Indazole-based fgfr2 / 3 selective inhibitors, pharmaceutical compositions, and uses thereof

Abstract

The present application provides a compound shown in formula (I) and its racemate, stereoisomer, tautomer, isotopically labeled, nitroxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof. Such compounds have good FGFR2 / 3 inhibitory effect, and can be used for treating or preventing FGFR2 / 3 mediated disorders and diseases, and preparing drugs for treating or preventing such disorders and diseases.

Description

[0001] This application claims priority to the prior application filed on July 13, 2023, with the China National Intellectual Property Office, Patent Application No. 202310860221.5, entitled "Indazole FGFR3 Selective Inhibitors, Pharmaceutical Compositions and Applications Thereof". The entire contents of the prior application are incorporated herein by reference. TECHNICAL FIELD

[0002] The present application belongs to the technical field of medicine, and specifically relates to indazole FGFR2 / 3 selective inhibitors, pharmaceutical compositions and applications thereof. BACKGROUND

[0003] Fibroblast growth factor receptor (FGFR) is an important member of the tyrosine kinase receptor family, which is a tyrosine kinase receptor composed of about 800 amino acids, including 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 tyrosine kinase receptors (FGFR1-4) and one FGFR5 lacking 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 phosphorylate themselves, and when FGF binds to FGFRs, the signal pathway can be activated and amplified, and the downstream signal pathway can be activated, such as the JAK / STAT pathway, the phospholipase C pathway, the phosphoinositide-3-kinase PI3K and the MAPK signal pathway (Turner, N., Grose, R., Nat. Ref. Cancer 2010; 10: 116-129; Brooks, N.S. et al., Clin Cancer Res. 2012; 18: 1855 1862; Dienstmann, R. et al., Ann. Oncol. 2014; 25: 552-563).

[0004] In 2015, a study published in the journal Clinical Cancer Research described the mutations in FGFR from 4853 patient samples across various cancers using next-generation sequencing, including mutations, amplifications, and rearrangements. Of the 4853 cancers sequenced, the study observed 360 FGFR mutations in 343 cases (17 cancers had multiple FGFR alterations), for a total 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 some preclinical models have provided compelling evidence of 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), a transmembrane tyrosine kinase receptor protein, plays an important role in both cartilage development and cartilage homeostasis maintenance. FGFR3 is considered as a negative regulatory molecule in the development of endochondral ossification, which is expressed in the chondrocytes of the mesenchymal condensations early in bone development, then in the proliferative and prehypertrophic zones of chondrocytes in the growth plate cartilage and articular cartilage. Mutations in the gene for human FGFR3 can cause a range of skeletal dysplasias.

[0006] Enhanced point mutations in FGFR3 lead to skeletal dysplasia with short stature as a clinical manifestation, including thanatophoric dysplasia (TD I / II), achondroplasia (ACH), etc.; while inactivating point mutations in human FGFR3 can cause CATSHL syndrome, i.e. hearing loss, tall stature, and flexed fingers.

[0007] Tyrosine kinase inhibitors can be divided into non-covalent inhibitors and covalent inhibitors. In non-covalent inhibitors, 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, etc., have activity 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 use in 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 limits the therapeutic dose. Therefore, more selective non-covalent FGFR inhibitors are developed. These drugs include AZD4547, Infigatinib, PD173074, LY2874455, Debio1347, ASP5878 and Rogaratinib, which have selectivity 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 proven to be effective in clinical trials for FGFR-dependent cancer, but have 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 cause changes in taste and other clinical side effects (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; but the pan-FGFR inhibitors have major side effects such as hyperphosphatemia and diarrhea, and there is an unmet clinical need for the development of highly selective FGFR inhibitors. SUMMARY

[0009] To improve the above technical problems, the present application provides a compound represented by formula (I) and its racemate, stereoisomer, tautomer, isotopically labeled, nitroxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof:

[0010]

[0011] in:

[0012] Rings A and B may be the same or different, and are independently selected from C. 6-14 Aromatic rings or 5-14 heterocyclic aromatic rings;

[0013] X is selected from O or NH;

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

[0015] Each R a R b R2 may be the same or different, and are independently selected from H, halogen, cyano, hydroxyl, unsubstituted, or optionally surrounded by one, two, or more R groups. a1 The following groups are substituted: amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclic groups; each R a1 They may be the same or different, and are independently selected from halogen, cyano, amino, hydroxyl, oxo (=O), and C. 1-6 Alkyl or C 1-6 Alkoxy;

