Fibroblast growth factor receptor inhibitor, pharmaceutical composition and use thereof

Abstract

A compound as shown in formula (I) and a racemate, a stereoisomer, a tautomer, an isotopic label, a nitrogen oxide, a solvate, a polymorph, a metabolite, an ester, a prodrug or a pharmaceutically acceptable salt thereof. Such a compound has a good inhibitory effect on FGFR2 and / or FGFR3, can be used for treating or preventing conditions and diseases mediated by FGFR2 and / or FGFR3, and can be used in the preparation of a drug for treating or preventing such conditions and diseases.

Description

Fibroblast growth factor receptor inhibitor, pharmaceutical composition and use thereof

[0001] This application claims priority from the following patent applications:

[0002] Priority to the prior application, patent application number 202310903124.X, filed with the State Intellectual Property Office of China on July 21, 2023, entitled “Fibroblast Growth Factor Receptor Inhibitors, Pharmaceutical Compositions, and Applications Thereof”;

[0003] Priority to the prior application, patent application number 202311106358.8, filed with the State Intellectual Property Office of China on August 30, 2023, entitled “Fibroblast Growth Factor Receptor Inhibitors, Pharmaceutical Compositions, and Applications Thereof”;

[0004] Priority to the prior application, patent application number 202311481944.0, filed with the State Intellectual Property Office of China on November 8, 2023, entitled “Fibroblast Growth Factor Receptor Inhibitors, Pharmaceutical Compositions, and Applications Thereof”;

[0005] Priority to the prior application, patent application number 202311790797.5, filed with the State Intellectual Property Office of China on December 22, 2023, entitled “Fibroblast Growth Factor Receptor Inhibitors, Pharmaceutical Compositions, and Applications Thereof”;

[0006] The entire contents of said prior application are incorporated herein by reference. Technical Field

[0007] The present invention belongs to the field of medicine, and in particular relates to a fibroblast growth factor receptor inhibitor, a pharmaceutical composition and applications thereof. Background Art

[0008] The fibroblast growth factor receptor (FGFR), a key member of the tyrosine kinase receptor family, is a tyrosine kinase receptor composed of approximately 800 amino acids, containing three extracellular immunoglobulin-like domains (I / II / III), a single-pass transmembrane structure, and a cytoplasmic tyrosine kinase domain. In humans, there are four typical FGFR tyrosine kinase receptors (FGFR1-4) and one, FGFR5, which lacks an intracellular tyrosine kinase domain. There are 18 FGFR ligands, namely fibroblast growth factor (FGF). Under normal physiological conditions, FGFRs bind to their ligand fibroblast growth factor, and FGFRs dimerize and phosphorylate themselves. When FGF binds to FGFRs, it can activate and amplify signal pathways, including downstream signal pathways such as the JAK / STAT pathway, phospholipase C pathway, phosphoinositide 3-kinase PI3K, and MAPK signaling pathway (Turner, N., Grose, R., Nat. Ref. Cancer 2010; 10: 116-129; Brooks, NS et al., Clin Cancer Res. 2012; 18: 1855-1862; Dienstmann, R. et al., Ann. Oncol. 2014; 25: 552-563).

[0009] In 2015, a study published in the journal Clinical Cancer Research described the mutational landscape of FGFR in 4853 patient samples from various cancers using next-generation sequencing technology, including mutations, amplifications, and rearrangements. Among the 4853 cancers sequenced, the study observed 360 FGFR mutations in 343 cases (17 cancers had multiple FGFR alterations), with an overall incidence of 7.1% (Helsten T, Elkin S, Arthur E, Tomson BN, Carter J, Kurzrock R. The FGFR Landscape in Cancer: Analysis of 4,853 Tumors by Next-Generation Sequencing. Clin Cancer Res. 2016; 22(1): 259-267. doi: 10.1158 / 1078-0432. CCR-14-3212). FGFR signaling components are frequently altered in human cancers, and several preclinical models have provided compelling evidence for the oncogenic potential of aberrant FGFR signaling in carcinogenesis, thus validating FGFR signaling as an attractive target for cancer therapy.

[0010] Fibroblast growth factor receptor 3 (FGFR3) is a transmembrane tyrosine kinase receptor protein that plays an important role in both cartilage development and cartilage homeostasis. FGFR3 is considered a negative regulator of endochondral ossification. During early bone development, FGFR3 is expressed in chondrocytes within the mesenchymal condensation center, followed by chondrocytes in the proliferative zone and prehypertrophic zone of growth plate and articular cartilage. Mutations in the human FGFR3 gene can lead to a range of skeletal deformities.

[0011] Enhanced point mutations in FGFR3 lead to skeletal dysplasia with clinical manifestations of short stature, including thanatophoric dysplasia (TD I / II) and achondroplasia (ACH); while inactivating point mutations in human FGFR3 can lead to CATSHL syndrome, which is characterized by hearing loss, tall stature and bowed fingers.

[0012] Tyrosine kinase inhibitors can be divided into non-covalent and covalent inhibitors. Among non-covalent inhibitors, a further distinction is made between multi-target or selective inhibitors. Non-covalent multi-target FGFR inhibitors such as dovitinib, nintedanib, lenvatinib, ponatinib, derazantinib, and e-7090 are active against FGFR, VEGFR, PDGFR (platelet-derived growth factor receptor), and other kinase proteins. Multi-targeted TKls (tyrosine kinase inhibitors) have demonstrated clinical benefit, with ponatinib and nintedanib approved for myeloid leukemia and non-small cell lung cancer in 2012 and 2014, respectively. The toxicity of multi-target FGFR inhibitors is related to the inhibition of multiple kinases, particularly VEGFRs, which limits therapeutic doses. Consequently, more selective non-covalent FGFR inhibitors have been developed. These drugs include AZD4547, Infigatinib, PD173074, LY2874455, Debio1347, ASP5878, and Rogaratinib, which are selective for FGFR1-3 over VEGFR and other kinases (Marseglia G, Lodola A, Mor M, Castelli R. Expert Opin Ther Pat. 2019 Dec; 29(12): 965-977.). These compounds have been shown to be effective against FGFR-dependent cancers in clinical trials, but they have toxic side effects such as hyperphosphatemia caused by FGFR1. In addition to hyperphosphatemia and diarrhea, FGFR inhibitors are also commonly associated with fatigue, skin toxicity such as hand-foot syndrome, hair loss, nail bed infection, onychomycosis, dry skin, dry mouth, and often lead to clinical side effects such as changes in taste (Kommalapati A, Tella SH, Borad M, Javle M, Mahipal A. Cancers (Basel). 2021 Jun 13; 13(12): 2968.).

[0013] In summary, the FGFR signaling pathway plays an important role in human cancer and bone development and is an attractive therapeutic target; however, pan-FGFR inhibitors have major toxic side effects such as hyperphosphatemia and diarrhea, and there is an unmet clinical need. The development of highly selective FGFR inhibitors is urgently needed.

