Indazole FGFR2 / 3 selective inhibitor, pharmaceutical composition and application thereof

Abstract

The invention provides a compound as shown in a formula (I) and a racemate, a stereoisomer, a tautomer, an isotope label, nitrogen oxide, a solvate, a polymorphic substance, a metabolite, ester, a prodrug or pharmaceutically acceptable salt thereof. The compound has a good FGFR2 / 3 inhibition effect, can be used for treating or preventing FGFR2 / 3 mediated diseases and diseases, and can be used for preparing medicines for treating or preventing the diseases and diseases. # imgabs0 #

Description

[0001] This application claims priority to a prior application filed with the State Intellectual Property Office of China on July 13, 2023, with patent application number 202310860221.5 and invention name “Indazole FGFR3 selective inhibitors, pharmaceutical compositions and their applications”. The entire text of the prior application is incorporated into this application by reference. Technical Field

[0002] The present invention belongs to the field of medical technology, and specifically relates to indazole FGFR2 / 3 selective inhibitors, pharmaceutical compositions and applications thereof. Background Art

[0003] Fibroblast growth factor receptor (FGFR), an important 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-channel transmembrane structure and a cytoplasmic tyrosine kinase domain. In humans, there are four typical tyrosine kinase receptors (FGFR1-4) and a FGFR5 that lacks an intracellular tyrosine kinase domain. There are 18 members of the ligand fibroblast growth factor (FGF) of FGFRs. Under normal physiological conditions, FGFRs bind to their ligand fibroblast growth factor, FGFRs dimerize and self-phosphorylate. When FGF binds to FGFRs, it can activate and amplify signal pathways, and can activate downstream signal pathways such as the JAK / STAT pathway, phospholipase C pathway, phosphoinositide-3-kinase PI3K and MAPK signal pathways (Turner, N., Grose, R., Nat. Ref. Cancer 2010; 10: 116-129; Brooks, NS et al., Clin Cancer Res. 2012; 18: 18551862; Dienstmann, R. et al., Ann. Oncol. 2014; 25: 552-563).

[0004] In 2015, a study published in the journal Clinical Cancer Research described the mutation of FGFR in 4853 patient samples from various cancers using next-generation sequencing technology, including mutation, amplification and rearrangement. Among the 4853 cancers sequenced, the study observed 360 FGFR mutations in 343 cases (17 cancers had multiple FGFR changes), with a total incidence of 7.1% (Helsten T, Elkin S, Arthur E, Tomson BN, Carter J, Kurzrock R. The FGFRLandscape 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, validating FGFR signaling as an attractive target for cancer therapy.

[0005] Fibroblast growth factor receptor 3 (FGFR3) is a transmembrane tyrosine kinase receptor protein that plays an important role in cartilage development and cartilage homeostasis. FGFR3 is considered to be a negative regulator in the development of endochondral ossification. In the early stages of bone development, it is first expressed in chondrocytes in the mesenchymal condensation center, and then in the proliferation zone and prehypertrophic zone of growth plate cartilage and articular cartilage. Genetic mutations in human FGFR3 can lead to a series of skeletal deformities.

[0006] The enhancing point mutation of FGFR3 leads to skeletal dysplasia with clinical manifestations of short stature, including thanatophoric dysplasia (TD I / II) and achondroplasia (ACH); while the inactivating point mutation of human FGFR3 can lead to CATSHL syndrome, which is characterized by hearing loss, tall stature and bowed fingers.

[0007] Tyrosine kinase inhibitors can be divided into non-covalent inhibitors and covalent inhibitors. Among non-covalent inhibitors, multi-target or selective inhibitors are further distinguished. 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-target TKls (tyrosine kinase inhibitors) have shown clinical benefits, and Ponatinib and Nintedanib were 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, especially the inhibition of VEGFRs, which limits the therapeutic dose. Therefore, 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.).

