FGFR2 / 3 selective inhibitor, pharmaceutical composition and application thereof

Abstract

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

Description

FGFR2 / 3 selective inhibitors, pharmaceutical compositions and applications thereof

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

[0002] Priority to the prior application, patent application number 202310593058.0, filed with the State Intellectual Property Office of China on May 24, 2023, entitled “FGFR3 selective inhibitors, pharmaceutical compositions and their uses”;

[0003] Priority to the prior application, patent application number 202311019921.8, filed with the State Intellectual Property Office of China on August 14, 2023, entitled “FGFR3 selective inhibitors, pharmaceutical compositions and their uses”;

[0004] Priority to the prior application, patent application number 202311275317.1, filed with the State Intellectual Property Office of China on September 28, 2023, entitled “FGFR3 selective inhibitors, pharmaceutical compositions and their uses”;

[0005] Priority to the prior application, patent application number 202311767590.6, filed with the State Intellectual Property Office of China on December 20, 2023, entitled “FGFR3 selective inhibitors, pharmaceutical compositions and their uses”;

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

[0007] The present invention belongs to the field of medical technology, and specifically relates to FGFR2 / 3 selective inhibitors, pharmaceutical compositions and applications thereof. Background Art

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

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

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

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

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

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

[0014] Summary of the Invention

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

[0016] in:

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

[0018] L is absent or selected from -N(R a )-C(=O)-、-CR b =CR c -; When L does not exist, ring A is directly connected to the pyrazole ring through a chemical bond;

[0019] R a Selected from hydrogen, unsubstituted or optionally substituted by one, two or more R a1 Substituted with the following groups: C 1-6 Alkyl, C 3-6 Cycloalkyl; each R a1 The same or different, independently selected from hydroxyl, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl;

[0020] R b 、R c The same or different, independently selected from hydrogen, halogen, unsubstituted or optionally substituted by one, two or more R b1 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl; each R b1 The same or different, independently selected from hydroxyl, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl;

[0021] X is selected from O, S or NH;

[0022] Y is absent or selected from unsubstituted or optionally substituted with one, two or more R y Substituted with the following groups: -S(=O)-R y1 、-S(=O)2-R y2 、-S(=O)(=NR y3 )-R y4 、C 3-12 Cycloalkyl, 3-14 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl; R y1 、R y2 、R y3 、R y4the same or different, which are absent or independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl; each R y are the same or different and are independently selected from hydrogen, hydroxy, cyano, halogen, oxo (=O), unsubstituted or optionally substituted by one, two or more R y’ Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, =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 );R y5 、R y6 、R y7 、R y8 、R y9 、R y10 、R y11 、R y12 the same or different, independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl; each R y’ are the same or different and are independently selected from hydrogen, hydroxy, cyano, halogen, oxo (=O), unsubstituted or optionally substituted by one, two or more R y” Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, -C(=O)-NR y13 R y14 、-C(=O)-R y15 、-C(=O)OR y16 、-OR y17 、-S(=O)2-R y18 , -S(=O)2-NH2, -S(=O)(=NR y19 )-R y20 、-P(=O)(R y21 )(R y22 ), amino group; each R y” The same or different, independently selected from hydrogen, hydroxy, cyano, halogen, oxo (=O), amino, C 1-6 Alkyl, C1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, -C(=O)-NR y23 R y24 、-C(=O)-R y25 、-C(=O)OR y26 、-OR y27 、-S(=O)2-R y28 、-S(=O)(=NR y29 )-R y30 、-P(=O)(R y31 )(R y32 );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 the same or different, independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl.

[0023] Each R 1 are the same or different and are independently selected from hydrogen, halogen, cyano, hydroxy, oxo (=O), unsubstituted or optionally substituted by one, two or more R 11 Substituted with the following groups: amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, -C(=O)-NH2, -S(=O)2-C 1-6 Alkyl, -S(=O)(=NH)-C 1-6 Alkyl; or, two R attached to the same atom 1 The atoms to which it is attached together form an unsubstituted or optionally substituted R 11 Substituted 3-12 membered heterocyclic or C 3-12 Alkyl ring; or, two R attached to different atoms 1Together with the atoms to which they are attached, they form an unsubstituted or optionally substituted R 11 Substituted 3-12 membered heterocyclic or C 3-12 Alkyl ring; each R 11 The same or different, independently selected from H, cyano, oxo (=O), halogen, unsubstituted or optionally substituted by one, two or more R 12 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, -S(=O)2-R y8 、-S(=O)(=NR y9 )-R y10 、C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 5-14 membered heteroaryl; each R 12 The same or different, independently selected from hydrogen, hydroxy, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 6-14 Aryl, 5-14 membered heteroaryl;

[0024] Each R 2 、R 4 are the same or different and are independently selected from hydrogen, halogen, cyano, hydroxy, oxo (=O), unsubstituted or optionally substituted by one, two or more R 21 Substituted with the following groups: amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, -C(=O)-NH2, -S(=O)2-C 1-6 Alkyl, C 6-14 Aryl, 5-14 membered heteroaryl; each R 21 the same or different, independently selected from halogen, CN, amino, hydroxy, oxo (=O), C 1-6 Alkyl, C 1-6 alkoxy;

[0025] R 3 Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, cyano-C 1-6 alkyl;

[0026] R 6 Selected from hydrogen, R 6a -C 1-4 Alkyl; R 6a Selected from

[0027] m and n are the same or different and are independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0028] r is selected from 0, 1 or 2.

[0029] According to some embodiments, Ring A is selected from C 6-10 aromatic ring, 5-10 membered heteroaromatic ring or 5-10 membered heterocyclic ring.

[0030] According to some embodiments, ring A is selected from 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,

[0031] According to some embodiments, ring B is selected from a benzene ring or a 5-6 membered heteroaromatic ring.

[0032] According to some embodiments, ring B is selected from a pyridine ring or a pyridazine ring.

[0033] According to some embodiments, L is absent or selected from -NH-C(=O)-, -CH=CH-.

[0034] According to some embodiments, X is selected from O.

[0035] According to some embodiments, Y is absent.

[0036] According to some embodiments, Y is selected from unsubstituted or optionally substituted with one, two or more R y Substituted with the following groups: -S(=O)-R y1 、-S(=O)2-R y2 、-S(=O)(=NR y3 )-R y4 、C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, 5-8 membered heteroaryl; R y1 、R y2 、R y3 、R y4 the same or different, which are absent or independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl.

[0037] According to some embodiments, Y is selected from unsubstituted or optionally substituted with one, two or more R y Substituted groups: phenyl, piperazinyl, piperidinyl, pyrazolyl,

[0038] According to some embodiments, each R y the same or different, independently selected from hydrogen, hydroxy, cyano, halogen, oxo (=O), C 1-6 Alkyl, halogenated C1-6 Alkyl, hydroxy-C 1-6 Alkyl, amino-C 1-6 Alkyl, cyano-C 1-6 Alkyl, carboxyl-C 1-6 Alkyl, C 1-6 Alkyl-NH-C 1-6 Alkyl, (C 1-6 alkyl)2N-C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, -C 1-6 Alkyl-(hydroxy substituted C 3-8 Cycloalkyl), -C 1-6 Alkyl-S(=O)2-C 1-6 Alkyl, -C 1-6 Alkyl-S(=O)2-NH2, C 6-10 Aryl, 5-10 membered heteroaryl, =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 optionally one, two or more R y’ substituted 3-8 membered heterocyclic group; each R y’ the same or different, independently selected from cyano, halogen, oxo (=O) or -S(=O)2-C 1-6 Alkyl; R y5 、R y6 、R y7 、R y8 、R y9 、R y10 、R y11 、R y12 the same or different, independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl.

[0039] According to some embodiments, each R y The same or different, independently selected from hydroxy, cyano, halogen, oxo (=O), C 1-3 Alkyl, halogenated C 1-3 Alkyl, hydroxy-C 1-4 Alkyl, amino-C 1-4 Alkyl, cyano-C 1-3 Alkyl, carboxyl-C 1-4 Alkyl, C 1-4 Alkyl NH-C1-4 Alkyl, (C 1-4 alkyl)2N-C 1-4 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, -C 1-3 Alkyl-(hydroxy substituted C 3-6 Cycloalkyl), -C 1-3 Alkyl-S(=O)2-C 1-3 Alkyl, -C 1-3 Alkyl-S(=O)2-NH2, phenyl, 5-6 membered heteroaryl, =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 optionally one, two or more R y’ substituted 3-6 membered heterocyclic group; each R y’ The same or different, independently selected from oxo (=O) or -S(=O)2-C 1-3 Alkyl; R y5 、R y6 、R y7 、R y8 、R y9 、R y10 、R y11 、R y12 the same or different, independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl.

[0040] According to some embodiments, each R y the same or different, independently selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, trifluoromethyl, 2-hydroxyethyl, oxo (= O), =N-CH3, -S(=O)2-CH3, -C(=O)O-CH3, -C(=O)O-C2H5, pyrimidinyl, -C(CH3)2OH, -C(CH3)2CN, -S(=O)2-C2H5, -S(=O)2-CH(CH3)2, -CH2COOH,

[0041] According to some embodiments, Y is selected from:

[0042] According to some embodiments, each R1 The same or different, independently selected from halogen, cyano, hydroxy, oxo (=O), unsubstituted or optionally substituted by one, two or more R 11 Substituted with the following groups: amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -C(=O)-NH2, -S(=O)2-C 1-3 Alkyl, -S(=O)(=NH)-C 1-3 Alkyl; or, two R attached to the same atom 1 The atoms to which it is attached together form an unsubstituted or optionally substituted R 11 substituted 3-8 membered heterocyclic ring; or, two R attached to different atoms 1 Together with the atoms to which they are attached, they form an unsubstituted or optionally substituted R 11 substituted 3-8 membered heterocyclic ring; each R 11 The same or different, independently selected from H, cyano, oxo (=O), halogen, unsubstituted or optionally substituted by one, two or more R 12 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, -S(=O)2-CH3, -S(=O)(=NH)-CH3, C 3-6 Cycloalkyl, 3-8 membered heterocyclyl, 5-6 membered heteroaryl; each R 12 The same or different, independently selected from hydrogen, hydroxy, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl.

[0043] According to some embodiments, each R 1 the same or different, independently selected from F, Cl, Br, cyano, oxo (= O), methoxy, -S (= O) 2 -CH 3 , -S (= O) (= NH) -CH 3 , -S (= O) (= N-CH 3 ) -CH 3 , or -C(=O)-N(CH3)2; or, two R 1 The atoms to which it is attached together form an unsubstituted or optionally substituted R 11 Substituted piperidinyl.

[0044] According to some embodiments, each R 11 The same or different, independently selected from hydrogen, 2,2,2-trifluoroethyl, -S(=O)2-CH3, cyclobutyl.

