused 6-membered heteroaryl, 6-membered heterocycloalkyl-fused 6-membered heterocycloalkyl, 6-membered heterocycloalkyl-fused 5-membered heteroaryl, 6-membered heterocycloalkyl-fused 6-membered heteroaryl etc. The heterocycloalkyl can be optionally substituted or unsubstituted. When substituted, the substituent can be substituted at any available attachment point). When the heterocycloalkyl is substituted by a substituent, the substituent is not further substituted.

[0119] The term "aryl" refers to a monocyclic all-carbon group (i.e., monocyclic aryl) or a fused polycyclic group (i.e., polycyclic aryl) having a conjugated π-electron system, having 6 to 14 (such as 6, 7, 8, 9, 10, 11, 12, 13 or 14) carbon atoms (i.e., C 6-14 aryl). The aryl preferably has 6 to 12 carbon atoms (i.e., C 6-12 aryl), more preferably has 6 to 10 carbon atoms (i.e., C 6-10 aryl), further preferably phenyl or naphthyl, and most preferably phenyl. The monocyclic aryl, for example, phenyl. Non-limiting examples of the polycyclic aryl include: naphthyl, anthracenyl, phenanthryl, etc.

[0120] The aryl group described includes polycyclic systems that can be fused to a heteroaryl, heterocycloalkyl, or cycloalkyl ring, where the ring connected to the parent structure is an aryl ring, including but not limited to benzo C 3-8 cycloalkyl, benzo 3- to 8-membered heterocycloalkyl, benzo 5- to 6-membered heteroaryl, preferably benzo C 4-6 cycloalkyl, benzo 4- to 6-membered heterocycloalkyl, benzo 5- to 6-membered heteroaryl, more preferably benzocyclobutyl, benzocyclopentyl, benzocyclohexyl, benzazetidinyl, benzoxetanyl, benzoxolanyl, benzazolinyl, benzoxanyl, benzazanyl, benzothienyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzopyridyl, benzopyrimidinyl, benzopyridinone, benzopyrazinyl, benzopyridazinyl, etc. The aryl group can be optionally substituted or unsubstituted. When substituted, the substituent can be substituted at any available attachment point. When the aryl group is substituted by a substituent, the substituent is not further substituted.

[0121] The term "heteroaryl" refers to a monocyclic heteroaryl group (i.e., monocyclic heteroaryl) or a fused polycyclic heteroaryl group (i.e., polycyclic heteroaryl) having a conjugated π-electron system, which has 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 5- to 14-membered heteroaryl), where one or more (e.g., 1, 2, 3, or 4) ring atoms are heteroatoms selected from nitrogen, oxygen, P(O) m and S(O) n (where m, n are integers from 0 to 2), preferably heteroatoms selected from nitrogen, oxygen, or sulfur, but excluding ring moieties of -O-O-, -O-S-, or -S-S-, and the remaining ring atoms are carbon. The heteroaryl preferably has a heteroaryl with 5 to 10 ring atoms (i.e., 5- to 10-membered heteroaryl). The monocyclic heteroaryl, preferably has a heteroaryl with 5 to 6 ring atoms (i.e., 5- to 6-membered heteroaryl), non-limiting examples include: furyl, pyranyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyridinone, pyrazinyl, pyridazinyl, etc. The polycyclic heteroaryl, preferably 5- to 6-membered heteroaryl and 5- to 6-membered heteroaryl, 5- to 10-membered heteroaryl and C 6-10 aryl or C 6-10Aryl fused to a 5- to 10-membered heteroaryl, more preferably a 5- to 6-membered heteroaryl fused to a 5- to 6-membered heteroaryl, a 5- to 6-membered heteroaryl fused to a phenyl, or a phenyl fused to a 5- to 6-membered heteroaryl. Non-limiting examples include: indolyl, indazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothienyl, thienylphenyl, quinazolinyl, benzothiazolyl, carbazolyl, thienylpyridyl, pyridylthienyl, pyridylpyrrolyl, benzopyrone, pyridylpyrone, etc.

[0122] The heteroaryl described above includes a polycyclic system fused to an aryl, heterocycloalkyl or cycloalkyl ring, where the ring connected to the parent structure is a heteroaryl ring, including but not limited to a 5- to 6-membered heteroaryl fused to a C 3-8 cycloalkyl, a 5- to 6-membered heteroaryl fused to a 3- to 8-membered heterocycloalkyl, a 5- to 6-membered heteroaryl fused to a phenyl, preferably a 5- to 6-membered heteroaryl fused to a C 4-6 cycloalkyl, a 5- to 6-membered heteroaryl fused to a 4- to 6-membered heterocycloalkyl, a 5- to 6-membered heteroaryl fused to a phenyl. The heteroaryl described above may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point. When the heteroaryl is substituted by a substituent, the substituent is not further substituted. Non-limiting examples include: etc.

[0123] The term "alkoxy" refers to -O-(alkyl) or -O-(unsubstituted cycloalkyl), where alkyl and cycloalkyl are defined as above and have 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms (i.e., C 1-10 alkoxy). The alkoxy preferably has 1 to 8 carbon atoms (i.e., C 1-8 alkoxy), more preferably has 1 to 6 carbon atoms (i.e., C 1-6 alkoxy), and most preferably has 1 to 3 carbon atoms (i.e., C 1-3 alkoxy). Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, etc. The alkoxy may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point. When the alkoxy is substituted by a substituent, the substituent is not further substituted.

[0124] The term "alkylthio" refers to -S-(alkyl) or -S-(unsubstituted cycloalkyl), where alkyl and cycloalkyl are defined as above and have 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms (i.e., C 1-10 alkylthio). The alkylthio preferably has 1 to 8 carbon atoms (i.e., C1-8 alkylthio), more preferably an alkylthio having 1 to 6 carbon atoms (i.e., C 1-6 alkylthio), most preferably an alkylthio having 1 to 3 carbon atoms (i.e., C 1-3 alkylthio). Non-limiting examples include: methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, etc. The alkylthio may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point. When the alkylthio is substituted by a substituent, the substituent is not further substituted.

[0125] The term "halo" or "halogen" or "halo-substituted" should be understood to mean a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom, preferably a fluorine, chlorine or bromine atom.

[0126] The term "haloalkyl" refers to an alkyl group substituted by one or more halogen atoms, wherein the alkyl group is as defined above. Non-limiting examples include: fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, chlorofluoromethyl, dichloromethyl, bromofluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, bromodifluoromethyl, bromochlorofluoromethyl, dibromofluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl, 2-chloro-2-fluoroethyl, 2,2-dichloroethyl, 2-bromo-2-fluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2-chloro-2-fluoroethyl, 2-bromo-2,2-dichloroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl, 1-chloro-1,2,2,2-tetrafluoroethyl, 2-chloro-1,1,2,2-tetrafluoroethyl, 1,2-dichloro-1,2,2-trifluoroethyl, 2-bromo-1,1,2,2-tetrafluoroethyl, etc., preferably fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl.

[0127] The term "haloalkoxy" refers to an alkoxy group substituted by one or more halogen atoms, where the alkoxy group is as defined above. Non-limiting examples include: fluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, difluoromethoxy, chlorofluoromethoxy, dichloromethoxy, bromofluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy, trichloromethoxy, bromodifluoromethoxy, bromochlorofluoromethoxy, dibromofluoromethoxy, etc.; preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy, 2-chloro-2-fluoroethoxy, 2,2-dichloroethoxy, 2-bromo-2-fluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, 2-bromo-2,2-difluoroethoxy, 2-bromo-2-chloro-2-fluoroethoxy, 2-bromo-2,2-dichloroethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy, 1-chloro-1,2,2,2-tetrafluoroethoxy, 2-chloro-1,1,2,2-tetrafluoroethoxy, 1,2-dichloro-1,2,2-trifluoroethoxy, 2-bromo-1,1,2,2-tetrafluoroethoxy, preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy.

[0128] The term "alkylidene" refers to a divalent free valence alkyl structure formed by the loss of two hydrogen atoms, where the alkyl group is as defined above. Non-limiting examples include: methylene ethylene 1-methylethylene

[0129] The term "haloalkylidene" refers to an alkylidene group substituted by one or more halogen atoms, where the alkylidene group is as defined above. Non-limiting examples include: fluoromethylene difluoromethylene

[0130] The term "cycloalkylalkyl" refers to an alkyl group substituted by one or more cycloalkyl groups, where the alkyl group is as defined above. Non-limiting examples include: cyclopropylmethyl, cyclopropylethyl.

[0131] The term "mercapto" refers to -SH.

[0132] The term "hydroxy" refers to -OH.