[0008] 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, and there is an urgent need to develop highly selective FGFR inhibitors. Summary of the invention

[0009] In order 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:

[0010]

[0011] in:

[0012] 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;

[0013] X is selected from O or NH;

[0014] R1 is selected from H, C 1-6 Alkyl, halogenated C 1-6 Alkyl or cyano-C 1-6 alkyl;

[0015] 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 or 3-8 membered heterocyclic group; 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;

[0016] Y is selected from unsubstituted or optionally substituted with one, two or more R y Substituted fused ring group; the fused ring group comprises two, three or four independently selected from C 3-14 Carbon ring, C 6-14 an aromatic ring, a 5- to 14-membered heteroaromatic ring, or a 3- to 14-membered heterocyclic ring;

[0017] Alternatively, Y is selected from unsubstituted or optionally substituted with one, two or more R e Replaced wherein ring E is selected from a 3-8 membered nitrogen-containing monocyclic heterocycle;

[0018] Each R y , R e are the same or different and are independently selected from H, halogen, cyano, hydroxyl, oxo (=O), unsubstituted or optionally substituted by one, two or more R y1 Substituted with the following groups: amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, -C(O)R y2 or-SO2R y3 ; R y2 , R y3The same or different, independently selected from C 1-6 Alkyl, C 1-6 Alkoxy; each R y1 are the same or different and are independently selected from H, halogen, cyano, amino, hydroxyl, oxo (=O), C 1-6 Alkyl or C 1-6 Alkoxy;

[0019] s and q are the same or different and are independently selected from 0, 1, 2, 3, 4 or 5;

[0020] p is selected from 0, 1, 2 or 3.

[0021] 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.

[0022] According to some embodiments, Ring A is selected from a pyridine ring.

[0023] According to some embodiments, ring B is selected from a pyridine ring or a pyridazine ring.

[0024] According to some embodiments, each R a The same or different, independently selected from C 1-6 Alkyl or halogen.

[0025] According to some embodiments, each R a are the same or different and are independently selected from F, Cl or methyl.

[0026] According to some embodiments, each R b The same or different, independently selected from C 1-6 Alkyl or halogen.

[0027] According to some embodiments, each R b are the same or different and are independently selected from methyl, F or Cl.

[0028] According to some embodiments, Selected from:

[0029] According to some embodiments, Selected from:

[0030] According to some embodiments, X is selected from O.

[0031] According to some embodiments, R1 is selected from methyl.

[0032] According to some embodiments, each R2 is the same or different and is independently selected from halogen, C 1-6 Alkyl or C 1-6 Alkoxy.

[0033] According to some embodiments, each R2 is the same or different and is independently selected from F, Cl, methyl or methoxy.

[0034] According to some embodiments, Y is selected from the following groups:

[0035]

[0036] Wherein, ring C is selected from C 3-14 Carbocyclic ring, 3-14 membered heterocyclic ring; Ring D is selected from C 6-14 Aromatic ring, 5-14 membered heteroaromatic ring;

[0037] Each R c are the same or different and are independently selected from H, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy or oxo (=O);

[0038] Each R d are the same or different and are independently selected from H, halogen, cyano, hydroxyl, unsubstituted or optionally substituted by one, two or more R d1 Substituted with the following groups: amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, -C(O)R d2 or-SO2R d3 ; R d2 , R d3 The same or different, independently selected from C 1-6 Alkyl or C 1-6 Alkoxy; each R d1 are the same or different and are independently selected from H, halogen, cyano, amino, hydroxyl, oxo (=O), C 1-6 Alkyl or C 1-6 Alkoxy;

[0039] m and n are the same or different and are independently selected from 0, 1, 2, 3, 4 or 5.

[0040] According to some embodiments, ring C is selected from C 5-6 Carbocyclic or 5-6 membered heterocyclic ring;

[0041] According to some embodiments, ring C is selected from in represents a single bond or a double bond, and the bond is a bond fused to the D ring;

[0042] According to some embodiments, ring D is selected from a benzene ring or a 5-6 membered heteroaromatic ring;

[0043] According to some embodiments, ring D is selected from a benzene ring, a triazole ring, an imidazole ring, a pyrazole ring, a thiazole ring, a pyridine ring or a pyrimidine ring.

[0044] According to some embodiments, each R c are the same or different and are independently selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or oxo (=O);

[0045] According to some embodiments, each R d are the same or different and are independently selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or -S(=O)2-C 1-6 alkyl;

[0046] According to some embodiments, each R d are identical or different and are independently selected from H, methyl, methoxy, isopropyl, trifluoromethyl or methanesulfonyl.

[0047] According to some embodiments, Selected from the following groups:

[0048]

[0049] wherein Z is selected from CH or N; W1 is selected from C, CH or N; W2 is selected from CH2, NH, O or S; and ring D has the definition described herein.