[0045] According to some embodiments, Selected from: phenyl,

[0046] According to some embodiments, each R 2 The same or different, independently selected from hydrogen, F, Cl, Br, cyano, unsubstituted or optionally substituted by one, two or more R 21 Substituted with the following groups: C 1-3 Alkyl, C 1-3 Alkoxy, pyrazolyl, pyrimidinyl; each R 21 are the same or different and are independently selected from halogen, CN, methyl;

[0047] According to some embodiments, each R 2 The same or different, independently selected from Cl, methyl,

[0048] According to some embodiments, Selected from:

[0049] According to some embodiments, each R 4 The same or different, independently selected from hydrogen, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy.

[0050] According to some embodiments, each R 4 are the same or different and are independently selected from halogen, cyano, methyl or methoxy.

[0051] According to some embodiments, R 3 Selected from hydrogen, C 1-3 Alkyl, halogenated C 1-3 alkyl.

[0052] According to some embodiments, R 3 Selected from methyl.

[0053] According to some embodiments, R 6 Selected from hydrogen.

[0054] According to some embodiments, R 6 Selected from

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

[0056] Among them, ring A, ring B, R 1 、R 2 、R 3 、R 4 , L, X, Y, m, n, and r have the definitions described herein.

[0057] According to some embodiments, the compound represented by formula (I) has the structure shown below:

[0058] Among them, ring A, ring B, R 1 、R 2 、R 3 、R 4 , L, X, Y, m, n, and r have the definitions described herein.

[0059] According to some embodiments, the compound represented by formula (I) has the structure shown below:

[0060] Among them, R 1 、R 2 、R 3 、R 4 、R y , X, m, n, r have the definitions described herein, W is selected from O, S, CH2, NH, Q1 and Q2 are the same or different and are independently selected from CH or N; T1 is selected from CH or N; T2 and U are the same or different and are independently selected from O, S, N, CH, NH or CH2; V is selected from N or C. When V is selected from N, R 5 Does not exist; R 5 Not present or selected from hydrogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy or C 3-6 Cycloalkyl; p, p1, p2, p3, p4 are the same or different and are independently selected from 0, 1, 2, 3, 4, 5; represents a single bond or a double bond;

[0061] According to some embodiments, the compound represented by formula (I) has the structure shown below:

[0062] Among them, R 1 、R 2 、R 3 、R 4 , X, m, n, r have the definitions described herein, W 1 Selected from O, S, CH2, NH, CH, N, Q1 and Q2 are the same or different and are independently selected from CH or N; V 1 Selected from N, C or CH; V 2 is selected from N, NH, C, CH or CH2; Indicates a single bond or a double bond.

[0063] According to some embodiments, the compound represented by formula (I) has the structure shown below:

[0064] Among them, R z With R as in this article y The definition, preferably, R z Selected from H, halogen, cyano, hydroxy, unsubstituted or optionally substituted by one, two or more R z1 Substituted with the following groups: amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl; each R z1 The same or different, independently selected from hydrogen, hydroxy, cyano, halogen, oxo (=O), amino, C 1-6 Alkyl, C 3-6 Cycloalkyl; more preferably, R z R is selected from H, halogen, cyano, methyl, ethyl, propyl, cyclopropyl; 1 、R 2 、R 4 、R y , Y, m, n, r have the definitions described herein, W is selected from O, S, CH2, NH, Q1 and Q2 are the same or different and are independently selected from CH or N; V is selected from N or C. When V is selected from N, R 5 Does not exist; V a 、V b are the same or different and are independently selected from CH, CH2, N, NH; R 5 Not present or selected from hydrogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy or C 3-6 Cycloalkyl; p is selected from 0, 1, 2, 3, 4, 5; t is selected from 0, 1, 2; Indicates a single bond or a double bond.

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

[0066] Among them, R 1 、R 2 、R 4 、R 6 、R y 、R z , Q1, Q2, m, n, t have the definitions described in this article

[0067] According to some embodiments, among the compounds represented by formula (I) and their racemates, stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts, illustrative, non-limiting specific examples of the compounds represented by formula (I) are as follows:

[0068] According to some embodiments, the compound of formula (I) is selected from the following structures:

[0069] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by formula (I) and at least one of its racemates, stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs, or pharmaceutically acceptable salts.

[0070] According to an embodiment of the present invention, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0071] The excipients in the pharmaceutical compositions are "acceptable" in the sense that they are compatible with the active ingredient of the composition (and preferably, capable of stabilizing the active ingredient) and not deleterious to the subject being treated. One or more pharmaceutical excipients can be used to deliver the active compound.

[0072] According to some embodiments of the present invention, the pharmaceutical composition may further contain one or more additional therapeutic agents.

[0073] The present invention further provides the use of a compound represented by formula (I) and at least one of its racemates, stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof, or said pharmaceutical composition in the preparation of a drug.

[0074] According to some embodiments, the medicament is a medicament for diagnosing, preventing and / or treating a disease or disorder mediated by FGFR2 and / or FGFR3.

[0075] According to some embodiments, the drug is a FGFR2 and / or FGFR3 inhibitor.

[0076] According to some embodiments, the disease is FGFR-related cancer.

[0077] According to some embodiments, the disease or disorder is selected from bladder cancer, brain cancer, breast cancer, bile duct cancer, head and neck cancer, lung cancer, multiple myeloma, rhabdomyosarcoma, urethral cancer, uterine cancer.

[0078] According to some embodiments, the disease is FGFR-related hypochondroplasia or achondroplasia.

[0079] According to some embodiments, the compound represented by formula (I) and its racemate, stereoisomer, tautomer, isotope label, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or at least one of its pharmaceutically acceptable salts can be made into a form suitable for administration by any appropriate route, and formulated using one or more pharmaceutically acceptable carriers by conventional methods. Therefore, the compound represented by formula (I) and its racemate, stereoisomer, tautomer, isotope label, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or at least one of its pharmaceutically acceptable salts can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular or subcutaneous) administration, inhalation or insufflation administration; can also be formulated into sustained release dosage forms, such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges or syrups.

[0080] The present invention also provides a method for diagnosing, preventing and / or treating diseases or conditions mediated by FGFR2 and / or FGFR3, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) and at least one of its racemates, stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts, or a pharmaceutical composition of the present invention, alone, or optionally, in combination with another compound of the present invention and / or at least one other type of therapeutic agent.

[0081] According to some embodiments, the FGFR2 and / or FGFR3 mediated disease or condition is selected from bladder cancer, brain cancer, breast cancer, bile duct cancer, head and neck cancer, lung cancer, multiple myeloma, rhabdomyosarcoma, urethral cancer, uterine cancer and achondroplasia.

[0082] In some embodiments, the patient is a mammal, preferably a human. Beneficial effects

[0083] The compounds provided by the present invention have good FGFR2 and / or FGFR3 inhibitory effects and can be used to treat or prevent conditions and diseases related to FGFR2 and / or FGFR3, as well as to prepare drugs for treating or preventing such conditions and diseases.

[0084] Definitions and Explanations of Terms

[0085] Unless otherwise indicated, the definitions of groups and terms in this specification and claims, including definitions used as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in the Examples, may be arbitrarily combined and coupled with one another. The group definitions and compound structures resulting from such combinations and couplings should be understood to be within the scope of this specification and / or claims.

[0086] The term "optional" (or "optionally", "optionally") in the general formula definitions of this application means the situation of being substituted by zero, one or more substituents, for example, "optionally substituted by one, two or more R" means that it may not be substituted by R (unsubstituted) or may be optionally substituted by one, two or more R.

[0087] "More" means three or more, for example, 3, 4, 5, 6, 7, 8, 9 or 10.

[0088] Unless otherwise indicated, numerical ranges recited in this specification and claims are equivalent to reciting at least each specific integer value therein. For example, the numerical range "1-12" is equivalent to reciting each integer value in the numerical range "1-12", namely, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12.

[0089] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0090] “HO-C 1-6 "Alkyl" refers to a C 1-6 of alkyl.

[0091] The term "C 1-6 The term "alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or the like or isomers thereof.

[0092] The term "C 3-8 "Cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic (such as bridged ring, spirocyclic) hydrocarbon ring having 3, 4, 5, 6, 7, 8 carbon atoms. 3-8The cycloalkyl group may be a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as borneol, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonyl, 2,6-diazaspiro[3,4]octyl.

[0093] The term "3-10 membered heterocyclyl" means a saturated or unsaturated non-aromatic ring or ring system, and contains at least one heteroatom selected from O, S and N. The heterocyclyl can be connected to the rest of the molecule through any one of the carbon atoms or the nitrogen atom (if present). The heterocyclyl can include fused or bridged rings and spirocyclic rings. In particular, the heterocyclyl can include, but is not limited to, 4-membered rings such as azetidinyl, oxetane; 5-membered rings such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered rings such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or 7-membered rings such as diazepanyl. Optionally, the heterocyclyl can be benzo-fused. The heterocyclic group may be bicyclic, such as, but not limited to, a 5,5-membered ring, such as a hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6-membered bicyclic ring, such as a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The heterocyclic group may be partially unsaturated, i.e., it may contain one or more double bonds, such as, but not limited to, dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl, or 4H-[1,4]thiazinyl, or it may be benzo-fused, such as, but not limited to, dihydroisoquinolinyl. When the 3-10 membered heterocyclic group is linked to other groups to form the compounds of the present invention, the linking may be to a carbon atom of the 3-10 membered heterocyclic group or to a heterocyclic atom on the 3-10 membered heterocyclic group ring. For example, when the 3-10 membered heterocyclic group is selected from piperazinyl, the nitrogen atom on the piperazinyl group may be connected to the other group. Or when the 3-10 membered heterocyclic group is selected from piperidinyl, the nitrogen atom on the piperidinyl ring and the carbon atom at the para position thereof may be connected to the other group.

[0094] The term "5-10 membered heteroaryl" is understood to include monovalent monocyclic or bicyclic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms and containing 1 to 5, preferably 1 to 3, heteroatoms independently selected from N, O and S and, in each case, may be benzofused. Examples of monocyclic "heteroaryl" groups include, for example, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazinyl, oxazinyl, triazinyl, thiadiazinyl or oxadiazinyl. "Heteroaryl" also refers to a group in which a heteroaromatic ring is fused to one or more aryl, alicyclic or heterocyclyl rings, wherein the point of attachment is on the heteroaromatic ring. Non-limiting examples include 1-, 2-, 3-, 5-, 6-, 7-, or 8-indolizinyl, 1-, 3-, 4-, 5-, 6-, or 7-isoindolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-indazolyl, 2-, 4-, 5-, 6-, 7-, or 8-purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolyl , 1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-naphthyridinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7-, or 8-cinnolinyl, 2-, 4-, 6-, or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-4aHcarbazolyl, 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-phenanthridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-piperidinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9- or 10-phenanthrolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenazinyl, 2-, 3-, 4-, 5-, 6-, or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-benzoisoquinolinyl, 2-, 3-, 4-, or thieno[2,3-b]furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-7H-pyrazino[2,3-c]carbazolyl, 2-, 3-, 5-, 6-, or 7-2H-furo[3,2-b]pyranyl, 2-, 3-, 4-, 5-, 7-, or 8-5H-pyrido[2,3-d]-o-oxazinyl, 1-, 3- or 5-1H-pyrazolo[4,3-d]-oxazolyl, 2-, 4- or 5-4H-imidazo[4,5-d]thiazolyl, 3-, 5- or 8-pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5- or 6-imidazo[2,1-b]thiazolyl, 1-, 3-, 6-, 7-, 8- or 9-furo[3,4-c]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10 or 11-4H-pyrido[2,3-c]carbazolyl, 2-, 3-, 6- or 7-imidazo[1,2-b][1,2, 4-, 5-, 6-, 7-, 8-, or 9-benzoxapinyl, 2-, 4-, 5-, 6-, 7-, or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-4H-pyrrolo[1,2-b][2]benzazepinyl. Typical fused heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, and 2-, 4-, 5-, 6-, or 7-benzothiazolyl. When the 5- to 10-membered heteroaryl group is linked to other groups to form a compound of the present invention, the carbon atoms on the 5- to 10-membered heteroaryl ring may be linked to the other groups, or heteroatoms on the 5- to 10-membered heteroaryl ring may be linked to the other groups. When the 5- to 10-membered heteroaryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, there is no limitation on the substitution site, for example, a hydrogen atom connected to a carbon atom on a heteroaryl ring may be substituted, or a hydrogen atom connected to a heteroatom on a heteroaryl ring may be substituted.

