FGFR2 / 3 selective inhibitors, pharmaceutical compositions and their use

Abstract

The present invention provides compounds represented by formula (I) and their racemates, stereoisomers, tautomers, isotopically labeled compounds, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs, or pharmaceutically acceptable salts thereof. These compounds have good FGFR2 / 3 inhibitory activity and can be used to treat or prevent FGFR2 / 3-mediated disorders and diseases, and can be used to manufacture drugs used for the treatment or prevention of such disorders and diseases. [Formula 1] TIFF2026518289000170.tif53170

Description

[Technical Field]

[0001] This application is granted priority to the prior application filed with the China National Intellectual Property Administration on May 24, 2023, patent application number 202310593058.0, titled "FGFR3 selective inhibitor, pharmaceutical composition and use thereof," and to the prior application filed with the China National Intellectual Property Administration on August 14, 2023, patent application number 202311019921.8, titled "FGFR3 selective inhibitor, pharmaceutical composition and use thereof," and to the China National Intellectual Property Administration on September 28, 2023. Priority is claimed to be granted to the prior application filed with the National Intellectual Property Administration of China, patent application number 202311275317.1, titled "FGFR3 selective inhibitor, pharmaceutical composition and use thereof," and to the prior application filed with the National Intellectual Property Administration of China on December 20, 2023, patent application number 202311767590.6, titled "FGFR3 selective inhibitor, pharmaceutical composition and use thereof," the said prior application is incorporated into this invention in its entirety by reference.

[0002] This invention belongs to the field of pharmaceutical technology, and more specifically relates to FGFR2 / 3 selective inhibitors, pharmaceutical compositions, and their use. [Background technology]

[0003] Fibroblast growth factor receptors (FGFRs) are important members of the tyrosine kinase receptor family. They are tyrosine kinase receptors consisting of approximately 800 amino acids, comprising three extracellular immunoglobulin-like domains (I / II / III), one single transmembrane structure, and one cytoplasmic tyrosine kinase domain. In humans, FGFRs include four typical tyrosine kinase receptors (FGFR1-4) and one intracellular tyrosine kinase domain, FGFR5. Fibroblast growth factor (FGF), the ligand for FGFRs, has a total of 18 members. Under normal physiological conditions, FGFRs bind to their ligand, fibroblast growth factor, and undergo dimerization and autophosphorylation. After binding of FGF and FGFRs, they can activate and amplify signaling pathways, including downstream signaling pathways such as the JAK / STAT pathway, the phospholipase C pathway, and the phosphoinositide-3-kinase PI3K and MAPK signaling pathways (Turner, N., Grose, R., Nat. Ref. Cancer 2010;10:116-129; Brooks, NS et al., Clin Cancer Res. 2012;18:1855-1862; Dienstmann, R. et al., Ann. Oncol. 2014;25:552-563).

[0004] In 2015, Clinical Cancer Research published a study on FGFR mutations in 4,853 patient samples from various cancers using next-generation sequencing technology, including mutations, amplifications, and rearrangements. Of the 4,853 cancers sequenced, 360 FGFR mutations were observed in 343 cases (17 cancers had multiple FGFR changes), with an overall incidence of 7.1% (Helsten T, Elkin S, Arthur E, Tomson BN, Carter J, Kurzrock R. The FGFR Landscape in Cancer: Analysis of 4,853 Tumors by Next-Generation Sequencing. Clin Cancer Res. 2016;22(1):259-267.doi:10.1158 / 1078-0432.CCR-14-3212). FGFR signaling components frequently alter in human cancers, and several preclinical models have provided noteworthy evidence regarding the carcinogenic potential of abnormal FGFR signaling in cancer development, demonstrating that FGFR signaling is a promising target in cancer treatment.

[0005] Fibroblast growth factor receptor 3 (FGFR3) is a transmembrane tyrosine kinase receptor protein that plays a crucial role in both cartilage formation and the maintenance of cartilage homeostasis. FGFR3 is considered a negative regulator in the developmental process of endochondral ossogenesis. In the early stages of bone development, it is first expressed in chondrocytes of the mesenchymal aggregation center, and then in chondrocytes of the growth plate cartilage and the proliferative and pre-hypertrophic zones of articular cartilage. Gene mutations in human FGFR3 cause a range of bone malformations.

[0006] Gain-of-function point mutations in FGFR3 result in skeletal dysplasias clinically characterized by short stature, including thanatophoric dysplasia (TD I / II) and achondroplasia (ACH), while loss-of-function point mutations in human FGFR3 result in CATSHL syndrome, which includes hearing loss, tall stature, and flexor dactyly.

[0007] Tyrosine kinase inhibitors can be divided into non-covalent and covalent inhibitors. Non-covalent inhibitors are further classified as multi-target or selective inhibitors. Non-covalent multi-target FGFR inhibitors include Dovitinib, Nintedanib, Lenvatinib, Ponatinib, derazantinib, and e-7090, which are active against FGFR, VEGFR, PDGFR (platelet-derived growth factor receptor), and other kinase proteins. Multi-target TKls (tyrosine kinase inhibitors) have already demonstrated clinical benefits, with Ponatinib and Nintedanib being approved for myeloid leukemia and non-small cell lung cancer in 2012 and 2014, respectively. The toxicity of multi-target FGFR inhibitors is associated with the inhibition of various kinases, particularly VEGFRs, limiting therapeutic doses. Therefore, more selective non-covalent FGFR inhibitors are being developed. These drugs include AZD4547, infigatinib, PD173074, LY2874455, Debio1347, ASP5878, and Rogaratinib, which are more selective for FGFR1-3 than for 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 due to FGFR1. In addition to hyperphosphatemia and diarrhea, FGFR inhibitors often cause clinical adverse reactions such as fatigue, skin toxicity including hand-foot syndrome, alopecia, nail bed infections, onychomycosis, dry skin, and dry mouth, as well as changes in taste (Kommalapati A, Tella SH, Borad M, Javle M, Mahipal A. Cancers (Basel). 2021 Jun 13;13(12):2968.).

[0008] To summarize, the FGFR signaling pathway plays an important role in human cancer and bone formation and is a promising therapeutic target. However, pan-FGFR inhibitors have major toxic side effects such as hyperphosphatemia and diarrhea, and there are unmet clinical requirements. The development of highly selective FGFR inhibitors is an urgent task. Summary of the Invention

[0009] To improve the above technical problems, the present invention provides a compound represented by formula (I) and its racemate, stereoisomer, tautomer, isotope label, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or a pharmaceutically acceptable salt thereof,

Chemical formula

[0010] Each R 1 is the same or different and independently of one another is hydrogen, halogen, cyano group, hydroxy group, oxo (=O), unsubstituted or optionally substituted by one, two or more R 11 amino group, C 1-6 alkyl group, C 1-6 alkoxy group, C 3-8 cycloalkyl group, 3-8 member heterocyclic group, -C(=O)-NH2, -S(=O)2-C 1-6 alkyl group, -S(=O)(=NH)-C 1-6 alkyl group, or two R 1 bonded to the same atom together with the atom to which it is bonded is an unsubstituted or optionally substituted by one, two or more R 11 3-12 member heterocyclic ring or C 3-12 alkyl ring, or two R 1 bonded to different atoms together with the atoms to which they are bonded is an unsubstituted or optionally substituted by one, two or more R 11 3-12 member heterocyclic ring or C 3-12 alkyl ring, each R 11 is the same or different and independently of one another is H, cyano group, oxo (=O), halogen, unsubstituted or optionally substituted by one, two or more R 12 C 1-6 alkyl group, C 1-6 alkoxy group, -S(=O)2-R y8 , -S(=O)(=NR y9 )-Ry10 , C 3-12 Selected from cycloalkyl groups, 3-12 membered heterocyclic groups, and 5-14 membered heteroaryl groups, each R 12 They are the same or different, and independently of each other are hydrogen, hydroxyl group, cyano group, halogen, and C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 6-14 Selected from aryl groups and 5-14 membered heteroaryl groups, Each R 2 , R 4 They are identical or different, and independently of each other, hydrogen, halogen, cyano group, hydroxyl group, oxo (=O), unsubstituted, or selectively one, two or more R groups. 21 The amino group substituted by C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, -C(=O)-NH2, -S(=O)2-C 1-6 Alkyl alkyl group, C 6-14 Selected from aryl groups and 5-14 membered heteroaryl groups, each R 21 They are the same or different, and independently of each other are halogen, CN, amino group, hydroxyl group, oxo (=O), and C 1-6 Alkyl alkyl group, C 1-6 Selected from alkoxy groups, R 3 is hydrogen, C 1-6 Alkyl, halo C 1-6 Alkyl group, cyano group -C 1-6 Selected from alkyl groups, R 6 is hydrogen, R 6a -C 1-4 Selected from alkyl groups, R 6a teeth [ka] Selected from, m and n are either the same or different, and are independently selected from 0, 1, 2, 3, 4, 5, or 6. r is selected from 0, 1, or 2.

[0011] According to some embodiments, ring A is C 6-10 Selected from an aromatic ring, a 5-10 membered heteroaromatic ring, or a 5-10 membered heterocycle.

[0012] According to some embodiments, ring A is a benzene ring, a pyridine ring, a pyrimidine ring, a naphthalene ring, a quinoline ring, a 1,8-naphthyridine ring, a piperidine ring, a piperazine ring, [ka] Selected from.

[0013] According to some embodiments, ring B is selected from a benzene ring or a 5-6 membered heteroaromatic ring.

[0014] According to some embodiments, ring B is selected from a pyridine ring or a pyridazine ring.

[0015] According to some embodiments, L is either nonexistent or selected from -NH-C(=O)- and -CH=CH-.

[0016] According to some embodiments, X is selected from O.

[0017] According to some embodiments, Y does not exist.

[0018] According to some embodiments, Y is unsubstituted or selectively has one, two or more R y -S(=O)-R is substituted by y1 -S(=O)2-R y2 -S(=O)(=NR y3 )-R y4 , C 3-10 Selected from cycloalkyl groups, 3-10 membered heterocyclyl groups, and 5-8 membered heteroaryl groups, R y1 , R y2 , R y3 , R y4 They are the same or different, they do not exist or they exist independently of each other as hydrogen, C 1-6 Alkyl alkyl group, C 3-6Selected from cycloalkyl groups.

[0019] According to some embodiments, Y is unsubstituted or selectively has one, two or more R y Phenyl group, piperazinyl group, piperidinyl group, pyrazolyl group, which are substituted by [ka] Selected from.

[0020] According to some embodiments, each R y They are the same or different, and independently of each other are hydrogen, hydroxyl group, cyano group, halogen, oxo (=O), and C. 1-6 Alkyl, halo C 1-6 Alkyl group, hydroxyl group -C 1-6 Alkyl group, amino group -C 1-6 Alkyl group, cyano group -C 1-6 Alkyl group, carboxyl group -C 1-6 Alkyl alkyl group, C 1-6 Alkyl-NH-C 1-6 Alkyl, (C 1-6 Alkyl(2N-C) 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, -C 1-6 Alkyl-(C substituted with a hydroxyl group) 3-8 Cycloalkyl group), -C 1-6 Alkyl-S(=O)2-C 1-6 Alkyl alkyl group, -C 1-6 Alkyl-S(=O)2-NH2, C 6-10 Aryl group, 5-10 membered heteroaryl group, =NR y5 -C(=O)-R y6 , -C(=O)OR y7 -S(=O)2-R y8 -S(=O)(=NR y9 )-R y10 -P(=O)(R y11 )(R y12 ), or selectively one, two or more R y’Selected from 3-8 member heterocyclyl groups substituted by, each R y’ These are identical or different, and independently of each other, they are cyano groups, halogens, oxo (=O), or -S(=O)2-C. 1-6 Selected from alkyl groups, R y5 , R y6 , R y7 , R y8 , R y9 , R y10 , R y11 , R y12 They are the same or different, and are independent of each other: hydrogen, C 1-6 Alkyl alkyl group, C 3-6 Selected from cycloalkyl groups.

[0021] According to some embodiments, each R y They are the same or different, and independently of each other are hydroxyl groups, cyano groups, halogens, oxo (=O), and C. 1-3 Alkyl, halo C 1-3 Alkyl group, hydroxyl group -C 1-4 Alkyl group, amino group -C 1-4 Alkyl group, cyano group -C 1-3 Alkyl group, carboxyl group -C 1-4 Alkyl alkyl group, C 1-4 Alkylalkyl NH-C 1-4 Alkyl, (C 1-4 Alkyl(2N-C) 1-4 Alkyl alkyl group, C 1-3 Alkoxy group, C 3-6 Cycloalkyl groups, -C 1-3 Alkyl-(C substituted with a hydroxyl group) 3-6 Cycloalkyl group), -C 1-3 Alkyl-S(=O)2-C 1-3 Alkyl alkyl group, -C 1-3 Alkyl-S(=O)2-NH2, phenyl group, 5-6 membered heteroaryl group, =NR y5 -C(=O)-R y6 , -C(=O)OR y7 -S(=O)2-R y8 -S(=O)(=NR y9 )-R y10 -P(=O)(R y11 )(Ry12 ), or selectively one, two or more R y’ Selected from 3-6 member heterocyclyl groups substituted by, each R y’ They are either the same or different, and independently of each other, they are oxo (=O) or -S (=O)2-C 1-3 Selected from alkyl groups, R y5 , R y6 , R y7 , R y8 , R y9 , R y10 , R y11 , R y12 Identical or different, each independently of the other, hydrogen, C 1-6 Alkyl alkyl group, C 3-6 Selected from cycloalkyl groups.

[0022] According to some embodiments, each R y These are the same or different groups, and independently of each other are methyl group, ethyl group, n-propyl group, isopropyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, trifluoromethyl group, 2-hydroxyethyl group, oxo(=O), =N-CH3, -S(=O)2-CH3, -C(=O)O-CH3, -C(=O)O-C2H5, pyrimidinyl group, -C(CH3)2OH, -C(CH3)2CN, -S(=O)2-C2H5, -S(=O)2-CH(CH3)2, -CH2COOH, [ka] Selected from.

[0023] According to some embodiments, Y is [ka] [ka] Selected from.