[0014] Summary of the Invention

[0015] To improve the above technical problems, the present invention provides a compound represented by formula (I) and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt:

[0016] in:

[0017] Ring A and Ring B are the same or different and are independently selected from C 6-14 Aromatic ring or 5-14 membered heteroaromatic ring;

[0018] Ring C is selected from C 10-14 Aromatic ring or 5-14 membered heteroaromatic ring;

[0019] X is selected from O or NH;

[0020] R1 is selected from H, C 1-6 Alkyl, halogenated C 1-6 Alkyl or cyano-C 1-6 alkyl;

[0021] Each R a 、R b , R2 are the same or different and are independently selected from H, halogen, cyano, hydroxyl, unsubstituted or optionally substituted by one, two or more R a1 Substituted with the following groups: amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, -OC 3-8 Cycloalkyl, 3-8 membered heterocyclyl or -O-(3-8 membered heterocyclyl); each R a1 the same or different, independently selected from halogen, cyano, amino, hydroxy, oxo (=O), C 1-6 Alkyl or C 1-6 alkoxy;

[0022] Each R c The same or different, independently selected from H, halogen, cyano, hydroxyl, unsubstituted or optionally substituted by one, two or more R c1 Substituted with the following groups: amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, -COR c11 or -S(O)2-R c12 ; R c11 、R c12 The same or different, independently selected from C 1-6 Alkyl, C 1-6 Alkoxy or amino; each R c1 the same or different, independently selected from halogen, cyano, amino, hydroxy, oxo (=O), C 1-6 Alkyl, C 1- 6-alkoxy, -S(O)2-C 1-6 Alkyl; or two R attached to the same carbon atom c1Together with the connected carbon atom, it forms C 3- 8 cycloalkyl rings;

[0023] R3 is selected from hydrogen, R 3a -C 1-4 Alkyl; R 3a Selected from

[0024] m, s, q are the same or different and are independently selected from 0, 1, 2, 3, 4 or 5;

[0025] p is selected from 0, 1, 2 or 3.

[0026] According to some embodiments, ring A and ring B are the same or different and are independently selected from a benzene ring or a 5-6 membered heteroaromatic ring.

[0027] According to some embodiments, Ring C is selected from a 5-6 membered heteroaromatic ring.

[0028] According to some embodiments, ring A is selected from a pyridine ring or a benzene ring.

[0029] According to some embodiments, ring B is selected from a pyridine ring or a pyridazine ring.

[0030] According to some embodiments, ring C is selected from a pyrazole ring, a pyridine ring, a pyrimidine ring or a 2(1H)-pyridone ring.

[0031] According to some embodiments, each R a The same or different, independently selected from C 1-6 Alkyl or halogen.

[0032] According to some embodiments, each R a are identical or different and are independently selected from F, Cl or methyl.

[0033] According to some embodiments, each R b The same or different, independently selected from C 1-6 Alkyl or halogen.

[0034] According to some embodiments, each R b are the same or different and are independently selected from methyl, F or Cl.

[0035] According to some embodiments, each R c The same or different, independently selected from H, unsubstituted or optionally substituted by one, two or more R c1 Substituted with the following groups: C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, -CONH2 or -S(O)2-C 1- 6 alkyl; each Rc1 The same or different, independently selected from cyano, hydroxy, oxo (=O), mesyl or C 1-6 Alkyl; or two R attached to the same carbon atom c1 Together with the connected carbon atom, it forms C 3-6 Cycloalkyl ring.

[0036] According to some embodiments, each R c are the same or different and are independently selected from H, methyl, ethyl, n-propyl, isopropyl, 2-cyanoisopropyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl,

[0037] According to some embodiments, Selected from Position 1 is connected to the indazole ring, and position 2 is connected to ring C.

[0038] According to some embodiments, Selected from

[0039] According to some embodiments, Selected from

[0040] According to some embodiments, Selected from

[0041] According to some embodiments, X is selected from O.

[0042] According to some embodiments, R1 is selected from methyl.

[0043] According to some embodiments, each R2 is the same or different and is independently selected from H, cyano, halogen, C 1-6 Alkyl, C 1- 6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-8 Cycloalkyl, -OC 3-8 Cycloalkyl, -O-(3-8 membered heterocyclic group).

[0044] According to some embodiments, each R2 is the same or different and is independently selected from H, F, Cl, methyl, methoxy, difluoromethoxy, cyano, ethyl, ethoxy, cyclopropyl,

[0045] According to some embodiments, R3 is selected from hydrogen.

[0046] According to some embodiments, R3 is selected from

[0047] According to some embodiments, the compound represented by formula (I) has the structure shown below:

[0048] Among them, ring A, ring B, ring C, X, R1, R2, R a 、R b 、R c , s, p, q, m have the definitions described in this document.

[0049] According to some embodiments, the compound represented by formula (I) has the structure shown below:

[0050] Among them, ring A, ring B, ring C, X, R1, R2, R a 、R b 、R c , s, p, q, m have the definitions described in this document.

[0051] According to some embodiments, the compound represented by formula (I) has the structure shown below:

[0052] Among them, ring A, ring B, ring C, R2, R a 、R b 、R c , s, p, q, m have the definitions described in this document.

[0053] According to some embodiments, the compound represented by formula (I) has the structure shown below:

[0054] Among them, R2, R a 、R b 、R c , s, p, q, m have the definitions described in this document.

[0055] According to some embodiments, the compound represented by formula (I) has the structure shown below:

[0056] Among them, R2, R3, R a 、R b 、R c , s, q, and m have the definitions described in this document.

[0057] According to some embodiments, among the compounds represented by formula (I) and their racemates, stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts, illustrative, non-limiting specific examples of the compounds represented by formula (I) are as follows:

[0058] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by formula (I) and at least one of its racemates, stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs, or pharmaceutically acceptable salts.

[0059] According to an embodiment of the present invention, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0060] The excipients in the pharmaceutical compositions are "acceptable" in the sense that they are compatible with the active ingredient of the composition (and preferably, capable of stabilizing the active ingredient) and not deleterious to the subject being treated. One or more pharmaceutical excipients can be used to deliver the active compound.

[0061] According to some embodiments of the present invention, the pharmaceutical composition may further contain one or more additional therapeutic agents.

[0062] The present invention further provides the use of a compound represented by formula (I) and at least one of its racemates, stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof, or said pharmaceutical composition in the preparation of a drug.

[0063] According to some embodiments, the medicament is a medicament for diagnosing, preventing and / or treating a disease or disorder mediated by FGFR2 and / or FGFR3.

[0064] According to some embodiments, the drug is a FGFR2 and / or FGFR3 inhibitor.

[0065] According to some embodiments, the disease is FGFR-related cancer.

[0066] According to some embodiments, the disease or disorder is selected from bladder cancer, brain cancer, breast cancer, bile duct cancer, head and neck cancer, lung cancer, multiple myeloma, rhabdomyosarcoma, urethral cancer, uterine cancer.

[0067] According to some embodiments, the disease is FGFR-related hypochondroplasia or achondroplasia.