[0095] The term "nitrogen oxide" refers to a compound formed by oxidation of a nitrogen atom in a tertiary amine or nitrogen-containing (aromatic) heterocyclic compound structure.

[0096] The term "spirocyclic" refers to a ring system in which two rings share one ring atom.

[0097] The term "fused ring" refers to a ring system in which two rings share two ring atoms.

[0098] The term "bridged ring" refers to a ring system in which two rings share three or more ring atoms.

[0099] Unless otherwise specified, a heterocyclic group, heteroaryl group, or heteroarylene group includes all possible isomeric forms thereof, such as positional isomers thereof. Thus, for some illustrative non-limiting examples, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-positions, etc. (if present) may include 1, 2, or more substituted or bonded forms thereof, including pyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene, pyridin-4-ylene, and pyridin-4-ylene; thienyl or thienylene group includes thien-2-yl, thien-2-ylene, thien-3-ylene, and thien-3-ylene; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, and pyrazol-5-yl.

[0100] The term "oxo" refers to a substituent in which a carbon atom, a nitrogen atom, or a sulfur atom is oxidized to form an oxy group (=O).

[0101] The term "alkylamino" refers to -NH-(alkyl) or -N-(alkyl)2, wherein alkyl is as defined above. Non-limiting examples of alkylamino include methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, methylethylamino, diethylamino, dipropylamino, methylpropylamino, diisopropylamino, dibutylamino, and the like.

[0102] The term "alkyloxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkyloxy, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, or heterocycloalkyloxy.

[0103] The terms "alkyleneoxy" and "oxyalkylene" refer to -alkylene-O- or -O-alkylene-, where alkylene represents a linear or branched saturated divalent hydrocarbon radical. The definition of "alkyl" with respect to the number of carbon atoms in "alkylene" applies as defined above. It will be understood by those skilled in the art that an alkyleneoxy or oxyalkylene group can be attached to the remainder of the molecule in which it is contained in any orientation, i.e., the two terms are used interchangeably.

[0104] "Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0105] When L is selected from -C(=O)-N(R a)-, it indicates that the group connected to ring A can be either the carbonyl group in L or the N group in L; when the carbonyl group is connected to ring A, the N group in L is connected to the pyrazolopyridine ring; when the N group is connected to the carbonyl group, the carbonyl group in L is connected to the pyrazolopyridine ring.

[0106] In the present invention, the compounds referred to also include isotopically labeled compounds, which are the same as those shown in Formula I, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of H, C, N, O, S, F, and Cl, such as 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 32 P. 35 S. 18 F and 36 Cl. Compounds of the invention, prodrugs thereof, or pharmaceutically acceptable salts of said compounds or prodrugs containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the invention. Certain isotopically labeled compounds of the invention, for example, those incorporating radioactive isotopes (such as 3 H and 14 C) compounds can be used in drug and / or substrate tissue distribution assays. 3 H) and carbon 14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. 2 Substitution with hydrogen (H or D) may provide certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) derived from greater metabolic stability and may therefore be preferred in certain circumstances. The compounds of the present invention as claimed in the claims may be specifically limited to substitution with deuterium or tritium. Furthermore, the absence of separate listing of the term deuterium or tritium for hydrogen present in a substituent does not exclude deuterium or tritium, but rather may also include deuterium or tritium.

[0107] It will be appreciated by those skilled in the art that the compounds of formula (I) may exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they may form acid addition salts; if these compounds have an acidic center, they may form base addition salts; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they may also form internal salts.

[0108] The compounds of the present invention may exist in the form of solvates (e.g., hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0109] Depending on their molecular structure, the compounds of the present invention may be chiral and therefore may exist in various enantiomeric forms. Thus, these compounds may exist in racemic or optically active forms. The compounds of the present invention encompass isomers or mixtures thereof, racemates, in which each chiral carbon is in the R or S configuration. The compounds of the present invention or their intermediates can be separated into enantiomeric compounds by chemical or physical methods well known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are prepared from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-phenylsulfonylproline) or various optically active camphorsulfonic acids. Chromatographic enantiomer resolution can also be advantageously performed with the aid of optically active resolving agents (e.g., dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chirally derivatized methacrylate polymers immobilized on silica gel). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, e.g., hexane / isopropanol / acetonitrile.

[0110] The corresponding stable isomers can be separated according to known methods, for example by extraction, filtration or column chromatography.

[0111] The term "patient" refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.

[0112] The term "therapeutically effective amount" refers to that amount of an active compound or drug that will elicit the biological or medical response that a researcher, veterinarian, physician, or other clinician is seeking in a tissue, system, animal, individual, or human, and includes one or more of the following: (1) prevents disease, e.g., prevents a disease, disorder, or condition in an individual who is susceptible to the disease, disorder, or condition but who is not yet experiencing or developing the pathology or symptoms of the disease. (2) inhibits disease, e.g., inhibits the disease, disorder, or condition (i.e., prevents further development of the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition. (3) alleviates disease, e.g., alleviates the disease, disorder, or condition (i.e., reverses the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition. DETAILED DESCRIPTION

[0113] The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are encompassed within the scope of protection that the present invention is intended to protect.

[0114] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0115] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, using deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as the solvents, with tetramethylsilane (TMS) as the internal standard.

[0116] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1200 Infinity Series mass spectrometer, and HPLC was performed using an Agilent 1200DAD high-pressure liquid chromatograph and a Waters 2695-2996 high-pressure liquid chromatograph.

[0117] Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0118] Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, with dry solvents and reaction temperatures in degrees Celsius.

[0119] Example 1

[0120] (5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)(imino)(methyl)-λ 6 -sulfonone

[0121] first step

[0122] Compound 1a (10 g, 4.9 mmol), ammonium acetate (0.6 g, 7.8 mmol) and iodophenyl diacetic acid (3.2 g, 9.9 mmol) were weighed and added to methanol (100 ml). The mixture was stirred at room temperature for three hours, concentrated under reduced pressure to remove the organic solvent, and purified by reverse phase preparative purification (ACN / H2O = 5% to 80%) to obtain compound 1b (8.7 g, yield 75%).

[0123] MS: m / z = 234.9 (M+H) + .

[0124] Step 2

[0125] Compound 1b (8.7 g, 37 mmol), bis-pinacol borate (18 g, 70.9 mmol), potassium carbonate (7.5 g, 54.3 mmol) and 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride (2.6 g, 3.6 mmol) were weighed and dissolved in a 1,4-dioxane / water = 5 / 1 solution (150 mL) under nitrogen protection, heated to 90 degrees, reacted for 16 hours, cooled to room temperature, added ethyl acetate (100 ml), extracted and separated, and the organic layer was washed three times with dilute hydrochloric acid (10%, 100 ml). The organic layers were combined, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated by column chromatography (mobile phase: ethyl acetate / n-hexane = 1 / 10 to 10 / 1) to give compound 1c (7 g, yield 94.5%).

[0126] MS: m / z = 201.1 (M+H) + .

[0127] Step 3

[0128] Commercially available compound 1d (5 g, 33.5 mol), sodium iodide (15.0 g, 100.7 mmol) and trimethylsilyl chloride (5.5 g, 50.6 mmol) were weighed and dissolved in anhydrous acetonitrile (100 ml). The mixture was heated to 80 degrees and reacted for 3 hours. The mixture was cooled to room temperature, and ethyl acetate (150 ml) and water (150 ml) were added. The mixture was vigorously stirred for 1 hour, and the organic layer was separated. The aqueous phase was extracted with ethyl acetate (150 ml). The organic phases were combined and concentrated under reduced pressure to obtain compound 1e (3.6 g, yield 80%).

[0129] MS: m / z = 136.0 (M+H) + .

[0130] Step 4

[0131] Compound 1e (3.6 g, 26.6 mmol) was weighed and dissolved in phosphorus oxychloride (50 ml), heated to 70 degrees, and kept warm for 3 hours. The phosphorus oxychloride was removed by concentration, and ethyl acetate (50 ml) and water (50 ml) were added. The product 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 give compound 1f (3.5 g, yield 85%).

[0132] MS: m / z = 154.0 (M+H) + .

[0133] Step 5

[0134] Compound 1f (3.5 g, 22.8 mmol) and potassium tert-butoxide (2.5 g, 22.0 mmol) were weighed and dissolved in tetrahydrofuran (50 ml). The mixture was cooled to 0 to 5 degrees Celsius in an ice bath and stirred for one hour. 2-(Trimethylsilyl)ethoxymethyl chloride (4.2 g, 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) and extracted with ethyl acetate (150 ml). The organic layers were combined, concentrated, and separated by column chromatography (mobile phase: ethyl acetate / n-hexane = 1 / 10 to 1 / 2) to give compound 1g (5.8 g, yield 89.6%).

[0135] MS: m / z = 284.1 (M+H) + .

[0136] Step 6

[0137] Commercially available compound 1h (1.0 g, 5.2 mmol) was weighed and dissolved in anhydrous tetrahydrofuran (50 ml). The mixture was stirred in an ice bath for half an hour. Sodium hydroxide (125 mg) was added and the mixture was stirred in an ice bath for another half an hour. Compound 1g (1.5 g, 5.3 mmol) was added and stirred in an ice bath for 2 hours. The mixture was stirred at room temperature for another hour. The reaction solution was poured into ice water (100 ml). The mixture was extracted with ethyl acetate (100 ml * 3). The organic layers were combined, concentrated, and purified by column chromatography (mobile phase: ethyl acetate / n-hexane = 1 / 10 to 1 / 1) to give compound 1i (2.2 g, yield 94.7%).

[0138] MS: m / z = 439.1 (M+H) + .

[0139] Step 7

[0140] 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 protected with nitrogen. The mixture was heated to 60 degrees and reacted for 3 hours. The temperature was cooled to room temperature and poured into ice water (100 ml). The mixture was extracted with ethyl acetate (100 ml*3). The organic layers were combined, concentrated, and purified by column chromatography (mobile phase: ethyl acetate / n-hexane = 1 / 10 to 1 / 1) to give compound 1j (2.0 g, yield 70.6%).