[0016] Y is selected from unsubstituted or optionally by one, two or more R. y Substituted fused-ring groups; said fused-ring groups comprise two, three, or four independently selected from C 3-14 Carbon ring, C 6-14 Aromatic rings, 5-14 membered heteroaromatic rings, or 3-14 membered heterocyclic rings;

[0017] Alternatively, Y is selected from unsubstituted or arbitrarily assigned to one, two or more R. e Replacement Among them, ring E is selected from 3-8 member nitrogen-containing mono-heterocyclic rings;

[0018] Each R y R e They may be the same or different, and are independently selected from H, halogen, cyano, hydroxyl, oxo (=O), unsubstituted, or optionally surrounded by one, two, or more R groups. y1 The following groups are substituted: amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, -C(O)R y2 or -SO2R y3 ;R y2 R y3the same or different, are independently of each other selected from H, halogen, cyano, amino, hydroxyl, oxo (=0), C 1-6 alkyl, C 1-6 alkoxy; each R y1 the same or different, are independently of each other selected from H, halogen, cyano, amino, hydroxyl, oxo (=0), C 1-6 alkyl or C 1-6 alkoxy;

[0019] s, q are the same or different, independently of each other 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, ring B are the same or different, independently of each other selected from a phenyl 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, are independently of each other selected from H, halogen, cyano, amino, hydroxyl, oxo (=0), C 1-6 alkyl or halogen.

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

[0026] According to some embodiments, each R b the same or different, are independently of each other selected from H, halogen, cyano, amino, hydroxyl, oxo (=0), C 1-6 alkyl or halogen.

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

[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, R1is selected from methyl.

[0032] According to some embodiments, each R2is the same or different, independently of each other selected from halogen, C 1-6 alkyl or C 1-6 alkoxy.

[0033] According to some embodiments, each R2is the same or different, independently of one another, selected from F, CI, 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, 3-14 membered heterocyclic; ring D is selected from C 6-14 aromatic, 5-14 membered heteroaromatic;

[0037] each R c is the same or different, independently of one another, selected from H, halogen, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy or oxo (=0);

[0038] each R d is the same or different, independently of one another, selected from H, halogen, cyano, hydroxyl, unsubstituted or optionally substituted with one, two or more R d1 substituted groups: amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -C(O)R d2 or -SO2R d3 ; R d2 , R d3 are the same or different, independently of one another, selected from C 1-6 alkyl or C 1-6 alkoxy; each R d1 is the same or different, independently of one another, selected from H, halogen, cyano, amino, hydroxyl, oxo (=0), C 1-6 alkyl or C 1-6 alkoxy;

[0039] m, n are the same or different, independently of one another, 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;

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

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

[0043] According to some embodiments, ring D is selected from a phenyl 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, independently of each other, selected from H, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy or oxo (=0);

[0045] According to some embodiments, each R d are the same or different, independently of each other, selected from H, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl or -S(=0)2-C 1-6 alkyl;

[0046] According to some embodiments, each R d are the same or different, independently of each other, selected from H, methyl, methoxy, isopropyl, trifluoromethyl or methylsulfonyl.

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

[0048]

[0049] wherein Z is selected from CH or N; W1is selected from C, CH or N; W2is selected from CH2, NH, O or S; ring D has the definition described herein.

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

[0051]

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

[0053] According to some embodiments, each R e are the same or different, independently of each other, selected from hydroxy-C 1-6 alkyl, -C(O)C 1-6 alkyl, -S(=0)2-C 1-6 alkyl or C 3-8 cycloalkyl;

[0054] According to some embodiments, each R e are the same or different, independently of each other, selected from 2-hydroxyisopropyl, propionyl, methylsulfonyl or cyclopropyl.

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

[0056]

[0057]

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

[0059]

[0060]

[0061] wherein, ring A, ring B, X, Y, R1, R2, R a , R b , s, p, q have the definitions described herein.

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

[0063]

[0064] wherein, 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 of formula (I) has the structure as shown below:

[0066]

[0067]

[0068] wherein, 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 herein.

[0069] According to some embodiments, exemplary, non-limiting specific examples of the compound of formula (I) and its racemates, stereoisomers, tautomers, isotopically-labeled, nitroxides, solvates, polymorphs, metabolites, esters, prodrugs, or pharmaceutically acceptable salts thereof include the following:

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076] The present application also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the compounds of Formula (I) and its racemates, stereoisomers, tautomers, isotopically-labeled, nitroxides, solvates, polymorphs, metabolites, esters, prodrugs, or pharmaceutically acceptable salts thereof.

