Pyrazole fused ring compound as well as preparation method and application thereof

Abstract

The invention relates to a pyrazole fused ring compound as well as a preparation method and application thereof. Specifically, the invention relates to a compound shown in a general formula (I), a preparation method of the compound, a pharmaceutical composition containing the compound and application of the compound serving as an FGFR inhibitor in tumor treatment. Wherein each group in the general formula (I) is defined in the specification. # imgabs0 #

Description

Pyrazole fused ring compound and its preparation method and use Technical Field

[0001] The present invention belongs to the field of medicinal chemistry and specifically relates to an FGFR (fibroblast growth factor receptor) and a mutation inhibitor thereof, a preparation method thereof, and the use of the compound in treating diseases such as cancer. Background Art

[0002] Fibroblast growth factor receptors (FGFRs) are a subfamily of tyrosine kinase receptors with four subtypes, including FGFR1, FGFR2, FGFR3, and FGFR4. Each FGFR is composed of three distinct domains: an extracellular ligand-binding domain, a single-pass transmembrane domain, and an intracellular TK domain. Upon binding to fibroblast growth factor ligands (FGFs), activated FGFRs phosphorylate several downstream signaling proteins, including PI3K-AKT, RAS-MAPK, and STAT. Consequently, FGFRs play a key role in numerous intracellular processes, including development, differentiation, survival, migration, and angiogenesis.

[0003] However, FGFR is susceptible to various somatic aberrations, with common mutations such as overexpression, point mutations, and gene translocations, leading to carcinogenesis. FGFR overexpression caused by gene amplification, mutations in the FGFR EC region (extracellular domain) / TK region (kinase domain), and FGFR fusions can all cause FGFR signaling disorders, thereby promoting tumor cell proliferation, survival, invasion, metastasis, and the development of drug resistance, as well as the occurrence of angiogenesis and immune evasion in the tumor microenvironment (TME). FGFR aberrations account for approximately 7.1% of all solid tumor patients. The cancers most commonly affected by FGFR aberrations are urothelial carcinoma (32%), liver cancer (30%), bile duct cancer (25%), breast cancer (18%), and gastric cancer (7%).

[0004] FGFR inhibitors inhibit tumor growth by blocking FGFR-mediated signaling pathways, making them a new option for targeted cancer treatment. Currently, three drugs targeting FGFR have been approved worldwide, including Johnson & Johnson's Balversa (Erdafitinib), Incyte's Pemigatinib, and BridgeBio / Helsinn's Infigratinib. However, in clinical trials, the three approved FGFR inhibitors still had some treatment-related adverse events, such as hyperphosphatemia, dry mouth, fatigue, skin changes, nail changes, and eye diseases. In addition, clinical trials have also found that mutations affecting amino acids in FGFR can lead to resistance to FGFR inhibitors or reduce sensitivity to FGFR inhibitors. Therefore, there is a highly unmet clinical need for the development of drugs targeting FGFR.

[0005] Summary of the Invention

[0006] The inventors of this application have developed a novel FGFR inhibitor after extensive and in-depth research. The compound of the present invention has excellent activity against FGFR, particularly FGFR3, and is expected to be a new generation of FGFR inhibitors.

[0007] The present invention provides a compound represented by general formula (I),

[0008] or a pharmaceutically acceptable salt, hydrate, solvate, isotope-substituted product or stereoisomer thereof,

[0009] X 1 N atom or CR 5 ;

[0010] X 2 N atom or CR 2 ;

[0011] X 3 N atom or CR 3 ;

[0012] R 1 Selected from

[0013] Y is selected from the group consisting of O atom, S atom, -S(O)-, -S(O)2- and NR 11 ;

[0014] R 2 and R 5 Each independently selected from H atom, -OH, -COOH, -NR 11 R 12 、-CN、halogen、C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 The 3- to 8-membered cycloalkyl and the 3- to 8-membered heterocyclic group are each independently optionally selected from C 1-6 Alkoxy, -OH, -COOH, -NR 11 R 12 、-CN、halogen、C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and C 1-6 substituted with one or more substituents of a hydroxyalkyl group;

[0015] R 3 Selected from H atoms, -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 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group and -OR 13 ;

[0016] The condition is that when X is CR 5 And R 1 for And C 2 When it is a 6-membered nitrogen-containing heteroaromatic ring, R 3 Not an H atom;

[0017] Ring C 1 Selected from C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, 5-10 membered heteroaryl fused with 3-8 membered heterocyclic group, C 6-10 5-10 membered heteroaryl fused to an aryl group, a 3-8 membered heterocyclyl fused to a 5-10 membered heteroaryl group, and a C 6-10 aryl;

[0018] Each L 1 independently selected from 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-, 3-8 membered heterocyclylene, C 3-8 Cycloalkylene, C 6-10 Arylene, 5-10 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 the C 1-6 The alkylene groups are each independently optionally selected from C 1-6 Alkyl, halogen, -OH, -COOH, -NR 11 R 12 、-CN、C 1-6Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 substituted by one or more substituents of a 3- to 8-membered cycloalkyl group and a 3- to 8-membered heterocyclic group;

[0019] Each R 4 independently selected from H atoms, -OH, -COOH, -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 Halogenated alkyl, 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 3-10 membered heterocyclic groups, wherein the C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 The 3- to 10-membered cycloalkyl and the 3- to 10-membered heterocyclic group are each independently optionally selected from -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(=NR11)-NR 11 R 12 、-S(O)2-NR 11 R 12 and -C 1-6 Alkylene-C(O)-NR11 R 12 is substituted by one or more substituents;

[0020] Ring C 2 Selected from C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 3-8 Cycloalkyl, C 6-10 5-10 membered heteroaryl fused to an aryl group, C 6-10 Aryl, and C 3-8 a 5- to 10-membered heteroaryl fused to a cycloalkyl group, a C 6-10 Aryl and C 6-10 an aryl-fused 3-8 membered heterocyclic group;

[0021] Ring C 3 Selected from C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 3-8 Cycloalkyl, C 6-10 Aryl-fused 5-10 membered heteroaryl, C 3-8 a 5- to 10-membered heteroaryl fused to a cycloalkyl group and a C 6-10 aryl;

[0022] R 6 Selected from H atoms, -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 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-NR 11 R 12 、C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 8-membered cycloalkyl and 3-8-membered heterocyclic group;

[0023] R 7 Selected from H atoms, -OH, -COOH, -C(O)-R 14 、-C(O)-NR 11 R 12 、-NR 11 R12 、-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 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 8-membered cycloalkyl and 3-8-membered heterocyclic group;

[0024] L 2 is selected from -C(O)-, -S(O)2- and -S(O)-;

[0025] L 3 and L 4 Each independently selected from 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 the C 1-6 The alkylene groups are each independently optionally selected from C 1-6 Alkyl, halogen, -OH, -COOH, -NR 11 R 12 、-CN、C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 substituted by one or more substituents of a 3- to 8-membered cycloalkyl group and a 3- to 8-membered heterocyclic group;

[0026] R 8 and R 10 Each independently selected from H atoms, -OH, -COOH, -CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 The 3- to 8-membered cycloalkyl and the 3- to 8-membered heterocyclic group are each independently optionally selected from -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 substituted with one or more substituents of halogen;

[0027] R 9 Selected from H atoms, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and C 1-6 hydroxyalkyl;

[0028] Each R 11 independently selected from H atoms, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl and C 3-8 membered cycloalkyl, the C 3-8 The membered cycloalkyl group is optionally selected from C 1-6 Alkyl, C 1-6 Alkoxy, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and C 1-6 substituted with one or more substituents of a hydroxyalkyl group;

[0029] Each R 12 independently selected from H atoms, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl and C 3-8 membered cycloalkyl, the C 3-8 The membered cycloalkyl group is optionally selected from C 1-6 Alkyl, C 1-6 Alkoxy, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and C 1-6 substituted with one or more substituents of a hydroxyalkyl group;

[0030] Or, R 11 、R 12 Together with the nitrogen atom to which it is attached, it forms a 3-8 membered heterocyclic group, wherein the 3-8 membered heterocyclic group is optionally selected from C 1-6 Alkyl, C 1-6 Alkoxy, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and C 1-6 substituted with one or more substituents of a hydroxyalkyl group;

[0031] R 13 Selected from 3-8 membered heterocyclic group, C 3-8 Cycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the 3-8 membered heterocyclic group, C 3-8 Cycloalkyl, C6-10 Aryl and 5-10 membered heteroaryl are each independently optionally selected from C 1-6 Alkoxy, -OH, -COOH, -NR 11 R 12 、-CN、halogen、C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and C 1-6 substituted with one or more substituents of a hydroxyalkyl group;

[0032] Each R 14 Selected from H atoms, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 3-8 -membered cycloalkyl, wherein the C 1-6 Alkyl and C 3-8 The cycloalkyl groups are each independently optionally selected from -CN, -OH, -COOH, -NR 11 R 12 , halogen and C 1-6 substituted by one or more substituents of an alkoxy group;

[0033] m is 0, 1, or 2;

[0034] n is 0 or 1; and

[0035] p is 0, 1 or 2.

[0036] In some embodiments, the compound represented by general formula (I) is a compound represented by general formula (II),

[0037] Among them, 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 the general formula (I).

[0038] In some embodiments, the compound represented by general formula (I) is a compound represented by general formula (II-1),

[0039] in,

[0040] Y is selected from the group consisting of O atom, S atom, -S(O)-, -S(O)2-, NH and NC 1-6 alkyl;

[0041] R 3Selected from H atoms, -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 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group and -OR 13 ;

[0042] C 1 、C 2 、R 2 -R 7 、R 11 -R 13 , L 1 , m, n and p are as defined in formula (I);

[0043] The condition is that when C 2 When R is a 6-membered nitrogen-containing heteroaromatic ring, preferably pyridine, pyridazine or pyrimidine, 3 Not an H atom;

[0044] In particular,

[0045] R 3 Selected from H atoms, -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 Halogenated alkyl, C 3-8 Cycloalkyl, -OC 3-8 -O-3-8 membered cycloalkyl, -O-3-8 membered heterocyclic group and -OC 6-10 aryl;

[0046] The condition is that when C 2 When R is a 6-membered nitrogen-containing heteroaromatic ring, preferably pyridine, pyridazine or pyrimidine, 3 Not an H atom;

[0047] More specifically,

[0048] R 3 is selected from the group consisting of H atom, F atom, -CF3, methyl, Cl atom, methoxy, cyclopropyl, isopropyl, -CN, isopropoxy, furan-O-, ethoxy, cyclopropyloxy, phenyl-O- and -N(CH3)2;

[0049] The condition is that when C 2 When R is a 6-membered nitrogen-containing heteroaromatic ring, preferably pyridine, pyridazine or pyrimidine, 3 Not an H atom.

[0050] In some embodiments, the compound represented by general formula (I) is a compound represented by general formula (II-2),

[0051] in,

[0052] Y is selected from the group consisting of O atom, S atom, -S(O)-, -S(O)2-, NH and NC 1-6 alkyl;

[0053] R 3 Selected from H atoms, -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 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group and -OR 13 ;

[0054] 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);

[0055] In particular,

[0056] R 3 Selected from H atoms, C 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 cycloalkyl;

[0057] More specifically,

[0058] R 3 is selected from the group consisting of an H atom, a methyl group, a methoxy group and a cyclopropyl group.

[0059] In some embodiments, the compound represented by general formula (I) is a compound represented by general formula (III),

[0060] in,

[0061] R 3 Selected from H atoms, -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 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group and -OR 13 Preferably, R 3 is an H atom or a halogen; more preferably, R 3 is a H atom or a F atom;

[0062] 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 the general formula (I).

[0063] In some embodiments, the compound represented by general formula (I) is a compound represented by general formula (III-1),

[0064] in,

[0065] R 3 Selected from H atoms, -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 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8cycloalkyl, 3-8 membered heterocyclic group and -OR 13 Preferably, R 3 is an H atom or a halogen; more preferably, R 3 is a H atom or a F atom;

[0066] 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 the general formula (I).

[0067] In some embodiments, the compound represented by general formula (I) is a compound represented by general formula (III-2),

[0068] in,

[0069] R 3 Selected from H atoms, -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 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group and -OR 13 Preferably, R 3 is an H atom or a halogen; more preferably, R 3 is a H atom or a F atom;

[0070] 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 the general formula (I).

[0071] In some embodiments, the compound represented by general formula (I) is a compound represented by general formula (IV),

[0072] in,

[0073] R 3 Selected from H atoms, -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 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group and -OR 13 Preferably, R 3 is an H atom or a halogen; more preferably, R 3 is a H atom;

[0074] 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 the general formula (I).

[0075] In particular,

[0076] C 3 Selected from C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group; preferably triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, thiazolyl, thienyl, furanyl, pyranyl, pyrrolyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydropyranyl, phenyl, naphthyl, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl; more preferably 1,2,3-triazolyl; even more preferably and / or

[0077] L 4 Selected from chemical bonds, -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 1-6Alkylene-; preferably a chemical bond, -CH2-, -CH2-CH2-, -CH2-CH2-NH-, -CH2-CH2-N(CH3)-, -NH-CH2-CH2- and -CH2-CH2-N(CH3)-; and / or

[0078] R 10 Selected from H atoms, -OH, -COOH, -CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkyl groups; preferably H atoms and methyl groups.

[0079] In some embodiments, in the compound represented by formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2) or (IV),

[0080] Ring C 1 Selected from 5-10 membered heteroaryl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, 5-10 membered heteroaryl fused with 3-8 membered heterocyclic group, C 6-10 5-10 membered heteroaryl fused to an aryl group, a 3-8 membered heterocyclyl fused to a 5-10 membered heteroaryl group, and a C 6-10 aryl;

[0081] Preferably, ring C 1 selected from the group consisting of triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, thiazolyl, thienyl, furanyl, pyranyl, pyrrolyl, pyrazinyl, pyridazinyl, pyrazolo[1,5-a]pyridinyl, tetrahydropyrazolo[1,5-a]pyridinyl, tetrahydropyrrolo[1,2-b]pyrazolyl, tetrahydropyrrolo[3,4-d]imidazolyl, benzo[d]imidazolyl, pyrazolo[5,1-b][1,3]oxazinyl, cyclopropyl and pyrrolidinyl;

[0082] More preferably, ring C 1 Selected from

[0083] In some embodiments, in the compound represented by formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2) or (IV),

[0084] Each L 1 independently selected from chemical bonds, -C1-6 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-, 3-8 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, 5-10 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 the C 1-6 The alkylene groups are each independently optionally selected from C 1-6 Alkyl, halogen, -OH, -COOH, -NH2, -CN, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and C 1-6 is substituted by one or more substituents of a hydroxyalkyl group; each R 11 independently H atoms and C 1-6 alkyl;

[0085] Preferably, each L1 independently selected from 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, 5-10 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 the C 1-6 The alkylene groups are each independently optionally selected from C 1-6 Alkyl, halogen and -OH are substituted with one or more substituents; each R 11 independently H atoms and C 1-6 alkyl;

[0086] More preferably, each L 1independently selected from 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-, -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-NCH3-, -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-CH2-.

[0087] In some embodiments, in the compound represented by formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2) or (IV),

[0088] Each R 4 independently selected from H atoms, -OH, -COOH, -CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, 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, 3-8 membered monocyclic heterocyclic group, 7-10 membered spiro heterocyclic group and 7-10 membered bridged heterocyclic group, wherein the C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 The 3-membered cycloalkyl and 3-8 membered monocyclic heterocyclic groups are each independently optionally selected from -CN, -OH, C 1-6 Alkyl, C 1-6Hydroxyalkyl, -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(=NR11)-NR 11 R 12 、-S(O)2-NR 11 R 12 and -C 1-6 Alkylene-C(O)-NR 11 R 12 is substituted by one or more substituents; each R 11 are independently H atoms, C 1-6 Alkyl and C 3-8 cycloalkyl; each R 12 are independently H atoms, C 1-6 Alkyl and C 3-8 cycloalkyl; each R 14 Selected from H atoms, C 1-6 Alkyl and C 3-8 -membered cycloalkyl, wherein the C 1-6 Alkyl and C 3-8 The cycloalkyl groups are each independently optionally selected from -CN, -OH, -NR 11 R 12 and C 1-6 substituted by one or more substituents of an alkoxy group;

[0089] Preferably, each R 4 independently selected from H atoms, -OH, -COOH, -CN, halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, -C(O)-NR 11 R 12 、-NR 11 R 12, phenyl, pyridinyl, imidazolyl, pyrazolyl, cyclopropyl, oxetanyl, azetidinyl, azopentyl, morpholinyl, piperidinyl, tetrahydropyranyl, piperazinyl, 1,1-dioxo-thiomorpholinyl, 1-oxo-1-imino-thiomorpholinyl, thiomorpholinyl, pyrrolidinyl, diazaspiro[4.5]decyl, diazabicyclo[2.2.1]heptyl and diazabicyclo[3.2.1]octyl, wherein the phenyl, pyridinyl, imidazolyl, pyrazolyl, cyclopropyl, oxetanyl, azetidinyl, azopentyl, morpholinyl, piperidinyl, tetrahydropyranyl, piperazinyl, 1,1-dioxo-thiomorpholinyl, 1-oxo-1-imino-thiomorpholinyl, thiomorpholinyl, pyrrolidinyl, diazaspiro[4.5]decyl, diazabicyclo[2.2.1]heptyl and diazabicyclo[3.2.1]octyl groups are substituted with phenyl, pyridinyl, imidazolyl, pyrazolyl, cyclopropyl, oxetanyl, azetidinyl, azopentyl, morpholinyl, piperidinyl, tetrahydropyranyl, piperazinyl, 1,1-dioxo-thiomorpholinyl, 1-oxo-1-imino-thiomorpholinyl, thiomorpholinyl, pyrrolidinyl, diazaspiro[4.5]decyl, diazabicyclo[2.2.1]heptyl and diazabicyclo[3.2.1]octyl groups. , imidazolyl, pyrazolyl, cyclopropyl, oxetanyl, azetidinyl, azopentyl, morpholinyl, piperidinyl, tetrahydropyranyl, piperazinyl, 1,1-dioxo-thiomorpholinyl, 1-oxo-1-imino-thiomorpholinyl, thiomorpholinyl, pyrrolidinyl, diazaspiro[4.5]decyl, diazabicyclo[2.2.1]heptyl and diazabicyclo[3.2.1]octyl are each independently optionally selected from -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(=NR11)-NR 11 R 12 、-S(O)2-NR 11 R 12 and -C 1-6 Alkylene-C(O)-NR 11 R 12 is substituted by one or more substituents; R 11 For H atoms, C 1-6 Alkyl and C 3-6 cycloalkyl; R 12 For H atoms, C 1-6 Alkyl and C 3-6 cycloalkyl; each R 14 Selected from H atoms, C 1-6 Alkyl and C 3-6 -membered cycloalkyl, wherein the C 1-6 Alkyl and C3-6 The cycloalkyl groups are each independently optionally selected from -CN, -OH, -NR 11 R 12 and C 1-6 substituted by one or more substituents of an alkoxy group;

[0090] More preferably, each R 4 Independently selected from H atoms, methyl groups, Propyl, Cyclopropyl, -OH, F atom, CN, Phenyl, -COOH, -C(O)-NH2, -N(CH3)2,

[0091] In some embodiments, in the compound represented by formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2) or (IV),

[0092] R 2 Selected from H atoms, -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 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, C 1-6 Alkoxy-C 6-10 Aryl-, 5-10 membered heteroaryl, C 3-8 8-membered cycloalkyl and 3-8-membered heterocyclic group;

[0093] Preferably, R 2 Selected from H atoms, halogens, C 1-6 Alkoxy, C 6-10 Aryl and C 1-6 Alkoxy-C 6-10 Aryl-;

[0094] More preferably, R 2 Selected from H atoms, methoxy group and F atom.

[0095] In some embodiments, in the compound represented by formula (I), (II), (II-1), (III), (III-1), (III-2) or (IV),

[0096] R 5 Selected from H atoms, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 8-membered cycloalkyl and 3-8-membered heterocyclic group;

[0097] Preferably, R 5 Selected from H atoms, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and C 1-6 hydroxyalkyl;

[0098] More preferably, R 5 For H atoms.

[0099] In some embodiments, in the compound represented by formula (I), (II), (II-1) or (II-2),

[0100] Ring C 2 is selected from 5-10 membered heteroaryl, 3-8 membered heterocyclic group, C 3-8 Cycloalkyl, C 6-10 5-10 membered heteroaryl fused to an aryl group, C 6-10 Aryl, and C 3-8 a 5- to 10-membered heteroaryl fused to a cycloalkyl group, a C 6-10 Aryl and C 6-10 an aryl-fused 3-8 membered heterocyclic group;

[0101] Preferably, ring C 2selected from the group consisting of triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, thiazolyl, thienyl, furanyl, pyranyl, pyrrolyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydropyranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, imidazo[1,2-a]pyridinyl, quinolinyl, isoquinolinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, triazolopyridinyl, benzodioxanyl, benzimidazolyl, cinnolinyl, benzoxazolyl, benzothiazolyl, indolyl, benzofuranyl, thienopyridinyl, pyrazolopyridinyl, and pyridopyrazinyl;

[0102] More preferably, ring C 2 Selected from and / or

[0103] R 6 Selected from H atoms, -OH, -COOH, -NR 11 R 12 、-CN、halogen、C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl and -C 1-6 Alkylene-NR 11 R 12 ; Each R 11 independently H atoms and C 1-6 Alkyl; each R 12 independently H atoms and C 1-6 alkyl;

[0104] Preferably, R 6 Selected from 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,

[0105] More preferably, R 6 Selected from methyl, ethyl, hydroxymethyl, -CN, trifluoromethyl and trideuteriomethyl; and / or

[0106] R 7 Selected from H atoms, -OH, -COOH, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -CN, halogen, oxo, C1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl and C 3-8 cycloalkyl;

[0107] Preferably, R 7 Selected from 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 1-6 Hydroxyalkyl, C 3-6 membered cycloalkyl and C 1-6 alkyl halide;

[0108] More preferably, R 7 Selected from H atom, -NH2, -N(CH3)2, -CN, Cl atom, F atom, bromine atom, oxo group, methyl group, ethyl group, isopropyl group, methoxy group, cyclopropyl group, difluoromethyl group, monofluoromethyl group, trifluoromethyl group, hydroxymethyl group and trideuteromethyl group.

[0109] In some embodiments, in the compound represented by formula (I), (III), (III-1) or (III-2),

[0110] L 3 Selected from chemical bonds, -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-, -OC1-6 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 the C 1-6 The alkylene groups are each independently optionally selected from C 1-6 Alkyl, halogen, -OH, -COOH, -NH2, -CN, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, and C 1-6 is substituted by one or more substituents of a hydroxyalkyl group; each R 11 independently H atoms and C 1-6 alkyl;

[0111] Preferably, L 3 Selected from chemical bonds, -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 the C 1-6 Each alkylene group is independently optionally substituted with one or more C 1-6 Alkyl or -OH substituted;

[0112] Preferably, L 3 Selected from chemical bonds, -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

[0113] R 8 Selected from H atoms, -OH, -COOH, -CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 The 3- to 8-membered cycloalkyl and the 3- to 8-membered heterocyclic group are each independently optionally selected from -CN, -OH, C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Hydroxyalkyl, C 1-6 substituted by one or more substituents of alkoxy, -NH2 and halogen;

[0114] Preferably, R 8 Selected from H atoms, -OH, C 6-10 Aryl, 5-10 membered heteroaryl and 3-8 membered heterocyclic group, wherein the C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted with one or more C 1-6 Alkyl or halogen substituted;

[0115] More preferably, R 8 Selected from H, methyl, -OH, and / or

[0116] R 9 Selected from H atoms, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 hydroxyalkyl;

[0117] Preferably, R 9 H atom or C 1-6 alkyl;

[0118] More preferably, R 9 is a H atom or a methyl group.

[0119] Typical compounds of the present invention represented by general formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2) or (IV) include but are not limited to the following compounds:

[0120] The present invention also provides a method for preparing the compound represented by general formula (II), which comprises:

[0121] The compound represented by general formula (IIA) reacts with the compound represented by general formula (IIB) to form the compound represented by general formula (II);

[0122] Among them, LG 1 is a leaving group, preferably halogen, methanesulfonyloxy or p-toluenesulfonyloxy; and

[0123] 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);

[0124] or

[0125] The compound represented by general formula (IIC) reacts with the compound represented by general formula (IID) to form the compound represented by general formula (II);

[0126] Among them, LG 2 is a leaving group, preferably halogen, methanesulfonyloxy or p-toluenesulfonyloxy;

[0127] W is R is a hydrogen atom or C 1-6 alkyl; and

[0128] 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);

[0129] or

[0130] The compound represented by the general formula (IIE) reacts with the compound represented by the general formula (IIF) to form the compound represented by the general formula (IIG), and the compound represented by the general formula (IIG) removes the protecting group R p To form a compound represented by general formula (II);

[0131] Among them, R p is tetrahydropyranyl, (trimethylsilyl)ethoxymethyl, p-toluenesulfonyl, tert-butyl formate, benzyl or p-methoxybenzyl;

[0132] Y is an O atom, R 6 is -CH2OH, n is 1, and

[0133] 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);

[0134] or

[0135] The compound represented by the general formula (IIH) reacts with the compound represented by the general formula (IIK) to form the compound represented by the general formula (IIL), and the compound represented by the general formula (IIL) removes the protecting group R p To form a compound represented by general formula (II);

[0136] Among them, R p is tetrahydropyranyl, (trimethylsilyl)ethoxymethyl, p-toluenesulfonyl, tert-butyl formate, benzyl or p-methoxybenzyl;

[0137] LG 1 is a leaving group, preferably halogen, methanesulfonyloxy or p-toluenesulfonyloxy; and

[0138] 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);

[0139] or

[0140] The compound represented by the general formula (IIM) reacts with the compound represented by the general formula (IID) to form the compound represented by the general formula (IIN), and the compound represented by the general formula (IIN) removes the protecting group R p To form a compound represented by general formula (II);

[0141] Among them, R p is tetrahydropyranyl, (trimethylsilyl)ethoxymethyl, p-toluenesulfonyl, tert-butyl formate, benzyl or p-methoxybenzyl;

[0142] LG2 is a leaving group, preferably halogen, methanesulfonyloxy or p-toluenesulfonyloxy;

[0143] W is R is a hydrogen atom or C 1-6 alkyl; and

[0144] 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);

[0145] or

[0146] The compound represented by general formula (IIO) reacts with the compound represented by general formula (IIP) to form the compound represented by general formula (II);

[0147] Where m is 1, L 1 -S(O)2-C 1-6 Alkyl-, R 15 C 1-6 Alkenyl or -C 1-6 an alkylene-halogen; and

[0148] X 1 、X 2 、X 3 , Y, C 1 、C 2 、R 4 、R 6 、R 7 , n and p are as defined in the general formula (II).

[0149] The present invention also provides a method for preparing a compound represented by general formula (III-1), the method comprising:

[0150] The compound represented by the general formula (III-1A) reacts with the compound represented by the general formula (IID) to form the compound represented by the general formula (III-1);

[0151] Among them, LG 3 is a leaving group, preferably halogen, methanesulfonyloxy or p-toluenesulfonyloxy;

[0152] W is R is a hydrogen atom or C 1-6 alkyl; and

[0153] C 1 、R 2 、R 4 、R 5 、R 8 、R 9 , L 1 , L 3 and m are as defined in the general formula (III-1).

[0154] The present invention also provides a method for preparing a compound represented by general formula (III-2), which comprises:

[0155] The compound represented by the general formula (III-2A) reacts with the compound represented by the general formula (III-2B) to form the compound represented by the general formula (III-2);

[0156] Among them, LG 4 is a halogen, preferably a Cl atom;

[0157] C 1 、R 2 、R 4 、R 5 、R 8 、R 9 , L 1 , L 3 and m are as defined in the general formula (III-2).

[0158] The present invention also provides a pharmaceutical composition comprising a compound represented by general formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2) or (IV) and one or more pharmaceutically acceptable excipients.

[0159] The present invention relates to the use of a compound represented by general formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2) or (IV) or a pharmaceutical composition containing the same in the preparation of an FGFR inhibitor.

[0160] The present invention also relates to the use of compounds represented by general formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2) or (IV) or pharmaceutical compositions containing the same in the preparation of drugs for treating and / or preventing tumors.

[0161] The present invention also relates to compounds represented by general formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2) or (IV) or pharmaceutical compositions containing the same, which are used as drugs.

[0162] The present invention also relates to compounds represented by general formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2) or (IV) or pharmaceutical compositions comprising the same, which are used as FGFR inhibitors.

[0163] The present invention also relates to compounds represented by general formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2) or (IV) or pharmaceutical compositions containing the same, which are used for treating and / or preventing tumors.

[0164] The present invention also relates to a method for inhibiting FGFR, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound represented by formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2) or (IV) or a pharmaceutical composition comprising the same.

[0165] The present invention also relates to a method for treating and / or preventing tumors, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound represented by general formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2) or (IV) or a pharmaceutical composition comprising the same.

[0166] In some embodiments, the tumor is cancer; the cancer is preferably selected from bile duct cancer, 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, kidney cancer, pancreatic cancer, bone cancer, lymphoma, melanoma, sarcoma, peripheral neuroepithelial tumor, glioma, ependymoma, neuroblastoma, gangliocytoma, medulloblastoma, pineal cell tumor, meningioma, neurofibroma, neurilemoma and Wilms' tumor; more preferably selected from bile duct cancer, liver cancer, breast cancer, prostate cancer, lung cancer, thyroid cancer, gastric cancer, ovarian cancer, colorectal cancer, endometrial cancer and urothelial cancer.

[0167] The pharmaceutical composition of the present invention can be in various conventional dosage forms, such as tablets, aqueous suspensions, oil suspensions, dispersible powders, dispersible granules, emulsions, hard capsules, soft capsules, sterile injectable aqueous solutions, sterile injectable oil-in-water microemulsions, or suppositories. Each of the above dosage forms can be prepared by conventional preparation methods.

[0168] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following: the activity of the specific compound used, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment method such as the mode of treatment, the daily dose of the compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.

[0169] Definition of terms

[0170] For terms not defined herein, they have the meanings commonly understood by those skilled in the art. For terms defined herein, they have the meanings set in the specification.

[0171] The term "substituted" or "substituent" means that one or more hydrogen atoms are replaced by a specified group. When the position of the substitution is not specified, the substitution can be at any position, but only if a stable or chemically feasible compound is formed.

[0172] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0173] When any variable (e.g., R) occurs more than once in a compound's structure, its definition at each occurrence is independent. For example, if a group is substituted with 0-2 R, then the group may be optionally substituted with up to 2 R, and each occurrence of R is independently selectable.

[0174] 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 1-6Alkyl. Examples of alkyl groups include, but are not limited to, 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-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.

[0175] The term "alkylene" refers to a divalent functional group formed by removing one hydrogen atom from an alkyl group, wherein alkyl is as defined above.

[0176] 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, wherein the carbon-carbon double bond may be located at any position within the alkenyl group, preferably C 2-5 Alkenyl. Examples of alkenyl groups 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.

[0177] 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, wherein the carbon-carbon triple bond may be located at any position within the alkynyl group, preferably C 2-5 Alkynyl. Examples of alkynyl groups include, but are not limited to, -C≡CH, -C≡C-CH3, -CH2-C≡CH, -C≡C-CH2-CH3, -CH2-CH2-C≡CH, -CH(CH3)C≡CH, and -CH2-C≡C-CH3.

[0178] The term "cycloalkyl" includes two types, one is a conventional cycloalkyl group and the other is a heterostructure cycloalkyl group.

[0179] 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 3-10Conventional cycloalkyl, more preferably C 3-8 Conventional cycloalkyl, most preferably C 3-6 Conventional cycloalkyl groups. Conventional cycloalkyl groups optionally contain one or more double or triple bonds.

[0180] Conventional cycloalkyl can be a monocyclic alkyl, and examples of monocyclic alkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl and cyclooctyl. Conventional cycloalkyl can also be polycyclic alkyl (such as bicyclic alkyl and tricyclic alkyl), and polycyclic alkyl includes spirocyclic alkyl, fused cyclic alkyl and bridged cyclic alkyl.

[0181] The term "spirocycloalkyl" refers to a 5-20 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 membered) spirocycloalkyl, preferably a 6-14 membered spirocycloalkyl, more preferably a 7-10 membered spirocycloalkyl. The spirocycloalkyl may be a monospirocycloalkyl, a dispirocycloalkyl, or a polyspirocycloalkyl, preferably a monospirocycloalkyl, more preferably a 4 membered / 4 membered, 4 membered / 5 membered, 4 membered / 6 membered, 5 membered / 5 membered, or 5 membered / 6 membered monospirocycloalkyl. Examples of spirocycloalkyl include, but are not limited to:

[0182] The term "fused cycloalkyl" refers to a 5-20 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 6-14 membered fused cycloalkyl, more preferably a 7-10 membered fused cycloalkyl. The fused cycloalkyl may be a bicyclic, tricyclic, tetracyclic, or pentacyclic or higher ring 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, but are not limited to:

[0183] The term "bridged cycloalkyl" refers to a 5-20 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 membered) bridged cycloalkyl group, preferably a 6-14 membered bridged cycloalkyl group, more preferably a 7-10 membered bridged cycloalkyl group. The bridged cycloalkyl group may be a bicyclic, tricyclic, tetracyclic, or pentacyclic or higher bridged cycloalkyl group, preferably a bicyclic, tricyclic, or tetracyclic bridged cycloalkyl group, more preferably a bicyclic or tricyclic bridged cycloalkyl group. Examples of bridged cycloalkyl groups include, but are not limited to:

[0184] The term "heterocyclic alkyl" includes monocyclic alkyl, spirocyclic alkyl, fused cyclic alkyl and bridged cyclic alkyl fused to any one of conventional aryl, conventional heteroaryl and conventional heterocyclic groups, and the connection point is located on the corresponding conventional cycloalkyl (referring to monocyclic alkyl, spirocyclic alkyl, fused cyclic alkyl or bridged cycloalkyl). Examples of heterocyclic alkyl groups include, but are not limited to:

[0185] The term "cycloalkylene" refers to a divalent functional group formed by removing one hydrogen atom from a cycloalkyl group, wherein the cycloalkyl group is as defined above.

[0186] The term "heterocyclic group" includes two types, one is a conventional heterocyclic group and the other is a heterostructure heterocyclic group.

[0187] Conventional heterocyclic groups refer to aliphatic, saturated or partially unsaturated, monovalent cyclic hydrocarbon groups 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, and one or more ring atoms are substituted by one or more elements selected from nitrogen, oxygen, S, S(O), and S(O)2, and the substitution does not form -OO-, -OS-, or -SS-; preferably, a 3- to 12-membered conventional heterocyclic group, of which 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, a 3- to 10-membered or 3-8-membered conventional heterocyclic group, of which 1 to 3 (e.g., 1, 2, and 3) are heteroatoms; and most preferably, a 5- to 7-membered or 4- to 6-membered conventional heterocyclic group, of which 1 to 2 or 1 to 3 are heteroatoms.

[0188] Conventional heterocyclic groups can be monocyclic heterocyclic groups. Examples of monocyclic heterocyclic groups include, but are not limited to, oxetanyl, 3-pyrrolinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and tetrahydropyranyl, preferably 1,2,5-oxadiazolyl, tetrahydropyranyl, or morpholinyl. Conventional heterocyclic groups can also be polycyclic heterocyclic groups, including spirocyclic heterocyclic groups, fused-ring heterocyclic groups, and bridged-ring heterocyclic groups.