[0141] MS: m / z = 565.0 (M+H) + .

[0142] Step 8

[0143] Compound 1j (200 mg, 0.35 mmol) was dissolved in a 10 mL mixture of 1,4-dioxane / water (10 / 1). Compound 1c (77 mg, 0.39 mmol), potassium carbonate (70 mg, 0.5 mmol), and 1,1'-bis(diphenylphosphinoferrocenepalladium) dichloride (10 mg) were added. The mixture was reacted at 90°C for 2 hours. After completion of the reaction, the organic phase was extracted, collected, dried, and concentrated. The residual liquid was purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to afford compound 1k (150 mg, 54.2% yield).

[0144] MS: m / z = 593.1 (M+H) + .

[0145] Step 9

[0146] Compound 1k (150 mg, 0.25 mmol) was weighed and dissolved in dichloromethane (10 mL). Trifluoroacetic acid (729 mg, 6.39 mmol) was added, and the reaction solution was stirred at 25 degrees Celsius for 16 hours. After the reaction, it was concentrated, and the pH was adjusted to 7-8 with 10% sodium bicarbonate aqueous solution. The product was extracted and concentrated with ethyl acetate (50 ml), and then separated and purified by high-performance liquid chromatography (mobile phase: acetonitrile / water = 44 / 56) to obtain Cpd-01 (110 mg).

[0147] Cpd-01 was subjected to the first chiral separation to obtain an isomer mixture Cpd-01M (30 mg, t R =2.604min), and optically pure compound Cpd-01C (10 mg, t R =2.691min) and Cpd-01D (12 mg, t R =3.352min). Cpd-01M was subjected to a second chiral separation to obtain optically pure compound Cpd-01A (10 mg, t R=1.836 min) and Cpd-01B (8 mg, t R =2.300min).

[0148] First split condition:

[0149] Instrument brand: SFC 150;

[0150] Preparative column model: Daicel CHIRALCEL OZ, 250 mm × 30 mm ID, 10 μm;

[0151] Mobile phase: CO2 / MeOH [0.2% NH3 (7M Solution in MeOH)] = 65 / 35;

[0152] Flow rate: 80g / min;

[0153] Column temperature: 35 degrees.

[0154] Second split condition:

[0155] Instrument brand: SFC 150;

[0156] Preparative column model: Daicel CHIRALCEL AD, 250 mm × 30 mm ID, 10 μm;

[0157] Mobile phase: CO2 / MeOH [0.2% NH3 (7M Solution in MeOH)] = 65 / 35;

[0158] Flow rate: 80g / min;

[0159] Column temperature: 35 degrees.

[0160] Cpd-01A

[0161] MS: m / z = 463.0 (M+H) + .

[0162] 1 H NMR (400MHz, CDCl3) δ9.51 (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).

[0163] Cpd-01B

[0164] MS: m / z = 463.0 (M+H)+ .

[0165] 1 H NMR (400MHz, CDCl3) δ9.49(s,1H),8.80(d,J=8.0Hz,1H),8.43(s,2H),8.18(s,1H),7.86(d,J =9.0Hz,1H),7.04(d,J=9.0Hz,1H),6.58(q,J=7.0Hz,1H),3.35(s,3H),1.81(d,J=6.8Hz,3H).

[0166] Cpd-01C

[0167] MS: m / z = 463.0 (M+H) + .

[0168] 1 H NMR (400MHz, CDCl3) δ9.51 (s, 1H), 8.82 (d, J = 8.2Hz, 1H), 8.42 (s, 2H), 8.18 (d, J = 8.2Hz, 1H),7.85(d,J=9.2Hz,1H),7.04(d,J=9.0Hz,1H),6.60(dd,J=13.8,6.8Hz,1H),3.35(s,3H),1.81(d,J=7.0Hz,3H).

[0169] Cpd-01D

[0170] MS: m / z = 463.0 (M+H) + .

[0171] 1 H NMR (400MHz, CDCl3) δ9.49(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=9.0Hz,1H),6.56(d,J=6.6Hz,1H),3.38(s,3H),1.81(d,J=6.8Hz,3H).

[0172] Synthesis of intermediate INT-1

[0173] first step

[0174] Tetrahydrofuran (100 mL) was added to 5-methoxy-4-azaindazole INT-1a (10 g, 0.067 mol), DHP (18.1 g, 0.216 mol) and PTSA (1.2 g, 0.0072 mol), and the reaction solution was stirred at room temperature for 16 hours. After completion of the reaction, the product was concentrated, washed with saturated ammonium chloride, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After concentration, the product was separated and purified on a silica gel column (petroleum ether / ethyl acetate = 5 / 1) to give 5-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-4-azaindazole INT-1b (14.0 g) in a yield of 89%.

[0175] MS m / z (ESI): 234.1 (M+H) + .

[0176] Step 2

[0177] Weigh 5-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-4-azaindazole INT-1b (14.0 g, 0.06 mol) and trimethylsilyl iodide (36.7 g, 0.18 mol), add acetonitrile (100 ml), heat to 80 degrees, react for 6 hours, cool to room temperature, add ethyl acetate (100 ml) and water (100 ml) for washing and extraction, concentrate the organic layer, and purify by column chromatography (ethyl acetate / petroleum ether = 1 / 5 to 1 / 1) to obtain compound INT-1c (9.2 g) with a yield of 70%.

[0178] MS m / z (ESI): 220.1 (M+H) + .

[0179] Step 3

[0180] Compound INT-1c (9.0 g, 0.041 mol) was weighed and dissolved in DMF (50 mL). Cesium carbonate (3.25 g, 10.0 mmol) and (R)-1-(3,5-dichloropyridin-4-yl)methanesulfonic acid ethyl ester (16.7 g, 0.062 mol) were added. The reaction solution was stirred at 80°C under nitrogen for 16 hours. Water (50 mL) was then added, the mixture was extracted with ethyl acetate and dried by swirl. Trifluoroacetic acid (5 mL) and dichloromethane (50.0 mL) were added, and the mixture was allowed to react at room temperature for 6 hours. After the reaction, water (50 mL) was added, the mixture was separated, and the mixture was extracted with ethyl acetate (50 mL). The mixture was concentrated and purified by column chromatography (mobile phase: ethyl acetate / petroleum ether = 1 / 10 to 10 / 1) to obtain compound INT-1d (10.0 g) in a yield of 78%.

[0181] MS m / z (ESI): 309.0 (M+H) + .

[0182] Step 4

[0183] 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 solution was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated and quenched by adding saturated sodium thiosulfate solution. After concentration, the product was separated and purified on a silica gel column (petroleum ether / ethyl acetate = 5 / 1) to obtain compound INT-1e (3.1 g) with a yield of 73%.

[0184] MS m / z(ESI):434.9(M+H) + .

[0185] 1 H NMR (400MHz, CDCl3) δ8.41 (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).

[0186] Step 5

[0187] Compound INT-1e (8 g, 0.018 mol), DHP (1.8 g, 0.02 mol) and PTSA (0.3 g, 0.002 mol) were weighed and tetrahydrofuran (50 mL) was added. The reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, it was concentrated, washed with saturated ammonium chloride, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After concentration, it was separated and purified on a silica gel column (petroleum ether / ethyl acetate = 5 / 1) to obtain compound INT-1 (7.4 g) with a yield of 80%.

[0188] MS m / z (ESI): 518.9 (M+H) + .

[0189] Example 2

[0190] (R)-4-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3,6-dihydro-2H-thiopyran 1,1-dioxide

[0191] first step

[0192] (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-iodo-1H-pyrazolo[4,3-b]pyridine INT-1e (60 mg, 0.1379 mmol), (6-chloropyridin-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) were dissolved in ethanol / water (2 / 0.5 mL), and the mixture was purged three times. The reaction solution was stirred at 90°C for 1 hour. After the reaction, the reaction solution was filtered through celite, extracted with ethyl acetate, dried, concentrated, and separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain (R)-3-(6-chloropyridin-3-yl)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-iodo-1H-pyrazolo[4,3-b]pyridine INT-1e.

[0266] The product was prepared from 1,4-dimethyl-1,4-diol-2-yl)ethoxy)-1H-pyrazolo[4,3-b]pyridine 02a (50 mg), yield 86%.

[0193] Step 2

[0194] (R)-3-(6-chloropyridin-3-yl)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-pyrazolo[4,3-b]pyridine 02a (60 mg, 0.1426 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-thiopyran 1,1-dioxide (40.49 mg, 0.15686 mmol), potassium carbonate (39.42 mg) were added. , 0.2852mmol) and Pd(dppf)Cl2 (10.43mg, 0.01426mmol) were dissolved in 1,4-dioxane / water (1 / 0.2mL), evacuated three times, and the reaction solution was stirred at 90 degrees Celsius for 1 hour. After the reaction, the reaction solution 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 a crude product. Finally, the crude product was prepared by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: Xbridge 5u C18 150x19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 9-minute gradient, gradient ratio: acetonitrile phase 50%-60%, flow rate: 25 mL / min) was used to obtain (R)-4-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3,6-dihydro-2H-thiopyran 1,1-dioxide Cpd-02A (8 mg) in an 11% yield.

[0195] 1HNMR (400MHz, DMSO-d6) δ13.51(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).

[0196] Example 3

[0197] (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(6-(4-methylsulfonyl)piperidin-3-yl)-1H-pyrazolo[4,3-b]pyridine

[0198] first step

[0199] 1-(5-bromopyridin-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 stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated to obtain the crude product. The crude product was purified on a silica gel column (petroleum ether / ethyl acetate = 1 / 1) to afford 1-(5-bromopyridin-2-yl)-4-(methylsulfonyl)piperazine 119b (400 mg). Yield: 54.4%.

[0200] MS m / z (ESI): 320.0 (M+H) + .

[0201] Step 2

[0202] 1-(5-Bromopyridin-2-yl)-4-(methylsulfonyl)piperazine 119b (200 mg, 0.625 mmol), bis(pinacolato)diboron (238 mg, 0.937 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium 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 under a nitrogen atmosphere for 2 hours. After completion of the reaction, the mixture was filtered and concentrated. The crude product was purified on a silica gel column (petroleum ether / ethyl acetate = 3 / 1) to afford (6-(4-(methylsulfonyl)piperazin-1-yl)pyridin-3-yl)boronic acid 119c (100 mg). Yield: 50.5%.

[0203] MS m / z (ESI): 286.1 (M+H) + .

[0204] Step 3

[0205] (6-(4-methylsulfonyl)piperazin-1-yl)pyridin-3-yl)boronic acid 119c (79 mg, 0.28 mmol), (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-iodo-1H-pyrazolo[4,3-b]pyridine INT-1e (80 mg, 0.18 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium chloride (13 mg, 0.02 mmol), and potassium acetate (36 mg, 0.37 mmol) were dissolved in ethanol:water (5 mL) and stirred at 90°C under nitrogen for 18 hours. After the reaction, the mixture was filtered and concentrated. The crude product was purified by preparative purification (FA, mobile phase: ACN:H2O (0.1% NH3) = 50%:50%) to afford (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(6-(4-methylsulfonyl)piperidin-3-yl)-1H-pyrazolo[4,3-b]pyridine Cpd-119A (4.13 mg). Yield: 3.92%.