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

[0078] The excipients in the pharmaceutical composition are "acceptable" in that they are compatible with the active ingredients of the composition (and preferably, capable of stabilizing the active ingredients) and not deleterious to the subject being treated. One or more pharmaceutical excipients can be used for delivery of the active compounds.

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

[0080] The present application further provides the use of at least one of the compounds of Formula (I) and its racemates, stereoisomers, tautomers, isotopically-labeled, nitroxides, solvates, polymorphs, metabolites, esters, prodrugs, or pharmaceutically acceptable salts thereof or the pharmaceutical composition in the manufacture of a medicament.

[0081] According to some embodiments, the medicament is a medicament for the diagnosis, prevention and / or treatment of a FGFR2 and / or FGFR3 mediated disease or disorder.

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

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

[0084] According to some embodiments, the disease or disorder is selected from bladder cancer, brain cancer, breast cancer, cholangiocarcinoma, head and neck cancer, lung cancer, multiple myeloma, rhabdomyosarcoma, urethral cancer, uterine cancer.

[0085] According to some embodiments, the disease is FGFR-related multiple synostosis syndrome or multiple synostosis syndrome.

[0086] According to some embodiments, the compound represented by Formula (I) and at least one of its racemates, stereoisomers, tautomers, isotopically-labeled, nitroxides, solvates, polymorphs, metabolites, esters, prodrugs, or pharmaceutically acceptable salts thereof can be formulated into forms suitable for administration by any appropriate route, by conventional methods using one or more pharmaceutically acceptable carriers. Thus, the compound represented by Formula (I) and at least one of its racemates, stereoisomers, tautomers, isotopically-labeled, nitroxides, solvates, polymorphs, metabolites, esters, prodrugs, or pharmaceutically acceptable salts thereof can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous) administration, inhalation or insufflation administration; also can be formulated into sustained release dosage forms, such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injection solutions, dispersible powders or granules, suppositories, lozenges or syrups.

[0087] The present application also provides a method for diagnosing, preventing and / or treating FGFR2 and / or FGFR3 mediated diseases or conditions, which comprises administering to a patient in need of such treatment a therapeutically effective amount of the compound represented by Formula (I) and at least one of its racemates, stereoisomers, tautomers, isotopically-labeled, nitroxides, solvates, polymorphs, metabolites, esters, prodrugs, or pharmaceutically acceptable salts thereof or the pharmaceutical composition of the present application, alone or, optionally, in combination with another compound of the present application 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, cholangiocarcinoma, 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 compound provided by the present application has good FGFR2 and / or FGFR3 inhibitory effect, and can be used for treating or preventing diseases and conditions associated with FGFR2 and / or FGFR3, and for preparing a medicament for treating or preventing such diseases and conditions.

[0092] Definitions and explanations of terms

[0093] Unless otherwise indicated, the definitions of groups and terms in the specification and claims hereof include definitions that are incorporated herein by reference, definitions that are exemplified in the examples of specific compounds, definitions that are set forth in tables, definitions that are set forth in the specification and / or claims, and the like. Such group definitions and compound structures, after such combinations and incorporations, shall be understood to be within the scope of the specification and / or claims.

[0094] The term "optional" (or "optionally", "option") in the general formula definitions herein means the occurrence of the indicated event or circumstance at zero, one, or more than one time, e.g., "optional R" means that there can be no R (no substitution) or there can be one, two, or more R.

[0095] "More than one" means three or more, e.g., 3, 4, 5, 6, 7, 8, 9, or 10.

[0096] Unless otherwise indicated, numerical ranges are understood to include each and every integer value within the range. For example, a range of 1 to 14 is understood to include each and every integer value within the range, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14.

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

[0098] "Ho-C 1-6 alkyl" means a C 1-6 alkyl group substituted with one hydroxy group.

[0099] The term "C 1-6 alkyl" means a straight-chain and branched-chain alkyl group 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, t-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, and the like or isomers thereof.