[0189] The term "spiroheterocyclyl" refers to a 5-20 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 membered) spiroheterocyclyl, preferably a 6-14 membered spiroheterocyclyl, more preferably a 7-10 membered spiroheterocyclyl. The spiroheterocyclyl may be a monospiroheterocyclyl, a bispiroheterocyclyl, or a polyspiroheterocyclyl, preferably a monospiroheterocyclyl or a bispiroheterocyclyl, 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 monospiroheterocyclyl. Examples of spiroheterocyclyls include, but are not limited to:

[0190] The term "fused heterocyclic group" refers to a 5-20 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 membered) fused heterocyclic group, preferably a 6-14 membered fused heterocyclic group, more preferably a 7-10 membered fused heterocyclic group. The fused heterocyclic group may be a bicyclic, tricyclic, tetracyclic, or pentacyclic or higher fused heterocyclic group, preferably a bicyclic or tricyclic fused heterocyclic group, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Examples of fused heterocyclic groups include, but are not limited to:

[0191] The term "bridged heterocyclic group" refers to a 5-14 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14 membered) bridged heterocyclic group, preferably a 6-14 membered bridged heterocyclic group, more preferably a 7-10 membered bridged heterocyclic group. The bridged heterocyclic group may be a bicyclic, tricyclic, tetracyclic, or pentacyclic or higher bridged heterocyclic group, preferably a bicyclic, tricyclic, or tetracyclic bridged heterocyclic group, more preferably a bicyclic or tricyclic bridged heterocyclic group. Examples of bridged heterocyclic groups include, but are not limited to:

[0192] The term "heterocyclic group" includes monocyclic heterocyclic groups, spirocyclic heterocyclic groups, fused heterocyclic groups and bridged heterocyclic groups fused to any one of conventional aryl groups, conventional heteroaryl groups and conventional cycloalkyl groups, and the connection point is located on the corresponding conventional heterocyclic group (referring to monocyclic heterocyclic groups, spirocyclic heterocyclic groups, fused heterocyclic groups or bridged heterocyclic groups). Examples of heterocyclic groups include, but are not limited to:

[0193] The term "heterocycloalkylene" refers to a divalent functional group formed by removing one hydrogen atom from a heterocycloalkyl group, wherein heterocycloalkyl is as defined above.

[0194] The term "aryl" includes two types, one is a conventional aryl group and the other is a heterostructure aryl group.

[0195] Conventional aryl refers to 6-14 membered (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14 membered) aromatic hydrocarbon groups, preferably C 6-10 Conventional aryl groups are more preferably phenyl, naphthyl, phenanthrenyl or anthracenyl.

[0196] The term "heteroaryl" includes a conventional aryl fused to any one of conventional heteroaryl, conventional heterocyclyl and conventional cycloalkyl, with the attachment point being located on the conventional aryl. Examples of heteroaryl groups include, but are not limited to:

[0197] The term "arylene" refers to a divalent functional group formed by removing one hydrogen atom from an aryl group, wherein the aryl group is as defined above.

[0198] The term "heteroaryl" includes two types, one is a conventional heteroaryl and the other is a heterostructural heteroaryl.

[0199] Conventional heteroaryl refers to a 5-14 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14 membered) aromatic hydrocarbon radical in which 1-4 (e.g., 1, 2, 3, and 4) carbon atoms are replaced with heteroatoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Preferably, the number of ring atoms is 5-10, wherein 1-3 (e.g., 1, 2, and 3) heteroatoms are present. More preferably, the number of ring atoms is 5 or 6, wherein 1-2 heteroatoms are present. Examples of conventional heteroaryl groups include, but are not limited to, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyridazinyl, pyrazinyl, quinolyl, isoquinolyl, naphthyridinyl and imidazopyridinyl, preferably imidazolyl, thiazolyl, pyrazolyl, pyrimidinyl or thiazolyl, more preferably pyrazolyl or thiazolyl.

[0200] The term "heteroaryl" includes a conventional heteroaryl fused to any one of a conventional aryl, a conventional cycloalkyl, and a conventional heterocyclic group, with the point of attachment being located on the conventional heteroaryl. Examples of heteroaryl groups include, but are not limited to:

[0201] The term "heteroarylene" refers to a divalent functional group formed by removing one hydrogen atom from a heteroaryl group, wherein the heteroaryl group is as defined above.

[0202] The term "alkoxy" includes -O-alkyl and -O-cycloalkyl, wherein "alkyl" and "cycloalkyl" are as defined above. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.

[0203] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0204] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0205] The term "hydroxy" refers to -OH.

[0206] The term "halogen" refers to -F, -Cl, -Br or -I.

[0207] The term "amino" refers to -NH2.

[0208] The term "cyano" refers to -CN.

[0209] The term "nitro" refers to -NO2.

[0210] The term "oxo" refers to =0.

[0211] The term "carboxyl" refers to -C(=O)OH.

[0212] The term "mercapto" refers to -SH.

[0213] The term "ester group" refers to a -C(=O)O-alkyl group or a -C(=O)O-cycloalkyl group, wherein alkyl and cycloalkyl are as defined above.

[0214] The term "acyl" refers to -C(=O)R, where R is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0215] symbol Refers to the attachment site.

[0216] The term "stereoisomer" refers to isomers that have the same structure but different arrangements of atoms in space. These include 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, mixtures of diastereomers). Additional asymmetric atoms may be present in the substituents in the compounds of the present invention. All of 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. An isomer of a compound of the present invention can be prepared by asymmetric synthesis or chiral auxiliary, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), by forming a diastereomeric salt with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art to obtain the pure isomer. Furthermore, separation of enantiomers and diastereoisomers is typically accomplished by chromatography.

[0217] In the chemical structure of the compound of the present invention, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or include both For all carbon-carbon double bonds, even if only one configuration is named, both the Z and E configurations are included.

[0218] The compounds and intermediates of the present invention may also exist in different tautomeric forms, and all such forms are included within the scope of the present invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine, lactam-lactim isomerizations.

[0219] The compounds of the present invention include all suitable isotopic substitutions of the compounds thereof. The term "isotopic substitution" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be introduced into the compounds of the present invention include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, for example, 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 and 131 I, etc., preferably deuterium.

[0220] As used herein, the singular form "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0221] When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, numbers are generally given for illustrative purposes only and are not limiting. DETAILED DESCRIPTION

[0222] The present invention is further described below with reference to examples, but these examples are not intended to limit the scope of the present invention.

[0223] The compounds of the present invention are prepared using convenient starting materials and general preparation procedures. Typical or preferred reaction conditions, such as reaction temperature, time, solvent, pressure, and molar ratio of reactants, are provided herein. However, other reaction conditions may be employed unless otherwise specified. Optimized conditions may vary depending on the specific reactants or solvents used, but generally, optimized reaction procedures and conditions are determined.

[0224] In addition, some protecting groups may be used in the present invention to protect certain functional groups to avoid unwanted reactions. Protecting groups suitable for various functional groups and their protection or deprotection conditions are already widely known to those skilled in the art.

[0225] The separation and purification of compounds and intermediates can be performed using appropriate methods and steps depending on specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin layer plate chromatography, preparative high performance liquid chromatography, or a combination of the above methods. Specific methods of use can be found in the examples described herein. Of course, other similar separation and purification methods can also be used. Conventional methods (including physical constants and spectral data) can be used to characterize the compounds and intermediates.

[0226] Purity analysis was performed using Kinetex EVO C18 (50 × 4.6 mm, 5 μm, ) column, acetonitrile-water was used as the mobile phase for gradient elution, the flow rate was 1.5 mL / min, and the detection wavelength was 220 nm.

[0227] MS was measured using an LC (Agilent 1260 Infinity II) / MS (G6125B single quadrupole) mass spectrometer (manufacturer: Agilent) (Photodiode Array Detector).

[0228] The structure of the compound was confirmed by hydrogen spectrum using WNMR-I-400MHz.

[0229] Preparative liquid chromatography was performed using an Agilent 1260 Infinity II high performance liquid chromatograph (manufacturer: Agilent), with a Daisogel C18 10 μm 100A column (30 mm × 250 mm) and acetonitrile / water as the mobile phase.

[0230] Thin layer chromatography (TLC) used Qingdao Ocean Chemical GF254 silica gel plates. The silica gel plates used for reaction monitoring were of a size of 0.20 mm to 0.25 mm, and the silica gel plates used for separation and purification were of a size of 0.5 mm.

[0231] Silica gel column chromatography method uses Qingdao marine silica gel 100-200 mesh, 200-300 mesh and 300-400 mesh silica gel as the carrier.

[0232] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from online shopping malls, Beijing Coupling, Sigma, Bailingwei, Yishiming, Shanghai Shuya, Shanghai Yinuokai, Anaiji Chemical, Shanghai Bid, etc.

[0233] Unless otherwise specified in the examples, all reactions were carried out under a nitrogen atmosphere.

[0234] Nitrogen atmosphere means that the reaction bottle is connected to a nitrogen balloon with a capacity of about 1L.

[0235] The reaction solvent, organic solvent or inert solvent is each expressed as the solvent used that does not participate in the reaction under the described reaction conditions, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, dichloromethane, diethyl ether, methanol, N-methylpyrrolidone (NMP).

[0236] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0237] The chemical reactions described herein are generally carried out under normal pressure. Reaction times and conditions are, for example, between -78°C and 200°C at atmospheric pressure, and are complete within approximately 1 to 24 hours. If the reaction is allowed to proceed overnight, the reaction time is generally 16 hours. Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0238] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention.

[0239] Unless otherwise specified, the mixing ratios of different solvents are by volume.

[0240] Unless otherwise specified, the KF aqueous solutions in the examples are all saturated solutions.

[0241] Synthesis of key intermediate A1

[0242] 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. The mixture was cooled to 0°C, and MsCl (6.23 g, 53.7 mmol) was slowly added dropwise. After the addition was complete, the reaction was allowed to react at room temperature for 5 h. LCMS monitoring showed no residual starting material. The reaction solution was washed once with aqueous ammonium chloride and once with water. The organic phase was dried over anhydrous sodium sulfate, filtered, and spun down to dryness to obtain A1 as a white solid (13.5 g, 95% yield, 98% purity).

[0243] Synthesis of key intermediate A2

[0244] Compound A2-1 (5.0 g, 23.25 mmol, 1.0 eq) was dissolved in dioxane (80 mL) and KOAc (4.6 g, 46.51 mmol, 2.0 eq), bis(pinacolato) borate (12 g, 46.51 mmol, 2.0 eq), and Pd(dppf)Cl2 (1.9 g, 2.3 mmol, 0.1 eq) were added. The mixture was reacted at 85°C for 12 hours under N2 protection. LCMS indicated the formation of the product. The reaction mixture was concentrated, silica gel was added, and the mixture was purified by silica gel column chromatography (eluent: CH3OH / CH2Cl2 = 0-5%) to afford 6.5 g of crude compound A2-2 as a white oil, which was used directly in the next step.

[0245] Compound A2-2 (6.5 g, 24.80 mmol, 1.0 eq) was dissolved in THF (70 mL), and DHP (4.2 g, 49.60 mmol, 2.0 eq) and TsOH (2.1 g, 12.40 mmol, 0.5 eq) were added. The mixture was reacted at 60°C for 4 hours. LCMS indicated the formation of the product. The reaction mixture was concentrated, silica gel was added, and the sample was purified by silica gel column chromatography (eluent: CH3OH / CH2Cl2 = 0-3%) to obtain 6.4 g of crude compound A2-3 as a white oil, which was used directly in the next reaction.

[0246] Compound A2-3 (6.4 g, 18.49 mmol, 1.0 eq) was dissolved in THF / H₂O (80 mL). NaOH (1.1 g, 27.74 mmol, 1.0 eq) and H₂O₂ (6 mL) were added under ice-cooling. The mixture was stirred at room temperature for 3 hours. LCMS indicated the formation of the product. The reaction solution was concentrated, dissolved in DCM, and then silica gel was added for mixing. The mixture was spin-dried and passed through a normal phase column to obtain 4.9 g of crude compound A2-4 as a white oil, which was used directly in the next step.

[0247] Compound A2-4 (4.9 g, 20.74 mmol, 1.0 eq) and compound A1 (8.6 g, 32 mmol, 1.5 eq) were dissolved in ACN (50 mL), and Cs2CO3 (20 g, 62.22 mmol, 3.0 eq) was added. The mixture was stirred at 80°C for 4 hours, and LCMS indicated the formation of the product. The reaction mixture was added with 50 mL of ice water, and then 200 mL of EA was added in three batches. The mixture was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, and then spin-dried. The sample was then washed with silica gel and purified by silica gel column chromatography (eluent: CH3OH / CH2Cl2 = 0-4%) to obtain 4.3 g of crude compound A2-5 as a white solid, which was used directly in the next step.

[0248] Compound A2-5 (4.3 g, 10.48 mmol, 1.0 eq) was dissolved in MeOH (20 mL). HCl / EA (30 mL) was added under ice-cooling and stirred at room temperature for 2 hours. LCMS indicated product formation. The reaction solution was neutralized with saturated NaHCO₃ solution and extracted with DCM. The organic phase was spin-dried to give 3.8 g of crude compound A2-6 as a white solid, which was used directly in the next reaction.

[0249] Compound A2-6 (3.8 g, 11.65 mmol, 1.0 eq) was dissolved in DMF (50 mL). NIS (5.2 g, 23.30 mmol, 2.0 eq) was added under ice-cooling and stirred at room temperature for 12 hours. LCMS indicated the formation of the product. The reaction mixture was added with 50 mL of water and extracted three times with 150 mL of EA in three batches. The mixture was then backwashed twice with a total of 100 mL of saturated NaCl solution. The organic phase was dried, concentrated, and the sample was washed with silica gel. Purification was performed by silica gel column chromatography (eluent: CH3OH / CH2Cl2 = 0-3%) to obtain 4.5 g of compound A2 as a white solid (total yield over 6 steps: 42.7%).

[0250] Synthesis of key intermediate A3

[0251] Compound A3-1 (15.0 g, 97.9 mmol, 1.0 eq), DHP (16.5 g, 196 mmol, 2.0 eq), and TsOH.H2O (1.9 g, 9.8 mmol, 0.1 eq) were dissolved in THF (10 mL) and stirred at 60°C for 8 hours. LCMS indicated the formation of the product. The reaction mixture was added with 100 mL of water, and then extracted and washed with EA (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, and purified on a silica gel column to afford 21.0 g of compound A3-2 as a white solid in a 90.1% yield.

[0252] Compound A3-2 (11 g, 46.4 mmol, 1.0 eq) was added to a 500 mL single-necked flask, followed by KOH (5.2 g, 927 mmol, 2.0 eq), H₂O (10 mL), DMF (100 mL), and Pd₂(dba)₃ (1.0 g, 4.64 mmol, 0.1 eq). After N₂ displacement, the mixture was stirred at 80°C for 14 h. LCMS indicated the formation of the product. The reaction mixture was cooled, spin-dried, and then purified on silica gel column (PE / EA = 1:1) to afford 4.6 g of compound A3-3 as a white solid in a 45.2% yield.

[0253] Compound A3-3 (4.6 g, 21 mmol, 1.0 eq), compound A2 (8.6 g, 32 mmol, 1.5 eq), and Cs2CO3 (20.3 g, 63 mmol, 3.0 eq) were dissolved in ACN (50 mL) and stirred at 80°C for 8 hours. LCMS indicated the formation of the product. The reaction mixture was added with water (30 mL), and then extracted and washed with EA (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and purified on a silica gel column to afford 4.3 g of compound A3-4 as a white solid in a 52.4% yield.

[0254] Compound A3-4 (4.3 g, 11 mmol, 1.0 eq) was added to a 25 mL single-necked vial. 4 M HCl / EA (50 mL) was added and stirred at room temperature for 3 h. LCMS indicated the formation of the product. The reaction mixture was dried by reverse-phase column chromatography to yield 4.2 g of crude compound A3-5 as a white solid, which was used directly in the next reaction.

[0255] Compound A3-5 (4.2 g, 13.6 mmol, 1.0 eq) and NIS (3.6 g, 20.5 mmol, 1.5 eq) were dissolved in DMF (40 mL) and stirred at 25°C for 8 hours. LCMS indicated product formation. Water (50 mL) was added to the reaction mixture, followed by EA (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, spin-dried, and mixed with silica gel. Purification was performed by silica gel column chromatography (eluent: CH3OH / CH2Cl2 = 0-5%) to afford 3.0 g of A3 as a white solid in a 50.8% yield.

[0256] Synthesis of key intermediate A4

[0257] Compound A4-1 (20 g, 149 mmol, 1.0 eq) and imidazole (20.3 g, 298 mmol, 2 eq.) were dissolved in MeCN (400 mL). TBSCl (44.9 g, 298.2 mmol, 2 eq.) was added at 0°C, and the reaction was stirred at 20°C for 12 hours. LCMS showed that the reaction of compound A4-1 was complete. 200 mL of saturated NaHCO3 solution was added, and the mixture was extracted with EA and washed with saturated brine. The organic phase was concentrated to obtain a yellow oily liquid. The crude product was purified on a 220 g silica gel column (0-5% EA) to obtain product A4-2 (35 g, yield: 94%). LCMS (ESI) m / z 249.1, (M+H) + .

[0258] To a solution of compound A4-2 (35 g, 140.9 mmol, 1.0 eq.) in DMF (300 mL) at 0°C was added NIS (29.25 g, 169.08 mol, 1.2 eq.) and stirred at room temperature for 2 hours. LCMS showed that the reaction of compound A-2 was complete. Ice water was added to the reaction solution, slurried with petroleum ether, and filtered to obtain a yellow solid compound A4-3 (50 g, yield 94.8%). LCMS (ESI) m / z 374.1, (M+H) + .

[0259] Compound A4-3 (50 g, 133.58 mmol, 1.0 eq.) and TsOH (2.3 g, 13.4 mmol, 2.0 eq.) were dissolved in DCM (300 mL) and DHP (22.47 g, 267.2 mmol, 2 eq.) was added dropwise at 0°C. The reaction was allowed to proceed at 25°C for 4 h. LCMS showed that compound A4-3 was completely reacted and product A4-4 was generated. The reaction mixture was extracted with aqueous NaHCO3 solution and DCM, and the organic phase was separated, dried, and spin-dried to obtain a yellow oily liquid compound A4-4 (30 mg, 45.5% yield, 70% purity), which was used directly in the next reaction. LCMS (ESI) m / z 459.1, (M+H) + .

[0260] Compound A4-4 (40 g, 61.08 mmol, 1.0 eq.), compound 1-4 (25.4 g, 122 mmol, 2 eq.) and K2CO3 (25.3 g, 183 mmol, 3 eq.) were dissolved in dioxane (400 mL), and Pd(dppf)Cl2 (4.5 g, 6.11 mmol, 0.1 eq.) was added. The atmosphere was purged with N2 three times and the reaction was carried out at 90°C for 6 hours. LCMS showed that compound A4-4 was completely reacted and the product was generated. The reaction mixture was filtered, silica gel powder was added, and the mixture was dried by rotary evaporation. The mixture was purified on a 330 g silica gel column to obtain compound A4-5 (22 g, 61% yield, 70% purity) as a brown oily liquid. LCMS (ESI) m / z 468.23, (M+H) + .

[0261] Compound A4-5 (15 g, 25.4 mmol, 1.0 eq.) was dissolved in MeOH (200 mL) and K2CO3 (7 g, 50.9 mmol, 2 eq.) was added. The mixture was reacted at 60°C for 2 hours. LCMS showed that the reaction was complete, and compound A-6 was formed. 1M HCl was added to the reaction solution, and the mixture was extracted with EtOAc. The liquid was separated, dried, and spin-dried to obtain a crude product. The product was purified on a 220 g silica gel column to obtain compound A4 (7 g, 92% yield) as an off-white solid; LCMS (ESI) m / z 299.2 (M+H) + .

[0262] Synthesis of key intermediates A5 and A6

[0263] At room temperature, compound A5-1 (1.2 g, 4.928 mmol) was dissolved in dioxane (12 mL), 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. The reaction mixture was stirred at 110°C for 48 h. LCMS indicated no residual starting material. After cooling the reaction mixture to room temperature, 100 mL of aqueous KF solution was added for quenching and stirring for 1 hour. The resulting solid was filtered through celite. The filtrate was extracted with ethyl acetate (100 mL x 3), and the organic phases were combined and dried by vortexing. The crude product was redissolved in ethyl acetate (30 mL), and 10 mL of 4 M ethyl acetate hydrochloride was added. The mixture was stirred at room temperature for 2 hours. LCMS indicated the product A5-2. The pH of the reaction mixture was adjusted to neutral with aqueous Na2CO3 solution. The organic phases were combined and dried by vortexing with ethyl acetate. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to give a brown solid product A5-2 (310 mg, purity 95%). LCMS (ESI) m / z 207.02, (M+H) +.

[0264] Compound A5-2 (310 mg, 1.5 mmol) was dissolved in MeOH (5 mL) at room temperature, and NaBH₄ (23 mg, 0.6 mmol) was added at 0°C. The mixture was stirred at room temperature for 5 min. TLC indicated complete reaction. The reaction mixture was quenched with saturated aqueous NH₄Cl and extracted with DCM (20 mL x 3). The combined organic phases were spin-dried. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 4:1) to afford A5-3 (259 mg, 90% purity) as a brown oil. LCMS (ESI) m / z 208.04, (M+H)⁺.

[0265] Compound A5-3 (250 mg, 1.2 mmol) was dissolved in DCM (3 mL) at room temperature, and SOCl2 (1 mL) was added at 0°C. The mixture was stirred at room temperature for 2 hours. LCMS indicated that the reaction was complete, and the reaction mixture was directly dried to give the crude product A5-4 (263 mg).

[0266] At room temperature, compound A5-4 (263 mg, 1.16 mmol) and compound A5-5 (400 mg, 1.16 mmol) were dissolved in DMF (4 mL), and Cs2CO3 (1.13 g, 3.48 mmol) was added. The reaction mixture was stirred at 50°C overnight. LCMS showed complete reaction of the starting materials. The reaction mixture was diluted with water and extracted with ethyl acetate (30 mL x 3). The organic phases were combined and dried by spin drying. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 3:1) to afford product A5 (533 mg, 78% purity) as a yellow oil. LCMS (ESI) m / z 535.03, (M+H)+.

[0267] At room temperature, compound A5 (533 mg, 0.777 mmol) and compound A6-1 were dissolved in dioxane / H2O (6 mL, v / v = 5 / 1), and K2CO3 (320 mg, 2.33 mmol) was added. Pd(dppf)Cl2 in DCM (126 mg, 0.155 mmol) was added under nitrogen. The reaction mixture was stirred at 80°C for 12 h. LCMS showed complete reaction of the starting materials. The reaction mixture was diluted with water and extracted with ethyl acetate (30 mL x 3). The organic phases were combined and dried by spin drying. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 1:1) to afford the product A6-2 (420 mg, 80% purity) as a brown oil. LCMS (ESI) m / z 630.25, (M+H)+.

[0268] Compound A6-2 (420 mg, 0.474 mmol) was dissolved in MeOH (5 mL) at room temperature, and HCl (4 mL, 4 M in dioxane) was added under ice. The reaction mixture was stirred at room temperature for 3 h. LCMS indicated complete reaction. The reaction mixture was directly dried to afford product A6 (244 mg, 70% purity, hydrochloride salt) as a brown oil. LCMS (ESI) m / z 446.14, (M+H)+.

[0269] Synthesis of key intermediate A7

[0270] Compound A5 (35 mg, 0.06 mmol, 1.0 eq) and compound A7-1 (19 mg, 0.09 mmol, 1.5 eq) were dissolved in dioxane (2 mL) and H₂O (2 mL). Cs₂CO₃ (64 mg, 0.19 mmol, 3 eq) and Pd(dppf)Cl₂ (9.5 mg, 0.013 mmol, 0.2 eq) were then added. The mixture was purged with nitrogen three times and stirred at 90°C for 6 hours. LCMS showed that compound A5 was completely reacted. The reaction mixture was filtered and dried, and the crude product was purified by TLC (PE:EA = 1:9) to afford compound A7 (28 mg, 90% yield). LCMS (ESI) m / z 475.2, (M+H)⁺.

[0271] Synthesis of key intermediates A8 and A9

[0272] Methylmagnesium bromide (4.9 g, 41.10 mmol, 1.3 eq) was added to a solution of compound A8-1 (5.0 g, 31.61 mmol, 1.0 eq) in tetrahydrofuran (5 mL) at 0°C. The atmosphere was replaced with nitrogen three times and stirred at room temperature for 1 hour. LCMS showed the formation of the product. The mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and dried, and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 4:1) to give an off-yellow solid A8-2 (4.7 g, yield 85%), LCMS (ESI) m / z 175.09, (M+H)+.

[0273] To a solution of compound A8-2 (4.7 g, 26.98 mmol, 1.0 eq.) in dichloromethane (40 mL) at 0°C was added thionyl chloride (6.4 mg, 53.96 mmol, 2.0 eq.) and stirred at room temperature for 1 hour. LCMS indicated the formation of the product. The reaction mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to afford A8-3 as a brown oil (5.0 g, 96% yield; LCMS (ESI) m / z 193.05, (M+H)+).

[0274] Compound A8-3 (5.0 g, 26.44 mmol, 1.3 eq.), compound A5-5 (7.0 g, 20.34 mmol, 1.0 eq.), and cesium carbonate (39.77 g, 122.04 mmol, 6 eq.) were dissolved in N,N-dimethylformamide (50 mL) and stirred at 45°C for 6 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 and dried, and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1) to obtain an off-yellow solid A8 (7.4 g, yield 73%, LCMS (ESI) m / z 501.34, (M+H)+).

[0275] 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 / H2O (20 mL, v / v = 3 / 1) at room temperature. Pd(PPh3)4 (462 mg, 0.399 mmol) was added under nitrogen, and the nitrogen atmosphere was replaced three times. The reaction solution was stirred at 85°C for 72 h. LCMS indicated the reaction was complete. The reaction solution was diluted with water and extracted with ethyl acetate (200 mL x 3). The organic phases were combined and dried by spin drying. The crude product was purified by silica gel column chromatography (eluent: dichloromethane:methanol = 20:1) to obtain the product A9 (1.59 g, 90% purity, 81.26% yield) as a yellow solid. LCMS (ESI) m / z 440.8, (M+H)+.

[0276] Example 1

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

[0278] Compound 1-1 (250 mg, 0.94 mmol, 1.0 eq), KOH (307 mg, 5.5 mmol, 5.8 eq), and iodine (479 mg, 1.89 mmol, 2.0 eq) were added sequentially to dioxane (12.0 mL) at room temperature. The reaction mixture was stirred at 75°C for 16 hours. The reaction mixture was cooled to room temperature, and aqueous sodium thiosulfate solution (50.0 mL) was added. The mixture was extracted with ethyl acetate (20.0 mL x 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 afford compound 1-2 (425 mg, 100% yield).

[0279] At 0°C, a solution of compound 1-2 (318 mg, 0.813 mmol, 1.0 eq) in THF (3.0 mL) was slowly added to a suspension of sodium hydroxide (59 mg, 1.46 mmol, 1.8 eq) in THF (5.0 mL). The reaction mixture was warmed to room temperature and stirred for 0.5 hours, then cooled to 0°C and SEMCl (0.19 mL, 1.06 mmol, 1.3 eq) was slowly added. The reaction mixture was warmed to room temperature and stirred for 2 hours. After cooling to 0°C, the reaction mixture was slowly poured into aqueous NH4Cl (30.0 mL) and extracted with EA (20.0 mL x 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: ethyl acetate / petroleum ether = 0-10%) to afford compound 1-3 (404 mg, 95.3% yield).

[0280] Compound 1-3 (404 mg, 0.775 mmol, 1.0 eq), compound 1-4 (170 mg, 0.817 mmol, 1.05 eq), Pd(dppf)Cl2 (64 mg, 0.078 mmol, 0.1 eq), and potassium carbonate (320 mg, 2.32 mmol, 3.0 eq) were added sequentially to dioxane / H2O (8 mL / 2 mL) at room temperature. The reaction mixture was stirred at 80°C for 10 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: ethyl acetate / petroleum ether = 0-22%) to afford compound 1-5 (245 mg, 66.6% yield).

[0281] Compound 1-5 (245 mg, 0.515 mmol, 1.0 eq), Pd(dba) (141.6 mg, 0.155 mmol, 0.3 eq), t-BuXphos (131 mg, 0.31 mmol, 0.6 eq), and KOH (116 mg, 2.06 mmol, 4.0 eq) were added sequentially to dioxane / H2O (5 mL / 1 mL) at room temperature. The reaction mixture was stirred at 90°C for 16 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 afford compound 1-6 (188 mg, 86.8% yield).

[0282] Compound 1-6 (188 mg, 0.45 mmol, 1.0 eq), compound A1 (130 mg, 0.48 mmol, 1.1 eq), and cesium carbonate (450 mg, 1.38 mmol, 3.0 eq) were added sequentially to acetonitrile (5.0 mL) at room temperature, and the reaction mixture was stirred at 80°C for 6 hours. The residue was concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: (dichloromethane:methanol = 4:1) / dichloromethane = 0-13%) to afford compound 1-7 (200 mg, 74.9% yield).

[0283] At room temperature, TFA (2.0 mL) was slowly added to a solution of compound 1-7 (200 mg, 0.34 mmol, 1.0 eq) in DCM (6.0 mL). The reaction mixture was stirred at room temperature for 3 hours. The residue was concentrated under reduced pressure, dissolved in THF (5.0 mL), and aqueous ammonia was added to adjust the pH to >10. The reaction mixture was stirred at room temperature for 0.5 hours. Water (10.0 mL) was added, and the mixture was extracted with DCM (10.0 mL x 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 = 0-15%) to afford compound 1 (75 mg, 48.4% yield, 100% purity). LCMS(ESI)m / z 456.1 / 458.1 / 460.1(M+H)+; 1 H NMR(400MHz,DMSO)δ13.43(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=6.6Hz,1H),3.98(s,3H),1.81(d,J=6.6Hz,3H).

[0284] The following compounds were synthesized by referring to the route of Example 1

[0285] Example 2

[0286] (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-7-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-indazole

[0287] Compound 2-1 (350 mg, 2.36 mmol, 1.0 eq), compound A1 (941 mg, 3.5 mmol, 1.5 eq), and Cs2CO3 (2.3 g, 7.0 mmol, 3.0 eq) were dissolved in ACN (8 mL) and stirred at 80°C for 8 hours. LCMS indicated the formation of the product. The reaction mixture was added with 30 mL of water, washed with 30 mL of EA, and extracted three times with EA. The organic phases were combined, dried over anhydrous sodium sulfate, and purified on a silica gel column to afford 270 mg of compound 2-2 as a white solid in a 35.5% yield.

[0288] Compound 2-2 (270 mg, 0.84 mmol, 1.0 eq), I2 (324 mg, 1.26 mmol, 1.5 eq), and KOH (190 mg, 1.69 mmol, 2.0 eq) were dissolved in DMF (10 mL) and stirred at 25°C for 8 hours. LCMS indicated the formation of the product. 50 mL of water was added to the reaction mixture, followed by 50 mL of EA. The mixture was extracted three times with EA. The combined organic phases were dried over anhydrous sodium sulfate, spin-dried, and mixed with silica gel. The mixture was purified on a silica gel column (eluent: petroleum ether / ethyl acetate = 3 / 1) to afford 120 mg of compound 2-3 as a white solid in a 31.9% yield.

[0289] Compound 2-3 (120 mg, 0.27 mmol, 1.0 eq), compound 1-4 (86 mg, 0.41 mmol, 1.5 eq), Cs2CO3 (270 mg, 0.81 mmol, 3.0 eq), Pd(dppf)Cl2 (40 mg, 0.027 mmol, 0.1 eq) were dissolved in dioxane (5 mL) and 1 mL of water was added. The atmosphere was replaced with nitrogen and stirred at 80°C for 8 hours. LCMS showed the formation of the product. 30 mL of water was added to the reaction mixture, followed by washing with 30 mL of EA. The EA was extracted three times, the organic phases were combined, dried over anhydrous sodium sulfate, purified on a silica gel column, and then purified on 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(400MHz,DMSO)δ8.59(s,2H),8.08(s,1H),7.80(s,1H),6.91(s,1H),6.88( s, 1H), 6.10 (q, J = 6.6Hz, 1H), 3.94 (s, 3H), 2.44 (s, 3H), 1.75 (d, J = 6.6Hz, 3H).

[0290] The following compounds were synthesized by referring to the route of Example 2

[0291] Example 7

[0292] (R)-7-Cyclopropyl-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(1-methyl-1H-pyrazol-4-yl)-1H-indazole

[0293] At room temperature, 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 (40.0 mL). The resulting mixture was stirred at 50°C for 4 hours. LCMS indicated the formation of the product. The reaction mixture was diluted with ethyl acetate (100.0 mL), washed sequentially with saturated aqueous sodium bicarbonate (40.0 mL) and water (40.0 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1, v / v) to afford compound 7-2 as a yellow solid (1.362 g, yield: 88%, purity: 95.03%). LCMS (ESI) m / z 352.9 (M+H)+.

[0294] Compound 7-2 (1.059 g, 3.0 mmol), compound 1-4 (0.811 g, 3.9 mmol), Pd(dppf)Cl2·CH2Cl2 (0.246 g, 0.30 mmol), and K2CO3 (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 hours, and LCMS showed product formation. 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 x 4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and 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 obtain a light brown solid compound 7-3 (0.719 g, yield: 78%, purity: 100%). LCMS (ESI) m / z 307.1 (M+H) +.

[0295] At room temperature, compound 7-3 (0.412 g, 1.34 mmol) was added to dichloromethane (10.0 mL), followed by the slow dropwise addition of a 2.0 M dichloromethane solution of boron tribromide (3.4 mL, 6.7 mmol). The resulting mixture was stirred at room temperature for 18 hours, and LCMS indicated the formation of the product. The reaction mixture was adjusted to a pH of 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 x 5). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and 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 / 1-10 / 1, v / v) to yield a dark brown solid (0.48 g). This solid was added to ethanol (1.5 mL), stirred at 80°C for 30 minutes, and then 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 in vacuo to give brown solid compound 7-4 (0.362 g, yield: 92%, purity: 96.3%). LCMS (ESI) m / z 293.0 (M+H)+.

[0296] At room temperature, 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). The resulting mixture was stirred at 65°C for 18 hours. LCMS indicated the formation of the product. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (15.0 mL), washed with water (10.0 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (gradient elution, eluent: dichloromethane / methanol = 50 / 1 to 30 / 1, v / v) to obtain compound 7-5 (0.303 g, yield: 53%, purity: 64.89%) as a light brown solid. LCMS (ESI) m / z 466.0 (M+H)+.

[0297] 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 indicated 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 x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The resulting residue was purified by thin-layer chromatography (developing solvent: dichloromethane / methanol = 30 / 1, v / v) to give a yellow solid compound 7 (0.0165 g, yield: 38%, purity: 92.68%). LCMS (ESI) m / z 428.0, (M+H) +; 1 H NMR (400MHz, DMSO) δ13.06(s,1H),8.61(s,2H),8.12(s,1H),7.82(s,1H),6.94(s,1H),6.57(d,J=2.0Hz,1H),6.11(q,J=6.6Hz,1H),3. 96(s,3H),2.30–2.20(m,1H),1.77(d,J=6.6Hz,3H),1.07(d,J=2.2Hz,1H),1.05(d,J=2.4Hz,1H),0.85–0.78(m,1H),0.74–0.67(m,1H).

[0298] The following compounds were synthesized by referring to the route of Example 7

[0299] Example 9

[0300] (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-7-methyl-3-(4-methyl-1H-imidazol-2-yl)-1H-indazole

[0301] NaNO2 (2.628 g, 38 mmol, 8.0 eq) was dissolved in water (30 mL) to prepare solution 1. Hydrogen chloride solution (38 mmol) was added to solution 1 and stirred at 0°C for 10 minutes. Compound 9-1 (1 g, 4.76 mmol, 1.0 eq) in DMF (50 mL) was then slowly added to solution 1 and allowed to react at room temperature for 3 hours. LCMS indicated the formation of the product. The reaction mixture was cooled and extracted three times with EA and water. The extract was concentrated in vacuo to afford crude compound 9-2, which was directly used in the next reaction. LCMS (ESI) m / z 238.97, (M+H)+.

