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 reactions, 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 one hand, the present invention provides a compound of formula (I), its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer, or an acceptable salt of its deuterated derivative. (I); 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 H, methyl, ethyl, propyl, or isopropyl; X 10 For O or S; 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 CHRe 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 yes Alkyl or R 2a ,in The alkyl group is optionally surrounded by one or more groups, each independently selected from halogen, hydroxyl, cyano, oxo, alkyl, cycloalkyl, L3 R 2b and R 2c Substituents in, wherein Alkyl and 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 yes Alkyl, -N(R) 6 )2, each R 6 Each is independently selected from hydrogen, alkyl, cycloalkyl, alkyl, alkyl, 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 3 6-membered cycloalkyl, 4 6-membered heterocyclic alkyl, 5 6-aryl or 5-aryl 6-membered heteroaryl groups, which are selectively associated with R 5 Fusing or being R 5 Replace; each R 5 Each is independently selected from halogen, 3 6-membered cycloalkyl, 4 6-membered heterocyclic alkyl, 5 6-aryl or 5-aryl 6-membered heteroaryl; L3 is a bond, -C(O)-, -SO2- or N(R 2d C(O)-, or independently selected from halogens, 3 6-membered cycloalkyl, 4 6-membered heterocyclic alkyl, 5 6-aryl or 5-aryl 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 3 6-membered cycloalkyl, 4 6-membered heterocyclic alkyl, 5 6-aryl or 5-aryl 6-membered heteroaryl groups, which are selectively associated 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, alkyl, cycloalkyl and L4 R 7a ,in Alkyl and 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 yes alkyl, cycloalkyl, -NH2, alkyl, cycloalkyl or ,in alkyl, Alkyl and 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.

[0005] R 9 Selected from cyano, halogen, Alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5 10-membered heteroaryl, 6 10 Yuan Aromatic alkyl, alkyl, , , alkyl or R 9 Optionally by one or more R 9c Instead, each of the R 9c Each group is independently selected from halogen, hydroxyl, cyano, nitro, amino, alkyl, Alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5 10-membered heteroaryl, 6 10 Yuan Aromatic alkyl, alkyl, , , alkyl, , alkyl, , or alkyl; In some implementations, R 9 Selected from CN, halogen, Alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5 10-membered heteroaryl, 6 10 Yuan Aromatic alkyl, alkyl, , , alkyl or 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, alkyl, Alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5 10-membered heteroaryl, 6 10 Yuan Aromatic alkyl, alkyl, , , alkyl, , alkyl, , or alkyl; Preferably, R 9Selected from CN, F, Cl, Br, methyl, ethyl, propyl, isopropyl, oxecyclobutyl, thiohexacyclobutyl, cyclobutyl, oxecyclopentyl, thiohexacyclopentyl, cyclopentyl , , .

[0006] In some implementations, R 4 It is hydrogen or related to R e The connection forms -CH2- or -CH2-CH2-.

[0007] In some embodiments, L2 is a bond, cyclobutylene, azapyridine, or piperidinyl.

[0008] In some embodiments, the compound has a structure of any of the following formulas: .

[0009] In some implementations, each R 1 Each is independently selected from F, methyl, hydroxy or cyclopropyl; n1 is preferably 0, 1 or 2.

[0010] 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.

[0011] Preferably, R c The ring B is methyl, and the ring B is preferably surrounded by 0 or 1 R. c replace.

[0012] Preferably, ring B is a pyrazole ring or a triazole ring.

[0013] In some embodiments, the compound has the structure of formula (IA) or (IB):

[0014] In some implementations, X6 is -CH-.

[0015] In some implementations, R 2 yes alkyl, The alkyl group is optionally selected by one, two, three, or four groups, each independently selected from halogen, hydroxyl, cyano, oxo, ... alkyl, cycloalkyl, L3 R 2b and R 2c Substituents in, wherein Alkyl and 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.

[0016] Preferably, R 2 Selected from:

[0017] ; It may be optionally selected by one, two, three, or four independently selected from halogen, hydroxyl, cyano, oxo, alkyl, cycloalkyl, L3 R 2b and R 2c Substituents in, wherein Alkyl and 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.

[0018] In some implementations, R 2 Selected from: .

