Pyrazole-fused ring compounds, and methods for their preparation and use

Abstract

The present invention relates to pyrazole-fused ring compounds, their preparation methods, and their uses. In particular, the present invention relates to compounds represented by general formula (I), their preparation methods, pharmaceutical compositions containing the compounds, and their use as FGFR inhibitors in tumor treatment. Each group in general formula (I) is as defined herein. JPEG2026500784000262.jpg32170

Description

[Technical Field]

[0001] The present invention is in the field of pharmaceutical chemistry. In particular, the present invention relates to inhibitors of FGFRs (fibroblast growth factor receptors) and their mutants, methods for their preparation, and the use of said compounds in the treatment of diseases such as cancer. [Background technology]

[0002] Fibroblast growth factor receptors (FGFRs) are a subfamily of tyrosine kinase receptors, including four subtypes: FGFR1, FGFR2, FGFR3, and FGFR4. Each FGFR consists of three distinct domains: an extracellular ligand-binding domain, a single transmembrane channel domain, and an intracellular TK domain. After binding to fibroblast growth factor (FGF) ligands, FGFRs become activated and phosphorylate several downstream signaling proteins, including PI3K-AKT, RAS-MAPK, and STAT. Therefore, FGFRs play crucial roles in many intracellular processes, including development, differentiation, survival, migration, and angiogenesis.

[0003] However, FGFRs are susceptible to various somatic abnormalities and mutations, including common overexpression, point mutations, and gene translocations, which can lead to carcinogenesis. Gene amplification-induced FGFR overexpression, mutations in the FGFR extracellular domain (EC) / kinase domain (TK) of FGFRs, and FGFR fusions can lead to dysregulation of FGFR signaling, thereby promoting tumor cell proliferation, survival, invasion, metastasis, and drug resistance, as well as angiogenesis and immune evasion in the tumor microenvironment (TME). FGFR abnormalities account for approximately 7.1% of all patients with solid tumors. The most common cancers affected by FGFR abnormalities include urothelial carcinoma (32%), liver cancer (30%), cholangiocarcinoma (25%), breast cancer (18%), and gastric cancer (7%).

[0004] FGFR inhibitors achieve the goal of inhibiting tumor growth by blocking FGFR-mediated signaling pathways, thus providing a new option for targeted cancer therapy. Currently, three drugs targeting FGFRs have been approved worldwide: Johnson & Johnson's Balversa (erdafitinib), Incyte's pemigatinib, and BridgeBio / Helsinn's infigratinib. However, in clinical trials, the three approved FGFR inhibitors still cause several treatment-related adverse events, such as hyperphosphatemia, dry mouth, fatigue, skin changes, nail changes, and eye disorders. Furthermore, clinical trials have shown that mutations affecting amino acids in FGFRs can cause resistance or reduce sensitivity to FGFR inhibitors. Therefore, there is a largely unmet clinical need for the development of drugs targeting FGFRs. Summary of the Invention [Means for solving the problem]

[0005] The inventors of the present application have conducted extensive and thorough research to develop novel FGFR inhibitors. The compounds of the present invention have good activity against FGFRs, particularly against FGFR3, and are expected to be developed into a new generation of FGFR inhibitors.

[0006] The present invention relates to a compound of formula (I):

[0007] [ka]

[0008] or a pharmaceutically acceptable salt, hydrate, solvate, isotopic substitution, or stereoisomer thereof, wherein: X 1 is a N atom or CR 5 and; X 2 is a N atom or CR 2 and; X3 is a N atom or CR 3 and; R 1 teeth

[0009] [ka]

[0010] selected from the group consisting of: Y is an O atom, an S atom, -S(O)-, -S(O)2-, or NR 11 selected from the group consisting of: R 2 and R 5 are independently H atoms, -OH, -COOH, and -NR 11 R 12 , -CN, halogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~8 cycloalkyl, and 3- to 8-membered heterocyclyl, wherein C 6~10 Aryl, 5-10 membered heteroaryl, C 3~8 Cycloalkyl and 3- to 8-membered heterocyclyl are each independently C 1~6 Alkoxy, -OH, -COOH, -NR 11 R 12 , -CN, halogen, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, and C 1~6 optionally substituted with one or more substituents selected from the group consisting of hydroxyalkyl; R 3 is H atom, -OH, -COOH, -NR 11 R 12 , -CN, halogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6Alkynyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~8 Cycloalkyl, 3- to 8-membered heterocyclyl, and -OR 13 is selected from the group consisting of However, X is CR 5 and R 1 but

[0011] [ka]

[0012] and C 2 When R is a 6-membered nitrogen-containing heteroaryl ring, 3 is not an H atom; C 1 Ring is C 6~10 Aryl, 5-10 membered heteroaryl, C 3~8 Cycloalkyl, 3- to 8-membered heterocyclyl, 5- to 10-membered heteroaryl fused to 3- to 8-membered heterocyclyl, C 6~10 5- to 10-membered heteroaryl fused with an aryl, 3- to 8-membered heterocyclyl fused with a 5- to 10-membered heteroaryl, and C fused with a 5- to 10-membered heteroaryl 6~10 aryl; Each L 1 are independently chemical bonds, -C 1~6 Alkylene-, -O-, -C 1~6 Alkylene-O-, -OC 1~6 Alkylene-, -C(O)-, -OC(O)-, -C(O)-O-, -S-, -S(O)-, -S(O)2-, -S(O)(=NR 11 )-, -C 1~6 Alkylene-C(O)-, -C(O)-C 1~6 Alkylene-, -C 1~6 Alkylene-S(O)2-, -S(O)2-C 1~6 Alkylene-, -C 1~6 Alkylene-S(O)(=NR11 )-, -S(O)(=NR 11 )-C 1~6 Alkylene, 3-8 membered heterocyclylene, C 3~8 Cycloalkylene, C 6~10 Arylene, 5- to 10-membered heteroarylene, -C 1~6 Alkylene-OC 1~6 Alkylene-O-, -OC 1~6 Alkylene-OC 1~6 Alkylene-, -NR 11 -, -NR 11 -C 1~6 Alkylene-, -C 1~6 Alkylene-NR 11 -, -C 1~6 Alkylene-NR 11 -C 1~6 Alkylene-O-, -OC 1~6 Alkylene-NR 11 -C 1~6 Alkylene-, -NH-C(O)-, -C(O)-NR 11 -, -C(O)-NR 11 -C 1~6 Alkylene-, -C 1~6 Alkylene-C(O)-NR 11 -, -C 1~6 Alkylene-NR 11 -C(O)- and -NR 11 -C(O)-C 1~6 alkylene-, wherein C 1~6 Each alkylene is independently C 1~6 Alkyl, halogen, -OH, -COOH, -NR 11 R 12 , -CN, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~8 optionally substituted with one or more substituents selected from the group consisting of cycloalkyl, and 3- to 8-membered heterocyclyl; Each R 4 are independently H atoms, -OH, -COOH, -CN, halogens, and C1~6 Alkyl, C 1~6 Deuterated alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, -C(O)-NR 11 R 12 , -NR 11 R 12 , C 1~6 Hydroxyalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~8 cycloalkyl, and 3- to 10-membered heterocyclyl, wherein C 6~10 Aryl, 5-10 membered heteroaryl, C 3~8 Cycloalkyl and 3- to 10-membered heterocyclyl are each independently —CN, —OH, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, -C(O)-R 14 , -C(O)-NR 11 R 12 , Oxo, C 1~6 Alkoxy, -S(O)2-C 1~6 Alkyl, -NR 11 R 12 , imino, halogen, -C 1~6 Alkylene-NR 11 R 12 , -NR 11 -C(O)-R 14 , -NR 11 -S(O)2-R 14 , -S(O)(=NR 11 )-R 14 , -S(O)2-R 14 , -C(=NR 11 )-NR 11 R 12 , -S(O)2-NR 11 R 12 , and -C 1~6 Alkylene-C(O)-NR 11 R 12 and optionally substituted with one or more substituents selected from the group consisting of: C 2 Ring is C 6~10Aryl, 5-10 membered heteroaryl, C 3~8 C fused with cycloalkyl, 3- to 8-membered heterocyclyl, or 5- to 10-membered heteroaryl 3~8 Cycloalkyl, C 6~10 5-10 membered heteroaryl fused with aryl, C fused with 3-8 membered heterocyclyl 6~10 Aryl, C 3~8 5-10 membered heteroaryl fused with cycloalkyl, C fused with 5-10 membered heteroaryl 6~10 Aryl, and C 6~10 selected from the group consisting of 3- to 8-membered heterocyclyl fused to an aryl; C 3 Ring is C 6~10 Aryl, 5-10 membered heteroaryl, C 3~8 C fused with cycloalkyl, 3- to 8-membered heterocyclyl, or 5- to 10-membered heteroaryl 3~8 Cycloalkyl, C 6~10 5-10 membered heteroaryl fused with aryl, C 3~8 5-10 membered heteroaryl fused with cycloalkyl, and C fused with 5-10 membered heteroaryl 6~10 aryl; R 6 is H atom, -OH, -COOH, -NR 11 R 12 , -CN, halogen, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, -C 1~6 Alkylene-NR 11 R 12 , C 6~10 Aryl, 5-10 membered heteroaryl, C 3~8 selected from the group consisting of cycloalkyl, and 3- to 8-membered heterocyclyl; R 7 is H atom, -OH, -COOH, -C(O)-R 14 , -C(O)-NR11 R 12 , -NR 11 R 12 , -CN, halogen, oxo, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, C 1~6 Deuterated alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~8 selected from the group consisting of cycloalkyl, and 3- to 8-membered heterocyclyl; L 2 is selected from the group consisting of —C(O)—, —S(O)—, and —S(O)—; L 3 and L 4 are each independently a chemical bond, -C 1~6 Alkylene-, -O-, -C 1~6 Alkylene-O-, -OC 1~6 Alkylene-, -C(O)-, -OC(O)-, -C(O)-O-, -S-, -S(O)-, -S(O)2-, -C 1~6 Alkylene-C(O)-, -C(O)-C 1~6 Alkylene-, -C 1~6 Alkylene-S(O)2-, -S(O)2-C 1~6 Alkylene-, -C 1~6 Alkylene-OC 1~6 Alkylene-O-, -OC 1~6 Alkylene-OC 1~6 Alkylene-, -NR 11 -, -NR 11 -C 1~6 Alkylene-, -C 1~6 Alkylene-NR 11 -, -C 1~6 Alkylene-NR 11 -C 1~6 Alkylene-O-, -OC 1~6 Alkylene-NR 11 -C 1~6 Alkylene-, -NR11 -C(O)-, -C(O)-NR 11 -, -C(O)-NR 11 -C 1~6 Alkylene-, -C 1~6 Alkylene-C(O)-NR 11 -, -C 1~6 Alkylene-NR 11 -C(O)- and -NR 11 -C(O)-C 1~6 alkylene-, wherein C 1~6 Each alkylene is independently C 1~6 Alkyl, halogen, -OH, -COOH, -NR 11 R 12 , -CN, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~8 optionally substituted with one or more substituents selected from the group consisting of cycloalkyl, and 3- to 8-membered heterocyclyl; R 8 and R 10 are independently H atoms, -OH, -COOH, -CN, halogens, and C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~8 cycloalkyl, and 3- to 8-membered heterocyclyl, wherein C 6~10 Aryl, 5-10 membered heteroaryl, C 3~8 Cycloalkyl and 3- to 8-membered heterocyclyl are each independently —CN, —OH, C 1~6 Alkyl, -C(O)-C 1~6 Alkyl, -C(O)-C 1~6 Hydroxyalkyl, -C(O)-NR 11 R12 , Oxo, C 1~6 Alkoxy, -S(O)2-C 1~6 Alkyl, -NR 11 R 12 and halogen; R 9 is H atom, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, and C 1~6 hydroxyalkyl; Each R 11 are independently H atoms, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, and C 3~8 cycloalkyl, wherein C 3~8 Cycloalkyl is C 1~6 Alkyl, C 1~6 Alkoxy, -OH, -COOH, -NH2, -CN, halogen, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, and C 1~6 optionally substituted with one or more substituents selected from the group consisting of hydroxyalkyl; Each R 12 are independently H atoms, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, and C 3~8 cycloalkyl, wherein C 3~8 Cycloalkyl is C 1~6 Alkyl, C 1~6 Alkoxy, -OH, -COOH, -NH2, -CN, halogen, C 1~6 Haloalkyl, C 1~6Haloalkoxy, and C 1~6 optionally substituted with one or more substituents selected from the group consisting of hydroxyalkyl; Or, R 11 and R 12 together with the N atom to which they are attached form a 3- to 8-membered heterocyclyl, where the 3- to 8-membered heterocyclyl is C 1~6 Alkyl, C 1~6 Alkoxy, -OH, -COOH, -NH2, -CN, halogen, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, and C 1~6 optionally substituted with one or more substituents selected from the group consisting of hydroxyalkyl; R 13 is 3-8 membered heterocyclyl, C 3~8 Cycloalkyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, wherein 3- to 8-membered heterocyclyl, C 3~8 Cycloalkyl, C 6~10 The aryl and the 5- to 10-membered heteroaryl are each independently C 1~6 Alkoxy, -OH, -COOH, -NR 11 R 12 , -CN, halogen, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, and C 1~6 optionally substituted with one or more substituents selected from the group consisting of hydroxyalkyl; Each R 14 are independently H atoms, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, and C 3~8 cycloalkyl, wherein C 1~6 Alkyl and C 3~8 Each cycloalkyl is independently —CN, —OH, —COOH, or —NR 11 R 12 , halogens, and C 1~6 optionally substituted with one or more substituents selected from the group consisting of alkoxy; m is 0, 1, or 2; n is 0 or 1; p is 0, 1, or 2).

[0013] In some embodiments, the compound of formula (I) is a compound of formula (II)

[0014] [ka]

[0015] (In the formula, X 1 , X 2 , X 3 , Y.C. 1 , C 2 , R 4 , R 6 , R 7 , L 1 , m, n, and p are as defined in formula (I).

[0016] In some embodiments, the compound of formula (I) is a compound of formula (II-1)

[0017] [ka]

[0018] (In the formula, Y is an O atom, an S atom, -S(O)-, -S(O)2-, NH, and NC 1~6 selected from the group consisting of alkyl; R 3 is H atom, -OH, -COOH, -NR 11 R 12 , -CN, halogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~8Cycloalkyl, 3- to 8-membered heterocyclyl, and -OR 13 selected from the group consisting of: C 1 , C 2 , R 2 ~R 7 , R 11 ~R 13 , L 1 , m, n, and p are as defined in formula (I), However, C 2 is a 6-membered nitrogen-containing heteroaryl ring, preferably pyridyl, pyridazinyl, or pyrimidinyl; 3 is not an H atom; In particular, R 3 is H atom, -N(C 1~6 alkyl)2, -NH2, -NH(C 1~6 Alkyl), -CN, halogen, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, -OC 3~8 Cycloalkyl, -O-3 to 8-membered heterocyclyl, and -OC 6~10 aryl, However, C 2 is a 6-membered nitrogen-containing heteroaryl ring, preferably pyridyl, pyridazinyl, or pyrimidinyl; 3 is not an H atom; More particularly, R 3 is selected from the group consisting of an H atom, an F atom, —CF3, methyl, a Cl atom, methoxy, cyclopropyl, isopropyl, —CN, isopropoxy, furanyl-O—, ethoxy, cyclopropoxy, phenyl-O—, and —N(CH3)2, However, C 2 is a 6-membered nitrogen-containing heteroaryl ring, preferably pyridyl, pyridazinyl, or pyrimidinyl; 3 is not a H atom).

[0019] In some embodiments, the compound of formula (I) is a compound of formula (II-2)

[0020] [ka]

[0021] (In the formula, Y is an O atom, an S atom, -S(O)-, -S(O)2-, NH, and NC 1~6 selected from the group consisting of alkyl; R 3 is H atom, -OH, -COOH, -NR 11 R 12 , -CN, halogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~8 Cycloalkyl, 3- to 8-membered heterocyclyl, and -OR 13 selected from the group consisting of: X 1 , C 1 , C 2 , R 3 , R 4 , R 6 , R 7 , R 11 ~R 13 , L 1 , m, n, and p are as defined in formula (I); In particular, R 3 is H atom, C 1~6 Alkyl, C 1~6 Alkoxy, and C 3~8 cycloalkyl; More particularly, R 3 is selected from the group consisting of an H atom, methyl, methoxy, and cyclopropyl.

[0022] In some embodiments, the compound of formula (I) is a compound of formula (III)

[0023] [ka]

[0024] (In the formula, R 3 is H atom, -OH, -COOH, -NR 11 R 12 , -CN, halogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~8 Cycloalkyl, 3- to 8-membered heterocyclyl, and -OR 13 Preferably, R 3 is a H atom or a halogen; more preferably, R 3 is a H atom or a F atom; C 1 , R 2 , R 4 , R 5 , R 8 , R 9 , R 11 ~R 13 , L 1 , L 2 , L 3 , and m is as defined in formula (I).

[0025] In some embodiments, the compound of formula (I) is a compound of formula (III-1)

[0026] [ka]

[0027] (In the formula, R 3 is H atom, -OH, -COOH, -NR 11 R12 , -CN, halogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~8 Cycloalkyl, 3- to 8-membered heterocyclyl, and -OR 13 Preferably, R 3 is a H atom or a halogen; more preferably, R 3 is a H atom or a F atom; C 1 , R 2 , R 4 , R 5 , R 8 , R 9 , R 11 ~R 13 , L 1 , L 3 , and m is as defined in formula (I).

[0028] In some embodiments, the compound of formula (I) is a compound of formula (III-2)

[0029] [ka]

[0030] (In the formula, R 3 is H atom, -OH, -COOH, -NR 11 R 12 , -CN, halogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~8Cycloalkyl, 3- to 8-membered heterocyclyl, and -OR 13 Preferably, R 3 is a H atom or a halogen; more preferably, R 3 is a H atom or a F atom; C 1 , R 2 , R 4 , R 5 , R 8 , R 9 , R 11 ~R 13 , L 1 , L 3 , and m is as defined in formula (I).

[0031] In some embodiments, the compound of formula (I) is a compound of formula (IV)

[0032] [ka]

[0033] (In the formula, R 3 is H atom, -OH, -COOH, -NR 11 R 12 , -CN, halogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~8 Cycloalkyl, 3- to 8-membered heterocyclyl, and -OR 13 Preferably, R 3 is a H atom or a halogen; more preferably, R 3 is an H atom; C 1 , C 3 , R 2 , R 4 , R 5 , R 10, R 11 ~R 13 , L 1 , L 4 and m are as defined in formula (I), In particular, C 3 is C 6~10 Aryl, 5-10 membered heteroaryl, C 3~8 Cycloalkyl and 3- to 8-membered heterocyclyl; preferably triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, thiazolyl, thienyl, furyl, pyranyl, pyrrolyl, pyrazinyl, pyridazinyl, piperidyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydropyranyl, phenyl, naphthyl, cyclohexyl, cyclopentyl, cyclobutyl, or cyclopropyl; more preferably 1,2,3-triazolyl; even more preferably

[0034] [ka]

[0035] and / or L 4 is a chemical bond, -C 1~6 Alkylene-, -C 1~6 Alkylene-NH-, -C 1~6 Alkylene-N(C 1~6 alkyl)-, -NH-C 1~6 Alkylene- and -N(C 1~6 Alkyl)-C 1~6 alkylene-; preferably selected from the group consisting of a chemical bond, -CH-, -CH-CH-, -CH-CH-NH-, -CH-CH-N(CH)-, -NH-CH-CH-, and -CH-CH-N(CH)-; and / or R 10 is H atom, -OH, -COOH, -CN, halogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6Haloalkoxy, and C 1~6 hydroxyalkyl; preferably selected from the group consisting of H atoms and methyl).

[0036] In some embodiments, C 1 The ring is a 5- to 10-membered heteroaryl, C 3~8 Cycloalkyl, 3- to 8-membered heterocyclyl, 5- to 10-membered heteroaryl fused to 3- to 8-membered heterocyclyl, C 6~10 5- to 10-membered heteroaryl fused with an aryl, 3- to 8-membered heterocyclyl fused with a 5- to 10-membered heteroaryl, and C fused with a 5- to 10-membered heteroaryl 6~10 aryl; Preferably, C 1 the ring is selected from the group consisting of triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, thiazolyl, thienyl, furyl, pyranyl, pyrrolyl, pyrazinyl, pyridazinyl, pyrazolo[1,5-a]pyridyl, tetrahydropyrazolo[1,5-a]pyridyl, tetrahydropyrrolo[1,2-b]pyrazolyl, tetrahydropyrrolo[3,4-d]imidazolyl, benzo[d]imidazolyl, pyrazolo[5,1-b][1,3]oxazinanyl, cyclopropyl, and pyrrolidinyl; More preferably, C 1 Ring

[0037] [ka]

[0038] The present invention provides a compound of formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2), or (IV), selected from the group consisting of:

[0039] In some embodiments, Each L 1 are independent chemical bonds, -C 1~6 Alkylene-, -O-, -C 1~6 Alkylene-O-, -OC 1~6Alkylene-, -S-, -S(O)-, -S(O)2-, -S(O)(=NR 11 )-, -C 1~6 Alkylene-C(O)-, -C(O)-C 1~6 Alkylene-, -C 1~6 Alkylene-S(O)2-, -S(O)2-C 1~6 Alkylene-, 3-8 membered heterocyclylene, -C 1~6 Alkylene-S(O)(=NR 11 )-, -S(O)(=NR 11 )-C 1~6 Alkylene-, C 3~8 Cycloalkylene, C 6~10 Arylene, 5- to 10-membered heteroarylene, -C 1~6 Alkylene-OC 1~6 Alkylene-O-, -OC 1~6 Alkylene-OC 1~6 Alkylene-, -NR 11 -, -C 1~6 Alkylene-NR 11 -, -NR 11 -C 1~6 Alkylene-, -C 1~6 Alkylene-NR 11 -C 1~6 Alkylene-O-, -OC 1~6 Alkylene-NR 11 -C 1~6 Alkylene-, -NR 11 -C(O)-, -C(O)-NR 11 -, -C 1~6 Alkylene-C(O)-NR 11 - and -NR 11 -C(O)-C 1~6 alkylene-, wherein C 1~6 Each alkylene is independently C 1~6 Alkyl, halogen, -OH, -COOH, -NH2, -CN, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, and C 1~6 and each R 11 are independently H atoms or C1~6 is alkyl; Preferably, each L 1 are independent chemical bonds, -C 1~6 Alkylene-, -C 1~6 Alkylene-O-, -OC 1~6 Alkylene-, -S(O)2-, -S(O)(=NR 11 )-, -C 1~6 Alkylene-C(O)-, -C(O)-C 1~6 Alkylene-, -C 1~6 Alkylene-S(O)2-, -S(O)2-C 1~6 Alkylene-, -C 1~6 Alkylene-S(O)(=NR 11 )-, -S(O)(=NR 11 )-C 1~6 Alkylene, 3-8 membered heterocyclylene, C 3~8 Cycloalkylene, C 6~10 Arylene, 5- to 10-membered heteroarylene, -C 1~6 Alkylene-OC 1~6 Alkylene-O-, -OC 1~6 Alkylene-OC 1~6 Alkylene-, -C 1~6 Alkylene-NR 11 -, -NR 11 -C 1~6 Alkylene-, -C 1~6 Alkylene-NR 11 -C 1~6 Alkylene-O-, -OC 1~6 Alkylene-NR 11 -C 1~6 Alkylene-, -C 1~6 Alkylene-C(O)-NR 11 - and -NR 11 -C(O)-C 1~6 alkylene-, wherein C 1~6 Each alkylene is independently C 1~6 and each R 11 are independently H atoms or C 1~6 is alkyl; More preferably, each L 1are independently chemical bonds, -CH2-CH2-, -CH2-, -CH2-CH2-CH2-, -S(O)2-, -S(O)(=NH)-, -S(O)2-CH2-CH2-, -NCH3-CH2-CH2-, -NH-C(O)-CH2-, -NCH3-CH2-CH2-CH2-CH2-, -C(O)-CH2-, -O-CH2-CH2-NCH3-CH2-CH2-, -O-CH2-CH2-O-CH2-CH2-, -C(CH3)2-CH2-, -C(CH3)(OH)-CH2-, -O-CH2-CH2-, -CH(F)-CH2-, -CH(CH3)-CH2-, azetidinyl, -CH2-CH2-S(O)2-, -CH2-CH2-NCH 3-, -CH2-C(O)-NH-, -CH2-CH2-CH2-NCH3-, -CH2-C(O)-, -CH2-CH2-NCH3-CH2-CH2-O-, -CH2-CH2-O-CH2-CH2-O-, -CH2-C(CH3)2-, -CH2-C(CH3)(OH)-, -CH2-CH2-O-, -CH2-CH(F)-, -CH2-CH(CH3)-, -CH2-CH2-CH2-S(O)(=NH)-, and -S(O)(=NH)-CH2-CH2-CH2-.

[0040] In some embodiments, Each R 4 are independently H atoms, -OH, -COOH, -CN, halogens, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, -C(O)-NR 11 R 12 , -NR 11 R 12 , C 6~10 Aryl, 5-10 membered heteroaryl, C 3~8 cycloalkyl, 3- to 8-membered monocyclic heterocyclyl, 7- to 10-membered spiroheterocyclyl, and 7- to 10-membered bridged heterocyclyl, wherein C 6~10Aryl, 5-10 membered heteroaryl, C 3~8 Cycloalkyl and 3- to 8-membered monocyclic heterocyclyl are each independently —CN, —OH, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, -C(O)-R 14 , -C(O)-NR 11 R 12 , Oxo, C 1~6 Alkoxy, -S(O)2-C 1~6 Alkyl, -NR 11 R 12 , imino, halogen, -C 1~6 Alkylene-NR 11 R 12 , -NR 11 -C(O)-R 14 , -NR 11 -S(O)2-R 14 , -S(O)(=NR 11 )-R 14 , -S(O)2-R 14 , -C(=NR 11 )-NR 11 R 12 , -S(O)2-NR 11 R 12 , and -C 1~6 Alkylene-C(O)-NR 11 R 12 and each R 11 are independently H atoms, C 1~6 Alkyl or C 3~8 is cycloalkyl; and each R 12 are independently H atoms, C 1~6 Alkyl or C 3~8 is cycloalkyl; and each R 14 are independently H atoms, C 1~6 Alkyl, and C 3~8 cycloalkyl, wherein C 1~6 Alkyl and C 3~8 Each cycloalkyl is independently —CN, —OH, or —NR 11 R 12 , and C 1~6 optionally substituted with one or more substituents selected from the group consisting of alkoxy; Preferably, each R 4 are independently H atoms, -OH, -COOH, -CN, halogens, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, -C(O)-NR 11 R 12 , -NR 11 R 12 , phenyl, pyridyl, imidazolyl, pyrazolyl, cyclopropyl, oxetanyl, azetidinyl, azolidinyl, morpholinyl, piperidyl, tetrahydropyranyl, piperazinyl, 1,1-dioxo-thiomorpholinyl, 1-oxo-1-imino-thiomorpholinyl, thiomorpholinyl, pyrrolidinyl, diazaspiro[4.5]decanyl, diazabicyclo[2.2.1]heptanyl, and diazabicyclo[3.2.1]octyl, wherein and each independently represents -CN, -OH, -C ... 1~6 Alkyl, C 1~6 Hydroxyalkyl, -C(O)-R 14 , -C(O)-NR 11 R 12 , Oxo, C 1~6 Alkoxy, -S(O)2-C 1~6 Alkyl, -NR 11 R 12 , Imino, -C 1~6 Alkylene-NR 11 R 12 , -NR 11 -C(O)-R 14 , -NR 11 -S(O)2-R 14 , -S(O)(=NR 11 )-R 14 , -S(O)2-R 14 , -C(=NR 11 )-NR 11 R12 , -S(O)2-NR 11 R 12 , and -C 1~6 Alkylene-C(O)-NR 11 R 12 and R 11 is H atom, C 1~6 Alkyl or C 3~6 is cycloalkyl; R 12 is H atom, C 1~6 Alkyl or C 3~6 is cycloalkyl; and each R 14 are independently H atoms, C 1~6 Alkyl, and C 3~6 cycloalkyl, wherein C 1~6 Alkyl and C 3~6 Each cycloalkyl is independently —CN, —OH, or —NR 11 R 12 , and C 1~6 optionally substituted with one or more substituents selected from the group consisting of alkoxy; More preferably, each R 4 are independently H atoms, methyl,

[0041] [ka]

[0042] , propyl,

[0043] [ka]

[0044] , cyclopropyl,

[0045] [ka]

[0046] , -OH, F atom, CN,

[0047] [ka]

[0048] , phenyl,

[0049] [ka]

[0050] , -COOH, -C(O)-NH2, -N(CH3)2,

[0051] [ka]

[0052] The present invention provides a compound of formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2), or (IV), selected from the group consisting of:

[0053] In some embodiments, R 2 is H atom, -OH, -COOH, -NR 11 R 12 , -CN, halogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 6~10 Aryl, C 1~6 Alkoxy-C 6~10 Aryl-, 5-10 membered heteroaryl, C 3~8 selected from the group consisting of cycloalkyl, and 3- to 8-membered heterocyclyl; Preferably, R 2 H atoms, halogens, C 1~6 Alkoxy, C 6~10 Aryl, and C 1~6 Alkoxy-C 6~10aryl- is selected from the group consisting of; More preferably, R 2 is a H atom,

[0054] [ka]

[0055] , methoxy, and a F atom.

[0056] In some embodiments, R 5 H atom, -OH, -COOH, -NH2, -CN, halogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~8 selected from the group consisting of cycloalkyl, and 3- to 8-membered heterocyclyl; Preferably, R 5 H atom, -OH, -COOH, -NH2, -CN, halogen, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, and C 1~6 hydroxyalkyl; More preferably, R 5 is a H atom.

[0057] In some embodiments, C 2C ring fused with 5- to 10-membered heteroaryl, 3- to 8-membered heterocyclyl, or 5- to 10-membered heteroaryl 3~8 Cycloalkyl, C 6~10 5-10 membered heteroaryl fused with aryl, C fused with 3-8 membered heterocyclyl 6~10 Aryl, C 3~8 5-10 membered heteroaryl fused with cycloalkyl, C fused with 5-10 membered heteroaryl 6~10 Aryl, and C 6~10 selected from the group consisting of 3- to 8-membered heterocyclyl fused to an aryl; Preferably, C 2 the ring is selected from the group consisting of triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, thiazolyl, thienyl, furyl, pyranyl, pyrrolyl, pyrazinyl, pyridazinyl, piperidyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydropyranyl, tetrahydroisoquinolyl, tetrahydroquinolyl, imidazo[1,2-a]pyridyl, quinolyl, isoquinolyl, naphthyridinyl, quinoxalinyl, quinazolinyl, triazolopyridyl, benzodioxanyl, benzimidazolyl, cinnolinyl, benzoxazolyl, benzothiazolyl, indolinyl, benzofuryl, thienopyridyl, pyrazolopyridyl, and pyridinopyrazinyl; More preferably, C 2 Ring

[0058] [ka]

[0059] and / or R 6 is H atom, -OH, -COOH, -NR 11 R 12 , -CN, halogen, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, and -C1~6 Alkylene-NR 11 R 12 each R 11 are independently H atoms or C 1~6 alkyl; each R 12 are independently H atoms or C 1~6 is alkyl; Preferably, R 6 C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Hydroxyalkyl, -C 1~6 Alkylene-NH(C 1~6 alkyl), -CN, and C 1~6 haloalkyl; More preferably, R 6 are methyl, ethyl, hydroxymethyl,

[0060] [ka]

[0061] , —CN, trifluoromethyl, and trideuteriomethyl; and / or R 7 are H atoms, -OH, -COOH, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl)2, -CN, halogen, oxo, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, and C 3~8 cycloalkyl; Preferably, R 7 are H atoms, -NH2, -N(C 1~6 Alkyl)2, -CN, halogen, oxo, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Alkoxy, C 1~6Hydroxyalkyl, C 3~6 Cycloalkyl, and C 1~6 haloalkyl; More preferably, R 7 is selected from the group consisting of an H atom, —NH, —N(CH), —CN, a Cl atom, an F atom, a Br atom, oxo, methyl, ethyl, isopropyl, methoxy, cyclopropyl, difluoromethyl, monofluoromethyl, trifluoromethyl, hydroxymethyl, and trideuteriomethyl.

[0062] In some embodiments, L 3 is a chemical bond, -C 1~6 Alkylene-, -O-, -C 1~6 Alkylene-O-, -OC 1~6 Alkylene-, -S-, -S(O)-, -S(O)2-, -C 1~6 Alkylene-C(O)-, -C(O)-C 1~6 Alkylene-, -C 1~6 Alkylene-S(O)2-, -S(O)2-C 1~6 Alkylene-, -C 1~6 Alkylene-OC 1~6 Alkylene-O-, -OC 1~6 Alkylene-OC 1~6 Alkylene-, -NR 11 -, -NR 11 -C 1~6 Alkylene-, -C 1~6 Alkylene-NR 11 -, -C 1~6 Alkylene-NR 11 -C 1~6 Alkylene-O-, -OC 1~6 Alkylene-NR 11 -C 1~6 Alkylene-, -NR 11 -C(O)-, -C(O)-NR 11 -, -C 1~6 Alkylene-C(O)-NR 11 - and -NR 11 -C(O)-C 1~6alkylene-, wherein C 1~6 Each alkylene is independently C 1~6 Alkyl, halogen, -OH, -COOH, -NH2, -CN, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, and C 1~6 and each R 11 are independently H atoms or C 1~6 is alkyl; Preferably, L 3 is a chemical bond, -C 1~6 Alkylene-, -C 1~6 Alkylene-NH-, -C 1~6 Alkylene-N(C 1~6 alkyl)-, -NH-C 1~6 Alkylene- and -N(C 1~6 Alkyl)-C 1~6 alkylene-, wherein C 1~6 Each alkylene independently represents one or more C 1~6 may be substituted with an alkyl group or an -OH group; Preferably, L 3 is selected from the group consisting of a chemical bond, -CH2-CH2-NCH3-, -CH2-CH2-NH-, -CH2-C(CH3)(OH)-, -CH2-C(CH3)2-, -NCH3-CH2-CH2-, -NH-CH2-CH2-, -C(CH3)(OH)-CH2-, and -C(CH3)2-CH2-; and / or R 8 H atom, -OH, -COOH, -CN, halogen, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~8 cycloalkyl, and 3- to 8-membered heterocyclyl, wherein C 6~10 Aryl, 5-10 membered heteroaryl, C3~8 Cycloalkyl and 3- to 8-membered heterocyclyl are each independently —CN, —OH, C 1~6 Alkyl, -C(O)-C 1~6 Alkyl, -C(O)-C 1~6 Hydroxyalkyl, C 1~6 optionally substituted with one or more substituents selected from the group consisting of alkoxy, -NH2, and halogen; Preferably, R 8 is H atom, -OH, C 6~10 aryl, 5- to 10-membered heteroaryl, and 3- to 8-membered heterocyclyl, wherein C 6~10 The aryl and the 5- to 10-membered heteroaryl each independently represent one or more C 1~6 may be substituted with alkyl or halogen groups; More preferably, R 8 H, methyl, -OH,

[0063] [ka]

[0064] and / or R 9 is H atom, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, and C 1~6 hydroxyalkyl; Preferably, R 9 is H atom or C 1~6 is alkyl; More preferably, R 9 is an H atom or methyl.

[0065] Representative compounds of formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2), or (IV) of the present invention include the following compounds:

[0066]

change

[0067]

change

[0068]

change

[0069]

change

[0070]

change

[0071]

change

[0072]

change

[0073]

change

[0074]

change

[0075]

change

[0076]

change

[0077] [ka]

[0078] [ka]

[0079] These include, but are not limited to:

[0080] The present invention also provides a process for preparing a compound of formula (II), comprising:

[0081] [ka]

[0082] A step of obtaining a compound of formula (II) by reacting a compound of formula (IIA) with a compound of formula (IIB). (In the formula, LG 1 is a leaving group, preferably halogen, methylsulfonyloxy, or p-tolylsulfonyloxy; X 1 , X 2 , X 3 , Y.C. 1 , C 2 , R 4 , R 6 , R 7 , L 1 , m, n, and p are as defined in formula (II); Or,

[0083] [ka]

[0084] A step of reacting a compound of formula (IIC) with a compound of formula (IID) to obtain a compound of formula (II). (In the formula, LG 2is a leaving group, preferably halogen, methylsulfonyloxy, or p-tolylsulfonyloxy; W is

[0085] [ka]

[0086] and R is a hydrogen atom or C 1~6 is alkyl; X 1 , X 2 , X 3 , Y.C. 1 , C 2 , R 4 , R 6 , R 7 , L 1 , m, n, and p are as defined in formula (II); Or,

[0087] [ka]

[0088] a step of reacting a compound of formula (IIE) with a compound of formula (IIF) to obtain a compound of formula (IIG), and a step of removing a protecting group R from the compound of formula (IIG). p to obtain the compound of formula (II) (In the formula, R p is tetrahydropyranyl, (trimethylsilyl)ethoxymethyl, p-tosyl, t-butyloxycarbonyl, benzyl, or p-methoxybenzyl; Y is an O atom, and R 6 is -CHOH, n is 1, X 1 , X 2 , X 3 , C 1 , C 2 , R 4 , R 7 , L 1 , m, and p are as defined in formula (II); Or,

[0089] [ka]

[0090] a step of reacting a compound of formula (IIH) with a compound of formula (IIK) to obtain a compound of formula (IIL), and a step of removing a protecting group R from the compound of formula (IIL). p to obtain the compound of formula (II) (In the formula, R p is tetrahydropyranyl, (trimethylsilyl)ethoxymethyl, p-tosyl, t-butyloxycarbonyl, benzyl, or p-methoxybenzyl; LG 1 is a leaving group, preferably halogen, methylsulfonyloxy, or p-tolylsulfonyloxy; X 1 , X 2 , X 3 , Y.C. 1 , C 2 , R 4 , R 6 , R 7 , L 1 , m, n, and p are as defined in formula (II); Or,

[0091] [ka]

[0092] a step of reacting a compound of formula (IIM) with a compound of formula (IID) to obtain a compound of formula (IIN), and a step of removing a protecting group R from the compound of formula (IIN). p to obtain the compound of formula (II) (In the formula, R p is tetrahydropyranyl, (trimethylsilyl)ethoxymethyl, p-tosyl, t-butyloxycarbonyl, benzyl, or p-methoxybenzyl; LG 2 is a leaving group, preferably halogen, methylsulfonyloxy, or p-tolylsulfonyloxy; W is

[0093] [ka]

[0094] and R is a hydrogen atom or C 1~6 is alkyl; X 1 , X 2 , X 3 , Y.C. 1 , C 2 , R 4 , R 6 , R 7 , L 1 , m, n, and p are as defined in formula (II); Or,

[0095] [ka]

[0096] A step of reacting a compound of formula (IIO) with a compound of formula (IIP) to obtain a compound of formula (II). (wherein m is 1 and L 1 -S(O)2-C 1~6 alkyl-, and R 15 is C 1~6 Alkenyl or -C 1~6 alkylene-halogen; X 1 , X 2 , X 3 , Y.C. 1 , C 2 , R 4 , R 6 , R 7 , n, and p are as defined in formula (II).

[0097] The present invention also provides a method for preparing a compound of formula (III-1), comprising:

[0098] [ka]

[0099] A step of obtaining a compound of formula (III-1) by reacting a compound of formula (III-1A) with a compound of formula (IID). (In the formula, LG 3 is a leaving group, preferably halogen, methylsulfonyloxy, or p-tolylsulfonyloxy; W is

[0100] [ka]

[0101] and R is a hydrogen atom or C 1~6 is alkyl; C 1 , R 2 , R 4 , R 5 , R 8 , R 9 , L 1 , L 3 and m is as defined in formula (III-1).

[0102] The present invention also provides a method for preparing a compound of formula (III-2), comprising the steps of:

[0103] [ka]

[0104] A step of obtaining a compound of formula (III-2) by reacting a compound of formula (III-2A) with a compound of formula (III-2B). (In the formula, LG 4 is a halogen atom, preferably a Cl atom; C 1 , R 2 , R 4 , R 5 , R 8 , R 9 , L 1 , L 3and m is as defined in formula (III-2).

[0105] The present invention also provides pharmaceutical compositions comprising a compound of Formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2), or (IV) and one or more pharmaceutically acceptable excipients.

[0106] The present invention relates to the use of a compound of formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2), or (IV), or a pharmaceutical composition comprising same, in the preparation of an FGFR inhibitor.

[0107] The present invention also relates to the use of a compound of formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2), or (IV), or a pharmaceutical composition comprising same, in the preparation of a medicament for treating and / or preventing tumors.

[0108] The present invention also relates to a compound of formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2), or (IV), or a pharmaceutical composition comprising same, for use as a medicament.

[0109] The present invention also relates to a compound of formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2), or (IV), or a pharmaceutical composition comprising same, for use as an FGFR inhibitor.

[0110] The present invention also relates to the use of a compound of formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2), or (IV), or a pharmaceutical composition comprising same, for use in treating and / or preventing tumors.

[0111] The present invention also relates to a method for inhibiting FGFR, comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2), or (IV), or a pharmaceutical composition comprising same.

[0112] The present invention also relates to a method for treating and / or preventing tumors, comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2), or (IV), or a pharmaceutical composition comprising same.

