FGFR3 inhibitor and composition and application thereof

Abstract

The invention relates to an FGFR3 (fibroblast growth factor receptor 3) inhibitor as well as a composition and application thereof. The compound can be used for treating or preventing bladder cancer, lung cancer, stomach cancer, urothelial cancer, bile duct cancer, skeletal dysplasia, breast cancer, liver cancer, ovarian cancer, cervical cancer and other diseases. The structure of the compound is shown in the specification.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry and relates to an FGFR3 inhibitor, its composition, and its uses. Background Technology

[0002] Fibroblast growth factor receptor 3 (FGFR3) is a member of a highly conserved family of four receptor tyrosine kinases (FGFR1-4), which share high homology and sequence identity. When it binds to its ligand FGF, it leads to dimerization, phosphorylation, and conformational changes in intracellular domains, stimulating protein kinase activity and recruiting numerous intracellular proteins. These protein interactions facilitate the activation of a range of intracellular signaling pathways, including Ras-MAPK, AKT-PI3K, and phosphatase C, which are crucial for cell growth, proliferation, and survival. Therefore, the FGF / FGFR signaling pathway is essential for many biological processes such as tumor cell proliferation, migration, invasion, and angiogenesis. Abnormalities in FGFR can lead to overactivation of the FGFR signaling pathway and further induce the transformation of normal cells into cancerous cells; FGFR gene abnormalities are prevalent in various cancers.

[0003] Although erdatinib is approved for locally advanced or metastatic urothelial carcinoma with FGFR2 or FGFR3 abnormalities, the severe hyperphosphatemia caused by FGFR1 inhibition necessitates the use of intermittent dosing for most pan-FGFR inhibitors to mitigate adverse effects, significantly reducing their efficacy. Selective small-molecule inhibitors targeting FGFR have shown promise in the treatment of cancer and other diseases. Currently, no selective FGFR3 inhibitors have been approved for marketing, indicating a significant unmet medical need in this patient population. Summary of the Invention

[0004] On the one hand, the present invention provides a compound of formula (II), its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer, or an acceptable salt of its deuterated derivative. (II); in, In ring A, X1, X2, X4, and X5 exist in any of the following cases: (1) X1 and X5 are both -CH2-, and X2 and X4 are each independently selected from the bond, -CH2-, or -CH2-CH2-; (2) One of X4 and X5 is CHR. a The other is -CH2-, -CH2-CH2-, or a bond. One of X1 and X2 is CHR. bThe other is a -CH2-, -CH2-CH2-, or bond; and CHR a With CHR b Connecting them makes ring A a bridge ring, R a With R b The resulting functional groups are -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -CH2-O-CH2-, -(CH2)2-O-CH2-, -CH2-O-(CH2)2-, or -(CH2)2-O-(CH2)2-. Each R 1 Each is independently selected from F, Cl, Br, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methoxymethylene, ethoxymethylene, propoxymethylene, isopropoxymethylene, or cyclopropyl; n1 is 0, 1, 2, 3, 4, 5, 6, 7, or 8; X3 is either -N- or -CR 4 -; Ring B is a pyrazole ring, triazole ring, thiadiazole ring, or oxadiazole ring, and is surrounded by 0, 1, or 2 R groups. c Replace; each R c Each of the following groups is independently selected from F, Cl, Br, cyano, methyl, ethyl, propyl, and isopropyl, and methyl, ethyl, propyl, and isopropyl are optionally substituted by one or more substituents independently selected from F, Cl, Br, hydroxy, and methoxy. Ring C is a heteroaromatic ring; X6 is -CH- or -N-; one of X7 and X8 is -C- and the other is -N-; X9 is -NR. d -、-O- or -S-, R d It can be H, methyl, ethyl, propyl, or isopropyl; L2 is a bond, CHR e , by 0-2 R L Substituted methylene, with 0-2 R L Substituted with ethylene, cyclobutylene, cyclopentylene, cyclohexylene, bicyclo(1.1.1)pentylene, bicyclo(2.1.1)hexylene, azapyridine, pyrrolidinyl, or piperidinyl, each R L Each is independently selected from F, Cl, Br, hydroxyl, methyl, ethyl, propyl, or isopropyl; and when L2 is a bond and is surrounded by 0-2 R... L Substituted methylene, with 0-2 R L When substituted with ethylene, cyclobutylene, cyclopentylene, cyclohexylene, bicyclo(1.1.1)pentylene, bicyclo(2.1.1)hexylene, azapyridine, pyrrolidinyl, or piperidinyl, L1 is a bond; when L2 is CHR eWhen L1 is -CH2-, -CH2-CH2-, or -CH2-O-CH2-; R 4 It is hydrogen, methyl, ethyl, propyl, isopropyl, or related to R. e The connection forms -CH2- or -CH2-CH2-; R 2 It is C 1-5 Alkyl or R 2a C 1-5 The alkyl group is optionally surrounded by one or more groups, each independently selected from halogen, hydroxyl, cyano, oxo, -OC. 1-4 Alkyl, -OC 3-5 cycloalkyl, -L3-R 2b and R 2c Substituents in, where -OC 1-4 Alkyl and -OC 3-5 The cycloalkyl group is optionally substituted by one or more substituents, each independently selected from halogen, hydroxyl, methoxy, -NH(CH3), -N(CH3)2 or cyano; R 2b It is C 1-4 Alkyl, -N(R) 6 )2, each R 6 Each is independently selected from hydrogen and C. 1-3 Alkyl, C 3-5 cycloalkyl, C 1-4 Alkyl, C 1-3 Alkyl, C 3-5 cycloalkyl, R 2b Optionally substituted with one or more substituents, each independently selected from halogen, hydroxyl, methoxy, -NH(CH3), -N(CH3)2, and -CN; R 2c It is a 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl, optionally with R 5 Fusing or being R 5 Replace; each R 5 Each is independently selected from 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl, or 5-6 membered heteroaryl; L3 is a bond, -C(O)-, -SO2-, or -N(R 2d )C(O)-, R 2d It can be hydrogen, methyl, ethyl, propyl, or isopropyl; R 2a It is a 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl, optionally with R 5 Fusing or being R 5 replace; R 2a R 2c and R 5Optionally by one or more R 7 Replace, each R 7 Each is independently selected from halogens, OH, CN, and -OC. 1-4 Alkyl, -OC 3-5 cycloalkyl and -L4-R 7a , where -OC 1-4 Alkyl and -OC 3-5 The cycloalkyl group is optionally substituted by one or more substituents, each independently selected from halogen, OH, -OCH3, -NH(CH3), -N(CH3)2, or CN; L4 is a bond, -C(O)-, -SO2-, or -N(R 2d )C(O)-;R 7a It is C 1-4 Alkyl, C 3-5 cycloalkyl, -NH2, -NHC 1-3 Alkyl, -NHC 3-5 cycloalkyl or -N(C) 1-3 Alkyl)2, wherein C 1-4 Alkyl, C 1-3 Alkyl and C 3-5 The cycloalkyl group is optionally substituted by one or more substituents, each independently selected from halogen, -OH, methoxy, -NH(CH3), -N(CH3)2 or -CN; R 3 Selected from methyl, ethyl, propyl, isopropyl, or cyclopropyl; R 9 Selected from cyano, halogen, C 1-6 Alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl, 6-10 membered aryl, -S(=O)2-C 1-6 Alkyl, -S(=O)-C 1-6 Alkyl groups, -SH(=O)2, -SH(=O), -C(=O)-C 1-6 Alkyl or -CH (=O), R 9 Optionally by one or more R 9c Instead, each of the R 9c Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl, 6-10 membered aryl, -S(=O)2-C 1-6 Alkyl, -S(=O)-C 1-6 Alkyl groups, -SH(=O)2, -SH(=O), -C(=O)-C 1-6 Alkyl, -CH(=O), -C(=O)-NH-C 1-6Alkyl, -C(=O)-NH2, -NHCH(=O) or -NHC(=O)-C 1-6 alkyl.

[0005] In some embodiments, the compound of formula (II) has the structure of formula (I): (I); In ring A, X1, X2, X4, and X5 exist in any of the following cases: (1) X1 and X5 are both -CH2-, and X2 and X4 are each independently selected from the bond, -CH2-, or -CH2-CH2-; (2) One of X4 and X5 is CHR. a The other is -CH2-, -CH2-CH2-, or a bond; one of X1 and X2 is CHR. b The other is a -CH2-, -CH2-CH2-, or bond; and CHR a With CHR b Connecting them makes ring A a bridge ring, R a With R b The resulting functional groups are -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -CH2-O-CH2-, -(CH2)2-O-CH2-, -CH2-O-(CH2)2-, or -(CH2)2-O-(CH2)2-. Each R 1 Each is independently selected from F, Cl, Br, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methoxymethylene, ethoxymethylene, propoxymethylene, isopropoxymethylene, or cyclopropyl; n1 is 0, 1, 2, 3, 4, 5, 6, 7, or 8; X3 is either -N- or -CR 4 -; Ring B is a pyrazole ring, triazole ring, thiadiazole ring, or oxadiazole ring, and is surrounded by 0, 1, or 2 R groups. c Replace; each R c Each of the following groups is independently selected from F, Cl, Br, cyano, methyl, ethyl, propyl, and isopropyl, and methyl, ethyl, propyl, and isopropyl are optionally substituted by one or more substituents independently selected from F, Cl, Br, hydroxy, and methoxy. Ring C is a heteroaromatic ring; X6 is -CH- or -N-; one of X7 and X8 is -C- and the other is -N-; X9 is -NR. d -、-O- or -S-, R d It can be H, methyl, ethyl, propyl, or isopropyl; L2 is a bond, CHR e , by 0-2 R LSubstituted methylene, with 0-2 R L Substituted with ethylene, cyclobutylene, cyclopentylene, cyclohexylene, bicyclo(1.1.1)pentylene, bicyclo(2.1.1)hexylene, azapyridine, pyrrolidinyl, or piperidinyl, each R L Each is independently selected from F, Cl, Br, hydroxyl, methyl, ethyl, propyl, or isopropyl; and when L2 is a bond and is surrounded by 0-2 R... L Substituted methylene, with 0-2 R L When substituted with ethylene, cyclobutylene, cyclopentylene, cyclohexylene, bicyclo(1.1.1)pentylene, bicyclo(2.1.1)hexylene, azapyridine, pyrrolidinyl, or piperidinyl, L1 is a bond; when L2 is CHR e When L1 is -CH2-, -CH2-CH2-, or -CH2-O-CH2-; R 4 It is hydrogen, methyl, ethyl, propyl, isopropyl, or related to R. e The connection forms -CH2- or -CH2-CH2-; R 2 It is C 1-5 Alkyl or R 2a C 1-5 The alkyl group is optionally surrounded by one or more groups, each independently selected from halogen, hydroxyl, cyano, oxo, -OC. 1-4 Alkyl, -OC 3-5 cycloalkyl, -L3-R 2b and R 2c Substituents in, where -OC 1-4 Alkyl and -OC 3-5 The cycloalkyl group is optionally substituted by one or more substituents, each independently selected from halogen, hydroxyl, methoxy, -NH(CH3), -N(CH3)2 or cyano; R 2b It is C 1-4 Alkyl, -N(R) 6 )2, each R 6 Each is independently selected from hydrogen and C. 1-3 Alkyl, C 3-5 cycloalkyl, C 1-4 Alkyl, C 1-3 Alkyl, C 3-5 The cycloalkyl group is optionally substituted by one or more substituents, each independently selected from halogens, hydroxyl groups, methoxy groups, -NH(CH3), -N(CH3)2, and -CN; R 2c It is a 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl, optionally with R 5 Fusing or being R 5 Replace; each R 5Each is independently selected from 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl, or 5-6 membered heteroaryl; L3 is a bond, -C(O)-, -SO2-, or -N(R 2d )C(O)-, R 2d It can be hydrogen, methyl, ethyl, propyl, or isopropyl; R 2a It is a 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl, optionally with R 5 Fusing or being R 5 replace; R 2a R 2c and R 5 Optionally by one or more R 7 Replace, each R 7 Each is independently selected from halogens, OH, CN, and -OC. 1-4 Alkyl, -OC 3-5 cycloalkyl and -L4-R 7a , where -OC 1-4 Alkyl and -OC 3-5 The cycloalkyl group is optionally substituted by one or more substituents, each independently selected from halogen, OH, -OCH3, -NH(CH3), -N(CH3)2, or CN; L4 is a bond, -C(O)-, -SO2-, or -N(R 2d )C(O)-;R 7a It is C 1-4 Alkyl, C 3-5 cycloalkyl, -NH2, -NHC 1-3 Alkyl, -NHC 3-5 cycloalkyl or -N(C) 1-3 Alkyl)2, wherein C 1-4 Alkyl, C 1-3 Alkyl and C 3-5 The cycloalkyl group is optionally substituted by one or more substituents, each independently selected from halogen, -OH, methoxy, -NH(CH3), -N(CH3)2 or -CN; R 3 It is selected from methyl, ethyl, propyl, isopropyl, or cyclopropyl.