[0050] According to some embodiments, Selected from the following groups:

[0051]

[0052] According to some embodiments, ring E is selected from

[0053] According to some embodiments, each R e the same or different, independently selected from hydroxy-C 1-6 Alkyl, -C(O)C 1-6 Alkyl, -S(=O)2-C 1-6 Alkyl or C 3-8 Cycloalkyl;

[0054] According to some embodiments, each R e are identical or different and are independently selected from 2-hydroxyisopropyl, propionyl, methanesulfonyl or cyclopropyl.

[0055] According to some embodiments, Y is selected from the following groups:

[0056]

[0057]

[0058] According to some embodiments, the compound represented by formula (I) has the structure shown below:

[0059]

[0060]

[0061] Among them, ring A, ring B, X, Y, R1, R2, R a , R b , s, p, q have the definitions described in this document.

[0062] According to some embodiments, the compound represented by formula (I) has the structure shown below:

[0063]

[0064] Among them, ring A, ring B, ring C, ring D, ring E, X, R1, R2, R a , R b , R c , R d , R e , s, p, q, m, n have the definitions described herein, and r is selected from 0, 1, 2, 3, 4 or 5.

[0065] According to some embodiments, the compound represented by formula (I) has the structure shown below:

[0066]

[0067]

[0068] Among them, ring A, ring B, ring D, X, Z, W1, W2, R1, R2, R a , R b , R c , R d , s, p, q, m, n have the definitions described in this document.

[0069] 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:

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076] 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.

[0077] According to an embodiment of the present invention, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0078] 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 may be used for delivery of the active compound.

[0079] According to some embodiments of the present invention, the pharmaceutical composition may further contain one or more additional therapeutic agents.

[0080] The present invention further provides the use of the 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 the pharmaceutical composition in the preparation of drugs.

[0081] According to some embodiments, the medicament is a medicament for diagnosing, preventing and / or treating a disease or condition mediated by FGFR2 and / or FGFR3.

[0082] According to some embodiments, the drug is a FGFR2 and / or FGFR3 inhibitor.

[0083] According to some embodiments, the disease is FGFR-related cancer.

[0084] 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.

[0085] According to some embodiments, the disease is FGFR-related hypochondroplasia or achondroplasia.

[0086] According to some embodiments, the compound shown in 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 prepared by conventional methods using one or more pharmaceutically acceptable carriers. Therefore, the compound shown in 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; It 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.

[0087] The present invention also provides a method for diagnosing, preventing and / or treating a disease or condition mediated by FGFR2 and / or FGFR3, which comprises administering to a patient in need of such treatment 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 thereof, or a pharmaceutical composition of the present invention, alone or in combination with another compound of the present invention and / or at least one other type of therapeutic agent.

[0088] 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.

[0089] In some embodiments, the patient is a mammal, preferably a human.

[0090] Beneficial Effects

[0091] The compounds provided by the present invention have good FGFR2 and / or FGFR3 inhibitory effects, and can be used to treat or prevent FGFR2 and / or FGFR3-related disorders and diseases, as well as to prepare drugs for treating or preventing such disorders and diseases.

[0092] Definition and explanation of terms

[0093] Unless otherwise specified, the definitions of groups and terms recorded in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be arbitrarily combined and combined with each other. The definitions of groups and compound structures after such combinations and combinations should be understood to be within the scope of the specification and / or claims of this application.

[0094] The term "optional" (or "optionally", "optionally") in the general formula definitions of the present 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 selectively substituted by one, two or more R.

[0095] "More" means three or more, for example 3, 4, 5, 6, 7, 8, 9 or 10.

[0096] Unless otherwise specified, the numerical ranges recorded in this specification and claims are equivalent to recording at least each specific integer value therein. For example, the numerical range "1-14" is equivalent to recording each integer value in the numerical range "1-14", namely 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14.

[0097] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0098] "HO-C 1-6 "Alkyl" refers to a hydroxy-substituted C 1-6 of alkyl.

[0099] 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.

[0100] The term "C 3-8 "Cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic (eg bridged, spiro) hydrocarbon ring having 3, 4, 5, 6, 7, 8 carbon atoms. 3-8The 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]nonanyl, 2,6-diazaspiro[3,4]octanyl.

[0101] The term "3-10 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 the 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, for example 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]pyrazine-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 3-10-membered heterocyclic group is connected to other groups to form the compounds of the present invention, the carbon atoms on the 3-10-membered heterocyclic group may be connected to other groups, or the heterocyclic atoms on the 3-10-membered heterocyclic group may be connected to other groups. For example, when the 3-10 membered heterocyclic group is selected from piperazinyl, the nitrogen atom on the piperazinyl group may be connected to other groups. Or when the 3-10 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 other groups.