[0302] At 0°, a 7N ammonia-methanol solution (7 mL) was added to a CH3OH solution (40 mL) of the crude product of compound 9-2. After stirring for 10 minutes, compound 9-3 (5 mL, 5.0 eq) was slowly added and reacted at room temperature for 3 hours. LCMS showed the formation of the product. The reaction mixture was cooled and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: CH3OH:DCM=1:10) and concentrated to give compound 9-4 (416 mg, yield 30.5%, LCMS (ESI) m / z 291.02 (M+H)+).

[0303] At 0°, NaH (120 mg, 3.0 mmol, 2.0 eq) was added to THF (15 mL) of compound 9-4 (416 mg, 1.43 mmol, 1.0 eq), the air was replaced with nitrogen, and the reaction was carried out at room temperature for 40 min. SEMCl (0.66 mL, 1.3 eq) was then added and the reaction was carried out at room temperature for 3 h. LCMS showed the formation of the product. The reaction solution was directly concentrated in vacuo, the mixture was cooled, extracted three times with EA and water, washed with saturated brine, and the residue was purified by silica gel column chromatography (eluent: PE:EA=10:1) and concentrated to give compound 9-5 (450 mg, yield 52.6%, LCMS (ESI) m / z 551.18, (M+H)+).

[0304] To a solution of compound 9-5 (450 mg, 0.82 mmol, 1.0 eq), Pd(dppf)Cl2 (134 mg, 0.162 mmol, 0.2 eq) and diboronic acid pinacol ester (622 mg, 2.45 mmol, 3.0 eq) in dioxane (9 mL) was added potassium acetate (321 mg, 3.28 mmol, 4.0 eq). The mixture was reacted at 90° for three hours. LCMS showed product formation. The reaction solution was directly concentrated in vacuo, and the residue was filtered through celite. The filtrate was concentrated in vacuo to give a crude product of compound 9-6 (LCMS (ESI) m / z 599.35, (M+H)+), with the formation of boronic acid as a byproduct.

[0305] Sodium perborate tetrahydrate (730 mg, 4.8 mmol, 6.0 eq) was added to a solution of crude compound 9-6 in THF / H₂O (8 mL / 2 mL). The mixture was allowed to react at room temperature for 2 hours. LCMS indicated product formation. The reaction solution was concentrated in vacuo, and the residue was extracted three times with DCM and water, then washed with saturated brine. The residue was purified by silica gel column chromatography (eluent: DCM:H₂O = 10:1). Concentration afforded the crude liquid compound 9-7, which was directly used in the next reaction. LCMS (ESI) m / z 489.26 (M+H)⁺.

[0306] To a solution of the crude compound 9-7 and compound A1 (270 mg, 0.96 mmol, 1.2 eq) in DMF (8 mL) was added cesium carbonate (750 mg, 2.0 mmol, 2.5 eq), and the mixture was allowed to react at room temperature for 12 h. LCMS indicated the formation of the product. The reaction solution was extracted three times with EA and water, and then washed with saturated brine. The residue was purified by silica gel column chromatography (eluent: DCM:CH3OH = 15:1) and concentrated to afford compound 9-8 (36 mg, 6.7% yield over three steps). LCMS (ESI) m / z 662.24, (M+H)+.

[0307] 2 mL of trifluoroacetic acid was added to a solution of compound 9-8 (36 mg) in DCM (4 mL), and the reaction was stirred at room temperature for 3 h. LCMS showed that the product was generated. The trifluoroacetate of compound 9 (5.3 mg, yield 24.3%, purity 94.45%) was prepared by high performance liquid chromatography. 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).

[0308] Example 10

[0309] (R)-4-(2-(4-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-7-fluoro-1H-indazol-3-yl)-1H-pyrazol-1-yl)ethyl)morpholine

[0310] Compound A2 (200 mg, 0.44 mmol, 1.0 eq) and compound 10-1 (209 mg, 0.88 mmol, 2.0 eq) were dissolved in dioxane / H₂O (5 mL). Cs₂CO₃ (432 mg, 1.33 mmol, 3.0 eq) and Pd(dppf)Cl₂ (33 mg, 0.04 mmol, 0.1 eq) were added. The mixture was stirred at 85°C for 12 hours under N₂ protection. LCMS indicated the formation of the product. The reaction mixture was added with 5 mL of water, and 15 mL of EA was added in three batches. The mixture was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and washed with silica gel. Purification was performed by silica gel column chromatography (eluent: DCM:CH₃OH = 20:1) to obtain 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 (400MHz, DMSO) δ13.41(s,1H),8.59(s,2H),8.16(s,1H),7.83(s,1H),6.97(s,2H),6.16(d,J= 6.4Hz, 1H), 4.15 (t, J = 6.4Hz, 2H), 1.92–1.80 (m, 2H), 1.76 (d, J = 6.0Hz, 3H), 0.87 (t, J = 7.2Hz, 3H).

[0311] The following compounds were synthesized by referring to the route of Example 10

[0312] Example 28

[0313] (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine

[0314] Compound A3 (120 mg, 0.28 mmol, 1.0 eq), compound 28-1 (118 mg, 0.41 mmol, 1.5 eq), Cs2CO3 (270 mg, 0.83 mmol, 3.0 eq), and Pd(dppf)Cl2 (22.5 mg, 0.027 mmol, 0.1 eq) were dissolved in dioxane (5 mL) and 1 mL of water was added. The atmosphere was replaced with nitrogen and stirred at 80°C for 8 hours. LCMS showed the formation of the product. The reaction mixture was added with 30 mL of water and washed with 30 mL of EA. The mixture was extracted three times with EA. The organic phases were combined, dried over anhydrous sodium sulfate, purified on a silica gel column, and then purified on 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(400MHz,)δ8.91(d,J=6.4Hz),8.50(d,J=1.3Hz),8.37(d,J=8.2Hz),8.30(d,J=0.92Hz),8. 12–8.05(m),8.01–7.93(m),6.96(t,J=3.8Hz),6.43(d,J=1.2Hz),5.71(s),1.69(d,J=6.8Hz).

[0315] The following compound was synthesized by referring to the route of Example 28

[0316] Example 65

[0317] 3-(1-methyl-1H-pyrazol-4-yl)-N-(2-(methylamino)ethyl)-1H-indazole-5-carboxamide

[0318] To a solution of compound 65-1 (300 mg, 1.04 mmol, 1.0 eq), compound 65-2 (0.3 mL, 1.56 mmol, 1.5 eq), and HATU (613 mg, 1.6 mmol, 1.5 eq) in DMF (10 mL) was added DIPEA (0.5 mL, 3.12 mmol, 3.0 eq). The mixture was allowed to react at room temperature for 12 hours. LCMS indicated the formation of the product. The reaction mixture was extracted with EA and water, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: DCM:methanol = 15:1) to afford compound 65-3 (600 mg, 70% purity, 90% yield). LCMS (ESI) m / z 445, (M+H)+.

[0319] To a solution of compound 65-3 (600 mg, 0.95 mmol, 1.0 eq), compound 65-4 (350 mg, 1.68 mmol, 1.1 eq), and sodium carbonate (497 mg, 4.79 mmol, 3.0 eq) in dioxane / water (12 mL / 3 mL) was added Pd(dppf)Cl2 (231 mg, 0.19 mmol, 0.2 eq). The mixture was reacted at 100° for 12 h. LCMS indicated the formation of the product. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: DCM:methanol = 10:1) to afford compound 65-5 (337 mg, 89% yield). LCMS (ESI) m / z 399.21, (M+H)+.

[0320] To a solution of compound 65-5 (150 mg, 0.38 mmol, 1.0 eq) in ethyl acetate (2 mL) was added 2 mL of EA-HCl, and the reaction was stirred at room temperature for 2 h. LCMS showed the formation of the product. The reaction mixture was directly concentrated under reduced pressure and prepared by high performance liquid chromatography to give compound 65 (11.7 mg, purity 100%, yield 10.3%), LCMS (ESI) m / z 299.21, (M+H)+. 1 H NMR (400MHz, DMSO) δ9.01 (t, J=5.4Hz, 1H), 8.86 (s, 2H), 8.67 (s, 1H), 8.63 (s, 1H), 8.10 (s, 1H), 7.96 (dd, J= 8.8,1.4Hz,1H),7.59(d,J=8.7Hz,1H),3.98(s,3H),3.64(s,3H),3.20–3.12(m,2H),2.63(t,J=5.4Hz,3H).

[0321] The following compound was synthesized by referring to the route of Example 65

[0322] Example 70

[0323] 7-Fluoro-N-(2-(methylamino)ethyl)-3-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-indazole-5-carboxamide

[0324] 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 x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 40 / 1, v / v) to give an off-white solid compound 70-2 (0.197 g, yield: 97%, purity: 100%). LCMS (ESI) m / z 359.2, (M+Na)+.

[0325] At room temperature, NIS (0.158 g, 0.70 mmol) was added to a solution of compound 70-2 (0.197 g, 0.59 mmol) in N,N-dimethylformamide (1.2 mL). The resulting mixture was stirred at room temperature for 17 hours, and LCMS indicated the formation of the product. The reaction mixture was diluted with ethyl acetate (10.0 mL), washed sequentially with saturated aqueous sodium bicarbonate (10.0 mL) and water (10.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 60 / 1, v / v) to afford compound 70-3 (0.247 g, yield: 91%, purity: 100%) as a yellow solid. LCMS (ESI) m / z 485.0, (M+Na)+.

[0326] Compound 70-3 (0.0647 g, 0.14 mmol), compound 70-4 (0.0731 g, 0.24 mmol), Pd(dppf)Cl2·CH2Cl2 (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 hours, and 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 x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (gradient elution, eluent: dichloromethane / methanol = 30 / 1-20 / 1, v / v) to obtain a light brown solid compound 70-5 (0.0355 g, yield: 49%, purity: 92.48%). LCMS (ESI) m / z 516.3, (M+H) +.

[0327] At room temperature, compound 70-5 (0.0355 g, 0.069 mmol) was added to a 2.0 M solution of hydrogen chloride in ethyl acetate (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 vacuum to obtain a light brown solid compound 70 (0.0176 g, yield: 52%, purity: 92.96%). LCMS (ESI) m / z 416.2, (M+H)+; 1 H NMR (400MHz, DMSO) δ9.27 (t, J = 5.2Hz, 1H), 9.08 (br s,2H),8.83(s,1H),8.64(s,1H),8.15(s,1H),7.76(d,J=12.2Hz,1H),4.00(s ,3H),3.68(dd,J=11.0,5.4Hz,2H),3.22–3.14(m,2H),2.64(t,J=5.2Hz,3H).

[0328] Example 71

[0329] 6-(3,5-Dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-N-(2-(methylamino)ethyl)-1H-indazole-5-carboxamide

[0330] To a solution of compound 71-1 (330 mg, 1.29 mmol, 1.0 eq) in DMF (13 mL) was added NIS (437 mg, 1.94 mmol, 1.5 eq) and the mixture was allowed to react at 50°C for 4 hours. LCMS indicated the formation of the product. The reaction mixture was cooled, extracted three times with EA and water, and washed with saturated brine. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (eluent: PE:EA = 4:1) to afford the crude product of compound 71-2 as a pale yellow oil, which was used directly in the next reaction (purity 90%, LCMS (ESI) m / z 380.87, (M+H)+).

[0331] To a solution of crude compound 71-2 and compound 1-4 (295 mg, 1.42 mmol, 1.1 eq) in dioxane / water (12 mL / 3 mL) were added Pd(dppf)Cl2 (187 mg, 0.258 mmol, 0.2 eq) and potassium carbonate (416 mg, 3.2 mmol, 2.5 eq). The air was replaced with N2 and the mixture was reacted at 80° for 12 h. LCMS showed the formation of the product. The reaction mixture was cooled and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: DCM:CH3OH = 15:1) to afford compound 71-3 (600 mg, 70% purity, 65% yield over two steps, LCMS (ESI) m / z 337.02 (M+H)+).

[0332] To a solution of compound 71-3 (420 mg, 1.24 mmol, 1.0 eq) in THF / H2O (10 mL / 10 mL) was added LiOH (120 mg, 4.98 mmol, 4.0 eq). The mixture was reacted at 50°C for 12 h. LCMS indicated the formation of the product. The reaction solution was concentrated in vacuo, and the residue was extracted with DCM and water. The extract was concentrated to afford the crude compound 71-4, which was used directly in the next reaction. LCMS (ESI) m / z 320.19, (M+H)+.

[0333] To a solution of the crude product of compound 71-4, compound 65-2 (0.2 mL, 1.12 mmol, 1.5 eq), and DIPEA (0.40 mL, 2.24 mmol, 3.0 eq) in DMF (8 mL) was added HATU (425 mg, 1.12 mmol, 1.5 eq) and HOAT (152 mg, 1.12 mmol, 3.0 eq), and the mixture was allowed to react at room temperature for 3 hours. LCMS indicated the formation of the product. The reaction solution was extracted three times with EA and HO, washed with saturated brine to ensure the absence of DMF, and purified by silica gel column chromatography (eluent: DCM:HO = 10:1) to afford compound 71-5 (100 mg, 30% yield over two steps, LCMS (ESI) m / z 477.12, (M+H)).

[0334] To a solution of compound 71-5 (100 mg, 0.2 mmol, 1.0 eq) and compound 71-6 (42 mg, 0.22 mmol, 1.1 eq) in dioxane / water (2 mL / 0.5 mL) were added Pd(dppf)Cl2 (30 mg, 0.04 mmol, 0.2 eq) and potassium carbonate (83 mg, 0.6 mmol, 3.0 eq). The atmosphere was replaced with N2 and the mixture was allowed to react at 90° for 12 h. LCMS indicated the formation of the product. The reaction solution was directly concentrated in vacuo, and the residue was purified by silica gel column chromatography (eluent: DCM:H2O = 10:1) to afford compound 71-7 (10 mg, 9.4% yield). LCMS (ESI) m / z 535.26, (M+H)+.

[0335] To a solution of compound 71-7 (10 mg) in DCM (2 mL) was added 2 mL of HCl-dioxane solution, and the mixture was stirred at room temperature for 3 h. LCMS showed the formation of the product. The hydrochloride of compound 71 (1 mg, purity 94.87%, yield 12.3%) was prepared by high performance liquid chromatography (LCMS (ESI) m / z 435, (M+H) + ); 1 H NMR(400MHz,DMSO)δ9.07(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 = 5.6Hz, 2H), 3.17–3.09 (m, 2H), 2.61 (t, J = 5.4Hz, 3H).

[0336] Example 72

[0337] 6-Methoxy-3-(1-methyl-1H-pyrazol-4-yl)-N-(2-(methylamino)ethyl)-1H-indazole-5-carboxamide

[0338] At room temperature, HATU (795 mg, 2.09 mmol, 1.5 eq) was slowly added to a solution of compound 72-1 (268 mg, 1.39 mmol, 1.0 eq), compound 65-2 (364 mg, 2.09 mmol, 1.5 eq), and DIPEA (0.75 mL, 4.17 mmol, 3.0 eq) in DMF (10 mL). The reaction was stirred at room temperature for 4 hours. Saturated aqueous sodium bicarbonate (40.0 mL) was added, and the mixture was extracted with ethyl acetate (20.0 mL x 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 = 0-16%) to afford compound 72-2 (464 mg, 95.5% yield).

[0339] Compound 72-2 (464 mg, 1.33 mmol, 1.0 eq) and NIS (330 mg, 1.46 mmol, 1.1 eq) were added sequentially to DMF (7.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was cooled to room temperature, and water (30.0 mL) was added. The mixture was extracted with ethyl acetate (15.0 mL x 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 afford compound 72-3 (490 mg, 77.6% yield).

[0340] Compound 72-3 (247 mg, 0.52 mmol, 1.0 eq), compound 1-4 (119 mg, 0.57 mmol, 1.1 eq), Pd(dppf)Cl2 (75.5 mg, 0.1 mmol, 0.2 eq), and sodium carbonate (165 mg, 1.56 mmol, 3.0 eq) were added sequentially to dioxane / H2O (5 mL / 1.3 mL) at room temperature. The reaction mixture was stirred at 90°C for 16 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 = 0-25%) to afford compound 72-4 (192 mg, 86.1% yield).

[0341] At room temperature, a solution of dioxane hydrochloride (4M, 5 mL, 20 mmol, 44 eq) was slowly added to a solution of compound 72-4 (192 mg, 0.45 mmol, 1.0 eq) in DCM (2.0 mL). The reaction was stirred at room temperature for 5 hours. The mixture was concentrated under reduced pressure, and EA (10 mL) was added to the resulting residue. The mixture was stirred for 15 minutes, filtered, and the filter cake was dried under reduced pressure to afford compound 72 (130 mg, 79.8% yield, 99.2% purity). LCMS (ESI) m / z 329.2 (M+H)+; 1 H NMR (400MHz, DMSO) δ8.98 (s, 2H), 8.54 (t, J = 5.7Hz, 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=5.8Hz,2H),3.10(t,J=5.8Hz,2H),2.61(t,J=5.4Hz,3H).

[0342] The following compound was synthesized by referring to the route of Example 72

[0343] Example 74

[0344] 3-(1-methyl-1H-1,2,3-triazol-4-yl)-N-(2-(methylamino)ethyl)-1H-indazole-5-carboxamide

[0345] To a solution of compound 74-1 (2 g, 7.84 mmol, 1.0 eq) in DMF (20 mL) were added 74-2 (1.15 g, 11.76 mmol, 1.5 eq), DIEA (2.0 g, 15.69 mmol, 2.0 eq), Pd(dppf)Cl2 (400 mg, 0.2 w), and CuI (200 mg, 0.1 w). The atmosphere was replaced with N2 three times and the temperature was raised to 100°C for 15 h. LCMS indicated the formation of the product. The reaction solution was concentrated and purified by column chromatography (PE:EA = 50%-80%) to afford compound 74-3 as a yellow solid (1.5 g, 70.4% yield, 95% purity). LCMS (ESI) m / z 273.4 (M+H)+.

[0346] To a solution of compound 74-3 (2.2 g, 8.08 mmol, 1.0 eq) in THF (20 mL) was added TBAF (3.17 g, 12.1 mmol, 1.5 eq) and allowed to react at 25°C for 2 h. LCMS indicated the formation of the product. The reaction mixture was added with water (50 mL) and EA (20 mL), separated, washed, and concentrated to afford compound 74-4 as a white solid (1.2 g, 74.0% yield, 95% purity). LCMS (ESI) m / z 201.2 (M+H)+.

[0347] To a solution of compound 74-4 (410 mg, 2.05 mmol, 1.0 eq) in DMF (5 mL) were added 74-5 (397.4 mg, 3.07 mmol, 1.5 eq), DIEA (615.82 mg, 4.10 mmol, 2.0 eq), and CuI (41 mg, 0.1 w), and the mixture was allowed to react at 25°C for 2 h. LCMS indicated the formation of the product. The reaction solution was concentrated and purified by column chromatography (PE:EA = 50%-80%) to afford compound 74-6 (600 mg, 90% yield, 95% purity). LCMS (ESI) m / z 330.4 (M+H)+.

[0348] To a solution of compound 74-6 (600 mg, 1.82 mmol, 1.0 eq) in THF (6 mL) was added TBAF (714.3 mg, 2.73 mmol, 1.5 eq) and allowed to react at 25°C for 2 h. LCMS indicated the formation of the product. The reaction mixture was added with water (50 mL) and EA (20 mL), separated, washed, and concentrated to afford compound 74-7 (374 mg, 80% yield, 95% purity). LCMS (ESI) m / z 258.3 (M+H)+.

[0349] To a solution of compound 74-7 (100 mg, 0.39 mmol, 1.0 eq) in MeOH / H₂O (5 mL / 1 mL) was added LiOH (28.0 mg, 1.17 mmol, 3 eq) and the mixture was allowed to react at 50°C for 15 h. LCMS indicated the formation of the product. The reaction mixture was spin-dried, and water (10 mL) and EA (10 mL) were added. The mixture was separated and washed. The aqueous phase was adjusted to pH 3-4 with dilute hydrochloric acid (20 mL, 1 N), filtered, and the filter cake dried to afford compound 74-8 (70 mg, 74% yield, 95% purity). LCMS (ESI) m / z 244.2, (M+H)⁺.

[0350] To a solution of compound 74-8 (70 mg, 0.29 mmol, 1.0 eq) in DMF (2 mL) were added HATU (142.3 mg, 0.37 mmol, 1.3 eq) and DIEA (74.3 mg, 0.58 mmol, 2.0 eq). The mixture was stirred for 20 min, and compound 65-2 (65.25 mg, 0.37 mmol, 1.3 eq) was added. The mixture was reacted at 25°C for 15 h. LCMS showed the formation of the product. The reaction solution was added with water (50 mL) and EA (20 mL), separated and washed, and concentrated by column chromatography (PE:EA = 50%-80%) to give compound 74-9 (40 mg, yield 35%, purity 95%). LCMS (ESI) m / z 400.5, (M+H)+.

[0351] To a solution of compound 74-9 (40 mg, 0.1 mmol, 1.0 eq) in MeOH (6 mL) was added HCl / EA (5 mL) and the mixture was allowed to react at 25°C for 2 h. LCMS indicated the formation of the product. The reaction solution was concentrated and purified by C18 reverse-phase column chromatography (H2O:ACN = 30%-50%) to afford compound 74 (4 mg, 13% yield, 95% purity). LCMS (ESI) m / z 300.4, (M+H)+; 1 H NMR (400MHz, DMSO) δ13.49(s,1H),8.87(d,J=12.2Hz,2H),8.70(d,J=11.6Hz,3H),7.96(d ,J=8.2Hz,1H),7.63(d,J=8.8Hz,1H),4.17(s,3H),3.60(s,2H),3.13(s,2H),2.60(s,3H).

[0352] Example 75

[0353] 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

[0354] At 0°C, NH3 / CH3OH (7M, 3.2 mL, 22.2 mmol, 10 eq) was slowly added to a solution of compound 75-1 (500 mg, 2.22 mmol, 1.0 eq) in CH3OH (6.0 mL). The reaction mixture was stirred at 0°C for 10 minutes, and compound 75-2 (40.81%, 2.0 mL, 11.1 mmol, 5 eq) was slowly added. The reaction mixture was stirred at 0°C for 10 minutes, then warmed to room temperature and stirred for 3 hours. The 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 afford compound 75-3 (415 mg, 67.5% yield).

[0355] At 0°C, a solution of compound 75-3 (415 mg, 1.498 mmol, 1.0 eq) in THF (8.0 mL) was slowly added to a suspension of sodium hydroxide (210 mg, 5.24 mmol, 3.5 eq) in THF (5.0 mL). The reaction mixture was warmed to room temperature and stirred for 0.5 hours, then cooled to 0°C and SEMCl (0.69 mL, 3.89 mmol, 2.6 eq) was slowly added. The reaction mixture was warmed to room temperature and stirred for 3 hours. After cooling to 0°C, the reaction mixture was slowly poured into aqueous NH4Cl (20.0 mL) and extracted with EA (10.0 mL x 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: ethyl acetate / petroleum ether = 0-10%) to afford compound 75-4 (316 mg, 39.3% yield).

[0356] Compound 75-4 (312 mg, 0.58 mmol, 1.0 eq), trimethylethynylsilane (0.41 mL, 2.9 mmol, 5.0 eq), Pd(PPh3)2Cl2 (122 mg, 0.17 mmol, 0.3 eq), CuI (34 mg, 0.17 mmol, 0.3 eq), and TEA (0.41 mL, 2.9 mmol, 5.0 eq) were added sequentially to DMF (4.5 mL) at room temperature. The reaction mixture was stirred at 80°C for 24 hours. The reaction mixture was cooled to room temperature, water (20.0 mL) was added, and the mixture was extracted with ethyl acetate (10.0 mL x 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 obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-8%) to obtain compound 75-5 (310 mg, yield 96.3%).

[0357] Potassium carbonate (820 mg, 5.9 mmol, 10.5 eq) was added to a solution of compound 75-5 (310 mg, 0.56 mmol, 1.0 eq) in CH3OH (8.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and water (10.0 mL) and DCM (10.0 mL) were added. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford compound 75-6 (270 mg, 100% yield).

[0358] Compound 75-6 (245 mg, 0.51 mmol, 1.0 eq), compound 75-7 (112 mg, 0.6 mmol, 1.2 eq), and Cu(CH3CN)4.PF6 (20 mg, 0.05 mmol, 0.1 eq) were added sequentially to chloroform (8.0 mL) at room temperature, and the reaction mixture was stirred at 40°C for 7 hours. The residue was concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: (dichloromethane:methanol=4:1) / dichloromethane=0-10%) to afford compound 75-8 (239 mg, 70.4% yield).

[0359] A solution of compound 75-8 (120 mg, 0.18 mmol, 1.0 eq) in THF (2.0 mL) was slowly added to a suspension of sodium hydroxide (14.5 mg, 0.36 mmol, 2.0 eq) in THF (2.0 mL) at 0°C. The reaction mixture was warmed to room temperature and stirred for 0.5 hours, then cooled to 0°C and CH3I (51 mg, 0.36 mmol, 2.0 eq) was slowly added. The reaction mixture was warmed to room temperature and stirred for 16 hours. The mixture was cooled to 0°C, and the reaction solution was slowly poured into an NH4Cl aqueous solution (10.0 mL), extracted with EA (10.0 mL × 2), and 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 give compound 75-9 (65 mg, yield 53.1%).

[0360] At room temperature, TFA (2.0 mL) was slowly added to a solution of compound 75-9 (65 mg, 0.095 mmol, 1.0 eq) in DCM (4.0 mL). The reaction mixture was stirred at room temperature for 5 hours. The residue was concentrated under reduced pressure, dissolved in THF (3.0 mL), and aqueous ammonia was added to adjust the pH to >10. The reaction mixture was stirred at room temperature for 0.5 hours. Water (10.0 mL) was added, and the mixture was extracted with DCM / i-PrOH = 85 / 15 (10.0 mL x 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 = 0-93.3%) to yield 75 (15 mg, 49% yield, 98.2% purity). LCMS (ESI) m / z 323.2 (M+H)+; 1 H NMR (400MHz, DMSO) δ13.27(s,1H),12.40(s,1H),8.82(s,1H),8.62(s,1H),7.91(d,J=8.5Hz,1H),7.64 (d, J = 8.5Hz, 1H), 6.84 (s, 1H), 4.58 (t, J = 6.0Hz, 2H), 3.15 (t, J = 6.0Hz, 2H), 2.41 (s, 3H), 2.28 (s, 3H).

[0361] Example 76

[0362] 3-(1-methyl-1H-pyrazol-4-yl)-N-(2-(methylamino)ethyl)-1H-indazole-5-sulfonamide

[0363] To a solution of compound 76-1 (2 g, 6.19 mmol, 1.0 eq) in DCM (60 mL) were added p-toluenesulfonic acid (TsOH) (122 mg, 0.64 mmol, 0.1 eq) and DHP (1.68 mL, 3.0 eq). The mixture was stirred at room temperature for 12 hours. LCMS indicated the formation of the product. The reaction mixture was cooled, extracted with EA and water, and washed with saturated brine. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (eluent: PE:EA = 10:1) to afford 76-2 as a white solid (2.36 g, 93.9% yield). LCMS (ESI) m / z 406.92, (M+H)+.

[0364] To a solution of compound 76-2 (2.31 g, 5.67 mmol, 1.0 eq) and compound 1-4 (1.3 mg, 6.25 mmol, 1.1 eq) in 1,4-dioxane / water (56 mL / 14 mL) were added sodium carbonate (1.8 g, 17.01 mmol, 3.0 eq) and Pd(dppf)Cl2 (800 mg, 1.1 mmol, 0.2 eq), the mixture was replaced with N2 three times, the temperature was 100°C and the reaction was allowed to react overnight. The reaction solution was directly concentrated in vacuo, and the residue was purified by silica gel column chromatography (eluent: PE:EA=2:1) ​​and concentrated to give compound 76-3 (855 mg, yield 74.1%), LCMS (ESI) m / z 361.06, (M+H)+.

[0365] To a dioxane solution (23 mL) of compound 76-3 (855 mg, 2.375 mmol, 1.0 eq) and compound 76-4 (0.3 mL, 1.1 eq) were added Pd2(dba)3 (105 mg, 0.115 mmol, 0.05 eq), DIPEA (0.7 mL, 3.0 eq) and Xant-tphos (133 mg, 0.23 mmol, 0.1 eq) and the mixture was reacted at 100° for 18 h. LCMS showed that the product was generated. The reaction solution was directly concentrated in vacuo 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, purity 74%), LCMS (ESI) m / z 405.17, (M+H)+.

[0366] Compound 76-5 (422 mg, 1.04 mmol, 1.0 eq) and 1 mL of acetic acid in THF / H2O (12 mL / 3 mL) were added to compound 76-6 (617 mg, 3.13 mmol, 3.0 eq) at 0°C and the reaction was maintained at this temperature for two hours. LCMS indicated the formation of the product. The reaction solution was directly concentrated in vacuo, 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 afford compound 76-7 (326 mg, 82% yield). LCMS (ESI) m / z 381.06, (M+H)+.

[0367] To a solution of compound 76-7 (284 mg, 0.75 mmol, 1.0 eq) and compound 65-2 (156 mg, 0.89 mmol, 1.2 eq) in DCM (8 mL) was added DIPEA (0.26 mL, 1.5 mmol, 2.0 eq). The mixture was allowed to react at room temperature for 1 hour. LCMS indicated the formation of the product. The reaction solution was directly concentrated in vacuo, and the residue was extracted with DCM and water, then washed with saturated brine. The residue was purified by silica gel column chromatography (eluent: DCM:H2O = 15:1) and concentrated to afford compound 76-8 (344 mg, 88.65% yield). LCMS (ESI) m / z 519.23, (M+H)+.

[0368] To a solution of compound 76-8 (344 mg, 0.66 mmol, 1.0 eq) in dioxane (3 mL) was added 3 mL of HCl-dioxane solution and stirred at room temperature for 2 h. LCMS indicated the formation of the product. Sodium bicarbonate solution was added to neutralize the pH of the reaction solution. 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 afford compound 76 (220.8 mg, 88% yield). LCMS (ESI) m / z 335.12, (M+H)+; 1 H NMR (400MHz, DMSO) δ8.91 (s, 2H), 8.54 (s, 1H), 8.50 (s, 1H), 8.14 (t, J = 5.6Hz, 1H), 8.03 ( s,1H),7.80(dt,J=19.6,5.1Hz,2H),3.99(s,3H),3.07–2.94(m,4H),2.56–2.53(m,3H). 1 H NMR (400MHz, DMSO) δ8.91 (s, 2H), 8.54 (s, 1H), 8.50 (s, 1H), 8.14 (t, J = 5.6Hz, 1H), 8.03 ( s,1H),7.80(dt,J=19.6,5.1Hz,2H),3.99(s,3H),3.07–2.94(m,4H),2.56–2.53(m,3H).

[0369] Example 79

[0370] 3-(4-methyl-1H-imidazol-2-yl)-N-(pyrrolidin-3-ylmethyl)-1H-indazole-5-carboxamide

[0371] At 0°C, NH3 / CH3OH (7M, 3.0 mL, 21 mmol, 11 eq) was slowly added to a solution of compound 79-1 (355 mg, 1.87 mmol, 1.0 eq) in CH3OH (5.0 mL). The reaction mixture was stirred at 0°C for 10 minutes, and compound 75-2 (40.81%, 1.6 mL, 9.35 mmol, 5 eq) was slowly added. The reaction mixture was stirred at 0°C for 10 minutes, then warmed to room temperature and stirred for 3 hours. The mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: (ethyl acetate:methanol = 4:1) / ethyl acetate = 0-49%) to provide compound 79-2 (445 mg, 98.45% yield).

[0372] At room temperature, HATU (240 mg, 0.63 mmol, 1.5 eq) was slowly added to a solution of compound 79-2 (102 mg, 0.42 mmol, 1.0 eq), compound 79-3 (127 mg, 0.63 mmol, 1.5 eq), and DIPEA (0.22 mL, 1.26 mmol, 3.0 eq) in DMF (2.0 mL). The reaction mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate (10.0 mL) was added, and the mixture was extracted with ethyl acetate (10.0 mL x 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 afford compound 79-4 (95 mg, 53.16% yield).

[0373] At room temperature, a solution of dioxane hydrochloride (4M, 5 mL, 20 mmol, 89 eq) was slowly added to a solution of compound 79-4 (95 mg, 0.224 mmol, 1.0 eq) in DCM / CH3OH (2.0 mL / 2.0 mL). The reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, and water (10 mL) and EA (10 mL) were added. The layers were separated, and the aqueous phase was lyophilized to afford compound 79 (80 mg, 90% yield, 96.43% purity). LCMS (ESI) m / z 325.2 (M+H)+; 1H NMR(400MHz,DMSO)δ15.04(s,1H),14.59(s,1H),9.41(s,1H),9.21(s,2H), 9.04(t,J=5.7Hz,1H),8.06(d,J=8.8Hz,1H),7.81(d,J=8.8Hz,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).

[0374] The following compounds were synthesized by referring to the route of Example 79:

[0375] Example 82

[0376] N-(2-(Methylamino)ethyl)-3-(4-phenyl-1H-imidazol-2-yl)-1H-indazole-5-carboxamide

[0377] Compound 79-1 (120 mg, 0.63 mmol, 1.00 eq) was dissolved in methanol (3 mL), cooled to 0°C, and NH3 / CH3OH (7N, 1.01 mL, 10.00 eq) was slowly added with stirring for 10 minutes. Compound 82-1 (480 mg, 3.15 mmol, 5 eq) was then added and allowed to react at 0°C for 10 minutes. The mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated in vacuo to obtain the crude product, which was then purified by column chromatography (eluent: 80% ethyl acetate / petroleum ether) to afford compound 82-2 as a yellow solid (110 mg, 57.3% yield, 90% purity). LCMS (ESI) m / z 305, (M+H)+.

[0378] Compound 82-2 (50 mg, 0.16 mmol, 1.00 eq), compound 65-2 (57 mg, 0.33 mmol, 2.0 eq), HATU (75 mg, 0.20 mmol, 1.2 eq), and DIPEA (64 mg, 0.49 mmol, 3.00 eq) were dissolved in DMF (2 mL) and reacted at room temperature for 2 hours. The reaction mixture was then cooled and quenched with water (50.0 mL). The mixture was extracted three times with ethyl acetate (80.0 mL). The organic layers were combined, washed twice with saturated brine (80.0 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate. The filtrate was concentrated in vacuo 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, yield 65.7%, purity 100%). LCMS (ESI) m / z 461, (M+H)+.

[0379] Compound 82-3 (50 mg, 0.11 mmol, 1.00 eq) was dissolved in dichloromethane (2.0 mL) and hydrochloric acid / dioxane (2.0 mL) was added. After complete addition, the mixture was stirred at 25°C for 1 hour. Filtering afforded 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 (400MHz, DMSO) δ14.36(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=9.0Hz,1H),7.58–7.50(m,2H),7.44(d,J=7.5Hz,1H),3.76–3.66(m,2H),3.22–3.12(m,2H),2.69–2.60(m,3H).

[0380] Example 83

[0381] 3-(5-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-N-(2-(methylamino)ethyl)-1H-indazole-5-carboxamide

[0382] Compound 79-1 (100 mg, 0.526 mmol, 1.0 eq), compound 83-1 (106 mg, 0.526 mmol, 1.0 eq), iodine (200 mg, 0.79 mmol, 1.5 eq), and potassium carbonate (218 mg, 1.58 mmol, 3.0 eq) were added sequentially to tert-butanol (20 mL) at room temperature. The reaction mixture was stirred at 70°C for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Methanol (20 mL) was added, stirred for 15 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 83-2 (270 mg), which was used directly in the next step without purification.