[0100] The term "C 3-8 cycloalkyl" is understood to mean a saturated, monovalent monocyclic, bicyclic (e.g., bridged ring, spirocyclic) hydrocarbon ring having 3, 4, 5, 6, 7, 8 carbon atoms. The C 3-8Cycloalkyl can be a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl, or a bicyclic hydrocarbon group such as borneolyl, 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 group can be attached to the remainder of the molecule through any of the carbon atoms or the nitrogen atom, if present. The heterocyclyl group can include fused or bridged rings as well as spirocyclic rings. In particular, the heterocyclyl group can 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 group can be benzo-fused. The heterocyclyl group can be bicyclic, for example, but not limited to, 5,5 membered rings such as hexahydrocyclopenta[c]pyrrol-2(lH)-yl ring, or 5,6 membered bicyclic rings such as hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl ring. The heterocyclyl group can be partially unsaturated, i.e. it can contain one or more double bonds, for example, but not limited to, dihydrofuranyl, dihydropyranyl, 2,5-dihydro-lH-pyrrolyl, 4H-[l,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl, or 4H-[l,4]thiazinyl, or it can be benzo-fused, for example, but not limited to, dihydroisoquinolinyl. When the 3-10 membered heterocyclyl group is attached to other groups to form a compound of the invention, it can be attached to other groups through a carbon atom on the 3-10 membered heterocyclyl group, or it can be attached to other groups through a heteroatom on the 3-10 membered heterocyclyl ring. For example, when the 3-10 membered heterocyclyl group is selected from piperazinyl, it can be attached to other groups through a nitrogen atom on the piperazinyl group. Or when the 3-10 membered heterocyclyl group is selected from piperidinyl, it can be attached to other groups through a nitrogen atom on the piperidinyl ring and the carbon atom in the para position thereof.

[0102] The term "5-10 membered heteroaryl" is to be understood as including monovalent monocyclic or bicyclic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms, and which contain 1-5, preferably 1-3 heteroatoms independently selected from N, O and S and, in addition, in each case can be benzo-fused. Examples of monocyclic "heteroaryl" groups include, for example, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazinyl, oxazinyl, triazinyl, thiodiazinyl or oxadiazinyl and the like. "Heteroaryl" also refers to groups in which a heteroaromatic ring is fused with one or more aryl, alicyclic or heterocyclyl rings, where the point 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-quinolizyl, 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-, 5-, 6-, 7- or 8-quinoxalinyl, 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, 1-, 3-, 4-, 5-, 6-, 7-, 8- or 9-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- indolizinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9- or 10-phenanthrolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-phenoxazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenoxazinyl, 2-, 3-, 4-, 5-, 6- or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-benzoisoquinolinyl, 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-, 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]triazinyl, 7-benzo[b]thiophenyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 4-, 5-, 6-, or 7-benzothiazolyl, 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]benzazapinyl. Typical fused heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thiophenyl, 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 is attached to other groups to form a compound of the invention, it can be attached to other groups through a carbon atom on the 5-10 membered heteroaryl ring or through a heteroatom on the 5-10 membered heteroaryl ring. When the 5-10 membered heteroaryl is substituted, it can be mono- or poly-substituted. Also, there is no limitation on the substitution site, for example, the hydrogen attached to a carbon atom on the heteroaryl ring can be substituted, or the hydrogen attached to a heteroatom on the heteroaryl ring can be substituted.

[0103] The term "nitroxide" refers to a compound formed by oxidation of a nitrogen atom in a tertiary amine or a nitrogen-containing (hetero)aromatic ring compound.

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

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

[0106] Unless otherwise indicated, heterocyclyl, heteroaryl or heteroarylenyl includes all possible isomeric forms thereof, e.g., positional isomers. Thus, for some illustrative, non-limiting examples, forms which can be included are substitution or bonding with other groups at one, two or more positions in its 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-positions, etc., if present, including pyridin-2-yl, pyridin-2-yl ene, pyridin-3-yl, pyridin-3-yl ene, pyridin-4-yl, and pyridin-4-yl ene; thienyl or thienylene includes thien-2-yl, thien-2-yl ene, thien-3-yl, and thien-3-yl ene; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl.

[0107] The term "oxo" refers to an oxy substituent (=O) formed by oxidation of a carbon atom, nitrogen atom, or sulfur atom in a substituent.

[0108] The term "alkylamino" refers to -NH-(alkyl) or -N-(alkyl)2, where alkyl is as defined above. Non-limiting examples of alkylamino groups include: methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, methylethylamino, diethylamino, dipropylamino, methylpropylamino, diisopropylamino, dibutylamino, and the like.

[0109] The term "alkyloxy" refers to -O-(alkyl), where alkyl is as defined above. Non-limiting examples of alkyloxy groups include: methoxy, ethoxy, propyloxy, butyloxy. The alkyloxy group can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkyloxy, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, or heterocycloalkyloxy.

[0110] The terms "alkyleneoxy" and "oxyalkylene" refer to -alkylene-O- or -O-alkylene-, where alkylene represents a straight-chained or branched saturated divalent hydrocarbon radical. The definition of the number of carbon atoms for "alkylene" applies to the above definition of "alkyl". Those skilled in the art will appreciate that the alkyleneoxy or oxyalkylene group can be attached in either direction to the remainder of the molecule of which it is a part, i.e., they can be used interchangeably.