[0068] According to some embodiments, the compound represented by formula (I) and its racemate, stereoisomer, tautomer, isotope label, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or at least one of its pharmaceutically acceptable salts can be made into a form suitable for administration by any appropriate route, and formulated using one or more pharmaceutically acceptable carriers by conventional methods. Therefore, the compound represented by formula (I) and its racemate, stereoisomer, tautomer, isotope label, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or at least one of its pharmaceutically acceptable salts can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular or subcutaneous) administration, inhalation or insufflation administration; can also be formulated into sustained release dosage forms, such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges or syrups.

[0069] The present invention also provides a method for diagnosing, preventing and / or treating diseases or conditions mediated by FGFR2 and / or FGFR3, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) and at least one of its racemates, stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts, or a pharmaceutical composition of the present invention, alone, or optionally, in combination with another compound of the present invention and / or at least one other type of therapeutic agent.

[0070] According to some embodiments, the FGFR2 and / or FGFR3 mediated disease or condition is selected from bladder cancer, brain cancer, breast cancer, bile duct cancer, head and neck cancer, lung cancer, multiple myeloma, rhabdomyosarcoma, urethral cancer, uterine cancer and achondroplasia.

[0071] In some embodiments, the patient is a mammal, preferably a human. Beneficial effects

[0072] The compounds provided by the present invention have good FGFR2 and / or FGFR3 inhibitory effects and can be used to treat or prevent conditions and diseases related to FGFR2 and / or FGFR3, as well as to prepare drugs for treating or preventing such conditions and diseases.

[0073] Definitions and Explanations of Terms

[0074] Unless otherwise indicated, the definitions of groups and terms in this specification and claims, including definitions used as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in the Examples, may be arbitrarily combined and coupled with one another. The group definitions and compound structures resulting from such combinations and couplings should be understood to be within the scope of this specification and / or claims.

[0075] The term "optional" (or "optionally", "optionally") in the general formula definitions of this application means the situation of being substituted by zero, one or more substituents, for example, "optionally substituted by one, two or more R" means that it may not be substituted by R (unsubstituted) or may be optionally substituted by one, two or more R.

[0076] "More" means three or more, for example, 3, 4, 5, 6, 7, 8, 9 or 10.

[0077] Unless otherwise indicated, numerical ranges recited in this specification and claims are equivalent to reciting at least each specific integer value therein. For example, the numerical range "1-12" is equivalent to reciting each integer value in the numerical range "1-12", namely, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12.

[0078] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0079] The term "C 1-6 The term "alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or the like or isomers thereof.

[0080] The term "C 3-8"Cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic (such as bridged ring, spirocyclic) hydrocarbon ring having 3, 4, 5, 6, 7, 8 carbon atoms. 3-8 The cycloalkyl group may be a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as borneol, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonyl, 2,6-diazaspiro[3,4]octyl.

[0081] The term "3-8 membered heterocyclyl" means a saturated or unsaturated non-aromatic ring or ring system, and contains at least one heteroatom selected from O, S and N. The heterocyclyl may be connected to the rest of the molecule through any one of the carbon atoms or nitrogen atom (if present). The heterocyclyl may include fused or bridged rings and spirocyclic rings. In particular, the heterocyclyl may include, but is not limited to, 4-membered rings such as azetidinyl, oxetanyl, 5-membered rings such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, or 6-membered rings such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl, or 7-membered rings such as diazepanyl. Optionally, the heterocyclyl may be benzo-fused. The heterocyclic group may be bicyclic, such as, but not limited to, a 5,5-membered ring, such as a hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6-membered bicyclic ring, such as a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The heterocyclic group may be partially unsaturated, i.e., it may contain one or more double bonds, such as, but not limited to, dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl, or 4H-[1,4]thiazinyl, or it may be benzo-fused, such as, but not limited to, dihydroisoquinolinyl. When the 3-8 membered heterocyclic group is linked to other groups to form the compounds of the present invention, the linking may be to a carbon atom of the 3-8 membered heterocyclic group or to a heterocyclic atom on the 3-8 membered heterocyclic group ring. For example, when the 3-8 membered heterocyclic group is selected from piperazinyl, the nitrogen atom on the piperazinyl group may be connected to the other group. Or when the 3-8 membered heterocyclic group is selected from piperidinyl, the nitrogen atom on the piperidinyl ring and the carbon atom at the para position thereof may be connected to the other group.

[0082] The term "5-6 membered heteroaromatic ring" is understood to include monovalent monocyclic rings having 5 or 6 ring atoms and containing 1 to 5, preferably 1 to 3, heteroatoms independently selected from N, O and S. Examples include, for example, pyrazole, thiophene, furan, imidazole, thiazole, oxazole, isoxazole, pyrimidine, pyridine, pyridone (e.g. ), pyrazine ring, pyridazine ring. When the 5-6 membered heteroaromatic ring is connected to other groups to form the compound of the present invention, the carbon atom on the 5-6 membered heteroaromatic ring can be connected to the other group, or the heteroatom on the 5-6 membered heteroaromatic ring can be connected to the other group. When the 5-6 membered heteroaromatic ring is substituted, it can be monosubstituted or polysubstituted. In addition, there is no limitation on the substitution site, for example, a hydrogen atom connected to a carbon atom on the heteroaromatic ring can be substituted, or a hydrogen atom connected to a heteroatom on the heteroaromatic ring can be substituted.

[0083] The term "nitrogen oxide" refers to a compound formed by oxidation of a nitrogen atom in a tertiary amine or nitrogen-containing (aromatic) heterocyclic compound structure.

[0084] The term "spirocyclic" refers to a ring system in which two rings share one ring atom.

[0085] The term "fused ring" refers to a ring system in which two rings share two ring atoms.

[0086] The term "bridged ring" refers to a ring system in which two rings share three or more ring atoms.

[0087] Unless otherwise specified, a heterocyclic group, heteroaryl group, or heteroarylene group includes all possible isomeric forms thereof, such as positional isomers thereof. Thus, for some illustrative non-limiting examples, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-positions, etc. (if present) may include 1, 2, or more substituted or bonded forms thereof, including pyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene, pyridin-4-ylene, and pyridin-4-ylene; thienyl or thienylene group includes thien-2-yl, thien-2-ylene, thien-3-ylene, and thien-3-ylene; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, and pyrazol-5-yl.

[0088] The term "oxo" refers to a substituent in which a carbon atom, a nitrogen atom, or a sulfur atom is oxidized to form an oxy group (=O).

[0089] The term "alkylamino" refers to -NH-(alkyl) or -N-(alkyl)2, wherein alkyl is as defined above. Non-limiting examples of alkylamino include methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, methylethylamino, diethylamino, dipropylamino, methylpropylamino, diisopropylamino, dibutylamino, and the like.

[0090] The term "alkyloxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkyloxy, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, or heterocycloalkyloxy.