[0383] At room temperature, HATU (410 mg, 1.08 mmol, 1.5 eq) was slowly added to a solution of compound 83-2 (270 mg, 0.727 mmol, 1.0 eq), compound 83-3 (265 mg, 1.08 mmol, 1.5 eq), and DIPEA (0.65 mL, 3.67 mmol, 5.0 eq) in DMF (6.0 mL). The reaction was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate (20.0 mL) was added, and the mixture was extracted with ethyl acetate (10.0 mL x 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 afford compound 83-4 (303 mg, 100% total yield for the two-step reaction).

[0384] At room temperature, compound 83-4 (150 mg, 0.267 mmol, 1.0 eq) and IBX (150 mg, 0.534 mmol, 2.0 eq) were added sequentially to DMSO (10 mL). The reaction mixture was stirred at 50°C for 10 hours. The reaction solution was cooled to room temperature, water (30.0 mL) was added, and the mixture was extracted with ethyl acetate (10.0 mL x 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 = 0-28%) to obtain compound 83-5 (80 mg, 53.5% yield).

[0385] Zinc bromide (131 mg, 0.58 mmol, 4.0 eq) was added to a solution of compound 83-5 (80 mg, 0.143 mmol, 1.0 eq) in THF (4.0 mL) at room temperature, and 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, and the layers were separated. The aqueous phase was lyophilized to afford compound 83-6 (150 mg), which was used directly in the next step without purification.

[0386] Compound 83-6 (100 mg, 0.22 mmol, 1.0 eq), aqueous formaldehyde solution (37%, 52 mg, 0.66 mmol, 3.0 eq), 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 minutes, and sodium triacetoxyborohydride (192 mg, 0.9 mmol, 4.0 eq) was added. The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC to afford compound 83-7 (20 mg, 44.4% total yield for the two-step reaction).

[0387] Compound 83-7 (20 mg, 0.04 mmol, 1.0 eq) and palladium / carbon (10 wt.%, palladium loading) (50 mg) were added sequentially to THF (2.0 mL) and DMF (2.0 mL) at room temperature. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours, filtered through celite, and the filtrate was concentrated under reduced pressure to obtain compound 83 (2.5 mg, 17.5% yield, 100% purity).

[0388] LCMS (ESI) m / z 340.2 (M+H)+; 1 H NMR (400MHz, DMSO) δ8.67(s,1H),7.96(dd,J=8.8,1.4Hz,1H),7.59(d,J=8.7Hz ,1H),3.52-3.68(m,6H),3.20-3.12(m,2H),2.63(t,J=5.4Hz,3H),2.20(s,3H).

[0389] Example 84

[0390] N-(2-(Methylamino)ethyl)-3-(5-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazole-5-carboxamide

[0391] Sodium bisulfite (147 mg, 1.41 mmol, 2.1 eq) was added to a solution of compound 79-1 (145 mg, 0.76 mmol, 1.1 eq) and compound 84-1 (140 mg, 0.68 mmol, 1.0 eq) in DMF (3.0 mL) at room temperature, and the reaction mixture was stirred at 160°C for 2 hours. The reaction mixture was cooled to room temperature, and water (10 mL) and EA (10 mL) were added. The mixture was stirred for 15 minutes, filtered, and the filter cake was dried under reduced pressure to obtain compound 84-2 (120 mg, 73% purity, 34.3% yield).

[0392] At room temperature, HATU (180 mg, 0.48 mmol, 1.5 eq) was slowly added to a solution of compound 84-2 (120 mg, 73% purity, 0.32 mmol, 1.0 eq), compound 65-2 (83 mg, 0.48 mmol, 1.5 eq), and DIPEA (0.17 mL, 0.96 mmol, 3.0 eq) in DMF (3.0 mL). The reaction mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate (10.0 mL) was added, and the mixture was extracted with ethyl acetate (10.0 mL x 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 = 0-65%) to afford compound 84-3 (100 mg, 80.65% yield).

[0393] At room temperature, a solution of dioxane hydrochloride (4M, 5 mL, 20 mmol, 105 eq) was slowly added to a solution of compound 84-3 (100 mg, 0.19 mmol, 1.0 eq) in DCM (2.0 mL). The reaction was stirred at room temperature for 6 hours. The mixture was concentrated under reduced pressure, and water (10 mL) and EA (10 mL) were added. The layers were separated, and the aqueous phase was lyophilized to afford compound 84 (95 mg, 87.9% yield, 97.9% purity). LCMS (ESI) m / z 433.2 (M+H)+; 1 H NMR (400MHz, DMSO) δ14.78(s,1H),11.07(s,1H),9.54(s,1H),9.10–9.03(m,1H),8.93(s,2H),8.11(dt,J=5.2,2.6Hz,1H),7.88(d,J=9 .1Hz,1H),7.80(d,J=9.1Hz,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).

[0394] Comparative Example 85

[0395] (5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)pyridin-2-yl)(imino)(methyl)-sulfanilamide

[0396] Compound 85-1 (2.0 g, 9.8 mmol, 1.0 eq) was added to a 100 mL single-necked flask, followed by dioxane / KOAc (20 mL), followed by the bis-linked lipid and Pd(dppf)Cl2 (800 mg, 0.98 mmol, 0.1 eq). After N2 displacement, the mixture was stirred at 80° for 12 h. LCMS indicated the formation of the product. The reaction mixture was added with 30 mL of water, followed by 30 mL of EA. The mixture was extracted three times with EA. The organic phases were combined, dried over anhydrous sodium sulfate, spin-dried, and then precipitated with silica gel. Purification by silica gel column chromatography afforded 2.0 g of compound 85-2 as a yellow solid in an 81.3% yield.

[0397] Compound 85-3 (2.0 g, 5.8 mmol, 1.0 eq) and compound A1 (2.35 g, 8.7 mmol, 1.5 eq) were dissolved in ACN (20 mL), and Cs2CO3 (5.7 g, 17.4 mmol, 3.0 eq) was added. The mixture was stirred at 80°C for 6 hours. LCMS indicated the formation of the product. The reaction mixture was added with 30 mL of water, followed by 30 mL of EA. The mixture was extracted three times with EA. The combined organic phases were dried over anhydrous sodium sulfate, spin-dried, and then precipitated with silica gel. Purification by silica gel column chromatography afforded 1.3 g of compound 85-4 as a white solid in a 43.3% yield.

[0398] Compound 85-4 (500 mg, 0.97 mmol, 1.0 eq) and compound 85-2 (364 mg, 1.44 mmol, 1.5 eq) were dissolved in dioxane / H2O. Cs2CO3 (948 mg, 2.91 mmol, 3.0 eq) and Pd(dppf)Cl2 (79.2 mg, 0.097 mmol, 0.1 eq) were added sequentially. The mixture was dissolved in dioxane (10 mL) and 2 mL of water was added. The atmosphere was replaced with nitrogen and stirred at 80°C for 12 h. LCMS indicated the formation of the product. The reaction mixture was added with 20 mL of water and then 20 mL of EA. The mixture was extracted three times with EA. The organic phases were combined, dried, concentrated, and then added with silica gel to dryness. The mixture was then passed through a normal phase column to afford 370 mg of compound 85-5 as a white solid in a 74.4% yield.

[0399] Compound 85-5 (370 mg, 0.72 mmol, 1.0 eq.) was dissolved in methanol, and CH3COONH4 (83.2 mg, 1.08 mmol, 1.5 eq.) and iodophenyldiacetic acid (463.7 mg, 1.44 mmol, 2.0 eq.) were added sequentially. The mixture was stirred at room temperature for 3 hours. LCMS indicated the formation of the product. The reaction mixture was added with 5 mL of water, followed by 10 mL of EA. The mixture was extracted three times with EA. The organic phases were combined, dried, concentrated, and then dried over silica gel. The mixture was then passed through a normal phase column to afford 320 mg of compound 85-6 as a white solid in an 81.6% yield.

[0400] Compound 85-6 (320 mg, 0.58 mmol, 1.0 eq) was dissolved in HCl / EA (4 mol, 10 mL) and stirred at room temperature for 1 h. LCMS indicated the formation of the product. The reaction solution was spin-dried, pumped dry, and then purified by reverse-phase column chromatography to afford 85 as a white solid (83.4 mg, 30.9% yield, 98.8% purity). LCMS (ESI) m / z 463.35, (M+H)+). 1 H NMR (400MHz, DMSO) δ9.28(s,1H),8.60(s,2H),8.55(dd,J=8.3,1.8Hz,1H),8.32(d,J=8.4Hz,1H),7.60(d,J=9.2Hz ,1H),7.40(d,J=1.6Hz,1H),7.17(dd,J=9.0,1.8Hz,1H),6.19(d,J=6.8Hz,1H),3.59(s,3H),1.79(d,J=6.6Hz,3H).

[0401] Example 86

[0402] 3-(1-methyl-1H-pyrazol-4-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)ethoxy)-1H-indazole

[0403] MsCl (176 mg, 1.54 mmol, 1.0 eq.) was added to a mixture of compound 86-1 (200 mg, 1.54 mmol, 1.0 eq.), TEA (311 mg, 3.07 mmol, 2.0 eq.), and DCM (5 mL) at 0°C and allowed to react for 0.5 h. TLC indicated completion of the reaction with the formation of product spots. 30 mL of water was added to the reaction solution, and the mixture was extracted three times with DCM (20 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford crude compound 86-2 (350 mg) as a colorless oil. 1H NMR(400MHz, CDCl3) δ4.56(t,J=6.4Hz,1H),3.97(dd,J=12.2,4.2Hz,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=6.4Hz,3H).

[0404] Cesium carbonate (98 mg, 0.30 mmol, 2.0 eq.) was added to a mixture of compound 86-2 (45 mg, 0.15 mmol, 1.0 eq.), compound A4 (46 mg, 0.23 mmol, 1.5 eq.), and acetonitrile (3 mL), and the mixture was allowed to react overnight at 70°C. TLC indicated the reaction was complete, and LCMS showed the formation of the product. The reaction solution was directly concentrated, 50 mL of water was added, and the mixture was extracted twice with ethyl acetate (30 mL x 2). The organic phases were combined and concentrated to obtain crude compound 86-3 (100 mg) as a colorless oil. LCMS (ESI) m / z 411.20, (M+1) + .

[0405] Compound 86-3 (50 mg, 0.12 mmol, 1.0 eq.) was added to HCl / dioxane (4 M, 2 mL), heated to 45°C, and reacted for 1 hour. TLC indicated the reaction was complete. 30 mL of saturated sodium bicarbonate solution was extracted twice with EA (20 mL x 2). The organic phases were combined and concentrated. Purification by HPLC yielded compound 86 (22 mg, 55%) as a white solid. LCMS (ESI) m / z 327.10, (M+1) + , purity 99%; 1 H NMR (400MHz, CDCl3) δ8.01(s,1H),7.86(s,1H),7.30(d,J=9.0Hz,1H),7.20(d,J=2.2Hz,1H),7.03(dd,J=9.0,2.2Hz,1H),4.13(t,J=6 .2Hz,1H),4.07–4.00(m,3H),3.98(s,3H),3.68(s,2H),3.40(t,J=11.5Hz,2H),1.94–1.76(m,3H),1.50(m,3H),1.28(d,J=6.1Hz,3H).

[0406] The following compound was synthesized according to the route of Example 86.

[0407] Example 87

[0408] 4-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)quinoline

[0409] Compound 87-1 (50 mg, 0.32 mmol, 1.0 eq.) was added to a dried 25 mL three-necked flask at room temperature, and dry THF (3.0 mL) was added. After replacing nitrogen several times, the temperature was lowered in an ice-salt bath. CH3MgBr (0.23 mL, 0.67 mmol, 2.1 eq.) was added dropwise at 0°C and the reaction was maintained at low temperature for 2 hours. TLC showed that the reaction was complete and product spots were generated. 10 mL of water was added to the reaction solution, and the solution 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 obtain the crude product compound 87-2 (60 mg), which was used directly in the next reaction. LCMS: (ESI) m / z 174.05, (M+H) + .

[0410] Compound 87-2 (60 mg, 0.35 mmol, 1.0 eq) was dissolved in DCM (3.0 mL) at room temperature. TEA (141 mg, 1.4 mmol, 4.0 eq) was added at room temperature. The atmosphere was replaced with nitrogen and MsCl (81 mg, 0.7 mmol, 2.0 eq) was added dropwise in an ice-water bath. The mixture was allowed to react for 2 hours at room temperature. TLC analysis showed the presence of a new production spot and the disappearance of the starting material spot. LCMS analysis indicated the formation of the product. 5.0 mL of water was added to the reaction solution, and the mixture was extracted twice with DCM (5.0 mL x 2). The organic phases were combined and washed twice with saturated aqueous NaHCO₃ (10.0 mL x 2). The organic phases were dried over anhydrous sodium sulfate and spin-dried to give compound 87-3 (80 mg, 91%). LCMS (ESI) m / z 252.05, (M+1) + .

[0411] Compound 87-3 (90 mg, 0.36 mmol, 1.5 eq) was dissolved in MeCN (5.0 mL) at room temperature, and compound A4 (70 mg, 0.23 mmol, 1.0 eq) and Cs2CO3 (150 mg, 0.46 mmol, 2.0 eq) were added with stirring. The atmosphere was purged with nitrogen and the reaction was allowed to proceed at 80°C overnight. TLC monitored the disappearance of the starting material and the formation of new spots. LCMS monitored the formation of the product. 10.0 mL of water was added to the reaction solution, and the product was extracted three times with EA (5.0 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, spin-dried, and washed on a large plate (DCM / MeOH = 20 / 1) to obtain the crude product of compound 87-4 (108 mg), which was used directly in the next step. LCMS (ESI) m / z 452.90, (M+1) + .

[0412] Compound 87-4 (100 mg, 0.22 mmol, 1.0 eq) was dissolved in MeOH (3.0 mL) and a 4.0 N HCl-dioxane solution was added. The mixture was allowed to react at room temperature for 3 hours. LCMS monitoring revealed the disappearance of compound 87-4, indicating complete conversion to the product. The reaction solution was concentrated to dryness and purified by HPLC to afford compound 87 (45.4 mg, 55.7%) as a white solid. LCMS (ESI) m / z 370.05, (M+H) + ; 1 H NMR (400MHz, CD3OD) δ8.81–8.76(m,1H),8.51(d,J=8.9Hz,1H),8.12(d,J=8.4Hz,1H),7.88(t,J=8.2Hz,1H),7.80(t,J=7.7Hz,1H),7.71(d,J=4.6Hz ,1H),7.62(d,J=4.9Hz,2H),7.40(d,J=9.0Hz,1H),7.22–7.17(m,1H),7.0 3–6.99(m,1H),6.33(q,J=6.5Hz,1H),3.85(s,3H),1.83(d,J=6.4Hz,3H).

[0413] The following compound was synthesized by referring to the route of Example 87.

[0414] Example 95

[0415] 6-Methyl-5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)quinoline

[0416] To a solution of compound 95-1 (300 mg, 1.35 mmol, 1.0 eq) and compound 95-2 (731.8 mg, 2.03 mmol, 1.5 eq) in dioxane (10 mL) was added palladium tetrakistriphenylphosphine (312.2 mg, 0.27 mmol, 0.2 eq). The atmosphere was purged with nitrogen three times and stirred at 110°C for 12 hours. LCMS indicated that compound 95-1 had reacted completely. The reaction mixture was cooled, and 20 mL of saturated KF solution was added. The mixture was stirred at room temperature for 30 minutes, filtered, extracted with EA, and washed with saturated brine. The organic phase was concentrated to yield a yellow oil. A solution of hydrochloric acid in dioxane (14 mL, 4 M) was added and stirred at room temperature for 30 minutes. LCMS indicated that the reaction was complete. The pH was adjusted to 7 with saturated NaHCO₃ (20 mL), and then extracted with ethyl acetate, the separated liquid was dried and spun down to obtain a yellow oily liquid. The crude product was purified on a 4 g silica gel column (0-50% EA) to obtain the product compound 95-3 (230 mg, yield: 92%). LCMS (ESI) m / z 186.2, (M+H) + .

[0417] To a solution of compound 95-3 (230 mg, 1.24 mmol, 1.0 eq.) in MeOH (15 mL) was added NaBH4 (94 mg, 2.48 mol, 2.0 eq.) and stirred at room temperature for 12 hours. LCMS indicated the formation of the product. The reaction mixture was quenched by the addition of saturated NH4Cl solution, extracted with EA, separated, dried, and spin-dried to afford a yellow solid. Column chromatography (0-50% EA) afforded compound 95-4 (200 mg, 86% yield) as an off-white solid. LCMS (ESI) m / z 188.24, (M+H) + .

[0418] Compound 95-4 (60 mg, 0.32 mmol, 1.0 eq.) and triethylamine (64 mg, 0.64 mmol, 2.0 eq.) were dissolved in DCM (3 mL), and MsCl (54 mg, 0.48 mmol, 1.5 eq.) was added dropwise at 0°C. The reaction mixture was added with a saturated aqueous solution of NaHCO₃ (15 mL) and extracted with DCM (15 mL x 3). The organic phase was separated, dried, and spun down to dryness. TLC (PE:EA = 1:1) was used to obtain compound 95-5 (30 mg, 45.5% yield) as a yellow solid. LCMS (ESI) m / z 206.07, (M+H) + .

[0419] Compound 95-5 (30 mg, 0.146 mmol, 1.0 eq.) and compound A4 (64 mg, 0.218 mmol, 1.5 eq.) were dissolved in DMF (2 mL), and Cs2CO3 (95 mg, 0.28 mmol, 2 eq.) was added. 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, and purified by TLC (DCM:MeOH = 10:1) to obtain compound 95-6 (25 mg, 36.6% yield) as a yellow solid. LCMS (ESI) m / z 468.23, (M+H) + .

[0420] Compound 95-6 (30 mg, 0.146 mmol, 1.0 eq.) was dissolved in DCM (2 mL) and TFA (1 mL) was added. The mixture was reacted at 25°C for 3 hours. LCMS showed that compound 95-6 was completely reacted and the product was generated. The reaction solution was dried to give a crude product, which was purified by TLC (DCM:MeOH = 10:1) to give compound 95 (15.8 mg, 73.2% yield) as an off-white solid. LCMS (ESI) m / z 384.17, (M+H) + ; 1 H NMR(400MHz,DMSO)δ 12.75(s,1H),9.24(d,J=8.4Hz,1H),8.86(d,J=3.2Hz,1H),7.92(s,1H),7.85(d,J=8.4Hz,1H),7.66(s,1H),7.60(dd,J=8.8, 4.0Hz,2H),7.35(d,J=8.8Hz,1H),7.11–7.04(m,2H),6.35(d,J=6.4Hz,1H),3.93(s,3H),2.72(s,3H),1.87(d,J=6.7Hz,3H).

[0421] The following compound was synthesized according to the route of Example 95.

[0422] Example 108

[0423] 5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)-1,7-naphthyridine

[0424] Compound 108-1 (0.26 g, 1.24 mmol), potassium vinyl trifluoroborate (0.25 g, 1.86 mmol), Pd(dppf)Cl2 (0.091 g, 0.124 mmol), and K2CO3 (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, and LCMS showed product formation. 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 x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and 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 a brown viscous liquid 108-2 (0.165 g, yield: 85%, purity: 97.25%). LCMS (ESI) m / z 157.2, (M+H) + .

[0425] At 0°C, compound 108-2 (0.165 g, 1.06 mmol) was added to a mixture of tetrahydrofuran (10.6 mL) and water (2.1 mL), followed by the addition of K₂OsO₄·2H₂O (0.0391 g, 0.106 mmol). The resulting mixture was stirred for 15 minutes, followed by the addition of NaIO₄ (0.907 g, 4.24 mmol). The reaction mixture was stirred at 0°C for 20 minutes, then warmed to room temperature and stirred for 13 hours. LCMS indicated the formation of the product. The reaction mixture was diluted with dichloromethane (20.0 mL), dried over anhydrous sodium sulfate, filtered, and 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 afford compound 108-3 as an orange solid (0.108 g, yield: 64%, purity: 99.06%). LCMS (ESI) m / z 159.1, (M+H)⁺.

[0426] Methylmagnesium bromide solution (3.0 M in 2-methyltetrahydrofuran) (0.34 mL, 1.02 mmol) was added dropwise to a solution of compound 108-3 (0.108 g, 0.68 mmol) in tetrahydrofuran (3.0 mL) at 0°C. The reaction mixture was stirred at 0°C for 20 minutes, then warmed to room temperature and stirred for 3 hours. LCMS indicated the formation of the product. The reaction mixture was diluted with ammonium chloride in methanol (0.3 M, 4.0 mL) and concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol = 20:1) to afford compound 108-4 as a light brown solid (0.116 g, yield: 98%, purity: 93.27%). LCMS (ESI) m / z 175.1, (M+H)+.

[0427] Thionyl chloride (0.197 g, 1.66 mmol) was added dropwise to a solution of compound 108-4 (0.116 g, 0.66 mmol) in dichloromethane (5.0 mL) at 0°C. The resulting mixture was stirred at 0°C for 10 minutes, then warmed to room temperature and stirred for 2 hours. LCMS indicated the formation of the product. The reaction mixture was diluted with dichloromethane (20.0 mL), and the pH of the aqueous phase was adjusted to approximately 7-8 by adding saturated aqueous sodium bicarbonate. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (10.0 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The resulting residue was dried under vacuum to afford the crude product of compound 108-5 (0.0272 g, crude yield: 21%, purity: 29.03%) as a dark brown gum. LCMS (ESI) m / z 193.1, 195.1, (M+H)+.

[0428] At room temperature, the crude product of 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). The resulting mixture was stirred at 65°C for 10 hours. LCMS indicated the formation of the product. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10.0 mL), and washed with water (5.0 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (eluent: dichloromethane:methanol = 35:1) to afford compound 108-6 (0.0187 g, yield: 29%, purity: 86.72%) as a dark yellow gum. LCMS (ESI) m / z 455.3, (M+H)+.

[0429] At room temperature, trifluoroacetic acid (0.0938 g, 0.82 mmol) was added to a dichloromethane (0.41 mL) solution of compound 108-6 (0.0187 g, 0.041 mmol). The resulting mixture was stirred for 26 hours, and 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 about 7-8. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (10.0 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and 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 compound 108 (0.0077 g, yield: 51%, purity: 90.73%). LCMS (ESI) m / z 371.1, (M+H) +; 1H NMR (400MHz, DMSO) δ12.78(s,1H),9.33(s,1H),9.12(s,1H),9.04(d,J=8.4Hz,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=8.8Hz,1H),6.43(q,J=6.8Hz,1H),3.93(s,3H),1.83(d,J=6.4Hz,3H).

[0430] The following compound was synthesized by referring to the route of Example 108

[0431] Example 110

[0432] 6-Methyl-5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazino[4,3-d]pyrimidin-5-yl)oxy)ethyl)quinoline

[0433] Compound 110-1 (400 mg, 1.43 mmol) was dissolved in DCM (5 mL) at room temperature. DHP (360 mg, 4.28 mmol) and TsOH·H₂O (27 mg, 0.14 mmol) were added at 0°C. The mixture was stirred at room temperature for 60 min. TLC indicated complete reaction. The reaction mixture was quenched with water and extracted with DCM (20 mL x 3). The organic phases were combined and dried, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 2:1) to afford 110-2 (233 mg, 85% purity, [M+H]⁺ = 365.0) as a yellow solid.

[0434] At room temperature, compound 110-2 (70 mg, 0.19 mmol) was dissolved in dioxane (5 mL) and H₂O (1 mL). 1-4 (42 mg, 0.20 mmol) was added, followed by Pd(dppf)Cl₂ (32 mg, 0.039 mmol) and sodium carbonate (57 mg, 0.54 mmol) under nitrogen. The reaction mixture was stirred at 90°C for 2 h. LCMS showed no residual starting material. After the reaction mixture was cooled to room temperature, the organic phases were combined and dried by spin drying. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 1:5) to afford 110-3 (60 mg, 85% purity, [M+H]⁺ = 320.1) as a black solid.

[0435] Compound 110-3 (60 mg, 0.19 mmol) was dissolved in dioxane (5 mL) and H₂O (1 mL), and KOH (42 mg, 0.75 mmol) was added. Pd₂(dba)₃ (86 mg, 0.094 mmol) and t-BuXPhos (80 mg, 0.19 mmol) were then added under nitrogen. The reaction mixture was stirred at 100°C for 16 h. LCMS showed no residual starting material. After the reaction mixture was cooled to room temperature, the organic phases were combined and dried by spin drying. The crude product was purified by silica gel column chromatography (eluent: dichloromethane:methanol = 10:1) to afford the product 110-4 (40 mg, 80% purity, [M+H]⁺ = 301.2) as a black solid.

[0436] 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 Cs2CO3 (43 mg, 0.13 mmol) was added. The reaction mixture was stirred at 40°C for 16 h. LCMS showed complete reaction of the starting materials. The reaction mixture was diluted with water and extracted with EA (30 mL x 3). The organic phases were combined and dried by spin drying. The crude product was purified by silica gel column chromatography (eluent: dichloromethane:methanol = 10:1) to afford compound 110-5 as a yellow oil (20 mg, 90% purity, LCMS: 470.0 [M+H]+).

[0437] Compound 110-5 (20 mg, 0.04 mmol) was dissolved in DCM (2 mL) at room temperature, and TFA (1 mL) was added under ice. The reaction mixture was stirred at room temperature for 1 h. LCMS showed complete reaction. The organic phase was concentrated and collected, and then purified by HPLC to yield Compound 110 (1.7 mg, purity: 100%, LCMS: 386.2 [M+H]+) as a white solid.

[0438] Example 113

[0439] 6-Methyl-5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)propyl)quinoline

[0440] Compound 113-1 (200 mg, 1.17 mmol, 1.0 eq.) was placed in a three-necked flask and dissolved in THF (10 mL). The atmosphere was replaced with nitrogen and the temperature was cooled to 0°C. Ethylmagnesium chloride (389.2 mg, 2.92 mmol, 2.5 eq.) was added dropwise. The mixture was stirred at room temperature for 1 hour. LC-MS and TLC monitoring indicated that compound 113-1 had reacted completely. The reaction mixture was cooled in an ice-water bath, quenched with water, and washed three times with ethyl acetate and water. The organic phase was dried over anhydrous Na2SO4, spin-dried, and purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to afford compound 113-2 (150 mg, 63.8%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ9.07(d,J=9.7Hz,1H),8.73(s,1H),7.76(d,J=8.4Hz,1H),7.49(d,J=8.6Hz,1H), 7.38(d,J=12.5Hz,1H),5.53(s,1H),5.18(s,1H),1.95(m,1H),1.73(m,7.0Hz,1H),0.86(t,J=7.4Hz,4H).

[0441] Compound 113-2 (150 mg, 0.76 mmol, 1.0 eq.) was dissolved in DCM (8 mL), and triethylamine (150.8 mg, 1.49 mmol, 2.0 eq.) was added. The atmosphere was replaced with nitrogen, cooled in an ice-water bath, and MsCl (127.4 mg, 1.12 mmol, 1.5 eq.) was added. The mixture was stirred at room temperature overnight. LC-MS and TLC monitoring indicated that compound 113-2 had reacted completely. The reaction mixture was washed three times with ethyl acetate and water. The organic phase was dried over anhydrous Na2SO4, spin-dried, and purified by thin-layer chromatography (developing solvent: DCM:MeOH = 15:1) to afford compound 113-3 (85 mg) as a yellow oil. 1 H NMR (400MHz, CD3OD) δ9.13(d,J=3.4Hz,1H),8.75(dd,J=17.0,5.6Hz,1H),7.86(dd,J=18.9,9.5Hz,1 H),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).

[0442] Compound 113-3 (95 mg, 0.32 mmol, 1.0 eq.) was dissolved in acetonitrile (10 mL), and cesium carbonate (210 mg, 0.64 mmol, 2.0 eq.) and compound A4 (85 mg, 0.39 mmol, 1.2 eq.) were added sequentially. The atmosphere was purged with nitrogen. The mixture was stirred at 80°C for 24 hours. LC-MS and TLC monitoring indicated the complete reaction of compound A4. The reaction mixture was washed three times with ethyl acetate and water. The organic phase was dried over anhydrous Na2SO4, dried by spin drying, and purified by thin-layer chromatography (developing solvent: DCM:MeOH = 15:1) to afford compound 113-4 (60 mg, 39.1%) as a yellow oil. LCMS (ESI) m / z 482.20, (M+H)+.

[0443] Compound 113-4 (120 mg, 0.31 mmol, 1.0 eq.) was dissolved in MeOH (2.0 mL) and added to dioxane (HCl) (5 mL). The mixture was stirred at room temperature for 2.5 hours. The reaction mixture was directly spin-dried and purified by high-performance liquid chromatography to afford compound 113 (36.5 mg, 73.71%, 99% purity) as a pale white solid. LCMS (ESI) m / z 398.25, (M+H)+; 1 H NMR (400MHz, CD3OD) δ9.28(s,1H),8.75(s,1H),7.86(d,J=8.8Hz,1H),7.61(d,J=10.1Hz,4H),7.32(d,J=8.9Hz,1H),7.11(d,J=8.9Hz,1H ), 6.91(s,1H),5.94(s,1H),3.93(s,3H),2.71(s,3H),2.46(dt,J=13.6,6.6Hz,1H),2.11(dt,J=14.1,6.9Hz,1H),1.19(t,J=7.3Hz,3H).

[0444] Example 114

[0445] 2-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)-2-(6-methylquinolin-5-yl)ethan-1-ol

[0446] NaOH (187 mg, 4.68 mmol, 2.0 eq) was dissolved in toluene (10.0 ml) at room temperature. Compound 114-2 (955 mg, 4.68 mmol, 2.0 eq) and N-benzyl-N,N,N-triethylammonium chloride (533 mg, 2.34 mmol, 1.0 eq) were added at room temperature. After replacing the nitrogen atmosphere, the mixture was allowed to react at room temperature for 0.5 hour. Compound 114-1 (300 mg, 2.34 mmol, 1.0 eq) was dissolved in 2.0 mL of toluene and added dropwise to the reaction mixture under an ice-water bath. The reaction was allowed to react at room temperature overnight. TLC 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 solution, and the mixture was extracted three times with EA (10.0 ml × 3). The organic phases were combined, washed 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 obtain compound 114-3 (160 mg, 49%). LCMS: (ESI) m / z 185.95, (M+H)+; 1 H NMR (400MHz, CD3OD) δ8.83–8.75(m,2H),7.90(d,J=8.7Hz,1H),7.61(d,J=8.7Hz,1H),7.54(dd ,J=8.7,4.3Hz,1H),4.32(s,1H),3.39–3.35(m,1H),2.84(dd,J=5.5,2.7Hz,1H),2.61(s,3H).

[0447] Compound 114-3 (93 mg, 0.5 mmol, 1.5 eq) was dissolved in acetonitrile (5.0 mL) at room temperature. Compound A4 (100 mg, 0.34 mmol, 1.0 eq) and Er(OTf)3 (420 mg, 0.68 mmol, 2.0 eq) were added. The atmosphere was replaced with nitrogen and the reaction was carried out at 80°C overnight under reflux. LCMS monitoring indicated the formation of compound 114-4. 15 mL of water was added and the mixture was extracted three times with ethyl acetate (10.0 mL x 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 afford compound 114-4 (120 mg, crude) as a yellow oil. LCMS: (ESI) m / z 484.25, (M+H)+.

[0448] Compound 114-4 (120 mg, crude product) was dissolved in 2.0 mL of methanol at room temperature, and 2.0 mL of 4N 1,4-dioxane hydrochloride was added. The mixture was allowed to react at room temperature for 1 hour. The reaction solution was then dried and purified by HPLC to obtain compound 114 (1.3 mg, white solid). LCMS (ESI) m / z 400.05, (M+H)+; 1 H NMR (400MHz, CD3OD) δ9.70(d,J=8.9Hz,1H),9.01(d,J=5.1Hz,1H),7.94(d,J =8.8Hz,1H),7.82(d,J=14.1Hz,1H),7.70(d,J=8.8Hz,1H),7.45(d,J=15.2H z,2H),7.07(s,1H),6.96(d,J=11.7Hz,1H),6.53(d,J=2.2Hz,1H),5.92(t,J =7.2Hz,1H),5.14(d,J=22.4Hz,1H),5.00(s,1H),3.75(s,3H),2.05(s,3H).

[0449] Example 115

[0450] 6-Methyl-5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)thio)ethyl)quinoline

[0451] Compound A4 (1.0 g, 3.35 mmol, 1.0 eq.) was dissolved in DCM (10 mL), and DIEA (1.7 g, 6.7 mmol, 4.0 eq.) was added to the reaction mixture. The atmosphere was purged with nitrogen three times. Tf2O (1.9 g, 6.7 mmol, 2.0 eq.) was slowly added dropwise to the reaction mixture under an ice bath. After complete addition, the reaction was stirred at room temperature overnight. TLC showed that most of the starting material was converted to product. The reaction mixture was extracted three times with dichloromethane and water (10 mL). The organic phases were combined, 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 afford Compound 115-1 as a white solid (596 mg, yield: 41%). 1H NMR (400MHz, DMSO-d6) δ8.48(s,1H),8.23(d,J=2.3Hz,1H),8.04(s,1H),7.93(d,J=9.2Hz,1H),7.57–7.51(m,1H),5.91(d ,J=9.3Hz,1H),3.94(s,4H),3.76(t,J=12.5Hz,1H),2.46–2.36(m,1H),2.00(d,J=15.5Hz,2H),1.76(s,1H),1.59(s,2H).

[0452] Compound 115-1 (500 mg, 1.16 mmol, 1.0 eq.) was dissolved in dioxane (10 mL), followed by the addition of compound 115-2 (506 mg, 2.32 mmol, 2.0 eq.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (69 mg, 0.12 mmol, 0.1 eq), Pd2(dba)3 (110 mg, 0.12 mmol, 0.1 eq), and DIPEA (449 mg, 3.48 mmol, 3.0 eq). After complete addition, the atmosphere was purged with nitrogen three times, and the reaction was stirred at 100°C overnight. LCMS indicated the presence of the desired product. The reaction solution 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 (DCM:MeOH=20:1) to obtain compound 115-3 as a yellow oil (500 mg, yield: 86.44%). 1 H NMR(400MHz,DMSO-d6)δ8.43(s,1H),8.02–7.95(m,2H),7.72(d,J=8.8Hz,1H) ,7.47(dd,J=8.7,1.6Hz,1H),5.86–5.80(m,1H),3.91(d,J=16.6Hz,6H),3.78 –3.69(m,1H),3.18(t,J=6.8Hz,2H),2.57(t,J=6.8Hz,2H),2.00(d,J=18.2Hz ,2H),1.82–1.39(m,4H),1.22(d,J=21.6Hz,8H),0.80(dd,J=9.6,5.5Hz,6H).

[0453] Compound 115-3 (500 mg, 1.0 mmol, 1.0 eq.) was dissolved in THF (10 mL). KOtBu (225 mg, 2.0 mmol, 2.0 eq.) was then added to the reaction mixture under ice-salt water. After complete addition, the mixture was warmed to room temperature and stirred for 1 hour. TLC indicated that most of the starting material had been converted to product. Filtration and concentration afforded compound 115-4 (265 mg, 84.39% yield) as a yellow solid. LCMS: (ESI) m / z 376, (M+H)+.