[0133] The term "nitro" refers to -NO2.

[0134] The term "amino" refers to -NH2.

[0135] The term "cyano" refers to -CN.

[0136] The term "carboxyl" means -C(O)OH.

[0137] The term "aldehyde group" means -CHO.

[0138] The term "oxo" or "oxo group" means =O.

[0139] The term "carbonyl group" means C=O.

[0140] The term "aminoacyl" means -C(O)NH2.

[0141] The term "sulfonyl group" means -S(O)2.

[0142] The term "deuterated alkyl" means an alkyl group substituted with one or more deuteriums, where the alkyl group is as defined above.

[0143] The term "deuterated alkoxy" means an alkoxy group substituted with one or more deuteriums, where the alkoxy group is as defined above.

[0144] The term "haloalkoxy" means an alkoxy group substituted with one or more halogens, where the alkoxy group is as defined above.

[0145] The term "hydroxyalkyl" means an alkyl group substituted with one or more hydroxyl groups, where the alkyl group is as defined above.

[0146] The term "alkylamino" means alkyl-NH-, where the alkyl group is as defined above.

[0147] The term "alkenylene" means a divalent straight-chain and branched alkenyl group.

[0148] The term "alkynylene" means a divalent straight-chain and branched alkynyl group.

[0149] The terms "comprises", "comprising", "has", "having", "includes", "including" or "relates to" and other variant forms thereof used herein are inclusive or open-ended and do not exclude other unrecited elements or method steps. Those skilled in the art should understand that the above terms such as "comprises" encompass the meaning of "consisting of".

[0150] The term "one or more" or a similar expression "at least one" can mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more.

[0151] When the lower and upper limits of a numerical range are disclosed, any numerical value and any included range falling within that range are specifically disclosed. In particular, each range of values disclosed herein should be understood to represent every numerical value and range encompassed within the broader range.

[0152] In this document, both "Z" and "-Z-" represent the same specific group and can be used interchangeably.

[0153] As used herein, the expression m-n refers to the range from m to n, the sub-ranges composed of each point value therein, and each point value. For example, the expression "C2-C8" or "C 2-8 " covers the range of 2 to 8 carbon atoms and should be understood to also cover any sub-range and each point value therein, such as C2-C5, C3-C4, C2-C6, C3-C6, C4-C6, C4-C7, C4-C8, etc., and C2, C3, C4, C5, C6, C7, C8, etc. For example, the expression "C3-C 10 " or "C 3-10 " should also be understood in a similar manner, for example, it can cover any sub-range and point value included therein, such as C3-C9, C6-C9, C6-C8, C6-C7, C7-C 10 、C7-C9、C7-C8、C8-C9, etc. and C3, C4, C5, C6, C7, C8, C9, C 10 etc. Again, for example, the expression "C1-C6" or "C 1-6 " covers the range of 1 to 6 carbon atoms and should be understood to also cover any sub-range and each point value therein, such as C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, etc., and C1, C2, C3, C4, C5, C6, etc. Again, for example, the expression "ternary to decyl" should be understood to cover any sub-range and each point value therein, such as ternary to quinary, ternary to hexyl, ternary to heptyl, ternary to octyl, quaternary to quinary, quaternary to hexyl, quaternary to heptyl, quaternary to octyl, quinary to heptyl, quinary to octyl, hexyl to heptyl, hexyl to octyl, nonyl to decyl, etc., and three, four, five, six, seven, eight, nine, ten yuan, etc. Other similar expressions in this article should also be understood in a similar manner.

[0154] As used herein, different expressions such as "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C", etc. all express the same meaning, that is, it means that X can be any one or several of A, B, and C.

[0155] The term "optionally" or "optionally" means that the subsequent described event or situation may or may not occur, and this description includes the occurrence and non-occurrence of the described event or situation. For example, "optionally (substituted) by alkyl cycloalkyl" means that the alkyl may or may not be present, and this description includes the case where the cycloalkyl is substituted by alkyl and the case where the cycloalkyl is not substituted by alkyl.

[0156] The terms "substituted" and "substituent" refer to the replacement of one or more (e.g., one, two, three, or four) hydrogens on the designated atom with a selection from the indicated groups, provided that the normal valence of the designated atom in the present context is not exceeded and the substitution results in a stable compound. Combinations of substituents and / or variables are permitted only when such combinations result in a stable compound. When a particular substituent is described as absent, it should be understood that the substituent may be one or more hydrogen atoms, provided that the structure allows the compound to achieve a stable state. When it is described that each carbon atom in a group may optionally be replaced by a heteroatom, the condition is that the normal valence of all atoms in the group is not exceeded in the present context and a stable compound is formed. Exemplary substituents include, but are not limited to: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3- to 8-membered heteroalkyl, C 5-12 aryl, 5- to 12-membered heteroaryl, -CO-(C 3-8 cycloalkyl), -CO-(3- to 8-membered heteroalkyl), -CO-(C 5-12 aryl), -CO-(5- to 12-membered heteroaryl), hydroxy, C 1-6 alkoxy, C 5-12 aryloxy, mercapto, C 1-6 alkylthio, cyano, halogen, oxo, aldehyde, SF5, SCF3, -N3, C 1-6 alkylthiocarbonyl, C 1-6 alkylcarbamoyl, N-carbamoyl, nitro, silyl, sulfinyl, sulfonyl, sulfoxide, carboxy, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, amino, phosphonic acid, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2, -HC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -CH=N(C 1-6 alkyl), -CH=N-O(C 1-6(alkyl), -NHSO2(C 1-6 (alkyl), -SO2N(C 1-6 )(alkyl)2, -SO2NH(C 1-6 )(alkyl), -SO2NH2, -SO2C 1-6 )(alkyl), etc.

[0157] If a substituent is described as "optionally... substituted", the substituent may be unsubstituted or may be substituted. If an atom or group is described as optionally substituted by one or more of a list of substituents, one or more hydrogens on that atom or group may be replaced by independently selected optional substituents. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. When the substituent is hydrogen, this may also indicate that the corresponding group is "unsubstituted" or "not substituted". Unless otherwise specified, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0158] When the bond of a substituent is shown passing through a bond connecting two atoms in a ring, such a substituent may be bonded to any ring-forming atom in the ring that can be substituted.

[0159] When any variable (e.g., R), and a variable with a label (e.g., R1, R2, R3, R4, R5, R6, R7, etc.) appears more than once in the composition or structure of a compound, its definition in each case is independent at each occurrence. For example, if a group is substituted by 0, 1, 2, 3, or 4 R substituents, the group may optionally be substituted by up to four R substituents, and the options for each R substituent in each case are independent of each other.

[0160] When the listed linking group does not specify its linking direction, its linking direction includes linking in the directions of the reading order from left to right and from right to left. For example, for A-L-B, when L is selected from -M-W-, it includes the cases of A-M-W-B and A-W-M-B.

[0161] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. All such compounds of the present invention, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomer- or diastereoisomer-enriched mixtures, are all within the scope of the present invention. Additional asymmetric carbon atoms may be present in the substituents of the compounds of the present invention. All such isomers and their mixtures are included within the scope of the present invention. In certain embodiments, preferred compounds are those isomeric compounds that exhibit superior biological activity. The purified or partially purified isomers and stereoisomers of the compounds of the present invention, or racemic mixtures or diastereoisomer mixtures, are also included within the scope of the present invention. The purification and separation of such substances can be achieved by standard techniques known in the art.

[0162] Any hydrogen atom in the present invention may be replaced by its isotope deuterium, and any hydrogen atom in the exemplified compounds of the present invention may also be replaced by a deuterium atom.

[0163] The compounds of the present invention include all suitable isotopic derivatives of the compounds. The term "isotopic derivative" 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 disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, etc., such as 2 H (deuterium, D), 3 H (tritium, T), 11 C, 13 C, 14 C, 15 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 I, etc., and deuterium is preferred.

[0164] Compared with non-deuterated drugs, deuterated drugs have advantages such as reducing toxic side effects, increasing drug stability, enhancing efficacy, and prolonging the biological half-life of drugs. All isotope composition transformations of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom, where the replacement of deuterium can be partial or complete. Partial replacement of deuterium means that at least one hydrogen is replaced by at least one deuterium.