[0006] It is important to note that when R 4 With R e When X3, L1, and L2 are linked together to form a ring, this ring forms a spirocycle with ring A that shares a single carbon atom.

[0007] In some implementations, R 9 Selected from halogens, C 1-6Alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl, 6-10 membered aryl, -S(=O)2-C 1-6 Alkyl, -S(=O)-C 1-6 Alkyl groups, -SH(=O)2, -SH(=O), -C(=O)-C 1-6 Alkyl or -CH (=O), R 9 Optionally by one or more R 9c Instead, each of the R 9c Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl, 6-10 membered aryl, -S(=O)2-C 1-6 Alkyl, -S(=O)-C 1-6 Alkyl groups, -SH(=O)2, -SH(=O), -C(=O)-C 1-6 Alkyl, -CH(=O), -C(=O)-NH-C 1-6 Alkyl, -C(=O)-NH2, -NHCH(=O) or -NHC(=O)-C 1-6 alkyl; Preferably, R 9 Selected from F, Cl, Br, methyl, ethyl, propyl, isopropyl, oxecyclobutyl, thiocyclobutyl, cyclobutyl, oxecyclopentyl, thiocyclopentyl, cyclopentyl, -S(=O)2-CH3, -S(=O)2-CH2CH3, -S(=O)2-CH2CH2CH3, -S(=O)2-CH(CH3)2, -SH(=O)2, -SH(=O), -S(=O)-CH3, -S(=O)-CH2CH3, -S(=O)-CH2CH2CH3, -S(=O)-CH(CH3)2, -C(=O)-CH3, -C(=O)-CH2CH3, -C(=O)-CH2CH2CH3, -C(=O)-CH(CH3)2.

[0008] In some implementations, R 4 It is hydrogen or related to R e The connection forms -CH2- or -CH2-CH2-.

[0009] In some embodiments, L2 is a bond, cyclobutylene, azapyridine, or piperidinyl.

[0010] In some embodiments, the compound has a structure of any of the following formulas:

[0011] In some embodiments, the compound has a structure of any of the following formulas: .

[0012] In some implementations, each R 1 Each is independently selected from F, methyl, hydroxy or cyclopropyl; n1 is preferably 0, 1 or 2.

[0013] In some implementations, each R c Each of the groups is independently selected from methyl, ethyl, propyl, and isopropyl, and the methyl, ethyl, propyl, and isopropyl groups may be optionally substituted by one or more substituents independently selected from F, Cl, Br, hydroxy, and methoxy groups.

[0014] In some implementations, R c The ring B is preferably methyl, and the ring B is preferably surrounded by 0 or 1 R. c replace.

[0015] In some embodiments, ring B is a pyrazole ring or a triazole ring.

[0016] In some implementations, ring B is ; This represents the end connected to L2.

[0017] In some embodiments, the compound has the structure of formula (IA) or (IB):

[0018] In some implementations, X6 is -CH-.

[0019] In some implementations, R 2 It is C 1-5 Alkyl, C 1-5 The alkyl group is optionally selected by one, two, three, or four groups, each independently selected from halogen, hydroxyl, cyano, oxo, -OC. 1-4 Alkyl, -OC 3-5 cycloalkyl, -L3-R 2b and R 2c Substituents in, where -OC 1-4 Alkyl and -OC 3-5 The cycloalkyl group is optionally substituted by one or more substituents, each independently selected from halogen, hydroxyl, methoxy, -NH(CH3), -N(CH3)2 or cyano groups.

[0020] In some implementations, R 2 Selected from:

[0021] ; It is optionally selected by one, two, three or four independently selected from halogen, hydroxyl, cyano, oxo, -OC 1-4 Alkyl, -OC 3-5 cycloalkyl, -L3-R 2b and R 2c Substituents in, where -OC 1-4 Alkyl and -OC 3-5 The cycloalkyl group is optionally substituted with one or more substituents, each independently selected from halogen, hydroxyl, methoxy, -NH(CH3), -N(CH3)2 or cyano groups; preferably, it is optionally substituted with one or two substituents, each independently selected from hydroxyl, -CF3 or methoxy groups.

[0022] “ "The wavy line represents the location of the broken key, that is, the location where it connects to the adjacent structure."

[0023] In some implementations, R 2 Selected from: .

[0024] In some implementations, R 2c Selected from:

[0025]

[0026]

[0027]

[0028] ; R8 is selected from F, Cl, Br, hydroxyl, cyano, nitro, amino, cyano, methyl, ethyl, propyl, isopropyl, -NH(CH3), -N(CH3)2, -N(CH2CH3)2, -N(CH2CH3)(CH3), -CCl3, -CF3, -CHCl2, -CHF2, -CH2CCl3, -CH2CF3, -CH2CHCl2, -CH2CHF2, -CH2CH2CCl3, -CH2CH2CF3, -CH(CCl3)2, -CH(CF3)2, methoxy, ethoxy, propoxy, isopropoxy, methoxymethylene, ethoxymethylene, propoxymethylene, isopropoxymethylene, cyclopropylmethylene, cyclopropylethylidene, cyclopropylpropylpropene, morpholino, -C(O)NH2, -C(O)NH(CH2) 0-3CH3, thiazolyl, oxazolyl, isoxazolyl, cyclobutyl, azacyclobutyl; n2 is 0, 1, 2, 3, 4 or 5.

[0029] In the above ring structures, the bond breaking position is unrestricted; bonds can be broken at any permitted location for connecting atoms. The substitution position of R8 is also unrestricted; it can be substituted at any permitted location within the ring.

[0030] In some embodiments, the compound has a structure of formula (IA-1) or (IB-1):

[0031] In some implementations, R 3 It is a methyl group.

[0032] In some embodiments, the compound of the present invention is:

[0033]

[0034] .

[0035] This compound has the effect of selectively inhibiting FGFR3 and can be used to treat or prevent related diseases.

[0036] On the other hand, the present invention provides a pharmaceutical composition comprising the aforementioned compound, its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer or an acceptable salt of its deuterated derivative; and at least one pharmaceutically acceptable excipient. On the other hand, the present invention provides the use of the aforementioned compound, its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer or an acceptable salt of its deuterated derivative; or the use of the pharmaceutical composition of the present invention in the preparation of a medicament for treating or preventing diseases related to FGFR3.

[0037] Diseases associated with FGFR3 include, but are not limited to, systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, lethal dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans, Muenke syndrome, or cancer. Cancers include, but are not limited to, 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 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.

[0038] In another aspect, the present invention provides a method for treating or preventing a subject with an FGFR3-related disease, the method comprising administering to the subject a therapeutically effective amount of the aforementioned compound, its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer, or an acceptable salt of its deuterated derivative; or a pharmaceutical composition according to the present invention; wherein the FGFR3-related disease includes, but is not limited to, systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, lethal dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans, Muenke syndrome, or cancer. Cancers include, but are not limited to, 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 urinary tract cancer, urethral cancer, stomach 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.

[0039] In another aspect, the present invention provides the use of the aforementioned compound, its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer or an acceptable salt of its deuterated derivative; or the use of the pharmaceutical composition of the present invention in the treatment or prevention of diseases related to FGFR3.

[0040] definition Unless otherwise stated, the wavy line in the chemical structure " "" indicates the position where the group breaks a bond.

[0041] Unless otherwise stated, the term "halogen" as used interchangeably herein refers to fluorine, chlorine, bromine, or iodine. Preferred halogen groups include -F, -Cl, and -Br.

[0042] Unless otherwise stated, the term "alkyl" as used herein includes saturated monovalent hydrocarbon groups having a straight chain or branched chain. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, and 2-methylpentyl, etc. Similarly, C 1-6 C in alkyl 1-6 Alkyl groups are defined as groups that identify straight or branched chains having 1, 2, 3, 4, 5, or 6 carbon atoms. Common alkyl abbreviations include: Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3) or i-Bu(-CH2CH(CH3)2).

[0043] Unless otherwise stated, the term "haloalkyl" as used herein refers to the alkyl group described above that is substituted with one or more (1, 2, 3, 4, 5, or 6) halogens (-F, -Cl, or -Br). In some embodiments, the haloalkyl group is interchangeably -C 1-6 Halogenated alkyl or halogenated C 1-6 Alkyl, wherein -C 1-6 Halogenated alkyl or halogenated C 1-6 C in alkyl 1-6 This indicates that the alkyl group has a total of 1 to 6 carbon atoms. In some embodiments, -C 1-6 Haloalkyl is -C 1-3 Haloalkyl. In some embodiments, -C 1-3 The haloalkyl group is substituted with 1, 2, 3, 4, 5, or 6 -F groups (methyl, ethyl, propyl, or isopropyl); preferably, -C 1-3 The alkyl halotype is -CF3.

[0044] The term "alkylene" refers to a bifunctional group obtained by removing an additional hydrogen atom from an alkyl group as defined above. Examples include methylene (i.e., -CH2-), ethylene (i.e., -CH2-CH2- or -CH(CH3)-), and propylene (i.e., -CH2-CH2-CH2-, -CH(-CH2-CH3)-, or -CH2-CH(CH3)-).

[0045] The term "alkenyl" refers to a straight-chain or branched hydrocarbon group containing one or more double bonds, typically ranging in length from 2 to 20 carbon atoms. For example, "-C 2-6"Alkenyl" contains 2 to 6 carbon atoms. For example, alkenyl includes, but is not limited to, vinyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, hexenyl, heptenyl, octenyl, etc.

[0046] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group containing one or more triple bonds, typically ranging in length from 2 to 20 carbon atoms. For example, "-C 2-6 The "alkynyl" group contains 2 to 6 carbon atoms. For example, representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, 2-butynyl, pentynyl, hexynyl, hepynyl, octyynyl, etc.

[0047] The term "alkoxy" refers to an oxygen ether formed from the aforementioned alkyl groups, including but not limited to -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -CH2OCH3, and -CH2CH2OCH3.

[0048] Unless otherwise stated, the term "haloalkoxy" as used herein refers to the aforementioned alkoxy group substituted with one or more (1, 2, 3, 4, 5, or 6) halogens (-F, -Cl, or -Br). In some embodiments, the haloalkoxy group is interchangeably -C 1-6 Halogenated alkoxy or halogenated C 1-6 Alkoxy, where -C 1-6 Halogenated alkoxy or halogenated C 1-6 C in alkoxy 1-6 This indicates that the total number of carbon atoms in the alkoxy group is 1 to 6. In some embodiments, -C 1-6 The haloalkoxy group can be substituted with 1, 2, 3, 4, 5, or 6 -F, -Cl, or -Br (methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy, hexoxy); preferably -C 1-3 The haloalkoxy group is -OCF3.

[0049] Unless otherwise stated, the terms "aryl" or "aromatic ring" as used herein refer to an unsubstituted or substituted monocyclic or polycyclic aromatic ring system containing only a carbon ring atom. Preferred aryl groups are 6-10 membered aromatic ring systems, either monocyclic or bicyclic. Phenyl and naphthyl are preferred aryl groups.