[0454] Compound 115-4 (200 mg, 0.64 mmol, 1.0 eq.) was dissolved in MeCN (10 mL), followed by the addition of compound 95-5 (197 mg, 0.96 mmol, 1.5 eq.) and Cs2CO3 (624 mg, 1.92 mmol, 3.0 eq.). After complete addition, the atmosphere was replaced with nitrogen three times, and the reaction was stirred at 80°C overnight. LCMS indicated the presence of the desired product. The reaction solution 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 (DCM:MeOH = 20:1) to afford compound 115-5 as a white oil (81 mg, yield: 40.31%). 1 H NMR(400MHz,CD3OD)δ9.36(d,J=8.8Hz,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=10.2Hz,1H),5.18(d,J=7.6Hz ,1H),3.98(s,4H),3.79(t,J=11.2Hz,1H),2.49(d,J=12.3Hz,1H),2.19(d,J= 17.7Hz, 4H), 2.07–1.95 (m, 1H), 1.90 (d, J = 7.4Hz, 3H), 1.66 (d, J = 5.3Hz, 2H).

[0455] Compound 115-5 (40 mg, 0.08 mmol, 1.0 eq.) was dissolved in MeCN (3 mL), and 10 mL of a hydrogen chloride-1,4-dioxane solution was added to the reaction system. The mixture was stirred at room temperature for 3 hours. LCMS showed complete conversion of the starting material. The reaction solution was concentrated and purified by HPLC to obtain compound 115 as a white solid (16.8 mg, yield: 43.49%, purity 98%). LCMS: (ESI) m / z 400, (M+H); 1H NMR (400MHz, DMSO-d6) δ13.05(s,1H),9.12(d,J=8.8Hz,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, 4.1Hz, 1H), 7.43 (dd, J = 14.3, 8.7Hz, 2H), 7.30 (d, J = 9.2Hz, 1H), 5.10 (d, J = 7.8Hz, 1H), 3.93 (s, 3H), 2.26 (s, 3H), 1.82 (d, J = 7.2Hz, 3H).

[0456] Example 116

[0457] 6-Cyclopropyl-5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)quinoline

[0458] At room temperature, 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). The resulting mixture was stirred at 120°C for 24 hours. LCMS indicated the formation of the product. The reaction mixture was cooled to room temperature, and a 1.0 M aqueous solution of KF (36.0 mL) was added. The resulting mixture was stirred vigorously for 10 minutes and filtered through celite. The filter cake was washed sequentially with dichloromethane (30.0 mL x 2) and water (30.0 mL x 2). The filtrates were combined, the organic phase was separated, and the aqueous phase was extracted with dichloromethane (20.0 mL x 3). The combined organic phases were washed sequentially with KF aqueous solution (1.0 M, 30.0 mL) and water (30.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to dryness under reduced pressure. The resulting residue was dried under vacuum to afford the crude product of compound 116-2 (3.92 g, crude yield: >100%, purity: 90.85%) as a dark brown viscous liquid. LCMS (ESI) m / z 215.0, (M+H)+.

[0459] At room temperature, aqueous HCl (3.0 M, 16.1 mL, 48.3 mmol) was slowly added dropwise to a solution of crude compound 116-2 (3.92 g, 4.83 mmol (theoretical amount)) in tetrahydrofuran (24.2 mL). The resulting mixture was stirred for 20 minutes, and LCMS indicated the formation of the product. Saturated aqueous sodium bicarbonate was slowly added dropwise to the reaction mixture, adjusting the pH of the aqueous phase to approximately 7-8. The resulting mixture was extracted with dichloromethane (30.0 mL x 6). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane:ethyl acetate = 10:1) to afford compound 116-3 (0.632 g, yield: 70%, purity: 98.38%) as a dark yellow liquid. LCMS (ESI) m / z 187.0, (M+H)+.

[0460] At room temperature, compound 116-3 (0.632 g, 3.4 mmol) and CuBr2 (0.908 g, 4.07 mmol) were added to acetonitrile (17.0 mL). The resulting mixture was stirred for 10 minutes, followed by the dropwise addition of isoamyl nitrite (0.516 g, 4.40 mmol). The reaction mixture was stirred at 30°C for 1 hour, and LCMS indicated 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 (20.0 mL x 3). The combined aqueous phases were extracted with ethyl acetate (30.0 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane: 100%) to afford compound 116-4 as a yellow solid (0.507 g, yield: 60%, purity: 98.10%). LCMS(ESI)m / z250.0,252.0,(M+H)+.

[0461] At room temperature, NaBH4 (0.115 g, 3.04 mmol) was added in three portions to a solution of compound 116-4 (0.206 g, 0.82 mmol) in methanol (4.1 mL). The resulting mixture was stirred for 8 hours, and LCMS indicated the formation of the product. The reaction mixture was concentrated to dryness under reduced pressure, and saturated aqueous ammonium chloride (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 x 4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and 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 afford compound 116-5 (0.183 g, yield: 89%, purity: 96.86%) as a yellow viscous liquid. LCMS (ESI) m / z 251.9, 253.9, (M+H)+.

[0462] At 0°C, thionyl chloride (0.257 g, 2.16 mmol) was added dropwise to a solution of compound 116-5 (0.183 g, 0.72 mmol) in dichloromethane (7.2 mL). The resulting mixture was stirred at 0°C for 10 minutes, then warmed to room temperature and stirred for 2 hours. LCMS showed product formation. The reaction mixture was diluted with dichloromethane (10.0 mL) and concentrated to dryness under reduced pressure. Dichloromethane (10.0 mL) was added to the resulting residue, and the mixture was again concentrated to dryness under reduced pressure. This operation was repeated, and the resulting residue was dried under vacuum to obtain a crude product of 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)+.

[0463] At room temperature, the crude product of 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). The resulting mixture was stirred for 2 minutes, followed by the addition of compound A4 (0.215 g, 0.72 mmol). The reaction mixture was stirred at 60°C for 9 hours, and LCMS indicated the formation of the product. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (30.0 mL), and washed with water (10.0 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether: dichloromethane: ethyl acetate = 1:1:1) to afford 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)+.

[0464] Compound 116-7 (0.0426 g, 0.080 mmol), cyclopropylboronic acid (0.0103 g, 0.12 mmol), Pd(dppf)Cl2 (0.0059 g, 0.0080 mmol), and Na2CO3 (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, and 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 x 4). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (eluent: ethyl acetate:petroleum ether = 4:1) to give compound 116-8 as a yellow gum (0.0251 g, yield: 63%, purity: 96.46%), LCMS (ESI) m / z 494.4, (M+H) +.

[0465] At room temperature, trifluoroacetic acid (0.290 g, 2.55 mmol) was added to a dichloromethane (0.25 mL) solution of compound 116-8 (0.0251 g, 0.051 mmol). The resulting mixture was stirred for 8 hours, and LCMS showed the formation of the product. The reaction mixture was diluted with dichloromethane (5.0 mL), and a saturated aqueous sodium bicarbonate solution was added to adjust the pH of the aqueous phase to about 7-8. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (5.0 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and 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 light brown solid 116 (0.0163 g, yield: 78%, purity: 100%), LCMS (ESI) m / z 410.2, (M+H)+; 1 H NMR (400MHz, DMSO) δ12.74(s,1H),9.27(d,J=8.8Hz,1H),8.83(dd,J=4.0,1.2Hz,1H),7.97(s,1H),7.84(d,J=8.8Hz,1H),7.70(s,1H),7.58(dd,J= 8.8,4.0Hz,1H),7.38(d,J=8.8Hz,1H),7.34(d,J=8.8Hz,1H),7.20(s,1H) ,7.07(dd,J=8.8,2.0Hz,1H),6.65(q,J=6.8Hz,1H),3.94(s,3H),2.63(br s, 1H), 1.94 (d, J = 6.8Hz, 3H), 1.28-1.24 (m, 2H), 1.97-1.21 (m, 2H).

[0466] Example 117

[0467] 6-Methyl-5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazino[3,4-b]pyridin-5-yl)oxy)ethyl)quinoline

[0468] Compound 117-1 (500 mg, 3.26 mmol, 1.0 eq) was dissolved in DMF (5.0 mL), and NIS (1.5 g, 6.52 mmol, 2.0 eq) was added. The reaction mixture was allowed to stand overnight at room temperature. LCMS monitored the complete conversion of compound 117-1 to compound 117-2. 20.0 ml of water was added to the reaction solution, and a large amount of solid precipitated. The solid was filtered and dried using an oil pump to obtain compound 117-2 (800 mg, 87%). 1 H NMR (400MHz, DMSO-d6) δ8.55 (d, J = 2.3Hz, 1H), 8.07–8.03 (m, 1H).

[0469] Compound 117-2 (900 mg, 3.2 mmol, 1.0 eq) was dissolved in DMF (5.0 mL) at room temperature. NaH (155 mg, 6.4 mmol, 2.0 eq) was added in an ice-water bath and stirred at room temperature for 0.5 hours. SEM-Cl (810 mg, 4.84 mmol, 1.5 eq) was then added in an ice-water bath and allowed to react overnight at room temperature. LCMS monitoring indicated the formation of compound 117-3. 15 mL of water was added and the mixture was extracted three times with ethyl acetate (10.0 mL x 3). The organic phases were combined and back-extracted twice with 5% aqueous LiCl solution. The organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to afford 117-3 (760 mg, 57.5%) as a yellow oil. 1 H NMR (400MHz, CD3OD) δ8.56(d,J=2.2Hz,1H),7.95(d,J=2.2Hz,1H),5.77(s,2H),3.64(t,J=8.0Hz,2H),0.84(t,J=8.0Hz,2H),-0.11(s,9H)+.

[0470] Compound 117-3 (400 mg, 0.96 mmol, 1.0 eq) was dissolved in 10.0 mL of tetrahydrofuran at room temperature, along with compound 1-4 (600 mg, 2.88 mmol, 3.0 eq), K2CO3 (400 mg, 2.88 mmol, 3.0 eq), Pd[PPh3]4 (111 mg, 0.096 mmol, 0.1 eq), and 2.0 mL of water. The mixture was purged with nitrogen and allowed to react at 75°C overnight. LCMS monitoring revealed the disappearance of compound 117-3 and the formation of compound 117-4. The reaction mixture was filtered through a pad of Celite, and the filter cake was rinsed with ethyl acetate. The filtrate was added with an appropriate amount of water and extracted with EA two to three times. The resulting organic phases were combined, dried over anhydrous sodium sulfate, and then purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to afford compound 117-4 (300 mg, 84%) as a yellow oil. 1 H NMR (400MHz, CD3OD) δ8.53(d,J=2.2Hz,1H),8.50(d,J=2.2Hz,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=8.0Hz,2H),-0.11(s,9H).

[0471] Compound 117-4 (200 mg, 0.55 mmol, 1.0 eq) was dissolved in dioxane (3.0 mL), and KOH (185 mg, 3.3 mmol, 6.0 eq), Pd2(dba)3 (45 mg, 0.055 mmol, 0.1 eq), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium were added. (II) (26 mg, 0.027 mml, 0.05 eq), water (3.0 mL), replaced with nitrogen, and heated at 100°C overnight. LCMS monitored the formation of compound 117-5. 5.0 ml of water was added to the reaction solution, and an appropriate amount of ethyl acetate was added for extraction. The resulting organic phases were combined, dried over anhydrous sodium sulfate, and spin-dried. The mixture was purified by thin-layer chromatography (developing solvent DCM / MeOH = 20 / 1) to give a yellow solid 117-5 (25 mg, yield: 13%). 1 H NMR (400MHz, DMSO-d6) δ9.77(s,1H),8.33(s,1H),8.22(d,J=2.6Hz,1H),7.91(d,J=0.8Hz,1H),7.68 (d,J=2.6Hz,1H),5.65(s,2H),3.89(s,3H),3.55(t,J=8.0Hz,2H),0.80–0.75(m,2H),-0.15(s,9H).

[0472] Compound 117-5 (25 mg, 0.07 mmol, 1.0 eq) was dissolved in acetonitrile (5.0 mL), and compound 95-5 (16 mg, 0.08 mmol, 1.2 eq) and Cs2CO3 (25 mg, 0.21 mmol, 3.0 eq) were added. The mixture was stirred at 80°C overnight. LCMS analysis indicated the formation of compound 117-6. 8.0 mL of water was added to the reaction mixture, and the mixture was extracted with an appropriate amount of ethyl acetate. The resulting organic phases were combined, dried over anhydrous sodium sulfate, and then purified by thin-layer chromatography (developing solvent: DCM / MeOH = 20 / 1) to give 117-6 as a white solid (23 mg, 61%). LCMS: (ESI) m / z 185.95, (M+H)+.

[0473] Compound 117-6 (23 mg) was dissolved in DCM (3.0 mL) and TFA (1.0 mL) was added. The mixture was allowed to react at room temperature for 1 hour. The reaction was complete as monitored by LCMS. The mixture was directly dried and purified by HPLC to give 117 (7.2 mg, 41%) as a white solid. LCMS: (ESI) m / z 385.25, (M+H)+; 1 H NMR(400MHz,CD3OD)δ9.27(d,J=9.4Hz,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).

[0474] The following compound was synthesized by referring to the route of Example 117

[0475] Example 118

[0476] 2-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)-2-(6-methylquinolin-5-yl)acetonitrile

[0477] Compound 118-1 (300 mg, 1.75 mmol, 1.0 eq) and AcOH (5.0 mL) were added to TMSCN (1.74 g, 17.5 mmol, 10.0 eq) in an ice-water bath. The reaction was allowed to proceed at room temperature for 3 days. The disappearance of the starting material was monitored by plate counting. Water was added and the mixture was extracted with EA. The organic phase was back-extracted with saturated sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate, spin-dried, slurried with an appropriate amount of DCM, filtered, and the solid was collected and spin-dried with an oil pump to obtain compound 118-2 (200 mg, 57%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.86 (dd, J=4.2, 1.5Hz, 1H), 8.81 (d, J=8.9Hz, 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).

[0478] Compound 118-2 (150 mg, 0.76 mmol, 1.0 eq) was dissolved in DCM (5.0 mL) at room temperature, and TEA (231 mg, 2.2 mmol, 3.0 eq) was added. MsCl (131 mg, 1.14 mmol, 1.5 eq) was added in an ice-water bath and allowed to react overnight at room temperature. LCMS monitoring indicated the formation of compound 118-3. 15 mL of water was added, and the mixture was extracted three times with DCM (10.0 mL x 3). The organic phases were combined and back-extracted twice with saturated aqueous sodium bicarbonate solution. The organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by thin-layer chromatography (developing solvent: petroleum ether:ethyl acetate = 1 / 1) to obtain compound 118-3 (80 mg, 48%) as a yellow solid. LCMS: (ESI) m / z 217.15, (M+H)+

[0479] Compound 118-3 (70 mg, 0.32 mmol, 1.5 eq) was dissolved in 10.0 mL of acetonitrile, along with compound A4 (64 mg, 0.21 mmol, 1.0 eq) and Cs2CO3 (206 mg, 0.63 mmol, 3.0 eq) at room temperature. The mixture was stirred at 80°C under nitrogen atmosphere for 10 minutes. LCMS analysis revealed the disappearance of compound 118-3 and the formation of compound 118-4. An appropriate amount of water was added to the reaction solution, and the mixture was extracted two to three times with EA. The resulting organic phases were combined, dried over anhydrous sodium sulfate, and then purified by thin-layer chromatography (developing solvent: DCM / MeOH = 20 / 1) to afford 118-4 (80 mg, 77%) as a yellow solid. LCMS: (ESI) m / z 185.95, (M+H)+; 1H NMR (400MHz, DMSO-d6) δ8.95(s,2H),8.28(s,1H),8.02(s,2H),7.83(s,1H),7.70(d,J=8.7Hz,3H),7.27(d,J=2.5Hz,2H),5.77(d,J=9.9Hz,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=13.0Hz,1H),1.93(d,J=12.8Hz,1H),1.71(s,1H),1.55(s,2H).

[0480] 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 confirmed the reaction was complete. The reaction solution was then dried and purified by HPLC to give 118 (2.8 mg, 4%) as a white solid. LCMS: (ESI) m / z 384.10, (M+H)+; 1 H NMR (400MHz, DMSO-d6) δ13.12(s,1H),8.93(s,1H),8.55(d,J=8.5Hz,1H),8.39(s,1H),8.12(d,J=8.7Hz,1H) ,8.03(s,1H),8.00(s,1H),7.78(s,1H),7.69–7.61(m,2H),7.44(d,J=9.0Hz,1H),3.91(s,3H),2.71(s,3H).

[0481] Example 119

[0482] 5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)cinnoline

[0483] At 0°C, NaNO2 (2663 mg, 38.6 mmol, 2.3 eq.) was slowly added to a mixture of compound 119-1 (5.0 g, 16.8 mmol, 1.0 eq.) in acetonitrile (50.0 mL), water (25.0 mL), and 37% concentrated hydrochloric acid (12.0 mL). The reaction mixture was stirred at 0°C for 1 hour. The resulting reaction solution was slowly added to a mixture of diethylamine (19.1 mL, 185 mmol, 11 eq.) and potassium carbonate (14.73 g, 107 mmol, 6.4 eq.) in acetonitrile (50.0 mL) and water (90.0 mL) at 0°C. The reaction mixture was stirred at room temperature for 16 hours. Water (100.0 mL) was added, and the mixture was extracted with ethyl acetate (100.0 mL x 2). The combined organic phases were washed with saturated brine (100.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-8.5%) to obtain compound 119-2 (4.9 g, yield 76.4%).

[0484] Compound 119-2 (2.0 g, 5.25 mmol, 1.0 eq.), trimethylethynylsilane (619 mg, 6.3 mmol, 1.2 eq.), Pd(PPh3)2Cl2 (1.1 g, 1.58 mmol, 0.3 eq.), CuI (301 mg, 1.58 mmol, 0.3 eq.), and triethylamine (137 mg, 0.42 mmol, 3.0 eq.) were added sequentially to DMF (20.0 mL) at room temperature, and the reaction mixture was stirred at 40°C for 16 hours. The reaction mixture was cooled to room temperature, and water (80.0 mL) was added. The mixture was extracted with ethyl acetate (100.0 mL x 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 obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-7%) to obtain compound 119-3 (1.2 g, yield 65%).

[0485] At room temperature, TBAF (1M, 6.8 mL, 6.8 mmol, 2.0 eq.) was slowly added to a solution of compound 119-3 (1.2 g, 3.4 mmol, 1.0 eq.) in THF (20.0 mL). The reaction mixture was stirred at room temperature for 3 hours. After cooling to 0°C, the reaction solution was slowly poured into an aqueous NH4Cl solution (40.0 mL) and extracted with EA (20.0 mL x 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 afford compound 119-4 (631 mg, 66% yield).

[0486] Compound 119-4 (631 mg, 2.25 mmol, 1.0 eq.) was added to 1,2-dichlorobenzene (12.0 mL) at room temperature. The reaction mixture was stirred in a microwave oven at 220°C under nitrogen for 1 hour. The product was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-25%) to afford compound 119-5 (303 mg, 64.4% yield).

[0487] Compound 119-5 (303 mg, 1.45 mmol, 1.0 eq.), tri-n-butyl(1-ethoxyvinyl)tin (785 mg, 2.17 mmol, 1.5 eq.), and Pd(PPh3)4 (335 mg, 0.29 mmol, 0.2 eq.) were added sequentially to dioxane (8.0 mL) at room temperature. The reaction mixture was stirred at 110°C under nitrogen for 16 hours. The reaction mixture was cooled to room temperature, and a saturated aqueous solution of KF (10.0 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was filtered, and the filtrate was extracted with ethyl acetate (10.0 mL x 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 solution was stirred at room temperature for 40 minutes. Saturated aqueous sodium bicarbonate was added to adjust the pH to >7, and then extracted with ethyl acetate (10.0 mL x 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: ethyl acetate / petroleum ether = 0-64%) to provide compound 119-6 (388 mg, 55% purity, 85.5% yield).

[0488] At 0°C, NaBH4 (120 mg, 3.16 mmol, 9.9 eq.) was slowly added to a mixture of compound 119-6 (100 mg, 55% purity, 0.32 mmol, 1.0 eq.) in THF (5.0 mL) and methanol (5.0 mL). The reaction mixture was stirred at room temperature for 2 hours. After cooling to 0°C, the reaction solution was slowly poured into aqueous NH4Cl (20.0 mL) and extracted with ethyl acetate (20.0 mL x 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 step without further purification.

[0489] Compound 119-7 (57 mg, 0.32 mmol, 1.0 eq.) and MnO2 (280 mg, 3.2 mmol, 10.0 eq.) were added sequentially to DCM (6.0 mL) at room temperature. The reaction mixture was stirred at 40°C for 6 hours. The resulting residue was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-69%) to afford compound 119-8 (25 mg, 45% total yield over two steps).

[0490] Methanesulfonyl chloride (18 mg, 0.157 mmol, 1.1 eq.) was slowly added to a solution of compound 119-8 (25 mg, 0.14 mmol, 1.0 eq.) and TEA (17 mg, 0.17 mmol, 1.2 eq.) in DCM (1.5 mL) at 0°C. The reaction mixture was warmed to room temperature and stirred for 3 hours. Water (10.0 mL) was added, and the mixture was extracted with dichloromethane (10.0 mL x 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, 119-9, was used directly in the next step without further purification.

[0491] Compound 119-9 (36 mg, 0.14 mmol, 1.0 eq.), compound A4 (46 mg, 0.15 mmol, 1.1 eq.), and cesium carbonate (137 mg, 0.42 mmol, 3.0 eq.) were added sequentially to DMF (1.5 mL) at room temperature, and the reaction mixture was stirred at 60°C for 3 hours. The reaction mixture was cooled to room temperature, and water (10.0 mL) was added. The mixture was extracted with ethyl acetate (10.0 mL x 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 = 0-22%) to afford compound 119-10 (80 mg, 60% purity, 73.8% total yield over two steps).

[0492] At room temperature, TFA (1.0 mL) was slowly added to a solution of compound 119-10 (80 mg, 60% purity, 0.106 mmol, 1.0 eq.) in DCM (3.0 mL). The reaction mixture was stirred at room temperature for 3 hours. The residue was concentrated under reduced pressure, dissolved in DCM (10.0 mL), and the pH was adjusted to >7 with aqueous sodium bicarbonate. The mixture was extracted with DCM (10.0 mL x 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 = 0-35%) to afford compound 119 (22 mg, 56.2% yield, 100% purity). LCMS (ESI) m / z = 371.2 (M+H)+; 1 H NMR (400MHz, DMSO) δ12.77(s,1H),9.49(d,J=6.1Hz,1H),8.76(d,J=6.2Hz,1H),8.39(t,J=13.0Hz,1H),8.13–8.04(m,2H),7.95(dt,J=17.9,9.0Hz,1 H),7.79(s,1H),7.39(d,J=9.0Hz,1H),7.34(d,J=1.5Hz,1H),7.13(dt,J=1 4.7, 7.3Hz, 1H), 6.45 (q, J = 6.2Hz, 1H), 3.91 (s, 3H), 1.78 (d, J = 6.2Hz, 3H).

[0493] Example 121

[0494] 6-Methyl-5-(2,2,2-trifluoro-1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)quinoline

[0495] Compound 121-1 (500 mg, 2.9 mmol, 1.0 eq.) was dissolved in DMF (10 ml). After nitrogen replacement, the temperature was lowered to 0°C, and CF3-TMS (4.15 g, 29.2 mmol, 10.0 eq.) was added. The mixture was stirred at room temperature overnight. TLC showed no residual starting material. The reaction solution was extracted three times with ethyl acetate (10 ml × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether: EtOAc = 0%-15% EA) to obtain compound 121-2 (300 mg, 42%) as a yellow solid. LCMS: (ESI) m / z 242, (M+H)+

[0496] Compound 121-2 (300 mg, 1.2 mmol, 1.0 eq.) was dissolved in DCM (6 ml) and TEA (376.9 mg, 3.7 mmol, 3.0 eq.) was added. MsCl (350.7 mg, 2.5 mmol, 2.0 eq.) was added with cooling, and the mixture was stirred at room temperature for 2 hours. TLC showed no starting material remaining, but new spots were generated. 10 mL of water was added, and the mixture was extracted three times with DCM (10 ml x 3). The organic phases were combined, washed with saturated NaHCO₃, dried over anhydrous sodium sulfate, filtered, and concentrated to afford Compound 121-3 (700 mg, crude) as a yellow oil. LCMS: (ESI) m / z 320, (M+H)⁺.

[0497] Compound A4 (150 mg, 0.5 mmol, 1.0 eq.) was dissolved in acetonitrile (10 ml), and cesium carbonate (327.6 mg, 1.0 mmol, 3.0 eq.) and compound 121-3 (402 mg, crude product) were added. After the addition was complete, the reaction was stirred at 80°C for 3 hours. TLC showed a small amount of starting material remaining. The mixture was directly filtered, the filtrate was drained, and purified by thin-layer chromatography (developing solvent DCM:MeOH = 20:1) to obtain compound 121-4 (21 mg, crude product) as a yellow oil. LCMS: (ESI) m / z 522, (M+H)+

[0498] Compound 121-4 (21 mg, 0.096 mmol, 1.0 eq) was dissolved in DCM / TFA (5 mL / 1 mL) and stirred at room temperature for 1 hour. TLC analysis revealed the disappearance of 121-4 and the formation of a more polar spot, which was confirmed by LCMS to be compound 121. The mixture was directly spin-dried and purified by HPLC to obtain compound 121 as a yellow solid (9.9 mg, yield: 56.3%, purity: 100%). LCMS: (ESI) m / z 438, (M+H)+; 1 H NMR(400MHz,DMSO-d6)δ13.00(s,1H),8.93(s,1H),8.28(s,1H),8.18–8.10(m,2H),7.95(s,1H),7. 75(d,J=8.7Hz,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).

[0499] Example 122

[0500] 6-Methyl-5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl-2,2,2-d3)quinoline

[0501] Compound 122-1 (100 mg, 0.58 mmol, 1.0 eq.) was dissolved in THF (5 mL), followed by the addition of compound 122-2 (1.1 mL, 1.16 mmol, 2.0 eq.). After complete addition, the atmosphere was replaced with nitrogen three times, and the reaction was stirred at -20°C for two hours. TLC showed no residual starting material, with most of the product converted. The reaction solution 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 (developing solvent: DCM:MeOH = 20:1) to afford compound 122-3 as a yellow solid (80 mg, yield: 72%). LCMS: (ESI) m / z 191, (M+H)+.

[0502] Compound 122-3 (80 mg, 0.42 mmol, 1.0 eq.) was dissolved in DCM (5.0 ml), followed by the addition of MsCl (0.05 ml, 0.63 mmol, 1.5 eq.) and TEA (127 mg, 1.26 mmol, 3.0 eq.). After complete addition, the atmosphere was purged with nitrogen three times, and the reaction was stirred at 25°C for two hours. TLC indicated no residual starting material, with most conversion to product. The reaction solution 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 pre-TLC (DCM:MeOH = 25:1) to afford Compound 122-4 (100 mg, 88%) as a yellow oil. LCMS: (ESI) m / z 209, (M+H)+.

[0503] Compound 122-4 (100 mg, 0.48 mmol, 1.5 eq.) was dissolved in acetonitrile (5 ml), followed by the addition of compound A4 (98 mg, 0.32 mmol, 1.0 eq.) and compound Cs2CO3 (312 mg, 0.96 mmol, 3.0 eq.). After the addition, the atmosphere was replaced with nitrogen three times, and the reaction was stirred at 80°C overnight. TLC showed no residual starting material, with most of the product converted. The reaction was quenched by the dropwise addition of saturated ammonium chloride solution. The reaction solution 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 (developing solvent: DCM:MeOH = 20:1) to afford compound 122-5 (80 mg, 53%) as a yellow solid. LCMS: (ESI) m / z 471, (M+H)+.

[0504] Compound 122-5 (80 mg, 0.17 mmol, 1.0 eq.) was dissolved in DCM (5 mL), and then compound TFA (2.0 ml) was added. After the addition, the atmosphere was replaced with nitrogen three times, and the reaction was stirred at 25 ° C for two hours. TLC showed that there was no starting material remaining, and most of it was converted into product. Saturated ammonium chloride solution was added dropwise to quench the reaction. 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 high performance liquid chromatography to obtain a yellow solid compound 122 (22 mg, purity: 98%, yield: 35%). LCMS: (ESI) m / z 387, (M+H) +; 1 H NMR (400MHz, CD3OD) δ9.29(d,J=9.1Hz,1H),8.75(s,1H),7.88–7.83(m,1H),7.67(s,1H),7.61(s,2H),7.54(d,J =11.8Hz,1H),7.32(d,J=9.2Hz,1H),7.10(d,J=11.3Hz,1H),6.90(s,1H),6.19(s,1H),3.93(s,3H),2.71(s,3H).

[0505] Example 127

[0506] 6-(Difluoromethyl)-5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)quinoline

[0507] At room temperature, compound 127-1 (1 g, 4.5 mmol) was dissolved in CCl4 (15 mL), and NBS (801 mg, 4.5 mmol) and AIBN (74 mg, 0.45 mmol) were added sequentially. The mixture was then heated at 85°C with stirring for 3 h under nitrogen. LCMS showed a ratio of starting material, product, and dibromo byproduct of 1:6:3. After cooling the reaction mixture to room temperature, DCM (30 mL x 3) was added for extraction. The organic phases were combined and dried by spin drying. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 3:1) to afford 127-2 (710 mg, 93% purity) as a yellow solid. LCMS (ESI) m / z 300.02 & 302.02, (M+H)+.

[0508] The mixture 127-2 (710 mg, 2.369 mmol) was dissolved in MeCN (15 mL) and NMO (1.1 g, 9.436 mmol) was added under ice-cooling. The mixture was stirred at room temperature overnight. LCMS showed product 3, with no starting material remaining. The reaction solution was diluted with water and extracted with DCM (30 mL × 3). The organic phases were combined and dried, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to give the white solid product 127-3 (546 mg, 90% purity). LCMS (ESI) m / z 236.07 & 308.07, (M+H)+.

[0509] Compound 127-3 (546 mg, 2.313 mmol) was dissolved in DCM (6 mL), cooled to 0°C, and DAST (620 mg, 2.775 mmol) was slowly added dropwise. Stir at room temperature overnight. LCMS showed that product 127-4 was produced, and no starting material 127-3 remained. The reaction solution was quenched with a saturated aqueous solution of NaHCO3 under an ice bath and extracted with DCM (30 mL × 3). The organic phases were combined and dried, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to obtain product 127-4 as a white solid (220 mg, purity 92%). LCMS (ESI) m / z 258.05 & 260.05, (M+H)+.

[0510] At room temperature, compound 127-4 (1.2 g, 4.65 mmol) was dissolved in dioxane (10 mL), and tri-n-butyl(1-ethoxyvinyl)tin (1.68 g, 4.65 mmol) was added. Pd(PPh3)4 (537 mg, 0.465 mmol) was then added under nitrogen. The reaction mixture was heated at 110°C overnight. LCMS revealed no residual starting material. After cooling to room temperature, the reaction mixture was quenched by the addition of 30 mL of aqueous KF solution and stirred for half an hour. The resulting solid was filtered through Celite. The filtrate was extracted with ethyl acetate (40 mL x 3), and the organic phases were combined and spin-dried. The crude product was redissolved in EA (10 mL), and 2 mL of aqueous hydrochloric acid (3 M) was added. The mixture was stirred at room temperature for 2 hours. LCMS indicated the formation of product 127-5. The pH of the reaction mixture was adjusted to neutral with aqueous Na2CO3 solution. The organic phases were extracted with ethyl acetate and the combined organic phases were spin-dried. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 1:1) to give the yellow oily product 127-5 (873 mg, purity 95%). LCMS (ESI) m / z 222.01, (M+H) +.

[0511] 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 mixture was stirred at room temperature for 5 hours. LCMS indicated complete reaction. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with DCM (50 mL x 3). The combined organic phases were spin-dried. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to afford compound 127-6 (435 mg, 80% purity) as a brown oil. LCMS (ESI) m / z 224.08, (M+H)+.

[0512] Compound 127-6 (435 mg, 1.95 mmol) was dissolved in DCM (10 mL) at room temperature, and SOCl2 (463 mg, 3.9 mmol) was added at 0°C. The mixture was stirred at room temperature for 4 hours. LCMS showed that the reaction was complete, and the reaction solution was directly dried to give the crude product, compound 127-7 (513 mg).

[0513] At room temperature, compound 127-7 (41 mg, 0.618 mmol) and compound A4 (50 mg, 0.618 mmol) were dissolved in DMF (1 mL), and Cs2CO3 (220 mg, 0.67 mmol) was added. The mixture was stirred at room temperature overnight. The reaction solution was diluted with water and extracted with EA (20 mL x 3). The organic phases were combined and dried by spin drying. The crude product was purified by silica gel column chromatography (eluent: DCM:MeOH = 10:1) to afford the product 127-8 (15 mg, 80% purity) as a brown solid. LCMS (ESI) m / z 504.21, (M+H)+.

[0514] Compound 127-8 (15 mg) was dissolved in MeOH (1 mL) at room temperature, and HCl (1 mL, 4 M in dioxane) was added. The mixture was stirred at room temperature for 2 h. LCMS indicated complete reaction. The reaction mixture was spin-dried and purified by HPLC to afford compound 127 (5.1 mg, 94.63% purity) as a yellow solid. LCMS (ESI) m / z 420.42, (M+H)+; 1H NMR (400MHz, DMSO) δ12.76(s,1H),9.37(d,J=8.6Hz,1H),9.06(d,J=3.4Hz,1H),8.13–7.94(m,3H),7.91(s,1H),7.77(dd,J= 8.8,4.0Hz,1H),7.65(s,1H),7.36(d,J=9.0Hz,1H),7.18(s,1H),7.09(dd ,J=9.0,2.0Hz,1H),6.64–6.57(m,1H),3.90(s,3H),1.91(d,J=6.6Hz,3H).

[0515] The following compound was synthesized by referring to the route of Example 127

[0516] Example 129

[0517] 6-Isopropyl-5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)quinoxaline

[0518] Compound 129-1 (3 g, 13.4 mmol, 1.0 eq.), tri-n-butyl(1-ethoxyvinyl)tin (7.25 g, 20.1 mmol, 1.5 eq.), and Pd(PPh3)4 (3.1 g, 2.68 mmol, 0.2 eq.) were added sequentially to dioxane (50.0 mL) at room temperature. The reaction mixture was stirred at 110°C under nitrogen for 48 hours. The reaction mixture was cooled to room temperature, and a saturated aqueous solution of KF (30.0 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was filtered, and the filtrate was extracted with ethyl acetate (50.0 mL x 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 solution was stirred at room temperature for 40 minutes. Saturated aqueous sodium bicarbonate was added to adjust the pH to >7, and the mixture was extracted with ethyl acetate (50.0 mL x 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 = 0-43%) to afford compound 129-2 (983 mg, 39.2% yield).

[0519] At room temperature, t-BuONO (722 mg, 90% purity, 6.3 mmol, 1.2 eq.) was slowly added to a solution of compound 129-2 (983 mg, 5.25 mmol, 1.0 eq.) and CuBr2 (1.41 g, 6.3 mmol, 1.2 eq.) in CH3CN (45.0 mL). The reaction mixture was stirred at room temperature for 16 hours. The residue was concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-31%) to afford compound 129-3 (970 mg, 73.6% yield).

[0520] Compound 129-3 (970 mg, 3.86 mmol, 1.0 eq.), compound 129-4 (1.3 g, 7.72 mmol, 2.0 eq.), Pd(dppf)Cl2 (560 mg, 0.77 mmol, 0.2 eq.), and potassium carbonate (1.6 g, 11.6 mmol, 3.0 eq.) were added sequentially to dioxane / H2O (30 mL / 7.5 mL) at room temperature. The reaction mixture was stirred at 95°C for 16 hours. The reaction mixture was cooled to room temperature, water (20.0 mL) was added, and the mixture was extracted with ethyl acetate (30.0 mL x 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 = 0-26%) to afford compound 129-5 (740 mg, 90.2% yield).