[0024] According to some embodiments, each R 1The R groups are identical or distinct, and independently of each other, they may be halogens, cyano groups, hydroxyl groups, oxo (=O), unsubstituted, or selectively one, two, or more R groups. 11 The amino group substituted by C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, -C(=O)-NH2, -S(=O)2-C 1-3 Alkyl group, -S(=O)(=NH)-C 1-3 Selected from alkyl groups, or two R groups bonded to the same atom. 1 It has one, two or more R atoms, either unsubstituted or selectively, along with the atom to which it is bonded. 11 A 3-8 membered heterocycle is formed by substitution, or two R atoms bonded to different atoms. 1 It has one, two or more R atoms, either unsubstituted or selectively, along with the atom to which it is bonded. 11 It forms a 3-8 member heterocycle substituted by each R 11 They are identical or different, and independently of each other, H, cyano group, oxo (=O), halogen, unsubstituted, or selectively one, two or more R 12 C is replaced by 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -S(=O)2-CH3, -S(=O)(=NH)-CH3, C 3-6 Selected from cycloalkyl groups, 3-8 membered heterocyclic groups, and 5-6 membered heteroaryl groups, each R 12 They are the same or different, and independently of each other are hydrogen, hydroxyl group, cyano group, halogen, and C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 3-6 Selected from cycloalkyl groups, phenyl groups, and 5-6 membered heteroaryl groups.

[0025] According to some embodiments, each R 1 These are identical or different, and independently of each other, F, Cl, Br, cyano group, oxo (=O), methoxy group, -S(=O)2-CH3, -S(=O)(=NH)-CH3, -S(=O)(=N-CH3)-CH3, [ka] Alternatively, selected from -C(=O)-N(CH3)2, or two R atoms bonded to the same atom. 1 It has one, two or more R atoms, either unsubstituted or selectively, along with the atom to which it is bonded. 11 It forms a piperidinyl group that is substituted by it.

[0026] According to some embodiments, each R 11 These are either the same or different, and are independently selected from hydrogen, a 2,2,2-trifluoroethyl group, -S(=O)2-CH3, and a cyclobutyl group.

[0027] According to some embodiments, [ka] is a phenyl group, [ka] Selected from.

[0028] According to some embodiments, each R 2 They are identical or different, and independently of each other, hydrogen, F, Cl, Br, cyano group, unsubstituted or selectively one, two or more R 21 C is replaced by 1-3 Alkyl alkyl group, C 1-3 Selected from alkoxy groups, pyrazolyl groups, and pyrimidinyl groups, each R 21 They are identical or different, and are independently selected from halogen, CN, and methyl groups. According to some embodiments, each R 2 They are the same or different, and independently of each other, Cl, methyl group, [ka] Selected from.

[0029] According to some embodiments, [ka] teeth [ka] Selected from.

[0030] According to some embodiments, each R 4 They are the same or different, and independently of each other are hydrogen, halogen, cyano group, hydroxyl group, amino group, and C 1-6 Alkyl alkyl group, C 1-6 Selected from alkoxy groups.

[0031] According to some embodiments, each R 4 These groups are identical or distinct, and are independently selected from halogen, cyano, methyl, or methoxy groups.

[0032] According to some embodiments, R 3 is hydrogen, C 1-3 Alkyl, halo C 1-3 Selected from alkyl groups.

[0033] According to some embodiments, R 3 The group is selected from methyl groups.

[0034] According to some embodiments, R 6 It is selected from hydrogen.

[0035] According to some embodiments, R 6 teeth [ka] Selected from.

[0036] According to some embodiments, the compound represented by formula (I) has the structure shown below, [ka] In the formula, ring A, ring B, R 1 , R 2 , R 3 , R4 L, X, Y, m, n, and r have the definitions set forth herein.

[0037] According to some embodiments, the compound represented by formula (I) has the structure shown below, [ka] In the formula, ring A, ring B, R 1 , R 2 , R 3 , R 4 L, X, Y, m, n, and r have the definitions set forth herein.

[0038] According to some embodiments, the compound represented by formula (I) has the structure shown below, [ka] In the formula, R 1 , R 2 , R 3 , R 4 , R y X, m, n, r have the definitions set forth herein, and W is O, S, CH2, NH, [ka] If selected from, Q1 and Q2 are the same or different and independently selected from CH or N, T1 is selected from CH or N, T2 and U are the same or different and independently selected from O, S, N, CH, NH or CH2, V is selected from N or C, and V is selected from N, then R 5 It does not exist, R 5 It does not exist or it is hydrogen, hydroxyl group, cyano group, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, Halo C 1-6 Alkyl, halo C 1-6 Alkoxy group or C 3-6 Selected from cycloalkyl groups, p, p1, p2, p3, p4 are identical or different, and independently selected from 0, 1, 2, 3, 4, 5. [ka] represents a single bond or a double bond, According to some embodiments, the compound represented by formula (I) has the structure shown below, [ka] In the formula, R 1 , R 2 , R 3 , R 4 X, m, n, r have the definitions set forth herein, and W 1 O, S, CH2, NH, CH, N, [ka] Selected from, Q1 and Q2 are the same or different, and independently selected from CH or N, V 1 V is selected from N, C, or CH. 2 It is selected from N, NH, C, CH, or CH2. [ka] The symbol represents a single bond or a double bond.

[0039] According to some embodiments, the compound represented by formula (I) has the structure shown below, [ka] [ka] In the formula, R z R in this specification y Having the definition described above, preferably R z R is H, halogen, cyano group, hydroxyl group, unsubstituted or selectively one, two or more R z1 The amino group substituted by C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 3-6 Selected from cycloalkyl groups, each R z1They are the same or different, and independently of each other are hydrogen, hydroxyl group, cyano group, halogen, oxo (=O), amino group, and C 1-6 Alkyl alkyl group, C 3-6 Selected from cycloalkyl groups, more preferably R z R is selected from H, halogen, cyano group, methyl group, ethyl group, propyl group, and cyclopropyl group. 1 , R 2 , R 4 , R y Y, m, n, r have the definitions set forth herein, and W is O, S, CH2, NH, [ka] If selected from, Q1 and Q2 are the same or different, and selected independently from CH or N, and V is selected from N or C, and V is selected from N, then R 5 It does not exist, V a , V b They are the same or different, and are independently selected from CH, CH2, N, NH, R 5 It does not exist or it is hydrogen, hydroxyl group, cyano group, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, Halo C 1-6 Alkyl, halo C 1-6 Alkoxy group or C 3-6 Selected from cycloalkyl groups, p is selected from 0, 1, 2, 3, 4, 5, and t is selected from 0, 1, 2. [ka] The symbol represents a single bond or a double bond.

[0040] According to some embodiments, the compound represented by formula (I) has the structure shown below, [ka] In the formula, R 1 , R 2 , R 4 , R 6 , R y , R zQ1, Q2, m, n, and t have the definitions set forth herein. According to some embodiments, exemplary and non-limiting specific examples of the compound represented by formula (I) and its racemates, stereoisomers, tautomers, isotopically labeled compounds, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs, or pharmaceutically acceptable salts thereof are as follows:

[0041] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0042] According to some embodiments, the compound of formula (I) is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] is selected from the structure of.

[0043] The present invention further provides a pharmaceutical composition comprising at least one of a therapeutically effective amount of a compound represented by formula (I) and its racemate, stereoisomer, tautomer, isotope label, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or a pharmaceutically acceptable salt thereof.

[0044] According to embodiments of the present invention, the pharmaceutical composition further comprises one or more pharmaceutically acceptable auxiliary materials.

[0045] The auxiliary materials in the pharmaceutical composition are "acceptable" in the sense that they are compatible with the active ingredient of the composition (and preferably can stabilize the active ingredient) and are not harmful to the target of treatment. One or more excipients may be used to deliver the active compound.

[0046] According to some embodiments of the present invention, the pharmaceutical composition may further contain one or more additional therapeutic agents.

[0047] The present invention further provides the use of at least one of the compounds represented by formula (I) and their racemates, stereoisomers, tautomers, isotopically labeled compounds, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs, or pharmaceutically acceptable salts thereof, or of the pharmaceutical compositions thereof, in the preparation of drugs.

[0048] According to some embodiments, the drug is a drug used to diagnose, prevent and / or treat FGFR2 and / or FGFR3-mediated diseases or disorders.

[0049] According to some embodiments, the drug is an FGFR2 and / or FGFR3 inhibitor.

[0050] According to some embodiments, the disease is a cancer related to FGFR.

[0051] According to some embodiments, the disease or disorder is selected from bladder cancer, brain tumor, breast cancer, bile duct cancer, head and neck cancer, lung cancer, multiple myeloma, rhabdomyosarcoma, urethral cancer, and uterine cancer.

[0052] According to some embodiments, the disease is chondrodysplasia or dysphagia related to FGFR.

[0053] According to several embodiments, at least one of the compounds represented by formula (I) and its racemates, stereoisomers, tautomers, isotope-labeled compounds, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs, or pharmaceutically acceptable salts thereof can be prepared in a form suitable for administration by any suitable route and prepared in a conventional manner using one or more pharmaceutically acceptable carriers. Accordingly, at least one of the compounds represented by formula (I) and its racemates, stereoisomers, tautomers, isotope-labeled compounds, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs, or pharmaceutically acceptable salts thereof can be prepared in various dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or inhalation administration, or in sustained-release dosage forms, such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, tablets, or syrups.

[0054] The present invention further provides methods for diagnosing, preventing and / or treating FGFR2 and / or FGFR3-mediated diseases or disorders, the methods comprising administering to a patient in need of such treatment at least one of the compounds represented by formula (I) and its racemates, stereoisomers, tautomers, isotope-labeled compounds, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof, or a pharmaceutical composition of the present invention, alone or selectively in combination with another compound of the present invention and / or at least one other type of therapeutic agent.

[0055] According to some embodiments, the FGFR2 and / or FGFR3-mediated disease or condition is selected from bladder cancer, brain tumor, breast cancer, cholangiocarcinoma, head and neck cancer, lung cancer, multiple myeloma, rhabdomyosarcoma, urethral cancer, uterine cancer, and chondrodysplasia.

[0056] In some embodiments, the patient is a mammal, preferably a human. [Effects of the Invention]

[0057] The compounds provided by the present invention have good inhibitory effects on FGFR2 and / or FGFR3, can be used for treating or preventing disorders and diseases related to FGFR2 and / or FGFR3, and are used for manufacturing drugs for treating or preventing such disorders and diseases.

[0058] The definitions and explanations of terms are as follows.

[0059] Unless otherwise specified, the groups and term definitions described in the specification and claims of this application include, as examples, definitions, exemplary definitions, preferred definitions, definitions described in tables, definitions of specific compounds in examples, etc., and may be arbitrarily combined and linked with each other. The definitions of groups and the structures of compounds after such combinations and linkages should be understood to be within the scope described in the specification and / or claims of this application.

[0060] The term "selective" (or "selectively", "selectively") in the definition of the general formula of this application means being substituted with 0, 1 or more substituents. For example, "selectively substituted by one, two or more Rs" means that it can be unsubstituted (non-substituted) or can be selected to be substituted by one, two or more Rs.

[0061] "More than" refers to 3 or more, for example 3, 4, 5, 6, 7, 8, 9 or 10.

[0062] Unless otherwise explained, the numerical ranges described in this specification and claims correspond to those that list at least each specific integer value therein. For example, the numerical range "1 to 12" corresponds to those that list each integer value within the numerical range "1 to 12", that is, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12.

[0063] The term "halogen" means fluorine, chlorine, bromine and iodine.

[0064] "HO-C 1-6"Alkyl group" is a C group substituted with a hydroxyl group. 1-6 It refers to the alkyl group.

[0065] "C 1-6 The term "alkyl group" refers to linear and branched alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of such alkyl groups include 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 their isomers.

[0066] "C 3-8 The term "cycloalkyl group" should be understood to mean a saturated monovalent monocyclic or bicyclic (e.g., bridging ring, spiro ring) hydrocarbon ring having 3, 4, 5, 6, 7, or 8 carbon atoms. 3-8 The cycloalkyl group may be a monocyclic hydrocarbon group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl, or a bicyclic hydrocarbon group, such as bornyl, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, dicyclo[2.1.1]hexyl, dicyclo[2.2.1]heptyl, dicyclo[2.2.1]heptenyl, 6,6-dimethyldicyclo[3.1.1]heptyl, 2,6,6-trimethyldicyclo[3.1.1]heptyl, dicyclo[2.2.2]octanyl, 2,7-diazaspiro[3,5]nonanyl, or 2,6-diazaspiro[3,4]octanyl.

[0067] The term "3-10 membered heterocyclyl group" 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 linked to other parts of the molecule via any one of the carbon atoms or a nitrogen atom (if present). The heterocyclyl group may include fused rings or bridging rings and spiro rings. In particular, the heterocyclyl group may include, but is not limited to, a four-membered ring such as an azetidinyl group or an oxetanyl group, a five-membered ring such as a tetrahydrofuranyl group, a dioxolyl group, a pyrrolidinyl group, an imidazolidinyl group, a pyrazolidinyl group, or a six-membered ring such as a tetrahydropyranyl group, a piperidine group, a morpholinyl group, a dithianyl group, a thiomorpholinyl group, a piperazinyl group, or a trithianyl group, or a seven-membered ring such as a diazepanyl group. Optionally, the heterocyclyl group may be benzo-fused. The heterocyclyl group may be bicyclic, for example, a 5,5-membered ring such as a hexahydrocyclopenta[c]pyrrole-2(1H)-yl ring, or a 5,6-membered bicyclic ring such as a hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl ring, but is not limited to these. The heterocyclyl group may be partially unsaturated, that is, it may contain one or more double bonds, for example, dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 1,2,3,5-tetrahydroxazolyl, or 4H-[1,4]thiadinyl, but is not limited to these, or it may be benzo-condensed, for example, dihydroisoquinolinyl, but is not limited to these. When the 3-10 membered heterocyclyl group is bonded to other groups to constitute the compound of the present invention, the carbon atoms on the 3-10 membered heterocyclyl group may be bonded to other groups, and the heteroatoms on the 3-10 membered heterocyclyl group may be bonded to other groups. For example, if the 3-10 membered heterocyclyl group is selected from piperazinyl groups, the nitrogen atom on the piperazinyl group may be bonded to other groups. If the 3-10 membered heterocyclyl group is selected from piperidinyl groups, the nitrogen atom on the piperidinyl ring and the carbon atom at its para position may be bonded to other groups.