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

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

[0113] In the present application, the compounds involved also include isotopically-labeled compounds, which are identical to those recited in Formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes of atoms that can be incorporated into a compound of the present application include isotopes of H, C, N, O, S, F, and CI, 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 present application, prodrugs thereof, or pharmaceutically acceptable salts of said compounds or of said prodrugs, which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present application. Certain isotopically-labeled compounds of the present application, for example those into which radioactive isotopes such as 3 H and 14 C) are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2 H or D, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, therefore, can be preferred in some circumstances. The present application as claimed in the claims can be particularly limited to substitution with deuterium or tritium. Moreover, the occurrence of hydrogen in the substituents not listed as terms deuterium or tritium alone does not exclude deuterium or tritium but can also comprise deuterium or tritium.

[0114] It will be appreciated by persons skilled in the art that the compounds represented by Formula (I) can exist in various pharmaceutically acceptable salt forms. If these compounds have basic centers, they can form acid addition salts; if these compounds have acidic centers, they can form base addition salts; if these compounds contain both acidic centers (for example, carboxyl groups) and basic centers (for example, amino groups), they can also form internal salts.

[0115] The compounds according to the application can exist in the form of solvates (e.g. hydrates), wherein the compounds according to the application contain as an element of the crystal lattice of the compound a polar solvent, in particular, for example, water, methanol or ethanol. The amount of polar solvent, in particular water, can be present in stoichiometric or non-stoichiometric amounts.

[0116] Depending on their molecular structure, the compounds according to the application can be chiral and thus can exist in various enantiomeric forms. The compounds can thus exist in the form of racemates or optically active forms. The compounds according to the application encompass the isomers in which the individual chiral carbons are in the R or S configuration or mixtures thereof, racemates. The compounds according to the application or intermediates thereof can be separated into the enantiomeric compounds by chemical or physical methods known to those skilled in the art or used in the synthesis in this form. In the case of racemic amines, the diastereomeric forms are prepared from the mixture by reaction with optically active resolving agents. Examples of suitable resolving agents are optically active acids, such as, for example, tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids, for example N-benzoylproline or N-benzenesulfonylproline, or various optically active camphorsulfonic acids. Chromatographic enantiomeric resolution with the aid of optically active resolving agents, for example dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatized methionine polymers, immobilized on silica gel, can also be advantageously carried out. 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, swine, cattle, sheep, horses, or primates, most preferably humans.

[0119] The term "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, and includes one or more of the following: (1) preventing the disease: for example, preventing a disease, disorder or condition from occurring in an individual that is predisposed or susceptible to the disease, but has not yet experienced or displayed symptoms of the pathology or condition; (2) inhibiting the disease: for example, arresting the development of a disease, disorder or condition in an individual that is experiencing or displaying the pathology or symptoms thereof (i.e., retarding the further development of the pathology and / or symptoms); (3) relieving the disease: for example, causing the regression of a disease, disorder or condition in an individual that is experiencing or displaying the pathology or symptoms thereof (i.e., reversing the pathology and / or symptoms). DETAILED DESCRIPTION

[0120] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory 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 covered within the scope of protection intended by the present invention.

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

[0122] The structures of the compounds of this invention were 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 with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as solvents, and tetramethylsilane (TMS) as the internal standard.

[0123] The determinations were performed using LC-MS with an Agilent 1200 Infinity Series mass spectrometer. The determinations were performed using an Agilent 1200DAD high-performance liquid chromatograph and a Waters 2695-2996 high-performance liquid chromatograph.

[0124] Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The standard size for TLC is 0.15mm to 0.20mm, while the standard size for TLC separation and purification is 0.4mm to 0.5mm. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0125] Unless otherwise specified, all reactions in this invention are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, using a dry solvent, and the reaction temperature is expressed 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] To a solution of 1H-indazol-5-ol INT-1a (11 g, 0.082 mol), TBSCl (14.8 g, 0.098 mol) and imidazole (8.4 g, 0.123 mol) in acetonitrile (100 mL) was stirred at room temperature for 16 hours. After the reaction was completed, the reaction mixture was concentrated, washed with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column (petroleum ether / ethyl acetate = 2 / 1) to give 5-((tert-butyldimethylsilyl)oxy)-1H-indazole INT-1b (20 g) in 99% yield. 1 H NMR (400 MHz, CDC13) δ 7.79 (s, 1H), 7.15 (d, J = 8.9 Hz, 1H), 6.93 (d, J = 2.0 Hz, 1H), 6.77 (dd, J = 8.9, 1.9 Hz, 1H), 0.80 (s, 9H), -0.00 (s, 6H).