[0091] The terms "alkyleneoxy" and "oxyalkylene" refer to -alkylene-O- or -O-alkylene-, where alkylene represents a linear or branched saturated divalent hydrocarbon radical. The definition of "alkyl" with respect to the number of carbon atoms in "alkylene" applies as defined above. It will be understood by those skilled in the art that an alkyleneoxy or oxyalkylene group can be attached to the remainder of the molecule in which it is contained in any orientation, i.e., the two terms are used interchangeably.

[0092] "Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0093] In the present invention, the compounds referred to also include isotopically labeled compounds, which are the same as those shown in Formula I, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of H, C, N, O, S, F, and Cl, such as 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 32 P. 35 S. 18 F and 36 Cl. Compounds of the invention, prodrugs thereof, or pharmaceutically acceptable salts of said compounds or prodrugs containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the invention. Certain isotopically labeled compounds of the invention, for example, those incorporating radioactive isotopes (such as 3 H and 14C) compounds can be used in drug and / or substrate tissue distribution assays. 3 H) and carbon 14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. 2 Substitution with hydrogen (H or D) may provide certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) derived from greater metabolic stability and may therefore be preferred in certain circumstances. The compounds of the present invention as claimed in the claims may be specifically limited to substitution with deuterium or tritium. Furthermore, the absence of separate listing of the term deuterium or tritium for hydrogen present in a substituent does not exclude deuterium or tritium, but rather may also include deuterium or tritium.

[0094] It will be appreciated by those skilled in the art that the compounds of formula (I) may exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they may form acid addition salts; if these compounds have an acidic center, they may form base addition salts; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they may also form internal salts.

[0095] The compounds of the present invention may exist in the form of solvates (e.g., hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0096] Depending on their molecular structure, the compounds of the present invention may be chiral and therefore may exist in various enantiomeric forms. Thus, these compounds may exist in racemic or optically active forms. The compounds of the present invention encompass isomers or mixtures thereof, racemates, in which each chiral carbon is in the R or S configuration. The compounds of the present invention or their intermediates can be separated into enantiomeric compounds by chemical or physical methods well known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are prepared from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, appropriate N-protected amino acids (e.g., N-benzoylproline or N-phenylsulfonylproline) or various optically active camphorsulfonic acids. Chromatographic enantiomer resolution can also be advantageously performed with the aid of optically active resolving agents (e.g., dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chirally derivatized methacrylate polymers immobilized on silica gel). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, e.g., hexane / isopropanol / acetonitrile.

[0097] The corresponding stable isomers can be separated according to known methods, for example by extraction, filtration or column chromatography.

[0098] The term "patient" refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.

[0099] The term "therapeutically effective amount" refers to that amount of an active compound or drug that will elicit the biological or medical response that a researcher, veterinarian, physician, or other clinician is seeking in a tissue, system, animal, individual, or human, and includes one or more of the following: (1) prevents disease, e.g., prevents a disease, disorder, or condition in an individual who is susceptible to the disease, disorder, or condition but who is not yet experiencing or developing the pathology or symptoms of the disease. (2) inhibits disease, e.g., inhibits the disease, disorder, or condition (i.e., prevents further development of the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition. (3) alleviates disease, e.g., alleviates the disease, disorder, or condition (i.e., reverses the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition. DETAILED DESCRIPTION

[0100] The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are encompassed within the scope of protection that the present invention is intended to protect.

[0101] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0102] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, using deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as the solvents, with tetramethylsilane (TMS) as the internal standard.

[0103] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1200 Infinity Series mass spectrometer, and HPLC was performed using an Agilent 1200DAD high-pressure liquid chromatograph and a Waters 2695-2996 high-pressure liquid chromatograph.

[0104] Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0105] Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, with dry solvents and reaction temperatures in degrees Celsius.

[0106] Example 1 Synthesis of intermediate INT-1

[0107] 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0108] first step

[0109] Acetonitrile (100 mL) was added to 1H-indazole-5-ol INT-1a (11 g, 0.082 mol), TBSCl (14.8 g, 0.098 mol) and imidazole (8.4 g, 0.123 mol), and the reaction solution was stirred at room temperature for 16 hours. After the reaction, it was concentrated, washed with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. After concentration, it was separated and purified on a silica gel column (petroleum ether / ethyl acetate = 2 / 1) to give 5-((tert-butyldimethylsilyl)oxy)-1H-indazole INT-1b (20 g) in a yield of 99%.

[0110] 1 H NMR (400MHz, CDCl3) δ7.79(s,1H),7.15(d,J=8.9Hz,1H),6.93(d,J=2.0Hz,1H),6.77(dd,J=8.9,1.9Hz,1H),0.80(s,9H),-0.00(s,6H).

[0111] Step 2

[0112] To a dichloromethane solution (200 mL) of 5-((tert-butyldimethylsilyl)oxy)-1H-indazole INT-1b (20 g, 0.081 mol) was added NIS (20 g, 0.089 mol) at 0 degrees Celsius. The reaction solution was stirred at room temperature for 4 hours. After completion of the reaction, the product was washed with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The product was separated and purified on a silica gel column (petroleum ether / ethyl acetate = 5 / 1) to give 5-((tert-butyldimethylsilyl)oxy)-3-iodo-1H-indazole INT-1c (27 g) in a yield of 89%.

[0113] 1 H NMR (400MHz, CDCl3) δ7.52(d,J=8.9Hz,1H),7.08(dd,J=8.9,2.2Hz,1H),6.89(d,J=1.9Hz,1H),1.05(s,9H),0.26(s,6H).

[0114] Step 3

[0115] Tetrahydrofuran (200 mL) was added to 5-((tert-butyldimethylsilyl)oxy)-3-iodo-1H-indazole INT-1c (27 g, 0.072 mol), DHP (18.1 g, 0.216 mol) and PTSA (1.2 g, 0.0072 mol), and the reaction solution was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was concentrated, washed with saturated ammonium chloride, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After concentration, the mixture was separated and purified on a silica gel column (petroleum ether / ethyl acetate = 5 / 1) to give 5-((tert-butyldimethylsilyl)oxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole INT-1d (28 g) in a yield of 85%.

[0116] 1 H NMR (400MHz, CDCl3) δ7.42(d,J=9.0Hz,1H),7.01(dd,J=8.9,2.2Hz,1H),6.81(d,J=2.2Hz,1H),5.63(dd,J=9.4,2.7Hz,1H),4.06–3.99(m ,1H),3.72(td,J=11.1,2.8Hz,1H),2.53(tdd,J=11.6,10.3,4.0Hz,1H),2.18–2.02(m,2H),1.80–1.62(m,3H),1.01(s,9H),0.21(s,6H).

[0117] Step 4

[0118] To a solution of 5-((tert-butyldimethylsilyl)oxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole INT-1d (28 g, 0.061 mol) in tetrahydrofuran (200 mL) was added 1 M tetrabutylammonium fluoride in tetrahydrofuran (67 mL, 0.067 mol), and the reaction solution was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated, washed twice with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated, separated and purified by silica gel column (petroleum ether / ethyl acetate = 2 / 1) to give 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-ol INT-1e (19 g) in a yield of 90%.