[0068] The term "5-10 membered heteroaryl group" should be 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 each heteroatom may be benzo-condensed. Examples of monocyclic "heteroaryl groups" include, for example, pyridyl, pyridadinyl, pyrimidinyl, pyrazinyl, thiadinyl, oxazinyl, triazinyl, thiadiadinyl, or oxadiadinyl groups. A "heteroaryl group" further refers to a group in which a heteroaromatic ring is condensed to one or more aryl, alicyclic, or heterocyclyl rings, and the binding site is located on the heteroaromatic ring. Non-limiting examples include 1-,2-,3-,5-,6-,7- or 8-indolidinyl, 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-prinyl, 1-,2-,3-,4-,6-,7-,8- or 9-quinolidinyl, 2- ,3-,4-,5-,6-,7- or 8-quinolinyl, 1-,3-,4-,5-,6-,7- or 8-isoquinolinyl, 1-,4-,5-,6-,7- or 8-phthalazinyl, 2-,3-,4-,5- or 6-naphthyridine, 2-,3-,5-,6-,7- or 8-quinazolinyl, 3-,4-,5-,6-,7- or 8-sinnolinyl, 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-carbazolylcarbazolyl, 1-,3-,4-,5-,6-,7-,8- or 9-carbolinyl, 1-,2-,3-,4-,6-,7-,8-,9- or 10-phenantridinyl, 1-,2-,3-,4-,5-,6 -, 7-, 8- or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-pyridyl, 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-, 7-, 8-,9- or 10-phenadinyl, 2-, 3-, 4-, 5-, 6- or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-benzoisoquinolinyl, 2-, 3-, 4- or thienono[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-flo[3,2-b]pyrani Lu, 2-, 3-, 4-, 5-, 7- or 8-5H-pyridyl[2,3-d]-o-oxazinyl, 1-, 3- or 5-1H-pyridino[4,3-d]-o-oxazolyl, 2-, 4- or 5-4H-imidazolo[4,5-d]thiazolyl, 3-, 5- or 8-pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5- or 6-imidazolo[2,1-b]thiazolyl, 1-, 3-, 6-, 7- , 8- or 9-fl[3,4-c]sinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10 or 11-4H-pyrido[2,3-c]carbazolyl, 2-, 3-, 6- or 7-imidazolo[1,2-b][1,2,4]triazinyl, 7-benzo[b]thienyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 2-, 4-, 5-, 6- or 7-benzimidazolyl, It contains 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, and 1-,2-,3-,5-,6-,7-,8-,9-,10- or 11-4H-pyrrolo[1,2-b][2]benzoazepinyl. Typical condensed 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]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 is bonded to other groups to constitute the compounds of the present invention, carbon atoms on the 5-10 membered heteroaryl ring may also be bonded to other groups.The heteroatoms on the 5-10 membered heteroaryl ring may be bonded to other groups. If the 5-10 membered heteroaryl is substituted, it may be monosubstituted or polysubstituted. Furthermore, the substitution position is not limited; for example, hydrogen bonded to a carbon atom on the heteroaryl ring may be substituted, or hydrogen bonded to a heteroatom on the heteroaryl ring may be substituted.

[0069] The term "nitrogen oxide" refers to compounds formed by the oxidation of nitrogen atoms in the structure of tertiary amines or nitrogen-containing (aromatic) heterocyclic compounds.

[0070] The term "spiro ring" refers to a ring system in which two rings share a single ring-forming atom.

[0071] The term "condensed ring" refers to a ring system in which two rings share two ring-forming atoms.

[0072] The term "bridged ring" refers to a ring system in which two rings share three or more ring-forming atoms.

[0073] Unless otherwise stated, heterocyclyl groups, heteroaryl groups, or heteroarylene groups include all possible isomeric forms thereof, e.g., positional isomers. Thus, some exemplary and non-limiting examples may include forms in which the group is substituted at one, two, or more positions, such as the 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-positions (if any), or bonded to another group, and include thienyl or thienylene groups containing pyridine-2-yl, pyridine-2-ylidene, pyridine-3-yl, pyridine-3-ylidene, pyridine-4-yl and pyridine-4-ylidene, thiophene-2-yl, thiophene-2-ylidene, thiophene-3-yl and thiophene-3-ylidene, pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl and pyrazole-5-yl.

[0074] The term "oxo" refers to a substituent that has been substituted with an oxo group (=O) formed after the oxidation of a carbon, nitrogen, or sulfur atom in the substituent.

[0075] The term "alkylamino group" refers to -NH-(alkyl) or -N-(alkyl)2, and the definition of alkyl is as described above. Non-limiting examples of alkylamino groups include methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, methylethylamino, diethylamino, dipropylamino, methylpropylamino, diisopropylamino, dibutylamino, etc.

[0076] The term "alkyloxy group" refers to -O-(alkyl), and the definition of alkyl is as described above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy groups. Alkoxy groups may be optionally substituted or unsubstituted. If substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkyloxy, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, or heterocycloalkyloxy.

[0077] The terms "alkylene oxy group" and "oxyalkylene group" refer to -alkylene-O- or -O-alkylene-, where alkylene represents a straight-chain or branched-chain saturated divalent hydrocarbon group. The definition of the number of carbon atoms in "alkylene" is the same as the definition for "alkyl" above. As will be understood by those skilled in the art, alkylene oxy groups and oxyalkylene groups can be bonded to the rest of the molecule containing them in any direction; that is, they are interchangeable.

[0078] A "haloalkyl group" refers to an alkyl group substituted with one or more halogens, and the definition of an alkyl group is as described above.

[0079] L is -C(=O)-N(R a When selected from ), the group bonded to ring A may be a carbonyl group in L, or it may be an N in L, where if a carbonyl group is bonded to ring A, the N in L is bonded to the pyrazolopyridine ring, and if N is bonded to a carbonyl group, the carbonyl group in L is bonded to the pyrazolopyridine ring.

[0080] In the present invention, references to compounds include isotope-labeled compounds, which are identical to those shown in formula I, but in which one or more atoms are substituted with atoms having atomic masses or mass numbers different from those normally found in nature. Examples of isotopes of compounds that can be incorporated into the present invention include isotopes of H, C, N, O, S, F, and Cl, for example 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 32 P, 35 S, 18 F and 36 Contains Cl. Compounds of the present invention containing the above isotopes and / or other isotopes of other atoms, their prodrugs, or pharmaceutically acceptable salts of the said compounds or prodrugs are within the scope of the present invention. Certain isotope-labeled compounds of the present invention, for example, radioisotopes ( 3 H and 14 Compounds incorporating tritium (i.e., C) can be used to measure the distribution of drugs and / or substrate tissues. 3 H) and carbon-14 (i.e.) 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Furthermore, relatively heavy isotopes (deuterium, i.e.) 2Substitution with H or D, etc., can provide certain therapeutic benefits resulting from higher metabolic stability (e.g., increased half-life in the body or reduced dose requirements), and is therefore preferable in some cases. The compounds of the present invention as claimed in the claims can be substituted with deuterium or tritium in particular. Furthermore, the hydrogen appearing in the substituents does not separately list the terms deuterium or tritium and does not exclude deuterium or tritium, and deuterium or tritium may be included as well.

[0081] As those skilled in the art will understand, the compounds represented by formula (I) may exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they can form acid-added salts; if they have an acidic center, they can form base-addition salts; and if they contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they can also form intramolecular salts.

[0082] The compounds of the present invention may exist in the form of solvates (e.g., hydrates), wherein the compounds of the present invention include a polar solvent, particularly water, methanol, or ethanol, as a component of the compound crystal lattice. The amount of the polar solvent, particularly water, may be in stoichiometric or non-stoichiometric ratios.

[0083] Depending on their molecular structure, the compounds of the present invention may be chiral, and therefore various enantiomer forms may exist. Accordingly, these compounds can exist in racemic or optically active forms. The compounds of the present invention cover isomers or mixtures thereof, where each chiral carbon is in an R or S configuration, and racemates. The compounds of the present invention or their intermediates can be separated into enantiomer compounds by chemical or physical methods known to those skilled in the art, or can be used in synthesis in such forms. In the case of racemized amines, diastereomers were prepared from the mixture by reaction with an optically active resolution reagent. Examples of suitable resolution reagents include optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid in R and S configurations, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline), or various optically active camphorsulfonic acids. Optically active resolution reagents (e.g., dinitrobenzoylphenylglycine, cellulose triacetate, or other carbohydrate derivatives or chiral derivatized methacrylate polymers immobilized on silica gel) can be used to advantageously perform enantiomeric resolution in chromatography. Suitable eluents for this purpose are water or alcohol-containing solvent mixtures, such as hexane / isopropanol / acetonitrile.

[0084] The corresponding stable isomers can be separated by known methods, such as extraction, filtration, or column chromatography.

[0085] The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, and most preferably humans.

[0086] The term “therapeutic dose” refers to the amount of an active compound or drug that researchers, veterinarians, physicians or other clinicians seek from a tissue, system, animal, individual or human to produce a biological or medical response, and it includes one or more of the following: (1) prevention of disease: e.g., preventing disease, disorder or disorder in an individual that is susceptible to infection but has not yet experienced or developed the pathology or symptoms of the disease; (2) inhibition of disease: e.g., inhibiting disease, disorder or disorder in an individual that has experienced or developed the pathology or symptoms of disease, disorder or disorder (i.e., preventing further progression of the pathology and / or symptoms); (3) remission of disease: e.g., relieving disease, disorder or disorder in an individual that has experienced or developed the pathology or symptoms of disease, disorder or disorder (i.e., reversing the pathology and / or symptoms). [Modes for carrying out the invention]

[0087] The following provides a more detailed explanation of the technical aspects of the present invention with specific examples. It should be understood that the following examples are merely illustrative and interpretive of the present invention and should not be interpreted as limiting the scope of protection of the present invention. Any technology realized based on the above-described aspects of the present invention falls within the intended scope of protection of the present invention.

[0088] Unless otherwise specified, all raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0089] The structure of the compounds of the present invention is determined by nuclear magnetic resonance (NMR) and / or liquid chromatography (LC-MS). The NMR chemical shift (δ) is given in parts per million (ppm). A Bruker AVANCE-400 nuclear magnetic resonance spectrometer is used for NMR measurements, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as the measurement solvents, and tetramethylsilane (TMS) as the internal standard.

[0090] For liquid chromatography-LC-MS measurements, an Agilent 1200 Infinity Series mass spectrometer was used. For HPLC measurements, an Agilent 1200DAD high-performance liquid chromatograph and a Waters 2695-2996 high-performance liquid chromatograph were used.

[0091] For thin-layer chromatography, Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used. The silica gel plates used for TLC are 0.15 mm to 0.20 mm in size, and the products separated and purified by thin-layer chromatography are 0.4 mm to 0.5 mm in size. For column chromatography, Yantai Huanghai silica gel of 200 to 300 mesh is generally used as the support.

[0092] 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 measured in degrees Celsius.

[0093] Example 1 (5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-pyrazolo[4,3-b]pyridyl-3-yl)pyridyl-2-yl)(imino)(methyl)-λ 6 -Sulfone [ka]

[0094] Step 1 Compound 1a (10 g, 4.9 mmol), ammonium acetate (0.6 g, 7.8 mmol), and iodobenzenediacetic acid (3.2 g, 9.9 mmol) were weighed, methanol (100 ml) was added, and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to remove the organic solvent, and then purified by reverse-phase preparative HPLC (ACN / H2O = 5%~80%) to obtain compound 1b (8.7 g, yield 75%). MS: m / z = 234.9 (M + H) + .

[0095] Step 2 Compound 1b (8.7g, 37 mmol), bis(pinacolato)diborone (18g, 70.9 mmol), potassium carbonate (7.5g, 54.3 mmol), and 1,1'-bisdiphenylphosphinoferocenedichloropalladium (2.6g, 3.6 mmol) were weighed and dissolved in a 1,4-dioxane / water = 5 / 1 (150 mL) solution. Under nitrogen protection, the mixture was heated to 90°C and reacted for 16 hours. After cooling to room temperature, ethyl acetate (100 ml) was added, and the mixture was separated by extraction. The organic phase was washed three times with dilute hydrochloric acid (10%, 100 ml), the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. After separation by column chromatography (mobile phase: ethyl acetate / n-hexane = 1 / 10~10 / 1), compound 1c (7g, yield 94.5%) was obtained. MS:m / z=201.1(M+H) + .

[0096] Step 3 Commercially available compound 1d (5 g, 33.5 mol), sodium iodide (15.0 g, 100.7 mmol), and chlorotrimethylsilane (5.5 g, 50.6 mmol) were weighed, dissolved in anhydrous acetonitrile (100 ml), heated to 80 degrees Celsius, reacted for 3 hours, cooled to room temperature, added ethyl acetate (150 ml) and water (150 ml), stirred vigorously for 1 hour, separated the organic phase, extracted the aqueous phase with ethyl acetate (150 ml), combined the organic phases, and concentrated under reduced pressure to obtain compound 1e (3.6 g, yield 80%). MS: m / z = 136.0 (M + H) + .

[0097] Step 4 Compound 1e (3.6 g, 26.6 mmol) was weighed and dissolved in phosphorus oxychloride (50 ml), heated to 70 degrees Celsius, incubated for 3 hours, concentrated to remove phosphorus oxychloride, ethyl acetate (50 ml) and water (50 ml) were added, and the mixture was extracted and separated. The organic phase was dried and separated by column chromatography (mobile phase: ethyl acetate / n-hexane = 1 / 10 to 1 / 1) to obtain compound 1f (3.5 g, yield 85%). MS: m / z = 154.0 (M + H) + .

[0098] Step 5 Compound 1f (3.5g, 22.8 mmol) and potassium tert-butoxide (2.5g, 22.0 mmol) were weighed and dissolved in tetrahydrofuran (50 ml). The mixture was cooled to 0-5°C in an ice bath and stirred for 1 hour. 2-(trimethylsilyl)ethoxymethyl chloride (4.2g, 25.2 mmol) was added, and the reaction was continued in an ice bath for 1 hour. The mixture was then stirred at room temperature for 2 hours. The reaction solution was poured into water (100 ml), extracted and separated with ethyl acetate (150 ml), and the organic phases were combined, concentrated, and separated by column chromatography (mobile phase: ethyl acetate / n-hexane = 1 / 10-1 / 2) to obtain 1 g of compound (5.8 g, yield 89.6%). MS: m / z = 284.1 (M + H) + .

[0099] Step 6 Weighed 1.0 g (5.2 mmol) of commercially available compound 1h and dissolved it in anhydrous tetrahydrofuran (50 ml). The mixture was stirred in an ice bath for 30 minutes, sodium hydride (125 mg) was added, stirring continued in an ice bath for another 30 minutes, 1 g (1.5 g (5.3 mmol)) of compound was added, the mixture was stirred in an ice bath for 2 hours, and then stirred at room temperature for another hour. The reaction mixture was poured into ice water (100 ml), the mixture was extracted with ethyl acetate (100 ml x 3), the organic phases were combined, concentrated, and purified by column chromatography (mobile phase: ethyl acetate / n-hexane = 1 / 10 to 1 / 1) to obtain compound 1i (2.2 g, yield 94.7%). MS: m / z = 439.1 (M + H) + .