[0113] In some embodiments, the tumor is a cancer; the cancer is preferably selected from the group consisting of cholangiocarcinoma, liver cancer, breast cancer, prostate cancer, lung cancer, thyroid cancer, gastric cancer, ovarian cancer, colorectal cancer, endometrial cancer, urothelial cancer, testicular cancer, cervical cancer, leukemia, skin cancer, squamous cell carcinoma, basal cell carcinoma, bladder cancer, esophageal cancer, head and neck cancer, renal cancer, pancreatic cancer, bone cancer, lymphoma, melanoma, sarcoma, peripheral neuroepithelioma, glioma, ependymoma, neuroblastoma, ganglioneuroma, medulloblastoma, pinealocytoma, meningioma, neurofibroma, Schwannoma, and Wilms' tumor; more preferably selected from the group consisting of cholangiocarcinoma, liver cancer, breast cancer, prostate cancer, lung cancer, thyroid cancer, gastric cancer, ovarian cancer, colorectal cancer, endometrial cancer, and urothelial carcinoma.

[0114] The pharmaceutical compositions of the present invention can be in various conventional dosage forms, such as tablets, aqueous suspensions, oily suspensions, dispersible powders, dispersible granules, emulsions, hard capsules, soft capsules, sterile aqueous solutions for injection, sterile oil-in-water microemulsions for injection, or suppositories. Each of the above dosage forms can be prepared by conventional methods.

[0115] It is well known to those skilled in the art that the dosage of a drug depends on various factors, including, but not limited to, the activity of the specific compound used, the patient's age, the patient's weight, the patient's overall health, the patient's behavior, the patient's diet, the time of administration, the route of administration, the rate of excretion, the combination of drugs, etc. Furthermore, the optimal treatment method, e.g., the treatment mode, the daily dose of the compound, or the type of pharmaceutically acceptable salt thereof, can be ascertained according to traditional therapeutic regimens.

[0116] Definition of Terms Terms not defined herein have the meanings commonly understood by those skilled in the art. Terms defined herein have the meanings defined herein.

[0117] The term "substituted" or "substituent" means that one or more hydrogen atoms have been replaced with the designated group. If no substitution position is specified, substitution can occur at any position, provided that the formation of a stable or chemically feasible chemical compound is possible.

[0118] The term "optional" or "optionally" means that the subsequently described event or circumstance may occur, but does not necessarily occur, and the description includes aspects in which the event or circumstance occurs or aspects in which the event or circumstance does not occur.

[0119] When any variable (e.g., R) occurs more than one time in the structure of a compound, its definition is independent at each occurrence. For example, if a group is substituted with 0 to 2 R, the group may be substituted with up to 2 R, and R has independent options at each occurrence.

[0120] The term "alkyl" refers to a saturated, linear or branched, monovalent hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20) carbon atoms, preferably C 1~10 Alkyl, more preferably C 1~6Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 2,2-dimethylpropyl, 2-methylbutyl, n-hexyl, 2,2-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2- These include, but are not limited to, dimethylpentyl, 3,3-dimethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-3-ethylhexyl, n-decyl, and 3,3-diethylhexyl.

[0121] The term "alkylene" refers to a divalent functional group formed by removing a hydrogen atom from an alkyl, as defined above.

[0122] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon group having 2 to 6 (e.g., 2, 3, 4, 5, and 6) carbon atoms and at least one carbon-carbon double bond, which can be located anywhere within the alkenyl. Alkenyl is preferably C 2~5 Examples of alkenyl include, but are not limited to, -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, -CH=CH-CH2-CH3, -CH2-CH=CH-CH3, -CH=CH-CH=CH2, -CH=C(CH3)-CH3, and -CH2-C(CH3)=CH2.

[0123] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon group having 2 to 6 (e.g., 2, 3, 4, 5, and 6) carbon atoms and at least one carbon-carbon triple bond, which can be located anywhere within the alkynyl. Alkynyl is preferably C2~5 Examples of alkynyl include, but are not limited to, -C≡CH, -C≡C-CH, -CH-C≡CH, -C≡C-CH-CH, -CH-CH-C≡CH, -CH(CH)C≡CH, and -CH-C≡C-CH.

[0124] The term "cycloalkyl" encompasses two classes: regular cycloalkyls and heterostructured cycloalkyls.

[0125] Conventional cycloalkyl refers to an aliphatic saturated or partially unsaturated monovalent cyclic hydrocarbon group having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20) carbon atoms, preferably C 3~12 Conventional cycloalkyl, more preferably C 3~10 Conventional cycloalkyl, more preferably C 3~8 Conventional cycloalkyl, most preferably C 3~6 This means a conventional cycloalkyl, which may contain one or more double or triple bonds.

[0126] A conventional cycloalkyl can be a monocyclic cycloalkyl. Examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl. A conventional cycloalkyl can also be a polycyclic cycloalkyl (e.g., bicycloalkyl and tricycloalkyl). Polycyclic cycloalkyls include spirocycloalkyls, fused cycloalkyls, and bridged cycloalkyls.

[0127] The term "spirocycloalkyl" refers to a 5- to 20-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20-membered) spirocycloalkyl, preferably a 6- to 14-membered spirocycloalkyl, more preferably a 7- to 10-membered spirocycloalkyl. The spirocycloalkyl can be a mono-spirocycloalkyl, a dispirocycloalkyl, or a poly-spirocycloalkyl, preferably a mono-spirocycloalkyl, more preferably a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered mono-spirocycloalkyl. Examples of spirocycloalkyls include:

[0128] [ka]

[0129] These include, but are not limited to:

[0130] The term "fused cycloalkyl" refers to a 5- to 20-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20-membered) fused cycloalkyl, preferably a 6- to 14-membered fused cycloalkyl, more preferably a 7- to 10-membered fused cycloalkyl. The fused cycloalkyl can be a bicyclic, tricyclic, tetracyclic, pentacyclic, or higher fused cycloalkyl, preferably a bicyclic or tricyclic fused cycloalkyl, more preferably a 5-membered / 5-membered or 5-membered / 6-membered fused cycloalkyl. Examples of fused cycloalkyls include:

[0131] [ka]

[0132] These include, but are not limited to:

[0133] The term "bridged cycloalkyl" refers to a 5- to 20-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20-membered) bridged cycloalkyl, preferably a 6- to 14-membered bridged cycloalkyl, more preferably a 7- to 10-membered bridged cycloalkyl. The bridged cycloalkyl can be a bicyclic, tricyclic, tetracyclic, pentacyclic, or higher cyclic bridged cycloalkyl, preferably a bicyclic, tricyclic, or tetracyclic bridged cycloalkyl, more preferably a bicyclic or tricyclic bridged cycloalkyl. Examples of bridged cycloalkyls include:

[0134] [ka]

[0135] These include, but are not limited to:

[0136] The term "heterostructured cycloalkyl" includes monocyclic cycloalkyls, spirocycloalkyls, fused cycloalkyls, and bridged cycloalkyls fused to any one selected from the group consisting of conventional aryls, conventional heteroaryls, and conventional heterocyclyls, where the point of attachment is on the corresponding conventional cycloalkyl (referring to monocyclic cycloalkyls, spirocycloalkyls, fused cycloalkyls, or bridged cycloalkyls). Examples of heterostructured cycloalkyls include:

[0137] [ka]

[0138] These include, but are not limited to:

[0139] The term "cycloalkylene" refers to a divalent functional group formed by removing a hydrogen atom from a cycloalkyl, as defined above.

[0140] The term "heterocyclyl" encompasses two classes, one is conventional heterocyclyl and the other is heterostructured heterocyclyl.

[0141] Conventional heterocyclyl refers to an aliphatic saturated or partially unsaturated monovalent cyclic hydrocarbon group having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20) ring atoms in which one or more ring atoms are replaced by one or more elements selected from the group consisting of N, O, S, S(O), and S(O)2, and in which the replacement does not result in -OO-, -OS-, or -SS-. The conventional heterocyclyl is preferably a 3- to 12-membered conventional heterocyclyl having 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms; more preferably a 3- to 10-membered or 3- to 8-membered conventional heterocyclyl having 1 to 3 (e.g., 1, 2, and 3) heteroatoms; and most preferably a 5- to 7-membered or 4- to 6-membered conventional heterocyclyl having 1 to 2 or 1 to 3 heteroatoms.

[0142] A conventional heterocyclyl may be a monocyclic heterocyclyl. Examples of monocyclic heterocyclyls include, but are not limited to, oxetanyl, 3-pyrrolinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and tetrahydropyranyl, preferably 1,2,5-oxadiazolyl, tetrahydropyranyl, or morpholinyl. A conventional heterocyclyl may also be a polycyclic heterocyclyl. Polycyclic heterocyclyls include spiroheterocyclyl, fused heterocyclyl, and bridged heterocyclyl.

[0143] The term "spiroheterocyclyl" refers to a 5- to 20-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20-membered) spiroheterocyclyl, preferably a 6- to 14-membered spiroheterocyclyl, more preferably a 7- to 10-membered spiroheterocyclyl. The spiroheterocyclyl can be a mono-spiroheterocyclyl, a di-spiroheterocyclyl, or a poly-spiroheterocyclyl, preferably a mono-spiroheterocyclyl or a di-spiroheterocyclyl, more preferably a 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered mono-spiroheterocyclyl. Examples of spiroheterocyclyls include:

[0144] [ka]

[0145] These include, but are not limited to:

[0146] The term "fused heterocyclyl" refers to a 5- to 20-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20-membered) fused heterocyclyl, preferably a 6- to 14-membered fused heterocyclyl, more preferably a 7- to 10-membered fused heterocyclyl. The fused heterocyclyl may be a bicyclic, tricyclic, tetracyclic, pentacyclic, or higher fused heterocyclyl, preferably a bicyclic or tricyclic fused heterocyclyl, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclyl. Examples of fused heterocyclyls include:

[0147] [ka]

[0148] These include, but are not limited to:

[0149] The term "bridged heterocyclyl" refers to a 5- to 14-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14-membered) bridged heterocyclyl, preferably a 6- to 14-membered bridged heterocyclyl, more preferably a 7- to 10-membered bridged heterocyclyl. The bridged heterocyclyl can be a bicyclic, tricyclic, tetracyclic, pentacyclic, or higher bridged heterocyclyl, preferably a bicyclic, tricyclic, or tetracyclic bridged heterocyclyl, more preferably a bicyclic or tricyclic bridged heterocyclyl. Examples of bridged heterocyclyls include:

[0150] [ka]

[0151] These include, but are not limited to:

[0152] The term "heterostructured heterocyclyl" includes monocyclic heterocyclyls, spiroheterocyclyls, fused heterocyclyls, and bridged heterocyclyls fused to any one selected from the group consisting of conventional aryls, conventional heteroaryls, and conventional cycloalkyls, where the point of attachment is on the corresponding conventional heterocyclyl (referring to monocyclic heterocyclyls, spiroheterocyclyls, fused heterocyclyls, or bridged heterocyclyls). Examples of heterostructured heterocyclyls include:

[0153] [ka]

[0154] These include, but are not limited to:

[0155] The term "heterocycloalkylene" refers to a divalent functional group formed by removing a hydrogen atom from a heterocycloalkyl, as defined above.

[0156] The term "aryl" encompasses two classes, the conventional aryl and the heterostructured aryl.

[0157] Conventional aryl refers to a 6- to 14-membered (e.g., 6, 7, 8, 9, 10, 11, 12, 13, and 14-membered) aromatic hydrocarbon group, preferably C 6~10 It usually means aryl, more preferably phenyl, naphthyl, phenanthryl or anthracenyl.

[0158] The term "heterostructured aryl" includes a conventional aryl fused to one selected from the group consisting of a conventional heteroaryl, a conventional heterocyclyl, and a conventional cycloalkyl, where the point of attachment is on the conventional aryl. Examples of heterostructured aryls include:

[0159] [ka]

[0160] These include, but are not limited to:

[0161] The term "arylene" refers to a divalent functional group formed by removing one hydrogen atom from an aryl, as defined above.

[0162] The term "heteroaryl" encompasses two classes: conventional heteroaryl and heterostructured heteroaryl.

[0163] Conventional heteroaryl refers to a 5- to 14-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14-membered) aromatic hydrocarbon group in which 1 to 4 (e.g., 1, 2, 3, and 4) carbon atoms are replaced by heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen. Preferably, the number of ring atoms is 5 to 10, including 1 to 3 (e.g., 1, 2, and 3) heteroatoms. More preferably, the number of ring atoms is 5 or 6, including 1 to 2 heteroatoms. Examples of conventional heteroaryls include, but are not limited to, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, pyridazinyl, pyrazinyl, quinolyl, isoquinolyl, naphthyridinyl, and imidazopyridyl, preferably imidazolyl, thiazolyl, pyrazolyl, pyrimidinyl, or thiazolyl, more preferably pyrazolyl or thiazolyl.

[0164] The term "heterostructured heteroaryl" includes a conventional heteroaryl fused to any one selected from the group consisting of a conventional aryl, a conventional cycloalkyl, and a conventional heterocyclyl, where the point of attachment is on the conventional heteroaryl. Examples of heterostructured heteroaryls include:

[0165] [ka]

[0166] These include, but are not limited to:

[0167] The term "heteroarylene" refers to a divalent functional group formed by removing a hydrogen atom from a heteroaryl, as defined above.

[0168] The term "alkoxy" includes -O-alkyl and -O-cycloalkyl, where "alkyl" and "cycloalkyl" are defined above. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.

[0169] The term "haloalkyl" means alkyl substituted with one or more halogens, where alkyl is as defined above.

[0170] The term "haloalkoxy" means an alkoxy substituted with one or more halogens, where alkoxy is as defined above.

[0171] The term "hydroxy" refers to the group --OH.

[0172] The term "halogen" means a -F, -Cl, -Br, or -I group.

[0173] The term "amino" refers to the group --NH.sub.2.

[0174] The term "cyano" refers to the radical --CN.

[0175] The term "nitro" refers to the group --NO.sub.2.

[0176] The term "oxo" refers to the group =O.

[0177] The term "carboxy" refers to the group --C(.dbd.O)OH.

[0178] The term "thiol" refers to a -SH group.

[0179] The term "alkoxycarbonyl" means a -C(=O)O-alkyl group or a -C(=O)O-cycloalkyl group in which alkyl and cycloalkyl are as previously defined.

[0180] The term "acyl" refers to a -C(=O)R group, where R is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0181] symbol

[0182] [ka]

[0183] means the point of attachment.

[0184] The term "stereoisomer" refers to isomers that have identical structure but differ in the arrangement of atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers, and mixtures thereof (e.g., racemates and diastereomeric mixtures). Substituents in the compounds of the present invention may contain additional asymmetric atoms. All these stereoisomers and mixtures thereof are included within the scope of the present invention. Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers, and (D)- and (L)-isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. Isomers of the compounds of the present invention can be prepared by asymmetric synthesis or chiral auxiliaries, or, if the molecule contains a basic (e.g., amino) or acidic (e.g., carboxyl) functional group, it can be made into a diastereomeric salt with an appropriate optically active acid or base, and the diastereoisomers can then be separated by conventional methods known in the art to give the pure isomers. Furthermore, resolution of enantiomers and diastereomers is usually achieved by chromatography.

[0185] In the chemical structure of the compound of the present invention,

[0186] [ka]

[0187] represents an unspecified configuration, i.e., if chiral isomers exist in the chemical structure, the bond

[0188] [ka]

[0189] teeth

[0190] [ka]

[0191] or

[0192] [ka]

[0193] For all carbon-carbon double bonds, both the Z and E configurations are included, even if only one configuration is listed.

[0194] Additionally, the compounds and intermediates of the present invention may exist in different tautomeric forms, and all of these forms are included within the scope of the present invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol, imine-enamine, and lactam-lactim isomerizations.

[0195] The compounds of the present invention include all suitable isotopic substitutions of the compounds. The term "isotopic substitution" refers to a compound in which at least one atom is replaced with an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be incorporated into the compounds of the present invention include stable radioisotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, iodine, etc., such as fluorine, chlorine, bromine, iodine, etc. 2 H (deuterium, D), 3 H (tritium, T), 11 C. 13 C. 14 C. 15 N, 17 O. 18 O. 32 p, 33 p, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I, 131 I, etc., preferably deuterium.

[0196] As used herein, the singular forms "a," "an," and "the" include plural referents and vice versa unless the context clearly dictates otherwise.

[0197] The term "about," when applied to parameters such as pH, concentration, temperature, etc., indicates that the parameter may vary within a range of ±10%, and in some cases more preferably ±5%. As one of ordinary skill in the art will appreciate, generally, a number is provided for illustrative purposes only and is not limiting. DETAILED DESCRIPTION OF THE INVENTION

[0198] The present invention will now be further described in connection with the following examples, which are not intended to limit the scope of the disclosure.

[0199] The compounds of the present invention are prepared using convenient starting materials and conventional preparation procedures. The present invention shows typical or preferred reaction conditions, such as reaction temperature, time, solvent, pressure, and molar ratio of reactants. However, unless otherwise specified, other reaction conditions may be used. Although optimal conditions may vary depending on the use of specific reactants or solvents, under normal circumstances, the optimized steps and conditions for the reaction can be determined.

[0200] Furthermore, several protecting groups can be used in the present invention to protect specific functional groups from unwanted reactions. Suitable protecting groups for various functional groups and their protection or deprotection conditions are already well known to those skilled in the art.

[0201] Isolation and purification of compounds and intermediates are carried out by suitable methods and processes according to specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin-layer chromatography, preparative high-performance liquid chromatography, or a combination of the above methods. The specific methods used may be mentioned in the examples described in the present invention. Of course, other similar isolation and purification methods may also be used. They may be characterized using conventional methods (including physical constants and spectral data).

[0202] The purity analysis method is as follows: a Kinetex EVO C18 (50 × 4.6 mm, 5 μm, 100 Å) chromatography column is used, acetonitrile-water is used as the mobile phase for gradient elution, the flow rate is 1.5 mL / min, and the detection wavelength is 220 nm.

[0203] MS is determined on a LC (Agilent 1260 Infinity II) / MS (G6125B single quadrupole) mass spectrometer (manufacturer: Agilent) (photodiode array detector).

[0204] The structure of the compound is identified by hydrogen nuclear magnetic resonance, and the instrument model is WNMR-I-400MHz.

[0205] Preparative liquid chromatography is performed using an Agilent 1260 Infinity II high performance liquid chromatograph (manufacturer: Agilent). The chromatography column is Daisogel C18 10 μm 100A (30 mm × 250 mm), and the mobile phase is acetonitrile / water.

[0206] Qingdao Haiyang Chemical Company's GF254 silica gel plates were used for thin-layer chromatography (TLC). The silica gel plate specifications were 0.20 mm to 0.25 mm for reaction monitoring and 0.5 mm for separation and purification.

[0207] Silica gel of 100-200 mesh, 200-300 mesh, and 300-400 mesh from Qingdao Haiyang Chemical Company is used as the carrier for silica gel column chromatography.

[0208] The known starting materials of the present invention may be prepared by methods known in the art or may be purchased from Wanghua Mall Co., Ltd., Beijing Ouhe Technology Co., Ltd., Sigma Co., Ltd., J&K Scientific Co., Ltd., Yishiming Co., Ltd., Shanghai Shuya Chemical Co., Ltd., Shanghai Innochem Science & Technology Co., Ltd., Energy Chemical Co., Ltd., Shanghai Bide Pharmatech Co., Ltd., etc.

[0209] Unless otherwise specified in the examples, all reactions are carried out under a nitrogen atmosphere.

[0210] Nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon with a volume of approximately 1 L.

[0211] The reaction solvent, organic solvent, or inert solvent is a solvent that does not participate in the reaction under the reaction conditions described, and examples thereof include benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, dichloromethane, ether, methanol, and N-methylpyrrolidone (NMP).

[0212] Unless otherwise specified in the examples, the solution means an aqueous solution.

[0213] Generally, the chemical reactions described in this invention are carried out under normal pressure. The reaction time and reaction conditions are, for example, -78°C to 200°C at 1 atmosphere, and the reaction is completed within about 1 to 24 hours. If the reaction is carried out overnight, the reaction time is generally 16 hours. Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20°C to 30°C.

[0214] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as understood by one of ordinary skill in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention.

[0215] Unless otherwise stated, the mixing ratios of different solvents are by volume.

[0216] Unless otherwise specified, the aqueous KF solutions in the examples are saturated solutions.

[0217] Synthesis of Key Intermediate A1

[0218] [ka]

[0219] Compound A1-1 (10 g, 52.1 mmol) was dissolved in 100 mL of dichloromethane, and TEA (8.0 mL, 57.3 mmol) was added. After cooling to 0 °C, MsCl (6.23 g, 53.7 mmol) was slowly added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 5 h. LCMS monitoring showed no remaining starting material, so the reaction mixture was washed once with aqueous ammonium chloride and then once with water. The organic phase was dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give white solid A1 (13.5 g, 95% yield, 98% purity).

[0220] Synthesis of Key Intermediate A2

[0221] [ka]

[0222] Compound A2-1 (5.0 g, 23.25 mmol, 1.0 equiv.) was dissolved in dioxane (80 mL), and KOAc (4.6 g, 46.51 mmol, 2.0 equiv.), bis(pinacolato)diboron (12 g, 46.51 mmol, 2.0 equiv.), and Pd(dppf)Cl (1.9 g, 2.3 mmol, 0.1 equiv.) were added. The mixture was reacted at 85 °C for 12 h under N protection. LCMS analysis showed the formation of the product. The reaction mixture was concentrated, mixed with silica gel, and purified by silica gel column chromatography (eluent: CHOH / CHCl = 0-5%) to obtain 6.5 g of crude compound A2-2 as a white oil, which was used directly in the next reaction step.

[0223] Compound A2-2 (6.5 g, 24.80 mmol, 1.0 equiv.) was dissolved in THF (70 mL), and DHP (4.2 g, 49.60 mmol, 2.0 equiv.) and TsOH (2.1 g, 12.40 mmol, 0.5 equiv.) were added. The mixture was then reacted at 60 °C for 4 h. LCMS showed the formation of the product. The reaction mixture was concentrated, mixed with silica gel, and purified by silica gel column chromatography (eluent: CHOH / CHCl = 0-3%) to obtain 6.4 g of crude compound A2-3 as a white oil, which was used directly in the next reaction step.

[0224] Compound A2-3 (6.4 g, 18.49 mmol, 1.0 equiv.) was dissolved in THF / HO (80 mL). NaOH (1.1 g, 27.74 mmol, 1.0 equiv.) and HO (6 mL) were added to the solution in an ice bath and the mixture was stirred at room temperature for 3 hours. LCMS showed the formation of the product. The reaction mixture was concentrated, dissolved in DCM, mixed with silica gel, and subjected to rotary evaporation and normal phase column chromatography to obtain 4.9 g of crude compound A2-4 as a white oil, which was used directly in the next reaction step.

[0225] Compound A2-4 (4.9 g, 20.74 mmol, 1.0 equiv.) and compound A1 (8.6 g, 32 mmol, 1.5 equiv.) were dissolved in ACN (50 mL), and Cs2CO3 (20 g, 62.22 mmol, 3.0 equiv.) was added. The mixture was stirred at 80 °C for 4 h. LCMS showed the formation of the product. After adding 50 mL of ice water to the reaction mixture, a total of 200 mL of EA was added in three portions, and the reaction mixture was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, rotary evaporated, mixed with silica gel, and purified by silica gel column chromatography (eluent: CH3OH / CHCl2 = 0-4%) to obtain 4.3 g of crude compound A2-5 as a white solid, which was used directly in the next reaction step.

[0226] Compound A2-5 (4.3 g, 10.48 mmol, 1.0 equiv) was dissolved in MeOH (20 mL), and HCl / EA (30 mL) was added to it in an ice bath and stirred at room temperature for 2 hours. LCMS showed the formation of the product. The reaction mixture was neutralized with saturated NaHCO3 solution and then extracted with DCM. The organic phase was subjected to rotary evaporation to give crude compound A2-6 (3.8 g) as a white solid, which was used directly in the next reaction step.

[0227] Compound A2-6 (3.8 g, 11.65 mmol, 1.0 equiv) was dissolved in DMF (50 mL). NIS (5.2 g, 23.30 mmol, 2.0 equiv) was added to the solution in an ice bath and stirred at room temperature for 12 h. LCMS showed the formation of the product. 50 mL of water was added to the reaction mixture, and the reaction mixture was extracted three times with 150 mL of EA in three portions. The organic phase was washed twice with a total of 100 mL of saturated NaCl solution in two portions. The organic phase was dried and concentrated, then mixed with silica gel, and purified by silica gel column chromatography (eluent: CHOH / CHCl = 0-3%) to give 4.5 g of compound A2 as a white solid (total yield for 6 steps: 42.7%).

[0228] Synthesis of key intermediate A3

[0229] [ka]

[0230] Compound A3-1 (15.0 g, 97.9 mmol, 1.0 equiv.), DHP (16.5 g, 196 mmol, 2.0 equiv.), and TsOH.HO (1.9 g, 9.8 mmol, 0.1 equiv.) were dissolved in THF (10 mL) and stirred at 60 °C for 8 h. LCMS showed the formation of the product. 100 mL of water was added to the reaction mixture, followed by EA (100 mL × 3) to extract and wash the reaction mixture. The organic phases were combined, dried over anhydrous sodium sulfate, and purified on a silica gel column to give 21.0 g of compound A3-2 as a white solid in a 90.1% yield.

[0231] Compound A3-2 (11 g, 46.4 mmol, 1.0 equiv.) was added to a 500 mL single-neck flask, followed by KOH (5.2 g, 927 mmol, 2.0 equiv.), HO (10 mL), DMF (100 mL), and Pd(dba) (1.0 g, 4.64 mmol, 0.1 equiv.). The mixture was purged with N and stirred at 80 °C for 14 h. LCMS showed the formation of the product. The reaction mixture was cooled, subjected to rotary evaporation, mixed with silica gel, and purified on a silica gel column (PE / EA = 1:1) to give 4.6 g of compound A3-3 as a white solid in 45.2% yield.

[0232] Compound A3-3 (4.6 g, 21 mmol, 1.0 equiv.), compound A2 (8.6 g, 32 mmol, 1.5 equiv.), and CsCO (20.3 g, 63 mmol, 3.0 equiv.) were dissolved in ACN (50 mL) and stirred at 80 °C for 8 h. LCMS showed the formation of the product. Water (30 mL) was added to the reaction mixture, followed by EA (30 mL × 3) to extract and wash the reaction mixture. The organic phases were combined, dried over anhydrous sodium sulfate, and purified on a silica gel column to give compound A3-4 (4.3 g) as a white solid in a 52.4% yield.

[0233] Compound A3-4 (4.3 g, 11 mmol, 1.0 equiv.) was added to a 25 mL single-neck flask, and 4 M HCl / EA (50 mL) was added and stirred at room temperature for 3 hours. LCMS showed the formation of the product. The reaction mixture was subjected to rotary evaporation and passed through a reverse-phase column to obtain 4.2 g of crude compound A3-5 as a white solid, which was used directly in the next reaction step.

[0234] Compound A3-5 (4.2 g, 13.6 mmol, 1.0 equiv.) and NIS (3.6 g, 20.5 mmol, 1.5 equiv.) were dissolved in DMF (40 mL) and stirred at 25 °C for 8 h. LCMS showed the formation of the product. Water (50 mL) was added to the reaction mixture, followed by EA (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, subjected to rotary evaporation, mixed with silica gel, and purified by silica gel column chromatography (eluent: CHOH / CHCl = 0-5%) to give 3.0 g of A3 as a white solid in 50.8% yield.

[0235] Synthesis of key intermediate A4

[0236] [ka]

[0237] Compound A4-1 (20 g, 149 mmol, 1.0 equiv.) and imidazole (20.3 g, 298 mmol, 2 equiv.) were dissolved in MeCN (400 mL), and TBSCl (44.9 g, 298.2 mmol, 2 equiv.) was added at 0 °C. The reaction mixture was stirred at 20 °C for 12 h. LCMS showed the completion of the reaction of compound A4-1. 200 mL of saturated NaHCO3 solution was added, and the reaction mixture was extracted with EA and washed with saturated brine. The organic phase was concentrated to give a liquid as a yellow oil. The crude product was purified on a 220 g silica gel column (0-5% EA) to give product A4-2 (35 g, yield: 94%). LCMS (ESI) m / z 249.1, (M+H) + .

[0238] To a solution of compound A4-2 (35 g, 140.9 mmol, 1.0 equiv.) in DMF (300 mL), NIS (29.25 g, 169.08 mol, 1.2 equiv.) was added at 0° C. and stirred at room temperature for 2 hours. LCMS analysis indicated the completion of the reaction of compound A-2 and the formation of the product. Ice water was added to the reaction mixture, and the reaction mixture was triturated with petroleum ether, filtered, and dried to give compound A4-3 as a yellow solid (50 g, 94.8% yield). LCMS (ESI) m / z 374.1, (M+H) + .

[0239] Compound A4-3 (50 g, 133.58 mmol, 1.0 equiv.) and TsOH (2.3 g, 13.4 mmol, 2.0 equiv.) were dissolved in DCM (300 mL), and DHP (22.47 g, 267.2 mmol, 2 equiv.) was added dropwise at 0 °C. The reaction was carried out at 25 °C for 4 h. LCMS showed the completion of the reaction of compound A4-3 and the formation of product A4-4. Aqueous NaHCO3 solution was added to the reaction mixture, and the reaction mixture was extracted with DCM. The organic phase was separated and dried by rotary evaporation to give liquid compound A4-4 as a yellow oil (30 mg, 45.5% yield, 70% purity), which was used directly in the next reaction step. LCMS (ESI) m / z 459.1, (M+H) + .

[0240] Compound A4-4 (40 g, 61.08 mmol, 1.0 equiv.), compound 1-4 (25.4 g, 122 mmol, 2 equiv.), and K2CO3 (25.3 g, 183 mmol, 3 equiv.) were dissolved in dioxane (400 mL), Pd(dppf)Cl2 (4.5 g, 6.11 mmol, 0.1 equiv.) was added, the mixture was purged with N2 three times, and the reaction was carried out at 90 °C for 6 h. LCMS analysis showed the completion of the reaction of compound A4-4 and the formation of the product. After filtration, the reaction mixture was added with silica gel powder, subjected to rotary evaporation, and purified on a 330 g silica gel column to obtain liquid compound A4-5 as a brown oil (22 g, 61% yield, 70% purity). LCMS (ESI) m / z 468.23, (M+H) + .

[0241] Compound A4-5 (15 g, 25.4 mmol, 1.0 equiv.) was dissolved in MeOH (200 mL), K2CO3 (7 g, 50.9 mmol, 2 equiv.) was added, and the mixture was allowed to react at 60 °C for 2 hours. LCMS analysis showed the completion of the reaction and the formation of compound A-6. 1M HCl was added to the reaction mixture, and the mixture was extracted with EtOAc, separated, and dried by rotary evaporation to obtain the crude product, which was purified on a 220 g silica gel column to give compound A4 as an off-white solid (7 g, 92% yield). LCMS (ESI) m / z 299.2 (M+H) + .

[0242] Synthesis of Key Intermediates A5 and A6

[0243] [ka]

[0244] Compound A5-1 (1.2 g, 4.928 mmol) was dissolved in dioxane (12 mL) at room temperature, and tri-n-butyl(1-ethoxyvinyl)tin (2.1 g, 5.91 mmol) was added. Pd(PPh3)4 (569 mg, 0.49 mmol) was then added under nitrogen protection. The reaction mixture was stirred at 110 °C for 48 h. LCMS showed no remaining starting material. After cooling to room temperature, the reaction mixture was quenched with 100 mL of aqueous KF solution and stirred for 1 h to give a solid, which was filtered through diatomaceous earth. The filtrate was extracted with ethyl acetate (100 mL × 3), and the combined organic phases were subjected to rotary evaporation. The crude product was redissolved in ethyl acetate (30 mL), and 10 mL of a 4 M solution of hydrochloric acid in ethyl acetate was added. The mixture was stirred at room temperature for 2 h. LCMS showed product A5-2. The reaction mixture was adjusted to neutral pH with aqueous Na2CO3 and extracted with ethyl acetate. The organic phases were then combined and subjected to rotary evaporation. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to obtain product A5-2 as a brown solid (310 mg, purity 95%). LCMS (ESI) m / z 207.02, (M+H)+.

[0245] Compound A5-2 (310 mg, 1.5 mmol) was dissolved in MeOH (5 mL) at room temperature, and NaBH (23 mg, 0.6 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 5 minutes. LCMS showed the reaction of the raw material was complete. The reaction mixture was quenched with saturated aqueous NH Cl and extracted with DCM (20 mL × 3). The organic phases were combined and then subjected to rotary evaporation. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 4:1) to give product A5-3 as a brown oil (259 mg, purity 90%). LCMS (ESI) m / z 208.04, (M+H)+.

[0246] Compound A5-3 (250 mg, 1.2 mmol) was dissolved in DCM (3 mL) at room temperature, and SOCl (1 mL) was added at 0 °C. The reaction mixture was stirred at room temperature for 2 h. LCMS showed the reaction of the starting material was complete. The reaction mixture was directly subjected to rotary evaporation to give crude product A5-4 (263 mg).

[0247] Compound A5-4 (263 mg, 1.16 mmol) and compound A5-5 (400 mg, 1.16 mmol) were dissolved in DMF (4 mL) at room temperature, and Cs2CO3 (1.13 g, 3.48 mmol) was added. The reaction mixture was stirred at 50 °C overnight. LCMS showed the reaction of the raw material was complete. The reaction mixture was diluted with water and extracted with ethyl acetate (30 mL × 3). The organic phases were combined and then subjected to rotary evaporation. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 3:1) to obtain product A5 as a yellow oil (533 mg, purity 78%). LCMS (ESI) m / z 535.03, (M+H)+.

[0248] Compound A5 (533 mg, 0.777 mmol) and compound A6-1 were dissolved in dioxane / HO (6 mL, v / v = 5 / 1) at room temperature, and KCO (320 mg, 2.33 mmol) was added. Pd(dppf)Cl.DCM (126 mg, 0.155 mmol) was added under nitrogen protection. The reaction mixture was stirred at 80 °C for 12 h. LCMS showed the reaction of the raw material was complete. The reaction mixture was diluted with water and extracted with ethyl acetate (30 mL × 3). The organic phases were combined and subjected to rotary evaporation. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1) to give product A6-2 as a brown oil (420 mg, purity 80%). LCMS (ESI) m / z 630.25, (M+H)+.

[0249] Compound A6-2 (420 mg, 0.474 mmol) was dissolved in MeOH (5 mL) at room temperature, and HCl (4 mL, 4 M dioxane solution) was added to it in an ice bath. The reaction was stirred at room temperature for 3 hours. LCMS showed the reaction of the raw material was complete. The reaction was directly subjected to rotary evaporation to give product A6 as a brown oil (244 mg, 70% purity, hydrochloride salt). LCMS (ESI) m / z 446.14, (M+H)+.

[0250] Synthesis of key intermediate A7

[0251] [ka]

[0252] Compound A5 (35 mg, 0.06 mmol, 1.0 equiv.) and compound A7-1 (19 mg, 0.09 mmol, 1.5 equiv.) were dissolved in dioxane (2 mL) and HO (2 mL). CsCO (64 mg, 0.19 mmol, 3 equiv.) and Pd(dppf)Cl (9.5 mg, 0.013 mmol, 0.2 equiv.) were added, purged with N three times, and stirred at 90 °C for 6 h. LCMS showed the completion of the reaction of compound A5. The reaction solution was filtered and subjected to rotary evaporation. The crude product was purified on a TLC plate (PE:EA = 1:9) to give compound A7 (28 mg, 90% yield). LCMS (ESI) m / z 475.2, (M+H)+.

[0253] Synthesis of Key Intermediates A8 and A9

[0254] [ka]

[0255] To a solution of compound A8-1 (5.0 g, 31.61 mmol, 1.0 equiv.) in tetrahydrofuran (5 mL), methylmagnesium bromide (4.9 g, 41.10 mmol, 1.3 equiv.) was added at 0 °C, purged with N2 three times, and stirred at room temperature for 1 h. LCMS showed the formation of the product. The reaction mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 4:1) to give a yellowish solid A8-2 (4.7 g, 85% yield). LCMS (ESI) m / z 175.09, (M+H)+.

[0256] To a solution of compound A8-2 (4.7 g, 26.98 mmol, 1.0 equiv.) in dichloromethane (40 mL), thionyl chloride (6.4 mg, 53.96 mmol, 2.0 equiv.) was added at 0 °C and stirred at room temperature for 1 hour. LCMS showed the formation of the product. The reaction mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to give brownish oil A8-3 (5.0 g, 96% yield). LCMS (ESI) m / z 193.05, (M+H)+.

[0257] Compound A8-3 (5.0 g, 26.44 mmol, 1.3 equiv.), compound A5-5 (7.0 g, 20.34 mmol, 1.0 equiv.), and cesium carbonate (39.77 g, 122.04 mmol, 6 equiv.) were dissolved in N,N-dimethylformamide (50 mL) and stirred at 45 °C for 6 h. LCMS showed the formation of the product. The reaction mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1) to give yellowish solid A8 (7.4 g, 73% yield). LCMS (ESI) m / z 501.34, (M+H)+.

[0258] Compound A8 (2 g, 3.997 mmol), compound A7-1 (7.75 g, 39.97 mmol), and Na2CO3 (1.69 g, 15.989 mmol) were dissolved in THF / HO (20 mL, v / v = 3 / 1) at room temperature. Pd(PPh3)4 (462 mg, 0.399 mmol) was added under nitrogen protection and purged with nitrogen three times. The reaction mixture was stirred at 85 °C for 72 h. LCMS showed the reaction was complete. The reaction mixture was diluted with water and extracted with ethyl acetate (200 mL × 3). The organic phases were combined and then subjected to rotary evaporation. The crude product was purified by silica gel column chromatography (eluent: dichloromethane:methanol = 20:1) to give product A9 as a yellow solid (1.59 g, purity 90%, yield 81.26%). LCMS (ESI) m / z 440.8, (M+H)+. [Example]

[0259] Example 1 (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(1-methyl-1H-pyrazol-4-yl)-7-(trifluoromethyl)-1H-indazole

[0260] [ka]

[0261] Compound 1-1 (250 mg, 0.94 mmol, 1.0 equiv.), KOH (307 mg, 5.5 mmol, 5.8 equiv.), and iodine (479 mg, 1.89 mmol, 2.0 equiv.) were added sequentially to dioxane (12.0 mL) at room temperature. The reaction mixture was stirred at 75 °C for 16 hours. After the reaction mixture was cooled to room temperature, aqueous sodium thiosulfate solution (50.0 mL) was added and the mixture was extracted with ethyl acetate (20.0 mL × 2). The organic phases were combined, washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 1-2 (425 mg, 100% yield).

[0262] A solution of compound 1-2 (318 mg, 0.813 mmol, 1.0 equiv) in THF (3.0 mL) was slowly added to a suspension of sodium hydride (59 mg, 1.46 mmol, 1.8 equiv) in THF (5.0 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 0.5 min. After that, it was cooled to 0 °C, and SEMCl (0.19 mL, 1.06 mmol, 1.3 equiv) was slowly added thereto. The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was cooled to 0 °C, poured slowly into aqueous NH4Cl (30.0 mL), and extracted with EA (20.0 mL × 2). The organic phases were combined, washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether=0-10%) to give compound 1-3 (404 mg, yield 95.3%).

[0263] Compound 1-3 (404 mg, 0.775 mmol, 1.0 equiv.), compound 1-4 (170 mg, 0.817 mmol, 1.05 equiv.), Pd(dppf)Cl2 (64 mg, 0.078 mmol, 0.1 equiv.), and potassium carbonate (320 mg, 2.32 mmol, 3.0 equiv.) were added sequentially to dioxane / HO (8 mL / 2 mL) at room temperature. The reaction mixture was stirred at 80 °C for 10 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-22%) to give compound 1-5 (245 mg, 66.6% yield).

[0264] Compound 1-5 (245 mg, 0.515 mmol, 1.0 equiv.), Pd2(dba)3 (141.6 mg, 0.155 mmol, 0.3 equiv.), t-BuXphos (131 mg, 0.31 mmol, 0.6 equiv.), and KOH (116 mg, 2.06 mmol, 4.0 equiv.) were added sequentially to a dioxane / HO (5 mL / 1 mL) solution at room temperature. The reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: (dichloromethane:methanol = 4:1) / dichloromethane = 0-20%) to give compound 1-6 (188 mg, 86.8% yield).

[0265] Compound 1-6 (188 mg, 0.45 mmol, 1.0 equiv.), compound A1 (130 mg, 0.48 mmol, 1.1 equiv.), and cesium carbonate (450 mg, 1.38 mmol, 3.0 equiv.) were added sequentially to acetonitrile (5.0 mL) at room temperature. The reaction mixture was stirred at 80 °C for 6 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: (dichloromethane:methanol = 4:1) / dichloromethane = 0-13%) to give compound 1-7 (200 mg, 74.9% yield).

[0266] To a solution of compound 1-7 (200 mg, 0.34 mmol, 1.0 equiv) in DCM (6.0 mL) was slowly added TFA (2.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in THF (5.0 mL). Aqueous ammonia was added to adjust the pH to >10. The reaction mixture was stirred at room temperature for 0.5 h. Water (10.0 mL) was added, and the reaction mixture was extracted with DCM (10.0 mL × 2). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: (dichloromethane:methanol = 4:1) / dichloromethane = 0-15%) to give compound 1 (75 mg, yield 48.4%, purity 100%). LCMS (ESI) m / z 456.1 / 458.1 / 460.1 (M+H)+; 1H NMR (400 MHz, DMSO) δ 13.43 (s, 1H), 8.63 (s, 2H), 8.24 (s, 1H), 7.90 (s, 1H), 7.54 (s, 1H), 7.43 (s, 1H), 6.27 (q, J = 6.6 Hz, 1H), 3.98 (s, 3H), 1.81 (d, J = 6.6 Hz, 3H).