[0119] 1 H NMR (400MHz, CD3OD_SPE) δ7.48(d,J=9.0Hz,1H),7.04(d,J=11.2Hz,1H),6.70(d,J=2.2Hz,1H),5.68(dd,J=9.8,2.6Hz,1H),3.95(d,J=11.5Hz,1H),3. 75(td,J=11.1,3.0Hz,1H),3.30(dt,J=3.1,1.5Hz,1H),2.50–2.37(m,1H), 2.08(ddd,J=7.7,6.6,3.8Hz,1H),1.96(d,J=3.3Hz,1H),1.84–1.57(m,3H).

[0120] Step 5

[0121] To 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-ol INT-1e (5 g, 0.014 mol), (S)-1-(3,5-dichloropyridin-4-yl)ethyl methanesulfonate (4.7 g, 0.017 mol) and cesium carbonate (7.1 g, 0.022 mol) was added DMF (50 mL), and the reaction solution was stirred at 80 degrees Celsius for 16 hours. After completion of the reaction, the mixture was filtered, washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and separated and purified on a silica gel column (petroleum ether / ethyl acetate = 5 / 1) to give 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole INT-1 (6.8 g) in a yield of 94%.

[0122] 1H NMR (400MHz, CDCl3) δ8.42 (s, 2H), 7.44 (dd, J=9.1, 2.9Hz, 1H), 7.15 (dd, J=9 .1,2.3Hz,1H),6.69(d,J=2.2Hz,1H),6.06(q,J=6.7Hz,1H),5.59(ddd,J=9.3 ,6.6,2.7Hz,1H),4.02–3.94(m,1H),3.73–3.63(m,1H),2.55–2.42(m,1H),2 .14–1.96(m,2H),1.81(d,J=6.7Hz,3H),1.68(ddd,J=23.1,12.9,5.1Hz,3H).

[0123] Example 2 Synthesis of Intermediate INT-2

[0124] first step

[0125] 2-Bromo-5-hydroxy-4-methoxybenzaldehyde INT-2a (3 g, 13 mmol) was dissolved in methanol (20.0 mL). p-Toluenesulfonylhydrazide (2.44 g, 1.31 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 5 hours. The solvent was then evaporated to dryness, and cuprous oxide (140 mg, 0.1 mmol) and 1,4-dioxane (10.0 mL) were added. The mixture was refluxed at 100°C for 12 hours. The reaction mixture was then filtered, concentrated, and purified by column chromatography (EA / PE = 30%) to obtain 6-methoxy-1-toluenesulfonyl-1H-indazol-5-ol INT-2b (2.3 g, 55%).

[0126] MS m / z (ESI): 319.1 (M+H) + .

[0127] Step 2

[0128] 6-Methoxy-1-tosyl-1H-indazol-5-ol INT-2b (2.3 g, 7.2 mmol) was dissolved in DMF (25 mL), and cesium carbonate (3.25 g, 10 mmol) and (R)-ethyl 1-(3,5-dichloropyridin-4-yl)methanesulfonate (2.69 g, 10 mmol) were added. The reaction mixture was stirred at 80°C under nitrogen for 16 hours. Water (20 mL) was then added, and the mixture was extracted with ethyl acetate and dried by evaporation. A solution of TBAF in THF (1.0 mol / mL, 10.0 mL) was then added, and the mixture was allowed to react at room temperature for 72 hours. After the reaction, water (20 mL) was added, and the mixture was extracted with ethyl acetate and dried by evaporation to obtain the crude product (S)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-1H-indazole INT-2c (850 mg, 35%).

[0129] MS m / z (ESI): 338.1 (M+H) + .

[0130] Step 3

[0131] (S)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-1H-indazole INT-2c (0.85 g, 2.5 mmol) was dissolved in THF (5.0 mL), and sodium hydroxide (200 mg, 5 mmol) and elemental iodine (635 mg, 5 mmol) were added. The reaction solution was stirred at room temperature for 3 hours. After completion of the reaction, saturated sodium thiosulfate solution (5.0 mL) was added, and the product was extracted with ethyl acetate and dried by spin chromatography (mobile phase: ethyl acetate / petroleum ether = 1 / 10 to 5 / 1) to produce (S)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-iodo-6-methoxy-1H-indazole INT-2 (750 mg, 65%).

[0132] MS m / z(ESI):463.9(M+H) + .

[0133] Example 3

[0134] first step

[0135] 5-(((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole INT-1 (300 mg, 0.58 mmol) was dissolved in a dioxane / water = 5 / 1 (5 mL) solution, and (6-chloropyridin-3-yl)boric acid (91 mg, 0.58 mmol), potassium carbonate (240 mg, 1.773 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (84 mg, 0.11 mmol) were added. Under a nitrogen atmosphere, the mixture was stirred at 90 degrees for 3 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (3x The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1) to give 3-(6-chloropyridin-3-yl)-5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole 01a (300 mg) in a yield of 92%.

[0136] MS m / z(ESI):503.3(M+H) + .

[0137] Step 2

[0138] 3-(6-chloropyridin-3-yl)-5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole 01a (280 mg, 0.55 mmol) was dissolved in a dioxane / water = 5 / 1 (5 mL) solution, and (1-methyl-1H-pyrazol-4-yl)boronic acid (70 mg, 0.55 mmol), potassium carbonate (230 mg, 1.60 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (80 mg, 0.11 mmol) were added. The mixture was stirred at 90 degrees under a nitrogen atmosphere for 3 hours. After the reaction was completed, water was added to quench the reaction and the mixture was extracted with ethyl acetate (3 x 30 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1) to give 5-(((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole 01b (230 mg) in a yield of 67.78%.

[0139] MS m / z (ESI): 549.2 (M+H) + .

[0140] Step 3

[0141] 5-(((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-1-(tetrahydro-2H-pyrazol-2-yl)-1H-indazole 01b (230 mg, 0.41 mmol) was dissolved in dichloromethane (2 mL), and trifluoroformic acid (238 mg, 2.09 mmol) was added. The reaction mixture was stirred at 20 degrees for 3 hours. After the reaction, the mixture was concentrated under reduced pressure to obtain a crude product, which was then purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: Xbridge 5u C18 150x 19 mm; mobile phase 1: water (containing 0.1% 0.1FA); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 47% to 100%, flow rate: 25 mL / min) purified and lyophilized to obtain (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-1H-indazole Cpd-01 (102.48 mg) in a 51% yield. MS m / z (ESI): 465.0 (M+H) + .

[0142] 1 H NMR (400MHz, DMSO-d6) δ13.27(s,1H),8.96(d,J=2.0Hz,1H),8.61(s,2H),8.39(s,1H),8.23–7.98(m,1H),7.83(d,J=8.4Hz,1H),7 .53(d,J=9.2Hz,1H),7.27(d,J=2.0Hz,1H),7.13(dd,J=9.2,2.2Hz,1H),6.16(d,J=6.8Hz,1H),3.93(s,3H),1.78(d,J=6.8Hz,3H).