[0100] Step 7 Compound 1i (2.2 g, 11.5 mmol) was weighed and dissolved in N,N-dimethylformamide (50 ml). N-iodosuccinimide (2.8 g, 12.4 mmol) was added, and the mixture was heated to 60 degrees Celsius under nitrogen protection and reacted for 3 hours. After cooling to room temperature, the mixture was poured into ice water (100 ml) and extracted with ethyl acetate (100 ml x 3). The organic phases were combined, concentrated, and purified by column chromatography (mobile phase: ethyl acetate / n-hexane = 1 / 10 to 1 / 1) to obtain compound 1j (2.0 g, yield 70.6%). MS: m / z = 565.0 (M + H) + .

[0101] Step 8 Compound 1J (200 mg, 0.35 mmol) was weighed and dissolved in a 1,4-dioxane / water = 10 / 1 (10 mL) mixed solvent. Compound 1c (77 mg, 0.39 mmol), potassium carbonate (70 mg, 0.5 mmol), and 1,1'-bisdiphenylphosphinoferocenedichloropalladium (10 mg) were added. The mixture was reacted at 90°C for 2 hours. After the reaction was complete, the mixture was extracted, the organic phase was collected, dried, and concentrated. The residue was passed through a silica gel column (mobile phase: petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to obtain compound 1k (150 mg, yield 54.2%). MS: m / z = 593.1 (M + H) + .

[0102] Step 9 Compound 1k (150 mg, 0.25 mmol) was weighed and dissolved in dichloromethane (10 mL) solution, trifluoroacetic acid (729 mg, 6.39 mmol) was added, and the reaction mixture was stirred at 25 degrees Celsius for 16 hours. After the reaction was complete, the mixture was concentrated, the pH was adjusted to 7-8 with 10% aqueous sodium bicarbonate solution, extracted with ethyl acetate (50 mL), concentrated, and separated and purified by high-performance liquid chromatography column (mobile phase: acetonitrile / water = 44 / 56) to obtain Cpd-01 (110 mg).

[0103] The first chiral resolution of Cpd-01 yields a stereoisomer mixture Cpd-01M (30 mg, t R(=2.604 min), and optically pure compound Cpd-01C (10 mg, t R =2.691 min) and Cpd-01D (12 mg, t R (=3.352 min) was obtained by the second chiral resolution of Cpd-01M. Furthermore, optically pure compound Cpd-01A (10 mg, t R =1.836 min) and Cpd-01B (8 mg, t R = 2.300 min) was obtained.

[0104] Conditions for the first split: Device brand: SFC 150 Preparative column model number: Daicel CHIRALCEL OZ, 250mm 30mm ID, 10μm Mobile phase: CO2 / MeOH[0.2%NH3(7M Solution in MeOH)]=65 / 35, Flow rate: 80g / min, Column temperature: 35 degrees.

[0105] Second split conditions: Device brand: SFC 150 Preparative column model number: Daicel CHIRALCEL AD, 250mm 30mm ID, 10μm Mobile phase: CO2 / MeOH[0.2%NH3(7M Solution in MeOH)]=65 / 35, Flow rate: 80 g / min, Column temperature: 35 degrees.

[0106] Cpd-01A MS:m / z=463.0(M+H) + . 1 H NMR(400MHz,CDCl3)δ 9.51(s,1H),8.81(d,J=7.6Hz,1H),8.42(s,2H),8.18(s,1H),7.86(d,J=9.0Hz,1H),7 .04(d,J=9.0Hz,1H),6.59(dd,J=13.8,6.8Hz,1H),3.36(s,3H),1.81(d,J=6.8Hz,3H). Cpd-01B MS: m / z = 463.0 (M+H) + . 1 1H NMR (400 MHz, CDCl3) δ 9.49 (s, 1H), 8.80 (d, J = 8.0 Hz, 1H), 8.43 (s, 2H), 8.18 (s, 1H), 7.86 (d, J = 9.0 Hz, 1H), 7.04 (d, J = 9.0 Hz, 1H), 6.58 (q, J = 7.0 Hz, 1H), 3.35 (s, 3H), 1.81 (d, J = 6.8 Hz, 3H). Cpd-01C MS: m / z = 463.0 (M+H) + . 1 1H NMR (400 MHz, CDCl3) δ 9.51 (s, 1H), 8.82 (d, J = 8.2 Hz, 1H), 8.42 (s, 2H), 8.18 (d, J = 8.2 Hz, 1H), 7.85 (d, J = 9.2 Hz, 1H), 7.04 (d, J = 9.0 Hz, 1H), 6.60 (dd, J = 13.8, 6.8 Hz, 1H), 3.35 (s, 3H), 1.81 (d, J = 7.0 Hz, 3H). Cpd-01D MS: m / z = 463.0 (M+H) + . 1 1H NMR (400 MHz, CDCl3) δ 9.49 (s, 1H), 8.79 (s, 1H), 8.44 (s, 2H), 8.17 (s, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.04 (d, J = 9.0 Hz, 1H), 6.56 (d, J = 6.6 Hz, 1H), 3.38 (s, 3H), 1.81 (d, J = 6.8 Hz, 3H).

[0107] Synthesis of Intermediate INT-1

Chemical Structure

[0108] Step 2 5-Methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-4-azaindol INT-1b (14.0 g, 0.06 mol) and trimethylsilyl iodide (36.7 g, 0.18 mol) were weighed, acetonitrile (100 ml) was added, and the mixture was heated to 80 degrees Celsius and reacted for 6 hours. After cooling to room temperature, ethyl acetate (100 ml) and water (100 ml) were added for washing and extraction. The organic phase was concentrated and purified by column chromatography (ethyl acetate / petroleum ether = 1 / 5 to 1 / 1) to obtain compound INT-1c (9.2 g) in 70% yield. MS m / z (ESI): 220.1 (M+H) + .

[0109] Step 3 Weigh compound INT-1c (9.0 g, 0.041 mol) and dissolve it in DMF (50 mL). Add cesium carbonate (3.25 g, 10.0 mmol) and (R)-1-(3,5-dichloropyridine-4-yl)ethylmethanesulfonate (16.7 g, 0.062 mol). Heat the reaction mixture under nitrogen gas protection at 80°C. oThe mixture was stirred in C for 16 hours. Then, water (50 mL) was added, and the mixture was extracted with ethyl acetate and evaporated by rotation. Trifluoroacetic acid (5 mL) and dichloromethane (50.0 mL) were added, and the mixture was reacted at room temperature for 6 hours. After the reaction was complete, water (50 mL) was added, the mixture was separated, and the mixture was further extracted with ethyl acetate (50 mL) to concentrate. The mixture was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether = 1 / 10 to 10 / 1) to obtain compound INT-1d (10.0 g) in yield of 78%. MS m / z (ESI): 309.0 (M+H) + .

[0110] Step 4 Compound INT-1d (3.0 g, 9.7 mmol) was weighed and dissolved in anhydrous DMF (30.0 mL). NIS (2.18 g, 9.7 mmol) was added to the DMF (30 mL) solution, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was concentrated and quenched with saturated sodium thiosulfate aqueous solution. After concentration, the compound INT-1e (3.1 g) was separated and purified using a silica gel column (petroleum ether / ethyl acetate = 5 / 1) with a yield of 73%. MS m / z (ESI): 434.9 (M+H) + . 1 H NMR(400MHz,CDCl3)δ 8.41(s,2H),7.77(d,J=9.0Hz,1H),6.99(d,J=9.0Hz,1H),6.59(q,J=7.0Hz,1H),1.80(d,J=7.0Hz,3H).

[0111] Step 5 Compound INT-1e (8g, 0.018mol), DHP (1.8g, 0.02mol), and PTSA (0.3g, 0.002mol) were weighed, and tetrahydrofuran (50mL) was added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was concentrated, washed with saturated ammonium chloride, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated again, and then separated and purified using a silica gel column (petroleum ether / ethyl acetate = 5 / 1) to obtain compound INT-1 (7.4g) in a yield of 80%. MS m / z (ESI): 518.9 (M+H) + .

[0112] Example 2 (R)-4-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-pyrazolo[4,3-b]pyridyl-3-yl)pyridyl-2-yl)-3,6-dihydro-2H-thiopyran 1,1-dioxide [ka]

[0113] Step 1 (R)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-3-iodo-1H-pyrazolo[4,3-b]pyridylINT-1e (60 mg, 0.1379 mmol), (6-chloropyridine-3-yl)boronic acid (28.21 mg, 0.17927 mmol), potassium acetate (40.6 mg, 0.4137 mmol), and Pd(AMPhos)Cl2 (10.09 mg, 0.01379 mmol) mixed with ethanol / water (2 The reaction mixture was dissolved in 0.5 mL of iodine, ventilated three times, and stirred at 90 degrees Celsius for 1 hour. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth, extracted with ethyl acetate, dried and concentrated, and then separated and purified by silica gel column (petroleum ether / ethyl acetate = 1 / 1) to obtain (R)-3-(6-chloropyridine-3-yl)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-pyrazolo[4,3-b]pyridyl 02a (50 mg), with a yield of 86%.

[0114] Step 2 (R)-3-(6-chloropyridine-3-yl)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-pyrazolo[4,3-b]pyridyl 02a (60 mg, 0.1426 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-thiopyran Dissolve 1,1-dioxide (40.49 mg, 0.15686 mmol), potassium carbonate (39.42 mg, 0.2852 mmol), and Pd(dppf)Cl2 (10.43 mg, 0.01426 mmol) in 1,4-dioxane / water (1 / 0.2 mL), ventilate three times, and stir the reaction mixture at 90 degrees Celsius for 1 hour. After the reaction is complete, filter the reaction mixture through diatomaceous earth, extract with ethyl acetate, dry and concentrate, then separate and purify using a silica gel column (petroleum ether / ethyl acetate = 1 / 1) to obtain the crude product. Finally, the crude product is subjected to high-performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: Xbridge 5u C18 150 x 19 mm, mobile phase 1: water (containing 0.1% formic acid); mobile phase 1 2: Acetonitrile; Separation and purification were performed using a 9-minute gradient, gradient mixing ratio: acetonitrile phase 50%~60%, flow rate: 25 mL / min) to obtain (R)-4-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-pyrazolo[4,3-b]pyridyl-3-yl)pyridyl-2-yl)-3,6-dihydro-2H-thiopyran 1,1-dioxide Cpd-02A (8 mg), with a yield of 11%. 1 HNMR(400MHz,DMSO-d6)δ 13.51(s,1H),9.16(d,J=1.8Hz,1H),8.63(s,2H),8.36(dd,J=8.3,2.1Hz,1H),8.07(d,J=9.0Hz,1H),7.72(d,J=8.4Hz,1H),7.07(d,J=9 .0Hz,1H),6.74(t,J=4.5Hz,1H),6.41(q,J=6.8Hz,1H),4.02(s,2H),3.42(t,J=6.1Hz,2H),3.25(d,J=5.6Hz,2H),1.75(d,J=6.8Hz,3H).

[0115] Example 3 (R)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-3-(6-(4-methylsulfonyl)piperidine-3-yl)-1H-pyrazolo[4,3-b]pyridyl [ka]

[0116] Step 1 1-(5-bromopyridine-2-yl)piperazine 119a (500 mg, 2.065 mmol), methanesulfonyl chloride (261 mg, 2.272 mmol), and triethylamine (418 mg, 4.130 mmol) were dissolved in dichloromethane (10 mL), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain 1-(5-bromopyridine-2-yl)-4-(methylsulfonyl)piperazine 119b (400 mg). The yield was 54.4%. MS m / z (ESI): 320.0 (M+H) + .

[0117] Step 2 1-(5-bromopyridine-2-yl)-4-(methylsulfonyl)piperazine 119b (200 mg, 0.625 mmol), bis(pinacolato)diborone (238 mg, 0.937 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium chloride (46 mg, 0.0625 mmol), and potassium acetate (123 mg, 1.249 mmol) were dissolved in 1,4-dioxane (5 mL) and stirred at 80°C for 2 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was filtered and concentrated. The crude product was purified by silica gel column (petroleum ether / ethyl acetate = 3 / 1) to obtain (6-(4-(methylsulfonyl)piperazine-1-yl)pyridyl-3-yl)boronic acid 119c (100 mg). The yield was 50.5%. MS m / z (ESI): 286.1 (M+H) + .

[0118] Step 3 (6-(4-methylsulfonyl)piperazin-1-yl)pyridyl-3-yl)boronic acid 119c (79 mg, 0.28 mmol), (R)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-3-iodo-1H-pyrazolo[4,3-b]pyridyl INT-1e (80 mg, 0.18 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium chloride (13 mg, 0.02 mmol), and potassium acetate (36 mg, 0.37 mmol) are dissolved in ethanol:water (5 mL) and stirred at 90°C under a nitrogen atmosphere for 18 hours. After the reaction is complete, the mixture is filtered and concentrated. The crude product was preparatively purified (FA, mobile phase: ACN:H2O(0.1% NH3)=50%:50%) to obtain (R)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-3-(6-(4-methylsulfonyl)piperidine-3-yl)-1H-pyrazolo[4,3-b]pyridyl Cpd-119A (4.13 mg). The yield was 3.92%.

[0119] MS m / z (ESI): 548.0 (M+H) + . 1 H NMR(400MHz,CDCl3)δ 8.95(s,1H),8.41(s,2H),8.30(d,J=8.4Hz,1H),7.75(d,J=8.8Hz,1H),6.98(d,J=9.0Hz,1H),6.74(d,J=8.8Hz,1H),6.56(q,J=7.0Hz,1H),3.83 - 3.78(m,4H),3.41 - 3.37(m,4H),2.84(s,3H),1.80(d,J=6.8Hz,3H).

[0120] Example 4 (R)-2-(1-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-pyrazolo[4,3-b]pyridyl-3-yl)pyridyl-2-yl)piperidine-4-yl)propan-2-ol [ka]

[0121] Step 1 Preparation of (R)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-3-(6-fluoropyridine-3-yl)-1H-pyrazolo[4,3-b]pyridyl (R)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-3-iodo-1H-pyrazolo[4,3-b]pyridylINT-1e (300 mg, 0.58 mmol) is dissolved in dioxane / water = 5 / 1 (5 mL) solution, and (6-fluoropyridine-3-yl)boronic acid (97 mg, 0.58 mmol), potassium carbonate (240 mg, 1.773 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (84 mg, 0.11 mmol) are added. The mixture is stirred at 90°C for 3 hours, and after the reaction is complete, water is added to quench the mixture and extract with ethyl acetate (3 x 30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. After purification by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1), (R)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-3-(6-fluoropyridine-3-yl)-1H-pyrazolo[4,3-b]pyridyl 124a (200 mg) was obtained, with a yield of 60.99%. MS m / z (ESI): 404.0 (M+H) + .