[0050] Unless otherwise stated, the term "heterocyclic group" as used herein refers to a saturated or unsaturated group having a cyclic carbon atom and one or more cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, and optionally contains 0, 1, 2, or 3 double bonds, including monocyclic heterocyclic groups, bicyclic heterocyclic groups, bridged heterocyclic groups, fused-ring heterocyclic groups, and spirocyclic heterocyclic groups. In heterocyclic groups containing one or more nitrogen atoms, the bonding point may be a carbon or nitrogen atom, provided the valence allows. In some embodiments, a 4-8 membered heterocyclic group is preferred, which is a 4- to 8 membered non-aromatic ring system having a ring carbon atom and one or more ring heteroatoms; the heterocyclic group also includes a ring system in which the aforementioned heterocyclic ring is fused with one or more cycloalkyl groups, wherein the connection point is on the heterocyclic ring, or a ring system in which the aforementioned heterocyclic ring is fused with one or more aryl or heteroaryl groups, wherein the connection point is on the heterocyclic ring; and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclic ring system. The heterocyclic group also includes the aforementioned heterocyclic ring in which substituents on any non-adjacent carbon or nitrogen atom are linked to form a bridged ring, together forming a polycyclic heteroalkane sharing two or more carbon or nitrogen atoms. The heterocyclic group also includes the aforementioned heterocyclic ring in which substituents on the same carbon atom are linked to form a ring, together forming a polycyclic heteroalkane sharing one carbon atom. Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirropropyl, oxadiol, and thiopropane. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirrobutyl, oxacyclobutyl, and thiohexacyclobutyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to: pyrazolyl, dioxacyclopentyl, oxothiocyclopentyl, dithiocyclopentyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thiohexyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithiohexyl, and dioxalyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, hexahydrotriazine. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxeheptyl, and thioheptyl. Exemplary bridged ring heterocyclic groups include, but are not limited to, groups formed by the loss of a hydrogen atom from the following rings: , , , Exemplary fused-ring heterocyclic groups include, but are not limited to, groups formed after the loss of a hydrogen atom from the following rings: , , Exemplary spirocyclic heterocyclic groups include, but are not limited to, groups formed after the loss of a hydrogen atom from the following rings: , , , .

[0051] Unless otherwise stated, the term "heteroaryl" as used herein refers to an aromatic ring system containing carbon and at least one heteroatom. Heteroaryl groups or heterocyclic rings can be monocyclic or polycyclic, substituted or unsubstituted. Monocyclic heteroaryl groups may have 1 to 4 heteroatoms in their ring, while polycyclic heteroaryl groups may contain 1 to 10 heteroatoms. Polycyclic heteroaryl rings may contain fused rings, spirocyclic rings, or bridged rings; for example, bicyclic heteroaryl groups are polycyclic heteroaryl groups. Bicyclic heteroaryl rings may contain 8 to 12 member atoms. Monocyclic heteroaryl rings may contain 5 to 8 member atoms (carbon and heteroatoms). Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrroleyl, thiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyridazinyl, indolyl, azaindolyl, indolyl, benzopyrimidinyl, benzimidazolyl, benzofuranyl, benzothienyl, benzoisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, adenine, quinolinyl, or isoquinolinyl.

[0052] The term "carbocyclic group" refers to a substituted or unsubstituted monocyclic, bicyclic, bridged, fused, or spirocyclic non-aromatic ring system containing only carbon atoms. Preferably, the ring is tri- to ten-membered and is either fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, preferably one, two, or three, are included within this definition. Carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloynyl groups. Exemplary "cycloalkyl" groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups. Exemplary bridged carbocyclic groups include, but are not limited to, groups formed by the loss of a hydrogen atom from the following rings: , , , Etc. Exemplary fused-ring carbocyclic groups include, but are not limited to, groups formed by the loss of a hydrogen atom from the following rings: , , , , , Etc. Exemplary spirocyclic carbocyclic groups include, but are not limited to, groups formed by the loss of a hydrogen atom from the following rings: , , wait.

[0053] The term "one or more" refers to one or more. In some embodiments, "one or more" refers to 1, 2, 3, 4, 5, or 6. In some embodiments, "one or more" refers to 1, 2, 3, or 4. In some embodiments, "one or more" refers to 1, 2, or 3. In some embodiments, "one or more" refers to 1 or 2. In some embodiments, "one or more" refers to 1. In some embodiments, "one or more" refers to 2. In some embodiments, "one or more" refers to 3. In some embodiments, "one or more" refers to 4. In some embodiments, "one or more" refers to 5. In some embodiments, "one or more" refers to 6.

[0054] In this invention, when a ring is substituted by one or more substituents, this means that each substituent can independently substitute for each ring atom of the ring, including but not limited to ring carbon atoms or cyclic heteroatoms (e.g., nitrogen, sulfur, etc.). Furthermore, when the ring is a polycyclic ring, such as a fused ring, bridged ring, or spirocyclic ring, each substituent can independently substitute for each ring atom of the polycyclic ring.

[0055] The term "oxo" refers to the process by which oxygen and the carbon atoms bonded to it together form oxygen. Group.

[0056] In this invention, the term "composition" is intended to cover a product containing a specific amount of a specific ingredient, as well as any product produced directly or indirectly from a combination of specific amounts of the specific ingredients. Therefore, pharmaceutical compositions containing compounds of this invention as active ingredients, and methods for preparing the compounds of this invention, are also part of this invention. Furthermore, some crystalline forms of the compounds may exist in polymorphic forms, and are therefore intended to be included in this invention. Additionally, some compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also included within the scope of this invention.

[0057] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic alkali or acid. When the compounds of the present invention are acidic, their corresponding salts can be readily prepared from pharmaceutically acceptable non-toxic alkalis, including inorganic and organic bases. When the compounds of the present invention are basic, their corresponding salts can be readily prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Since the compounds of the present invention are intended for pharmaceutical use, they are preferably provided in substantially pure form, for example, at least 60% pure, more preferably at least 75% pure, and especially at least 98% pure (% by weight).

[0058] This invention includes prodrugs of the compounds of this invention within its scope. Typically, such prodrugs are functional derivatives of compounds that readily convert in vivo to the desired compound. Therefore, in the treatment methods of this invention, the term "administration" should include treating various conditions with a specifically disclosed compound or with a compound that may not be specifically disclosed but is converted in vivo to a specific compound after administration to a subject. Conventional methods for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of Prodrugs" (ed. 25 H. Bundgaard, Elsevier, 1985).

[0059] The definition of any substituent or variable at a specific position in a molecule is intended to be independent of the definition of substituents or variables at other positions in the molecule. It should be understood that those skilled in the art can select the substituents and substitution patterns on the compounds of the present invention to provide chemically stable compounds that can be readily synthesized using techniques known in the art and the methods set forth herein.

[0060] The compounds of this invention may contain one or more asymmetric centers, and therefore may exist in a variety of stereoisomeric forms, producing diastereomers and optical isomers. This invention includes all such possible diastereomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and their pharmaceutically acceptable salts. Isomers can be separated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis.

[0061] This invention includes all stereoisomers of compounds and their pharmaceutically acceptable salts. It also includes mixtures of stereoisomers and isolated specific stereoisomers. The products of these steps, either during the synthetic steps used to prepare these compounds or during the use of racemic or epimerization methods known to those skilled in the art, can be mixtures of stereoisomers.

[0062] As used in this invention, "stereoisomer" refers to isomers in a molecule that have the same order of interconnection of atoms or groups of atoms but different spatial arrangements. Stereoisomers include configurational isomers and conformational isomers. Configurational isomers further include geometrical isomers and optical isomers, while optical isomers mainly include enantiomers and diastereomers. This invention encompasses all possible stereoisomers of the compound.

[0063] Some of the compounds described herein can exist as trans-isomers, which are conformational stereoisomers that occur when rotation around the single bonds in the molecule is prevented or significantly slowed down due to steric interactions with other parts of the molecule. The compounds described herein include all trans-isomers, including pure, standalone trans-isomers, individually enriched trans-isomers, or mixtures of their respective nonspecificities. Separation of trans-isomers can be allowed if the rotational barrier around the single bond is sufficiently high and the interconversion between conformations is slow enough.

[0064] This invention aims to include all atomic isotopes present in the compounds of this invention. An isotope is an atom having the same atomic number but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include deuterium and tritium. Hydrogen isotopes can be represented as 1H (hydrogen), 2H (deuterium), and 3H (tritium). They are also commonly represented as D (deuterium) and T (tritium). In this invention, CD3 represents methyl, where all hydrogen atoms are deuterium. Carbon isotopes include 13C and 14C. Using suitable isotopically labeled reagents instead of unlabeled reagents, the isotopically labeled compounds of this invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described herein.

[0065] Unless otherwise stated, the term "deuterated derivative" as used herein refers to a compound having the same chemical structure as the reference compound, but in which one or more hydrogen atoms are replaced by deuterium atoms ("D"). It will be appreciated that variations in the abundance of natural isotopes can occur in synthetic compounds depending on the source of the chemical materials used in the synthesis. The concentration of naturally abundant stable hydrogen isotopes is small and insignificant compared to the degree of stable isotopic substitution in the deuterated derivatives described herein. Therefore, unless otherwise stated, when referring to the "deuterated derivatives" of the compounds disclosed herein, at least one hydrogen atom is replaced by deuterium at a level well above its natural isotopic abundance (typically about 0.015%).

[0066] When the compounds of the present invention have tautomers, the present invention includes any possible tautomers and their pharmaceutically acceptable salts and mixtures thereof, unless otherwise specifically stated.

[0067] The pharmaceutical compositions of the present invention comprise, as the active ingredient, a compound of the present invention (or a pharmaceutically acceptable salt thereof), a pharmaceutically acceptable carrier, and optionally other therapeutic ingredients or adjuvants. While the most suitable route of administration in any given case will depend on the specific host and the nature and severity of the condition (to which the active ingredient is being administered for treatment of the condition), the compositions include those suitable for oral, rectal, topical, and non-gastrointestinal (including subcutaneous, intramuscular, and intravenous) administration. The pharmaceutical compositions can conveniently be present in unit dosage forms and prepared by any method well known in the pharmaceutical field. In practice, the compounds of the present invention, or their prodrugs, or their metabolites, or pharmaceutically acceptable salts thereof, can be combined as active ingredients with drug carriers in close mixtures according to conventional pharmaceutical formulation techniques. Depending on the desired formulation form for the route of administration, for example, the carrier can be in various forms, such as oral or parenteral (including intravenous) administration routes. Therefore, the pharmaceutical compositions of the present invention can be present as discrete units suitable for oral administration, such as capsules, pouches, or tablets, each containing a predetermined amount of the active ingredient. Furthermore, the composition can exist as a powder, granules, solution, suspension in an aqueous liquid, non-aqueous liquid, oil-in-water emulsion, or water-in-oil emulsion. In addition to the common dosage forms described above, compounds represented by Formula I or pharmaceutically acceptable salts thereof can also be administered via controlled-release methods and / or delivery devices. The composition can be prepared by any pharmaceutical method. Typically, such methods involve the step of combining the active ingredient with a carrier constituting one or more essential components. Typically, the composition is prepared by uniformly and tightly mixing the active ingredient with a liquid carrier or a finely chopped solid carrier, or both. The product can then be conveniently shaped into the desired form.

[0068] Therefore, the pharmaceutical compositions of the present invention may include pharmaceutically acceptable carriers and compounds or pharmaceutically acceptable salts. Compounds of Formula I or their pharmaceutically acceptable salts may also be included in the pharmaceutical composition in combination with one or more other therapeutically active compounds.

[0069] The drug carrier used can be, for example, solid, liquid, or gas. Examples of solid carriers include lactose, gypsum powder, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen. In preparing compositions for oral dosage forms, any convenient drug medium can be used. For example, water, ethylene glycol, oil, alcohol, flavoring agents, preservatives, coloring agents, etc., can be used to form oral liquid dosage forms such as suspensions, syrups, and solutions; while carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants, etc., can be used to form oral solid dosage forms such as powders, capsules, and tablets. Tablets and capsules are preferred oral dosage units that use solid drug carriers due to ease of administration. Optionally, tablets can be coated using standard aqueous or non-aqueous techniques.

[0070] Tablets containing the compositions of the present invention can be prepared by compression or molding, and optionally contain one or more excipients or adjuvants. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as powder or granules, in a suitable machine, and optionally mixing it with a binder, lubricant, inert diluent, surfactant, or dispersant. Molded tablets can be prepared by molding a mixture of powdered compounds wetted with an inert liquid diluent in a suitable machine. Each tablet preferably contains about 0.05 mg to about 5 g of the active ingredient, and each capsule or pouch preferably contains about 0.05 mg to about 5 g of the active ingredient. For example, formulations for oral administration to humans may contain about 0.5 mg to about 5 g of the active ingredient mixed with a suitable and convenient amount of a carrier substance, which may comprise about 0.05% to about 95% of the total composition. Unit dosage forms typically contain from about 0.01 mg to about 2 g of the active ingredient, usually in doses of 0.01 mg, 0.02 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, 1000 mg, 1500 mg, or 2000 mg.