[0102] The term "5-10 membered heteroaryl" is understood to include monovalent monocyclic or bicyclic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms and containing 1 to 5, preferably 1 to 3, heteroatoms independently selected from N, O and S and, in each case, may additionally be benzo-fused. Examples of monocyclic "heteroaryl" include, for example, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazinyl, oxazinyl, triazinyl, thiadiazinyl or oxadiazinyl, etc. "Heteroaryl" also refers to a group in which a heteroaromatic ring is fused to one or more aryl, alicyclic or heterocyclyl rings, wherein the site of attachment is on the heteroaromatic ring. Non-limiting examples include 1-, 2-, 3-, 5-, 6-, 7-, or 8-indolizinyl, 1-, 3-, 4-, 5-, 6-, or 7-isoindolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-indazolyl, 2-, 4-, 5-, 6-, 7-, or 8-purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl, 2-, 3-, 4-, 5- or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 6- or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-4aH carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-carbazolyl carbazolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8- or 9-carbazolyl -carbolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenanthridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-piperidinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9- or 10-phenanthrolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenothiazinyl, 1-, 2-, 3-, 4-, 6 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-phenazinyl, 2-, 3-, 4-, 5-, 6-, or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-benzoisoquinolyl, 2-, 3-, 4-, or thieno[2,3-b]furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-7H-pyrazino[2,3-c]carbazolyl, 2-, 3-, 5-, 6-, or 7-2H-furo[3,2-b]pyranyl, 2-, 3-, 4-, 5-, 7-, or 8-5H-pyrido[2,3-d]-o-oxazinyl, 1-, 3- or 5-1H-pyrazolo[4,3-d]-oxazolyl, 2-, 4- or 5-4H-imidazo[4,5-d]thiazolyl, 3-, 5- or 8-pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5- or 6-imidazo[2,1-b]thiazolyl, 1-, 3-, 6-, 7-, 8- or 9-furo[3,4-c]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10 or 11-4H-pyrido[2,3-c]carbazolyl, 2-, 3-, 6- or 7-imidazo[1,2-b][1,2, 4-, 5-, 6-, 7-, 8-, or 9-benzoxapinyl, 2-, 4-, 5-, 6-, 7-, or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-4H-pyrrolo[1,2-b][2]benzazepinyl. Typical fused heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, and 2-, 4-, 5-, 6-, or 7-benzothiazolyl. When the 5-10 membered heteroaryl group is connected to other groups to form the compound of the present invention, it can be a carbon atom on the 5-10 membered heteroaryl ring connected to other groups, or it can be a heteroatom on the 5-10 membered heteroaryl ring connected to other groups. When the 5-10 membered heteroaryl group is substituted, it can be monosubstituted or polysubstituted. Furthermore, there is no limitation on the substitution site, for example, the hydrogen bonded to the carbon atom on the heteroaryl ring may be substituted, or the hydrogen bonded to the heteroatom on the heteroaryl ring may be substituted.

[0103] 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.

[0104] The term "spirocyclic" refers to a ring system in which two rings share one ring-forming atom.

[0105] The term "bridged ring" refers to a ring system in which two rings share three or more ring atoms.

[0106] Unless otherwise specified, heterocyclic groups, heteroaryls or heteroarylene groups include all possible isomeric forms thereof, such as positional isomers thereof. Thus, for some illustrative non-limiting examples, forms substituted or bonded to other groups at 1, 2 or more positions in the 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-positions, etc. (if present) may include pyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene, pyridin-4-ylene and pyridin-4-ylene; thienyl or thienylene groups include thien-2-yl, thien-2-ylene, thien-3-ylene and thien-3-ylene; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl.

[0107] 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).

[0108] 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.

[0109] The term "alkyloxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkyloxy, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy or heterocycloalkyloxy.

[0110] The terms "alkyleneoxy" and "oxyalkylene" refer to -alkylene-O- or -O-alkylene-, wherein alkylene represents a straight or branched saturated divalent hydrocarbon group. The definition of the number of carbon atoms in "alkylene" applies to the definition of "alkyl" above. It will be understood by those skilled in the art that alkyleneoxy or oxyalkylene can be attached to the rest of the molecule containing it in any direction, i.e., the two can be used interchangeably.