[0122] Step 2 (R)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-3-(6-fluoropyridine-3-yl)-1H-pyrazolo[4,3-b]pyridyl 124a (30 mg, 0.07 mmol) is dissolved in N,N-dimethylacetamide (1 mL), and N,N-diisopropylethylamine (28 mg, 0.22 mmol) and 2-(piperidine-4-yl)propan-2-ol (21 mg, 0.14 mmol) are added. The reaction mixture is stirred at 80°C for 3 hours. After the reaction was complete, the reaction solution was separated by high-performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: WELCH Xtimate C18 21.2*250 mm 10 μm; mobile phase 1: water (containing 0.1% 0.1 FA), mobile phase 2: acetonitrile; gradient for 18 minutes, gradient ratio: acetonitrile phase 5%~100%, flow rate: 30 mL / min) to obtain (R)-2-(1-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-pyrazolo[4,3-b]pyridyl-3-yl)pyridyl-2-yl)piperidine-4-yl)propan-2-ol Cpd-124A (16.19 mg) with a yield of 41.37%. MS m / z (ESI): 527.1 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ 13.11(s,1H),8.71(s,1H),8.59(s,2H),8.06(d,J=7.2Hz,1H),7.98(d, J=9.2Hz,1H),7.00(d,J=9.2Hz,1H),6.86(d,J=9.2Hz,1H),6.38(d,J=6. 8Hz,1H),4.51(d,J=12.8Hz,2H),4.14(s,1H),2.75(t,J=12.0Hz,2H),1. 81(d,J=12.0Hz,2H),1.73(d,J=6.8Hz,3H),1.47(t,J=12.0Hz,1H),1.38 - 1.19 (m, 2H), 1.07 (s, 6H).

[0123] Example 5 (R)-4-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-pyrazolopyridyl-3-yl)-3-fluoropyridine-2-yl)-3,6-dihydro-2H-thiopyran-1,1-dioxide [ka]

[0124] Step 1 Under nitrogen gas protection, compound INT-1e (150 mg, 0.34 mmol) is dissolved in ethanol (3 mL) and water (0.5 mL), and (6-chloro-5-fluoropyridine-3-yl)boronic acid (91 mg, 0.52 mmol), 1,1'-bis(diphenylphosphino)ferocenedichloropalladium (25 mg, 0.03 mmol), and potassium acetate (68 mg, 0.69 mmol) are added in order. The reaction mixture was stirred at 90°C for 5 hours, and the quality of the liquid was monitored to confirm the completion of the reaction. The reaction mixture was filtered, the filtrate was collected, and the crude product was concentrated under reduced pressure. The obtained crude product was purified by chromatography column chromatography (eluate: petroleum ether:ethyl acetate = 4:1) to obtain (R)-3-(6-chloro-5-fluoropyridine-3-yl)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-pyrazolopyridyl Cpd-03a (100 mg). The yield was 66%. MS m / z (ESI): 438.0 (M+H) + .

[0125] Step 2 Under nitrogen gas protection, dissolve (R)-3-(6-chloro-5-fluoropyridine-3-yl)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-pyrazolopyridyl Cpd-03a (100 mg, 0.23 mmol) in 1,4-dioxane (5 mL) and water (1 mL), and add 1,1-dioxide-3,6-dihydro-2H-thiopyran-4-pinacol boronate (71 mg, 0.28 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (17 mg, 0.02 mmol), and potassium carbonate (63 mg, 0.46 mmol). Stir the reaction mixture at 90°C for 3 hours. The reaction was terminated by detecting the disappearance of the starting material due to the substrate, the reaction mixture was filtered, the filtrate was collected, and the crude product was concentrated under reduced pressure. The crude product was separated and purified by column chromatography (eluate: petroleum ether: ethyl acetate = 10:1 to 1:10) to obtain (R)-4-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-pyrazolopyridyl-3-yl)-3-fluoropyridine-2-yl)-3,6-dihydro-2H-thiopyran 1,1-dioxide Cpd-03A (56 mg), with a yield of 46%.

[0126] MS m / z (ESI): 534.0 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ 13.67(s,1H),9.05(s,1H),8.56(s,2H),8.16(d,J=12.6Hz,1H),8.09(d,J=9.0Hz,1H),7.09(d,J=9.0Hz,1H),6.52 - 6.38(m,2H),4.05(s,2H),3.44(t,J=6.0Hz,2H),3.24(t,J=6.0Hz,2H),1.74(d,J=6.8Hz,3H).

[0127] Example 6 R)-3-(6-(1-cyclopropyl-3-methyl-1H-pyrazolo-4-yl)pyridyl-3-yl)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-pyrazolo[4,3-b]pyridyl

[0128] [ka] Step 1 Under nitrogen gas protection, compound INT-1e (150 mg, 0.34 mmol) is dissolved in ethanol (3 mL) and water (0.5 mL), and (6-chloropyridine-3-yl)boronic acid (82 mg, 0.52 mmol), 1,1'-bis(diphenylphosphino)ferocenedichloropalladium (25 mg, 0.03 mmol), and potassium acetate (68 mg, 0.69 mmol) are added in order. The reaction mixture was stirred at 90°C for 5 hours, and the quality of the liquid was monitored to confirm the completion of the reaction. The reaction mixture was filtered, the filtrate was collected, and the crude product was concentrated under reduced pressure. The obtained crude product was purified by chromatography column chromatography (eluent: petroleum ether:ethyl acetate = 4:1) to obtain (R)-3-(6-chloropyridine-3-yl)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-pyrazolopyridyl Cpd-145a (110 mg) in yield of 75%. MS m / z (ESI): 420.0 (M+H) + .

[0129] Step 2 To a 6 mL mixture of (R)-3-(6-chloropyridine-3-yl)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-pyrazolo[4,3-b]pyridyl Cpd-145a (100 mg, 0.2 mmol) and 1,4-dioxane / water (volume ratio 5 / 1), add 1-cyclopropyl-3-methyl-1H-pyrazolo-4-pinacol boronate (100 mg, 0.4 mmol), potassium carbonate (66 mg, 0.5 mmol), and 1,1'-bis(diphenylphosphino)ferrocene (34 mg, 0.04 mmol). Stir the reaction mixture at 90°C for 1 hour. After the reaction is complete, terminate the reaction with water and extract with ethyl acetate (3 × 10 mL). Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate. The concentrate was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1 to 1 / 10) to obtain (R)-3-(6-(1-cyclopropyl-3-methyl-1H-pyrazolo-4-yl)pyridyl-3-yl)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-pyrazolo[4,3-b]pyridyl Cpd-145A (35 mg), with a yield of 27.98%. MS m / z (ESI): 506.1 (M+H) + . 1 H NMR(400MHz,CDCl3)δ 9.80(dd,J=5.8,2.9Hz,1H),9.34(s,1H),8.46(d,J=9.9Hz,1H),8.42(s,1H),7.96(s,1H),7.79(d,J=9.0Hz,1H),7.50(d,J=8.2Hz,1 H),7.01(d,J=9.1Hz,1H),6.60(dd,J=13.7,6.8Hz,1H),3.61(ddd,J=10.9,7.2,3.6Hz,1H),2.64(s,3H),1.81(d,J=6.9Hz,3H),1.20 - 1.16(m,2H),1.08 - 1.04(m,2H).

[0130] Example 7 5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-3-iodo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridyl INT-2 [ka]

[0131] Step 1 5-Bromo-2-methylpyridyl-3-amine INT-2a (10 g, 0.0535 mol) was dissolved in 1,4-dioxane (75 mL) and water (10 mL). Methylboronic acid (14.41 g, 0.24 mol), potassium carbonate (22.18 g, 0.16 mmol), and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium (2.9 g, 4 mmol) were added, and the reaction mixture was stirred at 100°C for 16 hours under nitrogen gas protection. After the reaction was complete, water (30 mL) was added, followed by extraction with ethyl acetate (60 mL). The organic phase was further washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the sample was stirred with silica gel. The sample was purified by column chromatography (mobile phase: dichloromethane / methanol = 40 / 1) to obtain 2,5-dimethylpyridine-3-amine INT-2b (6.2 g) in yield of 94%. MS m / z (ESI): 123.2 (M+H) + .

[0132] Step 2 2,5-dimethylpyridine-3-amine INT-2b (6.2 g, 0.0507 mol) was dissolved in N,N-dimethylformamide (20 mL), N-bromosuccinimide (9.02 g, 0.0507 mol) was added, and the mixture was stirred at 0°C for 3 hours. After the reaction was complete, water (30 mL) was added, followed by extraction with ethyl acetate (50 mL x 4). The organic phase was further washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, concentrated, and the sample was stirred with silica gel. The sample was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 68 / 32) to obtain 6-bromo-2,5-dimethylpyridine-3-amine INT-2c (5.1 g) in yield of 50%. MS m / z(ESI):201.0(M+H) + .

[0133] Step 3 Dissolve 6-bromo-2,5-dimethylpyridine-3-amine INT-2c (5.1 g, 25.40 mmol) in chloroform (60 mL), add potassium acetate (2.99 g, 30.48 mmol) and acetic anhydride (10.37 g, 101.60 mmol), and stir the reaction mixture at 55°C for 2 hours. Then cool the reaction mixture to 0°C and add 18-crown-6 (0.67 g, 2.54 mmol) and amyl nitrite (5.95 g, 50.8 mmol). Stir the reaction mixture at 80°C for a further 16 hours. After the reaction was complete, sodium bicarbonate solution was added to quench the reaction, and the organic phase was extracted with dichloromethane (100 ml). Further washing of the organic phase with saturated brine (100 ml) was performed, the mixture was dried over anhydrous sodium sulfate, concentrated, and the sample was stirred with silica gel. Purification by column chromatography (mobile phase: petroleum ether / dichloromethane = 75 / 25~70 / 30) yielded 1-(5-bromo-6-methyl-1H-pyrazolo[4,3-b]pyridyl-1-yl)ethane-1-one INT-2d (4.9 g) with a yield of 76%. MS m / z (ESI): 254.0 (M+H) + .

[0134] Step 4 Add 40 mL of ammonia / methanol solution to 1-(5-bromo-6-methyl-1H-pyrazolo[4,3-b]pyridyl-1-yl)ethane-1-one INT-2d (4.9 g, 19.29 mmol), and stir the reaction mixture at room temperature for 2 hours. After the reaction is complete, concentrate the reaction mixture to obtain 5-bromo-6-methyl-1H-pyrazolo[4,3-b]pyridyl INT-2e (4.6 g), which is used directly in the next step without further purification.

[0135] Step 5 5-Bromo-6-methyl-1H-pyrazolo[4,3-b]pyridyl INT-2e (4.6 g, 21.70 mmol) was dissolved in dichloromethane (40 mL), and 3,4-dihydro-2H-pyran (5.48 g, 65.10 mmol) and p-toluenesulfonic acid (0.37 g, 2.17 mmol) were added. The mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was concentrated, silica gel was added, and the sample was stirred. The mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 80 / 20) to obtain 5-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridyl INT-2f (5.1 g) in yield of 79%. MS m / z (ESI): 296.0 (M+H) + .

[0136] Step 6 Dissolve 5-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridyl INT-2f (5.1 g, 17.20 mmol) in toluene (50 mL), add (R)-1-(3,5-dichloropyridine-4-yl)ethane-1-ol (3.3 g, 17.20 mmol), sodium tert-butoxide (3.31 g, 34.40 mmol), S-(-)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine (2.14 g, 3.44 mmol), and tris(dibenzylideneacetone)dipalladium (790 mg, 0.86 mmol), and stir at 110°C for 12 hours under nitrogen protection. After the reaction was complete, the reaction mixture was concentrated, silica gel was added, and the sample was stirred. The mixture was then purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 91 / 9) to obtain 5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridyl INT-2g (6.4g) with a yield of 91%. MS m / z (ESI): 407.1 (M+H) + .

[0137] Step 7 5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridyl INT-2g (6.4g, 15.70 mmol) was mixed with methanol solution of hydrochloric acid (4M, 30 mL) and methanol (5 mL), and reacted at 50°C for 8 hours. The reaction mixture was then concentrated, dissolved in ethyl acetate (50 mL), neutralized with sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate (50 mL), the organic phase was washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate to obtain (R)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methyl-1H-pyrazolo[4,3-b]pyridyl INT-2h (4.7 g), with a yield of 93%. MS m / z (ESI): 323.0 (M+H) + .

[0138] Step 8 (R)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methyl-1H-pyrazolo[4,3-b]pyridyl INT-2h (4.7g, 14.50 mmol) is dissolved in dichloromethane (100 mL), and N-iodosuccinimide (3.26 g, 14.50 mmol) is added. The reaction mixture is stirred at room temperature for 2 hours. After the reaction is complete, sodium bisulfite solution (80 mL) is added to quench the mixture, and the mixture is separated. The organic phase is then washed with water and saturated brine, and the mixture is directly concentrated to obtain the crude product (R)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-3-iodo-6-methyl-1H-pyrazolo[4,3-b]pyridyl INT-2i (6.25 g), which is used directly in the next step.

[0139] Step 9 (R)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-3-iodo-6-methyl-1H-pyrazolo[4,3-b]pyridyl INT-2i crude product is dissolved in dichloromethane (100 mL), and 3,4-dihydro-2H-pyran (3.5 g, 41.70 mmol) and p-toluenesulfonic acid (0.24 g, 1.39 mmol) are added. The reaction mixture was stirred at room temperature for 16 hours, then reacted at 40°C for 3 hours. After the reaction was complete, the reaction solution was concentrated, silica gel was added, and the sample was stirred. The mixture was then purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 86 / 14) to obtain 5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-3-iodo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridyl INT-2 (6 g), with a yield of 81%. MS m / z (ESI): 533.0 (M+H) + .

[0140] Example 8 (R)-1-(4-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-pyrazolo[4,3-b]pyridyl-3-yl)pyridyl-2-yl)-3,5-dimethyl-1H-pyrazolo-1-yl)-2-methyl-2-propanol Cpd-158A [ka]

[0141] Step 1 (R)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-3-iodo-1H-pyrazolo[4,3-b]pyridylINT-1e (6.2 g, 14.3 mmol) is dissolved in dichloromethane (20 mL), and 3,4-dihydro-2H-pyran (3.5 g, 41.70 mmol) and p-toluenesulfonic acid (0.24 g, 1.39 mmol) are added to the reaction flask and the mixture is stirred at 25°C for 16 hours. After the reaction was complete, the product was concentrated and purified by silica gel column (ethyl acetate / petroleum ether = 13 / 100) to obtain 5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridyl INT-1 (6.1 g) in yield of 81%. MS m / z (ESI): 519.0 (M+H) + .