[0165] In the compounds of the present invention, when a position is specifically designated as deuterium D, that position should be understood to have a deuterium abundance that is at least 1000 times greater than the natural abundance (which is 0.015%) (i.e., at least 15% deuterium incorporation). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (i.e., at least 15% deuterium incorporation). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (i.e., at least 30% deuterium incorporation). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (i.e., at least 45% deuterium incorporation). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (i.e., at least 50.1% deuterium incorporation). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (i.e., at least 52.5% deuterium incorporation). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (i.e., at least 60% deuterium incorporation). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (i.e., at least 67.5% deuterium incorporation). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (i.e., at least 75% deuterium incorporation). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (i.e., at least 82.5% deuterium incorporation). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (i.e., at least 90% deuterium incorporation). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (i.e., at least 95% deuterium incorporation). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (i.e., at least 97% deuterium incorporation). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (i.e., at least 99% deuterium incorporation). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (i.e., at least 99.5% deuterium incorporation).

[0166] The term "pharmaceutically acceptable" substance refers to a substance that, within the scope of normal medical judgment, is suitable for contact with a patient's tissue without undue toxicity, irritation, allergic reaction, etc., has a reasonable benefit-risk ratio, and is effective for its intended use.

[0167] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that is safe and effective when used in a mammalian body and has the appropriate biological activity.

[0168] The term "pharmaceutical composition" refers to a composition containing one or more compounds of the present invention or their physiologically / pharmaceutically acceptable salts or prodrugs, as well as other components such as physiologically / pharmaceutically acceptable carriers or excipients. The purpose of the pharmaceutical composition is to facilitate the administration to an organism, facilitate the absorption of the active ingredient and thus exert its biological activity.

[0169] The term "pharmaceutically acceptable carrier" refers to those substances that do not cause significant irritation to an organism and do not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable carriers" include, but are not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents or emulsifiers.

[0170] The terms "administer" or "administering" etc. refer to methods by which a compound or composition can be delivered to a desired biological site of action. These methods include, but are not limited to, oral or parenteral (including intraventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration, etc. In particular, injection or oral administration.

[0171] As used herein, the term "treatment" includes alleviating, reducing or ameliorating a disease or symptom, preventing other symptoms, improving or preventing the underlying metabolic factors of a symptom, inhibiting a disease or symptom, e.g., preventing the development of a disease or symptom, reducing a disease or symptom, promoting the remission of a disease or symptom, or arresting the signs of a disease or symptom, and extends to include prevention. "Treatment" also includes achieving a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit refers to eradicating or ameliorating the treated condition. In addition, a therapeutic benefit is achieved by eradicating or ameliorating one or more physiological signs associated with the underlying disease, and although the patient may still have the underlying disease, an improvement in the patient's disease can be observed. A prophylactic benefit refers to a patient using a composition to prevent the risk of a certain disease, or a patient taking the composition when presenting with one or more physiological signs of a disease, although the disease has not yet been diagnosed.

[0172] The terms "active ingredient", "therapeutic agent", "active substance" or "active agent" refer to a chemical entity that can effectively treat or prevent a target disorder, disease or condition.

[0173] For a drug, drug unit, or active ingredient, the terms "effective amount", "therapeutically effective amount", or "prophylactically effective amount" refer to a sufficient amount of the drug or agent that has acceptable side effects but can achieve the desired effect. The determination of the effective amount varies from individual to individual, depending on the age and general condition of the individual, as well as the specific active substance. In a particular case, the appropriate effective amount can be determined by those skilled in the art through routine tests.

[0174] As used herein, "individual" includes human or non-human animals. Exemplary human individuals include human individuals suffering from a disease (such as the diseases described herein) (referred to as patients) or normal individuals. "Non-human animals" in the present invention include all vertebrates, such as non-mammals (such as birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals, and / or domesticated animals (such as sheep, dogs, cats, cows, pigs, etc.).

[0175] The term "room temperature" refers to a temperature ranging from 10°C to 40°C. In some embodiments, "room temperature" refers to a temperature ranging from 15°C to 30°C; in other embodiments, "room temperature" refers to a temperature ranging from 18°C to 25°C.

[0176] "Equivalent" or its abbreviation "eq" is the equivalent amount of other raw materials required based on the equivalent relationship of a chemical reaction, with the basic raw material used in each step as the reference (1 equivalent).

[0177] The following detailed description of the invention is intended to illustrate non-limiting embodiments, enabling other technicians in the art to more fully understand the technical solutions of the present invention, its principles, and its practical applications, so that other technicians in the art can modify and implement the present invention in many forms to best meet the requirements of specific uses.

[0178] Beneficial effects

[0179] The compounds of the present invention are FGFR inhibitors, particularly specific to FGFR3, having good pharmacokinetic characteristics, high bioavailability, good safety, high selectivity, low toxicity and side effects, and having the advantages of oral administration, fast absorption, high clearance rate, etc., and can be used for preventing and / or treating diseases mediated by FGFR, particularly FGFR3. Detailed Description of the Embodiments

[0180] The content of the present invention will be described in detail below through examples. For those not specified in the examples, the experimental methods under conventional conditions are used. The examples are given to better illustrate the content of the present invention, but it should not be understood that the content of the present invention is limited to the given examples. Non-essential improvements and adjustments made by those skilled in the art to the embodiments based on the above-described invention content still fall within the protection scope of the present invention.

[0181] The structure of the compound was determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) was given in units of 10 -6 (ppm). The NMR measurements were performed using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic resonance spectrometers, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD) as solvents, and tetramethylsilane (TMS) as the internal standard;

[0182] The MS measurements were performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0183] The HPLC measurements were performed using an Agilent 1260DAD high-performance liquid chromatograph (Zorbax SB-C 18 100×4.6 mm, 3.5 μM);

[0184] For thin-layer chromatography silica gel plates, Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates were used. The specifications of the silica gel plates used for thin-layer chromatography (TLC) were 0.15 mm - 0.20 mm, and the specifications of the silica gel plates used for separating and purifying products by thin-layer chromatography were 0.4 mm - 0.5 mm;

[0185] For column chromatography, silica gel with a mesh size of 200 - 300 from Yantai Huanghai was generally used as the carrier.

[0186] Examples

[0187] The embodiments of the present invention will be described in detail below in conjunction with the examples. However, those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention. For those not specified in the examples, the operations were carried out under conventional conditions or conditions recommended by the manufacturer. For reagents or instruments not specified by the manufacturer, they were all conventional products that could be obtained commercially. Unless otherwise specified, the ratios or percentages used herein are by weight.

[0188] Example 1

[0189]

[0190] The first step:

[0191] Dissolve 1A (2 g, 8.80 mmol) in dichloromethane (20 mL), add triethylamine (2.67 g, 26.40 mmol), and add methanesulfonyl chloride (1.21 g, 10.56 mmol) at 0 °C. React at room temperature for 1 hour. After the reaction is completed, extract the reaction solution (with dichloromethane) and concentrate it. The residue 1B is directly used in the next step.

[0192] Step 2:

[0193] Dissolve 1B in N,N-dimethylformamide (30 mL), add sodium azide (1.38 g, 21.27 mmol), and react at 80 °C for 16 hours. After the reaction is completed, extract the reaction solution (with ethyl acetate), wash it, and concentrate it to obtain the target compound 1C in dimethyl sulfoxide solution.

[0194] Step 3:

[0195] Dissolve 1C (dimethyl sulfoxide solution), ethyl acetoacetate (3.1 g, 23.79 mmol), and potassium carbonate (3.29 g, 23.79 mmol) in dimethyl sulfoxide (20 mL), and react at 100 °C for 16 hours. After the reaction is completed, extract the reaction solution (with ethyl acetate), wash it, and concentrate it. The residue is purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 1:1) to obtain the target compound 1D (2.4 g, yield 83%).

[0196] LC-MS (ESI): m / z = 365.1 [M+H] + .

[0197] Step 4:

[0198] Dissolve 1D (2.4 g, 6.59 mmol) in methanol (10 mL), tetrahydrofuran (10 mL), and water (10 mL), add lithium hydroxide monohydrate (0.55 g, 19.77 mmol), and react at room temperature for 2 hours. After the reaction is completed, adjust the pH of the reaction solution to 5-6, then extract (with ethyl acetate), wash it, and concentrate it to obtain the target compound 1E (2.1 g, yield 94%).

[0199] LC-MS (ESI): m / z = 337.1 [M+H] + .

[0200] Step 5:

[0201] Dissolve 1E (2.1 g, 6.24 mmol) in water (30 mL), then add potassium hydroxide (0.42 g, 7.49 mmol) and bromine (1.2 g, 7.49 mmol), and react at room temperature for 3 hours. After the reaction is completed, extract the reaction solution (ethyl acetate), wash, and concentrate. The residue is purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 1:1) to obtain the target compound 1F (1 g, yield 43%).

[0202] LC-MS (ESI): m / z = 371.1 [M+H] + .