[0111] "Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0112] When L is selected from -C(=O)-N(R a)-, it indicates that the group connected to ring A can be either the carbonyl group in L or the N group in L; when the carbonyl group is connected to ring A, the N group in L is connected to the pyrazolopyridine ring, and when the N group is connected to the carbonyl group, the carbonyl group in L is connected to the pyrazolopyridine ring.

[0113] In the present invention, the compounds involved 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 occurring 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 said prodrugs containing the above-mentioned 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 14 C) 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 H or D) substitution 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 invention as claimed in the claims may be specifically limited to substitution with deuterium or tritium. In addition, the presence of hydrogen in a substituent without the term deuterium or tritium being separately listed does not exclude deuterium or tritium, but may also include deuterium or tritium.

[0114] Those skilled in the art will appreciate 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 a base addition salt; 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 an inner salt.

[0115] The compounds of the present invention may exist in the form of solvates (e.g. hydrates), wherein the compounds of the present invention contain polar solvents as structural elements of the crystal lattice of the compounds, in particular water, methanol or ethanol. The amount of polar solvents, in particular water, may exist in a stoichiometric or non-stoichiometric ratio.

[0116] According to its molecular structure, the compounds of the present invention may be chiral, and therefore various enantiomeric forms may exist. Thus, these compounds may exist in racemic form or optically active form. The compounds of the present invention encompass isomers or mixtures, racemates in which each chiral carbon is in R or S configuration. The compounds of the present invention or their intermediates can be separated into enantiomeric compounds by chemical or physical methods 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 resolution agent. Examples of suitable resolution agents are optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-phenylsulfonylproline) or various optically active camphorsulfonic acids in R and S forms. Chromatographic enantiomer resolution can also be advantageously carried out with the aid of optically active resolving agents such as dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatized methacrylate polymers immobilized on silica gel. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example, hexane / isopropanol / acetonitrile.

[0117] The corresponding stable isomers can be separated according to known methods, for example by extraction, filtration or column chromatography.

[0118] 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.

[0119] The term "therapeutically effective amount" refers to the amount of an active compound or drug that elicits 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) Preventing disease: e.g., preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but does not yet experience or develop the pathology or symptoms of the disease. (2) Inhibiting disease: e.g., inhibiting a disease, disorder or condition (i.e., preventing 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) Alleviating disease: e.g., alleviating a disease, disorder or condition (i.e., reversing 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

[0120] The technical scheme of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary descriptions 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 included in the scope that the present invention is intended to protect.

[0121] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0122] The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shift (δ) is given in parts per million (ppm). The NMR is measured using a Bruker AVANCE-400 nuclear magnetic spectrometer, and the measurement solvents are deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD) and deuterated chloroform (CDCl3), and the internal standard is tetramethylsilane (TMS).

[0123] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1200 Infinity Series mass spectrometer, and HPLC was performed using an Agilent 1200 DAD high pressure liquid chromatograph and a Waters 2695-2996 high pressure liquid chromatograph.

[0124] 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.

[0125] Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature is in degrees Celsius.

[0126] Example 1 Synthesis of Intermediate (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-1H-indazole INT-1

[0127]

[0128] first step

[0129] 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 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 by silica gel column (petroleum ether / ethyl acetate = 2 / 1) to obtain 5-((tert-butyldimethylsilyl)oxy)-1H-indazole INT-1b (20 g) with a yield of 99%. 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).

[0130] Step 2

[0131] 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, and the reaction solution was stirred at room temperature for 4 hours. After the reaction, the mixture was washed with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and separated and purified on a silica gel column (petroleum ether / ethyl acetate = 5 / 1) to obtain 5-((tert-butyldimethylsilyl)oxy)-3-iodo-1H-indazole INT-1c (27 g) with a yield of 89%.

[0132] 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).

[0133] Step 3

[0134] 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 the reaction, it was concentrated, washed with saturated ammonium chloride, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After concentration, it was separated and purified by 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) with a yield of 85%.

[0135] 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).

[0136] Step 4

[0137] To a tetrahydrofuran solution (200 mL) of 5-((tert-butyldimethylsilyl)oxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole INT-1d (28 g, 0.061 mol) 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 the reaction, it was concentrated, washed twice with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and 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), with a yield of 90%.

[0138] 1H 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).

[0139] Step 5

[0140] DMF (50 mL) was added 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), and the reaction solution was stirred at 80 degrees Celsius for 16 h. After the reaction, it was filtered, washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and separated and purified by silica gel column (petroleum ether / ethyl acetate=5 / 1) to obtain 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole INT-1 (6.8 g) with a yield of 94%.