[0521] Compound 129-5 (150 mg, 0.707 mmol, 1.0 eq.) and palladium / carbon (10 wt.%, palladium loading) (50 mg) were added sequentially to THF (10.0 mL) at room temperature. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours, filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting residue, 129-6, was used directly in the next step without further purification.

[0522] At 0°C, NaBH4 (107 mg, 2.83 mmol, 4.0 eq.) was slowly added to a solution of compound 129-6 (154 mg, 0.707 mmol, 1.0 eq.) in methanol (9.0 mL). The reaction mixture was stirred at room temperature for 2 hours. After cooling to 0°C, the reaction solution was slowly poured into aqueous NH4Cl (20.0 mL) and extracted with EA (20.0 mL x 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, 129-7, was used directly in the next step without further purification.

[0523] Compound 129-7 (156 mg, 0.707 mmol, 1.0 eq.) and MnO2 (615 mg, 7.07 mmol, 10.0 eq.) were added sequentially to DCM (6.0 mL) at room temperature, and the reaction mixture was stirred at 40°C for 6 hours. The resulting residue was concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-23.5%) to afford compound 129-8 (71 mg, 46.4% total yield over three steps).

[0524] Thionyl chloride (81 mg, 0.68 mmol, 3.0 eq.) was slowly added to a solution of compound 129-8 (49 mg, 0.227 mmol, 1.0 eq.) in DCM (3.0 mL) at 0°C. The reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was concentrated under reduced pressure, and the resulting residue, 129-9, was used directly in the next step without further purification.

[0525] Compound 129-9 (53 mg, 0.227 mmol, 1.0 eq.), compound A4 (68 mg, 0.227 mmol, 1.0 eq.), and cesium carbonate (221 mg, 0.68 mmol, 3.0 eq.) were added sequentially to DMF (2.0 mL) at room temperature. The reaction mixture was stirred at 60°C for 16 hours. The reaction mixture was cooled to room temperature, water (10.0 mL) was added, and the mixture was extracted with ethyl acetate (10.0 mL x 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 afford compound 129-10 (51 mg, 82% purity, 37.1% total yield over two steps).

[0526] At room temperature, TFA (1.0 mL) was slowly added to a solution of compound 129-10 (51 mg, 82% purity, 0.106 mmol, 1.0 eq.) in DCM (3.0 mL). The reaction mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, the resulting residue was dissolved in DCM (10.0 mL) and adjusted to pH > 7 with aqueous sodium bicarbonate. The mixture was extracted with DCM (10.0 mL x 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 afford compound 129 (23 mg, 66.3% yield, 95.51% purity). LCMS (ESI) m / z = 413.2 (M+H)+; 1H NMR (400MHz, DMSO) δ12.70 (s, 1H), 9.21 (d, J = 1.8Hz, 1H), 9.09 (t, J = 9.1Hz, 1H), 8.0 2(d,J=8.9Hz,1H),7.94–7.83(m,1H),7.64(s,1H),7.37(d,J=9.0Hz,1H),7.32(t,J =6.7Hz,1H),7.28(s,1H),7.05(dd,J=9.0,2.2Hz,1H),6.99(s,1H),4.35–4.27(m,1 H), 3.90 (s, 3H), 1.82 (d, J = 6.7Hz, 3H), 1.34 (d, J = 6.9Hz, 3H), 1.04 (d, J = 6.9Hz, 3H).

[0527] The following compound was synthesized by referring to the route of Example 129

[0528] Example 130

[0529] 6-(Fluoromethyl)-5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)quinoline

[0530] 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 indicated 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 afford compound 130-2 (1.126 g, yield: 83%, purity: 88%) as a light yellow solid. LCMS (ESI) m / z 300.0, 301.9, 304.0, (M+H)+.

[0531] At room temperature, 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). The resulting mixture was stirred at 80°C for 2 hours, and LCMS showed product formation. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (30.0 mL) and water (20.0 mL). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (20.0 mL x 3). The organic phases were combined, washed with water (20.0 mL x 2), dried over anhydrous sodium sulfate, filtered, and 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 obtain 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)+.

[0532] At room temperature, compound 130-3 (0.664 g, 2.37 mmol) was added to a mixture of tetrahydrofuran (8.0 mL) and water (8.0 mL), followed by the addition of lithium hydroxide (0.114 g, 4.74 mmol). The resulting mixture was stirred for 2 hours, and LCMS indicated 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 x 5). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The resulting residue was dried under vacuum to afford the crude product of 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)+.

[0533] At room temperature, the crude product of compound 130-4 (0.310 g, 1.30 g (theoretical amount)) was added to dichloromethane (11.0 mL). The resulting mixture was cooled in an ice-water bath, and DAST (0.454 g, 2.82 mmol) was slowly added dropwise. The resulting mixture was stirred at 0°C for 5 minutes, then warmed to room temperature and stirred for 13 hours. LCMS showed product formation. 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. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (20.0 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and 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 obtain 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)+.

[0534] At room temperature, 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). The resulting mixture was stirred at 120°C for 12 hours, and LCMS indicated the formation of the product. The reaction mixture was cooled to room temperature, and a 1.0 M aqueous solution of KF (8.0 mL) was added. The resulting mixture was stirred vigorously for 30 minutes and filtered through celite. The filter cake was washed sequentially with dichloromethane (5.0 mL x 3) and water (5.0 mL x 2). The filtrates were combined, the organic phase was separated, and the aqueous phase was extracted with dichloromethane (10.0 mL x 3). The combined organic phases were washed sequentially with KF aqueous solution (1.0 M, 20.0 mL) and water (20.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to dryness under reduced pressure. The resulting residue was dried under vacuum to afford a crude product of compound 130-6 (0.294 g, 51.3% purity) as a brown viscous liquid. LCMS (ESI) m / z 232.0, (M+H)+.

[0535] At room temperature, aqueous HCl (3.0 M, 1.7 mL, 5.2 mmol) was slowly added dropwise to a solution of the crude product of compound 130-6 (0.294 g, 0.52 mmol (theoretical amount)) in tetrahydrofuran (2.6 mL). The resulting mixture was stirred for 2 hours, and LCMS showed the formation of the product. Saturated aqueous sodium bicarbonate solution was slowly added dropwise to the reaction mixture, and the pH of the aqueous phase was adjusted to approximately 7-8. The resulting mixture was extracted with dichloromethane (10.0 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 4:1) to give a yellow liquid compound 130-7 (0.0766 g, total yield from the fifth and sixth steps: 38%, purity: 51.7%). LCMS (ESI) m / z 204.0, (M+H)+.

[0536] At room temperature, NaBH4 (0.0285 g, 0.754 mmol) was added to a solution of compound 130-7 (0.0766 g, 0.377 mmol) in methanol (1.9 mL). The resulting mixture was stirred for 3.5 hours, and LCMS showed the formation of the product. The reaction mixture was diluted with saturated aqueous NH4Cl solution (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, filtered, and the filtrate was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel thin layer chromatography (eluent: petroleum ether: ethyl acetate = 1.5:1) to give a yellow liquid compound 130-8 (0.0561 g, yield: 52%, purity: 71.48%), LCMS (ESI) m / z 206.1, (M+H)+.

[0537] At 0°C, thionyl chloride (0.0976 g, 0.82 mmol) was added dropwise to a solution of compound 130-8 (0.0561 g, 0.273 mmol) in dichloromethane (2.7 mL). The resulting mixture was stirred at 0°C for 10 minutes, then warmed to room temperature and stirred for 2 hours. LCMS showed product formation. 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 operation was repeated twice, and the resulting residue was dried under vacuum to obtain a crude product of yellow solid compound 130-9 (0.0699 g, crude yield: 78%, purity: 79.24%). LCMS (ESI) m / z 223.8, 225.8, (M+H)+.

[0538] At room temperature, the crude product of 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). The resulting mixture was stirred at room temperature for 2 minutes, followed by the addition of compound A4 (0.0815 g, 0.273 mmol). The reaction mixture was stirred at 50°C for 14 hours, and LCMS indicated the formation of the product. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (20.0 mL), and washed with water (10.0 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The resulting residue was purified by thin-layer chromatography on silica gel (eluent: ethyl acetate:petroleum ether = 6:1) to afford 130-10 (0.0485 g, 31% yield, 83.73% purity) as a light brown gum. LCMS (ESI) m / z 486.2, (M+H)+.

[0539] At room temperature, 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). The resulting mixture was stirred for 4 hours, and LCMS indicated the formation of the product. The reaction mixture was diluted with dichloromethane (10.0 mL), and the pH of the aqueous phase was adjusted to approximately 7-8 by adding saturated aqueous sodium bicarbonate. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (5.0 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and 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 afford a dark yellow solid. This 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 boiling, 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 in vacuo to give compound 130 (0.0184 g, yield: 44%, purity: 96.76%). LCMS (ESI) m / z 402.0, (M+H) +; 1 H NMR (400MHz, DMSO) δ12.75(s,1H),9.31(d,J=8.6Hz,1H),8.97(d,J=3.2Hz,1H),8.0 0(d,J=8.4Hz,1H),7.91(s,1H),7.83(d,J=8.4Hz,1H),7.72–7.63(m,2H),7.35(d,J= 8.8Hz,1H),7.16(s,1H),7.09(d,J=8.8Hz,1H),6.47(q,J=6.4Hz,1H),6.07(dd,J=4 7.2, 11.2Hz, 1H), 5.84 (dd, J = 47.2, 11.2Hz, 1H), 3.90 (s, 3H), 1.89 (d, J = 6.4Hz, 3H).

[0540] Example 135

[0541] 3-(1-methyl-1H-pyrazol-4-yl)-N-(1-(quinoxalin-5-yl)ethyl)-1H-indazol-5-amine

[0542] Compound 135-1 (100 mg, 1.0 mmol, 1.0 eq.), compound 1-4 (323 mg, 1.6 mmol, 1.5 eq.), Pd(dppf)Cl2 (151 mg, 0.21 mmol, 0.2 eq.), and potassium carbonate (430 mg, 3.1 mmol, 3.0 eq.) were added sequentially to dioxane / H2O (4 mL / 0.4 mL) at room temperature. The atmosphere was replaced with nitrogen three times and stirred at 100°C for 12 hours. The reaction solution was poured into aqueous NaCl (10.0 mL) and extracted with EtOAc (10.0 mL x 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: EtOAc / PE = 4 / 1) to afford compound 135-2 (220 mg, 87.1% yield, as a yellow solid). LCMS: (ESI) m / z 244.2, (M+H)+.

[0543] Compound 135-2 (220 mg, 0.90 mmol, 1.0 eq) and DHP (228 mg, 2.7 mmol, 3.0 eq) were dissolved in DCM (5.0 mL), and p-toluenesulfonic acid monohydrate (17 mg, 0.091 mmol, 0.1 eq) was added. The mixture was stirred at room temperature for 16 hours. The reaction solution was poured into a NaCl aqueous solution (10.0 mL) and extracted with EtOAc (20.0 mL x 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 (developing solvent: EtOAc / PE = 1 / 1) to obtain compound 135-3 (120 mg, 40.5% yield, yellow solid). LCMS: (ESI) m / z 328.2, (M+H)+.

[0544] Compound 135-3 (120 mg, 0.37 mmol, 1.0 eq) was dissolved in EtOH (4.0 mL) and H₂O (4.0 mL). Iron powder (102 mg, 1.8 mmol, 5.0 eq) and NH₄Cl (192 mg, 3.7 mmol, 10.0 eq) were added and stirred at 65°C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to afford compound 135-4 (98 mg, 89.9% yield, light yellow solid). LCMS: (ESI) m / z 298.2, (M+H)⁺.

[0545] A solution of PBr3 (78 mg, 0.29 mmol, 1.0 eq.) in DCM (0.5 mL) was slowly added to a solution of compound 135-5 (50 mg, 0.29 mmol, 1.0 eq.) in DCM (3.0 mL) at 0°C and stirred at room temperature for 0.5 hours. The reaction solution was concentrated to afford compound 135-6 (68 mg, 99.9%, yellow oil). LCMS: (ESI) m / z 237.4, (M+H)+.

[0546] Compound 135-6 (41 mg, 0.17 mmol, 1.3 eq.), compound 135-4 (40 mg, 0.13 mmol, 1.0 eq.), and sodium bicarbonate (68 mg, 0.81 mmol, 6.0 eq.) were added sequentially to DMF (2.0 mL) at room temperature and stirred at 60°C for 4 hours. The reaction solution was poured into aqueous NaCl (10.0 mL) and extracted with EtOAc (10.0 mL x 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 afford compound 135-7 (42 mg, 68.8% yield, light yellow solid). LCMS: (ESI) m / z 454.2, (M+H)+.

[0547] At room temperature, 4 M dioxane hydrochloride (2.0 mL) was slowly added to a mixture of compound 135-7 (42 mg, 0.093 mmol) in DCM (2.0 mL) and MeOH (2.0 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the resulting residue was purified by HPLC to afford compound 135 (2.6 mg, 7.6% yield, 100% purity, pale yellow solid). LCMS: (ESI) m / z 370.2, (M+H)+; 1 H NMR (400MHz, DMSO-d6) δ12.45(s,1H),9.16(d,J=1.8Hz,1H),9.10(d,J=1.8Hz ,1H),8.03–7.88(m,2H),7.81(dd,J=8.4,7.2Hz,1H),7.59(s,1H),7.34(s,1H) ,7.22(d,J=8.9Hz,1H),6.91(dd,J=8.9,2.0Hz,1H),6.48(d,J=2.0Hz,1H),6. 35(d,J=7.4Hz,1H), 5.88(p,J=6.8Hz,1H), 3.83(s,3H), 1.59(d,J=6.7Hz,3H).

[0548] Example 138

[0549] 7-Ethyl-5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)quinoxaline

[0550] Compound 138-1 (1000 mg, 4.05 mmol, 1.0 eq.), iron powder (1133 mg, 20.23 mmol, 5 eq.), and ammonium chloride (2170 mg, 40.5 mmol, 10 eq.) were added sequentially to methanol / water (40 mL / 10 mL) at room temperature. The reaction mixture was stirred at 65°C for 7 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. Water (20.0 mL) was added to the resulting residue, and the mixture was extracted with dichloromethane (20.0 mL x 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: ethyl acetate / dichloromethane = 0-13%) to afford compound 138-2 (770 mg, 87.6% yield).

[0551] Compound 138-2 (2975 mg, 13.7 mmol, 1.0 eq.) and glyoxal (40% content, 3977 mg, 27.4 mmol, 2.0 eq.) were added sequentially to ethanol (50 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, water (30.0 mL) was added to the resulting residue, which was then extracted with ethyl acetate (30.0 mL x 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 = 0-30%) to afford compound 138-3 (1215 mg, 37.1% yield).

[0552] Compound 138-3 (570 mg, 2.38 mmol, 1.0 eq.) and pyridine hydrochloride (6.7 g) were stirred at 155°C for 4 hours. The reaction mixture was cooled to room temperature, and sodium bicarbonate aqueous solution was added to adjust the pH to >7. The mixture was extracted with dichloromethane (10.0 mL x 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: ethyl acetate / petroleum ether = 0-44%) to afford compound 138-4 (100 mg, 18.6% yield).

[0553] Compound 138-4 (100 mg, 0.44 mmol, 1.0 eq.), tributyl(1-ethoxyethylene)tin (241 mg, 0.66 mmol, 1.5 eq.), and Pd(PPh3)4 (103 mg, 0.088 mmol, 0.2 eq.) were added sequentially to dioxane (3.0 mL) at room temperature. The reaction mixture was stirred at 110°C under nitrogen for 16 hours. The reaction solution was cooled to room temperature, and aqueous KF solution (5.0 mL) was added. The reaction solution was stirred at room temperature for 1 hour. The mixture was filtered, and the filtrate was extracted with ethyl acetate (10.0 mL x 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 3N HCl (2.0 mL) was slowly added. The reaction solution was stirred at room temperature for 40 minutes. Saturated aqueous sodium bicarbonate was added to adjust the pH to >7, and then extracted with ethyl acetate (10.0 mL x 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 = 0-18%) to provide compound 138-5 (30 mg, 35.9% yield).

[0554] Trifluoromethanesulfonic anhydride (68 mg, 0.24 mmol, 1.5 eq.) was slowly added to a solution of compound 138-5 (30 mg, 0.16 mmol, 1.0 eq.) and pyridine (19 mg, 0.24 mmol, 1.5 eq.) in DCM (1.6 mL) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. Aqueous sodium bicarbonate was added to adjust the pH to >7, and the mixture was extracted with dichloromethane (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 (developing solvent: ethyl acetate / petroleum ether = 2:3) to afford compound 138-6 (35 mg, 68.6% yield).

[0555] Compound 138-6 (35 mg, 0.11 mmol, 1.0 eq.), potassium vinyl trifluoroborate (23.5 mg, 0.17 mmol, 1.6 eq.), Pd(dppf)Cl2 (16 mg, 0.022 mmol, 0.2 eq.), and potassium acetate (33 mg, 0.33 mmol, 3.0 eq.) were added sequentially to dioxane / H2O (2 mL / 0.5 mL) at room temperature. The reaction mixture was stirred at 90°C for 12 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: ethyl acetate / petroleum ether = 0-20%) to afford compound 138-7 (20 mg, 92.3% yield).

[0556] Compound 138-7 (20 mg, 0.1 mmol, 1.0 eq.) and palladium / carbon (10 wt.%, palladium loading) (20 mg) were added sequentially to THF (5.0 mL) at room temperature. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours, filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting residue, 138-8, was used directly in the next step without further purification.

[0557] At 0°C, NaBH4 (19 mg, 0.5 mmol, 5.0 eq.) was slowly added to a solution of compound 138-8 (21 mg, 0.1 mmol, 1.0 eq.) in methanol (3.0 mL). The reaction mixture was stirred at room temperature for 2 hours. After cooling to 0°C, the reaction solution was slowly poured into aqueous NH4Cl (5.0 mL) and extracted with EA (10.0 mL x 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, 138-9, was used directly in the next step without further purification.

[0558] Compound 138-9 (21 mg, 0.1 mmol, 1.0 eq.) and MnO2 (88 mg, 1.0 mmol, 10.0 eq.) were added sequentially to DCM (2.0 mL) at room temperature, and the reaction mixture was stirred at 40°C for 6 hours. The resulting residue was concentrated under reduced pressure, and purified by thin-layer chromatography (developing solvent: ethyl acetate / petroleum ether = 1:2) to afford compound 138-10 (6 mg, 29.4% total yield over three steps).

[0559] Thionyl chloride (11 mg, 0.09 mmol, 3.0 eq.) was slowly added to a solution of compound 138-10 (6 mg, 0.03 mmol, 1.0 eq.) in DCM (1.5 mL) at 0°C. The reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was concentrated under reduced pressure, and the resulting residue, 138-11, was used directly in the next step without further purification.

[0560] Compound 138-11 (6.7 mg, 0.03 mmol, 1.0 eq.), compound A4 (8 mg, 0.027 mmol, 0.9 eq.), and cesium carbonate (29 mg, 0.09 mmol, 3.0 eq.) were added sequentially to DMF (1.0 mL) at room temperature. The reaction mixture was stirred at 60°C for 3 hours. The reaction mixture was cooled to room temperature, water (5.0 mL) was added, and the mixture was extracted with ethyl acetate (10.0 mL x 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: dichloromethane / methanol = 12:1) to afford compound 138-12 (7.5 mg, 52.4% total yield over two steps).

[0561] At room temperature, TFA (1.0 mL) was slowly added to a solution of compound 138-12 (7.5 mg, 0.016 mmol, 1.0 eq.) in DCM (3.0 mL). The reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, and the resulting residue was dissolved in DCM (5.0 mL). Aqueous sodium bicarbonate was added to adjust the pH to >7, and the mixture 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 (developing solvent: dichloromethane / methanol = 12:1) to give compound 138 (5.5 mg, 89% yield, 97.04% purity). LCMS (ESI) m / z = 399.2 (M+H)+; 1 H NMR (400MHz, DMSO) δ12.70(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=9.0Hz,1H),7.23(s,1 H),7.12(dd,J=9.0,2.1Hz,1H),6.75–6.63(m,1H),3.90(s,3H),2.84(q,J=7.5Hz,2H),1.75(d,J=6.3Hz,3H),1.23(t,J=7.5Hz,3H).

[0562] Example 143

[0563] 7-Bromo-5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)quinoxaline

[0564] Tri-n-butyl(1-ethoxyvinyl)tin (3.3 g, 9.2 mmol, 1.0 eq) and Pd(PPh3)4 (286 mg, 1.8 mmol, 0.2 eq) were added sequentially to a solution of compound 143-1 (2.0 g, 9.2 mmol, 1.0 eq) in dioxane (25.0 ml). The atmosphere was replaced 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 solution and stirred for 1 hour. Saturated aqueous potassium fluoride (60.0 mL) was then added and stirred for 1 hour. The mixed solution was filtered through celite, and the filtrate was poured into a NaCl aqueous solution (15.0 mL) and extracted with EtOAc (60.0 mL x 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 obtain compound 143-2 (1.4 g, 84.3% yield, yellow solid). LCMS: (ESI) m / z 181.2, (M+H)+.

[0565] Compound 143-2 (1.0 g, 5.8 mmol, 1.0 eq) and NBS (1.2 g, 6.9 mmol, 1.2 eq) were added sequentially to HAOc (15.0 ml) and stirred at room temperature for 1 hour. The reaction solution was concentrated and poured into a NaHO3 aqueous solution (20.0 mL). The mixture was extracted with EtOAc (20.0 mL x 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 afford crude compound 143-3 (2.1 g, yellow solid). LCMS: (ESI) m / z 261.2, (M+H)+.

[0566] Compound 143-3 (2.1 g, 7.9 mmol, 1.0 eq) was dissolved in EtOH (30.0 mL) and H₂O (15.0 mL). Iron powder (1.8 g, 31.7 mmol, 4.0 eq) and NH₄Cl (2.1 g, 39.6 mmol, 5.0 eq) were added and stirred at 80°C for 4 hours. The reaction mixture was filtered and concentrated under reduced pressure to afford compound 143-4 (1.4 g, 77.2% yield, as a yellow solid). LCMS: (ESI) m / z 231.2, (M+H)⁺.

[0567] Compound 143-4 (1.4 g, 8.3 mmol, 1.0 eq) and 40% aqueous glyoxal solution (1.2 g, 8.3 mmol, 1.0 eq) were added to EtOH (25.0 mL) and stirred at 80°C for 1 hour. The reaction mixture was concentrated and poured into aqueous NaCl solution (20.0 mL). The mixture was extracted with EtOAc (20.0 mL x 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 (EtOAc / PE = 1 / 5) to afford compound 143-5 (565 mg, 27.1% yield over three steps, as a pale yellow solid). LCMS: (ESI) m / z 253.0, (M+H)+.

[0568] Compound 143-5 (565 mg, 2.3 mmol, 1.0 eq) was dissolved in MeOH (5.0 mL) at room temperature. NaBH4 (43 mg, 1.1 mmol, 0.5 eq) was added at 0°C and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to afford compound 143-6 (580 mg, yield >100%), light yellow solid. LCMS: (ESI) m / z 255.0, (M+H)+.

[0569] A solution of SOCl2 (122 mg, 1.0 mmol, 2.0 eq.) in DCM (0.5 mL) was slowly added to a solution of compound 143-6 (130 mg, 0.51 mmol, 1.0 eq.) in DCM (2.0 mL) at 0°C and stirred at room temperature for 2 hours. The reaction solution was concentrated to afford compound 143-7 (140 mg, 100%, brown solid). LCMS: (ESI) m / z 273.0, (M+H)+.

[0570] Compound 143-7 (136 mg, 0.50 mmol, 1.5 eq.), compound A4 (100 mg, 0.34 mmol, 1.0 eq.), and cesium carbonate (437 mg, 1.3 mmol, 4.0 eq.) were added sequentially to DMF (2.0 mL) at room temperature and stirred at 60°C for 2 hours. The reaction solution was poured into aqueous NaCl (20.0 mL) and extracted with EtOAc (20.0 mL x 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 (developing solvent: DCM / MeOH = 10 / 1) to afford compound 143-8 (170 mg, 95.1% yield, light yellow solid). LCMS: (ESI) m / z 535.2, (M+H)+.

[0571] 4M dioxane hydrochloride (2.0 mL) was slowly added to a mixture of compound 143-8 (30 mg, 0.056 mmol) in DCM (1.0 mL) and MeOH (1.0 mL) at room temperature and stirred for 1 hour. The reaction solution was concentrated and purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to afford compound 143 (10 mg, 39.6% yield, 100% purity, as a pale yellow solid).

[0572] LCMS: (ESI) m / z 499.1, (M+H)+; 1 H NMR (400MHz, DMSO-d6) δ12.79(s,1H),9.17(d,J=1.8Hz,1H),9.13(d,J=1.8Hz,1H),8.31(d,J=2.2Hz,1H),8.08(d,J=2.2Hz,1H),8.00(s,1H),7 .61(s,1H),7.42(d,J=9.0Hz,1H),7.24(d,J=2.3Hz,1H),7.13(dd,J=8.9,2.3Hz,1H),6.69(q,J=6.3Hz,1H),3.91(s,3H),1.75(d,J=6.3Hz,3H).

[0573] Example 144

[0574] 7-Isopropyl-5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)quinoxaline

[0575] Compound 144-1 (1040 mg, 4.27 mmol, 1.0 eq.), tributyl(1-ethoxyethylene)tin (1851 mg, 5.13 mmol, 1.2 eq.), and Pd(PPh3)4 (986 mg, 0.85 mmol, 0.2 eq.) were added sequentially to dioxane (15.0 mL) at room temperature. The reaction mixture was stirred at 100°C under nitrogen for 48 hours. The reaction solution was cooled to room temperature, and aqueous KF solution (15.0 mL) was added. The reaction solution was stirred at room temperature for 1 hour. The mixture was filtered, and the filtrate was extracted with ethyl acetate (20.0 mL x 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 solution was stirred at room temperature for 40 minutes. Saturated aqueous sodium bicarbonate was added to adjust the pH to >7, and then extracted with ethyl acetate (20.0 mL x 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: ethyl acetate / (dichloromethane / petroleum ether = 1:8) = 0-16%) to provide compound 144-2 (683 mg, 77.4% yield).

[0576] Compound 144-2 (90 mg, 0.435 mmol, 1.0 eq.), 129-4 (147 mg, 0.87 mmol, 2.0 eq.), Pd(dppf)Cl2 (63 mg, 0.087 mmol, 0.2 eq.), and potassium carbonate (180 mg, 1.3 mmol, 3.0 eq.) were added sequentially to 1,4-dioxane / H2O (4 mL / 1 mL) at room temperature. The reaction mixture was stirred at 105°C for 16 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: ethyl acetate / petroleum ether = 0-20%) to afford compound 144-3 (85 mg, 91.9% yield).

[0577] Compound 144-3 (85 mg, 0.4 mmol, 1.0 eq.) and palladium / carbon (10 wt.%, palladium loading) (30 mg) were added sequentially to THF (6.0 mL) at room temperature. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours, filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting residue, compound 144-4, was used directly in the next step without further purification.

[0578] At 0°C, NaBH4 (53 mg, 1.4 mmol, 3.5 eq.) was slowly added to a solution of compound 144-4 (90 mg, 0.4 mmol, 1.0 eq.) in methanol (5.0 mL). The reaction mixture was stirred at room temperature for 2 hours. After cooling to 0°C, the reaction solution was slowly poured into aqueous NH4Cl (10.0 mL) and extracted with EA (10.0 mL x 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, 144-5, was used directly in the next step without further purification.

[0579] Compound 144-5 (88 mg, 0.4 mmol, 1.0 eq.) and MnO2 (350 mg, 4.0 mmol, 10.0 eq.) were added sequentially to DCM (5.0 mL) at room temperature, and the reaction mixture was stirred at 40°C for 6 hours. The resulting residue was concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-27%) to afford compound 144-6 (50 mg, 57.7% total yield over three steps).

[0580] Thionyl chloride (84 mg, 0.7 mmol, 3.0 eq.) was slowly added to a solution of compound 144-6 (50 mg, 0.236 mmol, 1.0 eq.) in DCM (3 mL) at 0°C. The reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was concentrated under reduced pressure, and the resulting residue, 144-7, was used directly in the next step without further purification.

[0581] Compound 144-7 (55 mg, 0.236 mmol, 1.0 eq.), compound A4 (49 mg, 0.164 mmol, 0.7 eq.), and cesium carbonate (230 mg, 0.7 mmol, 3.0 eq.) were added sequentially to DMF (3.0 mL) at room temperature. The reaction mixture was stirred at 60°C for 8 hours. The reaction solution was cooled to room temperature, water (10.0 mL) was added, and the mixture was extracted with ethyl acetate (10.0 mL x 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 afford compound 144-8 (83 mg, 72.3% total yield over two steps).

[0582] At room temperature, TFA (2.0 mL) was slowly added to a solution of compound 144-8 (83 mg, 0.167 mmol, 1.0 eq.) in DCM (6.0 mL). The reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, and the resulting residue was dissolved in DCM (10.0 mL). Aqueous sodium bicarbonate was added to adjust the pH to >7, and the mixture was extracted with DCM (10.0 mL x 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: dichloromethane / methanol = 12:1) to give compound 144 (39 mg, 56.6% yield, 100% purity). LCMS (ESI) m / z = 413.3 (M+H)+; 1 H NMR (400MHz, DMSO) δ12.74(s,1H),9.04(d,J=4.4Hz,2H),8.03–7.92(m,2H),7.83(d,J=1.4Hz,1H),7.62(s,1H),7.38(d,J=9.0Hz,1H),7.27(s, 1H), 7.13 (dd, J=9.0, 1.9Hz, 1H), 6.70 (q, J=6.3Hz, 1H), 3.91 (s, 3H), 3.13 (dq, J=13.4, 6.9Hz, 1H), 1.76 (d, J=6.3Hz, 3H), 1.26 (d, J=6.9Hz, 6H).

[0583] The following compound was synthesized by referring to the route of Example 144

[0584] Example 146

[0585] 7-Ethynyl-5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)quinoxaline

[0586] At room temperature, compound 143-8 (70 mg, 0.13 mmol, 1.0 eq.), trimethylsilylacetylene (49 mg, 0.50 mmol, 3.8 eq.), Pd(dppf)Cl2 (18 mg, 0.026 mmol, 0.2 eq.), CuI (10 mg, 0.053 mmol, 0.4 eq.) and Et3N (85 mg, 0.84 mmol, 6.4 eq.) were added to THF (2.0 mL) in sequence, the atmosphere was replaced with nitrogen three times, and the mixture was stirred at 90°C for 4 hours. The reaction solution was poured into a NaCl aqueous solution (10.0 mL) and extracted with EtOAc (20.0 mL x 2). 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 thin-layer chromatography (developing solvent: DCM / MeOH = 10 / 1) to give compound 146-1 (44 mg, 60.9% yield, yellow solid). LCMS: (ESI) m / z 511.3, (M+H)+.

[0587] At room temperature, TFA (1.5 mL) was added to a solution of compound 146-1 (44 mg, 0.071 mmol) in DCM (1.5 mL) and stirred at 40°C for 4 hours. The reaction solution was poured into a NaHCO3 aqueous solution (10.0 mL) to adjust the pH to 8, and extracted with EtOAc (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 thin-layer chromatography (developing solvent DCM / MeOH = 10 / 1) to give compound 146 (9.6 mg, 34.4% yield, 100% purity, light yellow solid). LCMS: (ESI) m / z 395.2, (M+H)+; 1 H NMR (400MHz, DMSO-d6) δ12.77(s,1H),9.14(q,J=1.9Hz,2H),8.15(d,J=1.8Hz,1H),7.99–7.94(m,3H),7.58(s,1H),7.41(d,J=9.0 Hz, 1H), 7.21 (d, J = 2.3Hz, 1H), 7.12 (dd, J = 9.0, 2.3Hz, 1H), 6.68 (q, J = 6.3Hz, 1H), 4.53 (s, 1H), 3.90 (s, 3H), 1.75 (d, J = 6.3Hz, 3H).

[0588] Example 149

[0589] 4-(5-(5-(1-(quinoxalin-5-yl)ethoxy)-1H-indazol-3-yl)pyridin-2-yl)thiomorpholine 1,1-dioxide

[0590] Compound 149-1 (270 mg, 0.96 mmol, 1.3 eq.) was dissolved in toluene (10 ml), followed by the addition of compound 149-2 (100 mg, 0.74 mmol, 1.0 eq.), t-BuoNa (106 mg, 1.1 mmol, 1.5 eq.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (25.5 mg, 0.04 mmol, 0.06 eq.), and Pd2(dba)3 (13.9 mg, 0.15 mmol, 0.02 eq.). After complete addition, the atmosphere was purged with nitrogen three times, and the reaction was stirred at 98°C overnight. TLC indicated that no starting material remained, with most of the product converted. The reaction was quenched by the dropwise addition of saturated ammonium chloride solution. The reaction solution was extracted three times with ethyl acetate (20 ml), and 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 obtain compound 149-3 as a yellow solid (110 mg, 37%). LCMS: (ESI) m / z 292, (M+H)+; 1 H NMR (400MHz, CD3OD) δ8.19 (s, 1H), 7.67 (d, J = 9.1Hz, 1H), 6.91 (d, J = 9.1Hz, 1H), 4.11 (d, J = 10.0Hz, 4H), 3.09–3.02 (m, 4H).

[0591] Compound 149-3 (100 mg, 0.34 mmol, 1.0 eq.) was dissolved in dioxane (5 ml), followed by the addition of pinacol diboron (132 mg, 0.52 mmol, 1.5 eq.), KOAc (100.9 mg, 1.0 mmol, 3.0 eq.), and Pd(dppf)Cl2 (25 mg, 0.034 mmol, 0.1 eq.). After complete addition, the atmosphere was replaced with nitrogen three times, and the reaction was stirred at 110°C overnight. TLC showed no residual starting material, with most conversion to product. The reaction was quenched by the dropwise addition of saturated ammonium chloride solution. The reaction solution 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 (developing solvent: DCM:MeOH = 20:1) to afford Compound 149-4 (60 mg, 51%) as a yellow solid. LCMS: (ESI) m / z 339, (M+H)+; 1 H NMR (400MHz, CD3OD) δ8.44(s,1H),7.87(s,1H),6.96–6.90(m,1H),4.17(s,4H),3.06(s,4H),1.31(s,12H).

[0592] Compound 149-4 (60 mg, 0.2 mmol, 1.3 eq) was dissolved in THF / H₂O (5 / 1 ml), followed by the addition of compound A8 (75 mg, 0.15 mmol, 1.0 eq.), compound K₂CO₃ (61 mg, 0.44 mmol, 3.0 eq.), and Pd[PPh₃]₄ (17.3 mg, 0.02 mmol, 0.1 eq.). After the additions were complete, the atmosphere was replaced with nitrogen three times, and the reaction was stirred at 80°C overnight. TLC showed no residual starting material, with most of the product converted. The reaction was quenched by the dropwise addition of saturated ammonium chloride solution. The reaction solution 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 (developing solvent: DCM:MeOH = 20:1) to afford compound 149-5 (60 mg, 86%) as a yellow solid. LCMS: (ESI) m / z 585, (M+H)⁺.

[0593] Compound 149-5 (80 mg, 0.17 mmol, 1.0 eq.) was dissolved in MeOH (5 ml), and then a dioxane solution of HCl (2.0 ml) was added. After the addition, the atmosphere was replaced with nitrogen three times, and the reaction was stirred at 25°C for two hours. TLC showed that no starting material remained and most of it was converted into product. Saturated ammonium chloride solution was added dropwise to quench the reaction. 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 (developing solvent DCM:MeOH = 20:1) to obtain compound 149 as a yellow solid (19.3 mg, purity: 98%, yield: 38%). LCMS: (ESI) m / z 501, (M+H)+; 1 H NMR(399MHz,CD3OD)δ9.06(s,1H),8.96(s,1H),8.12(s,1H),7.98(s,2H),7.78(d,J=13.4Hz,2H),7.39(s,1H), 7.17(d,J=2.3Hz,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=6.4Hz,3H).