[0206] MS m / z(ESI):548.0(M+H) + .

[0207] 1 H NMR (400MHz, CDCl3) δ8.95(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).

[0208] Example 4

[0209] (R)-2-(1-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidin-4-yl)propan-2-ol

[0210] first step

[0211] Preparation of (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(6-fluoropyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine

[0212] (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-iodo-1H-pyrazolo[4,3-b]pyridine INT-1e (300 mg, 0.58 mmol) was dissolved in a dioxane / water = 5 / 1 (5 mL) solution, and (6-fluoropyridin-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) were added. The mixture was stirred at 90 degrees for 3 hours. After the reaction was completed, water was added to quench the reaction and the mixture was extracted with ethyl acetate (3 x 30 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1) to give (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(6-fluoropyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine 124a (200 mg) in a yield of 60.99%.

[0213] MS m / z(ESI):404.0(M+H) + .

[0214] Step 2

[0215] (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(6-fluoropyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine 124a (30 mg, 0.07 mmol) was dissolved in N,N-dimethylacetamide (1 mL), and N,N-diisopropylethylamine (28 mg, 0.22 mmol) and 2-(piperidin-4-yl)propan-2-ol (21 mg, 0.14 mmol) were added. The reaction mixture was stirred at 80°C for 3 hours. After the reaction, the reaction solution was prepared by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: WELCH Xtimate C18 21.2*250mm 10um; mobile phase 1: water (containing 0.1% 0.1FA); mobile phase 2: acetonitrile; 18-minute gradient, gradient ratio: acetonitrile phase 5% to 100%, flow rate: 30 mL / min) to obtain (R)-2-(1-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidin-4-yl)propan-2-ol Cpd-124A (16.19 mg) in a yield of 41.37%.

[0216] MS m / z(ESI):527.1(M+H) + .

[0217] 1 H NMR (400MHz, DMSO-d6) δ13.11(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=6.8H z,1H),4.51(d,J=12.8Hz,2H),4.14(s,1H),2.75(t,J=12.0Hz,2H),1.81(d,J=12.0H z,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).

[0218] Example 5

[0219] (R)-4-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-pyrazolopyridin-3-yl)-3-fluoropyridin-2-yl)-3,6-dihydro-2H-thiopyran 1,1-dioxide

[0220] first step

[0221] Under nitrogen, compound INT-1e (150 mg, 0.34 mmol) was dissolved in ethanol (3 mL) and water (0.5 mL). (6-Chloro-5-fluoropyridin-3-yl)boronic acid (91 mg, 0.52 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (25 mg, 0.03 mmol), and potassium acetate (68 mg, 0.69 mmol) were added sequentially. The reaction mixture was stirred at 90°C for 5 hours. Liquid chromatography-mass spectrometry indicated that the reaction was complete. The reaction mixture was filtered, the filtrate collected, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (eluent: petroleum ether:ethyl acetate = 4:1) to obtain (R)-3-(6-chloro-5-fluoropyridin-3-yl)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-pyrazolopyridine Cpd-03a (100 mg). Yield: 66%.

[0222] MS m / z(ESI):438.0(M+H) + .

[0223] Step 2

[0224] Under nitrogen, (R)-3-(6-chloro-5-fluoropyridin-3-yl)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-pyrazolopyridine Cpd-03a (100 mg, 0.23 mmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL). 1,1-dioxido-3,6-dihydro-2H-thiopyran-4-pinacol borate (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) were added. The reaction mixture was stirred at 90°C for 3 hours. Liquid chromatography-mass spectrometry detected the disappearance of the starting material, and the reaction was terminated. The reaction solution was filtered, and the filtrate was collected and concentrated under reduced pressure to give a crude product. The crude product was separated and purified by column chromatography (eluent: petroleum ether:ethyl acetate = 10:1 to 1:10) to give (R)-4-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-pyrazolopyridin-3-yl)-3-fluoropyridin-2-yl)-3,6-dihydro-2H-thiopyran 1,1-dioxide Cpd-03A (56 mg) in a yield of 46%.

[0225] MS m / z(ESI):534.0(M+H) + .

[0226] 1 H NMR (400MHz, DMSO-d6) δ13.67(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).

[0227] Example 6

[0228] R)-3-(6-(1-cyclopropyl-3-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-pyrazolo[4,3-b]pyridine

[0229] first step

[0230] Under nitrogen, compound INT-1e (150 mg, 0.34 mmol) was dissolved in ethanol (3 mL) and water (0.5 mL). (6-chloropyridin-3-yl)boronic acid (82 mg, 0.52 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (25 mg, 0.03 mmol), and potassium acetate (68 mg, 0.69 mmol) were added sequentially. The reaction mixture was stirred at 90°C for 5 hours. Liquid chromatography (LC-MS / MS) confirmed the reaction was complete. The reaction mixture was filtered, the filtrate collected, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (eluent: petroleum ether:ethyl acetate = 4:1) to obtain (R)-3-(6-chloropyridin-3-yl)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-pyrazolopyridine Cpd-145a (110 mg) in a 75% yield.

[0231] MS m / z (ESI): 420.0 (M+H) + .

[0232] Step 2

[0233] To a solution of (R)-3-(6-chloropyridin-3-yl)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-pyrazolo[4,3-b]pyridine Cpd-145a (100 mg, 0.2 mmol) in a 1,4-dioxane / water mixture (5 / 1 by volume) (6 mL) was added 1-cyclopropyl-3-methyl-1H-pyrazol-4-pinacol borate (100 mg, 0.4 mmol), potassium carbonate (66 mg, 0.5 mmol), and 1,1'-bis(diphenylphosphino)ferrocene (34 mg, 0.04 mmol). The reaction mixture was stirred at 90°C for 1 hour. After completion of the reaction, the mixture was quenched with water and extracted with ethyl acetate (3 x 10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The concentrate was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1 to 1 / 10) to give (R)-3-(6-(1-cyclopropyl-3-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-pyrazolo[4,3-b]pyridine Cpd-145A (35 mg) in a yield of 27.98%.

[0234] MS m / z(ESI):506.1(M+H) + .

[0235] 1H NMR(400MHz, CDCl3)δ9.80(dd,J=5.8,2.9Hz,1H),9.34(s,1H),8.46(d,J=9.9Hz,1H),8.4 2(s,1H),7.96(s,1H),7.79(d,J=9.0Hz,1H),7.50(d,J=8.2Hz,1H),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).

[0236] Example 7

[0237] 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-3-iodo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine INT-2

[0238] first step

[0239] 5-Bromo-2-methylpyridin-3-amine INT-2a (10 g, 0.0535 mol) was dissolved in 1,4-dioxane (75 mL) and water (10 mL). Methylboric acid (14.41 g, 0.24 mol), potassium carbonate (22.18 g, 0.16 mmol), and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (2.9 g, 4 mmol) were added. Under nitrogen, the reaction mixture was stirred at 100°C for 16 hours. After completion of the reaction, water (30 mL) was added, followed by extraction with ethyl acetate (60 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and mixed with silica gel. Purification by column chromatography (mobile phase: dichloromethane / methanol = 40 / 1) afforded 2,5-dimethylpyridin-3-amine INT-2b (6.2 g) in a 94% yield.

[0240] MS m / z(ESI):123.2(M+H) + .

[0241] Step 2

[0242] 2,5-Dimethylpyridin-3-amine INT-2b (6.2 g, 0.0507 mol) was dissolved in N,N-dimethylformamide (20 mL), and N-bromosuccinimide (9.02 g, 0.0507 mol) was added. The mixture was stirred at 0°C for 3 hours. After the reaction, water (30 mL) was added, followed by extraction with ethyl acetate (50 mL x 4). The organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, concentrated, mixed with silica gel, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 68 / 32) to give 6-bromo-2,5-dimethylpyridin-3-amine INT-2c (5.1 g) in a yield of 50%.

[0243] MS m / z(ESI):201.0(M+H) + .

[0244] Step 3

[0245] 6-Bromo-2,5-dimethylpyridin-3-amine INT-2c (5.1 g, 25.40 mmol) was dissolved in chloroform (60 mL). Potassium acetate (2.99 g, 30.48 mmol) and acetic anhydride (10.37 g, 101.60 mmol) were added, and the reaction mixture was stirred at 55°C for 2 hours. The reaction mixture was then cooled to 0°C, and 18-crown-6 (0.67 g, 2.54 mmol) and isoamyl nitrite (5.95 g, 50.8 mmol) were added. The reaction mixture was stirred at 80°C for 16 hours. After the reaction, sodium bicarbonate solution was added to quench the reaction, and the mixture was extracted with dichloromethane (100 ml). The organic phase was washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, concentrated, mixed with silica gel, and purified by column chromatography (mobile phase: petroleum ether / dichloromethane = 75 / 25 to 70 / 30) to give 1-(5-bromo-6-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl)ethan-1-one INT-2d (4.9 g) in a yield of 76%.

[0246] MS m / z(ESI):254.0(M+H) + .

[0247] Step 4

[0248] Ammonia / methanol solution (40 mL) was added to 1-(5-bromo-6-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl)ethan-1-one INT-2d (4.9 g, 19.29 mmol), and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated to obtain 5-bromo-6-methyl-1H-pyrazolo[4,3-b]pyridine INT-2e (4.6 g), which was used directly in the next reaction without further purification.

[0249] Step 5

[0250] 5-Bromo-6-methyl-1H-pyrazolo[4,3-b]pyridine 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, the reaction solution was concentrated, mixed with silica gel, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 80 / 20) to give 5-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine INT-2f (5.1 g) in a yield of 79%.

[0251] MS m / z(ESI):296.0(M+H) + .

[0252] Step 6

[0253] 5-Bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine INT-2f (5.1 g, 17.20 mmol) was dissolved in toluene (50 mL), and (R)-1-(3,5-dichloropyridin-4-yl)ethan-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) were added. The mixture was stirred at 110 degrees for 12 hours under nitrogen protection. After the reaction, the reaction solution was concentrated, silica gel was added and the sample was stirred, and the mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 91 / 9) to obtain 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine INT-2g (6.4 g) with a yield of 91%.

[0254] MS m / z(ESI):407.1(M+H) + .

[0255] Step 7

[0256] To 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine INT-2g (6.4 g, 15.70 mmol) were added a methanol solution of hydrochloric acid (4M, 30 mL) and methanol (5 mL). After reacting at 50 degrees for 8 hours, the reaction solution was concentrated and dissolved with ethyl acetate (50 mL). Sodium bicarbonate solution was added to neutralize the reaction. The aqueous phase was extracted with ethyl acetate (50 ml), and the organic phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate to obtain (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methyl-1H-pyrazolo[4,3-b]pyridine INT-2h (4.7 g) with a yield of 93%.

[0257] MS m / z(ESI):323.0(M+H) + .