[0203] Step 6:

[0204] Dissolve 1G (10 g, 42.01 mmol), (S)-1-(pyridin-2-yl)ethan-1-ol (5.69 g, 46.21 mmol), and cyanomethylenetributylphosphorane (20.28 g, 84.02 mmol) in toluene (150 mL), and react at 100 °C for 16 hours. After the reaction is completed, concentrate the reaction solution, and the residue is purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to obtain the target compound 1H (13 g, yield 90%).

[0205] LC-MS (ESI): m / z = 344.9 [M+H] + .

[0206] Step 7:

[0207] Dissolve 1H (0.25 g, 0.73 mmol), bis(pinacolato)diboron (0.28 g, 1.09 mmol), potassium acetate (0.21 g, 2.19 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (53 mg, 0.07 mmol) in 1,4-dioxane (5 mL), and react at 95 °C for 16 hours. Proceed directly to the next step (1I) after the reaction is completed.

[0208] LC-MS (ESI): m / z = 309.1 [M+H] + .

[0209] Step 8:

[0210] 1F (0.2 g, 0.54 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (40 mg, 0.05 mmol), and potassium carbonate (0.19 g, 1.35 mmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL) and added to the reaction mixture of 1I. The mixture was reacted at 95°C under nitrogen atmosphere for 16 hours. After completion of the reaction, the reaction mixture was extracted (ethyl acetate), washed, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 1:1) to obtain the target compound 1J (90 mg, 30% yield).

[0211] LC-MS (ESI): m / z = 555.4 [M+H] + .

[0212] Step 9:

[0213] 1J (90 mg, 0.16 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added and reacted at room temperature for 1 hour. After the reaction, the reaction solution was concentrated and the residue 1K (crude product) was directly used for the next step.

[0214] LC-MS (ESI): m / z = 455.3 [M+H] + .

[0215] Step 10:

[0216] 1K (crude product) was dissolved in dichloromethane (4 mL), and N,N-diisopropylethylamine (1 mL) and cyanogen bromide (24 mg, 0.22 mmol) were added. The mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by HPLC to obtain the target compound 1 (26.72 mg, 36% yield).

[0217] LC-MS (ESI): m / z = 480.3 [M+H] + .

[0218] 1 H NMR(400MHz,DMSO-d6)δ8.66-8.65(m,2H),8.59(d,1H),7.86-7.82(m,1H),7.61(d,1H),7.36-7.32(m,1H),7.16(s,1H),5.83(q,1H),5 .08-5.01(m,1H),3.54-3.50(m,2H),3.27(dd,2H),2.99-2.96(m,2H),2.40(s,3H),2.35-2.28(m,2H),2.08-2.02(m,2H),1.72(d,3H).

[0219] Example 2

[0220]

[0221] Step 1:

[0222] Dissolve compound 2A (4 g, 19.23 mmol) in DMF (30 mL), add NBS (3.25 g, 18.27 mmol), and react at room temperature for 3 h. After the reaction is completed, add water (60 mL), then extract with EA (20 mL × 3). Wash the organic phase with saturated brine, dry and concentrate the organic phase. The obtained crude product is purified by column chromatography (petroleum ether:ethyl acetate = 6:1 (v / v)) to obtain compound 2B (2.6 g, yield 47%).

[0223] LC-MS (ESI): m / z == 287.8 [M+H] + .

[0224] Step 2:

[0225] Dissolve compound 2B (1.4 g, 4.88 mmol), 2C (973 mg, 2.31 mmol), and copper(I) iodide (185 mg, 0.98 mmol) in DMF (30 mL), add triethylamine (8 mL), displace with nitrogen 3 times, add bis(triphenylphosphine)palladium(II) dichloride (343 mg, 0.49 mmol), displace with nitrogen 3 times again, and stir at room temperature for 16 h. Add water (50 mL) to the reaction system, extract with ethyl acetate (30 mL × 3). Wash the organic phase with saturated brine, dry and concentrate the organic phase. Separate by column chromatography (petroleum ether:ethyl acetate = 5:1 (v / v)) to obtain compound 2D (400 mg, yield 24%).

[0226] LC-MS (ESI): m / z = 340.1 [M+H] + .

[0227] Step 3:

[0228] Dissolve compound 2D (200 mg, 0.59 mmol), compound 1I (300 mg, 0.76 mmol), and potassium carbonate (244 mg, 1.77 mmol) in dioxane (15 mL) and water (5 mL), displace with nitrogen 3 times, add [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (44 mg, 0.06 mmol), displace with nitrogen 3 times again, and stir at 95 °C for 5 h. Cool the reaction to room temperature, add water (25 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure to obtain the crude product. Separate by column chromatography (petroleum ether:ethyl acetate = 5:1 (v / v)) to obtain compound 2E (100 mg, yield 32%).

[0229] LC-MS (ESI): m / z = 524.3 [M+H] + .

[0230] Step 4:

[0231] Dissolve compound 2E (100 mg, 0.19 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (1 mL), stir at room temperature for 2 hours. After the reaction is complete, concentrate and rotary evaporate to dryness to obtain compound 2F (70 mg), which is directly used for the next step.

[0232] LC-MS (ESI): m / z = 424.3 [M+H] + .

[0233] Step 5:

[0234] Dissolve compound 2G (70 mg, 0.16 mmol) in dichloromethane (5 mL), add N,N-diisopropylethylamine (62 mg, 0.48 mmol), add cyanogen bromide (33 mg, 0.32 mmol), and then stir at room temperature for 1 hour. Concentrate the system, and purify the crude product by preparative HPLC to obtain the target compound 2 (28 mg, yield 39%).

[0235] LC-MS (ESI): m / z = 449.1 [M+H] + .

[0236] 1 1H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.67 (s, 1H), 8.58 (d, 1H), 7.87 - 7.82 (m, 1H), 7.67 (d, 1H), 7.38 - 7.31 (m, 1H), 7.20 (s, 1H), 7.12 (s, 1H), 5.91 (q, 1H), 4.49 - 4.44 (m, 2H), 4.26 (t, 2H), 4.00 - 3.89 (m, 1H), 3.62 (s, 3H), 1.71 (d, 3H).

[0237] Example 3

[0238]

[0239] Step 1:

[0240] Compound 3A (0.11 g, 1.0 mmol) and 3B (0.25 g, 1.0 mmol) were dissolved in DMF (10 mL), potassium carbonate (0.41 g, 3.0 mmol) was added, and the mixture was stirred evenly and reacted at 80 °C for 3 hours. After the reaction was completed, water (30 mL) was added, and the mixture was extracted with ethyl acetate (50 mL×2). The combined organic phases were washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (DCM:MeOH (v / v) = 25:1) to obtain compound 3C (0.18 g, yield 65%).

[0241] LC-MS (ESI): m / z = 273.2 [M+H] + .

[0242] The second step:

[0243] Compound 3C (0.1 g, 0.37 mmol) and compound 1I (0.11 g, 0.37 mmol) were dissolved in 1,4-dioxane (20 ml) and water (4 ml), Pd(dppf)Cl2 (30 mg, 0.04 mmol) and potassium carbonate (0.15 g, 1.11 mmol) were added, and the mixture was stirred evenly. Then, the reaction was carried out at 100 °C for 16 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, water (40 mL) was added, and the mixture was extracted with ethyl acetate (60 mL×3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated and purified by silica gel column chromatography (DCM:MeOH (v / v) = 10:1) to obtain compound 3 (60 mg, yield 36%).

[0244] LC-MS (ESI): m / z = 457.1 [M+H] + .

[0245] 1 1H NMR (400 MHz, CDCl3) δ 8.61–8.60 (m, 1H), 8.55 (s, 1H), 7.84–7.77 (m, 2H), 7.33–7.27 (m, 2H), 5.87 (s, 1H), 3.85–3.78 (m, 2H), 3.67–3.60 (m, 2H), 3.00–2.94 (m, 1H), 2.14–1.99 (m, 5H), 1.88 (d, 3H).

[0246] Example 4

[0247]

[0248] The first step:

[0249] Compound 4A (2.0 g, 10.1 mmol) was dissolved in ethanol (50 mL). Lithium borohydride (1.11 g, 50.5 mmol) was slowly added thereto in portions at room temperature. After stirring evenly, the reaction was carried out at 50 °C for 16 hours. After the reaction was completed, water (50 mL) was added, and the mixture was extracted with dichloromethane (100 mL × 3). The combined organic phases were washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by silica gel column chromatography (DCM:MeOH (v / v) = 5:1) to obtain compound 4B (1.4 g, yield 68%).

[0250] LC-MS (ESI): m / z = 203.2 [M+H] + .