[0071] The pharmaceutical compositions of the present invention suitable for parenteral administration can be prepared as solutions or suspensions of the active compound in water. Suitable surfactants, such as hydroxypropyl cellulose, may be included. The dispersion can also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oil. Furthermore, preservatives may be included to prevent harmful microbial growth.

[0072] The pharmaceutical compositions of the present invention suitable for injection include sterile aqueous solutions or dispersions. Alternatively, the composition may be in the form of a sterile powder for the ad hoc preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively flowable for injection. The pharmaceutical composition must be stable under the conditions of manufacture and storage; therefore, it is best to preserve it to prevent contamination by microorganisms such as bacteria and fungi. The carrier may be, for example, a solvent or dispersion medium containing water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0073] The pharmaceutical compositions of the present invention can be in forms suitable for topical application, such as aerosols, creams, ointments, lotions, powders, etc. Furthermore, the compositions can be in forms suitable for transdermal devices. These formulations can be prepared using conventional processing methods, utilizing the compounds provided by the present invention or their pharmaceutically acceptable salts. For example, creams or ointments can be prepared by mixing a hydrophilic material and water with the compound to produce a cream or ointment with the desired consistency.

[0074] The pharmaceutical compositions of the present invention can be in a form suitable for rectal administration, wherein the carrier is solid. Preferably, the mixture is formed into a unit-dose suppository. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently formed by first mixing the composition with a softened or melted carrier, then cooling and molding it in a mold.

[0075] In addition to the carrier components described above, the pharmaceutical formulations may suitably include one or more other carrier components, such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants), etc. Furthermore, other adjuvants may be included to make the formulation isotonic with the blood of the intended recipient. Compositions containing the compound or its pharmaceutically acceptable salt may also be prepared in powder or liquid concentrate form.

[0076] Typically, dosage levels of approximately 0.001 mg / kg to approximately 150 mg / kg body weight per day are used to treat the aforementioned conditions, or approximately 0.05 mg to approximately 7 g per patient per day. For example, administering approximately 0.001 to 50 mg of the compound per kilogram of body weight per day, or approximately 0.05 mg to approximately 3.5 g of the compound per kilogram of body weight per day, can effectively treat or prevent diseases associated with FGFR3, such as bladder cancer, lung cancer, stomach cancer, urothelial carcinoma, bile duct cancer, skeletal dysplasia, breast cancer, liver cancer, ovarian cancer, and cervical cancer.

[0077] However, it should be understood that the specific dosage level for any particular patient will depend on a variety of factors, including age, weight, general health condition, sex, diet, timing of administration, route of administration, excretion rate, combination of drugs, and the severity of the specific disease being treated.

[0078] Unless the context otherwise indicates, when a value is expressed as “approximately” X or “about X”, the specified value of X shall be understood to be accurate to ±10%, preferably ±5%, ±2%.

[0079] These and other aspects will become apparent from the following written description of the invention. Detailed Implementation

[0080] The compounds of this invention can be synthesized from commercially available reagents using the synthetic methods and reaction schemes described herein. The examples outlining specific synthetic routes are intended to provide guidance to synthetic chemists in the art, who will readily understand that solvents, concentrations, reagents, protecting groups, the order of synthetic steps, time, temperature, etc., can be modified as needed within the technical skill and judgment of those skilled in the art.

[0081] Example The following examples are provided to better illustrate the invention. All temperatures are in degrees Celsius. Abbreviations from the following table are used in the examples:

[0082] Example 1

[0083]

[0084]

[0085] Will N -Boc-4-hydroxypiperidine (2 g, 1 eq) and PPh3 (3.12 g, 1.2 eq) were dissolved in THF (20 mL). The reaction system was cooled to 0 °C under N2 atmosphere. Then, DIAD (2.41 g, 1.2 eq) and DPPA (3.28 g, 1.2 eq) were added to the reaction system. After returning to room temperature, the reaction was carried out for about 12 h. After the reaction was complete, 15 mL of water was added to quench the reaction and the mixture was extracted with EtOAc (15 mL * 3). The organic phases were combined and dried. After concentration under reduced pressure, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 1-1, a yellow oily liquid (860 mg, 38%).

[0086] Compound 1-1 (21.25 g, 1 eq) was dissolved in DMSO (200 mL), K2CO3 (38.92 g, 3 e.q.) was added, and N2 was introduced. The reaction was carried out at 80 °C for about 6 h. After the reaction was completed, 200 mL of EtOAc and 100 mL of water were added, and the DMSO was washed away with saturated brine (200 mL * 3). The organic layers were combined and dried. The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound 1-2, a yellow oily liquid (8.5 g, 27%). LCMS: m / z = 339.3 [M+H] + .

[0087] Compounds 1-2 were dissolved in water (100 mL), followed by the addition of KOH (2.81 g, 2 eq). The mixture was stirred at 50 °C for 3 h. After the reaction was complete, the pH of the mixture was adjusted to 4 with 2 M HCl aqueous solution. The mixture was then extracted with EtOAc (100 mL * 3). The organic phases were combined and dried over anhydrous sodium sulfate. After concentration under reduced pressure, compounds 1-3 were given as a yellow solid (7.0 g, 90%). LCMS: m / z = 255.3 [M+H-56] + .

[0088] Compounds 1-3 (3.55 g, 1 eq), KOH (0.77 g, 1.2 eq), and water (60 mL) were added to a three-necked flask. Liquid bromine (2.2 g, 1.2 eq) was slowly added under a nitrogen atmosphere. The reaction system gradually became a viscous oil. After stirring at room temperature for about 3 h, the mixture was extracted with DCM (30 mL * 3). The organic phases were combined, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give compounds 1-4 as a brown solid (3.2 g, 97%). LCMS: m / z = 289.0 [M+H] + .

[0089] 2-Bromo-5-fluoropyridine (2.4 g, 1 eq) was dissolved in toluene (20 mL). The system was cooled to 0 °C under a nitrogen atmosphere. A THF solution of isopropyl magnesium chloride (2 M, 10.23 mL, 1.5 eq) was slowly added dropwise. After the addition was complete, the mixture was stirred at 0 °C for 40 min. Then, tert-butyldimethylsiloxane acetaldehyde (2.56 g, 1.5 eq) was slowly added dropwise, and the mixture was stirred at 0 °C for 2 h. After the reaction was complete, the mixture was quenched with 10 mL of methanol. The solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compounds 1-5 as a yellow liquid (1.7 g, 46%). LCMS: m / z = 272.1 [M+H] + .

[0090] 6-bromo-4-methoxypyrazole[1,5- a Pyridine (2.27 g, 1 eq), B2Pin2 (3.047 g, 1.2 eq), KOAc (2.94 g, 3 eq), and Pd(dppf)Cl2 (292 mg, 0.04 eq) were added to a three-necked flask. Under a nitrogen atmosphere, ultra-dry 1,4-dioxane (60 mL) was added, and the reaction was carried out at 80 °C for approximately 8 h. After returning to room temperature, the residue was removed by filtration. The filtrate was concentrated under reduced pressure to obtain crude solid compounds 1-6 (7 g, 99%). LCMS: m / z = 275.1 [M+H] + .

[0091] Crude compounds 1-6 (3.08 g, 1.1 eq), compounds 1-4 (1.38 g, 1 eq), K3PO4 (1.66 g, 3 eq), and Pd(dppf)Cl2 (293 mg, 0.1 eq) were added to a three-necked flask. Ultra-dry 1,4-dioxane (40 mL) was injected under a N2 atmosphere, and the reaction was carried out at 90 °C for approximately 1.5 h. After concentration under reduced pressure, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compounds 1-7 as a yellow solid (1.26 g, 76%). LCMS: m / z = 413.2 [M+H] + .

[0092] Compound 1-7 (1.26 g, 1 eq), sodium ethanethiol (2.57 g, 10 eq), and 20 mL of DMF were added to a reaction flask. The reaction system was incubated at 120 °C for 24 h. After the reaction was completed, the mixture was purified by C18 column chromatography (mobile phase: [water-acetonitrile]) to give compound 1-8 as a brown solid (910 mg, 75%). LCMS: m / z = 399.2 [M+H] + .

[0093] PPh3 (1.64 g, 3 eq) was dissolved in THF (15 mL) under N2 atmosphere. The reaction system was cooled to 0 °C, and DIAD (1.18 g, 2.8 eq) was added. After stirring for 30 min, compounds 1-8 (910 mg) were dissolved in 5 mL THF. The dissolved solution was injected into the THF solution of PPh3, followed by the addition of compounds 1-5 (848 mg, 1.5 eq). After returning to room temperature, the mixture was stirred for 2 h. After the reaction was complete, the solution was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / MeOH = 40 / 1) to give compounds 1-9 as a white solid (900 mg, 66%). LCMS: m / z = 652.5 [M+H] + .

[0094] Compounds 1-9 (273 mg, 1 eq) were dissolved in MeOH (10 mL), and (MeSe)₂ (39 mg, 0.5 eq) were added. The mixture was exposed to air under a blue lamp (300 W) and stirred at room temperature for 48 h. After the reaction was complete, the solution was concentrated under reduced pressure and purified by silica gel column chromatography (MeOH / DCM = 0%–10%) to give compound 1-10 (270 mg, 86.4%). LCMS: m / z = 764.4 [M+H] + .

[0095] Compound 1-10 (270 mg, 1 eq) was dissolved in 5 mL of DCM solution, and a dioxane solution of HCl (4 M, 2.5 mL) was added dropwise at room temperature. After reacting for 1 h at room temperature, the solution was concentrated under reduced pressure and purified by silica gel column chromatography (MeOH / DCM = 0%–10%) to give compound 1-11 as a white solid (85 mg, 44.2%). LCMS: m / z = 532.2 [M+H] + .

[0096] Compound 1-11 (85 mg, 1 eq) and BrCN (17 mg, 1 eq) were added to DCM (4 mL) under N2 atmosphere, followed by the injection of DIPEA (62 mg, 3 eq). After reacting at room temperature for 2 h, the mixture was concentrated under reduced pressure and purified by prep-HPLC to obtain racemic compound 1 (31.72 mg, 35.6%). This was then purified using a preparative chiral HPLC column under the following conditions: chiral column type CHIRAL PAK IF, 2*25 cm, 5 μm; elution was performed using MeOH:DCM in MTBE (0.5% 2 mM NH3-MeOH) (mobile phase A) to obtain isomer 1A, with a retention time of 1.102 min (12.69 mg), 99.42% ee, and LCMS: m / z = 557.2 [M+H]. + The retention time of isomer 1B was 1.972 min (10.68 mg), with 99.94% ee, LCMS: m / z = 557.2 [M+H] + .