[0143] Example 4 Synthesis of Intermediate INT-3

[0144] first step

[0145] To a solution of 4-amino-2,5-dimethylphenol INT-3a (2 g, 0.014 mol) and potassium acetate (2.87 g, 0.029 mol) in CHCl₃ (50 mL) at 0°C was added acetic anhydride (4.47 g, 0.043 mol) and stirred at room temperature for 30 minutes. 18-Crown-6-ether (0.195 g, 0.0007 mol) and isoamyl nitrite (3.85 g, 0.0328 mol) were added to the solution and stirred at 80°C for 20 hours. The mixture was quenched with NaHCO₃ (aq.), extracted with DCM, and dried over anhydrous sodium sulfate. The crude product was dissolved in methanolic ammonia and stirred at room temperature for 16 hours. The organic phase was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to afford 6-methyl-1H-indazol-5-ol INT-3b (1.2 g) in a 55.5% yield.

[0146] 1 H NMR (400MHz, DMSO-d6) δ12.60(s,1H),9.07(s,1H),7.78(s,1H),7.22(s,1H),6.97(s,1H),2.24(s,3H).

[0147] Step 2

[0148] Acetonitrile (20 mL) was added to 6-methyl-1H-indazol-5-ol INT-3b (1.2 g, 0.008 mol), TBSCl (1.46 g, 0.009 mol) and imidazole (0.8 g, 0.012 mol), and the reaction solution was stirred at room temperature for 16 hours. After the reaction, it was concentrated and washed with saturated ammonium chloride solution. The organic phase was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After concentration, it was separated and purified on a silica gel column (petroleum ether / ethyl acetate = 2 / 1) to give 5-((tert-butyldimethylsilyl)oxy)-6-methyl-1H-indazole INT-3c (1.7 g) in a yield of 57%.

[0149] Step 3

[0150] To a dichloromethane solution (20 mL) of 5-((tert-butyldimethylsilyl)oxy)-6-methyl-1H-indazole INT-3c (1.7 g, 0.0065 mol) was added NIS (1.61 g, 0.00715 mol) at 0 degrees Celsius. The reaction solution was stirred at room temperature for 4 hours. After completion of the reaction, the mixture was washed with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. After separation and purification on a silica gel column (petroleum ether / ethyl acetate = 5 / 1), 5-((tert-butyldimethylsilyl)oxy)-3-iodo-6-methyl-1H-indazole INT-3d (2.2 g) was obtained in a yield of 83%.

[0151] Step 4

[0152] Tetrahydrofuran (20 mL) was added to 5-((tert-butyldimethylsilyl)oxy)-3-iodo-6-methyl-1H-indazole INT-3d (2.2 g, 0.0057 mol), DHP (1.44 g, 0.0171 mol) and PTSA (0.1 g, 0.00057 mol), and the reaction solution was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was concentrated, washed with saturated ammonium chloride, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After concentration, the mixture was separated and purified on a silica gel column (petroleum ether / ethyl acetate = 5 / 1) to give 5-((tert-butyldimethylsilyl)oxy)-3-iodo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole INT-3e (2.8 g) in a yield of 98%.

[0153] 1 H NMR(400MHz, DMSO-d6)δ7.34(s,1H),6.43(s,1H),5.50(dd,J=9.7,2.4Hz,1H),3.56–3.43(m,2H), 2.08(s,3H),1.82–1.65(m,2H),1.57–1.44(m,2H),1.25–1.17(m,2H),0.78(s,9H),-0.00(s,6H).

[0154] Step 5

[0155] To a solution of 5-((tert-butyldimethylsilyl)oxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole INT-3e (3 g, 0.0064 mol) in tetrahydrofuran (20 mL) was added 1 M tetrabutylammonium fluoride in tetrahydrofuran (1.84 g, 0.007 mol). The reaction solution was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated, washed twice with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. After separation and purification on a silica gel column (petroleum ether / ethyl acetate = 2 / 1), 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-ol INT-3f (1.2 g) was obtained in a yield of 50%.

[0156] 1 H NMR (400MHz, DMSO-d6) δ9.53(s,1H),7.47(s,1H),6.67(s,1H),5.70(dd,J=9.8,2.3Hz,1H),3.86(d,J =11.3Hz,1H),3.78–3.65(m,1H),2.27(s,3H),1.95(ddd,J=13.1,10.2,3.3Hz,2H),1.79–1.42(m,4H).

[0157] Step 6

[0158] To 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-ol INT-3f (1.2 g, 3.4 mmol), (R)-1-(3,5-dichloropyridin-4-yl)ethyl methanesulfonate (1.1 g, 0.004 mol) and cesium carbonate (1.66 g, 0.0051 mol) was added DMF (10 mL), and the reaction solution was stirred at 80°C for 16 h. After completion of the reaction, the mixture was filtered, washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and separated and purified on a silica gel column (petroleum ether / ethyl acetate = 5 / 1) to give 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-3-iodo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole INT-3 (1.1 g) in a yield of 60%.

[0159] 1 H NMR(400MHz, DMSO-d6)δ8.63(s,2H),7.58(s,1H),6.38(s,1H),6.02(tt,J=10.0,5.1Hz,1H),5.74–5.67(m,1H),3.84(t,J=12.7Hz,1H), 3.75–3.63(m,1H),2.43(s,3H),2.36–2.24(m,1H),1.96-1.85(m,2H),1.78(d,J=6.6Hz,3H),1.73-1.63(m,1H),1.56(t,J=11.0Hz,2H).

[0160] Example 5

[0161] first step

[0162] Under nitrogen protection, a mixed solution of 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-3-iodo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole INT-3 (200 mg, 0.4436 mmol), (6-chloropyridin-3-yl)boranediol (105.35 mg, 0.6694 mmol), potassium carbonate (123.37 mg, 0.8926 mmol) and Pd(dppf)Cl2 (32.66 mg, 0.0446 mmol) in 1,4-dioxane / H2O (5 / 1,6 mL) was stirred at 80 °C for 4 hours. After the reaction, the mixture was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 3-(6-chloropyridin-3-yl)-5-[(1R)-1-(3,5-dichloropyridin-4-yl)ethoxy]-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole Cpd-26a (160 mg) in a yield of 78%.

[0163] Step 2

[0164] Under nitrogen protection, a mixed solution of 3-(6-chloropyridin-3-yl)-5-[(1R)-1-(3,5-dichloropyridin-4-yl)ethoxy]-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole Cpd-26a (160 mg, 0.3090 mmol), [1-(2-hydroxyethyl)pyrazol-4-yl]boranediol (72.28 mg, 0.4635 mmol), potassium carbonate (85.41 mg, 0.618 mmol) and Pd(dppf)Cl2 (22.61 mg, 0.0309 mmol) in 1,4-dioxane / H2O (5 / 1,6 mL) was stirred at 80 °C for 4 hours. After the reaction, the mixture was concentrated and separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 2-[4-(5-(5-[(1R)-1-(3,5-dichloropyridin-4-yl)ethoxy]-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyridin-2-yl)-1H-pyrazol-1-yl]ethan-1-ol Cpd-26b (123 mg) in a yield of 64%.