[0251] Step 2:

[0252] Compound 4B (0.5 g, 6.97 mmol) and triethylamine (1.4 g, 13.94 mmol) were dissolved in dichloromethane (30 ml), and di-tert-butyl dicarbonate (1.67 g, 7.67 mmol) was added. After stirring evenly, the reaction was carried out at room temperature for 1 hour. The reaction solution was concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v) = 1:1) to obtain compound 4C (1.85 g, yield 88%).

[0253] LC-MS (ESI): m / z = 303.2 [M+H] + .

[0254] Step 3:

[0255] Compound 4C (0.5 g, 1.66 mmol) and compound 1I (0.51 g, 1.66 mmol) were dissolved in 1,4-dioxane (20 ml) and water (4 ml). Pd(dppf)Cl2 (0.12 g, 0.17 mmol) and potassium carbonate (0.69 g, 4.98 mmol) were added. After stirring evenly, the reaction was carried out at 100 °C for 16 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, water (40 mL) was added, and the mixture was extracted with ethyl acetate (60 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then separated and purified by silica gel column chromatography (DCM:MeOH (v / v) = 20:1) to obtain compound 4D (0.5 g, yield 62%).

[0256] LC-MS (ESI): m / z = 487.1 [M+H] + .

[0257] Step 4:

[0258] Dissolve compound 4D (0.1 g, 0.21 mmol) in dichloromethane (10 mL). After stirring evenly, add trifluoroacetic acid (2 mL) dropwise. After the addition, react at room temperature for 1 hour. After the reaction, concentrate under reduced pressure. Add dichloromethane (10 mL) to the residue. After mixing evenly, adjust the pH to 8 - 10 with saturated sodium bicarbonate. Extract with dichloromethane (30 mL × 3). Wash the combined organic phases with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the target compound 4E (70 mg, yield 86%).

[0259] LC-MS (ESI): m / z = 387.1 [M + H] + .

[0260] Step 5:

[0261] Dissolve compound 4E (70 mg, 0.18 mmol) and triethylamine (54 mg, 0.54 mmol) in dichloromethane (10 ml). Add cyanogen bromide (38 mg, 0.36 mmol). After stirring evenly, react at room temperature for 1 hour. Concentrate the reaction solution and purify the residue by silica gel column chromatography (DCM:CH3OH (v / v) = 10:1) to obtain compound 4 (50 mg, yield 67%).

[0262] LC-MS (ESI): m / z = 412.1 [M + H] + .

[0263] 1 1H NMR (400 MHz, CDCl3) δ 8.87–8.85 (m, 1H), 8.60–8.58 (m, 1H), 8.23 (s, 1H), 7.78–7.76 (m, 2H), 7.49–7.39 (m, 1H), 7.40–7.39 (m, 1H), 5.83–5.78 (m 1H), 4.64 (s, 2H), 4.43–4.40 (m, 2H), 3.80–3.77 (m, 2H), 1.86 (d, 3H).

[0264] Example 5

[0265]

[0266] Step 1:

[0267] Dissolve 5A (2 g, 8.80 mmol) in tetrahydrofuran (20 mL), place it under stirring at 0 °C, and slowly add dropwise a 1 M solution of diisobutylaluminum hydride in tetrahydrofuran (26.4 mL, 26.40 mmol) under nitrogen protection. After the addition is complete, react at room temperature for 2.5 hours. LC-MS shows that the reaction is complete. Place it at 0 °C and slowly add dropwise water (1 mL), 15% aqueous sodium hydroxide solution (1 mL), and finally add water (2.6 mL). After stirring for 0.5 hours after the addition, add anhydrous sodium sulfate for drying, filter, wash the filter cake with ethyl acetate (30 mL × 2), and concentrate the filtrate under reduced pressure to obtain compound 5B (1.5 g, 74.3%).

[0268] LC-MS (ESI): m / z = 174.1 [M - 55] + .

[0269] Step 2:

[0270] Dissolve 5B (1.3 g, 5.67 mmol) in dichloromethane (20 mL), add triethylamine (1.72 g, 17.01 mmol), then place it under stirring at 0 °C, and finally slowly add dropwise methanesulfonyl chloride (0.78 g, 6.80 mmol). After the addition is complete, react at room temperature for 2 hours. LC-MS shows that the reaction is complete. Add water (20 mL), and then extract with dichloromethane (30 mL × 2). Dry the organic layer with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound 5C (1.6 g, 91.8%).

[0271] LC-MS (ESI): m / z = 252.1 [M - 55] + .

[0272] Step 3:

[0273] Dissolve 5C (1.6 g, 5.20 mmol) in N,N-dimethylformamide (20 mL), add sodium azide (0.85 g, 13.0 mmol), and react at 90 °C overnight. LC-MS shows that the reaction is complete. Add water (20 mL), and then extract with ethyl acetate (30 mL × 2). Wash the organic phase with saturated brine (20 mL × 2), dry with anhydrous sodium sulfate, filter and concentrate to obtain a dimethyl sulfoxide solution (20 mL) of the target compound 5D.

[0274] LC-MS (ESI): m / z = 155.2 [(M - Boc) + H] + .

[0275] Step 4:

[0276] Dissolve 5D (dimethyl sulfoxide solution), ethyl acetoacetate (2.7 g, 20.76 mmol), and potassium carbonate (2.87 g, 20.76 mmol) in dimethyl sulfoxide (20 mL), and react at 100 °C for 16 hours. After the reaction is completed, add water (30 mL) to the reaction solution, then extract with ethyl acetate (20 mL × 3). The organic layer is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The residue is separated and purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 5E (820.0 mg, 43.0%).

[0277] LC-MS (ESI): m / z = 367.1 [M+H] + .

[0278] Step 5:

[0279] Dissolve 5E (0.67 g, 1.83 mmol) in methanol (3 mL), tetrahydrofuran (3 mL), and water (3 mL), then add lithium hydroxide (0.22 g, 9.15 mmol). After addition, react at room temperature for 2 hours. After the reaction is completed, adjust the reaction solution to about pH = 3, then extract with ethyl acetate (20 mL × 3). The organic phase is dried over anhydrous sodium sulfate, filtered and concentrated to obtain the target compound 5F (0.54 g, 87.2%).

[0280] LC-MS (ESI): m / z = 339.1 [M+H] + .

[0281] Step 6:

[0282] Dissolve 5F (0.54 g, 1.60 mmol) in water (10 mL), add potassium hydroxide (0.11 g, 1.92 mmol) and bromine (0.31 g, 1.92 mmol) respectively. After addition, react at room temperature for 3 hours. After the reaction is completed, add water (30 mL) to the reaction solution, then extract with ethyl acetate (20 mL × 3). The organic layer is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The residue is separated and purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 5G (0.47 g, 78.9%).

[0283] LC-MS (ESI): m / z = 373.0 [M+H] + .

[0284] Step 7:

[0285] 5G (0.30 g, 0.80 mmol), 1I (0.30 g, 0.96 mmol), and potassium carbonate (0.33 g, 2.40 mmol) were dissolved in 1,4-dioxane (8 mL) and water (0.8 mL). Finally, 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II) (59 mg, 0.08 mmol) was added. After adding, the mixture was purged with nitrogen three times and then reacted at 95 °C for 5 hours. After the reaction was completed, water (30 mL) was added to the reaction solution, and then it was extracted with ethyl acetate (20 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 5H (90 mg, 20.1%).

[0286] LC-MS (ESI): m / z = 557.5 [M+H] + .

[0287] Step 8:

[0288] 5H (90 mg, 0.16 mmol) was dissolved in dichloromethane (6 mL), and then trifluoroacetic acid (2 mL) was added. The reaction was carried out at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated to obtain 5I directly for the next step.

[0289] LC-MS (ESI): m / z = 457.3 [M+H] + .

[0290] Step 9:

[0291] 5I was dissolved in dichloromethane (5 mL), and then N,N-diisopropylethylamine (1 mL) and cyanogen bromide (25 mg, 0.24 mmol) were added. The reaction was carried out at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the crude product was purified by preparative HPLC to obtain the target compound 5 (15.0 mg, 19.2%).

[0292] LC-MS (ESI): m / z = 482.2 [M+H] + .

[0293] 1 1H NMR (400 MHz, CDCl3) δ 8.58 (d, 1H), 8.48 (s, 1H), 8.22 (s, 1H), 7.84 - 7.81 (m, 2H), 7.33 - 7.30 (m, 1H), 7.09 (s, 1H), 5.85 (s, 1H), 4.36 - 4.30 (m, 1H), 3.27 - 3.23 (m, 1H), 2.91 (s, 3H), 2.42 - 2.28 (m, 7H), 2.00 - 1.96 (m, 2H), 1.87 (d, 3H), 1.85 - 1.78 (m, 2H).