[0258] Step 8

[0259] (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methyl-1H-pyrazolo[4,3-b]pyridine INT-2h (4.7 g, 14.50 mmol) was dissolved in dichloromethane (100 mL) and N-iodosuccinimide (3.26 g, 14.50 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, sodium bisulfite solution (80 mL) was added to quench the reaction. The layers were separated, and the organic layer was washed with water and saturated brine and concentrated directly to give the crude product (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-iodo-6-methyl-1H-pyrazolo[4,3-b]pyridine INT-2i (6.25 g), which was used directly in the next step.

[0260] Step 9

[0261] The crude (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-iodo-6-methyl-1H-pyrazolo[4,3-b]pyridine INT-2i was 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) were added. The reaction mixture was stirred at room temperature for 16 hours and reacted at 40 degrees for 3 hours. After the reaction was complete, the reaction solution was concentrated, silica gel was added to mix the sample, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 86 / 14) to obtain 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-3-iodo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine INT-2 (6 g) with a yield of 81%.

[0262] MS m / z(ESI):533.0(M+H) + .

[0263] Example 8

[0264] (R)-1-(4-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3,5-dimethyl-1H-pyrazol-1-yl)-2-methyl-2-propanol Cpd-158A

[0265] first step

[0266] (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-iodo-1H-pyrazolo[4,3-b]pyridine INT-1e (6.2 g, 14.3 mmol) was dissolved in dichloromethane (20 mL). 3,4-dihydro-2H-pyran (3.5 g, 41.70 mmol) and p-toluenesulfonic acid (0.24 g, 1.39 mmol) were added to the reaction flask and stirred at 25°C for 16 hours. After completion of the reaction, the mixture was concentrated and the crude product was purified on a silica gel column (ethyl acetate / petroleum ether = 13 / 100) to afford 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine INT-1 (6.1 g) in an 81% yield.

[0267] MS m / z(ESI):519.0(M+H) + .

[0268] Step 2

[0269] 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine INT-1 (3 g, 5.8 mmol), (6-chloropyridin-3-yl)-boronic acid (commercially available) (1 g, 6.4 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium chloride (420 mg, 0.6 mmol) and potassium carbonate (1.6 g, 11.6 mmol) were dissolved in a mixed solution of 1,4-dioxane and water (25 mL) and stirred at 90 degrees under nitrogen protection for 16 hours. After the reaction, the mixture was filtered and concentrated, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 8 / 100) to give 3-(6-chloropyridin-3-yl)-5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine Cpd-158a (2.2 g) in a yield of 75%.

[0270] MS m / z (ESI): 504.0 (M+H) + .

[0271] Step 3

[0272] 3-(6-chloropyridin-3-yl)-5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-oxazolo[4,3-b]pyridine Cpd-158a (2.1 g, 4.2 mmol), 1-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-1-yl)-2-methyl-2-propanol Cpd-158b (commercially available) (1.48 g, 5.0 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium chloride (300 mg, 0.4 mmol), and potassium carbonate (1.2 g, 8.4 mmol) were dissolved in a mixture of 1,4-dioxane and water (25 mL) and stirred at 110°C for 16 hours under nitrogen. After the reaction, the mixture was extracted with ethyl acetate, and the organic phase was collected and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 50 / 100) to give 1-(4-(5-(5-(R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3,5-dimethyl-1H-pyrazol-1-yl)-2-methyl-2-propanol Cpd-158c (1.7 g), yield: 64%.

[0273] MS m / z (ESI): 636.2 (M+H) + .

[0274] Step 4

[0275] 1-(4-(5-(5-(R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3,5-dimethyl-1H-pyrazol-1-yl)-2-methyl-2-propanol Cpd-158c (1.7 g, 2.7 mmol) was dissolved in methanolic hydrogen chloride (20 mL). The reaction mixture was stirred at 50°C for 5 h. After completion of the reaction, saturated sodium bicarbonate solution was added to adjust the pH to 7-9. The mixture was extracted with dichloromethane (100 mL), and the organic phase was collected and concentrated. The concentrated crude product was purified by silica gel column chromatography (methanol / dichloromethane = 8 / 100) to give (R)-1-(4-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3,5-dimethyl-1H-pyrazol-1-yl)-2-methyl-2-propanol Cpd-158A (1.1 g). Yield: 74%.

[0276] MS m / z(ESI):552.2(M+H) + .

[0277] 1 H NMR (400MHz, CDCl3) δ9.50(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=9.2H z,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).

[0278] Example 9

[0279] (R)-1-(4-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-pyrazolo[4,3-b]pyridin-3-yl)-3-fluoropyridin-2-yl)-3,5-dimethyl-1H-pyrazol-1-yl)-2-methyl-2-propanol Cpd-161A

[0280] first step

[0281] 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine INT-1 (4.8 g, 9.2 mmol), (6-chloro-5-fluoropyridin-3-yl)-boronic acid (commercially available) (1.94 g, 11.0 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium chloride (670 mg, 0.9 mmol) and potassium carbonate (2.54 g, 18.4 mmol) were dissolved in a mixed solution of 1,4-dioxane and water (150 mL) and stirred at 90 degrees under nitrogen for 16 hours. After the reaction was completed, the mixture was filtered and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 8 / 100) to give 3-(6-chloro-5-fluoropyridin-3-yl)-5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine Cpd-161a (4.6 g), yield: 95%.

[0282] MS m / z(ESI):522.5(M+H) + .

[0283] Step 2

[0284] 3-(6-chloro-5-fluoropyridin-3-yl)-5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine Cpd-161a (4.6 g, 8.8 mmol), 1-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine A mixture of (1,1'-bis(diphenylphosphino)ferrocenepalladium chloride (640 mg, 0.9 mmol), (1,1'-bis(diphenylphosphino)ferrocenepalladium chloride) (640 mg, 0.9 mmol), and potassium carbonate (2.4 g, 17.6 mmol) was dissolved in a mixture of 1,4-dioxane and water (150 mL) and stirred at 90°C for 16 hours under nitrogen. After the reaction, the mixture was extracted with ethyl acetate, and the organic phase was collected and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 60 / 100) to give 1-(4-(5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-3-fluoropyridin-2-yl)-3,5-dimethyl-1H-pyrazol-1-yl)-2-methyl-2-propanol Cpd-161b (3.9 g), yield: 68%.

[0285] MS m / z (ESI): 654.2 (M+H)+ .

[0286] Step 3

[0287] 1-(4-(5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-3-fluoropyridin-2-yl)-3,5-dimethyl-1H-pyrazol-1-yl)-2-methyl-2-propanol Cpd-161b (3.9 g, 6.0 mmol) was dissolved in methanolic hydrogen chloride (40 mL). The reaction mixture was stirred at 50°C for 16 h. After the reaction, saturated sodium bicarbonate solution was added to adjust the pH of the reaction solution to 7-9. The reaction solution was extracted with ethyl acetate, and the organic phase was collected and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 60 / 100 to 100 / 1) to obtain (R)-1-(4-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-pyrazolo[4,3-b]pyridin-3-yl)-3-fluoropyridin-2-yl)-3,5-dimethyl-1H-pyrazol-1-yl)-2-methyl-2-propanol Cpd-161A (2.5 g). Yield: 70%.

[0288] MS m / z (ESI): 570.4 (M+H) + .

[0289] 1 H NMR (400MHz, DMSO-d6) δ13.59(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).

[0290] Example 10

[0291] (R)-1-(4-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-pyrazolo[4,3-b]pyridin-3-yl)-3-fluoropyridin-2-yl)-3-methyl-1H-pyrazol-1-yl)-2-methyl-2-propanol Cpd-162A

[0292] first step

[0293] Under nitrogen protection, 3-(6-chloro-5-fluoropyridin-3-yl)-5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine Cpd-161a (10.0 g, 0.02 mol), 2-methyl-1-(3-methyl-4-(4,4,5,5-tetramethyl-1, A mixed solution of 3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (6.96 g, 0.025 mol), potassium carbonate (7.9 g, 0.06 mol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium chloride (2.37 g, 0.003 mol) in 1,4-dioxane / water (10 / 1,88 mL) was stirred at 90°C for 10 hours. After the reaction, the reaction solution was concentrated and extracted with ethyl acetate. The organic phases were combined and concentrated, and then separated and purified by silica gel column (petroleum ether / ethyl acetate = 1 / 1) to give 1-(4-(5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro 2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-3-fluoropyridin-2-yl)-3-methyl-1H-pyrazol-1-yl)-2-methyl-2-propanol Cpd-162a (8 g) in a yield of 39%.

[0294] MS m / z (ESI): 640.2 (M+H) + .

[0295] Step 2

[0296] -(4-(5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-3-fluoropyridin-2-yl)-3-methyl-1H-pyrazol-1-yl)-2-methyl-2-propanol Cpd-162a (8 g, 0.012 mol) was dissolved in a 4 M solution of hydrogen chloride in methanol (80 mL), and the mixed solution was stirred at 55°C for 2 hours. After the reaction, the reaction mixture was concentrated, the pH was adjusted to 7-8 with a saturated sodium bicarbonate solution, and then extracted with dichloromethane. The organic phases were combined and concentrated, and then separated and purified on a silica gel column (dichloromethane / methanol = 1 / 20) to obtain a relatively pure product. The product was then subjected to chiral separation (column: Daicel CHIRALCEL IB-N; mobile phase: CO2 / MeOH [0.2% NH3 (7M Solution in MeOH)] = 50 / 50) to obtain (R)-1-(4-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-pyrazolo[4,3-b]pyridin-3-yl)-3-fluoropyridin-2-yl)-3-methyl-1H-pyrazol-1-yl)-2-methyl-2-propanol Cpd-162A (2.3 g) in a yield of 33%.

[0297] MS m / z (ESI): 556.1 (M+H) + .

[0298] 1 H NMR (400MHz, CDCl3) δ9.34 (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,1H),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).

[0299] Example 11

[0300] (R)-1-(4-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3,5-dimethyl-1H-pyrazol-1-yl)-2-methyl-2-propanol Cpd-175A

[0301] first step

[0302] 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-3-iodo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine INT-2 (3 g, 5.6 mmol), (6-chloropyridin-3-yl)-boronic acid (commercially available) (1 g, 6.4 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium chloride (420 mg, 0.6 mmol) and potassium carbonate (1.6 g, 11.6 mmol) were dissolved in a mixed solution of 1,4-dioxane and water (25 mL) and stirred at 90 degrees under nitrogen protection for 16 hours. After the reaction, the mixture was filtered and concentrated, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 8 / 100) to give 3-(6-chloropyridin-3-yl)-5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine Cpd-175a (2.2 g) in a yield of 75%.

[0303] MS m / z (ESI): 518.0 (M+H) + .