[0019] In some implementations, R 2c Selected from: Preferably, R 2c Selected from ; Each R8 group is independently selected from F, Cl, Br, hydroxyl, cyano, nitro, amino, cyano, methyl, ethyl, propyl, isopropyl, etc. , , , methoxy, ethoxy, propoxy, isopropoxy, methoxymethylene, ethoxymethylene, propoxymethylene, isopropoxymethylene, cyclopropylmethylene, cyclopropylethylene, cyclopropylpropylpropene, morpholino, -C(O)NH2, Thiazolyl, oxazolyl, isoxazolyl, cyclobutyl, azacyclobutyl; n2 is 0, 1, 2, 3, 4 or 5.

[0020] In some embodiments, the compound has a structure of formula (IA-1) or (IB-1):

[0021] In some implementations, R 3 It is a methyl group.

[0022] In some embodiments, the compound is: .

[0023] The compounds provided by this invention, their stereoisomers, their deuterated derivatives, their pharmaceutically acceptable salts, pharmaceutically acceptable salts of their stereoisomers, or acceptable salts of their deuterated derivatives, have the effect of selectively inhibiting FGFR3 and can be used to treat or prevent related diseases.

[0024] 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.

[0025] 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.

[0026] 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.

[0027] 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.

[0028] definition Unless otherwise stated, the wavy line in the chemical structure " "" indicates the position where the group breaks a bond.

[0029] 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.

[0030] 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 1-6Alkyl 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).

[0031] 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).

[0032] In some embodiments, the haloalkyl group is interchangeable with -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.

[0033] 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)-). The term "alkenyl" refers to a straight-chain or branched hydrocarbon group containing one or more double bonds, typically with a length of 2 to 20 carbon atoms. For example, "-C 2-6 "Alkenyl" contains 2 to 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, hexenyl, heptenyl, octenyl, etc. The term "alkynyl" refers to a straight-chain or branched hydrocarbon group containing one or more triple bonds, typically with a length of 2 to 20 carbon atoms. For example, "-C 2-6The term "alkynyl" contains 2 to 6 carbon atoms. Representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, 2-butynyl, pentyynyl, hexynyl, heptyynyl, and octyynyl. 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.

[0034] 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.

[0035] 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.

[0036] 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: , , , .

[0037] 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.

[0038] 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.

[0039] 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. 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, a bridged ring, or a spirocyclic ring, each substituent can independently substitute for each ring atom of the polycyclic ring.

[0040] The term "oxo" refers to the process by which oxygen and the carbon atoms bonded to it together form oxygen. Group.

[0041] 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.

[0042] 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).

[0043] 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).

[0044] 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.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] 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.

[0050] 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%).

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] 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. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oil. Furthermore, preservatives may be included to prevent harmful microbial growth. Pharmaceutical compositions of the present invention suitable for injectable use comprise sterile aqueous solutions or dispersions. Additionally, 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 preferable 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.

[0057] 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 with the compounds represented by formula (I) of 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.

[0058] 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.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] 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%.

[0063] These and other aspects will become apparent from the following written description of the invention. Detailed Implementation

[0064] 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.

[0065] Example The following examples are provided to better illustrate the invention. Unless otherwise explicitly stated, all parts and percentages are by weight, and all temperatures are in degrees Celsius. The abbreviations in the following table are used in the examples:

[0066] Example 1

[0067] Dissolve 1-1 (500 mg, 1 eq) in DCM (15 mL), add NIS (199 mg, 1.15 eq), and react at room temperature for 2 h. After the reaction is complete, concentrate under reduced pressure and purify by silica gel column chromatography (MeOH / DCM = 0%~10%) to obtain 1-2 (470 mg). LCMS: m / z = 722.2 [M-56+H] + . Add 1-2 (470 mg, 1 eq), Pd2(dba)3 (55 mg, 0.1 eq), Xanthphos (70 mg, 0.2 eq), Cs2CO3 (394 mg, 2 eq), and NaSMe (51 mg, 1.2 eq) to a two-necked flask. Inject ultra-dry dioxane (7 mL) under N2 atmosphere and react overnight at 120 °C. After the reaction is complete, concentrate under reduced pressure and purify by silica gel column chromatography (EA / PE = 0%~50%) to obtain crude 1-3 (500 mg). LCMS: m / z = 698.4 [M+H] + . Add 1-3 (153 mg) to the reaction flask, then slowly add 1.5 mL of HCl solution of 1,4-dioxane. Stir at room temperature for 1 h. Purify by C18 column chromatography (mobile phase: [MeCN / H2O = 5%~50%]) to obtain 1-4 as a white solid (100 mg). LCMS: m / z = 484.3 [M+H] + . 1-4 (100 mg, 1 eq) and BrCN (24 mg, 1.1 eq) were added to DCM (3 mL) under N2 atmosphere, followed by the injection of DIPEA (80 mg, 3 eq). After reacting at room temperature for 1 h, the mixture was concentrated under reduced pressure and purified by prep-HPLC to obtain 1 (22.06 mg). LCMS: m / z = 509.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.60 (d, J = 2.8 Hz, 1H), 8.43 (s, J = 0.7 Hz,1H), 7.98 (s, 1H), 7.77 (td, J = 8.7, 2.9 Hz, 1H), 7.69 (dd, J= 8.7, 4.6 Hz,1H), 6.85 (s, 1H), 5.64 (t, J = 5.1 Hz, 1H), 5.10 (t, J = 5.6 Hz, 1H), 4.69 –4.55 (m, 1H), 3.96 (t, J = 5.4 Hz, 2H), 3.56 (d, J = 12.9 Hz, 2H), δ 3.32 (s,3H), 3.27 (d, J = 10.1 Hz, 2H), 2.39 (s, 3H), 2.21 – 2.10 (m, 2H), 2.04 (dd, J =22.2, 10.3 Hz, 2H). Following the synthetic route of Example 1, compounds 16, 18, 20, 22, 24 and 26 were synthesized. The structures of the compounds are shown in the table below.

[0068]