[0267] The following compounds were synthesized according to the route in Example 1:

[0268] [Table 1A]

[0269] [Table 1B]

[0270] Example 2 (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-7-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-indazole

[0271] [ka]

[0272] Compound 2-1 (350 mg, 2.36 mmol, 1.0 equiv.), compound A1 (941 mg, 3.5 mmol, 1.5 equiv.), and CsCO (2.3 g, 7.0 mmol, 3.0 equiv.) were dissolved in ACN (8 mL) and stirred at 80 °C for 8 h. LCMS showed the formation of the product. 30 mL of water was added to the reaction mixture, followed by 30 mL of EA to wash and extract the reaction mixture three times. The organic phases were combined, dried over anhydrous sodium sulfate, and purified on a silica gel column to give 270 mg of compound 2-2 as a white solid in a 35.5% yield.

[0273] Compound 2-2 (270 mg, 0.84 mmol, 1.0 equiv.), I2 (324 mg, 1.26 mmol, 1.5 equiv.), and KOH (190 mg, 1.69 mmol, 2.0 equiv.) were dissolved in DMF (10 mL) and stirred at 25 °C for 8 h. LCMS showed the formation of the product. 50 mL of water was added to the reaction mixture, followed by extraction with 50 mL of EA three times. The organic phases were combined, dried over anhydrous sodium sulfate, rotary evaporated, mixed with silica gel, and purified on a silica gel column (eluent: petroleum ether / ethyl acetate = 3 / 1) to give 120 mg of compound 2-3 as a white solid in a 31.9% yield.

[0274] Compound 2-3 (120 mg, 0.27 mmol, 1.0 equiv.), compound 1-4 (86 mg, 0.41 mmol, 1.5 equiv.), Cs2CO3 (270 mg, 0.81 mmol, 3.0 equiv.), and Pd(dppf)Cl2 (40 mg, 0.027 mmol, 0.1 equiv.) were dissolved in dioxane (5 mL), followed by addition of 1 mL of water, purging with nitrogen, and stirring at 80 °C for 8 h. LCMS showed the formation of the product. 30 mL of water was added to the reaction mixture, followed by 30 mL of EA for washing and extraction three times. The organic phases were combined, dried over anhydrous sodium sulfate, and purified using a silica gel column followed by a reverse-phase column to obtain 18.6 mg of compound 2 as a white solid (yield: 17.4%, purity: 95.5%). LCMS (ESI) m / z 402.08, (M+H)+; 1 H NMR (400 MHz, DMSO) δ 8.59 (s, 2H), 8.08 (s, 1H), 7.80 (s, 1H), 6.91 (s, 1H), 6.88 (s, 1H), 6.10 (q, J = 6.6 Hz, 1H), 3.94 (s, 3H), 2.44 (s, 3H), 1.75 (d, J = 6.6 Hz, 3H).

[0275] The following compounds were synthesized according to the route in Example 2:

[0276] [Table 2]

[0277] Example 7 (R)-7-Cyclopropyl-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(1-methyl-1H-pyrazol-4-yl)-1H-indazole

[0278] [ka]

[0279] NIS (1.486 g, 6.6 mmol) was added to a solution of compound 7-1 (1.0 g, 4.4 mmol) in N,N-dimethylformamide (40 mL) at room temperature. The resulting mixture was stirred at 50 °C for 4 h. LCMS showed the formation of the product. The reaction mixture was diluted with ethyl acetate (100 mL), washed sequentially with saturated aqueous sodium bicarbonate (40 mL) and water (40 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1, v / v) to give compound 7-2 as a yellow solid (1.362 g, yield: 88%, purity: 95.03%). LCMS (ESI) m / z 352.9 (M+H)+.

[0280] Compound 7-2 (1.059 g, 3.0 mmol), compound 1-4 (0.811 g, 3.9 mmol), Pd(dppf)Cl2·CHCl2 (0.246 g, 0.30 mmol), and KCO3 (0.829 g, 6.0 mmol) were added to a mixture of 1,4-dioxane (15.0 mL) and water (7.5 mL) at room temperature. The resulting mixture was stirred at 100 °C for 15 h. LCMS showed the formation of the product. The reaction mixture was cooled to room temperature and diluted with dichloromethane (20.0 mL) and water (10.0 mL). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (10.0 mL × 4). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 60 / 1, v / v) to give compound 7-3 as a light brown solid (0.719 g, yield: 78%, purity: 100%). LCMS (ESI) m / z 307.1 (M+H)+.

[0281] Compound 7-3 (0.412 g, 1.34 mmol) was added to dichloromethane (10.0 mL) at room temperature, followed by the slow dropwise addition of a 2.0 M solution of boron tribromide in dichloromethane (3.4 mL, 6.7 mmol). The resulting mixture was stirred at room temperature for 18 hours. LCMS showed the formation of the product. The pH of the reaction mixture was adjusted to approximately 7–8 with saturated aqueous sodium bicarbonate. The organic phase was separated, and the aqueous phase was extracted with a mixture of dichloromethane and methanol (dichloromethane / methanol = 5 / 1, v / v) (10.0 mL × 5). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (gradient elution, eluent: dichloromethane / methanol = 50 / 1 to 10 / 1, v / v) to give a dark brown solid (0.48 g). The solid was added to ethanol (1.5 mL), stirred at 80 °C for 30 minutes, and cooled to room temperature. The resulting mixture was filtered under reduced pressure, and the filter cake was washed with ethanol (1.0 mL × 2) and dried under reduced pressure to give compound 7-4 as a brown solid (0.362 g, yield: 92%, purity: 96.3%). LCMS (ESI) m / z 293.0 (M+H)+.

[0282] Compound 7-4 (0.362 g, 1.23 mmol), compound A1 (0.332 g, 1.23 mmol), and cesium carbonate (0.240 g, 0.74 mmol) were added to N,N-dimethylformamide (3.1 mL) at room temperature. The resulting mixture was stirred at 65 °C for 18 h. LCMS showed the formation of the product. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (15 mL), washed with water (10 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution, eluent: dichloromethane / methanol = 50 / 1 to 30 / 1, v / v) to give compound 7-5 as a light brown solid (0.303 g, yield: 53%, purity: 64.89%). LCMS (ESI) m / z 466.0 (M+H)+.

[0283] Compound 7-5 (0.0467 g, 0.10 mmol), cyclopropylboronic acid (0.0146 g, 0.17 mmol), palladium acetate (0.0033 g, 0.015 mmol), tricyclohexylphosphine (0.0084 g, 0.03 mmol), and potassium carbonate (0.0276 g, 0.20 mmol) were added to a mixture of 1,4-dioxane (0.5 mL) and water (0.25 mL) at room temperature. The resulting mixture was stirred at 100 °C for 20 hours. LCMS showed the formation of the product. The reaction mixture was cooled to room temperature and diluted with dichloromethane (10.0 mL) and water (5.0 mL). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (5.0 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure. The resulting residue was purified by thin-layer chromatography (eluent: dichloromethane / methanol = 30 / 1, v / v) to obtain compound 7 as a yellow solid (0.0165 g, yield: 38%, purity: 92.68%). LCMS (ESI) m / z 428.0, (M+H)+; 1H NMR (400 MHz, DMSO) δ 13.06 (s, 1H), 8.61 (s, 2H), 8.12 (s, 1H), 7.82 (s, 1H), 6.94 (s, 1H), 6.57 (d, J = 2.0 Hz, 1H), 6.11 (q, J = 6.6 Hz, 1H), 3.96 (s, 3H), 2.30 - 2.20 (m, 1H), 1.77 (d, J = 6.6 Hz, 3H), 1.07 (d, J = 2.2 Hz, 1H), 1.05 (d, J = 2.4 Hz, 1H), 0.85 - 0.78 (m, 1H), 0.74 - 0.67 (m, 1H).

[0284] The following compounds were synthesized according to the route in Example 7:

[0285] [Table 3]

[0286] Example 9 (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-7-methyl-3-(4-methyl-1H-imidazol-2-yl)-1H-indazole

[0287] [ka]

[0288] NaNO (2.628 g, 38 mmol, 8.0 equiv) was dissolved in water (30 mL) to obtain solution 1. Hydrogen chloride solution (38 mmol) was added to solution 1 and the mixture was stirred at 0 °C for 10 minutes. After that, a solution of compound 9-1 (1 g, 4.76 mmol, 1.0 equiv) in DMF (50 mL) was slowly added to solution 1 and the mixture was allowed to react at room temperature for 3 hours. LCMS showed the formation of the product. The reaction mixture was cooled and extracted three times with EA and water. The extract was concentrated under reduced pressure to obtain the crude product, compound 9-2, which was used directly in the next reaction step. LCMS (ESI) m / z 238.97, (M+H)+.

[0289] To a solution of the crude product, compound 9-2, in CHOH (40 mL), was added 7N aqueous ammonia-methanol solution (7 mL) at 0 °C. The mixture was stirred for 10 minutes, and then compound 9-3 (5 mL, 5.0 equiv.) was slowly added and the mixture was allowed to react at room temperature for 3 hours. LCMS analysis showed the formation of the product. The reaction mixture was cooled and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHOH:DCM = 1:10) and concentrated to give compound 9-4 (416 mg, 30.5% yield). LCMS (ESI) m / z 291.02 (M+H)+.

[0290] To a solution of compound 9-4 (416 mg, 1.43 mmol, 1.0 equiv) in THF (15 mL) was added NaH (120 mg, 3.0 mmol, 2.0 equiv) at 0 °C, purged with nitrogen to remove air, and reacted at room temperature for 40 min. SEMCl (0.66 mL, 1.3 equiv) was then added and reacted at room temperature for 3 h. LCMS showed the formation of the product. The reaction was directly concentrated under reduced pressure, and the cooled mixture was extracted three times with EA and water and washed with saturated brine. The residue was purified by silica gel column chromatography (eluent: PE:EA = 10:1) and concentrated to give compound 9-5 (450 mg, 52.6% yield). LCMS (ESI) m / z 551.18, (M+H)+.

[0291] To a solution of compound 9-5 (450 mg, 0.82 mmol, 1.0 equiv.), Pd(dppf)Cl (134 mg, 0.162 mmol, 0.2 equiv.), and bis(pinacolato)diboron (622 mg, 2.45 mmol, 3.0 equiv.) in dioxane (9 mL), potassium acetate (321 mg, 3.28 mmol, 4.0 equiv.) was added and the reaction mixture was heated at 90 °C for 3 h. LCMS analysis showed the formation of the product. The reaction mixture was directly concentrated under reduced pressure, and the residue was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to give crude compound 9-6 (LCMS (ESI) m / z 599.35, (M+H)+), along with the boronic acid formed as a by-product.

[0292] To a solution of the crude product, compound 9-6, in THF / HO (8 mL / 2 mL), sodium perborate tetrahydrate (730 mg, 4.8 mmol, 6.0 equiv.) was added and the mixture was allowed to react at room temperature for 2 hours. LCMS analysis showed the formation of the product. The reaction mixture was directly concentrated under reduced pressure, and the residue was extracted three times with DCM and water and washed with saturated brine. The residue was purified by silica gel column chromatography (eluent: DCM:HO = 10:1) and concentrated to give the liquid crude product, compound 9-7, which was used directly in the next reaction step. LCMS (ESI) m / z 489.26 (M+H)+.

[0293] To a solution of crude compound 9-7 and compound A1 (270 mg, 0.96 mmol, 1.2 equiv.) in DMF (8 mL), cesium carbonate (750 mg, 2.0 mmol, 2.5 equiv.) was added and the mixture was allowed to react at room temperature for 12 hours. LCMS analysis showed the formation of the product. The reaction mixture was extracted three times with EA and water and washed with saturated brine. The residue was purified by silica gel column chromatography (eluent: DCM:CH3OH = 15:1) and concentrated to give compound 9-8 (36 mg, 6.7% yield over three steps). LCMS (ESI) m / z 662.24, (M+H)+.

[0294] To a solution of compound 9-8 (36 mg) in DCM (4 mL), 2 mL of trifluoroacetic acid was added and the mixture was stirred at room temperature for 3 hours. LCMS analysis indicated the formation of the product. Preparative HPLC analysis yielded the trifluoroacetate salt of compound 9 (5.3 mg, 24.3% yield, 94.45% purity). LCMS (ESI) m / z 402.3 (M+H)+; 8.60 (s, 2H), 7.60 (s, 1H), 6.90 (s, 1H), 6.87 (s, 1H), 6.10 (q, J = 6.6 Hz, 1H), 2.44 (s, 3H), 2.42 (s, 3H), 1.75 (d, J = 6.6 Hz, 3H).

[0295] Example 10 (R)-4-(2-(4-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-7-fluoro-1H-indazol-3-yl)-1H-pyrazol-1-yl)ethyl)morpholine

[0296] [ka]

[0297] Compound A2 (200 mg, 0.44 mmol, 1.0 equiv.) and compound 10-1 (209 mg, 0.88 mmol, 2.0 equiv.) were dissolved in dioxane / HO (5 mL). CsCO (432 mg, 1.33 mmol, 3.0 equiv.) and Pd(dppf)Cl (33 mg, 0.04 mmol, 0.1 equiv.) were added and the mixture was stirred at 85 °C for 12 h under N protection. LCMS showed the formation of the product. After 5 mL of water was added to the reaction mixture, a total of 15 mL of EA was added in three portions to extract the reaction mixture three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, mixed with silica gel, and purified by silica gel column chromatography (eluent: DCM:CHOH = 20:1) to give 24.6 mg of compound 10 as a white solid (yield 12.8%, purity 97.5%). LCMS (ESI) m / z 435.3 (M+H)+; 1 H NMR (400 MHz, DMSO) δ 13.41 (s, 1H), 8.59 (s, 2H), 8.16 (s, 1H), 7.83 (s, 1H), 6.97 (s, 2H), 6.16 (d, J = 6.4 Hz, 1H), 4.15 (t, J = 6.4 Hz, 2H), 1.92 - 1.80 (m, 2H), 1.76 (d, J = 6.0 Hz, 3H), 0.87 (t, J = 7.2 Hz, 3H).

[0298] The following compounds were synthesized according to the route in Example 10:

[0299] [Table 4A]

[0300] [Table 4B]

[0301] [Table 4C]

[0302] [Table 4D]

[0303] [Table 4E]

[0304] Example 28 (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine

[0305] [ka]

[0306] Compound A3 (120 mg, 0.28 mmol, 1.0 equiv.), compound 28-1 (118 mg, 0.41 mmol, 1.5 equiv.), Cs2CO3 (270 mg, 0.83 mmol, 3.0 equiv.), and Pd(dppf)Cl2 (22.5 mg, 0.027 mmol, 0.1 equiv.) were dissolved in dioxane (5 mL), followed by addition of 1 mL of water, purging with nitrogen, and stirring at 80 °C for 8 h. LCMS showed the formation of the product. 30 mL of water was added to the reaction mixture, followed by addition of 30 mL of EA to wash and extract the reaction mixture three times. The organic phases were combined, dried over anhydrous sodium sulfate, and purified using a silica gel column followed by a reverse-phase column to obtain 52.2 mg of compound 28 as a yellow powder (yield: 40.5%, purity: 97.2%). LCMS (ESI) m / z 467.32(M+H)+);1 H NMR (400 MHz, ) δ 8.91 (d, J = 6.4 Hz), 8.50 (d, J = 1.3 Hz), 8.37 (d, J = 8.2 Hz), 8.30 (d, J = 0.92 Hz), 8.12 - 8.05 (m), 8.01 - 7.93 (m), 6.96 (t, J = 3.8 Hz), 6.43 (d, J = 1.2 Hz), 5.71 (s), 1.69 (d, J = 6.8 Hz).

[0307] The following compounds were synthesized according to the route in Example 28:

[0308] [Table 5A]

[0309] [Table 5B]

[0310] [Table 5C]

[0311] [Table 5D]

[0312] [Table 5E]

[0313] [Table 5F]

[0314] [Table 5G]

[0315] [Table 5H]

[0316] [Table 5I]

[0317] [Table 5J]

[0318] Example 65 3-(1-methyl-1H-pyrazol-4-yl)-N-(2-(methylamino)ethyl)-1H-indazole-5-carboxamide

[0319] [ka]

[0320] To a solution of compound 65-1 (300 mg, 1.04 mmol, 1.0 equiv.), compound 65-2 (0.3 mL, 1.56 mmol, 1.5 equiv.), and HATU (613 mg, 1.6 mmol, 1.5 equiv.) in DMF (10 mL) was added DIPEA (0.5 mL, 3.12 mmol, 3.0 equiv.), and the mixture was allowed to react at room temperature for 12 hours. LCMS analysis showed the formation of the product. The reaction mixture was extracted with EA and water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: DCM:methanol = 15:1) to give compound 65-3 (600 mg, purity 70%, yield 90%). LCMS (ESI) m / z 445, (M+H)+.

[0321] To a solution of compound 65-3 (600 mg, 0.95 mmol, 1.0 equiv.), compound 65-4 (350 mg, 1.68 mmol, 1.1 equiv.), and sodium carbonate (497 mg, 4.79 mmol, 3.0 equiv.) in dioxane / water (12 mL / 3 mL) was added Pd(dppf)Cl2 (231 mg, 0.19 mmol, 0.2 equiv.) and the mixture was reacted at 100 °C for 12 h. LCMS analysis showed the formation of the product. The reaction mixture was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: DCM:methanol = 10:1) to give compound 65-5 (337 mg, 89% yield). LCMS (ESI) m / z 399.21, (M+H)+.

[0322] To a solution of compound 65-5 (150 mg, 0.38 mmol, 1.0 equiv.) in ethyl acetate (2 mL), 2 mL of EA-HCl was added and the mixture was stirred at room temperature for 2 hours. LCMS showed the formation of the product. The reaction mixture was directly concentrated under reduced pressure and subjected to preparative high-performance liquid chromatography to give compound 65 (11.7 mg, 100% purity, 10.3% yield). LCMS (ESI) m / z 299.21, (M+H)+. 1 H NMR (400 MHz, DMSO) δ 9.01 (t, J = 5.4 Hz, 1H), 8.86 (s, 2H), 8.67 (s, 1H), 8.63 (s, 1H), 8.10 (s, 1H), 7.96 (dd, J = 8.8, 1.4 Hz, 1H), 7.59 (d, J = 8.7 Hz, 1H), 3.98 (s, 3H), 3.64 (s, 3H), 3.20 - 3.12 (m, 2H), 2.63 (t, J = 5.4 Hz, 3H).

[0323] The following compounds were synthesized according to the route in Example 65:

[0324] [Table 6A]

[0325] [Table 6B]

[0326] Example 70 7-Fluoro-N-(2-(methylamino)ethyl)-3-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-indazole-5-carboxamide

[0327] [ka]

[0328] Compound 70-1 (0.108 g, 0.60 mmol), compound 65-2 (0.125 g, 0.72 mmol), HATU (0.342 g, 0.90 mmol), and N,N-diisopropylethylamine (0.233 g, 1.8 mmol) were added to N,N-dimethylformamide (1.2 mL) at room temperature. The reaction mixture was stirred at room temperature for 14 hours. LCMS showed the formation of the product. The reaction mixture was diluted with ethyl acetate (10.0 mL), washed with saturated aqueous sodium bicarbonate (5.0 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 40 / 1, v / v) to obtain compound 70-2 as an off-white solid (0.197 g, yield: 97%, purity: 100%). LCMS (ESI) m / z 359.2, (M+Na)+.

[0329] To a solution of compound 70-2 (0.197 g, 0.59 mmol) in N,N-dimethylformamide (1.2 mL) was added NIS (0.158 g, 0.70 mmol) at room temperature. The resulting mixture was stirred at room temperature for 17 hours. LCMS showed the formation of the product. The reaction mixture was diluted with ethyl acetate (10 mL), washed successively with saturated aqueous sodium bicarbonate (10 mL) and water (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 60 / 1, v / v) to give compound 70-3 as a yellow solid (0.247 g, yield: 91%, purity: 100%). LCMS (ESI) m / z 485.0, (M+Na)+.

[0330] Compound 70-3 (0.0647 g, 0.14 mmol), compound 70-4 (0.0731 g, 0.24 mmol), Pd(dppf)Cl2·CHCl2 (0.0172 g, 0.021 mmol), and Na2CO3 (0.0297 g, 0.28 mmol) were added to a mixture of 1,4-dioxane (0.7 mL) and water (0.35 mL) at room temperature. The resulting mixture was stirred at 100 °C for 19 h. LCMS showed the formation of the product. The reaction mixture was cooled to room temperature and diluted with dichloromethane (10 mL) and water (5 mL). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (5 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution, eluent: dichloromethane / methanol = 30 / 1 to 20 / 1, v / v) to give compound 70-5 as a light brown solid (0.0355 g, yield: 49%, purity: 92.48%). LCMS (ESI) m / z 516.3, (M+H)+.

[0331] At room temperature, compound 70-5 (0.0355 g, 0.069 mmol) was added to a solution of hydrogen chloride in ethyl acetate (2.0 M) (0.35 mL). The resulting mixture was stirred at room temperature for 4 hours. LCMS showed the formation of the product. The reaction mixture was diluted with ethyl acetate (0.3 mL) and filtered under reduced pressure. The filter cake was washed with ethyl acetate (0.1 mL × 3) and dried under reduced pressure to give compound 70 as a light brown solid (0.0176 g, yield: 52%, purity: 92.96%). LCMS (ESI) m / z 416.2, (M+H)+; 1 H NMR (400 MHz, DMSO) δ 9.27 (t, J = 5.2 Hz, 1H), 9.08 (br s, 2H), 8.83 (s, 1H), 8.64 (s, 1H), 8.15 (s, 1H), 7.76 (d, J = 12.2 Hz, 1H), 4.00 (s, 3H), 3.68 (dd, J = 11.0, 5.4 Hz, 2H), 3.22 - 3.14 (m, 2H), 2.64 (t, J = 5.2 Hz, 3H).

[0332] Example 71 6-(3,5-Dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-N-(2-(methylamino)ethyl)-1H-indazole-5-carboxamide

[0333] [ka]

[0334] To a solution of compound 71-1 (330 mg, 1.29 mmol, 1.0 equiv.) in DMF (13 mL) was added NIS (437 mg, 1.94 mmol, 1.5 equiv.), and the mixture was reacted at 50 °C for 4 hours. LCMS showed the formation of the product. The reaction mixture was cooled, extracted three times with EA and water, washed with saturated brine, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE:EA = 4:1) and concentrated to give crude compound 71-2 as a light yellow oily liquid (purity 90%, LCMS (ESI) m / z 380.87, (M+H)+), which was used directly in the next reaction step.

[0335] To a solution of crude compound 71-2 and compound 1-4 (295 mg, 1.42 mmol, 1.1 equiv.) in dioxane / water (12 mL / 3 mL), Pd(dppf)Cl2 (187 mg, 0.258 mmol, 0.2 equiv.) and potassium carbonate (416 mg, 3.2 mmol, 2.5 equiv.) were added, purged with N2 to remove air, and the reaction mixture was heated at 80 °C for 12 h. LCMS analysis showed the formation of the product. The reaction mixture was cooled and concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (eluent: DCM:CH3OH = 15:1) and concentrated to give compound 71-3 (600 mg, 70% purity, 65% yield over two steps). LCMS (ESI) m / z 337.02 (M+H)+.

[0336] To a solution of compound 71-3 (420 mg, 1.24 mmol, 1.0 equiv) in THF / HO (10 mL / 10 mL) was added LiOH (120 mg, 4.98 mmol, 4.0 equiv), and the mixture was reacted at 50 °C for 12 h. LCMS showed the formation of the product. The reaction mixture was directly concentrated under reduced pressure, and the residue was extracted with DCM and water. The extract was concentrated to give crude compound 71-4, which was used directly in the next reaction step. LCMS (ESI) m / z 320.19, (M+H)+.

[0337] To a solution of crude compound 71-4 and compound 65-2 (0.2 mL, 1.12 mmol, 1.5 equiv.) and DIPEA (0.40 mL, 2.24 mmol, 3.0 equiv.) in DMF (8 mL), HATU (425 mg, 1.12 mmol, 1.5 equiv.) and HOAT (152 mg, 1.12 mmol, 3.0 equiv.) were added and the mixture was allowed to react at room temperature for 3 h. LCMS analysis showed the formation of the product. The reaction mixture was extracted three times with EA and HO and washed with saturated brine to ensure that the reaction mixture was free of DMF. The extract was purified by silica gel column chromatography (eluent: DCM:HO = 10:1) to give compound 71-5 (100 mg, 30% yield over two steps, LCMS (ESI) m / z 477.12, (M+H)+).

[0338] To a solution of compound 71-5 (100 mg, 0.2 mmol, 1.0 equiv.) and compound 71-6 (42 mg, 0.22 mmol, 1.1 equiv.) in dioxane / water (2 mL / 0.5 mL), Pd(dppf)Cl (30 mg, 0.04 mmol, 0.2 equiv.) and potassium carbonate (83 mg, 0.6 mmol, 3.0 equiv.) were added, and the mixture was purged with N to remove air and reacted at 90 °C for 12 h. LCMS analysis showed the formation of the product. The reaction mixture was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: DCM:HO = 10:1) and concentrated to give compound 71-7 (10 mg, 9.4% yield). LCMS (ESI) m / z 535.26, (M+H)+.

[0339] To a solution of compound 71-7 (10 mg) in DCM (2 mL), 2 mL of HCl-dioxane solution was added and the mixture was stirred at room temperature for 3 hours. LCMS showed the formation of the product. Preparative high-performance liquid chromatography (HPLC) afforded the hydrochloride salt of compound 71 (1 mg, purity 94.87%, yield 12.3%). LCMS (ESI) m / z 435, (M+H)+; 1H NMR (400 MHz, DMSO) δ 9.07 (s, 2H), 8.70 (s, 1H), 8.61 (s, 1H), 8.45 (s, 1H), 8.03 (s, 1H), 7.39 (s, 1H), 7.01 (s, 2H), 6.50 (s, 1H), 3.96 (s, 3H), 3.90 (s, 6H), 3.61 (q, J = 5.6 Hz, 2H), 3.17 - 3.09 (m, 2H), 2.61 (t, J = 5.4 Hz, 3H)).

[0340] Example 72 6-Methoxy-3-(1-methyl-1H-pyrazol-4-yl)-N-(2-(methylamino)ethyl)-1H-indazole-5-carboxamide

[0341] [ka]

[0342] To a solution of compound 72-1 (268 mg, 1.39 mmol, 1.0 equiv.), compound 65-2 (364 mg, 2.09 mmol, 1.5 equiv.), and DIPEA (0.75 mL, 4.17 mmol, 3.0 equiv.) in DMF (10 mL) was slowly added HATU (795 mg, 2.09 mmol, 1.5 equiv.) at room temperature. The reaction mixture was stirred at room temperature for 4 h. Saturated aqueous sodium bicarbonate (40 mL) was added, and the reaction mixture was extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: (dichloromethane:methanol = 4:1) / dichloromethane = 0-16%) to give compound 72-2 (464 mg, 95.5% yield).

[0343] Compound 72-2 (464 mg, 1.33 mmol, 1.0 equiv) and NIS (330 mg, 1.46 mmol, 1.1 equiv) were added sequentially to DMF (7.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was cooled to room temperature, water (30.0 mL) was added, and the reaction mixture was extracted with ethyl acetate (15.0 mL × 2). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: (dichloromethane:methanol = 4:1) / dichloromethane = 0-15%) to give compound 72-3 (490 mg, 77.6% yield).

[0344] Compound 72-3 (247 mg, 0.52 mmol, 1.0 equiv.), compound 1-4 (119 mg, 0.57 mmol, 1.1 equiv.), Pd(dppf)Cl2 (75.5 mg, 0.1 mmol, 0.2 equiv.), and sodium carbonate (165 mg, 1.56 mmol, 3.0 equiv.) were added sequentially to dioxane / HO (5 mL / 1.3 mL) at room temperature. The reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: (dichloromethane:methanol = 4:1) / dichloromethane = 0-25%) to give compound 72-4 (192 mg, 86.1% yield).

[0345] To a solution of compound 72-4 (192 mg, 0.45 mmol, 1.0 equiv) in DCM (2.0 mL) was slowly added hydrochloric acid-dioxane solution (4 M, 5 mL, 20 mmol, 44 equiv) at room temperature. The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and EA (10 mL) was added to the resulting residue. The mixture was stirred for 15 minutes and filtered. The filter cake was dried under reduced pressure to give compound 72 (130 mg, 79.8% yield, 99.2% purity). LCMS (ESI) m / z 329.2 (M+H)+; 1H NMR (400 MHz, DMSO) δ 8.98 (s, 2H), 8.54 (t, J = 5.7 Hz, 1H), 8.41 (s, 1H), 8.40 (s, 1H), 7.95 (s, 1H), 7.04 (s, 1H), 3.96 (s, 6H), 3.64 (t, J = 5.8 Hz, 2H), 3.10 (t, J = 5.8 Hz, 2H), 2.61 (t, J = 5.4 Hz, 3H).

[0346] The following compounds were synthesized according to the route in Example 72:

[0347] [Table 7]

[0348] Example 74 3-(1-methyl-1H-1,2,3-triazol-4-yl)-N-(2-(methylamino)ethyl)-1H-indazole-5-carboxamide

[0349] [ka]

[0350] To a solution of compound 74-1 (2 g, 7.84 mmol, 1.0 equiv.) in DMF (20 mL), compound 74-2 (1.15 g, 11.76 mmol, 1.5 equiv.), DIEA (2.0 g, 15.69 mmol, 2.0 equiv.), Pd(dppf)Cl2 (400 mg, 0.2 wt.), and CuI (200 mg, 0.1 wt.) were added. The mixture was purged with N2 three times, heated to 100 °C, and reacted for 15 h. LCMS analysis showed the formation of the product. The reaction mixture was concentrated and subjected to column chromatography (PE:EA = 50% to 80%) to give compound 74-3 as a yellow solid (1.5 g, 70.4% yield, 95% purity). LCMS (ESI) m / z 273.4 (M+H)+.

[0351] To a solution of compound 74-3 (2.2 g, 8.08 mmol, 1.0 equiv) in THF (20 mL) was added TBAF (3.17 g, 12.1 mmol, 1.5 equiv), and the mixture was allowed to react at 25 °C for 2 h. LCMS showed the formation of the product. Water (50 mL) and EA (20 mL) were added, and the reaction mixture was separated and washed. The mixture was concentrated to give compound 74-4 as a white solid (1.2 g, 74.0% yield, 95% purity). LCMS (ESI) m / z 201.2 (M+H)+.

[0352] Compound 74-4 (410 mg, 2.05 mmol, 1.0 equiv) in DMF (5 mL) was added to compound 74-5 (397.4 mg, 3.07 mmol, 1.5 equiv), DIEA (615.82 mg, 4.10 mmol, 2.0 equiv), and CuI (41 mg, 0.1 wt.) and reacted at 25 °C for 2 h. LCMS analysis showed the formation of the product. The reaction mixture was concentrated and subjected to column chromatography (PE:EA = 50% to 80%) to give compound 74-6 (600 mg, 90% yield, 95% purity). LCMS (ESI) m / z 330.4 (M+H)+.

[0353] To a solution of compound 74-6 (600 mg, 1.82 mmol, 1.0 equiv) in THF (6 mL), TBAF (714.3 mg, 2.73 mmol, 1.5 equiv) was added and the mixture was allowed to react at 25 °C for 2 h. LCMS showed the formation of the product. Water (50 mL) and EA (20 mL) were added, and the reaction mixture was separated and washed. The mixture was concentrated to give compound 74-7 (374 mg, 80% yield, 95% purity). LCMS (ESI) m / z 258.3 (M+H)+.

[0354] To a solution of compound 74-7 (100 mg, 0.39 mmol, 1.0 equiv) in MeOH / HO (5 mL / 1 mL) was added LiOH (28.0 mg, 1.17 mmol, 3 equiv), and the mixture was allowed to react at 50 °C for 15 h. LCMS showed the formation of the product. The reaction mixture was subjected to rotary evaporation, and water (10 mL) and EA (10 mL) were added to separate and wash the reaction mixture. The pH of the aqueous phase was adjusted to 3-4 with dilute HCl (20 mL, 1N), and the aqueous phase was subjected to suction filtration. The filter cake was dried to give compound 74-8 (70 mg, 74% yield, 95% purity). LCMS (ESI) m / z 244.2, (M+H)+.

[0355] To a solution of compound 74-8 (70 mg, 0.29 mmol, 1.0 equiv) in DMF (2 mL), HATU (142.3 mg, 0.37 mmol, 1.3 equiv) and DIEA (74.3 mg, 0.58 mmol, 2.0 equiv) were added and stirred for 20 min. Compound 65-2 (65.25 mg, 0.37 mmol, 1.3 equiv) was added and the mixture was allowed to react at 25 °C for 15 h. LCMS analysis showed the formation of the product. The reaction mixture was separated and washed with water (50 mL) and EA (20 mL). Concentration and column chromatography (PE:EA = 50% to 80%) gave compound 74-9 (40 mg, 35% yield, 95% purity). LCMS (ESI) m / z 400.5, (M+H)+.

[0356] To a solution of compound 74-9 (40 mg, 0.1 mmol, 1.0 equiv.) in MeOH (6 mL), HCl / EA (5 mL) was added and the mixture was allowed to react at 25°C for 2 hours. LCMS analysis showed the formation of the product. The reaction mixture was concentrated and subjected to C18 reverse-phase column chromatography (HO:ACN = 30%-50%) to give compound 74 (4 mg, 13% yield, 95% purity). LCMS (ESI) m / z 300.4, (M+H)+; 1H NMR (400 MHz, DMSO) δ 13.49 (s, 1H), 8.87 (d, J = 12.2 Hz, 2H), 8.70 (d, J = 11.6 Hz, 3H), 7.96 (d, J = 8.2 Hz, 1H), 7.63 (d, J = 8.8Hz, 1H), 4.17 (s, 3H), 3.60 (s, 2H), 3.13 (s, 2H), 2.60 (s, 3H).

[0357] Example 75 N-Methyl-2-(4-(3-(4-methyl-1H-imidazol-2-yl)-1H-indazol-5-yl)-1H-1,2,3-triazol-1-yl)ethan-1-amine

[0358] [ka]

[0359] To a solution of compound 75-1 (500 mg, 2.22 mmol, 1.0 equiv) in CHOH (6.0 mL) at 0 °C, NH / CHOH (7 M, 3.2 mL, 22.2 mmol, 10 equiv) was slowly added. The reaction mixture was stirred at 0 °C for 10 min, and compound 75-2 (40.81%, 2.0 mL, 11.1 mmol, 5 equiv) was slowly added. The reaction mixture was stirred at 0 °C for 10 min, then warmed to room temperature and stirred for 3 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: (dichloromethane:methanol = 4:1) / dichloromethane = 0-20%) to give compound 75-3 (415 mg, 67.5% yield).

[0360] A solution of compound 75-3 (415 mg, 1.498 mmol, 1.0 equiv) in THF (8.0 mL) was slowly added to a suspension of sodium hydride (210 mg, 5.24 mmol, 3.5 equiv) in THF (5.0 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 0.5 min. After that, it was cooled to 0 °C, and SEMCl (0.69 mL, 3.89 mmol, 2.6 equiv) was slowly added thereto. The reaction mixture was warmed to room temperature and stirred for 3 h. The reaction mixture was cooled to 0 °C, poured slowly into aqueous NH4Cl (20.0 mL), and extracted with EA (10.0 mL × 2). The organic phases were combined, washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether=0-10%) to give compound 75-4 (316 mg, yield 39.3%).

[0361] Compound 75-4 (312 mg, 0.58 mmol, 1.0 equiv.), trimethylethynylsilane (0.41 mL, 2.9 mmol, 5.0 equiv.), Pd(PPh3)2Cl2 (122 mg, 0.17 mmol, 0.3 equiv.), CuI (34 mg, 0.17 mmol, 0.3 equiv.), and TEA (0.41 mL, 2.9 mmol, 5.0 equiv.) were added sequentially to DMF (4.5 mL) at room temperature. The reaction mixture was stirred at 80 °C for 24 h. The reaction mixture was cooled to room temperature, water (20 mL) was added, and the reaction mixture was extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0 to 8%) to give compound 75-5 (310 mg, yield 96.3%).

[0362] To a solution of compound 75-5 (310 mg, 0.56 mmol, 1.0 equiv) in CHOH (8.0 mL) was added potassium carbonate (820 mg, 5.9 mmol, 10.5 equiv) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and water (10.0 mL) and DCM (10.0 mL) were added to separate the reaction mixture. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 75-6 (270 mg, 100% yield).

[0363] Compound 75-6 (245 mg, 0.51 mmol, 1.0 equiv.), compound 75-7 (112 mg, 0.6 mmol, 1.2 equiv.), and Cu(CHCN)PF (20 mg, 0.05 mmol, 0.1 equiv.) were added sequentially to chloroform (8.0 mL) at room temperature. The reaction mixture was stirred at 40 °C for 7 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: (dichloromethane:methanol = 4:1) / dichloromethane = 0-10%) to give compound 75-8 (239 mg, 70.4% yield).

[0364] A solution of compound 75-8 (120 mg, 0.18 mmol, 1.0 equiv) in THF (2.0 mL) was slowly added to a suspension of sodium hydride (14.5 mg, 0.36 mmol, 2.0 equiv) in THF (2.0 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 0.5 min. After that, it was cooled to 0 °C, and CHCl (51 mg, 0.36 mmol, 2.0 equiv) was slowly added. The reaction mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was cooled to 0 °C, slowly poured into aqueous NHCl (10.0 mL), and extracted with EA (10.0 mL × 2). The organic phases were combined, washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: (dichloromethane:methanol=4:1) / dichloromethane=0-18%) to obtain compound 75-9 (65 mg, yield 53.1%).

[0365] To a solution of compound 75-9 (65 mg, 0.095 mmol, 1.0 equiv) in DCM (4.0 mL) was slowly added TFA (2.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in THF (3.0 mL). Aqueous ammonia was added to adjust the pH to >10. The reaction mixture was stirred at room temperature for 0.5 h. Water (10.0 mL) was added, and the reaction mixture was extracted with DCM / i-PrOH = 85 / 15 (10.0 mL × 2). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: (dichloromethane:methanol = 4:1) / dichloromethane = 0-93.3%) to give 75 (15 mg, 49% yield, 98.2% purity). LCMS (ESI) m / z 323.2 (M+H)+; 1 H NMR (400 MHz, DMSO) δ 13.27 (s, 1H), 12.40 (s, 1H), 8.82 (s, 1H), 8.62 (s, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 6.84 (s, 1H), 4.58 (t, J = 6.0 Hz, 2H), 3.15 (t, J = 6.0 Hz, 2H), 2.41 (s, 3H), 2.28 (s, 3H).

[0366] Example 76 3-(1-methyl-1H-pyrazol-4-yl)-N-(2-(methylamino)ethyl)-1H-indazole-5-sulfonamide

[0367] [ka]

[0368] To a solution of compound 76-1 (2 g, 6.19 mmol, 1.0 equiv.) in DCM (60 mL), p-toluenesulfonic acid TsOH (122 mg, 0.64 mmol, 0.1 equiv.) and DHP (1.68 mL, 3.0 equiv.) were added and stirred at room temperature for 12 hours. LCMS showed the formation of the product. The reaction mixture was cooled, extracted with EA and water, washed with saturated brine, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE:EA=10:1) and concentrated to give 76-2 as a white solid (2.36 g, 93.9% yield). LCMS (ESI) m / z 406.92, (M+H)+.

[0369] To a solution of compound 76-2 (2.31 g, 5.67 mmol, 1.0 equiv.) and compound 1-4 (1.3 mg, 6.25 mmol, 1.1 equiv.) in 1,4-dioxane / water (56 mL / 14 mL) was added sodium carbonate (1.8 g, 17.01 mmol, 3.0 equiv.) and Pd(dppf)Cl (800 mg, 1.1 mmol, 0.2 equiv.), purged with N three times, and reacted overnight at 100 °C. The reaction mixture was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: PE:EA = 2:1) and concentrated to give compound 76-3 (855 mg, 74.1% yield). LCMS (ESI) m / z 361.06, (M+H)+.

[0370] A solution of compound 76-3 (855 mg, 2.375 mmol, 1.0 equiv.) and compound 76-4 (0.3 mL, 1.1 equiv.) in dioxane (23 mL) was added with Pd2(dba)3 (105 mg, 0.115 mmol, 0.05 equiv.), DIPEA (0.7 mL, 3.0 equiv.), and Xant-tphos (133 mg, 0.23 mmol, 0.1 equiv.) and reacted at 100 °C for 18 h. LCMS analysis showed the formation of the product. The reaction mixture was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: PE:EA = 2:1) and concentrated to give compound 76-5 (1.122 g, 74% purity). LCMS (ESI) m / z 405.17, (M+H)+.

[0371] Compound 76-6 (617 mg, 3.13 mmol, 3.0 equiv) was added to a solution of compound 76-5 (422 mg, 1.04 mmol, 1.0 equiv) and 1 mL of acetic acid in THF / HO (12 mL / 3 mL) at 0 °C, and the temperature was maintained at this level for 2 hours. LCMS showed the formation of the product. The reaction mixture was directly concentrated under reduced pressure, and the residue was extracted with EA and water and washed with saturated brine. The residue was purified by silica gel column chromatography (eluent: PE:EA = 4:1) and concentrated to give compound 76-7 (326 mg, 82% yield). LCMS (ESI) m / z 381.06, (M+H)+.

[0372] To a solution of compound 76-7 (284 mg, 0.75 mmol, 1.0 equiv.) and compound 65-2 (156 mg, 0.89 mmol, 1.2 equiv.) in DCM (8 mL), DIPEA (0.26 mL, 1.5 mmol, 2.0 equiv.) was added and the mixture was allowed to react at room temperature for 1 hour. LCMS analysis showed the formation of the product. The reaction mixture was directly concentrated under reduced pressure, and the residue was extracted with DCM and water and washed with saturated brine. The residue was purified by silica gel column chromatography (eluent: DCM:HO = 15:1) and concentrated to give compound 76-8 (344 mg, 88.65% yield). LCMS (ESI) m / z 519.23, (M+H)+.