[0304] Step 2

[0305] 3-(6-chloropyridin-3-yl)-5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine Cpd-175a (100 mg, 0.19 mmol, 1.0 eq) was dissolved in 1,4-dioxane (8 mL) and water (1.5 mL), and 1-(3,5-dimethyl-4-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)-2-methyl-2-propanol (commercially available) (68 mg, 0.23 mmol, 1.2 eq), potassium carbonate (80 mg, 0.58 mmol, 3 eq) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (14 mg, 0.02 mmol, 0.1 eq), under nitrogen protection, the reaction mixture was stirred at 90 degrees for 8 hours. After the reaction, the reaction solution was concentrated, mixed with silica gel, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 37 / 63) to give 1-(4-(5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3,5-dimethyl-1H-pyrazol-1-yl)-2-methyl-2-propanol Cpd-175b (50 mg) in a yield of 40%.

[0306] MS m / z(ESI):650.2(M+H) + .

[0307] Step 3

[0308] A dioxane solution (4 M, 3 mL) of hydrogen chloride was added to 1-(4-(5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3,5-dimethyl-1H-pyrazol-1-yl)-2-methyl-2-propanol Cpd-175b (50 mg, 0.08 mmol), followed by reaction at 50°C for 2 hours. After the reaction, the reaction solution was concentrated and purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150x19 mm; mobile phase 1: water (containing 0.1% FA); mobile phase 2: acetonitrile; 16-min gradient, gradient ratio: acetonitrile phase 65%-75%, flow rate: 20 mL / min) to obtain (R)-1-(4-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3,5-dimethyl-1H-pyrazol-1-yl)-2-methyl-2-propanol Cpd-175A (21.7 mg) in a yield of 47%.

[0309] MS m / z(ESI):566.1(M+H) + .

[0310] 1 H NMR (400MHz, DMSO-d6) δ13.30(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).

[0311] Using conditions similar to those in the above examples, the compounds listed in Table 1 were prepared. The structural characterization data of these compounds are listed in Table 1.

[0312] Table 1

[0313] Biological evaluation

[0314] Test Example 1 Inhibitory effect of representative compounds of the present invention on FGFR1 and FGFR3 kinases

[0315] The inhibitory activity of the compounds against FGFR1 and FGFR3 kinases was tested using the HTRF method. The highest concentration tested was 3000 nM, with three-fold serial dilutions, 10 concentrations, and duplicate well detection.

[0316] 1.1 Experimental Materials

[0317] 1.1.1 Reagents and consumables

[0318] 1.1.2 Instruments

[0319] 1.2 Experimental steps

[0320] a) Compounds were diluted into the test plate using an ECHO pipetting workstation (784075, Greiner) and centrifuged at 1000 rpm for 30 s.

[0321] b) Prepare FGFR kinase solution at 2x final concentration using 1X kinase buffer.

[0322] c) Add 5 μL of FGFR kinase solution at 2 times the final concentration to the 384-well test plate, centrifuge, and let stand at room temperature for 10 minutes.

[0323] d) Prepare a mixture of Biotin-conjugated tyrosine kinase substrate and ATP at 2 times the final concentration using 1X kinase buffer.

[0324] e) Add 5 μL of a mixture of tyrosine kinase substrate coupled with Biotin at 2 times the final concentration and ATP to the test plate to initiate the reaction.

[0325] f) Centrifuge the 384-well test plate at 1000 g for 30 seconds, mix thoroughly, and incubate at room temperature for 50 minutes.

[0326] g) Prepare 4-fold concentration of Sa-XL665 using HTRF detection buffer.

[0327] h) Add 5 μL of four-fold concentration of Sa-XL665 and 5 μL of coupled Eu into the reaction plate. 3 -Cryptate's TK antibody.

[0328] i) Centrifuge at 1000 g for 30 seconds and allow to react at room temperature for 1 hour.

[0329] j) The fluorescence signals at 665 nM and 615 nM in each well were read using an Envision 2014 microplate reader, and the ratio was calculated.

[0330] %inhibition=100%-(Ratio cmpd -Ratio noATP / Ratio DMSO -Ratio noATP )*100%

[0331] 1.3 Experimental Results

[0332] Table 2 Test results of kinase inhibitory activity of representative compounds of the present invention

[0333] The experimental results show that the representative compounds of the present invention have good kinase inhibitory activity.

[0334] Test Example 2: Inhibitory effect and selectivity of the compounds of the present invention on the proliferation of Ba / F3-FGFR1 / 2 / 3 / 4 cells

[0335] The CTG method was used to detect the inhibitory effect of the compounds on the proliferation of Ba / F3-FGFR1, Ba / F3-FGFR2, Ba / F3-FGFR3 and Ba / F3-FGFR4 cells. The highest concentration tested was 3000 nM, with a three-fold dilution gradient, 10 concentrations, and duplicate well detection.

[0336] 2.1 Experimental Materials

[0337] 2.1.1 Reagents and consumables

[0338] 2.1.2 Instruments

[0339] 2.2 Experimental steps

[0340] a) Culture Ba / F3-FGFR1, Ba / F3-FGFR2, Ba / F3-FGFR3, and Ba / F3-FGFR4 until exponential growth phase. Complete medium: RPMI 1640 medium, 10% FBS, 1% GlutaMAX and P / S, 10 ng / mL FGF1, 10 μg / mL Heparin, 10 μM 2-mercaptoethanol, 2 μg / mL puromycin.

[0341] b) Using an ECHO pipetting station, dilute the compound stock solution from 3000 nM into a 384-well plate and centrifuge at 1000 g for 1 min.

[0342] c) The cells were digested, and 30 μL of Ba / F3-FGFR1, Ba / F3-FGFR2, Ba / F3-FGFR3, or Ba / F3-FGFR4 (500 / well) were evenly plated in a 384-well black-edged cell culture plate containing the compound. The edge wells were blocked with 50 μL of PBS and the plate was cultured in a 37°C CO2 incubator for 72 h.

[0343] d) Add 30 μL of Cell-Titer-Glo reagent to each well, shake on a shaker to mix, and then incubate at 37°C for 30 min. After the signal stabilizes, detect it on a microplate reader.

[0344] 2.3 Experimental Results

[0345] Table 3 Test results of the inhibitory activity of representative compounds of the present invention on Ba / F3 cells

[0346] The experimental results show that the representative compounds of the present invention have potent inhibitory activity and good selectivity against Ba / F3-FGFR2 / 3 cells.

[0347] Test Example 3 Pharmacokinetic Study of Representative Compounds of the Invention

[0348] 3.1 Experimental Purpose

[0349] SD rats were used as test animals, and the drug concentration in plasma at different time points after oral administration of the compound of the present invention was determined by LC / MS / MS. The pharmacokinetic behavior of the compound of the present invention in SD rats was studied, and its pharmacokinetic characteristics were evaluated.

[0350] 3.2 Experimental plan

[0351] (1) Experimental animals

[0352] Twenty-four SD rats, half male and half female, were divided into six groups and purchased from Shanghai Jihui Experimental Animal Breeding Co., Ltd., with animal production license SCXK (Shanghai) 2017-0012.

[0353] (2) Drug preparation

[0354] The formulation is 5% DMSO + 60% PEG300 + 35% aqueous glucose solution. First, weigh an appropriate amount of a representative compound of this invention (calculated for purity and salt coefficient), add the prescribed amount of DMSO, and vortex to obtain a clear, transparent solution. Then, add the prescribed amount of PEG300, vortex to mix thoroughly, and then add the prescribed amount of aqueous glucose solution. A 0.6 mg / mL or 2 mg / mL solution is obtained. If a solution cannot be obtained during preparation, try sonicating in a water bath at no higher than 60°C to aid dissolution.

[0355] (3) Administration

[0356] The rats were fasted overnight and then given the drugs by gavage (2 mpk).

[0357] (4) Sample collection

[0358] 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. Approximately 30 μL of blood samples were collected at each time point and placed in anticoagulant tubes containing EDTA-K2 anticoagulant. Plasma was obtained by centrifugation within 30 minutes. Whole blood samples were placed on wet ice before centrifugation. All collected plasma samples were stored on dry ice or at a temperature not exceeding -70°C until analysis. Liquid chromatography-tandem mass spectrometry (LC / MS / MS) was used to determine the concentration of the unchanged drug in plasma and the dosing solution.

[0359] 3.3 Experimental Results

[0360] 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.

[0361] Table 4 Pharmacokinetic results of the compounds of the present invention in rats

[0362] Conclusion: The half-life (T 1 / 2 ), exposure (AUC) and in vivo residence time and other pharmacokinetic properties are good, which can meet the requirements of oral administration.

[0363] The above is an exemplary description of the implementation methods of the technical solution of the present invention. It should be understood that the scope of protection of the present invention is not limited to the above implementation methods. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art within the spirit and principles of the present invention shall be included in the scope of protection of the claims of this application.

Claims

1. A compound represented by formula (I) and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt: in: Ring A and Ring B are the same or different and are independently selected from C 6-14 Aromatic ring, 5-14 membered heteroaromatic ring or 5-14 membered heterocyclic ring; L is absent or selected from -N(R a )-C(=O)-, -CR b =CR c -; When L does not exist, ring A is directly connected to the pyrazole ring through a chemical bond; R a is selected from hydrogen, unsubstituted or optionally substituted with one, two or more R a1 Substituted with the following groups: C 1-6 Alkyl, C 3-6 Cycloalkyl; each R a1 are the same or different and are independently selected from hydroxyl, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl; R b , R c are the same or different and are independently selected from hydrogen, halogen, unsubstituted or optionally substituted by one, two or more R b1 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl; each R b1 are the same or different and are independently selected from hydroxyl, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl; X is selected from O, S or NH; Y is absent or selected from unsubstituted or optionally substituted with one, two or more R y Substituted with the following groups: -S(=O)-R y1 、-S(=O)2-R y2 、-S(=O)(=NR y3 )-R y4 , C 3-12 Cycloalkyl, 3-14 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl; R y1 , R y2 , R y3 , R y4 are the same or different, which are absent or are independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl; each R y are the same or different and are independently selected from hydrogen, hydroxy, cyano, halogen, oxo (=O), unsubstituted or optionally substituted by one, two or more R y’ Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, =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 );R y5 , R y6 , R y7 , R y8 , R y9 , R y10 , R y11 , R y12 are the same or different and are independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl; each R y’ are the same or different and are independently selected from hydrogen, hydroxy, cyano, halogen, oxo (=O), unsubstituted or optionally substituted by one, two or more R y "substituted by the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, -C(=O)-NR y13 R y14 , -C(=O)-R y15 、-C(=O)OR y16 、-OR y17 、-S(=O)2-R y18 , -S(=O)2-NH2, -S(=O)(=NR y19 )-R y20 ,-P(=O)(R y21 )(R y22 ), amino group; each R y " are the same or different and are independently selected from hydrogen, hydroxy, cyano, halogen, oxo (=O), amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, -C(=O)-NR y23 R y24 , -C(=O)-R y25 、-C(=O)OR y26 、-OR y27 , -S(=O)2-R y28 、-S(=O)(=NR y29 )-R y30 ,-P(=O)(R y31 )(R y32 );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 are the same or different and are independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl; Each R 1 are the same or different and are independently selected from hydrogen, halogen, cyano, hydroxyl, oxo (=O), unsubstituted or optionally substituted by one, two or more R 11 Substituted with the following groups: amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, -C(=O)-NH2, -S(=O)2-C 1-6 Alkyl, -S(=O)(=NH)-C 1-6 Alkyl; or, two R attached to the same atom 1 The atoms to which it is attached together form an unsubstituted or optionally substituted R 11 Substituted 3-12 membered heterocyclic or C 3-12 Alkyl ring; or, two R attached to different atoms 1 Together with the atoms to which they are attached, they form an unsubstituted or optionally substituted R 11 Substituted 3-12 membered heterocyclic or C 3-12 Alkyl ring; each R 11 are the same or different and are independently selected from H, cyano, oxo (=O), halogen, unsubstituted or optionally substituted by one, two or more R 12 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, -S(=O)2-R y8 、-S(=O)(=NR y9 )-R y10 , C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 5-14 membered heteroaryl; each R 12 are the same or different and are independently selected from hydrogen, hydroxy, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 6-14 Aryl, 5-14 membered heteroaryl; Each R 2 , R 4 are the same or different and are independently selected from hydrogen, halogen, cyano, hydroxyl, oxo (=O), unsubstituted or optionally substituted by one, two or more R 21 Substituted with the following groups: amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, -C(=O)-NH2, -S(=O)2-C 1-6 Alkyl, C 6-14 Aryl, 5-14 membered heteroaryl; each R 21 are the same or different and are independently selected from halogen, CN, amino, hydroxy, oxo (=O), C 1-6 Alkyl, C 1-6 Alkoxy; R 6 Selected from hydrogen, R 6a -C 1-4 Alkyl; R 6a Selected from R 3 Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, cyano-C 1-6 alkyl; m and n are 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.