[0141] 1 H 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).

[0142] Example 2 Synthesis of Intermediate (S)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-iodo-6-methoxy-1H-indazole INT-2

[0143]

[0144] first step

[0145] 2-Bromo-5-hydroxy-4-methoxybenzaldehyde INT-2a (3 g, 13 mmol) was dissolved in methanol (20.0 mL), p-toluenesulfonyl hydrazide (2.44 g, 1.31 mmol) was added at room temperature, and the reaction solution was stirred at room temperature for 5 hours. The solvent was then dried, and cuprous oxide (140 mg, 0.1 mmol) and 1,4-dioxane (10.0 mL) were added, and refluxed at 100°C for 12 hours. The reaction solution was then filtered, concentrated, and purified by column chromatography (EA / PE = 30%) to obtain the product 6-methoxy-1-toluenesulfonyl-1H-indazole-5-ol INT-2b (2.3 g, 55%).

[0146] MS m / z (ESI): 319.1 (M+H).

[0147] Step 2

[0148] 6-Methoxy-1-tosyl-1H-indazole-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)-1-(3,5-dichloropyridin-4-yl) ethyl methanesulfonate (2.69 g, 10 mmol) were added. The reaction solution was stirred at 80 ° C for 16 hours under nitrogen protection. Then water (20 mL) was added, extracted with ethyl acetate and dried by rotation, and TBAF THF solution (1.0 mol / mL, 10.0 mL) was added and reacted at room temperature for 72 hours. After the reaction was completed, water (20 mL) was added, extracted with ethyl acetate and dried by rotation to obtain the crude product (S)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-1H-indazole INT-2c (850 mg, 35%).

[0149] MS m / z (ESI): 338.1 (M+H).

[0150] Step 3

[0151] (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 iodine (635 mg, 5 mmol) were added. The reaction solution was stirred at room temperature for 3 hours. After the reaction was completed, saturated sodium thiosulfate solution (5.0 mL) was added, extracted with ethyl acetate and dried by spin drying, and purified by column chromatography (mobile phase: ethyl acetate / petroleum ether = 1 / 10 to 5 / 1) to obtain the product (S)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-iodo-6-methoxy-1H-indazole INT-2 (750 mg, 65%).

[0152] MS m / z (ESI): 463.9 (M+H).

[0153] Example 3

[0154] Synthesis of (R)-7-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)pyridin-2-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine Cpd-015

[0155]

[0156] first step

[0157] 5-Bromo-2-fluoropyridine (274 mg, 1 mmol) and N,N-diisopropylethylamine (403 mg, 3 mmol) were added to a solution of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine 15a (300 mg, 1 mmol) in dimethyl sulfoxide (5 mL). The reaction mixture was stirred at 90 degrees for 1 hour. After the reaction was completed, water was added to quench the reaction and the mixture was extracted with ethyl acetate (3 x 10 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 obtain 7-(5-bromopyridin-2-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine 15b (70 mg) with a yield of 11.59%.

[0158] MS m / z (ESI): 348.0 (M+H).

[0159] Step 2

[0160] 7-(5-bromopyridin-2-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine 15b (70 mg, 0.2 mmol) was dissolved in 1,4-dioxane (5 mL), and diboron ester (76 mg, 0.3 mmol), potassium acetate (39 mg, 0.4 mmol) and 1,1'-bis(diphenylphosphino)ferrocene (14 mg, 0.02 mmol) were added. The reaction mixture was stirred at 90 degrees for 16 hours. After the reaction was completed, water was added to quench and extracted with ethyl acetate (3x 10 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: dichloromethane / methanol=93 / 7) to give (6-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)pyridin-3-yl)boronic acid 15c (50 mg) in a yield of 71.5%.

[0161] MS m / z (ESI): 314.0 (M+H).

[0162] Step 3

[0163] To a solution of (6-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)pyridin-3-yl)boronic acid 15c (50 mg, 0.1 mmol) in 1,4-dioxane:water=5:1 (6 mL) was added 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-3-iodo-1-(tetrahydro 2H-pyran-2-yl)-1H-indazole INT-1 (65 mg, 0.1 mmol), potassium carbonate (34 mg, 0.2 mmol) and 1,1'-bis(diphenylphosphino)ferrocene (9 mg, 0.01 mmol). The reaction mixture was stirred at 90 degrees for 1 hour. After the reaction was completed, water was added to quench and extracted with ethyl acetate (3x 10 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: dichloromethane / methanol=93 / 7) to give 7-(5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyridin-2-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine 15d (50 mg), yield: 53.9%.