[0130] Second step

[0131] To a solution of 5-((tert-butyldimethylsilyl)oxy)-1H-indazole INT-1b (20 g, 0.081 mol) in dichloromethane (200 mL) was added NIS (20 g, 0.089 mol) at 0 degree Celsius. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction mixture was washed with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column (petroleum ether / ethyl acetate = 5 / 1) to give 5-((tert-butyldimethylsilyl)oxy)-3-iodo-1H-indazole INT-1c (27 g) in 89% yield.

[0132] 1 H NMR (400 MHz, CDC13) δ 7.52 (d, J = 8.9 Hz, 1H), 7.08 (dd, J = 8.9, 2.2 Hz, 1H), 6.89 (d, J = 1.9 Hz, 1H), 1.05 (s, 9H), 0.26 (s, 6H).

[0133] Third step

[0134] To a solution of 5-((tert-butyldimethylsilyl)oxy)-3-iodo-l-(tetrahydro-2H-pyran-2- yl)-lH-indazole INT-ld (28 g, 0.061 mol) in tetrahydrofuran (200 mL) was added 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (67 mL, 0.067 mol) and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, it was concentrated, washed with saturated ammonium chloride solution twice, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column (petroleum ether / ethyl acetate = 2 / 1) to give 3-iodo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-5-ol INT-le (19 g) in 90% yield.

[0135] 1 H NMR (400 MHz, CDC13) δ 7.42 (d, J = 9.0 Hz, 1H), 7.01 (dd, J = 8.9, 2.2 Hz, 1H), 6.81 (d, J = 2.2 Hz, 1H), 5.63 (dd, J = 9.4, 2.7 Hz, 1H), 4.06 - 3.99 (m, 1H), 3.72 (td, J = 11.1, 2.8 Hz, 1H), 2.53 (tdd, J = 11.6, 10.3, 4.0 Hz, 1H), 2.18 - 2.02 (m, 2H), 1.80 - 1.62 (m, 3H), 1.01 (s, 9H), 0.21 (s, 6H).

[0136] Fourth step

[0137] To a solution of 5-((tert-butyldimethylsilyl)oxy)-3-iodo-l-(tetrahydro-2H-pyran-2- yl)-lH-indazole INT-ld (28 g, 0.061 mol) in tetrahydrofuran (200 mL) was added 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (67 mL, 0.067 mol) and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, it was concentrated, washed with saturated ammonium chloride solution twice, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column (petroleum ether / ethyl acetate = 2 / 1) to give 3-iodo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-5-ol INT-le (19 g) in 90% yield.

[0138] 1H NMR (400 MHz, CD3OD_SPE) δ 7.48 (d, J = 9.0 Hz, 1H), 7.04 (d, J = 11.2 Hz, 1H), 6.70 (d, J = 2.2 Hz, 1H), 5.68 (dd, J = 9.8, 2.6 Hz, 1H), 3.95 (d, J = 11.5 Hz, 1H), 3.75 (td, J = 11.1, 3.0 Hz, 1H), 3.30 (dt, J = 3.1, 1.5 Hz, 1H), 2.50 - 2.37 (m, 1H), 2.08 (ddd, J = 7.7, 6.6, 3.8 Hz, 1H), 1.96 (d, J = 3.3 Hz, 1H), 1.84 - 1.57 (m, 3H).

[0139] Fifth step

[0140] To 3-iodo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-5-ol INT-le (5 g, 0.014 mol), (S)-l-(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), the reaction was stirred at 80 degree Celsius for 16 h, after the reaction was completed, filtered, washed with water, extracted with ethyl acetate, dried with anhydrous sodium sulfate, concentrated and separated and purified by silica gel column (petroleum ether / ethyl acetate = 5 / 1) to obtain 5-((R)-l-(3,5-dichloropyridin-4-yl)ethoxy)-3-iodo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole INT-l (6.8 g), yield 94%.

[0141] 1 H NMR (400 MHz, CDCl3) δ 8.42 (s, 2H), 7.44 (dd, J = 9.1, 2.9 Hz, 1H), 7.15 (dd, J = 9.1, 2.3 Hz, 1H), 6.69 (d, J = 2.2 Hz, 1H), 6.06 (q, J = 6.7 Hz, 1H), 5.59 (ddd, J = 9.3, 6.6, 2.7 Hz, 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 = 6.7 Hz, 3H), 1.68 (ddd, J = 23.1, 12.9, 5.1 Hz, 3H).