[0594] Example 151

[0595] N,N-Dimethyl-5-(1-(3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)quinolin-7-amine

[0596] Tributyl(1-ethoxyethylene)tin (178 mg, 0.49 mmol, 1.1 eq) and Pd(PPh3)4 (103 mg, 0.090 mmol, 0.2 eq) were added sequentially to a solution of compound 151-1 (100 mg, 0.45 mmol, 1.0 eq) in dioxane (3.0 ml). The atmosphere was replaced 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 solution and stirred for 1 hour. Saturated aqueous potassium fluoride (3.0 mL) was then added and stirred for 1 hour. The mixed solution was filtered through celite, and the filtrate was poured into a NaCl aqueous solution (15.0 mL) and extracted with EtOAc (15.0 mL x 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 thin-layer chromatography (developing solvent: DCM / MeOH = 10 / 1) to obtain compound 151-2 (70 mg, 83.9% yield, light yellow solid). LCMS: (ESI) m / z 187.2, (M+H)+.

[0597] Compound 151-2 (70 mg, 0.38 mmol, 1.0 eq) was dissolved in MeOH (2.0 mL) at room temperature. NaBH4 (14 mg, 0.38 mmol, 1.0 eq) 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 x 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 afford compound 151-3 (75 mg, 95.4% yield, light yellow solid). LCMS: (ESI) m / z 189.2, (M+H)+.

[0598] A solution of SOCl2 (569 mg, 4.8 mmol, 12.0 eq.) in DCM (0.5 mL) was slowly added to a solution of compound 151-3 (75 mg, 0.40 mmol, 1.0 eq.) in DCM (3.0 mL) at 0°C and stirred at room temperature for 1 hour. The reaction solution was concentrated to afford compound 151-4 (80 mg, 97.1%, yellow oil). LCMS: (ESI) m / z 207.2, (M+H)+.

[0599] Compound 151-4 (62 mg, 0.30 mmol, 1.3 eq.), compound A4 (60 mg, 0.20 mmol, 1.0 eq.), and cesium carbonate (327 mg, 1.0 mmol, 5.0 eq.) were added sequentially to DMF (3.0 mL) at room temperature and stirred at 60°C for 2 hours. The reaction solution was poured into aqueous NaCl (10.0 mL) and extracted with EtOAc (10.0 mL x 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 obtain compound 151-5 (60 mg, 63.7% yield, light yellow solid). LCMS: (ESI) m / z 469.2, (M+H)+.

[0600] Compound 151-5 (30 mg, 0.064 mmol, 1.0 eq) was dissolved in MeOH (3.0 ml), and 40% aqueous formaldehyde (95 mg, 1.3 mmol, 20.0 eq), AcOH (0.77 mg, 0.013 mmol, 0.2 eq), and NaCNBH3 (20 mg, 0.32 mmol, 5.0 eq) were added sequentially. The mixture was allowed to react at room temperature for 24 hours. The reaction solution was poured into aqueous NaCl (10.0 mL) and extracted with EtOAc (10.0 mL x 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 afford compound 151-6 (34 mg, yield >100%), as a yellow solid. LCMS: (ESI) m / z 497.0, (M+H)+.

[0601] At room temperature, 4 M dioxane hydrochloride (2.0 mL) was slowly added to a mixed solution of compound 151-6 (34 mg, 0.068 mmol) in DCM (2.0 mL) and MeOH (2.0 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the resulting residue was purified by HPLC to afford compound 151 (7.7 mg, 26.4% yield, 96.7% purity, yellow solid). LCMS: (ESI) m / z 413.2, (M+H)+; 1H NMR (400MHz, DMSO-d6) δ12.75(s,1H),8.88(d,J=8.4Hz,1H),8.74(d,J=4.5Hz,1H),8.08(s,1H),7.78(s,1H),7.61(d,J=2.6Hz,1H),7. 41–7.31(m,3H),7.13(dd,J=8.9,2.2Hz,1H),6.90(d,J=2.5Hz,1H),6.33(q,J=6.4Hz,1H),3.90(s,3H),3.07(s,6H),1.80–1.77(m,3H).

[0602] Example 152

[0603] Imino(methyl)(5-(5-(1-(quinoxalin-5-yl)ethoxy)-1H-indazol-3-yl)pyridin-2-yl)-aminosulfonone

[0604] Compound 152-1 (200 mg, 0.98 mmol, 1.0 eq) was dissolved in dioxane (10 ml), and then pinacol diboronate (373.3 mg, 1.5 mmol, 1.5 eq.), KOAc (288.5 mg, 3.0 mmol, 3.0 eq.), and Pd(dppf)Cl2 (71.7 mg, 0.1 mmol, 0.1 eq.) were added. After complete addition, the atmosphere was replaced with nitrogen, and the reaction was stirred at 105°C overnight. TLC showed no residual starting material. The filtrate was directly filtered through a pad of Celite, and the filtrate was drained and slurried with ethyl acetate and then petroleum ether to obtain compound 152-2 (330 mg, crude) as a green oil. LCMS: (ESI) m / z 252, (M+H)+.

[0605] Compound A8 (100 mg, 0.2 mmol, 1.0 eq.) was dissolved in dioxane (8 mL) and H₂O (2 mL). Compound 152-2 (176 mg, crude), K₂CO₃ (82.9 mg, 0.6 mmol, 3.0 eq.), and Pd[PPh₃]₄ (23.1 mg, 0.02 mmol, 0.1 eq.) were added and stirred at 105°C overnight. TLC showed no residual starting material, but new spots were generated. Ethyl acetate was added for elution, the mixture was spin-dried, and purified by thin-layer chromatography (developing solvent: petroleum ether:ethyl acetate = 3:1) to afford compound 152-3 (70 mg, crude) as a yellow oil. LCMS: (ESI) m / z 514, (M+H)⁺.

[0606] Compound 152-3 (70 mg, crude) was dissolved in MeOH (5 mL) and CH3COONH4 (16.3 mg, 0.21 mmol, 1.5 eq.) and iodophenyldiacetic acid (95.2 mg, 0.3 mmol, 2.0 eq.) were added. The mixture was stirred at room temperature for 1 hour. TLC showed a small amount of starting material remaining, but new spots were generated. Water was added and the 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 afford compound 152-4 (25 mg, crude) as a yellow oil. LCMS: (ESI) m / z 529, (M+H)+.

[0607] Compound 152-4 (25 mg, crude) was dissolved in DCM / TFA (6 mL / 1 mL) and stirred at room temperature for 2 hours. TLC showed the disappearance of compound 152-4 and the formation of a more polar spot, which was confirmed by LCMS to be compound 152. The product was directly spin-dried and purified by high-pressure liquid chromatography to obtain compound 152 as a yellow solid (5.4 mg, 25.7% yield, 98.8% purity). LCMS: (ESI) m / z 445, (M+H)+; 1 H NMR (400MHz, CDCl3) δ9.11(s,1H),8.99(s,1H),8.92(d,J=16.6Hz,1H),8.33(d,J=12.0Hz,1H),8.18(d,J=8.2Hz,1H),8.01(d,J=10.8H z,2H),7.82(s,1H),7.48(d,J=9.3Hz,1H),7.28(s,1H),7.22(d,J=11.3Hz,1H),6.82(s,1H),3.61(d,J=6.6Hz,3H),1.81–1.76(m,3H).

[0608] The following compound was synthesized by referring to the route of Example 152

[0609] Example 156

[0610] (5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)quinolin-6-yl)methanol

[0611] At room temperature, 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). The reaction mixture was cooled in an ice-water bath, and tert-butyldiphenylsilyl chloride (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 (25.0 mL) and saturated aqueous sodium bicarbonate solution (10.0 mL). The organic phase was separated, washed with water (10.0 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane: petroleum ether = 1.5:1) to obtain compound 156-2 (0.497 g, yield: 91%, purity: 92.95%) as a colorless, transparent liquid. LCMS(ESI) m / z 476.0, 478.0, (M+H)+.

[0612] Compound 156-2 (0.497 g, 1.04 mmol), potassium vinyl trifluoroborate (0.210 g, 1.57 mmol), Pd(dppf)Cl2 (0.0764 g, 0.104 mmol), and Na2CO3 (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, and 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 x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and 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 a slightly yellow liquid compound 156-3 (0.355 g, yield: 74%, purity: 91.99%). LCMS (ESI) m / z 424.0, (M+H) + .

[0613] 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 minutes, followed by the addition of NaIO4 (0.718 g, 3.36 mmol). The reaction mixture was stirred at 0°C for 15 minutes, then warmed to room temperature and stirred for 48 hours. LCMS indicated the formation of the product. The reaction mixture was diluted with dichloromethane (30.0 mL) and water (15.0 mL). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (15.0 mL × 3). The combined organic phases were washed with saturated aqueous sodium sulfite (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and 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 a light yellow viscous liquid 156-4 (0.252 g, yield: 67%, purity: 95.58%). LCMS (ESI) m / z 426.0, (M+H) +.

[0614] At 0°C, a 3.0M solution of methylmagnesium bromide (0.30 mL, 0.90 mmol) in 2-methyltetrahydrofuran (3.0 mL) was added dropwise to a solution of compound 156-4 (0.252 g, 0.59 mmol) in tetrahydrofuran (3.0 mL). The reaction mixture was stirred at 0°C for 5 minutes, then warmed to room temperature and stirred for 28 hours. LCMS indicated 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 x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 3:1) to afford compound 156-5 as a white solid (0.238 g, yield: 86%, purity: 94.31%). LCMS (ESI) m / z 442.0, (M+H)+.

[0615] At 0°C, thionyl chloride (0.0999 g, 0.84 mmol) was added dropwise to a solution of compound 156-5 (0.124 g, 0.28 mmol) in dichloromethane (2.8 mL). The resulting mixture was stirred at 0°C for 5 minutes, then warmed to room temperature and stirred for 8 hours. LCMS showed product formation. The reaction mixture was concentrated to dryness under reduced pressure. Dichloromethane (5.0 mL) was added to the residue, and the mixture was concentrated to dryness under reduced pressure again. This operation was repeated three times, and the residue was dried under vacuum to give a crude product of light yellow solid 156-6 (0.139 g, crude yield: 63%, purity: 63.44%). LCMS (ESI) m / z 460.2 (M+H)+.

[0616] At room temperature, the crude product of 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). The resulting mixture was stirred at room temperature for 2 minutes, followed by the addition of compound A4 (0.0838 g, 0.28 mmol). The reaction mixture was stirred at 45°C for 26 hours, and LCMS indicated the formation of the product. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (20.0 mL) and saturated aqueous ammonium chloride (10.0 mL). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10.0 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and 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 obtain light brown solid compound 156-7 (0.0468 g, yield: 28%, purity: 81.88%). LCMS (ESI) m / z 484.0, (M+H) +.

[0617] At room temperature, 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). The resulting mixture was stirred for 8 hours, and 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 organic phases were combined, dried over anhydrous sodium sulfate, filtered, and 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 obtain compound 156 (0.0238 g, yield: 60%, purity: 97.88%) as a beige solid. LCMS (ESI) m / z 400.2, (M+H)+; 1H NMR (400MHz, DMSO) δ12.71(s,1H),9.27(d,J=8.8Hz,1H),8.87(d,J=2.8Hz,1H),7.98(s,1 H),7.93(d,J=8.8Hz,1H),7.88(d,J=8.8Hz,1H),7.71(s,1H),7.58(dd,J=8.8,4.0Hz,1H) ,7.33(d,J=8.8Hz,1H),7.23(s,1H),7.08(d,J=8.8Hz,1H),6.38(d,J=6.4Hz,1H),5.69(s ,1H),5.09(d,J=12.8Hz,1H),4.83(d,J=12.8Hz,1H),3.92(s,3H),1.89(d,J=6.4Hz,3H).

[0618] Example 158

[0619] 5-(1-((3-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)quinoxaline

[0620] Compound A8 (200 mg, 0.4 mmol, 1.0 eq.) was dissolved in THF / H₂O (5 / 1 ml), followed by the addition of compound 158-1 (168 mg, 0.48 mmol, 1.2 eq.), compound K₂CO₃ (165.6 mg, 1.2 mmol, 3.0 eq.), and compound Pd(pph₃)₄ (46 mg, 0.04 mmol, 0.1 eq.). After the additions were complete, the atmosphere was purged with nitrogen three times, and the reaction was stirred at 75°C overnight. TLC showed no residual starting material, with most of the product converted. The product was then 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 thin-layer chromatography (developing solvent: petroleum ether:ethyl acetate = 2:1) to afford compound 158-2 (60 mg, 25%) as a yellow solid. LCMS: (ESI) m / z 596, (M+H)⁺.

[0621] Compound 158-2 (60 mg, 0.1 mmol, 1.0 eq.) was dissolved in DCM / TFA (5 mL / 0.5 mL). After complete addition, the reaction was stirred at 25°C for 0.2 hours. TLC showed no starting material remaining, with most of the product converted. The reaction solution 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 (developing solvent: DCM:MeOH = 20:1) to obtain compound 158-3 (40 mg, 80%) as a yellow solid. LCMS: (ESI) m / z 496, (M+H)+.

[0622] Compound 158-3 (50 mg, 0.1 mmol, 1.0 eq.) was dissolved in methanol (4 mL), and formaldehyde (9.8 mg, 0.12 mmol, 1.2 eq.) and acetic acid (1 drop) were added. The mixture was stirred at room temperature for 1 hour, and then NaBH(OAc)3 (64.1 mg, 0.3 mmol, 3.0 eq.) was added while cooling. After the addition, the mixture was stirred at room temperature for 1 hour. When TLC showed a small amount of starting material remaining, 10 mL of water was added and the 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 (developing solvent: DCM:MeOH = 20:1) to obtain compound 158-4 (26 mg, crude product) as a yellow oil. LCMS: (ESI) m / z 510, (M+H)+;

[0623] Compound 158-4 (26 mg, crude) was dissolved in DCM / TFA (5 mL / 1 mL) and stirred at room temperature for 2 hours. TLC indicated the reaction was complete, and the mixture was directly dried and purified by HPLC to give Compound 158 (2.7 mg, 12%) as a yellow solid. LCMS: (ESI) m / z 426, (M+H)+; 1 H NMR (400MHz, CD3OD) δ9.05(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=9.7Hz,1H),7.17(d,J=7.3Hz ,1H),7.12(s,1H),6.75(d,J=6.5Hz,1H),5.23(d,J=8.7Hz,1H),4.40(t, J=9.0Hz, 2H), 4.20 (t, J=8.2Hz, 2H), 2.89 (s, 3H), 1.77 (d, J=6.3Hz, 3H).

[0624] Example 160

[0625] N,N-Dimethyl-2-(4-(5-(1-(quinoxalin-5-yl)ethoxy)-1H-indazol-3-yl)-1H-pyrazol-1-yl)ethane-1-sulfonamide

[0626] To a solution of compound A9 (40 mg, 0.091 mmol, 1.0 eq) and compound 160-1 (14.45 mg, 0.14 mmol, 1.5 eq) in dioxane (10 mL) was added DBU (41.47 mg, 0.27 mmol, 3 eq). The atmosphere was replaced with nitrogen three times and the mixture was stirred at 90°C for 6 hours. LCMS showed that compound A9 was completely reacted. The reaction mixture was cooled, 20 mL of water was added, and then extracted with ethyl acetate. The separated liquid was dried and spin-dried to dryness to obtain a yellow oil. The crude product was purified by 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)+.

[0627] Compound 160-2 (40 mg, 0.07 mmol, 1.0 eq.) was dissolved in DCM (2 mL) and TFA (1 mL) was added. The mixture was reacted at 25°C for 3 hours. LCMS showed that the reaction of compound 160-2 was complete, resulting in the formation of the product. The reaction mixture was evaporated to dryness to obtain the crude product, which was purified by thin-layer chromatography (developing solvent: DCM:MeOH = 10:1) to afford Compound 160 (20.5 mg, 60% yield) as a white solid. LCMS (ESI) m / z 492.2, (M+H)+). 1 H NMR (400MHz, DMSO) δ9.10 (dd, J=15.6, 1.6Hz, 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=9.2Hz,1H),7.27( d,J=2.0Hz,1H),7.10(dd,J=9.2,2.4Hz,1H),6.74(q,J=6.4Hz,1H),4.56( t, J=7.2Hz, 2H), 3.68 (d, J=7.6Hz, 4H), 2.77 (s, 7H), 1.75 (d, J=6.4Hz, 3H).

[0628] Example 162

[0629] 4-(4-(5-(1-(quinoxalin-5-yl)ethoxy)-1H-indazol-3-yl)-1H-pyrazol-1-yl)piperidine-1-carbonitrile

[0630] Compound 162-1 (113 mg, 0.30 mmol, 1.5 eq.), compound A8 (100 mg, 0.20 mmol, 1.0 eq.), potassium carbonate (83 mg, 0.60 mmol, 3.0 eq.), Pd(dppf)Cl 2 (15 mg, 0.02 mmol, 0.1 eq.) was dissolved in a mixed solution of dioxane (2 mL) and water (0.4 mL) and stirred at 90°C for 12 hours. LCMS showed the formation of the product. The reaction mixture was cooled, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and dried, and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1) to give an off-white solid 162-2 (100 mg, yield 80.20%, LCMS (ESI) m / z 624.32, (M+H)+).

[0631] To a solution of compound 162-2 (100 mg, 0.16 mmol, 1.0 eq.) in dichloromethane (2 mL) was added 1 mL of trifluoroacetic acid and stirred at room temperature for 1 hour. LCMS indicated the formation of the product. The reaction mixture was directly concentrated and dried to afford compound 162-3 as a brown oil (70 mg, 99.36% yield; LCMS (ESI) m / z 440.21, (M+H)+).

[0632] Compound 162-3 (40 mg, 0.06 mmol, 1.0 eq.), cyanogen bromide (10 mg, 0.10 mmol, 1.5 eq.), and N,N-diisopropylethylamine (25 mg, 0.20 mmol, 3.0 eq.) were dissolved in dichloromethane (2 mL) and stirred at room temperature for 2 hours. LCMS indicated the formation of the product. The reaction mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then purified by HPLC to give compound 162 (1.5 mg, 100.00% purity, LCMS (ESI) m / z 465.2, (M+H)+).

[0633] Example 163

[0634] 5-(1-((3-(1-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1-indazol-5-yl)oxy)ethyl)quinoxaline

[0635] To a solution of compound 162-3 (40 mg, 0.09 mmol, 1.0 eq) in dichloromethane (1 mL) was added triethylamine (28 mg, 0.27 mmol, 3.0 eq), and to the mixture was added methylsulfonyl chloride (16 mg, 0.14 mmol, 1.5 eq) at 0°C, and stirred at room temperature for 2 hours. LCMS showed the formation of the product. The product was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and dried, and purified by high performance liquid chromatography to give the product compound 163 (4.0 mg, purity 100.00%). LCMS (ESI) m / z 518.2, (M+H)+); 1H NMR (400MHz, DMSO) δ13.47–13.34(m,1H),12.77(s,1H),9.12(d,J=2.0Hz,1H),9.09(d,J=1.6Hz,1H),8 .04(d,J=6.4Hz,2H),7.99(d,J=7.2Hz,1H),7.86(dd,J=15.2,7.2Hz,1H),7.63(s,1H),7.39(d,J=8.8Hz ,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=5.6Hz,5H),2.08(dd,J=36.0,11.2Hz,3H),2.06–1.90(m,2H),1.75(d,J=6.4Hz,3H).

[0636] Example 164

[0637] 7-Cyclopropyl-5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)quinoline

[0638] To a solution of compound 164-1 (1 g, 4.2 mmol, 1.0 eq) and tributyl(1-ethoxyethylene)tin (2.28 g, 6.3 mmol, 1.5 eq) in dioxane (6 mL) was added tetrakistriphenylphosphine palladium (970 mg, 0.84 mmol, 0.2 eq). The mixture was purged with nitrogen three times, and the mixture was stirred at 110° C. for 12 hours. LCMS showed that the reaction of compound 164-1 was complete. The reaction mixture was cooled, and 20 mL of KF solution was added. The mixture was stirred at room temperature for 30 min, filtered, extracted with EA, and washed with saturated brine. The organic phase was concentrated to give a yellow oil. Dioxane (10 mL) and 4M HCl (6 mL) were added, and the mixture was stirred at room temperature for 30 min. LCMS showed that the reaction was complete. The pH was adjusted to 7 with saturated NaHCO₃ (20 mL), and the mixture was extracted with ethyl acetate, dried, and spin-dried to give a yellow oil. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 3:1) to give compound 164-2 (750 mg, yield: 88%). LCMS (ESI) m / z 202.2, (M+H)⁺.

[0639] Compound 164-2 (750 mg, 3.37 mmol, 1.0 eq.) and pyridine hydrochloride (10 g) were heated to 160°C and stirred for 4 hours. LCMS indicated the formation of the product. After cooling, the reaction mixture was added with saturated Na2CO3 solution and adjusted to pH 8. The mixture was extracted with EA, separated, dried, and spin-dried to obtain a yellow solid. Purification by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 2:1) afforded compound 164-3 (450 mg, 65% yield) as a yellow solid. LCMS (ESI) m / z 188.2, (M+H)+.

[0640] Compound 164-3 (450 mg, 2.4 mmol, 1.0 eq.) and pyridine (380 mg, 4.81 mmol, 2 eq.) were dissolved in DCM (10 mL). Tf2O (1.36 g, 4.81 mmol, 2 eq.) was added dropwise at 0°C. The reaction was allowed to react at 25°C for 2 h. LCMS showed the disappearance of compound 164-3 and the formation of the product. The reaction mixture was added with saturated aqueous NaHCO3 (50 mL) and extracted with DCM. The organic phase was separated, dried, and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 4:1) to afford compound 164-4 as a yellow oil (300 mg, 40% yield).

[0641] LCMS (ESI) m / z 320.2, (M+H)+).

[0642] Compound 164-4 (120 mg, 0.376 mmol, 1.0 eq.) and cyclopropylboronic acid (32.3 mg, 0.376 mmol, 1 eq.) were dissolved in toluene (2 mL) and water (0.2 mL). Cs2CO3 (167 mg, 0.51 mmol, 2 eq.) and Pd(dppf)Cl2 (61 mg, 0.07 mmol, 0.2 eq.) were added and reacted at 90°C for 6 hours. LCMS showed that compound 5 was completely reacted. The reaction solution was filtered, dried, and purified by thin-layer chromatography (developing solvent: petroleum ether:ethyl acetate = 3:1) to afford compound 164-5 as a colorless oil (70 mg, 88% yield). LCMS (ESI) m / z 212.2, (M+H)+.

[0643] Compound 164-5 (70 mg, 0.33 mmol, 1.0 eq.) was dissolved in EtOAc (10 mL), and NaBH4 (9.5 mg, 0.25 mol, 1 eq.) was added. The mixture was stirred at room temperature for 30 min. LCMS indicated the formation of the product. The reaction mixture was quenched by the addition of saturated NH4Cl solution, extracted with EtOAc, and the resulting mixture was separated, dried, and spin-dried to afford a yellow solid. Thin-layer chromatography (developing solvent: petroleum ether:ethyl acetate = 1:1) afforded compound 164-6 (70 mg, 99% yield) as an off-white solid. LCMS (ESI) m / z 214.2 (M+H)+ was obtained.

[0644] Compound 164-6 (70 mg, 0.33 mmol, 1.0 eq.) was dissolved in DCM (3 mL) and SOCl2 (78 mg, 0.66 mmol, 2 eq.) was added dropwise at 0°C. The mixture was allowed to react at room temperature for 1 h. LCMS showed the disappearance of compound 164-6 and the formation of the product. The reaction mixture was extracted with aqueous NaHCO3 and DCM. The organic phase was separated, dried, and spin-dried to afford compound 164-7 as a yellow oil (70 mg, 92% yield). LCMS (ESI) m / z 232.2, (M+H)+).

[0645] Compound 164-7 (70 mg, 0.3 mmol, 1.0 eq.) and compound A4 (90 mg, 0.3 mmol, 1 eq.) were dissolved in DMF (2 mL). Cs2CO3 (196 mg, 0.6 mmol, 2 eq.) was added and reacted at 60°C for 6 hours. LCMS showed that compound 164-7 was completely reacted and the product was formed. The reaction mixture was extracted with water and EtOAc. The organic phase was separated, dried, and purified by thin-layer chromatography (developing solvent: DCM:MeOH = 10:1) to afford compound 164-8 as a yellow solid (110 mg, 74% yield). LCMS (ESI) m / z 494.2, (M+H)+).

[0646] Compound 164-8 (110 mg, 0.16 mmol, 1.0 eq.) was dissolved in DCM (2 mL) and TFA (1 mL) was added. The mixture was reacted at 25°C for 3 hours. LCMS showed that compound 164-8 was completely reacted and the product was formed. The reaction solution was dried to give the crude product, which was purified by thin-layer chromatography (developing solvent: DCM:MeOH = 10:1) to give compound 164 as a white solid (85 mg, 93% yield). LCMS (ESI) m / z 410.2, (M+H)+). 1H NMR (400MHz, DMSO) δ9.04(d,J=8.4Hz,1H),8.94(d,J=4.4Hz,1H),8.08(s,1H),7.77(s, 1H),7.63(t,J=5.2Hz,4H),7.38(d,J=9.2Hz,1H),7.30(d,J=2.0Hz,1H),7.12(dd,J=9. 2,2.4Hz,1H),6.36(q,J=6.4Hz,1H),3.91(s,3H),2.20–2.12(m,1H),1.78(d,J=6.4Hz, 3H), 1.09 (dd, J=8.4, 2.3Hz, 2H), 0.87 (dd, J=18.4, 13.2Hz, 1H), 0.78 (t, J=16.4Hz, 1H).

[0647] Example 165

[0648] 6-Methyl-5-(1-((3-(1-methyl-1H-1,2,3-triazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)quinoline

[0649] At room temperature, 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, and Cs2CO3 (12.12 g, 37.19 mmol) was added. The reaction mixture was incubated at 60°C for 12 h. LCMS showed that the reaction was complete, with no residual starting material. The reaction mixture was quenched with water and extracted with EA (100 mL x 3). The organic phases were combined and dried by spin drying. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 3:1) to obtain a white solid (5.93 g, 62.11% yield, 98% purity). LCMS (ESI) m / z 514.01, (M+H)+.

[0650] At room temperature, compound 165-1 (50 mg, 0.12 mmol) was dissolved in DMF (2 mL), and trimethylsilylacetylene (17 mg, 0.17 mmol) was added. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (9 mg, 0.011 mmol), DIEA (30 mg, 0.23 mmol), and CuI (2.2 mg, 0.011 mmol) were then added under nitrogen. The reaction mixture was stirred at 100°C for 16 h. LCMS showed no residual starting material. After the reaction mixture was cooled to room temperature, 100 mL of aqueous solution was added for quenching, and the resulting solid was filtered through celite. The filtrate was extracted with ethyl acetate (100 mL x 3), and the organic phases were combined and dried. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1) to give a yellow solid product 165-2 (40 mg, purity 100%, yield 71%, [M+H] + = 484.0).

[0651] Compound 165-2 (110 mg, 0.23 mmol) was dissolved in MeOH (5 mL) at room temperature, and KCO (31 mg, 0.23 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 h. TLC indicated complete reaction of the starting material. The organic phases were combined and dried by spin drying. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 1:3) to afford 165-3 as a yellow oil (88 mg, 100% purity, 94% yield, [M+H]+ = 412.0).

[0652] Compound 165-3 (50 mg, 0.12 mmol) was dissolved in DMF (2 mL) at room temperature. Trimethylsilylazide (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 mixture was stirred at room temperature for 2 hours. LCMS indicated complete reaction. The reaction mixture was directly dried to afford the crude product, which was then purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to afford compound 165-4 as a yellow oil (19 mg, 100% purity, >29% yield; [M+H] + = 540.8).

[0653] 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 indicated complete reaction of the starting materials. The reaction mixture was diluted with water and extracted with EA (30 mL x 3). The combined organic phases were spin-dried to dryness. The crude product was purified by silica gel column chromatography (eluent: DCM:MeOH = 10:1) to afford 165-5 as a yellow oil (20 mg, 90% purity, LCMS: 469.2 [M+H]+).

[0654] Compound 165-5 (20 mg, 0.04 mmol) was dissolved in DCM (2 mL) at room temperature, and TFA (1 mL) was added under ice-cooling. The reaction mixture was stirred at room temperature for 1 h. LCMS showed complete reaction of the starting material. The reaction mixture was concentrated, the organic phase was collected, and purified by HPLC to afford Compound 165 as a white solid (7.1 mg, purity: 100%, LCMS: 385.0 [M+H]+). 1 H NMR (400MHz, DMSO) δ12.95 (s, 1H), 9.21 (d, J = 8.6Hz, 1H), 8.83–8.74 (m, 1H ),8.36(s,1H),7.80(d,J=8.6Hz,1H),7.65(s,1H),7.58(d,J=8.7Hz,1H),7 .53(dd,J=8.8,4.1Hz,1H),7.38(d,J=9.0Hz,1H),7.09(dd,J=9.0,2.4Hz,1 H), 6.23 (d, J = 6.7Hz, 1H), 4.14 (s, 3H), 2.81 (s, 3H), 1.87 (d, J = 6.7Hz, 3H).

[0655] Example 166

[0656] 6-Ethynyl-5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)quinoline

[0657] Compound 166-1 (800 mg, 3.4 mmol, 1.0 eq.) was dissolved in toluene (20.0 ml), followed by the addition of compound DIBAL-H (965 mg, 6.8 mmol, 2.0 eq.). After complete addition, the atmosphere was replaced with nitrogen three times, and the reaction was stirred at -10°C for 1 hour. TLC indicated no starting material remained, with most of the product converted. The product 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 = 100:1-30:1) to afford compound 166-2 (460 mg, 56%) as a yellow solid. LCMS: (ESI) m / z 237, (M+H)+.

[0658] Compound 166-2 (70 mg, 0.3 mmol, 1.0 eq.) was dissolved in dioxane (10 mL), followed by the addition of trimethylsilylacetylene (63.0 mg, 0.6 mmol, 2.0 eq.), CuI (12.2 mg, 0.065 mmol, 0.2 eq.), TEA (97 mg, 0.96 mmol, 3.0 eq.), and Pd(pph2)Cl2 (22.4 mg, 0.03 mmol, 0.1 eq.). After the additions were complete, the reaction was stirred at 25°C for 12 hours. TLC showed no residual starting material, with most of the product converted. The reaction solution 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 (developing solvent: DCM:MeOH = 20:1) to afford Compound 166-3 (40 mg, 50%) as a yellow solid. LCMS: (ESI) m / z 254, (M+H)+.

[0659] Compound 166-3 (40 mg, 0.15 mmol, 1.0 eq.) was dissolved in THF (5 mL) and the atmosphere was replaced with nitrogen three times. Then, CH3MgBr (0.6 mL, 0.3 mmol, 2.0 eq.) was added separately. After the addition was complete, the reaction was stirred at 0-25°C for 2 hours. TLC showed no residual starting material, with most of the product converted. The reaction solution 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 (developing solvent: DCM:MeOH = 20:1) to obtain Compound 166-4 (25 mg, 62%) as a yellow solid. LCMS: (ESI) m / z 270, (M+H)+.

[0660] Compound 166-4 (25 mg, 0.09 mmol, 1.0 eq.) was dissolved in DCM (5 mL), followed by the addition of TEA (28 mg, 0.28 mmol, 3.0 eq.) and MsCl (31.0 mg, 0.186 mmol, 1.5 eq.). After complete addition, the atmosphere was purged with nitrogen three times, and the reaction was stirred at 25°C for 2 hours. TLC indicated no residual starting material, with most conversion to product. The reaction solution 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 (developing solvent: DCM:MeOH = 30:1) to afford Compound 166-5 (20 mg, 46%) as a yellow solid. LCMS: (ESI) m / z 348 (M+H)+.

[0661] Compound 166-5 (15 mg, 0.05 mmol, 1.0 eq.) was dissolved in MeCN (5 mL), followed by the addition of Cs2CO3 (23.0 mg, 0.15 mmol, 3.0 eq.) and compound A4 (20 mg, 0.1 mmol, 1.5 eq.). After the additions were complete, the atmosphere was replaced with nitrogen three times, and the reaction was stirred at 80°C for 3 hours. TLC showed no residual starting material, with most of the product converted. The reaction solution 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 (developing solvent: DCM:MeOH = 30:1) to afford compound 166-6 (10 mg, 57%) as a yellow solid.

[0662] LCMS: (ESI) m / z 478 (M+H)+.

[0663] Compound 166-6 (10 mg, 0.02 mmol, 1.0 eq.) was dissolved in DCM (3.0 ml), and then compound TFA (1.0 mL) was added. After the addition was complete, the atmosphere was replaced with nitrogen three times, and the reaction was stirred at 25°C for 2.0 hours. TLC showed that no starting material remained and most of it was converted into 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 high performance liquid chromatography to obtain compound 166 (2.0 mg, purity 99%, yield 28%) as a white solid. LCMS: (ESI) m / z 394, (M+H)+; 1H NMR (400MHz, CD3OD) δ9.38 (d, J=11.6Hz, 1H),8.80(s,1H),7.98–7.85(m,4H),7.56(d,J=14.3Hz,1H),7.31(d,J=9.7Hz,1H),7.2 1–7.11(m,2H),6.58(d,J=6.2Hz,1H),4.46(s,1H),4.01(s,3H),1.94(d,J=6.9Hz,3H).

[0664] Example 168

[0665] 6-Methyl-5-(1-((3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)ethyl)cinnoline

[0666] Compound 119-5 (905 mg, 4.33 mmol, 1.0 eq.), compound 168-1 (942 mg, 5.2 mmol, 1.2 eq.), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II) (625 mg, 0.65 mmol, 0.15 eq.), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (376 mg, 0.65 mmol, 0.15 eq.), and cesium carbonate (2.8 g, 8.66 mmol, 2.0 eq.) were added sequentially to dioxane (16.0 mL) at room temperature. The reaction mixture was stirred at 100°C for 3 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The obtained 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%).

[0667] At room temperature, concentrated hydrochloric acid (12M, 12.0 mL, 144 mmol, 40.2 eq.) was slowly added to a solution of compound 168-2 (1107 mg, 3.58 mmol, 1.0 eq.) in THF (12.0 mL). The reaction mixture was stirred at room temperature for 1 hour. Water (30.0 mL) was added, and the mixture was extracted with ethyl acetate (20.0 mL x 2). The organic phase was discarded. Aqueous sodium bicarbonate was added to the aqueous phase to adjust the pH to >7, and the mixture was extracted with DCM / i-PrOH = 85:15 (30.0 mL x 3). 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 = 0-30%) to afford compound 168-3 (502 mg, 96.6% yield).

[0668] At room temperature, NBS (647 mg, 3.63 mmol, 1.05 eq.) was slowly added to a mixture of compound 168-3 (502 mg, 3.46 mmol, 1.0 eq.) in acetonitrile (8.0 mL) and DMF (8.0 mL). The reaction mixture was stirred at room temperature for 3 hours. Water (30.0 mL) was added to the reaction solution, and the mixture was extracted with EA (20.0 mL x 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 = 0-21.6%) to afford compound 168-4 (680 mg, 87.8% yield).

[0669] Compound 168-4 (680 mg, 3.03 mmol, 1.0 eq.), tributyl(1-ethoxyethylene)tin (1644 mg, 4.55 mmol, 1.5 eq.), and Pd(PPh3)4 (700 mg, 0.606 mmol, 0.2 eq.) were added sequentially to dioxane (20.0 mL) at room temperature. The reaction mixture was stirred at 110°C under nitrogen for 16 hours. The reaction mixture was cooled to room temperature, and aqueous KF solution (20.0 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was filtered, and the filtrate was extracted with ethyl acetate (20.0 mL x 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 solution was stirred at room temperature for 40 minutes. Saturated aqueous sodium bicarbonate was added to adjust the pH to >7, and then extracted with ethyl acetate (20.0 mL x 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 = 0-19%) to provide compound 168-5 (403 mg, 71% yield).