[0294] Example 6

[0295]

[0296] Step 1:

[0297] Dissolve 6A (3.0 g, 13.93 mmol) in dichloromethane (50 mL), add triethylamine (4.23 g, 41.79 mmol), place the mixture under stirring at 0 °C, and finally slowly add methanesulfonyl chloride (1.76 g, 15.32 mmol). After dropping, react at room temperature for 2 hours. After the reaction is complete, add water (30 mL), then extract with dichloromethane (30 mL × 2). The organic layer is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain compound 6B (3.6 g, 88.0%).

[0298] Step 2:

[0299] Dissolve 6B (3.6 g, 12.27 mmol) in N,N-dimethylformamide (40 mL), add sodium azide (1.99 g, 30.67 mmol), and react at 90 °C overnight. After the reaction is complete, add water (20 mL), then extract with ethyl acetate (30 mL × 2). The organic phase is washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a dimethyl sulfoxide solution (30 mL) of the target compound 6C.

[0300] LC-MS (ESI): m / z = 155.2 [(M - Boc) + H] + .

[0301] Step 3:

[0302] Dissolve 6C (dimethyl sulfoxide solution), ethyl acetoacetate (6.32 g, 48.6 mmol), and potassium carbonate (6.72 g, 48.6 mmol) in dimethyl sulfoxide (30 mL), and react at 100 °C for 16 hours. After the reaction is completed, add water (30 mL) to the reaction solution, then extract with ethyl acetate (20 mL × 3). The organic layer is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The residue is separated and purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 6D (1.75 g, 40.8%).

[0303] LC-MS (ESI): m / z = 353.1 [M + H] + .

[0304] Step 4:

[0305] Dissolve 6D (1.75 g, 1.83 mmol) in methanol (10 mL), tetrahydrofuran (10 mL), and water (10 mL), then add lithium hydroxide (0.60 g, 24.85 mmol). After addition, react at room temperature for 2 hours. After the reaction is completed, adjust the reaction solution to about pH = 3, then extract with ethyl acetate (30 mL x 3). The organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the target compound 6E (1.3 g, 80.7%).

[0306] LC-MS (ESI): m / z = 325.1 [M+H] + .

[0307] Step 5:

[0308] Dissolve 6E (1.30 g, 4.01 mmol) in water (20 mL), add potassium hydroxide (0.27 g, 4.81 mmol) and bromine (0.77 g, 4.81 mmol) respectively. After addition, react at room temperature for 3 hours. After the reaction is completed, add water (30 mL) to the reaction solution, then extract with ethyl acetate (20 mL x 3). The organic layer is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The residue is separated and purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 6F (1.0 g, 69.4%).

[0309] LC-MS (ESI): m / z = 359.1 [M+H] + .

[0310] Step 6:

[0311] Dissolve 6F (0.65 g, 1.81 mmol), 1I (0.67 g, 2.17 mmol), and potassium carbonate (0.75 g, 5.43 mmol) in 1,4-dioxane (10 mL) and water (1 mL). Finally, add 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II) (0.13 g, 0.18 mmol). After addition, displace with nitrogen 3 times and react at 95°C for 5 hours. After the reaction is completed, add water (30 mL) to the reaction solution, then extract with ethyl acetate (20 mL x 3). The organic layer is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The residue is separated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 6G (0.4 g, 40.7%).

[0312] LC-MS (ESI): m / z = 543.2 [M+H] + .

[0313] Step 7:

[0314] Dissolve 6G (400 mg, 0.74 mmol) in dichloromethane (12 mL), then add trifluoroacetic acid (4 mL), and react at room temperature for 1 hour. After the reaction, concentrate the reaction solution to obtain 6H directly for the next step.

[0315] LC-MS (ESI): m / z = 443.3 [M+H] + .

[0316] Step 8:

[0317] Dissolve 6H in dichloromethane (10 mL), then add N,N-diisopropylethylamine (2 mL) and cyanogen bromide (120 mg, 1.11 mmol), and react at room temperature for 2 hours. After the reaction, concentrate the reaction solution under reduced pressure, and purify the residue by column chromatography (petroleum ether / ethyl acetate = 1 / 5) to obtain compound 6I (210 mg, 60.9%).

[0318] Step 9:

[0319] Dissolve 6I (200 mg, 0.43 mmol) in tetrahydrofuran (10 mL), stir at 0 °C, add sodium hydride (31 mg, 1.29 mmol) under nitrogen protection, continue to stir at this temperature for 10 minutes, and finally add cyanogen bromide (68 mg, 0.65 mmol). After addition, react at room temperature for 2 hours. After the reaction, add saturated ammonium chloride solution (15 mL) to the reaction solution, extract with ethyl acetate (20 mL x 3), dry the organic layer with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography (petroleum ether / ethyl acetate = 1 / 20) to obtain compound 6 (10 mg, 4.7%).

[0320] LC-MS (ESI): m / z = 493.3 [M+H]+.

[0321] 1H NMR (400 MHz, CDCl3) δ 8.57 (d, 1H), 8.45 (s, 1H), 8.23 (s, 1H), 7.79 - 7.71 (m, 2H), 7.26 - 7.24 (m, 1H), 7.06 (s, 1H), 5.76 - 5.71 (m, 1H), 4.40 - 4.37 (m, 1H), 3.98 - 3.94 (m, 1H), 2.47 - 2.35 (m, 7H), 2.11 - 2.04 (m, 4H), 1.86 (d, 3H).

[0322] Biological test evaluation

[0323] The present invention will be further described and explained below in combination with test examples, but these examples do not mean to limit the scope of the present invention.

[0324] 1. FGFR1-3 Kinase Activity Test

[0325] The compound was diluted with DMSO to 2.5× the detection concentration. Transfer 4 μL of the compound to a 384-well reaction plate (784075, Greiner) using an electric pipette. Dilute FGFR1, 2, and 3 proteins (working concentration: 0.3 nM) with kinase reaction buffer (5x Buffer, 5 mM MgCl2, 1 mM DTT, 1% Tween 20), and transfer 2 μL of the kinase solution to the 384-well reaction plate. Centrifuge at 1000 rpm for 1 minute and incubate at 25 °C for 10 minutes. Dilute the mixture of substrate (TK-substrate working concentration: 1 μM) and ATP (working concentration: 50 μM) with kinase reaction buffer, add 4 μL of the substrate and ATP mixture to the reaction plate, and centrifuge at 1000 rpm for 1 minute. Seal the 384-well reaction plate with a sealing film, incubate at 25 °C to initiate the reaction, and incubate for 60 min to end the reaction. Prepare XL665 and antibody detection reagents with detection buffer. Add 5 μL of kinase detection reagent to each well of the 384-well reaction plate, centrifuge at 1000 rpm for 60 seconds, and incubate at 25 °C for 60 min. Read the fluorescence signals at 620 nm (Cryptate) and 665 nm (XL665) using a microplate reader. Calculate the inhibition rate of the compound by the formula: Inhibition rate % = (Ratio compound – Ratio solvent) / (Ratio positive control – Ratio solvent) * 100%. Use the Graphpad software log(inhibitor) vs. response--Variable slope (four parameters) equation for fitting analysis to calculate the IC 50 value.

[0326] Experimental results: The compounds of the present invention have inhibitory effects on the enzyme activities of FGFR1, FGFR2, and FGFR3 in vitro, especially have significant inhibitory effects on the enzyme activity of FGFR3. The IC 50 value of the compounds in Example on FGFR3 enzyme activity is less than 100 nM. The IC 50 value is represented by grades A, B, C, and D. A represents 0 < IC 50 ≤ 10 nM, B represents 10 nM < IC 50 ≤ 30 nM, C represents 30 nM < IC 50 ≤ 100 nM, D represents IC 50 > 100 nM. Among them, the test results of some examples are shown in Table 1.

[0327] Table 1

[0328]

[0329] Conclusion: The compounds of the present invention, such as the compounds of the examples, have a significant inhibitory effect on FGFR3 kinase activity.