[0069] Example 2

[0070] Compound 2-1 (30 g, 1 eq) was dissolved in a dry DCM solution (300 mL), and AlCl3 (26.6 g, 1.5 eq) was added. The solution was then cooled to 0 °C. o AcCl (42 g, 4 eq) was added dropwise under a C, N2 atmosphere, and the reaction was carried out at room temperature for 4 h. After the reaction was complete, the reaction solution was poured into ice water, extracted with dichloromethane, and washed with water and saturated NaCl. The organic phase was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by column chromatography (EA / PE = 0%~40%) to obtain a 2-2 brown solid (10 g). LCMS: m / z = 269.0 / 271.0 [M+H] + . Add 2-2 (5 g, 1 eq), sodium ethanethiol (3.1 g, 2 eq), and 35 mL DMF to the reaction flask. Incubate the reaction at 80 °C for 4 h. After the reaction is complete, cool to room temperature and purify by C18 column chromatography (MeCN / H2O = 10%–80%) to obtain 2-3 as a brown solid (2.13 g). LCMS: m / z = 254.9 / 257.0 [M+H] + . PPh3 (5.9 g, 3 eq) was dissolved in THF (30 mL) under N2 atmosphere. DEAD (3.6 g, 2.8 eq) was added at 0 ℃, and the mixture was stirred for 30 min. Then, 2-4 (2.2 g, 1.1 eq) and 2-3 (1.9 g, 1 eq) of THF solution were added separately, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, the solution was concentrated under reduced pressure and purified by silica gel column chromatography (EA / PE = 0%~35%) to obtain 2-5 as a white solid (2 g). LCMS: m / z = 508.4 / 510.4 [M+H] + . Will m -CPBA (1.6 g, 85% purity, 2 eq) was dissolved in dry DCM (30 mL) and cooled to 0. o TFA (1 mL) was added under a C, N2 atmosphere, followed by dropwise addition of 2-5 (2 g, 1 eq) of DCM (10 mL). The mixture was stirred at room temperature for 3 h. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse-phase separation on a C18 column (MeCN / H2O = 10%–80%) to obtain the target compound 2-6 (1.64 g). LCMS: m / z = 524.2 / 526.3 [M+H] + . Compounds 2-6 (1.64 g, 1 e.q.) were dissolved in a mixed solution of THF / H₂O (10 mL / 10 mL) and cooled to 0 °C. o After reaction C, LiOH (150 mg, 2 eq) was added, and the mixture was stirred at room temperature for 1 h. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse-phase separation on a C18 column (MeCN / H2O = 15%–80%) to obtain the target compound 2-7 (580 mg). LCMS: m / z = 482.2 / 484.2 [M+H] + . Compound 2-7 (580 mg, 1 eq) and K₂CO₃ (333 mg, 2.4 eq) were placed in a dry two-necked flask, DMF (4 mL) was added, and MeI (257 mg, 1.8 eq) was added dropwise under a N₂ atmosphere. The mixture was heated to 55°C. o C. The reaction was monitored after 2 hours. After the reaction was complete, it was cooled to room temperature, quenched with ice water, extracted with ethyl acetate, and washed with water and saturated NaCl water, respectively. The organic phase was dried over anhydrous Na₂SO₄, filtered, concentrated under reduced pressure, and separated by column chromatography (EA / PE = 0%–30%) to give the target compound 2-8 (424 mg, 71%) in an oily form. LCMS: m / z = 496.2 [M+H] + . 2-8 (424 mg, 1 eq), B2Pin2 (3435 mg, 2 eq), KOAc (252 mg, 3 eq), and Pd(dppf)Cl2 (63 mg, 0.1 eq) were added to a three-necked flask. Ultra-dry 1,4-dioxane (10 mL) was injected under a nitrogen atmosphere, and the reaction was carried out overnight at 100 °C. After the reaction was complete, the mixture was cooled to room temperature, filtered to remove the residue, and the filtrate was concentrated under reduced pressure to obtain crude 2-9 solid (600 mg). LCMS: m / z = 544.4 [M+H] + . Crude products 2-9 (600 mg, 1.1 eq), 2-10 (265 mg, 1 eq), K3CO4 (212 mg, 2 e.q.), and Pd(dppf)Cl2 (56 mg, 0.1 eq) were added to a three-necked flask. Dioxane / H2O (8 mL / 0.8 mL) was injected under N2 atmosphere, and the reaction was carried out at 100 °C for 3 h. After the reaction was complete, the product was concentrated under reduced pressure and purified by silica gel column chromatography (MeOH / DCM = 0%~10%) to obtain 2-11 (510 mg). LCMS: m / z = 682.5 [M+H] + . Add 2-11 (510 mg, 1 eq) to the reaction flask, then slowly add 6 mL of HCl in 1,4-dioxane. Stir at room temperature for 1 h. Purify by C18 column chromatography (mobile phase: [MeCN / H2O = 5%–50%]) to obtain 2-12 as a white solid (320 mg). LCMS: m / z = 468.2 [M+H] + . Under a nitrogen atmosphere, 2-12 (500 mg, 1 eq) and DIPEA (415 mg, 3 eq) were added to DCM (8 mL), followed by BrCN (124 mg, 1.1 eq). The reaction was carried out at room temperature for 1 h. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by prep-HPLC to obtain racemic compound 2 (103.8 mg). Purification was then performed 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 (mobile phase A) to provide isomer 2A, with a retention time of 1.668 min, 100% ee, and LCMS: m / z = 493.3 [M+H]. +The retention time of isomer 2B is 2.517 min, with 99.89% ee, LCMS: m / z = 493.3 [M+H] + .

[0071] 1 H NMR (400 MHz, DMSO) δ 8.60 (d, J = 2.8 Hz, 1H), 8.43 (s, J = 0.7 Hz,1H), 7.98 (s, 1H), 7.77 (td, J = 8.7, 2.9 Hz, 1H), 7.69 (dd, J = 8.7, 4.6 Hz,1H), 6.85 (s, 1H), 5.64 (t, J = 5.1 Hz, 1H), 5.10 (t, J = 5.6 Hz, 1H), 4.69 –4.55 (m, 1H), 3.96 (t, J = 5.4 Hz, 2H), 3.56 (d, J = 12.9 Hz, 2H), 3.27 (d, J =10.1 Hz, 2H), 2.50 (s, J = 1.3 Hz, 3H), 2.39 (s, 3H), 2.21 – 2.10 (m, 2H), 2.04(dd, J = 22.2, 10.3 Hz, 2H).

[0072]

[0073] Following the synthetic route of Example 2, compounds 3-13, 17, 19, 21, 23, 25, and 27-28 were synthesized. The structures of the compounds are shown in the table below.

[0074] control compound The structure of the control compound LOXO-435 used in the following experiment is as follows: .

[0075] In vitro activity data 1. FGFR3 enzyme activity inhibition detection 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. Then, 1 μM of 2× kinase solution (FGFR3, ICE, Cat No: S2301T-H11G, ICE, Cat No: S2303T-H31G) was used to achieve a final concentration of 0.2 nM. The test 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 test 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. Finally, 5 μL of 2×ATP / substrate solution was added, and the plate was 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).