[0142] Step 2 Dissolve 5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridyl INT-1 (3g, 5.8 mmol), (6-chloropyridine-3-yl)-boronic acid (commercially available) (1g, 6.4 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium chloride (420 mg, 0.6 mmol), and potassium carbonate (1.6 g, 11.6 mmol) in a 25 mL mixture of 1,4-dioxane and water, and stir at 90 degrees Celsius for 16 hours under nitrogen gas protection. After the reaction was complete, the mixture was filtered and concentrated, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 8 / 100) to obtain 3-(6-chloropyridine-3-yl)-5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridyl Cpd-158a (2.2 g) in yield of 75%. MS m / z (ESI): 504.0 (M+H) + .

[0143] Step 3 3-(6-chloropyridine-3-yl)-5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-oxazolo[4,3-b]pyridyl Cpd-158a (2.1g, 4.2 mmol), 1-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- Pyrazolo-1-yl)-2-methyl-2-propanol Cpd-158b (commercially available) (1.48 g, 5.0 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium chloride (300 mg, 0.4 mmol), and potassium carbonate (1.2 g, 8.4 mmol) are dissolved in a 25 mL mixture of 1,4-dioxane and water, and stirred at 110°C for 16 hours under nitrogen gas protection. After the reaction is complete, the organic phase is collected by extraction with ethyl acetate and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 50 / 100) to obtain 1-(4-(5-(5-(R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridyl-3-yl)pyridyl-2-yl)-3,5-dimethyl-1H-pyrazolo-1-yl)-2-methyl-2-propanol Cpd-158c (1.7g) in yield of 64%. MS m / z (ESI): 636.2 (M+H) + .

[0144] Step 4 Dissolve 1-(4-(5-(5-(R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridyl-3-yl)pyridyl-2-yl)-3,5-dimethyl-1H-pyrazolo-1-yl)-2-methyl-2-propanol Cpd-158c (1.7g, 2.7 mmol) in a methanol solution of hydrogen chloride (20 mL). Stir the reaction mixture at 50°C for 5 hours. After the reaction is complete, add saturated sodium bicarbonate solution to adjust the pH to 7-9, extract with dichloromethane (100 mL), collect the organic phase, and concentrate it. The concentrated crude product was purified by silica gel column chromatography (methanol / dichloromethane = 8 / 100) to obtain product (R)-1-(4-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-pyrazolo[4,3-b]pyridyl-3-yl)pyridyl-2-yl)-3,5-dimethyl-1H-pyrazolo-1-yl)-2-methyl-2-propanol Cpd-158A (1.1 g). The yield was 74%. MS m / z (ESI): 552.2 (M+H) + . 1 H NMR(400MHz,CDCl3)δ 9.50(s,1H),8.73(s,1H),8.40(s,2H),7.87(d,J=8.8Hz,1H),7.62 - 7.43(m,1H),7.01(d,J=9.2Hz,1H),6.58(q,J=6.8Hz,1H),4.66(s,1H),4 .03(s,2H),2.55(s,3H),2.46(s,3H),1.80(d,J=6.8Hz,3H),1.26(s,6H).

[0145] Example 9 (R)-1-(4-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-pyrazolo[4,3-b]pyridyl-3-yl)-3-fluoropyridine-2-yl)-3,5-dimethyl-1H-pyrazolo-1-yl)-2-methyl-2-propanol Cpd-161A

[0146] [ka] Step 1 Dissolve 5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridyl INT-1 (4.8g, 9.2mmol), (6-chloro-5-fluoropyridine-3-yl)-boronic acid (commercially available) (1.94g, 11.0mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium chloride (670mg, 0.9mmol), and potassium carbonate (2.54g, 18.4mmol) in a mixture of 1,4-dioxane and water (150mL), and stir at 90°C for 16 hours under nitrogen gas protection. After the reaction is complete, filter and concentrate. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 8 / 100) to obtain 3-(6-chloro-5-fluoropyridine-3-yl)-5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridyl Cpd-161a (4.6 g) in yield of 95%. MS m / z (ESI): 522.5 (M+H) + .

[0147] Step 2 3-(6-chloro-5-fluoropyridine-3-yl)-5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridyl Cpd-161a (4.6g, 8.8mmol), 1-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Dissolve 1,1'-(1H-pyrazolo-1-yl)-2-methyl-2-propanol Cpd-158b (3.1g, 10.6 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium chloride (640 mg, 0.9 mmol), and potassium carbonate (2.4 g, 17.6 mmol) in a 150 mL mixture of 1,4-dioxane and water, and stir at 90°C for 16 hours under nitrogen gas protection. After the reaction is complete, extract with ethyl acetate, collect the organic phase, and concentrate it. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 60 / 100) to obtain 1-(4-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridyl-3-yl)-3-fluoropyridine-2-yl)-3,5-dimethyl-1H-pyrazolo-1-yl)-2-methyl-2-propanol Cpd-161b (3.9g) in yield of 68%. MS m / z (ESI): 654.2 (M+H) + .

[0148] Step 3 Dissolve 1-(4-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridyl-3-yl)-3-fluoropyridine-2-yl)-3,5-dimethyl-1H-pyrazolo-1-yl)-2-methyl-2-propanol Cpd-161b (3.9 g, 6.0 mmol) in methanol (40 mL). Stir the reaction mixture at 50°C for 16 hours. After the reaction was complete, saturated sodium bicarbonate solution was added to adjust the pH of the reaction mixture to 7-9. The reaction was then extracted with ethyl acetate solution, the organic phase was collected and concentrated, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 60 / 100-100 / 1) to obtain product (R)-1-(4-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-pyrazolo[4,3-b]pyridyl-3-yl)-3-fluoropyridine-2-yl)-3,5-dimethyl-1H-pyrazolo-1-yl)-2-methyl-2-propanol Cpd-161A (2.5g). The yield was 70%. MS m / z (ESI): 570.4 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ 13.59(s,1H),9.08(s,1H),8.51(s,2H),8.13(dd,J=11.0,1.6Hz,1H),8.07(d,J=9.0Hz,1H),7.06(d,J=9.0Hz,1H ),6.40(t,J=6.8Hz,1H),4.75(s,1H),3.98(s,2H),2.33(s,3H),2.22(s,3H),1.72(d,J=6.8Hz,3H),1.18(s,6H).

[0149] Example 10 (R)-1-(4-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-pyrazolo[4,3-b]pyridyl-3-yl)-3-fluoropyridine-2-yl)-3-methyl-1H-pyrazolo-1-yl)-2-methyl-2-propanol Cpd-162A [ka]

[0150] Step 1 Under nitrogen gas protection, 3-(6-chloro-5-fluoropyridine-3-yl)-5-((R)-1-(35-dichloropyridine-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridyl Cpd-161a A mixture of 1,4-dioxane / water (10 / 1.88 mL) containing (10.0 g, 0.02 mol), 2-methyl-1-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo-1-yl)propan-2-ol (6.96 g, 0.025 mol), potassium carbonate (7.9 g, 0.06 mol), and 1,1'-bis(diphenylphosphino)ferrocene palladium chloride (2.37 g, 0.003 mol) was stirred at 90°C for 10 hours. After the reaction was complete, the reaction solution was concentrated and further extracted with ethyl acetate. The organic phase was then combined and concentrated, followed by separation and purification using a silica gel column (petroleum ether / ethyl acetate = 1 / 1) to obtain 1-(4-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1-(tetrahydro2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridyl-3-yl)-3-fluoropyridine-2-yl)-3-methyl-1H-pyrazolo-1-yl)-2-methyl-2-propanol Cpd-162a (8g), with a yield of 39%.

[0151] MS m / z (ESI): 640.2 (M+H) + .

[0152] Step 2 Dissolve 1-(4-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1-(tetrahydro2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridyl-3-yl)-3-fluoropyridine-2-yl)-3-methyl-1H-pyrazolo-1-yl)-2-methyl-2-propanol Cpd-162a (8g, 0.012mol) in a methanol solution of hydrogen chloride (4M, 80mL), and stir the mixed solution at 55°C for 2 hours. After the reaction was complete, the solution was concentrated, the pH was adjusted to 7-8 with a saturated sodium bicarbonate solution, and then extracted with dichloromethane. The organic phase was combined and concentrated, and then separated and purified using a silica gel column (dichloromethane / methanol = 1 / 20) to obtain the pure product. Further chiral resolution (column: Daicel CHIRALCEL IB-N, mobile phase: CO2 / MeOH [0.2% NH3 (7M Solution in MeOH)] = 50 / 50) was performed to obtain (R)-1-(4-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-pyrazolo[4,3-b]pyridyl-3-yl)-3-fluoropyridine-2-yl)-3-methyl-1H-pyrazolo-1-yl)-2-methyl-2-propanol Cpd-162A (2.3g) in yield of 33%. MS m / z (ESI): 556.1 (M+H) + . 1 H NMR(400MHz,CDCl3)δ 9.34(s,1H),8.51-8.42(m,3H),8.18(s,1H),7.90(d,J=9.2Hz,1H),7.02(d,J=9.2Hz,1 H),6.59(q,J=6.8Hz,1H),4.15(s,2H),2.63(s,3H),1.80(d,J=6.8Hz,3H),1.27(s,6H).

[0153] Example 11 (R)-1-(4-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methyl-1H-pyrazolo[4,3-b]pyridyl-3-yl)pyridyl-2-yl)-3,5-dimethyl-1H-pyrazolo-1-yl)-2-methyl-2-propanol Cpd-175A [ka]

[0154] Step 1 Dissolve 5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-3-iodo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridyl INT-2 (3g, 5.6 mmol), (6-chloropyridine-3-yl)-boronic acid (commercially available) (1g, 6.4 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium chloride (420 mg, 0.6 mmol), and potassium carbonate (1.6 g, 11.6 mmol) in a 25 mL mixture of 1,4-dioxane and water, and stir at 90 degrees Celsius for 16 hours under nitrogen gas protection. After the reaction was complete, the mixture was filtered and concentrated, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 8 / 100) to obtain 3-(6-chloropyridine-3-yl)-5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridyl Cpd-175a (2.2g) in yield of 75%. MS m / z (ESI): 518.0 (M+H) + .

[0155] Step 2 Dissolve 3-(6-chloropyridine-3-yl)-5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridyl Cpd-175a (100 mg, 0.19 mmol, 1.0 eq) in 1,4-dioxane (8 mL) and water (1.5 mL), and add 1-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo-1-yl)-2-methyl-2-propanol (commercial) (68 mg, 0.23 mmol, 1.2 eq), potassium carbonate (80 mg, 0.58 mmol, 3) Add 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium (14 mg, 0.02 mmol, 0.1 eq) and 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium (14 mg, 0.02 mmol, 0.1 eq), and stir the reaction mixture at 90°C for 8 hours under nitrogen gas protection. After the reaction is complete, concentrate the reaction solution, add silica gel and stir the sample, and purify by column chromatography (mobile phase: petroleum ether / ethyl acetate = 37 / 63) to obtain 1-(4-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridyl-3-yl)pyridyl-2-yl)-3,5-dimethyl-1H-pyrazolo-1-yl)-2-methyl-2-propanol Cpd-175b (50 mg) in yield: 40%. MS m / z (ESI): 650.2 (M+H) + .

[0156] Step 3 Add a 4M, 3mL solution of hydrogen chloride dioxane to 1-(4-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridyl-3-yl)pyridyl-2-yl)-3,5-dimethyl-1H-pyrazolo-1-yl)-2-methyl-2-propanol Cpd-175b (50 mg, 0.08 mmol), then add a 4M, 3mL solution of hydrogen chloride dioxane, and then 50 oThe reaction was carried out in 1C for 2 hours. After the reaction was complete, the reaction mixture was concentrated and preparatively purified by high-performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150 x 19 mm, mobile phase 1: water (containing 0.1% FA), mobile phase 2: acetonitrile, gradient for 16 minutes, gradient ratio: acetonitrile phase 65%-75%, flow rate: 20 mL / min) to obtain (R)-1-(4-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-6-methyl-1H-pyrazolo[4,3-b]pyridyl-3-yl)pyridyl-2-yl)-3,5-dimethyl-1H-pyrazolo-1-yl)-2-methyl-2-propanol Cpd-175A (21.7 mg) in yield: 47%. MS m / z (ESI): 566.1 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ 13.30(s,1H),9.19(d,J=2.2Hz,1H),8.58(s,2H),8.33(dd,J=8.2,2.2Hz,1H),7.90(d,J=1.0Hz,1H),7.46(d,J=8.4Hz,1H), 6.43(q,J=6.8Hz,1H),4.74(s,1H),3.98(s,2H),2.53(s,3H),2.44(s,3H),2.39(s,3H),1.77(d,J=6.8Hz,3H),1.17(s,6H).

[0157] The compounds listed in Table 1 below were prepared using the same conditions as in the above examples. The structural characteristics of these compounds are summarized in Table 1.

[0158] [Table 1(1)] [Table 1(2)] [Table 1(3)] [Table 1(4)]

[0159] Biological evaluation Test Example 1: Inhibitory effect of representative compounds of the present invention on FGFR1 and FGFR3 kinases The inhibitory activity of the compound against FGFR1 and FGFR3 kinases was measured using the HTRF method. The maximum concentration measured was 3000 nM, which was then diluted 3-fold using a gradient dilution to obtain 10 different concentrations, and detection was performed in multiple wells.

[0160] 1.1 Experimental Materials 1.1.1 Reagents and Consumables

[0161] [Table 2]

[0162] 1.1.2 Equipment

[0163] [Table 3]

[0164] 1.2 Experimental Steps a) Dilute the compound in a test plate (784075, Greiner) using an ECHO automated dispensing workstation and centrifuge at 1000 rpm for 30 seconds.

[0165] b) Prepare a 2x FGFR kinase solution using 1X kinase buffer.

[0166] c) Add 5 μL of 2x final concentration FGFR kinase solution to a 384-well test plate, centrifuge, and then allow to stand at room temperature for 10 minutes.

[0167] d) Prepare a mixture of biotin-coupled tyrosine kinase substrate and ATP with 1X kinase buffer to a final concentration of 2x.