[0373] To a solution of compound 76-8 (344 mg, 0.66 mmol, 1.0 equiv.) in dioxane (3 mL), 3 mL of HCl-dioxane solution was added and stirred at room temperature for 2 hours. LCMS showed the formation of the product. The pH of the reaction mixture was adjusted to neutral by adding sodium bicarbonate solution, and the residue was extracted with DCM and water and washed with saturated brine. The residue was purified by silica gel column chromatography (eluent: DCM:CH3OH = 15:1) and concentrated to give compound 76 (220.8 mg, 88% yield). LCMS (ESI) m / z 335.12, (M+H)+; 1H NMR (400 MHz, DMSO) δ 8.91 (s, 2H), 8.54 (s, 1H), 8.50 (s, 1H), 8.14 (t, J = 5.6 Hz, 1H), 8.03 (s, 1H), 7.80 (dt, J = 19.6, 5.1 Hz, 2H), 3.99 (s, 3H), 3.07 - 2.94 (m, 4H), 2.56 - 2.53 (m, 3H). 1 H NMR (400 MHz, DMSO) δ 8.91 (s, 2H), 8.54 (s, 1H), 8.50 (s, 1H), 8.14 (t, J = 5.6 Hz, 1H), 8.03 (s, 1H), 7.80 (dt, J = 19.6, 5.1 Hz, 2H), 3.99 (s, 3H), 3.07 - 2.94 (m, 4H), 2.56 - 2.53 (m, 3H).

[0374] Example 79 3-(4-methyl-1H-imidazol-2-yl)-N-(pyrrolidin-3-ylmethyl)-1H-indazole-5-carboxamide

[0375] [ka]

[0376] To a solution of compound 79-1 (355 mg, 1.87 mmol, 1.0 equiv) in CHOH (5.0 mL) was slowly added NH / CHOH (7 M, 3.0 mL, 21 mmol, 11 equiv) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min, and compound 75-2 (40.81%, 1.6 mL, 9.35 mmol, 5 equiv) was slowly added. The reaction mixture was stirred at 0 °C for 10 min, then warmed to room temperature and stirred for 3 h. After concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent: (ethyl acetate:methanol = 4:1) / ethyl acetate = 0-49%) to give compound 79-2 (445 mg, yield 98.45%).

[0377] To a solution of compound 79-2 (102 mg, 0.42 mmol, 1.0 equiv.), compound 79-3 (127 mg, 0.63 mmol, 1.5 equiv.), and DIPEA (0.22 mL, 1.26 mmol, 3.0 equiv.) in DMF (2.0 mL) was slowly added HATU (240 mg, 0.63 mmol, 1.5 equiv.) at room temperature. The reaction mixture was stirred at room temperature for 2 h. Saturated aqueous sodium bicarbonate (10.0 mL) was added, and the reaction mixture was extracted with ethyl acetate (10.0 mL × 2). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: (dichloromethane:methanol = 4:1) / dichloromethane = 0-29%) to give compound 79-4 (95 mg, 53.16% yield).

[0378] To a solution of compound 79-4 (95 mg, 0.224 mmol, 1.0 equiv.) in DCM / CHOH (2.0 mL / 2.0 mL) was slowly added a solution of hydrochloric acid in dioxane (4 M, 5 mL, 20 mmol, 89 equiv.) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and water (10 mL) and EA (10 mL) were added to separate the reaction mixture. The aqueous phase was lyophilized to give compound 79 (80 mg, 90% yield, 96.43% purity). LCMS (ESI) m / z 325.2 (M+H)+; 1 H NMR (400 MHz, DMSO) δ 15.04 (s, 1H), 14.59 (s, 1H), 9.41 (s, 1H), 9.21 (s, 2H), 9.04 (t, J = 5.7 Hz, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.57 (s, 1H), 3.64-3.57 (m, 2H), 3.37-3.3 (m, 1H), 3.29-3.21 (m, 1H), 3.22-3.09 (m, 1H), 3.06-2.98 (m, 1H), 2.71-2.59 (m, 1H), 2.45 (s, 3H), 2.14 - 2.03 (m, 1H), 1.84 - 1.71 (m, 1H).

[0379] The following compounds were synthesized according to the route in Example 79:

[0380] [Table 8]

[0381] Example 82 N-(2-(methylamino)ethyl)-3-(4-phenyl-1H-imidazol-2-yl)-1H-indazole-5-carboxamide

[0382] [ka]

[0383] Compound 79-1 (120 mg, 0.63 mmol, 1.00 equiv) was dissolved in methanol (3 mL) and cooled to 0 °C. NH3 / CH3OH (7N, 1.01 mL, 10.00 equiv) was slowly added and stirred for 10 min. Compound 82-1 (480 mg, 3.15 mmol, 5 equiv) was then added and the mixture was stirred at 0 °C for 10 min. The reaction mixture was then stirred at room temperature for 3 h and concentrated under reduced pressure to give the crude product. The crude product was subjected to column chromatography (eluent: 80% ethyl acetate / petroleum ether) to give compound 82-2 as a yellow solid (110 mg, 57.3% yield, 90% purity). LCMS (ESI) m / z 305, (M+H)+.

[0384] Compound 82-2 (50 mg, 0.16 mmol, 1.00 equiv.), compound 65-2 (57 mg, 0.33 mmol, 2.0 equiv.), HATU (75 mg, 0.20 mmol, 1.2 equiv.), and DIPEA (64 mg, 0.49 mmol, 3.00 equiv.) were dissolved in DMF (2 mL) and reacted at room temperature for 2 h. The reaction mixture was then cooled, quenched with water (50 mL), and extracted three times with ethyl acetate (80 mL). The combined organic phases were washed twice with saturated brine (80 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (eluent: 100% ethyl acetate / petroleum ether) to obtain compound 82-3 as a yellow solid (50 mg, 65.7% yield, 100% purity). LCMS (ESI) m / z 461, (M+H)+.

[0385] Compound 82-3 (50 mg, 0.11 mmol, 1.00 equiv) was dissolved in dichloromethane (2.0 mL), and hydrochloric acid / dioxane (2.0 mL) was added, followed by stirring at 25 °C for 1 hour. The reaction mixture was then filtered to give the target compound 82 as a white solid (33.5 mg, 85% yield, 100% purity). LCMS (ESI) m / z 360.42, (M+H)+; 1 H NMR(400 MHz, DMSO) δ 14.36 (s, 1H), 9.21 (s, 1H), 9.03 (s, 1H), 8.92 (s, 2H), 8.22 (s, 1H), 8.11 - 8.03 (m, 3H), 7.80 (d,J = 9.0 Hz, 1H), 7.58 - 7.50 (m, 2H), 7.44 (d,J = 7.5 Hz, 1H), 3.76 - 3.66 (m, 2H), 3.22 - 3.12 (m, 2H), 2.69 - 2.60 (m, 3H).

[0386] Example 83 3-(5-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-N-(2-(methylamino)ethyl)-1H-indazole-5-carboxamide

[0387] [ka]

[0388] Compound 79-1 (100 mg, 0.526 mmol, 1.0 equiv.), compound 83-1 (106 mg, 0.526 mmol, 1.0 equiv.), iodine (200 mg, 0.79 mmol, 1.5 equiv.), and potassium carbonate (218 mg, 1.58 mmol, 3.0 equiv.) were added sequentially to tert-butanol (20 mL) at room temperature. The reaction mixture was stirred at 70 °C for 3 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and methanol (20 mL) was added. The mixture was stirred for 15 min and filtered. The filtrate was concentrated under reduced pressure to give compound 83-2 (270 mg), which was used directly in the next reaction step without purification.

[0389] To a solution of compound 83-2 (270 mg, 0.727 mmol, 1.0 equiv.), compound 83-3 (265 mg, 1.08 mmol, 1.5 equiv.), and DIPEA (0.65 mL, 3.67 mmol, 5.0 equiv.) in DMF (6.0 mL) was slowly added HATU (410 mg, 1.08 mmol, 1.5 equiv.) at room temperature. The reaction mixture was stirred at room temperature for 2 h. Saturated aqueous sodium bicarbonate (20.0 mL) was added, and the reaction mixture was extracted with ethyl acetate (10.0 mL × 2). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: (dichloromethane:methanol = 4:1) / dichloromethane = 0-32%) to give compound 83-4 (303 mg, 100% overall yield for two steps).

[0390] Compound 83-4 (150 mg, 0.267 mmol, 1.0 equiv) and IBX (150 mg, 0.534 mmol, 2.0 equiv) were added sequentially to DMSO (10 mL) at room temperature. The reaction mixture was stirred at 50 °C for 10 h. The reaction mixture was cooled to room temperature, water (30 mL) was added, and the reaction mixture was extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: (dichloromethane:methanol = 4:1) / dichloromethane = 0-28%) to give compound 83-5 (80 mg, 53.5% yield).

[0391] To a solution of compound 83-5 (80 mg, 0.143 mmol, 1.0 equiv) in THF (4.0 mL) was added zinc bromide (131 mg, 0.58 mmol, 4.0 equiv) at room temperature. The reaction mixture was stirred at 50° C. for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Water (10.0 mL) and EA (10.0 mL) were added to separate the reaction mixture. The aqueous phase was lyophilized to give compound 83-6 (150 mg), which was used directly in the next reaction step without further purification.

[0392] Compound 83-6 (100 mg, 0.22 mmol, 1.0 equiv.), aqueous formaldehyde (37%, 52 mg, 0.66 mmol, 3.0 equiv.), and two drops of acetic acid were added sequentially to methanol (3.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 15 min. Sodium triacetoxyborohydride (192 mg, 0.9 mmol, 4.0 equiv.) was added, and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give compound 83-7 (20 mg, 44.4% overall yield for two steps).

[0393] Compound 83-7 (20 mg, 0.04 mmol, 1.0 equiv.) and palladium on carbon (palladium loading: 10 wt%) (50 mg) were added sequentially to THF (2.0 mL) and DMF (2.0 mL) at room temperature. The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 5 hours, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give compound 83 (2.5 mg, yield 17.5%, purity 100%). LCMS (ESI) m / z 340.2 (M+H)+; 1 H NMR (400 MHz, DMSO) δ 8.67 (s, 1H), 7.96 (dd, J = 8.8, 1.4 Hz, 1H), 7.59 (d, J = 8.7 Hz, 1H), 3.52-3.68 (m, 6H), 3.20 - 3.12 (m, 2H), 2.63 (t, J = 5.4 Hz, 3H), 2.20(s, 3H).

[0394] Example 84 N-(2-(methylamino)ethyl)-3-(5-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazole-5-carboxamide

[0395] [ka]

[0396] To a solution of compound 79-1 (145 mg, 0.76 mmol, 1.1 equiv) and compound 84-1 (140 mg, 0.68 mmol, 1.0 equiv) in DMF (3.0 mL) was added sodium bisulfite (147 mg, 1.41 mmol, 2.1 equiv) at room temperature. The reaction mixture was stirred at 160 °C for 2 h. The reaction mixture was cooled to room temperature, and water (10 mL) and EA (10 mL) were added. The mixture was stirred for 15 min, filtered, and the filter cake was dried under reduced pressure to give compound 84-2 (120 mg, purity 73%, yield 34.3%).

[0397] To a solution of compound 84-2 (120 mg, 73% purity, 0.32 mmol, 1.0 equiv.), compound 65-2 (83 mg, 0.48 mmol, 1.5 equiv.), and DIPEA (0.17 mL, 0.96 mmol, 3.0 equiv.) in DMF (3.0 mL) was slowly added HATU (180 mg, 0.48 mmol, 1.5 equiv.) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate solution (10.0 mL) was added, and the reaction mixture was extracted with ethyl acetate (10.0 mL × 2). The organic phases were combined, washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: (dichloromethane:methanol=4:1) / dichloromethane=0-65%) to obtain compound 84-3 (100 mg, yield 80.65%).

[0398] To a solution of compound 84-3 (100 mg, 0.19 mmol, 1.0 equiv.) in DCM (2.0 mL) was slowly added hydrochloric acid-dioxane solution (4 M, 5 mL, 20 mmol, 105 equiv.) at room temperature. The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, and water (10 mL) and EA (10 mL) were added to separate the reaction mixture. The aqueous phase was lyophilized to give compound 84 (95 mg, 87.9% yield, 97.9% purity). LCMS (ESI) m / z 433.2 (M+H)+; 1 H NMR (400 MHz, DMSO) δ 14.78 (s, 1H), 11.07 (s, 1H), 9.54 (s, 1H), 9.10 - 9.03 (m, 1H), 8.93 (s, 2H), 8.11 (dt, J = 5.2, 2.6 Hz, 1H), 7.88 (d, J = 9.1 Hz, 1H), 7.80 (d, J = 9.1 Hz, 1H), 7.44 - 7.39 (m, 1H), 7.31 (s, 1H), 3.72 - 3.69 (m, 4H), 3.29-3.19 (m, 6H), 2.87 (s, 3H), 2.68-2.62 (m, 5H).

[0399] (Comparative Example 85) (5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)pyridin-2-yl)(imino)(methyl)-sulfanone

[0400] [ka]

[0401] Compound 85-1 (2.0 g, 9.8 mmol, 1.0 equiv) was added to a 100 mL single-neck flask, and dioxane / KOAc (20 mL) was added. Then, bis(pinacolato)diboron and Pd(dppf)Cl2 (800 mg, 0.98 mmol, 0.1 equiv) were added sequentially. After purging with N2, the mixture was stirred at 80 °C for 12 h. LCMS showed the formation of the product. 30 mL of water was added to the reaction mixture, followed by 30 mL of EA for extraction three times. The organic phases were combined, dried over anhydrous sodium sulfate, rotary evaporated, mixed with silica gel, and purified by silica gel column chromatography to give 2.0 g of compound 85-2 as a yellow solid in 81.3% yield.

[0402] Compound 85-3 (2.0 g, 5.8 mmol, 1.0 equiv.) and compound A1 (2.35 g, 8.7 mmol, 1.5 equiv.) were dissolved in ACN (20 mL), and CsCO (5.7 g, 17.4 mmol, 3.0 equiv.) was added. The mixture was stirred at 80 °C for 6 h. LCMS showed the formation of the product. 30 mL of water was added to the reaction mixture, followed by 30 mL of EA to extract the reaction mixture three times. The organic phases were combined, dried over anhydrous sodium sulfate, rotary evaporated, mixed with silica gel, and purified by silica gel column chromatography to give 1.3 g of compound 85-4 as a white solid in a 43.3% yield.

[0403] Compound 85-4 (500 mg, 0.97 mmol, 1.0 equiv.) and compound 85-2 (364 mg, 1.44 mmol, 1.5 equiv.) were dissolved in dioxane / HO, and CsCO (948 mg, 2.91 mmol, 3.0 equiv.) and Pd(dppf)Cl (79.2 mg, 0.097 mmol, 0.1 equiv.) were added sequentially. The mixture was dissolved in dioxane (10 mL), followed by addition of 2 mL of water, purging with nitrogen, and stirring at 80 °C for 12 h. LCMS showed the formation of the product. 20 mL of water was added to the reaction mixture, followed by addition of 20 mL of EA for three extractions. The organic phases were combined, dried, concentrated, mixed with silica gel, subjected to rotary evaporation, and passed through a normal phase column to obtain 370 mg of compound 85-5 as a white solid in 74.4% yield.

[0404] Compound 85-5 (370 mg, 0.72 mmol, 1.0 equiv) was dissolved in methanol, and CH3COONH4 (83.2 mg, 1.08 mmol, 1.5 equiv) and iodobenzene diacetate (463.7 mg, 1.44 mmol, 2.0 equiv) were added sequentially. The mixture was stirred at room temperature for 3 h. LCMS showed the formation of the product. 5 mL of water was added to the reaction mixture, followed by extraction with 10 mL of EA three times. The organic phases were combined, dried, and concentrated. The mixture was mixed with silica gel, rotary evaporated, and then passed through a normal phase column to give 320 mg of compound 85-6 as a white solid in 81.6% yield.

[0405] Compound 85-6 (320 mg, 0.58 mmol, 1.0 equiv) was dissolved in HCl / EA (4 mol, 10 mL) and stirred at room temperature for 1 hour. LCMS showed the formation of the product. The reaction mixture was subjected to rotary evaporation and dried under reduced pressure with an oil pump, then passed through a reverse-phase column to obtain 83.4 mg of compound 85 as a white solid (yield: 30.9%, purity: 98.8%). LCMS (ESI) m / z 463.35, (M+H)+; 1H NMR (400 MHz, DMSO) δ 9.28 (s, 1H), 8.60 (s, 2H), 8.55 (dd, J = 8.3, 1.8 Hz, 1H), 8.32 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 9.2 Hz, 1H), 7.40 (d, J = 1.6 Hz, 1H), 7.17 (dd, J = 9.0, 1.8 Hz, 1H), 6.19 (d, J = 6.8 Hz, 1H), 3.59 (s, 3H), 1.79 (d, J = 6.6 Hz, 3H).

[0406] Example 86 3-(1-methyl-1H-pyrazol-4-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)ethoxy)-1H-indazole

[0407] [ka]

[0408] To a mixture of compound 86-1 (200 mg, 1.54 mmol, 1.0 equiv.), TEA (311 mg, 3.07 mmol, 2.0 equiv.), and DCM (5 mL) was added MsCl (176 mg, 1.54 mmol, 1.0 equiv.) at 0 °C, and the mixture was allowed to react at 0 °C for 0.5 h. TLC showed the completion of the reaction and the formation of a product spot. After adding 30 mL of water to the reaction mixture, the reaction mixture was extracted three times with DCM (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude compound 86-2 as a colorless oil (350 mg). 1 H NMR (400 MHz, CDCl3) δ 4.56 (t, J = 6.4 Hz, 1H), 3.97 (dd, J = 12.2, 4.2 Hz, 2H), 3.32 (m, 2H), 2.97 (s, 3H), 1.81 - 1.72 (m, 1H), 1.68 (m, 1H), 1.57 - 1.49 (m, 1H), 1.43 (m, 2H), 1.36 (d, J = 6.4 Hz, 3H).

[0409] Cesium carbonate (98 mg, 0.30 mmol, 2.0 equiv.) was added to a mixture of compound 86-2 (45 mg, 0.15 mmol, 1.0 equiv.), compound A4 (46 mg, 0.23 mmol, 1.5 equiv.), and acetonitrile (3 mL), and the mixture was allowed to react at 70 °C overnight. TLC showed the reaction was complete, and LCMS showed the formation of the product. The reaction mixture was directly concentrated, and 50 mL of water was added. The reaction mixture was then extracted twice with ethyl acetate (30 mL × 2). The organic phases were combined and concentrated to give the crude product, compound 86-3, as a colorless oil (100 mg). LCMS (ESI) m / z 411.20, (M+1) + .

[0410] Compound 86-3 (50 mg, 0.12 mmol, 1.0 equiv) was added to HCl / dioxane (4 M, 2 mL), and the mixture was heated to 45° C. and reacted for 1 h. TLC showed the reaction was complete. After adding 30 mL of saturated sodium bicarbonate solution, the reaction mixture was extracted twice with EA (20 mL×2). The organic phases were combined, concentrated, and purified by preparative high-performance liquid chromatography to give compound 86 as a white solid (22 mg, 55%). LCMS (ESI) m / z 327.10, (M+1) + , 99% purity; 1 H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.86 (s, 1H), 7.30 (d, J = 9.0 Hz, 1H), 7.20 (d, J = 2.2 Hz, 1H), 7.03 (dd, J = 9.0, 2.2 Hz, 1H), 4.13 (t, J = 6.2 Hz, 1H), 4.07 - 4.00 (m, 3H), 3.98 (s, 3H), 3.68 (s, 2H), 3.40 (t, J = 11.5 Hz, 2H), 1.94 - 1.76 (m, 3H), 1.50 (m, 3H), 1.28 (d, J = 6.1 Hz, 3H).

[0411] The following compounds were synthesized according to the route in Example 86:

[0412] [Table 9A]

[0413] [Table 9B]

[0414] Example 87 4-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)quinoline

[0415] [ka]

[0416] Compound 87-1 (50 mg, 0.32 mmol, 1.0 equiv) was added to a 25 mL dry three-neck flask at room temperature, and dry THF (3.0 mL) was added. The flask was purged with nitrogen several times and then cooled in an ice-salt bath. CHClMgBr (0.23 mL, 0.67 mmol, 2.1 equiv) was added dropwise at 0 °C, and the reaction was continued for 2 h while maintaining a low temperature. TLC showed the completion of the reaction and the formation of a product spot. 10 mL of water was added to the reaction mixture, and the reaction mixture was extracted three times with EA (5.0 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude compound 87-2 (60 mg), which was used directly in the next reaction step. LCMS: (ESI) m / z 174.05, (M+H) + .

[0417] Compound 87-2 (60 mg, 0.35 mmol, 1.0 equiv) was completely dissolved in DCM (3.0 mL) at room temperature. TEA (141 mg, 1.4 mmol, 4.0 equiv) was added at room temperature, the mixture was purged with nitrogen, and the mixture was cooled in an ice-water bath. MsCl (81 mg, 0.7 mmol, 2.0 equiv) was added dropwise and the reaction was allowed to proceed at room temperature for 2 hours. TLC monitoring showed the formation of a new spot and the disappearance of the starting spot. LCMS monitoring showed the formation of the product. After adding 5.0 mL of water to the reaction mixture, the reaction mixture was extracted twice with DCM (5.0 mL x 2). The organic phases were combined and washed and extracted twice with saturated aqueous NaHCO3 (10.0 mL x 2). The organic phase was dried over anhydrous sodium sulfate and subjected to rotary evaporation to give compound 87-3 (80 mg, 91%). LCMS (ESI) m / z 252.05, (M+1) + .

[0418] Compound 87-3 (90 mg, 0.36 mmol, 1.5 equiv) was dissolved in MeCN (5.0 mL) at room temperature, and compound A4 (70 mg, 0.23 mmol, 1.0 equiv) and CsCO (150 mg, 0.46 mmol, 2.0 equiv) were added under stirring. The mixture was purged with nitrogen and reacted at 80 °C overnight. TLC monitoring showed the disappearance of the starting material and the formation of a new spot, and LCMS monitoring showed the formation of the product. 10.0 mL of water was added to the reaction solution, and the reaction solution was extracted three times with EA (5.0 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and subjected to rotary evaporation and preparative TLC (DCM / MeOH = 20 / 1) to give crude compound 87-4 (108 mg), which was used directly in the next step. LCMS (ESI) m / z 452.90, (M+1). + .

[0419] Compound 87-4 (100 mg, 0.22 mmol, 1.0 equiv) was completely dissolved in MeOH (3.0 mL), and 4.0 N HCl-dioxane solution was added. The mixture was allowed to react at room temperature for 3 hours. LCMS monitoring showed the disappearance of compound 87-4, which was completely converted to the product. The reaction mixture was concentrated to dryness and purified by preparative high-performance liquid chromatography to give the final product, compound 87, as a white solid (45.4 mg, 55.7%). LCMS (ESI) m / z 370.05, (M+H) + ; 1 H NMR (400 MHz, CD3OD) δ 8.81 - 8.76 (m, 1H), 8.51 (d, J = 8.9 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.88 (t, J = 8.2 Hz, 1H), 7.80 (t, J = 7.7 Hz, 1H), 7.71 (d, J = 4.6 Hz, 1H), 7.62 (d, J = 4.9 Hz, 2H), 7.40 (d, J = 9.0 Hz, 1H), 7.22 - 7.17 (m, 1H), 7.03 - 6.99 (m, 1H), 6.33 (q, J = 6.5 Hz, 1H), 3.85 (s, 3H), 1.83 (d, J = 6.4 Hz, 3H).

[0420] The following compounds were synthesized according to the route in Example 87:

[0421] [Table 10A]

[0422] [Table 10B]

[0423] Example 95 6-methyl-5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)quinoline

[0424] [ka]

[0425] To a solution of compound 95-1 (300 mg, 1.35 mmol, 1.0 equiv.) and compound 95-2 (731.8 mg, 2.03 mmol, 1.5 equiv.) in dioxane (10 mL), tetrakis(triphenylphosphine)palladium (312.2 mg, 0.27 mmol, 0.2 equiv.) was added, purged with N2 three times, and stirred at 110 °C for 12 h. LCMS showed the completion of the reaction of compound 95-1. The reaction mixture was cooled, 20 mL of saturated KF solution was added, and the mixture was stirred at room temperature for 30 min. After filtration, the mixture was extracted with EA and washed with saturated brine. The organic phase was concentrated to give a liquid as a yellow oil. To the mixture was added hydrochloric acid-dioxane solution (14 mL, 4 M), and the mixture was stirred at room temperature for 30 min. LCMS showed the completion of the reaction. After adjusting the pH to 7 with saturated NaHCO3 (20 mL), the reaction mixture was extracted with ethyl acetate, separated, and dried by rotary evaporation to give the liquid as a yellow oil. The crude product was purified on a 4 g silica gel column (0-50% EA) to give the product, compound 95-3 (230 mg, yield: 92%). LCMS (ESI) m / z 186.2, (M+H). + .

[0426] To a solution of compound 95-3 (230 mg, 1.24 mmol, 1.0 equiv) in MeOH (15 mL), NaBH4 (94 mg, 2.48 mol, 2.0 equiv) was added and stirred at room temperature for 12 h. LCMS showed the formation of the product. The reaction was quenched with saturated NH4Cl solution, extracted with EA, separated, and dried by rotary evaporation to give a yellow solid, which was subjected to column chromatography (0-50% EA) to give compound 95-4 as an off-white solid (200 mg, 86% yield). LCMS (ESI) m / z 188.24, (M+H) + .

[0427] Compound 95-4 (60 mg, 0.32 mmol, 1.0 equiv) and triethylamine (64 mg, 0.64 mmol, 2.0 equiv) were dissolved in DCM (3 mL), and MsCl (54 mg, 0.48 mmol, 1.5 equiv) was added dropwise at 0 °C. After adding saturated aqueous NaHCO3 solution (15 mL) to the reaction mixture, the reaction mixture was extracted with DCM (15 mL × 3). The organic phase was separated, dried by rotary evaporation, and purified by TLC (PE:EA = 1:1) to give compound 95-5 as a yellow solid (30 mg, 45.5% yield). LCMS (ESI) m / z 206.07, (M+H) + .

[0428] Compound 95-5 (30 mg, 0.146 mmol, 1.0 equiv.) and compound A4 (64 mg, 0.218 mmol, 1.5 equiv.) were dissolved in DMF (2 mL), CsCO (95 mg, 0.28 mmol, 2 equiv.) was added, and the mixture was reacted at 80 °C for 3 hours. The reaction mixture was extracted with water and EtOAc. The organic phase was separated, dried by rotary evaporation, and purified by TLC (DCM:MeOH = 10:1) to give compound 95-6 as a yellow solid (25 mg, 36.6% yield). LCMS (ESI) m / z 468.23, (M+H). + .

[0429] Compound 95-6 (30 mg, 0.146 mmol, 1.0 equiv) was dissolved in DCM (2 mL), TFA (1 mL) was added, and the mixture was allowed to react at 25° C. for 3 hours. LCMS analysis showed the completion of the reaction of compound 95-6 and the formation of the product. The reaction mixture was subjected to rotary evaporation to obtain the crude product, which was purified by TLC (DCM:MeOH=10:1) to obtain compound 95 as an off-white solid (15.8 mg, 73.2% yield). LCMS (ESI) m / z 384.17, (M+H) + ; 1H NMR (400 MHz, DMSO) δ 12.75 (s, 1H), 9.24 (d, J = 8.4 Hz, 1H), 8.86 (d, J = 3.2 Hz, 1H), 7.92 (s, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.66 (s, 1H), 7.60 (dd, J = 8.8, 4.0 Hz, 2H), 7.35 (d, J = 8.8 Hz, 1H), 7.11 - 7.04 (m, 2H), 6.35 (d, J = 6.4 Hz, 1H), 3.93 (s, 3H), 2.72 (s, 3H), 1.87 (d, J = 6.7 Hz, 3H).

[0430] The following compounds were synthesized in Example 95.

[0431] Table 11A

[0432] Table 11B

[0433] Table 11C

[0434]

Table 11D

[0435] Table 11E

[0436] Table 11F

[0437] [Table 11G]

[0438] [Table 11H]

[0439] [Table 11I]

[0440] [Table 11J]

[0441] [Table 11K]

[0442] Example 108 5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)-1,7-naphthyridine

[0443] [ka]

[0444] Compound 108-1 (0.26 g, 1.24 mmol), potassium vinyltrifluoroborate (0.25 g, 1.86 mmol), Pd(dppf)Cl (0.091 g, 0.124 mmol), and KCO (0.343 g, 2.48 mmol) were added to a mixture of 1,4-dioxane (6.2 mL) and water (3.1 mL) at room temperature. The resulting mixture was stirred at 90 °C for 13 hours. LCMS showed the formation of the product. The reaction mixture was cooled to room temperature and diluted with dichloromethane (10 mL) and water (5 mL). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (5 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 2:1) to give brown viscous liquid 108-2 (0.165 g, yield: 85%, purity: 97.25%). LCMS (ESI) m / z 157.2, (M+H)+.

[0445] Compound 108-2 (0.165 g, 1.06 mmol) was added to a mixture of tetrahydrofuran (10.6 mL) and water (2.1 mL) at 0 °C, followed by the addition of KOsO·2H O (0.0391 g, 0.106 mmol). The resulting mixture was stirred for 15 min, and then NaIO (0.907 g, 4.24 mmol) was added. The reaction mixture was stirred at 0 °C for 20 min, warmed to room temperature, and stirred for 13 h. LCMS showed the formation of the product. The reaction mixture was diluted with dichloromethane (20.0 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane:ethyl acetate = 5:1) to give orange solid 108-3 (0.108 g, yield: 64%, purity: 99.06%). LCMS (ESI) m / z 159.1, (M+H)+.

[0446] To a solution of compound 108-3 (0.108 g, 0.68 mmol) in tetrahydrofuran (3.0 mL) was added dropwise a solution of methylmagnesium bromide (3.0 M, 2-methyltetrahydrofuran solution) (0.34 mL, 1.02 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 20 min, then warmed to room temperature and stirred for 3 h. LCMS showed the formation of the product. The reaction mixture was diluted with a solution of ammonium chloride in methanol (0.3 M, 4.0 mL) and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol = 20:1) to give a light brown solid 108-4 (0.116 g, yield: 98%, purity: 93.27%). LCMS (ESI) m / z 175.1, (M+H)+.

[0447] To a solution of compound 108-4 (0.116 g, 0.66 mmol) in dichloromethane (5.0 mL) was added dropwise thionyl chloride (0.197 g, 1.66 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 10 min, warmed to room temperature, and stirred for 2 h. LCMS showed the formation of the product. The reaction mixture was diluted with dichloromethane (20.0 mL), and saturated aqueous sodium bicarbonate solution was added to adjust the pH of the aqueous phase to approximately 7–8. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (10.0 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. The resulting residue was dried under reduced pressure to give crude compound 108-5 as a dark brown jelly (0.0272 g, crude yield: 21%, purity: 29.03%). LCMS (ESI) m / z 193.1, 195.1, (M+H)+.

[0448] The crude product, compound 108-5 (0.0272 g, 0.14 mmol), compound A4 (0.0418 g, 0.14 mmol), and cesium carbonate (0.0684 g, 0.21 mmol) were added to N,N-dimethylformamide (1.4 mL) at room temperature. The resulting mixture was stirred at 65 °C for 10 hours. LCMS showed the formation of the product. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), and washed with water (5 mL × 2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel thin-layer chromatography (eluent: dichloromethane:methanol = 35:1) to give compound 108-6 as a dark yellow jelly (0.0187 g, yield: 29%, purity: 86.72%). LCMS (ESI) m / z 455.3, (M+H)+.

[0449] Trifluoroacetic acid (0.0938 g, 0.82 mmol) was added to a solution of compound 108-6 (0.0187 g, 0.041 mmol) in dichloromethane (0.41 mL) at room temperature. The resulting mixture was stirred for 26 h. LCMS showed the formation of the product. The reaction mixture was diluted with dichloromethane (10.0 mL), and saturated aqueous sodium bicarbonate solution was added to adjust the pH of the aqueous phase to approximately 7-8. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (10.0 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (eluent: dichloromethane:methanol = 20:1) to give compound 108 as a dark yellow solid (0.0077 g, yield: 51%, purity: 90.73%). LCMS (ESI) m / z 371.1, (M+H)+; 1H NMR (400 MHz, DMSO) δ 12.78 (s, 1H), 9.33 (s, 1H), 9.12 (s, 1H), 9.04 (d, J = 8.4 Hz, 1H), 8.85 (s, 1H), 8.16 (s, 1H), 7.942 - 7.888 (m, 1H), 7.82 (s, 1H), 7.435 - 7.364 (m, 2H), 7.15 (d, J = 8.8 Hz, 1H), 6.43 (q, J = 6.8 Hz, 1H), 3.93 (s, 3H), 1.83 (d, J = 6.4 Hz, 3H).

[0450] The following compounds were synthesized according to the route in Example 108:

[0451] [Table 12]

[0452] Example 110 6-methyl-5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazino[4,3-d]pyrimidin-5-yl)oxy)ethyl)quinoline

[0453] [ka]

[0454] Compound 110-1 (400 mg, 1.43 mmol) was dissolved in DCM (5 mL) at room temperature, and DHP (360 mg, 4.28 mmol) was added at 0 °C, followed by TsOH·HO (27 mg, 0.14 mmol). The reaction mixture was stirred at room temperature for 60 min. LCMS showed the reaction of the starting material was complete. The reaction mixture was quenched with water and extracted with DCM (20 mL × 3). The combined organic phase was then subjected to rotary evaporation, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 2:1) to give product 110-2 as a yellow solid (233 mg, purity 85%, [M+H]+ = 365.0).

[0455] Compound 110-2 (70 mg, 0.19 mmol) was dissolved in dioxane (5 mL) and HO (1 mL) at room temperature, and compound 1-4 (42 mg, 0.20 mmol) was added. Then, Pd(dppf)Cl (32 mg, 0.039 mmol) and sodium carbonate (57 mg, 0.54 mmol) were added under nitrogen protection. The reaction mixture was stirred at 90 °C for 2 h. LCMS showed no remaining starting material. After the reaction mixture was cooled to room temperature, the organic phases were combined and then rotary evaporated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 1:5) to give product 110-3 as a black solid (60 mg, purity 85%, [M+H]+ = 320.1).

[0456] Compound 110-3 (60 mg, 0.19 mmol) was dissolved in dioxane (5 mL) and HO (1 mL), and KOH (42 mg, 0.75 mmol) was added. Next, Pd(dba) (86 mg, 0.094 mmol) and t-BuXPhos (80 mg, 0.19 mmol) were added under nitrogen protection. The reaction mixture was stirred at 100 °C for 16 h. LCMS showed no remaining starting material. After the reaction mixture was cooled to room temperature, the organic phases were combined and then rotary evaporated. The crude product was purified by silica gel column chromatography (eluent: dichloromethane:methanol = 10:1) to give product 110-4 as a black solid (40 mg, 80% purity, [M+H] = 301.2).

[0457] Compound 110-4 (40 mg, 0.13 mmol) and compound 95-5 (30 mg, 0.15 mmol) were dissolved in DMF (2 mL) at room temperature, and CsCO (43 mg, 0.13 mmol) was added. The reaction mixture was stirred at 40 °C for 16 h. LCMS showed the reaction of the raw material was complete. The reaction mixture was diluted with water and extracted with EA (30 mL × 3). The organic phases were combined and then subjected to rotary evaporation. The crude product was purified by silica gel column chromatography (eluent: dichloromethane:methanol = 10:1) to obtain the product compound 110-5 as a yellow oil (20 mg, purity 90%, LCMS: 470.0 [M+H]).

[0458] Compound 110-5 (20 mg, 0.04 mmol) was dissolved in DCM (2 mL) at room temperature, and TFA (1 mL) was added to it in an ice bath. The reaction mixture was stirred at room temperature for 1 hour. LCMS showed the reaction of the raw material was complete. The reaction mixture was concentrated, and the organic phase was collected and subjected to preparative high-performance liquid chromatography to obtain compound 110 as a white solid (1.7 mg, purity: 100%, LCMS: 386.2 [M+H]).

[0459] Example 113 6-methyl-5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)propyl)quinoline

[0460] [ka]

[0461] Compound 113-1 (200 mg, 1.17 mmol, 1.0 equiv) was placed in a three-necked flask, dissolved in THF (10 mL), purged with nitrogen, and cooled to 0 °C. Ethyl magnesium chloride (389.2 mg, 2.92 mmol, 2.5 equiv) was added dropwise. The mixture was stirred at room temperature for 1 h. LC-MS and TLC monitoring indicated the completion of the reaction of compound 113-1. The reaction mixture was cooled in an ice-water bath, quenched with water, washed and extracted three times with ethyl acetate and water. The organic phase was dried over anhydrous Na2SO4, subjected to rotary evaporation, and purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to give compound 113-2 as a yellow solid (150 mg, 63.8%). 1 H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J = 9.7 Hz, 1H), 8.73 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.38 (d, J = 12.5 Hz, 1H), 5.53 (s, 1H), 5.18 (s, 1H), 1.95 (m, 1H), 1.73 (m, 7.0 Hz, 1H), 0.86 (t, J = 7.4 Hz, 4H).

[0462] Compound 113-2 (150 mg, 0.76 mmol, 1.0 equiv) was dissolved in DCM (8 mL), triethylamine (150.8 mg, 1.49 mmol, 2.0 equiv) was added, the mixture was purged with nitrogen, cooled in an ice-water bath, and MsCl (127.4 mg, 1.12 mmol, 1.5 equiv) was added. The mixture was stirred at room temperature overnight. LC-MS and TLC monitoring indicated the completion of the reaction of compound 113-2. The reaction mixture was washed and extracted three times with ethyl acetate and water. The organic phase was dried over anhydrous Na2SO4, rotary evaporated, and purified by thin-layer chromatography (developing solvent: DCM:MeOH = 15:1) to give compound 113-3 as a yellow oil (85 mg). 1 H NMR (400 MHz, CD3OD) δ 9.13 (d, J = 3.4 Hz, 1H), 8.75 (dd, J = 17.0, 5.6 Hz, 1H), 7.86 (dd, J = 18.9, 9.5 Hz, 1H), 7.59 (s, 1H), 7.48 - 7.41 (m, 1H), 4.97 (s, 1H), 2.56 (s, 3H), 2.13 (s, 1H), 1.85 (s, 1H), 0.96 (s, 3H).

[0463] Compound 113-3 (95 mg, 0.32 mmol, 1.0 equiv.) was dissolved in acetonitrile (10 mL), and cesium carbonate (210 mg, 0.64 mmol, 2.0 equiv.) and compound A4 (85 mg, 0.39 mmol, 1.2 equiv.) were added sequentially, followed by purging with nitrogen. The mixture was stirred at 80 °C for 24 h. LC-MS and TLC monitoring indicated the completion of the reaction of compound A4. The reaction mixture was washed and extracted three times with ethyl acetate and water. The organic phase was dried over anhydrous Na2SO4, subjected to rotary evaporation, and purified by thin-layer chromatography (developing solvent: DCM:MeOH = 15:1) to give compound 113-4 as a yellow oil (60 mg, 39.1%). LCMS (ESI) m / z 482.20, (M+H)+.

[0464] Compound 113-4 (120 mg, 0.31 mmol, 1.0 equiv) was dissolved in MeOH (2.0 mL) and added to dioxane (HCl) (5 mL), and the mixture was stirred at room temperature for 2.5 h. The reaction mixture was evaporated to dryness and then directly subjected to preparative high-performance liquid chromatography to give compound 113 as a bright white solid (36.5 mg, 73.71%, purity 99%). LCMS (ESI) m / z 398.25, (M+H) +; 1 H NMR (400 MHz, CD3OD) δ 9.28 (s, 1H), 8.75 (s, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.61 (d, J = 10.1 Hz, 4H), 7.32 (d, J = 8.9 Hz, 1H), 7.11 (d, J = 8.9 Hz, 1H), 6.91 (s, 1H), 5.94 (s, 1H), 3.93 (s, 3H), 2.71 (s, 3H), 2.46 (dt, J = 13.6, 6.6 Hz, 1H), 2.11 (dt, J = 14.1, 6.9 Hz, 1H), 1.19 (t, J = 7.3 Hz, 3H).

[0465] Example 114 2-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)-2-(6-methylquinolin-5-yl)ethan-1-ol

[0466] [ka]

[0467] NaOH (187 mg, 4.68 mmol, 2.0 equiv) was dissolved in toluene (10.0 mL) at room temperature, and compound 114-2 (955 mg, 4.68 mmol, 2.0 equiv) and N-benzyl-N,N,N-triethylammonium chloride (533 mg, 2.34 mmol, 1.0 equiv) were added at room temperature. After purging with nitrogen, the mixture was reacted at room temperature for 0.5 hours. Compound 114-1 (300 mg, 2.34 mmol, 1.0 equiv) was dissolved in 2.0 mL of toluene and added dropwise to the reaction mixture in an ice-water bath. The mixture was reacted overnight at room temperature. TLC plate monitoring indicated the disappearance of compound 114-1 and the formation of a new spot. LCMS monitoring indicated the formation of compound 114-3. 30.0 mL of water was added to the reaction mixture, and the mixture was extracted three times with EA (10.0 mL × 3). The organic phases were combined, washed and extracted twice with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (eluent: ethyl acetate:petroleum ether=1:5) to give compound 114-3 (160 mg, 49%). LCMS: (ESI) m / z 185.95, (M+H) +; 1 H NMR (400 MHz, CD3OD) δ 8.83 - 8.75 (m, 2H), 7.90 (d, J = 8.7 Hz, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.54 (dd, J = 8.7, 4.3 Hz, 1H), 4.32 (s, 1H), 3.39 - 3.35 (m, 1H), 2.84 (dd, J = 5.5, 2.7 Hz, 1H), 2.61 (s, 3H).