2. The compound according to claim 1, characterized in that Ring A is selected from C 6-10 Aromatic ring, 5-10 membered heteroaromatic ring or 5-10 membered heterocyclic ring; Preferably, ring A is selected from 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, 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 are the same or different and are independently selected from halogen, cyano, hydroxyl, oxo (=O), unsubstituted or optionally substituted by one, two or more R 11 Substituted with the following groups: amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 ring Alkyl, 3-6 membered heterocyclic group, -C(=O)-NH2, -S(=O)2-C 1-3 Alkyl, -S(=O)(=NH)-C 1-3 Alkyl; or, two R attached to the same atom 1 The atoms to which it is attached together form an unsubstituted or optionally substituted R 11 substituted 3-8 membered heterocyclic ring; or, two R attached to different atoms 1 Together with the atoms to which they are attached, they form an unsubstituted or optionally substituted R 11 substituted 3-8 membered heterocyclic ring; each R 11 are the same or different and are independently selected from H, cyano, oxo (=O), halogen, unsubstituted or optionally substituted by one, two or more R 12 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, -S(=O)2-CH3, -S(=O)(=NH)-CH3, C 3-6 Cycloalkyl, 3-8 membered heterocyclyl, 5-6 membered heteroaryl; each R 12 are the same or different and are independently selected from hydrogen, hydroxy, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl; Preferably, each R 1 are the same or different and are independently selected from F, Cl, Br, cyano, oxo (=O), methoxy, -S(=O)2-CH3, -S(=O)(=NH)-CH3, -S(=O)(=N-CH3)-CH3, or -C(=O)-N(CH3)2; or, two R attached to the same atom 1 The atoms to which it is attached together form an unsubstituted or optionally substituted R 11 substituted piperidinyl; Preferably, each R 11 are the same or different and are independently selected from hydrogen, 2,2,2-trifluoroethyl, -S(=O)2-CH3, cyclobutyl; Preferably, Selected from: phenyl, 3. The compound according to any one of claims 1 to 2, characterized in that Y is absent, or Y is selected from unsubstituted or optionally substituted with one, two or more R y Substituted with the following groups: -S(=O)-R y1 、-S(=O)2-R y2 、-S(=O)(=NR y3 )-R y4 , C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, 5-8 membered heteroaryl; R y1 , R y2 , R y3 , R y4 are the same or different, which are absent or are independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl; Preferably, Y is selected from unsubstituted or optionally substituted with one, two or more R y Substituted with the following groups: phenyl, piperazinyl, piperidinyl, pyrazolyl, Preferably, each R y are the same or different and are independently selected from hydrogen, hydroxy, cyano, halogen, oxo (=O), C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino-C 1-6 Alkyl, cyano C 1-6 Alkyl, carboxyl-C 1-6 Alkyl, C 1-6 Alkyl-NH-C 1-6 Alkyl, (C 1-6 Alkyl)2N-C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, -C 1-6 Alkyl-(hydroxy substituted C 3-8 Cycloalkyl), -C 1-6 Alkyl-S(=O)2-C 1-6 Alkyl, -C 1-6 Alkyl-S(=O)2-NH2, C 6-10 Aryl, 5-10 membered heteroaryl, =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 optionally one, two or more R y’ Substituted 3-8 membered heterocyclic group; each R y’ are the same or different and are independently selected from cyano, halogen, oxo (=O) or -S(=O)2-C 1-6 Alkyl; R y5 , R y6 , R y7 , R y8 , R y9 , R y10 , R y11 , R y12 are the same or different and are independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl; Preferably, each R y are the same or different and are independently selected from hydroxy, cyano, halogen, oxo (=O), C 1-3 Alkyl, halogenated C 1-3 Alkyl, hydroxyl C 1-4 Alkyl, amino-C 1-4 Alkyl, cyano C 1-3 Alkyl, carboxyl-C 1-4 Alkyl, C 1-4 Alkyl NH-C 1-4 Alkyl, (C 1-4 Alkyl)2N-C 1-4 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, -C 1-3 Alkyl-(hydroxy substituted C 3-6 Cycloalkyl), -C 1-3 Alkyl-S(=O)2-C 1-3 Alkyl, -C 1-3 Alkyl-S(=O)2-NH2, phenyl, 5-6 membered heteroaryl, =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 optionally one, two or more R y’ Substituted 3-6 membered heterocyclic group; each R y’ the same or different, independently selected from oxo (=O) or -S(=O)2-C 1-3 Alkyl; R y5 , R y6 , R y7 , R y8 , R y9 , R y10 , R y11 , R y12 Same or different, choose independently From hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl; Preferably, each R y are the same or different and are independently selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, trifluoromethyl, 2-hydroxyethyl, oxo(═O), ═N-CH3, -S(═O)2-CH3, -C(═O)O-CH3, -C(═O)O-C2H5, pyrimidinyl, -C(CH3)2OH, -C(CH3)2CN, -S(═O)2-C2H5, -S(═O)2-CH(CH3)2, -CH2COOH, More preferably, Y is selected from:

4. The compound according to any one of claims 1 to 3, characterized in that Each R 2 are the same or different and are independently selected from hydrogen, F, Cl, Br, cyano, unsubstituted or optionally substituted by one, two or more R 21 Substituted with the following groups: C 1-3 Alkyl, C 1-3 Alkoxy, pyrazolyl, pyrimidinyl; Preferably, each R 21 are the same or different and are independently selected from halogen, CN, methyl; Preferably, each R 2 The same or different, independently selected from Cl, methyl, Preferably, Selected from: Preferably, each R 4 are the same or different and are independently selected from hydrogen, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy; Preferably, each R 4 are the same or different and are independently selected from halogen, cyano, methyl or methoxy; Preferably, R 3 Selected from hydrogen, C 1-3 Alkyl, halogenated C 1-3 alkyl; Preferably, R 3 Selected from methyl; Preferably, R 6 Selected from hydrogen, 5. The compound according to any one of claims 1 to 4, characterized in that The compound represented by formula (I) has the structure shown below: Among them, ring A, ring B, R 1 , R 2 , R 3 , R 4 , L, X, Y, m, n, r have the definitions described in any one of claims 1-4; Preferably, the compound represented by formula (I) has the structure shown below: Among them, 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 1-4; Preferably, the compound represented by formula (I) has the structure shown below: Among them, R 1 , R 2 , R 3 , R 4 , R y , X, m, n, r have the definitions described in any one of claims 1 to 4, and W is selected From O, S, CH2, NH, Q1 and Q2 are the same or different and are independently selected from CH or N; T1 is selected from CH or N; T2 and U are the same or different and are independently selected from O, S, N, CH, NH or CH2; V is selected from N or C. When V is selected from N, R 5 Does not exist; R 5 is absent or is selected from hydrogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy or C 3-6 Cycloalkyl; p, p1, p2, p3, p4 are the same or different and are independently selected from 0, 1, 2, 3, 4, 5; represents a single bond or a double bond; Preferably, the compound represented by formula (I) has the structure shown below: Among them, R 1 , R 2 , R 3 , R 4 , X, m, n, r have the definitions given in any one of claims 1 to 4, W 1 Selected from O, S, CH2, NH, CH, N, Q1, Q2 are the same or different and are independently selected from CH or N; V 1 is selected from N, C or CH; V 2 is selected from N, NH, C, CH or CH2; represents a single bond or a double bond; Preferably, the compound represented by formula (I) has the structure shown below: Among them, R 1 , R 2 , R 4 , Y, R y , m, n, r have the definitions given in any one of claims 1 to 4, R z R in any one of claims 1 to 4 y The above definition, preferably, R z is selected from H, halogen, cyano, hydroxyl, unsubstituted or optionally substituted with one, two or more R z1 Substituted with the following groups: amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl; each R z1 are the same or different and are independently selected from hydrogen, hydroxy, cyano, halogen, oxo (=O), amino, C 1-6 Alkyl, C 3-6 More preferably, R z is selected from H, halogen, cyano, methyl, ethyl, propyl, cyclopropyl; W is selected from O, S, CH2, NH, Q1 and Q2 are the same or different and are independently selected from CH or N; V is selected from N or C. When V is selected from N, R 5 Does not exist; V a 、V b are the same or different and are independently selected from CH, CH2, N, NH; R 5 is absent or is selected from hydrogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy or C 3-6 Cycloalkyl; p is selected from 0, 1, 2, 3, 4, 5; represents a single bond or a double bond; Alternatively, the compound represented by formula (I) has the structure shown below: Among them, R 1 , R 2 , R 4 , R 6 , R y , R z , Q1, Q2, m, n, t have the definitions in any one of claims 1 to 4, R z R in any one of claims 1 to 4 y The definition described.

6. The compound according to any one of claims 1 to 5, characterized in that The compound is selected from the following structures: According to some embodiments, the compound of formula (I) is selected from the following structures:

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

8. Use of at least one of the compound according to any one of claims 1 to 6 and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 7 in the preparation of a drug, Preferably, the drug is a FGFR2 and / or FGFR3 inhibitor; Preferably, the medicament is used for diagnosing, preventing and / or treating FGFR-related diseases or disorders.

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

10. The use according to claim 8 or the method according to claim 9, characterized in that The FGFR-related disease or disorder is selected from cancer, chondrodysplasia or hypochondroplasia. Preferably, the cancer is selected from bladder cancer, brain cancer, breast cancer, bile duct cancer, head and neck cancer, lung cancer, multiple myeloma, rhabdomyosarcoma, urethral cancer, and uterine cancer.

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