[0168] e) Add 5 μL of a mixture of biotin-coupling tyrosine kinase substrate and ATP to a test plate to initiate the reaction.

[0169] f) Centrifuge the 384-well test plate at 1000g for 30s, mix uniformly, and then allow to react at room temperature for 50 minutes.

[0170] g) Prepare a 4x concentrated solution of Sa-XL665 using HTRF detection buffer.

[0171] h) Add 5 μL of 4x concentration Sa-XL665 and 5 μL of coupling Eu to the reaction plate. 3 - Add the TK antibody for cryptate.

[0172] i) Centrifuge 1000g for 30s and allow to react at room temperature for 1h.

[0173] j) Read the fluorescence signals at 665 nM and 615 nM in each well using the Envision2014 microblade reader and calculate the ratio. %inhibition=100%-(Ratio cmpd -Ratio noATP / Ratio DMSO -Ratio noATP )*100%

[0174] 1.3 Experimental Results

[0175] [Table 4]

[0176] The experimental results demonstrate that the representative compound of the present invention possesses good kinase inhibitory activity.

[0177] Test Example 2: Inhibitory effect and selectivity of the compound of the present invention on Ba / F3-FGFR1 / 2 / 3 / 4 cell proliferation. The inhibitory effect of the compound on the proliferation of Ba / F3-FGFR1, Ba / F3-FGFR2, Ba / F3-FGFR3, and Ba / F3-FGFR4 cells was measured using the CTG method. The maximum concentration measured was 3000 nM, and a 3-fold dilution gradient was applied, resulting in 10 concentrations, with detection performed in multiple wells.

[0178] 2.1 Experimental Materials 2.1.1 Reagents and Consumables

[0179] [Table 5]

[0180] 2.1.2 Equipment

[0181] [Table 6]

[0182] 2.2 Experimental Steps a) Cultivate Ba / F3-FGFR1, Ba / F3-FGFR2, Ba / F3-FGFR3, and Ba / F3-FGFR4 until they reach the exponential growth stage and prepare them for use.

[0183] Complete medium: RPMI1640 medium, 10% FBS, 1% GlutaMAX and P / S, 10 ng / mL; FGF1, 10 μg / mL; Heparin, 10 μM; 2-mercaptoethanol, 2 μg / mL; puromycin b) Dilute the compound stock solution from 3000 nM to 384 cell culture plates using an ECHO automated dispensing workstation, and centrifuge at 1000 g for 1 minute.

[0184] c) Digest the cells and uniformly seed 30 μL of Ba / F3-FGFR1, Ba / F3-FGFR2, Ba / F3-FGFR3, or Ba / F3-FGFR4 (500 / well) into a 384-well black edge cell culture plate containing the compound. Seal the edge wells with 50 μL of PBS and culture in a 37°C CO2 incubator for 72 hours.

[0185] d) 30 μL of Cell-Titer-Glo reagent was added to each well, and the mixture was homogenized by shaking in a shaker. The mixture was then incubated at 37°C for 30 minutes, and after the signal stabilized, it was detected using a microplate reader.

[0186] 2.3 Experimental Results

[0187] [Table 7]

[0188] The experimental results demonstrate that the representative compound of the present invention exhibits potent inhibitory activity and good selectivity against Ba / F3-FGFR2 / 3 cells.

[0189] Test Example 3: Pharmacokinetic study of a representative compound of the present invention 3.1 Objectives of the Experiment SD rats were used as test animals, and the drug concentrations in plasma were measured at different time points after intragastric administration of the compound of the present invention to SD rats using LC / MS / MS. The pharmacokinetic behavior of the compound of the present invention in SD rats was studied, and its pharmacokinetic characteristics were evaluated.

[0190] 3.2 Experimental Method (1) Laboratory animals We purchased 24 SD rats, half male and half female, divided into 6 groups, from Shanghai Jihui Laboratory Animal Husbandry Co., Ltd., animal production license SCXK (Shanghai) 2017-0012.

[0191] (2) Drug compounding The formulation is 5% DMSO + 60% PEG300 + 35% glucose aqueous solution. First, an appropriate amount of the representative compound of the present invention is weighed (to calculate purity and salt coefficient), the prescribed amount of DMSO is added, and a clear transparent solution is obtained by vortex mixing. Then, the prescribed amount of PEG300 is added and uniformly vortex mixed, and then the prescribed amount of glucose aqueous solution is added. A solution of 0.6 mg / mL or 2 mg / mL is obtained. If a solution cannot be obtained during the formulation process, sonication in a water bath at 60°C or below may be performed to aid dissolution.

[0192] (3) Drug administration After fasting the rats overnight, each drug was administered intragastricly (2mpk).

[0193] (4) Sample collection Tests were performed at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. Approximately 30 μL of blood sample was collected at each time point, placed in an anticoagulation tube containing EDTA-K2 anticoagulant, and centrifuged within 30 minutes to obtain plasma. Whole blood samples were placed on ice before centrifugation. All collected plasma samples were stored on dry ice or at -70°C or below until analytical testing was performed. The concentrations of the unchanged drug in the plasma and administration solution were measured using liquid chromatography-tandem mass spectrometry (LC / MS / MS).

[0194] 3.3 Experimental Results The pharmacokinetic parameters of representative compounds of the present invention, Cpd-03A / Cpd-145A / Cpd-168A / Cpd-175A / Cpd-203A and Infigratinib, in SD rats are shown in Table 4.

[0195] [Table 8]

[0196] Conclusion: The representative compound of the present invention has a half-life (T) in rats. 1 / 2), its pharmacokinetic properties such as exposure level (AUC) and residence time in the body are favorable, and it can meet the conditions for oral administration.

[0197] The embodiments of the technical solutions of the present invention have been described above with examples. It should be understood that the scope of protection of the present invention is not limited to the embodiments described above. Any modifications, equivalent substitutions, improvements, etc., made by those skilled in the art within the spirit and principles of the present invention should all be included within the scope of protection of the claims of this application.

Claims

1. Compounds represented by formula (I) and their racemates, stereoisomers, tautomers, isotopically labeled compounds, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs, or pharmaceutically acceptable salts thereof, 【Chemistry 1】 During the ceremony, Rings A and B are either identical or different, and C is independent of each other. ６－１４ Selected from an aromatic ring, a 5-14 membered heteroaromatic ring, or a 5-14 membered heterocycle, L does not exist or -N(R) ａ )-C(=O)-,-CR ｂ =CR ｃ - If selected from and L is not present, ring A is directly bonded to the pyrazole ring via a chemical bond, R ａ is hydrogen, an unsubstituted or optionally substituted by one, two or more R ａ１ substituted C １－６ alkyl group, C ３－６ selected from cycloalkyl groups, each R ａ１ is the same or different and independently of one another is a hydroxy group, a cyano group, a halogen, C １－６ alkyl group, C １－６ alkoxy group, C ３－６ selected from cycloalkyl groups, R ｂ , R ｃ R are identical or different, and independently of each other, hydrogen, halogen, unsubstituted, or selectively one, two or more R ｂ１ C is replaced by １－６ alkyl group, C １－６ Alkoxy group, C ３－６ Selected from cycloalkyl groups, each R ｂ１ They are the same or different, and independently of each other, they are hydroxyl groups, cyano groups, halogens, and C １－６ alkyl group, C １－６ Alkoxy group, C ３－６ Selected from cycloalkyl groups, X is selected from O, S, or NH. Y is either nonexistent or unsubstituted, or selectively one, two or more R ｙ -S (=O) -R is substituted by ｙ１ , -S (=O) ２ -R ｙ２ , -S(=O)(=NR ｙ３ )-R ｙ４ , C ３－１２ Cycloalkyl group, 3-14 membered heterocyclyl group, C ６－１４ Selected from aryl groups and 5-14 membered heteroaryl groups, R ｙ１ , R ｙ２ , R ｙ３ , R ｙ４ They are the same or different, they do not exist or they exist independently of each other as hydrogen, C １－６ alkyl group, C ３－６ Selected from cycloalkyl groups, each R ｙ These are identical or distinct, and independently of each other, hydrogen, hydroxyl group, cyano group, halogen, oxo (=O), unsubstituted, or selectively one, two or more R groups. ｙ’ C is replaced by １－６ alkyl group, C １－６ Alkoxy group, C ３－６ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１４ Aryl group, 5-14 membered heteroaryl group, =N-R ｙ５ , -C(=O)-R ｙ６ , -C(=O)OR ｙ７ , -S (=O) ２ -R ｙ８ , -S(=O)(=NR ｙ９ )-R ｙ１０ , -P (=O) (R ｙ１１ ) (Caution ｙ１２ ) is selected from, R ｙ５ , R ｙ６ , R ｙ７ , R ｙ８ , R ｙ９ , R ｙ１０ , R ｙ１１ , R ｙ１２ They are the same or different, and are independent of each other: hydrogen, C １－６ alkyl group, C ３－６ Selected from cycloalkyl groups, each R ｙ’ are the same or different and independently of one another are hydrogen, a hydroxy group, a cyano group, a halogen, oxo(=O), unsubstituted or optionally substituted by one, two or more R ｙ’’ substituted C １－６ alkyl group, C １－６ alkoxy group, C ３－６ cycloalkyl group, 3- to 8-membered heterocyclyl group, -C(=O)-NR ｙ１３ R ｙ１４ , -C(=O)-R ｙ１５ , -C(=O)O-R ｙ１６ , -OR ｙ１７ , -S(=O) ２ -R ｙ１８ , -S(=O) ２ -NH ２ , -S(=O)(=NR ｙ１９ )-R ｙ２０ , -P(=O)(R ｙ２１ )(R ｙ２２ ), selected from an amino group, each R ｙ’’ are the same or different and independently of one another are hydrogen, a hydroxy group, a cyano group, a halogen, oxo(=O), an amino group, C １－６ alkyl group, C １－６ alkoxy group, C ３－６ cycloalkyl group, C ３－６ cycloalkyl group, 3- to 8-membered heterocyclyl group, -C(=O)-NR ｙ２３ R ｙ２４ , -C(=O)-R ｙ２５ , -C(=O)O-R ｙ２６ , -OR ｙ２７ , -S(=O) ２ -R ｙ２８ , -S(=O)(=NR ｙ２９ )-R ｙ３０ , -P(=O)(R ｙ３１ )(R ｙ３２ ), selected from R ｙ１３ , R ｙ１４ , R ｙ１５ , R ｙ１６ , R ｙ１７ , R ｙ１８ , R ｙ１９ , R ｙ２０ , R ｙ２１ , R ｙ２２ , R ｙ２３ , R ｙ２４ , R ｙ２５ , R ｙ２６ , R ｙ２７ , R ｙ２８ , R ｙ２９ , R ｙ３０ , R ｙ３１ , R ｙ３２ They are the same or different, and are independent of each other: hydrogen, C １－６ alkyl group, C ３－６ Selected from cycloalkyl groups, Each R １ These are identical or distinct, and independently of each other, hydrogen, halogen, cyano group, hydroxyl group, oxo (=O), unsubstituted, or selectively one, two or more R groups. １１ The amino group substituted by C １－６ alkyl group, C １－６ Alkoxy group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclic group, -C(=O)-NH ２ , -S (=O) ２ -C １－６ Alkyl alkyl group, -S(=O)(=NH)-C １－６ Selected from alkyl groups, or two Rs bonded to the same atom １ It has one, two, or more R atoms, either unsubstituted or selectively, along with the atom to which it is bonded. １１ A 3-12 membered heterocycle or C substituted by ３－１２ Two R atoms that form an alkyl ring or are bonded to different atoms １ It has one, two, or more R atoms, either unsubstituted or selectively, along with the atom to which it is bonded. １１ A 3-12 membered heterocycle or C substituted by ３－１２ Forms an alkyl ring, and each R １１ They are the same or different, and independently of each other, H, cyano group, oxo (=O), halogen, unsubstituted, or selectively one, two or more R １２ C is replaced by １－６ alkyl group, C １－６ Alkoxy group, -S (=O) ２ -R ｙ８ , -S(=O)(=NR ｙ９ )-R ｙ１０ , C ３－１２ Selected from cycloalkyl groups, 3-12 membered heterocyclic groups, and 5-14 membered heteroaryl groups, each R １２ They are the same or different, and independently of each other are hydrogen, hydroxyl group, cyano group, halogen, and C １－６ alkyl group, C １－６ Alkoxy group, C ３－６ Cycloalkyl groups, C ６－１４ Selected from aryl groups and 5-14 membered heteroaryl groups, Each R ２ , R ４ These are identical or distinct, and independently of each other, hydrogen, halogen, cyano group, hydroxyl group, oxo (=O), unsubstituted, or selectively one, two or more R groups. ２１ The amino group substituted by C １－６ alkyl group, C １－６ Alkoxy group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, -C(=O)-NH ２ , -S (=O) ２ -C １－６ alkyl group, C ６－１４ Selected from aryl groups and 5-14 membered heteroaryl groups, each R ２１ They are the same or different, and independently of each other are halogen, CN, amino group, hydroxyl group, oxo (=O), and C １－６ alkyl group, C １－６ Selected from alkoxy groups, R ６ is hydrogen, R ６ａ -C １－４ Selected from alkyl groups, R ６ａ teeth 【Chemistry 2】 Selected from, R ３ is hydrogen, C １－６ Alkyl, halo C １－６ Alkyl group, cyano group - C １－６ Selected from alkyl groups, m and n are the same or different, and are independently selected from 0, 1, 2, 3, 4, 5, or 6. r is a compound selected from 0, 1, or 2.