[0468] Compound 114-3 (93 mg, 0.5 mmol, 1.5 equiv) was dissolved in acetonitrile (5.0 mL) at room temperature, and compound A4 (100 mg, 0.34 mmol, 1.0 equiv) and Er(OTf) (420 mg, 0.68 mmol, 2.0 equiv) were added. The mixture was purged with nitrogen, sealed, and refluxed at 80 °C for overnight reaction. LCMS monitoring showed the formation of compound 114-4. After adding 15 mL of water, the reaction mixture was extracted three times with ethyl acetate (10.0 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by thin-layer chromatography (developing solvent: DCM / MeOH = 20 / 1) to give compound 114-4 (120 mg, crude product) as a yellow oil. LCMS: (ESI) m / z 484.25, (M+H)+.

[0469] Compound 114-4 (120 mg, crude product) was dissolved in 2.0 mL of methanol at room temperature, and 2.0 mL of 4N hydrochloric acid in 1,4-dioxane was added. The mixture was allowed to react at room temperature for 1 hour. The reaction mixture was subjected to rotary evaporation and purified by preparative high-performance liquid chromatography to obtain compound 114 (1.3 mg, white solid). LCMS (ESI) m / z 400.05, (M+H)+; 1 H NMR (400 MHz, CD3OD) δ 9.70 (d, J = 8.9 Hz, 1H), 9.01 (d, J = 5.1 Hz, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.82 (d, J = 14.1 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.45 (d, J = 15.2 Hz, 2H), 7.07 (s, 1H), 6.96 (d, J = 11.7 Hz, 1H), 6.53 (d, J = 2.2 Hz, 1H), 5.92 (t, J = 7.2 Hz, 1H), 5.14 (d, J = 22.4 Hz, 1H), 5.00 (s, 1H), 3.75 (s, 3H), 2.05 (s, 3H).

[0470] Example 115 6-methyl-5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)thio)ethyl)quinoline

[0471] [ka]

[0472] Compound A4 (1.0 g, 3.35 mmol, 1.0 equiv.) was dissolved in DCM (10 mL). Compound DIEA (1.7 g, 6.7 mmol, 4.0 equiv.) was added to the reaction mixture and purged with nitrogen three times. TfO (1.9 g, 6.7 mmol, 2.0 equiv.) was slowly added dropwise to the reaction mixture in an ice bath, and the mixture was stirred at room temperature overnight. TLC showed that most of the starting material was converted to the product. The reaction mixture was extracted three times with 10 mL of dichloromethane and water. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 100:1 to 50:1) to give compound 115-1 as a white solid (596 mg, yield: 41%). 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.23 ​​(d, J = 2.3 Hz, 1H), 8.04 (s, 1H), 7.93 (d, J = 9.2 Hz, 1H), 7.57 - 7.51 (m, 1H), 5.91 (d, J = 9.3 Hz, 1H), 3.94 (s, 4H), 3.76 (t, J = 12.5 Hz, 1H), 2.46 - 2.36 (m, 1H), 2.00 (d, J = 15.5 Hz, 2H), 1.76 (s, 1H), 1.59 (s, 2H).

[0473] Compound 115-1 (500 mg, 1.16 mmol, 1.0 equiv) was dissolved in dioxane (10 mL), followed by the addition of compound 115-2 (506 mg, 2.32 mmol, 2.0 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (69 mg, 0.12 mmol, 0.1 equiv), Pd2(dba)3 (110 mg, 0.12 mmol, 0.1 equiv), and DIPEA (449 mg, 3.48 mmol, 3.0 equiv). The mixture was then purged with nitrogen three times and stirred at 100 °C overnight. LCMS indicated the presence of the target product. The reaction mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thin layer chromatography (DCM:MeOH=20:1) to give compound 115-3 as a yellow oil (500 mg, yield: 86.44%). 1 H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 8.02 - 7.95 (m, 2H), 7.72 (d, J = 8.8 Hz, 1H), 7.47 (dd, J = 8.7, 1.6 Hz, 1H), 5.86 - 5.80 (m, 1H), 3.91 (d, J = 16.6 Hz, 6H), 3.78 - 3.69 (m, 1H), 3.18 (t, J = 6.8 Hz, 2H), 2.57 (t, J = 6.8 Hz, 2H), 2.00 (d, J = 18.2 Hz, 2H), 1.82 - 1.39 (m, 4H), 1.22 (d, J = 21.6 Hz, 8H), 0.80 (dd, J = 9.6, 5.5 Hz, 6H).

[0474] Compound 115-3 (500 mg, 1.0 mmol, 1.0 equiv) was dissolved in THF (10 mL), and then KOtBu (225 mg, 2.0 mmol, 2.0 equiv) was added to the reaction mixture in an ice-salt bath. The mixture was then warmed to room temperature and stirred for 1 h. TLC showed that most of the starting material had been converted to product. The reaction mixture was filtered and concentrated to give compound 115-4 as a yellow solid (265 mg, yield: 84.39%). LCMS: (ESI) m / z 376, (M+H)+.

[0475] Compound 115-4 (200 mg, 0.64 mmol, 1.0 equiv) was dissolved in MeCN (10 mL), and then compound 95-5 (197 mg, 0.96 mmol, 1.5 equiv) and CsCO (624 mg, 1.92 mmol, 3.0 equiv) were added, respectively. The mixture was then purged with nitrogen three times and reacted overnight at 80 °C under stirring. LCMS showed the presence of the target product. The reaction solution was extracted three times with ethyl acetate (10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thin-layer chromatography (DCM:MeOH = 20:1) to give compound 115-5 as a white oil (81 mg, yield: 40.31%). 1 H NMR (400 MHz, CD3OD) δ 9.36 (d, J = 8.8 Hz, 1H), 8.84 (s, 1H), 7.83 - 7.75 (m, 3H), 7.64 - 7.50 (m, 3H), 7.42 - 7.37 (m, 2H), 5.74 (d, J = 10.2 Hz, 1H), 5.18 (d, J = 7.6 Hz, 1H), 3.98 (s, 4H), 3.79 (t, J = 11.2 Hz, 1H), 2.49 (d, J = 12.3 Hz, 1H), 2.19 (d, J = 17.7 Hz, 4H), 2.07 - 1.95 (m, 1H), 1.90 (d, J = 7.4 Hz, 3H), 1.66 (d, J = 5.3 Hz, 2H).

[0476] Compound 115-5 (40 mg, 0.08 mmol, 1.0 equiv) was dissolved in MeCN (3 mL), and then 10 mL of hydrogen chloride-1,4-dioxane solution was added to the reaction mixture and stirred at room temperature for 3 hours. LCMS showed complete conversion of the starting material. The reaction mixture was concentrated and purified by preparative high-performance liquid chromatography to give compound 115 as a white solid (16.8 mg, yield: 43.49%, purity: 98%). LCMS: (ESI) m / z 400, (M+H); 1H NMR (400 MHz, DMSO-d6) δ 13.05 (s, 1H), 9.12 (d, J = 8.8 Hz, 1H), 8.88 (s, 1H), 8.14 (s, 1H), 7.87 (s, 1H), 7.84 - 7.76 (m, 2H), 7.60 (dd, J = 8.9, 4.1 Hz, 1H), 7.43 (dd, J = 14.3, 8.7 Hz, 2H), 7.30 (d, J = 9.2 Hz, 1H), 5.10 (d, J = 7.8 Hz, 1H), 3.93 (s, 3H), 2.26 (s, 3H), 1.82 (d, J = 7.2 Hz, 3H).

[0477] Example 116 6-Cyclopropyl-5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)quinoline

[0478] [ka]

[0479] Compound 116-1 (1.078 g, 4.83 mmol), tri-n-butyl(1-ethoxyvinyl)tin (2.617 g, 7.25 mmol), and Pd(PPh3)4 (0.558 g, 0.483 mmol) were added to 1,4-dioxane (24.0 mL) at room temperature. The resulting mixture was stirred at 120 °C for 24 hours. LCMS showed the formation of the product. The reaction mixture was cooled to room temperature, and aqueous KF solution (1.0 M, 36.0 mL) was added. The resulting mixture was stirred vigorously for 10 minutes and filtered through diatomaceous earth. The filter cake was washed successively with dichloromethane (30.0 mL × 2) and water (30.0 mL × 2). The filtrates were combined, the organic phase was separated, and the aqueous phase was extracted with dichloromethane (20.0 mL × 3). The organic phases were combined, washed successively with aqueous KF solution (1.0 M, 30.0 mL) and water (30.0 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure. The resulting residue was dried under reduced pressure to give crude compound 116-2 as a dark brown viscous liquid (3.92 g, crude yield: >100%, purity: 90.85%). LCMS (ESI) m / z 215.0, (M+H)+.

[0480] To a solution of crude compound 116-2 (3.92 g, 4.83 mmol (theoretical amount)) in tetrahydrofuran (24.2 mL) at room temperature, aqueous HCl (3.0 M, 16.1 mL, 48.3 mmol) was slowly added dropwise. The resulting mixture was stirred for 20 min. LCMS showed the formation of the product. Saturated aqueous sodium bicarbonate solution was slowly added dropwise to the reaction mixture to adjust the pH of the aqueous phase to approximately 7-8, and the resulting mixture was extracted with dichloromethane (30.0 mL × 6). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane:ethyl acetate = 10:1) to give compound 116-3 as a dark yellow liquid (0.632 g, yield: 70%, purity: 98.38%). LCMS (ESI) m / z 187.0, (M+H)+.

[0481] Compound 116-3 (0.632 g, 3.4 mmol) and CuBr (0.908 g, 4.07 mmol) were added to acetonitrile (17.0 mL) at room temperature. The resulting mixture was stirred for 10 minutes, and then amyl nitrite (0.516 g, 4.40 mmol) was added dropwise. The reaction mixture was stirred at 30 °C. LCMS showed the formation of the product. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (60.0 mL), and washed with saturated aqueous sodium bicarbonate solution (20.0 mL × 3). The aqueous phases were combined and extracted with ethyl acetate (30.0 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane: 100%) to give compound 116-4 as a yellow solid (0.507 g, yield: 60%, purity: 98.10%). LCMS (ESI) m / z 250.0, 252.0, (M+H)+.

[0482] To a solution of compound 116-4 (0.206 g, 0.82 mmol) in methanol (4.1 mL) was added NaBH4 (0.115 g, 3.04 mmol) in three portions at room temperature. The resulting mixture was stirred for 8 hours. LCMS showed the formation of the product. The reaction mixture was concentrated to dryness under reduced pressure, and saturated aqueous ammonium chloride solution (10.0 mL) and ethyl acetate (10.0 mL) were added to the resulting residue. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10.0 mL × 4). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 2:1) to give compound 116-5 as a yellow viscous liquid (0.183 g, yield: 89%, purity: 96.86%). LCMS (ESI) m / z 251.9, 253.9, (M+H)+.

[0483] To a solution of compound 116-5 (0.183 g, 0.72 mmol) in dichloromethane (7.2 mL) was added thionyl chloride (0.257 g, 2.16 mmol) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 10 min, warmed to room temperature, and stirred for 2 h. LCMS showed the formation of the product. The reaction mixture was diluted with dichloromethane (10.0 mL) and concentrated to dryness under reduced pressure. To the resulting residue, dichloromethane (10.0 mL) was added and again concentrated to dryness under reduced pressure. This procedure was repeated once more, and the resulting residue was dried under reduced pressure to give crude compound 116-6 as a dark yellow solid (0.222 g, crude yield: 100%, purity: 47.06%). LCMS (ESI) m / z 269.9, 271.9, 273.9, (M+H)+.

[0484] The crude product, compound 116-6 (0.222 g, 0.72 mmol (theoretical amount)) and cesium carbonate (1.173 g, 3.60 mmol) were added sequentially to N,N-dimethylformamide (7.2 mL) at room temperature. The resulting mixture was stirred for 2 minutes, and then compound A4 (0.215 g, 0.72 mmol) was added. The reaction mixture was stirred at 60 °C for 9 hours. LCMS showed the formation of the product. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), and then washed with water (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: dichloromethane: ethyl acetate = 1:1:1) to give compound 116-7 as a yellow solid (0.0872 g, yield: 23%, purity: 93.42%). LCMS (ESI) m / z 532.1, 534.1, (M+H)+.

[0485] Compound 116-7 (0.0426 g, 0.080 mmol), cyclopropylboronic acid (0.0103 g, 0.12 mmol), Pd(dppf)Cl (0.0059 g, 0.0080 mmol), and NaCO (0.017 g, 0.16 mmol) were added to a mixture of 1,4-dioxane (0.80 mL) and water (0.40 mL) at room temperature. The resulting mixture was stirred at 95 °C for 12 hours. LCMS showed the formation of the product. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (15.0 mL) and water (5.0 mL). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (5.0 mL × 4). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel thin layer chromatography (eluent: ethyl acetate:petroleum ether=4:1) to give compound 116-8 as a yellow jelly (0.0251 g, yield: 63%, purity: 96.46%). LCMS (ESI) m / z 494.4, (M+H)+.

[0486] To a solution of compound 116-8 (0.0251 g, 0.051 mmol) in dichloromethane (0.25 mL) was added trifluoroacetic acid (0.290 g, 2.55 mmol) at room temperature. The resulting mixture was stirred for 8 hours. LCMS showed the formation of the product. The reaction mixture was diluted with dichloromethane (5.0 mL), and saturated aqueous sodium bicarbonate solution was added to adjust the pH of the aqueous phase to approximately 7-8. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (5.0 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (eluent: dichloromethane:methanol = 20:1) to give light brown solid 116 (0.0163 g, yield: 78%, purity: 100%). LCMS (ESI) m / z 410.2, (M+H)+; 1H NMR (400 MHz, DMSO) δ 12.74 (s, 1H), 9.27 (d, J = 8.8 Hz, 1H), 8.83 (dd, J = 4.0, 1.2 Hz, 1H), 7.97 (s, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.70 (s, 1H), 7.58 (dd, J = 8.8, 4.0 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.20 (s, 1H), 7.07 (dd, J = 8.8, 2.0 Hz, 1H), 6.65 (q, J = 6.8 Hz, 1H), 3.94 (s, 3H), 2.63 (br s, 1H), 1.94 (d, J = 6.8 Hz, 3H), 1.28 - 1.24 (m, 2H), 1.97 - 1.21 (m, 2H).

[0487] Example 117 6-methyl-5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazino[3,4-b]pyridin-5-yl)oxy)ethyl)quinoline

[0488] [ka]

[0489] Compound 117-1 (500 mg, 3.26 mmol, 1.0 equiv) was dissolved in DMF (5.0 mL), NIS (1.5 g, 6.52 mmol, 2.0 equiv) was added, and the mixture was kept at room temperature overnight. LCMS monitoring showed complete conversion of compound 117-1 to compound 117-2. 20.0 mL of water was added to the reaction mixture, and a large amount of solid precipitated. The solid was filtered and dried on a rotary evaporator to give compound 117-2 (800 mg, 87%). 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 2.3 Hz, 1H), 8.07 - 8.03 (m, 1H).

[0490] Compound 117-2 (900 mg, 3.2 mmol, 1.0 equiv) was dissolved in DMF (5.0 mL) at room temperature. NaH (155 mg, 6.4 mmol, 2.0 equiv) was added in an ice-water bath and stirred at room temperature for 0.5 h. SEM-Cl (810 mg, 4.84 mmol, 1.5 equiv) was then added in an ice-water bath and the mixture was allowed to react overnight at room temperature. LCMS monitoring showed the formation of compound 117-3. After adding 15 mL of water, the reaction mixture was extracted three times with ethyl acetate (10.0 mL × 3). The combined organic phases were washed twice with 5% aqueous LiCl, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to give yellow oil 117-3 (760 mg, 57.5%). 1 H NMR (400 MHz, CD3OD) δ 8.56 (d, J = 2.2 Hz, 1H), 7.95 (d, J = 2.2 Hz, 1H), 5.77 (s, 2H), 3.64 (t, J = 8.0 Hz, 2H), 0.84 (t, J = 8.0 Hz, 2H), -0.11 (s, 9H) +.

[0491] Compound 117-3 (400 mg, 0.96 mmol, 1.0 equiv) was dissolved in 10.0 mL of tetrahydrofuran at room temperature. Compound 1-4 (600 mg, 2.88 mmol, 3.0 equiv), K2CO3 (400 mg, 2.88 mmol, 3.0 equiv), Pd[PPh3]4 (111 mg, 0.096 mmol, 0.1 equiv), and 2.0 mL of water were added, purged with nitrogen, and reacted at 75 °C overnight. LCMS monitoring indicated the disappearance of compound 117-3 and the formation of compound 117-4. The reaction mixture was subjected to suction filtration through diatomaceous earth, and the filter cake was washed with ethyl acetate. An appropriate amount of water was added to the filtrate, which was then extracted with EA two to three times. The resulting organic phases were combined, dried over anhydrous sodium sulfate, subjected to rotary evaporation, and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to give compound 117-4 as a yellow oil (300 mg, 84%). 1H NMR (400 MHz, CD3OD) δ 8.53 (d, J = 2.2 Hz, 1H), 8.50 (d, J = 2.2 Hz, 1H), 8.29 (s, 1H), 8.05 (s, 1H), 5.79 (s, 2H), 3.98 (s, 3H), 3.70 - 3.62 (m, 2H), 0.86 (t, J = 8.0 Hz, 2H), -0.11 (s, 9H).

[0492] Compound 117-4 (200 mg, 0.55 mmol, 1.0 equiv) was dissolved in dioxane (3.0 mL). KOH (185 mg, 3.3 mmol, 6.0 equiv), Pd(dba) (45 mg, 0.055 mmol, 0.1 equiv), methanesulfonato(2-di-t-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphen-2-yl)palladium(II) (26 mg, 0.027 mml, 0.05 equiv), and water (3.0 mL) were added. The mixture was purged with nitrogen and heated to 100 °C overnight. LCMS monitoring indicated the formation of compound 117-5. 5.0 mL of water was added to the reaction mixture, which was then extracted with an appropriate amount of ethyl acetate. The resulting organic phases were combined, dried over anhydrous sodium sulfate, subjected to rotary evaporation, and purified by thin layer chromatography (developing solvent: DCM / MeOH=20 / 1) to obtain a yellow solid 117-5 (25 mg, yield 13%). 1 H NMR (400 MHz, DMSO-d6) δ 9.77 (s, 1H), 8.33 (s, 1H), 8.22 (d, J = 2.6 Hz, 1H), 7.91 (d, J = 0.8 Hz, 1H), 7.68 (d, J = 2.6 Hz, 1H), 5.65 (s, 2H), 3.89 (s, 3H), 3.55 (t, J = 8.0 Hz, 2H), 0.80 - 0.75 (m, 2H), -0.15 (s, 9H).

[0493] Compound 117-5 (25 mg, 0.07 mmol, 1.0 equiv) was dissolved in acetonitrile (5.0 mL), and compound 95-5 (16 mg, 0.08 mmol, 1.2 equiv) and CsCO (25 mg, 0.21 mmol, 3.0 equiv) were added. The mixture was purged with nitrogen and maintained at 80 °C overnight. LCMS monitoring showed the formation of compound 117-6. After adding 8.0 mL of water, the reaction mixture was extracted with an appropriate amount of ethyl acetate. The resulting organic phases were combined, dried over anhydrous sodium sulfate, rotary evaporated, and purified by thin-layer chromatography (developing solvent: DCM / MeOH = 20 / 1) to give white solid 117-6 (23 mg, 61%). LCMS: (ESI) m / z 185.95, (M+H)+.

[0494] Compound 117-6 (23 mg) was dissolved in DCM (3.0 mL), TFA (1.0 mL) was added, and the mixture was allowed to react at room temperature for 1 hour. LCMS monitoring showed the reaction was complete. The reaction solution was directly subjected to rotary evaporation and purified by preparative high-performance liquid chromatography to give white solid 117 (7.2 mg, 41%). LCMS: (ESI) m / z 385.25, (M+H) +; 1 H NMR (400 MHz, CD3OD) δ 9.27 (d, J = 9.4 Hz, 1H), 8.81 - 8.76 (m, 1H), 8.27 (s, 1H), 7.90 - 7.81 (m, 2H), 7.68 (s, 1H), 7.64 - 7.57 (m, 2H), 7.49 (s, 1H), 6.36 - 6.27 (m, 1H), 3.95 (s, 3H), 2.72 (s, 3H), 1.99 - 1.94 (m, 3H).

[0495] The following compounds were synthesized according to the route in Example 117:

[0496] [Table 13]

[0497] Example 118 2-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)-2-(6-methylquinolin-5-yl)acetonitrile

[0498] [ka]

[0499] Compound 118-1 (300 mg, 1.75 mmol, 1.0 equiv.) and AcOH (5.0 mL) were added to TMSCN (1.74 g, 17.5 mmol, 10.0 equiv.) in an ice-water bath and reacted at room temperature for 3 days. TLC plate monitoring showed the disappearance of the starting material. After adding water, the reaction mixture was extracted with EA. The organic phase was washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, rotary evaporated, triturated with a suitable amount of DCM, suction filtered, and the solid was collected and rotary evaporated using an oil pump to give compound 118-2 as a white solid (200 mg, 57%). 1 H NMR (400 MHz, DMSO-d6) δ 8.86 (dd, J = 4.2, 1.5 Hz, 1H), 8.81 (d, J = 8.9 Hz, 1H), 7.95 (d, J = 8.7 Hz, 1H), 7.62 (d, J = 8.9 Hz, 1H), 7.14 (d, J = 4.6 Hz, 1H), 6.36 (d, J = 4.6 Hz, 1H), 2.59 (s, 3H).

[0500] Compound 118-2 (150 mg, 0.76 mmol, 1.0 equiv) was dissolved in DCM (5.0 mL) at room temperature, and TEA (231 mg, 2.2 mmol, 3.0 equiv) was added. Then, MsCl (131 mg, 1.14 mmol, 1.5 equiv) was added in an ice-water bath, and the mixture was allowed to react overnight at room temperature. LCMS monitoring indicated the formation of compound 118-3. After adding 15 mL of water, the reaction mixture was extracted three times with DCM (10.0 mL × 3). The combined organic phases were washed twice with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, concentrated, and purified by thin-layer chromatography (developing solvent: petroleum ether:ethyl acetate = 1 / 1) to give compound 118-3 as a yellow solid (80 mg, 48%). LCMS: (ESI) m / z 217.15, (M+H)+

[0501] Compound 118-3 (70 mg, 0.32 mmol, 1.5 equiv) was dissolved in 10.0 mL of acetonitrile at room temperature. Compound A4 (64 mg, 0.21 mmol, 1.0 equiv) and Cs2CO3 (206 mg, 0.63 mmol, 3.0 equiv) were added, and the mixture was purged with nitrogen and reacted at 80 °C for 10 min. LCMS monitoring indicated the disappearance of compound 118-3 and the formation of compound 118-4. An appropriate amount of water was added to the reaction mixture, and the mixture was extracted with EA two to three times. The resulting organic phases were combined, dried over anhydrous sodium sulfate, rotary evaporated, and purified by thin-layer chromatography (developing solvent: DCM / MeOH = 20 / 1) to give yellow solid 118-4 (80 mg, 77%). LCMS: (ESI) m / z 185.95, (M+H) +; 1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 2H), 8.28 (s, 1H), 8.02 (s, 2H), 7.83 (s, 1H), 7.70 (d, J = 8.7 Hz, 3H), 7.27 (d, J = 2.5 Hz, 2H), 5.77 (d, J = 9.9 Hz, 1H), 3.94 (s, 3H), 3.85 (s, 1H), 3.69 (s, 1H), 2.74 (s, 3H), 2.30 (s, 1H), 2.01 (d, J = 13.0 Hz, 1H), 1.93 (d, J = 12.8 Hz, 1H), 1.71 (s, 1H), 1.55 (s, 2H).

[0502] Compound 118-4 (60 mg) was dissolved in 1.0 mL of methanol, and 1.0 mL of 4N HCl in dioxane was added. The mixture was allowed to react at room temperature for 0.5 hours. LCMS monitoring showed the reaction was complete. The reaction solution was subjected to rotary evaporation and purified by preparative high-performance liquid chromatography to give white solid 118 (2.8 mg, 4%). LCMS: (ESI) m / z 384.10, (M+H) +; 1 H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 8.93 (s, 1H), 8.55 (d, J = 8.5 Hz, 1H), 8.39 (s, 1H), 8.12 (d, J = 8.7 Hz, 1H), 8.03 (s, 1H), 8.00 (s, 1H), 7.78 (s, 1H), 7.69 - 7.61 (m, 2H), 7.44 (d, J = 9.0 Hz, 1H), 3.91 (s, 3H), 2.71 (s, 3H).

[0503] Example 119 5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)cinnoline

[0504] [ka]

[0505] To a solution of compound 119-1 (5.0 g, 16.8 mmol, 1.0 equiv.) in acetonitrile (50.0 mL), water (25.0 mL), and 37% concentrated hydrochloric acid (12.0 mL) was slowly added NaNO (2663 mg, 38.6 mmol, 2.3 equiv.) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. To a solution of diethylamine (19.1 mL, 185 mmol, 11 equiv.) and potassium carbonate (14.73 g, 107 mmol, 6.4 equiv.) in acetonitrile (50.0 mL) and water (90.0 mL) at 0 °C, the resulting reaction mixture was slowly added. The reaction mixture was stirred at room temperature for 16 hours. After adding water (100.0 mL), the reaction mixture was extracted with ethyl acetate (100.0 mL × 2). The combined organic phase was washed with saturated brine (100.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-8.5%) to give compound 119-2 (4.9 g, yield 76.4%).

[0506] Compound 119-2 (2.0 g, 5.25 mmol, 1.0 equiv.), trimethylethynylsilane (619 mg, 6.3 mmol, 1.2 equiv.), Pd(PPh3)2Cl2 (1.1 g, 1.58 mmol, 0.3 equiv.), CuI (301 mg, 1.58 mmol, 0.3 equiv.), and triethylamine (137 mg, 0.42 mmol, 3.0 equiv.) were added sequentially to DMF (20.0 mL) at room temperature. The reaction mixture was stirred at 40 °C for 16 h. The reaction mixture was cooled to room temperature, water (80.0 mL) was added, and the reaction mixture was extracted with ethyl acetate (100.0 mL × 2). The organic phases were combined, washed with saturated brine (100.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0 to 7%) to give compound 119-3 (1.2 g, yield 65%).

[0507] To a solution of compound 119-3 (1.2 g, 3.4 mmol, 1.0 equiv.) in THF (20.0 mL) was slowly added TBAF (1 M, 6.8 mL, 6.8 mmol, 2.0 equiv.) at room temperature. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was cooled to 0 °C, slowly poured into aqueous NH4Cl (40.0 mL), and extracted with EA (20.0 mL × 2). The combined organic phases were washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-6.5%) to give compound 119-4 (631 mg, 66% yield).

[0508] Compound 119-4 (631 mg, 2.25 mmol, 1.0 equiv) was added to 1,2-dichlorobenzene (12.0 mL) at room temperature. The reaction mixture was stirred at 220 °C for 1 h under nitrogen protection using a microwave. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-25%) to give compound 119-5 (303 mg, yield 64.4%).

[0509] Compound 119-5 (303 mg, 1.45 mmol, 1.0 equiv.), tri-n-butyl(1-ethoxyvinyl)tin (785 mg, 2.17 mmol, 1.5 equiv.), and Pd(PPh3)4 (335 mg, 0.29 mmol, 0.2 equiv.) were added sequentially to dioxane (8.0 mL) at room temperature. The reaction mixture was stirred at 110 °C for 16 h under nitrogen protection. The reaction mixture was cooled to room temperature, and saturated aqueous KF solution (10.0 mL) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate (10.0 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was dissolved in THF (10.0 mL), and 3 N HCl (5.0 mL) was slowly added. The reaction mixture was stirred at room temperature for 40 minutes. After adjusting the pH to >7 with saturated aqueous sodium bicarbonate, the mixture was extracted with ethyl acetate (10.0 mL × 2). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-64%) to give compound 119-6 (388 mg, purity 55%, yield 85.5%).

[0510] To a mixture of compound 119-6 (100 mg, 55% purity, 0.32 mmol, 1.0 equiv.) in THF (5.0 mL) and methanol (5.0 mL) was added NaBH (120 mg, 3.16 mmol, 9.9 equiv.) slowly at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0 °C, poured slowly into aqueous NH Cl (20.0 mL), and extracted with ethyl acetate (20.0 mL × 2). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue, compound 119-7, was used directly in the next reaction step without further purification.

[0511] Compound 119-7 (57 mg, 0.32 mmol, 1.0 equiv) and MnO2 (280 mg, 3.2 mmol, 10.0 equiv) were added sequentially to DCM (6.0 mL) at room temperature. The reaction mixture was stirred at 40 °C for 6 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-69%) to give compound 119-8 (25 mg, total yield for two steps: 45%).

[0512] Methylsulfonyl chloride (18 mg, 0.157 mmol, 1.1 equiv) was slowly added to a solution of compound 119-8 (25 mg, 0.14 mmol, 1.0 equiv) and TEA (17 mg, 0.17 mmol, 1.2 equiv) in DCM (1.5 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 3 h. After adding water (10 mL), the reaction mixture was extracted with dichloromethane (10 mL × 2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue 119-9 was used directly in the next reaction step without purification.

[0513] Compound 119-9 (36 mg, 0.14 mmol, 1.0 equiv.), compound A4 (46 mg, 0.15 mmol, 1.1 equiv.), and cesium carbonate (137 mg, 0.42 mmol, 3.0 equiv.) were added sequentially to DMF (1.5 mL) at room temperature. The reaction mixture was stirred at 60 °C for 3 h. The reaction mixture was cooled to room temperature, water (10 mL) was added, and the reaction mixture was extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: (dichloromethane:methanol = 4:1) / dichloromethane = 0-22%) to give compound 119-10 (80 mg, purity 60%, total yield for two steps 73.8%).

[0514] To a solution of compound 119-10 (80 mg, 60% purity, 0.106 mmol, 1.0 equiv.) in DCM (3.0 mL) was slowly added TFA (1.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in DCM (10.0 mL). After adding aqueous sodium bicarbonate, the pH was adjusted to >7. The resulting residue was extracted with DCM (10.0 mL × 2). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: (dichloromethane:methanol = 4:1) / dichloromethane = 0-35%) to give compound 119 (22 mg, 56.2% yield, 100% purity). LCMS (ESI) m / z = 371.2 (M+H)+; 1 H NMR (400 MHz, DMSO) δ 12.77 (s, 1H), 9.49 (d, J = 6.1 Hz, 1H), 8.76 (d, J = 6.2 Hz, 1H), 8.39 (t, J = 13.0 Hz, 1H), 8.13 - 8.04 (m, 2H), 7.95 (dt, J = 17.9, 9.0 Hz, 1H), 7.79 (s, 1H), 7.39 (d, J = 9.0 Hz, 1H), 7.34 (d, J = 1.5 Hz, 1H), 7.13 (dt, J = 14.7, 7.3 Hz, 1H), 6.45 (q, J = 6.2 Hz, 1H), 3.91 (s, 3H), 1.78 (d, J = 6.2 Hz, 3H).

[0515] Example 121 6-methyl-5-(2,2,2-trifluoro-1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)quinoline

[0516] [ka]

[0517] Compound 121-1 (500 mg, 2.9 mmol, 1.0 equiv) was dissolved in DMF (10 ml), purged with nitrogen, and then cooled to 0 °C. CF3-TMS (4.15 g, 29.2 mmol, 10.0 equiv) was added and stirred at room temperature overnight. TLC showed no remaining starting material. The reaction mixture was extracted three times with ethyl acetate (10 ml × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether: EtOAc = 0% to 15% EA) to give compound 121-2 as a yellow solid (300 mg, 42%). LCMS: (ESI) m / z 242, (M+H)+

[0518] Compound 121-2 (300 mg, 1.2 mmol, 1.0 equiv) was dissolved in DCM (6 ml), TEA (376.9 mg, 3.7 mmol, 3.0 equiv) was added, and after cooling, MsCl (350.7 mg, 2.5 mmol, 2.0 equiv) was added and stirred at room temperature for 2 hours. TLC showed no remaining starting material and the formation of a new spot. After adding 10 mL of water, the reaction mixture was extracted three times with DCM (10 mL × 3). The organic phases were combined, washed with saturated NaHCO₃, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 121-3 as a yellow oil (700 mg, crude product). LCMS: (ESI) m / z 320, (M+H)+.

[0519] Compound A4 (150 mg, 0.5 mmol, 1.0 equiv.) was dissolved in acetonitrile (10 mL), followed by the addition of cesium carbonate (327.6 mg, 1.0 mmol, 3.0 equiv.) and compound 121-3 (402 mg, crude product). After the addition was complete, the reaction mixture was stirred at 80°C for 3 hours. TLC showed a small amount of starting material remaining. The reaction mixture was directly filtered, and the filtrate was evaporated to dryness and purified by thin-layer chromatography (eluent: DCM:MeOH = 20:1) to give compound 121-4 as a yellow oil (21 mg, crude product). LCMS: (ESI) m / z 522, (M+H)+

[0520] Compound 121-4 (21 mg, 0.096 mmol, 1.0 equiv) was dissolved in DCM / TFA (5 mL / 1 mL) and stirred at room temperature for 1 h. TLC monitoring showed the disappearance of 121-4 and the formation of a spot with increased polarity, while LCMS monitoring showed the formation of compound 121. The reaction solution was directly subjected to rotary evaporation and purified by preparative high-performance liquid chromatography to give compound 121 as a yellow solid (9.9 mg, yield: 56.3%, purity: 100%). LCMS: (ESI) m / z 438, (M+H)+; 1 H NMR (400 MHz, DMSO-d6) δ 13.00 (s, 1H), 8.93 (s, 1H), 8.28 (s, 1H), 8.18 - 8.10 (m, 2H), 7.95 (s, 1H), 7.75 (d, J = 8.7 Hz, 1H), 7.60 (s, 2H), 7.48 (s, 1H), 7.05 (s, 2H), 6.90 (s, 0H), 3.93 (s, 3H), 2.53 (s, 3H).

[0521] Example 122 6-methyl-5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl-2,2,2-d3)quinoline

[0522] [ka]

[0523] Compound 122-1 (100 mg, 0.58 mmol, 1.0 equiv) was dissolved in THF (5 mL), followed by the addition of compound 122-2 (1.1 mL, 1.16 mmol, 2.0 equiv). After the addition was complete, the reaction mixture was purged with nitrogen three times and stirred at −20° C. for 2 hours. TLC showed no remaining starting material, indicating that most of the starting material had been converted to product. The reaction mixture was extracted three times with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thin layer chromatography (eluent: DCM:MeOH=20:1) to give compound 122-3 as a yellow solid (80 mg, yield: 72%). LCMS: (ESI) m / z 191, (M+H)+.

[0524] Compound 122-3 (80 mg, 0.42 mmol, 1.0 equiv) was dissolved in DCM (5.0 mL), followed by the addition of compound MsCl (0.05 mL, 0.63 mmol, 1.5 equiv) and compound TEA (127 mg, 1.26 mmol, 3.0 equiv). After the addition was complete, the reaction mixture was purged with nitrogen three times and stirred at 25 °C for 2 hours. TLC showed no remaining starting material, indicating that most of the starting material had been converted to product. The reaction mixture was extracted three times with ethyl acetate (20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative TLC (DCM:MeOH = 25:1) to give compound 122-4 as a yellow oil (100 mg, 88%). LCMS: (ESI) m / z 209, (M+H)+.

[0525] Compound 122-4 (100 mg, 0.48 mmol, 1.5 equiv) was dissolved in acetonitrile (5 mL), followed by the addition of compound A4 (98 mg, 0.32 mmol, 1.0 equiv) and compound Cs2CO3 (312 mg, 0.96 mmol, 3.0 equiv). After the addition was complete, the reaction mixture was purged with nitrogen three times and stirred at 80 °C overnight. TLC showed no remaining starting material, indicating that most of the starting material had been converted to product. The reaction was quenched by the dropwise addition of saturated ammonium chloride solution. The reaction mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thin-layer chromatography (eluent: DCM:MeOH = 20:1) to give compound 122-5 as a yellow solid (80 mg, 53%). LCMS: (ESI) m / z 471, (M+H)+.

[0526] Compound 122-5 (80 mg, 0.17 mmol, 1.0 equiv) was dissolved in DCM (5 mL), and then compound TFA (2.0 mL) was added. After the addition was complete, the reaction mixture was purged with nitrogen three times and stirred at 25° C. for 2 hours. TLC showed no remaining starting material, indicating that most of the starting material had been converted to the product. The reaction was quenched by adding saturated ammonium chloride solution dropwise. The reaction mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative high-performance liquid chromatography to give compound 122 as a yellow solid (22 mg, purity: 98%, yield: 35%). LCMS: (ESI) m / z 387, (M+H)+; 1 H NMR (400 MHz, CD3OD) δ 9.29 (d, J = 9.1 Hz, 1H), 8.75 (s, 1H), 7.88 - 7.83 (m, 1H), 7.67 (s, 1H), 7.61 (s, 2H), 7.54 (d, J = 11.8 Hz, 1H), 7.32 (d, J = 9.2 Hz, 1H), 7.10 (d, J = 11.3 Hz, 1H), 6.90 (s, 1H), 6.19 (s, 1H), 3.93 (s, 3H), 2.71 (s, 3H).

[0527] Example 127 6-(Difluoromethyl)-5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)quinoline

[0528] [ka]

[0529] Compound 127-1 (1 g, 4.5 mmol) was dissolved in CCl4 (15 mL) at room temperature, and NBS (801 mg, 4.5 mmol) and AIBN (74 mg, 0.45 mmol) were added sequentially. The mixture was heated under nitrogen protection and stirred at 85 °C for 3 h. LCMS analysis showed that the ratio of starting material, product, and dibromide by-product was 1:6:3. After cooling to room temperature, the reaction mixture was extracted with DCM (30 mL × 3). The combined organic phases were then subjected to rotary evaporation. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 3:1) to give product 127-2 as a yellow solid (710 mg, purity 93%). LCMS (ESI) m / z 300.02 and 302.02, (M+H)+.

[0530] Mixture 127-2 (710 mg, 2.369 mmol) was dissolved in MeCN (15 mL), and NMO (1.1 g, 9.436 mmol) was added to it in an ice bath and stirred at room temperature overnight. LCMS showed the formation of product 3, with no remaining starting material. The reaction mixture was diluted with water and then extracted with DCM (30 mL × 3). The organic phases were combined and subjected to rotary evaporation. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to give product 127-3 as a white solid (546 mg, purity 90%). LCMS (ESI) m / z 236.07 and 308.07, (M+H)+.

[0531] Compound 127-3 (546 mg, 2.313 mmol) was dissolved in DCM (6 mL) and cooled to 0 °C. DAST (620 mg, 2.775 mmol) was slowly added dropwise and stirred at room temperature overnight. LCMS showed the formation of product 127-4, with no remaining starting material 127-3. The reaction mixture was quenched with saturated aqueous NaHCO3 in an ice bath and extracted with DCM (30 mL x 3). The combined organic phases were then subjected to rotary evaporation, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to give product 127-4 as a white solid (220 mg, purity 92%). LCMS (ESI) m / z 258.05 and 260.05, (M+H)+.

[0532] Compound 127-4 (1.2 g, 4.65 mmol) was dissolved in dioxane (10 mL) at room temperature, and tri-n-butyl(1-ethoxyvinyl)tin (1.68 g, 4.65 mmol) was added. Then, Pd(PPh3)4 (537 mg, 0.465 mmol) was added under nitrogen protection. The reaction mixture was heated at 110 °C overnight. LCMS showed no remaining starting material. The reaction mixture was cooled to room temperature, quenched with 30 mL of aqueous KF solution, and stirred for 0.5 h. The resulting solid was filtered through diatomaceous earth. The filtrate was extracted with ethyl acetate (40 mL × 3), and the combined organic phase was subjected to rotary evaporation. The crude product was redissolved in EA (10 mL), and 2 mL of aqueous hydrochloric acid (3 M) solution was added. The mixture was stirred at room temperature for 2 h. LCMS showed the formation of product 127-5. The reaction mixture was adjusted to neutral pH with aqueous Na2CO3 and extracted with ethyl acetate. The organic phases were then combined and subjected to rotary evaporation. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1) to give product 127-5 as a yellow oil (873 mg, purity 95%). LCMS (ESI) m / z 222.01, (M+H)+.

[0533] Compound 127-5 (873 mg, 3.94 mmol) was dissolved in DCM:MeOH = 1:1 (10 mL) at room temperature, and NaBH4 (298 mg, 7.89 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 5 h. LCMS showed the reaction of the raw material was complete. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with DCM (50 mL × 3). The organic phases were combined and then subjected to rotary evaporation. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to give the product compound 127-6 as a brown oil (435 mg, purity 80%). LCMS (ESI) m / z 224.08, (M+H)+.

[0534] Compound 127-6 (435 mg, 1.95 mmol) was dissolved in DCM (10 mL) at room temperature, and SOCl (463 mg, 3.9 mmol) was added at 0 °C. The reaction was stirred at room temperature for 4 h. LCMS showed the reaction of the raw material was complete. The reaction was directly subjected to rotary evaporation to give crude product compound 127-7 (513 mg).

[0535] Compound 127-7 (41 mg, 0.618 mmol) and compound A4 (50 mg, 0.618 mmol) were dissolved in DMF (1 mL) at room temperature, and CsCO (220 mg, 0.67 mmol) was added. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with EA (20 mL × 3). The combined organic phase was subjected to rotary evaporation. The crude product was purified by silica gel column chromatography (eluent: DCM:MeOH = 10:1) to give product 127-8 as a brown solid (15 mg, purity 80%). LCMS (ESI) m / z 504.21, (M+H)+.