[0164] MS m / z (ESI): 659.0 (M+H).

[0165] Step 4

[0166] 7-(5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyridin-2-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine 15d (50 mg, 0.07 mmol) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (1 mL) was added dropwise. The reaction mixture was stirred at 25 degrees for 1 hour. After the reaction was completed, the reaction was quenched with water and extracted with ethyl acetate (3×10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The concentrate was purified by preparative purification and lyophilized to give (R)-7-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)pyridin-2-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine Cpd-015 (8.7 mg), yield: 19.6%. MS m / z (ESI): 575.0 (M+H).

[0167] 1 H NMR (400MHz, CDCl3) δ8.71(s,1H),8.44(s,2H),8.06(d,J=8.3Hz,1H),7.40(d,J=8.9Hz,1H),7.18(d,J=3.1Hz,1H),7.15 (d,J=1.7Hz,1H),6.89(d,J=8.2Hz,1H),6.06(d,J=6.7Hz,1H),5.05(s,2H),4.32(d,J=4.5Hz,4H),1.83(d,J=6.6Hz,3H).

[0168] With reference to the similar conditions in the above Example 3, the compounds shown in Table 1 below were prepared, and their structural characterization data are shown in Table 1.

[0169] Table 1

[0170]

[0171]

[0172] Biological evaluation

[0173] Test Example 1: Inhibitory effect of the disclosed compounds on the proliferation of Ba / F3-FGFR1, Ba / F3-FGFR2 and BaF3-FGFR3 cells.

[0174] The CTG method was used to detect the inhibitory effect of the compounds on the proliferation of Ba / F3-FGFR1, Ba / F3-FGFR2 and BaF3-FGFR3 cells. The highest concentration tested was 3000nM, with a three-fold dilution gradient, 10 concentrations, and duplicate well detection.

[0175] 1.1 Experimental Materials

[0176] 1.1.1 Reagents and consumables

[0177]

[0178] 1.1.2 Instruments

[0179]

[0180]

[0181] 1.2 Experimental procedures

[0182] a) Ba / F3-FGFR1, Ba / F3-FGFR2 and BaF3-FGFR3 cells were cultured to exponential growth phase for later use.

[0183] Complete culture medium: RPMI1640 medium, 10% FBS, 1% GlutaMAX and P / S, 10ng / mL FGF1, 10μg / mL Heparin, 10μM 2-mercaptoethanol, 2μg / mL puromycin

[0184] b) Using the ECHO Liquid Handling Station, dilute the compound stock solution from 3000 nM into a 384-well plate and centrifuge at 1000 g for 1 min.

[0185] c) Digest the cells, evenly spread 30 μL of Ba / F3-FGFR1, Ba / F3-FGFR2 and BaF3-FGFR3 (500 / well) in a 384-well black-edged cell culture plate containing the compound, seal the edge wells with 50 μL of PBS, and continue culturing in a 37°C CO2 incubator for 72 h.

[0186] d) Add 30 μL of Cell-Titer-Glo reagent to each well, place on a shaker to mix, and then incubate at 37°C for 30 min. After the signal is stable, detect it on an enzyme reader.

[0187] 1.3 Experimental Results

[0188] Table 1 Test results of representative compounds of the present invention for the inhibitory activity against Ba / F3 cells

[0189]

[0190] 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.