[0330] 2. Proliferation inhibition of RT112 cells (FGFR3-TACC3 fusion)

[0331] LI7 cells (Kobio Biotech, CBP60316) were cultured in DMEM complete medium (+10% FBS) in a CO2 incubator at 37 °C for 48 h. The cells were digested with trypsin and counted, and then the density was adjusted to 1.67×10 4 cells / mL. 90 μL (3000 cells) of the cells were seeded into each well of a clear-bottom 96-well plate and transferred to a CO2 incubator for overnight culture at 37 °C. After the cells were incubated overnight, 10 μL of the diluted compound (starting from a final concentration of 10 μM, 3-fold dilution, 10 concentrations) was added to each well using a multi-channel pipette. The positive control was serum-free medium containing DMSO. After mixing evenly, it was placed in a CO2 incubator at 37 °C for 96 h. After the incubation was completed, the detection solution of the kit (Vazyme, DD1101-03) was restored to room temperature. 100 μL of CellCounting-Lite2.0 detection solution was added to each well, sealed with a sealing film, and the plate was placed on an oscillator and shaken for 15 min (the whole process needs to be carried out in the dark). The fluorescence signal value LUM of each well was detected using the Luminescence module of an enzyme-linked immunosorbent assay (ELISA) reader (BMG LRBTECH). The inhibition rate of the compound was calculated by the formula. The equation of log(inhibitor) vs. response--Variableslope (four parameters) of Graphpad software was used for fitting analysis to calculate the IC 50 value. The ordinate of the data was the percentage of inhibition rate, and the abscissa was the logarithm of the sample concentration (Log10).

[0332] Conclusion: The compounds of the present invention, such as the compounds of the examples, have a significant inhibitory effect on the proliferation of RT112 cells.

Claims

1. A compound of formula (I), its stereoisomers or its pharmaceutically acceptable salts: Wherein: Cy1 is selected from C 3-11 cycloalkyl, 4- to 11-membered heteroalkyl, 5- to 6-membered heteroaryl fused to 5- to 6-membered heteroaryl, optionally further substituted by 1 to 4 R c1 substituents; Cy2 is present or absent; when Cy2 is present, Cy2 is a 3- to 8-membered heterocycloalkyl or a 5- to 10-membered heteroaryl, optionally further substituted by 1 to 5 R c2 substituents; Cy3 is selected from C 3-14 cycloalkyl, 5- to 14-membered heteroalkyl, C 6-14 aryl or 5- to 14-membered heteroaryl, optionally further substituted by 1 to 4 R c3 substituents; Each R c1 is independently deuterium, halogen, hydroxyl, cyano, amino, oxo, SF5, SCF3, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkylidene, C 1-6 haloalkylidene, where the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino are optionally further substituted by 1 - 3 groups selected from halogen, oxo, C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, C 1-3 alkylidene or C 1-3 haloalkylidene; Each R c2 and R c3 are each independently deuterium, a halogen, a hydroxyl group, a cyano group, an amino group, an oxo group, SF5, SCF3, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkylidene, C 1-6 haloalkylidene, C 3-8 cycloalkyl, 3- to 8-membered heteroalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl or C 3-8 cycloalkylalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heteroalkyl, aryl or heteroaryl is optionally further substituted by 1 to 3 groups selected from halogen, oxo, C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, C 1-3 alkylidene or C 1-3 haloalkylidene; Alternatively, any one of R c1 and any one of R c2 are linked to the ring atoms to which they are attached to form a 5- to 8-membered heteroalkyl or 5- to 8-membered heteroaryl group, optionally further substituted by 1 to 3 groups selected from halogen, oxo, C 1-3 alkyl, halo-C 1-3 alkyl, C 1-3 alkoxy, halo-C 1-3 alkoxy, C 1-3 alkylidene or C 1-3 haloalkylidene; X1 and X2 are each independently a bond, -CO-, C 1-3 alkylene, C 2-4 alkenylene or C 2-4 alkynylene, where the alkylene is optionally further substituted by 1 - 3 groups selected from halogen, C 2-4 alkenyl or C 2-4 alkynyl; Y is a bond, -O-, -NR y -, or -O-NR y -; R y is hydrogen or C 1-3 alkyl; R is cyano, -N(C 1-2 alkyl)-CN, -N(CN)2, amino, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio or C 1-6 alkylamino, and the amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio or alkylamino is optionally further substituted by 1 - 3 groups selected from halogen, hydroxy, cyano, amino, oxo, halo C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, C 1-3 alkylidene, C 1-3 haloalkylidene, C 3-6 cycloalkyl; Provided that, (1) When Cy2 is absent and X1 is a bond, Cy1 is not a substituted or unsubstituted pyrazole, pyridine, or pyrazine; (2) not Unless otherwise specified, the heterocycloalkyl and heteroaryl contain 1 - 5 heteroatoms selected from N, O, S, P, Si or oxidized groups of N, S, P.

2. The compound represented by the general formula (I) according to claim 1, its stereoisomers or its pharmaceutically acceptable salts, characterized in that, It satisfies one or more of the following conditions: (1) Cy1 is selected from C 3-6 monocyclic cycloalkyl, 4- to 6-membered monocyclic saturated heterocycloalkyl, 4- to 6-membered monocyclic partially saturated heterocycloalkyl, 4- to 6-membered heterocycloalkyl fused to 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl fused to 4- to 6-membered heterocycloalkyl, 4- to 6-membered heterocycloalkyl fused to 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl fused to 5- to 6-membered heteroaryl, 5- to 8-membered bridged heterocycloalkyl, 6- to 8-membered spiroheterocycloalkyl, optionally further substituted by 1 to 4 R c1 substituted; preferably Cy1 is selected from C 4-6 monocyclic cycloalkyl, 4- to 6-membered saturated monocyclic heterocycloalkyl containing 1 to 2 nitrogen atoms, 4- to 6-membered partially unsaturated monocyclic heterocycloalkyl containing 1 to 2 nitrogen atoms, 5- to 8-membered saturated bridged heterocycloalkyl containing 1 to 2 nitrogen atoms, 4- to 6-membered heterocycloalkyl fused to 3- to 6-membered cycloalkyl containing 1 to 2 nitrogen atoms, 6- to 8-membered saturated spiroheterocycloalkyl containing 1 to 2 nitrogen atoms, 4- to 6-membered heterocycloalkyl fused to 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl fused to 5- to 6-membered heteroaryl, optionally further substituted by 1 to 4 R c1 substituted; preferably Cy1 is selected from optionally further substituted by 1 to 4 R c1 substituted; (2) Cy2 is present or absent. When Cy2 is present, Cy2 is selected from 5- to 6-membered heterocycloalkyl or 5- to 6-membered heteroaryl, optionally further substituted by 1 to 4 R c2 ; preferably Cy2 is absent or Cy2 is selected from 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, 5-membered heteroaryl or 6-membered heteroaryl, optionally further substituted by 1 to 4 R c2 ; more preferably Cy2 is absent or Cy2 is selected from optionally further substituted by 1 to 4 R c2 ; (3) X1 is a bond, -CO-, C 1-3 alkylene, C 2-4 alkenylene or C 2-4 alkynylene, preferably a bond, -C≡C-; (4)R is selected from cyano, -N(C 1-2 alkyl)-CN, -N(CN)2, amino, -COOH, C 1-3 alkyl, C 2-4 alkenyl or C 2-4 alkynyl, and the amino, alkyl, alkenyl or alkynyl is optionally further substituted by 1-3 groups selected from halogen, hydroxy, cyano, amino, oxo, halo-C 1-3 alkyl, C 1-3 alkoxy, halo-C 1-3 alkoxy, C 1-3 alkylidene, C 1-3 haloalkylidene, C 3-6 cycloalkyl, R is preferably selected from cyano, -N(C 1-2 alkyl)-CN or C 2-4 alkynyl, and the alkynyl is optionally further substituted by 1-3 groups selected from hydroxy, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 3-4 cycloalkyl, more preferably cyano; (5) Cy3 is selected from C 4-6 cycloalkyl, 4- to 6-membered heteroalkyl, 5- to 6-membered heteroaryl, C 4-6 cycloalkylphenyl, C 4-6 cycloalkyl-5- to 6-membered heteroaryl, 4- to 6-membered heteroalkylphenyl, 4- to 6-membered heteroalkyl-5- to 6-membered heteroaryl, optionally further substituted by 1 to 4 R c3 substituents, preferably Cy3 is selected from cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, pyridyl, cyclopentyl-5-membered heteroaryl, cyclopentyl-6-membered heteroaryl, pyrrolidinylphenyl, pyrrolidinyl-5-membered heteroaryl, pyrrolidinyl-6-membered heteroaryl, optionally further substituted by 1 to 4 R c3 substituents, more preferably Cy3 is selected from optionally further substituted by 1 to 4 R c3 substituents; (6) X2 is selected from a bond, -CO-, -CH(CH3)-, -CH=C(CH3)-, -C≡C-, -CH(CH=CH2)-, -CH(C≡CH)-; (7) Y is selected from a bond, -O-, -NCH3-, -O-NCH3-; (8)R c1 Selected from deuterium or C 1-6 alkyl, preferably selected from deuterium or C 1-3 alkyl, more preferably selected from deuterium or methyl; (9)R c2 selected from deuterium, halogen, hydroxy, cyano, amino, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-8 membered heteroalkyl, C 6-10 aryl or 5-10 membered heteroaryl, preferably R c2 selected from deuterium, halogen, oxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 3-4 cycloalkyl, more preferably R c2 selected from deuterium, fluorine, chlorine, oxo, methyl, vinyl, ethynyl or cyclopropyl; (10)R c3 selected from deuterium, halogen, hydroxy, cyano, amino, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkylidene, C 1-6 haloalkylidene, C 3-8 cycloalkyl, 3- to 8-membered hetero cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl or C 3-8 cycloalkylalkyl, preferably R c3 selected from deuterium, halogen, oxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkylidene, C 1-3 haloalkylidene or C 3-4 cycloalkylmethyl, more preferably R c3 selected from deuterium, fluorine, chlorine, oxo, methyl, methylidene, ethylidene, 1-methylethylidene, fluoromethylidene, difluoromethylidene, vinyl, ethynyl or cyclopropylmethyl.