[0536] Compound 127-8 (15 mg) was dissolved in MeOH (1 mL) at room temperature, and HCl (1 mL, 4 M dioxane solution) was added. The mixture was stirred at room temperature for 2 hours. LCMS showed the reaction of the starting material was complete. The reaction mixture was subjected to rotary evaporation and then purified by preparative high-performance liquid chromatography to obtain the product, compound 127, as a yellow solid (5.1 mg, purity 94.63%). LCMS (ESI) m / z 420.42, (M+H)+;1 H NMR (400 MHz, DMSO) δ 12.76 (s, 1H), 9.37 (d, J = 8.6 Hz, 1H), 9.06 (d, J = 3.4 Hz, 1H), 8.13 - 7.94 (m, 3H), 7.91 (s, 1H), 7.77 (dd, J = 8.8, 4.0 Hz, 1H), 7.65 (s, 1H), 7.36 (d, J = 9.0 Hz, 1H), 7.18 (s, 1H), 7.09 (dd, J = 9.0, 2.0 Hz, 1H), 6.64 - 6.57 (m, 1H), 3.90 (s, 3H), 1.91 (d, J = 6.6 Hz, 3H).

[0537] The following compounds were synthesized according to the route in Example 127:

[0538] [Table 14]

[0539] Example 129 6-Isopropyl-5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)quinoxaline

[0540] [ka]

[0541] Compound 129-1 (3 g, 13.4 mmol, 1.0 equiv.), tri-n-butyl(1-ethoxyvinyl)tin (7.25 g, 20.1 mmol, 1.5 equiv.), and Pd(PPh3)4 (3.1 g, 2.68 mmol, 0.2 equiv.) were added sequentially to dioxane (50.0 mL) at room temperature. The reaction mixture was stirred at 110 °C for 48 hours under nitrogen protection. The reaction mixture was cooled to room temperature, and saturated aqueous KF solution (30.0 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate (50.0 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was dissolved in THF (30.0 mL), and 3N HCl (20.0 mL) was slowly added. The reaction mixture was stirred at room temperature for 40 minutes. After adjusting the pH to >7 with saturated aqueous sodium bicarbonate, the mixture was extracted with ethyl acetate (50.0 mL × 2). The combined organic phases were washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-43%) to give compound 129-2 (983 mg, 39.2% yield).

[0542] To a solution of compound 129-2 (983 mg, 5.25 mmol, 1.0 equiv.) and CuBr (1.41 g, 6.3 mmol, 1.2 equiv.) in CHCN (45.0 mL) was slowly added t-BuONO (722 mg, 90% purity, 6.3 mmol, 1.2 equiv.) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-31%) to give compound 129-3 (970 mg, 73.6% yield).

[0543] Compound 129-3 (970 mg, 3.86 mmol, 1.0 equiv.), compound 129-4 (1.3 g, 7.72 mmol, 2.0 equiv.), Pd(dppf)Cl (560 mg, 0.77 mmol, 0.2 equiv.), and potassium carbonate (1.6 g, 11.6 mmol, 3.0 equiv.) were added sequentially to dioxane / HO (30 mL / 7.5 mL) at room temperature. The reaction mixture was stirred at 95 °C for 16 h. The reaction mixture was cooled to room temperature, water (20 mL) was added, and the reaction mixture was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0 to 26%) to give compound 129-5 (740 mg, yield 90.2%).

[0544] Compound 129-5 (150 mg, 0.707 mmol, 1.0 equiv.) and palladium on carbon (palladium loading: 10 wt%) (50 mg) were added sequentially to THF (10 mL) at room temperature. The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 16 hours, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The resulting residue 129-6 was used directly in the next reaction step without further purification.

[0545] To a solution of compound 129-6 (154 mg, 0.707 mmol, 1.0 equiv) in methanol (9.0 mL) was slowly added NaBH (107 mg, 2.83 mmol, 4.0 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0 °C, slowly poured into aqueous NH Cl (20.0 mL), and extracted with EA (20.0 mL × 2). The organic phases were combined, washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue 129-7 was used directly in the next reaction step without purification.

[0546] Compound 129-7 (156 mg, 0.707 mmol, 1.0 equiv) and MnO (615 mg, 7.07 mmol, 10.0 equiv) were added sequentially to DCM (6.0 mL) at room temperature. The reaction mixture was stirred at 40 °C for 6 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0 to 23.5%) to give compound 129-8 (71 mg, total yield for three steps: 46.4%).

[0547] To a solution of compound 129-8 (49 mg, 0.227 mmol, 1.0 equiv) in DCM (3.0 mL) was added thionyl chloride (81 mg, 0.68 mmol, 3.0 equiv) slowly at 0 °C. The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue 129-9 was used directly in the next reaction step without purification.

[0548] Compound 129-9 (53 mg, 0.227 mmol, 1.0 equiv.), compound A4 (68 mg, 0.227 mmol, 1.0 equiv.), and cesium carbonate (221 mg, 0.68 mmol, 3.0 equiv.) were added sequentially to DMF (2.0 mL) at room temperature. The reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was cooled to room temperature, water (10.0 mL) was added, and the reaction mixture was extracted with ethyl acetate (10.0 mL × 2). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: (dichloromethane:methanol = 4:1) / dichloromethane = 0-21%) to give compound 129-10 (51 mg, 82% purity, 37.1% total yield for two steps).

[0549] To a solution of compound 129-10 (51 mg, 82% purity, 0.106 mmol, 1.0 equiv.) in DCM (3.0 mL) was slowly added TFA (1.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in DCM (10.0 mL). After adding aqueous sodium bicarbonate, the pH was adjusted to >7. The resulting residue was extracted with DCM (10.0 mL × 2). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: (dichloromethane:methanol = 4:1) / dichloromethane = 0-27%) to give compound 129 (23 mg, 66.3% yield, 95.51% purity). LCMS (ESI) m / z = 413.2 (M+H)+; 1 H NMR (400 MHz, DMSO) δ 12.70 (s, 1H), 9.21 (d, J = 1.8 Hz, 1H), 9.09 (t, J = 9.1 Hz, 1H), 8.02 (d, J = 8.9 Hz, 1H), 7.94 - 7.83 (m, 1H), 7.64 (s, 1H), 7.37 (d, J = 9.0 Hz, 1H), 7.32 (t, J = 6.7 Hz, 1H), 7.28 (s, 1H), 7.05 (dd, J = 9.0, 2.2 Hz, 1H), 6.99 (s, 1H), 4.35 - 4.27 (m, 1H), 3.90 (s, 3H), 1.82 (d, J = 6.7 Hz, 3H), 1.34 (d, J = 6.9 Hz, 3H), 1.04 (d, J = 6.9 Hz, 3H).

[0550] The following compounds were synthesized according to the route in Example 129:

[0551] [Table 15]

[0552] Example 130 6-(fluoromethyl)-5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)quinoline

[0553] [ka]

[0554] Compound 130-1 (1.004 g, 4.52 mmol), NBS (0.845 g, 4.75 mmol), and AIBN (0.111 g, 0.678 mmol) were added to carbon tetrachloride (23.0 mL) at room temperature. The resulting mixture was stirred at 80 °C for 4 hours. LCMS showed the formation of the product. The reaction mixture was cooled to room temperature and concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane:petroleum ether = 1.2:1) to give compound 130-2 as a light yellow solid (1.126 g, yield: 83%, purity: 88%). LCMS (ESI) m / z 300.0, 301.9, 304.0, (M+H)+.

[0555] Compound 130-2 (1.005 g, 3.34 mmol) and anhydrous sodium acetate (0.685 g, 8.35 mmol) were added to N,N-dimethylformamide (8.3 mL) at room temperature. The resulting mixture was stirred at 80 °C for 2 hours. LCMS showed the formation of the product. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (30 mL) and water (20 mL). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with water (20 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane:petroleum ether = 4:1) to give compound 130-3 as a white solid (0.664 g, yield: 71%, purity: 95.52%). LCMS (ESI) m / z 280.0, 282.0, (M+H)+.

[0556] Compound 130-3 (0.664 g, 2.37 mmol) was added to a mixture of tetrahydrofuran (8.0 mL) and water (8.0 mL) at room temperature, followed by the addition of lithium hydroxide (0.114 g, 4.74 mmol). The resulting mixture was stirred for 2 h. LCMS showed the formation of the product. Aqueous HCl (3.0 M) was added to adjust the pH of the aqueous phase to approximately 7–8. The resulting mixture was extracted with a mixture of ethyl acetate and methanol (ethyl acetate:methanol = 10:1, v / v) (20.0 mL × 5). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure. The resulting residue was dried under reduced pressure to give crude compound 130-4 as a white solid (0.603 g, crude yield: >100%, purity: 96.93%). LCMS (ESI) m / z 238.0, 240.0, (M+H)+.

[0557] The crude product, compound 130-4 (0.310 g, 1.30 (theoretical amount)), was added to dichloromethane (11.0 mL) at room temperature. The resulting mixture was cooled in an ice-water bath, and then DAST (0.454 g, 2.82 mmol) was slowly added dropwise. The resulting mixture was stirred at 0 °C for 5 min, warmed to room temperature, and stirred for 13 h. LCMS showed the formation of the product. The reaction mixture was diluted with dichloromethane (30.0 mL), and the pH of the aqueous phase was adjusted to approximately 7-8 by adding saturated aqueous sodium bicarbonate solution. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (20.0 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane: petroleum ether = 3:1) to give compound 130-5 as a white solid (0.124 g, yield: 40%, purity: 97.84%). LCMS (ESI) m / z 240.0, 242.0, (M+H)+.

[0558] Compound 130-5 (0.124 g, 0.517 mmol), tri-n-butyl(1-ethoxyvinyl)tin (0.280 g, 0.775 mmol), and Pd(PPh3)4 (0.060 g, 0.0517 mmol) were added to 1,4-dioxane (2.6 mL) at room temperature. The resulting mixture was stirred at 120 °C for 12 hours. LCMS showed the formation of the product. The reaction mixture was cooled to room temperature, and an aqueous KF solution (1.0 M, 8.0 mL) was added. The resulting mixture was stirred vigorously for 30 minutes and filtered through diatomaceous earth. The filter cake was washed successively with dichloromethane (5.0 mL × 3) and water (5.0 mL × 2). The filtrates were combined, the organic phase was separated, and the aqueous phase was extracted with dichloromethane (10.0 mL × 3). The organic phases were combined, washed successively with aqueous KF solution (1.0 M, 20 mL) and water (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure. The resulting residue was dried under reduced pressure to obtain crude compound 130-6 as a brown viscous liquid (0.294 g, purity: 51.3%). LCMS (ESI) m / z 232.0, (M+H)+.

[0559] To a solution of crude compound 130-6 (0.294 g, 0.52 mmol (theoretical amount)) in tetrahydrofuran (2.6 mL) was slowly added dropwise HCl (3.0 M, 1.7 mL, 5.2 mmol) at room temperature. The resulting mixture was stirred for 2 h. LCMS showed the formation of the product. Saturated aqueous sodium bicarbonate solution was slowly added dropwise to the reaction mixture to adjust the pH of the aqueous phase to approximately 7–8, and the resulting mixture was extracted with dichloromethane (10.0 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 4:1) to give compound 130-7 as a yellow liquid (0.0766 g, total yield of the fifth and sixth steps: 38%, purity: 51.7%). LCMS (ESI) m / z 204.0, (M+H)+.

[0560] To a solution of compound 130-7 (0.0766 g, 0.377 mmol) in methanol (1.9 mL) was added NaBH4 (0.0285 g, 0.754 mmol) at room temperature. The resulting mixture was stirred for 3.5 hours. LCMS showed the formation of the product. The reaction mixture was diluted with saturated aqueous NH4Cl (5.0 mL), and the resulting mixture was extracted with ethyl acetate (5.0 mL × 5). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel thin-layer chromatography (eluent: petroleum ether: ethyl acetate = 1.5:1) to give compound 130-8 as a yellow liquid (0.0561 g, yield: 52%, purity: 71.48%). LCMS (ESI) m / z 206.1, (M+H)+.

[0561] To a solution of compound 130-8 (0.0561 g, 0.273 mmol) in dichloromethane (2.7 mL) was added thionyl chloride (0.0976 g, 0.82 mmol) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 10 min, then warmed to room temperature and stirred for 2 h. LCMS showed the formation of the product. The reaction mixture was concentrated to dryness under reduced pressure. Dichloromethane (3.0 mL) was added to the resulting residue, and the mixture was again concentrated to dryness under reduced pressure. This procedure was repeated twice more, and the resulting residue was dried under reduced pressure to give crude compound 130-9 as a yellow solid (0.0699 g, crude yield: 78%, purity: 79.24%). LCMS (ESI) m / z 223.8, 225.8, (M+H)+.

[0562] The crude product, compound 130-9 (0.0699 g, 0.273 mmol (theoretical amount)) and cesium carbonate (0.445 g, 1.366 mmol) were added sequentially to N,N-dimethylformamide (2.7 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 minutes, and then compound A4 (0.0815 g, 0.273 mmol) was added. The reaction mixture was stirred at 50 °C for 14 hours. LCMS showed the formation of the product. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (20 mL), and washed with water (10 mL × 2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel thin layer chromatography (eluent: ethyl acetate:petroleum ether = 6:1) to give light brown jelly 130-10 (0.0485 g, yield: 31%, purity: 83.73%). LCMS (ESI) m / z 486.2, (M+H)+.

[0563] Trifluoroacetic acid (0.745 g, 6.53 mmol) was added to a solution of compound 130-10 (0.0485 g, 0.10 mmol) in dichloromethane (0.5 mL) at room temperature. The resulting mixture was stirred for 4 hours. LCMS showed the formation of the product. The reaction mixture was diluted with dichloromethane (10.0 mL), and saturated aqueous sodium bicarbonate was added to adjust the pH of the aqueous phase to approximately 7-8. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (5.0 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (eluent: dichloromethane:methanol = 20:1) to give a dark yellow solid. The solid was added to a mixture of tert-butyl methyl ether and ethyl acetate (tert-butyl methyl ether:ethyl acetate = 10:1, v / v) (3.0 mL), heated to the boiling point, and then cooled to room temperature. The resulting mixture was filtered under reduced pressure. The filter cake was washed with a mixture of tert-butyl methyl ether and ethyl acetate (tert-butyl methyl ether:ethyl acetate=10:1, v / v) (0.5×2 mL) and dried under reduced pressure to give compound 130 (0.0184 g, yield: 44%, purity: 96.76%). LCMS (ESI) m / z 402.0, (M+H)+;1 H NMR (400 MHz, DMSO) δ 12.75 (s, 1H), 9.31 (d, J = 8.6 Hz, 1H), 8.97 (d, J = 3.2 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.91 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.72 - 7.63 (m, 2H), 7.35 (d, J = 8.8 Hz, 1H), 7.16 (s, 1H), 7.09 (d, J = 8.8 Hz, 1H), 6.47 (q, J = 6.4 Hz, 1H), 6.07 (dd, J = 47.2, 11.2 Hz, 1H), 5.84 (dd, J = 47.2, 11.2 Hz, 1H), 3.90 (s, 3H), 1.89 (d, J = 6.4 Hz, 3H).

[0564] Example 135 3-(1-methyl-1H-pyrazol-4-yl)-N-(1-(quinoxalin-5-yl)ethyl)-1H-indazol-5-amine

[0565] [ka]

[0566] Compound 135-1 (100 mg, 1.0 mmol, 1.0 equiv.), compound 1-4 (323 mg, 1.6 mmol, 1.5 equiv.), Pd(dppf)Cl (151 mg, 0.21 mmol, 0.2 equiv.), and potassium carbonate (430 mg, 3.1 mmol, 3.0 equiv.) were added sequentially to dioxane / HO (4 mL / 0.4 mL) at room temperature, purged with nitrogen three times, and stirred at 100 °C for 12 h. The reaction mixture was poured into aqueous NaCl (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by thin layer chromatography (eluent: EtOAc / PE = 4 / 1) to give compound 135-2 (220 mg, yield 87.1%, yellow solid). LCMS: (ESI) m / z 244.2, (M+H)+.

[0567] Compound 135-2 (220 mg, 0.90 mmol, 1.0 equiv) and DHP (228 mg, 2.7 mmol, 3.0 equiv) were dissolved in DCM (5.0 mL), followed by the addition of p-toluenesulfonic acid monohydrate (17 mg, 0.091 mmol, 0.1 equiv) and stirring at room temperature for 16 h. The reaction mixture was poured into aqueous NaCl (10.0 mL) and extracted with EtOAc (20.0 mL × 2). The combined organic phases were washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (eluent: EtOAc / PE = 1 / 1) to give compound 135-3 (120 mg, 40.5% yield, yellow solid). LCMS: (ESI) m / z 328.2, (M+H)+.

[0568] Compound 135-3 (120 mg, 0.37 mmol, 1.0 equiv) was dissolved in EtOH (4.0 mL) and HO (4.0 mL), and iron powder (102 mg, 1.8 mmol, 5.0 equiv) and NH4Cl (192 mg, 3.7 mmol, 10.0 equiv) were added. The mixture was stirred at 65 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give compound 135-4 (98 mg, 89.9% yield, light yellow solid). LCMS: (ESI) m / z 298.2, (M+H)+.

[0569] A solution of PBr3 (78 mg, 0.29 mmol, 1.0 equiv) in DCM (0.5 mL) was slowly added to a solution of compound 135-5 (50 mg, 0.29 mmol, 1.0 equiv) in DCM (3.0 mL) at 0 °C, and the mixture was stirred at room temperature for 0.5 h. The reaction mixture was concentrated to give compound 135-6 (68 mg, 99.9%, yellow oil). LCMS: (ESI) m / z 237.4, (M+H)+.

[0570] Compound 135-6 (41 mg, 0.17 mmol, 1.3 equiv.), compound 135-4 (40 mg, 0.13 mmol, 1.0 equiv.), and sodium bicarbonate (68 mg, 0.81 mmol, 6.0 equiv.) were added sequentially to DMF (2.0 mL) at room temperature and stirred at 60 °C for 4 hours. The reaction mixture was poured into aqueous NaCl solution (10.0 mL) and extracted with EtOAc (10.0 mL × 2). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by thin-layer chromatography (eluent: DCM / MeOH = 10 / 1) to give compound 135-7 (42 mg, 68.8% yield, light yellow solid). LCMS: (ESI) m / z 454.2, (M+H)+.

[0571] To a solution of compound 135-7 (42 mg, 0.093 mmol) in DCM (2.0 mL) and MeOH (2.0 mL) was slowly added 4 M hydrochloric acid in dioxane (2.0 mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative high-performance liquid chromatography to give compound 135 (2.6 mg, yield 7.6%, purity 100%, light yellow solid). LCMS: (ESI) m / z 370.2, (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 9.16 (d, J = 1.8 Hz, 1H), 9.10 (d, J = 1.8 Hz, 1H), 8.03 - 7.88 (m, 2H), 7.81 (dd, J = 8.4, 7.2 Hz, 1H), 7.59 (s, 1H), 7.34 (s, 1H), 7.22 (d, J = 8.9 Hz, 1H), 6.91 (dd, J = 8.9, 2.0 Hz, 1H), 6.48 (d, J = 2.0 Hz, 1H), 6.35 (d, J = 7.4 Hz, 1H), 5.88 (p, J = 6.8 Hz, 1H), 3.83 (s, 3H), 1.59 (d, J = 6.7 Hz, 3H).

[0572] Example 138 7-Ethyl-5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)quinoxaline

[0573] [ka]

[0574] Compound 138-1 (1000 mg, 4.05 mmol, 1.0 equiv.), iron powder (1133 mg, 20.23 mmol, 5 equiv.), and ammonium chloride (2170 mg, 40.5 mmol, 10 equiv.) were added sequentially to methanol / water (40 mL / 10 mL) at room temperature. The reaction mixture was stirred at 65 °C for 7 h. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. Water (20 mL) was added to the resulting residue, which was then extracted with dichloromethane (20 mL × 2). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / dichloromethane = 0-13%) to give compound 138-2 (770 mg, 87.6% yield).

[0575] Compound 138-2 (2975 mg, 13.7 mmol, 1.0 equiv.) and glyoxal (40% content, 3977 mg, 27.4 mmol, 2.0 equiv.) were added sequentially to ethanol (50 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure, and water (30 mL) was added to the resulting residue. The resulting residue was then extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-30%) to give compound 138-3 (1215 mg, 37.1% yield).

[0576] Compound 138-3 (570 mg, 2.38 mmol, 1.0 equiv) and pyridine hydrochloride (6.7 g) were stirred at 155 °C for 4 h. The reaction mixture was cooled to room temperature, and aqueous sodium bicarbonate was added to adjust the pH to >7. The reaction mixture was then extracted with dichloromethane (10.0 mL × 2). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-44%) to give compound 138-4 (100 mg, 18.6% yield).

[0577] Compound 138-4 (100 mg, 0.44 mmol, 1.0 equiv.), tributyl(1-ethoxyvinyl)tin (241 mg, 0.66 mmol, 1.5 equiv.), and Pd(PPh3)4 (103 mg, 0.088 mmol, 0.2 equiv.) were added sequentially to dioxane (3.0 mL) at room temperature. The reaction mixture was stirred at 110 °C for 16 h under nitrogen protection. The reaction mixture was cooled to room temperature, and an aqueous KF solution (5.0 mL) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate (10.0 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was dissolved in THF (5.0 mL), and 3 N HCl (2.0 mL) was slowly added. The reaction mixture was stirred at room temperature for 40 minutes. After adjusting the pH to >7 with saturated aqueous sodium bicarbonate, the reaction mixture was extracted with ethyl acetate (10.0 mL × 2). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: (dichloromethane:methanol = 4:1) / dichloromethane = 0-18%) to give compound 138-5 (30 mg, yield 35.9%).

[0578] Trifluoromethanesulfonic anhydride (68 mg, 0.24 mmol, 1.5 equiv) was slowly added to a solution of compound 138-5 (30 mg, 0.16 mmol, 1.0 equiv) and pyridine (19 mg, 0.24 mmol, 1.5 equiv) in DCM (1.6 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. After adjusting the pH to >7 with aqueous sodium bicarbonate, the reaction mixture was extracted with dichloromethane (5.0 mL × 2). The combined organic phases were washed with saturated brine (5.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by thin-layer chromatography (eluent: ethyl acetate / petroleum ether = 2:3) to give compound 138-6 (35 mg, 68.6% yield).

[0579] Compound 138-6 (35 mg, 0.11 mmol, 1.0 equiv.), potassium vinyltrifluoroborate (23.5 mg, 0.17 mmol, 1.6 equiv.), Pd(dppf)Cl (16 mg, 0.022 mmol, 0.2 equiv.), and potassium acetate (33 mg, 0.33 mmol, 3.0 equiv.) were added sequentially to dioxane / HO (2 mL / 0.5 mL) at room temperature. The reaction mixture was stirred at 90 °C for 12 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-20%) to give compound 138-7 (20 mg, 92.3% yield).

[0580] Compound 138-7 (20 mg, 0.1 mmol, 1.0 equiv.) and palladium on carbon (palladium loading: 10 wt%) (20 mg) were added sequentially to THF (5.0 mL) at room temperature. The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 5 hours, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The resulting residue 138-8 was used directly in the next reaction step without further purification.

[0581] To a solution of compound 138-8 (21 mg, 0.1 mmol, 1.0 equiv) in methanol (3.0 mL) was added NaBH (19 mg, 0.5 mmol, 5.0 equiv) slowly at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0 °C, poured slowly into aqueous NH Cl (5.0 mL), and extracted with EA (10.0 mL × 2). The organic phases were combined, washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue 138-9 was used directly in the next reaction step without purification.

[0582] Compound 138-9 (21 mg, 0.1 mmol, 1.0 equiv) and MnO (88 mg, 1.0 mmol, 10.0 equiv) were added sequentially to DCM (2.0 mL) at room temperature. The reaction mixture was stirred at 40 °C for 6 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by thin-layer chromatography (eluent: ethyl acetate / petroleum ether = 1:2) to give compound 138-10 (6 mg, total yield for three steps: 29.4%).

[0583] To a solution of compound 138-10 (6 mg, 0.03 mmol, 1.0 equiv.) in DCM (1.5 mL) was added thionyl chloride (11 mg, 0.09 mmol, 3.0 equiv.) slowly at 0 °C. The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue 138-11 was used directly in the next reaction step without purification.

[0584] Compound 138-11 (6.7 mg, 0.03 mmol, 1.0 equiv.), compound A4 (8 mg, 0.027 mmol, 0.9 equiv.), and cesium carbonate (29 mg, 0.09 mmol, 3.0 equiv.) were added sequentially to DMF (1.0 mL) at room temperature. The reaction mixture was stirred at 60 °C for 3 h. The reaction mixture was cooled to room temperature, water (5.0 mL) was added, and the reaction mixture was extracted with ethyl acetate (10.0 mL × 2). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by thin-layer chromatography (eluent: dichloromethane / methanol = 12:1) to give compound 138-12 (7.5 mg, total yield for two steps: 52.4%).

[0585] To a solution of compound 138-12 (7.5 mg, 0.016 mmol, 1.0 equiv.) in DCM (3.0 mL) was slowly added TFA (1.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in DCM (5.0 mL). After adding aqueous sodium bicarbonate, the pH was adjusted to >7. The resulting residue was extracted with DCM (5.0 mL x 2). The combined organic phases were washed with saturated brine (5.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by thin-layer chromatography (eluent: dichloromethane / methanol = 12:1) to give compound 138 (5.5 mg, 89% yield, 97.04% purity). LCMS (ESI) m / z = 399.2 (M+H)+; 1H NMR (400 MHz, DMSO) δ 12.70 (s, 1H), 9.09 - 9.01 (m, 2H), 7.96 - 7.88 (m, 2H), 7.83 (s, 1H), 7.58 (s, 1H), 7.39 (d, J = 9.0 Hz, 1H), 7.23 (s, 1H), 7.12 (dd, J = 9.0, 2.1 Hz, 1H), 6.75 - 6.63 (m, 1H), 3.90 (s, 3H), 2.84 (q, J = 7.5 Hz, 2H), 1.75 (d, J = 6.3 Hz, 3H), 1.23 (t, J = 7.5 Hz, 3H).

[0586] (Example 143) 7-Bromo-5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)quinoxaline

[0587] [ka]

[0588] To a solution of compound 143-1 (2.0 g, 9.2 mmol, 1.0 equivalent) in dioxane (25.0 mL), compound tri-n-butyl(1-ethoxyvinyl)tin (3.3 g, 9.2 mmol, 1.0 equivalent) and Pd(PPh3)4 (286 mg, 1.8 mmol, 0.2 equivalent) were added in that order, and the mixture was purged with nitrogen three times and stirred at 130 °C for 16 hours. Dilute hydrochloric acid (3 M, 60.0 mL) was added to the reaction mixture, which was stirred for 1 minute. After stirring, saturated aqueous potassium fluoride solution (60.0 mL) was added, and the mixture was stirred for 1 hour. The mixture was stirred for 1 hour. The mixture was filtered through diatomaceous earth, and the filtrate was poured into aqueous NaCl (15.0 mL) and extracted with EtOAc (60.0 mL × 2). The organic phases were combined, washed with saturated brine (60.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc / PE: 10% to 100%) to give compound 143-2 (1.4 g, 84.3% yield, yellow solid). LCMS: (ESI) m / z 181.2, (M+H)+.

[0589] Compound 143-2 (1.0 g, 5.8 mmol, 1.0 equiv) and NBS (1.2 g, 6.9 mmol, 1.2 equiv) were added sequentially to HAOc (15.0 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated, poured into aqueous NaHO (20.0 mL), and extracted with EtOAc (20.0 mL × 2). The combined organic phases were washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 143-3 (2.1 g, yellow solid). LCMS: (ESI) m / z 261.2, (M+H)+.

[0590] Compound 143-3 (2.1 g, 7.9 mmol, 1.0 equiv) was dissolved in EtOH (30.0 mL) and HO (15.0 mL). Iron powder (1.8 g, 31.7 mmol, 4.0 equiv) and NH4Cl (2.1 g, 39.6 mmol, 5.0 equiv) were added and the mixture was stirred at 80 °C for 4 h. The reaction mixture was filtered and concentrated under reduced pressure to give compound 143-4 (1.4 g, 77.2% yield, yellow solid). LCMS: (ESI) m / z 231.2, (M+H)+.

[0591] Compound 143-4 (1.4 g, 8.3 mmol, 1.0 equiv) and 40% aqueous glyoxal solution (1.2 g, 8.3 mmol, 1.0 equiv) were added to EtOH (25.0 mL) and stirred at 80 °C for 1 h. The reaction mixture was concentrated and poured into aqueous NaCl solution (20.0 mL) and extracted with EtOAc (20.0 mL × 2). The combined organic phases were washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / PE = 1 / 5) to give compound 143-5 (565 mg, 27.1% overall yield for three steps, light yellow solid). LCMS: (ESI) m / z 253.0, (M+H)+.

[0592] Compound 143-5 (565 mg, 2.3 mmol, 1.0 equiv) was dissolved in MeOH (5.0 mL) at room temperature, and NaBH (43 mg, 1.1 mmol, 0.5 equiv) was added at 0 °C and stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give compound 143-6 (580 mg, >100% yield, light yellow solid). LCMS: (ESI) m / z 255.0, (M+H)+.

[0593] A solution of compound 143-6 (130 mg, 0.51 mmol, 1.0 equiv) in DCM (2.0 mL) was slowly added with a solution of SOCl (122 mg, 1.0 mmol, 2.0 equiv) in DCM (0.5 mL) at 0 °C and stirred at room temperature for 2 h. The reaction mixture was concentrated to give compound 143-7 (140 mg, 100%, brown solid). LCMS: (ESI) m / z 273.0, (M+H)+.

[0594] Compound 143-7 (136 mg, 0.50 mmol, 1.5 equiv.), compound A4 (100 mg, 0.34 mmol, 1.0 equiv.), and cesium carbonate (437 mg, 1.3 mmol, 4.0 equiv.) were added sequentially to DMF (2.0 mL) at room temperature and stirred at 60 °C for 2 hours. The reaction mixture was poured into aqueous NaCl solution (20.0 mL) and extracted with EtOAc (20.0 mL × 2). The combined organic phases were washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by thin-layer chromatography (eluent: DCM / MeOH = 10 / 1) to give compound 143-8 (170 mg, 95.1% yield, light yellow solid). LCMS: (ESI) m / z 535.2, (M+H)+.

[0595] To a solution of compound 143-8 (30 mg, 0.056 mmol) in DCM (1.0 mL) and MeOH (1.0 mL) was slowly added 4 M hydrochloric acid in dioxane (2.0 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated and then purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give compound 143 (10 mg, yield 39.6%, purity 100%, light yellow solid). LCMS: (ESI) m / z 499.1, (M+H)+; 1 H NMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 9.17 (d, J = 1.8 Hz, 1H), 9.13 (d, J = 1.8 Hz, 1H), 8.31 (d, J = 2.2 Hz, 1H), 8.08 (d, J = 2.2 Hz, 1H), 8.00 (s, 1H), 7.61 (s, 1H), 7.42 (d, J = 9.0 Hz, 1H), 7.24 (d, J = 2.3 Hz, 1H), 7.13 (dd, J = 8.9, 2.3 Hz, 1H), 6.69 (q, J = 6.3 Hz, 1H), 3.91 (s, 3H), 1.75 (d, J = 6.3 Hz, 3H).

[0596] Example 144 7-Isopropyl-5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)quinoxaline

[0597] [ka]

[0598] Compound 144-1 (1040 mg, 4.27 mmol, 1.0 equiv.), tributyl(1-ethoxyvinyl)tin (1851 mg, 5.13 mmol, 1.2 equiv.), and Pd(PPh3)4 (986 mg, 0.85 mmol, 0.2 equiv.) were added sequentially to dioxane (15.0 mL) at room temperature. The reaction mixture was stirred at 100 °C for 48 hours under nitrogen protection. The reaction mixture was cooled to room temperature, and an aqueous KF solution (15.0 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate (20.0 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was dissolved in THF (10.0 mL), and 3N HCl (5.0 mL) was slowly added. The reaction mixture was stirred at room temperature for 40 minutes. After adjusting the pH to >7 with saturated aqueous sodium bicarbonate, the mixture was extracted with ethyl acetate (20.0 mL × 2). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / (dichloromethane / petroleum ether = 1:8) = 0-16%) to give compound 144-2 (683 mg, yield 77.4%).

[0599] Compound 144-2 (90 mg, 0.435 mmol, 1.0 equiv.), 129-4 (147 mg, 0.87 mmol, 2.0 equiv.), Pd(dppf)Cl2 (63 mg, 0.087 mmol, 0.2 equiv.), and potassium carbonate (180 mg, 1.3 mmol, 3.0 equiv.) were added sequentially to 1,4-dioxane / HO (4 mL / 1 mL) at room temperature. The reaction mixture was stirred at 105 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-20%) to give compound 144-3 (85 mg, 91.9% yield).

[0600] Compound 144-3 (85 mg, 0.4 mmol, 1.0 equiv.) and palladium on carbon (palladium loading: 10 wt%) (30 mg) were added sequentially to THF (6.0 mL) at room temperature. The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 16 hours, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The resulting residue, compound 144-4, was used directly in the next reaction step without further purification.

[0601] To a solution of compound 144-4 (90 mg, 0.4 mmol, 1.0 equiv) in methanol (5.0 mL) was added NaBH (53 mg, 1.4 mmol, 3.5 equiv) slowly at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0 °C, poured slowly into aqueous NH Cl (10.0 mL), and extracted with EA (10.0 mL × 2). The organic phases were combined, washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue 144-5 was used directly in the next reaction step without purification.

[0602] Compound 144-5 (88 mg, 0.4 mmol, 1.0 equiv) and MnO2 (350 mg, 4.0 mmol, 10.0 equiv) were added sequentially to DCM (5.0 mL) at room temperature. The reaction mixture was stirred at 40 °C for 6 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-27%) to give compound 144-6 (50 mg, total yield for three steps: 57.7%).

[0603] To a solution of compound 144-6 (50 mg, 0.236 mmol, 1.0 equiv) in DCM (3 mL) was slowly added thionyl chloride (84 mg, 0.7 mmol, 3.0 equiv) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue 144-7 was used directly in the next reaction step without further purification.

[0604] Compound 144-7 (55 mg, 0.236 mmol, 1.0 equiv.), compound A4 (49 mg, 0.164 mmol, 0.7 equiv.), and cesium carbonate (230 mg, 0.7 mmol, 3.0 equiv.) were added sequentially to DMF (3.0 mL) at room temperature. The reaction mixture was stirred at 60 °C for 8 h. The reaction mixture was cooled to room temperature, water (10.0 mL) was added, and the reaction mixture was extracted with ethyl acetate (10.0 mL × 2). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: (dichloromethane:methanol = 4:1) / dichloromethane = 0-16%) to give compound 144-8 (83 mg, total yield for two steps: 72.3%).

[0605] To a solution of compound 144-8 (83 mg, 0.167 mmol, 1.0 equiv.) in DCM (6.0 mL) was slowly added TFA (2.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in DCM (10.0 mL). The pH was adjusted to >7 with aqueous sodium bicarbonate solution, and the mixture was extracted with DCM (10.0 mL × 2). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by thin-layer chromatography (eluent: dichloromethane / methanol = 12:1) to give compound 144 (39 mg, yield 56.6%, purity 100%). LCMS (ESI) m / z = 413.3 (M+H)+; 1H NMR (400 MHz, DMSO)δ 12.74 (s, 1H), 9.04 (d, J = 4.4 Hz, 2H), 8.03 - 7.92 (m, 2H), 7.83 (d, J = 1.4 Hz, 1H), 7.62 (s, 1H), 7.38 (d, J = 9.0 Hz, 1H), 7.27 (s, 1H), 7.13 (dd, J = 9.0, 1.9 Hz, 1H), 6.70 (q, J = 6.3 Hz, 1H), 3.91 (s, 3H), 3.13 (dq, J = 13.4, 6.9 Hz, 1H), 1.76 (d, J = 6.3 Hz, 3H), 1.26 (d, J = 6.9 Hz, 6H).

[0606] The following compounds were synthesized according to the route in Example 144:

[0607] [Table 16]

[0608] Example 146 7-ethynyl-5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)quinoxaline

[0609] [ka]

[0610] Compound 143-8 (70 mg, 0.13 mmol, 1.0 equiv.), trimethylsilylacetylene (49 mg, 0.50 mmol, 3.8 equiv.), Pd(dppf)Cl (18 mg, 0.026 mmol, 0.2 equiv.), CuI (10 mg, 0.053 mmol, 0.4 equiv.), and EtN (85 mg, 0.84 mmol, 6.4 equiv.) were added sequentially to THF (2.0 mL) at room temperature, purged with nitrogen three times, and stirred at 90 °C for 4 h. The reaction mixture was poured into aqueous NaCl (10.0 mL) and extracted with EtOAc (20.0 mL × 2). The combined organic phase was washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by thin layer chromatography (eluent: DCM / MeOH = 10 / 1) to give compound 146-1 (44 mg, yield 60.9%, yellow solid). LCMS: (ESI) m / z 511.3, (M+H)+.

[0611] To a solution of compound 146-1 (44 mg, 0.071 mmol) in DCM (1.5 mL) was added TFA (1.5 mL) at room temperature, and the mixture was stirred at 40 °C for 4 hours. After adding aqueous NaHCO (10.0 mL) to the reaction mixture to adjust the pH to 8, the reaction mixture was extracted with EtOAc (10.0 mL × 2). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by thin-layer chromatography (developing solvent: DCM / MeOH = 10 / 1) to give compound 146 (9.6 mg, 34.4% yield, 100% purity, bright yellow solid). LCMS: (ESI) m / z 395.2, (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 9.14 (q, J = 1.9 Hz, 2H), 8.15 (d, J = 1.8 Hz, 1H), 7.99 - 7.94 (m, 3H), 7.58 (s, 1H), 7.41 (d, J = 9.0 Hz, 1H), 7.21 (d, J = 2.3 Hz, 1H), 7.12 (dd, J = 9.0, 2.3 Hz, 1H), 6.68 (q, J = 6.3 Hz, 1H), 4.53 (s, 1H), 3.90 (s, 3H), 1.75 (d, J = 6.3 Hz, 3H).

[0612] Example 149 4-(5-(5-(1-(quinoxalin-5-yl)ethoxy)-1H-indazol-3-yl)pyridin-2-yl)thiomorpholine 1,1-dioxide

[0613] [ka]

[0614] Compound 149-1 (270 mg, 0.96 mmol, 1.3 equiv.) was dissolved in toluene (10 mL), followed by the addition of compound 149-2 (100 mg, 0.74 mmol, 1.0 equiv.), t-BuoNa (106 mg, 1.1 mmol, 1.5 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (25.5 mg, 0.04 mmol, 0.06 equiv.), and Pd2(dba)3 (13.9 mg, 0.15 mmol, 0.02 equiv.). After the addition was complete, the reaction mixture was purged with nitrogen three times and stirred at 98 °C overnight. TLC showed no remaining starting material, indicating that most of the starting material had been converted to product. The reaction was quenched by the dropwise addition of saturated ammonium chloride solution. The reaction mixture was extracted three times with ethyl acetate (20 mL). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thin layer chromatography (eluent: DCM:MeOH=20:1) to give compound 149-3 as a yellow solid (110 mg, 37%). LCMS: (ESI) m / z 292, (M+H)+; 1 H NMR (400 MHz, CD3OD) δ 8.19 (s, 1H), 7.67 (d, J = 9.1 Hz, 1H), 6.91 (d, J = 9.1 Hz, 1H), 4.11 (d, J = 10.0 Hz, 4H), 3.09 - 3.02 (m, 4H).

[0615] Compound 149-3 (100 mg, 0.34 mmol, 1.0 equiv.) was dissolved in dioxane (5 mL), and then bis(pinacolato)diboron (132 mg, 0.52 mmol, 1.5 equiv.), KOAc (100.9 mg, 1.0 mmol, 3.0 equiv.), and Pd(dppf)Cl (25 mg, 0.034 mmol, 0.1 equiv.) were added. After the addition was complete, the reaction mixture was purged with nitrogen three times and stirred at 110 °C overnight. TLC showed no remaining starting material, indicating that most of the starting material had been converted to product. The reaction was quenched by dropwise addition of saturated ammonium chloride solution. The reaction mixture was extracted three times with ethyl acetate (10 mL). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thin layer chromatography (developing solvent: DCM:MeOH=20:1) to give compound 149-4 as a yellow solid (60 mg, 51%). LCMS: (ESI) m / z 339, (M+H)+; 1 H NMR (400 MHz, CD3OD) δ 8.44 (s, 1H), 7.87 (s, 1H), 6.96 - 6.90 (m, 1H), 4.17 (s, 4H), 3.06 (s, 4H), 1.31 (s, 12H).

[0616] Compound 149-4 (60 mg, 0.2 mmol, 1.3 equiv.) was dissolved in THF / HO (5 / 1 mL) and compound A8 (75 mg, 0.15 mmol, 1.0 equiv.), KCO (61 mg, 0.44 mmol, 3.0 equiv.), and Pd[PPh] (17.3 mg, 0.02 mmol, 0.1 equiv.) were added. After the addition was complete, the reaction mixture was purged with nitrogen three times and stirred at 80 °C overnight. TLC showed no remaining starting material, indicating that most of the starting material had been converted to product. The reaction was quenched by dropwise addition of saturated ammonium chloride solution. The reaction mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thin layer chromatography (developing solvent: DCM:MeOH=20:1) to give compound 149-5 as a yellow solid (60 mg, 86%). LCMS: (ESI) m / z 585, (M+H)+.