[0097] 1 H NMR (400 MHz, DMSO) δ 8.60 (d, J = 2.8 Hz, 1H), 8.43 (s, 1H), 7.95(s, 1H), 7.77 (td, J = 8.8, 2.9 Hz, 1H), 7.71 – 7.62 (m, 1H), 6.80 (s, 1H), 5.62 (t, J = 5.2 Hz, 1H), 5.09 (t, 1H), 4.64 – 4.56 (m, 1H), 3.98 – 3.95 (m,2H), 3.56 (d, J = 13.0 Hz, 2H), 3.29 – 3.23 (m, 2H), 2.38 (d, 6H), 2.14 (ddd, J =15.5, 12.4, 4.1 Hz, 2H), 2.04 (d, J = 11.0 Hz, 2H). Example 2

[0098] Product 1 (56 mg, 1 eq) was dissolved in THF (3 mL), the system was cooled to 0 °C, N2 was introduced, and NaH (60%, 5 mg, 1.2 eq) was added. After reacting at 0 °C for 30 min, CH3I (17 mg, 1.2 eq) was added, and the reaction was allowed to return to room temperature for 2 h. The reaction was then quenched with water, and the product 2 (27.1 mg) was obtained by high performance liquid chromatography (column: Phenomenex C18 packing; mobile phase: [water-acetonitrile]). 1 HNMR (400 MHz, DMSO- d 6): d 8.62 (d, J = 2.8Hz, 1H), 8.45 (s, 1H), 7.96 (s, 1H), 7.78 (td, J = 8.8, 2.8 Hz, 1H), 7.66 (dd, J = 8.8, 4.4 Hz, 1H), 6.79 (s, 1H), 5.81 (dd, J = 6.4, 3.6 Hz, 1H), 4.60 (tt, J =10.8, 4.0 Hz, 1H), 3.96 (dd, J = 10.8, 6.4 Hz, 1H), 3.88 (dd, J = 10.8, 3.6 Hz,1H),3.58 – 3.55 (m, 2H), 3.38 (s, 3H), 3.29 – 3.25 (m, 2H), 2.39 (s, 3H),2.37 (s, 3H), 2.12 (td, J = 12.4, 4.0 Hz, 2H), 2.06 – 2.02 (m, 2H). LCMS: m / z =571.18 [M+H] + . Example 3

[0099] 1-(5-fluoropyridin-2-yl)acetone (2 g, 1 eq) was dissolved in THF (3 mL). The system was cooled to 0 °C, N2 was introduced, and NaBH4 (1.08 g, 2 eq) was added. After restoring to room temperature for 3 h, the reaction was quenched with water, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to obtain 3-1 (730 mg). LCMS: m / z = 142.1 [M+H] + . PPh3 (2.67 g, 3 eq) was dissolved in THF (40 mL) under N2 atmosphere. DIAD (2.06 g, 3 eq) was added at 0 °C, and the mixture was stirred for 30 min. Then, 3-2 (1350 mg, 1.0 eq) and 3-1 (717 mg, 1.5 eq) were added. After refilling with N2 and restoring to room temperature, the mixture was stirred for 16 h to complete the reaction. The solution was concentrated under reduced pressure and purified by C18 column chromatography (mobile phase: [water-acetonitrile]) to obtain 3-3 (1.14 g). LCMS: m / z = 522.4 [M+H] + . 3-3 (1.14 g, 1 eq) was dissolved in a dioxane solution of HCl (4 M, 15 mL). The reaction was allowed to proceed for 2 h at room temperature, followed by concentration under reduced pressure to remove the solvent. The solution was then redissolved with MeOH (15 mL), and the mixture was adjusted to alkalinity by dropwise addition of ammonia. The solution was then concentrated under reduced pressure to obtain a white solid of 3-4 (920 mg). LCMS: m / z = 422.0 [M+H] + . 3-4 (307 mg, 1 eq) and BrCN (93 mg, 1.2 eq) were added to DCM (5 mL) under N2 atmosphere, followed by the injection of DIEA (0.28 g, 3 eq). After reacting at room temperature for 2 h, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to obtain crude 3-5 (350 mg). LCMS: m / z = 452.33 [M+H] + . Under a nitrogen atmosphere, 3-5 (350 mg, 1 eq), dimethyl diselenyl ether (556 mg, 4 eq), and I2 (751 mg, 4 eq) were added to a mixed solvent of THF (10 mL) and DCE (7 mL). After reacting at room temperature for 2 h, the mixture was concentrated under reduced pressure and then separated by high performance liquid chromatography (HPLC) (column: Phenomenex C18 packing; mobile phase: [water-acetonitrile]) to obtain the desired product 3 (16.5 mg). 1 HNMR (400 MHz, DMSO-d 6): d 8.59 (d, J = 3.2 Hz, 1H), 8.44 (d, J = 0.4 Hz, 1H), 7.95 (s, 1H), 7.79 (td, J = 8.8, 3.2 Hz, 1H), 7.67 (dd, J = 8.8,4.4 Hz, 1H), 6.77 (s, 1H), 5.78 (q, J = 6.0 Hz, 1H), 4.61 (tt, J = 11.2, 4.4 Hz,1H), 3.58 – 3.55 (m, 2H), 3.28 (dd, J = 15.6, 3.2 Hz, 2H), 2.38 (s, 3H), 2.37(s, 3H), 2.21 – 2.08 (m, 2H), 2.05 (dd, J = 12.8, 2.8 Hz, 2H), 1.72 (d, J = 6.4Hz, 3H). LCMS: m / z = 541.06 [M+H] + . Example 4

[0100] 4-1 (542 mg, 1 eq) was dissolved in THF (10 mL), the system was cooled to 0 °C, N2 was introduced, and NaH (60%, 96 mg, 1.2 eq) was added. The reaction was carried out at 0 °C for 30 min, then CH3I (341 mg, 1.2 eq) was added, and the reaction was allowed to return to room temperature for 2 h. The reaction was quenched with water, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EtOAc = 5 / 1) to obtain crude 4-2 (580 mg). LCMS: m / z = 286.3 [M+H] + . 4-2 (580 mg, 1 eq) was dissolved in a dioxane solution of HCl (4 M, 10 mL). After reacting at room temperature for 2 h, the solvent was removed by concentration under reduced pressure. The solution was then redissolved with MeOH (15 mL), and the system was adjusted to alkalinity by dropwise addition of ammonia. The solution was then concentrated under reduced pressure and purified by silica gel column chromatography (PE / EtOAc = 1 / 1) to obtain 4-3 as a yellow oily solid (235 mg). LCMS: m / z = 172.1 [M+H] +. PPh3 (0.786 g, 3 eq) was dissolved in THF (40 mL) under N2 atmosphere. DIAD (0.6 g, 3 eq) was added at 0 °C, and the mixture was stirred for 30 min. Then, 4-5 (398 mg, 1.0 eq) and 4-3 (210 mg, 1.5 eq) were added. After refilling with N2 and restoring to room temperature, the reaction was stirred for 2 h until the reaction was complete. The mixture was concentrated under reduced pressure and purified by C18 column chromatography (mobile phase: [water-acetonitrile]) to obtain 4-6 (270 mg). LCMS: m / z = 552.2 [M+H] + . 4-6 (270 mg, 1 eq) was dissolved in a dioxane solution of HCl (4 M, 10 mL). After reacting at room temperature for 2 h, the solvent was removed by concentration under reduced pressure. The solution was then redissolved with MeOH (15 mL), and the system was adjusted to alkalinity by dropwise addition of ammonia. The solution was then concentrated under reduced pressure to give 4-7 as a white solid (221 mg). LCMS: m / z = 452.33 [M+H] + . Under a nitrogen atmosphere, 4-7 (221 mg, 1 eq) and BrCN (62 mg, 1.2 eq) were added to DCM (5 mL), followed by the injection of DIEA (190 mg, 3 eq). After reacting at room temperature for 2 h, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to obtain crude 4-8 (80 mg). LCMS: m / z = 477.4 [M+H] + . Under a nitrogen atmosphere, 4-8 (70 mg, 1 eq), dimethyl diselenyl ether (111 mg, 4 eq), and I2 (150 mg, 4 eq) were added to a mixed solvent of THF (2 mL) and DCE (1.5 mL). After reacting at room temperature for 2 h, the mixture was concentrated under reduced pressure and then separated by high performance liquid chromatography (HPLC) (column: Phenomenex C18 packing; mobile phase: [water-acetonitrile]) to obtain the desired product 4 (18.4 mg). 1 HNMR (400 MHz, DMSO- d 6): d 8.60 (d, J = 2.0 Hz, 1H), 8.47 (s,1H), 7.90 (s, 1H), 7.81 (td, J = 8.4, 2.4 Hz, 1H), 7.73 (dd, J= 8.4, 4.4 Hz,1H), 6.96 (s, 1H), 4.83 – 4.81 (m, 1H), 4.69 – 4.61 (m, 1H), 4.51 – 4.50 (m,2H), 3.58 (d, J = 12.8 Hz, 2H), 3.30 (t, J LCMS: m / z = 570.95 [M+H] + . Example 5

[0101] 5-1 (600 mg, 1 eq), 3-oxetane (205 mg, 2 eq), and CH3COOH (17 mg, 0.2 eq) were added to THF (10 mL) under N2 atmosphere. The mixture was then purged with N2 and reacted at room temperature for 30 min. NaBH3CN (179 mg, 2 eq) was added, and the mixture was stirred at room temperature for another 3 h. The reaction was then quenched with water, concentrated under reduced pressure, and purified by C18 column chromatography (mobile phase: [water-acetonitrile]) to obtain 5-2 (300 mg). LCMS: m / z = 478.3 [M+H] + . 5-2 (270 mg, 1 eq), dimethyl diselenyl ether (425 mg, 4 eq), and I2 (573 mg, 4 eq) were added to a mixed solvent of THF (6 mL) and DCE (4 mL) under N2 atmosphere. After reacting at room temperature for 2 h, the mixture was concentrated under reduced pressure and then separated by high performance liquid chromatography (HPLC) (column: Phenomenex C18 packing; mobile phase: [water-acetonitrile]) to obtain the desired product 5 (15.2 mg). 1 HNMR (400 MHz, DMSO- d 6): d 8.60 (d, J = 2.8 Hz, 1H), 8.43 (s,1H), 7.95 (s, 1H), 7.79 (td, J = 8.8, 2.8 Hz, 1H), 7.68 (dd, J= 8.8, 4.4 Hz,1H), 6.77 (s, 1H), 5.78 (q, J = 6.0 Hz, 1H), 4.58 – 4.40 (m, 5H), 3.51 – 3.47(m, 1H), 2.84 (s, 2H), 2.38 (s, 3H), 2.37 (s, 3H), 2.10 – 2.00 (m, 6H), 1.72(d, J = 6.4 Hz, 3H). LCMS: m / z = 572.30 [M+H] + . Example 6

[0102] PPh3 (4.25 g, 3 eq) was dissolved in THF (80 mL) under N2 atmosphere. DIAD (3.28 g, 3 eq) was added at 0 °C, and the mixture was stirred for 30 min. Then, 6-1 (2.15 g, 1.0 eq) and 2-(1-hydroxyethyl)pyridine (1 g, 1.5 eq) were added. The mixture was then re-purged with N2 and stirred at room temperature for 2 h until the reaction was complete. The solution was concentrated under reduced pressure and purified by C18 column chromatography (mobile phase: [water-acetonitrile]) to obtain 6-2 (2.06 g). LCMS: m / z = 504.4 [M+H] + . 6-2 (2.06 g, 1 eq) was dissolved in a dioxane solution of HCl (4 M, 15 mL). The reaction was allowed to proceed for 2 h at room temperature, followed by concentration under reduced pressure to remove the solvent. The solution was then redissolved with MeOH (15 mL), and the mixture was adjusted to alkalinity by dropwise addition of ammonia. The solution was then concentrated under reduced pressure to obtain 6-3 as a white solid (1.65 g). LCMS: m / z = 403.3 [M+H] + . 6-3 (1.65 g, 1 eq), 3-oxetane (590 mg, 2 eq), and CH3COOH (49 mg, 0.2 eq) were added to THF (40 mL) under N2 atmosphere. The mixture was then purged with N2 and reacted at room temperature for 30 min. NaBH3CN (515 mg, 2 eq) was added, and the mixture was stirred at room temperature for another 3 h. The reaction was then quenched with water, concentrated under reduced pressure, and purified by C18 column chromatography (mobile phase: [water-acetonitrile]) to obtain 6-4 (920 mg). LCMS: m / z = 460.4 [M+H] + . Under a nitrogen atmosphere, 6-4 (300 mg, 1 eq), dimethyl diselenyl ether (491 mg, 4 eq), and I2 (662 mg, 4 eq) were added to a mixed solvent of THF (6 mL) and DCE (4 mL). After reacting at room temperature for 2 h, the mixture was concentrated under reduced pressure and then separated by high performance liquid chromatography (HPLC) (column: Phenomenex C18 packing; mobile phase: [water-acetonitrile]) to obtain the desired product 6 (155.3 mg). 1 HNMR (400 MHz, DMSO- d 6): d 8.60 – 8.58 (m, 1H), 8.42 (d, J =0.4 Hz, 1H), 7.95 (s, 1H), 7.84 (td, J = 7.6, 1.6 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.33 (ddd, J = 7.2, 4.8, 0.8 Hz, 1H), 6.75 (s, 1H), 5.72 (q, J = 6.4 Hz,1H), 4.58 – 4.38 (m, 5H), 3.47 (s, 1H), 2.85 – 2.83 (m, 2H), 2.38 (s, 3H), 2.35 (s, 3H), 2.12 – 2.01 (m, 6H), 1.73 (d, J = 6.4 Hz, 3H). LCMS: m / z = 554.25[M+H] + . Example 7