2. Ring A is C ６－１０ Selected from an aromatic ring, a 5-10 membered heteroaromatic ring, or a 5-10 membered heterocycle, Preferably, ring A is a benzene ring, pyridine ring, pyrimidine ring, naphthalene ring, quinoline ring, 1,8-naphthyridine ring, piperidine ring, piperazine ring, 【Transformation 3】 Selected from, Preferably, ring B is selected from a benzene ring or a 5-6 membered heteroaromatic ring. Preferably, ring B is selected from a pyridine ring or a pyridazine ring. Preferably, L is absent or selected from -NH-C(=O)-, -CH=CH-, Preferably, X is selected from O, Preferably, each R １ These are identical or distinct, and independently of each other, they are halogens, cyano groups, hydroxyl groups, oxo (=O), unsubstituted, or selectively one, two, or more R groups. １１ The amino group substituted by C １－６ alkyl group, C １－６ Alkoxy group, C ３－６ Cycloalkyl group, 3-6 membered heterocyclic group, -C(=O)-NH ２ , -S (=O) ２ -C １－３ Alkyl alkyl group, -S(=O)(=NH)-C １－３ Selected from alkyl groups, or two Rs bonded to the same atom １ It has one, two, or more R atoms, either unsubstituted or selectively, along with the atom to which it is bonded. １１ A 3-8 membered heterocycle is formed by substitution, or two R atoms bonded to different atoms. １ It has one, two, or more R atoms, either unsubstituted or selectively, along with the atom to which it is bonded. １１ It forms a 3-8 membered heterocycle substituted by each R １１ They are the same or different, and independently of each other, H, cyano group, oxo (=O), halogen, unsubstituted, or selectively one, two or more R １２ C is replaced by １－６ alkyl group, C １－６ Alkoxy group, -S (=O) ２ -CH ３ , -S(=O)(=NH)-CH ３ , C ３－６ Selected from cycloalkyl groups, 3-8 membered heterocyclic groups, and 5-6 membered heteroaryl groups, each R １２ They are the same or different, and independently of each other are hydrogen, hydroxyl group, cyano group, halogen, and C １－６ alkyl group, C １－６ Alkoxy group, C ３－６ Selected from cycloalkyl groups, phenyl groups, and 5-6 membered heteroaryl groups, Preferably, each R １ These are identical or different, and independently of each other, F, Cl, Br, cyano group, oxo (=O), methoxy group, -S (=O) ２ -CH ３ , -S(=O)(=NH)-CH ３ , -S(=O)(=N-CH ３ ) - CH ３ , 【Chemistry 4】 or -C(=O)-N(CH ３ ) ２ Selected from, or two R atoms bonded to the same atom １ It has one, two, or more R atoms, either unsubstituted or selectively, along with the atom to which it is bonded. １１ Forms a piperidinyl group substituted by, Preferably, each R １１ They are the same or different, and independently of each other are hydrogen, a 2,2,2-trifluoroethyl group, and -S (=O) ２ -CH ３ Selected from the cyclobutyl group, Preferably, 【Transformation 5】 is a phenyl group, 【Transformation 6】 The compound according to claim 1, characterized by being selected from among.

3. Y does not exist, or Y is unsubstituted or selectively has one, two or more R ｙ -S (=O) -R is substituted by ｙ１ , -S (=O) ２ -R ｙ２ , -S(=O)(=NR ｙ３ )-R ｙ４ , C ３－１０ Selected from cycloalkyl groups, 3-10 membered heterocyclyl groups, and 5-8 membered heteroaryl groups, R ｙ１ , R ｙ２ , R ｙ３ , R ｙ４ They are the same or different, they do not exist or they exist independently of each other as hydrogen, C １－６ alkyl group, C ３－６ Selected from cycloalkyl groups, Preferably, Y is unsubstituted or selectively has one, two or more R ｙ Phenyl group, piperazinyl group, piperidinyl group, pyrazolyl group, which are substituted by 【Transformation 7】 Selected from, Preferably, each R ｙ They are the same or different, and independently of each other are hydrogen, hydroxyl group, cyano group, halogen, oxo (=O), and C. １－６ Alkyl, halo C １－６ Alkyl group, hydroxyl group - C １－６ Alkyl group, amino group - C １－６ Alkyl group, cyano group - C １－６ Alkyl group, carboxyl group - C １－６ alkyl group, C １－６ Alkyl-NH-C １－６ Alkyl alkyl group, (C １－６ (Alkyl group) ２ N-C １－６ alkyl group, C １－６ Alkoxy group, C ３－６ Cycloalkyl group, -C １－６ Alkylalkyl group (C substituted with a hydroxyl group) ３－８ Cycloalkyl groups), -C １－６ Alkyl alkyl group -S (=O) ２ -C １－６ Alkyl alkyl group, -C １－６ Alkyl alkyl group -S (=O) ２ -NH ２ , C ６－１０ Aryl group, 5-10 membered heteroaryl group, =N-R ｙ５ , -C(=O)-R ｙ６ , -C(=O)OR ｙ７ , -S (=O) ２ -R ｙ８ , -S(=O)(=NR ｙ９ )-R ｙ１０ , -P (=O) (R ｙ１１ ) (Caution ｙ１２ ), or selectively one, two or more R ｙ’ Selected from 3-8 membered heterocyclyl groups substituted by each R ｙ’ These are identical or different, and independently of each other, they are cyano groups, halogens, oxo (=O) or -S (=O). ２ -C １－６ Selected from alkyl groups, R ｙ５ , R ｙ６ , R ｙ７ , R ｙ８ , R ｙ９ , R ｙ１０ , R ｙ１１ , R ｙ１２ They are the same or different, and are independent of each other: hydrogen, C １－６ alkyl group, C ３－６ Selected from cycloalkyl groups, Preferably, each R ｙ They are the same or different, and independently of each other are hydroxyl groups, cyano groups, halogens, oxo (=O), and C. １－３ Alkyl, halo C １－３ Alkyl group, hydroxyl group - C １－４ Alkyl group, amino group - C １－４ Alkyl group, cyano group - C １－３ Alkyl group, carboxyl group - C １－４ alkyl group, C １－４ Alkylalkyl NH-C １－４ Alkyl alkyl group, (C １－４ (Alkyl group) ２ N-C １－４ alkyl group, C １－３ Alkoxy group, C ３－６ Cycloalkyl group, -C １－３ Alkylalkyl group (C substituted with a hydroxyl group) ３－６ Cycloalkyl groups), -C １－３ Alkyl alkyl group -S (=O) ２ -C １－３ Alkyl alkyl group, -C １－３ Alkyl alkyl group -S (=O) ２ -NH ２ , phenyl group, 5-6 membered heteroaryl group, =N-R ｙ５ , -C(=O)-R ｙ６ , -C(=O)OR ｙ７ , -S (=O) ２ -R ｙ８ , -S(=O)(=NR ｙ９ )-R ｙ１０ , -P (=O) (R ｙ１１ ) (Caution ｙ１２ ), or selectively one, two or more R ｙ’ Selected from 3-6 member heterocyclyl groups substituted by, each R ｙ’ They are either the same or different, and are mutually independent of oxo (=O) or -S (=O). ２ -C １－３ Selected from alkyl groups, R ｙ５ , R ｙ６ , R ｙ７ , R ｙ８ , R ｙ９ , R ｙ１０ , R ｙ１１ , R ｙ１２ Identical or different, each independently of the other, hydrogen, C １－６ alkyl group, C ３－６ Selected from cycloalkyl groups, Preferably, each R ｙ These are identical or different, and independently of each other, they are methyl group, ethyl group, n-propyl group, isopropyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, trifluoromethyl group, 2-hydroxyethyl group, oxo(=O), =N-CH ３ , -S (=O) ２ -CH ３ , -C(=O)O-CH ３ , -C(=O)OC ２ H ５ , pyrimidinyl group, -C (CH ３ ) ２ OH, -C(CH ３ ) ２ CN, -S (=O) ２ -C ２ H ５ , -S (=O) ２ -CH(CH ３ ) ２ ien-CH ２ COOH, 【Transformation 8】 Selected from, More preferably, Y is 【Chemistry 9】 【Chemistry 10】 A compound according to any one of claims 1 to 2, characterized by being selected from among.

4. Each R ２ They are the same or different, and independently of each other, hydrogen, F, Cl, Br, cyano group, unsubstituted or selectively one, two or more R ２１ C is replaced by １－３ alkyl group, C １－３ Selected from alkoxy groups, pyrazolyl groups, and pyrimidinyl groups, Preferably, each R ２１ They are identical or different, and are independently selected from halogen, CN, and methyl groups. Preferably, each R ２ They are the same or different, and independently of each other, Cl, methyl group, 【Chemistry 11】 Selected from, Preferably, 【Chemistry 12】 teeth 【Chemistry 13】 Selected from, Preferably, each R ４ They are the same or different, and independently of each other are hydrogen, halogen, cyano group, hydroxyl group, amino group, and C １－６ alkyl group, C １－６ Selected from alkoxy groups, Preferably, each R ４ They are identical or different, and are independently selected from halogen, cyano, methyl, or methoxy groups. Preferably, R ３ is hydrogen, C １－３ Alkyl, halo C １－３ Selected from alkyl groups, Preferably, R ３ The methyl group is selected from the methyl group, Preferably, R ６ is hydrogen, 【Chemistry 14】 A compound according to any one of claims 1 to 3, characterized by being selected from among.

5. The compound shown in formula (I) has the structure shown below, 【Chemistry 15】 In the formula, ring A, ring B, R １ , R ２ , R ３ , R ４ L, X, Y, m, n, r have the definitions described in any one of claims 1 to 4. Preferably, the compound represented by formula (I) has the structure shown below, 【Chemistry 16】 In the formula, ring A, ring B, R １ , R ２ , R ３ , R ４ L, X, Y, m, n, r have the definitions described in any one of claims 1 to 4. Preferably, the compound represented by formula (I) has the structure shown below, 【Chemistry 17】 In the formula, R １ , R ２ , R ３ , R ４ , R ｙ X, m, n, and r have the definitions described in any one of claims 1 to 4, and W is O, S, or CH. ２ NH, [Chemistry 18] Selected from, Q １ Q ２ They are identical or different, and are independently selected from CH or N, T １ is selected from CH or N, T ２ U is the same or different, and is independent of O, S, N, CH, NH or CH ２ If selected from, and V is selected from N or C, and V is selected from N, then R ５ It does not exist, R ５ Either they do not exist, or they are hydrogen, hydroxyl groups, cyano groups, C １－６ alkyl group, C １－６ Alkoxy group, Halo C １－６ Alkyl, halo C １－６ Alkoxy group or C ３－６ Selected from cycloalkyl groups, p, p1, p2, p3, p4 are the same or different, and independently selected from 0, 1, 2, 3, 4, 5. 【Chemistry 19】 represents a single bond or a double bond, Preferably, the compound represented by formula (I) has the structure shown below, 【Chemistry 20】 In the formula, R １ , R ２ , R ３ , R ４ X, m, n, r have the definitions described in any one of claims 1 to 4, and W １ O, S, CH ２ NH, CH, N, 【Chemistry 21】 Selected from, Q １ Q ２ They are identical or different, and are independently selected from CH or N, V １ is selected from N, C, or CH, V ２ is N, NH, C, CH or CH ２ Selected from, 【Chemistry 22】 represents a single bond or a double bond, Preferably, the compound represented by formula (I) has the structure shown below, 【Chemistry 23】 【Chemistry 24】 In the formula, R １ , R ２ , R ４ , Y, R ｙ ,m,n,r have the definitions described in any one of claims 1 to 4, and R ｚ R in any one of claims 1 to 4 ｙ Having the definition described above, preferably R ｚ R is H, halogen, cyano group, hydroxyl group, unsubstituted or selectively one, two or more R ｚ１ The amino group substituted by C １－６ alkyl group, C １－６ Alkoxy group, C ３－６ Selected from cycloalkyl groups, each R ｚ１ They are the same or different, and independently of each other are hydrogen, hydroxyl group, cyano group, halogen, oxo (=O), amino group, and C １－６ alkyl group, C ３－６ Selected from cycloalkyl groups, more preferably R ｚ The group is selected from H, halogen, cyano group, methyl group, ethyl group, propyl group, and cyclopropyl group, and W is O, S, CH ２ NH, 【Chemistry 25】 Selected from, Q １ Q ２ If CH or N are the same or different and selected independently from each other, and V is selected from N or C, and V is selected from N, then R ５ It does not exist, V ａ , V ｂ CH and CH are identical or different, and are independent of each other. ２ Selected from , N, NH, R ５ Either they do not exist, or they are hydrogen, hydroxyl groups, cyano groups, C １－６ alkyl group, C １－６ Alkoxy group, Halo C １－６ Alkyl, halo C １－６ Alkoxy group or C ３－６ Selected from cycloalkyl groups, p is selected from 0, 1, 2, 3, 4, 5. 【Chemistry 26】 represents a single bond or a double bond, Alternatively, the compound represented by formula (I) has the structure shown below, 【Chemistry 27】 In the formula, R １ , R ２ , R ４ , R ６ , R ｙ , R ｚ Q １ Q ２ , m, n, t have the definitions described in any one of claims 1 to 4, R ｚ R in any one of claims 1 to 4 ｙ A compound according to any one of claims 1 to 4, characterized by having the definition described above.

6. The aforementioned compound, 【Chemistry 28】 【Chemistry 29】 【Transformation 30】 【Chemistry 31】 【Chemistry 32】 【Transformation 33】 【Transformation 34】 【Chemistry 35】 【Transformation 36】 【Chemistry 37】 【Transformation 38】 【Chemistry 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 【Chemistry 44】 【Chemistry 45】 【Chemistry 46】 【Chemistry 47】 【Chemistry 48】 【Chemistry 49】 It is selected from this structure. According to some embodiments, the compound of formula (I) is [Transformation 50] 【Chemistry 51】 【Chemistry 52】 【Chemistry 53】 【Chemistry 54】 【Transformation 55】 【Transformation 56】 【Chemistry 57】 【Chemistry 58】 【Chemistry 59】 【Transformation 60】 【Chemistry 61】 【Transformation 62】 【Transformation 63】 【Chemistry 64】 【Transformation 65】 【Chemical Formula 66】 【Transformation 67】 【Transformation 68】 【Transformation 69】 【Transformation 70】 【Chemistry 71】 【Chemistry 72】 【Transformation 73】 A compound according to any one of claims 1 to 5, characterized in that it is selected from the following structures.

7. A pharmaceutical composition comprising a therapeutically effective amount of the compound described in any one of claims 1 to 6 and at least one of its racemic mixture, stereoisomer, tautomer, isotope-labeled compound, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof.

8. Use in the preparation of a drug of at least one of the compounds described in any one of claims 1 to 6 and their racemic mixtures, stereoisomers, tautomers, isotope labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof, or the pharmaceutical composition described in claim 7, Preferably, the drug is an FGFR2 and / or FGFR3 inhibitor. Preferably, the drug is used for the diagnosis, prevention and / or treatment of diseases or disorders related to FGFR.

9. A method for diagnosing, preventing and / or treating a disease or disorder related to FGFR, comprising administering to a patient requiring such treatment an effective amount of at least one compound according to claims 1 to 6 or the pharmaceutical composition according to claim 7, alone or selectively 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, wherein the disease or disorder associated with FGFR is selected from cancer, chondrodysplasia or chondrodysplasia, and preferably the cancer is selected from bladder cancer, brain tumor, breast cancer, bile duct cancer, head and neck cancer, lung cancer, multiple myeloma, rhabdomyosarcoma, urethral cancer, and uterine cancer.

Images