[0617] Compound 149-5 (80 mg, 0.17 mmol, 1.0 equiv) was dissolved in MeOH (5 ml), followed by the addition of HCl in dioxane (2.0 ml). After the addition was complete, the reaction mixture was purged with nitrogen three times and stirred at 25 °C for 2 hours. TLC showed no remaining starting material, indicating that most of the starting material had been converted to product. The reaction was quenched by the dropwise addition of saturated ammonium chloride solution. The reaction mixture was extracted three times with ethyl acetate (10 ml). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thin layer chromatography (eluent: DCM:MeOH = 20:1) to give compound 149 as a yellow solid (19.3 mg, purity: 98%, yield: 38%). LCMS: (ESI) m / z 501, (M+H)+; 1 H NMR (399 MHz, CD3OD) δ 9.06 (s, 1H), 8.96 (s, 1H), 8.12 (s, 1H), 7.98 (s, 2H), 7.78 (d, J = 13.4 Hz, 2H), 7.39 (s, 1H), 7.17 (d, J = 2.3 Hz, 1H), 7.08 (s, 1H), 6.93 (s, 1H), 6.74 (s, 1H), 4.22 (s, 4H), 3.15 (s, 4H), 1.76 (d, J = 6.4 Hz, 3H).

[0618] Example 151 N,N-Dimethyl-5-(1-(3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)quinolin-7-amine

[0619] [ka]

[0620] To a solution of compound 151-1 (100 mg, 0.45 mmol, 1.0 equivalent) in dioxane (3.0 mL), compound tributyl(1-ethoxyvinyl)tin (178 mg, 0.49 mmol, 1.1 equivalent) and Pd(PPh3)4 (103 mg, 0.090 mmol, 0.2 equivalent) were added in that order, purged with nitrogen three times, and stirred at 100 °C for 16 hours. Dilute hydrochloric acid (3 M, 3.0 mL) was added to the reaction mixture, and the mixture was stirred for 1 minute. After that, saturated aqueous potassium fluoride solution (3.0 mL) was added and stirred for 1 hour. The mixture was filtered through diatomaceous earth, and the filtrate was poured into aqueous NaCl solution (15.0 mL) and extracted with EtOAc (15.0 mL × 2). The organic phases were combined, washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was analyzed by thin layer chromatography (eluent: DCM / MeOH = 10 / 1) to give compound 151-2 (70 mg, 83.9% yield, light yellow solid). LCMS: (ESI) m / z 187.2, (M+H)+.

[0621] Compound 151-2 (70 mg, 0.38 mmol, 1.0 equiv) was dissolved in MeOH (2.0 mL) at room temperature, and NaBH (14 mg, 0.38 mmol, 1.0 equiv) was added at 0 °C and stirred at room temperature for 1 hour. The reaction mixture was poured into ice water (10.0 mL) and extracted with DCM (10.0 mL × 2). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 151-3 (75 mg, 95.4% yield, light yellow solid). LCMS: (ESI) m / z 189.2, (M+H)+.

[0622] A solution of compound 151-3 (75 mg, 0.40 mmol, 1.0 equiv) in DCM (3.0 mL) was slowly added with a solution of SOCl (569 mg, 4.8 mmol, 12.0 equiv) in DCM (0.5 mL) at 0 °C and stirred at room temperature for 1 hour. The reaction mixture was concentrated to give compound 151-4 (80 mg, 97.1%, yellow oil). LCMS: (ESI) m / z 207.2, (M+H)+.

[0623] Compound 151-4 (62 mg, 0.30 mmol, 1.3 equiv.), compound A4 (60 mg, 0.20 mmol, 1.0 equiv.), and cesium carbonate (327 mg, 1.0 mmol, 5.0 equiv.) were added sequentially to DMF (3.0 mL) at room temperature and stirred at 60 °C for 2 hours. The reaction mixture was poured into aqueous NaCl solution (10.0 mL) and extracted with EtOAc (10.0 mL × 2). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by thin-layer chromatography (eluent: DCM / MeOH = 10 / 1) to give compound 151-5 (60 mg, 63.7% yield, light yellow solid). LCMS: (ESI) m / z 469.2, (M+H)+.

[0624] Compound 151-5 (30 mg, 0.064 mmol, 1.0 equiv) was dissolved in MeOH (3.0 mL) and 40% aqueous formaldehyde (95 mg, 1.3 mmol, 20.0 equiv), AcOH (0.77 mg, 0.013 mmol, 0.2 equiv), and NaCNBH (20 mg, 0.32 mmol, 5.0 equiv) were added sequentially. The reaction mixture was allowed to react at room temperature for 24 hours. The reaction mixture was poured into aqueous NaCl (10.0 mL) and extracted with EtOAc (10.0 mL × 2). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by thin-layer chromatography (eluent: DCM / MeOH = 10 / 1) to give compound 151-6 (34 mg, yield >100%, yellow solid). LCMS: (ESI) m / z 497.0, (M+H)+.

[0625] To a solution of compound 151-6 (34 mg, 0.068 mmol) in DCM (2.0 mL) and MeOH (2.0 mL) was slowly added 4 M hydrochloric acid in dioxane (2.0 mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative high-performance liquid chromatography to give compound 151 (7.7 mg, yield 26.4%, purity 96.7%, yellow solid). LCMS: (ESI) m / z 413.2, (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ 12.75 (s, 1H), 8.88 (d, J = 8.4 Hz, 1H), 8.74 (d, J = 4.5 Hz, 1H), 8.08 (s, 1H), 7.78 (s, 1H), 7.61 (d, J = 2.6 Hz, 1H), 7.41 - 7.31 (m, 3H), 7.13 (dd, J = 8.9, 2.2 Hz, 1H), 6.90 (d, J = 2.5 Hz, 1H), 6.33 (q, J = 6.4 Hz, 1H), 3.90 (s, 3H), 3.07 (s, 6H), 1.80 - 1.77 (m, 3H).

[0626] Example 152 Imino(methyl)(5-(5-(1-(quinoxalin-5-yl)ethoxy)-1H-indazol-3-yl)pyridin-2-yl)-sulfanone

[0627] [ka]

[0628] Compound 152-1 (200 mg, 0.98 mmol, 1.0 equiv.) was dissolved in dioxane (10 mL), followed by the addition of bis(pinacolato)diboron (373.3 mg, 1.5 mmol, 1.5 equiv.), KOAc (288.5 mg, 3.0 mmol, 3.0 equiv.), and Pd(dppf)Cl (71.7 mg, 0.1 mmol, 0.1 equiv.). After the addition was complete, the reaction was purged with nitrogen and stirred at 105 °C overnight. TLC showed no remaining starting material. The reaction was directly filtered through diatomaceous earth, and the filtrate was evaporated to dryness and triturated with ethyl acetate and then petroleum ether to give compound 152-2 as a green oil (330 mg, crude). LCMS: (ESI) m / z 252, (M+H)+.

[0629] Compound A8 (100 mg, 0.2 mmol, 1.0 equiv) was dissolved in dioxane (8 mL) and HO (2 mL). Compound 152-2 (176 mg, crude), KCO (82.9 mg, 0.6 mmol, 3.0 equiv), and Pd[PPh] (23.1 mg, 0.02 mmol, 0.1 equiv) were added and stirred at 105 °C overnight. TLC showed no remaining starting material and the formation of a new spot. The reaction mixture was washed and extracted with ethyl acetate, rotary evaporated, and purified by thin-layer chromatography (developing solvent: petroleum ether:ethyl acetate = 3:1) to give compound 152-3 as a yellow oil (70 mg, crude). LCMS: (ESI) m / z 514, (M+H)+.

[0630] Compound 152-3 (70 mg, crude) was dissolved in MeOH (5 mL), CH3COONH4 (16.3 mg, 0.21 mmol, 1.5 equiv.) and iodobenzene diacetate (95.2 mg, 0.3 mmol, 2.0 equiv.) were added, and the mixture was stirred at room temperature for 1 h. TLC showed a small amount of starting material remaining and the formation of a new spot. After adding water, the reaction mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thin-layer chromatography (developing solvent: petroleum ether:ethyl acetate = 3:1) to give compound 152-4 as a yellow oil (25 mg, crude). LCMS: (ESI) m / z 529, (M+H)+.

[0631] Compound 152-4 (25 mg, crude product) was dissolved in DCM / TFA (6 mL / 1 mL) and stirred at room temperature for 2 hours. TLC monitoring showed the disappearance of compound 152-4 and the formation of a spot with increased polarity, and LCMS monitoring showed the formation of compound 152. The reaction solution was directly subjected to rotary evaporation and purified by preparative high-pressure liquid chromatography to give compound 152 as a yellow solid (5.4 mg, yield 25.7%, purity 98.8%). LCMS: (ESI) m / z 445, (M+H)+; 1H NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 8.99 (s, 1H), 8.92 (d, J = 16.6 Hz, 1H), 8.33 (d, J = 12.0 Hz, 1H), 8.18 (d, J = 8.2 Hz, 1H), 8.01 (d, J = 10.8 Hz, 2H), 7.82 (s, 1H), 7.48 (d, J = 9.3 Hz, 1H), 7.28 (s, 1H), 7.22 (d, J = 11.3 Hz, 1H), 6.82 (s, 1H), 3.61 (d, J = 6.6 Hz, 3H), 1.81 - 1.76 (m, 3H).

[0632] The following compounds were synthesized according to the route in Example 152:

[0633] [Table 17]

[0634] Example 156 (5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)quinolin-6-yl)methanol

[0635] [ka]

[0636] Compound 156-1 (0.293 g, 1.23 mmol) and imidazole (0.210 g, 3.08 mmol) were added to N,N-dimethylformamide (6.2 mL) at room temperature. The resulting reaction mixture was cooled in an ice-water bath, and then tert-butyldiphenylchlorosilane (0.508 g, 1.85 mmol) was slowly added dropwise. The resulting mixture was stirred at 0 °C for 5 minutes, then warmed to room temperature and stirred for 18 hours. LCMS showed the formation of the product. The reaction mixture was diluted with ethyl acetate (25 mL) and saturated aqueous sodium bicarbonate solution (10 mL). The organic phase was separated, washed with water (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane:petroleum ether=1.5:1) to give compound 156-2 as a colorless transparent liquid (0.497 g, yield: 91%, purity: 92.95%). LCMS (ESI) m / z 476.0, 478.0, (M+H)+.

[0637] Compound 156-2 (0.497 g, 1.04 mmol), potassium vinyltrifluoroborate (0.210 g, 1.57 mmol), Pd(dppf)Cl (0.0764 g, 0.104 mmol), and NaCO (0.221 g, 2.08 mmol) were added to a mixture of 1,4-dioxane (5.2 mL) and water (2.6 mL) at room temperature. The resulting mixture was stirred at 90 °C for 24 hours. LCMS showed the formation of the product. The reaction mixture was cooled to room temperature and diluted with dichloromethane (20 mL) and water (10 mL). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1) to give compound 156-3 as a light yellow liquid (0.355 g, yield: 74%, purity: 91.99%). LCMS (ESI) m / z 424.0, (M+H)+.

[0638] Compound 156-3 (0.355 g, 0.84 mmol) was added to a mixture of tetrahydrofuran (8.4 mL) and water (1.7 mL) at 0 °C, followed by the addition of K2OsO4·2H2O (0.031 g, 0.084 mmol). The resulting mixture was stirred for 20 min, and then NaIO4 (0.718 g, 3.36 mmol) was added. The reaction mixture was stirred at 0 °C for 15 min, warmed to room temperature, and stirred for 48 h. LCMS showed the formation of the product. The reaction mixture was diluted with dichloromethane (30 mL) and water (15 mL). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (15 mL × 3). The organic phases were combined, washed with saturated aqueous sodium sulfite solution (20 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 6:1) to give 156-4 as a light yellow viscous liquid (0.252 g, yield: 67%, purity: 95.58%). LCMS (ESI) m / z 426.0, (M+H)+.

[0639] To a solution of compound 156-4 (0.252 g, 0.59 mmol) in tetrahydrofuran (3.0 mL) was added dropwise a solution of methylmagnesium bromide (3.0 M, 2-methyltetrahydrofuran solution) (0.30 mL, 0.90 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 5 minutes, then warmed to room temperature and stirred for 28 hours. LCMS showed the formation of the product. The reaction mixture was diluted with saturated aqueous ammonium chloride (5.0 mL), and the resulting mixture was extracted with ethyl acetate (10.0 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 3:1) to give compound 156-5 as a white solid (0.238 g, yield: 86%, purity: 94.31%). LCMS (ESI) m / z 442.0, (M+H)+.

[0640] To a solution of compound 156-5 (0.124 g, 0.28 mmol) in dichloromethane (2.8 mL) was added thionyl chloride (0.0999 g, 0.84 mmol) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 5 minutes, then warmed to room temperature and stirred for 8 hours. LCMS showed the formation of the product. The reaction mixture was concentrated to dryness under reduced pressure. Dichloromethane (5.0 mL) was added to the resulting residue, and the mixture was again concentrated to dryness under reduced pressure. This procedure was repeated three more times, and the resulting residue was dried under reduced pressure to give crude product 156-6 as a light yellow solid (0.139 g, crude yield: 63%, purity: 63.44%). LCMS (ESI) m / z 460.2 (M+H)+.

[0641] The crude product, compound 156-6 (0.139 g, 0.28 mmol (theoretical amount)) and cesium carbonate (0.458 g, 1.40 mmol) were added sequentially to N,N-dimethylformamide (1.4 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 minutes, and then compound A4 (0.0838 g, 0.28 mmol) was added. The reaction mixture was stirred at 45° C. for 26 hours. LCMS showed the formation of the product. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (20 mL) and saturated aqueous ammonium chloride solution (10 mL). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel thin layer chromatography (eluent: dichloromethane:methanol=25:1) to give compound 156-7 as a light brown solid (0.0468 g, yield: 28%, purity: 81.88%). LCMS (ESI) m / z 484.0, (M+H)+.

[0642] Trifluoroacetic acid (0.552 g, 4.84 mmol) was added to a solution of compound 156-7 (0.0468 g, 0.0968 mmol) in dichloromethane (0.48 mL) at room temperature. The resulting mixture was stirred for 8 hours. LCMS showed the formation of the product. The reaction mixture was diluted with dichloromethane (10.0 mL), and saturated aqueous sodium bicarbonate solution was added to adjust the pH of the aqueous phase to approximately 7-8. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (5.0 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (eluent: dichloromethane:methanol = 12:1) to give compound 156 as a beige solid (0.0238 g, yield: 60%, purity: 97.88%). LCMS (ESI) m / z 400.2, (M+H)+;1H NMR (400 MHz, DMSO) δ 12.71 (s, 1H), 9.27 (d, J = 8.8 Hz, 1H), 8.87 (d, J = 2.8 Hz, 1H), 7.98 (s, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.71 (s, 1H), 7.58 (dd, J = 8.8, 4.0 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 7.23 (s, 1H), 7.08 (d, J = 8.8 Hz, 1H), 6.38 (d, J = 6.4 Hz, 1H), 5.69 (s, 1H), 5.09 (d, J = 12.8 Hz, 1H), 4.83 (d, J = 12.8 Hz, 1H), 3.92 (s, 3H), 1.89 (d, J = 6.4 Hz, 3H).

[0643] Example 158 5-(1-((3-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)quinoxaline

[0644] [ka]

[0645] Compound A8 (200 mg, 0.4 mmol, 1.0 equiv.) was dissolved in THF / HO (5 / 1 mL), followed by the addition of compound 158-1 (168 mg, 0.48 mmol, 1.2 equiv.), KCO (165.6 mg, 1.2 mmol, 3.0 equiv.), and Pd(pph) (46 mg, 0.04 mmol, 0.1 equiv.). After the addition was complete, the reaction mixture was purged with nitrogen three times and stirred at 75 °C overnight. TLC showed no remaining starting material, indicating that most of the starting material had been converted to product. The reaction mixture was then extracted three times with 20 mL of ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thin-layer chromatography (eluent: petroleum ether: ethyl acetate = 2:1) to give compound 158-2 as a yellow solid (60 mg, 25%). LCMS: (ESI) m / z 596, (M+H)+.

[0646] Compound 158-2 (60 mg, 0.1 mmol, 1.0 equiv) was dissolved in DCM / TFA (5 mL / 0.5 mL). After the addition was complete, the reaction mixture was stirred at 25° C. for 0.2 h. TLC showed no remaining starting material, indicating that most of the starting material had been converted to product. The reaction mixture was extracted three times with 10 ml of ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thin layer chromatography (developer: DCM:MeOH=20:1) to give compound 158-3 as a yellow solid (40 mg, 80%). LCMS: (ESI) m / z 496, (M+H)+.

[0647] Compound 158-3 (50 mg, 0.1 mmol, 1.0 equiv) was dissolved in methanol (4 mL), followed by the addition of formaldehyde (9.8 mg, 0.12 mmol, 1.2 equiv) and acetic acid (1 drop). The mixture was stirred at room temperature for 1 h, cooled, and NaBH(OAc)3 (64.1 mg, 0.3 mmol, 3.0 equiv) was added. The mixture was stirred at room temperature for 1 h. TLC showed a small amount of starting material remaining. After adding 10 mL of water, the reaction mixture was extracted three times with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thin layer chromatography (eluent: DCM:MeOH = 20:1) to give compound 158-4 as a yellow oil (26 mg, crude product). LCMS: (ESI) m / z 510, (M+H)+.

[0648] Compound 158-4 (26 mg, crude product) was dissolved in DCM / TFA (5 mL / 1 mL) and stirred at room temperature for 2 hours. TLC showed the reaction was complete. The reaction was directly subjected to rotary evaporation and purified by preparative high-performance liquid chromatography to give compound 158 as a yellow solid (2.7 mg, 12%). LCMS: (ESI) m / z 426, (M+H)+; 1 H NMR (400 MHz, CD3OD) δ 9.05 (s, 1H), 8.97 (s, 1H), 7.99 (s, 2H), 7.93 (s, 1H), 7.84 - 7.79 (m, 1H), 7.72 (s, 1H), 7.37 (d, J = 9.7 Hz, 1H), 7.17 (d, J = 7.3 Hz, 1H), 7.12 (s, 1H), 6.75 (d, J = 6.5 Hz, 1H), 5.23 (d, J = 8.7 Hz, 1H), 4.40 (t, J = 9.0 Hz, 2H), 4.20 (t, J = 8.2 Hz, 2H), 2.89 (s, 3H), 1.77 (d, J = 6.3 Hz, 3H).

[0649] Example 160 N,N-Dimethyl-2-(4-(5-(1-(quinoxalin-5-yl)ethoxy)-1H-indazol-3-yl)-1H-pyrazol-1-yl)ethane-1-sulfonamide

[0650] [ka]

[0651] To a solution of compound A9 (40 mg, 0.091 mmol, 1.0 equiv.) and compound 160-1 (14.45 mg, 0.14 mmol, 1.5 equiv.) in dioxane (10 mL), DBU (41.47 mg, 0.27 mmol, 3 equiv.) was added, purged with N2 three times, and stirred at 90 °C for 6 h. LCMS showed the completion of the reaction of compound A9. The reaction mixture was cooled, and 20 mL of water was added. The reaction mixture was extracted with ethyl acetate, separated, and dried by rotary evaporation to obtain the liquid as a yellow oil. The crude product was subjected to thin-layer chromatography (developing solvent: petroleum ether:ethyl acetate = 1:8) to obtain compound 160-2 (40 mg, yield: 76%). LCMS (ESI) m / z 576.2, (M+H)+.

[0652] Compound 160-2 (40 mg, 0.07 mmol, 1.0 equiv.) was dissolved in DCM (2 mL), TFA (1 mL) was added, and the mixture was allowed to react at 25° C. for 3 hours. LCMS analysis indicated the completion of the reaction of compound 160-2 and the formation of the product. The reaction mixture was subjected to rotary evaporation to obtain a crude product, which was purified by thin-layer chromatography (developing solvent: DCM:MeOH=10:1) to obtain compound 160 as a white solid (20.5 mg, 60% yield). LCMS (ESI) m / z 492.2, (M+H)+; 1H NMR (400 MHz, DMSO) δ 9.10 (dd, J = 15.6, 1.6 Hz, 2H), 8.19 (s, 1H), 8.09 - 7.96 (m, 2H), 7.92 - 7.82 (m, 1H), 7.70 - 7.55 (m, 2H), 7.39 (d, J = 9.2 Hz, 1H), 7.27 (d, J = 2.0 Hz, 1H), 7.10 (dd, J = 9.2, 2.4 Hz, 1H), 6.74 (q, J = 6.4 Hz, 1H), 4.56 (t, J = 7.2 Hz, 2H), 3.68 (d, J = 7.6 Hz, 4H), 2.77 (s, 7H), 1.75 (d, J = 6.4 Hz, 3H).

[0653] Example 162 4-(4-(5-(1-(quinoxalin-5-yl)ethoxy)-1H-indazol-3-yl)-1H-pyrazol-1-yl)piperidine-1-carbonitrile

[0654] [ka]

[0655] Compound 162-1 (113 mg, 0.30 mmol, 1.5 equiv.), compound A8 (100 mg, 0.20 mmol, 1.0 equiv.), potassium carbonate (83 mg, 0.60 mmol, 3.0 equiv.), and Pd(dppf)Cl (15 mg, 0.02 mmol, 0.1 equiv.) were dissolved in a mixture of dioxane (2 mL) and water (0.4 mL) and stirred at 90 °C for 12 h. LCMS analysis showed the formation of the product. The reaction mixture was cooled, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, rotary evaporated, and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1) to give an off-white solid 162-2 (100 mg, 80.20% yield). LCMS (ESI) m / z 624.32, (M+H)+.

[0656] To a solution of compound 162-2 (100 mg, 0.16 mmol, 1.0 equiv) in dichloromethane (2 mL) was added 1 mL of trifluoroacetic acid and stirred at room temperature for 1 hour. LCMS showed the formation of the product. The reaction was directly concentrated by rotary evaporation to give brownish oil 162-3 (70 mg, 99.36% yield). LCMS (ESI) m / z 440.21, (M+H)+.

[0657] Compound 162-3 (40 mg, 0.06 mmol, 1.0 equiv.), cyanogen bromide (10 mg, 0.10 mmol, 1.5 equiv.), and N,N-diisopropylethylamine (25 mg, 0.20 mmol, 3.0 equiv.) were dissolved in a dichloromethane solution (2 mL) and stirred at room temperature for 2 hours. LCMS showed the formation of the product. The reaction mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, subjected to rotary evaporation, and purified by preparative high-performance liquid chromatography to give the product, Compound 162 (1.5 mg, purity 100.00%). LCMS (ESI) m / z 465.2, (M+H)+).

[0658] Example 163 5-(1-((3-(1-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1-indazol-5-yl)oxy)ethyl)quinoxaline

[0659] [ka]

[0660] To a solution of compound 162-3 (40 mg, 0.09 mmol, 1.0 equiv.) in dichloromethane (1 mL) was added triethylamine (28 mg, 0.27 mmol, 3.0 equiv.), and the mixture was added methylsulfonyl chloride (16 mg, 0.14 mmol, 1.5 equiv.) at 0° C. and stirred at room temperature for 2 hours. LCMS showed the formation of the product. The reaction mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, rotary evaporated, and purified by preparative high-performance liquid chromatography to give the product, compound 163 (4.0 mg, purity 100.00%). LCMS (ESI) m / z 518.2, (M+H)+; 1 H NMR (400 MHz, DMSO) δ 13.47 - 13.34 (m, 1H), 12.77 (s, 1H), 9.12 (d, J = 2.0 Hz, 1H), 9.09 (d, J = 1.6 Hz, 1H), 8.04 (d, J = 6.4 Hz, 2H), 7.99 (d, J = 7.2 Hz, 1H), 7.86 (dd, J = 15.2, 7.2 Hz, 1H), 7.63 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.20 (s, 1H), 7.11 (dt, J = 11.2, 5.6Hz, 1H), 6.76 - 6.68 (m, 1H), 4.40 - 4.30 (m, 1H), 3.74 (d, J = 10.4 Hz, 2H), 2.99 (d, J = 5.6 Hz, 5H), 2.08 (dd, J = 36.0, 11.2 Hz, 3H), 2.06 - 1.90 (m, 2H), 1.75 (d, J = 6.4 Hz, 3H).

[0661] Example 164 7-Cyclopropyl-5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)quinoline

[0662] [ka]

[0663] To a solution of compound 164-1 (1 g, 4.2 mmol, 1.0 equiv.) and tributyl(1-ethoxyvinyl)tin (2.28 g, 6.3 mmol, 1.5 equiv.) in dioxane (6 mL), tetrakis(triphenylphosphine)palladium (970 mg, 0.84 mmol, 0.2 equiv.) was added, purged with N2 three times, and stirred at 110 °C for 12 h. LCMS showed the completion of the reaction of compound 164-1. The reaction mixture was cooled, 20 mL of KF solution was added, and the mixture was stirred at room temperature for 30 min. After filtration, the mixture was extracted with EA and washed with saturated brine. The organic phase was concentrated to give a liquid as a yellow oil. Dioxane (10 mL) and 4 M HCl (6 mL) were added, and the mixture was stirred at room temperature for 30 min. LCMS showed the completion of the reaction. After adjusting the pH to 7 with saturated NaHCO3 (20 mL), the reaction mixture was extracted with ethyl acetate, separated, and dried by rotary evaporation to obtain the liquid as a yellow oil. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 3:1) to obtain compound 164-2 (750 mg, yield: 88%). LCMS (ESI) m / z 202.2, (M+H)+.

[0664] Compound 164-2 (750 mg, 3.37 mmol, 1.0 equiv) and pyridine hydrochloride (10 g) were mixed and heated to 160 °C and stirred for 4 h. LCMS showed the formation of the product. The reaction mixture was cooled, and saturated Na2CO3 solution was added to the reaction mixture to adjust the pH to 8. The reaction mixture was then extracted with EA, separated, and dried by rotary evaporation to give a yellow solid. This was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate=2:1) ​​to give compound 164-3 as a yellow solid (450 mg, 65% yield). LCMS (ESI) m / z 188.2, (M+H)+.

[0665] Compound 164-3 (450 mg, 2.4 mmol, 1.0 equiv) and pyridine (380 mg, 4.81 mmol, 2 equiv) were dissolved in DCM (10 mL), and TfO (1.36 g, 4.81 mmol, 2 equiv) was added dropwise at 0 °C. The mixture was allowed to react at 25 °C for 2 h. LCMS showed the completion of the reaction and the formation of the product of compound 164-3. After adding saturated aqueous NaHCO (50 mL) to the reaction mixture, the reaction mixture was extracted with DCM. The organic phase was separated, dried by rotary evaporation, and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 4:1) to give compound 164-4 as a yellow oily liquid (300 mg, 40% yield). LCMS (ESI) m / z 320.2, (M+H)+).

[0666] Compound 164-4 (120 mg, 0.376 mmol, 1.0 equiv.) and cyclopropylboronic acid (32.3 mg, 0.376 mmol, 1 equiv.) were dissolved in toluene (2 mL) and water (0.2 mL). CsCO (167 mg, 0.51 mmol, 2 equiv.) and Pd(dppf)Cl (61 mg, 0.07 mmol, 0.2 equiv.) were added and the mixture was reacted at 90 °C for 6 h. LCMS analysis indicated the completion of the reaction and the formation of compound 5. The reaction mixture was filtered, dried by rotary evaporation, and purified by thin-layer chromatography (developing solvent: petroleum ether:ethyl acetate = 3:1) to give compound 164-5 as a colorless oil (70 mg, 88% yield). LCMS (ESI) m / z 212.2, (M+H)+.

[0667] Compound 164-5 (70 mg, 0.33 mmol, 1.0 equiv) was dissolved in EtOAc (10 mL), and NaBH4 (9.5 mg, 0.25 mol, 1 equiv) was added. The mixture was stirred at room temperature for 30 min. LCMS showed the formation of the product. The reaction mixture was quenched with saturated NH4Cl solution, extracted with EtOAc, separated, and dried by rotary evaporation to give a yellow solid. Thin layer chromatography (eluent: petroleum ether:ethyl acetate = 1:1) gave compound 164-6 as an off-white solid (70 mg, 99% yield). LCMS (ESI) m / z 214.2 (M+H)+.

[0668] Compound 164-6 (70 mg, 0.33 mmol, 1.0 equiv) was dissolved in DCM (3 mL), and SOCl (78 mg, 0.66 mmol, 2 equiv) was added dropwise at 0 °C, followed by reaction at room temperature for 1 hour. LCMS showed the completion of the reaction of compound 164-6 and the formation of the product. The reaction mixture was extracted with aqueous NaHCO and DCM. The organic phase was separated and dried by rotary evaporation to give compound 164-7 as a yellow oily liquid (70 mg, 92% yield). LCMS (ESI) m / z 232.2, (M+H)).

[0669] Compound 164-7 (70 mg, 0.3 mmol, 1.0 equiv.) and compound A4 (90 mg, 0.3 mmol, 1 equiv.) were dissolved in DMF (2 mL), and CsCO (196 mg, 0.6 mmol, 2 equiv.) was added. The mixture was allowed to react at 60 °C for 6 h. LCMS analysis indicated the completion of the reaction of compound 164-7 and the formation of the product. The reaction mixture was extracted with water and EtOAc. The organic phase was separated, dried by rotary evaporation, and purified by thin-layer chromatography (developing solvent: DCM:MeOH = 10:1) to give compound 164-8 as a yellow solid (110 mg, 74% yield). LCMS (ESI) m / z 494.2, (M+H)+).

[0670] Compound 164-8 (110 mg, 0.16 mmol, 1.0 equiv.) was dissolved in DCM (2 mL), TFA (1 mL) was added, and the mixture was allowed to react at 25° C. for 3 hours. LCMS analysis indicated the completion of the reaction of compound 164-8 and the formation of the product. The reaction mixture was subjected to rotary evaporation to obtain a crude product, which was purified by thin-layer chromatography (developing solvent: DCM:MeOH=10:1) to obtain compound 164 as a white solid (85 mg, 93% yield). LCMS (ESI) m / z 410.2, (M+H)+; 1H NMR (400 MHz, DMSO) δ 9.04 (d, J = 8.4 Hz, 1H), 8.94 (d, J = 4.4 Hz, 1H), 8.08 (s, 1H), 7.77 (s, 1H), 7.63 (t, J = 5.2 Hz, 4H), 7.38 (d, J = 9.2 Hz, 1H), 7.30 (d, J = 2.0 Hz, 1H), 7.12 (dd, J = 9.2, 2.4 Hz, 1H), 6.36 (q, J = 6.4 Hz, 1H), 3.91 (s, 3H), 2.20 - 2.12 (m, 1H), 1.78 (d, J = 6.4 Hz, 3H), 1.09 (dd, J = 8.4, 2.3 Hz, 2H), 0.87 (dd, J = 18.4, 13.2 Hz, 1H), 0.78 (t, J = 16.4 Hz, 1H).

[0671] Example 165 6-methyl-5-(1-((3-(1-methyl-1H-1,2,3-triazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)quinoline

[0672] [ka]

[0673] Compound A5-5 (6.4 g, 18.587 mmol) and compound 95-5 (3.8 g, 18.597 mmol) were dissolved in 60 mL of DMF at room temperature, and Cs2CO3 (12.12 g, 37.19 mmol) was added. The reaction mixture was reacted at 60 °C for 12 h. LCMS showed the reaction was complete, with no remaining starting material. The reaction mixture was quenched with water and extracted with EA (100 mL × 3). The organic phases were combined and then subjected to rotary evaporation. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 3:1) to give the product as a white solid (5.93 g, yield 62.11%, purity 98%). LCMS (ESI) m / z 514.01, (M+H)+.

[0674] Compound 165-1 (50 mg, 0.12 mmol) was dissolved in DMF (2 mL) at room temperature, and trimethylsilylacetylene (17 mg, 0.17 mmol) was added. Next, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride·dichloromethane complex (9 mg, 0.011 mmol), DIEA (30 mg, 0.23 mmol), and CuI (2.2 mg, 0.011 mmol) were added under nitrogen protection. The reaction mixture was stirred at 100 °C for 16 h. LCMS showed no remaining starting material. After cooling to room temperature, the reaction mixture was quenched with 100 mL of aqueous solution, and the resulting solid was filtered through diatomaceous earth. The filtrate was extracted with ethyl acetate (100 mL × 3), and the combined organic phases were subjected to rotary evaporation. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1) to give the product 165-2 as a yellow solid (40 mg, purity 100%, yield 71%, [M+H] + = 484.0).

[0675] Compound 165-2 (110 mg, 0.23 mmol) was dissolved in MeOH (5 mL) at room temperature, and K2CO3 (31 mg, 0.23 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 hours. LCMS showed the reaction of the raw material was complete. The organic phases were combined and then subjected to rotary evaporation. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:3) to give product 165-3 as a yellow oil (88 mg, 100% purity, 94% yield, [M+H]+ = 412.0).

[0676] Compound 165-3 (50 mg, 0.12 mmol) was dissolved in DMF (2 mL) at room temperature, and trimethylsilylazidomethane (23 mg, 0.18 mmol), DIEA (31 mg, 0.24 mmol), and CuI (2.3 mg, 0.01 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 2 hours. LCMS showed the reaction of the raw material was complete. The reaction mixture was directly subjected to rotary evaporation to obtain the crude product, which was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to obtain product 165-4 as a yellow oil (19 mg, 100% purity, >29% yield, [M+H]+ = 540.8).

[0677] Compound 165-4 (30 mg, 0.05 mmol) and compound TBAF (22 mg, 0.08 mmol) were dissolved in THF (2 mL) at room temperature, and CsCO (136 mg, 0.42 mmol) was added. The reaction mixture was stirred at 60 °C for 2 h. LCMS showed the reaction of the raw material was complete. The reaction mixture was diluted with water and extracted with EA (30 mL × 3). The organic phases were combined and then subjected to rotary evaporation. The crude product was purified by silica gel column chromatography (eluent: DCM:MeOH = 10:1) to give product 165-5 as a yellow oil (20 mg, purity 90%, LCMS: 469.2 [M+H]).

[0678] Compound 165-5 (20 mg, 0.04 mmol) was dissolved in DCM (2 mL) at room temperature, and TFA (1 mL) was added to it in an ice bath. The reaction mixture was stirred at room temperature for 1 hour. LCMS showed the reaction of the raw material was complete. The reaction mixture was concentrated, and the organic phase was collected and purified by preparative high-performance liquid chromatography to give compound 165 as a white solid (7.1 mg, purity: 100%, LCMS: 385.0 [M+H]). 1H NMR(400 MHz, DMSO) δ 12.95 (s, 1H), 9.21 (d,J = 8.6 Hz, 1H), 8.83 - 8.74 (m, 1H), 8.36 (s, 1H), 7.80 (d,J = 8.6 Hz, 1H), 7.65 (s, 1H), 7.58 (d,J = 8.7 Hz, 1H), 7.53 (dd,J = 8.8, 4.1 Hz, 1H), 7.38 (d,J = 9.0 Hz, 1H), 7.09 (dd,J = 9.0, 2.4 Hz, 1H), 6.23 (d,J = 6.7 Hz, 1H), 4.14 (s, 3H), 2.81 (s, 3H), 1.87 (d,J = 6.7 Hz, 3H).

[0679] Example 166 6-ethynyl-5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)quinoline

[0680] [ka]

[0681] Compound 166-1 (800 mg, 3.4 mmol, 1.0 equiv.) was dissolved in toluene (20.0 mL), followed by the addition of compound DIBAL-H (965 mg, 6.8 mmol, 2.0 equiv.). After the addition was complete, the reaction mixture was purged with nitrogen three times and stirred at -10 °C for 1 h. TLC showed no remaining starting material, indicating that most of the starting material had been converted to product. The reaction mixture was then extracted three times with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (eluent: DCM:MeOH = 100:1 to 30:1) to give compound 166-2 as a yellow solid (460 mg, 56%). LCMS: (ESI) m / z 237, (M+H)+.

[0682] Compound 166-2 (70 mg, 0.3 mmol, 1.0 equiv.) was dissolved in dioxane (10 mL), followed by the addition of trimethylsilylacetylene (63.0 mg, 0.6 mmol, 2.0 equiv.), CuI (12.2 mg, 0.065 mmol, 0.2 equiv.), TEA (97 mg, 0.96 mmol, 3.0 equiv.), and Pd(pph2)Cl2 (22.4 mg, 0.03 mmol, 0.1 equiv.). After the addition was complete, the reaction mixture was stirred at 25 °C for 12 h. TLC showed no remaining starting material, indicating that most of the starting material had been converted to product. The reaction mixture was extracted three times with 10 mL of ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thin layer chromatography (eluent: DCM:MeOH=20:1) to give compound 166-3 as a yellow solid (40 mg, 50%). LCMS: (ESI) m / z 254, (M+H)+.

[0683] Compound 166-3 (40 mg, 0.15 mmol, 1.0 equiv) was dissolved in THF (5 mL) and purged with nitrogen three times. Then, compound CHMgBr (0.6 mL, 0.3 mmol, 2.0 equiv) was added. After the addition was complete, the reaction mixture was stirred at 0–25°C for 2 h. TLC showed no remaining starting material, indicating that most of the starting material had been converted to product. The reaction mixture was extracted three times with 10 mL of ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thin-layer chromatography (eluent: DCM:MeOH = 20:1) to give compound 166-4 as a yellow solid (25 mg, 62%). LCMS: (ESI) m / z 270, (M+H)+.

[0684] Compound 166-4 (25 mg, 0.09 mmol, 1.0 equiv) was dissolved in DCM (5 mL), followed by the addition of compound TEA (28 mg, 0.28 mmol, 3.0 equiv) and compound MsCl (31.0 mg, 0.186 mmol, 1.5 equiv). After the addition was complete, the reaction mixture was purged with nitrogen three times and stirred at 25 °C for 2 h. TLC showed no remaining starting material, indicating that most of the starting material had been converted to product. The reaction mixture was extracted three times with ethyl acetate (10 ml). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thin-layer chromatography (eluent: DCM:MeOH = 30:1) to give compound 166-5 as a yellow solid (20 mg, 46%). LCMS: (ESI) m / z 348 (M+H)+.

[0685] Compound 166-5 (15 mg, 0.05 mmol, 1.0 equiv.) was dissolved in MeCN (5 mL), followed by the addition of CsCO (23.0 mg, 0.15 mmol, 3.0 equiv.) and A4 (20 mg, 0.1 mmol, 1.5 equiv.). After the addition was complete, the reaction mixture was purged with nitrogen three times and stirred at 80 °C for 3 h. TLC showed no remaining starting material, indicating that most of the starting material had been converted to product. The reaction mixture was extracted three times with ethyl acetate (10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thin-layer chromatography (eluent: DCM:MeOH = 30:1) to give compound 166-6 as a yellow solid (10 mg, 57%). LCMS: (ESI) m / z 478 (M+H)+.

[0686] Compound 166-6 (10 mg, 0.02 mmol, 1.0 equiv) was dissolved in DCM (3.0 ml), and then compound TFA (1.0 ml) was added. After the addition was complete, the reaction mixture was purged with nitrogen three times and stirred at 25° C. for 2.0 hours. TLC showed no remaining starting material, indicating that most of the starting material had been converted to product. The reaction mixture was extracted three times with ethyl acetate (10 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative high-performance liquid chromatography to give compound 166 as a white solid (2.0 mg, 99% purity, 28% yield). LCMS: (ESI) m / z 394, (M+H) +; 1 H NMR (400 MHz, CD3OD) δ 9.38 (d, J = 11.6 Hz, 1H), 8.80 (s, 1H), 7.98 - 7.85 (m, 4H), 7.56 (d, J = 14.3 Hz, 1H), 7.31 (d, J = 9.7 Hz, 1H), 7.21 - 7.11 (m, 2H), 6.58 (d, J = 6.2 Hz, 1H), 4.46 (s, 1H), 4.01 (s, 3H), 1.94 (d, J = 6.9 Hz, 3H).

[0687] Example 168 6-methyl-5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)cinnoline

[0688] [ka]

[0689] Compound 119-5 (905 mg, 4.33 mmol, 1.0 equiv.), compound 168-1 (942 mg, 5.2 mmol, 1.2 equiv.), methanesulfonato(2-di-t-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphen-2-yl)palladium(II) (625 mg, 0.65 mmol, 0.15 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (376 mg, 0.65 mmol, 0.15 equiv.), and cesium carbonate (2.8 g, 8.66 mmol, 2.0 equiv.) were added sequentially to dioxane (16.0 mL) at room temperature. The reaction mixture was stirred at 100 °C for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: (dichloromethane:methanol=4:1) / dichloromethane=0-20%) to obtain compound 168-2 (1.107 g, yield 82.7%).

[0690] To a solution of compound 168-2 (1107 mg, 3.58 mmol, 1.0 equiv.) in THF (12.0 mL) was slowly added concentrated hydrochloric acid (12 M, 12.0 mL, 144 mmol, 40.2 equiv.) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After adding water (30.0 mL), the reaction mixture was extracted with ethyl acetate (20.0 mL × 2). The organic phase was discarded. After adjusting the pH to >7 with aqueous sodium bicarbonate, the aqueous phase was extracted with DCM / i-PrOH = 85:15 (30.0 mL × 3). The organic phases were combined, washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: (dichloromethane:methanol=4:1) / dichloromethane=0-30%) to obtain compound 168-3 (502 mg, yield 96.6%).

[0691] NBS (647 mg, 3.63 mmol, 1.05 equiv) was slowly added to a solution of compound 168-3 (502 mg, 3.46 mmol, 1.0 equiv) in acetonitrile (8.0 mL) and DMF (8.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 h. Water (30.0 mL) was added to the reaction mixture, and the reaction mixture was extracted with EA (20.0 mL × 2). The combined organic phases were washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: (dichloromethane:methanol = 4:1) / dichloromethane = 0 to 21.6%) to give compound 168-4 (680 mg, 87.8% yield).

[0692] Compound 168-4 (680 mg, 3.03 mmol, 1.0 equiv.), tributyl(1-ethoxyvinyl)tin (1644 mg, 4.55 mmol, 1.5 equiv.), and Pd(PPh3)4 (700 mg, 0.606 mmol, 0.2 equiv.) were added sequentially to dioxane (20.0 mL) at room temperature. The reaction mixture was stirred at 110 °C for 16 h under nitrogen protection. The reaction mixture was cooled to room temperature, and an aqueous KF solution (20.0 mL) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate (20.0 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was dissolved in THF (10.0 mL), and 3 N HCl (5.0 mL) was slowly added. The reaction mixture was stirred at room temperature for 40 minutes. After adjusting the pH to >7 with saturated aqueous sodium bicarbonate, the mixture was extracted with ethyl acetate (20.0 mL × 2). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: (dichloromethane:methanol = 4:1) / dichloromethane = 0-19%) to give compound 168-5 (403 mg, 71% yield).