[0191] The above is an exemplary description of the implementation of the technical solution of the present invention. It should be understood that the protection scope of the present invention is not limited to the above implementation. Any modification, equivalent substitution, improvement, etc. made by those skilled in the art within the spirit and principle of the present invention should be included in the protection scope 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; 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 or 3-8 membered heterocyclic group; 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; Y is selected from unsubstituted or optionally substituted with one, two or more R y Substituted fused ring group; the fused ring group comprises two, three or four independently selected from C 3-14 Carbon ring, C 6-14 an aromatic ring, a 5- to 14-membered heteroaromatic ring, or a 3- to 14-membered heterocyclic ring; Alternatively, Y is selected from unsubstituted or optionally substituted with one, two or more R e Replaced wherein ring E is selected from a 3-8 membered nitrogen-containing monocyclic heterocycle; Each R y , R e are the same or different and are independently selected from H, halogen, cyano, hydroxyl, oxo (=O), unsubstituted or optionally substituted by one, two or more R y1 Substituted with the following groups: amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, -C(O)R y2 or-SO2R y3 ; R y2 , R y3 The same or different, independently selected from C 1-6 Alkyl, C 1-6 Alkoxy; each R y1 are the same or different and are independently selected from H, halogen, cyano, amino, hydroxyl, oxo (=O), C 1-6 Alkyl or C 1-6 Alkoxy; s and 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; Preferably, ring A is selected from a pyridine ring; Preferably, ring B is selected from a pyridine ring or a pyridazine 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, Selected from: Preferably, Selected from: Preferably, X is selected from O; Preferably, R1 is selected from methyl; Preferably, each R2 is the same or different and is independently selected from halogen, C 1-6 Alkyl or C 1-6 Alkoxy; Preferably, each R2 is the same or different and independently selected from F, Cl, methyl or methoxy.

3. The compound according to any one of claims 1 to 2, characterized in that Y is selected from the following groups: Wherein, ring C is selected from C 3-14 Carbocyclic ring, 3-14 membered heterocyclic ring; Ring D is selected from C 6-14 Aromatic ring, 5-14 membered heteroaromatic ring; Each R c are the same or different and are independently selected from H, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy or oxo (=O); Each R d are the same or different and are independently selected from H, halogen, cyano, hydroxyl, unsubstituted or optionally substituted by one, two or more R d1 Substituted with the following groups: amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, -C(O)R d2 or-SO2R d3 ; R d2 , R d3 The same or different, independently selected from C 1-6 Alkyl or C 1-6 Alkoxy; each R d1 are the same or different and are independently selected from H, halogen, cyano, amino, hydroxyl, oxo (=O), C 1-6 Alkyl or C 1-6 Alkoxy; m and n are the same or different and are independently selected from 0, 1, 2, 3, 4 or 5; Preferably, ring C is selected from C 5-6 Carbocyclic or 5-6 membered heterocyclic ring; Preferably, ring C is selected from middle represents a single bond or a double bond, and the bond is a bond fused with the D ring; Preferably, ring D is selected from a benzene ring or a 5-6 membered heteroaromatic ring; Preferably, ring D is selected from a benzene ring, a triazole ring, an imidazole ring, a pyrazole ring, a thiazole ring, a pyridine ring or a pyrimidine ring; Preferably, each R c are the same or different and are independently selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or oxo (=O); Preferably, each R d are the same or different and are independently selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or -S(=O)2-C 1-6 alkyl; Preferably, each R d are the same or different and are independently selected from H, methyl, methoxy, isopropyl, trifluoromethyl or methanesulfonyl; Preferably, Selected from the following groups: wherein Z is selected from CH or N; W1 is selected from C, CH or N; W2 is selected from CH2, NH, O or S; Ring D has the definition described herein; Preferably, Selected from the following groups: Preferably, ring E is selected from Preferably, each R e the same or different, independently selected from hydroxy-C 1-6 Alkyl, -C(O)C 1-6 Alkyl, -S(=O)2-C 1-6 Alkyl or C 3-8 Cycloalkyl; Preferably, each R e are identical or different and are independently selected from 2-hydroxyisopropyl, propionyl, methanesulfonyl or cyclopropyl.

4. The compound according to any one of claims 1 to 3, characterized in that Y is selected from the following groups:

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, X, Y, R1, R2, R a , R b , s, p, q have the definitions as described in claims 1-4; Preferably, the compound represented by formula (I) has the structure shown below: Among them, ring A, ring B, ring C, ring D, ring E, X, R1, R2, R a , R b , R c , R d , R e , s, p, q, m, n have the definitions as described in claims 1-4, and r is selected from 0, 1, 2, 3, 4 or 5. Preferably, the compound represented by formula (I) has the structure shown below: Among them, ring A, ring B, ring D, X, Z, W1, W2, R1, R2, R a , R b , R c , R d , s, p, q, m, n have the definitions as described in 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 used for diagnosing, preventing and / or treating FGFR-related diseases or disorders.

9. A method for diagnosing, preventing and / or treating a FGFR-related disease or condition, the method comprising administering to a patient in need of such treatment 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.

10. The use according to claim 8 or the method according to claim 9, characterized in that The FGFR-related disease or disorder 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, uterine cancer.

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