[0142] Synthesis of intermediate (S)-5-(l-(3,5-dichloropyridin-4-yl)ethoxy)-3-iodo-6-methoxy-lH-indazole INT-2 in Example 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-tolylsulfonylhydrazide (2.44 g, 1.31 mmol) was added at room temperature, the reaction was stirred at room temperature for 5 hours. Then the solvent was evaporated, cuprous oxide (140 mg, 0.1 mmol) and 1,4-dioxane (10.0 mL) were added, refluxed at 100 °C for 12 hours. Then the reaction was filtered, concentrated and purified by column chromatography (EA / PE = 30%) to obtain the product 6-methoxy-1-tolylsulfonyl-1H-indazol-5-ol INT-2b (2.3 g, 55%).

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

[0147] Second Step

[0148] 6-methoxy-1-tolylsulfonyl-1H-indazol-5-ol INT-2b (2.3 g, 7.2 mmol) was dissolved in DMF (25 mL), cesium carbonate (3.25 g, 10 mmol) and (R)-1-(3,5-dichloropyridin-4-yl)methanesulfonic acid ethyl ester (2.69 g, 10 mmol) were added. The reaction was stirred at 80 °C for 16 hours under nitrogen protection. Then water (20 mL) was added, extracted with ethyl acetate and evaporated, TBAF THF solution (1.0 mol / mL, 10.0 mL) was added, and the reaction was stirred at room temperature for 72 hours. After the reaction was completed, water (20 mL) was then added, extracted with ethyl acetate and evaporated 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] Third Step

[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), sodium hydroxide (200 mg, 5 mmol) and iodine (635 mg, 5 mmol) were added. The reaction 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 in vacuo, and the product (S)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-iodo-6-methoxy-1H-indazole INT-2 (750 mg, 65%) was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether = 1 / 10 to 5 / 1).

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

[0153] Example 3

[0154] (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] 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) was added 5-bromo-2-fluoropyridine (274 mg, 1 mmol) and N,N-diisopropyl ethylamine (403 mg, 3 mmol). The reaction mixture was stirred at 90 degrees for 1 hour. After the reaction was completed, water was added to quench, extracted with ethyl acetate (3 x 10 mL). The organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1) to give 7-(5-bromopyridin-2-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine 15b (70 mg), yield: 11.59%.

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

[0159] Second step

[0160] To a solution of 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) in 1,4-dioxane (5 mL) was added bis(pinacolato)diboron (76 mg, 0.3 mmol), potassium acetate (39 mg, 0.4 mmol) and 1,1’- bis(diphenylphosphino)ferrocene (14 mg, 0.02 mmol). The reaction mixture was stirred at 90 degrees for 16 hours. After the reaction was completed, water was added to quench, extracted with ethyl acetate (3 x 10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and 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]pyrazin-7(8H)-yl)pyridin-3- yl)boronic acid 15c (50 mg), yield: 71.5%.

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

[0162] Third step

[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, extracted with ethyl acetate (3 x 10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and 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] Fourth step

[0166] To a solution of 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) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL) dropwise. The reaction mixture was stirred at 25 degree for 1 hour. After completion of the reaction, the reaction was quenched with water and extracted with ethyl acetate (3 x 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 obtain (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 (400 MHz, CDCl3) δ 8.71 (s, 1H), 8.44 (s, 2H), 8.06 (d, J = 8.3 Hz, 1H), 7.40 (d, J = 8.9 Hz, 1H), 7.18 (d, J = 3.1 Hz, 1H), 7.15 (d, J = 1.7 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.06 (d, J = 6.7 Hz, 1H), 5.05 (s, 2H), 4.32 (d, J = 4.5 Hz, 4H), 1.83 (d, J = 6.6 Hz, 3H).

[0168] Referring to the similar conditions as described above in Example 3, the following compounds in Table 1 were prepared, and their structure characterization data are shown in Table 1.

[0169] Table 1

[0170]

[0171]

[0172] Biological evaluation

[0173] Test Example 1: Inhibition of Ba / F3-FGFR1, Ba / F3-FGFR2 and BaF3-FGFR3 cell proliferation by the compounds of the present disclosure.

[0174] The method of CTG was used to detect the proliferation inhibition of compounds on Ba / F3-FGFR1, Ba / F3-FGFR2 and BaF3-FGFR3 cells, the highest concentration was 3000nM, three-fold dilution gradient, 10 concentrations, and duplicate hole 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 steps

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

[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) The compound stock solution was diluted from 3000nM to 384 cell culture plates using an ECHO pipetting workstation, and centrifuged at 1000g for 1min.