[0693] To a solution of compound 168-5 (403 mg, 2.15 mmol, 1.0 equiv.) and CuBr (577 mg, 2.58 mmol, 1.2 equiv.) in CHCN (25.0 mL) was slowly added t-BuONO (296 mg, 90% purity, 2.58 mmol, 1.2 equiv.) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / dichloromethane = 0-10%) to give compound 168-6 (437 mg, 80.9% yield).

[0694] Compound 168-6 (145 mg, 0.58 mmol, 1.0 equiv.), compound methylboronic acid (290 mg, 50% purity, 1.16 mmol, 2.0 equiv.), Pd(dppf)Cl (83 mg, 0.116 mmol, 0.2 equiv.), and potassium carbonate (239 mg, 1.74 mmol, 3.0 equiv.) were added sequentially to dioxane / HO (6 mL / 1.5 mL) at room temperature. The reaction mixture was stirred at 95 °C for 16 h. The reaction mixture was cooled to room temperature, water (10 mL) was added, and the reaction mixture was extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: (dichloromethane:methanol=4:1) / dichloromethane=0-18%) to give compound 168-7 (35 mg, yield 32.5%).

[0695] To a solution of compound 168-7 (35 mg, 0.188 mmol, 1.0 equiv) in methanol (3.0 mL) was slowly added NaBH4 (8 mg, 0.207 mmol, 1.1 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to 0 °C, slowly poured into aqueous NH4Cl (10.0 mL), and extracted with EA (10.0 mL × 2). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purifi...

Claims

1. A compound of formula (I), 【Chemistry 1】 or a pharmaceutically acceptable salt, hydrate, solvate, isotopically substituted derivative, or stereoisomer thereof, wherein X 1 is a N atom or CR 5 and; X 2 is a N atom or CR 2 and; X 3 is a N atom or CR 3 and; R 1 teeth 【Chemistry 2】 selected from the group consisting of: Y is an O atom, an S atom, -S(O)-, -S(O) 2 - and NR 11 selected from the group consisting of: R 2 and R 5 are independently H atoms, -OH, -COOH, and -NR 11 R 12 , -CN, halogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 6～10 Aryl, 5- to 10-membered heteroaryl, C 3～8 cycloalkyl, and 3- to 8-membered heterocyclyl, wherein C 6～10 Aryl, 5- to 10-membered heteroaryl, C 3～8 Cycloalkyl and 3- to 8-membered heterocyclyl are each independently C 1～6 Alkoxy, -OH, -COOH, -NR 11 R 12 , -CN, halogen, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, and C 1～6 optionally substituted with one or more substituents selected from the group consisting of hydroxyalkyl; R 3 is H atom, -OH, -COOH, -NR 11 R 12 , -CN, halogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 6～10 Aryl, 5- to 10-membered heteroaryl, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, and -OR 13 is selected from the group consisting of However, X is CR 5 and R 1 but 【Transformation 3】 and C 2 When R is a 6-membered nitrogen-containing heteroaryl ring, 3 is not an H atom; C 1 Ring is C 6～10 Aryl, 5- to 10-membered heteroaryl, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, 5- to 10-membered heteroaryl fused to 3- to 8-membered heterocyclyl, C 6～10 5- to 10-membered heteroaryl fused with an aryl, 3- to 8-membered heterocyclyl fused with a 5- to 10-membered heteroaryl, and C fused with a 5- to 10-membered heteroaryl 6～10 aryl; Each L 1 are independently chemical bonds, -C 1～6 Alkylene-, -O-, -C 1～6 Alkylene-O-, -OC 1～6 Alkylene-, -C(O)-, -OC(O)-, -C(O)-O-, -S-, -S(O)-, -S(O) 2 -, -S(O)(=NR 11 )-, -C 1～6 Alkylene-C(O)-, -C(O)-C 1～6 Alkylene-, -C 1～6 Alkylene-S(O) 2 -, -S(O) 2 -C 1～6 Alkylene-, -C 1～6 Alkylene-S(O)(=NR 11 )-, -S(O)(=NR 11 )-C 1～6 Alkylene-, 3- to 8-membered heterocyclylene, C 3～8 Cycloalkylene, C 6～10 Arylene, 5- to 10-membered heteroarylene, -C 1～6 Alkylene-OC 1～6 Alkylene-O-, -OC 1～6 Alkylene-OC 1～6 Alkylene-, -NR 11 -, -NR 11 -C 1～6 Alkylene-, -C 1～6 Alkylene-NR 11 -, -C 1～6 Alkylene-NR 11 -C 1～6 Alkylene-O-, -OC 1～6 Alkylene-NR 11 -C 1～6 Alkylene-, -NH-C(O)-, -C(O)-NR 11 -, -C(O)-NR 11 -C 1～6 Alkylene-, -C 1～6 Alkylene-C(O)-NR 11 -, -C 1～6 Alkylene-NR 11 -C(O)- and -NR 11 -C(O)-C 1～6 alkylene-, wherein C 1～6 Each alkylene is independently C 1～6 Alkyl, halogen, -OH, -COOH, -NR 11 R 12 , -CN, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 6～10 Aryl, 5- to 10-membered heteroaryl, C 3～8 optionally substituted with one or more substituents selected from the group consisting of cycloalkyl, and 3- to 8-membered heterocyclyl; Each R 4 are independently H atoms, -OH, -COOH, -CN, halogens, and C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, -C(O)-NR 11 R 12 , -NR 11 R 12 , C 1～6 Hydroxyalkyl, C 6～10 Aryl, 5- to 10-membered heteroaryl, C 3～8 cycloalkyl, and 3- to 10-membered heterocyclyl, wherein C 6～10 Aryl, 5- to 10-membered heteroaryl, C 3～8 Cycloalkyl and 3- to 10-membered heterocyclyl are each independently —CN, —OH, C 1～6 Alkyl, C 1～6 Hydroxyalkyl, -C(O)-R 14 , -C(O)-NR 11 R 12 , Oxo, C 1～6 Alkoxy, -S(O) 2 -C 1～6 Alkyl, -NR 11 R 12 , imino, halogen, -C 1～6 Alkylene-NR 11 R 12 , -NR 11 -C(O)-R 14 , -NR 11 -S(O) 2 -R 14 , -S(O)(=NR 11 )-R 14 , -S(O) 2 -R 14 , -C(=NR 11 )-NR 11 R 12 , -S(O) 2 -NR 11 R 12 , and -C 1～6 Alkylene-C(O)-NR 11 R 12 and optionally substituted with one or more substituents selected from the group consisting of: C 2 Ring is C 6～10 Aryl, 5- to 10-membered heteroaryl, C 3～8 C fused to cycloalkyl, 3- to 8-membered heterocyclyl, 5- to 10-membered heteroaryl 3～8 Cycloalkyl, C 6～10 5- to 10-membered heteroaryl fused with aryl, C fused with 3- to 8-membered heterocyclyl 6～10 Aryl, C 3～8 5- to 10-membered heteroaryl fused to cycloalkyl, C fused to 5- to 10-membered heteroaryl 6～10 Aryl, and C 6～10 selected from the group consisting of 3- to 8-membered heterocyclyl fused to an aryl; C 3 Ring is C 6～10 Aryl, 5- to 10-membered heteroaryl, C 3～8 C fused to cycloalkyl, 3- to 8-membered heterocyclyl, 5- to 10-membered heteroaryl 3～8 Cycloalkyl, C 6～10 5-10 membered heteroaryl fused to aryl, C 3～8 5- to 10-membered heteroaryl fused to cycloalkyl and C fused to 5- to 10-membered heteroaryl 6～10 aryl; R 6 is H atom, -OH, -COOH, -NR 11 R 12 , -CN, halogen, C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, -C 1～6 Alkylene-NR 11 R 12 , C 6～10 Aryl, 5- to 10-membered heteroaryl, C 3～8 selected from the group consisting of cycloalkyl, and 3- to 8-membered heterocyclyl; R 7 is H atom, -OH, -COOH, -C(O)-R 14 , -C(O)-NR 11 R 12 , -NR 11 R 12 , -CN, halogen, oxo, C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Alkoxy, C 1～6 Deuterated alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 6～10 Aryl, 5- to 10-membered heteroaryl, C 3～8 selected from the group consisting of cycloalkyl, and 3- to 8-membered heterocyclyl; L 2 -C(O)-, -S(O) 2 -, and -S(O)-; L 3 and L 4 are each independently a chemical bond, -C 1～6 Alkylene-, -O-, -C 1～6 Alkylene-O-, -OC 1～6 Alkylene-, -C(O)-, -OC(O)-, -C(O)-O-, -S-, -S(O)-, -S(O) 2 -, -C 1～6 Alkylene-C(O)-, -C(O)-C 1～6 Alkylene-, -C 1～6 Alkylene-S(O) 2 -, -S(O) 2 -C 1～6 Alkylene-, -C 1～6 Alkylene-OC 1～6 Alkylene-O-, -OC 1～6 Alkylene-OC 1～6 Alkylene-, -NR 11 -, -NR 11 -C 1～6 Alkylene-, -C 1～6 Alkylene-NR 11 -, -C 1～6 Alkylene-NR 11 -C 1～6 Alkylene-O-, -OC 1～6 Alkylene-NR 11 -C 1～6 Alkylene-, -NR 11 -C(O)-, -C(O)-NR 11 -, -C(O)-NR 11 -C 1～6 Alkylene-, -C 1～6 Alkylene-C(O)-NR 11 -, -C 1～6 Alkylene-NR 11 -C(O)- and -NR 11 -C(O)-C 1～6 alkylene-, wherein C 1～6 Each alkylene is independently C 1～6 Alkyl, halogen, -OH, -COOH, -NR 11 R 12 , -CN, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 6～10 Aryl, 5- to 10-membered heteroaryl, C 3～8 optionally substituted with one or more substituents selected from the group consisting of cycloalkyl, and 3- to 8-membered heterocyclyl; R 8 and R 10 are independently H atoms, -OH, -COOH, -CN, halogens, and C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 6～10 Aryl, 5- to 10-membered heteroaryl, C 3～8 cycloalkyl, and 3- to 8-membered heterocyclyl, wherein C 6～10 Aryl, 5- to 10-membered heteroaryl, C 3～8 Cycloalkyl and 3- to 8-membered heterocyclyl are each independently —CN, —OH, C 1～6 Alkyl, -C(O)-C 1～6 Alkyl, -C(O)-C 1～6 Hydroxyalkyl, -C(O)-NR 11 R 12 , Oxo, C 1～6 Alkoxy, -S(O) 2 -C 1～6 Alkyl, -NR 11 R 12 and halogen; R 9 is H atom, C 1～6 Alkyl, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, and C 1～6 hydroxyalkyl; Each R 11 are independently H atoms, C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, and C 3～8 cycloalkyl, wherein C 3～8 Cycloalkyl is C 1～6 Alkyl, C 1～6 Alkoxy, -OH, -COOH, -NH 2 , -CN, halogen, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, and C 1～6 optionally substituted with one or more substituents selected from the group consisting of hydroxyalkyl; Each R 12 are independently H atoms, C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, and C 3～8 cycloalkyl, wherein C 3～8 Cycloalkyl is C 1～6 Alkyl, C 1～6 Alkoxy, -OH, -COOH, -NH 2 , -CN, halogen, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, and C 1～6 optionally substituted with one or more substituents selected from the group consisting of hydroxyalkyl; Or, R 11 and R 12 together with the N atom to which they are attached form a 3- to 8-membered heterocyclyl, where the 3- to 8-membered heterocyclyl is C 1～6 Alkyl, C 1～6 Alkoxy, -OH, -COOH, -NH 2 , -CN, halogen, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, and C 1～6 optionally substituted with one or more substituents selected from the group consisting of hydroxyalkyl; R 13 is 3- to 8-membered heterocyclyl, C 3～8 Cycloalkyl, C 6～10 aryl, and 5- to 10-membered heteroaryl, wherein 3- to 8-membered heterocyclyl, C 3～8 Cycloalkyl, C 6～10 Aryl and 5- to 10-membered heteroaryl are each independently C 1～6 Alkoxy, -OH, -COOH, -NR 11 R 12 , -CN, halogen, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, and C 1～6 optionally substituted with one or more substituents selected from the group consisting of hydroxyalkyl; Each R 14 are independently H atoms, C 1～6 Alkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, and C 3～8 cycloalkyl, wherein C 1～6 Alkyl and C 3～8 Each cycloalkyl is independently —CN, —OH, —COOH, or —NR 11 R 12 , halogens, and C 1～6 optionally substituted with one or more substituents selected from the group consisting of alkoxy; m is 0, 1, or 2; n is 0 or 1; p is 0, 1, or 2).

2. The compound of claim 1, which is a compound of formula (II) 【Chemistry 4】 (In the formula, X 1 , X 2 , X 3 , Y.C. 1 , C 2 , R 4 , R 6 , R 7 , L 1 , m, n, and p are as defined in claim 1).

3. The compound according to claim 1 or 2, which is a compound of formula (II-1) 【Transformation 5】 (In the formula, Y is an O atom, an S atom, -S(O)-, -S(O) 2 -, NH, and NC 1～6 selected from the group consisting of alkyl; R 3 is H atom, -OH, -COOH, -NR 11 R 12 , -CN, halogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 6～10 Aryl, 5- to 10-membered heteroaryl, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, and -OR 13 selected from the group consisting of: C 1 , C 2 , R 2 ~R 7 , R 11 ~R 13 , L 1 , m, n, and p are as defined in claim 1, However, C 2 is a 6-membered nitrogen-containing heteroaryl ring, preferably pyridyl, pyridazinyl, or pyrimidinyl; 3 is not an H atom; In particular, R 3 is H atom, -N(C 1～6 alkyl) 2 , -NH 2 , -NH(C 1～6 Alkyl), -CN, halogen, C 1～6 Alkyl, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 3～8 Cycloalkyl, -OC 3～8 Cycloalkyl, -O-3 to 8-membered heterocyclyl, and -OC 6～10 aryl, However, C 2 is a 6-membered nitrogen-containing heteroaryl ring, preferably pyridyl, pyridazinyl, or pyrimidinyl; 3 is not an H atom; More particularly, R 3 is H atom, F atom, -CF 3 , methyl, Cl atom, methoxy, cyclopropyl, isopropyl, -CN, isopropoxy, furanyl-O-, ethoxy, cyclopropoxy, phenyl-O-, and -N(CH 3 ) 2 is selected from the group consisting of However, C 2 is a 6-membered nitrogen-containing heteroaryl ring, preferably pyridyl, pyridazinyl, or pyrimidinyl; 3 is not a H atom).

4. The compound according to claim 1 or 2, which is a compound of formula (II-2) 【Transformation 6】 (In the formula, Y is an O atom, an S atom, -S(O)-, -S(O) 2 -, NH, and NC 1～6 selected from the group consisting of alkyl; R 3 is H atom, -OH, -COOH, -NR 11 R 12 , -CN, halogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 6～10 Aryl, 5- to 10-membered heteroaryl, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, and -OR 13 selected from the group consisting of: X 1 , C 1 , C 2 , R 3 , R 4 , R 6 , R 7 , R 11 ~R 13 , L 1 , m, n, and p are as defined in claim 1; In particular, R 3 is H atom, C 1～6 Alkyl, C 1～6 Alkoxy, and C 3～8 cycloalkyl; More particularly, R 3 is selected from the group consisting of an H atom, methyl, methoxy, and cyclopropyl.

5. The compound of claim 1, which is a compound of formula (III) 【Transformation 7】 (In the formula, R 3 is H atom, -OH, -COOH, -NR 11 R 12 , -CN, halogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 6～10 Aryl, 5- to 10-membered heteroaryl, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, and -OR 13 Preferably, R 3 is a H atom or a halogen; more preferably, R 3 is a H atom or a F atom; C 1 , R 2 , R 4 , R 5 , R 8 , R 9 , R 11 ~R 13 , L 1 , L 2 , L 3 , and m are as defined in claim 1).

6. The compound according to claim 1 or 5, which is a compound of formula (III-1) 【Transformation 8】 (In the formula, R 3 is H atom, -OH, -COOH, -NR 11 R 12 , -CN, halogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 6～10 Aryl, 5- to 10-membered heteroaryl, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, and -OR 13 Preferably, R 3 is a H atom or a halogen; more preferably, R 3 is a H atom or a F atom; C 1 , R 2 , R 4 , R 5 , R 8 , R 9 , R 11 ~R 13 , L 1 , L 3 , and m are as defined in claim 1).

7. The compound according to claim 1 or 5, which is a compound of formula (III-2) 【Chemistry 9】 (In the formula, R 3 is H atom, -OH, -COOH, -NR 11 R 12 , -CN, halogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 6～10 Aryl, 5- to 10-membered heteroaryl, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, and -OR 13 Preferably, R 3 is a H atom or a halogen; more preferably, R 3 is a H atom or a F atom; C 1 , R 2 , R 4 , R 5 , R 8 , R 9 , R 11 ~R 13 , L 1 , L 3 , and m are as defined in claim 1).

8. The compound of claim 1, which is a compound of formula (IV) 【Chemistry 10】 (In the formula, R 3 is H atom, -OH, -COOH, -NR 11 R 12 , -CN, halogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 6～10 Aryl, 5- to 10-membered heteroaryl, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, and -OR 13 Preferably, R 3 is a H atom or a halogen; more preferably, R 3 is an H atom; C 1 , C 3 , R 2 , R 4 , R 5 , R 10 , R 11 ~R 13 , L 1 , L 4 and m is as defined in claim 1; In particular, C 3 is C 6～10 Aryl, 5- to 10-membered heteroaryl, C 3～8 Cycloalkyl, and 3- to 8-membered heterocyclyl; preferably triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, thiazolyl, thienyl, furyl, pyranyl, pyrrolyl, pyrazinyl, pyridazinyl, piperidyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydropyranyl, phenyl, naphthyl, cyclohexyl, cyclopentyl, cyclobutyl, or cyclopropyl; more preferably 1,2,3-triazolyl; even more preferably 【Chemistry 11】 and / or L 4 is a chemical bond, -C 1～6 Alkylene-, -C 1～6 Alkylene-NH-, -C 1～6 Alkylene-N(C 1～6 alkyl)-, -NH-C 1～6 Alkylene- and -N(C 1～6 Alkyl)-C 1～6 Alkylene-; preferably a chemical bond, -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -NH-, -CH 2 -CH 2 -N(CH 3 )-, -NH-CH 2 -CH 2 - and -CH 2 -CH 2 -N(CH 3 )-; and / or R 10 is H atom, -OH, -COOH, -CN, halogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, and C 1～6 hydroxyalkyl; preferably selected from the group consisting of H atoms and methyl).

9. C 1 5- to 10-membered heteroaryl ring, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, 5- to 10-membered heteroaryl fused to 3- to 8-membered heterocyclyl, C 6～10 5- to 10-membered heteroaryl fused with an aryl, 3- to 8-membered heterocyclyl fused with a 5- to 10-membered heteroaryl, and C fused with a 5- to 10-membered heteroaryl 6～10 aryl; Preferably, C 1 the ring is selected from the group consisting of triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, thiazolyl, thienyl, furyl, pyranyl, pyrrolyl, pyrazinyl, pyridazinyl, pyrazolo[1,5-a]pyridyl, tetrahydropyrazolo[1,5-a]pyridyl, tetrahydropyrrolo[1,2-b]pyrazolyl, tetrahydropyrrolo[3,4-d]imidazolyl, benzo[d]imidazolyl, pyrazolo[5,1-b][1,3]oxazinanyl, cyclopropyl, and pyrrolidinyl; More preferably, C 1 Ring 【Chemistry 12】 The compound according to any one of claims 1 to 8, selected from the group consisting of:

10. Each L 1 are independent chemical bonds, -C 1～6 Alkylene-, -O-, -C 1～6 Alkylene-O-, -OC 1～6 Alkylene-, -S-, -S(O)-, -S(O) 2 -, -S(O)(=NR 11 )-, -C 1～6 Alkylene-C(O)-, -C(O)-C 1～6 Alkylene-, -C 1～6 Alkylene-S(O) 2 -, -S(O) 2 -C 1～6 Alkylene-, 3- to 8-membered heterocyclylene, -C 1～6 Alkylene-S(O)(=NR 11 )-, -S(O)(=NR 11 )-C 1～6 Alkylene-, C 3～8 Cycloalkylene, C 6～10 Arylene, 5- to 10-membered heteroarylene, -C 1～6 Alkylene-OC 1～6 Alkylene-O-, -OC 1～6 Alkylene-OC 1～6 Alkylene-, -NR 11 -, -C 1～6 Alkylene-NR 11 -, -NR 11 -C 1～6 Alkylene-, -C 1～6 Alkylene-NR 11 -C 1～6 Alkylene-O-, -OC 1～6 Alkylene-NR 11 -C 1～6 Alkylene-, -NR 11 -C(O)-, -C(O)-NR 11 -, -C 1～6 Alkylene-C(O)-NR 11 - and -NR 11 -C(O)-C 1～6 alkylene-, wherein C 1～6 Each alkylene is independently C 1～6 Alkyl, halogen, -OH, -COOH, -NH 2 , -CN, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, and C 1～6 and each R 11 are independently H atoms or C 1～6 is alkyl; Preferably, each L 1 are independent chemical bonds, -C 1～6 Alkylene-, -C 1～6 Alkylene-O-, -OC 1～6 Alkylene-, -S(O) 2 -, -S(O)(=NR 11 )-, -C 1～6 Alkylene-C(O)-, -C(O)-C 1～6 Alkylene-, -C 1～6 Alkylene-S(O) 2 -, -S(O) 2 -C 1～6 Alkylene-, -C 1～6 Alkylene-S(O)(=NR 11 )-, -S(O)(=NR 11 )-C 1～6 Alkylene-, 3- to 8-membered heterocyclylene, C 3～8 Cycloalkylene, C 6～10 Arylene, 5- to 10-membered heteroarylene, -C 1～6 Alkylene-OC 1～6 Alkylene-O-, -OC 1～6 Alkylene-OC 1～6 Alkylene-, -C 1～6 Alkylene-NR 11 -, -NR 11 -C 1～6 Alkylene-, -C 1～6 Alkylene-NR 11 -C 1～6 Alkylene-O-, -OC 1～6 Alkylene-NR 11 -C 1～6 Alkylene-, -C 1～6 Alkylene-C(O)-NR 11 - and -NR 11 -C(O)-C 1～6 alkylene-, wherein C 1～6 Each alkylene is independently C 1～6 and each R 11 are independently H atoms or C 1～6 is alkyl; More preferably, each L 1 are independently chemical bonds, -CH 2 -CH 2 -, -CH 2 -, -CH 2 -CH 2 -CH 2 -, -S(O) 2 -, -S(O)(=NH)-, -S(O) 2 -CH 2 -CH 2 -, -NCH 3 -CH 2 -CH 2 -, -NH-C(O)-CH 2 -, -NCH 3 -CH 2 -CH 2 -CH 2 -, -C(O)-CH 2 -, -O-CH 2 -CH 2 -NCH 3 -CH 2 -CH 2 -, -O-CH 2 -CH 2 -O-CH 2 -CH 2 -, -C(CH 3 ) 2 -CH 2 -, -C(CH 3 )(OH)-CH 2 -, -O-CH 2 -CH 2 -, -CH(F)-CH 2 -, -CH(CH 3 )-CH 2 -, azetidinyl, -CH 2 -CH 2 -S(O) 2 -, -CH 2 -CH 2 -NCH 3 -, -CH 2 -C(O)-NH-, -CH 2 -CH 2 -CH 2 -NCH 3 -, -CH 2 -C(O)-, -CH 2 -CH 2 -NCH 3 -CH 2 -CH 2 -O-, -CH 2 -CH 2 -O-CH 2 -CH 2 -O-, -CH 2 -C(CH 3 ) 2 -, -CH 2 -C(CH 3 )(OH)-, -CH 2 -CH 2 -O-, -CH 2 -CH(F)-, -CH 2 -CH(CH 3 )-, -CH 2 -CH 2 -CH 2 -S(O)(=NH)- and -S(O)(=NH)-CH 2 -CH 2 -CH 2 10. The compound according to any one of claims 1 to 9, selected from the group consisting of:

11. Each R 4 are independently H atoms, -OH, -COOH, -CN, halogens, C 1～6 Alkyl, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, -C(O)-NR 11 R 12 , -NR 11 R 12 , C 6～10 Aryl, 5- to 10-membered heteroaryl, C 3～8 is selected from the group consisting of cycloalkyl, 3- to 8-membered monocyclic heterocyclyl, 7- to 10-membered spiroheterocyclyl, and 7- to 10-membered bridged heterocyclyl, wherein C 6～10 Aryl, 5- to 10-membered heteroaryl, C 3～8 Cycloalkyl and 3- to 8-membered monocyclic heterocyclyl are each independently —CN, —OH, C 1～6 Alkyl, C 1～6 Hydroxyalkyl, -C(O)-R 14 , -C(O)-NR 11 R 12 , Oxo, C 1～6 Alkoxy, -S(O) 2 -C 1～6 Alkyl, -NR 11 R 12 , imino, halogen, -C 1～6 Alkylene-NR 11 R 12 , -NR 11 -C(O)-R 14 , -NR 11 -S(O) 2 -R 14 , -S(O)(=NR 11 )-R 14 , -S(O) 2 -R 14 , -C(=NR 11 )-NR 11 R 12 , -S(O) 2 -NR 11 R 12 , and -C 1～6 Alkylene-C(O)-NR 11 R 12 and each R 11 are independently H atoms, C 1～6 Alkyl or C 3～8 is cycloalkyl; each R 12 are independently H atoms, C 1～6 Alkyl or C 3～8 is cycloalkyl; each R 14 are independently H atoms, C 1～6 Alkyl, and C 3～8 cycloalkyl, wherein C 1～6 Alkyl and C 3～8 Each cycloalkyl is independently —CN, —OH, or —NR 11 R 12 , and C 1～6 optionally substituted with one or more substituents selected from the group consisting of alkoxy; Preferably, each R 4 are independently H atoms, -OH, -COOH, -CN, halogens, C 1～6 Alkyl, C 1～6 Hydroxyalkyl, -C(O)-NR 11 R 12 , -NR 11 R 12 , phenyl, pyridyl, imidazolyl, pyrazolyl, cyclopropyl, oxetanyl, azetidinyl, azolidinyl, morpholinyl, piperidyl, tetrahydropyranyl, piperazinyl, 1,1-dioxo-thiomorpholinyl, 1-oxo-1-imino-thiomorpholinyl, thiomorpholinyl, pyrrolidinyl, diazaspiro[4.5]decanyl, diazabicyclo[2.2.1]heptanyl, and diazabicyclo[3.2.1]octyl, wherein and each independently represents -CN, -OH, -C ... 1～6 Alkyl, C 1～6 Hydroxyalkyl, -C(O)-R 14 , -C(O)-NR 11 R 12 , Oxo, C 1～6 Alkoxy, -S(O) 2 -C 1～6 Alkyl, -NR 11 R 12 , Imino, -C 1～6 Alkylene-NR 11 R 12 , -NR 11 -C(O)-R 14 , -NR 11 -S(O) 2 -R 14 , -S(O)(=NR 11 )-R 14 , -S(O) 2 -R 14 , -C(=NR 11 )-NR 11 R 12 , -S(O) 2 -NR 11 R 12 , and -C 1～6 Alkylene-C(O)-NR 11 R 12 and R 11 is H atom, C 1～6 Alkyl or C 3～6 is cycloalkyl; R 12 is H atom, C 1～6 Alkyl or C 3～6 is cycloalkyl; each R 14 are independently H atoms, C 1～6 Alkyl, and C 3～6 cycloalkyl, wherein C 1～6 Alkyl and C 3～6 Each cycloalkyl is independently —CN, —OH, or —NR 11 R 12 , and C 1～6 optionally substituted with one or more substituents selected from the group consisting of alkoxy; More preferably, each R 4 are independently H atoms, methyl, 【Chemistry 13】 , propyl, 【Chemistry 14】 , cyclopropyl, 【Chemistry 15】 , -OH, F atom, CN, 【Chemistry 16】 , phenyl, 【Chemistry 17】 、-COOH、-C(O)-NH 2 、-N(CH 3 ) 2 、 [Chemistry 18] The compound according to any one of claims 1 to 10, selected from the group consisting of:

12. R 2 is H atom, -OH, -COOH, -NR 11 R 12 , -CN, halogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 6～10 Aryl, C 1～6 Alkoxy-C 6～10 Aryl-, 5- to 10-membered heteroaryl, C 3～8 selected from the group consisting of cycloalkyl, and 3- to 8-membered heterocyclyl; Preferably, R 2 H atoms, halogens, C 1～6 Alkoxy, C 6～10 Aryl, and C 1～6 Alkoxy-C 6～10 aryl- is selected from the group consisting of; More preferably, R 2 is a H atom, 【Chemistry 19】 12. The compound of any one of claims 1, 3, and 5-11, wherein the aryl group is selected from the group consisting of , methoxy, and an F atom.

13. R 5 is H atom, -OH, -COOH, -NH 2 , -CN, halogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 6～10 Aryl, 5- to 10-membered heteroaryl, C 3～8 selected from the group consisting of cycloalkyl, and 3- to 8-membered heterocyclyl; Preferably, R 5 is H atom, -OH, -COOH, -NH 2 , -CN, halogen, C 1～6 Alkyl, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, and C 1～6 hydroxyalkyl; More preferably, R 5 The compound according to any one of claims 1, 3, and 5 to 12, wherein is a H atom.

14. C 2 C ring fused with 5- to 10-membered heteroaryl, 3- to 8-membered heterocyclyl, 5- to 10-membered heteroaryl 3～8 Cycloalkyl, C 6～10 5- to 10-membered heteroaryl fused with aryl, C fused with 3- to 8-membered heterocyclyl 6～10 Aryl, C 3～8 5- to 10-membered heteroaryl fused to cycloalkyl, C fused to 5- to 10-membered heteroaryl 6～10 Aryl, and C 6～10 selected from the group consisting of 3- to 8-membered heterocyclyl fused to an aryl; Preferably, C 2 the ring is selected from the group consisting of triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, thiazolyl, thienyl, furyl, pyranyl, pyrrolyl, pyrazinyl, pyridazinyl, piperidyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydropyranyl, tetrahydroisoquinolyl, tetrahydroquinolyl, imidazo[1,2-a]pyridyl, quinolyl, isoquinolyl, naphthyridinyl, quinoxalinyl, quinazolinyl, triazolopyridyl, benzodioxanyl, benzimidazolyl, cinnolinyl, benzoxazolyl, benzothiazolyl, indolinyl, benzofuryl, thienopyridyl, pyrazolopyridyl, and pyridinopyrazinyl; More preferably, C 2 Ring 【Chemistry 20】 and / or R 6 is H atom, -OH, -COOH, -NR 11 R 12 , -CN, halogen, C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, and -C 1～6 Alkylene-NR 11 R 12 each R 11 are independently H atoms or C 1～6 alkyl; each R 12 are independently H atoms or C 1～6 is alkyl; Preferably, R 6 C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Hydroxyalkyl, -C 1～6 Alkylene-NH(C 1～6 alkyl), -CN, and C 1～6 haloalkyl; More preferably, R 6 are methyl, ethyl, hydroxymethyl, 【Chemistry 21】 , —CN, trifluoromethyl, and trideuteriomethyl; and / or R 7 is H atom, -OH, -COOH, -NH 2 , -NH(C 1～6 alkyl), -N(C 1～6 alkyl) 2 , -CN, halogen, oxo, C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, and C 3～8 cycloalkyl; Preferably, R 7 is H atom, -NH 2 , -N(C 1～6 alkyl) 2 , -CN, halogen, oxo, C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Alkoxy, C 1～6 Hydroxyalkyl, C 3～6 Cycloalkyl, and C 1～6 haloalkyl; More preferably, R 7 is H atom, -NH 2 , -N(CH 3 ) 2 , —CN, a Cl atom, an F atom, a Br atom, oxo, methyl, ethyl, isopropyl, methoxy, cyclopropyl, difluoromethyl, monofluoromethyl, trifluoromethyl, hydroxymethyl, and trideuteriomethyl.

15. L 3 is a chemical bond, -C 1～6 Alkylene-, -O-, -C 1～6 Alkylene-O-, -OC 1～6 Alkylene-, -S-, -S(O)-, -S(O) 2 -, -C 1～6 Alkylene-C(O)-, -C(O)-C 1～6 Alkylene-, -C 1～6 Alkylene-S(O) 2 -, -S(O) 2 -C 1～6 Alkylene-, -C 1～6 Alkylene-OC 1～6 Alkylene-O-, -OC 1～6 Alkylene-OC 1～6 Alkylene-, -NR 11 -, -NR 11 -C 1～6 Alkylene-, -C 1～6 Alkylene-NR 11 -, -C 1～6 Alkylene-NR 11 -C 1～6 Alkylene-O-, -OC 1～6 Alkylene-NR 11 -C 1～6 Alkylene-, -NR 11 -C(O)-, -C(O)-NR 11 -, -C 1～6 Alkylene-C(O)-NR 11 - and -NR 11 -C(O)-C 1～6 alkylene-, wherein C 1～6 Each alkylene is independently C 1～6 Alkyl, halogen, -OH, -COOH, -NH 2 , -CN, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, and C 1～6 and each R 11 are independently H atoms or C 1～6 is alkyl; Preferably, L 3 is a chemical bond, -C 1～6 Alkylene-, -C 1～6 Alkylene-NH-, -C 1～6 Alkylene-N(C 1～6 alkyl)-, -NH-C 1～6 Alkylene- and -N(C 1～6 Alkyl)-C 1～6 alkylene-, wherein C 1～6 Each alkylene independently represents one or more C 1～6 may be substituted with an alkyl group or an -OH group; Preferably, L 3 is a chemical bond, -CH 2 -CH 2 -NCH 3 -, -CH 2 -CH 2 -NH-, -CH 2 -C(CH 3 )(OH)-, -CH 2 -C(CH 3 ) 2 -, -NCH 3 -CH 2 -CH 2 -, -NH-CH 2 -CH 2 -, -C(CH 3 )(OH)-CH 2 - and -C(CH 3 ) 2 -CH 2 and / or R 8 H atom, -OH, -COOH, -CN, halogen, C 1～6 Alkyl, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 6～10 Aryl, 5- to 10-membered heteroaryl, C 3～8 cycloalkyl, and 3- to 8-membered heterocyclyl, wherein C 6～10 Aryl, 5- to 10-membered heteroaryl, C 3～8 Cycloalkyl and 3- to 8-membered heterocyclyl are each independently —CN, —OH, C 1～6 Alkyl, -C(O)-C 1～6 Alkyl, -C(O)-C 1～6 Hydroxyalkyl, C 1～6 Alkoxy, -NH 2 and halogen; Preferably, R 8 is H atom, -OH, C 6～10 aryl, 5- to 10-membered heteroaryl, and 3- to 8-membered heterocyclyl, wherein C 6～10 The aryl and 5- to 10-membered heteroaryl each independently represent one or more C 1～6 may be substituted with alkyl or halogen groups; More preferably, R 8 H, methyl, -OH, 【Chemistry 22】 and / or R 9 is H atom, C 1～6 Alkyl, C 1～6 Alkoxy, C 1～6 Haloalkyl, and C 1～6 hydroxyalkyl; Preferably, R 9 is H atom or C 1～6 is alkyl; More preferably, R 9 is an H atom or methyl. 【Request Item 16】 【Chemical Engineering 23A】 【Chemical 23B】 【Chemical 23C】 【Transformation 23D】 [Chemistry 23E] [Chemical 23F] [23G] [Chemical 23H] 【Chemical 23I】 【Chemical 23J】 [23K] [23L] [23M] 16. The compound according to any one of claims 1 to 15, selected from the group consisting of:

17. A process for preparing a compound of formula (II) according to claim 2, comprising: 【Chemistry 24】 A step of obtaining a compound of formula (II) by reacting a compound of formula (IIA) with a compound of formula (IIB). (In the formula, LG 1 is a leaving group, preferably halogen, methylsulfonyloxy, or p-tolylsulfonyloxy; X 1 , X 2 , X 3 , Y.C. 1 , C 2 , R 4 , R 6 , R 7 , L 1 , m, n, and p are as defined in claim 2); Or, 【Chemistry 25】 A step of reacting a compound of formula (IIC) with a compound of formula (IID) to obtain a compound of formula (II). (In the formula, LG 2 is a leaving group, preferably halogen, methylsulfonyloxy, or p-tolylsulfonyloxy; W is 【Chemistry 26】 and R is a hydrogen atom or C 1～6 is alkyl; X 1 , X 2 , X 3 , Y.C. 1 , C 2 , R 4 , R 6 , R 7 , L 1 , m, n, and p are as defined in claim 2); Or, 【Chemistry 27】 a step of reacting a compound of formula (IIE) with a compound of formula (IIF) to obtain a compound of formula (IIG), and a step of removing a protecting group R from the compound of formula (IIG). p to obtain the compound of formula (II) (In the formula, R p is tetrahydropyranyl, (trimethylsilyl)ethoxymethyl, p-tosyl, t-butyloxycarbonyl, benzyl, or p-methoxybenzyl; Y is an O atom, and R 6 Ha-CH 2 OH, n is 1, X 1 , X 2 , X 3 , C 1 , C 2 , R 4 , R 7 , L 1 , m, and p are as defined in claim 2); Or, 【Chemistry 28】 a step of reacting a compound of formula (IIH) with a compound of formula (IIK) to obtain a compound of formula (IIL), and a step of removing a protecting group R from the compound of formula (IIL). p to obtain the compound of formula (II) (In the formula, R p is tetrahydropyranyl, (trimethylsilyl)ethoxymethyl, p-tosyl, t-butyloxycarbonyl, benzyl, or p-methoxybenzyl; LG 1 is a leaving group, preferably halogen, methylsulfonyloxy, or p-tolylsulfonyloxy; X 1 , X 2 , X 3 , Y.C. 1 , C 2 , R 4 , R 6 , R 7 , L 1 , m, n, and p are as defined in claim 2); Or, 【Chemistry 29】 a step of reacting a compound of formula (IIM) with a compound of formula (IID) to obtain a compound of formula (IIN), and a step of removing a protecting group R from the compound of formula (IIN). p to obtain the compound of formula (II) (In the formula, R p is tetrahydropyranyl, (trimethylsilyl)ethoxymethyl, p-tosyl, t-butyloxycarbonyl, benzyl, or p-methoxybenzyl; LG 2 is a leaving group, preferably halogen, methylsulfonyloxy, or p-tolylsulfonyloxy; W is 【Transformation 30】 and R is a hydrogen atom or C 1～6 is alkyl; X 1 , X 2 , X 3 , Y.C. 1 , C 2 , R 4 , R 6 , R 7 , L 1 , m, n, and p are as defined in claim 2); Or, 【Chemistry 31】 A step of reacting a compound of formula (IIO) with a compound of formula (IIP) to obtain a compound of formula (II). (wherein m is 1 and L 1 -S(O) 2 -C 1～6 alkyl-, and R 15 is C 1～6 Alkenyl or -C 1～6 alkylene-halogen; X 1 , X 2 , X 3 , Y.C. 1 , C 2 , R 4 , R 6 , R 7 , n, and p are as defined in claim 2.

18. A process for preparing a compound of formula (III-1) according to claim 6, comprising: 【Chemistry 32】 A step of obtaining a compound of formula (III-1) by reacting a compound of formula (III-1A) with a compound of formula (IID). (In the formula, LG 3 is a leaving group, preferably halogen, methylsulfonyloxy, or p-tolylsulfonyloxy; W is 【Transformation 33】 and R is a hydrogen atom or C 1～6 is alkyl; C 1 , R 2 , R 4 , R 5 , R 8 , R 9 , L 1 , L 3 and m is as defined in claim 6.

19. A process for preparing a compound of formula (III-2) according to claim 7, comprising: 【Transformation 34】 A step of obtaining a compound of formula (III-2) by reacting a compound of formula (III-2A) with a compound of formula (III-2B). (In the formula, LG 4 is a halogen atom, preferably a Cl atom; C 1 , R 2 , R 4 , R 5 , R 8 , R 9 , L 1 , L 3 and m is as defined in claim 7.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16 and one or more pharmaceutically acceptable excipients.

21. Use of a compound according to any one of claims 1 to 16 or a pharmaceutical composition according to claim 20 in the preparation of an FGFR inhibitor.

22. Use of a compound according to any one of claims 1 to 16 or a pharmaceutical composition according to claim 20 in the preparation of a medicament for treating and / or preventing a tumor, in particular the tumor is cancer; the cancer is preferably bile duct cancer, liver cancer, breast cancer, prostate cancer, lung cancer, thyroid cancer, stomach cancer, ovarian cancer, colorectal cancer, endometrial cancer, urothelial cancer, testicular cancer, cervical cancer, leukemia, skin cancer, squamous cell carcinoma, basal cell carcinoma, bladder cancer, esophageal cancer, The cancer is selected from the group consisting of head and neck cancer, renal cancer, pancreatic cancer, bone cancer, lymphoma, melanoma, sarcoma, peripheral neuroepithelioma, glioma, ependymoma, neuroblastoma, ganglioneuroma, medulloblastoma, pinealocytoma, meningioma, neurofibroma, Schwannoma, and Wilms' tumor; more preferably selected from the group consisting of cholangiocarcinoma, liver cancer, breast cancer, prostate cancer, lung cancer, thyroid cancer, gastric cancer, ovarian cancer, colorectal cancer, endometrial cancer, and urothelial cancer.

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