[0076] 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:

[0077] Average value of positive control wells Average value of negative control wells Table 1. Inhibitory activity against FGFR1-4

[0078] 2. UMUC-14 cell proliferation activity assay UMUC-14 cells were resuspended in culture medium and seeded into 96-well assay plates at a density of 3500 cells / well, with double replicates. After overnight culture, a 3 mM DMSO stock solution was prepared and serially diluted 3-fold to generate 10 concentration points. Positive control wells (cells + 100 nM erdatinib) and negative control wells (cells + 0.1% DMSO) were also included. 210 nL of the diluted compound was transferred to an intermediate plate using an ultrasonic pipetting system, and 70 μL of culture medium was added and mixed. 50 μL of the compound-containing culture medium was transferred to the cell seeding plate. After incubation at 37°C and 5% CO2 for 4 days, the old culture medium was removed, 50 μL of CellTiter-Glo® 3D reagent was added, and the reaction was carried out with shaking for 20 minutes before detecting the chemiluminescence signal.

[0079] The negative control (0.1% DMSO well) was set to 0% inhibition rate, and the positive control (100 nM erdatinib well) 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 (results are shown in Table 2). Data analysis was the same as in Experiment 1.

[0080] Table 2 Inhibitory activity against UMUC-14

[0081] Compound 2A exhibited superior inhibitory activity against the proliferation of FGFR3 S249C mutant UMUC-14 cells compared to the control compound, achieving selectivity for FGFR3 S249C.

[0082] 3. DMS114 cell proliferation activity assay 1000 cells (40 μL suspension) were seeded into each well of a 384-well plate in duplicate. After overnight incubation, a 10 mM DMSO stock solution was prepared and serially diluted 3-fold to create 10 concentration spots. Positive control wells (culture medium wells) and negative control wells (cells + 0.1% DMSO) were also included. 40 nL of the test compound was added to the seeding plate, and the plate was incubated at 37°C for 4 days. After incubation, 3D CellTiter-Glo reagent was added to each well, and the reaction was incubated with shaking for 20 minutes at room temperature, followed by 60 minutes of incubation. The chemiluminescence signal was detected using a BMG microplate reader.

[0083] The negative control (0.1% DMSO wells) was set to 0% inhibition rate, and the positive control (culture medium wells) 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 was the same as in Experiment 1.

[0084] Table 3 Inhibitory activity against DMS114

[0085] Compound 2A inhibited the proliferation of FGFR1-amplified cells DMS114 at an IC50 level. 50 The concentration of FGFR3 was >10 mM, which was greater than that of the control compound, indicating that 2A was more selective for inhibiting cell proliferation than the control compound. Other compounds 3-13, 17, 19, 21, 23, 25, and 27-28 also showed similar levels to compound 2A.

[0086] 4. In vitro study on the metabolic stability of liver microsomes The metabolic stability of the compound in liver microsomes of different species under in vitro conditions was evaluated. The compound was incubated in phosphate-buffered saline (pH 7.4) containing coenzyme factors in liver microsomes of different species for 60 min in two parallel incubation cycles. Samples were taken at 0.5, 5, 10, 15, 30, and 60 min, and the samples were analyzed using UPLC-MS / MS to determine the compound concentration. The elimination rate constant (k) was determined by linearly fitting the natural logarithm of the remaining percentage of parent drug to time. The intrinsic clearance and half-life (t) were calculated. 1 / 2 ), where t 1 / 2 = 0.693 / k; clearance rate = kV / N, where V = incubation volume per well, and N = microparticle content per well.

[0087] Table 4. Results of in vitro liver microsomal metabolism

[0088] Compound 2A exhibited better metabolic stability in human liver microsomes than the control compound, while other compounds 3-13, 17, 19, 21, 23, 25, and 27-28 also showed similar levels to compound 2A.

[0089] 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.

[0090] All publicly available texts, patents, patent applications, and published patent applications used in this article are incorporated herein by reference in their entirety.