[0670] t-BuONO (296 mg, 90% purity, 2.58 mmol, 1.2 eq.) was slowly added to a solution of compound 168-5 (403 mg, 2.15 mmol, 1.0 eq.) and CuBr2 (577 mg, 2.58 mmol, 1.2 eq.) in CH3CN (25.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The residue was concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: ethyl acetate / dichloromethane = 0-10%) to afford compound 168-6 (437 mg, 80.9% yield).

[0671] Compound 168-6 (145 mg, 0.58 mmol, 1.0 eq.), methylboronic acid (290 mg, 50% purity, 1.16 mmol, 2.0 eq.), Pd(dppf)Cl2 (83 mg, 0.116 mmol, 0.2 eq.), and potassium carbonate (239 mg, 1.74 mmol, 3.0 eq.) were added sequentially to dioxane / H2O (6 mL / 1.5 mL) at room temperature. The reaction mixture was stirred at 95°C for 16 hours. The reaction solution was cooled to room temperature, water (10.0 mL) was added, and the 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 = 0-18%) to give compound 168-7 (35 mg, yield 32.5%).

[0672] At 0°C, NaBH4 (8 mg, 0.207 mmol, 1.1 eq.) was slowly added to a solution of compound 168-7 (35 mg, 0.188 mmol, 1.0 eq.) in methanol (3.0 mL). The reaction mixture was stirred at room temperature for 1 hour. After cooling to 0°C, the reaction solution was slowly poured into aqueous NH4Cl (10.0 mL) and extracted with EA (10.0 mL x 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 = 0-25%) to afford compound 168-8 (21 mg, 59% yield).

[0673] Thionyl chloride (34 mg, 0.29 mmol, 3.0 eq.) was slowly added to a solution of compound 168-8 (18 mg, 0.096 mmol, 1.0 eq.) in DCM (2.0 mL) at 0°C. The reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was concentrated under reduced pressure. The resulting residue, compound 168-9, was used directly in the next step without further purification.

[0674] Compound 168-9 (19.8 mg, 0.096 mmol, 1.0 eq.), compound A4 (28.5 mg, 0.096 mmol, 1.0 eq.), and cesium carbonate (93 mg, 0.29 mmol, 3.0 eq.) were added sequentially to DMF (1.5 mL) at room temperature. The reaction mixture was stirred at 60°C for 16 hours. The reaction mixture was cooled to room temperature, water (10.0 mL) was added, and the mixture was extracted with ethyl acetate (10.0 mL x 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 = 0-19%) to afford compound 168-10 (18 mg, 57.5% purity, 23.1% total yield over two steps).

[0675] At room temperature, TFA (1.0 mL) was slowly added to a solution of compound 168-10 (18 mg, 57.5% purity, 0.022 mmol, 1.0 eq.) in DCM (3.0 mL). The reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, and the resulting residue was dissolved in DCM (10.0 mL). Aqueous sodium bicarbonate was added to adjust the pH to >7, and the mixture was extracted with DCM (10.0 mL x 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: petroleum ether:ethyl acetate (developing solvent: dichloromethane:methanol = 12:1)) to afford compound 168 (6 mg, 70.7% yield, 89.18% purity). LCMS (ESI) m / z = 385.2 (M+H)+; 1 H NMR (400MHz, DMSO) δ12.73 (s, 1H), 9.37 (d, J = 6.3Hz, 1H), 8.92 (t, J = 7.9Hz, 1H),8.26(t,J=8.0Hz,1H),7.97(d,J=5.5Hz,1H),7.82–7.75(m,1H),7.71( s,1H),7.33(t,J=10.0Hz,1H),7.13(d,J=8.7Hz,1H),7.05(dt,J=11.7,5.8 Hz,1H),6.41–6.31(m,1H),3.92(s,3H),2.76(s,3H),1.85(d,J=6.6Hz,3H).

[0676] Example 169

[0677] 3-(4-(5-(1-(7-chloroquinoxalin-5-yl)ethoxy)-1H-indazol-3-yl)-1H-pyrazol-1-yl)azetidine-1-carboxamide

[0678] At room temperature, trifluoroacetic acid (7.01 g, 61.52 mmol) was added dropwise to a solution of compound 169-1 (1.07 g, 3.076 mmol) in dichloromethane (15.4 mL). The resulting reaction solution was stirred for 12 hours, and LCMS showed the formation of the product. The reaction mixture was concentrated to dryness under reduced pressure, and anhydrous ethanol (10.0 mL) was added to the residue, and the mixture was concentrated to dryness under reduced pressure again. This operation was repeated twice, and the residue was dried under vacuum to obtain a crude product of light brown solid compound 169-2 (1.27 g, purity: 83.06%). LCMS (ESI) m / z 250.2, (M+H) + .

[0679] At room temperature, the crude product of compound 169-2 (0.660 g, 1.60 mmol (theoretical amount)) and triethylamine (0.648 g, 6.40 mmol) were added to tetrahydrofuran (8.0 mL), and trimethylsilyl isocyanate (0.346 g, 2.40 mmol) was slowly added dropwise. The resulting mixture was stirred for 3 hours, and LCMS showed the formation of the product. The reaction mixture was concentrated to dryness under reduced pressure and dried in vacuo to obtain the crude product of compound 169-3 (1.024 g, purity: 70.36%) as a light brown waxy solid. LCMS (ESI) m / z 293.2, (M+H) + .

[0680] Compound A5 (35 mg, 0.06 mmol, 1.0 eq.) and compound 169-3 (28 mg, 0.09 mmol, 1 eq.) were dissolved in dioxane (2 mL) and water (0.2 mL). Cs2CO3 (63 mg, 0.19 mmol, 2 eq.) and Pd(dppf)Cl2 (10 mg, 0.01 mmol, 0.2 eq.) were added and reacted at 90°C for 3 hours. LCMS showed that compound 7 was completely reacted. The reaction mixture was filtered, dried, and purified by thin-layer chromatography (developing solvent: petroleum ether:ethyl acetate = 1:8) to afford compound 169-4 as a colorless oil (30 mg, 80% yield). LCMS (ESI) m / z 573.2, (M+H)+.

[0681] Compound 169-4 (30 mg, 0.05 mmol, 1.0 eq.) was dissolved in DCM (2 mL) and TFA (1 mL) was added. The mixture was allowed to react at 25°C for 3 hours. LCMS indicated the reaction was complete and the product was formed. The reaction mixture was dried to give the crude product, which was purified by HPLC to afford Compound 169 (10.7 mg, 41% yield) as an off-white solid. LCMS (ESI) m / z 489.2, (M+H)+). 1H NMR (400MHz, DMSO) δ9.13–9.09(m,2H),8.18(d,J=8.4Hz,1H),8.12(t,J=12.0Hz ,1H),7.94(t,J=13.2Hz,1H),7.79(d,J=14.0Hz,1H),7.41(t,J=7.2Hz,1H),7.2 9(t,J=8.8Hz,1H),7.12(dt,J=7.6,4.0Hz,1H),6.73–6.66(m,1H),5.31–5.12(m ,1H),4.40–4.24(m,2H),4.14(dd,J=22.8,14.6Hz,2H),1.72(t,J=20.4Hz,3H).

[0682] The following compound was synthesized by referring to the route of Example 169

[0683] Example 170

[0684] N,N-Dimethyl-3-(4-(5-(1-(quinoxalin-5-yl)ethoxy)-1H-indazol-3-yl)-1H-pyrazol-1-yl)cyclobutan-1-amine

[0685] Compound 170-1 (100 mg, 0.53 mmol, 1.0 eq) and Et3N (162 mg, 1.6 mmol, 3.0 eq) were added to DCM (2.0 ml). MsCl (67 mg, 0.59 mmol, 1.1 eq) was added at 0°C and stirred at room temperature for 3 hours. The reaction solution was poured into NaCl (10.0 mL) and extracted with DCM (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 to obtain crude compound 170-2 (150 mg, white solid). LCMS: (ESI) m / z 166.2, (M-100+H)+

[0686] Compound 170-2 (60 mg, 0.13 mmol, 1.0 eq.), compound A9 (150 mg, 0.52 mmol, 4.0 eq.), and cesium carbonate (266 mg, 0.82 mmol, 6.0 eq.) were added sequentially to DMF (2.0 mL) at room temperature and stirred at 80°C for 2 hours. The reaction solution was poured into a NaCl aqueous solution (10.0 mL) and extracted with EtOAc (10.0 mL x 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: petroleum ether:ethyl acetate = 1 / 1) to afford compound 170-3 (82 mg, 98.7% yield, light yellow solid). LCMS: (ESI) m / z 610.2, (M+H)+.

[0687] At room temperature, 4M dioxane hydrochloride (2.0 mL) was slowly added to a mixture of compound 170-3 (82 mg, 0.13 mmol) in DCM (2.0 mL) and MeOH (2.0 mL). The mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, the mixture was extracted with EtOAc (15.0 mL × 2) and aqueous Na2CO3 (15.0 mL). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford compound 170-4 (45 mg, 78.6% yield, as a light yellow solid).

[0688] LCMS: (ESI) m / z 426.2, (M+H)+.

[0689] Compound 170-4 (40 mg, 0.094 mmol, 1.0 eq) was dissolved in MeOH (2.0 ml), and 40% aqueous formaldehyde solution (35 mg, 0.47 mmol, 5.0 eq), AcOH (0.56 mg, 0.0094 mmol, 0.1 eq), and NaCNBH3 (13 mg, 0.21 mmol, 2.2 eq) were added sequentially. The reaction mixture was allowed to react at room temperature for 4 hours. The reaction solution was poured into aqueous NaCl solution (10.0 mL) and extracted with EtOAc (10.0 mL x 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 HPLC to afford 170 (10.1 mg, 23.5% yield, 99.2% purity, as a light yellow solid). LCMS: (ESI) m / z 454.3, (M+H)+; 1H NMR(400MHz,DMSO-d6)δ12.75(s,0.3H),9.15–9.06(m,2H),8.19(s,1H),8.07–7.97(m,3H) ,7.91–7.83(m,1H),7.66(d,J=9.2Hz,1H),7.39(d,J=9.0Hz,1H),7.22(d,J=2.3Hz,1H),7. 11(dd,J=9.0,2.2Hz,1H),6.72(q,J=6.3,5.8Hz,1H),4.87(p,J=7.0Hz,1H),2.99(q,J=6.3 Hz,1H),2.64–2.55(m,1H),2.47(d,J=6.8Hz,2H),2.19(d,J=6.4Hz,6H),1.82–1.70(m,3H).

[0690] Example 173

[0691] (3-(4-(5-(1-(7-chloroquinoxalin-5-yl)ethoxy)-1H-indazol-3-yl)-1H-pyrazol-1-yl)propyl)(imino)(methyl)-aminosulfonone

[0692] Compound 173-1 (70 mg, 0.13 mmol, 1.0 eq.) and compound 173-2 (70 mg, 0.386 mmol, 1.5 eq.) were dissolved in DMF and Cs2CO3 (170 mg, 0.52 mmol, 4 eq.) was added. The mixture was reacted at 50°C for 1.2 hours. LCMS showed that the reaction of 173-1 was complete and the product was formed. The reaction mixture was extracted with water and EtOAc. The organic phase was separated, dried, and spin-dried to give compound 173-3 as a yellow oil (70 mg, 60% purity). LCMS (ESI) m / z 283.2, (M+H)+).

[0693] Compound A5 (70 mg, 0.06 mmol, 1.0 eq) and compound 173-3 (19 mg, 0.09 mmol, 1.5 eq) were dissolved in dioxane (2 mL) and H₂O (2 mL). Cs₂CO₃ (64 mg, 0.19 mmol, 3 eq) and Pd(dppf)Cl₂ (19.1 mg, 0.026 mmol, 0.2 eq) were then added. The mixture was purged with nitrogen three times and stirred at 90°C for 3 hours. LCMS showed that compound A5 was completely reacted. The reaction mixture was filtered and dried, and the crude product was purified by thin-layer chromatography (developing solvent: petroleum ether:ethyl acetate = 1:9) to afford compound 173-4 (60 mg, 81% yield). LCMS (ESI) m / z 563.2, (M+H)⁺.

[0694] Compound 173-4 (50 mg, 0.08 mmol, 1.0 eq) and ammonium carbamate (20.79 mg, 0.26 mmol, 3 eq) were added to a mixt...

Claims

1. A compound represented by general formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, isotope-substituted product or stereoisomer thereof, X 1 N atom or CR 5 ; X 2 N atom or CR 2 ; X 3 N atom or CR 3 ; R 1 Selected from Y is selected from the group consisting of O atom, S atom, -S(O)-, -S(O)2- and NR 11 ; R 2 and R 5 Each independently selected from 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 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 The 3- to 8-membered cycloalkyl and the 3- to 8-membered heterocyclic group are each independently optionally selected from C 1-6 Alkoxy, -OH, -COOH, -NR 11 R 12 、-CN、halogen、C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and C 1-6 substituted with one or more substituents of a hydroxyalkyl group; R 3 Selected from H atoms, -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 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group and -OR 13 ; The condition is that when X is CR 5 And R 1 for And C 2 When it is a 6-membered nitrogen-containing heteroaromatic ring, R 3 Not an H atom; Ring C 1 Selected from C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, 5-10 membered heteroaryl fused with 3-8 membered heterocyclic group, C 6-10 5-10 membered heteroaryl fused to an aryl group, a 3-8 membered heterocyclyl fused to a 5-10 membered heteroaryl group, and a C 6-10 aryl; Each L 1 independently selected from chemical bonds, -C 1-6 Alkylene-, -O-, -C 1-6 Alkylene-O-, -OC 1-6 Alkylene Base-, -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-, 3-8 membered heterocyclylene, C 3-8 Cycloalkylene, C 6-10 Arylene, 5-10 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 the C 1-6 The alkylene groups are each independently optionally selected from C 1-6 Alkyl, halogen, -OH, -COOH, -NR 11 R 12 、-CN、C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 substituted by one or more substituents of a 3- to 8-membered cycloalkyl group and a 3- to 8-membered heterocyclic group; Each R 4 independently selected from H atoms, -OH, -COOH, -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 Halogenated alkyl, 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 3-10 membered heterocyclic groups, wherein the C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 The 3- to 10-membered cycloalkyl and the 3- to 10-membered heterocyclic group are each independently optionally selected from -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(=NR11)-NR 11 R 12 、-S(O)2-NR 11 R 12 and -C 1-6 Alkylene-C(O)-NR 11 R 12 is substituted by one or more substituents; Ring C 2 Selected from C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 3-8 Cycloalkyl, C 6-10 5-10 membered heteroaryl fused to an aryl group, C 6-10 Aryl, and C 3-8 a 5- to 10-membered heteroaryl fused to a cycloalkyl group, a C 6-10 Aryl and C 6-10 an aryl-fused 3-8 membered heterocyclic group; Ring C 3 Selected from C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 3-8 Cycloalkyl, C 6-10 Aryl-fused 5-10 membered heteroaryl, C 3-8 a 5- to 10-membered heteroaryl fused to a cycloalkyl group and a C 6-10 aryl; R 6 Selected from H atoms, -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 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-NR 11 R 12 、C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 8-membered cycloalkyl and 3-8-membered heterocyclic group; R 7 Selected from H atoms, -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 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 8-membered cycloalkyl and 3-8-membered heterocyclic group; L 2 is selected from -C(O)-, -S(O)2- and -S(O)-; L 3 and L 4 Each independently selected from 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 the C 1-6 The alkylene groups are each independently optionally selected from C 1-6 Alkyl, halogen, -OH, -COOH, -NR 11 R 12 、-CN、C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 substituted by one or more substituents of a 3- to 8-membered cycloalkyl group and a 3- to 8-membered heterocyclic group; R 8 and R 10 Each independently selected from H atoms, -OH, -COOH, -CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 The 3- to 8-membered cycloalkyl and the 3- to 8-membered heterocyclic group are each independently optionally selected from -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 substituted with one or more substituents of halogen; R 9 Selected from H atoms, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and C 1-6 hydroxyalkyl; Each R 11 independently selected from H atoms, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl and C 3-8 membered cycloalkyl, the C 3-8 The membered cycloalkyl group is optionally selected from C 1-6 Alkyl, C 1-6 Alkoxy, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and C 1-6 substituted with one or more substituents of a hydroxyalkyl group; Each R 12 independently selected from H atoms, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl and C 3-8 membered cycloalkyl, the C 3-8 The membered cycloalkyl group is optionally selected from C 1-6 Alkyl, C 1-6 Alkoxy, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and C 1-6 substituted with one or more substituents of a hydroxyalkyl group; Or, R 11 、R 12 Together with the nitrogen atom to which it is attached, it forms a 3-8 membered heterocyclic group, wherein the 3-8 membered heterocyclic group is optionally selected from C 1-6 Alkyl, C 1-6 Alkoxy, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and C 1-6 substituted with one or more substituents of a hydroxyalkyl group; R 13 Selected from 3-8 membered heterocyclic group, C 3-8 Cycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the 3-8 membered heterocyclic group, C 3-8 Cycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally selected from C 1-6 Alkoxy, -OH, -COOH, -NR 11 R 12 、-CN、halogen、C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and C 1-6 substituted with one or more substituents of a hydroxyalkyl group; Each R 14 Selected from H atoms, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 3-8 -membered cycloalkyl, wherein the C 1-6 Alkyl and C 3-8 The cycloalkyl groups are each independently optionally selected from -CN, -OH, -COOH, -NR 11 R 12 , halogen and C 1-6 substituted by one or more substituents of an alkoxy group; m is 0, 1, or 2; n is 0 or 1; and p is 0, 1 or 2.

2. The compound according to claim 1, which is a compound represented by general formula (II), in, 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 represented by general formula (II-1), in, Y is selected from the group consisting of O atom, S atom, -S(O)-, -S(O)2-, NH and NC 1-6 alkyl; R 3 Selected from H atoms, -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 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group and -OR 13 ; C 1 、C 2 、R 2 -R 7 、R 11 -R 13 , L 1 , m, n and p as defined in claim 1; The condition is that when C 2 When R is a 6-membered nitrogen-containing heteroaromatic ring, preferably pyridine, pyridazine or pyrimidine, 3 Not an H atom; In particular, R 3 Selected from H atoms, -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 Halogenated alkyl, C 3-8 Cycloalkyl, -OC 3-8 -O-3-8 membered cycloalkyl, -O-3-8 membered heterocyclic group and -OC 6-10 aryl; The condition is that when C 2 When R is a 6-membered nitrogen-containing heteroaromatic ring, preferably pyridine, pyridazine or pyrimidine, 3 Not an H atom; More specifically, R 3 is selected from the group consisting of H atom, F atom, -CF3, methyl, Cl atom, methoxy, cyclopropyl, isopropyl, -CN, isopropoxy, furan-O-, ethoxy, cyclopropyloxy, phenyl-O- and -N(CH3)2; The condition is that when C 2 When R is a 6-membered nitrogen-containing heteroaromatic ring, preferably pyridine, pyridazine or pyrimidine, 3 Not an H atom.

4. The compound according to claim 1 or 2, which is a compound represented by general formula (II-2), in, Y is selected from the group consisting of O atom, S atom, -S(O)-, -S(O)2-, NH and NC 1-6 alkyl; R 3 Selected from H atoms, -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 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group and -OR 13 ; X 1 、C 1 、C 2 、R 3 、R 4 、R 6 、R 7 、R 11 -R 13 , L 1 , m, n and p as defined in claim 1; In particular, R 3 Selected from H atoms, C 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 cycloalkyl; More specifically, R 3 is selected from the group consisting of an H atom, a methyl group, a methoxy group and a cyclopropyl group.

5. The compound according to claim 1, which is a compound represented by general formula (III), in, R 3 Selected from H atoms, -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 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group and -OR 13 Preferably, R 3 is an 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 as defined in claim 1.

6. The compound according to claim 1 or 5, which is a compound represented by general formula (III-1), in, R 3 Selected from H atoms, -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 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group and -OR 13 Preferably, R 3 is an 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 as defined in claim 1.

7. The compound according to claim 1 or 5, which is a compound represented by general formula (III-2), in, R 3 Selected from H atoms, -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 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group and -OR 13 Preferably, R 3 is an 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 as defined in claim 1.

8. The compound according to claim 1, which is a compound represented by general formula (IV), in, R 3 Selected from H atoms, -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 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group and -OR 13 Preferably, R 3 is an H atom or a halogen; more preferably, R 3 is a H atom; C 1 、C 3 、R 2 、R 4 、R 5 、R 10 、R 11 -R 13 , L 1 , L 4 and m as defined in claim 1; In particular, C 3 Selected from C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group; preferably triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, thiazolyl, thienyl, furanyl, pyranyl, pyrrolyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydropyranyl, phenyl, naphthyl, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl; more preferably 1,2,3-triazolyl; even more preferably and / or L 4 Selected from chemical bonds, -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, -CH2-, -CH2-CH2-, -CH2-CH2-NH-, -CH2-CH2-N(CH3)-, -NH-CH2-CH2- and -CH2-CH2-N(CH3)-; and / or R 10 Selected from H atoms, -OH, -COOH, -CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkyl groups; preferably H atoms and methyl groups.

9. The compound according to any one of claims 1 to 8, wherein Ring C 1 Selected from 5-10 membered heteroaryl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, 5-10 membered heteroaryl fused with 3-8 membered heterocyclic group, C 6-10 5-10 membered heteroaryl fused to an aryl group, a 3-8 membered heterocyclyl fused to a 5-10 membered heteroaryl group, and a C 6-10 aryl; Preferably, ring C 1 selected from the group consisting of triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, thiazolyl, thienyl, furanyl, pyranyl, pyrrolyl, pyrazinyl, pyridazinyl, pyrazolo[1,5-a]pyridinyl, tetrahydropyrazolo[1,5-a]pyridinyl, tetrahydropyrrolo[1,2-b]pyrazolyl, tetrahydropyrrolo[3,4-d]imidazolyl, benzo[d]imidazolyl, pyrazolo[5,1-b][1,3]oxazinyl, cyclopropyl and pyrrolidinyl; More preferably, ring C 1 Selected from 10. The compound according to any one of claims 1 to 9, wherein Each L 1 independently selected from 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-, 3-8 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, 5-10 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 the C 1-6 The alkylene groups are each independently optionally selected from C 1-6 Alkyl, halogen, -OH, -COOH, -NH2, -CN, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and C 1-6 is substituted by one or more substituents of a hydroxyalkyl group; each R 11 independently H atoms and C 1-6 alkyl; Preferably, each L 1 independently selected from 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, 5-10 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 the C 1-6 The alkylene groups are each independently optionally selected from C 1-6 Alkyl, halogen and -OH are substituted with one or more substituents; each R 11 independently H atoms and C 1-6 alkyl; More preferably, each L 1 Independently selected from 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-, -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-NCH3-、-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-.

11. The compound according to any one of claims 1 to 10, wherein Each R 4 independently selected from H atoms, -OH, -COOH, -CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, 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, 3-8 membered monocyclic heterocyclic group, 7-10 membered spiro heterocyclic group and 7-10 membered bridged heterocyclic group, wherein the C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 The 3-membered cycloalkyl and 3-8 membered monocyclic heterocyclic groups are each independently optionally selected from -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(=NR11)-NR 11 R 12 、-S(O)2-NR 11 R 12 and -C 1-6 Alkylene-C(O)-NR 11 R 12 is substituted by one or more substituents; each R 11 are independently H atoms, C 1-6 Alkyl and C 3-8 cycloalkyl; each R 12 are independently H atoms, C 1-6 Alkyl and C 3-8 cycloalkyl; each R 14 Selected from H atoms, C 1-6 Alkyl and C 3-8 -membered cycloalkyl, wherein the C 1-6 Alkyl and C 3-8 The cycloalkyl groups are each independently optionally selected from -CN, -OH, -NR 11 R 12 and C 1-6 substituted by one or more substituents of an alkoxy group; Preferably, each R 4 independently selected from H atoms, -OH, -COOH, -CN, halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, -C(O)-NR 11 R 12 、-NR 11 R 12 , phenyl, pyridinyl, imidazolyl, pyrazolyl, cyclopropyl, oxetanyl, azetidinyl, azopentyl, morpholinyl, piperidinyl, tetrahydropyranyl, piperazinyl, 1,1-dioxo-thiomorpholinyl, 1-oxo-1-imino-thiomorpholinyl, thiomorpholinyl, pyrrolidinyl, diazaspiro[4.5]decyl, diazabicyclo[2.2.1]heptyl and diazabicyclo[3.2.1]octyl, wherein the phenyl, pyridinyl, imidazolyl, pyrazolyl, cyclopropyl, oxetanyl, azetidinyl, azopentyl, morpholinyl, piperidinyl, tetrahydropyranyl, piperazinyl, 1,1-dioxo-thiomorpholinyl, 1-oxo-1-imino-thiomorpholinyl, thiomorpholinyl, pyrrolidinyl, diazaspiro[4.5]decyl, diazabicyclo[2.2.1]heptyl and diazabicyclo[3.2.1]octyl groups are substituted with phenyl, pyridinyl, imidazolyl, pyrazolyl, cyclopropyl, oxetanyl, azetidinyl, azopentyl, morpholinyl, piperidinyl, tetrahydropyranyl, piperazinyl, 1,1-dioxo-thiomorpholinyl, 1-oxo-1-imino-thiomorpholinyl, thiomorpholinyl, pyrrolidinyl, diazaspiro[4.5]decyl, diazabicyclo[2.2.1]heptyl and diazabicyclo[3.2.1]octyl groups. , imidazolyl, pyrazolyl, cyclopropyl, oxetanyl, azetidinyl, azopentyl, morpholinyl, piperidinyl, tetrahydropyranyl, piperazinyl, 1,1-dioxo-thiomorpholinyl, 1-oxo-1-imino-thiomorpholinyl, thiomorpholinyl, pyrrolidinyl, diazaspiro[4.5]decyl, diazabicyclo[2.2.1]heptyl and diazabicyclo[3.2.1]octyl are each independently optionally selected from -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(=NR11)-NR 11 R 12 、-S(O)2-NR 11 R 12 and -C 1-6 Alkylene-C(O)-NR 11 R 12 is substituted by one or more substituents; R 11 For H atoms, C 1-6 Alkyl and C 3-6 cycloalkyl; R 12 For H atoms, C 1-6 Alkyl and C 3-6 cycloalkyl; each R 14 Selected from H atoms, C 1-6 Alkyl and C 3-6 -membered cycloalkyl, wherein the C 1-6 Alkyl and C 3-6 The cycloalkyl groups are each independently optionally selected from -CN, -OH, -NR 11 R 12 and C 1-6 substituted by one or more substituents of an alkoxy group; More preferably, each R 4 Independently selected from H atoms, methyl groups, Propyl, Cyclopropyl, -OH, F atom, CN, Phenyl, -COOH、-C(O)-NH2、-N(CH3)2、 12. The compound according to any one of claims 1, 3 and 5-11, wherein R 2 Selected from H atoms, -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 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, C 1-6 Alkoxy-C 6-10 Aryl-, 5-10 membered heteroaryl, C 3-8 8-membered cycloalkyl and 3-8-membered heterocyclic group; Preferably, R 2 Selected from H atoms, halogens, C 1-6 Alkoxy, C 6-10 Aryl and C 1-6 Alkoxy-C 6-10 Aryl-; More preferably, R 2 Selected from H atoms, methoxy group and F atom.

13. The compound according to any one of claims 1, 3 and 5-12, wherein R 5 Selected from H atoms, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 8-membered cycloalkyl and 3-8-membered heterocyclic group; Preferably, R 5 Selected from H atoms, -OH, -COOH, -NH2, -CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and C 1-6 hydroxyalkyl; More preferably, R 5 For H atoms.

14. The compound according to any one of claims 1-4 and 9-13, wherein Ring C 2 is selected from 5-10 membered heteroaryl, 3-8 membered heterocyclic group, C 3-8 Cycloalkyl, C 6-10 5-10 membered heteroaryl fused to an aryl group, C 6-10 Aryl, and C 3-8 a 5- to 10-membered heteroaryl fused to a cycloalkyl group, a C 6-10 Aryl and C 6-10 an aryl-fused 3-8 membered heterocyclic group; Preferably, ring C 2 selected from the group consisting of triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, thiazolyl, thienyl, furanyl, pyranyl, pyrrolyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydropyranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, imidazo[1,2-a]pyridinyl, quinolinyl, isoquinolinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, triazolopyridinyl, benzodioxanyl, benzimidazolyl, cinnolinyl, benzoxazolyl, benzothiazolyl, indolyl, benzofuranyl, thienopyridinyl, pyrazolopyridinyl, and pyridopyrazinyl; More preferably, ring C 2 Selected from and / or R 6 Selected from H atoms, -OH, -COOH, -NR 11 R 12 、-CN、halogen、C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl and -C 1-6 Alkylene-NR 11 R 12 ; Each R 11 independently H atoms and C 1-6 Alkyl; each R 12 independently H atoms and C 1-6 alkyl; Preferably, R 6 Selected from 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 Selected from methyl, ethyl, hydroxymethyl, -CN, trifluoromethyl and trideuteriomethyl; and / or R 7 Selected from 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 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl and C 3-8 cycloalkyl; Preferably, R 7 Selected from 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 1-6 Hydroxyalkyl, C 3-6 membered cycloalkyl and C 1-6 alkyl halide; More preferably, R 7 Selected from H atom, -NH2, -N(CH3)2, -CN, Cl atom, F atom, bromine atom, oxo group, methyl group, ethyl group, isopropyl group, methoxy group, cyclopropyl group, difluoromethyl group, monofluoromethyl group, trifluoromethyl group, hydroxymethyl group and trideuteromethyl group.

15. The compound according to any one of claims 1, 5-7 and 9-14, wherein L 3 Selected from chemical bonds, -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 the C 1-6 The alkylene groups are each independently optionally selected from C 1-6 Alkyl, halogen, -OH, -COOH, -NH2, -CN, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, and C 1-6 is substituted by one or more substituents of a hydroxyalkyl group; each R 11 independently H atoms and C 1-6 alkyl; Preferably, L 3 Selected from chemical bonds, -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 the C 1-6 Each alkylene group is independently optionally substituted with one or more C 1-6 Alkyl or -OH substituted; Preferably, L 3 Selected from chemical bonds, -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 Selected from H atoms, -OH, -COOH, -CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 The 3- to 8-membered cycloalkyl and the 3- to 8-membered heterocyclic group are each independently optionally selected from -CN, -OH, C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Hydroxyalkyl, C 1-6 substituted by one or more substituents of alkoxy, -NH2 and halogen; Preferably, R 8 Selected from H atoms, -OH, C 6-10 aryl, 5-10 membered heteroaryl and 3-8 membered heterocyclic group, wherein the C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted with one or more C 1-6 Alkyl or halogen substituted; More preferably, R 8 Selected from H, methyl, -OH, and / or R 9 Selected from H atoms, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 hydroxyalkyl; Preferably, R 9 H atom or C 1-6 alkyl; More preferably, R 9 is a H atom or a methyl group.

16. A compound according to any one of claims 1 to 15, selected from 17. A method for preparing the compound represented by general formula (II) according to claim 2, the method comprising: The compound represented by general formula (IIA) reacts with the compound represented by general formula (IIB) to form the compound represented by general formula (II); Among them, LG 1 is a leaving group, preferably halogen, methanesulfonyloxy or p-toluenesulfonyloxy; and X 1 、X 2 、X 3 , Y, C 1 、C 2 、R 4 、R 6 、R 7 , L 1 , m, n and p as defined in claim 2; or The compound represented by the general formula (IIC) reacts with the compound represented by the general formula (IID) to form the compound represented by the general formula (II) compound; Among them, LG 2 is a leaving group, preferably halogen, methanesulfonyloxy or p-toluenesulfonyloxy; W is R is a hydrogen atom or C 1-6 alkyl; and X 1 、X 2 、X 3 , Y, C 1 、C 2 、R 4 、R 6 、R 7 , L 1 , m, n and p as defined in claim 2; or The compound represented by the general formula (IIE) reacts with the compound represented by the general formula (IIF) to form the compound represented by the general formula (IIG), and the compound represented by the general formula (IIG) removes the protecting group R p To form a compound represented by general formula (II); Among them, R p is tetrahydropyranyl, (trimethylsilyl)ethoxymethyl, p-toluenesulfonyl, tert-butyl formate, benzyl or p-methoxybenzyl; Y is an O atom, R 6 is -CH2OH, n is 1, and X 1 、X 2 、X 3 、C 1 、C 2 、R 4 、R 7 , L 1 , m and p as defined in claim 2; or The compound represented by the general formula (IIH) reacts with the compound represented by the general formula (IIK) to form the compound represented by the general formula (IIL), and the compound represented by the general formula (IIL) removes the protecting group R p To form a compound represented by general formula (II); Among them, R p is tetrahydropyranyl, (trimethylsilyl)ethoxymethyl, p-toluenesulfonyl, tert-butyl formate, benzyl, p-methoxybenzyl; LG 1 is a leaving group, preferably halogen, methanesulfonyloxy or p-toluenesulfonyloxy; and X 1 、X 2 、X 3 , Y, C 1 、C 2 、R 4 、R 6 、R 7 , L 1 , m, n and p as defined in claim 2; or The compound represented by the general formula (IIM) reacts with the compound represented by the general formula (IID) to form the compound represented by the general formula (IIN), and the compound represented by the general formula (IIN) removes the protecting group R p To form a compound represented by general formula (II); Among them, R p is tetrahydropyranyl, (trimethylsilyl)ethoxymethyl, p-toluenesulfonyl, tert-butyl formate, benzyl, p-methoxybenzyl; LG 2 is a leaving group, preferably halogen, methanesulfonyloxy or p-toluenesulfonyloxy; W is R is a hydrogen atom or C 1-6 alkyl; and X 1 、X 2 、X 3 , Y, C 1 、C 2 、R 4 、R 6 、R 7 , L 1 , m, n and p as defined in claim 2; or The compound represented by general formula (IIO) reacts with the compound represented by general formula (IIP) to form the compound represented by general formula (II); Where m is 1, L 1 -S(O)2-C 1-6 Alkyl-, R 15 C 1-6 Alkenyl or -C 1-6 an alkylene-halogen; and 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 method for preparing the compound represented by general formula (III-1) according to claim 6, comprising: The compound represented by the general formula (III-1A) reacts with the compound represented by the general formula (IID) to form the compound represented by the general formula (III-1); Among them, LG 3 is a leaving group, preferably halogen, methanesulfonyloxy or p-toluenesulfonyloxy; W is R is a hydrogen atom or C 1-6 alkyl; and C 1 、R 2 、R 4 、R 5 、R 8 、R 9 , L 1 , L 3 and m as defined in claim 6.

19. A method for preparing the compound represented by general formula (III-2) according to claim 7, the method comprising: The compound represented by the general formula (III-2A) reacts with the compound represented by the general formula (III-2B) to form the compound represented by the general formula (III-2); Among them, LG 4 is a halogen, preferably a Cl atom; C 1 、R 2 、R 4 、R 5 、R 8 、R 9 , L 1 , L 3 and m 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 the compound according to any one of claims 1 to 16 or the 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 selected from bile duct cancer, 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, kidney cancer, pancreatic cancer, bone cancer, lymphoma, melanoma, sarcoma, peripheral neuroepithelioma, glioma, ependymoma, neuroblastoma, gangliocytoma, medulloblastoma, pineal cell tumor, meningioma, neurofibroma, neurilemoma and Wilms' tumor; more preferably selected from bile duct cancer, 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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