[0165] Step 3

[0166] 2-[4-(5-(5-[(1R)-1-(3,5-dichloropyridin-4-yl)ethoxy]-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyridin-2-yl)-1H-pyrazol-1-yl]ethan-1-ol Cpd-26b (123 mg, 0.2072 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1.5 mL) was added, and the mixture was stirred at room temperature for 2 h. After completion of the reaction, the mixture was concentrated and prepared to afford (R)-2-(4-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methyl-1H-indazol-3-yl)pyridin-2-yl)-1H-pyrazol-1-yl)ethan-1-ol Cpd-26 (20 mg) in an 18% yield.

[0167] MS m / z (ESI): 509.39 (M+H) + .

[0168] 1 H NMR (400MHz, DMSO-d6) δ13.15(s,1H),8.91(d,J=2.1Hz,1H),8.66(s,2H),8.41(s,1H),8.13(s,1H),8.04(s,1H),7.86(d,J=7.3Hz,1 H),7.42(s,1H),6.97(s,1H),6.10(q,J=6.5Hz,1H),4.23(t,J=5.4Hz,2H),3.81(t,J=5.4Hz,2H),2.43(s,3H),1.81(d,J=6.6Hz,3H).

[0169] Example 6 Synthesis of Intermediates INT-4A and INT-4B

[0170] To a solution of 3-methyl-1H-pyrazole-4-boronic acid pinacol ester (commercially available) (5.0 g, 24.0 mmol) in DMF (25 mL) were added cesium carbonate (7.82 g, 24.0 mmol) and 2,2-dimethyloxirane (5.19 g, 72.0 mmol). The reaction solution was stirred at 100 degrees Celsius for 2.5 hours. After the reaction was completed, the filtrate was collected by filtration, quenched with water, extracted twice with ethyl acetate, and the organic phase was collected and washed five times with saturated brine. After concentration, the mixture INT-4M was obtained, which was separated by supercritical fluid (SFC) (mobile phase: CO2 / MeOH [0.2% NH3 (7M Solution in MeOH)]=50 / 50) were used to obtain 2-methyl-1-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol INT-4A (tR =0.810 min) (3.1 g), 2-methyl-1-(5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol INT-4B (t R =1.046 min) (2.5 g), yield 83%.

[0171] INT-4A

[0172] 1 H NMR (400MHz, DMSO-d6) δ7.71(s,1H),3.92(s,2H),2.23(s,3H),1.25(s,12H),1.04(s,6H).

[0173] INT-4B

[0174] 1 H NMR (400MHz, DMSO-d6) δ7.47(s,1H),3.93(s,2H),2.41(s,3H),1.25(s,12H),1.09(s,6H).

[0175] Example 7

[0176] first step

[0177] Under N2 protection, 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-3-iodo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole INT-3 (1.10 g, 2.06 mmol), (6-chloro-5-fluoropyridin-3-yl)boronic acid (commercially available) (0.47 g, 2.68 mmol), potassium carbonate (0.57 g, 4.12 mmol) and Pd(dppf)Cl2 (0.1 g) were stirred in a 1,4-dioxane / water (volume ratio 10 / 1, 10 mL) solution at 90 °C for 3 h. After the reaction, the reaction solution was concentrated and separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 3-(6-chloro-5-fluoropyridin-3-yl)-5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole Cpd-67a (900 mg) in a yield of 82%.

[0178] Step 2

[0179] Under N2 protection, compound Cpd-67a (200 mg, 0.37 mmol), INT-4A (135 mg, 0.48 mmol), potassium carbonate (153 mg, 1.11 mmol) and Pd(dppf)Cl2 (40 mg) were stirred in a 1,4-dioxane / water = 10 / 1 (10 mL) solution at 100 °C for 7 h. After the reaction, the reaction solution was concentrated and separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 1-(4-(5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-3-fluoropyridin-2-yl)-3-methyl-1H-pyrazol-1-yl)-2-methyl-2-propanol Cpd-67c (170 mg) in a yield of 70%.

[0180] MS m / z(ESI):653.2(M+H)

[0181] Step 3

[0182] To Cpd-67c (170 mg, 0.26 mmol) was added a 4 M methanol solution of hydrogen chloride (5 mL), and the reaction mixture was stirred at 45 degrees Celsius for 2 hours. After completion of the reaction, the mixture was concentrated directly and separated and purified on a silica gel column (dichloromethane / methanol = 10 / 1) to give (R)-1-(4-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methyl-1H-indazol-3-yl)-3-fluoropyridin-2-yl)-3-methyl-1H-pyrazol-1-yl)-2-methyl-2-propanol Cpd-67 (110 mg) in a yield of 74%.

[0183] MS m / z(ESI):569.2(M+H) + .

[0184] 1 HNMR(400MHz,DMSO-d6)δ8.80(t,J=1.6Hz,1H),8.61(s,2H),8.16(d,J=3.6Hz,1H),7.91 (dd,J=12.4,1.6Hz,1H),7.44(s,1H),6.98(s,1H),6.12(q,J=6.8Hz,1H), 4.06(s,2H),2.56(s,3H),2.44(s,3H),1.81(d,J=6.4Hz,3H),1.12(s,6H).

[0185] Using conditions similar to those in the above examples, the compounds listed in Table 1 were prepared. The structural characterization data of these compounds are listed in Table 1.

[0186] Table 1

[0187] Biological evaluation

[0188] Test Example 1: Inhibitory effect of the disclosed compounds on the proliferation of Ba / F3-FGFR1, Ba / F3-FGFR2, Ba / F3-FGFR3 and Ba / F3-FGFR4 cells.

[0189] The CTG method was used to detect the inhibitory effect of the compounds on the proliferation of Ba / F3-FGFR1 and Ba / F3-FGFR3 cells. The highest concentration tested was 3000 nM, with a three-fold dilution gradient, 10 concentrations, and duplicate well detection.

[0190] 1.1 Experimental Materials

[0191] 1.1.1 Reagents and consumables

[0192] 1.1.2 Instruments

[0193] 1.2 Experimental steps

[0194] a) Ba / F3-FGFR1, Ba / F3-FGFR2, Ba / F3-FGFR3 and Ba / F3-FGFR4 are cultured to the exponential growth phase for later use.

[0195] Complete culture medium: RPMI1640 medium, 10% FBS, 1% GlutaMAX and P / S, 10 ng / mL FGF1, 10 μg / mL Heparin, 10 μM 2-mercaptoethanol, 2 μg / mL puromycin.

[0196] b) Using an ECHO pipetting station, dilute the compound stock solution from 3000 nM into a 384-well plate and centrifuge at 1000 g for 1 min.

[0197] c) The cells were digested and 30 μL of Ba / F3-FGFR1, Ba / F3-FGFR2, Ba / F3-FGFR3, or Ba / F3-FGFR4 (500 / well) were evenly plated in a 384-well black-edged cell culture plate containing the compound. The edge wells were blocked with 50 μL of PBS and the plate was cultured in a 37°C CO2 incubator for 72 h.