[0091] 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 (I), its stereoisomers, its deuterated derivatives, its pharmaceutically acceptable salts, pharmaceutically acceptable salts of its stereoisomers, or acceptable salts of its deuterated derivatives, （I）； 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 H, methyl, ethyl, propyl, or isopropyl; X 10 For O or S; 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 yes Alkyl or R 2a ,in The alkyl group is optionally surrounded by one or more groups, each independently selected from halogen, hydroxyl, cyano, oxo, alkyl, cycloalkyl, L3 R 2b and R 2c Substituents in, wherein Alkyl and 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 yes Alkyl, -N(R) 6 )2, each R 6 Each is independently selected from hydrogen, alkyl, cycloalkyl, alkyl, alkyl, 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 3 6-membered cycloalkyl, 4 6-membered heterocyclic alkyl, 5 6-aryl or 5-aryl 6-membered heteroaryl groups, which are selectively associated with R 5 Fusing or being R 5 Replace; each R 5 Each is independently selected from halogen, 3 6-membered cycloalkyl, 4 6-membered heterocyclic alkyl, 5 6-aryl or 5-aryl 6-membered heteroaryl; L3 is a bond, -C(O)-, -SO2- or N(R 2d C(O)-, or independently selected from halogens, 3 6-membered cycloalkyl, 4 6-membered heterocyclic alkyl, 5 6-aryl or 5-aryl 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 3 6-membered cycloalkyl, 4 6-membered heterocyclic alkyl, 5 6-aryl or 5-aryl 6-membered heteroaryl groups, which are selectively associated 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, alkyl, cycloalkyl and L4 R 7a ,in Alkyl and 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 yes alkyl, cycloalkyl, -NH2, alkyl, cycloalkyl or ,in alkyl, Alkyl and 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, Alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5 10-membered heteroaryl, 6 10 Yuan Aromatic alkyl, alkyl, , , alkyl or R 9 Optionally by one or more R 9c Instead, each of the R 9c Each group is independently selected from halogen, hydroxyl, cyano, nitro, amino, alkyl, Alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5 10-membered heteroaryl, 6 10 Yuan Aromatic alkyl, alkyl, , , alkyl, , alkyl, , or alkyl; 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.

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, characterized in that, The compound has a structure of any of the following formulas: 。 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, 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 is independently selected from methyl, ethyl, propyl, isopropyl, methyl, ethyl, propyl, isopropyl, R c It may be optionally substituted by one or more substituents, each independently selected from F, Cl, Br, hydroxyl, and methoxy; Preferably, R c The ring B is preferably 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.

4. 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 a structure of formula (IA) or (IB): 。 5. 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, characterized in that, X6 is -CH-; Preferably, R 2 yes alkyl, The alkyl group is optionally selected by one, two, three, or four groups, each independently selected from halogen, hydroxyl, cyano, oxo, ... alkyl, cycloalkyl, L3 R 2b and R 2c Substituents in, wherein Alkyl and 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 may be optionally selected by one, two, three, or four independently selected from halogen, hydroxyl, cyano, oxo, alkyl, cycloalkyl, L3 R 2b and R 2c Substituents in, wherein Alkyl and 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: ； Each R8 group is independently selected from F, Cl, Br, hydroxyl, cyano, nitro, amino, cyano, methyl, ethyl, propyl, isopropyl, etc. , , , methoxy, ethoxy, propoxy, isopropoxy, methoxymethylene, ethoxymethylene, propoxymethylene, isopropoxymethylene, cyclopropylmethylene, cyclopropylethylene, cyclopropylpropylpropene, morpholino, -C(O)NH2, Thiazolyl, oxazolyl, isoxazolyl, cyclobutyl, azacyclobutyl; n2 is 0, 1, 2, 3, 4 or 5.

6. 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, characterized in that, The compound has a structure of formula (IA-1) or (IB-1): 。 7. 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, characterized in that, R 3 It is methyl; Preferably, R 9 Selected from CN, halogen, Alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5 10-membered heteroaryl, 6 10 Yuan Aromatic alkyl, alkyl, , , alkyl or 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, alkyl, Alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5 10-membered heteroaryl, 6 10 Yuan Aromatic alkyl, alkyl, , , alkyl, , alkyl, , or alkyl; Preferably, R 9 Selected from CN, F, Cl, Br, methyl, ethyl, propyl, isopropyl, oxecyclobutyl, thiohexacyclobutyl, cyclobutyl, oxecyclopentyl, thiohexacyclopentyl, cyclopentyl , , .

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 is: 。 9. A pharmaceutical composition comprising a compound according to any one of claims 1-8, 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.

10. Use of a compound according to any one of claims 1-8, 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 9 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 dysplasia, 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 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.

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