[0103] 6-bromo-4-methoxypyrazole[1,5- a Pyridine (2.27 g, 1 eq), B2Pin2 (3.047 g, 1.2 eq), KOAc (2.94 g, 3 eq), and Pd(dppf)Cl2 (292 mg, 0.04 eq) were added to a three-necked flask. Ultra-dry dioxane (60 mL) was injected under a N2 atmosphere. The reaction was carried out at 80 °C for 8 h. After filtration to remove the residue, the filtrate was concentrated under reduced pressure and then unpurified to obtain crude solid 7-1 (39% purity, 7 g). LCMS: m / z = 275.1 [M+H] + . Crude product 7-1 (39% purity, 3.08 g, 1.1 eq), 7-2 (1.38 g, 1 eq), K2CO3 (1.66 g, 3 eq), and Pd(dppf)Cl2 (293 mg, 0.1 eq) were added to a three-necked flask. Ultra-dry dioxane (40 mL) was injected under N2 atmosphere. The reaction was stopped at 90 °C for 1.5 h. After concentration under reduced pressure, the product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain 7-3 as a yellow solid (1.26 g). LCMS: m / z = 413.2 [M+H] + . 7-3 (1.26 g, 1 eq), sodium ethanethiol (2.57 g, 10 eq), and 20 mL of DMF were added to the reaction flask. The reaction was carried out at 120 °C for 24 h. The solution was purified by C18 column chromatography (mobile phase: [water-acetonitrile]) to obtain 7-4 as a brown solid (910 mg). LCMS: m / z = 399.2 [M+H] + . PPh3 (1.64 g, 3 eq) was dissolved in THF (15 mL) under N2 atmosphere. DIAD (1.18 g, 2.8 eq) was added at 0 °C, and the mixture was stirred for 30 min. 7-4 was dissolved in 5 mL THF, and the solution was injected into the THF solution of PPh3. 7-5 (848 mg, 1.5 eq) was added, and the mixture was stirred at room temperature for 2 h. After the reaction was complete, the solution was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / MeOH = 40 / 1) to obtain 7-6 as a white solid (900 mg). LCMS: m / z = 652.5 [M+H] + . 7-6 (500 mg, 1 eq) was dissolved in a dioxane solution of HCl (4 M, 12 mL). After reacting at room temperature for 2 h, the solvent was removed by concentration under reduced pressure. The solution was then redissolved with MeOH (15 mL), and the system was adjusted to alkalinity by dropwise addition of ammonia. The solution was then concentrated under reduced pressure to obtain a white solid of 7-7 (335 mg). LCMS: m / z = 438.3 [M+H] + . 7-7 (335 mg, 1 eq), 3-oxetane (111 mg, 2 eq), and CH3COOH (9 mg, 0.2 eq) were added to THF (12 mL) under N2 atmosphere. The mixture was then purged with N2 and reacted at room temperature for 30 min. NaBH3CN (97 mg, 2 eq) was added, and the mixture was stirred at room temperature for another 3 h. The reaction was then quenched with water, concentrated under reduced pressure, and purified by C18 column chromatography (mobile phase: [water-acetonitrile]) to obtain 7-8 (120 mg). LCMS: m / z = 494.3 [M+H] + . Under a nitrogen atmosphere, 7-8 (90 mg, 1 eq), dimethyl diselenyl ether (132 mg, 4 eq), and I2 (183 mg, 4 eq) were added to a mixed solvent of THF (1.5 mL) and DCE (1 mL). After reacting at room temperature for 2 h, the mixture was concentrated under reduced pressure and then separated by high performance liquid chromatography (HPLC) (column: Phenomenex C18 packing; mobile phase: [water-acetonitrile]) to obtain the desired product 7 (21.7 mg). 1 HNMR (400 MHz, DMSO- d 6): d 8.61 (d, J = 3.2 Hz, 1H), 8.43 (d, J = 0.8 Hz, 1H), 7.95 (s, 1H), 7.78 (td, J = 8.8, 2.8 Hz, 1H), 7.68 (dd, J = 8.8,4.4 Hz, 1H), 6.81 (s, 1H), 5.63 (t, J = 5.2 Hz, 1H), 5.10 (t, J = 5.6 Hz, 1H), 4.57 (t, J = 6.8 Hz, 2H), 4.47 (t, J = 6.0 Hz, 2H), 4.43 – 4.36 (m, 1H), 3.98 –3.95 (m, 2H), 3.49 – 3.46 (m, 1H), 2.86 – 2.84 (m, 2H), 2.39 (s, 6H), 2.14 –1.99 (m, 6H).LCMS: m / z = 588.42 [M+H] + . Example 8

[0104] 8-1 (66 mg, 1 eq), 3-oxetane (212 mg, 2 eq), and CH3COOH (18 mg, 0.2 eq) were added to THF (10 mL) under N2 atmosphere. The mixture was then purged with N2 and reacted at room temperature for 30 min. NaBH3CN (185 mg, 2 eq) was added, and the mixture was stirred at room temperature for another 3 h. The reaction was then quenched with water, concentrated under reduced pressure, and purified by C18 column chromatography (mobile phase: [water-acetonitrile]) to obtain 8-2 (273 mg). LCMS: m / z = 508.4 [M+H] + . Under a nitrogen atmosphere, 8-2 (253 mg, 1 eq), dimethyl diselenyl ether (376 mg, 4 eq), and I2 (507 mg, 4 eq) were added to a mixed solvent of THF (6 mL) and DCE (4 mL). After reacting at room temperature for 2 h, the mixture was concentrated under reduced pressure and then separated by high performance liquid chromatography (HPLC) (column: Phenomenex C18 packing; mobile phase: [water-acetonitrile]) to obtain the desired product 8 (57.9 mg). 1 HNMR (400 MHz, DMSO- d 6): d 8.60 (d, J = 3.2 Hz, 1H), 8.46 (d, J =0.8 Hz, 1H), 7.90 (s, 1H), 7.82 (td, J = 8.8, 3.2 Hz, 1H), 7.73 (dd, J = 8.8, 4.8Hz, 1H), 6.96 (d, J = 0.4 Hz, 1H), 4.82 (dd, J = 5.6, 4.4 Hz, 1H), 4.59 – 4.47(m, 7H), 3.49 (s, 1H), 3.33 (s, 3H), 2.86 (s, 2H), 2.51 (s, 3H), 2.24 (s,3H), 2.18 – 1.98 (m, 6H). LCMS: m / z = 602.34 [M+H] + . Example 9

[0105] 9-1 (1.6 g, 1 eq) was dissolved in DCM (15 mL), and a TABF-THF solution (1 M, 4.92 mL) was added. The mixture was reacted at room temperature for 3 h, then concentrated under reduced pressure to remove the solvent. The solution was then redissolved in MeOH (10 mL), and purified by C18 column chromatography (mobile phase: [water-acetonitrile]) to obtain 9-2 (580 mg). LCMS: m / z = 538.4 [M+H] + . Dissolve 9-2 (560 mg, 1 eq) in THF (7 mL), cool the system to 0 °C, introduce N2, add NaH (60%, 50 mg, 1.2 eq), react at 0 °C for 30 min, then add CH3I (177 mg, 1.2 eq), restore to room temperature for 2 h, quench with water, concentrate under reduced pressure to obtain crude 9-3 (573 mg). LCMS: m / z = 552.4 [M+H] + . 9-3 (573 mg, 1 eq) was dissolved in a dioxane solution of HCl (4 M, 5 mL). The reaction was allowed to proceed for 2 h at room temperature, followed by concentration under reduced pressure to remove the solvent. The solution was then redissolved with MeOH (15 mL), and the mixture was adjusted to alkalinity by dropwise addition of ammonia. The solution was then concentrated under reduced pressure to obtain a white solid of 9-4 (420 mg). LCMS: m / z = 452.3 [M+H] + . 9-4 (420 mg, 1 eq), 3-oxetane (138 mg, 2 eq), and CH3COOH (11 mg, 0.2 eq) were added to THF (5 mL) under N2 atmosphere. The mixture was then purged with N2 and reacted at room temperature for 30 min. NaBH3CN (117 mg, 2 eq) was added, and the mixture was stirred at room temperature for another 3 h. The reaction was then quenched with water, concentrated under reduced pressure, and purified by C18 column chromatography (mobile phase: [water-acetonitrile]) to obtain 9-5 (270 mg). LCMS: m / z = 508.3 [M+H] + . Under a nitrogen atmosphere, 9-5 (250 mg, 1 eq), dimethyl diselenyl ether (370 mg, 4 eq), and I2 (500 mg, 4 eq) were added to a mixed solvent of THF (6 mL) and DCE (4 mL). After reacting at room temperature for 2 h, the mixture was concentrated under reduced pressure and then separated by high performance liquid chromatography (HPLC) (column: Phenomenex C18 packing; mobile phase: [water-acetonitrile]) to obtain the desired product 9 (33.9 mg). 1 HNMR (400 MHz, DMSO-d 6): d 8.63 (d, J = 2.8 Hz, 1H), 8.44 (d, J =0.8 Hz, 1H), 7.96 (s, 1H), 7.78 (td, J = 8.8, 2.8 Hz, 1H), 7.67 (dd, J = 8.8, 4.8Hz, 1H), 6.79 (s, 1H), 5.81 (dd, J = 6.4, 3.6 Hz, 1H), 4.57 (t, J = 6.8 Hz, 2H), 4.47 (t, J = 6.4 Hz, 2H), 4.43 – 4.36 (m, 1H), 3.96 (dd, J = 10.8, 6.4 Hz, 1H), 3.88 (dd, J = 10.8, 3.6 Hz, 1H), 3.49 – 3.46 (m, 1H), 3.36 (s, 3H), 2.85 (d, J =10.4 Hz, 2H), 2.39 (s, 3H), 2.37 (s, 3H), 2.12 – 1.98 (m, 6H). LCMS: m / z =602.41 [M+H] + . Example 10

[0106] 10⁻¹ (2 g, 1 eq) was dissolved in DCM (500 mL), and Boc₂O (1.93 g, 1.2 eq) and DMAP (90 mg, 0.1 eq) were added. The mixture was reacted at room temperature for 2 h, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EtOAc = 10 / 1) to obtain a yellow liquid 10⁻² (2.015 g). LCMS: m / z = 372.2 [M+H] + . 10⁻² (1.6 g, 1 eq) was dissolved in DCM (15 mL), and a TABF-THF solution (1 M, 4.92 mL) was added. The mixture was reacted at room temperature for 3 h, then concentrated under reduced pressure to remove the solvent. The solution was then redissolved in MeOH (10 mL), and purified by C18 column chromatography (mobile phase: [water-acetonitrile]) to obtain 10⁻³ (580 mg). LCMS: m / z = 258.2 [M+H₂] + . PPh3 (1.22 g, 3 eq) was dissolved in THF (20 mL) under N2 atmosphere. DIAD (0.94 g, 3 eq) was added at 0 °C, and the mixture was stirred for 30 min. Then, 10⁻⁴ (619 mg, 1.0 eq) and 10⁻³ (600 mg, 1.5 eq) were added. The mixture was then re-purged with N2 and stirred at room temperature for 2 h until the reaction was complete. The solution was concentrated under reduced pressure and purified by C18 column chromatography (mobile phase: [water-acetonitrile]) to obtain 10⁻⁵ (950 mg). LCMS: m / z = 638.5 [M+H] + . 10⁻⁵ (950 mg, 1 eq) was dissolved in a dioxane solution of HCl (4 M, 5 mL). The reaction was allowed to proceed for 2 h at room temperature, followed by concentration under reduced pressure to remove the solvent. The solution was then redissolved with MeOH (15 mL), and the mixture was adjusted to alkalinity by dropwise addition of ammonia. The solution was then concentrated under reduced pressure to obtain 10⁻⁶ as a white solid (651 mg). LCMS: m / z = 438.4 [M+H] + . 10⁻⁶ (651 mg, 1 eq), 3-oxetane (215 mg, 2 eq), and CH₃COOH (18 mg, 0.2 eq) were added to MeOH (12 mL) under a N₂ atmosphere. The mixture was purged with N₂ and reacted at room temperature for 30 min. Then, NaBH₃CN (187 mg, 2 eq) was added, and the mixture was stirred at room temperature for another 3 h. The reaction was then quenched with water, concentrated under reduced pressure, and purified by C18 column chromatography (mobile phase: [water-acetonitrile]) to obtain 10⁻⁷ (250 mg). LCMS: m / z = 494.4 [M+H] + . 10⁻⁷ (250 mg, 1 eq), dimethyl diselenyl ether (376 mg, 4 eq), and I₂ (507 mg, 4 eq) were added to a mixed solvent of THF (6 mL) and DCE (4 mL) under N₂ atmosphere. After reacting at room temperature for 2 h, the mixture was concentrated under reduced pressure and then separated by high performance liquid chromatography (HPLC) (column: Phenomenex C18 packing; mobile phase: [water-acetonitrile]) to obtain the desired product 10 (30.5 mg). 1 H NMR (400 MHz, DMSO) d 8.61 (d, J = 2.8 Hz, 1H), 8.43 (d, J =0.8 Hz, 1H), 7.95 (s, 1H), 7.78 (td, J = 8.8, 2.8 Hz, 1H), 7.68 (dd, J = 8.8, 4.8Hz, 1H), 6.81 (s, 1H), 5.63 (t, J = 5.6 Hz, 1H), 5.10 (t, J = 6.4 Hz, 1H), 4.57(t, J = 6.0 Hz, 2H), 4.47 (t, J = 6.1 Hz, 2H), 4.43 – 4.37 (m, 1H), 3.98 – 3.96 (m, 2H), 3.49 – 3.46 (m, 1H), 2.85 (d, J = 10.8 Hz, 2H), 2.38 (s, 6H), 2.13 –1.99 (m, 6H). LCMS: m / z = 588.38 [M+H] + . Example 11