[0198] d) Add 30 μL of Cell-Titer-Glo reagent to each well, shake on a shaker to mix, and then incubate at 37°C for 30 min. After the signal stabilizes, detect it on a microplate reader.

[0199] 1.3 Experimental Results

[0200] Table 2 Test results of the inhibitory activity of representative compounds of the present invention on Ba / F3 cells

[0201] The experimental results show that the representative compounds of the present invention have potent inhibitory activity and good selectivity against Ba / F3-FGFR2 / 3 cells.

[0202] The above is an exemplary description of the implementation methods of the technical solution of the present invention. It should be understood that the scope of protection of the present invention is not limited to the above implementation methods. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art within the spirit and principles of the present invention shall be included in the scope of protection of the claims of this application.

Claims

1. A compound represented by formula (I) and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt: in: Ring A and Ring B are the same or different and are independently selected from C 6-14 Aromatic ring or 5-14 membered heteroaromatic ring; Ring C is selected from C 10-14 Aromatic ring or 5-14 membered heteroaromatic ring; X is selected from O or NH; R1 is selected from H, C 1-6 Alkyl, halogenated C 1-6 Alkyl or cyano-C 1-6 alkyl; Each R a , R b , R2 are the same or different and are independently selected from H, halogen, cyano, hydroxyl, unsubstituted or optionally substituted by one, two or more R a1 Substituted with the following groups: amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, -OC 3- 8-membered cycloalkyl, 3-8-membered heterocyclyl or -O-(3-8-membered heterocyclyl); each R a1 are the same or different and are independently selected from halogen, cyano, amino, hydroxyl, oxo (=O), C 1-6 Alkyl or C 1-6 Alkoxy; Each R c are the same or different and are independently selected from H, halogen, cyano, hydroxyl, unsubstituted or optionally substituted by one, two or more R c1 Substituted with the following groups: amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, -COR c11 or -S(O)2-R c12 ; R c11 , R c12 The same or different, independently selected from C 1-6 Alkyl, C 1-6 Alkoxy or amino; each R c1 are the same or different and are independently selected from halogen, cyano, amino, hydroxyl, oxo (=O), C 1-6 Alkyl, C 1- 6-alkoxy, -S(O)2-C 1-6 Alkyl; or two R attached to the same carbon atom c1 Together with the carbon atom to which it is attached, it forms C 3-8 Cycloalkyl ring; R3 is selected from hydrogen, R 3a -C 1-4 Alkyl; R 3a Selected from m, s, q are the same or different and are independently selected from 0, 1, 2, 3, 4 or 5; p is selected from 0, 1, 2 or 3.

2. The compound according to claim 1, characterized in that Ring A and Ring B are the same or different and are independently selected from a benzene ring or a 5-6-membered heteroaromatic ring; Ring C is selected from a 5-6-membered heteroaromatic ring; Preferably, ring A is selected from a pyridine ring or a benzene ring; Preferably, ring B is selected from a pyridine ring or a pyridazine ring; Preferably, ring C is selected from a pyrazole ring, a pyridine ring, a pyrimidine ring or a 2(1H)-pyridone ring. Preferably, each R a The same or different, independently selected from C 1-6 Alkyl or halogen; Preferably, each R a are the same or different and are independently selected from F, Cl or methyl; Preferably, each R b The same or different, independently selected from C 1-6 Alkyl or halogen; Preferably, each R b are the same or different and are independently selected from methyl, F or Cl; Preferably, each R c are the same or different and are independently selected from H, unsubstituted or optionally substituted with one, two or more R c1 Substituted with the following groups: C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, -CONH2 or -S(O)2-C 1-6 Alkyl; each R c1 are the same or different and are independently selected from cyano, hydroxy, oxo (=O), mesyl or C 1-6 Alkyl; or two R attached to the same carbon atom c1 Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl ring; Preferably, each R c are the same or different and are independently selected from H, methyl, ethyl, n-propyl, isopropyl, 2-cyanoisopropyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, Preferably, Selected from The 1 position is connected to the indazole ring, and the 2 position is connected to ring C; Preferably, Selected from Preferably, Selected from Preferably, Selected from 3. The compound according to claim 1, characterized in that X is selected from O; Preferably, R1 is selected from methyl; Preferably, each R2 is the same or different and is independently selected from H, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-8 Cycloalkyl, -OC 3-8 Cycloalkyl, -O-(3-8 membered heterocyclyl); Preferably, each R2 is the same or different and is independently selected from H, F, Cl, methyl, methoxy, difluoromethoxy, Cyano, ethyl, ethoxy, cyclopropyl, Preferably, R3 is selected from hydrogen, 4. The compound according to any one of claims 1 to 3, characterized in that The compound represented by formula (I) has the structure shown below: Among them, ring A, ring B, ring C, X, R1, R2, R a , R b , R c , s, p, q, m have the definitions as described in any one of claims 1-3; Preferably, the compound represented by formula (I) has the structure shown below: Among them, ring A, ring B, ring C, X, R1, R2, R a , R b , R c , s, p, q, m have the characteristics as claimed in claims 1-3 Any of the definitions above.

5. The compound according to any one of claims 1 to 4, characterized in that The compound represented by formula (I) has the structure shown below: Among them, ring A, ring B, ring C, R2, R a , R b , R c , s, p, q, m have the definitions as described in any one of claims 1-4; Preferably, the compound represented by formula (I) has the structure shown below: Among them, R2, R a , R b , R c , s, p, q, m have the definitions as described in any one of claims 1-4; Alternatively, the compound represented by formula (I) has the structure shown below: Among them, R2, R3, R a , R b , R c , s, q, and m have the definitions as defined in any one of claims 1-4.

6. The compound according to any one of claims 1 to 5, characterized in that The compound is selected from the following structures:

7. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 6 and at least one of its racemates, stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof.

8. Use of at least one of the compound according to any one of claims 1 to 6 and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 7 in the preparation of a drug, Preferably, the drug is a FGFR2 and / or FGFR3 inhibitor; Preferably, the medicament is for use in the diagnosis, prevention and / or treatment of a disease or condition mediated by FGFR2 and / or FGFR3.

9. A method for diagnosing, preventing and / or treating a disease or condition mediated by FGFR2 and / or FGFR3, the method comprising administering an effective amount of at least one compound according to any one of claims 1 to 6 or a pharmaceutical composition according to claim 7 alone, or optionally, in combination with at least one other type of therapeutic agent, to a patient in need of such treatment.

10. The use according to claim 8 or the method according to claim 9, characterized in that The FGFR2 and / or FGFR3 mediated disease or symptom is selected from cancer, chondrodysplasia or achondroplasia. Preferably, the cancer is selected from bladder cancer, brain cancer, breast cancer, bile duct cancer, head and neck cancer, lung cancer, multiple myeloma, rhabdomyosarcoma, urethral cancer, and uterine cancer.

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