[0185] c) The cells were digested, and 30μL of Ba / F3-FGFR1, Ba / F3-FGFR2 and BaF3-FGFR3 (500 / well) were evenly plated in 384-well black edge cell culture plates containing compounds, the edge wells were sealed with 50μL of PBS, and incubated at 37℃ in a CO2 incubator for 72h.

[0186] d) Add 30μL of Cell-Titer-Glo reagent per well, shake well on a shaker, then incubate at 37℃ for 30min, and detect on a microplate reader after the signal is stable.

[0187] 1.3 Experimental results

[0188] Table 1 Test results of representative compounds of the present application on Ba / F3 cell inhibition activity

[0189]

[0190] The experimental results show that the representative compounds of the present application have strong inhibitory activity and good selectivity on Ba / F3-FGFR2 / 3 cells.

[0191] The above has carried out the exemplary description to the technical scheme implementation of the present application. It should be understood that the protection scope of the present application is not limited to the above-mentioned embodiments. Any modification, equivalent replacement, improvement, etc. made by the skilled in the art within the spirit and principle of the present application shall be included in the protection scope of the claims of the present application.

Claims

1. A compound of Formula III-1 and racemates, stereoisomers thereof, or pharmaceutically acceptable salts thereof: ###0001### Formula III-1 wherein: X is selected from O; R1 is selected from methyl; R2 is selected from F, CI, methyl or methoxy; p is selected from 0 or 1 ; m, n are the same or different, independently of each other selected from 0, 1 or 2. The compound is selected from the following structures: ###0002### ###0003### ###0004### ###0005### ###0006### ###0007### ###0008### ###0009### ###0010### ###0011### ###0012### ###0013### ###0014### ###0015### ###0016### ###0017### ###0018### ###0019### ###0020### ###0021### ###0022### ###0023### ###0024### ###0025### ###0026### ###0027### ###0028### ###0029### ###0030### ###0031### ###0032### ###0033### ###0034### ###0035### ###0036### ###0037### ###0038### ###0039### ###0040### ###0041### ###0042### ###0043### ###0044### ###0045### ###0046### ###0047### ###0048### ###0049### ###0050### ###0051### ###0052### ###0053### ###0054### ###0055### ###0056### ###0057### ###0058### ###0059### ###0060### ###0061### ###0062### ###0063### ###0064### ###0065### ###0066### ###0067### ###0068### ###0069### ###0070### ###0071### ###0072### ###0073### ###0074### ###0075### ###0076### ###0077### ###0078### ###0079### ###0080### ###0081### ###0082### ###0083### ###0084### ###0085### ###0086### ###0087### ###0088### ###0089### ###0090### ###0091### ###0092### ###0093### ###0094### ###0095### ###0096### ###0097### ###0098### ###0099### ###0100### ###0101### ###0102### ###0103### ###0104### ###0105### ###0106### ###0107### ###0108### ###0109### ###0110### ###0111### ###0112### ###0113### ###0114### ###0115### ###0116### ###0117### ###0118### ###0119### ###0120### ###0121### ###0122### ###0123### ###0124### ###0125### ###0126### ###0127### ###0128### ###0129### ###0130### ###0131### ###0132### ###0133### ###0134### ###0135### ###0136### ###0137### ###0138### ###0139### ###0140### ###0141### ###0142### ###0143### ###0144### ###0145### ###0146### ###0147### ###0148### ###0149### ###0150### ###0151### ###0152### ###0153### ###0154### ###0155### ###0156### ###0157### ###0158### ###0159### ###0160 ​ ​ ​ ​ ​ selected from the group consisting of: , , , ; selected from the group consisting of: , , ; selected from the group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ； each R is independently selected from the group consisting of halogen, cyano, C c the same or different, independently of one another, are selected from the group consisting of halogen, cyano, C 1-6 alkyl or C 1-6 alkoxy or oxo (=0); each R is independently selected from halo, cyano, C d the same or different, independently of one another, are selected from halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl or -S(=0)2-C 1-6 alkyl; ​ 2. The compound according to claim 1, and racemates, stereoisomers thereof, or a pharmaceutically acceptable salt thereof, characterized in that, selected from the group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 3. The compound according to claim 1 or 2, and racemates, stereoisomers thereof, or a pharmaceutically acceptable salt thereof, characterized in that, ​ 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 ​ ​ 6. Use according to claim 5, characterized in that, ​ 7. Use according to claim 6, characterized in that, ​ 8. Use according to claim 6, characterized in that, ​ 9. Use according to claim 7, characterized in that, ​

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