[0107] 11-1 (2.2 g, 1 eq) was dissolved in DCM (20 mL), N2 was introduced, TEA (828 mg, 2 eq) and TBDPSCl (1.68 g, 1.5 eq) were added, the reaction was carried out at room temperature for 3 h, water was added to quench the reaction, the mixture was concentrated under reduced pressure, and purified by C18 column chromatography (mobile phase: [water-acetonitrile]) to obtain 11-2 (2.5 g). 11-2 (2.5 g, 1 eq) was dissolved in 4M HCl-Dioxane (20 mL), reacted at room temperature for 3 h, quenched with water, and concentrated under reduced pressure to give crude 11-3 (2.2 g). LCMS: m / z = 676.5 [M+H] + . 11-3 (252 mg, 1 eq) was dissolved in MeOH (3 mL), N2 was introduced, and HCHO aqueous solution (37%, 90.7 mg, 3 eq) and NaBH3CN (93.7 mg, 4 eq) were added. The reaction was carried out at room temperature for 4 h. The reaction solution was filtered, washed with MeOH, and the filtrate was evaporated to dryness. It was extracted with water and EA, and the organic phase was concentrated under reduced pressure. The solution was purified by silica gel column chromatography (mobile phase: [petroleum ether-ethyl acetate]) to obtain 11-4 (187 mg). LCMS: m / z = 690.4 [M+H] + . 11-4 (187 mg, 1 eq) was dissolved in 1 M TBAF-THF (820 μL, 3 eq) and DCM (2 mL), and the mixture was purged with N2 and reacted at room temperature for 3 h. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (mobile phase: [dichloromethane-methanol]) to obtain 11-5 (63 mg). LCMS: m / z = 452.3 [M+H] + . Under a nitrogen atmosphere, 11-5 (60 mg, 1 eq), dimethyl diselenyl ether (100 mg, 4 eq), and I2 (135 mg, 4 eq) were added to a mixed solvent of THF (600 μL) and DCE (400 μL). After reacting at room temperature for 2 h, the mixture was concentrated under reduced pressure and then separated by high performance liquid chromatography (HPLC) (column: Phenomenex C18 packing; mobile phase: [water-acetonitrile]) to obtain the desired product 11 (8 mg). LCMS: m / z = 546.3 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 8.60(d, J = 2.9 Hz, 1H), 8.42 (d, J = 1.0 Hz, 1H), 7.95 (s, 1H), 7.77 (td, J = 8.7, 2.9Hz, 1H), 7.66 (dd, J = 8.8, 4.5 Hz, 1H), 6.80 (d, J= 1.1 Hz, 1H), 5.62 (t, J = 5.3Hz, 1H), 5.09 (t, J = 5.6 Hz, 1H), 4.42 – 4.29 (m, 1H), 4.01 – 3.90 (m, 2H), 2.96 (d, J = 10.7 Hz, 2H), 2.38 (s, 6H), 2.29 (s, 3H), 1.99 (td, J = 11.4, 6.2Hz, 3H), 1.23 (d, J = 3.2 Hz, 3H). Example 12

[0108] 12-1 (229 mg, 1 eq) was dissolved in MeOH (3 mL), N2 was introduced, acetone (59 mg, 3 e.q.), and NaBH3CN (85 mg, 4 eq) were added, and the reaction was carried out at 40°C for 4 h. The reaction solution was filtered, washed with MeOH, and the filtrate was evaporated to dryness. It was extracted with water and EA, and the organic phase was concentrated under reduced pressure. The solution was purified by silica gel column chromatography (mobile phase: [petroleum ether-ethyl acetate]) to obtain 12-2 (185 mg). LCMS: m / z = 718.5 [M+H] + . 12-2 (185 mg, 1 eq) was dissolved in 1 M TBAF-THF (780 μL, 3 eq) and DCM (2 mL), and the mixture was purged with N2 and reacted at room temperature for 3 h. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (mobile phase: [dichloromethane-methanol]) to obtain 12-3 (64 mg). LCMS: m / z = 480.3 [M+H] + . Under a nitrogen atmosphere, 12-3 (60 mg, 1 eq), dimethyl diselenyl ether (94 mg, 4 eq), and I2 (127 mg, 4 eq) were added to a mixed solvent of THF (600 μL) and DCE (400 μL). After reacting at room temperature for 2 h, the mixture was concentrated under reduced pressure and then separated by high performance liquid chromatography (HPLC) (column: Phenomenex C18 packing; mobile phase: [water-acetonitrile]) to obtain the desired product 12 (8 mg). LCMS: m / z = 574.3 [M+H] + . 1 H NMR (400 MHz, DMSO- d6) δ 8.60(d, J = 2.9 Hz, 1H), 8.43 (d, J = 1.0 Hz, 1H), 7.95 (s, 1H), 7.77 (td, J = 8.7, 2.9Hz, 1H), 7.67 (dd, J = 8.8, 4.5 Hz, 1H), 6.80 (d, J = 1.1 Hz, 1H), 5.62 (t, J = 5.3Hz, 1H), 5.09 (t, J = 5.6 Hz, 1H), 3.96 (t, J = 5.9 Hz, 2H), 2.38 (d, J = 3.0 Hz,6H), 2.22 – 2.05 (m, 4H), 2.05 – 1.93 (m, 2H), 1.28 – 1.20 (m, 4H), 1.11 (s,6H). Example 13

[0109] 13-1 (225 mg, 1 eq) was dissolved in DCM (3 mL), N2 was introduced, and methanesulfonic anhydride (232 mg, 4 eq) and TEA (169 mg, 5 eq) were added. The mixture was reacted at room temperature for 3 h, extracted with water and EA, and the organic phase was concentrated under reduced pressure. The solution was purified by silica gel column chromatography (mobile phase: [petroleum ether-ethyl acetate]) to obtain 13-2 (170 mg). LCMS: m / z = 754.4 [M+H] + . 13-2 (170 mg, 1 eq) was dissolved in 1 M TBAF-THF (680 μL, 3 eq) and DCM (2 mL), and the mixture was purged with N2 and reacted at room temperature for 3 h. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (mobile phase: [dichloromethane-methanol]) to obtain 13-3 (61 mg). LCMS: m / z = 516.3 [M+H] + . Under a nitrogen atmosphere, 13-3 (60 mg, 1 eq), dimethyl diselenyl ether (87 mg, 4 eq), and I2 (118 mg, 4 eq) were added to a mixed solvent of THF (600 μL) and DCE (400 μL). After reacting at room temperature for 2 h, the mixture was concentrated under reduced pressure and then separated by high performance liquid chromatography (HPLC) (column: Phenomenex C18 packing; mobile phase: [water-acetonitrile]) to obtain the desired product 13 (4 mg). LCMS: m / z = 610.3 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 8.60(d, J = 2.9 Hz, 1H), 8.43 (d, J = 1.0 Hz, 1H), 7.95 (s, 1H), 7.77 (td, J = 8.7, 2.9Hz, 1H), 7.67 (dd, J = 8.7, 4.5 Hz, 1H), 6.81 (d, J = 1.2 Hz, 1H), 5.63 (t, J = 5.3Hz, 1H), 5.09 (t, J = 5.6 Hz, 1H), 4.59 (q, J = 7.8 Hz, 1H), 4.02 – 3.92 (m, 2H), 3.72 (d, J = 12.0 Hz, 2H), 3.01 (dd, J = 13.0, 7.5 Hz, 2H), 2.95 (s, 3H), 2.39(d, J = 7.3 Hz, 4H), 2.12 (dd, J = 7.8, 3.9 Hz, 3H), 1.33 – 1.18 (m, 3H). The structures of the control compounds used in the following experiments are as follows: .

[0110] In vitro activity data 1. Detection of FGFR3 / FGFR3 V555M enzyme activity inhibition Enzyme activity was detected using the HTRF KinEASE TK kit (PerkinElmer, Cat No: 62TK0PEJ). First, a 2×ATP / substrate solution was prepared using kinase reaction buffer to a final concentration of 50 μM / 1 μM with 2× kinase solution (FGFR3, ICE, Cat No: S2301T-H11G or FGFR3 V555M, ICE, Cat No: S2303T-H31G), resulting in a final concentration of 0.2 nM. The compound was dissolved in DMSO at an initial concentration of 10 μM or 1 μM, and diluted 3- or 4-fold for a total of 10 concentrations. 100 nL of the diluted compound was transferred to a 384-well plate, centrifuged, and 5 μL of 2× kinase solution was added. The plate was centrifuged at 1000 rpm for 1 minute and incubated at 25°C for 10 minutes. Then, 5 μL of 2×ATP / substrate solution was added, centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 60 minutes. Prepare 2× XL665 fluorescent dye and antibody detection reagents using detection buffer. Add 10 μL of kinase detection reagent to the detection plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C in the dark for 1 hour. Read the dual-channel fluorescence signal on a microplate reader: 620 nm channel (Cryptate fluorophore) and 665 nm channel (XL665 fluorophore).

[0111] The negative control (1% DMSO wells) was set to 0% inhibition rate, and the positive control (background wells without enzyme) was set to 100% inhibition rate. The inhibition rate of each test solution was calculated. Inhibition curves were plotted using Graphpad Prism software, and the relative IC50 was calculated. Data analysis:

[0112] Average value of positive control wells Average value of negative control wells Table 1. Inhibitory activity against FGFR3

[0113] Table 2 Inhibitory activity against FGFR3 V555M

[0114] The compounds of this invention exhibit superior inhibitory activity against the enzyme activity of the FGFR3 resistance mutant V555M compared to the control compound.

[0115] 2. Beagle PK Test Two male beagle dogs were required for each compound. The beagle dogs were administered a single dose of 4 mg / kg (orally). Blood samples were collected from each dog at 0.083, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours post-administration. Whole blood samples were placed in tubes containing EDTA-K2, inverted several times, and then centrifuged at 2000 g, 4°C for 10 minutes to obtain plasma. The concentration of the compound in the plasma samples was determined using LC-MS / MS. Pharmacokinetic parameters were calculated using a non-compartmental model analysis.

[0116] Table 3 Beagle Comparison Results

[0117] The compounds of this invention exhibit superior oral absorption characteristics compared to the control compounds in rats and beagle dogs, demonstrating good drug-like properties.

[0118] It should be understood that if this invention references any prior art publications, such reference does not imply an admission that such publication is part of common general knowledge in the field in any country.

[0119] All publicly available texts, patents, patent applications, and published patent applications used in this article are incorporated herein by reference in their entirety.

[0120] Although the invention has been described in considerable detail by way of illustration and examples for purposes of clarity, it will be apparent to those skilled in the art that certain minor changes and modifications will be apparent. Therefore, the description and examples should not be construed as limiting the scope of the invention.