3. The compound, stereoisomer or pharmaceutically acceptable salt thereof represented by the general formula (I) according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1) Cy1 is selected from C 4-6 monocyclic cycloalkyl, 4- to 5-membered saturated monocyclic heterocycloalkyl containing 1 to 2 nitrogen atoms, 6-membered saturated monocyclic heterocycloalkyl containing 2 nitrogen atoms, 4- to 6-membered partially unsaturated monocyclic heterocycloalkyl containing 1 to 2 nitrogen atoms, 5- to 8-membered saturated bridged heterocycloalkyl containing 1 to 2 nitrogen atoms, 4- to 6-membered heterocycloalkyl fused to 3- to 6-membered cycloalkyl, 6- to 8-membered saturated spiro heterocycloalkyl containing 1 to 2 nitrogen atoms, 4- to 6-membered heterocycloalkyl fused to 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl fused to 5- to 6-membered heteroaryl, optionally further substituted by 1 to 4 R c1 substituted; preferably Cy1 is selected from optionally further substituted by 1 to 4 R c1 substituted; (2) Cy2 is absent or Cy2 is selected from 5-membered heteroaryl groups containing 1-2 nitrogen heteroatoms and 0-2 heteroatoms selected from O and S, 6-membered heteroaryl groups containing 1-3 heteroatoms selected from N, O, and S, and the heteroaryl groups are optionally further substituted by 1-2 R c2 substituents; preferably Cy2 is selected from the is optionally further substituted by 1-2 R c2 substituents; (3)R is selected from -N(C 1-2 alkyl)-CN, -N(CN)2, amino, -COOH, C 1-3 alkyl, C 2-4 alkenyl or C 2-4 alkynyl, and the amino, alkyl, alkenyl or alkynyl is optionally further substituted by 1 - 3 groups selected from halogen, hydroxy, cyano, amino, oxo, C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, C 1-3 alkylidene, C 1-3 haloalkylidene, C 3-6 cycloalkyl, and preferably R is selected from -N(C 1-2 alkyl)-CN or C 2-4 alkynyl, and the alkynyl is optionally further substituted by 1 - 3 groups selected from hydroxy, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 3-4 cycloalkyl; (4) Cy3 is selected from C 4-6 cycloalkyl, 4- to 6-membered heteroalkyl, 5-membered heteroaryl, C 4-6 cycloalkylphenyl, C 4-6 cycloalkyl-5- to 6-membered heteroaryl, 5- to 6-membered heteroalkylphenyl, 5- to 6-membered heteroalkyl-5- to 6-membered heteroaryl, wherein Cy3 is optionally further substituted by 1 to 3 R c3 substituents, Cy3 is preferably selected from cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, pyridyl, cyclopentyl-5-membered heteroaryl, cyclopentyl-6-membered heteroaryl, pyrrolidinylphenyl, pyrrolidinyl-5-membered heteroaryl, pyrrolidinyl-6-membered heteroaryl, optionally further substituted by 1 to 4 R c3 substituents, Cy3 is more preferably selected from optionally further substituted by 1 to 4 R c3 substituents; (5) Any one of R c1 and any one of R c2 are linked to the ring atoms to which they are attached to form a 5- to 8-membered heteroalkyl or 5- to 8-membered heteroaryl group, optionally further substituted by 1 or 2 groups selected from halogen, oxo, C 1-2 alkyl, halo-C 1-2 alkyl, C 1-2 alkoxy, halo-C 1-2 alkoxy, C 1-2 alkylidene or C 1-2 haloalkylidene groups.

4. The compound, stereoisomer or pharmaceutically acceptable salt thereof represented by the general formula (I) according to claim 1, characterized in that, The general formula (I) is further represented by general formulas (II-1), (II-2), (III-1), (III-2), (IV-1), (IV-2), (V-1), (V-2), (VI-1), (VI-2), (VII-1), (VII-2): R c21 selected from C 3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl; C y11 Selected from C 4-6 monocyclic cycloalkyl, 4-5 membered saturated monocyclic heterocycloalkyl, 6 membered saturated monocyclic heterocycloalkyl containing 2 nitrogen atoms, 4-6 membered partially unsaturated monocyclic heterocycloalkyl containing 1-2 nitrogen atoms, 5-8 membered saturated bridged heterocycloalkyl containing 1-2 nitrogen atoms, 4-6 membered heterocycloalkyl fused to 3-6 membered cycloalkyl, 6-8 membered saturated spiro heterocycloalkyl containing 1-2 nitrogen atoms, 4-6 membered heterocycloalkyl fused to 5-6 membered heteroaryl, 5-6 membered heteroaryl fused to 5-6 membered heteroaryl, optionally further substituted by 1-4 R c1 substituents; C y12 Selected from 4- to 6-membered heterocycloalkyl-fused 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl-fused 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl-fused 5- to 6-membered heteroaryl containing 1 to 2 nitrogen atoms, optionally further substituted by 1 to 2 R c1 substituted; C y21 Selected from 5-membered heteroaryl groups containing 1 to 2 nitrogen heteroatoms and 0 to 2 heteroatoms selected from O and S, and 6-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, said heteroaryl groups being optionally further substituted by 1 to 2 R c2 substituents.

5. The compound represented by the general formula (I), its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1-4, characterized in that, Selected from one of the structures in Table 1 or Table 2.

6. A pharmaceutical composition comprising a therapeutically effective dose of the compound, its stereoisomers or its pharmaceutically acceptable salts as shown in any one of claims 1 - 5, and one or more pharmaceutically acceptable carriers or excipients.

7. The pharmaceutical composition according to claim 6, which comprises 1 - 1500 mg of the compound, its stereoisomers or its pharmaceutically acceptable salts as shown in any one of claims 1 - 5, and one or more pharmaceutically acceptable carriers or excipients.

8. Use of the compound, its stereoisomers or its pharmaceutically acceptable salts as shown in any one of claims 1 - 5, or the pharmaceutical composition according to claim 6 or 7 in the preparation of a drug, preferably the drug is for preventing and / or treating an FGFR3-mediated disease.

9. According to the use of claim 8, the FGFR3-mediated diseases are selected from systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, lethal dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome or cancer, wherein the cancer is selected from breast cancer, invasive ductal breast cancer, invasive lobular breast cancer, lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small cell lung cancer, urothelial carcinoma, bladder cancer, urothelial bladder cancer, non-muscle invasive bladder cancer, muscle invasive bladder cancer, upper urinary tract cancer, urothelial upper urinary tract cancer, urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma, cutaneous melanoma, head and neck cancer, oral cancer, thyroid cancer, kidney cancer, renal pelvic cancer, glioblastoma, endometrial cancer, cervical cancer, ovarian cancer and testicular cancer.

10. A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of the compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1-5, or the pharmaceutical composition according to claim 6 or 7, wherein the therapeutically effective amount is preferably 1-1500 mg, and the disease is selected from systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, lethal dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome or cancer, wherein the cancer is selected from breast cancer, invasive ductal breast cancer, invasive lobular breast cancer, lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small cell lung cancer, urothelial carcinoma, bladder cancer, urothelial bladder cancer, non-muscle invasive bladder cancer, muscle invasive bladder cancer, upper urinary tract cancer, urothelial upper urinary tract cancer, urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma, cutaneous melanoma, head and neck cancer, oral cancer, thyroid cancer, kidney cancer, renal pelvic cancer, glioblastoma, endometrial cancer, cervical cancer, ovarian cancer and testicular cancer.

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