Claims

1. A compound of formula (II), its stereoisomers, its deuterated derivatives, its pharmaceutically acceptable salts, pharmaceutically acceptable salts of its stereoisomers, or acceptable salts of its deuterated derivatives, (II); in, In ring A, X1, X2, X4, and X5 exist in any of the following cases: (1) X1 and X5 are both -CH2-, and X2 and X4 are each independently selected from the bond, -CH2-, or -CH2-CH2-; (2) One of X4 and X5 is CHR. a The other is -CH2-, -CH2-CH2-, or a bond; one of X1 and X2 is CHR. b The other is a -CH2-, -CH2-CH2-, or bond; and CHR a With CHR b Connecting them makes ring A a bridge ring, R a With R b The resulting functional groups are -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -CH2-O-CH2-, -(CH2)2-O-CH2-, -CH2-O-(CH2)2-, or -(CH2)2-O-(CH2)2-. Each R 1 Each is independently selected from F, Cl, Br, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methoxymethylene, ethoxymethylene, propoxymethylene, isopropoxymethylene, or cyclopropyl; n1 is 0, 1, 2, 3, 4, 5, 6, 7, or 8; X3 is either -N- or -CR 4 -; Ring B is a pyrazole ring, triazole ring, thiadiazole ring, or oxadiazole ring, and is surrounded by 0, 1, or 2 R groups. c Replace; each R c Each of the following groups is independently selected from F, Cl, Br, cyano, methyl, ethyl, propyl, and isopropyl, and methyl, ethyl, propyl, and isopropyl are optionally substituted by one or more substituents independently selected from F, Cl, Br, hydroxy, and methoxy. Ring C is a heteroaromatic ring; X6 is -CH- or -N-; one of X7 and X8 is -C- and the other is -N-; X9 is -NR. d -、-O- or -S-, R d It can be H, methyl, ethyl, propyl, or isopropyl; L2 is a bond, CHR e , by 0-2 R L Substituted methylene, with 0-2 R L Substituted with ethylene, cyclobutylene, cyclopentylene, cyclohexylene, bicyclo(1.1.1)pentylene, bicyclo(2.1.1)hexylene, azapyridine, pyrrolidinyl, or piperidinyl, each R L Each is independently selected from F, Cl, Br, hydroxyl, methyl, ethyl, propyl, or isopropyl; and when L2 is a bond and is surrounded by 0-2 R... L Substituted methylene, with 0-2 R L When substituted with ethylene, cyclobutylene, cyclopentylene, cyclohexylene, bicyclo(1.1.1)pentylene, bicyclo(2.1.1)hexylene, azapyridine, pyrrolidinyl, or piperidinyl, L1 is a bond; when L2 is CHR e When L1 is -CH2-, -CH2-CH2-, or -CH2-O-CH2-; R 4 It is hydrogen, methyl, ethyl, propyl, isopropyl, or related to R. e The connection forms -CH2- or -CH2-CH2-; R 2 It is C 1-5 Alkyl or R 2a C 1-5 The alkyl group is optionally surrounded by one or more groups, each independently selected from halogen, hydroxyl, cyano, oxo, -OC. 1-4 Alkyl, -OC 3-5 cycloalkyl, -L3-R 2b and R 2c Substituents in, where -OC 1-4 Alkyl and -OC 3-5 The cycloalkyl group is optionally substituted by one or more substituents, each independently selected from halogen, hydroxyl, methoxy, -NH(CH3), -N(CH3)2 or cyano groups; R 2b It is C 1-4 Alkyl, -N(R) 6 )2, each R 6 Each is independently selected from hydrogen and C. 1-3 Alkyl, C 3-5 cycloalkyl, C 1-4 Alkyl, C 1-3 Alkyl, C 3-5 cycloalkyl, R 6 Optionally substituted with one or more substituents, each independently selected from halogens, hydroxyl groups, methoxy groups, -NH(CH3), -N(CH3)2, and -CN substituents; R 2c It is a 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl, or 5-6 membered heteroaryl, optionally with R 5 Fusing or being R 5 Replace; each R 5 Each is independently selected from 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl, or 5-6 membered heteroaryl; L3 is a bond, -C(O)-, -SO2-, or -N(R)-. 2d )C(O)-, R 2d It can be hydrogen, methyl, ethyl, propyl, or isopropyl; R 2a It is a 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl, or 5-6 membered heteroaryl, optionally with R 5 Fusing or being R 5 replace; R 2a R 2c and R 5 Optionally by one or more R 7 Replace, each R 7 Each is independently selected from halogens, OH, CN, and -OC. 1-4 Alkyl, -OC 3-5 cycloalkyl and -L4-R 7a , where -OC 1-4 Alkyl and -OC 3-5 The cycloalkyl group is optionally substituted by one or more substituents, each independently selected from halogen, OH, -OCH3, -NH(CH3), -N(CH3)2, or CN; L4 is a bond, -C(O)-, -SO2-, or -N(R 2d )C(O)-;R 7a It is C 1-4 Alkyl, C 3-5 cycloalkyl, -NH2, -NHC 1-3 Alkyl, -NHC 3-5 cycloalkyl or -N(C) 1-3 Alkyl)2, wherein C 1-4 Alkyl, C 1-3 Alkyl and C 3-5 The cycloalkyl group is optionally substituted by one or more substituents, each independently selected from halogen, -OH, methoxy, -NH(CH3), -N(CH3)2 or -CN; R 3 Selected from methyl, ethyl, propyl, isopropyl, or cyclopropyl; R 9 Selected from cyano, halogen, C 1-6 Alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl, 6-10 membered aryl, -S(=O)2-C 1-6 Alkyl, -S(=O)-C 1-6 Alkyl groups, -SH(=O)2, -SH(=O), -C(=O)-C 1-6 Alkyl or -CH (=O), R 9 Optionally by one or more R 9c Instead, each of the R 9c Selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl, 6-10 membered aryl, -S(=O)2-C 1-6 Alkyl, -S(=O)-C 1-6 Alkyl groups, -SH(=O)2, -SH(=O), -C(=O)-C 1-6 Alkyl, -CH(=O), -C(=O)-NH-C 1-6 Alkyl, -C(=O)-NH2, -NHCH(=O) or -NHC(=O)-C 1-6 alkyl.

2. The compound according to claim 1, its stereoisomers, its deuterated derivatives, its pharmaceutically acceptable salts, pharmaceutically acceptable salts of its stereoisomers, or acceptable salts of its deuterated derivatives, wherein the compound has the structure of formula (I): （I）； The definitions of each substituent in formula (I) are as described in claim 1.

3. The compound according to claim 1, its stereoisomers, its deuterated derivatives, its pharmaceutically acceptable salts, pharmaceutically acceptable salts of its stereoisomers, or acceptable salts of its deuterated derivatives, R 9 Selected from halogens, C 1-6 Alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl, 6-10 membered aryl, -S(=O)2-C 1-6 Alkyl, -S(=O)-C 1-6 Alkyl groups, -SH(=O)2, -SH(=O), -C(=O)-C 1-6 Alkyl or -CH (=O), R 9 Optionally by one or more R 9c Instead, each of the R 9c Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl, 6-10 membered aryl, -S(=O)2-C 1-6 Alkyl, -S(=O)-C 1-6 Alkyl groups, -SH(=O)2, -SH(=O), -C(=O)-C 1-6 Alkyl, -CH(=O), -C(=O)-NH-C 1-6 Alkyl, -C(=O)-NH2, -NHCH(=O) or -NHC(=O)-C 1-6 alkyl; Preferably, R 9 Selected from F, Cl, Br, methyl, ethyl, propyl, isopropyl, oxecyclobutyl, thiocyclobutyl, cyclobutyl, oxecyclopentyl, thiocyclopentyl, cyclopentyl, -S(=O)2-CH3, -S(=O)2-CH2CH3, -S(=O)2-CH2CH2CH3, -S(=O)2-CH(CH3)2, -SH(=O)2, -SH(=O), -S(=O)-CH3, -S(=O)-CH2CH3, -S(=O)-CH2CH2CH3, -S(=O)-CH(CH3)2, -C(=O)-CH3, -C(=O)-CH2CH3, -C(=O)-CH2CH2CH3, -C(=O)-CH(CH3)2; Preferably, R 4 It is hydrogen or related to R e The connection forms -CH2- or -CH2-CH2-; Preferably, L2 is a bond, cyclobutylene, azacyclobutane, or piperidinylene.

4. The compound, its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer, or an acceptable salt of its deuterated derivative according to any one of claims 1-3, characterized in that, The compound has a structure of any of the following formulas: Preferably, the compound has the structure of any of the following formulas: 。 5. The compound, its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer, or an acceptable salt of its deuterated derivative according to any one of claims 1-4, characterized in that, Each R 1 Each is independently selected from F, methyl, hydroxy or cyclopropyl; n1 is preferably 0, 1 or 2; Preferably, each R c Each of the groups is independently selected from methyl, ethyl, propyl, and isopropyl, and methyl, ethyl, propyl, and isopropyl may be optionally substituted by one or more substituents independently selected from F, Cl, Br, hydroxy, and methoxy. Preferably, R c The ring B is methyl, and the ring B is preferably surrounded by 0 or 1 R. c replace; Preferably, ring B is a pyrazole ring or a triazole ring.

6. The compound according to any one of claims 1-5, its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer, or an acceptable salt of its deuterated derivative, wherein the compound has a structure of formula (IA) or (IB): 。 7. The compound, its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer, or an acceptable salt of its deuterated derivative according to any one of claims 1-10, characterized in that, X6 is -CH-; Preferably, R 2 It is C 1-5 Alkyl, C 1-5 The alkyl group is optionally selected by one, two, three, or four groups, each independently selected from halogen, hydroxyl, cyano, oxo, -OC. 1-4 Alkyl, -OC 3-5 cycloalkyl, -L3-R 2b and R 2c Substituents in, where -OC 1-4 Alkyl and -OC 3-5 The cycloalkyl group is optionally substituted by one or more substituents, each independently selected from halogen, hydroxyl, methoxy, -NH(CH3), -N(CH3)2 or cyano; Preferably, R 2 Selected from: ； It is optionally selected by one, two, three or four independently selected from halogen, hydroxyl, cyano, oxo, -OC 1-4 Alkyl, -OC 3-5 cycloalkyl, -L3-R 2b and R 2c Substituents in, where -OC 1-4 Alkyl and -OC 3-5 The cycloalkyl group is optionally substituted with one or more substituents, each independently selected from halogen, hydroxyl, methoxy, -NH(CH3), -N(CH3)2 or cyano; preferably, it is optionally substituted with one or two substituents, each independently selected from hydroxyl, -CF3 or methoxy. Preferably, R 2 Selected from: ； Preferably, R 2c Selected from: ； R8 is selected from F, Cl, Br, hydroxyl, cyano, nitro, amino, cyano, methyl, ethyl, propyl, isopropyl, -NH(CH3), -N(CH3)2, -N(CH2CH3)2, -N(CH2CH3)(CH3), -CCl3, -CF3, -CHCl2, -CHF2, -CH2CCl3, -CH2CF3, -CH2CHCl2, -CH2CHF2, -CH2CH2CCl3, -CH2CH2CF3, -CH(CCl3)2, -CH(CF3)2, methoxy, ethoxy, propoxy, isopropoxy, methoxymethylene, ethoxymethylene, propoxymethylene, isopropoxymethylene, cyclopropylmethylene, cyclopropylethylidene, cyclopropylpropylpropene, morpholino, -C(O)NH2, -C(O)NH(CH2) 0-3 CH3, thiazolyl, oxazolyl, isoxazolyl, cyclobutyl, azacyclobutyl; n2 is 0, 1, 2, 3, 4 or 5.

8. The compound, its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer, or an acceptable salt of its deuterated derivative according to any one of claims 1-7, characterized in that, The compound has a structure of formula (IA-1) or (IB-1): Preferably, R 3 It is a methyl group.

9. The compound, its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer, or an acceptable salt of its deuterated derivative according to any one of claims 1-8, characterized in that, The compound is: 。 10. A pharmaceutical composition comprising a compound according to any one of claims 1-9, a stereoisomer thereof, a deuterated derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, or an acceptable salt of a deuterated derivative thereof; and at least one pharmaceutically acceptable excipient.

11. Use of a compound according to any one of claims 1-9, its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer or an acceptable salt of its deuterated derivative, or the pharmaceutical composition according to claim 10 in the preparation of a medicament for treating or preventing diseases associated with FGFR3. Preferably, the diseases include, but are not limited to, systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, lethal achondroplasia, severe achondroplasia with developmental delay and acanthosis nigricans, Muenke syndrome, or cancer; preferably, 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.

Images